Today we joined the Dorset Wildlife Trust and visited one of their sites, a field in Corfe Mullen, about 20 minutes drive away. This was a traditional English farmer's field set out for growing hay which will be harvested in a couple of weeks before being put out for stock until February.
The field grows grass and wild flowers during the Spring and early summer and is a good spot for seeing orchids in the wild. Traditional hedging and ditching are used, though I doubt that the hay is cut by scythe.
We decided to visit all 42 sites in Dorset after seeing a field bought on the TV program "Homes under the hammer", which is a program about restoring derelict homes bought at auction. I don't really feel up to long car journeys this summer so we will make use of local nature resources over the next few months.
We have all been watching the murder trial at Winchester where today an Italian who murdered Heather Barnett was given Life imprisonment without parole. He lived just around the corner from us when the murder was committed 9 years ago; it is scarcely a quarter of a mile away. The murderer had a hair fetish; he used to cut hair from women he sat behind on buses. Bournemouth has been the venue for several famous murders, one of which was made into a play by Terence Rattigan
In our garden we have been visited by a jay all day. He has been flying in to take stale bread from a bird table. He comes so close he is almost tame with his bright blue wing feather standing out. Only thing is while he is here the blue tits have vanished next door. The blackbirds and wood pigeons don't mind him though.
Thursday, June 30, 2011
Strikes for pensions
Public sector workers in the UK are on strike because their pensions are under threat.
I have to declare an interest in that I have a public sector pension that paid me half my final salary, index linked, as well as 3 times my final salary as a lump sum on retirement at 60. This was an extremely generous scheme, but it was available at a time when private pensions were even more generous and I could have earned three times my public sector salary had I elected to work in the private sector, though with much less security of tenure. When I die my widow will be entitled to half my pension (also index linked)
When I was young the average life expectancy for a man was 68; now it is 78. It is still increasing. I am 68 with a terminal illness.
Times have changed. Currently public sector teachers are entitled to a pension of an average of £24,000 a year, index linked. Assuming the typical teacher starts work at age 23, having obtained a post graduate certificate of education, and then retires at age 60, as all members who joined the teachers’ pension scheme before January, 2007, are entitled to do, that gives a career of 37 years; you would need about £500,000 to buy an index-linked pension of £24,000 in the private sector. Calculations are that public sector employees earning £32,000 a year are retiring with pension pots worth £500,000.
In order to save £500,000 over that length of time, assuming investment returns of 6pc per annum net of charges, you would need to start by setting aside £600 per month from outset, even if contributions rise with earnings during their career.
Assuming initial salary of £25,000 per annum, that level of saving would be equivalent to 29pc of earnings. By contrast, the current teachers’ pension scheme requires members to contribute just 6.4pc of earnings while the Government contributes 14.1pc.
But this is an unfunded scheme. There is no pot of money. Today’s teachers’ contributions and the taxpayers’ subsidy is used to pay pensions to teachers who have already retired, leaving the benefits being accrued by teachers still working today to be funded by teachers and taxpayers of the future.
By contrast, the average lump sum used to buy an annuity by people retiring in the private sector has fallen to £22,000 following recent stock market setbacks, according to the Office for National Statistics. That’s less than one twentieth of the pot enjoyed by our example teacher; even allowing for the fact that there is a wide range of salaries for public sector workers.
It may seem very unfair that the Government is now attempting to water down earlier administrations’ extravagant pension promises. But it will be interesting to see how much public sympathy there is for strikers today. Specifically, how much enthusiasm will there be to go on paying higher taxes to subsidise pensions for the public sector which people in the private sector can never hope to enjoy themselves?
I always say that socialists are very good at spending other people's money until it runs out; then we have a right wing government that takes the blame for public spending cuts. When we replenish the exchequer no doubt another spendthrift left wing administration will be elected.
The Greek problem is mainly caused by successive governments spending more than they earn on pensions and public sector jobs. It is not surprising that there is resistance among those who must work until they are 68 to fund pensions for those who would like to retire to sunny beaches at 57.
I have to declare an interest in that I have a public sector pension that paid me half my final salary, index linked, as well as 3 times my final salary as a lump sum on retirement at 60. This was an extremely generous scheme, but it was available at a time when private pensions were even more generous and I could have earned three times my public sector salary had I elected to work in the private sector, though with much less security of tenure. When I die my widow will be entitled to half my pension (also index linked)
When I was young the average life expectancy for a man was 68; now it is 78. It is still increasing. I am 68 with a terminal illness.
Times have changed. Currently public sector teachers are entitled to a pension of an average of £24,000 a year, index linked. Assuming the typical teacher starts work at age 23, having obtained a post graduate certificate of education, and then retires at age 60, as all members who joined the teachers’ pension scheme before January, 2007, are entitled to do, that gives a career of 37 years; you would need about £500,000 to buy an index-linked pension of £24,000 in the private sector. Calculations are that public sector employees earning £32,000 a year are retiring with pension pots worth £500,000.
In order to save £500,000 over that length of time, assuming investment returns of 6pc per annum net of charges, you would need to start by setting aside £600 per month from outset, even if contributions rise with earnings during their career.
Assuming initial salary of £25,000 per annum, that level of saving would be equivalent to 29pc of earnings. By contrast, the current teachers’ pension scheme requires members to contribute just 6.4pc of earnings while the Government contributes 14.1pc.
But this is an unfunded scheme. There is no pot of money. Today’s teachers’ contributions and the taxpayers’ subsidy is used to pay pensions to teachers who have already retired, leaving the benefits being accrued by teachers still working today to be funded by teachers and taxpayers of the future.
By contrast, the average lump sum used to buy an annuity by people retiring in the private sector has fallen to £22,000 following recent stock market setbacks, according to the Office for National Statistics. That’s less than one twentieth of the pot enjoyed by our example teacher; even allowing for the fact that there is a wide range of salaries for public sector workers.
It may seem very unfair that the Government is now attempting to water down earlier administrations’ extravagant pension promises. But it will be interesting to see how much public sympathy there is for strikers today. Specifically, how much enthusiasm will there be to go on paying higher taxes to subsidise pensions for the public sector which people in the private sector can never hope to enjoy themselves?
I always say that socialists are very good at spending other people's money until it runs out; then we have a right wing government that takes the blame for public spending cuts. When we replenish the exchequer no doubt another spendthrift left wing administration will be elected.
The Greek problem is mainly caused by successive governments spending more than they earn on pensions and public sector jobs. It is not surprising that there is resistance among those who must work until they are 68 to fund pensions for those who would like to retire to sunny beaches at 57.
Searching for Surrogates for IGHV mutations in chronic lymphocytic leukemia
I posted this accidentally the other day. It is the draft for an article I am writing for Leukemia Research. The idea is that a lot of people are beavering away trying to find simple tests that will give the same information as IGHV mutations but are not so difficult to do. My conclusion is that these tests don't deliver the goods and that anyway we can get even more worthwhile information from IGHV mutations and in any case the tests has become at least as easy to do as flow cytometry tests.
Searching for Surrogates for IGHV mutations in chronic lymphocytic leukemia
Abstract
Despite a startling separation of chronic lymphocytic leukemia (CLL) into two clinically different diseases with average survivals of 8 years and 25 years, the mutational status of immunoglobulin variable region (IGHV) genes has not entered routine clinical practice to assess prognosis, although their assessment is regarded as an essential for clinical trials. Instead, surrogates that may be measured by flow cytometry have been sought. Measurements of the expression of CD38 and ZAP-70 have been the most popular assays for prognosis although both are in their own ways unsatisfactory. Many other candidates have emerged, but none has been universally endorsed.
As the assay for IGHV mutations has been standardized the standard of difficulty has diminished and as greater numbers of cases have been assessed it has become clear that there is even more information to be gathered from the study of the sequence of IGHV genes. It has been recognised that stereotypy within CLL is associated with more specific clinical features than mere longevity and an even greater heterogeneity has been revealed. It seems clear that the genetic prognostic markers cannot be replaced by expression markers and the search for surrogacy and IGHV mutational status should become a routine investigation in CLL.
Introduction
More than a decade ago the simultaneous publication of two papers seemed to explain the marked heterogeneity that clinicians had observed in the natural history of chronic lymphocytic leukemia (CLL). [1, 2] The rearrangement of immunoglobulin (Ig) genes is an essential process in the maturation of normal B cells, whereby each lymphocyte acquires a unique B cell receptor (BCR) formed by the selection and recombination of individual gene segments from a large repertoire.
For the heavy chain of Ig, selection and recombination takes place from one each from 51 VH genes, 27 D genes and 6 JH genes.[3] The junctions of VH to D and D to JH are imprecise, with the deletion by exonucleases of templated nucleotides or the insertion by terminal deoxytransferase (TdT) of non-templated nucleotides in a random manner [4]. This introduces a further huge diversity into the shape of the Ig molecule, especially as the D segment can be read in any of the three frames [5]. The consequence is that the third complementarity-determining region (CDR3) of any given lymphocyte is virtually unique, and provides a clonal signature for any tumor deriving from it. Rearrangement of the light chain variable region genes occurs in a similar manner, involving single-step recombinations of V/J gene segments but with no D segments.
On completion of this maturation the B-cell leaves the bone marrow for the periphery where it may encounter antigen. It then undergoes affinity maturation, usually in the germinal centers of the peripheral lymphoid organs. Here, somatic mutation is induced under the influence of CD40+ve T cells, cytokines and antigen-bearing follicular dendritic cells [6]. The rate of introduction of base pair changes is of the order of 10e4 – 10e3 per generation. The mutations tend to cluster in the CDRs, possibly for structural reasons and possibly because of antigenic selection.
Interest in immunoglobulin genes in CLL originally stemmed from attempts to recognize the normal cell counterpart to the CLL cell. Because CLL cells express CD5 many authorities had accepted that CLL cells derived from the minor population of CD5+ve naïve B cells. Early sequences of the IGHV genes of tumor cells from patients with CLL found them to be in germline configuration [7-9] tending to confirm their origin from a naïve B cell. However, reports began to appear in the literature detailing cases with evidence of somatic mutation culminating in 1994 with a review of the literature by Schroeder and Dighiero [10] which found that 36/75 reported cases had IGHV genes with less than 98% sequence homology to the appropriate germline gene. The figure of 98% was chosen because polymorphisms, which are quite common in IGHV genes, can account for that degree of disparity [11]. Subsequently, a multicenter study of 64 patients with undoubted and classical CLL also found two groups of roughly equal numbers with respectively mutated and unmutated IGHV genes [12].
IGHV genes as prognostic factors
The first suggestion that IGHV mutations might have prognostic significance came from Oscier et al [13] who examined 22 patients with classical CLL segregated according to karyotype. Tumors with trisomy 12 had unmutated IGHV genes but those with 13q14 abnormalities detected by conventional cytogenetics had evidence of somatic mutations. By 1998 this series had been extended and presented at several meetings, demonstrating a more aggressive disease and a shorter survival for patients with unmutated IGVH genes [14-16] before the definitive publication of the two papers that documented and mutually corroborated the finding that IGVH mutational status identifies two subsets of CLL, one with a median survival of 8 years and one with a median survival of approximately 25 years [1,2].
Searching for surrogates
From the beginning it was recognized that sequencing of IGVH genes would not be available to most laboratories, especially if the technique involved a post-doctoral student, a sheet of X-ray film, a ruler and a lot of patience. One of the original papers proposed the percentage of B-cells expressing CD38 measured by flow cytometry as a surrogate measurement [1]. Despite its initial attraction CD38 expression later proved to be discordant with IGHV mutational status in 30% of cases and vary during the course of the disease in up to 25% of cases [17]. In fact, CD38 expression is an independent prognostic variable that can be combined with IGHV mutational status to enhance prognostic predictability [17].
Once IGHV mutational status had so comprehensively separated CLL into two clinical types, the question was asked as to whether it was one or two diseases [18]. Gene expression profiling demonstrated a distinct pattern for CLL distinguishing it from other lymphoid tumors and any particular B-cell population, although the closest normal cell profile was that of a memory B-cell [19, 20]. However, the expression of a small number of genes in the mutated and unmutated subtypes was different, with ZAP-70 standing out as the gene that most stringently separated the subsets.
Flow cytometric assays for ZAP-70 expression have proved difficult, especially as it is an intracellular antigen so that the cells require permeabilization, but at least three different methods have been reported [21-23]. Seen as surrogate assays for IGHV gene mutations, the first two assays performed similarly with around 94% concordance, but the third, which used a different and directly conjugated antibody, had only a 77% concordance with IGHV gene mutations. On the other hand, in this study ZAP-70 expression performed better than VH mutations in predicting treatment-free survival. Patients who were ZAP-70 positive; IGHV mutated had a worse survival than those who were ZAP-70 negative; IGHV unmutated.
Nevertheless, establishing a standardized assay for ZAP-70 expression has proved difficult [24] and many of the most experienced laboratories have dropped it from their repertoire as being unreliable. The need for a dependable surrogate for IGHV mutational status remains. Although no other prognostic factor has been widely adopted, there has been no shortage of candidates. A recent review described nineteen new prognostic markers: TCL1 gene expression, CLLU1 expression, miRNA signature, mRNA signature, and expression of Lipoprotein lipase A, ADAM29, HEM1, Septin 10, DMD, and PEG 10, levels of VEGF and thrombopoietin; telomere length and activity; surface expression of CD49d, CD69 and FCRL, expression of anti-apoptotic genes such as MCL-1 and the Bcl-2/Bax ratio, MDR1/MDR-3 genes, and AID mRNA [25].
Combinations of prognostic factors might be more useful than individual factors. CD38 and IGHV mutations [17] or CD38 and ZAP70 [26, 27] both perform better than any one factor. A scoring system based on six surface molecules (CD62L, CD54, CD49c, CD49d, CD38, and CD79b) detectable by flow cytometry has been proposed [28].
Immature laminin receptor
In a recent issue of Leukemia Research, Friedrichs et al [29] proposed that as high expression of the immature laminin receptor (iLR) protein predicted a favorable prognosis for CLL correlating with mutated IGHV genes and being detectable by flow cytometry, it might be used as a surrogate. ILR is an oncofetal antigen overexpressed in several tumor tissues but absent in the normal differentiation process. It is the precursor molecule of the mature 67 kDa protein that plays a role in the cell adhesion-associated processes initiated by laminin binding.
Friedrichs et al studied 134 patients with CLL. The flow cytometry assay used direct staining with a FITC-conjugated mouse anti-ILR monoclonal antibody and cells were double stained with an anti-CD19-PE antibody or an isotope control in the conventional way. ILR scores over CD38 and ZAP-70 in not being present on T cells nor on normal B cells. A cut-off 30% cells staining was determined best to distinguish between positive and negative. 41% of CLLs in their series were judged to be positive. There was a correlation between the expression of iLR and low ZAP-70 expression, mutated IGHV status and low CD38 expression. There was no change in iLR expression over time as there sometimes is with CD38 and ZAP-70 expression [17, 30]. However, the correlation of high expression of iLR with mutated IGHV genes was no better than for ZAP-70 or CD38. Only 78.9% of patients with mutated IGHV genes were iLR positive and 81.7% of unmutated cases were iLR negative. ILR negativity therefore behaves with a similar degree of concordance to IGHV mutations as ZAP-70 or CD38 expression. In a multivariate analysis iLR expression retained some independent predictive value for prognosis.
In summary, iLR expression is not an exact surrogate for IGHV mutational status, but yet another prognostic factor with some independent value.
Stereotypy
Perhaps the time has come to draw a line under the search for surrogates. Over time the technology for sequencing IGHV genes in CLL has improved and a recent study reported over 7500 sequences among patients worldwide [31]. The striking feature of these sequences was stereotypy, the finding that the IGHV sequences of large numbers of CLL patients were identical or very similar. The implication is that perhaps a third of all CLLs are derived from populations of B cells responding to a restricted range of antigens or superantigens. Originally at least 48 separate stereotypes could be identified, each subset comprising between 2 and 20 cases [32] but the wider collaboration [31] identified 952 ground-level clusters of cases with between 2 and 56 cases in each, though clearly most of these had very small numbers of cases. Common sequences among ground-level clusters made it possible to group them into considerably larger higher order clusters that displayed biased features with regard to IGHV usage, somatic hypermutation and VH CDR3 pattern composition. The largest higher order cluster with 213 sequences is clearly recognizable as subset 2 which uses IGHV3-21 with an acidic residue at VH CDR3 position 107. This well known subset has been identified as the major exception to the prognostic importance of IGHV gene mutations in which CLLs with up to 4% somatic mutations behave aggressively [33].
These stereotypes are often confined to a single IGHV gene, but not necessarily so and B cell receptors can derive their gene sequence from a number of VDJ combinations, all belonging to the same phylogenetic clan. For example, the second largest higher order cluster which included 184 sequences used 6 different IGHV genes of clan 1 (IGHV1-2, 1-3, 1-8, 1-18, 5a and 7-4-1) with a QWL motif at VH CDR3 positions 108-110.
Of relevance to our current topic is the fact that different stereotypic subtypes appear to be associated with distinct patterns of clinical behaviour. For example, subtype 8 which uses the VH4-39 gene in an unmutated form but class-switched to IgG production is associated with a 24-fold greater risk of Richter transformation and has a higher frequency than expected of trisomy 12 yet no significant association with progressive disease [34]. On the other hand, subtype 4 which uses VH4-34 in a mutated form tends to present in the fifth decade and be non-progressive [32]. As further cases are assembled it is to be expected that even greater heterogeneity will be recognised and assigned to specific subtypes.
References
1. Damle, R.N., Wasil, T., Fais ,F. et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999; 94:1840-1847.
2. Hamblin, T.J., Davis, Z., Gardiner, A., Oscier, D.G., Stevenson, F.K. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999; 94:1848-1854.
3. D Lewis S, Gellert M. The mechanism of antigen receptor gene assembly. Cell 1989; 59:585-588.
4. Desiderio SV, Yancopoulos GD, Paskind M et al. Insertion of N regions into heavy chain genes is correlated with the expression of terminal deoxytransferase in B cells. Nature 1984; 311:752-755
5. Corbett SJ, Tomlinson IM, Sonnhammer EL, Buck D, Winter G. Sequence of the human immunoglobulin diversity (D) segment locus: a systematic analysis provides no evidence for the use of DIR segments, inverted D segments, "minor" D segments or D-D recombination. J Mol Biol 1997; 270:587-597
6. MacLennan IC. Germinal centers. Annu Rev Immunol 1994; 12:117-139.
7. Kipps TJ, Tomhave E, Pratt LF, Duffey S, Chen PP, Carson DA. Developmentally restricted immunoglobulin heavy chain variable region gene expressed at high frequency in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 1989; 86:5913-5917.
8. Deane M, Norton JD. Preferential rearrangement of developmentally regulated immunoglobulin VH1 genes in human B-lineage leukaemias. Leukemia 1991; 5:646-50.
9. Ebeling SB, Schutte MEM, Akkermans-Koolhaas KE, Bloem AC, Gmelig-Meyling FHJ, Logtenberg T. Expression of members of the immunoglobulin VH3 gene families is not restricted at the level of individual genes in human chronic lymphocytic leukemia. Int Immunol 1992; 4:313-20.
10. Schroeder HWJr, Dighiero G. The pathogenesis of chronic lymphocytic leukemia: analysis of the antibody repertoire. Immunology Today 1994; 15:288-94.
11. Matsuda F, Shin EK, Nagaoka H et al. Structural and physical map of the 64 variable segments in the 3’ 0.8 megabase region of the human immunoglobulin heavy chain locus. Nature Genet 1993; 3:88-94.
12. Fais F, Ghiotto F, Hashimoto S et al. Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. J Clin Invest 1998; 102:1515-35.
13. Oscier DG, Thompsett A, Zhu D, Stevenson FK. Differential rates of somatic hypermutation in VH genes among subsets of chronic lymphocytic leukemia defined by chromosomal abnormalities. Blood 1997; 89:4153-60.
14. Hamblin TJ, Davis Z, Oscier DG, Stevenson FK. The use of immunoglobulin heavy chain variable region genes in chronic lymphocytic leukaemia. B-cell Lymphoproliferative Disorders Imedex: New York (1998) 27a
15. Hamblin T, Davis Z, Oscier DG, Stevenson FK The use of immunoglobulin heavy chain variable region genes in chronic lymphocytic leukaemia.. Brit J Haematol 1998; 101 (suppl 1) : 44a.
16. Hamblin TJ, Davies Z, Oscier DG, Stevenson FK. In chronic lymphocytic leukemias germline configuration of immunoglobulin heavy chain genes is associated with a more aggressive form of the disease. Blood 1998; 92 (Suppl 1): 515a.
17. Hamblin TJ, Orchard JA, Ibbotson RE, et al. CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease. Blood 2002; 99: 1023-1029.
18. Hamblin T. Chronic Lymphocytic Leukaemia: One Disease or Two? Annals of Hematology 2002; 81:299-303
19. Rosenwald A, Alizadeh AA, Widhopf G et al. Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med 2001; 194:1639-1647.
20. Klein U, Tu Y, Stolovitzky GA, et al. Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J Exp Med 2001; 194:1625-38.
21. Crespo M, Bosch F, Villamor N et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med 2003; 348:1764-75.
22. Orchard JA, Ibbotson RE, Davis Z et al. ZAP-70 expression by flow cytometry is a good prognostic marker in CLL and a potential surrogate for immunoglobulin VH gene mutations. Lancet 2004; 363:105-11.
23. Rassenti LZ, Huynh L, Toy TL et al. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med. 2004; 351:893-901.
24. Marti G, Orfao A, Goolsby C. ZAP-70 in CLL: towards standardization of a biomarker for patient management: history of clinical cytometry special issue. Cytometry. Part B, Clinical Cytometry 2006; 70B: 197–200.
25. Codony C, Crespo N, Abrisqueta P, Montserrat E, Bosch F. Gene expression profiling in chronic lymphocytic leukaemia. Best Pract Res Clin Haematol. 2009; 22:211–22
26. Del Giudice I, Morilla A, Osuji N, et al. Zeta chain associated protein 70 and CD38 combined predict the time to first treatment in patients with chronic lymphocytic leukemia. Cancer 2005; 104: 2124–32.
27. Schroers R, Griesinger F, Trumper L, et al. Combined analysis of ZAP-70 and CD38 expression as a predictor of disease progression in B-cell chronic lymphocytic leukemia. Leukemia 2005; 19: 750–58.
28. Zucchetto A, Bomben R, Dal Bo M, et al. A scoring system based on the expression of six surface molecules allows the identification of three prognostic risk groups in B-cell chronic lymphocytic leukemia. J Cell Physiol 2006; 207: 354–63.
29. Friedrichs B, Siegel S, Reimer R et al. High expression of the immature laminin receptor protein correlates with mutated IGVH status and predicts a favorable prognosis in chronic lymphocytic leukemia. Leukemia Research 2011; 35:721-9.
30. Hamblin TJ. ZAP-70 levels do change in CLL but not very often. Leukemia & Lymphoma 2007; 48:1059-60.
31. Agathaggelidis A, Darzentas N, Hadzidimitriou A, et al. The composition of the B cell receptor repertoire in 7428 cases of chronic lymphocytic leukemia: one third stereotyped, two thirds heterogeneous - what does this mean? Blood 2010; 116: Number 21: 43a.
32. Stamatopoulos K, Belessi C, Moreno C et al. Over 20% of patients with chronic lymphocytic leukaemia carry stereotyped receptors: pathogenetic implications and clinical correlations. Blood 2007; 109:259-70.
33. Tobin G, Thunberg U, Johnson A, et al. Somatically mutated IgV(H)3-21 genes characterize a new subset of chronic lymphocytic leukemia. Blood 2002; 99:2262-4.
34. Rossi D, Spina V, Cerri M, et al. Stereotyped B-cell receptor is an independent risk factor of chronic lymphocytic leukemia transformation to Richter syndrome. Clin Cancer Res 2009; 15:4415-22.
Searching for Surrogates for IGHV mutations in chronic lymphocytic leukemia
Abstract
Despite a startling separation of chronic lymphocytic leukemia (CLL) into two clinically different diseases with average survivals of 8 years and 25 years, the mutational status of immunoglobulin variable region (IGHV) genes has not entered routine clinical practice to assess prognosis, although their assessment is regarded as an essential for clinical trials. Instead, surrogates that may be measured by flow cytometry have been sought. Measurements of the expression of CD38 and ZAP-70 have been the most popular assays for prognosis although both are in their own ways unsatisfactory. Many other candidates have emerged, but none has been universally endorsed.
As the assay for IGHV mutations has been standardized the standard of difficulty has diminished and as greater numbers of cases have been assessed it has become clear that there is even more information to be gathered from the study of the sequence of IGHV genes. It has been recognised that stereotypy within CLL is associated with more specific clinical features than mere longevity and an even greater heterogeneity has been revealed. It seems clear that the genetic prognostic markers cannot be replaced by expression markers and the search for surrogacy and IGHV mutational status should become a routine investigation in CLL.
Introduction
More than a decade ago the simultaneous publication of two papers seemed to explain the marked heterogeneity that clinicians had observed in the natural history of chronic lymphocytic leukemia (CLL). [1, 2] The rearrangement of immunoglobulin (Ig) genes is an essential process in the maturation of normal B cells, whereby each lymphocyte acquires a unique B cell receptor (BCR) formed by the selection and recombination of individual gene segments from a large repertoire.
For the heavy chain of Ig, selection and recombination takes place from one each from 51 VH genes, 27 D genes and 6 JH genes.[3] The junctions of VH to D and D to JH are imprecise, with the deletion by exonucleases of templated nucleotides or the insertion by terminal deoxytransferase (TdT) of non-templated nucleotides in a random manner [4]. This introduces a further huge diversity into the shape of the Ig molecule, especially as the D segment can be read in any of the three frames [5]. The consequence is that the third complementarity-determining region (CDR3) of any given lymphocyte is virtually unique, and provides a clonal signature for any tumor deriving from it. Rearrangement of the light chain variable region genes occurs in a similar manner, involving single-step recombinations of V/J gene segments but with no D segments.
On completion of this maturation the B-cell leaves the bone marrow for the periphery where it may encounter antigen. It then undergoes affinity maturation, usually in the germinal centers of the peripheral lymphoid organs. Here, somatic mutation is induced under the influence of CD40+ve T cells, cytokines and antigen-bearing follicular dendritic cells [6]. The rate of introduction of base pair changes is of the order of 10e4 – 10e3 per generation. The mutations tend to cluster in the CDRs, possibly for structural reasons and possibly because of antigenic selection.
Interest in immunoglobulin genes in CLL originally stemmed from attempts to recognize the normal cell counterpart to the CLL cell. Because CLL cells express CD5 many authorities had accepted that CLL cells derived from the minor population of CD5+ve naïve B cells. Early sequences of the IGHV genes of tumor cells from patients with CLL found them to be in germline configuration [7-9] tending to confirm their origin from a naïve B cell. However, reports began to appear in the literature detailing cases with evidence of somatic mutation culminating in 1994 with a review of the literature by Schroeder and Dighiero [10] which found that 36/75 reported cases had IGHV genes with less than 98% sequence homology to the appropriate germline gene. The figure of 98% was chosen because polymorphisms, which are quite common in IGHV genes, can account for that degree of disparity [11]. Subsequently, a multicenter study of 64 patients with undoubted and classical CLL also found two groups of roughly equal numbers with respectively mutated and unmutated IGHV genes [12].
IGHV genes as prognostic factors
The first suggestion that IGHV mutations might have prognostic significance came from Oscier et al [13] who examined 22 patients with classical CLL segregated according to karyotype. Tumors with trisomy 12 had unmutated IGHV genes but those with 13q14 abnormalities detected by conventional cytogenetics had evidence of somatic mutations. By 1998 this series had been extended and presented at several meetings, demonstrating a more aggressive disease and a shorter survival for patients with unmutated IGVH genes [14-16] before the definitive publication of the two papers that documented and mutually corroborated the finding that IGVH mutational status identifies two subsets of CLL, one with a median survival of 8 years and one with a median survival of approximately 25 years [1,2].
Searching for surrogates
From the beginning it was recognized that sequencing of IGVH genes would not be available to most laboratories, especially if the technique involved a post-doctoral student, a sheet of X-ray film, a ruler and a lot of patience. One of the original papers proposed the percentage of B-cells expressing CD38 measured by flow cytometry as a surrogate measurement [1]. Despite its initial attraction CD38 expression later proved to be discordant with IGHV mutational status in 30% of cases and vary during the course of the disease in up to 25% of cases [17]. In fact, CD38 expression is an independent prognostic variable that can be combined with IGHV mutational status to enhance prognostic predictability [17].
Once IGHV mutational status had so comprehensively separated CLL into two clinical types, the question was asked as to whether it was one or two diseases [18]. Gene expression profiling demonstrated a distinct pattern for CLL distinguishing it from other lymphoid tumors and any particular B-cell population, although the closest normal cell profile was that of a memory B-cell [19, 20]. However, the expression of a small number of genes in the mutated and unmutated subtypes was different, with ZAP-70 standing out as the gene that most stringently separated the subsets.
Flow cytometric assays for ZAP-70 expression have proved difficult, especially as it is an intracellular antigen so that the cells require permeabilization, but at least three different methods have been reported [21-23]. Seen as surrogate assays for IGHV gene mutations, the first two assays performed similarly with around 94% concordance, but the third, which used a different and directly conjugated antibody, had only a 77% concordance with IGHV gene mutations. On the other hand, in this study ZAP-70 expression performed better than VH mutations in predicting treatment-free survival. Patients who were ZAP-70 positive; IGHV mutated had a worse survival than those who were ZAP-70 negative; IGHV unmutated.
Nevertheless, establishing a standardized assay for ZAP-70 expression has proved difficult [24] and many of the most experienced laboratories have dropped it from their repertoire as being unreliable. The need for a dependable surrogate for IGHV mutational status remains. Although no other prognostic factor has been widely adopted, there has been no shortage of candidates. A recent review described nineteen new prognostic markers: TCL1 gene expression, CLLU1 expression, miRNA signature, mRNA signature, and expression of Lipoprotein lipase A, ADAM29, HEM1, Septin 10, DMD, and PEG 10, levels of VEGF and thrombopoietin; telomere length and activity; surface expression of CD49d, CD69 and FCRL, expression of anti-apoptotic genes such as MCL-1 and the Bcl-2/Bax ratio, MDR1/MDR-3 genes, and AID mRNA [25].
Combinations of prognostic factors might be more useful than individual factors. CD38 and IGHV mutations [17] or CD38 and ZAP70 [26, 27] both perform better than any one factor. A scoring system based on six surface molecules (CD62L, CD54, CD49c, CD49d, CD38, and CD79b) detectable by flow cytometry has been proposed [28].
Immature laminin receptor
In a recent issue of Leukemia Research, Friedrichs et al [29] proposed that as high expression of the immature laminin receptor (iLR) protein predicted a favorable prognosis for CLL correlating with mutated IGHV genes and being detectable by flow cytometry, it might be used as a surrogate. ILR is an oncofetal antigen overexpressed in several tumor tissues but absent in the normal differentiation process. It is the precursor molecule of the mature 67 kDa protein that plays a role in the cell adhesion-associated processes initiated by laminin binding.
Friedrichs et al studied 134 patients with CLL. The flow cytometry assay used direct staining with a FITC-conjugated mouse anti-ILR monoclonal antibody and cells were double stained with an anti-CD19-PE antibody or an isotope control in the conventional way. ILR scores over CD38 and ZAP-70 in not being present on T cells nor on normal B cells. A cut-off 30% cells staining was determined best to distinguish between positive and negative. 41% of CLLs in their series were judged to be positive. There was a correlation between the expression of iLR and low ZAP-70 expression, mutated IGHV status and low CD38 expression. There was no change in iLR expression over time as there sometimes is with CD38 and ZAP-70 expression [17, 30]. However, the correlation of high expression of iLR with mutated IGHV genes was no better than for ZAP-70 or CD38. Only 78.9% of patients with mutated IGHV genes were iLR positive and 81.7% of unmutated cases were iLR negative. ILR negativity therefore behaves with a similar degree of concordance to IGHV mutations as ZAP-70 or CD38 expression. In a multivariate analysis iLR expression retained some independent predictive value for prognosis.
In summary, iLR expression is not an exact surrogate for IGHV mutational status, but yet another prognostic factor with some independent value.
Stereotypy
Perhaps the time has come to draw a line under the search for surrogates. Over time the technology for sequencing IGHV genes in CLL has improved and a recent study reported over 7500 sequences among patients worldwide [31]. The striking feature of these sequences was stereotypy, the finding that the IGHV sequences of large numbers of CLL patients were identical or very similar. The implication is that perhaps a third of all CLLs are derived from populations of B cells responding to a restricted range of antigens or superantigens. Originally at least 48 separate stereotypes could be identified, each subset comprising between 2 and 20 cases [32] but the wider collaboration [31] identified 952 ground-level clusters of cases with between 2 and 56 cases in each, though clearly most of these had very small numbers of cases. Common sequences among ground-level clusters made it possible to group them into considerably larger higher order clusters that displayed biased features with regard to IGHV usage, somatic hypermutation and VH CDR3 pattern composition. The largest higher order cluster with 213 sequences is clearly recognizable as subset 2 which uses IGHV3-21 with an acidic residue at VH CDR3 position 107. This well known subset has been identified as the major exception to the prognostic importance of IGHV gene mutations in which CLLs with up to 4% somatic mutations behave aggressively [33].
These stereotypes are often confined to a single IGHV gene, but not necessarily so and B cell receptors can derive their gene sequence from a number of VDJ combinations, all belonging to the same phylogenetic clan. For example, the second largest higher order cluster which included 184 sequences used 6 different IGHV genes of clan 1 (IGHV1-2, 1-3, 1-8, 1-18, 5a and 7-4-1) with a QWL motif at VH CDR3 positions 108-110.
Of relevance to our current topic is the fact that different stereotypic subtypes appear to be associated with distinct patterns of clinical behaviour. For example, subtype 8 which uses the VH4-39 gene in an unmutated form but class-switched to IgG production is associated with a 24-fold greater risk of Richter transformation and has a higher frequency than expected of trisomy 12 yet no significant association with progressive disease [34]. On the other hand, subtype 4 which uses VH4-34 in a mutated form tends to present in the fifth decade and be non-progressive [32]. As further cases are assembled it is to be expected that even greater heterogeneity will be recognised and assigned to specific subtypes.
References
1. Damle, R.N., Wasil, T., Fais ,F. et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999; 94:1840-1847.
2. Hamblin, T.J., Davis, Z., Gardiner, A., Oscier, D.G., Stevenson, F.K. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999; 94:1848-1854.
3. D Lewis S, Gellert M. The mechanism of antigen receptor gene assembly. Cell 1989; 59:585-588.
4. Desiderio SV, Yancopoulos GD, Paskind M et al. Insertion of N regions into heavy chain genes is correlated with the expression of terminal deoxytransferase in B cells. Nature 1984; 311:752-755
5. Corbett SJ, Tomlinson IM, Sonnhammer EL, Buck D, Winter G. Sequence of the human immunoglobulin diversity (D) segment locus: a systematic analysis provides no evidence for the use of DIR segments, inverted D segments, "minor" D segments or D-D recombination. J Mol Biol 1997; 270:587-597
6. MacLennan IC. Germinal centers. Annu Rev Immunol 1994; 12:117-139.
7. Kipps TJ, Tomhave E, Pratt LF, Duffey S, Chen PP, Carson DA. Developmentally restricted immunoglobulin heavy chain variable region gene expressed at high frequency in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 1989; 86:5913-5917.
8. Deane M, Norton JD. Preferential rearrangement of developmentally regulated immunoglobulin VH1 genes in human B-lineage leukaemias. Leukemia 1991; 5:646-50.
9. Ebeling SB, Schutte MEM, Akkermans-Koolhaas KE, Bloem AC, Gmelig-Meyling FHJ, Logtenberg T. Expression of members of the immunoglobulin VH3 gene families is not restricted at the level of individual genes in human chronic lymphocytic leukemia. Int Immunol 1992; 4:313-20.
10. Schroeder HWJr, Dighiero G. The pathogenesis of chronic lymphocytic leukemia: analysis of the antibody repertoire. Immunology Today 1994; 15:288-94.
11. Matsuda F, Shin EK, Nagaoka H et al. Structural and physical map of the 64 variable segments in the 3’ 0.8 megabase region of the human immunoglobulin heavy chain locus. Nature Genet 1993; 3:88-94.
12. Fais F, Ghiotto F, Hashimoto S et al. Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. J Clin Invest 1998; 102:1515-35.
13. Oscier DG, Thompsett A, Zhu D, Stevenson FK. Differential rates of somatic hypermutation in VH genes among subsets of chronic lymphocytic leukemia defined by chromosomal abnormalities. Blood 1997; 89:4153-60.
14. Hamblin TJ, Davis Z, Oscier DG, Stevenson FK. The use of immunoglobulin heavy chain variable region genes in chronic lymphocytic leukaemia. B-cell Lymphoproliferative Disorders Imedex: New York (1998) 27a
15. Hamblin T, Davis Z, Oscier DG, Stevenson FK The use of immunoglobulin heavy chain variable region genes in chronic lymphocytic leukaemia.. Brit J Haematol 1998; 101 (suppl 1) : 44a.
16. Hamblin TJ, Davies Z, Oscier DG, Stevenson FK. In chronic lymphocytic leukemias germline configuration of immunoglobulin heavy chain genes is associated with a more aggressive form of the disease. Blood 1998; 92 (Suppl 1): 515a.
17. Hamblin TJ, Orchard JA, Ibbotson RE, et al. CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease. Blood 2002; 99: 1023-1029.
18. Hamblin T. Chronic Lymphocytic Leukaemia: One Disease or Two? Annals of Hematology 2002; 81:299-303
19. Rosenwald A, Alizadeh AA, Widhopf G et al. Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med 2001; 194:1639-1647.
20. Klein U, Tu Y, Stolovitzky GA, et al. Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J Exp Med 2001; 194:1625-38.
21. Crespo M, Bosch F, Villamor N et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med 2003; 348:1764-75.
22. Orchard JA, Ibbotson RE, Davis Z et al. ZAP-70 expression by flow cytometry is a good prognostic marker in CLL and a potential surrogate for immunoglobulin VH gene mutations. Lancet 2004; 363:105-11.
23. Rassenti LZ, Huynh L, Toy TL et al. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med. 2004; 351:893-901.
24. Marti G, Orfao A, Goolsby C. ZAP-70 in CLL: towards standardization of a biomarker for patient management: history of clinical cytometry special issue. Cytometry. Part B, Clinical Cytometry 2006; 70B: 197–200.
25. Codony C, Crespo N, Abrisqueta P, Montserrat E, Bosch F. Gene expression profiling in chronic lymphocytic leukaemia. Best Pract Res Clin Haematol. 2009; 22:211–22
26. Del Giudice I, Morilla A, Osuji N, et al. Zeta chain associated protein 70 and CD38 combined predict the time to first treatment in patients with chronic lymphocytic leukemia. Cancer 2005; 104: 2124–32.
27. Schroers R, Griesinger F, Trumper L, et al. Combined analysis of ZAP-70 and CD38 expression as a predictor of disease progression in B-cell chronic lymphocytic leukemia. Leukemia 2005; 19: 750–58.
28. Zucchetto A, Bomben R, Dal Bo M, et al. A scoring system based on the expression of six surface molecules allows the identification of three prognostic risk groups in B-cell chronic lymphocytic leukemia. J Cell Physiol 2006; 207: 354–63.
29. Friedrichs B, Siegel S, Reimer R et al. High expression of the immature laminin receptor protein correlates with mutated IGVH status and predicts a favorable prognosis in chronic lymphocytic leukemia. Leukemia Research 2011; 35:721-9.
30. Hamblin TJ. ZAP-70 levels do change in CLL but not very often. Leukemia & Lymphoma 2007; 48:1059-60.
31. Agathaggelidis A, Darzentas N, Hadzidimitriou A, et al. The composition of the B cell receptor repertoire in 7428 cases of chronic lymphocytic leukemia: one third stereotyped, two thirds heterogeneous - what does this mean? Blood 2010; 116: Number 21: 43a.
32. Stamatopoulos K, Belessi C, Moreno C et al. Over 20% of patients with chronic lymphocytic leukaemia carry stereotyped receptors: pathogenetic implications and clinical correlations. Blood 2007; 109:259-70.
33. Tobin G, Thunberg U, Johnson A, et al. Somatically mutated IgV(H)3-21 genes characterize a new subset of chronic lymphocytic leukemia. Blood 2002; 99:2262-4.
34. Rossi D, Spina V, Cerri M, et al. Stereotyped B-cell receptor is an independent risk factor of chronic lymphocytic leukemia transformation to Richter syndrome. Clin Cancer Res 2009; 15:4415-22.
Crazy Heart
We watched Crazy Heart last night. This won an Oscar for Jeff Bridges a couple of years ago as well as one for T-Bone Burnett for best song.
The story is an old one. C & W songwriter becomes famous, gets a lot of money, squanders it on cheap whiskey and loose women, is reduced to performing in bowling alleys, is redeemed by a good woman, goes back to writing songs, blows it, gets himself clean again, but the woman won't take him back.
The story is hackneyed and the appearance of Robert Duvall reminds us that he made a similar film several years ago. This is one that definitely needs the subtitles since the speech in unintelligible. Perhaps that's just as well since the language that one can hear is foul. On the other hand you get the impression of the story without the actual words.
Still I enjoyed the music. Advice? Don't bother with the film, get the CD.
The story is an old one. C & W songwriter becomes famous, gets a lot of money, squanders it on cheap whiskey and loose women, is reduced to performing in bowling alleys, is redeemed by a good woman, goes back to writing songs, blows it, gets himself clean again, but the woman won't take him back.
The story is hackneyed and the appearance of Robert Duvall reminds us that he made a similar film several years ago. This is one that definitely needs the subtitles since the speech in unintelligible. Perhaps that's just as well since the language that one can hear is foul. On the other hand you get the impression of the story without the actual words.
Still I enjoyed the music. Advice? Don't bother with the film, get the CD.
Galatians 6:18. Benediction
The grace of our Lord Jesus Christ be with your spirit, brothers. Amen
So we come to the end of the letter. Paul has admonished us for getting things dangerously wrong, yet he still calls us 'brother'. His wish for us is to be united with the Holy Spirit and under his control. Elsewhere we learn that love covers a multitude of sins. This is not as full a benediction as some but it is sincere.
So we come to the end of the letter. Paul has admonished us for getting things dangerously wrong, yet he still calls us 'brother'. His wish for us is to be united with the Holy Spirit and under his control. Elsewhere we learn that love covers a multitude of sins. This is not as full a benediction as some but it is sincere.
John 5: 17-18. Blasphemy
In his defense Jesus said to them, “My Father is always at his work to this very day, and I too am working.” For this reason they tried all the more to kill him; not only was he breaking the Sabbath, but he was even calling God his own Father, making himself equal with God.
It was a matter of dispute among the Rabbis as to whether God continued to rest on the seventh day. Eventually, by the end of the first century the majority accepted Jesus' point that God does not stop working. However, here as elsewhere in this gospel Jesus makes himself 'equal with God and this is blasphemy to them.
Jews, Muslims, JWs and Mormons are all caught in the same blasphemous trap; the failure to recognize Jesus as God. Are you?
It was a matter of dispute among the Rabbis as to whether God continued to rest on the seventh day. Eventually, by the end of the first century the majority accepted Jesus' point that God does not stop working. However, here as elsewhere in this gospel Jesus makes himself 'equal with God and this is blasphemy to them.
Jews, Muslims, JWs and Mormons are all caught in the same blasphemous trap; the failure to recognize Jesus as God. Are you?
Wednesday, June 29, 2011
Galatians 6:17. The Marks of Jesus
Finally, let no one cause me trouble, for I bear on my body the marks of Jesus.
Whatever does this mean? Nothing to do with the 'stigmata' of Francis of Assisi. Paul certainly had the scars of suffering for Jesus, but these were physical scars from beatings and hardship. I suppose it means two things: that after what he had suffered for Christ he was immune to mere earthly troubles and that as an ambassador for Christ anything aimed at him was aimed at his savior.
Whatever does this mean? Nothing to do with the 'stigmata' of Francis of Assisi. Paul certainly had the scars of suffering for Jesus, but these were physical scars from beatings and hardship. I suppose it means two things: that after what he had suffered for Christ he was immune to mere earthly troubles and that as an ambassador for Christ anything aimed at him was aimed at his savior.
More Muslim atrocities
There is a trend for the Western media to increasingly support the Muslim cause in Africa and the Middle East. I have already commented on what is going on in Syria. Syria is a secular country with freedom of religion. It may be autocratic and no doubt it has come down hard against what it perceives as sedition, but we have to remember that in Western countries civilization was not built in a day. What is masquerading as a civil rights movement in Syria is in fact an extreme radical Muslim movement that intends to impose Sharia law and ban Christian churches.
There was enormous support for the democratically elected Muslim in the Ivory Coast, Alassane Ouattara and correct criticism of his predecessor, Laurent Gbagbo, who tried to hold on to power. However, we have heard nothing of the atrocities committed by Ouattara's supporters since they gained power. Here is an example: Two peasant brothers were brutally crucified after “the example of Christ” on 29 May by forces loyal to the new Muslim president. Raphael Aka Kouame died of his injuries; incredibly his younger brother, Kouassi Privat Kacou, survived the ordeal. The pair were badly beaten and tortured before being crudely nailed to cross-shaped planks by their hands and feet with steel spikes.
The brothers were falsely accused of hiding weapons in their home village of Binkro. The brothers repeatedly denied any involvement, but their pleas were ignored. After crucifying them, Ouattara’s men took them on an extensive search of Binkro, but they found only a store of medical equipment and supplies. The seriously wounded pair were then taken to prison in Oumé, where Raphael died that night.
This contrasts strongly with what is happening in next-door Nigeria where in the fairest election for generations, the Christian, Goodluck Jonathon won the election.
Christians and churches in Northern Nigeria have come under sustained attack since the re-election of the president in April, from supporters of the defeated Muslim candidate. Around 200 churches have been burned or destroyed and over 1,200 houses razed, and at least 800 people are estimated to have been killed.
A Nigerian missionary pastor in Bauchi State has been tortured and murdered by a group of Muslims after refusing to renounce his faith in Christ. The pastor was travelling in a van when it was pulled over by Muslims posing as police. They asked if anyone in the vehicle was a Christian, and the pastor said that he was. The men pulled him out of the van and told him repeatedly to renounce Christ. When he refused, they first beat him, then gouged out his eyes, and finally killed him and burned his body. He has left a widow and eight children.
Also an entire Christian village in Kaduna State has been burned to ashes by a mob of Muslim militants and its water supply contaminated. On 18 April the village of Ung. Kerau was attacked by more than 300 men armed with various weapons. The Christian villagers fled, and the mob torched the village. A local church leader said that the mob threw pepper, clothes, firewood and rubbish into the village’s two wells. He added that the villagers “were attacked simply because they are Christians”.
Elsewhere, the so-called Arab-Spring has not brought about the movement towards democracy that the West was hoping for. Some Christians in Tunisia who have tried to share their faith after the uprising earlier this year have been forced to flee the country or move to a safer location after receiving threats from Islamists. There are also signs that the influence of radical Islam is increasing across the country, raising fears that it is hijacking the revolution. Ennahda, Tunisia’s largest Islamist party, looks set to become the largest group in the new constitutional assembly following elections to be held on 23 July.
The Muslim Brotherhood, the leading Islamic party in Egypt, has formed a political alliance with Jama’a al-Islamiyya, a radical group that was behind a number of terrorist attacks in the 1990s (though it has recently renounced violence). The two groups announced that they will form a coalition to contest September’s parliamentary elections, in order to combat secular forces in the country.
Jama'a al-Islamiyya spokesman Osama Hafez underlined the parties’ commitment to upholding the place of Islam in Egyptian society: “Allah’s words must rule and Islam must be in the hearts of the citizens.”
Another political party has been formed by Salafist groups. Salafism is an ultra-conservative, strict and puritanical version of Islam related to Wahhabism, the official state creed of Saudi Arabia. The party says that if they gain power, Christians will be given “the right to refer to their religion”, but “the higher reference will be for Islamic sharia”.
There are real concerns that the Muslim Brotherhood might become the ruling party in Egypt, which would make life very difficult for the churches. A Jama'a al-Islamiyya leader recently called on Christians to secure their own safety by submitting to the god of Islam (by becoming Muslims). And Salafists were behind assaults on two churches and homes in Imbaba district, Cairo, in May in which 12 people were killed and scores injured. This is only one of a barrage of attacks that Christians have suffered since the revolution. Their position is precarious.
The changes that we are watching in Africa and the Middle East are largely paid for by Western aid. So far the ousting of the Libyan president has cost the UK economy £260 million. It is time for the citizens of the West, especially the Christian citizens, to bring pressure on our governments to make recipients of our largesse more accountable for the aid.
I see that in Pakistan an important Islamic political party has called for the Supreme Court to ban the Bible. A leader of Jamiat Ulema-e-Islam, Maulana Abdul Rauf Farooqi, made the appeal at a press conference at a mosque in Lahore on 30 May. Farooqi described the Bible as “pornographic”. He claimed that “blasphemous” portions had been added, which charged some prophets with “a variety of moral crimes, which undermine the sanctity of the holy figures”. Farooqi said such “insertions” strongly offended Muslims, who hold all prophets and holy books in high esteem. He said that if the Supreme Court did not respond by banning the Bible, Islamic clerics would formally petition the court, and added that the move was an act of revenge against the desecration of the Quran by that idiot Terry Jones in Florida.
Imagine if the UK or USA decided to ban the Quran? Can you inmagine the outcry?
There was enormous support for the democratically elected Muslim in the Ivory Coast, Alassane Ouattara and correct criticism of his predecessor, Laurent Gbagbo, who tried to hold on to power. However, we have heard nothing of the atrocities committed by Ouattara's supporters since they gained power. Here is an example: Two peasant brothers were brutally crucified after “the example of Christ” on 29 May by forces loyal to the new Muslim president. Raphael Aka Kouame died of his injuries; incredibly his younger brother, Kouassi Privat Kacou, survived the ordeal. The pair were badly beaten and tortured before being crudely nailed to cross-shaped planks by their hands and feet with steel spikes.
The brothers were falsely accused of hiding weapons in their home village of Binkro. The brothers repeatedly denied any involvement, but their pleas were ignored. After crucifying them, Ouattara’s men took them on an extensive search of Binkro, but they found only a store of medical equipment and supplies. The seriously wounded pair were then taken to prison in Oumé, where Raphael died that night.
This contrasts strongly with what is happening in next-door Nigeria where in the fairest election for generations, the Christian, Goodluck Jonathon won the election.
Christians and churches in Northern Nigeria have come under sustained attack since the re-election of the president in April, from supporters of the defeated Muslim candidate. Around 200 churches have been burned or destroyed and over 1,200 houses razed, and at least 800 people are estimated to have been killed.
A Nigerian missionary pastor in Bauchi State has been tortured and murdered by a group of Muslims after refusing to renounce his faith in Christ. The pastor was travelling in a van when it was pulled over by Muslims posing as police. They asked if anyone in the vehicle was a Christian, and the pastor said that he was. The men pulled him out of the van and told him repeatedly to renounce Christ. When he refused, they first beat him, then gouged out his eyes, and finally killed him and burned his body. He has left a widow and eight children.
Also an entire Christian village in Kaduna State has been burned to ashes by a mob of Muslim militants and its water supply contaminated. On 18 April the village of Ung. Kerau was attacked by more than 300 men armed with various weapons. The Christian villagers fled, and the mob torched the village. A local church leader said that the mob threw pepper, clothes, firewood and rubbish into the village’s two wells. He added that the villagers “were attacked simply because they are Christians”.
Elsewhere, the so-called Arab-Spring has not brought about the movement towards democracy that the West was hoping for. Some Christians in Tunisia who have tried to share their faith after the uprising earlier this year have been forced to flee the country or move to a safer location after receiving threats from Islamists. There are also signs that the influence of radical Islam is increasing across the country, raising fears that it is hijacking the revolution. Ennahda, Tunisia’s largest Islamist party, looks set to become the largest group in the new constitutional assembly following elections to be held on 23 July.
The Muslim Brotherhood, the leading Islamic party in Egypt, has formed a political alliance with Jama’a al-Islamiyya, a radical group that was behind a number of terrorist attacks in the 1990s (though it has recently renounced violence). The two groups announced that they will form a coalition to contest September’s parliamentary elections, in order to combat secular forces in the country.
Jama'a al-Islamiyya spokesman Osama Hafez underlined the parties’ commitment to upholding the place of Islam in Egyptian society: “Allah’s words must rule and Islam must be in the hearts of the citizens.”
Another political party has been formed by Salafist groups. Salafism is an ultra-conservative, strict and puritanical version of Islam related to Wahhabism, the official state creed of Saudi Arabia. The party says that if they gain power, Christians will be given “the right to refer to their religion”, but “the higher reference will be for Islamic sharia”.
There are real concerns that the Muslim Brotherhood might become the ruling party in Egypt, which would make life very difficult for the churches. A Jama'a al-Islamiyya leader recently called on Christians to secure their own safety by submitting to the god of Islam (by becoming Muslims). And Salafists were behind assaults on two churches and homes in Imbaba district, Cairo, in May in which 12 people were killed and scores injured. This is only one of a barrage of attacks that Christians have suffered since the revolution. Their position is precarious.
The changes that we are watching in Africa and the Middle East are largely paid for by Western aid. So far the ousting of the Libyan president has cost the UK economy £260 million. It is time for the citizens of the West, especially the Christian citizens, to bring pressure on our governments to make recipients of our largesse more accountable for the aid.
I see that in Pakistan an important Islamic political party has called for the Supreme Court to ban the Bible. A leader of Jamiat Ulema-e-Islam, Maulana Abdul Rauf Farooqi, made the appeal at a press conference at a mosque in Lahore on 30 May. Farooqi described the Bible as “pornographic”. He claimed that “blasphemous” portions had been added, which charged some prophets with “a variety of moral crimes, which undermine the sanctity of the holy figures”. Farooqi said such “insertions” strongly offended Muslims, who hold all prophets and holy books in high esteem. He said that if the Supreme Court did not respond by banning the Bible, Islamic clerics would formally petition the court, and added that the move was an act of revenge against the desecration of the Quran by that idiot Terry Jones in Florida.
Imagine if the UK or USA decided to ban the Quran? Can you inmagine the outcry?
Tuesday, June 28, 2011
Galatians 6:16. The Israel of God
Peace and mercy to all who follow this rule, even to the Israel of God
Which rule? The rule of the Spirit. Those who regulate their lives by putting complete trust in Christ crucified. They have the peace, the serenity of heart of those who have been justified by faith, having received unjustified mercy.
The Israel of God is a phrase only used by Paul here and it signifies that the blessings of the chosen people are now conferred upon believers; not on those who can trace their racial dependency from Jacob.
Which rule? The rule of the Spirit. Those who regulate their lives by putting complete trust in Christ crucified. They have the peace, the serenity of heart of those who have been justified by faith, having received unjustified mercy.
The Israel of God is a phrase only used by Paul here and it signifies that the blessings of the chosen people are now conferred upon believers; not on those who can trace their racial dependency from Jacob.
The King's Speech
We finally got around to watching The King's Speech on DVD, courtesy of my daughter and son-in-law.
So many Oscar winning movies have disappointed, but I am glad to say this film didn't. It is clear to see that the movie emerged from British Television. Colin Firth and Jennifer Ehle were the hero and heroine of Pride and Prejudice and David Bamber was also in that; Anthony Andrews starred in Brideshead Revisited, Derek Jacobi in I Claudius (as another famous stammerer) and Cadfael, Helena Bonham Carter has been in many classical dramas but has been seen fairly recently on TV as Enid Blyton, Anne Boleyn, Morgan Le Fey and Vera Brittain. Only the Australians, Geoffrey Rush (Shine) and Guy Pearce (L.A. Confidential) are really big film stars. Timothy Spall has been the star of several Mike Leigh low-budget successes.
The Oscar-winning director, Tom Hooper had previously made The Damned United, which I watched earlier in the year, but he also cut his teeth in television with one of the Prime Suspects and the John Adams mini-series.
I thought the sense of period was well captured and the playing of the principlals excellent. It was a serious piece of movie making and an unusual subject that was well worth the acclaim.
So many Oscar winning movies have disappointed, but I am glad to say this film didn't. It is clear to see that the movie emerged from British Television. Colin Firth and Jennifer Ehle were the hero and heroine of Pride and Prejudice and David Bamber was also in that; Anthony Andrews starred in Brideshead Revisited, Derek Jacobi in I Claudius (as another famous stammerer) and Cadfael, Helena Bonham Carter has been in many classical dramas but has been seen fairly recently on TV as Enid Blyton, Anne Boleyn, Morgan Le Fey and Vera Brittain. Only the Australians, Geoffrey Rush (Shine) and Guy Pearce (L.A. Confidential) are really big film stars. Timothy Spall has been the star of several Mike Leigh low-budget successes.
The Oscar-winning director, Tom Hooper had previously made The Damned United, which I watched earlier in the year, but he also cut his teeth in television with one of the Prime Suspects and the John Adams mini-series.
I thought the sense of period was well captured and the playing of the principlals excellent. It was a serious piece of movie making and an unusual subject that was well worth the acclaim.
John 5:16. The Sabbath
So, because Jesus was doing these things on the Sabbath, the Jewish leaders began to persecute him.
At this stage all Jesus had done was to tell the man to pick up his bed and walk on the Sabbath, but the language technocrats tell me that the tenses used here suggest that the battle lines between the Jews and Jesus had already been drawn over Sabbath observance by part of the story that John omits.
We have to recognize that Sabbath observance is one of those old things that was being replaced by the new.
How does this reflect on today's society? Some years ago the Keep Sunday Special campaign fought a partially effective battle against Sunday degenerating in just another day of the week. I was half-hearted about this because although I perceived some merit in the case, I do not believe from Scripture that our Sunday equates to the Jewish Sabbath with all its restrictions and Laws.
The sabbath was made for man; not man for the sabbath. It is good that the working week is broken up one day in seven. Work is good for men, but so is rest, and we need time to contemplate and think, that is not compromised by physical activity. In the same way, those whose work is sedentary need time for physical activity. I cannot blame my son whose job is about sitting in an office or a car or an airplane, taking time to play cricket on a Sunday.
Societies that have tried a 10 day week have found that it is not satisfactory. Nor is it possible in modern society to shut down power generators every 7 days and the devices that some modern Jews use to avoid 'work' on the Sabbath are ridiculous.
I am pleased that we don't have to work on a Sunday and that there is time to go to church, but in a Muslim society where Friday is the Holy day I would have no problem in calling Friday my Sunday and using it in the same way that I do in the UK. Perhaps we would not sing 'This is the day' but every day is a good day for worship and being close to God.
At this stage all Jesus had done was to tell the man to pick up his bed and walk on the Sabbath, but the language technocrats tell me that the tenses used here suggest that the battle lines between the Jews and Jesus had already been drawn over Sabbath observance by part of the story that John omits.
We have to recognize that Sabbath observance is one of those old things that was being replaced by the new.
How does this reflect on today's society? Some years ago the Keep Sunday Special campaign fought a partially effective battle against Sunday degenerating in just another day of the week. I was half-hearted about this because although I perceived some merit in the case, I do not believe from Scripture that our Sunday equates to the Jewish Sabbath with all its restrictions and Laws.
The sabbath was made for man; not man for the sabbath. It is good that the working week is broken up one day in seven. Work is good for men, but so is rest, and we need time to contemplate and think, that is not compromised by physical activity. In the same way, those whose work is sedentary need time for physical activity. I cannot blame my son whose job is about sitting in an office or a car or an airplane, taking time to play cricket on a Sunday.
Societies that have tried a 10 day week have found that it is not satisfactory. Nor is it possible in modern society to shut down power generators every 7 days and the devices that some modern Jews use to avoid 'work' on the Sabbath are ridiculous.
I am pleased that we don't have to work on a Sunday and that there is time to go to church, but in a Muslim society where Friday is the Holy day I would have no problem in calling Friday my Sunday and using it in the same way that I do in the UK. Perhaps we would not sing 'This is the day' but every day is a good day for worship and being close to God.
Monday, June 27, 2011
Galatians 6:15. A changed heart.
Neither circumcision nor uncircumcision means anything; what counts is a new creation.
It's not what laws you obey or what rituals that you follow that matter. Are you born again. It is just coincidence that I am studying John's gospel and Galatians at the same time. Yet they have the same theme. The old has gone the new has come. New wine at Cana. You must be born again to Nicodemus. A spring of water welling up to eternal life for the woman at the well. It is all referring to this new creation. We must live in the Spirit. We used to talk about asking Jesus into our hearts. Another generation spoke about practising the presence of Jesus. It is all the same, different words for the same thing. Do we have a Spiritual life?
We cling to ritual as a child clings to a comfort blanket. It may be our hymns or whether we sit of stand or the clothes we wear or our order of service or whether the minister weras a dog collar or a tie. I remember going into a Roman Catholic Cathedral with a friend. He crossed himself with Holy Water and genuflected towards the alter. I did teh same and he asked me why I had done it. I replied that I had copied him out of politeness. He told me that for me it didn't mean anything. That was true, but for him it really meant nothing either. It was a ritual which had psychological effect but no effectual effect. God would not have been watching. I do not desire your sacrifices or burnt offerings. It is a changed heart that God requires.
It's not what laws you obey or what rituals that you follow that matter. Are you born again. It is just coincidence that I am studying John's gospel and Galatians at the same time. Yet they have the same theme. The old has gone the new has come. New wine at Cana. You must be born again to Nicodemus. A spring of water welling up to eternal life for the woman at the well. It is all referring to this new creation. We must live in the Spirit. We used to talk about asking Jesus into our hearts. Another generation spoke about practising the presence of Jesus. It is all the same, different words for the same thing. Do we have a Spiritual life?
We cling to ritual as a child clings to a comfort blanket. It may be our hymns or whether we sit of stand or the clothes we wear or our order of service or whether the minister weras a dog collar or a tie. I remember going into a Roman Catholic Cathedral with a friend. He crossed himself with Holy Water and genuflected towards the alter. I did teh same and he asked me why I had done it. I replied that I had copied him out of politeness. He told me that for me it didn't mean anything. That was true, but for him it really meant nothing either. It was a ritual which had psychological effect but no effectual effect. God would not have been watching. I do not desire your sacrifices or burnt offerings. It is a changed heart that God requires.
John 5:9b-15. Again
The day on which this took place was a Sabbath, and so the Jewish leaders said to the man who had been healed, “It is the Sabbath; the law forbids you to carry your mat.” But he replied, “The man who made me well said to me, ‘Pick up your mat and walk.’ ” So they asked him, “Who is this fellow who told you to pick it up and walk?” The man who was healed had no idea who it was, for Jesus had slipped away into the crowd that was there. Later Jesus found him at the temple and said to him, “See, you are well again. Stop sinning or something worse may happen to you.” The man went away and told the Jewish leaders that it was Jesus who had made him well.
Was I being unfair to this man yesterday? I said that he could not remember who had healed him and that was perhaps inaccurate; rather it was that he was not curious. I mean, if you had been there 38 years and someone had healed you without ever disturbing the water, wouldn't you have asked how and why? It seems churlish not to. I don't think that Jesus suddenly disappeared like Philip before the Ethiopian Eunuch - there is nothing to suggest that.
Jesus' response that he should go and sin no more, I'm sure does not mean that his paralysis was the consequence of past sin. Jesus does not normally relate physical punishment to individual sin; everyone of us is a sinner and we don't attract paralysis. I think it much more likely that Jesus was referring to the man's response to the act of grace. Remember Jesus' response to the leper who came to thank him? Were there not ten lepers who were cleansed?
At the beginning of John's gospel we read, "To all who received him, to all who believed in his name he gave the right to become the children of God." This man didn't even ask for Jesus' name to believe in.
I believe that salvation is all of grace; there is nothing that we do to contribute to our salvation. But grace is not like a bit of paint that we get splashed by and there it is indelible, unable to be washed off. Salvation has to be accepted and there is no evidence that it was here. Healing was accepted but not salvation. Rather than defend Jesus for his healing, he blames Jesus before the Jews.
But you might ask, "In requiring that we accept our salvation aren't we claiming a part in it?" By no means since without the Holy Spirit's enabling we cannot accept. Yet if we reject salvation, as we surely must without the Holy Spirit, it is totally our responsibility. In telling him to sin no more, Jesus is asking for the Spirit's enabling in the Man's life. Will it happen? It is not inevitable. We are told that it is not God's will that any should perish, yet some will be so stiff necked as to do so. There is a difference between what God wants and what he wills.
How do we know the will of God? We know his desires but whether he has effectually willed his desires in some one's life will usually be seen in a change in their lives; if we do not see it we might doubt it, but short of heaven we will never know.
Was I being unfair to this man yesterday? I said that he could not remember who had healed him and that was perhaps inaccurate; rather it was that he was not curious. I mean, if you had been there 38 years and someone had healed you without ever disturbing the water, wouldn't you have asked how and why? It seems churlish not to. I don't think that Jesus suddenly disappeared like Philip before the Ethiopian Eunuch - there is nothing to suggest that.
Jesus' response that he should go and sin no more, I'm sure does not mean that his paralysis was the consequence of past sin. Jesus does not normally relate physical punishment to individual sin; everyone of us is a sinner and we don't attract paralysis. I think it much more likely that Jesus was referring to the man's response to the act of grace. Remember Jesus' response to the leper who came to thank him? Were there not ten lepers who were cleansed?
At the beginning of John's gospel we read, "To all who received him, to all who believed in his name he gave the right to become the children of God." This man didn't even ask for Jesus' name to believe in.
I believe that salvation is all of grace; there is nothing that we do to contribute to our salvation. But grace is not like a bit of paint that we get splashed by and there it is indelible, unable to be washed off. Salvation has to be accepted and there is no evidence that it was here. Healing was accepted but not salvation. Rather than defend Jesus for his healing, he blames Jesus before the Jews.
But you might ask, "In requiring that we accept our salvation aren't we claiming a part in it?" By no means since without the Holy Spirit's enabling we cannot accept. Yet if we reject salvation, as we surely must without the Holy Spirit, it is totally our responsibility. In telling him to sin no more, Jesus is asking for the Spirit's enabling in the Man's life. Will it happen? It is not inevitable. We are told that it is not God's will that any should perish, yet some will be so stiff necked as to do so. There is a difference between what God wants and what he wills.
How do we know the will of God? We know his desires but whether he has effectually willed his desires in some one's life will usually be seen in a change in their lives; if we do not see it we might doubt it, but short of heaven we will never know.
13 Elements: Europium, Terbium and Yttrium
Europium, Terbium and Yttrium
Rare earth elements
Atomic numbers: 63; 65; 39
Used in: energy-efficient lighting
Criticality ratings: critical; critical; critical
Europium and terbium have long been an entertaining double act: their phosphorescent properties – terbium in yellow-green and europium in blue and red – help to produce the images on most television screens. Their rare earth cousin yttrium plays a quiet but crucial supporting role, hosting the red-releasing europium ions.
These colourful qualities have recently secured the europium-terbium duo another gig in energy-saving compact fluorescent light bulbs. These bulbs work by exciting mercury vapour to emit ultraviolet light, which is then absorbed by phosphorescent materials coating their insides to produce visible frequencies of light. One complaint made about early versions was that they did not produce the same warm light as the incandescent tungsten bulbs they replaced – a problem resolved by switching the coating to the right blend of terbium and europium.
The next generation of energy-efficient lighting, based on LEDs, might see europium strike out alone: adding europium ions to a blue LED turns some of its light yellow, giving a white output overall. That could free up terbium to pursue its own projects, such as perhaps replacing dysprosium in the manufacture of high temperature permanent magnets.
All that depends on securing additional supplies, however. According to the DoE, europium could be in short supply as early as 2015 – and terbium even sooner. For yttrium we have already reached crunch time: demand outstripped supply in 2010.
Lymphoma sufferers will recognize 90 Yttrium as the isotope that is used in Zevelin used as a treatment
Rare earth elements
Atomic numbers: 63; 65; 39
Used in: energy-efficient lighting
Criticality ratings: critical; critical; critical
Europium and terbium have long been an entertaining double act: their phosphorescent properties – terbium in yellow-green and europium in blue and red – help to produce the images on most television screens. Their rare earth cousin yttrium plays a quiet but crucial supporting role, hosting the red-releasing europium ions.
These colourful qualities have recently secured the europium-terbium duo another gig in energy-saving compact fluorescent light bulbs. These bulbs work by exciting mercury vapour to emit ultraviolet light, which is then absorbed by phosphorescent materials coating their insides to produce visible frequencies of light. One complaint made about early versions was that they did not produce the same warm light as the incandescent tungsten bulbs they replaced – a problem resolved by switching the coating to the right blend of terbium and europium.
The next generation of energy-efficient lighting, based on LEDs, might see europium strike out alone: adding europium ions to a blue LED turns some of its light yellow, giving a white output overall. That could free up terbium to pursue its own projects, such as perhaps replacing dysprosium in the manufacture of high temperature permanent magnets.
All that depends on securing additional supplies, however. According to the DoE, europium could be in short supply as early as 2015 – and terbium even sooner. For yttrium we have already reached crunch time: demand outstripped supply in 2010.
Lymphoma sufferers will recognize 90 Yttrium as the isotope that is used in Zevelin used as a treatment
Sunday, June 26, 2011
Aphorisms 15
Just over a quarter of UK aid goes direct to other governments and little of this ever goes anywhere else.
Development spending is the process by which poor people in rich countries subsidize rich people in poor countries.
Every dollar of aid counted because every dollar got counted. – Bill Gates
Corruption is the lubrication of the Olympic industry and of FIFA too.
“Corruption is our right. Think about everyone else who is engaging in corruption. If we don’t do the same thing, won’t it be to our loss?” – Senior Pakistani Minister
The hope of preferment can be kept going indefinitely, but the bitterness of dismissal is instant, and long-lasting.
Kindness takes but a moment longer.
Capitalism takes flawed human acts and transforms them into good. Socialism turns good intentions into evil consequences.
The wise and virtuous man is at all times willing that his own private interest should be sacrificed to the public interest of his own particular order or society – Adam Smith
Some people spread happiness and light wherever they go: some whenever they go.
Development spending is the process by which poor people in rich countries subsidize rich people in poor countries.
Every dollar of aid counted because every dollar got counted. – Bill Gates
Corruption is the lubrication of the Olympic industry and of FIFA too.
“Corruption is our right. Think about everyone else who is engaging in corruption. If we don’t do the same thing, won’t it be to our loss?” – Senior Pakistani Minister
The hope of preferment can be kept going indefinitely, but the bitterness of dismissal is instant, and long-lasting.
Kindness takes but a moment longer.
Capitalism takes flawed human acts and transforms them into good. Socialism turns good intentions into evil consequences.
The wise and virtuous man is at all times willing that his own private interest should be sacrificed to the public interest of his own particular order or society – Adam Smith
Some people spread happiness and light wherever they go: some whenever they go.
Our kind of traitor
I have just finished the latest (and perhaps last) John le Carre novel, Our Kind of Traitor. This is I think the 21st and I have read most of them. The general theme is of betrayal and since le Carre worked as a spy in the cold war period, he probably knows more about betrayal than most. I particularly liked this book because it was set in places that I am familiar with. Part is set in Paris where we enjoyed a few days break a few years ago, bringing back memories of the Rodin Museum and the department store Printemps and part is set in the Bernese Oberland reminding me of the best holiday I ever had, in Wengen in August.
le Carre is a local man with connections to Dorset and Wiltshire. I think his father had some connection to local government in Poole and he went to school at Sherborne. His writing is excellent, much more a mainstream novelist than a genre writer.
The story of this latest book is ostensibly about the Russian Mafia, but really about the corruption of the higher echelons of British society where money talks louder than morals. I think it was triggered by stories of Peter Mandelson and George Osborne seen together on the yacht of a Russian oligarch a few years ago.
The ending will be familiar to anyone who has read le Carre's other books.
le Carre is a local man with connections to Dorset and Wiltshire. I think his father had some connection to local government in Poole and he went to school at Sherborne. His writing is excellent, much more a mainstream novelist than a genre writer.
The story of this latest book is ostensibly about the Russian Mafia, but really about the corruption of the higher echelons of British society where money talks louder than morals. I think it was triggered by stories of Peter Mandelson and George Osborne seen together on the yacht of a Russian oligarch a few years ago.
The ending will be familiar to anyone who has read le Carre's other books.
13 elements: Lanthanum and Cerium
Lanthanum and Cerium
Rare earth elements
Atomic numbers: 57; 58
Used in: Batteries
Criticality ratings: near-critical; near-critical
When it comes to batteries, lithium is the true Olympian. Lithium-ion batteries are unsurpassed in energy density, and dominate the market in laptops, cellphones and other devices where a slimline figure is all-important.
Yet they are also rather explosive characters: computer manufacturer Dell recalled four million lithium laptop batteries in 2006 amid fears they might burst into flames if overheated. That risk makes them unsuitable for use in electric and hybrid electric cars, leaving the market to the less explosion-prone nickel-metal-hydride batteries.
This is where lanthanum and cerium come in. They are the main components of a “mischmetal” mixture of rare earth elements that makes up the nickel-metal-hydride battery's negative electrode. The increased demand for electric cars, and the elements' subsidiary roles as phosphorescents in energy-saving light bulbs, place lanthanum and cerium on the US DoE's short-term “near-critical” list for green technologies – a position also assumed by lithium in the medium term.
Meanwhile, a mischmetal mixture is not totally inert: strike one and it produces a spark. This property has seen it being widely adopted as the ignition element in cigarette lighters – clearly no skill for would-be Olympians.
Rare earth elements
Atomic numbers: 57; 58
Used in: Batteries
Criticality ratings: near-critical; near-critical
When it comes to batteries, lithium is the true Olympian. Lithium-ion batteries are unsurpassed in energy density, and dominate the market in laptops, cellphones and other devices where a slimline figure is all-important.
Yet they are also rather explosive characters: computer manufacturer Dell recalled four million lithium laptop batteries in 2006 amid fears they might burst into flames if overheated. That risk makes them unsuitable for use in electric and hybrid electric cars, leaving the market to the less explosion-prone nickel-metal-hydride batteries.
This is where lanthanum and cerium come in. They are the main components of a “mischmetal” mixture of rare earth elements that makes up the nickel-metal-hydride battery's negative electrode. The increased demand for electric cars, and the elements' subsidiary roles as phosphorescents in energy-saving light bulbs, place lanthanum and cerium on the US DoE's short-term “near-critical” list for green technologies – a position also assumed by lithium in the medium term.
Meanwhile, a mischmetal mixture is not totally inert: strike one and it produces a spark. This property has seen it being widely adopted as the ignition element in cigarette lighters – clearly no skill for would-be Olympians.
Galatians 6:14 What's to boast about?
May I never boast except in the cross of or Lord Jesus Christ, through which the world has been crucified to me and I to the world.
The cross is a strange symbol for a religion. Nowadays we would have adopted a gallows or the French a Guillotine. It is a symbol of execution. Yet it is a very correct symbol for a Christian. The Jews may have cut off their foreskins, but Christians have cut off their lives. They have been offered something better than this temporary strutting and fretting upon a stage. They have been offered eternal life and it starts now, not just when we die.
No wonder we boast in the cross, for it is through the death and Resurrection of Jesus that we obtain it. It takes us back to that sinless pre-fall life when we had complete communion with God. It is not our achievement but his.
The cross is a strange symbol for a religion. Nowadays we would have adopted a gallows or the French a Guillotine. It is a symbol of execution. Yet it is a very correct symbol for a Christian. The Jews may have cut off their foreskins, but Christians have cut off their lives. They have been offered something better than this temporary strutting and fretting upon a stage. They have been offered eternal life and it starts now, not just when we die.
No wonder we boast in the cross, for it is through the death and Resurrection of Jesus that we obtain it. It takes us back to that sinless pre-fall life when we had complete communion with God. It is not our achievement but his.
John 5:9b-15. Are you saved? Are you changed?
The day on which this took place was a Sabbath, and so the Jewish leaders said to the man who had been healed, “It is the Sabbath; the law forbids you to carry your mat.” But he replied, “The man who made me well said to me, ‘Pick up your mat and walk.’ ” So they asked him, “Who is this fellow who told you to pick it up and walk?” The man who was healed had no idea who it was, for Jesus had slipped away into the crowd that was there. Later Jesus found him at the temple and said to him, “See, you are well again. Stop sinning or something worse may happen to you.” The man went away and told the Jewish leaders that it was Jesus who had made him well.
The chap who was healed was not healed because he was a good man. Indeed he seems to be a bit of a coward. When the Pharisees catch him carrying his mat on the Sabbath he quickly passes the blame and he can't even remember who healed him. Later when he meets Jesus again he tells tales.
So much for those who believe you just need a little more faith and you will be healed. So much for those who believe healing is part of salvation. The healing here was an act of grace. Given out of compassion, not deserved, not a reward for faith. Some may have called it wasted on him. We sing a hymn "Jesus thou art all compassion..." and so he is. Grace, grace upon grace; it is never exhausted.
Jesus admonishes the man, "Stop sinning or something worse may happen to you." He emphasizes that simply healing is not enough; those who are saved must show a change in their behavior if it is genuine salvation.
The chap who was healed was not healed because he was a good man. Indeed he seems to be a bit of a coward. When the Pharisees catch him carrying his mat on the Sabbath he quickly passes the blame and he can't even remember who healed him. Later when he meets Jesus again he tells tales.
So much for those who believe you just need a little more faith and you will be healed. So much for those who believe healing is part of salvation. The healing here was an act of grace. Given out of compassion, not deserved, not a reward for faith. Some may have called it wasted on him. We sing a hymn "Jesus thou art all compassion..." and so he is. Grace, grace upon grace; it is never exhausted.
Jesus admonishes the man, "Stop sinning or something worse may happen to you." He emphasizes that simply healing is not enough; those who are saved must show a change in their behavior if it is genuine salvation.
Saturday, June 25, 2011
Scientific snippets
The following are in this week's new Scientist:
RABIES may not deserve its reputation.
It looks like the immune system sometimes defeats the disease on its own.
This month 8-year-old Precious Reynolds of California became only the sixth person known to survive rabies without receiving a vaccine within a few days. Doctors treated her with the experimental Milwaukee protocol, plunging her into a drug-induced coma to take her brain “offline” while immune cells scrubbed away the virus. But the protocol is no miracle cure: tried with at least 35 people, only five had previously survived.
On 15 June, Iran put its second ever satellite, Rasad-1, into orbit
It is 260 kilometres above the Earth. Iran hopes to use the experience to launch a monkey into space this year and, by 2019, a human. The worry is that such rockets could also be used to fire missiles at targets on Earth.
At 15 kilograms, Rasad-1 may be tiny, but it is a boost to Iran's space capabilities, says Brian Weeden of the Secure World Foundation think tank, headquartered in Washington DC. “Now that they've put two satellites up there, that indicates perhaps it wasn't a fluke the first time. It demonstrates that their rocket technology is pretty good.”
Rasad-1 is reportedly taking low resolution images of Earth. Its purpose seems mainly to gain experience in launching and operating satellites. Iran's state-run television company says the country will launch a monkey into orbit on a one-way trip “later this year”.
There has been concern in western countries, especially in the US, about Iran's space programme, enhanced by suspicions that the country is trying to develop nuclear weapons, which it denies. However, the rocket that launched Rasad-1 (pictured) appears to be very similar in capability to the Safir-2 rocket used to launch Iran's first satellite in 2009, which is not powerful enough to send a nuclear warhead as far as the US.
More Nuclear ReactorsI
In the wake of the nuclear meltdown at the Fukushima Daiichi power plant in Japan in March, several countries have announced plans to reject nuclear power. Japan will not build any more reactors. Germany plans to phase out its nuclear power plants, Switzerland will not replace its reactors, and last week Italy voted against starting a nuclear programme. But the UK has announced plans to replace another 7 of its nuclear power stations.
The International Atomic Energy Authority lists 65 reactors under construction, and those figures are just the tip of the iceberg because they do not include reactors that are contracted to be built, or those being planned. Neither do they acknowledge the significance of the United Arab Emirates being on course to become the first country to go nuclear since China in 1985: the UAE has signed a deal with a consortium led by the Korea Electric Power Corporation to build four reactors. Saudi Arabia is following suit, having announced earlier this month that it will build 16 reactors by 2030. Turkey plans to build two new plants.
Of 52 countries that have recently asked the IAEA to help them start a nuclear programme only 10 meet all of their criteria, Jewell says. Another 10 had the motivation and resources but were politically unstable. That second group includes Egypt, the most likely to gain nuclear power of the five north African countries with stated intentions. Continuing political uncertainty in Egypt makes nuclear an unlikely option there in the near term, however.
Meanwhile, the plants already under construction in established nuclear countries are feeling the ripples of Fukushima. Just under half of the reactors listed as under construction by the IAEA are in China – but following events in Japan, the Chinese government has suspended approvals for new plants while it reviews their safety.
Can we sense magnetism?
Sea turtles, pigeons and honeybees are among the animals that have an incredibly useful skill that we do not – they can sense the Earth's magnetic field with their bodies. But perhaps our magnetovision is just latent – when a light-sensitive protein was transferred from humans to fruit flies, the insects adopted the protein for their own magnetovision.
Steven Reppert of the University of Massachusetts in Worcester and his colleagues study cryptochromes – light-sensitive proteins that regulate the circadian clocks of many creatures. Reppert knew that cryptochromes also help fruit flies and birds sense the Earth's magnetic fields, and he wanted to see whether human cryptochromes could do the same thing. To find out Reppert replaced those found in fruit flies with a human version, hCRY2, which is found in the retina.
The mutant flies could be trained to associate a sugar reward with a magnetic field. When given the option to fly down either a magnetised or non-magnetised arm of a maze they opted for the magnetised one. Flies genetically engineered to lack cryptochrome altogether were indifferent to the magnetic field in one arm and were evenly distributed down both arms of the maze. Apparently, fruit flies have no problem using human cryptochrome to sense magnetic fields, which implies humans have the hardware to do the same, but for some reason do not activate the ability.
Gains form Chinese Medicine?
For more than 2000 years Chinese doctors have treated Parkinson's-like symptoms with gou teng, a herb with hook-like branches. Early this year, 115 people with Parkinson's were given a combination of Chinese medical herbs, including gou teng, or a placebo for 13 weeks. At the end of the study, volunteers who had taken the herbs slept better and had more fluent speech. Li Min, a traditional Chinese doctor at Hong Kong Baptist University who was not involved in the study, thinks she knows how it works. Parkinson's is caused by the destruction of brain cells that produce dopamine. Studies have suggested this destruction is caused by an abundance of a protein called alpha-synuclein, triggering interest in substances that get rid of the protein by encouraging the programmed cell death – autophagy – of the cells that contain it.
Li's team has found one such substance, the alkaloid isorhy, in gou teng. It induced autophagy at a similar rate to rapamycin, which has recently been touted as a candidate for Parkinson's treatment. However, because rapamycin depresses the immune system, it would have serious side effects, whereas gou teng has been taken for centuries with no apparent ill effects. Li, who presented her results at last month's Keystone Symposia on Molecular and Cellular Biology in Whistler, British Columbia, will begin trials of synthesised isorhy in rodents later this year.
Meanwhile, Zhaoxiang Bian, also at Hong Kong Baptist University, is developing a drug called JCM-16021 for Irritable bowel syndrome using seven herbal plants, based on a formulation called tong xie yao fang, which has been used to treat IBS in China since the 1300s.
In 2007, Bian gave 80 people with IBS either JCM-16021 with Holopon – a drug that interrupts nerve impulses responsible for digestion – or Holopon alone. After eight weeks, 52 per cent of those given JCM-16021 with Holopon had reduced IBS symptoms, compared with 32 per cent of those given just Holopon.
IBS is partly caused by high levels of serotonin in the gut. Last year, Bian found that giving JCM-16021 to rats with IBS-like symptoms broke down serotonin in their bowel faster than normal, reducing their discomfort. His team has since isolated several compounds in JCM-16021 that block serotonin's activity in the rat gut, including magnolol, a herb taken from magnolia trees.
RABIES may not deserve its reputation.
It looks like the immune system sometimes defeats the disease on its own.
This month 8-year-old Precious Reynolds of California became only the sixth person known to survive rabies without receiving a vaccine within a few days. Doctors treated her with the experimental Milwaukee protocol, plunging her into a drug-induced coma to take her brain “offline” while immune cells scrubbed away the virus. But the protocol is no miracle cure: tried with at least 35 people, only five had previously survived.
On 15 June, Iran put its second ever satellite, Rasad-1, into orbit
It is 260 kilometres above the Earth. Iran hopes to use the experience to launch a monkey into space this year and, by 2019, a human. The worry is that such rockets could also be used to fire missiles at targets on Earth.
At 15 kilograms, Rasad-1 may be tiny, but it is a boost to Iran's space capabilities, says Brian Weeden of the Secure World Foundation think tank, headquartered in Washington DC. “Now that they've put two satellites up there, that indicates perhaps it wasn't a fluke the first time. It demonstrates that their rocket technology is pretty good.”
Rasad-1 is reportedly taking low resolution images of Earth. Its purpose seems mainly to gain experience in launching and operating satellites. Iran's state-run television company says the country will launch a monkey into orbit on a one-way trip “later this year”.
There has been concern in western countries, especially in the US, about Iran's space programme, enhanced by suspicions that the country is trying to develop nuclear weapons, which it denies. However, the rocket that launched Rasad-1 (pictured) appears to be very similar in capability to the Safir-2 rocket used to launch Iran's first satellite in 2009, which is not powerful enough to send a nuclear warhead as far as the US.
More Nuclear ReactorsI
In the wake of the nuclear meltdown at the Fukushima Daiichi power plant in Japan in March, several countries have announced plans to reject nuclear power. Japan will not build any more reactors. Germany plans to phase out its nuclear power plants, Switzerland will not replace its reactors, and last week Italy voted against starting a nuclear programme. But the UK has announced plans to replace another 7 of its nuclear power stations.
The International Atomic Energy Authority lists 65 reactors under construction, and those figures are just the tip of the iceberg because they do not include reactors that are contracted to be built, or those being planned. Neither do they acknowledge the significance of the United Arab Emirates being on course to become the first country to go nuclear since China in 1985: the UAE has signed a deal with a consortium led by the Korea Electric Power Corporation to build four reactors. Saudi Arabia is following suit, having announced earlier this month that it will build 16 reactors by 2030. Turkey plans to build two new plants.
Of 52 countries that have recently asked the IAEA to help them start a nuclear programme only 10 meet all of their criteria, Jewell says. Another 10 had the motivation and resources but were politically unstable. That second group includes Egypt, the most likely to gain nuclear power of the five north African countries with stated intentions. Continuing political uncertainty in Egypt makes nuclear an unlikely option there in the near term, however.
Meanwhile, the plants already under construction in established nuclear countries are feeling the ripples of Fukushima. Just under half of the reactors listed as under construction by the IAEA are in China – but following events in Japan, the Chinese government has suspended approvals for new plants while it reviews their safety.
Can we sense magnetism?
Sea turtles, pigeons and honeybees are among the animals that have an incredibly useful skill that we do not – they can sense the Earth's magnetic field with their bodies. But perhaps our magnetovision is just latent – when a light-sensitive protein was transferred from humans to fruit flies, the insects adopted the protein for their own magnetovision.
Steven Reppert of the University of Massachusetts in Worcester and his colleagues study cryptochromes – light-sensitive proteins that regulate the circadian clocks of many creatures. Reppert knew that cryptochromes also help fruit flies and birds sense the Earth's magnetic fields, and he wanted to see whether human cryptochromes could do the same thing. To find out Reppert replaced those found in fruit flies with a human version, hCRY2, which is found in the retina.
The mutant flies could be trained to associate a sugar reward with a magnetic field. When given the option to fly down either a magnetised or non-magnetised arm of a maze they opted for the magnetised one. Flies genetically engineered to lack cryptochrome altogether were indifferent to the magnetic field in one arm and were evenly distributed down both arms of the maze. Apparently, fruit flies have no problem using human cryptochrome to sense magnetic fields, which implies humans have the hardware to do the same, but for some reason do not activate the ability.
Gains form Chinese Medicine?
For more than 2000 years Chinese doctors have treated Parkinson's-like symptoms with gou teng, a herb with hook-like branches. Early this year, 115 people with Parkinson's were given a combination of Chinese medical herbs, including gou teng, or a placebo for 13 weeks. At the end of the study, volunteers who had taken the herbs slept better and had more fluent speech. Li Min, a traditional Chinese doctor at Hong Kong Baptist University who was not involved in the study, thinks she knows how it works. Parkinson's is caused by the destruction of brain cells that produce dopamine. Studies have suggested this destruction is caused by an abundance of a protein called alpha-synuclein, triggering interest in substances that get rid of the protein by encouraging the programmed cell death – autophagy – of the cells that contain it.
Li's team has found one such substance, the alkaloid isorhy, in gou teng. It induced autophagy at a similar rate to rapamycin, which has recently been touted as a candidate for Parkinson's treatment. However, because rapamycin depresses the immune system, it would have serious side effects, whereas gou teng has been taken for centuries with no apparent ill effects. Li, who presented her results at last month's Keystone Symposia on Molecular and Cellular Biology in Whistler, British Columbia, will begin trials of synthesised isorhy in rodents later this year.
Meanwhile, Zhaoxiang Bian, also at Hong Kong Baptist University, is developing a drug called JCM-16021 for Irritable bowel syndrome using seven herbal plants, based on a formulation called tong xie yao fang, which has been used to treat IBS in China since the 1300s.
In 2007, Bian gave 80 people with IBS either JCM-16021 with Holopon – a drug that interrupts nerve impulses responsible for digestion – or Holopon alone. After eight weeks, 52 per cent of those given JCM-16021 with Holopon had reduced IBS symptoms, compared with 32 per cent of those given just Holopon.
IBS is partly caused by high levels of serotonin in the gut. Last year, Bian found that giving JCM-16021 to rats with IBS-like symptoms broke down serotonin in their bowel faster than normal, reducing their discomfort. His team has since isolated several compounds in JCM-16021 that block serotonin's activity in the rat gut, including magnolol, a herb taken from magnolia trees.
Chronic fatigue.
I still have a degree of fatigue following my chemotherapy. It is getting better, but I am still apt to fall asleep during the day. Next week I am going to restart some graduated exercises.
There are studies that show that graduated exercise following chemotherapy not only improves one's clinical situation, but also makes one live longer. Last time I started this program in the middle of my chemotherapy, I collapsed and had to abandon it. I was suffering from postural hypotension from an autonomic neuropathy. Since I have started on dexamethasone 4mg, my autonomic neuropathy has improved, as has my peripheral neuropathy. One strange effect has been that whenever I eat, salivation leads to my nose running.
In the world of chronic fatigue syndrome there has been uproar at the apparent proof that the suggestion that it is all due to a mouse retrovirus was down to a laboratory error and that CFS existed long before this fusion virus was created in a laboratory.
I feel a bit responsible for the idea that a virus might cause chronic fatigue, because I published a paper in the British Medical Journal in 1983. Here is the abstract:
Immunological reason for chronic ill health after infectious
mononucleosis T J HAMBLIN, J HUSSAIN, A N AKBAR, Y C TANG, J L SMITH, D B JONES BRITISH MEDICAL JOURNAL VOLUME 287: 85-88 9 JULY 1983
In a group of patients who suffered from chronic ill health after an attack of acute infectious mononucleosis a disorder of T cell regulation was found. By means of cytochemical reactions the staining pattern associated with T suppressor cells was found in a greater percentage and that associated with T helper cells in a smaller percentage than in normal subjects. In a few patients this finding was confirmed in a functional suppressor assay. The patients were unwell for at least a year but most later made a complete recovery, which was associated with return to normal of the lymphocyte subsets.
I was quite interested in this subject at that time and even conducted a small clinical trial with the anti-worm drug, Levamisole, which had been shown to boost some aspects of the immune response in a non-specific way. There was no effect.
I was being referred patients from my esteemed colleague, Chris Moran, and I was surprised at the variety of patients I saw who all had this catch all diagnosis, ME or CFS. Some were indeed post-glandular fever. I estimated that most patients with infectious mononucleosus caused by EBV got better within 6 weeks of catching the disease. A small group were unwell for about 6 months and an even smaller group remained unwell more of less permanently.
But in the majority of patients with ME/CFS the condition had nothing to do with EBV. Some had had CMV or toxoplasmosis, some were clearly depressed, occasionally there was a strong family history and I remember one woman who developed the syndrome after being bitten by a grey squirrel.
The symptomatology was different, too. Some patients just complained of tiredness; in some of these exercise made it worse. Some complained of painful muscles but not all did. Some complained of an inability to concentrate and some had all three symptoms.
My conclusion when I left the field was that this was not one syndrome, that some of the symptoms were similar to those seen with treatment with interferon so that cytokines may be involved, that since viruses are one way of triggering cytokine release, in some cases there might be a chronic viral infection, that in some cases there was chronic depression whether as the cause or the effect of the syndrome, and that there were a lot of cranks associated with the syndrome who were convinced that they were right and everybody else was wrong. In my view everybody was right and everybody was wrong and those who were most switched on were those who admitted their ignorance about the field.
When I got involved in CLL it was clear that there were similarities in the fatigue associated with CLL and the topic of 'chemo-brain' as well. (Perhaps cytokines were involved again). When I started on chemotherapy I appreciated the reality of both these conditions. I also recognized that high doses of steroids gave me mood swings and that the knowledge that I had an incurable cancer sometimes made me depressed.
There was a big ME/CFS conference in Lons=don in May 2011 called "Invest in ME". Even the title of the Conference gives away that this was very self-centered. There has recently been a large clinical trial on this condition published in the Lancet which concluded that the only effective treatment for this syndrome is cognitive behavioral therapy (CBT) with graduated exercise. This paper has roused the ire of patients who see that they are being labeled as nutcases, CBT being the preferred therapy for chronic depression. Psychiatrists who follow this line have been subjected to outrageous persecution by patient groups, even being reported to the General Medical Council, which has behaved in its usual callous and unthinking manner. (I shall be very glad next month when I resign from being a licensed doctor and no longer have to pay any more fees to this disgusting organisation).
If you have access to the current BMJ you will be able to read several articles on this topic. You could start here
There are studies that show that graduated exercise following chemotherapy not only improves one's clinical situation, but also makes one live longer. Last time I started this program in the middle of my chemotherapy, I collapsed and had to abandon it. I was suffering from postural hypotension from an autonomic neuropathy. Since I have started on dexamethasone 4mg, my autonomic neuropathy has improved, as has my peripheral neuropathy. One strange effect has been that whenever I eat, salivation leads to my nose running.
In the world of chronic fatigue syndrome there has been uproar at the apparent proof that the suggestion that it is all due to a mouse retrovirus was down to a laboratory error and that CFS existed long before this fusion virus was created in a laboratory.
I feel a bit responsible for the idea that a virus might cause chronic fatigue, because I published a paper in the British Medical Journal in 1983. Here is the abstract:
Immunological reason for chronic ill health after infectious
mononucleosis T J HAMBLIN, J HUSSAIN, A N AKBAR, Y C TANG, J L SMITH, D B JONES BRITISH MEDICAL JOURNAL VOLUME 287: 85-88 9 JULY 1983
In a group of patients who suffered from chronic ill health after an attack of acute infectious mononucleosis a disorder of T cell regulation was found. By means of cytochemical reactions the staining pattern associated with T suppressor cells was found in a greater percentage and that associated with T helper cells in a smaller percentage than in normal subjects. In a few patients this finding was confirmed in a functional suppressor assay. The patients were unwell for at least a year but most later made a complete recovery, which was associated with return to normal of the lymphocyte subsets.
I was quite interested in this subject at that time and even conducted a small clinical trial with the anti-worm drug, Levamisole, which had been shown to boost some aspects of the immune response in a non-specific way. There was no effect.
I was being referred patients from my esteemed colleague, Chris Moran, and I was surprised at the variety of patients I saw who all had this catch all diagnosis, ME or CFS. Some were indeed post-glandular fever. I estimated that most patients with infectious mononucleosus caused by EBV got better within 6 weeks of catching the disease. A small group were unwell for about 6 months and an even smaller group remained unwell more of less permanently.
But in the majority of patients with ME/CFS the condition had nothing to do with EBV. Some had had CMV or toxoplasmosis, some were clearly depressed, occasionally there was a strong family history and I remember one woman who developed the syndrome after being bitten by a grey squirrel.
The symptomatology was different, too. Some patients just complained of tiredness; in some of these exercise made it worse. Some complained of painful muscles but not all did. Some complained of an inability to concentrate and some had all three symptoms.
My conclusion when I left the field was that this was not one syndrome, that some of the symptoms were similar to those seen with treatment with interferon so that cytokines may be involved, that since viruses are one way of triggering cytokine release, in some cases there might be a chronic viral infection, that in some cases there was chronic depression whether as the cause or the effect of the syndrome, and that there were a lot of cranks associated with the syndrome who were convinced that they were right and everybody else was wrong. In my view everybody was right and everybody was wrong and those who were most switched on were those who admitted their ignorance about the field.
When I got involved in CLL it was clear that there were similarities in the fatigue associated with CLL and the topic of 'chemo-brain' as well. (Perhaps cytokines were involved again). When I started on chemotherapy I appreciated the reality of both these conditions. I also recognized that high doses of steroids gave me mood swings and that the knowledge that I had an incurable cancer sometimes made me depressed.
There was a big ME/CFS conference in Lons=don in May 2011 called "Invest in ME". Even the title of the Conference gives away that this was very self-centered. There has recently been a large clinical trial on this condition published in the Lancet which concluded that the only effective treatment for this syndrome is cognitive behavioral therapy (CBT) with graduated exercise. This paper has roused the ire of patients who see that they are being labeled as nutcases, CBT being the preferred therapy for chronic depression. Psychiatrists who follow this line have been subjected to outrageous persecution by patient groups, even being reported to the General Medical Council, which has behaved in its usual callous and unthinking manner. (I shall be very glad next month when I resign from being a licensed doctor and no longer have to pay any more fees to this disgusting organisation).
If you have access to the current BMJ you will be able to read several articles on this topic. You could start here
Galatians 6:12-13. Evangelism: a lifetime commitment
Those who want to impress people by means of the flesh are trying to compel you to be circumcised. The only reason they do this is to avoid being persecuted for the cross of Christ. Not even those who are circumcised keep the law, yet they want you to be circumcised that they may boast about your circumcision in the flesh.
Now we get to the nub of the motive of the Judaizers. They have no concern for the Galatian Christians - they simply want to keep in well with the unconverted Jews. They are hypocrites. They see the Galatians as a series of scalps to be taken.
We should be wary of our evangelism that we don't have the same attitude. Winning souls for Christ is not a numbers game, but implies a love of people who are lost and a lifetime commitment to them.
Now we get to the nub of the motive of the Judaizers. They have no concern for the Galatian Christians - they simply want to keep in well with the unconverted Jews. They are hypocrites. They see the Galatians as a series of scalps to be taken.
We should be wary of our evangelism that we don't have the same attitude. Winning souls for Christ is not a numbers game, but implies a love of people who are lost and a lifetime commitment to them.
13 elements: Dysprosium
Dysprosium
Rare earth element
Atomic number: 66
Used in: High-temperature magnets
Criticality rating: critical
Like neodymium, dysprosium is prized for its magnetic properties – not least, when mixed with terbium and iron to form the alloy Terfenol D. It has the peerless ability to change shape in response to a magnetic field.
This “magnetostrictive” property has led to some far-out uses. The US navy has used Terfenol-D to develop an advanced active sonar transducer, producing and then picking up high-powered “pings” underwater.
Dysprosium's greatest selling point, however, is how it handles the heat. Magnets made from a pure neodymium-iron-boron alloy lose their magnetisation at temperatures above 300 °C. Adding in a small amount of dysprosium, at about 5 per cent by weight, solves that problem, making the element a vital component in high-performance magnets found in countless technologies from turbines to hard discs.
According to the US DoE, the wide range of its current and projected uses, together with the lack of any immediately suitable replacement, makes dysprosium the single most critical element for emerging clean energy technologies. China is the only country with significant known deposits, with the new mines opening in Australia and Canada only containing small quantities of the element in their rare earth ores. Even the US DoE's most conservative projections predict a shortfall of dysprosium before 2015.
Rare earth element
Atomic number: 66
Used in: High-temperature magnets
Criticality rating: critical
Like neodymium, dysprosium is prized for its magnetic properties – not least, when mixed with terbium and iron to form the alloy Terfenol D. It has the peerless ability to change shape in response to a magnetic field.
This “magnetostrictive” property has led to some far-out uses. The US navy has used Terfenol-D to develop an advanced active sonar transducer, producing and then picking up high-powered “pings” underwater.
Dysprosium's greatest selling point, however, is how it handles the heat. Magnets made from a pure neodymium-iron-boron alloy lose their magnetisation at temperatures above 300 °C. Adding in a small amount of dysprosium, at about 5 per cent by weight, solves that problem, making the element a vital component in high-performance magnets found in countless technologies from turbines to hard discs.
According to the US DoE, the wide range of its current and projected uses, together with the lack of any immediately suitable replacement, makes dysprosium the single most critical element for emerging clean energy technologies. China is the only country with significant known deposits, with the new mines opening in Australia and Canada only containing small quantities of the element in their rare earth ores. Even the US DoE's most conservative projections predict a shortfall of dysprosium before 2015.
John 5: 5-9a. Do you even want to be healed?
One who was there had been an invalid for thirty-eight years. When Jesus saw him lying there and knew that he had been in this condition for a long time, he asked him, “Do you want to get well?” “Sir,” the invalid replied, “I have no one to help me into the pool when the water is stirred. While I am trying to get in, someone else goes down ahead of me.” Then Jesus said to him, “Get up! Pick up your mat and walk.” At once the man was cured; he picked up his mat and walked.
We are back to the theme of water again with the same implication; the ritual of water is insufficient: the power of Christ is sufficient. We do not know what caused this man's invalidity, but we must assume it is some form of paralysis that had lasted a very long time. Indeed, Jesus questions his faith, "Don't you even want to get well?" From the rest of teh story we do not get the impression that this man was a very nice sort. But there we are; it isn't just nice people that are saved.
There is no written record elsewhere of this first come-first served dispensation of healing and it may have been mere superstition. Just as the Christian faith can lapse into superstition, so could Judaism. Jesus' healing does not use the pool or water at all, merely the word of command. and like the man let down through the roof, he picked up his bed and walked.
The healing was complete and instantaneous. The muscles regrew to make him strong enough to carry the mat and any contractions stretched to make him able to walk.
We are back to the theme of water again with the same implication; the ritual of water is insufficient: the power of Christ is sufficient. We do not know what caused this man's invalidity, but we must assume it is some form of paralysis that had lasted a very long time. Indeed, Jesus questions his faith, "Don't you even want to get well?" From the rest of teh story we do not get the impression that this man was a very nice sort. But there we are; it isn't just nice people that are saved.
There is no written record elsewhere of this first come-first served dispensation of healing and it may have been mere superstition. Just as the Christian faith can lapse into superstition, so could Judaism. Jesus' healing does not use the pool or water at all, merely the word of command. and like the man let down through the roof, he picked up his bed and walked.
The healing was complete and instantaneous. The muscles regrew to make him strong enough to carry the mat and any contractions stretched to make him able to walk.
Blinotumamab 3. Adult ALL
I want to concentrate on two papers which describe the treatment of acute lymphoblastic leukemia with blinatumomab. The first is published in J Clin Oncol this week (June 20th 2011) and descrbes a study of treatment of patients with minimal residual disease detected by PCR following their induction and consolidation treatment. These were all adult patients who carry a bad prognosis. I have a few remaining patients with this disease, but most have quite bad GVHD having required a transplant to salvage them. Most who have not have really bee young adults with what amounts to the same disease that occurs in childhood, which has a much better prognosis.
Although about 80% of adult ALLs have a CR after induction chemotherapy, 50% experience relapse and chemoresistant disease. In this trial patients were treated with Blinatumomab 15 microgm/sq m/24 hours by iv infusion for 4 weeks if they had MRD by PCR following the completion of their induction and consolidation treatment. In patients with an allogeneic donor transplant was offered at any time after the first course of blinatumomab. Responders were permitted to receive three further cycles of blinatumomab.
21 patients entered the trial of whom 20 were evaluable for response and 16 converted to MRD negative, all at the end of the first cycle of treatment. At a median of 405 days follow-up 16/20 patients eligible for follow up remained in ongoing hematological remission. 8 patients had allografts and remain in remission with no treatment associated mortality. 4 patients who did not have allografts have had a clinical relapse in the first 200 days post blinatumomab. In 2 cases the relapse was extramedullary (CSF, testis) and two had marrow relapse (one an initial responder to blinatumomab).
81% had transient grade 3 or 4 adverse events most commonly lymphopenia (this was really an intended event) and hypogammaglobulinemia. There were no drug associated deaths. There were 4 cases of infection. There was no cytokine storm and although there were transient increases in serum levels of some inflammatory cytokins, these increases were of short duration.
This was trial of patients with a more than 90% risk of relapse whose only chance of cure was an allograft (about a 30% success rate).
The second paper was an abstract presented at the recent meeting of EHA (abstract 552) This was a phase 2 study in adult patients with relapsed/refractory ALL of the same treatment detailed above for a first cohort of 5 patients and a second cohort had a dose reduction for the first 7 days to 5 microgm/sq m/24 hours, presumably while there were large numbers of circulating blasts.
Of the first 5 evaluable patients, 2 had CRs and 2 CRis within the first cycle. 3 had become MRD negative. One responder had an extramedullary relapse during cycle 3.
The commonest adverse events were fever and chills and one patient with a high leucocyte count had reversible cytokine storm. the second non-evaluable patient had a reversible event of encephalopathy and disorientation. Despite discontinuation of treatment, he reached MRD negativity. Recruitment of the second cohort is ongoing.
In essense this is the same study as the first, only given after relapse, not before it. I am sure there is a lot of impatience among CLL patients to see this drug used in CLL, but for now adult ALL, although less common, is a more urgent problem. The company involved here is Micromet Inc. of Munich and I guess if there were patient power to get this drug there might be a result.
Although about 80% of adult ALLs have a CR after induction chemotherapy, 50% experience relapse and chemoresistant disease. In this trial patients were treated with Blinatumomab 15 microgm/sq m/24 hours by iv infusion for 4 weeks if they had MRD by PCR following the completion of their induction and consolidation treatment. In patients with an allogeneic donor transplant was offered at any time after the first course of blinatumomab. Responders were permitted to receive three further cycles of blinatumomab.
21 patients entered the trial of whom 20 were evaluable for response and 16 converted to MRD negative, all at the end of the first cycle of treatment. At a median of 405 days follow-up 16/20 patients eligible for follow up remained in ongoing hematological remission. 8 patients had allografts and remain in remission with no treatment associated mortality. 4 patients who did not have allografts have had a clinical relapse in the first 200 days post blinatumomab. In 2 cases the relapse was extramedullary (CSF, testis) and two had marrow relapse (one an initial responder to blinatumomab).
81% had transient grade 3 or 4 adverse events most commonly lymphopenia (this was really an intended event) and hypogammaglobulinemia. There were no drug associated deaths. There were 4 cases of infection. There was no cytokine storm and although there were transient increases in serum levels of some inflammatory cytokins, these increases were of short duration.
This was trial of patients with a more than 90% risk of relapse whose only chance of cure was an allograft (about a 30% success rate).
The second paper was an abstract presented at the recent meeting of EHA (abstract 552) This was a phase 2 study in adult patients with relapsed/refractory ALL of the same treatment detailed above for a first cohort of 5 patients and a second cohort had a dose reduction for the first 7 days to 5 microgm/sq m/24 hours, presumably while there were large numbers of circulating blasts.
Of the first 5 evaluable patients, 2 had CRs and 2 CRis within the first cycle. 3 had become MRD negative. One responder had an extramedullary relapse during cycle 3.
The commonest adverse events were fever and chills and one patient with a high leucocyte count had reversible cytokine storm. the second non-evaluable patient had a reversible event of encephalopathy and disorientation. Despite discontinuation of treatment, he reached MRD negativity. Recruitment of the second cohort is ongoing.
In essense this is the same study as the first, only given after relapse, not before it. I am sure there is a lot of impatience among CLL patients to see this drug used in CLL, but for now adult ALL, although less common, is a more urgent problem. The company involved here is Micromet Inc. of Munich and I guess if there were patient power to get this drug there might be a result.
Friday, June 24, 2011
How BiTE antibodies work
Blinatumomab is a bispecific molecule of very small size made from a single polypeptide chain comprising the variable heavy chain and light chain of an anti-CD3 monoclonal antibody joined to the variable heavy chain and light chain of an anti-CD19 monoclonal antibody. The idea is that the antibody redirects the T-cell lysis to the tumor B-cell.
The BiTE antibody transiently creates a cytolytic synapse between a cytotoxic T-cell and the cancer target cell; in this case a B-cell lymphoma cell. Granules containing granzymes and the pore-forming protein, perforin, fuse with the T-cell membrane and discharge their toxic content leading to the death of the target cellBlinatumomab has a very short serum half-life of only 2-3 hours and therefore must be administered by continuous infusion over 4-8 weeks using portable minipumps.
Has the French trial put an end to ASCT?
The French group has looked at autologous stem cell transplant in CLL It is unusual for transplanters to do a randomized trial so we must take it seriously.
It is a complicated trial. Patients aged between 18 and 65 with Binet stage B or C disease diagnosed according to NCI 1996 guidelines were entered. Exclusions included AIHA, another uncured malignancy, severe concomitant disease, Richter’s syndrome, PLL, impaired renal, hepatic, cardiac or respiratory function or HIV seropositivity.
All patients were first treated with3 monthly courses of mini-CHOP followed by 3 courses of fludarabine. Patients then in CR were randomized between ASCT and observation. Those not in CR were rescued with 1 or 2 cycles of DHAP were then randomized to ASCT or 3 courses of FC. Transplant conditioning was with cyclo/TBI (10 Gy). CRs were determined after a CT scan and with bone marrow lymphocytes counted on an aspirate not a trephine (therefore they missed out on nodular PRs).
There were 105 in the CR group and 94 in the non-CR group. In the former 37 had ASCT and 68 observation (15 failed to mobilize stem cells or refused treatment); in the latter group, 34 had ASCT (7 failed to randomize, and a further 5 defaulted through death, progression or refusal) and 41 FC.
In the CR group the 3 year event-free survival was 79.8% v 35.4% in favour of ASCT. By multivariate analysis unmutated IGHV and del 11q were predictors of poor survival. However, at 3 years there was no difference in overall survival between the two arms. In the non-CR group there was no difference in event-free survival or overall survival. Unmutated IGVH and del 17p were predictors of poor outcome.
Mobilization after the 6 courses of preliminary chemotherapy failed in 40% of cases. Mobilization after mini-CHOP and before the fludarabine failed in only 8.3% of cases. This mirrors previous experience that fludarabine influences stem cell mobilization.
These results are broadly in line with the phase 2 data on ASCT. Do they now show that ASCT should be abandoned? I do not think so. The follow-up is too short to ascertain whether there will be an overall survival advantage. It does suggest that obtaining a CR before ASCT is vital, but this trial was started before rituximab was widely available in France and with it more CRs should be obtained. I suspect that for bulky or extensive CLL with mutated IGHV genes ASCT might still be the best treatment out there
It is a complicated trial. Patients aged between 18 and 65 with Binet stage B or C disease diagnosed according to NCI 1996 guidelines were entered. Exclusions included AIHA, another uncured malignancy, severe concomitant disease, Richter’s syndrome, PLL, impaired renal, hepatic, cardiac or respiratory function or HIV seropositivity.
All patients were first treated with3 monthly courses of mini-CHOP followed by 3 courses of fludarabine. Patients then in CR were randomized between ASCT and observation. Those not in CR were rescued with 1 or 2 cycles of DHAP were then randomized to ASCT or 3 courses of FC. Transplant conditioning was with cyclo/TBI (10 Gy). CRs were determined after a CT scan and with bone marrow lymphocytes counted on an aspirate not a trephine (therefore they missed out on nodular PRs).
There were 105 in the CR group and 94 in the non-CR group. In the former 37 had ASCT and 68 observation (15 failed to mobilize stem cells or refused treatment); in the latter group, 34 had ASCT (7 failed to randomize, and a further 5 defaulted through death, progression or refusal) and 41 FC.
In the CR group the 3 year event-free survival was 79.8% v 35.4% in favour of ASCT. By multivariate analysis unmutated IGHV and del 11q were predictors of poor survival. However, at 3 years there was no difference in overall survival between the two arms. In the non-CR group there was no difference in event-free survival or overall survival. Unmutated IGVH and del 17p were predictors of poor outcome.
Mobilization after the 6 courses of preliminary chemotherapy failed in 40% of cases. Mobilization after mini-CHOP and before the fludarabine failed in only 8.3% of cases. This mirrors previous experience that fludarabine influences stem cell mobilization.
These results are broadly in line with the phase 2 data on ASCT. Do they now show that ASCT should be abandoned? I do not think so. The follow-up is too short to ascertain whether there will be an overall survival advantage. It does suggest that obtaining a CR before ASCT is vital, but this trial was started before rituximab was widely available in France and with it more CRs should be obtained. I suspect that for bulky or extensive CLL with mutated IGHV genes ASCT might still be the best treatment out there
Galatians 6:11. Reading glasses
See what large letters I use as I write to you with my own hand!
We know that Paul had a Secretary to write his letters for him. Perhaps this was the 'thorn in the flesh' that he complained about. Perhaps it was just presbyopia. Perhaps he had macular degeneration.
We should thank God for the invention of reading glasses that help old men to pass on their wisdom.
We know that Paul had a Secretary to write his letters for him. Perhaps this was the 'thorn in the flesh' that he complained about. Perhaps it was just presbyopia. Perhaps he had macular degeneration.
We should thank God for the invention of reading glasses that help old men to pass on their wisdom.
John 5:3: Scripture does not need defending
Here a great number of disabled people used to lie - the blind the lame, the paralyzed and they waited for the moving of the waters
Less reliable Ms have the second clause about the moving of the waters and also verse 4 From time to time an angel of the Lord would come down and stir up the waters. The first one into the pool after each such disturbance would be cured of every disease he had.
How should we deal with the fact that there are discrepancies in the different Ms that we have our translations from? Carson suggests that this might have started life as a marginal note that explained the popular belief at the time. We know that the two Bethesda pools were fed from a larger Solomon's pool and the stirring of the waters might have a purely natural explanation.
It hardly matters to John's narrative whether the second half of verse 3 and verse 4 are in at all. So it's not worth making a fuss about. Trying to defend every last phrase in the KJV is likely to lead us into dark alleys. that's why most confessions of faith contain the words 'as originally given'.
Less reliable Ms have the second clause about the moving of the waters and also verse 4 From time to time an angel of the Lord would come down and stir up the waters. The first one into the pool after each such disturbance would be cured of every disease he had.
How should we deal with the fact that there are discrepancies in the different Ms that we have our translations from? Carson suggests that this might have started life as a marginal note that explained the popular belief at the time. We know that the two Bethesda pools were fed from a larger Solomon's pool and the stirring of the waters might have a purely natural explanation.
It hardly matters to John's narrative whether the second half of verse 3 and verse 4 are in at all. So it's not worth making a fuss about. Trying to defend every last phrase in the KJV is likely to lead us into dark alleys. that's why most confessions of faith contain the words 'as originally given'.
13 Elements: Tellurium
Tellurium
Metalloid
Atomic number: 52
Used in: solar cells
Criticality rating: near-critical
In 2009, solar cells made from thin films of cadmium telluride became the first to undercut bulky silicon panels in cost per watt of electricity generating capacity. That points to a cheaper future for solar power – perhaps.
Both cadmium and tellurium are mining by-products – cadmium from zinc, and tellurium from copper. Cadmium's toxicity means it is in plentiful supply: zinc producers are obliged to remove it during refining, and it has precious few other uses. “The people who manufacture cadmium telluride photocells often say one of the best things you can do with cadmium is to put it between two sheets of glass and leave it there,” says Robert Jaffe, a physicist at the Massachusetts Institute of Technology.
For tellurium, the situation is reversed. Because the global market for the element has been minute compared with that for copper – some $100 million against over $100 billion – there has been little incentive to extract it. That will change as demand grows, but better extraction methods are expected to only double the supply, which will be nowhere near enough to cover the predicted demand if the new-style solar cells take off. The US DoE anticipates a supply shortfall by 2025.
The US DoE puts a “critical” alarm on supplies of indium for the next five years, but will reduce this to “near-critical” for the period 2015 to 2025 as we get better at extracting the element or develop indium-free technologies such as conductive polymers or nanowires (New Scientist, 23 October 2010, p 40). Even so, without expanded production after 2015, the DoE says reductions in “non-clean energy demand” will be needed “to prevent shortages and price spikes”. In other words, we might need to choose which is the more important – smartphones or solar cells.
Metalloid
Atomic number: 52
Used in: solar cells
Criticality rating: near-critical
In 2009, solar cells made from thin films of cadmium telluride became the first to undercut bulky silicon panels in cost per watt of electricity generating capacity. That points to a cheaper future for solar power – perhaps.
Both cadmium and tellurium are mining by-products – cadmium from zinc, and tellurium from copper. Cadmium's toxicity means it is in plentiful supply: zinc producers are obliged to remove it during refining, and it has precious few other uses. “The people who manufacture cadmium telluride photocells often say one of the best things you can do with cadmium is to put it between two sheets of glass and leave it there,” says Robert Jaffe, a physicist at the Massachusetts Institute of Technology.
For tellurium, the situation is reversed. Because the global market for the element has been minute compared with that for copper – some $100 million against over $100 billion – there has been little incentive to extract it. That will change as demand grows, but better extraction methods are expected to only double the supply, which will be nowhere near enough to cover the predicted demand if the new-style solar cells take off. The US DoE anticipates a supply shortfall by 2025.
The US DoE puts a “critical” alarm on supplies of indium for the next five years, but will reduce this to “near-critical” for the period 2015 to 2025 as we get better at extracting the element or develop indium-free technologies such as conductive polymers or nanowires (New Scientist, 23 October 2010, p 40). Even so, without expanded production after 2015, the DoE says reductions in “non-clean energy demand” will be needed “to prevent shortages and price spikes”. In other words, we might need to choose which is the more important – smartphones or solar cells.
Thursday, June 23, 2011
Melanoma and bran
While most cancers seem to have an environmental cause that is diminished by rising on the social scale, melanoma becomes commoner the more upper class you are. The role of ultra violet rays is well established and the upper classes take more foreign holidays. The blame is put on hair spray and oven cleaner. It is supposed that their fluorocarbon propellants have punched a hole in the ozone layer at the South Pole, which has allowed the UV to seep through.
Now, I think this is all Baloney. For a start there’s not much melanoma in Antarctica, and for another hair spray has been around much longer than the hole in the ozone. Remember those bouffant hairstyles of the fifties? That was when hair spray was at its zenith.
The social phenomenon that correlates best with the loss of the ozone is bran. I tried it once. Not only do you almost choke trying to swallow the vile little particles, you certainly choke if you stand down wind of anyone on the stuff. Methane is the link. Vegetarians chewing on cabbage, artichokes and endives, but most of all on bran, are producing millions of litres of methane. Until the vegetarians came along the chief methane producers were the termites chewing down the trees in the tropical rain forest, but thank goodness someone has had the wisdom to chop the wretched trees down and deny the termites their feast.
If you remember your chemistry, the formula for methane is CH4. What that carbon and hydrogen cry out for is oxygen. They are trying to become carbon dioxide and water. And where do they get their oxygen from? That’s right, the ozone layer. After all why make do with O2 when you can get hold of O3?
All those open-toed-sandled, hairy, corduroyed, lib-dem-voting, bran-eating vegetarians are sucking the ozone out of the atmosphere and giving the rest of us melanoma.
I have proof of this. Before we even knew that ozone had a layer, the only place you found it was at the seaside. Of course, the pundits told us that it wasn’t ozone we could smell but rotting seaweed. The truth is it was both. The methane produced by the decaying seaweed drew in the ozone for the benefit of the bathers. But this inordinate and unnatural consumption of vegetables has thrown the environment into a fearful imbalance. It’s time to act. Ban bran now.
Now, I think this is all Baloney. For a start there’s not much melanoma in Antarctica, and for another hair spray has been around much longer than the hole in the ozone. Remember those bouffant hairstyles of the fifties? That was when hair spray was at its zenith.
The social phenomenon that correlates best with the loss of the ozone is bran. I tried it once. Not only do you almost choke trying to swallow the vile little particles, you certainly choke if you stand down wind of anyone on the stuff. Methane is the link. Vegetarians chewing on cabbage, artichokes and endives, but most of all on bran, are producing millions of litres of methane. Until the vegetarians came along the chief methane producers were the termites chewing down the trees in the tropical rain forest, but thank goodness someone has had the wisdom to chop the wretched trees down and deny the termites their feast.
If you remember your chemistry, the formula for methane is CH4. What that carbon and hydrogen cry out for is oxygen. They are trying to become carbon dioxide and water. And where do they get their oxygen from? That’s right, the ozone layer. After all why make do with O2 when you can get hold of O3?
All those open-toed-sandled, hairy, corduroyed, lib-dem-voting, bran-eating vegetarians are sucking the ozone out of the atmosphere and giving the rest of us melanoma.
I have proof of this. Before we even knew that ozone had a layer, the only place you found it was at the seaside. Of course, the pundits told us that it wasn’t ozone we could smell but rotting seaweed. The truth is it was both. The methane produced by the decaying seaweed drew in the ozone for the benefit of the bathers. But this inordinate and unnatural consumption of vegetables has thrown the environment into a fearful imbalance. It’s time to act. Ban bran now.
Coincidences
You could distinguish them: one was tall and gaunt and the other short and putting on weight. But Brown is a very common name and Browns of this age were quite likely to have been named after the old queen’s consort. They both attended my clinic regularly and for a very long time, for one had chronic lymphocytic leukaemia and the other polycythaemia rubra vera.
They were both born, in different parts of the country, on the same day in October 1896. It was a coincidence that they should at different times have bought the same house in the very same street, though not, I should hasten to add, from each other. It was a coincidence that they should both have lost their prostates to the very same surgeon. But what do you call it when I discover that for the three years that they had been attending my clinic they had been sharing the same hospital number and the very same set of case notes?
They were both born, in different parts of the country, on the same day in October 1896. It was a coincidence that they should at different times have bought the same house in the very same street, though not, I should hasten to add, from each other. It was a coincidence that they should both have lost their prostates to the very same surgeon. But what do you call it when I discover that for the three years that they had been attending my clinic they had been sharing the same hospital number and the very same set of case notes?
Shooting America
Despite the public revulsion with guns over here, there are more than 120 million firearms in private hands in the USA. About half the homes in America contain one or more gun. If you ask an American why he keeps a handgun in his house he will likely tell you that it’s to protect his property, or perhaps for self defence.
The real reason is less obvious. In a classic study Kellerman and Reay reviewed all the gunshot deaths in a five-year period in and around Seattle. Among one and a quarter million people there were 743 firearms-related deaths, of which just over half occurred at the residence where the gun was kept.
Only two of these 398 involved an intruder shot while attempting entry to the premises while another seven people were killed in self defence. There were 12 accidental deaths and 41 criminal homicides. In both categories the victim was usually a family member or friend.
But by far the largest group of firearms related deaths, accounting for 80% of the total, were suicides, often alcohol related. So the real reason that Americans keep a gun in the house is to shoot themselves with.
The real reason is less obvious. In a classic study Kellerman and Reay reviewed all the gunshot deaths in a five-year period in and around Seattle. Among one and a quarter million people there were 743 firearms-related deaths, of which just over half occurred at the residence where the gun was kept.
Only two of these 398 involved an intruder shot while attempting entry to the premises while another seven people were killed in self defence. There were 12 accidental deaths and 41 criminal homicides. In both categories the victim was usually a family member or friend.
But by far the largest group of firearms related deaths, accounting for 80% of the total, were suicides, often alcohol related. So the real reason that Americans keep a gun in the house is to shoot themselves with.
Is this the truth about the Arab Spring?
From a Syrian Christian friend:
I have hesitated many times to write about Syria. Yesterday a friend encouraged me to write something to help friends have a better understanding of the situation. It has been very sad to hear and see what is happening but sadder still to see the contradictions between what is said on the news and what I hear from friends within the country. On Tuesday the streets of each city was full to bursting with hundreds of thousands who were Pro Assad demonstrators. He is to some of you a dictator, but he isn’t to the majority of the people of Syria, to us he is someone who allowed different groups and different religions to coexist in harmony without allowing one to dominate the others! This must be said. He has protected the Christians since the time his father took power and continues to do so. Where in the world does the government give you a free land to build your churches, where do they call you in only to say that they are proud of you and of your community? This happened there. I spent the first few years in my life there. It was such a lovely life and such freedom to live our faith and to be who we are. After living in other countries I now appreciate that even more. He also allowed the Muslims, Alaouits, Drouz... and others to exercise their religions in freedom. Syria is not a Muslim state. It signed to laïcity many decades ago. And this is unacceptable to some parties. What we hear on the news is not the real picture at times, like the incident that happened in 1985 in Hamma. What happened there was punishing a radical group that killed hundreds of innocent people by placing bombs in every bus and train to go off at the same day and hour! No one heard of this. In that incident I lost my best friend! As people of Syria we were so pleased he held back extremist and radicals under control. Today most people I talk to – not just the Christians – in Syria are urging him not to allow the extremists to take power!
Today what is going on is not in search of democracy. The problems started in cities that are the hub of radicals, and if you watch carefully things are worse on the Friday as there are those who go in the mosques and preach a message against the West, Israel and the president of Syria.
What baffles me that the West supports the people that will hurt Syria and the West in the future. If they take the power in that region then the church will suffer more than you could imagine, not forgetting the seriousness of the political situation of the region and who or what else might suffer.
When the twin towers were bombed in the United States we all tasted the power of evil. I pray that this evil won’t prevail against any peoples or country... please pray for Syria
I have hesitated many times to write about Syria. Yesterday a friend encouraged me to write something to help friends have a better understanding of the situation. It has been very sad to hear and see what is happening but sadder still to see the contradictions between what is said on the news and what I hear from friends within the country. On Tuesday the streets of each city was full to bursting with hundreds of thousands who were Pro Assad demonstrators. He is to some of you a dictator, but he isn’t to the majority of the people of Syria, to us he is someone who allowed different groups and different religions to coexist in harmony without allowing one to dominate the others! This must be said. He has protected the Christians since the time his father took power and continues to do so. Where in the world does the government give you a free land to build your churches, where do they call you in only to say that they are proud of you and of your community? This happened there. I spent the first few years in my life there. It was such a lovely life and such freedom to live our faith and to be who we are. After living in other countries I now appreciate that even more. He also allowed the Muslims, Alaouits, Drouz... and others to exercise their religions in freedom. Syria is not a Muslim state. It signed to laïcity many decades ago. And this is unacceptable to some parties. What we hear on the news is not the real picture at times, like the incident that happened in 1985 in Hamma. What happened there was punishing a radical group that killed hundreds of innocent people by placing bombs in every bus and train to go off at the same day and hour! No one heard of this. In that incident I lost my best friend! As people of Syria we were so pleased he held back extremist and radicals under control. Today most people I talk to – not just the Christians – in Syria are urging him not to allow the extremists to take power!
Today what is going on is not in search of democracy. The problems started in cities that are the hub of radicals, and if you watch carefully things are worse on the Friday as there are those who go in the mosques and preach a message against the West, Israel and the president of Syria.
What baffles me that the West supports the people that will hurt Syria and the West in the future. If they take the power in that region then the church will suffer more than you could imagine, not forgetting the seriousness of the political situation of the region and who or what else might suffer.
When the twin towers were bombed in the United States we all tasted the power of evil. I pray that this evil won’t prevail against any peoples or country... please pray for Syria
John 5:1-2. Jesus' Jerusalem ministry begins
Some time later, Jesus went up to Jerusalem for one of the Jewish festivals. Now there is in Jerusalem near the Sheep Gate a pool, which in Aramaic is called Bethesda and which is surrounded by five covered colonnades.
We have completed the first part of Jesus' public ministry; from Cana to Cana. The second part goes from Colonnade to Colonnade (John 10:23). Jesus' ministry in Jerusalem is often associated with Jewish Feast days - Passover, Tabernacles - but here we are given no clue which Jewish Feast is associated with this visit to the capital.
If John is referring here to the same Sheep gate as Nehemiah he means a little opening in the north wall of the city near the north-east corner. . The name of the pool has various spellings in the different manuscripts, but Bethesda is probably most likely to be correct and it means the 'house of outpouring'. We have hard evidence of the existence of this pool. A Bordeaux pilgrim visited Jerusalem in 333 AD and described a pair of pools with five arcades. It was located near the Church of St Anne in the north-east quarter of the Old City. there were two pools lying north and south surrounded by four covered colonnades with a fifth colonnade separating the two pools
We have completed the first part of Jesus' public ministry; from Cana to Cana. The second part goes from Colonnade to Colonnade (John 10:23). Jesus' ministry in Jerusalem is often associated with Jewish Feast days - Passover, Tabernacles - but here we are given no clue which Jewish Feast is associated with this visit to the capital.
If John is referring here to the same Sheep gate as Nehemiah he means a little opening in the north wall of the city near the north-east corner. . The name of the pool has various spellings in the different manuscripts, but Bethesda is probably most likely to be correct and it means the 'house of outpouring'. We have hard evidence of the existence of this pool. A Bordeaux pilgrim visited Jerusalem in 333 AD and described a pair of pools with five arcades. It was located near the Church of St Anne in the north-east quarter of the Old City. there were two pools lying north and south surrounded by four covered colonnades with a fifth colonnade separating the two pools
Galatians 6:7-10. Don't give up.
Do not be deceived: God cannot be mocked. A man reaps what he sows. Whoever sows to please their flesh, from the flesh will reap destruction; whoever sows to please the Spirit, from the Spirit will reap eternal life. Let us not become weary in doing good, for at the proper time we will reap a harvest if we do not give up. Therefore, as we have opportunity, let us do good to all people, especially to those who belong to the family of believers.
There is a false dichotomy in some people's minds between the Law and the Spirit. Sometimes people think that without the Law, it doesn't matter what you do. Let sin abound that grace may more abound! But of all places, here in Galatians we have Paul invoking us to be good. Warning us that the Lord sees everything that we do. We must not become weary in well-doing, doing good to all people especially to Christians.
The other false dichotomy is between doing things ourselves and letting the Holy Spirit do them for us. It's not either/or, it's both/and. There is divine sovereignty and human responsibility here. We are to work out our own salvation by keeping in step with the Spirit.
I've told this story before; it's one of David Pawson's. When he was serving in the RAF in the Middle East, during Ramadan his servant was found hiding in a wardrobe scoffing delicacies, thinking that Allah would not be able to observe him there. Do not be fooled. God is not mocked! Everything is recorded. He is concerned that the death of Christ is sufficient to cover every sin. He would not want any to be missed out on.
Calvinists talk about the final preservation of the Saints. But we have the responsibility here, not to give up. Note also the responsibility that we have to the family of believers. From time to time I post about the work of Open Doors and Barnabas Trust which focus on the plight of Christians in difficult circumstances. Your money would be nice, but they really covet your prayers.
There is a false dichotomy in some people's minds between the Law and the Spirit. Sometimes people think that without the Law, it doesn't matter what you do. Let sin abound that grace may more abound! But of all places, here in Galatians we have Paul invoking us to be good. Warning us that the Lord sees everything that we do. We must not become weary in well-doing, doing good to all people especially to Christians.
The other false dichotomy is between doing things ourselves and letting the Holy Spirit do them for us. It's not either/or, it's both/and. There is divine sovereignty and human responsibility here. We are to work out our own salvation by keeping in step with the Spirit.
I've told this story before; it's one of David Pawson's. When he was serving in the RAF in the Middle East, during Ramadan his servant was found hiding in a wardrobe scoffing delicacies, thinking that Allah would not be able to observe him there. Do not be fooled. God is not mocked! Everything is recorded. He is concerned that the death of Christ is sufficient to cover every sin. He would not want any to be missed out on.
Calvinists talk about the final preservation of the Saints. But we have the responsibility here, not to give up. Note also the responsibility that we have to the family of believers. From time to time I post about the work of Open Doors and Barnabas Trust which focus on the plight of Christians in difficult circumstances. Your money would be nice, but they really covet your prayers.
13 elements: Tantalum
Tantalum
Transition metal
Atomic number: 73
Used in: Almost all handheld electronics
Criticality rating: not rated
Your smartphone or tablet computer is a veritable wonder of modern materials technology, with its touchscreen interface incorporating indium (page 40), compact lithium-ion battery and tiny processors packed with nanoscale transistors (see hafnium).
This also extends to its capacitors, the humble components that store energy and smooth power flow in electronic circuits. It is thanks to two-faced tantalum that they remain so slimline. In its pure form, this metal forms one of two conducting plates on which charge is stored. As an oxide, meanwhile, it makes a highly effective insulator, only a thin layer of which is needed to prevent leakage between the plates. As a bonus, the oxide is self-healing, rapidly reforming to plug any leak that lets current through.
It is fortunate, then, that the US Geological Survey believes that tantalum is in plentiful supply, with known deposits covering projected need. In fact, during the recent global economic slowdown, several mines were temporarily shut down as demand dropped.
Transition metal
Atomic number: 73
Used in: Almost all handheld electronics
Criticality rating: not rated
Your smartphone or tablet computer is a veritable wonder of modern materials technology, with its touchscreen interface incorporating indium (page 40), compact lithium-ion battery and tiny processors packed with nanoscale transistors (see hafnium).
This also extends to its capacitors, the humble components that store energy and smooth power flow in electronic circuits. It is thanks to two-faced tantalum that they remain so slimline. In its pure form, this metal forms one of two conducting plates on which charge is stored. As an oxide, meanwhile, it makes a highly effective insulator, only a thin layer of which is needed to prevent leakage between the plates. As a bonus, the oxide is self-healing, rapidly reforming to plug any leak that lets current through.
It is fortunate, then, that the US Geological Survey believes that tantalum is in plentiful supply, with known deposits covering projected need. In fact, during the recent global economic slowdown, several mines were temporarily shut down as demand dropped.
BiTE technology. Blinatumomab I
The astonishing effect of monoclonal antibodies on B-cell tumors is there for everybody to see, but antibodies are really not designed to kill lymphocytes. They are splendid at killing bacteria, and good for killing cells without nuclei, like red cells and platelets, but nucleated cells have defences against them. Although there are natural autoimmune diseases like ITP and AIHA which are caused by antibody, it is very doubtful whether antibody has anything to do with autoimmune diseases where the damaged tissue has nucleated cells. Take pernicious anemia (PA) for example. A large proportion of the female population had natural antibodies against gastric parietal cells, but very few go down with PA. It’s the same with thyroid disease. Antibodies against thyroid microsomes are common, but myxedema is rare.
On the other hand we have now come to see that stem cell transplants work by T-cells attacking what they see as foreign. Graft versus leukemia is what saves lives, not rescuing the bone marrow following huge doses of chemo- or radiotherapy (as we used to think). The problem with allografts is that along with graft versus leukemia we have graft versus host disease which itself makes the procedure dangerous and gives us death rates of about 20% from the procedure.
It would be nice to use the efficiency of T-cell effectors coupled with the direction finding of monoclonal antibodies. In fact my daughter has just completed 4 years studying for a PhD on this very subject. The obvious way to attempt this is to couple together a monoclonal antibody that attacks the tumor cell with a monoclonal antibody that activates a T cell.
This technology has been in the public domain for nearly three years now and can be accessed through the Science website without charge (though it does require registration.
Briefly we are talking about single chain bispecific antibodies one end of which attacks the tumor cell (in this case an anti-CD19 and the other engages the T cell (an anti-CD3) They have been given the name BiTE (which stands for bispecific T cell engagers). The one that has drawn the interest of CLL patients is blinatumomab.
The Science paper reported on a phase I dose escalation clinical trial in 38 patients with non-Hodgkins lymphoma who had relapsed following standard therapies. They had had a median of three previous chemotherpeutic regimens and 87% had had rituximab. Most of the patients were follicular lymphomas or mantle cell lymphomas, but there were 3 with CLL/SLL. One important factor is that the dose used was minute - about 100,000 times smaller than the dose of rituximab and therefore it ought to be a lot cheaper to make (Ha! Ha!). Patients were offered 8 weeks of daily treatment as long as they had not progressed after four.
The reason for the very low dose was the fear of cytokine storm as happened a few years ago at Northwick Park. We had known that this was a risk when you activated T cells and I give an example our own use of a trispecific antibody back in the 1990s. The illustrations show a 'before and after' shot of a patient’s melanoma recurring in the skin of a previous excision. We treated him with a very low dose of an Anti-CD3/anti-CD2/anti-CD28 trispecific antibody with no attempt to direct the antibody at the melanoma, simply relying on the activated T cells to do their work. We had experience at the time of using systemic IL-2 to activate T cells but although this had been fairly successful with 50% response rates including 20% CRs, the toxicity was severe with cytokine storm like affects. For this reason we began using the trispecific antibody at doses of 200 nanograms – roughly 2 million times smaller than the dose of rituximab.
The Science paper gave two bits of useful information on this subject. First, they actually measured the release of cytokines by their treatment and second they have demonstrated that giving high doses of steroids does not detract from the killing ability of the bispecific antibody. In fact patients were given methylprednisolone and low molecular weight heparin during the first treatment days as prophylaxis against cytokine release problems. The side effects of the treatment were mostly well managed. One patient with a history of near fatal sepsis died after developing an infection on this treatment. Another patient with hypogammaglobulinemia had treatment discontinued because of the development of pneumonia. One patient with a history of renal insufficiency had the drug stopped because of metabolic acidosis accompanied by a seizure. Five patients had the drug stopped because of CNS-related events; two with confusion, two with cerebellar symptoms and one with the seizure already alluded to. Al these events were fully reversible after a couple of days. There has been a suspicion that CD19 might be on some cerebral tissues as a result of these side effects.
TNF-alpha was transiently increased in 6 patients. There was a transient elevation of IL-10 in 25/39 patients of whom 19 also showed transient elevations of IL-6 or gamma interferon.
Those patients with a peripheral lymphocytosis showed rapid and long-lasting clearance of lymphocytes from the blood. There was an increase in blood levels of effector memory CD8+ and CD4+ T cells but no change in naive, central memory and CD45RA+ effector memory T cells.
All seven patients who received more than 0.06 mg/sqm/d responded, with 2 CRs and 5 PRs. At smaller doses there were 2 CRs and 2 PRs (one of the PRs being in CLL/SLL). The three CLLs received very small doses of 5 and 15 micrograms/sq m/d and the one who responded received 150 micrograms/sq m/d. This is very preliminary but we should remember that CD19 is not low on the surface of CLL the way that CD20 is so there is no reason to believe that CLL would behave any differently than other forms of NHL. In fact, the one CLL patient who only received 5 micrograms/sq m/d had a minimal response (25% shrinkage of disease).
On the other hand we have now come to see that stem cell transplants work by T-cells attacking what they see as foreign. Graft versus leukemia is what saves lives, not rescuing the bone marrow following huge doses of chemo- or radiotherapy (as we used to think). The problem with allografts is that along with graft versus leukemia we have graft versus host disease which itself makes the procedure dangerous and gives us death rates of about 20% from the procedure.
It would be nice to use the efficiency of T-cell effectors coupled with the direction finding of monoclonal antibodies. In fact my daughter has just completed 4 years studying for a PhD on this very subject. The obvious way to attempt this is to couple together a monoclonal antibody that attacks the tumor cell with a monoclonal antibody that activates a T cell.
This technology has been in the public domain for nearly three years now and can be accessed through the Science website without charge (though it does require registration.
Briefly we are talking about single chain bispecific antibodies one end of which attacks the tumor cell (in this case an anti-CD19 and the other engages the T cell (an anti-CD3) They have been given the name BiTE (which stands for bispecific T cell engagers). The one that has drawn the interest of CLL patients is blinatumomab.
The Science paper reported on a phase I dose escalation clinical trial in 38 patients with non-Hodgkins lymphoma who had relapsed following standard therapies. They had had a median of three previous chemotherpeutic regimens and 87% had had rituximab. Most of the patients were follicular lymphomas or mantle cell lymphomas, but there were 3 with CLL/SLL. One important factor is that the dose used was minute - about 100,000 times smaller than the dose of rituximab and therefore it ought to be a lot cheaper to make (Ha! Ha!). Patients were offered 8 weeks of daily treatment as long as they had not progressed after four.
The reason for the very low dose was the fear of cytokine storm as happened a few years ago at Northwick Park. We had known that this was a risk when you activated T cells and I give an example our own use of a trispecific antibody back in the 1990s. The illustrations show a 'before and after' shot of a patient’s melanoma recurring in the skin of a previous excision. We treated him with a very low dose of an Anti-CD3/anti-CD2/anti-CD28 trispecific antibody with no attempt to direct the antibody at the melanoma, simply relying on the activated T cells to do their work. We had experience at the time of using systemic IL-2 to activate T cells but although this had been fairly successful with 50% response rates including 20% CRs, the toxicity was severe with cytokine storm like affects. For this reason we began using the trispecific antibody at doses of 200 nanograms – roughly 2 million times smaller than the dose of rituximab.
The Science paper gave two bits of useful information on this subject. First, they actually measured the release of cytokines by their treatment and second they have demonstrated that giving high doses of steroids does not detract from the killing ability of the bispecific antibody. In fact patients were given methylprednisolone and low molecular weight heparin during the first treatment days as prophylaxis against cytokine release problems. The side effects of the treatment were mostly well managed. One patient with a history of near fatal sepsis died after developing an infection on this treatment. Another patient with hypogammaglobulinemia had treatment discontinued because of the development of pneumonia. One patient with a history of renal insufficiency had the drug stopped because of metabolic acidosis accompanied by a seizure. Five patients had the drug stopped because of CNS-related events; two with confusion, two with cerebellar symptoms and one with the seizure already alluded to. Al these events were fully reversible after a couple of days. There has been a suspicion that CD19 might be on some cerebral tissues as a result of these side effects.
TNF-alpha was transiently increased in 6 patients. There was a transient elevation of IL-10 in 25/39 patients of whom 19 also showed transient elevations of IL-6 or gamma interferon.
Those patients with a peripheral lymphocytosis showed rapid and long-lasting clearance of lymphocytes from the blood. There was an increase in blood levels of effector memory CD8+ and CD4+ T cells but no change in naive, central memory and CD45RA+ effector memory T cells.
All seven patients who received more than 0.06 mg/sqm/d responded, with 2 CRs and 5 PRs. At smaller doses there were 2 CRs and 2 PRs (one of the PRs being in CLL/SLL). The three CLLs received very small doses of 5 and 15 micrograms/sq m/d and the one who responded received 150 micrograms/sq m/d. This is very preliminary but we should remember that CD19 is not low on the surface of CLL the way that CD20 is so there is no reason to believe that CLL would behave any differently than other forms of NHL. In fact, the one CLL patient who only received 5 micrograms/sq m/d had a minimal response (25% shrinkage of disease).
Subscribe to:
Posts (Atom)