Last night I watched the DVD of Harry Potter and the Deathly Hallows (PART 1). I read the book some time ago and the film follows the book pretty straightforwardly. Every English actor who's ever worked must have got a day's pay from this production since apart from the three children and Ralph Fiennes most appearances are very brief.
The youngsters are now 17 and we get a lot of teenage angst as well as the features of puppy love. We are still at the derring-do stage of the adventure, though the death of the house-elf is a bit moving and we can grieve also over the demise of Dead-Eye. But we had all that with Sirius Black and Dumbledore in previous episodes.
With one film to go, can we evaluate the whole series? As a saga of good versus evil, it doesn't have the sweep of Lord of the Rings. Some have made a fuss about all the sorcery being anti-Christian, but those are just the accoutrement's of the genre.
In the story of the three brothers that explains the Deathly Hallows we begin to see the morality behind the series. Ambition and pride and selfishness are all denigrated; humility is prized. Not very deep then. Betrayal for selfish ends is what haunts them, but Harry is going to have to do something big to defeat Voldemort. I wonder what it could be?
Friday, July 01, 2011
Harry Christophers
For the past couple of days I have been catching up with my Christmas viewing. Having a PWR recorder on my television I managed to record some rather High Brow programs that I am finally watching, six months late. In particular there were two programs of early choral Christmas music presented by the actor Simon Russel Beale and featuring the choir "Sixteen" whose leader is Harry Christophers. The DVD is available from Amazon and there are many CDs of Harry Christophers' Sixteen. I thoroughly recommend them.
Thursday, June 30, 2011
Local matters
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.
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.
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.
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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.
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