Contribution of job control and other risk factors to social variations in coronary heart disease incidence

BACKGROUND: The first Whitehall Study showed an inverse social gradient in mortality from coronary heart disease (CHD) among British civil servants--namely, that there were higher rates in men of lower employment grade. About a quarter of this gradient could be attributed to coronary risk factors. We analysed 5-year CHD incidence rates from the Whitehall II study to assess the contribution to the social gradient of psychosocial work environment, social support, coronary risk factors, and physical height. METHODS: Data were collected in the first three phases of examination of men and women in the Whitehall II study. 7372 people were contacted on all three occasions. Mean length of follow-up was 5.3 years. Characteristics from the baseline, phase 1, questionnaire, and examination were related to newly reported CHD in people without CHD at baseline. Three self-reported CHD outcomes were examined: angina and chest pain from the Rose questionnaire, and doctor-diagnosed ischaemia. The contribution of different factors to the socioeconomic differences in incident CHD was assessed by adjustment of odds ratios. FINDINGS: Compared with men in the highest grade (administrators), men in the lowest grade (clerical and office-support staff) had an age-adjusted odds ratio of developing any new CHD of 1.50. The largest difference was for doctor-diagnosed ischaemia (odds ratio for the lowest compared with the highest grade 2.27). For women, the odds ratio in the lowest grade was 1.47 for any CHD. Of factors examined, the largest contribution to the socioeconomic gradient in CHD frequency was from low control at work. Height and standard coronary risk factors made smaller contributions. Adjustment for all these factors reduced the odds ratios for newly reported CHD in the lowest grade from 1.5 to 0.95 in men, and from 1.47 to 1.07 in women. INTERPRETATION: Much of the inverse social gradient in CHD incidence can be attributed to differences in psychosocial work environment. Additional contributions were made by coronary risk factors--mainly smoking--and from factors that act early in life, as represented by physical height.     

Opitz C trigonocephaly syndrome and midline brain anomalies

Using the Halstead-Reitan Battery profiles of 796 people, a formula for the detection of malingering was partially cross-validated to assess the false positive rate. Subjects included normals, psychiatric cases, and persons with all major types of brain disorder. The formula incorrectly designated 32% of the sample as fakers (i.e., as false positives). Of the 120 head-trauma cases, 39 (32%) obtained Fake scores, whereas 81 (67%) were correctly assessed as not malingering. The correlation of the results of the formula and the severity of the profile (as measured by the Average Impairment Rating) was 67, p < .0001.     

Modulation of the inhibitory substrate properties of oligodendrocytes by platelet-derived growth factor

Although growth cones typically collapse after encountering O1/galactocerebroside (GalC)-positive oligodendrocytes, the majority of growth cones traversed oligodendrocytes, which were raised for 8-10 d in medium containing 10 ng/ml platelet-derived growth factor (PDGF). Oligodendrocytes raised 8-10 d in control medium caused growth cone collapse as they normally do, but failed to elicit this response after being transferred to PDGF-containing medium for an additional 8-10 d. The opposite was observed when PDGF-treated oligodendrocytes were brought to control medium. Growth cones collapsed when contacting these cells. Oligodendrocytes also lost their collapse-inducing activity when raised in medium conditioned by astrocytes, known to produce PDGF. Antibody IN-1 is directed against against neurite growth inhibitors (NI), proteins of 35 and 250 kDa on the surface of O1/GalC-positive oligodendrocytes, which are known to elicit growth cone collapse. IN-1 immunoreactivity was markedly reduced in PDGF-treated oligodendrocytes. However, both PDGF-treated and control oligodendrocytes exhibited myelin-associated glycoprotein, proteolipid protein, and myelin basic protein immunoreactivity. This suggests that PDGF-treatment affects NI expression but does not interfere with the expression of advanced myelin marker proteins. Because NI cause growth cone collapse, the loss of collapse-inducing activity by PDGF-treated oligodendrocytes suggests that PDGF regulates, directly or indirectly, the expression of these proteins.     

Transgene expression of bcl-xL permits anti-immunoglobulin (Ig)-induced proliferation in xid B cells

Mutations in the tyrosine kinase, Btk, result in a mild immunodeficiency in mice (xid). While B lymphocytes from xid mice do not proliferate to anti-immunoglobulin (Ig), we show here induction of the complete complement of cell cycle regulatory molecules, though the level of induction is about half that detected in normal B cells. Cell cycle analysis reveals that anti-Ig stimulated xid B cells enter S phase, but fail to complete the cell cycle, exhibiting a high rate of apoptosis. This correlated with a decreased ability to induce the anti-apoptosis regulatory protein, Bcl-xL. Ectopic expression of Bcl-xL in xid B cells permitted anti-Ig induced cell cycle progression demonstrating dual requirements for induction of anti-apoptotic proteins plus cell cycle regulatory proteins during antigen receptor mediated proliferation. Furthermore, our results link one of the immunodeficient traits caused by mutant Btk with the failure to properly regulate Bcl-xL.     

Mechanism of cardiovascular actions of the chromogranin A fragment catestatin in vivo

Catestatin (bovine chromogranin A(344-364); RSMRLSFRARGYGFRGPGLQL), reduces catecholamine secretion from chromaffin cells in vitro. We investigated the effects of this peptide on catecholamine release and blood pressure in vivo. Intravenous catestatin reduced pressor responses to activation of sympathetic outflow by electrical stimulation in rats, and the catestatin effect persisted even after adrenergic (alpha plus beta) blockade. Catestatin did not alter plasma norepinephrine levels, but increased plasma epinephrine 11-fold. Catestatin also blunted pressor responses to exogenous neuropeptide Y agonists. A control peptide (chromogranin A(141-160)) did not alter pressor or catecholamine responses to electrical stimulation. Pretreatment with a histamine H1 receptor antagonist blocked both the vasodepressor response to catestatin and the elevation in plasma epinephrine. Catestatin elevated endogenous circulating histamine 21-fold, and exogenous histamine mimicked both the epinephrine elevation and the vasodepressor actions of catestatin. We conclude that catestatin is a potent vasodilator in vivo whose actions appear to be mediated, at least in part, by histamine release and action at H1 receptors.     

Lack of immunotoxicity of saquinavir (Ro 31-8959) used alone or in double or triple combination with AZT and ddC

Poly(ADP-ribosyl)ation is a posttranslational modification of nuclear proteins which is catalyzed by poly(ADP-ribose) polymerase and represents an immediate response of eukaryotic cells to oxidative and other types of DNA damage. Previously a strong correlation had been detected between maximal poly(ADP-ribose) polymerase activity in permeabilized mononuclear leukocytes of various mammalian species and species-specific life span. To study a possible relation between longevity and poly(ADP-ribosyl)ation in humans we measured maximal oligonucleotide-stimulated poly(ADP-ribose) polymerase activity in permeabilized, Epstein-Barr virus transformed lymphoblastoid cell lines from a French population of 49 centenarians and 51 controls aged 20-70 years. Maximal enzyme activity was significantly higher in centenarians than in controls [median of controls: 9035 cpm/10(6) cells (lower quartile: 6156; upper quartile: 11,410); median of centenarians: 10,380 cpm/10(6) cells (lower quartile: 7994; upper quartile: 12,991); P=0.031 by Mann-Whitney U test]. In a subset of 16 controls and 24 centenarians, cellular poly(ADP-ribose) polymerase content was determined by quantitative western blotting, thus allowing the calculation of specific enzyme activity. The latter was significantly higher in centenarians (P=0.006), the median value for centenarians being about 1.6-fold that of controls. Specific poly(ADP-ribose) polymerase activity was a more powerful parameter for differentiating between centenarians and controls than enzyme activity relative to cell number. In addition, in a genetic association study we analyzed 437 DNA samples (239 centenarians and 198 controls) by PCR amplification of a polymorphic dinucleotide repeat located in the promoter region of the poly(ADP-ribose) polymerase gene in an attempt to detect an association between this polymorphic marker and variability of enzyme activity or human longevity. However, this genetic analysis revealed no significant enrichment of any of the alleles or genotypes identified among centenarians or controls, but its power was limited by the relatively weak heterozygosity of this polymorphic marker in our population (51%). Viewed together with previous results on poly(ADP-ribose) polymerase activity in various mammalian species, the present data provide further evidence for the notion that longevity is associated with a high poly(ADP-ribosyl)ation capacity.