Myocardial infarction among professional drivers

BACKGROUND: Professional drivers are at an increased risk of myocardial infarction but the underlying causes for this increased risk are uncertain. METHODS: We identified all first events of myocardial infarction among men age 45-70 years in Stockholm County for 1992 and 1993. We selected controls randomly from the population. Response rates of 72% and 71% resulted in 1067 cases and 1482 controls, respectively. We obtained exposure information from questionnaires. We calculated odds ratios (ORs), with and without adjustment for socioeconomic status, tobacco smoking, alcohol drinking, physical inactivity at leisure time, overweight status, diabetes and hypertension. RESULTS: The crude OR among bus drivers was 2.14 (95% confidence interval = 1.34-3.41), among taxi drivers 1.88 (1.19-2.98) and among truck drivers 1.66 (1.22-2.26). Adjustment for potential confounders gave lower ORs: 1.49 (0.90-2.45), 1.34 (0.82-2.19) and 1.10 (0.79-1.53), respectively. Additional adjustment for job strain lowered the ORs only slightly. An exposure-response pattern (by duration of work) was found for bus and taxi drivers. CONCLUSIONS: The high risk among bus and taxi drivers was partly explained by unfavorable life-style factors and social factors. The work environment may contribute to their increased risk. Among truck drivers, individual risk factors seemed to explain most of the elevated risk.     

The CYP19 gene and associations with androgens and abdominal obesity in premenopausal women

OBJECTIVE: Elevated androgens in women are associated with type 2 diabetes and are dependent on the conversion to estrogens by aromatase cytochrome P450. Polymorphisms of a tetranucleotide repeat [TTTA](n) in the fourth intron of the CYP19 gene are associated with endocrine-dependent diseases and were examined in relation to hormone levels and disease risk factors in premenopausal women. RESEARCH METHODS AND PROCEDURES: A population sample of women born in 1956 (n = 270) were genotyped for this polymorphism and the results set in relation to steroid hormones, including saliva cortisol, anthropometric variables, estimates of insulin, glucose and lipid metabolism, and blood pressure. RESULTS: Seven tetranucleotide repeat [TTTA](n) alleles were detected with allelic sizes of 168 to 195 bp, with a TCT deletion/insertion (168/171 bp) upstream of this microsatellite. Smoking was associated with elevated androgens (p = 0.005 to 0.019). Using the median (average stretch, 177.5 bp) as a dividing line, nonsmoking women with the shorter microsatellite had higher free testosterone (p = 0.018) and lower sex hormone binding globulin (p = 0.033). These differences were pronounced with the 168-bp allele. Such women were also characterized by a less-substantial decrease of morning cortisols ("unwinding"; p = 0.035) and central obesity (abdominal sagittal diameter, p = 0.049) and had waist/hip circumference ratios of borderline significance (p = 0.064). DISCUSSION: The results indicate that, in premenopausal women, a short microsatellite in the fourth intron of the CYP19 gene, caused by a TCT deletion upstream the [TTTA](n) tract, is associated with elevated androgens, perturbed regulation of the hypothalamic-pituitary-adrenal axis, and abdominal obesity.     

Synthesis and structure-activity relationship of aminobenzophenones. A novel class of p38 MAP kinase inhibitors with high antiinflammatory activity

We wish to report the synthesis and structure-activity relationship (SAR) of a series of 4-aminobenzophenones, as a novel compound class with high antiinflammatory activity. Our initial lead, (4-[(2-aminophenyl)amino]phenyl)(phenyl)methanone (3), was systematically optimized and resulted in compounds that potently inhibited the release of the proinflammatory cytokines IL-1beta and TNF-alpha in human peripheral blood mononuclear cells stimulated by LPS. One of the most potent compounds, among others, was (4-[(2-aminophenyl)amino]-2-chlorophenyl)(2-methylphenyl)methanone (45) with IC(50) values of 14 and 6 nM for the inhibition of IL-1beta and TNF-alpha, respectively. Furthermore, we found these types of compounds to be potent and selective p38 MAP kinase inhibitors, e.g. 45 had an IC(50) value of 10 nM. Molecular modeling was used to rationalize our SAR data and to propose a model for the interaction of compound 45 with the p38 MAP kinase. The model involved a favorable hydrogen bond between the carbonyl group of the benzophenone and the NH of Met-109, positioning ring A in the hydrophobic pocket I of the enzyme. Good antiinflammatory effects were demonstrated in two murine models of dermatitis after topical application (oxazolone and TPA model).     

Improving structure-based virtual screening by multivariate analysis of scoring data

Three different multivariate statistical methods, PLS discriminant analysis, rule-based methods, and Bayesian classification, have been applied to multidimensional scoring data from four different target proteins: estrogen receptor alpha (ERalpha), matrix metalloprotease 3 (MMP3), factor Xa (fXa), and acetylcholine esterase (AChE). The purpose was to build classifiers able to discriminate between active and inactive compounds, given a structure-based virtual screen. Seven different scoring functions were used to generate the scoring matrices. The classifiers were compared to classical consensus scoring and single scoring functions. The classifiers show a superior performance, with rule-based methods being most effective. The precision of correctly predicting an active compound is about 90% for three of the targets and about 25% for acetylcholine esterase. On the basis of these results, a new two-stage approach is suggested for structure-based virtual screening where limited activity information is available.     

The pharmacophore of short cationic antibacterial peptides

Cationic antibacterial peptides have been proclaimed as new drugs against multiresistant bacteria. Their limited success so far is partially due to the size of the peptides, which gives rise to unresolved issues regarding administration, bioavailability, metabolic stability, and immunogenicity. We have systematically investigated the minimum antibacterial motif of cationic antibacterial peptides regarding charge and lipophilicity/bulk and found that the pharmacophore was surprisingly small, opening the opportunity for development of short antibacterial peptides for systemic use.     

Study of suboptimum treatment response: lessons from breast cancer

Drug resistance is the main cause of therapeutic failure and death in patients with cancer. However, there have been surprisingly few studies designed specifically to investigate the mechanisms underlying poor treatment response in vivo, compared with the number of phase II and III trials investigating treatment effects. We can now analyse the expression patterns of multiple genes by use of microarrays, rapid gene sequencing, and proteomics, and so need to reassess the way we design clinical trials to take full advantage of these new opportunities. I discuss the concept of clinical studies of chemoresistance in terms of the collection of tumour samples for biological studies, the use of appropriate clinical settings, and the importance of trial design. Ideally, such studies should investigate specific biological features in relation to measurable antitumour effects of single drugs.     

Cross-national comparisons of the Cambridge Cognitive Examination-revised: the CAMCOG-R: results from the European Harmonization Project for Instruments in Dementia

BACKGROUND: Transnational and psychometrically appropriate versions of instruments used in the diagnosis of dementia are essential for comparing information between different countries. The Cambridge Examination for Mental Disorders of the Elderly incorporates a brief neuropsychological test battery, Cambridge Cognitive Examination (recently revised version), which provides objective data on performance across a number of cognitive domains. OBJECTIVE: To harmonise the Cambridge Cognitive Examination between seven European countries. METHOD: 40 patients with probable or possible Alzheimer's disease of each of the seven countries were administered the Cambridge Cognitive Examination. The Nurse Observation Scale for Geriatrics was used to assess concordance between cognitive and behavioural measures. RESULTS: Only small differences between the various Cambridge Cognitive Examination versions were found, and patterns of correlation between Cambridge Cognitive Examination and the Nurse Observation Scale for Geriatrics were consistent. CONCLUSION: These findings indicate that the harmonisation of the Cambridge Cognitive Examination was successful.