Stereoselective inhibition of monoamine oxidase and semicarbazide-sensitive amine oxidase by 4-dimethylamino-2,α-dimethylphenethylamine (FLA 336)

Summary The in vitro inhibition by amiflamine [FLA 336(+)] and related compounds of the activity of rat monoamine oxidase (MAO)-A and-B, rat semicarbazide sensitive amine oxidase (SSAO) and human platelet poor plasma benzylamine oxidase was studied. Amiflamine was an MAO-A selective inhibitor, but also inhibits SSAO with both a reversible (competitive, K _i=200 mol/l) and a small time-dependent component which was irreversible in nature. The optical isomer FLA 336(–) was ten times less potent towards MAO-A. However, this compound was much more potent an inhibitor of SSAO (competitive, K _i=4.6 mol/l). The amiflamine metabolites FLA 788(+) and FLA 668(+) inhibited SSAO, but only at concentrations considerably higher than required for MAO-A inhibition. Ex vivo experiments indicated that there was no significant irreversible inhibition of rat heart and lung SSAO after both single and repeated administration of amiflamine at doses up to 20 times higher than required for inhibition of MAO-A within central serotoninergic neurones.     

The incidence and distribution of RSI in South Australia 1980-81 to 1986-87

Despite the human and financial cost of repetition strain injury (RSI), comprehensive incidence data have been lacking. A unique opportunity exists to obtain such data in South Australia, where since 1980-81 the Australian Bureau of Statistics has assigned all injuries, not explicitly diagnosed as diseases but stated as having been caused by repetitive movement, to a unique "type of accident" code, and has subclassified them according to bodily location. The statistical profile of diseases and accidents affecting the upper limb resulting from repetitive movement is not simply one of a keyboard operators' epidemic. Rather, it has revealed a problem which is endemic in sections of the blue-collar workforce, in whom both the numbers and the incidence rates are higher than in keyboard operators, and were higher even when the incidence in keyboard operators peaked in 1984-85. These conditions have been especially frequent in particular sections of the female blue-collar workforce, and interventions which have resulted in (or coincided with) benefits to keyboard operators have failed to improve the situation in the former group. It is suggested that the groups most at risk are female workers performing unfulfilling, unskilled tasks, and that interventions to benefit these workers will have to give attention to more fundamental issues than those hitherto addressed.     

慢性支气管炎性急性发作期危重病人外周血B和T细胞CD分子的检测

目的 对慢性支气管炎急性期和缓解期患者外周血B细胞和T细胞CD分子检测并了解其变化。方法 用荧光单抗CD19^ 、CD4^ 、CD8^ ／CD28^ 对B细胞和T细胞亚群进行标记和记数。结果 慢性支气管炎急性发作期患者与缓解期患者相比,体内辅助性T淋巴细胞无明显变化,抑制性T淋巴细胞增加,细胞毒性T淋巴细胞减少,B淋巴细胞二者间无差异。结论 因慢性支气管炎急性期危重病人T淋巴细胞亚群变化,造成免疫功能紊乱。因此,在治疗疾病过程中,除对症处理外,另须配合使用提高免疫功能的药物,改善免疫功能。     

MDA in plasma as a biomarker of exposure to pyrolysed MDI-based polyurethane: correlations with estimated cumulative dose and genotype for N-acetylation

The object of this study was to investigate whether exposure of pipe-layers to thermal degradation products of diphenylmethane diisocyanate (MDI) could be assessed by analysing 4,4-methylenedianiline (MDA) in hydrolysed plasma and urine, and whether the genotype for N-acetylation affected these biomarker levels. Blood and urine samples were drawn from 30-pipe-layers who had been welding polyurethane (PUR) insulated pipes during the preceding 3 months. MDA in hydrolysed plasma and urine was determined with a gas chromatography-mass spectrometry technique, and genotype for N-acetylation was analysed with a polymerase chain reaction technique. MDA in plasma was detected in 18 of the 30 pipe-layers. Their plasma concentrations of MDA varied from 0.05 to 8.48 g/1. There was a significant negative correlation between time since last welding of PUR-insulated pipes and P-MDA (r _s = 0.50, P = 0.005). There was also a significant positive correlation between the estimated number of welded PUR-insulated pipes during the preceding 3 months and P-MDA (r _s = 0.68, P = < 0.001). No significant association between genotype of N-acetylation and P-MDA was observed in a multiple regression analysis when adjustment was made for the estimated cumulative exposure to thermal degradation products of MDI. MDA in urine was detected in only four of the 30 pipe-layers. These four subjects had been welding PUR pipes on the same day as the sampling, or on the day before. The present results indicate the spot plasma samples analysed for MDA may give a rather good estimate of exposure to MDI during the preceding months. P-MDA, but not U-MDA, therefore seems to be a useful biomarker of long-term exposure to MDI. The individual N-acetylation capacity did not affect the plasma levels of MDA.     

TP53 gene mutations predict the response to neoadjuvant treatment with 5-fluorouracil and mitomycin in locally advanced breast cancer.

PURPOSE: Recent studies have found an association between certain TP53 mutations and resistance to anthracycline-based primary medical therapy in breast cancer. The purpose of this study was to investigate whether TP53 mutational status also might influence the response to a non-anthracycline-containing regimen in primary breast cancer. EXPERIMENTAL DESIGN: Thirty-five patients with locally advanced breast cancer were investigated for TP53 mutations before receiving combination chemotherapy with 5-fluorouracil (1000 mg/m(2) on days 1 and 2) and mitomycin (6 mg/m(2) on day 2), administered every 3 weeks for 2-10 cycles in the neoadjuvant setting. RESULTS: Mutations in the TP53 gene, in particular those affecting loop domains L2 or L3 of the p53 protein, were associated with lack of response to chemotherapy (i.e., increase in the diameter product of tumor lesion by >/=25%; P = 0.177 for all mutations and P = 0.006 for those affecting L2/L3 domains, respectively). No statistically significant correlation between TP53 LOH and response to therapy was seen. CONCLUSION: This study revealed a significant association between lack of response to 5-fluorouracil and mitomycin and mutations affecting the L2/L3 domains of the p53 protein. Together with our previous finding that such mutations predict resistance to weekly doxorubicin, our data suggest that mutations affecting this particular domain of the p53 protein may cause resistance to several different cytotoxic compounds applied in breast cancer treatment.     

Neonatal perforated appendicitis in incarcerated inguinal hernia in the differential diagnosis of testis torsion

Appendicitis in newborns is uncommon and difficult to diagnose. Reports on neonatal appendicitis subsequent to inguinal hernia incarceration are exceptionally rare. We present the case of a 26‐day‐old infant with perforated appendicitis due to incarceration of a right inguinal hernia, mimicking right testicular torsion.     

The sexual brain,genes, and cognition: A machine‐predicted brain sex score explains individual differences in cognitive intelligence and genetic influence in young children

Sex impacts the development of the brain and cognition differently across individuals. However, the literature on brain sex dimorphism in humans is mixed. We aim to investigate the biological underpinnings of the individual variability of sexual dimorphism in the brain and its impact on cognitive performance. To this end, we tested whether the individual difference in brain sex would be linked to that in cognitive performance that is influenced by genetic factors in prepubertal children (N = 9,658, ages 9–10 years old; the Adolescent Brain Cognitive Development study). To capture the interindividual variability of the brain, we estimated the probability of being male or female based on the brain morphometry and connectivity features using machine learning (herein called a brain sex score). The models accurately classified the biological sex with a test ROC–AUC of 93.32%. As a result, a greater brain sex score correlated significantly with greater intelligence (p _fdr < .001, ηp2 = .011–.034; adjusted for covariates) and higher cognitive genome‐wide polygenic scores (GPSs) (p _fdr < .001, ηp2 < .005). Structural equation models revealed that the GPS‐intelligence association was significantly modulated by the brain sex score, such that a brain with a higher maleness score (or a lower femaleness score) mediated a positive GPS effect on intelligence (indirect effects = .006–.009; p = .002–.022; sex‐stratified analysis). The finding of the sex modulatory effect on the gene–brain–cognition relationship presents a likely biological pathway to the individual and sex differences in the brain and cognitive performance in preadolescence.     

The incidence of preterm deliveries decreases in Finland

Objective  We examined the trends and risk factors of preterm delivery.
Design  Register-based retrospective cohort study from Finland.
Setting  National Medical Birth Register data during 1987–2005.
Population  The study population consisted of 1 137 515 deliveries, of which 59 025 were preterm (5.2%).
Methods  We calculated the population attributable risks for using the risk factor prevalence rates in the population. We further calculated odds ratios with 95% CI by multivariate logistic regression to adjust for confounders.
Main outcome measures  Preterm delivery rate subclassified into moderately preterm (32–36 weeks), very preterm (28–31 weeks) and extremely preterm (less than 28 weeks).
Results  Preterm delivery rates increased from 5.1% in the late 1980s to 5.4% in the late 1990s but then decreased to 5.2% for 2001–05. The proportion of extremely preterm deliveries decreased substantially by 12% ( P < 0.01). The greatest risk factors were multiplicity (OR 13.72, 95% CI 13.26–14.19), followed by elective delivery (OR 1.86, 95% CI 1.82–1.89), primiparity (OR 1.47, 95% CI 1.45–1.50), in vitro fertilisation treatment (OR 1.39, 95% CI 1.31–1.47), maternal smoking (OR 1.31, 95% CI 1.29–1.34) and advanced maternal age (OR 1.02, 95% CI 1.02–1.03 for each additional year of age). Prematurity rates decreased by 1.8% after adjusting for risk variables.
Conclusions  The rate of preterm delivery has not increased from 1987 to 2005 in Finland, while the risk for extremely preterm delivery has decreased. This finding is in contrast with recent trends in other countries.