Early-onset of illicit substance use is associated with greater axis-II comorbidity, not with axis-I comorbidity

In the present study the relationship between early-onset (相似文献   

No evidence of tumor growth stimulation in human tumors in vitro following treatment with recombinant human growth hormone

In a recent study we demonstrated that recombinant human growth hormone (r-hGH; Saizen) delayed tumor-induced cachexia in human tumor xenografts in vivo. Such a therapeutic effect could have a great impact in the supportive care of advanced cancer patients. Before large clinical studies are initiated possible growth stimulation should be excluded. This question was investigated in vitro in 20 human tumor models, which had been established in serial passage in nude mice. The effect of continuous exposure of r-hGH was investigated at dose levels ranging from 0.3 ng/ml up to 0.1 microg/ml in colorectal (n=2), gastric (n=1), non-small cell lung (n=4), small cell lung (n=1), mammary (n=3), ovarian (n=2), prostate (n=2) and renal cancers (n=2), and melanoma (n=3) using a modified Hamburger and Salmon clonogenic assay. The results show that there was neither tumor growth inhibition nor any evidence for tumor growth stimulation in any of the tumors studies. Therefore this preclinical study in 20 human tumor models indicated no direct risk for tumor growth enhancement.     

Immunoreactivity of Presenilin-1 and Tau in Alzheimer''s Disease Brain

Mutations in the presenilin-1 gene (PS-1) on chromosome 14 are causative for early-onset familial Alzheimer's disease (AD). In order to study the localization of PS-1 in human brain, a polyclonal antibody, SB63, against a N-terminal epitope of PS-1 (²⁵VRSQNDNRERQEHND⁴⁰), was raised in rabbits and characterized. Immunolabeling with SB63 of formalin-fixed sections of hippocampus from cases of PS-1-linked AD (PS-1 I143T (AD/A), G384A (AD/B)), sporadic AD, and controls showed a predominant neuronal staining pattern with a stronger immunoreactivity in pyramidal neurons. Staining was mainly granular and localized in the neuronal cell body as well as in neuronal processes. In AD some dystrophic neurites surrounding the amyloid plaques were stained, but no immunoreactivity was observed in the amyloid core. Although PS-1 was present in tangle bearing neurons, colocalization of PS-1 and tau could not be detected using immunofluorescence double labeling. Our data indicate that the pattern of PS-1 immunoreactivity in the hippocampus does not substantially differ between PS-1-linked AD, sporadic AD, and controls.     

Meta-analysis of intrinsic rates of increase and carrying capacity of populations affected by toxic and other stressors

Most of the thousands of substances and species that are of concern for environmental management will not be investigated empirically at ecologically relevant levels because of financial, practical, and ethical constraints. To allow risk assessment for these less well-known categories, we have developed a mechanistic model with classical equations from toxicology and ecology. The parameters are linked to well-known properties, such as the octanol-water partition ratio K(ow), acute lethal (body) concentrations, and organism size. This allows estimation of intrinsic rates of increase r and carrying capacity K over a wide range of substances and species. The model was calibrated with parameter values (micro +/- 95% confidence interval) obtained in reviews and validated by a meta-analysis with largely independent data from 200 laboratory experiments. For single substances, the 5 to 95% interval of the observations on intrinsic rates of increase overlapped with the range predicted by the model. Model and experiments independently indicated that population growth ceased below 1% of the acute median lethal concentration in about 5% of the cases. Exceptional values and possible explanations were identified. The reduction of the carrying capacity K was nearly proportional to the inhibition of the population growth r. Population-level effects of mixtures as estimated by concentration addition were confirmed by observations in the experiments. The impact of a toxicant and another stressor could generally be described by response multiplication, with the exception of cases with extreme stress. Data sets on population laboratory experiments are biased to metals and crustaceans. This field will benefit from empirical studies on chemicals, conditions, and species, identified as risky by the model. Other implications of the model for environmental management and research are discussed.     

Prognostic variables for high titres in a fluorescent antibody test to diagnose tuberculosis

SETTING: The four hospitals and a tuberculosis clinic in the province of Zeeland, The Netherlands. OBJECTIVE: To assess the usefulness of PPD antibody measurement in the diagnosis of tuberculosis in patients admitted to hospital. PATIENTS AND METHODS: Sixty-one patients presenting with active tuberculosis, and 215 control patients were included in the study. Initial serum PPD antibody titres were determined with a macrophage uptake Fluorescent antibody test (MuFat) to construct a discrimination model between Tuberculosis (TB) and non-TB. We also retrospectively collected clinical parameters of the TB patients at presentation. Univariate and multivariate logistic regression are used to identify variables predicting high antibody titres. RESULTS: In TB patients, the presence of clinical symptoms (OR=10.63) and the presence of at least two concurrent non-lymph node disease localizations outside thorax and abdomen (OR=13.94) are necessary and sufficient to predict high titres. The logistic model shows a significant contribution of the 2log (titre) to the discrimination between TB and non-TB patients. At a cut-off value of 128, a specificity, sensitivity, and positive predictive and negative predictive values of 97%, 39%, 80% and 85%, respectively, are calculated in the study cohort. CONCLUSION: Our data suggest an application of the test at high cut-off values for timely diagnosis of difficult-to-diagnose TB patients. The results of this retrospective study will have to be confirmed in further prospective studies.     

Diamine-extended glutaraldehyde- and carbodiimide crosslinks act synergistically in mitigating bioprosthetic aortic wall calcification

BACKGROUND AND AIM OF THE STUDY: The extension of glutaraldehyde (GA) crosslinks with diamine bridges was shown previously to reduce bioprosthetic heart valve calcification to a significant degree. The aim of the present study was to investigate whether the additional crosslinking of functional carboxyl groups could augment this anticalcific effect at the low glutaraldehyde concentrations typically used in commercial heart valve production. METHODS: Entire aortic roots of medium-sized pigs were fixed after 48 h of cold storage. Crosslinking of amino-functional groups was achieved either by GA fixation alone (0.2% or 0.7%) or with an interim treatment with the diamine L-lysine (25, 50 or 100 mM; 37 degrees C; 2 days). Carboxyl groups were activated with carbodiimide (N'-{3-dimethylaminopropyl}-N-ethyl carbodiimide hydrochloride (EDC), 240 mM) and crosslinked with an oligomeric diamine (polypropylene glycol-bis-aminopropyl ether (Jeffamine), 60 mM, 230D). By permutation of treatments and combinations thereof, a total of 17 groups was compared. Aortic wall discs (12 mm diameter) were implanted subcutaneously into seven-week-old Long-Evans rats for 60 days. Tissue calcification was determined by histology and atomic absorption spectrophotometry. RESULTS: There was no significant difference in tissue calcification if either GA or carbodiimide fixation was used alone. Equally, the combined crosslinking with GA and EDC/Jeffamine did not achieve a mitigation of tissue calcification below levels seen in at least one of the two treatments alone. When commercial GA fixation was mildly diamine-enhanced with L-lysine (25 mM), additional EDC/Jeffamine crosslinking of carboxyl groups resulted in a distinct additive effect in both 0.2% (-31%; p < 0.0002) and 0.7% (-36%; p = 0.0073) GA-fixed tissue. Relative to conventional GA fixation, this combination mitigated aortic wall calcification by 43% (p < 0.0001) and 34% (p = 0.0014) in 0.2% and 0.7% GA-fixed tissue, respectively. An increase in L-lysine concentration to 100 mM further reduced calcification of 0.7% GA-fixed tissue (18.5%; p = 0.016), but had no additional effect on 0.2% GA-fixed tissue (0.6%; p = 0.463). CONCLUSION: A distinct reduction in bioprosthetic aortic wall calcification can be achieved by combining diamine-extended conventional GA fixation with a diamine-extended carbodiimide based crosslinking step.     

Proinsulin concentration is an independent predictor of all-cause and cardiovascular mortality: an 11-year follow-up of the Hoorn Study

OBJECTIVE: High proinsulin concentration may be a better predictor for cardiovascular disease (CVD) mortality than insulin concentration. Previous observations may have been confounded by glucose tolerance status or lack of precision because of high intraindividual variability. We investigated the longitudinal relation of means of duplicate measurements of insulin and proinsulin with all-cause and CVD mortality in a population-based cohort taking glucose tolerance status into account. RESEARCH DESIGN AND METHODS: Fasting and post-75-g glucose-load (2-h) glucose, insulin, and proinsulin values were determined in duplicate on separate days in 277 participants with normal glucose metabolism, 208 participants with impaired glucose metabolism, and 119 newly detected patients with type 2 diabetes of the Hoorn Study. Insulin resistance and beta-cell function were estimated by homeostasis model assessment (HOMA-IR and HOMA-B, respectively), and the fasting proinsulin-to-insulin ratio was calculated. Subjects were followed with respect to mortality until January 2003. RESULTS: Fasting proinsulin levels were significantly associated with all-cause and CVD mortality. The hazard ratios (HRs) per increase in interquartile range adjusted for age and sex were 1.21 (95% CI 1.04-1.42) for all-cause mortality and 1.33 (1.06-1.66) for CVD mortality. Adjustment for glucose tolerance status and HOMA-IR did not substantially change the associations. CONCLUSIONS: Fasting proinsulin was associated with all-cause and CVD mortality, independent of glucose tolerance status and insulin resistance and largely independent of other CVD risk factors. Proinsulin might play a role in the relationship between insulin resistance and CVD.