Chemokine receptor CXCR3 desensitization by IL-16/CD4 signaling is dependent on CCR5 and intact membrane cholesterol

Previous work has shown that IL-16/CD4 induces desensitization of both CCR5- and CXCR4-induced migration, with no apparent effect on CCR2b or CCR3. To investigate the functional relationship between CD4 and other chemokine receptors, we determined the effects of IL-16 interaction with CD4 on CXCR3-induced migration. In this study we demonstrate that IL-16/CD4 induced receptor desensitization of CXCR3 on primary human T cells. IL-16/CD4 stimulation does not result in surface modulation of CXCR3 or changes in CXCL10 binding affinity. This effect does require p56(lck) enzymatic activity and the presence of CCR5, because desensitization is not transmitted in the absence of CCR5. Treatment of human T cells with methyl-beta-cyclodextrin, a cholesterol chelator, prevented the desensitization of CXCR3 via IL-16/CD4, which was restored after reloading of cholesterol, indicating a requirement for intact cholesterol. These studies demonstrate an intimate functional relationship among CD4, CCR5, and CXCR3, in which CCR5 can act as an adaptor molecule for CD4 signaling. This process of regulating Th1 cell chemoattraction may represent a mechanism for orchestrating cell recruitment in Th1-mediated diseases.     

Denial of Risk Behavior Does Not Exclude Asymptomatic Anorectal Sexually Transmitted Infection in HIV-Infected Men

Background

The Centers for Disease Control recommend screening for asymptomatic sexually transmitted infection (STI) among HIV-infected men when there is self-report of unprotected anal-receptive exposure. The study goals were: (1) to estimate the validity and usefulness for screening policies of self-reported unprotected anal-receptive exposure as a risk indicator for asymptomatic anorectal infection with Neisseria gonorrhoeae (GC) and/or Chlamydia trachomatis (CT). (2) to estimate the number of infections that would be missed if anal diagnostic assays were not performed among patients who denied unprotected anorectal exposure in the preceding month.

Methods and Findings

Retrospective analysis in HIV primary care and high resolution anoscopy (HRA) clinics. HIV-infected adult men were screened for self-reported exposure during the previous month at all primary care and HRA appointments. Four sub-cohorts were defined based on microbiology methodology (GC culture and CT direct fluorescent antibody vs. GC/CT nucleic acid amplification test) and clinical setting (primary care vs. HRA). Screening question operating characteristics were estimated using contingency table methods and then pooled across subcohorts. Among 803 patients, the prevalence of anorectal GC/CT varied from 3.5–20.1% in the 4 sub-cohorts. The sensitivity of the screening question for self-reported exposure to predict anorectal STI was higher in the primary care than in the HRA clinic, 86–100% vs. 12–35%, respectively. The negative predictive value of the screening question to predict asymptomatic anorectal STI was ≥90% in all sub-cohorts. In sensitivity analyses, the probability of being an unidentified case among those denying exposure increased from 0.4–8.1% in the primary care setting, and from 0.9–18.8% in the HRA setting as the prevalence varied from 1–20%.

Conclusion

As STI prevalence increases, denial of unprotected anal-receptive exposure leads to an increasingly unacceptable proportion of unidentified asymptomatic anorectal STI if used as a criterion not to obtain microbiologic assays.     

HBV preS/S基因克隆及其在酿酒酵母中的表达

目的:探索利用酿酒酵母系统表达乙型肝炎病毒(HBV)preS／S基因。方法:利用PCR技 术,以HBV病毒DNA为模板,体外扩增HBV preS／S基因。然后构建重组表达载体pESC-preS／S。 用LiAc法转化酿酒酵母YPH50,选取重组菌进行培养,并诱导表达外源蛋白。提取蛋白浓缩后 进行SDS-PAGE分析,并经Western blot分析鉴定。结果:实验结果表明重组菌能够表达HBV preS／S蛋白。结论:利用酿酒酵母系统可成功表达HBV preS／S基因,为制备新型预防性疫苗提供 条件。     

Stroke and coronary heart disease in mild hypertension: risk factors and the value of treatment

Further analyses of the Medical Research Council''s trial of drug treatment of mild hypertension were carried out to provide more detailed information on the benefits associated with treatment in various subgroups. The four main considerations in establishing a rational treatment policy were, firstly, the significant reduction in the stroke rate with active treatment; secondly, the absence of a significant overall treatment effect on myocardial infarction; thirdly, the knowledge that of 100 untreated men in the highest risk group (those aged 55-64 with high systolic pressure at entry who smoked), five would be expected to suffer a stroke and 10 a coronary event within five years; and, fourthly, the cost, in clinical and financial terms, of prolonged treatment. In the high risk group of 100 men treatment with bendrofluazide would result in the prevention of three or four of the five strokes but would have little effect on the expected numbers of myocardial infarctions. Treatment with propranolol in non-smoking men in the highest age and blood pressure categories would lead to a reduction in the number having strokes from three to one or two and might possibly reduce the number experiencing myocardial infarction from seven to four. Smokers treated with propranolol would not be expected to benefit. In women avoiding smoking was particularly important. The considerations for preventing stroke were similar to those in men, but no clear guideline was possible on the effect of lowering blood pressure for preventing myocardial infarction in women.Drug treatment reduces the attack rate of certain events in mild hypertension but should not be prescribed routinely for all patients with the disorder.     

菲律宾海北部底质沉积中的深海介形类

对琉球群岛东侧的菲律宾海北部海区(27.0°-30.0°N,129.5°-135.5°E)水深1 666 m至6 616 m的123个表层沉积物样品进行了定量微体古生物学研究.仅在38个样品中发现介形类,主要分布在4 000 m以浅水深区.初步鉴定有21属35种,其中Krithe在样品中的出现率和丰度最高,其次常见的还...     

Enrichment and Stratification for Predementia Alzheimer Disease Clinical Trials

The tau and amyloid pathobiological processes underlying Alzheimer disease (AD) progresses slowly over periods of decades before clinical manifestation as mild cognitive impairment (MCI), then more rapidly to dementia, and eventually to end-stage organ failure. The failure of clinical trials of candidate disease modifying therapies to slow disease progression in patients already diagnosed with early AD has led to increased interest in exploring the possibility of early intervention and prevention trials, targeting MCI and cognitively healthy (HC) populations. Here, we stratify MCI individuals based on cerebrospinal fluid (CSF) biomarkers and structural atrophy risk factors for the disease. We also stratify HC individuals into risk groups on the basis of CSF biomarkers for the two hallmark AD pathologies. Results show that the broad category of MCI can be decomposed into subsets of individuals with significantly different average regional atrophy rates. By thus selectively identifying individuals, combinations of these biomarkers and risk factors could enable significant reductions in sample size requirements for clinical trials of investigational AD-modifying therapies, and provide stratification mechanisms to more finely assess response to therapy. Power is sufficiently high that detecting efficacy in MCI cohorts should not be a limiting factor in AD therapeutics research. In contrast, we show that sample size estimates for clinical trials aimed at the preclinical stage of the disorder (HCs with evidence of AD pathology) are prohibitively large. Longer natural history studies are needed to inform design of trials aimed at the presymptomatic stage.     

Epidemiology and Outcome of Severe Sepsis and Septic Shock in Intensive Care Units in Mainland China

Introduction

Information about sepsis in mainland China remains scarce and incomplete. The purpose of this study was to describe the epidemiology and outcome of severe sepsis and septic shock in mixed ICU in mainland China, as well as the independent predictors of mortality.

Methods

We performed a 2-month prospective, observational cohort study in 22 closed multi-disciplinary intensive care units (ICUs). All admissions into those ICUs during the study period were screened and patients with severe sepsis or septic shock were included.

Results

A total of 484 patients, 37.3 per 100 ICU admissions were diagnosed with severe sepsis (n = 365) or septic shock (n = 119) according to clinical criteria and included into this study. The most frequent sites of infection were the lung and abdomen. The overall ICU and hospital mortality rates were 28.7% (n = 139) and 33.5% (n = 162), respectively. In multivariate analyses, APACHE II score (odds ratio[OR], 1.068; 95% confidential interval[CI], 1.027–1.109), presence of ARDS (OR, 2.676; 95%CI, 1.691–4.235), bloodstream infection (OR, 2.520; 95%CI, 1.142–5.564) and comorbidity of cancer (OR, 2.246; 95%CI, 1.141–4.420) were significantly associated with mortality.

Conclusions

Our results indicated that severe sepsis and septic shock were common complications in ICU patients and with high mortality in China, and can be of help to know more about severe sepsis and septic shock in China and to improve characterization and risk stratification in these patients.     

Nonselective oviposition by a fastidious insect: the laboratory host range of the melaleuca gall midge Lophodiplosis trifida (Diptera: Cecidomyiidae)

Invasion by the Australian paperbark, Melaleuca quinquenervia, has degraded large areas of south Florida wetlands. Restoration of these wetlands requires the removal of expansive monocultures of this large tree while simultaneously curtailing its spread. Management strategies developed by federal and state agencies include biological control to halt the spread of this species and to prevent reinfestation of cleared areas. This requires biological agents able to reduce flowering, seed production, and growth while increasing mortality of seedlings and saplings. Two of the three introduced agents (Oxyops vitiosa Pascoe and Boreioglycaspis melaleucae Moore) partially meet these needs but outcomes are not spatially or temporally consistent. Thus, additional agents are needed. The bud-gall fly Fergusonina turneri Taylor, with its mutualistic nematode Fergusobia quinquenerviae Davies and Giblin-Davis, is actively being released but has not established. A fourth promising agent, the gall midge Lophodiplosis trifida Gagné, manifested an extremely narrow host range during laboratory testing. Oviposition was indiscriminant in caged environments. Small, incipient, unilocular galls were initiated on Melaleuca viminalis, but larval development ensued only on M. quinquenervia. The unilocular galls on M. viminalis did not grow and produced no adult flies. As a result, M. viminalis test plants suffered only minor cosmetic damage. Observations from both Australia and Florida attest to the ability of this midge to impede M. quinquenervia growth and kill small plants. Thus, L. trifida is safe to release and will likely contribute to management objectives for control of this pernicious wetland invader.     

Studies on an Endonuclease Activity Associated with the Bacteriophage T7 DNA-Membrane Complex

Infection of Escherichia coli with bacteriophage T7 results in the formation of an endonuclease which is selectively associated with the T7 DNA-membrane complex. A specificity of association with the complex is indicated by the finding that the enzyme is completely resolved from a previously described T7 endonuclease I. When membrane complexes containing (3)H-labeled in vivo synthesized DNA are incubated in the standard reaction mixture a specific cleavage product is formed which is about one-fourth the size of T7 DNA. The endonuclease associated with the complex produces a similar cleavage product after extensive incubation with native T7 DNA or T7 concatemers. Degradation of concatemers occurs by a mechanism in which the DNA is converted to molecules one-half the size of T7. This product is in turn converted to fragments one-fourth the size of mature phage DNA. The endonuclease is not present in membrane complexes from uninfected cells or cells infected with gene 1 mutants. The enzyme activity is, however, present in cells infected with mutants defective in T7 DNA synthesis or maturation.