A role for cell migration in the sexual transmission of HIV-1?

The issue of how human immunodeficiency virus-1 (HIV-1) enters the body following sexual contact has been the subject of considerable controversy. Several possible routes for the initial infection have been suggested [1-6], including the possibility that the transmission is mediated by HIV-1-infected lymphocytes or macrophages in serum and female genital tract secretions, rather than by free virus. We recently reported that HIV-1-infected, activated primary monocytes can migrate between epithelial cells grown in confluent monolayer cultures in vitro [7]. We report here on experiments carried out in mice to test the hypothesis that mononuclear blood cells are capable of migrating through intact epithelia, and thus of carrying a virus into an animal. We placed double-stained, activated mononuclear blood cells into the vaginas of mice; four hours later, numerous double-stained cells were observed in the connective tissue beneath the vaginal epithelium and the iliac lymph nodes of the experimental mice. We speculate that such migration may be involved in the sexual transmission of HIV-1.     

GHB: a home brew

To test whether the binding of insulin to an endogenous serum protein can be used to extend the time action of insulin, human insulin was acylated at the epsilon-amino group of Lys(B29) with palmitic acid to promote binding to serum albumin. Size-exclusion chromatography was used to demonstrate specific binding of the resulting analog, [N(epsilon)-palmitoyl Lys(B29)] human insulin, to serum albumin in vitro, and the time action and activity of the analog were determined in vivo using overnight-fasted, insulin-withdrawn diabetic dogs. In the diabetic animal model, the duration of action of [N(epsilon)-palmitoyl Lys(B29)] human insulin administered intravenously was nearly twice that of unmodified human insulin, and the plasma half-life was nearly sevenfold that of the unmodified protein. Administered subcutaneously, [N(epsilon)-palmitoyl Lys(B29)] human insulin had a longer duration of action; a flatter more basal plasma insulin profile; and a lower intersubject variability of response than the intermediate-acting insulin suspension Humulin L (Lilly, Indianapolis, IN). These studies support the concept that modification of insulin to promote binding to an existing serum protein can be used to extend the time action of human insulin. In addition, the time action, pattern, and decreased variability of response to [N(epsilon)-palmitoyl Lys(B29)] human insulin support the development and further testing of this soluble insulin analog as a basal insulin to increase the safety of intensive insulin therapy.     

Effects of chronic arterial hypertension on constitutive and induced intercellular adhesion molecule-1 expression in vivo

Recent reports indicate that bacterial endotoxin (lipopolysaccharide) and cytokines elicit a more profound increase in the surface expression of intercellular adhesion molecule-1 (ICAM-1) in cultured endothelial cells derived from spontaneously hypertensive (SHR) versus normotensive Wistar-Kyoto rats (WKY). Our objective in this study was to characterize and compare in vivo ICAM-1 expression in SHR and WKY under basal conditions and after 5 hours of endothelial cell activation with either lipopolysaccharide (5 mg/kg i.p.) or tumor necrosis factor-alpha (TNF-alpha; 1, 5, and 10 micrograms/kg i.p.). ICAM-1 expression was quantified in different tissues by the double-radiolabeled monoclonal antibody technique. When constitutive (baseline) ICAM-1 expression was corrected for endothelial cell surface area, significantly higher values were noted in SHR than WKY but only in splanchnic organs. Lipopolysaccharide and TNF-alpha elicited significant increases in ICAM-1 expression in all tissues of both WKY and SHR. However, the magnitude of the lipopolysaccharide-induced ICAM-1 upregulation in heart, stomach, skeletal muscle, and brain was significantly lower in SHR than WKY. A similar blunted ICAM-1 upregulation was noted in the stomach of SHR after administration of 5 micrograms/kg TNF-alpha. The differences in induced ICAM-1 expression between SHR and WKY do not appear to be due to differences in endothelial cell surface area or plasma glucocorticoid levels. These results suggest that chronic arterial hypertension results in altered ICAM-1 expression on the endothelium, which may contribute to the abnormal inflammatory responses associated with this disease.     

TRAM regulates the exposure of nascent secretory proteins to the cytosol during translocation into the endoplasmic reticulum

Translocational pausing is a mechanism used by certain specialized secretory proteins whereby discrete domains of a nascent chain destined for the endoplasmic reticulum lumen are transiently exposed to the cytosol. Proteoliposomes reconstituted from total endoplasmic reticulum proteins properly assemble translocationally paused intermediates. The capacity of the translocon to correctly pause the nascent chain is dependent on a glycoprotein fraction whose active component is TRAM. In the absence of TRAM, the normally sealed ribosome-membrane junction still opens in response to a pause transfer sequence. However, nascent chain domains that are not exposed to the cytosol in the presence of TRAM are so exposed in its absence. Thus, TRAM regulates which domains of the nascent chain are visible to the cytosol during a translocational pause.     

Tuberculosis and iron overload in Africa: a review

Both pulmonary tuberculosis and dietary iron overload are common conditions in sub-Saharan Africa. The incidence of tuberculosis has increased markedly over the last decade, primarily as a result of the rapid spread of infection with the human immunodeficiency virus (HIV). Dietary iron overload affects up to 10% of adults in rural populations and is characterized by heavy iron deposition both in parenchymal cells and in macrophages. Mycobacterium tuberculosis grows within macrophages and, at the same time, the antimicrobial function of macrophages is important in the body's defence against tuberculosis. In vitro, the loading of macrophages with iron reduces the response of these cells to activation by interferon-gamma and diminishes their toxicity against micro-organisms. In the clinical setting, dietary iron overload appears to increase the risk for death from tuberculosis even in the absence of the acquired immunodeficiency syndrome. The combination of dietary iron overload and infection with the HIV, with impaired function of both macrophages and T-cells, may make patients especially vulnerable to tuberculosis. It is possible that the prevention and treatment of dietary iron overload could contribute to the control of tuberculosis in African populations.     

Anti-MOC-31: a potential addition to the pulmonary adenocarcinoma versus mesothelioma immunohistochemistry panel

MOC-31 expression has recently been advocated as an immunohistochemical marker for distinguishing mesothelioma from adenocarcinoma in tissue sections. We studied formalin-fixed, paraffin-embedded tissue from 23 pleural mesotheliomas and 23 primary pulmonary adenocarcinomas for immunoreactivity with anti-MOC-31, a human epithelial-related antigen. All of the 23 adenocarcinomas strongly expressed the marker, whereas only one of the mesotheliomas showed weak reactivity. These results demonstrate the usefulness of anti-MOC-31 in differentiating pulmonary adenocarcinoma from mesothelioma.     

Production of tumor necrosis factor (TNF) by macrophages and T-lymphocytes of rodents as affected by acute gamma-irradiation

BACKGROUND: The current classification dividing patients with functional gastrointestinal symptoms into subgroups remains controversial. AIMS: To determine whether distinct symptom groupings exist in the community. METHODS: A random sample of Sydney residents in Penrith, Australia was mailed a validated self report questionnaire. Gastrointestinal symptoms including the Rome criteria for irritable bowel syndrome (IBS) and dyspepsia were measured. RESULTS: Among 730 respondents, the 12 month age and gender adjusted prevalence (adjusted to the Australian population) of IBS, dyspepsia, and gastro-oesophageal reflux were 11.8% (95% confidence interval (CI) 9.3 to 14.3%), 11.5% (95% CI 9.6 to 14.6%), and 17.5% (95% CI 14.2 to 19.9%), respectively. In total, 60% of the population reported four or more gastrointestinal symptoms. There was considerable overlap of IBS with dyspepsia and among the dyspepsia subgroups by application of the Rome criteria. Independently, 10 symptom groupings were identified by factor analysis. The underlying constructs measured by these factors were generally the major abdominal syndromes recognised by the Rome classification: dyspepsia, IBS, reflux, painless constipation, painless diarrhoea, and bloating, in addition to a number of more specific symptom groupings. CONCLUSION: Gastrointestinal symptoms are common and overlap in the community, but distinct upper and lower abdominal symptom groupings can be identified.