STRL33, A novel chemokine receptor-like protein, functions as a fusion cofactor for both macrophage-tropic and T cell line-tropic HIV-1

The chemokine receptors CXCR4, CCR2B, CCR3, and CCR5 have recently been shown to serve along with CD4 as coreceptors for HIV-1. The tropisms of HIV-1 strains for subgroups of CD4(+) cells can be explained, at least partly, by the selective use of G protein-coupled receptors (GPCRs). We have identified a novel human gene, STRL33, located on chromosome 3 that encodes a GPCR with sequence similarity to chemokine receptors and to chemokine receptor-like orphan receptors. STRL33 is expressed in lymphoid tissues and activated T cells, and is induced in activated peripheral blood lymphocytes. When transfected into nonhuman NIH 3T3 cells expressing human CD4, the STRL33 cDNA rendered these cells competent to fuse with cells expressing HIV-1 envelope glycoproteins (Envs). Of greatest interest, STRL33, in contrast with CXCR4 or CCR5, was able to function as a cofactor for fusion mediated by Envs from both T cell line-tropic and macrophage-tropic HIV-1 strains. STRL33-transfected Jurkat cell lines also supported enhanced productive infection with HIV-1 compared with control Jurkat cells. Despite the sequence similarities between STRL33 and chemokine receptors, STRL33-transfected cell lines did not respond to any in a panel of chemokines. Based on the pattern of tissue expression of the STRL33 mRNA, and given the ability of STRL33 to function with Envs of differing tropisms, STRL33 may play a role in the establishment and/or progression of HIV-1 infection.     

In vivo formation of 8-Epi-prostaglandin F2 alpha is increased in hypercholesterolemia

F2-isoprostanes are bioactive prostaglandin (PG)-like compounds that are produced from arachidonic acid through a nonenzymatic process of lipid peroxidation catalyzed by oxygen free-radicals. 8-Epi-PGF2 alpha may amplify the platelet response to agonists, circulates in plasma, and is excreted in urine. We examined the hypothesis that the formation of 8-epi-PGF2 alpha is altered in patients with hypercholesterolemia and contributes to platelet activation in this setting. Urine samples were obtained from 40 hypercholesterolemic patients and 40 age- and sex-matched control subjects for measurement of immunoreactive 8-epi-PGF2 alpha. Urinary excretion of 11-dehydro-thromboxane (TX) B2, a major metabolite of TXA2, was measured as an in vivo index of platelet activation. Low-dose aspirin, indobufen, and vitamin E were used to investigate the mechanism of formation and effects of 8-epi-PGF2 alpha on platelet activation. Urinary 8-epi-PGF2 alpha was significantly (P = .0001) higher in hypercholesterolemic patients than in control subjects: 473 +/- 305 versus 205 +/- 95 pg/mg creatinine. Its rate of excretion was inversely related to the vitamin E content of LDL and showed a positive correlation with urinary 11-dehydro-TXB2. Urinary 8-epi-PGF2 alpha was unchanged after 2-week dosing with aspirin and indobufen despite complete suppression of TX metabolite excretion. Vitamin E supplementation was associated with dose-dependent reductions in both urinary 8-epi-PGF2 alpha and 11-dehydro-TXB2 by 34% to 36% and 47% to 58% at 100 and 600 mg daily, respectively. We conclude that the in vivo formation of the F2-isoprostane 8-epi-PGF2 alpha is enhanced in the vast majority of patients with hypercholesterolemia. This provides an aspirin-insensitive mechanism possibly linking lipid peroxidation to amplification of platelet activation in the setting of hypercholesterolemia. Dose-dependent suppression of enhanced 8-epi-PGF2 alpha formation by vitamin E supplementation may contribute to the beneficial effects of antioxidant treatment.     

A rare cause of accidental selective intubation: right upper lobar bronchus originating from the trachea

IKs channels are composed of IsK and KvLQT1 subunits and underly the slowly activating, voltage-dependent IKs conductance in heart. Although it appears clear that the IsK protein affects both the biophysical properties and regulation of IKs channels, its role in channel pharmacology is unclear. In the present study we demonstrate that KvLQT1 homopolymeric K+ channels are inhibited by the IKs blockers 293B, azimilide and 17-beta-oestradiol. However, IKs channels induced by the coexpression of IsK and KvLQT1 subunits have a 6-100 fold higher affinity for these blockers. Moreover, the IKs activators mefenamic acid and DIDS had little effect on KvLQT1 homopolymeric channels, although they dramatically enhanced steady-state currents through heteropolymeric IKs channels by arresting them in an open state. In summary, the IsK protein modulates the effects of both blockers and activators of IKs channels. This finding is important for the action and specificity of these drugs as IsK protein expression in heart and other tissues is regulated during development and by hormones.     

Antibodies of the anti-Yo and anti-Ri type in the absence of paraneoplastic neurological syndromes: a long-term survey of ovarian cancer patients

PURPOSE: To determine the association between lipids, microalbuminuria and systemic blood pressure. Urinary albumin excretion rate (AER) was determined in timed overnight urine samples by radioimmunoassay. Microalbuminuria was defined when two out of three urine samples had AER ranging 20-200 micrograms/min. Lipids were determined by colorimetric methods (total cholesterol, HDL cholesterol and triglycerides). METHODS: Fifty patients with insulin dependent diabetes mellitus (28 females, 22 males) aged 21.9 +/- 7 years and with diabetes duration of 6.8 +/- 5.8 years attending the outpatients diabetes clinic were studied cross-sectionally. RESULTS: Microalbuminuria was present in 12% of our patients. A high systolic blood pressure (SBP) was found in microalbuminuric patients (p = 0.003). No difference concerning serum lipids were found in comparison between normo and microalbuminuric patients, although 20% of all patients had increased cholesterol and LDL cholesterol and 4% had high HDL cholesterol and triglycerides levels. Stepwise multiple regression analysis showed that SBP was the only significant independent variable to influence AER (r = 0.42 r2 = 0.18 p = 0.002). CONCLUSION: Although in our study, microalbuminuria was associated only with SBP, the independent alteration of lipids in young IDDM patients must be considered as a possible additional risk factor for cardiovascular disease.     

Comparisons of pulmonary and sinonasal lesions in patients with cystic fibrosis. Evaluation using computerized tomography

INTRODUCTION: Cystic fibrosis is a recessive genetic systemic exocrinopathy caused by a variety of mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). The disease is characterized by alterations of the secretions, which become thickened and viscous. Both the paranasal sinuses and the lung parenchyma are involved in all cases. The aim of this study was to assess a correlation between the rhinosinusal and lung parenchyma changes in cystic fibrosis patients. MATERIAL AND METHODS: Eighteen patients (11 men and 7 women, age range: 8 to 22 years) were examined with chest HRCT and sinonasal low dose CT. Lung symptoms were found in all patients; 13 of them, also affected with rhinosinusal symptoms, had been examined with ENT and nasal endoscopy. The other 5 patients, without rhinosinusal symptoms and previously examined with ENT, were evaluated as control group. Chest CT was performed with the high-resolution technique, 2 mm slice thickness and 10 mm table feed. Rhinosinusal CT was performed with the low dose technique, acquiring contiguous 2-4 mm thickness coronal sections. The CT patterns were analyzed by two radiologists and scored as slight, medium and diffuse involvement of both districts. RESULTS: No statistically significant correlation between lung and sinonasal damage was found in our study. Parenchymal lung involvement appeared more severe than sinonasal involvement in 14/18 patients. The retention of secretions in the paranasal sinuses, even if limited, was demonstrated in all symptomatic and asymptomatic patients. CONCLUSIONS: The absence of correlation between pulmonary and sinonasal damage and more generally, the different severity of cystic fibrosis can be caused by different allele mutations of the cystic fibrosis transmembrane conductance regulator gene, the most frequent of which is Delta F-508.     

Postoperative enteral feeding does not prevent intestinal bacterial translocation, but reduces the rate of pulmonary infections in pigs undergoing total orthotopic small bowel transplantation

OBJECTIVE: To assess the effects of a non-elemental liquid diet on nutritional state, composition of bowel flora, intestinal translocation, and pulmonary infections after small bowel transplantation in pigs. DESIGN: Prospective randomised experiment. SETTING: Teaching hospital, Italy. MATERIAL: 32 female Large White pigs. INTERVENTIONS: Group 1 (n = 6) underwent small bowel transplantation, were treated with immunosuppression, and fed on commercial chow. Group 2 (n = 6) were treated similarly except that they were fed with an enteral feed through a tube gastrostomy starting on day 4 postoperatively. Group 3 (n = 6) were treated similarly to group 1 except that they had no immunosuppression, and Group 4 (n = 6) underwent orthotopic small bowel autotransplantation; 8 further pigs underwent a sham operation only to act as controls. MAIN OUTCOME MEASURES: Signs of rejection, graft-versus-host-disease, luminal bacterial overgrowth, bacterial translocation, pneumonia, and the pigs' nutritional state. RESULTS: All animals in group 3 showed signs of acute rejection. There was appreciable overgrowth of aerobic and anaerobic bacteria in all three groups after allotransplantation compared with controls. The counts of anaerobic bacteria were significantly lower in group 2 (enterally fed animals) compared with those given free access to commercial chow [mean (SD) 2.81 (1.39) log CFU/cm2 compared with 4.80 (1.65), p = 0.047]. Bacterial translocation developed to a similar degree after autografts and allografts and pneumonia developed in fewer animals after enteral feeding (1/6) than after conventional feeding (5/6) but the difference was not significant (p = 0.08, odds ratio 25.0, 95% confidence interval of odds ratio 1.20 to 521.13). Enterally fed animals also lost less weight than conventionally fed animals [2.32 (1.23) kg compared with 4.53 (1.74), p = 0.016]. CONCLUSIONS: Enteral feeding for up to a month slightly reduced the rate of pneumonia and resulted in a better nutritional state in pigs after small bowel transplantation. It had no effect on luminal bacterial overgrowth or translocation.     

Protein expression profiles in human breast ductal carcinoma and histologically normal tissue

Reference two-dimensional (2-D) gels are presented for human breast ductal carcinoma and histologically normal tissue. Whole biopsy fragments were analyzed, including epithelial and nonepithelial components. Thirty-five spots have been assigned by gel matching to the human liver SWISS-2DPAGE reference map and/or to the human primary keratinocyte IPG map from the Danish Center for Human Genome. N-terminal microsequencing was applied to confirm randomly chosen matching assignments and to identify six new spots. Protein expression profiles in ductal carcinoma and in normal breast tissue appeared to be similar, except for a pattern consisting of 32 spots, which were highly expressed in all carcinoma specimens, and less intense and occasionally undetectable in normal tissue. This difference was statistically significant. Assignment has been obtained for several spots, namely GRP94, GRP78, GRP75, mitochondrial HSP60, calreticulin, protein disulfide isomerase, peptidyl-prolyl cis-trans isomerase, collagen-binding protein 2, fructose bisphosphate aldolase, glyceraldehyde-3-phosphate dehydrogenase, thioredoxin, cytochrome c oxidase VA subunit, tubulin beta isoform and macrophage migration inhibitory factor (MIF). The cancer- and tissue-specificity of the described pattern was assessed by matching to the Swiss-2DPAGE human liver, hepatoma, lymphoma, erythroleukemia reference maps. The pattern of 32 spots was found to be indicative of epithelial neoplasia.     

Menadione-induced oxidative stress accelerates onset of Emory mouse cataract in vivo

This article takes issue with procedural reductionism, which is the inclination to reduce all matters of judgement and responsibility to the following of some procedure or rule. Two scenarios provide content for a discussion of professional discretion in the context of accountability. The author shows that in professional life there will always be situations that stand beyond the rules of procedures and require the unique judgement of the professional at the time. While this judgement may be determined by the facts available in a situation of uncertainty, it cannot be reduced to the facts (including facts about rules and procedures). The moral judgement will still have an essential indeterminancy about it.