Tryptophan depletion and HIV infection: a metabolic link to pathogenesis

HIV-1-infected patients have low circulating tryptophan concentrations despite evidence of adequate dietary intake of this essential amino acid. A chronic increase in inducible tryptophan oxidation is the basis of HIV-1-associated tryptophan depletion. This metabolic process results in the irretrievable loss of tryptophan molecules from the available pool. Such sustained disruption of normal tryptophan metabolism over time disturbs the many metabolic processes involving this amino acid, and has been implicated in some features of AIDS pathogenesis. Normal T-cell function is adversely affected by tryptophan depletion, but the extent of the effect in HIV-1-infected patients is still unclear. Attempting to directly supplement tryptophan is not advised given the potential increase in circulating concentrations of neurotoxic intermediates. Although only preliminary data are available, evidence suggests that antiretroviral and nicotinamide treatments can boost plasma tryptophan concentrations in HIV-1-infected patients and impact the secondary effects of tryptophan depletion. Additional study of this metabolism could lead to improved treatment strategies for patients with HIV infection. In this review I focus on the potential links between disturbed tryptophan metabolism and pathogenesis.     

Preferential adsorption, internalization and resistance to degradation of the major isoform of the Alzheimer's amyloid peptide, A beta 1-42, in differentiated PC12 cells

A central question in Alzheimer's disease (AD) is the role of amyloid in pathogenesis. Recent discoveries implicating the longer A beta 1-42 form of amyloid in pathogenesis led us to characterize the interaction of A beta with cells to elucidate differences that might account for these observations. We characterized the adsorption, internalization and degradation of radiolabeled A beta in NGF-differentiated PC12 cells under conditions that are not acutely toxic. All A beta peptides examined absorb to the surface of PC12 cells and are internalized; however the adsorption and internalization of A beta 1-42 is significantly greater than that of A beta 1-40 and A beta 1-28. The adsorption of A beta 1-42 is decreased by treatment of the cells with neuraminidase, but not heparitinase. The fate of the internalized A beta 1-42 is also very different than shorter A beta peptides; a fraction of the internalized A beta 1-42 accumulates intracellularly and is resistant to degradation for at least 3 days while A beta 1-40 and shorter peptides are eliminated with a half life of about 1 h. A beta 1-42 does not appear to inhibit lysosomal hydrolases, since A beta 1-28 is degraded at the same rate in the presence or absence of A beta 1-42. The intracellular A beta 1-42 is located in a dense organellar compartment and colocalizes with the lysosomal markers Lucifer Yellow and horseradish peroxidase. These data indicate that there are significant differences in the cell surface adsorption, internalization and catabolism of A beta 1-42 compared to A beta 1-40 and A beta 1-28. These differences may be important for the preferential accumulation of the longer A beta 1-42 isoform and its association with AD pathogenesis.     

Prostacyclin analogue (OP-2507) attenuates hepatic microcirculatory derangement, energy depletion, and lipid peroxidation in a rat model of reperfusion injury

Between 1985 and 1994, 1223 patients with malleolar fractures of the ankle were treated by open reduction and internal fixation with absorbable pins and screws, of whom 74 (6.1%) had an obvious inflammatory foreign-body reaction to the implants. Of these 74, ten later developed moderate to severe osteoarthritis of the ankle despite no evidence of incongruity of the articular surface. The implants used in these patients were made from polyglycolide, polylactide or glycolide-lactide copolymer. The joint damage seemed to be due to polymeric debris entering the articular cavity through an osteolytic extension of an implant track. The ten patients had a long clinical course which included a vigorous local foreign-body reaction, synovial irritation and subsequent degeneration. At a follow-up of three to nine years, ankle arthrodesis had been necessary in two patients and is being considered for another two. The incidence of these changes in the whole series was 0.8%, which is not high, but awareness of this possible late complication is essential.     

Uptake of suramin by human microvascular endothelial cells

BACKGROUND: There are many causes of ulcer of the lower limb. In the elderly, venous ulcers and arteriosclerosis often coexist; for this reason pressure bandages might be contraindicated for the risk of precipitating a potentially critical arterial flow. In this work, the conditions which allow a safely treatment with pressure bandage in the elderly are evaluated. MATERIAL AND METHOD: Eleven self-sufficient elderly, with venous ulcerations to one leg only, and ankle pressure/omeral pressure between 0.92 and 0.86 were treated with elastic bandaging of the leg. RESULTS: All patients completed the treatment, with healing of the ulcer obtained in 3-8 months time. So far none of them relapsed. CONCLUSIONS: In the elderly, in selected cases, when Pc/Po > 0.86, pressure bandages can be safely applied to heal the ulcer, without running the risk of endangering arterial circulation.     

Dynamic imaging of the pancreas using real-time endoscopic ultrasonography with secretin stimulation

BACKGROUND: Tissue factor (TF) is a transmembrane glycoprotein that, after binding to factor VII/VIIa, initiates the extrinsic coagulation pathway, resulting in thrombin generation and its sequelae. Thrombin has been shown to induce TF mRNA in endothelium, monocytes, and smooth muscle cells, further perpetuating the thrombogenic cycle. This study was designed to determine the effect of specific inhibition of thrombin by recombinant hirudin (r-hirudin) on TF distribution after balloon angioplasty in the cholesterol-fed rabbit femoral artery and porcine coronary artery models. METHODS AND RESULTS: Thirty-five femoral arteries from 32 cholesterol-fed New Zealand White rabbits and 84 coronary arteries from 55 Yorkshire-Albino swine were studied by use of a recently developed in situ method of TF localization based on digoxigenin labeling of recombinant factor VIIa (Dig-VIIa), with correlative studies of TF immunoreactivity by use of anti-rabbit (AP-1) or anti-human (sTF) antibodies. At sites of balloon angioplasty in rabbit femoral or pig coronary arteries (double or single injury), TF-antibody and Dig-VIIa staining were noted in association with endothelial cells, smooth muscle cells, and foam cells and within the fibrous tissue matrix primarily of the adventitia and neointima. Staining was significantly greater after balloon angioplasty than in vessels that had not undergone angioplasty but was similar after single and double balloon injury. Animals treated with r-hirudin (rabbits, 1 mg/kg bolus plus 2-hour infusion; pigs, 1 mg/kg bolus plus 0.7 mg x kg(-1) x d(-1) infusion for 14 days with implantable pump) had diminished TF-antibody and Dig-VIIa staining 28 days after balloon angioplasty compared with controls (bolus heparin only). This effect was more prominent on the neointima and was more striking in the porcine than the rabbit model. CONCLUSIONS: TF expression, persistent 1 month after balloon angioplasty in rabbit femoral arteries and porcine coronary arteries, is attenuated by specific thrombin inhibition with hirudin. These results suggest that thrombin inhibition, in addition to its effect on acute thrombus formation and its effect on luminal narrowing by plaque in experimental animals, may result in a prolonged reduction in thrombogenicity of the restenotic plaque through this effect on TF expression.     

Chemotherapy in advanced ovarian cancer: four systematic meta-analyses of individual patient data from 37 randomized trials. Advanced Ovarian Cancer Trialists' Group

The purpose of this systematic study was to provide an up to date and reliable quantitative summary of the relative benefits of various types of chemotherapy (non-platinum vs platinum, single-agent vs combination and carboplatin vs cisplatin) in the treatment of advanced ovarian cancer. Also, to investigate whether well-defined patient subgroups benefit more or less from cisplatin- or carboplatin-based therapy. Meta-analyses were based on updated individual patient data from all available randomized controlled trials (published and unpublished), including 37 trials, 5667 patients and 4664 deaths. The results suggest that platinum-based chemotherapy is better than non-platinum therapy, show a trend in favour of platinum combinations over single-agent platinum, and suggest that cisplatin and carboplatin are equally effective. There is no good evidence that cisplatin is more or less effective than carboplatin in any particular subgroup of patients.     

Using anthropology to analyse healthcare situations

An anthropological approach to caring has much to offer practising health workers, especially nurses. While its attitude towards knowledge differs from that used in much traditional medical and clinical education, its capacity to draw on the observations and life experiences of both carers and those cared for in the design of care plans can provide insights and information crucial to recovery and to an extended healthy life. This article models Claude Lévi-Strauss' structural anthropological method within nursing care situations.