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Biomedical subjects

S Forster

Publications and source records attributed to S Forster.

At least 19 recordsLinked to original sources
PubMed1990

Ultrastructure of the jejunal mucosa in human immunodeficiency virus infection.

The ultrastructural changes in the jejunal mucosa of 11 male patients, three with clinical AIDS, five with AIDS related complex-progressive generalized lymphadenopathy (ARC-PGL), and three who were only HIV antibody positive, were studied. In the enterocytes, major abnormalities were proliferation of smooth endoplasmic reticulum mitochondrial changes, vacuolization of cells, and fat hold up. In the lamina propria, degeneration of enteric nerve axons and smooth muscle were seen. Microvasculature showed both endothelial cell degeneration and hyperplasia. The presence of tubuloreticular inclusions in endothelial cells paralleled the stage of the disease. Since none of the 11 patients had any opportunistic infection, these changes are likely to be the effect of HIV infection.

AIDS-Related Complex↗
PubMed1990

Mechanism of cystine reaccumulation by cystinotic fibroblasts in vitro.

It is well established that when cystine-depleted cystinotic cells are cultured in cystine-containing medium, they reaccumulate cystine within their lysosomes more rapidly than when cultured in cystine-free medium. This has been a puzzling result, since the lysosome membrane of cystinotic cells is impermeable to cystine. To probe the mechanism of cystine reaccumulation, we have measured reaccumulation in the presence of colchicine, an inhibitor of pinocytosis, or of glutamate, a competitive inhibitor of cystine transport into human fibroblasts. Colchicine had no effect, thus eliminating pinocytosis as a putative mechanism for cystine translocation from the culture medium to the lysosomes. Glutamate, however, strongly inhibited cystine reaccumulation. It is concluded that the true mechanism is as follows. 1. Exogenous cystine crosses the plasma membrane on the cystine-glutamate porter. 2. Cystine is reduced in the cytoplasm by GSH. 3. The cysteine that is generated enters the lysosome, where it becomes cystine by participating in the reduction of cystine residues during intralysosomal proteolysis, or by autoxidation.

Biological Transport↗
PubMed1990

Mechanisms and modulation of multidrug resistance in primary human renal cell carcinoma.

Human renal cell carcinomas show a high degree of intrinsic multidrug resistance. In experimental cell lines, the membrane bound P-170 glycoprotein and the glutathione redox cycle seem to contribute to this phenomenon. P-170 may be inactivated by calcium antagonists; the glutathione redox cycle by buthionine sulfoximine. We studied the resistance patterns of 35 human renal cell carcinomas against vinblastine, doxorubicin and carboplatinum in a tetrazolium-based microculture assay. Concomitantly, P-170 expression was traced immunohistochemically using moab C219 and the glutathione content was determined enzymatically. Reversal of multidrug resistance was examined by applying the R-stereoisomer of verapamil and/or by addition of buthionine sulfoximine. A high degree of chemoresistance was seen in 27 tumors against vinblastine, in 30 tumors against doxorubicin and in 31 tumors against carboplatinum. Chemoresponse was found in eight, five or four cases respectively. P-170 was detected in 70% of highly vinblastine resistant and in 63% of highly doxorubicin resistant tumors, but in none of the less resistant cases. Resistance against carboplatinum and doxorubicin was significantly associated with elevated glutathione levels as compared to less resistant renal cell carcinomas. R-verapamil lead to a strong reversal of vinblastine resistance and to a distinct circumvention of doxorubicin resistance, but revealed no effect in carboplatinum resistance. Buthionine sulfoximine overcame carboplatinum resistance and modified doxorubicin resistance, but had no influence on vinblastine resistance. The combined application of R-verapamil and buthionine sulfoximine reversed doxorubicin resistance but did not act synergistically in vinblastine or carboplatinum resistance. Both mechanisms, P-170 and glutathione, occurred independently of each other and may well explain multidrug resistance of human renal cell carcinomas.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1989

The effects of decreased growth temperature on the cystine content of cystinotic fibroblasts.

Cystinotic fibroblasts transferred from 37 degrees C to 28 degrees C accumulated additional cystine over the period from 4 to 7 days of incubation at 28 degrees C, after which the additional cystine was lost; warming (to 37 degrees C) of cells with elevated cystine stores led to rapid cystine loss. These results, taken together with previously published data showing cystine release from cystinotic fibroblasts incubated at above-normal temperature, are interpreted as indicating the presence in the cystinotic fibroblast lysosome membrane of a cystine-porter whose efficacy is increased by an increase in membrane fluidity. This porter may be the residual activity of the cystine porter that is known to be deficient in cystinosis, or it may be a second as yet unrecognized porter. It is further proposed that this porter is responsible for the presumed efflux of cystine from cystinotic lysosomes.

Cell Division↗
PubMed1989

Kaposi's sarcoma of the head and neck in patients with AIDS.

Over a 40 month period, 219 patients with AIDS were seen at St. Mary's Hospital, London. Kaposi's sarcoma, one of the criteria for diagnosing the syndrome, was the presenting feature in 62 patients. Eighty four patients developed Kaposi's sarcoma at some stage of their disease and the head and neck region was involved in 56 of them. Although Kaposi's sarcoma is rarely life threatening in AIDS, potential airway obstruction, pain or cosmetic disfigurement may justify treating the lesion. Whilst cutaneous tumours may be managed by using radiotherapy (16 Gray in four fractions over four days), this treatment produces a sever mucositis when used to treat mucosal disease; we, therefore use a combination of vincristine and bleomycin for this.

Acquired Immunodeficiency Syndrome↗
PubMed1989

The recognition and management of the otolaryngological manifestations of AIDS.

Between October 1984 and December 1987, 219 patients who fulfilled the criteria for Acquired Immune Deficiency Syndrome (AIDS), as set out by the Centers for Disease Control, Georgia, were seen at St. Mary's Hospital, London. The most common otolaryngological manifestations of the disease in these patients were oral candidiasis (60%), oesophageal candidiasis (16%), persistent generalized lymphadenopathy (27%) and Kaposi's sarcoma (26%). Our management of the patients is described.

AIDS-Related Complex↗
PubMed1989

Interferon effects on osteoinduction.

Xenografts of human osteosarcoma growing in athymic mice are inhibited in growth rate by human interferon-alpha (IFN-alpha) treatment. In addition, differentiation of trabecular bone occurs external to the osteosarcomatous tissue and this is entirely dependent on IFN treatment. We have used species-specific anticollagens and antivimentin antibodies to determine the species origins of this trabecular bone. By using immunohistochemical procedures, it was found that this bone is host-derived. These results suggest that IFN provoked the production of a bone-inducing agent by the human osteosarcomas.

Animals↗
PubMed1988

Acute meningo-encephalitis on dose reduction of zidovudine.

In a study of treatment by zidovudine in 106 patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex, an acute meningo-encephalitic illness developed in 4 of 21 patients within 17 days after the dose of zidovudine had had to be reduced because of myelotoxicity. 3 of the 4 patients had previous clinical evidence of HIV encephalopathy. AIDS-related opportunist infection of the central nervous system was excluded. This acute meningo-encephalitic illness probably results from an increase in HIV replication following dose reduction.

AIDS-Related Complex↗
PubMed1988

Cell-cycle-related metabolic and enzymatic events in proliferating rat thymocytes.

Cell-cycle progression of rat thymocytes stimulated with concanavalin A and interleukin 2 was monitored at 12-h intervals by pulse labeling aliquots of the cell culture with [3H]thymidine, by measuring cellular DNA and protein content and by counting the number of cells in the cultures. The cell cycle was completed after 96 h of culture with the S phase peaking at 48 h. Early events in thymocyte activation were enhanced phosphatidylinositol turnover and the induction of ornithine decarboxylase. Concomitant changes were observed in the rates of DNA synthesis and glycolysis accompanied by a 20-fold increase in glucose uptake 48 h after stimulation. However, the maximal increment in the glycolytic rate preceded that of DNA synthesis by 12 h. Apart from the quantitative changes which occurred during the cell-cycle progression, there was also a change from partial aerobic glucose degradation to CO2 (26%) to almost complete anaerobic conversion of glucose to lactate (85%) and less than 3% to CO2. Glycolytic enzyme levels increased fourfold to tenfold and reached their maxima 48 h after mitogenic stimulation. Maximal increments of glycolytic enzyme activities preceded or coincided with the maximal increments of the glycolytic rate. Actinomycin D (1.5 ng/ml) completely inhibited DNA and RNA synthesis but did not show any inhibitory effect either on glycolytic enzyme induction or on enhanced glycolysis. During mitosis and return of the cells to the non-proliferative state, all of the enhanced metabolic rates returned to their initial levels and the elevated enzyme activities were decreased also. The marked changes of metabolic rates and enzyme activities observed at the various phases of the cell cycle suggest that these biochemical events may also serve as suitable parameters for evaluating the response of lymphocytes towards mitogens and lymphokines.

Animals↗
PubMed1988

Interferon-inhibited human osteosarcoma xenografts induce host bone in nude mice.

The growth of human osteosarcoma xenografts in nude mice can be inhibited by human interferon-alpha (IFN-alpha). Histologic examination of growth-inhibited tumors has revealed mineralization and partial replacement of the tumor by normal bone tissue. We have investigated whether the normal bone tissue was formed by differentiated tumor cells or by induction of host stroma to differentiate into bone tissue. Employing antibodies to both murine and human type I collagen, it was found that the normal bone produced in IFN-inhibited osteosarcomas was host derived. These results suggest that IFN induced the osteosarcoma cells to produce a bone-inductive agent that interacts with the host cells, and leads to the formation of mature normal bone tissue in a heterotopic site.

Animals↗
PubMed1988

Protein microinjection by protease permeabilization of fibroblasts.

Exposure of cultured diploid fibroblasts to protease solutions induces a hyperpermeable state which permits entry of exogenous macromolecules directly into the cytosol. We have exploited this finding to devise a microinjection method whose chief advantages are simplicity and good retention of cell viability. Proteins successfully injected by this technique range from insulin to thyroglobulin. The amounts injected range from 4 X 10(5) to 5 X 10(6) molecules/cell.

Cell Membrane Permeability↗
PubMed1988

Antibody-dependent cell-mediated cytotoxicity: comparison between HTLV-I and HIV-1 assays.

This study confirms the presence of detectable antibody-dependent cell-mediated cytotoxicity (ADCC) towards both HTLV-I- and HIV-1-infected cell lines, mediated by normal donor peripheral blood mononuclear cells and either by antibody from adult T-cell lymphoma and tropical spastic paraparesis patients (HTLV-I) or by antibody from sera of patients with persistent generalized lymphadenopathy, AIDS-related complex, AIDS and asymptomatic patients seropositive for HIV-1 infection. A comparison of ADCC towards these two retroviruses, under carefully controlled laboratory conditions, indicates major differences between the capacity of HTLV-I-seropositive sera and HIV-1-seropositive sera to mediate ADCC. In all cases, HIV sera showed low-titre ADCC, in contrast to the high titre (greater than 1:800,000) ADCC mediated by HTLV-I-positive sera. Both sets of sera showed the prozone phenomenon, and heat inactivation may abolish ADCC towards HIV-1-infected cells. Quantitation of surface antigen expression on HTLV-I- and HIV-1-infected cell lines indicated the presence of easily detectable amounts of virus-specific antigen. We conclude that, in contrast to some previous reports, ADCC mediated by HIV-1-specific immunoglobulin G (IgG) antibody is rather weak and of low titre when compared with HTLV-I ADCC. This is true for all cell lines and HIV-1 virus isolate combinations tested.

Antibodies, Monoclonal↗
PubMed1987

Translocation of sugars into rat liver lysosomes. Evidence against a common carrier for D-glucose and D-ribose.

A conflict exists in the literature concerning the mode of translocation of D-glucose and D-ribose across the lysosome membrane. The more rapid net uptake of ribose, when measured by the osmotic-protection technique, has been attributed either to its smaller size and lower hydrogen-bonding capacity, or to a lower affinity for a transport system shared by both sugars. The latency of acid beta-hexosaminidase in isolated rat liver lysosomes was measured after preincubation for periods up to 1 h in various solutions containing glucose and/or ribose, and in some cases sucrose. After confirmation of the superior osmotic protection afforded by glucose (than by ribose), it was shown that a solution 0.125 M in both glucose and ribose provided protection intermediate between that given by 0.25 M-glucose and that given by 0.25 M-ribose. This result is inconsistent with the common-carrier hypothesis.

Animals↗
PubMed1987

The effect of lysosomotropic detergents on the permeability properties of the lysosome membrane.

Compounds such as N-dodecylimidazole and N-dodecylmorpholine kill cells in culture. Their cytotoxicity has been attributed to accumulation in lysosomes where protonation confers detergent properties resulting in membrane destabilization. This hypothesis has been tested by examining the ability of N-dodecylimidazole and N-dodecylmorpholine to decrease the latency of alpha-glucosidase in isolated rat liver lysosomes. No effect was observed. Nor was N-dodecylimidazole apparently able to increase the permeability of isolated rat liver lysosomes to L-alanine, as no diminution of the disruptive effect of L-alanine methyl ester was seen. N-Dodecylimidazole (10-20 micrograms per ml) caused lactate dehydrogenase release from cystinotic fibroblasts, but marginally toxic concentrations failed to induce cystine release, as might have been expected if lysosome membrane damage had occurred. It is concluded that the cytotoxic effects of lysosomotropic detergents may be mediated by a non-lysosomal mechanism.

Animals↗
PubMed1987

Cytomegalovirus colitis and oesophageal ulceration in the context of AIDS: clinical manifestations and preliminary report of treatment with Foscarnet (phosphonoformate).

Three patients with biopsy diagnosed invasive cytomegalovirus infection of the colon have been seen in the context of the acquired immune deficiency syndrome (AIDS). Cytomegalovirus colitis presented with fever, abdominal distention, bloody diarrhoea and weight loss. Plain abdominal radiographs showed generalised large bowel dilatation in one patient. Cytomegalovirus infection was shown histologically, but the virus could not be cultured from the stool; no other gastrointestinal pathogens could be demonstrated. The patients were treated with a 14 day continuous infusion of Foscarnet 0.08 mg/kg/min (phosphonoformate, Astra Pharmaceuticals). One patient showed a partial response to therapy, but the cytomegalovirus colitis relapsed; the second patient had a symptomatic response only and the third patient died of non-cytomegalovirus opportunist infection while on treatment. Two other patients with biopsy proven cytomegalovirus ulceration of the oesophagus were seen, presenting with dysphagia, fever and weight loss. Invasive infection of the gastrointestinal tract with cytomegalovirus is now a major clinical problem in AIDS. Treatment with Foscarnet may be initially effective, but does not eliminate cytomegalovirus infection.

Acquired Immunodeficiency Syndrome↗