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Biomedical subjects

C Chandler

Publications and source records attributed to C Chandler.

At least 55 records · Page 3Linked to original sources
PubMed1993

Transplant rejection. Mechanisms and treatment.

In this review, we summarize the cellular and molecular events in the rejection of transplanted allografts, as well as the rationale for the evolving techniques to suppress such rejection. Allogenic major histocompatibility complex antigens expressed on the allograft and/or on the "passenger leukocytes" within the graft are the major antigenic stimuli recognized as being foreign by receptors of CD4+/T helper cells of the host. Host macrophages provide a second signal, interleukin (IL) 1, essential to the activation of T helper cells. Subsequent production of IL-2 by T helper cells leads to activation and proliferation of cytotoxic T cells and lymphokine-activated killer cells and the release of IL-4 and IL-6. In addition, IL-2 promotes release of interferon gamma as well as tumor necrosis factor and other proinflammatory cytokines. Therapeutic options to "downregulate" this cascade have gradually evolved from global nonspecific immunosuppressive techniques (total body irradiation, antilymphocyte serum) to increasingly specific modalities currently being studied, including monoclonal antibodies against the IL-2 receptor (thus targeting only vigorously proliferating T cells), antibodies against specific cytokines (interferon gamma, tumor necrosis factor), and now "designer" antibody-toxin conjugate molecules that deliver toxins to selected receptor targets. Finally, work continues toward inducing preoperative antigen-specific (graft) tolerance, including utilization of gene transfection techniques to transfect donor major histocompatibility complex antigens to recipients before surgery, which has been shown to prolong murine cardiac allografts, perhaps by priming specific suppressor cells. Further understanding of the initiation of, and subsequent events in, transplantation rejection will lead to increasingly effective prolongation of graft survival while minimizing adverse effects on the host.

Graft Rejection↗
PubMed1993

Malignant arterial tumor embolization.

Malignant arterial tumor emboli large enough to cause ischemia or organ infarction are a rare, but often fatal, complication of neoplastic disease. The majority of arterial emboli are associated with primary or secondary pulmonary malignancies. The sites where they impact are similar in distribution to arteriosclerotic emboli, and the treatment follows well-established principles developed for the treatment of arteriosclerotic emboli. The results of embolectomy in accessible sites are very good, thus treatment should always be attempted. A case of a superior mesenteric tumor embolus occurring after pneumonectomy is reported, together with a review of all published cases of arterial tumor emboli of sufficient size to cause organ infarction or ischemia.

Carcinoma, Squamous Cell↗
PubMed1993

No major differences in energy metabolism between matched and unmatched groups of 'large-eating' and 'small-eating' men.

Rates of energy expenditure (J/kg fat-free mass (FFM) per min) in normal weight, 'small-eating' men were compared with those obtained for normal weight (n 8) and underweight (n 5) 'large-eating' men. For the matched groups of 'large-' and 'small-eaters' there were no differences in resting metabolic rate (RMR) measurements but during controlled daily activities there was a small but significant increase (P < 0.05) in energy expenditure in the 'large-eaters'. These results contrast with those obtained for the unmatched groups where energy requirements were about 10% (P < 0.01) higher in the underweight 'large-eaters' at rest but were not different during the more energetic (walking) activities. However, after adjustment for differences in FFM between these two groups, the resting energy expenditures of the 'large-eaters' (82.54 (SE 1.51) J/kg FFM per min) were similar to those of the 'small-eaters' (81.87 (SE 1.51) J/kg FFM per min). Oral temperatures were significantly higher in the matched (0.35-0.65 degrees) and unmatched (0.7-0.9 degrees) 'large-eaters' both at rest and during the different activities, but the thermic effect of food (50 kJ/kg FFM) was one fifth lower (not significant) in both groups of 'large-eaters'. These results provide little evidence for any major metabolic differences between groups of 'large-eating' and 'small-eating' men.

Adult↗
PubMed1992

Differences in energy metabolism between normal weight 'large-eating' and 'small-eating' women.

Nine 'large-eating' (approximately 12 MJ/d) and nine 'small-eating' (approximately 5.3 MJ/d) women were selected from the population on the basis of diet and activity diaries. At rest and in the post-absorptive state the rate of oxygen consumption (VO2)/kg fat-free mass (FFM) and rate of carbon dioxide production (VCO2)/kg FFM were 9-17% higher (P < 0.05) in the 'large-eaters' than in the 'small-eaters'. As energy expenditure was increased by walking at 2.4, 3.9 and 5.4 km/h the differences between the two experimental groups for both VO2/kg FFM and VCO2/kg FFM were decreased to negligible values, but energy expended on a body-weight basis (MJ/kg per min) remained significantly higher (5-10%) in 'large-eaters'. Oral temperature was also consistently higher (up to 0.5 degrees) in this group both at rest and during sitting, standing and walking activities. Although the average thermic effect of a standardized liquid meal tended to be higher (27%; not significant) in the 'small-eaters', the other results demonstrate that the 'large-eating' females had a markedly higher rate of energy expenditure at rest and during light physical activities.

Adult↗
PubMed1992

A pilot study of prophylactic aerosolized amphotericin B in patients at risk for prolonged neutropenia.

Invasive aspergillosis continues to be a significant cause of morbidity and mortality in patients with prolonged neutropenia. We performed a phase I trial of escalating doses of aerosolized amphotericin B given by a face mask nebulizer system with a disposable bacterial exhale filter. Five, 10, 15, and 20 mg of drug were dissolved in sterile water and inhaled over 10 to 15 minutes twice daily. Tolerance was studied in 26 patients (18 transplant recipients, and 8 leukemia patients). No side effects were observed at any dose level. Prophylactic treatment ended for 14 patients (54%) when intravenous (IV) amphotericin B was begun empirically for antifungal coverage following fevers. Eleven patients (43%) continued inhaled amphotericin B until blood counts recovered. One patient was taken off study when she developed cardiogenic pulmonary edema. No patient developed clinically suspicious or pathologically documented infection with invasive aspergillosis. Prophylactic aerosolized amphotericin B is well tolerated at 5, 10, 15, and 20 mg twice daily dosing. In addition, prophylactic aerosolized amphotericin B does not appear to sensitize patients to the subsequent use of IV amphotericin B. Although this study suggests that prophylactic inhaled amphotericin B is well tolerated and effective, a large scale controlled trial is needed.

Adult↗
PubMed1992

Phase I study of busulfan, cyclophosphamide, and timed sequential escalating doses of cytarabine followed by bone marrow transplantation.

In both animal models and human studies in leukemia, residual disease on day 8 following myelosuppressive therapy is in a proliferative phase and therefore may be sensitive to the S-phase specific drug cytarabine. Based on this concept, 17 patients with refractory or relapsed leukemia or lymphoma undergoing either autologous or allogeneic bone marrow transplantation (BMT) were treated on a Phase I protocol using high doses of busulfan (16 mg/kg, days -10, -9, -8, -7) and cyclophosphamide (120 mg/kg, days -6, -5) followed by escalating doses of a 48-h continuous infusion of cytarabine (starting dose 1000 mg/m2/48 h, days -3, -2). Ten patients received autologous transplants (two with Hodgkin's disease, seven with non-Hodgkin's lymphoma, one with chronic myelogenous leukemia (CML) in blast phase). Seven received allogeneic BMT (two with refractory acute myelocytic leukemia (AML), one with refractory acute lymphoblastic leukemia (ALL) undergoing a second BMT, one with Burkitt's-type leukemia, one with ALL in fifth relapse and two with CML in accelerated/blast phase). Two of these patients received a T cell-depleted haploidentical transplant. The maximum tolerated dose of cytarabine was 1500 mg/m2/48 h; a pulmonary syndrome including dyspnea, hypoxemia, and interstitial infiltrates which responded to aggressive diuresis was the dose limiting toxicity. Of the 10 patients who received cytarabine doses of 2000 or 2500 mg/m2/48 h, five patients developed adult respiratory distress syndrome (ARDS) with three patients requiring intubation; two recovered. Of the nine patients with lymphoma, seven responded with complete tumor clearance (CTC) with two patients tumor-free 13 and 15 months post-BMT, one remained refractory and one died too early to evaluate (TETE).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1991

Solution conformation of endothelin, a potent vaso-constricting bicyclic peptide. A combined use of 1H NMR spectroscopy and distance geometry calculations.

The solution structure of endothelin-1, a newly discovered potent bicyclic peptide vaso-constrictor agent, has been investigated using 1H NMR conformational constraints and distance geometry calculations. The conformation is constrained by two disulphide bridges between Cys1-Cys15 and Cys3-Cys11 but the NMR data and computed conformers show additional helical structure between residues Leu6 and Cys11. Our results are compared with previous conflicting reports on the solution conformation of this peptide.

Amino Acid Sequence↗
PubMed1991

Immunohistochemical localization of transforming growth factor-beta in human photoreceptors.

Transforming growth factor-beta (TGF-beta) is a multifunctional growth factor that can either stimulate or inhibit cellular proliferation depending on cell type and culture conditions. The immunohistochemical localization of TGF-beta was investigated in human retinas and choroids using streptavidin peroxidase immunohistochemistry and a polyclonal rabbit antibody directed against the N-terminal 30 amino acids of TGF-beta 1. This antibody recognizes the beta 1 form of TGF-beta but not beta 2. TGF-beta localization was observed exclusively in photoreceptors in all adult non-diabetic and non-insulin dependent diabetic eyes, and 4 of 6 insulin dependent eyes. It was determined that TGF-beta was associated with both rods and cones using localization of peanut agglutinin (PNA), a lectin which binds to cone sheaths, on serial sections. Chondroitinase ABC digestion of sections prior to immunohistochemistry did not reduce TGF-beta immunoreactivity, suggesting that binding was not to glycosaminoglycans in the interphotoreceptor matrix. TGF-beta immunoreactivity was not observed in 2 premature human eyes in which photoreceptor outer segments had not yet developed. Localization in photoreceptors was also not observed in photocoagulation scars, in atrophic regions in a diabetic retina, nor in detached areas of retina from a young victim of head trauma. Based on PNA binding, succinate dehydrogenase enzyme histochemistry and phase contrast microscopy on adjacent sections, the TGF-beta negative areas of these retinas did not appear to have viable photoreceptors. This work demonstrates that TGF-beta is found exclusively in viable adult human retinal photoreceptors. It's function in these cells is currently not known.

Adult↗
PubMed1991

Immunolocalization of tissue plasminogen activator in the diabetic and nondiabetic retina and choroid.

Retinal capillary closure is a common finding in many patients with diabetic retinopathy. The cause of this capillary occlusion is unknown. Since occlusions in microthromboembolic disease can occur because of deficiencies in tissue plasminogen activator (tPA) and since systemic tPA decreases with an increasing duration of diabetes mellitus, the immunohistochemical localization of tPA in the retinas and choroids of diabetic and nondiabetic patients was investigated. The localization of tPA was confined to arteries and arterioles in peripheral retinas from nondiabetics. Both veins and arteries were positive in these choroids. Two of three noninsulin-dependent diabetics had normal levels of immunoreactivity in their retinas, and all had normal levels of immunolocalization in their choroids. All but 2 of the 12 insulin-dependent diabetic eyes (IDDM), however, had reduced levels of retinal tPA immunoreactivity which was most pronounced in their peripheral retinas. Seven eyes from patients with IDDM had no reaction product in their peripheral retinas. Two such eyes also had reduced tPA immunoreactivity in their choroidal vessels. Some tPA-positive vessels were observed in the central retinas of these eyes, but the number of positive vessels and amount of reaction product was greatly reduced compared with eyes from nondiabetic patients. These observations suggest that IDDM patients have reduced fibrinolytic activity in their retinas, which might predispose them to thromboembolic disease.

Adult↗
PubMed1986

Presence of endothelial cell growth factor activity in normal and diabetic eyes.

Two classes of growth factors affecting endothelial cell proliferation have been found previously in ocular tissues: a heat labile mitogen from retina (RDGF) and a heat stable inhibitor of proliferation from vitreous. The relative amounts of these growth factors in normal and diabetic cadaver eyes were investigated using fetal bovine aortic endothelial cell proliferation as an assay. Equivalent levels of RDGF activity were extracted from diabetic and normal sensory retinas. An extract from pigment epithelium and choroid was found to have similar levels of mitogenic activity, but this activity was not as heat labile as RDGF. Like RDGF, equivalent amounts of mitogen were extracted from diabetic and normal tissue. Normal human vitreous inhibited endothelial cell proliferation, and this activity was enhanced by heating the material (10 min., 95 degrees C). Four of the five individual diabetic vitreous samples of identical postmortem times were mitogenic when not heated, and exhibited little or no inhibitory activity when heated. Vitreous of identical postmortem times was pooled and fractionated by heparin-Sepharose chromatography to determine if the heat labile mitogen in vitreous was RDGF. From the insulin-dependent diabetic (IDDM) pooled vitreous sample, a prominent protein of 18 Kd was eluted from the column with 1.2 M NaC1, a characteristic of RDGF. This work suggests that both RDGF and the vitreous inhibitor are found in human vitreous, but their relative concentrations may change in the diabetic state so that retinal neovascularization from retina can occur.

Animals↗
PubMed1985

The assessment of ovulation by a combination of ultrasound and detailed serial hormone profiles in 35 women with long-standing unexplained infertility.

We have examined for the presence of subtle hormonal abnormalities in women with long-standing unexplained infertility. For a full cycle serum LH, FSH, progesterone and oestradiol levels were measured about three times a week, and serial ultrasound scans of the ovaries made until the time of apparent ovulation. The results on 45 cycles in 35 women with unexplained infertility and in three normal volunteers are presented. Normal ovulatory cycles were defined by a length of 26-32 d, and progressive follicular maturation followed by disappearance or abrupt reduction in size of a follicle within 48 h of the recorded LH peak, followed by progressive and sustained rise in serum progesterone levels to more than 25 nmol/l and a luteal phase length of greater than or equal to 13 d. Thirty spontaneous cycles (28 women) were clearly normal while 15 spontaneous cycles (12 women) were abnormal. Abnormalities included luteinization of an unruptured follicle (eight cycles), absence of follicular development (two cycles), poor follicular development (two cycles), persistence of a large ovarian cyst from the preceeding cycle (two cycles) and one aluteal cycle. Six of the abnormal cycles were characterized hormonally by inappropriate elevation of serum LH levels throughout. If this study had been based only on serial ultrasound scans, all results on abnormal cycles might have been misinterpreted. If it had been conducted only with (multiple) progesterone determinations and the level of greater than 25 nmol/l had been taken as indicative of ovulation nine clearly abnormal cycles would have been considered as normal. We conclude that the combination of the hormonal and ultrasound assessment of ovulation increases our confidence for confirmation of normality and reveals various ovulatory disorders which are possibly due to an endocrinological defect or defects.

Adult↗
PubMed1985

Regulation of cell growth by vitreous humour.

Extracts of normal vitreous have been found to inhibit angiogenesis in two animal models: tumour-induced neovascularization in the rabbit corneal micropocket and retinal extract-induced angiogenesis in the chick chorioallantoic membrane assay. Using in vitro assays, we have found recently that an extract of bovine vitreous, free of hyaluronic acid, inhibits proliferation of cells in the aortic wall, i.e. endothelium and smooth muscle cells, as well as capillary and corneal endothelium. The inhibition is dose-dependent, as determined by either cell count or [3H]thymidine incorporation, and not due to cytotoxicity, as demonstrated with a double-label thymidine assay. The inhibitor is trypsin-sensitive and heat-stable (95 degrees C for 10 min). Conversely, proliferation of pericytes, lens epithelium and fibroblasts (dermal and corneal) was stimulated by the vitreous extract. This mitogenic activity was heat-labile. Growth of pigment epithelium and several tumour cell lines was unaffected. The data demonstrate that normal vitreous contains a heat-stable growth inhibitor specific for endothelium and smooth muscle cells, and a non-specific heat-labile mitogen. The paradoxical effect of this antiangiogenic factor on arterial and capillary contractile cells, smooth muscle and pericytes, suggests a basic difference in the regulation of the two vasculatures. The results suggest that a substance in normal vitreous may be important in controlling neovascularization that results from diabetic and other retinopathies, and could be useful for inhibiting tumour-induced angiogenesis.

Animals↗