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Biomedical subjects

J Cunningham

Publications and source records attributed to J Cunningham.

At least 109 records · Page 6Linked to original sources
PubMed1994

Novel pattern of p53 gene mutations in an American black cohort with high mortality from breast cancer.

The pattern of acquired mutations in the p53 gene can be used to study differences in factors contributing to carcinogenesis. We investigated mutations in exons 5-9 and adjacent intronic regions in 47 breast cancers of black women from Michigan, a population with the highest breast-cancer mortality in the US. The 16 mutations detected differed from those of other populations. In particular, the black women had an excess of A:T-->G:C transitions compared with rural white US midwest women. While the causes of the different pattern of acquired mutation remain to be determined, this molecular epidemiological approach detects the consequences of mutagenic processes in specific populations. Mutation patterns will constrain hypotheses to mechanisms consistent with the observed biochemical alterations.

Base Sequence↗
PubMed1994

Cloning, characterization, and functional expression of cDNAs encoding glucose transporter proteins from the human parasite Schistosoma mansoni.

The blood-dwelling adult form of the parasitic worm, Schistosoma mansoni, consumes prodigious quantities of host glucose following its transport across the tegument. Immunologic or pharmacologic targeting of the relevant transporter proteins might form the basis of a schistosome control strategy. Here we report the isolation and characterization of three different full-length cDNAs whose predicted protein sequences show a high degree of sequence and structural similarity to the facilitated diffusion transporter proteins of other animals, plants, and bacteria. Functional expression of two cDNAs has been achieved by injection of Xenopus oocytes with in vitro derived sense strand RNA. Injected oocytes have a significantly increased ability to take up radiolabeled glucose analogues over controls. S. mansoni glucose transporters expressed in oocytes exhibit stereospecificity for D-glucose, have relaxed specificity for different hexoses, exhibit sodium independence, and are markedly inhibited by phloretin and cytochalasin B. These two transporters, expressed in oocytes, have a Km for 3-O-methylglucose of 1.3 and 2 mM. A third glucose transporter homologue cDNA appears to derive from a recent pseudogene. Both of the functional S. mansoni glucose transporter genes are expressed in larval and adult male and female schistosomes.

Animals↗
PubMed1994

Phase II radioimmunotherapy trial with 131I-CC49 in colorectal cancer.

BACKGROUND: Radiolabeled CC49, a second generation high affinity monoclonal antibody (MoAb) reactive with tumor-associated glycoprotein 72 (TAG72) has undergone previous Phase I testing in patients with colon cancer. Based on this report, the authors treated 15 refractory metastatic colon cancer patients with 131I-CC49 to determine its overall toxicity and the response to therapy of patients treated with it. METHODS: Patients received 75 mCi/m2 131I-CC49 (20 mg MoAb) intravenously for a period of 30-60 minutes. Whole body retention was derived from the measured dose-rate of I-131 monitored daily at 1 m using an ion chamber. Two whole-body and static-gamma camera images were taken of patients on days 4 and 7 after the infusion. RESULTS: Nonhematologic toxicity (Grade 1-2) consisted of nausea (two patients), arthralgias (three patients), transient fever and chills (two patients), and transient blood pressure changes (two patients). At 4-5 weeks posttreatment, reversible Grade 3-4 thrombocytopenia was observed in 7 of 15 patients, and reversible Grade 3-4 granulocytopenia was observed in 6 of 15 patients. Twelve of 13 patients tested developed human anti-mouse antibody (range, 161 to > 20,000 ng/ml) at 6-8 weeks postinfusion. Mean +/- SD whole-body half-life (whole-body retention) of 131I-CC49 was 57.3 +/- 13.4 hours. Tumors were seen in all patients. In two of three patients treated a second time, an increased whole body clearance rate correlated with elevated human anti-mouse antibody, reduced uptake in tumor, and enhanced uptake in the thyroid. Estimated tumor doses ranged from 19-667 rads. Red marrow dose estimated from whole body retention ranged from 60 to 117 rads and correlated with decreases in platelet count. No objective tumor responses (i.e., partial or complete) were observed. CONCLUSIONS: Despite minimal toxicity and favorable tumor uptake, efficacy has been limited at this dose and schedule.

Animals↗
PubMed1994

A human amphotropic retrovirus receptor is a second member of the gibbon ape leukemia virus receptor family.

Retrovirus infection is initiated by binding of the viral envelope glycoprotein to a cell-surface receptor. The envelope proteins of type C retroviruses of mammals demonstrate similarities in structural organization and protein sequence. These similarities suggest the possibility that retroviruses from different interference groups might use related proteins as receptors, despite the absence of any relationship between retrovirus receptors isolated to date. To investigate this possibility, we have identified a human cDNA clone encoding a protein closely related to the receptor for gibbon ape leukemia virus and have found that it functions as the receptor for the amphotropic group of murine retroviruses. Expression of this protein (GLVR-2) is likely to be a requirement for infection of human cells by amphotropic retroviral vectors for purposes of gene therapy.

3T3 Cells↗
PubMed1994

A multicenter review of the treatment of major truncal necrotizing infections with and without hyperbaric oxygen therapy.

To examine the effectiveness of hyperbaric oxygen (HBO) therapy in the treatment of major truncal necrotizing infections, a retrospective (1980 to 1992) analysis of the medical records of 30 patients treated with HBO therapy and 24 patients treated without HBO therapy was undertaken. The two groups were similar; however, there was a selection bias towards more frequent clostridial infections in a younger population in the HBO group. There was no difference in length of hospital stay, intensive care unit (ICU) stay, or duration of antibiotic therapy between groups. The mortality rates were 9/30 (30%) in the HBO group versus 10/24 (42%) (nonsignificant difference) in the non-HBO group. The total number of operations was greater in the HBO-treated group. This study failed to show that the use of HBO in the treatment of major truncal necrotizing infections statistically reduced mortality or the number of débridements. We believe, however, that the apparent selection bias and the trend towards increased survival in the HBO-treated group (12%) justifies the continued use of and research with HBO therapy.

Anti-Bacterial Agents↗
PubMed1994

Aggressive medulloblastoma with high-level N-myc amplification.

A 27-year-old man was treated for an aggressive cerebellar medulloblastoma that, at operation, exhibited dural invasion. Six months after gross total resection and radiation therapy, a "surgical metastasis" developed in the lower portion of the surgical scar. The tumor grew rapidly down into the right side of his neck. Chemotherapy failed, and he subsequently died. Cytogenetic and molecular genetic studies revealed multiple numeric and structural chromosome abnormalities, including an abnormal chromosome 17p arm, more than 100-fold N-myc amplification, a rearranged c-myc gene, and a 16-base pair deletion involving exon 7 of the p53 gene. We postulate that these genetic features may have contributed to the aggressive behavior of the tumor.

Adult↗
PubMed1994

Oral granisetron alone and in combination with dexamethasone: a double-blind randomized comparison against high-dose metoclopramide plus dexamethasone in prevention of cisplatin-induced emesis. The Granisetron Study Group.

PATIENTS AND METHODS: Three anti-emetic treatment regimens were compared in 357 patients receiving cisplatin therapy (mean dose 81 mg/m2) in this double-blind randomized study. Regimens studied were i) granisetron 1 mg bd orally for 7 days (granisetron alone); ii) gran 1 mg bd orally for 7 days plus prophylactic dexamethasone (12 mg i.v.) on the first day only (gran/dex); iii) metoclopramide (3 mg/kg i.v. loading dose; 4 mg/kg i.v. infusion) plus dex (12 mg i.v.) on the first day followed by met 10 mg orally tds for a further 6 days (met/dex). RESULTS: At 24 hours, gran/dex was significantly superior to met/dex in terms of total anti-emetic control, defined as no nausea, no vomiting, no rescue anti-emetic therapy, not withdrawn (54.7% gran/dex vs. 37.2% met/dex; P < 0.01). There was also a significant delay in time to onset of nausea (P < 0.01) and vomiting (P < 0.01) following gran/dex compared with met/dex. Oral granisetron alone was as effective as met/dex in control of acute emesis in all parameters examined. There were no significant differences between the three groups in the control of delayed nausea and vomiting. The most common adverse experiences in both granisetron groups were headache and constipation, both characteristic of 5-HT3 antagonists. Agitation, somnolence, diarrhoea and decreased appetite were reported more frequently by the met/dex group. CONCLUSIONS: Oral granisetron as a single agent is as effective as high doses of i.v. met/dex in preventing cisplatin-induced emesis. Oral granisetron in combination with a corticosteroid provides superior anti-emetic control to the met/dex regimen in patients undergoing highly emetogenic chemotherapy.

Administration, Oral↗
PubMed1994

Modulation by endogenous ATP of the light-evoked release of ACh from retinal cholinergic neurones.

The retina is an area of the central nervous system that possesses intrinsic cholinergic neurones which release acetylcholine (ACh) in response to stimulation with flickering light. Using an eye-cup preparation in anaesthetized rabbits we found that when the retina was exposed to the P2-purinoceptor antagonist, PPADS, the light-evoked release of ACh was strikingly increased (by over 40%). In contrast, ATP reduced the light-evoked release of ACh by 20%. The inhibitory effect of ATP was not due to its catabolism to adenosine because it was not affected by the A1-adenosine receptor antagonist, DPCPX, in combination with adenosine deaminase. The actions of both ATP and PPADS were completely blocked by strychnine. We conclude that during physiological stimulation of the retina with light, ATP is co-released with ACh and partially inhibits ACh release by activating (with ACh) an inhibitory glycinergic feedback loop.

Acetylcholine↗
PubMed1994

Loss of regional bone mineral density in the first 12 months following renal transplantation.

A high incidence of osteopenia is likely in renal transplant recipients in whom pre-existing uraemic osteodystrophy, persisting hyperparathyroidism and glucocorticoids constitute a formidable array of risk factors. The correction of some biochemical and hormonal abnormalities, an increase in body weight and an increase in physical activity following transplantation could favour improvements in skeletal integrity. Using dual energy X-ray absorptiometry (DEXA), we studied prospectively the regional bone mineral density (BMD) of 34 consecutive cadaveric renal allograft recipients who were already established on dialysis. BMD of these patients was measured at the time of transplantation and was repeated at 3, 6 and 12 months following the transplantation. Immunosuppression was achieved using triple therapy: azathioprine, cyclosporin-A and prednisolone. At baseline, total BMD and BMD at the lumbar spine and femoral neck did not differ from age- and sex-matched controls. Females experienced marked and progressive bone loss at the lumbar spine, with less marked changes at the femoral neck. Males, in contrast, experienced substantial reduction of BMD at the femoral neck at 6 months and a recovery at 12 months without significant change at the lumbar spine. Whole body bone mineral content fell transiently in males, with partial recovery by 6 months. No significant correlation was found with the cumulative doses of either corticosteroids or cyclosporin-A, the duration of hospitalisation, the function of the transplant, patient age or menopausal status.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorptiometry, Photon↗
PubMed1994

In vivo dihydrotachysterol2 metabolism in normal man: 1 alpha- and 1 beta-hydroxylation of 25-hydroxydihydrotachysterol2 and effects on plasma parathyroid hormone and 1 alpha,25-dihydroxyvitamin D3 concentrations.

It has recently been shown that in the rat, dihydrotachysterol (DHT) is extensively metabolized in the side-chain in vivo along pathways similar to those of vitamin D. In addition 25-hydroxy-DHT2 [25OHDHT2] is hydroxylated at C1, producing both 1 alpha- and 1 beta- hydroxy compounds. An in vivo study in 1988 demonstrated that in normal adult subjects receiving oral DHT2, plasma 1 alpha,25-dihydroxyvitamin D [1,25-(OH)2D] concentrations fell, but with unchanged plasma PTH levels. Down-regulation of 1,25-(OH)2D3 production by 25-(OH)DHT2 or some other unknown metabolite was also suggested as an explanation for these observations. To investigate whether either of the newly characterized 1 alpha,25- or 1 beta,25-(OH)2DHT2 was formed in vivo in normal man, DHT2 (approximately 1 mg/day, orally) was administered to healthy volunteers (three males and one female). Plasma was analyzed by high performance liquid chromatography and gas chromatography-mass spectrometry, demonstrating the formation of both 1 alpha,25- and 1 beta,25-(OH)2DHT2 in vivo in normal human subjects. Plasma levels of 1,25-(OH)2D3, PTH, ionized and total calcium, inorganic phosphate, and alkaline phosphatase were monitored. The plasma concentrations of DHT2, 25OHDHT2, and 1 alpha,25- and 1 beta,25-(OH)2DHT2 were measured by gas chromatography-mass spectrometry. In all volunteers, plasma ionized calcium increased slightly during DHT2 administration; 1,25-(OH)2D3 and PTH concentrations fell. Plasma levels of DHT2 and its metabolites rose over the same period. The average fall in the level of plasma 1,25-(OH)2D (60-70 pmol/L) was mirrored by a rise in the concentration of 1 alpha,25-(OH)2DHT2 (550 pmol/L). This ratio is appropriate, because it has previously been shown that in a reconstituted COS cell, 1 alpha,25-(OH)2DHT3 has roughly one tenth the potency of 1,25-(OH)2D3. At maximum concentration, the ratios of DHT2/25OHDHT2/1 beta,25-(OH)2DHT2/1 alpha,25-(OH)2DHT2 were approximately 10:1:2:0.1. The concentration of 1 beta,25-(OH)2DHT2 was greater than that of 25OHDHT2, and the ratio of 1 alpha,25- to 1 beta,25-(OH)2DHT2 (1:20) was substantially lower than that in rat plasma (3:10). The data presented here suggest that the active DHT2 metabolite in man is 1 alpha,25-(OH)2DHT2 and that the fall in plasma 1,25-(OH)2D seen during DHT therapy may be partly the result of suppressed PTH secretion.

Administration, Oral↗
PubMed1994

Increased erythropoietin requirements in patients with failed renal transplants returning to a dialysis programme.

The response to erythropoietin (Epo) is dose dependent but, for various poorly understood reasons, variable. In a cross-sectional study we determined the Epo requirement of 60 patients in a dialysis population to identify those patients requiring a high dose of Epo, and ascertained the reasons for higher requirements, paying particular attention to the effect of previous transplantation. All 289 patients attending a single centre were surveyed. Of these, 164 were receiving renal replacement therapy by continuous ambulatory peritoneal dialysis (CAPD) and 125 were on haemodialysis (HD). Patients on HD needed more Epo than those on CAPD (129.0 +/- 14.9 U/kg/week versus 86.9 +/- 10.7 U/kg/week, P < 0.05). However, this difference was accounted for by a subgroup of patients who had a previously failed transplant. The Epo requirement in those patients on HD with a failed transplant was significantly greater than those on HD who had never been transplanted (164.0 +/- 24.5 U/kg/week versus 96.6 +/- 11.9 U/kg/week, P < 0.05). The seven patients who retain their transplanted kidney had the highest Epo requirement of all (213.4 +/- 46.6 U/kg/week). These studies have shown that previous transplantation is a significant determinant of Epo requirement upon return to dialysis. They also show that it is necessary to 'correct' for the effect of previous transplantation when investigating generally accepted determinants of Epo need. Interpretation of previously published studies needs to take account of this.

Anemia↗
PubMed1994

p53 gene mutations in breast cancers in midwestern US women: null as well as missense-type mutations are associated with poor prognosis.

We determined the pattern of mutations in exons 2-11 and adjacent intronic regions in breast cancers from Midwestern US white women. Twenty-one mutations were detected in 53 tumors (39.6%). Comparisons of the pattern of mutations within exons 5-9 showed that the frequency of missense mutations (44%) was lower in breast cancers of US Midwestern women than in most tumor types including breast cancers in other populations. Compared to breast cancers reported in a Scottish population, US women had a high frequency of G:C-->T:A transversions (P = 0.046). These findings suggest that environmental or endogenous factors contribute to p53 mutagenesis in mammary tissue to different extents among different populations. With a median follow-up of 19 months, the presence of a mutation was associated with shorter time to disease recurrence (P = 0.05) and shorter survival (P = 0.003). Putative dominant negative missense-type mutations (missense and in-frame microdeletions; P = 0.001) and null mutations (hemizygous nonsense and frameshift mutations; P = 0.007) were equally ominous. Thus, tumors with missense p53 mutations resulting in over-expression of a dysfunctional but otherwise intact protein have a clinical outcome similar to tumors with null mutations resulting in a truncated or garbled protein.

Adult↗
PubMed1993

Parathyroid sensing of the direction of change of calcium in uremia.

It could be advantageous for the parathyroids to be able to sense not only the absolute concentration of extracellular Ca2+, but also the rate and direction of change of Ca2+, thereby allowing the parathyroids to respond earlier to threats to Ca2+ homeostasis. By using high and low Ca2+ dialysis in a single session, we examined the parathyroid response to direction of change of Ca2+ during acute Ca2+ perturbation in nine hemodialysis patients. Separate PTH/ionized calcium (PTH/iCa) response curves were generated for rising Ca2+ and falling Ca2+. Significant directional hysteresis (higher PTH level during falling than during rising Ca2+) was found. During hypercalcemia, PTH levels were between 2.2 and 1.6 times higher at iCa concentrations of between 0 and +0.1 mM above the baseline iCa, when Ca2+ was falling than when it was rising. During the phase of induced hypocalcemia, parathyroid fatigue was seen in six of the nine patients. Fatigue patients tended to have higher basal PTH (1-84) levels than those not showing fatigue. The existence of fatigue provides an explanation for directional hysteresis during hypocalcemia, and therefore parathyroid sensing of the direction of change of Ca2+ could not be assessed during hypocalcemia. These studies demonstrate a capacity of the parathyroids to sense the direction of movement of Ca2+ during hypercalcemia.

Adult↗