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Biomedical subjects

A J Watson

Publications and source records attributed to A J Watson.

At least 199 records · Page 11Linked to original sources
PubMed1988

A protective effect of sulindac against chemically-induced primary colonic tumours in mice.

Sulindac, a non-steroidal anti-inflammatory drug, has been reported to lead to tumour regression in cases of human polyposis coli. We have investigated the effects of this drug on the growth of 1,2-dimethylhydrazine (DMH)-induced mouse colonic tumours. In one experiment, DMH and oral sulindac were administered concurrently to a group of mice for a period of up to 24 weeks, while a control group of animals received DMH only for the same period. Sulindac caused a significant reduction in both the number of mice with colonic tumours and the number of tumours per mouse. In a second experiment, two groups of mice which had already been treated with DMH for 17 weeks received either sulindac or not for 78 days. In this experiment sulindac had no effect. These results demonstrate that sulindac has a protective effect against the chemical induction of colonic tumours in mice, but does not cause the regression of established tumours.

1,2-Dimethylhydrazine↗
PubMed1988

Immunofluorescence assessment of the timing of appearance and cellular distribution of Na/K-ATPase during mouse embryogenesis.

We have employed immunofluorescence with a rat kidney Na+/K+-ATPase polyclonal antibody to investigate the cellular distribution and timing of appearance of this enzyme during preimplantation development. The enzyme is first detected in the late morula within the cytoplasm of each blastomere. When cavitation begins this distribution changes dramatically to a ring encircling the blastocoel, restricted to the basolateral cell margins. Using this enzyme as a marker for cavitation, we examined its expression in embryos that had been treated with wheat germ agglutinin (WGA), which causes cleavage arrest and was reported to trigger premature compaction- and cavitation-like events in early cleavage stages (L. V. Johnson, 1986, Dev. Biol. 113, 1-9). Although WGA-treated 2-,4-, and 8-cell embryos quickly underwent compaction- and cavitation-like events, no Na+/K+-ATPase expression was observed. Thus the WGA effect does not likely involve acceleration of the developmental program for cavitation. Embryos arrested at the 8-cell stage but cultured overnight to Day 4, however, expressed the enzyme in the typical blastocyst pattern (around each fluid-filled cavity). We conclude that Na+/K+-ATPase expression is initiated or increases dramatically in the late morula and is independent of cytokinesis. The enzyme assumes a distribution during cavitation consistent with its presumed role in transtrophectodermal fluid transport.

Animals↗
PubMed1988

Water, electrolyte, glucose, and glycine absorption in rat small intestinal transplants.

Water, electrolyte, glucose, and glycine absorption were studied in vivo in successful rat small intestinal transplants. Isolated bowel loops were transplanted from F1 hybrids into parental strain Lewis rats. A 7-day course of cyclosporin A was given for immunosuppression. Absorption was studied using a steady-state perfusion technique at either 9 or 21 days after transplantation. Histologic examination showed there was villus shortening with time but no evidence of rejection. When perfused with isotonic saline, both allografts and controls secreted water. However, allografts and denervated controls secreted chloride, whereas innervated controls absorbed chloride (p less than 0.05). There was a marked reduction in water and sodium absorption from 30 mM glucose-saline in transplanted loops and denervated controls, whereas glucose absorption was relatively preserved in these groups at 9 days (p less than 0.01). These changes could not be accounted for by rejection or ischemia. These studies demonstrate that denervation may be a major limiting factor in intestinal transplantation.

Animals↗
PubMed1988

Syndrome of idiopathic hyperammonemia after high-dose chemotherapy: review of nine cases.

PURPOSE: The syndrome of idiopathic hyperammonemia occurs in patients who have received high-dose cytoreductive therapy for the treatment of hematologic malignancy. It is characterized by abrupt alteration in mental status and respiratory alkalosis associated with markedly elevated plasma ammonium levels in the absence of any identifiable cause, and frequently results in intractable coma and death. Our goal was to survey clinical and pathologic manifestations of the disorder and discuss treatment options. PATIENTS AND METHODS: Plasma ammonium levels were measured in patients on the acute leukemia service or on the bone marrow transplant service at The Johns Hopkins Hospital, and a level more than twice normal was considered diagnostic of hyperammonemia. The syndrome was identified in nine patients; in eight, hyperammonemia occurred after administration of intensive cytoreductive therapy that resulted in profound leukopenia. The disorder occurred in the ninth patient two months after allogeneic bone marrow transplantation. RESULTS: Three of the nine patients survived an episode of idiopathic hyperammonemia; one patient subsequently died of leukemia and one of recurrent idiopathic hyperammonemia. The one long-term survivor is currently alive and well without neurologic sequelae 250 days after autologous bone marrow transplantation. CONCLUSION: Because neurologic function can deteriorate rapidly, early recognition of this disorder and close monitoring of the patient's neurologic status are critical.

Adolescent↗
PubMed1988

Verapamil sensitizes normal and neoplastic rodent intestinal tissues to the stathmokinetic effect of vincristine in vivo.

A morphological method has been developed allowing measurement of the effect on intestinal epithelia of vincristine. In routinely prepared tissue sections the proportion of mitotic events progressing beyond metaphase is counted by microscopy. When estimated over a range of doses of vincristine this post-metaphase index (PMI) can be used to compare the sensitivity of differing intact tissues. Intestinal tumours were induced in rats by chemical carcinogenesis. Administration of vincristine in the presence or absence of verapamil was performed in these tumour-bearing animals. Sections were prepared from colonic and small-bowel tumours and from normal mucosa. The results show that verapamil increases the sensitivity of the tissues studied to vincristine. A dose dependent effect of verapamil on vincristine sensitisation was demonstrated in colonic tissues. These findings indicate a shared pharmacological property between the resistance of primary tumour tissue and the multidrug-resistance phenotype.

Animals↗
PubMed1988

DNA transfection of a gene repressing aryl hydrocarbon hydroxylase induction.

High mol. wt genomic DNA from a genetically dominant aryl hydrocarbon hydroxylase (AHH)-deficient mutant cell line derived from the mouse hepatoma cell line Hepa-1 was used to transfect the parent cell line. AHH-deficient transfectants were recovered following single-step selection in medium containing the carcinogen benzo[a]pyrene. The transfectants arose at a frequency of 2 x 10(-7). This frequency was at least 4-fold greater than the frequency of spontaneous forward mutation in this cell line. In another set of experiments, dominant mutant DNA was co-transfected along with the selectable plasmid pSV2ecogpt into parental Hepa-1 cells. The frequency of co-transfection was determined to be 3 x 10(-8). This frequency was approximately 150 times greater than that expected on the basis of coincident but unrelated spontaneous mutation and plasmid uptake. Both types of transfectants were judged, following somatic cell hybridizations, to possess the dominant phenotype of the mutant cell line, demonstrating that a trans-acting dominant negative regulator of AHH was transferred in these experiments. DNA transfection should therefore provide a means for the molecular cloning of the gene that encodes the dominant regulator.

Animals↗
PubMed1988

Effect of bicarbonate on efficacy of oral rehydration therapy: studies in an experimental model of secretory diarrhoea.

In situ perfusion of rat intestine was used to evaluate the effect of bicarbonate on the efficacy of a low sodium (35 mmol/l) glucose-electrolyte oral rehydration solution in normal and cholera toxin-treated rat small intestine. In normal intestine, absorption of water was greater (108 (8.1) microliters/min/g; p less than 0.01) and sodium secretion less (-4.3 (0.3) mumol/min/g; p less than 0.01) from the oral rehydration solution containing bicarbonate than from the solution in which bicarbonate was replaced by chloride ions (59.5 (7.2) microliters/min/g and -7.8 (0.8) mumol/min/g, respectively). Glucose absorption in normal intestine was similar with both solutions. In the secreting intestine, both oral rehydration solutions reversed net water secretion to absorption, but inclusion of bicarbonate resulted in significantly less net absorption of both water (2.18 (6.9) microliters/min/g; p less than 0.05) and glucose (18.7 (2.1) mumol/min/g; p less than 0.001) compared with bicarbonate free oral rehydration solution (19.4 (3.9) microliters/min/g and 35.8 (3.7) mumol/min/g, respectively). Net sodium secretion occurred in normal and secreting intestine but was significantly less with the bicarbonate containing oral rehydration solution. These findings suggest that the demonstrable advantage of bicarbonate in promoting water absorption from this oral rehydration solution in normal rat intestine does not apply to cholera toxin treated secreting intestine.

Animals↗
PubMed1988

Hypertension and renal dysfunction in bone marrow transplant recipients.

The incidence of acute renal failure, hypertension and electrolyte disorders in 64 bone marrow transplant recipients randomized to receive either cyclosporin or cyclophosphamide was investigated. Sixty-four per cent of patients developed acute renal failure, 75 per cent hypertension, and 88 per cent significant hypomagnesemia. The incidence of diastolic hypertension and hypomagnesemia was greater in the patents treated with cyclosporin. Hypomagnesemia was due to magnesium wasting by the kidney. Both groups received similar cumulative doses of aminoglycoside antibiotics. Significant proteinuria developed in all but one patient and nephrotic-range proteinuria was noted in 21 per cent. The cause of the proteinuria is unclear; no obvious morphologic changes were seen at autopsy in patients who exhibited nephrotic-range proteinuria. The abnormalities of renal function were shown to be transient in patients who were observed for periods ranging from one to three years. It is concluded that hypertension, renal failure and hypomagnesemia are common in the setting of bone marrow transplantation. Whereas cyclosporin probably aggravates the severity of these disorders, it is likely that other factors (e.g., aminoglycoside antibiotics) play a major role as shown by the high incidence of renal and electrolyte disorders in patients treated with cyclophosphamide alone.

Acute Kidney Injury↗
PubMed1987

The novel therapeutic implications of azlocillin's dose-dependent pharmacokinetics: contributing physiologic mechanisms and a prospective, cross-over designed trial.

Azlocillin is an important acylureido penicillin antibiotic for the management of complex gram-negative infections particularly those caused by Pseudomonas species. The current studies demonstrate that it manifests dose-dependent pharmacokinetics during the usual regimens of clinical dosing, that enterohepatic recirculation does not occur and that renal tubular secretion (maximum renal tubular secretory capacity 300 +/- 30 micrograms/min) and hepatic metabolism appear to be the dominant contributors to the dose-dependent nature of azlocillin. The possible therapeutic implications of azlocillin's dose dependency were evaluated by undertaking a six-day randomized, prospective, cross-over design study to evaluate the pharmacokinetic disposition of the drug during a 3-g q4h (typically used in adults) regimen versus a 5-g q8h regimen. By using the area under the serum-time concentration curve (AUC) as the major comparative parameter for these two regimens, the results demonstrate that both regimens provide approximately equal quantitative amounts of the drug systemically as a result of azlocillin's dose dependency. The AUC values, although not therapeutic end points, nonetheless correlate well with clinical response to antibiotic therapy. The 5-g q8h regimen was well tolerated. It is less disruptive for patients, requires half the number of intravenous administrations, 17% less drug, and is more cost effective than the 3-g q4h regimen.

Adult↗
PubMed1987

Calcium channel blockade in experimental aminoglycoside nephrotoxicity.

Calcium channel blocker therapy has proved protective in certain models of ischemic-induced acute renal failure. This effect may be related to the prevention of calcium influx into injured cells or by the vasodilatory effects of verapamil that may result in an improvement in renal blood flow. In the current study, the effect of verapamil treatment on the development of renal insufficiency and renal tissue calcium accumulation following aminoglycoside administration was investigated. The degree of functional damage and cortical tissue calcium accumulation after six or nine days of gentamicin administration (120 mg/kg body weight/day) was not significantly different in rats whose drinking water contained verapamil (10 mg/100 cc) than corresponding values in control animals. The tissue calcium accumulation correlated with the degree of reduction of creatinine clearance and probably reflects the extent of lethal tubular cell injury.

Animals↗
PubMed1987

A trophic effect of epidermal growth factor (EGF) on rat colonic mucosa in organ culture.

The development of an organ-culture system for rat colonic mucosa has enabled a direct assessment of the effect of epidermal growth factor (EGF) on cell division. An augmented mitotic index (AIm) has been employed to identify changes in cell proliferation. Explants of colonic mucosa from four animals were maintained in a medium containing serum for five days. On the fifth day of culture, half of the explants received fresh medium containing EGF (40 ng/ml) and the remainder (controls) fresh medium only. At 6, 12, 24 and 48 hr thereafter groups of both experimental and control explants received the metaphase-arresting drug vincristine (4 micrograms/ml) for 3 hr prior to fixation. The proportions of vincristine-arrested metaphases within the explants were determined. Analysis of the data indicates that when serum is present exogenous EGF exerts a trophic effect which increases with time (P less than 0.001). In a second experiment colonic explants from four animals were maintained for five days in a serum-free medium and were then divided into groups, each of which received one of a range of concentrations of EGF. The AIm was determined for each group after 36 hr. It was found that increasing concentrations of EGF produce a small but significant increase in cell proliferation (P less than 0.01). This effect, however, was less pronounced than that seen when serum was present. These results suggest that EGF has a trophic action on the colon and interacts with additional factors found in serum.

Animals↗
PubMed1987

Hepatic metastasis from intracranial meningioma.

A 38 year old man presented with a hepatic mass which biopsy showed to be a metastasis from an intracranial meningioma. The meningioma originally followed cranial radiotherapy. Previous reports of extracranial metastases are reviewed.

Adult↗
PubMed1987

Calcium channel blockade in dialysis patients with left ventricular hypertrophy and well-preserved systolic function.

Echocardiographic evidence of left ventricular hypertrophy with well-preserved systolic function was established in 4 chronic hemodialysis patients with a history of refractory pulmonary congestion. In each patient a trial of treatment with verapamil (40 mg t.i.d.) resulted in symptomatic improvement, an increase in nadir intradialysis blood pressure, and a marked reduction in intradialytic symptomatic hypertensive episodes and the need for intravenous saline administration. These data suggest that (a) a subset of chronic hemodialysis patients with refractory congestive heart failure and dialysis-related hypotension have hypertrophic cardiomyopathy with well-preserved systolic function, and (b) such patients may derive greater benefit from verapamil treatment than from the more conventional approach to drug therapy with digoxin and nitrates.

Aged↗
PubMed1987

Parathyroidectomy increases peripheral vascular responsiveness to exogenous noradrenaline in the uraemic rat.

The effect of surgical parathyroidectomy and/or cyclo-oxygenase inhibition on noradrenaline-induced blood pressure (BP) responses were investigated in a rat model of chronic uraemia. The blood pressure responses to noradrenaline were significantly lower in uraemic rats when compared with the responses of non-uraemic animals. Blood pressure responses of previously parathyroidectomized uraemic rats were significantly greater than sham-operated uraemic rats, as were the responses of uraemic rats pretreated with the cyclo-oxygenase inhibitor, indomethacin. Pretreatment of uraemic rats with both indomethacin and parathyroidectomy improved blood pressure responses to a degree equal to either manoeuvre alone, but did not exhibit an additive effect. These data suggest a role for parathyroid hormone and prostaglandins in the pathogenesis of the diminished noradrenaline responsiveness in uraemia, and suggest a common mechanism.

Animals↗