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Biomedical subjects

M J Field

Publications and source records attributed to M J Field.

At least 109 records · Page 6Linked to original sources
PubMed1991

Evidence for an involvement of the brain cholecystokinin B receptor in anxiety.

The effect of neuropeptide cholecystokinin (CCK) receptor agonists and antagonists was examined in the rat elevated X-maze model of anxiety. The selective CCK-B receptor antagonists CI-988 (PD 134308) and L-365,260 produced anxiolytic-like effects, whereas MK-329, a CCK-A receptor antagonist, was respectively less potent by factors of 313 and 200. The intracerebroventricular administration of the nonselective CCK receptor agonist caerulein or the selective CCK-B receptor agonist pentagastrin increased dose dependently the level of anxiety. CI-988 dose dependently antagonized the anxiogenic response to pentagastrin but not that induced by pentylenetetrazol. These results strongly suggest that activation of the brain CCK-B receptor induces anxiety and that selective antagonists of this receptor represent a separate class of anxiolytic agents.

Animals↗
PubMed1991

Proximal tubular cell sodium concentration in early diabetic nephropathy assessed by electron microprobe analysis.

Electron microprobe X-ray analysis techniques were employed in order to assess the changes that occur in proximal tubular cell sodium concentration during the hyperfiltration phase of early diabetes mellitus induced by streptozotocin in Sprague Dawley rats. Intracellular rubidium accumulation following intravenous infusion of rubidium chloride was used as a marker of basolateral Na/K-ATPase activity. The diabetic animals studied had a significantly higher glomerular filtration rate compared with controls [1.44 +/- 0.07 vs. 1.00 +/- 0.07 ml min-1 (100 g body weight)-1; mean +/- SEM, P less than 0.001]. Intracellular Na concentration was significantly higher in diabetic animals (19.5 +/- 0.6 vs. 17.8 +/- 0.4 mmol/kg wet weight; P less than 0.01). Concurrent measurement of Rb demonstrated significantly higher intracellular accumulation in the proximal tubules of diabetic animals compared with control (7.9 +/- 0.5 vs. 5.5 +/- 0.5 mmol/kg wet weight; P less than 0.001). These results indicate that proximal tubular Na/K-ATPase activity is enhanced in the hyperfiltration phase of diabetes mellitus. Since, however, intracellular Na concentration is increased under these conditions, it may be inferred that apical Na entry into proximal tubular cells is stimulated beyond the rate of basal exit during the initial development of hyperfiltration. The reasons for these alterations in cellular Na transport are unclear but similar changes have been implicated in the pathogenesis of cell growth.

Animals↗
PubMed1991

Beneficial and detrimental effects of RBC-adsorbed antilymphocyte globulin and prednisone on purified canine islet autograft and allograft function.

We have examined the effects of prednisone, cyclosporine, azathioprine, and RBC-adsorbed goat antidog antilymphocyte globulin on islet graft function in totally pancreatectomized canines with purified, quantitatively defined, autologous, or allogeneic islets transplanted to the liver. The objectives were twofold: (1) to determine the potential detrimental effects to islet autograft function of the aforementioned agents, and (2) to determine the relative efficacy of the "nontoxic" agents in prolonging purified islet allograft function administered in doses that would be considered tolerable in human. The islet autograft studies demonstrated that prednisone given in doses of 1-2 mg/kg/day had a detrimental effect on islet autograft function, and that the combinations of immunosuppression involving CsA, azathioprine, and ALG were not detrimental to islet autograft function to the extent that hyperglycemia would ensue. In the subsequent allograft studies, three groups of canines received islet transplants: (1) controls (n = 5; 7860 +/- 750 islets/kg/weight), (2) canines given CsA and azathioprine (n = 6; 6810 +/- 890 islets/kg/body weight), and (3) canines given CsA, azathioprine, and RBC-adsorbed goat antidog ALG (n = 8; 6540 +/- 710 islets/kg/body weight). The mean (+/- SE) day of rejection (serum glucose greater than or equal to 200 mg/dl) in the group of canine islet allograft recipients receiving CsA, azathioprine, and ALG was 11.8 +/- 1.4 days--significantly prolonged versus islet allograft recipients receiving no immunosuppression (mean survival 4.8 +/- 1.1 days, P less than 0.03), and versus allograft recipients receiving CsA/azathioprine without ALG (mean survival 4.4 +/- 1.4 days, P less than 0.05). Prednisone appears to be detrimental to islet graft function, even at low doses. ALG was not toxic, and significantly extended the survival of canine islet allografts. The inclusion of steroids as part of maintenance immunosuppression, or as treatment for acute rejection of islets, in human islet transplants should be reconsidered, whereas ALG or other antilymphocyte agents should continue to be used.

Adsorption↗
PubMed1991

Total pancreatectomy in the pig for islet transplantation. Technical alternatives.

Pigs appear to be a suitable biological and logistical animal donor of islets for xenotransplantation in human diabetic type I recipients. To improve the islet isolation technique in this species, to evaluate the islet function in vivo, and to assess the toxic effects of various immunosuppressive regiments on transplanted islets will necessitate a model of the pancreatectomized pig suitable for islet autotransplantation. We describe three techniques of total pancreatectomy in pigs. The first removed the pancreas in order to study postoperative management and pig survival; no attempt was made to preserve the pancreas for islet isolation. The second consisted of a pancreatectomy in a surviving pig, with careful preservation of the whole pancreas for subsequent islet isolation. The third was rapid en bloc procurement of the pancreas and duodenum, to obtain a pancreas solely for the purpose of islet isolation. We conclude that pigs tolerate and survive a total pancreatectomy--they are suitable animals for islet isolation and possible autotransplantation. The result of islet isolation does not appear related to the pancreas procurement technique; however, the islet yield must be improved before autotransplantation can be functionally successful.

Animals↗
PubMed1991

Electron probe X-ray microanalysis of intracellular element concentrations in cryosections in the presence of changes in cell volume.

The interpretation of element concentration data for X-ray microanalyses of biological tissues, which are subjected to some experimental treatment, can be complicated by changes in cell volume and total cell dry matter induced by the treatment. We have examined the manner in which such changes would affect the values measured in frozen-dried cryosections of soft tissues, and how they may be taken into account in the interpretation of the results. The element content (mass per unit dry weight) measured by the peak-to-continuum or Hall method is independent of changes in cell volume, but is sensitive to a change in the local dry mass. Conversely, intracellular concentrations in terms of mass per unit volume, as determined by the peripheral or internal standard technique, are dependent on volume changes but independent of dry mass. The estimated dry weight fraction is affected by changes in both volume and dry mass. The results obtained from both quantification methods can therefore provide information on the combination of changes in cellular element levels, volume and total dry mass that may occur following the experimental treatment. In a study of the late effect of the drug cisplatin on electrolyte concentrations in kidney proximal tubules, both quantification methods have been used to obtain wet weight and dry weight concentrations. By applying the above considerations, the analytical results have been interpreted as a combination of changes in element levels and a shrinkage of the tubule cells. Cell shrinkage was confirmed by morphometric analysis of tubular cross-sections.

Animals↗
PubMed1991

Renal sodium excretion following systemic infusion of vasoactive intestinal peptide in the rat.

1. The aim of this clearance study was to examine the renal effects of systemic infusion of vasoactive intestinal peptide (VIP) in the intact rat. 2. Mean arterial blood pressure (MAP), plasma electrolytes and haematocrit, glomerular filtration rate (GFR), and urinary sodium and potassium excretion were measured in a baseline period and following VIP infusion (0.1-1.2 nmol/h per 200 g), as well as during a time control study. 3. During infusion of low doses of VIP (0.1 and 0.4 nmol/h per 200 g), a small increase in fractional and absolute excretion of sodium occurred but this did not differ from that occurring in the time control group. In the high dose VIP group (1.2 nmol/h per 200 g), significant falls occurred in MAP and GFR, and absolute sodium excretion fell (though not significantly) from its baseline level. 4. These findings suggest that systemic VIP has no net natriuretic effect in the rat, but produces haemodynamic changes associated with reduced sodium excretion at high doses. This study does not exclude the possibility of direct effects on tubular sodium transport of VIP released from renal nerves.

Animals↗
PubMed1991

The behavioural properties of CI-988, a selective cholecystokininB receptor antagonist.

1. The behavioural effects of a selective cholecystokininB (CCKB) receptor antagonist CI-988 were investigated in rodents. 2. In three rodent tests of anxiety (rat elevated X-maze, rat social interaction test and mouse light/dark box) CI-988 over the dose range 0.001-10.0 mg kg-1, (i.p.) produced an anxiolytic-like action. The magnitude of this effect was similar to that of chlordiazepoxide (CDP). In contrast, the selective CCKA receptor antagonist, devazepide, was inactive. CI-988 also showed anxiolytic-like action in the rat conflict test but the magnitude of this effect was about 2.5 fold less than that of CDP. 3. Central but not peripheral administration of the selective CCKB receptor agonist, pentagastrin, like FG 7142, produced an anxiogenic-like action. 4. The pentagastrin-induced anxiety was dose-dependently antagonized by CI-988, whereas devazepide was inactive. However, ten times higher doses of CI-988 were required to block a similar action of FG 7142. 5. In contrast to CDP, CI-988 up to 3000 fold higher doses than those inducing anxiolysis was inactive in tests measuring sedation and ataxia. It also failed to antagonize pentylenetetrazol-induced tonic seizures. Furthermore, CI-988 did not interact with alcohol or barbiturates. Thus, CI-988 appears to be an anxioselective compound. 6. The anxiolytic-like action of CDP in the rat elevated X-maze was dose-dependently antagonized by flumazenil. In contrast, the benzodiazepine receptor antagonist failed to block a similar effect of CI-988. 7. Thus, CI-988 shows anxiolytic-like activity in several animal models of anxiety. The anxiolytic-like effect of CI-988 involves a novel mechanism of action, that is likely to be mediated by selective antagonism of the brain CCKB receptor. It is suggested that CI-988 should have a better side-effect profile in man than the benzodiazepines.

Animals↗
PubMed1991

Tubular sodium handling and tubuloglomerular feedback in experimental diabetes mellitus.

Tubular Na handling and tubuloglomerular feedback (TGF) activity were assessed using micropuncture techniques during the hyperfiltration phase of streptozotocin-induced diabetes mellitus in Sprague-Dawley rats. Three animal groups were studied, designated as having severe diabetes [blood sugar level (BSL) 18-25 mmol/l], moderate diabetes (BSL 13-18 mmol/l) and control (BSL less than 10 mmol/l). Single-nephron glomerular filtration rate (SNGFR) measured at both late proximal (LP) and early distal (ED) sites was elevated in severe diabetes compared with both other groups. TGF activity, determined as the difference between LP and ED measurements of SNGFR, was significantly increased in severe diabetes (46.4 +/- 6.6 vs. 30.1 +/- 6.5 vs. 14.8 +/- 1.9 nl/min). Tubular Na transport was higher in severe diabetes compared with control, as demonstrated by a decrease in fractional delivery of Na to the LP (42.9 +/- 3.0 vs. 52.9 +/- 1.9%), as well as to the ED site (4.5 +/- 0.4 vs. 12.3 +/- 0.9%). Administration of phlorizin to severely diabetic animals resulted in a BSL comparable to that observed in moderate diabetes, and whole animal GFR, as well as SNGFR, TGF activity, and tubular Na handling were also similar to those found in moderate diabetes. Studies performed during mannitol infusion demonstrated that osmotic diuresis alone was not associated with the changes in TGF and tubular Na handling observed in the diabetic state. These data suggest that the hyperfiltration occurring in early diabetes is associated with enhanced proximal and loop resorption of Na independent of Na-glucose cotransport and osmotic diuresis. Activation of TGF serves to limit the rise in GFR, which results from factors as yet unrecognized in the diabetic state.

Animals↗
PubMed1991

Autotransplantation of dispersed pancreatic islet tissue combined with total or near-total pancreatectomy for treatment of chronic pancreatitis.

Chronic pancreatitis is difficult to treat in patients with a nondilated duct. Patients experiencing intractable pain unresponsive to or judged untreatable by lesser procedures must decide between total pancreatectomy and resultant diabetes or a continuation of their pancreatitis. From 1977 through 1990, 26 patients underwent extensive pancreatectomy and dispersed pancreatic islet tissue autotransplantation for treatment of chronic pancreatitis pain and prophylaxis of surgical diabetes. Of these 26 patients, total (Whipple) or near-total (greater than 95%) pancreatectomy was performed in 24 patients. Of these 24 patients, pain relief could be assessed in 21 patients at 5 to 155 months (mean, 5.7 years), and 19 patients (90%) reported partial or complete remission. Of the patients who underwent total or near-total pancreatectomy, islets were injected intraportally in 22 patients and into the renal subcapsule in two patients. The latter two patients have required insulin since surgery. Of the other 22, one patient died from a complication of the pancreatectomy. Nine of the 21 evaluable recipients of intraportal islet autografts were insulin independent for at least several months after surgery. Five patients are currently insulin independent at 6 years, 4 years, 1.5 years, 9 months, and 5 months after surgery. Of the other four patients, one patient died insulin independent at 6 years, and three patients required insulin beginning 8 to 18 months after surgery. Insulin independence correlated with the number of islets recovered, which in turn correlated inversely with the degree of pancreatic fibrosis. Of our four most recent patients, three patients had mildly to moderately fibrotic glands, and higher numbers of islets were obtained. After total (Whipple) pancreatectomy, these three patients are insulin independent. A liver biopsy was performed in one patient 8 months after total pancreatectomy and islet autotransplantation; numerous clusters of islet cells staining strongly for insulin and glucagon were detected within portal triads on both wedge and needle biopsy specimens. Morbidity related to the intraportal-dispersed pancreatic islet tissue transplantation was low (no disseminated intravascular coagulation, significant portal hypertension, or hepatic dysfunction). Islet autotransplantation can be an effective and safe adjunct to extensive pancreatic resection for those patients who risk surgical diabetes for relief of their chronic pancreatitis pain.

Abdominal Pain↗
PubMed1990

Metolazone in treatment of severe refractory congestive cardiac failure.

17 patients with New York Heart Association (NYHA) class IV congestive cardiac failure, refractory to conventional treatment, were additionally treated with oral metolazone (1.25-10 mg daily). 12 improved sufficiently to be discharged from hospital (NYHA class II or III, mean weight loss 8.3 kg), 1 of whom died at home 4 weeks later. The other 5 patients were treated with intravenous dobutamine for 72 h; 2 responded (average weight loss 4.4 kg), and 2 responded to subsequent reintroduction of metolazone. 4 of these 5 patients died, 2 in hospital of acute myocardial infarction. Overall, 15 patients with very severe refractory cardiac failure improved sufficiently to be discharged from hospital. Treatment was associated with mild transient hypokalaemia in 7 patients, and hyponatraemia and renal impairment in 1, for whom metolazone dosage had to be reduced. Failure to respond to the introduction of metolazone may indicate an especially poor prognosis.

Aged↗
PubMed1990

Calibration of polyacrylamide gel columns for the separation of oligonucleotides by capillary electrophoresis.

Polyacrylamide-filled gel columns are used to separate oligonucleotide samples. For homopolymeric standard samples, plots of migration time versus molecular size are presented over a range of 30-160 bases. With 2.5-4% T and 3.3% C gels, good resolution over the examined mass range, with peak width at half height of 3 to 6 s, is obtained by applying electrical fields of 200-400 V/cm. The separation of heteropolymeric nucleotides by slab gel electrophoresis under routine conditions was compared with capillary gel electrophoresis. Using the same column and the same separation conditions, the plot of migration time versus base number is linear with an identical slope for three oligonucleotide samples which were examined, allowing a calibration of a gel-filled capillary for molecular mass determination.

Base Sequence↗
PubMed1990

Morphological and physiological responses to aldosterone: time course and sodium dependence.

The time course and Na+ dependence of morphological responses to a physiological elevation of aldosterone were examined in the renal cortical collecting duct. Male Sprague-Dawley rats were adrenalectomized and given a basal replacement infusion of aldosterone and dexamethasone by osmotic minipump. The animals were given additional aldosterone by either intravenous infusion or by a second implanted osmotic minipump for either 5 h or 1, 3, 7, or 14 days. Animals were fed either a Na(+)-replete or a low-Na+ diet. After these treatments we conducted a morphometric analysis on kidneys processed for electron microscopy by standard techniques. Increased aldosterone induced detectable proliferation of the basolateral membrane of principal cells after 24 h. Basolateral membrane continued to increase rapidly through 3 days of exposure and thereafter at a modest rate. Cell area and the surface density of the basolateral membrane were also increased by aldosterone treatment. The morphological response to aldosterone was markedly inhibited by maintaining animals on a low-Na+ diet. Acute exposure to elevated aldosterone levels (5 h) increased K+ secretion by principal cells without alterations in basolateral membrane area. Chronic (greater than 24 h) exposure to aldosterone induces morphological adaptations that are accompanied by further elevations in K+ secretion.

Aldosterone↗
PubMed1990

Canine pancreatic islet transplantation: a comparison of two isolation techniques.

A new method (type B) for isolation of canine islets was developed, utilizing intraductal collagenase perfusion, stationary digestion, filtration and tissue separation by means of a dextran density gradient. The results of this technique were compared with those of a previously established method (type A). Islets were autotransplanted either via the splenic or the portal vein. Lasting normoglycemia was obtained in 5/8 intrasplenic type B transplants (63%), 6/8 intrahepatic type B transplants (75%), 5/6 intrasplenic type A transplants (83%) and 0/3 intrahepatic type A transplants. No difference was found in metabolic parameters 2 weeks after successful transplantation following type A or B islet isolation. Islet yield was higher with type A and purification better with type B isolation. Both techniques are relatively simple and inexpensive. Because of its higher purification rate and the success of intrahepatic islet transplantation method B has replaced method A as the routine procedure in our laboratory.

Animals↗