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Biomedical subjects

R G Clark

Publications and source records attributed to R G Clark.

At least 91 records · Page 5Linked to original sources
PubMed1988

Growth hormone-deficient dwarfism in the rat: a new mutation.

Mutations in animals have provided insight into many aspects of normal and pathological human physiology. This paper reports the discovery and initial characterization of a new mutant dwarf rat. The mutation, inherited as an autosomal recessive, arose spontaneously in a breeding colony of Lewis rats at the Medical Research Council Cellular Immunology Unit, Sir William Dunn School of Pathology, Oxford, U.K., in 1985 and the strain has now been established both in Oxford and at Mill Hill. Body growth in the mutant is retarded such that at 3 months of age both males and females weigh approximately 40% less than their normal litter-mates, and continue to grow at a slower rate. The mutants show a selective reduction in pituitary GH synthesis and storage (pituitary GH concentrations were approximately 10% of normal in males and 6% in females). The concentration of their anterior pituitary trophic hormones (LH, TSH, prolactin and ACTH) were within the normal range in dwarf animals. Exogenous GH treatment for 5 days resulted in an increase in growth rate from 1.5 +/- 0.3 to 3.9 +/- 0.4 g/day in male mutants, and 0.8 +/- 0.2 to 3.1 +/- 0.1 g/day in females. Longitudinal bone growth rates were more than doubled by this treatment from 49 +/- 5 to 100 +/- 10 micron/day in females and from 52 +/- 11 to 131 +/- 16 micron/day in males. Dot blot and Northern blot analysis of pituitary mRNA extracts revealed that the GH message in mutants was between 20 and 25% of normal, and that the GH transcript was of normal size.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Growth hormone (GH) secretion in the conscious rat: negative feedback of GH on its own release.

The negative-feedback effects of GH on its own secretion were studied in conscious male and female rats bearing indwelling double-bore venous cannulae. Intravenous infusions of human GH (hGH; 20-60 micrograms/h) or somatostatin (SS; 10 micrograms/h) were given while frequent serial microsamples of blood were withdrawn using an automatic blood-sampling system. In both sexes, i.v. infusions of hGH for 6 h inhibited endogenous GH secretory pulses, with a slow onset of the inhibition. There was no rebound GH secretion immediately following the removal of the hGH infusion, but spontaneous GH secretion gradually returned to normal. Infusions of hGH did not inhibit the pituitary GH response to repeated GH-releasing factor (GRF) injections (1 microgram) given i.v. every 40 min to female rats. By contrast, infusions of SS, which also blocked spontaneous GH release, dramatically reduced the GH responses to serial GRF injections. When SS Infusions were stopped, the subsequent GRF-induced GH secretory responses were enhanced. These results show that GH can inhibit its own release when given by i.v. infusion to conscious male and female rats. Since GH responses to GRF are maintained during a GH infusion, the feedback effect of GH is unlikely to be exerted directly on the pituitary or by increasing SS release. Our results are consistent with the idea that GH feedback in the conscious rat involves an inhibition of GRF release.

Animals↗
PubMed1988

The rebound release of growth hormone (GH) following somatostatin infusion in rats involves hypothalamic GH-releasing factor release.

We have studied the rebound secretion of GH following short-term somatostatin (SS) infusions in conscious rats, using an automatic sampling system for withdrawing frequent microsamples of blood. Intravenous infusions of SS (5-50 micrograms/h per rat) inhibited spontaneous GH secretion, but when SS was withdrawn there was a large burst of rebound GH secretion. A sub-anaesthetic dose of urethane reduced such rebound bursts of GH, suggesting a hypothalamic involvement in rebound GH secretion. Passive immunization with an antibody against rat GH-releasing factor (GRF) attenuated the rebound GH secretory response to the withdrawal of an SS infusion (GH concentration during rebound secretion was 26 +/- 21 micrograms/l vs 475 +/- 127 micrograms/l (mean +/- S.E.M.), after 0.5 ml anti-GRF serum or non-immune serum respectively). The inhibition of GH rebound secretion was related to the dose of anti-GRF serum administered. Intravenous infusions of human GH (20-100 micrograms/h per rat) also reduced the size of the rebound GH secretion following SS withdrawal, in both male and female rats. We suggest that the rebound GH secretion that follows SS withdrawal in vivo is caused mainly by a hypothalamic release of GRF. Exogenous GH inhibits SS-induced rebound GH secretion in the conscious rat, possibly by inhibiting hypothalamic GRF release.

Animals↗
PubMed1988

Growth promoting activity of IGF-I in the rat.

According to the original somatomedin hypothesis, GH promotes growth by generating 'somatomedins' or insulin-like growth factors (IGFs) in the liver. The advent of large amounts of IGF-I produced by recombinant DNA technology has now allowed testing of this hypothesis, by comparing the growth promoting activity of IGF-I and GH in three animal models of growth deficiency. When injected or infused subcutaneously, or infused intravenously, IGF-I is a weak growth promoter in the hypophysectomized rat compared with GH, even when infused in combination with small amounts of GH. Growth arrest in the diabetic rat was corrected by insulin infusion which also restored GH secretion. Insulin or IGF-I caused a large initial weight gain in diabetic rats, accompanied by a partial correction of food and water balance, even in the presence of persistent hyperglycaemia. A new mutant GH deficient dwarf rat grows in response to both GH and IGF-I infusions, but these agents elicit different patterns of organ growth. For the same overall body growth, GH was more effective in stimulating bone growth, whereas IGF-I stimulated renal and splenic growth. This new dwarf rat may prove useful for the study of the relative growth promoting effects of IGF-I and GH in more detail in future.

Animals↗
PubMed1987

The ability of biochemical and haematological tests to predict recovery in periparturient recumbent cows.

Blood samples from 433 periparturient recumbent cows submitted by veterinary practitioners to Ruakura Animal Health Laboratory during 1983 and 1984 were analysed and results related to whether cows recovered, died or were euthanased. Generally cows were sampled only once and the time varied from 15 minutes to 20 days after becoming recumbent. During 1983 serum calcium, magnesium, phosphorus, creatine phosphokinase (CK), aspartate amino transferase (AST), glutamate dehydrogenase (GDH), gamma glutamyl transferase (GGT) were analysed. In 1984 serum urea, creatinine, fibrinogen and haematological examination (haemoglobin, haematocrit, total and differential white cell counts) were added to the panel. Overall 39% of cows recovered, 30% died and 32% were destroyed. Precalving cows had 111% more deaths and 7% less survivors than postcalving recumbent cows (P<0.1). There was little difference (3%) in euthanasia prevalence. Tests that were most useful in predicting a lack of recovery were serum urea and muscle enzymes. Using these tests and duration of recumbency when sampled a model was produced to predict the probability of recovery from 254 cases.

Journal Article↗
PubMed1987

Recombinant human insulin-like growth factor: testing the somatomedin hypothesis in hypophysectomized rats.

The in-vivo biological activity of recombinant methionyl insulin-like growth factor I (met-IGF-I) was demonstrated in hypophysectomized rats by following blood glucose after an i.v. bolus injection of met-IGF-I; a dose-dependent decrease in blood sugar was seen. Membrane transport was studied using the non-metabolizable amino acid alpha-aminoisobutyric acid; stimulation was obtained with the highest dose used (90 micrograms/rat). To test the original somatomedin hypothesis, growth studies were performed in hypophysectomized rats. Two or three doses of met-IGF-I were given with three different administration regimes (i.v. or s.c. infusion, or s.c. injections twice daily) for 6 or 8 days. Little growth-promoting activity was observed, with a significant effect on body weight gain obtained only when met-IGF-I was given continuously at the highest dose used (180 micrograms/day). No effect was seen on the in-vivo uptake of radioactive sulphate into cartilage. Epiphyseal cartilage width increased slightly at the highest dose of met-IGF-I, but only when the hormone was given by infusion. When 180 micrograms met-IGF-I/day were given by injections, a significant effect on longitudinal bone growth was obtained (90 micron above control). The levels of IGF in the serum were not measurably increased after s.c. administration of met-IGF-I, whereas after i.v. infusion, significantly raised levels were obtained at the higher dose rates (3.0 +/- 0.3 and 2.8 +/- 0.1 units/ml). Growth hormone was much more effective than met-IGF-I even at 50-fold lower doses. Priming the animals with 10 mu. bovine GH/day followed by combined infusions of GH and met-IGF-I did not reveal any potentiating effects of met-IGF-I in the presence of GH. We conclude that met-IGF-I is a relatively poor growth-promoting agent when given systemically, and that somatomedins are more likely to act as local growth factors rather than as circulating mediators of the growth-promoting effects of GH.

Animals↗
PubMed1987

Growth hormone secretory profiles in conscious female rats.

An automatic method for repetitive microsampling of blood from conscious animals was used to obtain detailed GH secretory profiles from normal female rats, which were compared with those in males and ovariectomized females. Female rats showed a highly variable GH secretory pattern, with sustained periods of low, almost continuous secretion, followed by very rapid bursts of high amplitude and short duration, occurring mostly at night. There was no clear relationship between the pattern of GH secretion and the phase of the oestrous cycle in rats continuously sampled over a 5-day period. In ovariectomized rats, the day:night difference was maintained, though the nocturnal GH surges were larger and of longer duration than in intact females. Male rats produced multicomponent GH bursts which continued unchanged throughout the day and night. This study shows for the first time that female rats switch to a rapid, highly pulsatile pattern of GH release at night, which can only be resolved by rapid blood sampling over extended periods in conscious undisturbed animals.

Animals↗
PubMed1986

Automated repetitive microsampling of blood: growth hormone profiles in conscious male rats.

A system is described for the automatic collection of small samples of blood from conscious rats. Rats bearing chronic indwelling i.v. catheters were connected via swivels to a multichannel peristaltic pump, solenoid valves and a fraction collector. A microcomputer controlled the operations involved in the removal of blood and its deposition into a fraction collector for subsequent direct radioimmunoassay for GH. Blood samples of 10-20 microliter could be collected, into a total volume of 100 microliter heparinized saline, from up to eight rats simultaneously every few minutes for many hours. This collection method avoided major blood loss and did not require transfusions of donor blood to maintain blood volume. Using a double-lumen cannula it was possible to inject or infuse into the animals while sampling blood. The system was used to investigate in detail the secretion of GH in conscious male rats. The 3-hourly endogenous secretory rhythm of GH was maintained for up to 44 h with episodes of GH secretion being multicomponent. Endogenous secretion was suppressed by constant i.v. infusions of somatostatin, with repetitive sampling showing in detail a rapid rebound secretion of GH after terminating the somatostatin infusions. Four injections of a fragment of GH-releasing factor, given at 3-hourly intervals, produced entrained GH responses, but the subsequent recovery of endogenous GH pulsing was delayed for up to 12 h. This method for the automatic microsampling of blood in small animals gives a very detailed description of the blood levels of hormones secreted in a highly episodic fashion, and could be widely applicable to other endocrine studies.

Animals↗
PubMed1985

Loss of responsiveness to glucagon following underperfusion of the isolated rat liver.

Increases in glucose and urea output in response to increasing glucagon concentration have been studied in isolated livers perfused with physiological concentrations of amino acids. Glucose output was more sensitive to glucagon than urea output. A period of non-perfusion caused a subsequent loss of responsiveness to glucagon concentrations, at the high end of the physiological range, but the response to glucagon at the low end of the physiological range was unaffected. This probably represents a post-receptor effect rather than alterations at the receptor level.

Amino Acids↗
PubMed1985

Long term parenteral nutrition in the management of severe Crohn's disease.

Twelve patients with active severe Crohn's disease, who failed to respond to medical treatment, received total parenteral nutrition (T.P.N.) via a Broviac long term feeding catheter for periods of 35-190 days prior to surgery. The 10 patients who were non-oedematous increased their mean weight by 3.3 Kg (p<0.01) and their mean plasma albumin by 5.80 g/l (p<0.025) after 28 days T.P.N. There were two episodes of catheter-related sepsis. Although the mean Crohn's disease activity index was significantly reduced from 364.50 (+/-91.51) to 236.75 (+/-121.29) (p<0.005) after 28 days T.P.N., all 12 patients were found to have active disease at operation. There was no post-operative mortality and the only major post-operative morbidity was a pelvic abscess following a panproctocolectomy. It is concluded that long term T.P.N. does not eliminate the need for surgery, but it may improve the nutritional status and reduce the post operative morbidity of malnourished patients with severe Crohn's disease.

Journal Article↗
PubMed1985

Jejunal perforation secondary to metastatic bronchogenic carcinoma.

A case of peritonitis secondary to the perforation of a bronchogenic small bowel metastasis is reported. To our knowledge this is only the fourth case in which peritonitis was the presenting feature of a squamous cell carcinoma of the bronchus. The publications to date are reviewed and the need to biopsy every small bowel perforation found at laparotomy is stressed.

Aged↗