Biomedical subjects
Publications and source records attributed to I Whitehouse.
Fibromyalgia is a common syndrome. Rapid diagnosis and education of the patient are very important. "State of the art"-therapy is interdisciplinary and multimodal in a facility permitting coordinated and comprehensive management.
Genetic and biochemical approaches have indicated that the packaging of DNA into chromatin can be repressive to transcription. ATP-dependent chromatin remodelling activities can facilitate transcription from chromatin templates. Consistent with this, biochemical assays have shown that the action of ATP-dependent chromatin remodelling activities increase the accessibility of DNA within chromatin templates. However more recent functional studies suggest that many ATP-dependent chromatin remodelling activities can also function as repressors of transcription. Here we review recent advances to our understanding of the biological function of these complexes. We then consider some of the mechanisms by which ATP-dependent chromatin remodelling activities together with other forms of chromatin remodelling or modifying enzymes may act to regulate genomic accessibility either positively or negatively.
A considerable proportion of chronic non-organic pain patients suffer from insomnia, and alpha sleep has been suggested to be specifically associated with fibromyalgia. However, the clinical significance of those symptoms is not clear. This study was carried out to investigate this question. Twenty-six middle-aged, non-organic pain patients complaining of persistent insomnia were compared with 25 chronic primary insomniacs in a polysomnographic investigation. Alpha sleep was measured by automatic EEG analysis. A postsleep inventory allowed a separation of those pain patients with actual pain in the recording night to examine its possible influence on sleep. Both groups of patients displayed severe disturbance of sleep maintenance. The pain group did not differ in any of the insomnia variables or in sleep stages from chronic primary insomniacs. The occurrence of alpha sleep was high in either group which suggests that this is not a phenomenon specifically related to pain syndromes. A comparison of the pain subgroups revealed no difference between those with or without actual pain in the recording night. It is concluded that insomnia in chronic pain is of the same type and degree as primary insomnia. Apparently, the chronic process made insomnia so persistent that there was no response to actual night-time pain. Our study suggests that the interpretation of insomnia as secondary to pain, as it is usually made by the pain patients themselves, is a misattribution. It is suggested that insomnia in chronic pain patients should be taken seriously and treated by its specific methods.
Gene regulation involves the generation of a local chromatin topology that is conducive to transcription. Several classes of chromatin remodelling activity have been shown to play a role in this process. ATP-dependent chromatin-remodelling activities use energy derived from the hydrolysis of ATP to alter the structure of chromatin, making it more accessible for transcription factor binding. The yeast SWI-SWF complex is the founding member of this family of ATP-dependent chromatin-remodelling activities. We have developed a model system to study the ability of the SWI-SWF complex to alter chromatin structure. Using this system, we find that SWI-SWF is able to alter the position of nucleosomes along the DNA. This is consistent with recent reports that other ATP-dependent chromatin-remodelling activities can alter the positions of nucleosomes along DNA. This suggests that nucleosome mobilization may be a general feature of the activity of ATP-dependent chromatin-remodelling activities. Some of the mechanisms by which nucleosomes may be moved along DNA are discussed.
The generation of a local chromatin topology conducive to transcription is a key step in gene regulation. The yeast SWI/SNF complex is the founding member of a family of ATP-dependent remodelling activities capable of altering chromatin structure both in vitro and in vivo. Despite its importance, the pathway by which the SWI/SNF complex disrupts chromatin structure is unknown. Here we use a model system to demonstrate that the yeast SWI/SNF complex can reposition nucleosomes in an ATP-dependent reaction that favours attachment of the histone octamer to an acceptor site on the same molecule of DNA (in cis). We show that SWI/SNF-mediated displacement of the histone octamer is effectively blocked by a barrier introduced into the DNA, suggesting that this redistribution involves sliding or tracking of nucleosomes along DNA, and that it is achieved by a catalytic mechanism. We conclude that SWI/SNF catalyses the redistribution of nucleosomes along DNA in cis, which may represent a general mechanism by which ATP-dependent chromatin remodelling occurs.
We studied the effect of four graded doses of SMS 201-995, a synthetic octapeptide somatostatin analogue (27, 80, 240, and 720 ng/kg/h) on the basal and secretin-plus-cerulein-stimulated exocrine pancreatic function and pancreatic polypeptide (PP) release in five healthy volunteers. Duodenal fluid secretion and bicarbonate output under basal and stimulated conditions were not significantly affected by any dose of SMS. The basal and stimulated enzyme secretion were decreased in a non-dose-dependent manner by all SMS doses used in the study and showed a 75% inhibition of the secretin-plus-cerulein-stimulated trypsin and amylase output. The cerulein-stimulated PP release was significantly suppressed by all four SMS doses. SMS appears to be a strong inhibitor of pancreatic enzyme secretion, at the same time affecting the PP release.
Somatostatin, a peptide present in hypothalamus, gastric mucosa, and pancreas suppresses several gastrointestinal functions. Its short half life has prevented clinical use. We have therefore evaluated the effect of subcutaneous administration of a new synthetic somatostatin analogue, in comparison with a placebo, on pentagastrin stimulated acid secretion in six healthy volunteers. On different days, acid secretion was measured continuously, after a basal 30 minutes, for six hours during 3 micrograms/kg/h of intravenous pentagastrin. Acid secretion was measured with a marker technique (0.1% phenol red) to correct for duodenal volume loss. Blood was drawn in regular intervals to measure plasma somatostatin concentrations by radio immunoassay. One hour after starting the pentagastrin infusion, a single subcutaneous injection of either 100 micrograms somatostatin analogue, or placebo (isotonic saline) was given. In a follow up study, somatostatin was given subcutaneously in a dose of 200 micrograms. No difference in efficacy was observed between the two doses. A single subcutaneous injection of the somatostatin analogue significantly suppressed acid secretion for five hours (p less than 0.01). Maximal inhibition was approximately 75%. Mean elimination half life of the analogue was approximately 80 minutes. We suggest that the new somatostatin analogue might be useful for clinical use.
Several secretagogues of exocrine pancreatic secretion have been proposed to act as regulators of pancreatic D-cell function. To characterize this relationship, we measured incremental responses of protein, bicarbonate, and circulating somatostatin to graded doses of intravenous cholecystokinin (CCK-33), CCK-8, caerulein, bombesin, secretin, and intraduodenally perfused HCl, sodium oleate, and L-phenylalanine in conscious dogs with gastric and pancreatic fistulas and compared them with postprandial values (to a beef meal). Bombesin produced dose-related increases in somatostatin secretion (maximal, 46% of meal response), but caerulein, CCK-33, and CCK-8 released only small amounts of somatostatin at doses equivalent for pancreatic protein secretion. Secretin did not stimulate somatostatin release at any dose studied, whereas intraduodenal HCl at a load submaximal for pancreatic bicarbonate secretion increased somatostatin levels slightly (maximal, 16% of meal response). L-Phenylalanine and sodium oleate markedly increased protein secretion, but only oleate clearly stimulated somatostatin release (maximal, 11% of meal response). Our results suggest a greater quantitative importance of the intestinal phase for exocrine pancreatic stimulation than for somatostatin release.
The aim of this study was to identify the somatostatin (SST-14) dose dissolved in 0.1% human albumin solution equivalent to the commonly used therapeutic dose (3.5 micrograms kg-1 h-1) dissolved in saline in inhibiting pentagastrin-stimulated gastric acid secretion in healthy volunteers. Gastric acid secretion was stimulated for 3.5 h by intravenous pentagastrin (3 micrograms kg-1 h-1). 0.875 or 1.75 micrograms kg-1 h-1 SST-14 dissolved in 0.1% albumin was significantly (p less than 0.05) less effective in inhibiting stimulated gastric acid secretion than the standard therapeutic dose. There was no difference achieved in the degree of inhibition with albumin added or not to the 3.5 micrograms kg-1 h-1 dose of SST-14. However, an intermediate dose (2.625 micrograms kg-1 h-1) of SST-14, whether dissolved in albumin or saline alone, was as effective as the standard therapeutic SST-14 dose. We conclude that at these high does the absorption of a small quantity of SST-14 to glass and plastic surfaces of the infusion sets has no influence on the therapeutic effect.
The inhibition of pentagastrin-stimulated-(3 micrograms kg-1 h-1) gastric acid secretion by various doses of intravenous and subcutaneous SMS 201-995, a somatostatin analogue, was investigated in healthy volunteers by means of gastric aspiration, using phenol red as a volume marker. The intravenous doses were compared with the standard dose of somatostatin-14, 3.5 micrograms kg-1 h-1. Similarly, SMS 201-995-induced inhibition of gastric acid secretion was compared with that of exocrine pancreatic secretion assessed by gastroduodenal aspiration. The results can be summarized as follows: SMS 201-995 is a potent inhibitor of gastric acid secretion, exerting near maximal inhibition at a dose of greater than or equal to 0.56 micrograms kg-1 h-1. Near maximal inhibition equals that achieved with SST-14 (3.5 micrograms kg-1 h-1). Pancreatic enzyme secretion appears to be strongly inhibited by lower doses of SMS 201-995 than gastric secretion. Single subcutaneous injections of SMS 201-995 produce an inhibition of gastric acid secretion lasting for many hours. Near maximal inhibition was obtained with a dose of 100 micrograms.
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Pancreatic trypsin output and plasma secretin and cholecystokinin (CCK) levels were measured in five healthy volunteers to investigate the mechanisms involved in regulating postprandial pancreatic secretion. The pancreas was stimulated by a liquid test meal or by either intravenous secretin (1-82 pmol/kg-1 per h-1) or caerulein, a CCK analogue (2.3-37 pmol/kg-1 per h-1), or by a combination of secretin and caerulein. Pancreatic secretion was assessed by a marker perfusion technique (polyethylene glycol [PEG 4000]), plasma secretin, and CCK by specific radioimmunoassays. Increasing doses of secretin produced increasing bicarbonate output (P less than 0.01), whereas trypsin was not stimulated over basal. Graded caerulein produced a stepwise increase in trypsin and bicarbonate output (P less than 0.01). Potentiation occurred for bicarbonate secretion between secretin and caerulein, but not for trypsin output. Postprandial trypsin secretion averaged 29.1 IU/min-1 over 150 min (equal to 55% of maximal response to caerulein). The peak trypsin response amounted to 90% of maximal caerulein. Significant increases of plasma secretion (P less than 0.05) and CCK (P less than 0.01) were observed after the meal. Comparison of enzyme and CCK responses to the testmeal or to exogenous caerulein suggested that the amount of CCK released after the meal could account for the postprandial trypsin secretion. We conclude that (a) the postprandial enzyme response in man is submaximal in comparison to maximal exogenous hormone stimulation; (b) CCK is a major stimulatory mechanism of postprandial trypsin secretion, whereas secretin is not involved; and (c) Potentiation of enzyme secretion is not a regulatory mechanism of the postprandial secretory response.
In five conscious dogs we studied the effect of proglumide, a cholecystokinin (CCK) antagonist, on caerulein-stimulated pancreatic secretion and release of pancreatic polypeptide (PP). Graded doses of caerulein (15-240 ng/kg per h) were infused intravenously. Experiments were repeated with a fixed infusion of proglumide (40 mg/kg per h). Release of PP following increasing doses of caerulein was significantly inhibited by proglumide (P less than 0.01). However, proglumide did not significantly affect caerulein-stimulated pancreatic protein secretion. Proglumide might be useful in defining the physiological role of CCK.
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Using an open, randomised study design, the efficacy and tolerance of SMS 201-995 (a synthetic octapeptide SST-14 analogue with a plasma half-life of 45 min) was compared with that of SST-14 in inhibiting pentagastrin-stimulated gastric acid secretion. In 10 healthy volunteers gastric acid secretion was stimulated for 3.5 hours by an infusion of 3 microgram kg-1 h-1 pentagastrin. One hour after the start of pentagastrin a 2-hour i.v. infusion of either SST-14 (3.5 microgram kg-1 h-1) or one of 4 dosages of SMS 201-995 (0.14, 0.28, 0.56 or 1.12 microgram kg-1 h-1) was started. SMS 201-995 inhibited acid secretion in a dose-dependent manner. The inhibition achieved with the 0.56 and 1.12 microgram kg-1 h-1 dosages was comparable with that obtained with 3.5 microgram kg-1 h-1 SST-14. SMS 201-995 (1.12 microgram kg-1 h-1) appeared to have a longer duration of action than SST-14. No side effects were recorded under either of the test substances.