Biomedical subjects
S Tomlin
Publications and source records attributed to S Tomlin.
Fermilab's Tevatron. Back in business.
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Pharmaceutical care: improving practice for children in hospital.
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A pilot study of N-acetyl glucosamine, a nutritional substrate for glycosaminoglycan synthesis, in paediatric chronic inflammatory bowel disease.
BACKGROUND: The breakdown of glycosaminoglycans is an important consequence of inflammation at mucosal surfaces, and inhibition of metalloprotease activity may be effective in treating chronic inflammation. AIM: To report an alternative approach, using the nutriceutical agent N-acetyl glucosamine (GlcNAc), an amino-sugar directly incorporated into glycosaminoglycans and glycoproteins, as a substrate for tissue repair mechanisms. METHODS: GlcNAc (total daily dose 3-6 g) was administered orally as adjunct therapy to 12 children with severe treatment-resistant inflammatory bowel disease (10 Crohn's disease, 2 ulcerative colitis). Seven of these children suffered from symptomatic strictures. In addition, similar doses were administered rectally as sole therapy in nine children with distal ulcerative colitis or proctitis resistant to steroids and antibiotics. Where pre- and post-treatment biopsies were available (nine cases), histochemical assessment of epithelial and matrix glycosaminoglycans and GlcNAc residues was made. FINDINGS: Eight of the children given oral GlcNAc showed clear improvement, while four required resection. Of the children with symptomatic Crohn's stricture, only 3 of 7 have required surgery over a mean follow-up of > 2.5 years, and endoscopic or radiological improvement was detected in the others. Rectal administration induced remission in two cases, clear improvement in three and no effect in two. In all cases biopsied there was evidence of histological improvement, and a significant increase in epithelial and lamina propria glycosaminoglycans and intracellular GlcNAc. CONCLUSIONS: GlcNAc shows promise as an inexpensive and nontoxic treatment in chronic inflammatory bowel disease, with a mode of action which is distinct from conventional treatments. It may have the potential to be helpful in stricturing disease. However, controlled trials and an assessment of enteric-release preparations are required to confirm its efficacy and establish indications for use.
Topical tacrolimus may be effective in the treatment of oral and perineal Crohn's disease.
BACKGROUND: Crohn's disease of the mouth or perineum is more common in young people, and notably resistant to treatment. However, there is increasing evidence that topical therapy with tacrolimus (FK506) may be effective in skin diseases resistant to cyclosporin because of its high uptake in inflamed skin and subsequent reduction in keratinocyte chemokine production. PATIENTS AND METHODS: Tacrolimus ointment was made up inhouse from the intravenous or oral formulation and suspended in appropriate vehicles for perioral or perianal administration at an initial concentration of 0.5 mg/g. This was administered open label to eight children (aged 5-18 years) with treatment resistant oral (three patients) and/or ulcerating perineal (six patients) Crohn's disease. RESULTS: Marked improvement was seen in 7/8 patients within six weeks and healing within 1-6 months. One child with gross perineal and colonic disease showed little response. Two of the responders showed rebound worsening when tacrolimus was stopped or the dosage reduced rapidly, and one of these eventually required proctectomy. Slower weaning of drug concentration has been successful in 6/8 patients, with four receiving intermittent treatment and two on regular reduced dosage (0.1-0.3 mg/g) with follow up times of six months to 3.5 years. Serum concentrations of tacrolimus were undetectable in all patients. CONCLUSIONS: Topical tacrolimus at low concentrations (0.5 mg/g) shows promise in the management of childhood perineal and oral Crohn's disease, with no evidence of significant systemic absorption. However, rapid weaning or abrupt cessation of therapy may cause rebound worsening of disease. Further controlled studies are required to assess the efficacy and safety of this treatment.
International maternal mortality reduction: outcome of traditional birth attendant education and intervention in Angola.
BACKGROUND: As a result of war and periodic natural disasters, Angola has among the highest infant and maternal mortality rates in the world. In response to the acute health needs of the population, the International Medical Corps (IMC) developed a traditional birth attendant educational course designed to reduce the preventable causes of maternal and infant mortality. METHODS: From 1994 until 1998, Angolan traditional birth attendants (TBAs) participated in an intensive 38-hr training course on prenatal, delivery, and postnatal care. Following the birth of a child, the trained TBAs completed a registration form containing information regarding the health of the mother. Previous studies of Angolan maternal mortality served as historic comparisons. FINDINGS: Complete data including maternal mortality data were available for 19,666 deliveries (83% of total). Fifty five maternal deaths were recorded, which corresponds to a maternal mortality rate of 293 per 100,000 live births. The average historic maternal mortality rate for available comparison groups was 1241 per 100,000 live births. INTERPRETATION: The maternal mortality rate was reduced among women managed by IMC-trained TBAs when compared with historical control data.
Alpha-adrenergic stimulation of corticotropin secretion by a specific central mechanism in man.
In a double-blind study in normal subjects, methoxamine, a highly selective agonist at alpha-1-adrenoceptors, significantly increased circulating ACTH and cortisol. The stimulant effect of methoxamine on cortisol secretion was dose dependent in the range 3.5-7 micrograms/kg/min, was abolished by concomitant administration of the strong alpha-1-adrenergic (and weak H1) antagonist thymoxamine but unaffected by the antihistamine, chlorpheniramine. In order to test whether the action of methoxamine on ACTH secretion was exerted centrally or peripherally, the effects of norepinephrine (NE), an alpha-1-agonist that does not cross the blood-brain barrier, were studied. Doses of NE (1-12 micrograms/min) that increased systolic blood pressure by amounts similar to the changes produced by methoxamine, did not result in any rise in plasma cortisol in normal subjects. The effect of methoxamine, which is more lipid soluble than NE, on plasma ACTH and cortisol, appears to be exerted on the CNS and not at the pituitary or via nonspecific peripheral mechanisms. In addition to its water solubility, NE differs from methoxamine in its beta-1-, beta-2- and alpha-2-agonist actions. However, prenalterol (2 mg) and salbutamol (250 micrograms), respectively beta-1- and beta-2-adrenergic agonist drugs, had no effect on the secretion of ACTH or cortisol and the alpha-2-antagonist yohimbine in an effective dose did not unmask a stimulant effect of intravenous NE on plasma cortisol. At high infusion rates, NE significantly inhibited cortisol secretion. Stimulation of central alpha-1-adrenergic mechanisms results in secretion of ACTH in man, presumably by increased release of a corticotropin-releasing factor.
RIA/chromatographic evidence for novel opioid peptide(s) in Squilla mantis ganglia.
Proteins extracted from suboesophageal ganglia of Squilla mantis, an arthropod shown to be sensitive in vivo to opiates and to contain native opioid like peptide(s), were fractionated by gel filtration into three pools according to their molecular weight: A (Mr greater than 65,000), B (10,000 less than Mr less than 65,000) and C (Mr less than 10,000). None of these pools showed any immunoreactivity when radioimmunoassayed using antisera raised against Met-enkephalin either before or after sequential trypsin/carboxypeptidase B proteolysis. Further purification of pool C by HPLC followed by RIA using antibodies directed to Met-O-enkephalin,Leu-enkephalin,Dynorphin 1-13 and human beta-endorphin, showed only a trace amount of Met-enkephalin cross-reactivity (about 10 fmoles/mg of protein extract). No detectable amount of Leu- or Met-enkephalin was found after HPLC fractionation of proteolyzed pool B. Radioreceptor assay of HPLC fractions derived from trypsin/carboxypeptidase B treated pools B and C showed major areas of activity common to both pools, but nevertheless with differing retention times compared to the standard opioid peptides used.
Neuroendocrine and cardiovascular changes in septic shock and after cardiac surgery: effect of high-dose corticosteroid therapy.
Plasma levels of beta-endorphin-like immunoreactivity (BLI) were similarly elevated in patients with septic shock (group A) and in normotensive subjects recovering from cardiac surgery (group B) (1231 +/- 483 pg ml-1 and 1,240 +/- 355 pg ml-1, respectively). In neither group was cardiac output reduced, but total peripheral resistance index (TPRI) was low in group A and low or normal in group B. Intravenous methylprednisolone (MP) 30 mg kg-1 variably suppressed BLI by a mean of only 30% in group A, while in group B, BLI usually rose and then fell following MP. In group A percentage changes in BLI were positively correlated with percentage changes in cardiac index (CI) and mean arterial pressure (MAP) (r = .83, P less than .01, r = .59, P less than .05 respectively). No such correlations were found in group B. These findings suggest that increases in circulating beta-endorphin are unlikely to be responsible for myocardial depression or hypotension in septic shock. ACTH levels were in general normal in group A but were consistently elevated in group B, although plasma cortisol was similarly elevated in both groups. Furthermore there was a good correlation between percentage changes in ACTH and BLI following MP in group B (r = .87, P less than .01) but not in group A. Possible explanations for these findings are discussed.
Release of beta endorphin and met-enkephalin during exercise in normal women: response to training.
Plasma beta endorphin and met-enkephalin concentrations were measured in response to treadmill exercises in 15 normal women before, during, and after an intensive programme of exercise training. Significant release of beta endorphin occurred in all three test runs, and the pattern and amount of release were not altered by training. Before training dramatic release of met-enkephalin was observed in seven subjects and smaller rises observed in a further four, and this response was almost abolished by training. This represents the first observed "physiological" stimulus to met-enkephalin release. Endogenous opioid peptides play a part in adaptive changes to exercise training and probably contribute to the menstrual disturbances of women athletes.
Corticotrophin releasing factor: responses in normal subjects and patients with disorders of the hypothalamus and pituitary.
Synthetic CRF-41 has been given to 43 patients with hypothalamic, pituitary or adrenal diseases and contrasted with the responses in 20 normal subjects. In the normal subjects the mean increment in serum cortisol (+/- SE) was 276 +/- 38 nmol/l; the increments showed a significant negative correlation with the basal serum cortisol levels (r = -0.56; P less than 0.02). The mean peak serum cortisol was 662 +/- 34 nmol/l and the mean peak corticosterone was 28.6 +/- 3.8 nmol/l. There was a significant positive correlation between the peak serum corticosterone and cortisol concentrations (r = 0.84; P less than 0.0001). Dexamethasone pretreatment abolished the rise in cortisol in response to CRF-41. The peak serum cortisol following CRF-41 was not significantly different between the normal subjects and those patients with pituitary disease who had normal cortisol responses to insulin-induced hypoglycaemia. However, in individual patients the peak cortisol levels induced by hypoglycaemia were greater than, but significantly correlated with, those induced by 100 micrograms of CRF-41. Seven patients were ACTH deficient in response to hypoglycaemia, and of these six responded normally to CRF-41. Only one of these patients had a lesion clearly originating in the hypothalamus; four had pituitary tumours with suprasellar extensions and the remaining patient had idiopathic GH and ACTH deficiency. Our data suggest that these patients have a functional defect of ACTH secretion due to the failure of CRF to reach the corticotroph. Of the four patients with pituitary-dependent Cushing's disease who were on no treatment at the time of testing, three showed an exaggerated and one a normal response to CRF-41. These normal or enhanced responses of hypercortisolaemic patients with Cushing's syndrome contrast with the complete inhibition of the responses to CRF-41 in normal subjects given dexamethasone. In the treated patients with Cushing's syndrome and normal serum cortisol levels, those with pituitary-dependent disease showed an enhanced ACTH response to CRF-41 as compared with the ectopic ACTH group, but there was some overlap between the two groups. Acromegalic patients did not show a GH response to CRF-41. We conclude that administration of CRF-41 is a safe new method for investigating disorders of the hypothalamo-pituitary axis.
A study of the relationship between circulating beta-endorphin-like immunoreactivity and post partum 'blues'.
Plasma beta-endorphin-like immunoreactivity was studied in 43 pregnant women at 36 weeks gestation and in 23 of these at delivery and 24 h post-partum; an attempt made to correlate changes with various social, psychological and obstetric factors, including the 'post-natal blues'. Beta-endorphin levels were elevated at 36 weeks gestation and term, increased to very high levels during labour and fell rapidly within 1 h of delivery. A negative correlation was observed between the woman's estimate of her pain in labour and the beta-endorphin levels post-partum, suggesting an analgesic role for beta-endorphin in labour. A positive correlation was also observed between the levels of beta-endorphin at delivery and the woman's attitude to her pregnancy at 36 weeks and a negative correlation between the 'post-natal blues score' and the beta-endorphin level at 36 weeks. However, the 'blues' did not correlate either with the beta-endorphin level at delivery or 24 h post-partum nor with its rate of fall in the first 24 h. Our general finding that there was no consistent social, psychological or obstetric factor which predisposes women to develop 'post-natal blues' still supports the hypothesis that humoral factors, of which beta-endorphin may be one, rather than psychological factors are important in the genesis of this syndrome.
Regional distribution of pro-opiomelanocortin-derived peptides in the human brain.
The regional distribution of pro-opiocortin-derived peptides and methionine enkephalin was investigated in human brain post-mortem. Sequence-directed radioimmunoassays for beta-endorphin, gamma-lipotropin, adrenocorticotrophin, corticotrophin-like intermediate lobe peptide (ACTH18-39, CLIP) alpha-MSH and methionine enkephalin were used and 40 different human brain areas were assayed. The regional distribution of all the pro-opiomelanocortin-derived immunoreactivities were correlated with highest amounts of beta-endorphin, gamma-lipotropin and ACTH in the hypothalamus, amygdala, periventricular grey, substantia nigra and superior colliculus. The distribution of beta-endorphin, gamma-lipotropin and ACTH did not parallel the distribution of methionine-enkephalin immunoreactivity which was present in the globus pallidus, nucleus accumbens and substantia nigra. Gel exclusion chromatography (G-50) showed that pro-opiocortin-related peptides in the human hypothalamus and periventricular grey separated in positions consistent with the major immunoreactive forms being beta-endorphin, gamma-lipotropin, ACTH and CLIP.
CRF-41 stimulates the release of beta-lipotrophin and beta-endorphin in normal human subjects.
A prompt rise in circulating immunoreactive N- and C-terminal lipotrophin (LPH) accompanied the increase in ACTH when 100 micrograms CRF-41 was given to 6 normal male subjects. Chromatography of the basal and peak 15-min values showed that there was an equimolar increase in beta-LPH and beta-endorphin, to cause parallel release of ACTH, beta-endorphin and beta-LPH from the pro-opiocortin precursor.
Methionine-enkephalin precursor in neuroblastoma x glioma hybrid cells: in vivo and in vitro evidence.
The peptides obtained by proteolysis of both extracted proteins and in vitro translation products from Neuroblastoma x Glioma hybrids were purified by means of HPLC and then submitted to radioimmunoassay. Met-Enkephalin and Met-Enkephalin sulphoxide immunoreactivity was found.
Endogenous opioid peptides in pregnancy.
Plasma levels of two endogenous opioid peptides, beta-endorphin and met-enkephalin, as well as immunoreactive N-terminal beta-lipotrophin (N-LPH) were studied in normal pregnant women from 8 to 41 weeks gestation. A total of 116 samples were assayed for beta-endorphin-like immunoreactivity (C-LPH), 103 for N-LPH and 75 for met-enkephalin. Plasma beta-endorphin-like immunoreactivity and N-LPH levels rose progressively throughout gestation and reached a maximum at term. Plasma met-enkephalin immunoreactivity did not significantly change throughout pregnancy. These results reflect an increasing and consistent adrenocorticotrophin (ACTH)/beta-LPH and beta-endorphin secretion throughout pregnancy, while the unchanged met-enkephalin levels are compatible with its known derivation from a separate precursor system.
New hypothalamic hormone, corticotropin-releasing factor, specifically stimulates the release of adrenocorticotropic hormone and cortisol in man.
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Experience with selective venous sampling in diagnosis of ACTH-dependent Cushing's syndrome.
Twenty-three patients with adrenocorticotrophic hormone-(ACTH)-dependent Cushing's syndrome were subjected to selective venous catheterisation and sampling for ACTH on a total of 26 occasions. Out of 10 patients with pituitary-dependent disease, nine had raised ACTH concentrations in one or both high internal jugular vein samples. Eight patients had 11 proved sites of ectopic hormone production: of these, six were correctly identified by the sampling technique, and in four of them this was the only accurate method of localisation. The results of one catheterisation were misleading, and on 10 occasions they were inconclusive; five patients remained undiagnosed by any method. Overall, 15 of the 26 catheterisations provided diagnostically valuable information. Selective venous catheterisation and sampling for ACTH is effective in confirming a pituitary source of the hormone and may be valuable in locating the source of ectopic ACTH production in some cases.