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Biomedical subjects

V Marks

Publications and source records attributed to V Marks.

At least 19 recordsLinked to original sources

Best practice No 173: clinical and laboratory investigation of adult spontaneous hypoglycaemia.

Adult spontaneous hypoglycaemia is not a diagnosis per se but a manifestation of a disease. Although rare, it is important to identify spontaneous hypoglycaemia and its causes because treatment may be preventative or curative. Hypoglycaemia can occur as an epiphenomenon in many serious diseases. It is sufficient to recognise the disease's association with hypoglycaemia and then take appropriate action to prevent the recurrence of hypoglycaemia. In investigating apparently healthy individuals, common pitfalls to avoid are: failure to recognise subacute neuroglycopenia clinically; failure to document hypoglycaemia adequately during symptoms; failure to measure pancreatic hormones, counter-regulatory hormones, and ketones in hypoglycaemic samples; failure to recognise pre-analytical and analytical limitations of laboratory assays; and failure to abandon obsolete and inappropriate investigations. Providing these caveats are met, appropriate laboratory and radiological investigations will almost always uncover the cause of spontaneous hypoglycaemia.

Acute Disease↗

The biochemical investigation of cases of hypoglycaemia: an assessment of the clinical effectiveness of analytical services.

AIM: To assess the extent to which biochemical analytical services contribute to the diagnosis and management of clinical cases of hypoglycaemia. METHODS: All cases of confirmed hypoglycaemia, referred during a six month period, were included in the survey. Questionnaires were sent to each referring laboratory requesting information on the clinical progress and current status of the patient. RESULTS: The level of influence exerted by analytical data was assigned in each case and those with similar outcomes combined. Identifiable case groups were: (1) Results not recorded in the patients' notes (15.7%). (2) Inappropriate requesting of insulin and C peptide measurements in cases of diabetes (11.4%). (3) Patient died soon after investigation (20.0%). (4) Patient recovered spontaneously (17.1%). (5) Patient received effective medical or surgical treatment (12.9%). (6) Patient awaiting or not requiring pathology based treatment (31.4%). (7) Inconclusive outcome prompting further investigation (5.7%). CONCLUSIONS: Within the timescale of the survey (approximately 12 months), positive progress had been made towards diagnosis and subsequent treatment in only 10% of cases. Another 30% were either awaiting some form of treatment or further diagnostic tests. The remaining 60% did not appear to benefit in any way from the biochemical investigations.

Adolescent↗

Polyethylated aromatic rings: conformation and rotational barriers of 1,2,3,4,5,6,7,8-octaethylanthracene, 1,2,3,4,6,7,8-heptaethylfluorene, and 1,2,3,4,5,6,7,8-octaethylfluorene.

1,2,3,4,5,6,7,8-Octaethylanthracene (5), 1,2,3,4,6,7,8-heptaethylfluorene (7), and 1,2,3,4,5,6,7,8-octaethylfluorene (8) were synthesized by Friedel-Crafts ethylations of 9,10-dihydroanthracene and fluorene. MM3 calculations indicate that the two ethylated six-membered rings of 5 and 7 are conformationally independent. According to the calculations, two low-energy conformers of each compound are possible with the ethyl groups attached to the external aryl rings arranged in an alternated "up-down" orientation. MM3 calculations indicate that in the lowest energy conformation the central fluorene core of 8 adopts a twisted conformation to avoid repulsive steric interactions between the ethyls at the bay region. Two fully alternated up-down conformations are possible for 8, differing in the orientation ("in" or "out") of the ethyls in the bay region. MM3 calculations predict that the lowest energy conformer is the fully alternated "out" form of C(2)() symmetry. The rotational barriers of 5, 7, and 8 are in the 8.7-11.3 kcal mol(-1) range, the largest barrier corresponding to the more crowded octaethylfluorene 8. Anthracene 5 adopts in the crystal a conformation of approximate C(2)(h) symmetry with pairs of peri groups on the same edge of the molecule oriented syn. The conformations adopted in the crystal by 7 and 8 do not correspond to the calculated lowest energy form. In the conformation of 7 in the crystal the ethyl groups on the trisubstituted ring adopt the unusual all syn arrangement. Octaethylfluorene 8 adopts a conformation with a twisted central fluorene core but with a syn arrangement of a pair of vicinal ethyl groups.

Journal Article↗

Hypoglycemic disorders.

Hypoglycemia occurs as an epiphenomenon in many serious diseases and further investigation may be unnecessary. In other, often seemingly healthy individuals, it is responsible for their presenting symptoms. In them preliminary diagnosis depends on demonstrating a low blood glucose concentration during spontaneous symptoms by ambulatory self-collection of capillary blood and its analysis for glucose in the laboratory. Subsequent investigation requires appropriate plasma hormone analysis on blood collected while the patient is hypoglycemic.

Blood Glucose↗

Preparation and conformation of octaethylbiphenylene.

Dimerization of tetraethylbenzyne (generated by reaction of 1, 2-dibromo-3,4,5,6-tetraethylbenzene (8) with 1 equiv of BuLi) afforded in low yield octaethylbiphenylene (3), together with a major product which was characterized as 2,3,4,5,3',4', 5'-heptaethyl-2'-vinylbiphenyl (9). X-ray diffraction indicates that biphenylene 3 adopts in the crystal a conformation of approximate C(2)(h )()symmetry with the ethyl groups within each phenylene ring arranged in an alternated up-down fashion. Notably, pairs of vicinal ethyl groups located at peri positions are oriented in a syn arrangement in the crystal. Low temperature NMR spectroscopy is consistent with the presence in solution of either the crystal conformation or a fully alternated conformation lacking any syn interaction. Molecular mechanics (MM3), semiempirical (AM1, PM3), and ab initio calculations indicate that the crystal conformation is a high energy form, and that the lowest energy conformation is the fully alternated form. The topomerization barrier of the methylene protons of the ethyl groups of 3 is 9.4 +/- 0.1 kcal mol(-)(1), which is between the rotational barriers of 8 and 1,2,3, 4-tetraethylbenzene 7 (9.9 +/- 0.1 and 8.2 +/- 0.1 kcal mol(-)(1), respectively). The similarity in rotational barriers suggests that a given tetraethylphenylene subunit does not markedly affect the rotational barrier of the ethyl groups of the other subunit.

Journal Article↗

Hyperproinsulinaemia in elderly subjects: evidence for age-related pancreatic beta-cell dysfunction.

We investigated whether pancreatic beta-cell dysfunction has a role in the pathogenesis of glucose intolerance in the elderly by comparing plasma glucose, immunoreactive insulin, C-peptide and proinsulin concentrations during a 100-g oral glucose load in six healthy older male volunteers [aged 69 (65.9-74.9) years; median (95% confidence limits)] and seven young male controls [aged 24.0 (21.9-26.3) years]. Fasting and integrated concentrations of glucose and C-peptide were similar in the elderly and young. Although fasting, insulin and proinsulin levels were similar, integrated insulin (P=0.05) and proinsulin (P<0.05) concentrations were higher in the elderly than in controls. Insulin resistance, measured as homeostasis model assessment, was greater (P<0.05) in the elderly than in controls. Elderly men had greater molar ratios of integrated insulin:C-peptide (P<0.05) and proinsulin:C-peptide (P<0.01) but their respective fasting molar ratios were similar when compared with controls. Pancreatic beta-cell secretion in older subjects, as assessed by C-peptide concentrations, was inappropriately low in the presence of insulin resistance. Their post-prandial 'hyperinsulinaemia' is probably due to a combination of hyperproinsulinaemia and reduced metabolic clearance of insulin. Older subjects had disproportionately high proinsulin to C-peptide levels, suggesting pancreatic beta-cell dysfunction. These results are consistent with the notion that decreased insulin sensitivity and pancreatic beta-cell dysfunction may predispose the elderly to glucose intolerance.

Adult↗

Drug-induced hypoglycemia.

Therapeutically administered antidiabetic drugs, notably insulin and the sulfonylureas, are undoubtedly the most common cause of hypoglycemia encountered in clinical practice. Nevertheless, an impressive list of other drugs can produce hypoglycemia unpredictably in seemingly healthy individuals in whom it may masquerade as spontaneous hypoglycemia. Unless the true cause is identified when the patient is first seen, fruitless and expensive overinvestigation may ensue. The most important drugs are discussed herein and brief mention made of those for which coincidence has not been eliminated.

Central Nervous System Depressants↗

Hypoglycemia: factitious and felonious.

Factitious diseases are characterized by physical or psychologic symptoms that are voluntarily self-induced. These diseases are as old as mankind. Once called "malingerers," these patients must be distinguished from hysterics in whom symptoms are produced unconsciously. In factitious diseases, illness is produced by deliberate acts by the patient who when seeking medical help omits to mention them and may continue strenuously to deny them even when confronted with the evidence. Factitious diseases occur in patients who simulate or exaggerate symptoms or disability to obtain some kind of discernible personal gain or avoid an unpleasant situation; however, such actions may only produce disadvantages by exposing the patient to the risk of death or permanent injury. This has been described as Munchausen syndrome, which is probably a manifestation of severe psychiatric disease. The use of medicines or poisons to induce illness in others also produces a type of factitial disease and presents similar or greater difficulties in diagnosis. In both situations, the clinical history, ordinarily the most important clue to the correct diagnosis, is not only incomplete but often misleading. Sometimes referred to as Munchausen by proxy, this form of factitial disease may be impossible to distinguish from attempted murder or grievous bodily harm. The subtle differences between these disorders, if any, have not been discussed herein.

Factitious Disorders↗

Inhibition of carbohydrate-mediated glucagon-like peptide-1 (7-36)amide secretion by circulating non-esterified fatty acids.

Two studies were performed to assess the entero-insular axis in simple obesity and the possible effect of variations in the level of circulating non-esterified fatty acids (NEFA) on one of the components of the entero-insular axis, glucagon-like peptide-1 [(7-36) amide]. In the first study, we compared the entero-pancreatic hormone response to oral carbohydrate in obese and lean women. Obese subjects demonstrated hyperinsulinaemia and impaired glucose tolerance but this was not associated with an increased secretion of either glucose-dependent insulinotropic polypeptide or glucagon-like peptide-1 (GLP-1). These findings therefore provide no support for the hypothesis that overactivity of the entero-insular axis contributes to the hyperinsulinaemia seen in obesity. Indeed, the plasma GLP-1 response to carbohydrate was markedly attenuated in obese subjects, confirming previous observations. In the second study, in which carbohydrate-stimulated GLP-1 responses were again evaluated in obese and lean women, circulating NEFA levels were modulated using either heparin (to increase serum NEFA) or acipimox (to reduce serum NEFA). Treatment with acipimox resulted in complete suppression of NEFA levels and in a markedly higher GLP-1 response than the response to carbohydrate alone or to carbohydrate plus heparin. We suggest that higher fasting and postprandial NEFA levels in obesity may tonically inhibit nutrient-mediated GLP-1 secretion, and that this results in attenuation of the GLP-1 response to carbohydrate. However, although serum NEFA levels post-acipimox were similarly suppressed in both lean and obese subjects, the GLP-1 response was again significantly lower in obese subjects, suggesting the possibility of an intrinsic defect of GLP-1 secretion in obesity. The reduction of GLP-1 levels in obesity may be important both in relation to its insulinotropic effect and to its postulated role as a satiety factor.

Adult↗

The effect of circulating non-esterified fatty acids on the entero-insular axis.

BACKGROUND: Circulating non-esterified fatty acids (NEFAs) have been causally associated with impairment of glucose metabolism, although their effect on the entero-insular axis, either in obesity or health, is unknown. MATERIALS AND METHODS: Glucose, insulin, glucagon-like peptide-1 (7-36 amide) (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) responses to 100 g of carbohydrate in 400 mL water were evaluated during simultaneous modulation of circulating non-esterified fatty acids (NEFAs). A total of 10,000 units of heparin (to increase serum NEFAs) and 500 mg of acipimox (2 h before oral carbohydrate ingestion to reduce serum NEFAs) were administered to seven obese [mean +/- SEM: age 40 +/- 3.7 years; body mass index (BMI) 38.9 +/- 2.1 kg m-2] and seven lean (age 39.6 +/- 3.6 years; BMI 22.4 +/- 0.4 kg m-2) women. RESULTS: Higher fasting levels and post-heparin total integrated NEFAs (P < 0.05) and glycerol (P < 0.05) responses were seen in the obese than in the lean group. Incremental integrated GLP-1 responses to oral carbohydrate post-heparin in lean (P < 0.01) and obese (P < 0.05) subjects were significantly lower than after acipimox. Total integrated GIP (P < 0.05) and glucose (P < 0.01) responses were higher post heparin than after acipimox in obese subjects only. CONCLUSION: The inverse relationship in GIP and GLP-1 responses in the obese group after modulation of NEFAs indicates that reciprocal changes between these two hormones may exist to ensure constancy of B-cell stimulation. Our results suggest that in obese subjects compensatory secretion of GIP was incomplete and could not prevent impairment in glucose tolerance after heparin-induced rise in NEFAs. These results may be important in understanding the role of the insulinotropic hormones in carbohydrate metabolism characterized by high NEFA levels such as obesity and diabetes mellitus.

Adult↗

Proinsulin and insulin responses to a mixed meal in hypertriglyceridaemic men.

AIM: To investigate the contribution of proinsulin to the "hyperinsulinaemia" of hypertriglyceridaemia. METHODS: Plasma glucose, triglyceride, immunoreactive insulin, and intact proinsulin concentrations were measured before and after a mixed meal in 11 hypertriglyceridaemic men and six healthy normotriglyceridaemic male controls. RESULTS: Hypertriglyceridaemic subjects had greater fasting (101 v 50 pmol/l) and integrated (139 v 81 x 0(-3) pmol/l/h) insulin concentrations than controls. Fasting and integrated glucose and proinsulin concentrations were similar in the two groups. CONCLUSIONS: Proinsulin does not contribute to the hyperinsulinaemia observed in hypertriglyceridaemic subjects and is therefore unlikely to contribute to the increased cardiovascular risk associated with hypertriglyceridaemia.

Adult↗

Synthesis of photoaffinity label analogues of alpha-tocopherol.

Photoaffinity analogues of alpha-tocopherol have been synthesized that incorporate the photosensitive 4-azido-2,3,5,6-tetrafluorobenzyloxy group at the terminus of unbranched analogues of the naturally occurring phytyl side chain. An intermediate from these syntheses has also been used to generate a supported ligand for bioaffinity chromatography of alpha-tocopherol binding proteins.

Chromatography, Affinity↗

Delayed gastric emptying occurs following acarbose administration and is a further mechanism for its anti-hyperglycaemic effect.

The therapeutic effect of acarbose is generally attributed to inhibition of amylase and brush border glucosidases and consequent impaired digestion and absorption of carbohydrates. We have investigated the possibility that acarbose may also influence the rate of gastric emptying by comparing plasma glucose and gastrointestinal hormone responses to an oral sucrose load with and without acarbose in 11 healthy subjects. Gastric emptying was assessed indirectly by measuring circulating paracetamol concentrations following administration of paracetamol along with the sucrose load. Peak plasma glucose, insulin, and glucose-dependent insulinotropic polypeptide (GIP) responses were reduced when sucrose was given with acarbose. There was a significant reduction in post-sucrose paracetamol levels with acarbose suggestive of a significant delay in gastric emptying. The failure of acarbose to induce change in circulating paracetamol concentrations until after 60 min is indicative of a delay in gastric emptying rather than an osmotic malabsorption. The exaggerated and sustained release of glucagon-like peptide-1 (7-36)amide (GLP-1) seen when sucrose was given with acarbose may play a part in the inhibition of gastric emptying. This study indicates that a significant delay in gastric emptying may be an added mechanism contributing to the therapeutic effect of acarbose.

Acarbose↗

The ageing entero-insular axis.

Ageing is one of the major risk factors for glucose intolerance including impaired glucose tolerance and Type II (non-insulin-dependent) diabetes mellitus. Reduced insulin secretion has been described as part of normal ageing although there is no information on age-related changes in the secretion of the major insulinotropic hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (7-36 amide) (GLP-1). We assessed the entero-insular axis in 6 young premenopausal and 6 older postmenopausal women following treatment with oral carbohydrate. Insulin and glucose integrated responses were similar in the younger and older groups. Total integrated responses for GIP and GLP-1 were considerably greater in the older subjects. A positive correlation between age and total integrated responses for glucose (r = 0.65; p < 0.02) as well as GLP-1 (r = 0.85; p < 0.001) was seen. We hypothesise that an age-related impairment of insulin secretion to insulinotropic hormones, GIP and GLP-1, contributes to a reduction in glucose tolerance in this age group. The pronounced compensatory increase in postprandial secretion of GIP and GLP-1 provides further evidence not only for the negative feedback relation between incretin and insulin secretion but also for the importance of the entero-insular axis in the regulation of insulin secretion.

Acetaminophen↗

Glucocorticoid therapy suppresses abnormal secretion of big IGF-II by non-islet cell tumours inducing hypoglycaemia (NICTH)

OBJECTIVE: To assess the relative efficacy of hGH and glucocorticoids in the treatment of non-islet cell tumour hypoglycaemia (NICTH) by examination of their influence on the composition of the various molecular species involving tumour and mature forms of IGF-II in association with IGFBP-3. DESIGN: Two groups each of 4 patients, all diagnosed as cases of NICTH, were treated with either hGH or glucocorticoids. Through the use of acidic size exclusion chromatography serum levels of tumour (big) and mature IGF-II were evaluated. Neutral size exclusion chromatography was used in the separation of molecular species before assay for immunoreactive IGF-II and IGFBP-3 content. RESULTS: High-dose hGH treatment produced increases in serum levels of big and mature IGF-II and IGFBP-3 but without generation of high molecular weight complexes. Glucocorticoid treatment suppressed big IGF-II permitting re-establishment of normal IGF/IGFBP association patterns. CONCLUSION: Glucocorticoid therapy has been demonstrated to consistently reverse the biochemical abnormalities caused by tumour-derived big IGF-II compared with the potentially adverse stimulatory effects of hGH treatment in causing increases in serum levels of big IGF-II.

Adult↗