Glucagon-like peptide I enhances the insulinotropic effect of glibenclamide in NIDDM patients and in the perfused rat pancreas

OBJECTIVE: To investigate the acute effects of glibenclamide and glucagon-like peptide I (GLP-I) and their combination in perfused isolated rat pancreas and in patients with secondary failure to sulfonylureas. RESEARCH DESIGN AND METHODS: Rat islets were perfused with 10 nmol/l GLP-I in combination with 2 mumol/l glibenclamide. In human experiments, GLP-I (0.75 pmol. kg-1.min-1) was given as a continuous infusion during 240 min, while glibenclamide (3.5 mg) was administered orally. Eight patients participated in the study (age 57.6 +/- 2.7 years, BMI 28.7 +/- 1.5 kg/m2, mean +/- SE). In all subjects, blood glucose was first normalized by insulin infusion administered by an artificial pancreas (Biostator). RESULTS: GLP-I increased the insulinotropic effect of glibenclamide fourfold in the perfused rat pancreas. In human experiments, treatment with GLP-I alone and in combination with glibenclamide significantly decreased basal glucose levels (5.1 +/- 0.4 and 4.5 +/- 0.1 vs. 6.0 +/- 0.3 mmol/l, P < 0.01), while with only glibenclamide, glucose concentrations remained unchanged. GLP-I markedly decreased total integrated glucose response to the meal (353 +/- 60 vs. 724 +/- 91 mmol.l-1. min-1, area under the curve [AUC] [-30-180 min], P < 0.02), whereas glibenclamide had no effect (598 +/- 101 mmol.l-1. min-1, AUC [-30-180 min], NS). The combined treatment further enhanced the glucose lowering effect of GLP-I (138 +/- 24 mmol. l-1.min, AUC [-30-180 min], P < 0.001). GLP-I, glibenclamide, and combined treat-stimulated meal-induced insulin release as reflected by insulinogenic indexes (control 1.44 +/- 0.4; GLP-I 6.3 +/- 1.6, P < 0.01; glibenclamide 6.8 +/- 2.1, P < 0.01; combination 20.7 +/- 5.0, P < 0.001). GLP-I inhibited basal but not postprandial glucagon responses. Using paracetamol as a marker for gastric emptying rate of the test meal, treatment with GLP-I decreased gastric emptying at 180 min by approximately 50% compared with the control subjects (P < 0.01). CONCLUSIONS: In acute experiments on overweight patients with NIDDM, GLP-I exerted a marked antidiabetogenic action on the basal and postprandial state. The peptide stimulated insulin, suppressed basal glucagon release, and prolonged gastric emptying. The glucose-lowering effect of GLP-I was further enhanced by glibenclamide. This action may be at least partially accounted for by a synergistic effect of these two compounds on insulin release. Glibenclamide per se enhanced postprandial but not basal insulin release and exerted a less pronounced antidiabetogenic effect compared with GLP-I.     

Is there a myofascial, temporomandibular disorder personality?

It is widely accepted that abnormal personality factors play an important role in the etiology and maintenance of myofascial-type temporomandibular disorder, or M/TMD. However, the foundation on which this belief rests is based largely on clinical lore, rather than on any evidence. The continued belief in the stress theory has important implications. Clinicians continue to be trained in unproven but traditionally sanctioned treatments. Such approaches not only may lead to problems of patient care, they may forge an unstable foundation for future research. Two theories are examined in this article: the psychosomatic and psychophysiological models. The findings show that both theories lack evidence, and further research is warranted because definitive studies are unavailable. The data from this study do not support the contention that M/TMD cases are characterized by a specific premorbid personality.     

Application of tandem mass spectrometry for the analysis of long-chain carboxylic acids

The application of MS-MS for the analysis of long-chain carboxylic acids and their esters has proved enormously successful but expensive. It is discussed mainly on basis of results obtained with different instruments with lesser attention to principles of the method, which have been adequately reviewed elsewhere. The use of electrospray ionization (ESI) has greatly increased the sensitivity of the method and has permitted assay of total lipid extracts. The combination of HPLC with electrospray and single quadrupole mass spectrometry, LC-ESI-CID-MS, rivals the triple quadrupole MS-MS application in many instances at considerably lower cost. However, LC-ESI-MS-MS remains the most desirable system at the present time for lipid ester analyses.     

Induction of a local anti-IpaC antibody response in mice by use of a Shigella flexneri 2a vaccine candidate: implications for use of IpaC as a protein carrier

The capacity of Shigella flexneri to act as a delivery system for stimulation of local immunity was investigated by use of an S. Flexneri 2a vaccine candidate (SC602). This vaccine strain was constructed by deletion of virulence genes responsible for dissemination (icsA) and survival (iuc:iut) of bacteria within the colonic mucosa. Among the most immunogenic S. flexneri 2a proteins inducing a local immunoglobulin A antibody response, the IpaC invasion was selected as a potential protein carrier. Overexpression of IpaC from a plasmid in trans within SC602 (SC602/pIpaC) was shown to be required for the induction of optimal anti-IpaC antibody response in the murine pulmonary infection model. A weak anti-IpaC antibody response was obtained after intranasal inoculations with SC602/pIpaC live bacteria. This response was enhanced by combining systemic priming with SC602/pIpaC killed bacteria and local boosting with SC602/pIpaC live bacteria. These results suggest that naive B cells primed systemically could account for local antibody production. This immunization protocol will allow further evaluation of the immunogenicity of IpaC hybrid proteins expresses in SC602.     

A comparison of the shake test, optical density, L/S ratio (planimetric and stechiometric) and PG for the assessment of fetal lung maturity

Our aim was to determine the diagnostic accuracy and reliability of four tests for the assessment of fetal lung maturity (FLM): shake test, optical density at 650 nm (OD650), lecithin to sphingomyelin ratio (L/S) by planimetry and stechiometry, and presence of phosphatydylglycerol. Amniotic fluid was obtained from 74 patients at various gestational ages. The shake test and the OD650 were performed according to published methods L/S was determined by TLC (thin-layer chromatography) and the ratio assessed by planimetry and stechiometrically by measurement of organic phosphorus from the chromatographic spots. PG was assessed similarly by TLC. When correlated with gestational age at amniocentesis, all tests correlated positively: shake test (r = 0.46, p < 0.005); OD650 (r = 0.31, p < 0.005); planimetric L/S (r = 0.77, p < 0.005); stechiometric L/S (r = 0.52, p < 0.005) and PG (r = 0.54, p < 0.005). The diagnostic accuracy of each test was as follows: the shake test and the OD650 had a sensitivity of 50%, while the steciometric L/S had a sensitivity of 75%, the planimetric L/S and the presence of PG were 100%. All four tests demonstrated a specificity greater than 64%, the highest for the PG presence being (83%) and the shake test (86%). Predictive negative values for lung maturity were > 93% for all tests, with the highest for the planimetric L/S and presence of PG being (100%). The study confirms that the determination of L/S ratio is still superior to other tests in terms of overall diagnostic accuracy. In addition, it was found that presence of PG was highly associated with the absence of respiratory complications in the newborn.     

A high proportion of novel mutations in BRCA1 with strong founder effects among Dutch and Belgian hereditary breast and ovarian cancer families

We have identified 79 mutations in BRCA1 in a set of 643 Dutch and 23 Belgian hereditary breast and ovarian cancer families collected either for research or for clinical diagnostic purposes. Twenty-eight distinct mutations have been observed, 18 of them not previously reported and 12 of them occurring more than once. Most conspicuously, a 2804delAA mutation has been found 19 times and has never been reported outside the Netherlands. A common haplotype spanning > or = 375 kb could be identified for each of the nine examined recurrent mutations, indicating the presence of multiple BRCA1 founder mutations in the Dutch population. The 2804delAA mutation has been estimated to have originated approximately 32 generations ago. No specific breast or ovarian cancer phenotype could be assigned to any of the common mutations, and the ovarian cancer incidence among 18 families with the 2804delAA mutation was heterogeneous.     

Cisapride reduces neonatal postoperative ileus: randomised placebo controlled trial

AIM: To assess the efficacy of cisapride in reducing ileus persisting to the tenth postoperative day after neonatal abdominal surgery. METHODS: A prospective, randomised, double blind trial comparing rectal cisapride (1.4-2.3 mg/kg/day) with placebo over seven days was undertaken in 33 neonates. RESULTS: Seven of 12 (58%) patients receiving placebo and eight of 11 (73%) receiving cisapride achieved a first sustained feed during treatment. Of those receiving cisapride, the first sustained feed occurred at 2.3 days (SEM 0.6) compared with 4.7 days (SEM 0.8) with placebo. By the seventh day the mean daily net enteral balance was 69 (SEM 18) ml/kg in the cisapride subgroup and 17 (SEM 8) ml/kg for those receiving placebo. Stool was passed on 6.3 (SEM 0.4) treatment days in the cisapride subgroup compared with 4.1 (SEM 1.0) treatment days in the placebo subgroup. CONCLUSION: Cisapride is effective in neonates with a prolonged ileus after abdominal surgery.