Effect of Chronic Central Administration of Glucagon-Like Peptide-1 (7–36) Amide on Food Consumption and Body Weight in Normal and Obese Rats

Glucagon-like peptide (7–36) amide (GLP-1) acutely inhibits food and water consumption in rats after intrace-rebroventricular (icv) administration. To assess the potential for desensitization of these effects, we investigated the effects of chronic icv administration of GLP-1 on food consumption and body weight in Sprague-Dawley (SD) rats and Zucker (fa/fa) obese rats. In vitro functional densensitization of the GLP-1 receptor was not observed after overnight exposure of Rin m5F insulinoma cells to GLP-1 at concentrations up to 10 nM. Administration of GLP-1 to SD rats (30 ug icv twice a day for 6 days) resulted in significant reductions in 24-hour food consumption each day (25 ±1%). Continuous icv infusion of GLP-1 for 7 and 14 days significantly inhibited cumulative food consumption and reduced body weight in SD rats. In the genetically obese Zucker rat, chronic dosing with GLP-1 (30 ug icv) once a day for 6 days caused significant reductions in food consumption each day and a reduction in body weight. These results indicate that the GLP-1 pathways in the central nervous system controlling food consumption do not desensitize after chronic exposure to GLP-1 and suggest that agonists of the central GLP-1 receptor may be effective agents for the treatment of obesity.     

Segregation analysis of cleft lip with or without cleft palate in the First Nations (Amerindian) people of British Columbia and review of isolated cleft palate etiologies

BACKGROUND: The First Nations (Amerindian) population of British Columbia, Canada, has the highest reported birth prevalence in the world of cleft lip with or without cleft palate (CL/P) at nearly 3 per 1000 births. In addition, a substantial proportion of cleft palate only (CPO) cases in this population has been reported to be X‐linked. The aims of this study were to perform complex segregation analysis to investigate the mode of inheritance of CL/P in the First Nations people of British Columbia and to review the etiology of the CPO cases. METHODS: All First Nations children born in British Columbia between 1952 and 1971 with an orofacial cleft were included in the study. Multiple sources of ascertainment were used, so that nearly 100% of live births were identified and included during this time. No stillbirths were found but would likely have been ascertained. Extended pedigrees were constructed from these probands and examination of immediate family members, e.g., parents and siblings, was done wherever possible. Complex segregation analysis included all family members. In addition, a CPO case review was conducted. RESULTS: Complex segregation analysis supports the hypothesis that the most likely mode of inheritance of CL/P in this population is a mixed model; that is, an autosomal major gene with polygenic component. The review of 26 CPO cases showed that a substantial proportion are syndromic. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.     

Levels of 16-alpha-hydroxydehydroepiandrosterone, dehydroepiandrosterone and pregnenolone in cord plasma of human normal and anencephalic fetuses

Total levels of 16α-hydroxydehydroepiandrosterone, dehydroepiandrosterone and pregnenolone were measured by gas chromatography in mixed arterio-venous cord plasma of 15 normal fetuses and 5 anencephalic fetuses. The mean concentrations luith standard deviations of 16α-hydroxydehydroepiandrosterone, dehydroepiandrosterone and pregnenolone for the group of normal fetuses were 171.4 ± 82. 5μg/100ml, 83.3 ± 34.9μg/100ml and 62.1 ± 31.1 μg/100ml respectively. Levels of the three steroids were low or not detectable in the cord plasma of the anencephalic fetuses. Concentrations of free 16α-hydroxydehydroepiandrosterone, dehydroepiandrosterone and pregnenolone in a pool of normal cord plasma mere respectively 2.96 μg/100ml, 1.78μg/100ml and 1.73μg/100ml. The values reported for 16α-hydroxydehydroepiandrosterone are not corrected for losses. The subnormal cord plasma concentrations of 16a-hydroxydehydroepiandrosterone and dehydroepiandrosterone in anencephalic pregnancy reflect the low level of steroidogenesis by the hypoplastic fetal adrenals. The low concentrations of free pregnenolone in normal cord plasma and of total pregnenolone in cord plasma in anencephaly suggest that; pregnenolone in cord blood chiefly arises from fetal rather than placental secretion.     

Cimetidine reduces hyperoxic lung injury in lambs

We previously reported that pretreatment with endotoxin significantly reduced acute pulmonary O2 toxicity in lambs (J. Appl. Physiol. 65: 1579-1585, 1988). One of endotoxin's many effects is to inhibit cytochrome P-450 mono-oxygenation reactions, which are believed to produce toxic O2 species. Therefore, one possible explanation for endotoxin's beneficial effect is that it inhibited P-450-mediated O2 radical production during hyperoxia. To test this hypothesis, we administered a single dose of cimetidine, a noncompetitive inhibitor of P-450 activity, to nine lambs before continuous exposure to greater than 95% O2. Compared with six control O2-exposed lambs, the cimetidine-treated O2-exposed lambs maintained normal gas exchange for a longer period of time (P less than 0.01), accumulated lung water at a slower rate (P less than 0.01), and had normal microvascular permeability after 72 h of O2 exposure. Postmortem levels of antioxidant enzymes in blood-free lung homogenate were not increased in cimetidine-treated lambs. However, the levels of oxidized glutathione were significantly lower in cimetidine-treated lambs, and the ratio of reduced to oxidized glutathione concentrations (GSH/GSSG ratio) was sevenfold higher than the ratio measured in control O2-exposed lambs (P less than 0.001). In four lambs, pretreatment with ranitidine (a drug chemically related to cimetidine but without P-450 inhibitory activity) had no effect either on the time course of O2 injury or on postmortem antioxidants. Microsomes were isolated from blood-free lung of all study animals and P-450 activity of the form 2 isozyme was measured.(ABSTRACT TRUNCATED AT 250 WORDS)     

High level expression of human apolipoprotein A-I in transgenic rats raises total serum high density lipoprotein cholesterol and lowers rat apolipoprotein A-I

To examine the consequences of increased apolipoprotein A-I production on cholesterol and lipoprotein metabolism, we have produced two lines of transgenic rats; one expressing moderate and one very high levels of human apolipoprotein A-I. The rats were produced by microinjection of a 13 kbp DNA fragment containing the human apolipoprotein A-I gene plus 10 kbp of its 5′ flanking sequence and 1 kbp of its 3′ flanking sequence. Both lines of transgenic rats express human apolipoprotein A-I mRNA in liver and human apolipoprotein A-I in plasma. Sera from these rats contain significantly higher levels of total apolipoprotein A-I, high density lipoprotein cholesterol and phospholipid than sera from non-transgenic littermates. Transgenic rats expressing high levels of human apolipoprotein A-I have reduced levels of serum rat apolipoprotein A-I suggesting a mechanism exists to down-regulate apolipoprotein A-I production. These transgenic rats provide a unique animal model to examine the effects of increased apolipoprotein A-I production on lipid and lipoprotein metabolism.     

Hematology and serum chemistry of harp (Phoca groenlandica) and hooded seals (Cystophora cristata) during the breeding season, in the Gulf of St. Lawrence, Canada

Standard hematologic and serum chemistry parameters were determined from 28 harp seals (Phoca groenlandica) and 20 hooded seals (Cystophora cristata) sampled from 6 March 2001 to 13 March 2001 during the breeding season. Whole blood was collected immediately postmortem from harp seal mother-pup pairs and from six hooded seal pups, and from live-captured adult hooded seals and three hooded seal pups; blood was analyzed within 24 hr at a local human hospital. A certified veterinary laboratory validated subsamples of whole blood and analyzed all serum chemistry parameters. Significant interlaboratory differences in mean values of packed cell volume (PCV) and mean cell volume (MCV) were found. Significant differences were found between samples from the five seal groups (adult male hooded seals, lactating female hooded seals, unweaned hooded seal pups; lactating female harp seals, and unweaned harp seal pups) for hematology and most serum chemistry parameters. In general, age-class influenced mean values of PCV, hemoglobin (HB), red blood cell (RBC) counts, MCV, mean cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC), and nucleated red blood cell (NRBC) counts per 100 leucocytes, but most age-related variations were species specific. Harp seal pups had significantly lower mean values of HB, PCV, MCH, and MCHC than did other seal groups, and significantly lower mean RBC counts than did hooded seal pups. Mean NRBC counts per 100 leukocytes were more than three times higher in harp seal pups than in hooded seal pups, but this difference was not statistically significant. Mean MCV were significantly lower in harp and hooded seal pups compared to those of adult harp and hooded seals. Differences in hemograms between pup species were likely because of the precocious development of hooded seal pups, which are weaned within 4 days, compared to 12 days for harp seal pups. Among adult seal groups, male hooded seals had significantly higher mean values of PCV and HB than did female harp and hooded seals, and significantly higher mean RBC counts than did adult female hooded seals. Among adult females, mean values of MCH and MCHC were statistically higher in hooded seals than in harp seals. Adult female harp and hooded seals did not differ significantly in other RBC parameters and mean leukocyte counts. Mean values of glucose, blood urea nitrogen, total bilirubin, alanine aminotransferase (ALT), alkaline phosphatase (ALP), total protein, and albumin showed species-specific variations between adults and pups. Except for ALP, few significant differences in mean enzyme activities of aspartate aminotransferase (AST), ALT, creatine kinase and gamma-glutamyltransferase were found between seal groups. Mean concentrations of electrolytes (calcium, phosphorus, sodium, potassium, chloride, magnesium, and total carbon dioxide) varied with age class, but variations in potassium and magnesium were species specific. Harp seal pups had significantly higher mean phosphorus and potassium levels compared to other seal groups.     

Nanoflagellate predation on auto- and heterotrophic picoplankton in the oligotrophic Mediterranean Sea

Dynamics of autotrophic and heterotrophic prokaryotes and theirconsumption by nanoflagellates were studied in the euphoticzone at nine stations located from the Levantine Basin (34°E)to the Balearic sea (5°E) in June 1999. Bacterial biomassconstituted the largest proportion of living biomass at allstations. Integrated bacterial production at the furthest eaststation, was sixfold lower than integrated bacterial productionat the furthest west (13 and 75 mg C m^-2 d^-1 respectively).Estimated heterotrophic nanoflagellate bacterivory accountedfor 45–87% of bacterial production. Small protists (<3µm) dominated the bacterivore assemblage and accountedfor more than 90% of the heterotrophic bacterial consumption.Our results indicated that there was no negative selection againstSynechococcus and that both picoplankton groups were grazedaccording to their standing stocks. An estimated consumptionof Synechococcus derived from food vacuole content analysisof nanoflagellates revealed that they consumed from 0.5 to 45%(mean 13%) of Synechococcus stock per day. These data are amongthe first documenting the relative grazing impact of heterotrophicnanoflagellates on bacteria and Synechococcus in situ. Assumingthat there was no selection for or against Prochlorococcus,heterotrophic nanoflagellates could ingest from 1.4 to 21% (mean6%) of Prochlorococcus stock per day. The amount of organiccarbon obtained by heterotrophic nanoflagellates from photosyntheticprokaryotes represented 27% of the total amount of carbon obtainedfrom total prokaryotes     

Increased local levels of granulocyte colony-stimulating factor are associated with the beneficial effect of pre-elafin (SKALP/trappin-2/WAP3) in experimental emphysema

Few therapeutic options are offered to treat inflammation and alveolar wall destruction in emphysema. The effect of recombinant human pre-elafin, an elastase inhibitor, was evaluated in porcine pancreatic elastase (PPE)-induced emphysema in C57BL/6 mice. In a first protocol, mice received a single instillation of pre-elafin (17.5 pmol/mouse) at 1 h post-PPE and were sacrificed up to 72 h post-PPE. A single instillation of pre-elafin significantly reduced PPE-induced neutrophil accumulation in lungs, as assessed by bronchoalveolar lavage (BAL), by 51%, 71% and 67% at 24, 48 and 72 h, respectively. In a second protocol, mice also received a single dose of PPE, but pre-elafin three times a week for 2 weeks. After 2 weeks, pre-elafin significantly reduced the PPE-induced increase in BAL macrophage numbers, airspace dimensions and lung hysteresivity by 74%, 62% and 52%, respectively. Since G-CSF was previously shown to reduce emphysematous changes in mice, the BAL levels of this mediator were measured 6 h post-PPE in animals treated as described in the first protocol. Pre-elafin significantly increased G-CSF levels in PPE-exposed mice compared to sham- and PPE only-exposed animals. This suggests that the beneficial effects of pre-elafin could be mediated, at least in part, by its ability to increase G-CSF levels in the lung.