K(ATP) channels and pancreatic islet blood flow in anesthetized rats: increased blood flow induced by potassium channel openers

K(ATP) channels are important for insulin secretion and depolarization of vascular smooth muscle. In view of the importance of drugs affecting K(ATP) channels in the treatment of diabetes, we investigated the effects of these channels on splanchnic blood perfusion in general and pancreatic islet blood flow in particular. We treated anesthetized Sprague-Dawley rats with the K(ATP) channel openers diazoxide or NNC 55-0118 or the K(ATP) channel closer glipizide. Both diazoxide and NNC 55-0118 dose-dependently increased total pancreatic and islet blood flow in the presence of moderate hyperglycemia, but had no effects on the blood perfusion of other splanchnic organs. Diazoxide markedly lowered the mean arterial blood pressure and thus increased vascular conductance in all organs studied. NNC 55-0118 had much smaller effects on the blood pressure. Glipizide did not affect total pancreatic blood flow, but decreased islet blood flow by 50% in the presence of hypoglycemia. We conclude that K(ATP) channels actively participate in the blood flow regulation of the pancreatic islets and that substances affecting such channels may also influence islet blood flow.     

Flow-volume curves in healthy non-smokers and in smokers

Summary. Maximum expiratory flow-volume curves were recorded in lung healthy non-smokers and in smokers. Multiple linear regression analysis was performed with regard to sex, age, height and weight. The regressions for maximum expiratory flow at 50% and 25% of vital capacity (MEF₅₀ and MEF₂₅, respectively) on age were significantly different for non-smokers and smokers, in males as well as females, but the large scatter around the regression line resulted in more than 50% of presently studied smokers to fall within 1 SD of the reference values for non-smokers. A skew distribution of MEF₂₅ around the mean was observed at ages above 60 years and so set an upper limit for the linear regression. Above 60 years no linear age dependence was found for MEF₂₅. There was a minor reduction (2%) in the residual standard deviation of the peak expiratory flow (PEF), MEF₅₀ and MEF₂₅ regressions when height was added as an independent variable besides age, while the addition of weight did not reduce the scatter. We conclude that the inter-individual variability in MEF^ and MEF25 is relatively large even when sex and age are accounted for and that there is no further benefit in including height or weight in the regression equations. The discriminating ability of the MEF₅₀ and MEF₂₅ variables is small, indicated by considerable overlapping between non-smokers and smokers.     

Autism as a Natural Human Variation: Reflections on the Claims of the Neurodiversity Movement

Neurodiversity has remained a controversial concept over the last decade. In its broadest sense the concept of neurodiversity regards atypical neurological development as a normal human difference. The neurodiversity claim contains at least two different aspects. The first aspect is that autism, among other neurological conditions, is first and foremost a natural variation. The other aspect is about conferring rights and in particular value to the neurodiversity condition, demanding recognition and acceptance. Autism can be seen as a natural variation on par with for example homosexuality. The broad version of the neurodiversity claim, covering low-functioning as well as high-functioning autism, is problematic. Only a narrow conception of neurodiversity, referring exclusively to high-functioning autists, is reasonable. We will discuss the effects of DSM categorization and the medical model for high functioning autists. After a discussion of autism as a culture we will analyze various possible strategies for the neurodiversity movement to claim extra resources for autists as members of an underprivileged culture without being labelled disabled or as having a disorder. We will discuss their vulnerable status as a group and what obligation that confers on the majority of neurotypicals.     

The effect of capsule composition in the reversal of hyperglycemia in diabetic mice transplanted with microencapsulated allogeneic islets

The transplantation of microencapsulated islets may allow reversal of hyperglycemia in the absence of immunosuppression. Poly-L-lysine (PLL) on capsules may potentiate the fibrotic reaction against implanted capsules. The aims of this study were to investigate how the biocompatibility of such capsules affects their function in vivo and to compare their efficacy relative to naked islets after intraperitoneal transplantation to nude or immune competent mice. Alloxan-diabetic C57BL/6 wild-type or nude (nu/nu) mice were transplanted with naked BALB/c islets, empty capsules, or microencapsulated BALB/c islets. Three types of capsules were used, one containing a high guluronic acid (G) alginate and PLL, one with a high mannuronic acid (M) alginate and PLL, and one high M alginate capsule with no PLL. Hyperglycemia in nude mice was reversed after transplantation of naked islets or islets encapsulated in a capsule containing high M alginate. Nude mice transplanted with islets encapsulated in the high G capsules showed only a transient reversal of hyperglycemia. In an allogeneic system, naked BALB/c islets were rejected by day 10 after transplantation, whereas the islets encapsulated in high M capsules continued to function for at least a month. When PLL was excluded from the capsules, the grafts functioned for up to 8 weeks. Islets microencapsulated in high G alginate capsules fail to reverse hyperglycemia for more than a few days in nude mice. However, islets in high M alginate capsules can reverse hyperglycemia in nude and immune competent mice. Islets microencapsulated in PLL-free high M alginate capsules function for 8 weeks in immune competent mice.     

Sulfation of budesonide by human cytosolic sulfotransferase, dehydroepiandrosterone-sulfotransferase (DHEA-ST).

Budesonide, a synthetic glucocorticosteroid, is used in the treatment of asthma and allergic reactions, rhinitis, and inflammatory bowel disease. It is distributed as a mixture of two epimers, 22R and 22S, and has a high ratio of topical to systemic activity due to extensive first-pass metabolism to metabolites with minimal activity. Previous studies have shown that the epimers are metabolized by the cytochrome P450 monooxygenase system. Metabolism and inactivation of the epimers by the phase II enzymes has not been well characterized. This study describes the conjugation of budesonide by human cytosolic sulfotransferases (SULTs). Seven human SULTs were analyzed to determine which were capable of catalyzing the sulfation of the epimers of budesonide. Only dehydroepiandrosterone-sulfotransferase (DHEA-ST, SULT2A1) was capable of forming a sulfated budesonide product. The epimeric forms of budesonide display different kinetic activities with the 22R epimer having a 3.5-fold greater rate of sulfation activity than the 22S epimer. The structure of budesonide shows two hydroxyl sites that are potential sites for sulfate conjugation, but analysis by mass spectrometry indicates the formation of only a monosulfated budesonide product. A modeling approach was used to define the site of sulfation as that of the 21-hydroxyl group. Although sulfation of budesonide by DHEA-ST may not be an important factor in its use as an antiasthmatic, intestinal and hepatic sulfation will be important for its proposed systemic use as an anti-inflammatory agent.