Prior in vitro exposure to GLP-1 with or without GIP can influence the subsequent beta cell responsiveness

Glucagon-like peptide-1 (7-36) amide (GLP-1) and glucose-dependent insulinotropic peptide (GIP) potentiate glucose-induced insulin release when present at the time of nutrient stimulation. This study examines whether they can also influence rat beta cell responsiveness to subsequent stimulations. When rat beta cells were cultured for 24 h with 1 nM GLP-1, they progressively desensitized to subsequent GLP-1 stimuli, as evidenced by cellular cAMP production. This GLP-1-induced desensitization did not occur when the incretin was only present during three periods of 1 h at 10 mM glucose that alternated with 6-9 h culture at 3 mM glucose. After these 24h, the beta cells exhibited the same secretory response to glucose (10 mM) and GLP-1 (10 nM at 10 mM glucose), whether GLP-1 was present during the pulses or not. Similarly the presence of 1 nM GIP during these one hour pulses did not influence subsequent secretory responses to glucose and GLP-1. However, when both GLP-1 and GIP, each at 0.5 nM, were added to the one hour pulses, they not only amplified insulin release during the pulses, as was the case with their single addition, but also increased the secretory response to a subsequent stimulation by glucose and GLP-1. These data distinguish between a desensitization effect of a prolonged exposure to GLP-1 and a positive priming effect of a discontinuous exposure to a combination of GLP-1 plus GIP. They may have to be taken into account in drug treatment strategies aiming the mimicking of physiologic patterns in the regulation of insulin release.     

Variations in estrogen receptor alpha gene and risk of dementia, and brain volumes on MRI

The role of estrogens in Alzheimer's disease (AD) is controversial. We investigated the association between well-recognized, and potentially functional, polymorphisms in the estrogen receptor (ER) alpha gene and the risk of AD in a prospective study of 6056 Caucasian older men and women aged 55 years and over. In a subset of 468 participants, we assessed volumes of the hippocampus and amygdala, which have a high density of ER alpha, with brain magnetic resonance imaging (MRI) (1.5 T MR unit). During a total of 35 405 person-years of follow-up (mean per persons 5.8 years), 312 new cases of dementia were detected, of whom 230 were diagnosed with AD. Neither the PvuII nor the XbaI polymorphism or haplotypes thereof were associated with the risk of all-cause dementia or AD. In contrast, we found that nondemented women who carried the PvuII p allele or haplotype 'px' had smaller amygdalar volumes on MRI in an allele-dose-dependent fashion. Total amygdalar volume was 4.50 (SE 0.10) in PP genotype, 4.45 (SE 0.06) in Pp genotype, and 4.18 ml (SE 0.08) in pp genotype (P trend=0.008). Further studies are required to investigate whether this smaller amygdalar volume has functional significance.     

Cerebral white matter lesions and the risk of dementia

OBJECTIVE: To study the association between white matter lesions (WML) in specific locations and the risk of dementia. DESIGN: The Rotterdam Scan Study, a prospective population-based cohort study. We scored periventricular and subcortical WML on magnetic resonance imaging and observed participants until January 2002 for incident dementia. SETTING: General population. PARTICIPANTS: We included 1077 people aged 60 to 90 years who did not have dementia at baseline. MAIN OUTCOME MEASURE: Incident dementia by Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM III-R) criteria. RESULTS: During a mean follow-up of 5.2 years, 45 participants developed dementia. Higher severity of periventricular WML increased the risk of dementia, whereas the association between subcortical WML and dementia was less prominent. The adjusted hazard ratio of dementia for each standard deviation increase in periventricular WML severity was 1.67 (95% confidence interval, 1.25-2.24). This increased risk was independent of other risk factors for dementia and partly independent of other structural brain changes on magnetic resonance imaging. CONCLUSION: White matter lesions, especially in the periventricular region, increase the risk of dementia in elderly people.     

Physical activity and cognitive decline, the role of the apolipoprotein e4 allele

PURPOSE: The purpose of this study was to investigate the association between level of physical activity and risk of cognitive decline at older age and its variation across carriers and noncarriers of the apolipoprotein e4 allele. METHODS: The association was studied in a cohort of 347 elderly Dutch men. Mean age of the study subjects was 74.6 +/- 4.3 yr in 1990. Physical activity was categorized in "maximal 1 h per day" versus "more than 1 h per day." Cognitive decline was defined as a drop MMSE score > 3 points between 1990 and 1993. RESULTS: After adjusting for age, education, alcohol consumption, smoking and cognitive functioning at baseline, subjects with maximal 1 h of physical activity per day had a two-fold increased risk of cognitive decline (OR 2.0, 95% CI: 0.9-4.8) as compared with the rest. Risk of cognitive decline was particularly strong in carriers of the APOE*4 allele (adjusted OR 3.7, 95% CI: 1.1-12.6). CONCLUSION: The authors conclude that promotion of physical activity at older age may reduce the risk of cognitive decline. The existence of subgroups with a particularly high risk may have important implications for prevention strategies.     

Propofol versus midazolam for procedural sedation in the emergency department: A study on efficacy and safety

Background

Procedural sedation for painful procedures in the emergency department (ED) can be accomplished with various pharmacological agents. The choice of the sedative used is highly dependent on procedure- and patient characteristics and on personal- or local preferences.

Evaluation of the Novel PET Tracer [11C]HACH242 for Imaging the GluN2B NMDA Receptor in Non-Human Primates

Purpose

There are currently no positron emission tomography (PET) radiotracers for the GluN2B (NR2B) binding sites of brain N-methyl-d-aspartate (NMDA) receptors. In rats, the GluN2B antagonist Ro25-6981 reduced the binding of N-((5-(4-fluoro-2-[¹¹C]methoxyphenyl)pyridin-3-yl)methyl)cyclopentanamin ([¹¹C]HACH242). This paper reports the evaluation of [¹¹C]HACH242 PET in non-human primates at baseline and following administration of the GluN2B negative allosteric modulator radiprodil.

Procedures

Eight 90-min dynamic [¹¹C]HACH242 PET scans were acquired in three male anaesthetised rhesus monkeys, including a retest session of subject 1, at baseline and 10 min after intravenous 10 mg/kg radiprodil. Standardised uptake values (SUV) were calculated for 9 brain regions. Arterial blood samples were taken at six timepoints to characterise pharmacokinetics in blood and plasma. Reliable input functions for kinetic modelling could not be generated due to variability in the whole-blood radioactivity measurements.

Results

[¹¹C]HACH242 entered the brain and displayed fairly uniform uptake. The mean (±?standard deviation, SD) T_max was 17?±?7 min in baseline scans and 24?±?15 min in radiprodil scans. The rate of radioligand metabolism in plasma (primarily to polar metabolites) was high, with mean parent fractions of 26?±?10 % at 20 min and 8?±?5 % at 85 min. Radiprodil increased [¹¹C]HACH242 whole-brain SUV in the last PET frame by 25 %, 1 %, 3 and 17 % for subjects 1, 2, 3 and retest of subject 1, respectively. The mean brain to plasma ratio was 5.4?±?2.6, and increased by 39 to 110 % in the radiprodil condition, partly due to lower parent plasma radioactivity of ?11 to ?56 %.

Conclusions

The present results show that [¹¹C]HACH242 has a suitable kinetic profile in the brain and low accumulation of lipophilic radiometabolites. Radiprodil did not consistently change [¹¹C]HACH242 brain uptake. These findings may be explained by variations in cerebral blood flow, a low fraction of specifically bound tracer, or interactions with endogenous NMDA receptor ligands at the binding site. Further experiments of ligand interactions are necessary to facilitate the development of radiotracers for in vivo imaging of the ionotropic NMDA receptor.

     

A pilot study for one-stop endoscopic total extraperitoneal inguinal hernia repair

Background  

One-stop surgery was developed for patients to undergo surgical evaluation, anesthesia, surgery, and discharge all within 1 day. This study aimed to assess the feasibility, patient satisfaction, and potential of one-stop endoscopic total extraperitoneal (TEP) inguinal hernia surgery.     

Home literacy environment of pre‐school children with intellectual disabilities

Background For pre‐school children, the home literacy environment (HLE) plays an important role in the development of language and literacy skills. As there is little known about the HLE of children with intellectual disabilities (ID), the aim of the present study was to investigate the HLE of children with ID in comparison with children without disabilities. Method Parent questionnaires concerning aspects of the HLE were used to investigate differences between 48 children with ID, 107 children without disabilities of the same chronological age and 36 children without disabilities of the same mental age (MA). Furthermore, for the children with ID, correlations were computed between aspects of the HLE and children's non‐verbal intelligence, speech intelligibility, language and early literacy skills. Results and conclusions From the results of the multivariate analyses of variance it could be concluded that the HLE of children with ID differed from that of children in the chronological age group on almost all aspects. When compared with children in the MA group, differences in the HLE remained. However, differences mainly concerned child‐initiated activities and not parent‐initiated activities. Correlation analyses showed that children's activities with literacy materials were positively related with MA, productive syntax and vocabulary age, and book orientation skills. Also, children's involvement during storybook reading was related with their MA, receptive language age, productive syntax and vocabulary age, book orientation and rapid naming of pictures. The amount of literacy materials parents provided was related to a higher productive syntax age and level of book orientation of the children. Parent play activities were also positively related to children's speech intelligibility. The cognitive disabilities of the children were the main cause of the differences found in the HLE between children with ID and children without disabilities. Parents also adapt their level to the developmental level of their child, which may not always be the most stimulating for the children.