Hyperaemia in rat neocortex produced by acute exposure to methylenedioxymethamphetamine

Cerebral blood flow and glucose utilization were measured in rat neocortex, hippocampus and striatum following methylenedioxymethamphetamine injection (5 mg/kg, i.v.), using the tracers [¹⁴C]iodoantipyrine and [¹⁴C]2-deoxyglucose, respectively. In control rats, blood flow was coupled to glucose metabolism, but in methylenedioxymethamphetamine-treated rats, marked hyperperfusion was measured in frontal and parietal cortex with no change in glucose use. This suggests that methylenedioxymethamphetamine has the potential to disrupt cerebrovascular control.     

18F-FDG assessment of glucose disposal and production rates during fasting and insulin stimulation: a validation study.

The glucose analog (18)F-FDG is commonly used to quantify regional glucose uptake in vivo. The aim of this study was to test whether the analysis of plasma (18)F-FDG kinetics could be used to estimate endogenous glucose production (EGP) and the total rate of appearance (Ra), total rate of disappearance (Rd), and the metabolic clearance rate (MCR) of glucose. METHODS: Fourteen pigs were coinjected with (18)F-FDG and 6,6-(2)H-glucose ((2)H-G) during fasting (n = 6) and during physiologic (1.0 mU.kg(-1).min(-1), n = 4) and supraphysiologic (5.0 mU.kg(-1).min(-1), n = 4) euglycemic hyperinsulinemia. Arterial plasma was sampled for 180 min to quantify the parameters for the 2 tracers. RESULTS: Fasting Rd((2))(H-G) and Rd(FDG) were 12.3 +/- 2.1 and 13.3 +/- 1.3 micromol.kg(-1).min(-1) (difference not statistically significant [NS]). M values were more than doubled between the 2 clamp studies (P < 0.0001). Rd((2))(H-G) and Rd(FDG) were dose-dependently higher during the hyperinsulinemic state (19.8 +/- 3.7 vs. 18.9 +/- 1.1 and 31.4 +/- 4.1 vs. 31.9 +/- 2.3 in 1.0 and 5.0 mU.kg(-1).min(-1) studies, respectively; difference between tracers NS) than during the fasting state, with a parallel suppression of EGP((2))(H-G) and EGP(FDG). Parameters estimated by (18)F-FDG and (2)H-G were equivalent in all groups; their agreement was confirmed by Bland-Altman examination. Total Rd(FDG) correlated with Rd((2))(H-G) (r = 0.74; P = 0.003), M (r = 0.92; P = 0.001), MCR((2))(H-G) (r = 0.52; P = 0.037), and EGP((2))(H-G) (r = -0.71; P = 0.004). EGP(FDG) correlated with EGP((2))(H-G) (r = 0.62; P = 0.018), Rd((2))(H-G) (r = -0.78; P = 0.001), and MCR((2))(H-G) (r = -0.67; P = 0.008). The (18)F-FDG mean transit time correlated inversely with the M and Rd values and positively with EGP. CONCLUSION: The glucose analog (18)F-FDG can be used in the simultaneous estimation of whole-body glucose turnover and production and regional (18)F-FDG PET measurements under both fasting and insulin-stimulated conditions.     

Haploinsufficiency of Pkd2 is associated with increased tubular cell proliferation and interstitial fibrosis in two murine Pkd2 models.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited human kidney disease and is caused by germline mutations in PKD1 (85%) or PKD2 (15%). It has been estimated that around 1% of tubular cells give rise to cysts, and cell hyperproliferation has been noted to be a cardinal feature of cystic epithelium. Nevertheless, it is uncertain whether the increase in proliferative index observed is an early or late feature of the cystic ADPKD kidney. METHODS: Two Pkd2 mouse mutants (WS25 and WS183) have been recently generated as orthologous models of PKD2. To determine the effect of Pkd2 dosage on cell proliferation, cyst formation and renal fibrosis, we studied renal tissue from Pkd2(WS25/WS25) and Pkd2(+/-) mice by histological analysis. We also examined the proliferative index in archival nephrectomy tissue obtained from patients with ADPKD and normal controls. RESULTS: The proliferative index of non-cystic tubules in Pkd2 mutant mice as assessed by proliferating cell nuclear antigen and Ki67-positive nuclei was between 1-2%, values 5-10 times higher than control tissue. Similarly, the proliferative index of non-cystic tubules in human ADPKD kidneys was 40 times higher than corresponding controls. In Pkd2 mutant mice, significant correlations were found between the fibrosis score and the mean cyst area as well as with the proliferative index. Of significance, proliferating tubular cells were uniformly positive for polycystin-2 expression in Pkd2(+/-) kidney. CONCLUSION: These results suggest that an increase in cell proliferation is an early event preceding cyst formation and can result from haploinsufficiency at Pkd2. The possible pathogenic link between tubular cell proliferation, interstitial fibrosis and cyst formation is discussed.     

Neonatal Exposure to a Combination of N-Methyl-d-aspartate and γ-Aminobutyric Acid Type A Receptor Anesthetic Agents Potentiates Apoptotic Neurodegeneration and Persistent Behavioral Deficits

Background: During the brain growth spurt, the brain develops and modifies rapidly. In rodents this period is neonatal, spanning the first weeks of life, whereas in humans it begins during the third trimester and continues 2 yr. This study examined whether different anesthetic agents, alone and in combination, administered to neonate mice, can trigger apoptosis and whether behavioral deficits occur later in adulthood.

Methods: Ten-day-old mice were injected subcutaneously with ketamine (25 mg/kg), thiopental (5 mg/kg or 25 mg/kg), propofol (10 mg/kg or 60 mg/kg), a combination of ketamine (25 mg/kg) and thiopental (5 mg/kg), a combination of ketamine (25 mg/kg) and propofol (10 mg/kg), or control (saline). Fluoro-Jade staining revealed neurodegeneration 24 h after treatment. The behavioral tests-spontaneous behavior, radial arm maze, and elevated plus maze (before and after anxiolytic)-were conducted on mice aged 55-70 days.

Results: Coadministration of ketamine plus propofol or ketamine plus thiopental or a high dose of propofol alone significantly triggered apoptosis. Mice exposed to a combination of anesthetic agents or ketamine alone displayed disrupted spontaneous activity and learning. The anxiolytic action of diazepam was less effective when given to adult mice that were neonatally exposed to propofol.     

Serial in vivo MR tracking of magnetically labeled neural spheres transplanted in chronic EAE mice.

Neural stem cell (NSC) transplantation has been shown to attenuate the severity of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Central to the future success of NSC transplantation in MS is the ability of transplanted cells to migrate from the site of transplantation to relevant foci of disease. Using magnetically labeled mouse neurospheres and human embryonic stem cell (hESC)-derived neurospheres, we applied serial magnetic resonance imaging (MRI) to assess the biodynamics of transplanted cell migration in a chronic mouse EAE model. Magnetic labeling did not affect the in vitro and in vivo characteristics of cells as multipotential precursors. Cell migration occurred along white matter (WM) tracts (especially the corpus callosum (CC), fimbria, and internal capsule), predominantly early in the acute phase of disease, and in an asymmetric manner. The distance of cell migration correlated well with clinical severity of disease and the number of microglia in the WM tracts, supporting the notion that inflammatory signals promote transplanted cell migration. This study shows for the first time that hESC-derived neural precursors also respond to tissue signals in an MS model, similarly to rodent cells. The results are directly relevant for designing and optimizing cell therapies for MS, and achieving a better understanding of in vivo cell dynamics and cell-tissue interactions.     

Compliance with ambulatory saliva sampling in the Chicago Health, Aging, and Social Relations Study and associations with social support

Background: Noncompliance with instructed saliva sampling times in ambulatory settings can compromise resulting cortisol findings.Purpose and Methods: Here, the impact of noncompliance on the cortisol awakening response (CAR), an established marker for hypothalamic-pituitary-adrenal axis activity, was examined over 3 sampling days in middle- and older-age participants in the Chicago Health, Aging, and Social Relations Study.Results: Noncompliant participants had a significantly lower cortisol rise after awakening (assessed by an awakening sample and a 30-min after awakening sample) on 2 of the 3 sampling days (Day 1, ns; Days 2 & 3, ps<.02). Furthermore, social support measured by the Interpersonal Support Evaluation List correlated negatively with the number of “noncompliant” samples (r=−.19, p<.05), indicating that participants reporting more social support had more “compliant” samples.Conclusion: The results confirm that nonadherence to saliva sampling in ambulatory settings can exert a significant impact on the resulting CAR. Furthermore, the data raise the idea that the extent of nonadherence might be systematically associated with psychosocial factors like social support. For future studies on the relationship between CAR and psychological factors, we therefore recommend controlling for saliva sampling adherence because noncompliance might be systematically associated with the phenomenon being investigated. Funding was provided by the National Institute of Aging Grant No. PO1 AG18911 and the John Templeton Foundation. Brigitte M. Kudielka was supported by grants from the German Research Foundation (DFG grant KU 1401/3-1 and KU 140/4-1).     

STAFF BURNOUT AND ABSENTEEISM THROUGH SERVICE TRANSITION: FROM HOSPITAL TO HOSTEL

Residential nursing staff were asked to complete the Maslach Burnout Inventory (MBI) each month for a total of six months throughout a service transition involving the move of a group of men with profound learning disabilities, some with additional challenging behaviours, from two hospital wards to a community-living orientated hostel. The MBI was used to measure the effect on staff of the intense reorganisation in their working environment. Significant increases in Emotional Exhaustion and Depersonalisation, and a (non significant) decrease in Personal Accomplishment were found during the transition. Levels reverted to baseline following the move, but burnout remained above the mean of a previously published study, for two of the three dimensions. Levels of absenteeism largely mirrored the pattern of the MBI scores, with a one-month lapse between high burnout and high absenteeism, supporting previous research indicating an association between the two.     

Milgram and Tuskegee—Paradigm Research Projects in Bioethics

This paper discusses the use of the Milgram obedience experiments and the Tuskegee syphilis study in the bioethical literature. The two studies are presented and a variety of uses of them identified and discussed. It is argued that the use of these studies as paradigms of problematic research relies on a reduction of their complexity. What is discussed is thus often constructions of these studies that are closer to hypothetical examples than to the real studies.     

The human desmin gene: A specific regulatory programme in skeletal muscle both in vitro and in transgenic mice

Desmin synthesis is restricted to cardiac, skeletal and smooth muscles. In several familial myopathies involving fibre disorganization, filamentous aggregation of desmin has been characterized. During the development of the mouse embryo, desmin is one of the first muscle proteins detected in both the heart and the somites. To identify the DNA sequences involved in the regulation of desmin gene expression a 4.5 kb 5′-flanking region of the human desmin gene has been isolated. Different mutants were used to characterize specific enhancers in vitro and in vivo. The results obtained with transgenic mice provide evidence that the 1 kb cis-regulatory sequences, functional in skeletal muscle cells in vitro, confer specific developmental control for skeletal muscles. Furthermore, distinct programmes for cardiac and skeletal muscle-specific expression of the desmin gene are revealed.