Cognitive disorders and neurogenesis deficits in Huntington's disease mice are rescued by fluoxetine

Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded CAG trinucleotide repeat encoding an extended polyglutamine tract in the huntingtin protein. Affected individuals display progressive motor, cognitive and psychiatric symptoms (including depression), leading to terminal decline. Given that transgenic HD mice have decreased hippocampal cell proliferation and that a deficit in neurogenesis has been postulated as an underlying cause of depression, we hypothesized that decreased hippocampal neurogenesis contributes to depressive symptoms and cognitive decline in HD. Fluoxetine, a serotonin-reuptake inhibitor commonly prescribed for the treatment of depression, is known to increase neurogenesis in the dentate gyrus of wild-type mouse hippocampus. Here we show that hippocampal-dependent cognitive and depressive-like behavioural symptoms occur in HD mice, and that the administration of fluoxetine produces a marked improvement in these deficits. Furthermore, fluoxetine was found to rescue deficits of neurogenesis and volume loss in the dentate gyrus of HD mice.

Male reproductive tactics and female choice in the solitary, promiscuous bridled nailtail wallaby (Onychogalea fraenata)

Several behavioral studies of large, gregarious, and sexually dimorphic macropods have shown that males form dominance hierarchies and large males have the highest reproductive success. The bridled nailtail wallaby (Onychogalea fraenata) is a smaller and strongly sexually dimorphic macropod, but is also highly solitary and males do not form dominance hierarchies that are maintained temporally or spatially. Genetic studies of paternity have shown that large males are the most reproductively successful and only one-quarter of males sire offspring at any one time. The aim of this study was to investigate the tactics that males adopt to secure access to females at the time of estrus and to investigate whether females can influence which males have access to them. This study was conducted using 2 wild, free-ranging populations of bridled nailtail wallabies. Females in estrus were located and observed. and the total number of males present, the relative weight rank of each mate, and interactions between individuals were recorded. Females showed a preference for large males and incited male-male competition when the group of males present was large. Unlike other dimorphic macropods, fights among males were rare and were restricted to males of similar size. Large males gained access to females by guarding and following them closely and threatening other males who attempted to gain access. Smaller males spent less time with females, suggesting that small males may leave multimale groups in an attempt to locate unguarded females. Given the solitary nature of this species and the lack of a stable dominance hierarchy to influence male reproductive success. mate searching and mate guarding may be important male reproductive tactics in this species.

A pathology of the animal spirits - the clinical neurology of Thomas Willis (1621-1675) Part I - Background, and disorders of intrinsically normal animal spirits

Thomas Willis (1621-1675), author of the classical work Cerebri Anatome (1664), was arguably the father of the modem era of neurology. As compared with his neuroanatomy, relatively little attention has been paid to Willis' clinical neurology, as described in his Pathologiae Cerebri (1667) and Do Anima Brutorum (1672), where he gave a structured account of disease of the nervous system as it was known in his day. His account was largely derived from personal observations and not from traditional authorities and was based around his concept of the animal spirits, a fictitious entity in many ways analogous to the present day idea of the nerve impulse. This concept allowed him to develop a pathology of the animal spirits which embraced the whole content of the clinical neurology and psychiatry of his times. The anatomical and physiological background to Willis! concepts of animal spirit dysfunction, and those disorders he regarded as due to disturbed function of intrinsically normal animal spirits (mainly headache, disorders of consciousness, apoplexy and palsy) are dealt with in the present paper. The disorders he attributed to inherently abnormal animal spirits are considered in a second part of the paper. (C) 2002 Elsevier Science Ltd. All eights reserved.

No Association Between MTHFR A1298C and MTRR A66G Polymorphisms, and MS in an Australian Cohort

Multiple sclerosis (MS) is a complex neurological disease that affects the central nervous system (CNS) resulting in debilitating neuropathology. Pathogenesis is primarily defined by CNS inflammation and demyelination of nerve axons. Methionine synthase reductase (MTRR) is an enzyme that catalyzes the remethylation of homocysteine (Hcy) to methionine via cobalamin and folate dependant reactions. Cobalamin acts as an intermediate methyl carrier between methylenetetrahydrofolate reductase (MTHFR) and Hcy. MTRR plays a critical role in maintaining cobalamin in an active form and is consequently an important determinant of total plasma Hcy (pHcy) concentrations. Elevated intracellular pHcy levels have been suggested to play a role in CNS dysfunction, neurodegenerative, and cerebrovascular diseases. Our investigation entailed the genotyping of a cohort of 140 cases and matched controls for MTRR and MTHFR, by restriction length polymorphism (RFLP) techniques. Two polymorphisms: MTRR A66G and MTHFR A1298C were investigated in an Australian age and gender matched case-control study. No significant allelic frequency difference was observed between cases and controls at the α = 0.05 level (MTRR χ^2 = 0.005, P = 0.95, MTHFR χ^2 = 1.15, P = 0.28). Our preliminary findings suggest no association between the MTRR A66G and MTHFR A1298C polymorphisms and MS.

Test–retest repeatability of self-reported environmental exposures in Parkinson’s disease cases and healthy controls

There is substantial disagreement among published epidemiological studies regarding environmental risk factors for Parkinson’s disease (PD). Differences in the quality of measurement of environmental exposures may contribute to this variation. The current study examined the test–retest repeatability of self-report data on risk factors for PD obtained from a series of 32 PD cases recruited from neurology clinics and 29 healthy sex-, age-and residential suburb-matched controls. Exposure data were collected in face-to-face interviews using a structured questionnaire derived from previous epidemiological studies. High repeatability was demonstrated for ‘lifestyle’ exposures, such as smoking and coffee/tea consumption (kappas 0.70–1.00). Environmental exposures that involved some action by the person, such as pesticide application and use of solvents and metals, also showed high repeatability (kappas>0.78). Lower repeatability was seen for rural residency and bore water consumption (kappa 0.39–0.74). In general, we found that case and control participants provided similar rates of incongruent and missing responses for categorical and continuous occupational, domestic, lifestyle and medical exposures.

Cerebrospinal fluid and plasma concentrations of morphine, morphine-3-glucuronide, and morphine-6-glucuronide in patients before and after initiation of intracerebroventricular morphine for cancer pain management

Twenty-three patients treated with intracerebroventricular (ICV) morphine in this study not only obtained excellent pain relief without rapid increases in dose, but also experienced a reduction in morphine-related side effects. By 24 h after initiation of ICV morphine, the mean trough cerebrospinal fluid (CSF) morphine concentration (approximately 20 mu M) was 50-fold higher than the baseline concentration (approximately 0.4 mu M), and the CSF concentration of morphine-6-glucuronide (M6G) was undetectable (

Effects of beta-escin and saponin on the transverse-tubular system and sarcoplasmic reticulum membranes of rat and toad skeletal muscle

Mechanically skinned skeletal muscle fibres from rat and toad were exposed to the permeabilizing agents beta-escin and saponin. The effects of these agents on the sealed transverse tubular system (t-system) and sarcoplasmic reticulum (SR) were examined by looking at changes in the magnitude of the force responses to t-system depolarization, the time course of the fluorescence of fura-2 trapped in the sealed t-system, and changes in the magnitude of caffeine-induced contractures following SR loading with Ca2+ under defined conditions. In the presence of 2 mu g ml(-1) beta-escin and saponin, the response to t-system depolarization was not completely abolished, decreasing to a plateau, and a large proportion of fura-2 remained in the sealed t-system. At 10 mu g ml(-1), both agents abolished the ability of both rat and toad preparations to respond to t-system depolarization after 3 min of exposure, but a significant amount of fura-2 remained in sealed t-tubules even after exposure to 100 mu g ml(-1) beta-escin and saponin for 10 min. beta-Escin took longer than saponin to reduce the t-system depolarizations and fura-2 content of the sealed t-system to a similar level. The ability of the SR to load Ca2+ was reduced to a lower level after treatment with beta-escin than saponin. This direct effect on the SR occurred at much lower concentrations for rat (2 mu g ml(-1) beta-escin and 10 mu g ml(-1) saponin) than toad (10 mu g ml(-1) beta-escin and 150 mu g ml(-1) saponin). The reverse order in sensitivities to beta-escin and saponin of t-system and SR membranes indicates that the mechanisms of action of beta-escin and saponin are different in the two types of membrane. In conclusion, this study shows that: (1) beta-escin has a milder action on the surface membrane than saponin; (2) beta-escin is a more potent modifier of SR function; (3) simple permeabilization of membranes is not sufficient to explain the effects of beta-escin and saponin on muscle membranes; and (4) the t-system network within muscle fibres is not a homogeneous compartment.

Analysis of proximal femur DXA scans in growing children: Comparisons of different protocols for cross-sectional 8-month and 7-year longitudinal data

Dual-energy X-ray absorptiometry (DXA) is a widely used method for measuring bone mineral in the growing skeleton. Because scan analysis in children offers a number of challenges, we compared DXA results using six analysis methods at the total proximal femur (PF) and five methods at the femoral neck (FN), In total we assessed 50 scans (25 boys, 25 girls) from two separate studies for cross-sectional differences in bone area, bone mineral content (BMC), and areal bone mineral density (aBMD) and for percentage change over the short term (8 months) and long term (7 years). At the proximal femur for the short-term longitudinal analysis, there was an approximate 3.5% greater change in bone area and BMC when the global region of interest (ROI) was allowed to increase in size between years as compared with when the global ROI was held constant. Trend analysis showed a significant (p < 0.05) difference between scan analysis methods for bone area and BMC across 7 years. At the femoral neck, cross-sectional analysis using a narrower (from default) ROI, without change in location, resulted in a 12.9 and 12.6% smaller bone area and BMC, respectively (both p < 0.001), Changes in FN area and BMC over 8 months were significantly greater (2.3 %, p < 0.05) using a narrower FN rather than the default ROI, Similarly, the 7-year longitudinal data revealed that differences between scan analysis methods were greatest when the narrower FN ROI was maintained across all years (p < 0.001), For aBMD there were no significant differences in group means between analysis methods at either the PF or FN, Our findings show the need to standardize the analysis of proximal femur DXA scans in growing children.