Mechanisms of Parkinson's Disease: Lessons from Drosophila.

The power of Drosophila genetics has attracted attention in tackling important biomedical challenges such as the understanding and prevention of neurodegenerative diseases. Parkinson's disease (PD) is the most common neurodegenerative movement disorder which results from the relentless degeneration of midbrain dopaminergic neurons. Over the past two decades tremendous advances have been made in identifying genes responsible for inherited forms of PD. The ease of genetic manipulation in Drosophila has spurred the development of numerous models of PD, including expression of human genes carrying pathogenic mutations or the targeted mutation of conserved orthologs. The genetic and cellular analysis of these models is beginning to reveal fundamental insights into the pathogenic mechanisms. Numerous pathways and processes are disrupted in these models but some common themes are emerging. These often implicate aberrant synaptic function, protein aggregation, autophagy, oxidative stress, and mitochondrial dysfunction. Moreover, an impressive list of small molecule compounds have been identified as effective in reversing pathogenic phenotypes, paving the way to explore these for therapeutic interventions.

Effects of five Ayurvedic herbs on locomotor behaviour in a Drosophila melanogaster Parkinson's disease model.

Current conventional treatments for Parkinson's disease (PD) are aimed at symptom management, as there is currently no known cure or treatment that can slow down its progression. Ayurveda, the ancient medical system of India, uses a combination of herbs to combat the disease. Herbs commonly used for this purpose are Zandopa (containing Mucuna pruriens), Withania somnifera, Centella asiatica, Sida cordifolia and Bacopa monnieri. In this study, these herbs were tested for their potential ability to improve climbing ability of a fruit fly (Drosophila melanogaster) PD model based on loss of function of phosphatase and tensin-induced putative kinase 1 (PINK1). Fruit flies were cultured on food containing individual herbs or herbal formulations, a combination of all five herbs, levodopa (positive control) or no treatment (negative control). Tests were performed in both PINK1 mutant flies and healthy wild-type (WT) flies. A significant improvement in climbing ability was observed in flies treated with B. monnieri compared with untreated PINK1 mutant flies. However, a significant decrease in climbing ability was observed in WT flies for the same herb. Centella asiatica also significantly decreased climbing ability in WT flies. No significant effects were observed with any of the other herbs in either PINK1 or WT flies compared with untreated flies.

Olanzapine and breast-feeding: changes of plasma concentrations of olanzapine in a breast-fed infant over a period of 5 months.

We here report on a psychotic mother and her breast-fed infant who was treated with olanzapine. Consecutively olanzapine concentrations in the milk and plasma of the mother and in the infant were measured with tandem mass spectroscopy over a period of five month. The results show a relatively high plasma level in the infant aged four month, probably referring to an immature hepatic transformation system, especially CYP1A2. In the following four months plasma levels of olanzapine decreased to very low, even undetectable concentrations in the infant. The infant developed normally and showed no side effects during the treatment period.

Drosophila HtrA2 is dispensable for apoptosis but acts downstream of PINK1 independently from Parkin.

High temperature requirement A2 (HtrA2/Omi) is a mitochondrial protease that exhibits proapoptotic and cell-protective properties and has been linked to Parkinson's disease (PD). Impaired mitochondrial function is a common trait in PD patients, and is likely to play a significant role in pathogenesis of parkinsonism, but the molecular mechanisms remain poorly understood. Genetic studies in Drosophila have provided valuable insight into the function of other PD-linked genes, in particular PINK1 and parkin, and their role in maintaining mitochondrial integrity. Recently, HtrA2 was shown to be phosphorylated in a PINK1-dependent manner, suggesting it might act in the PINK1 pathway. Here, we describe the characterization of mutations in Drosophila HtrA2, and genetic analysis of its function with PINK1 and parkin. Interestingly, we find HtrA2 appears to be dispensable for developmental or stress-induced apoptosis. In addition, we found HtrA2 mutants share some phenotypic similarities with parkin and PINK1 mutants, suggesting that it may function in maintaining mitochondrial integrity. Our genetic interaction studies, including analysis of double-mutant combinations and epistasis experiments, suggest HtrA2 acts downstream of PINK1 but in a pathway parallel to Parkin.

[Differences between men and women in side effects of second-generation antipsychotics]. / Neuere Antipsychotika. Unterschiede im Nebenwirkungsprofil bei Frauen und Männern.

In this review we investigate whether sex differences exist for side effects of second-generation antipsychotics. Results are based on a MEDLINE search for the years 1974 through 2005. Even if pharmacokinetics differ between females and males, significantly higher plasma levels for women have been demonstrated only for olanzapine and clozapine. Hyperprolactinaemia is mainly induced by treatment with risperidone and amisulpride, and there is evidence for more pronounced prolactin levels in females. Most studies reviewed indicate that clozapine and olanzapine are associated with more body weight gain, once more especially in female patients. Furthermore, the few published studies indicate that metabolic syndrome is more frequent in females and there are likely no gender-specific differences between the new antipsychotic medications concerning frequency and degree of acute or chronic movement disturbance. The risk of QT prolongation with torsades de pointes arrhythmia is again higher in females. In conclusion, there is some evidence of sex differences in the side effects of second-generation antipsychotics. For better understanding of the basic mechanisms in sex differences, future studies with a primary focus on this topic are required. More specific data will help to determine how these differences shall affect clinical management.

Cardiomyopathy after long-term treatment with lithium - more than a coincidence?

We describe a patient suffering from dilative cardiomyopathy after 16 years of treatment with lithium carbonate. The literature concerning lithium and cardiac adverse reactions is briefly reviewed. There is good evidence for acute cardiac reactions, especially cardiac arrhythmia but a rather speculative association with long-term reactions such as cardiomyopathy. Nevertheless clinicians should be aware of this rare but life threatening conjunction of cardiac disease and lithium treatment.

Person, place or time? The effect of individual circumstances, area and changes over time on mortality in men, 1995-2001.

This article uses the ONS Longitudinal Study to explore, for a cohort of adult males who were aged 26 or over in 1971, the relative influence on mortality in 1995-2001 of their place of residence and individual socioeconomic circumstances, at three censuses over a 20-year period. Factors examined in this analysis include social class, neighbourhoo deprivation (at ward level), unemployment, residence in the South East region in 1971 or 1981 housing tenure, and change in social class and housing tenure between 1971 and 1991. The variation in mortality attributable to the local authority district of residence in 1991 was also investigated.

Risperidone and breast-feeding.

We present the case of a breast-feeding woman with acute psychotic symptoms after delivery, which were treated with the antipsychotic agent risperidone. Serum levels of risperidone and 9-hydroxyrisperidone could be detected in both the mother and her infant. Drug-levels in breast milk were ten-fold lower compared to maternal serum. The patient responded well to antipsychotic treatment. Her infant did not display any adverse effects and psychomotor development was normal. In this case, risperidone was a safe treatment option for the breast-feeding mother and her infant. We also provide a brief overview of the clinically relevant data concerning antipsychotics and breast-feeding.

A comparison of nutritional regulation in solitarious- and gregarious-phase nymphs of the desert locust Schistocerca gregaria.

Nutritional regulatory responses were compared for the cryptic 'solitarious' and the conspicuously coloured, aggregating 'gregarious' phases of the desert locust Schistocerca gregaria. The desert locust has the genetic potential to exist in either phase, changing between them within a lifetime and epigenetically across generations. Our aim was to compare final-instar nymphs of the two phases with respect to key nutritional variables, including (i) points of regulated intake (the 'intake target') for protein and carbohydrate, (ii) the nature of trade-offs between over-eating nutrients in excess and under-eating those in deficit when fed nutritionally unbalanced foods, (iii) diet-related patterns of nutrient utilisation, and (iv) the performance consequences of eating nutritionally unbalanced diets. When provided with pairs of nutritionally unbalanced but complementary foods, both phases regulated their intake of protein and carbohydrate to a similar point. However, when confined to foods that were of unbalanced protein to carbohydrate ratio, gregarious nymphs ate more than solitarious insects. Both phases regulated protein growth, but gregarious insects did so to a lower adult body protein content and converted ingested protein to growth less efficiently. When fed a food high in carbohydrate and low in protein, gregarious nymphs deposited more body lipid and survived less well than did solitarious insects. Solitarious nymphs developed more quickly than gregarious nymphs except on the two most extremely unbalanced diets, on which development time was similar. The results are discussed with respect to the different nutritional ecologies of the two phases and used to develop the hypothesis that animals have evolved to trade-off the cost of eating excess of a nutritionally unbalanced diet against the probability of encountering foods of complementary composition in the future.

Semantic memory is impaired in both dementia with Lewy bodies and dementia of Alzheimer's type: a comparative neuropsychological study and literature review.

OBJECTIVE: To test the hypothesis that semantic impairment is present in both patients with dementia with Lewy bodies (DLB) and those with dementia of Alzheimer's type (DAT). METHODS: A comprehensive battery of neuropsychological tasks designed to assess semantic memory, visuoperceptual function, verbal fluency, and recognition memory was given to groups of patients with DLB (n=10), DAT (n=10) matched pairwise for age and mini mental state examination (MMSE), and age matched normal controls (n=15). RESULTS: Both DLB and DAT groups exhibited impaired performance across the range of tasks designed to assess semantic memory. Whereas patients with DAT showed equivalent comprehension of written words and picture stimuli, patients with DLB demonstrated more severe semantic deficits for pictures than words. As in previous studies, patients with DLB but not those with DAT were found to have impaired visuoperceptual functioning. Letter and category fluency were equally reduced for the patients with DLB whereas performance on letter fluency was significantly better in the DAT group. Recognition memory for faces and words was impaired in both groups. CONCLUSIONS: Semantic impairment is not limited to patients with DAT. Patients with DLB exhibit particular problems when required to access meaning from pictures that is most likely to arise from a combination of semantic and visuoperceptual impairments.

A comparison of patterns of tranquiliser intake, anxiety and health locus of control between short- and long-term benzodiazepine users.

This study investigates the impact of physical illness, health locus of control and anxiety level on long- and short-term benzodiazepine (BZD) use in patients of an internal medicine department. There was no significant difference observed between the continuing and discontinuing group after hospital admission in terms of average daily dose of BZD. However, the continuing patients rated the condition of their somatic illness significantly higher than the discontinuing group, although this difference was not confirmed by the objective assessment of the treating physician. The non-continuing group displayed significantly higher control over health- and sickness-related events. The somatic and physical anxiety factor was significantly higher in the continuing group at initial investigation as well as at follow-up. On the basis of these results, we conclude that an increased focus on the psychosomatic element might reduce the risk of long-term tranquiliser use in patients with physical illness.

Intravenous versus oral administration of amitriptyline in patients with major depression.

Antidepressants can be administered by different routes. Advantages for either the oral or the intravenous administration have been suggested from pharmacokinetic as well as from clinical points of view. Controlled comparison studies of the two routes do not provide unequivocal recommendations. In this investigation, amitriptyline was studied over a 4-week period consisting of a 2-week, double-blind/double-dummy phase with either oral (150 mg/day), high-dose intravenous (150 mg/day), or medium-dose intravenous (100 mg/day) treatment and a 2-week phase of open oral treatment in 80 patients with major depression. A psychopathologic assessment was made using the Hamilton Rating Scale for Depression, the Clinical Global Impressions Scale, the von Zerssen's "Befindlichkeitsskala," an adjective checklist, and a Visual Analog Scale. No significant differences were found concerning the mean scores of the rating scales or time of onset of action in the physicians' ratings. In the patients' self-ratings, there was an earlier therapeutic effect in the high-dose intravenous group. The number of improvers after 7 days was significantly higher in the high-dose intravenous group compared with both other groups. After 14 days, no significant differences in the numbers of improvers and responders between groups were detected. The results of this study do not clearly favor one of the tested options. The main differences found in this study seem to be dose-related rather than differentiating between oral and intravenous routes of administration.

T-cell subsets in schizophrenia: a comparison between drug-naive first episode patients and chronic schizophrenic patients.

T-cell subsets (CD3+, CD4+, CD8+, NK-cells) and the CD4+/CD8+ ratio were measured in 56 schizophrenic patients admitted to hospital with an acute psychosis. Thirty-five patients with chronic schizophrenia and 21 drug-naive first episode schizophrenic patients were compared with 16 healthy controls. T-cell subsets were quantified in the acute state of the illness (day 0), after 7 days of treatment and at the time of discharge. In the acute state, schizophrenic patients showed higher CD3+ and CD4+ cells (p = 0.05) and a higher CD4/CD8 ratio (p = 0.02) than healthy controls, while NK-cells were lower (p = 0.05). In first episode patients, all T-cell alterations normalized during treatment. In the chronic group the ratio remained high, whereas the initially low number of NK-cells normalized over time. These findings, supporting immune system dysregulation in schizophrenia, are discussed in relation to psychopathology, the stage of illness and effects of medication.

Hippocampal volume reduction in male schizophrenic patients.

Using magnetic resonance imaging of the brain, we examined volumetric measurements of total brain, hemispheres, lateral ventricles and the hippocampus/amygdala complex in male subjects (41 first-episode schizophrenics, 30 chronic schizophrenic patients and 32 healthy controls). We found significantly smaller total brain size in the chronic schizophrenic group, significantly larger lateral ventricles in both patient groups and hippocampal volume reduction bilaterally in first-episode patients (-13.2% left, -12.05% right) and chronic patients (-10.6% left, -10.5% right) compared to controls--irrespective of diagnostic subtype, family history for psychiatric diseases, psychopathology, duration of illness or age at onset.

In vivo cytokine response to Escherichia coli alpha-hemolysin determined with genetically engineered hemolytic and nonhemolytic E. coli variants.

Alpha-hemolysin is an Escherichia coli exotoxin that enhances bacterial virulence, has profound effects on leukocytes in vitro, and induces the release of interleukin-1 (IL-1) but not tumor necrosis factor (TNF) from human monocytes in vitro. The purpose of this study was to examine alpha-hemolysin's influence on virulence and TNF and IL-1 production in vivo. Two genetically engineered, isogeneic strains of E. coli were used; one variant produces alpha-hemolysin, and the other does not. Male BALB/c mice were injected with either of the two variants and serum TNF and IL-1 were assayed. These results were compared with those obtained from the injection of either of two serotypes of lipopolysaccharide (LPS). The nonhemolytic E. coli strain produced no mortality and no significant elevation of serum TNF or IL-1 levels. In contrast, equal inocula of the hemolytic E. coli strain produced significant mortality and elevation of serum IL-1 levels. No significant elevation of TNF levels was detected in this group despite high-level mortality. A pattern of induction of mortality and elevation of serum IL-1 levels without elevation of serum TNF levels is distinct from the pattern typical of LPS. In these experiments, both serotypes of LPS caused elevations of TNF and IL-1 levels whether or not mortality was induced. Thus, alpha-hemolysin produces a cytokine response in vivo that is similar to that previously demonstrated in vitro by Bhakdi et al. (S. Bhakdi, M. Muhly, S. Korom, and G. Schmidt, J. Clin. Invest. 85:1746-1753, 1990) and appears to induce mortality independently of serum TNF.

Comparison of acamprosate and placebo in long-term treatment of alcohol dependence.

BACKGROUND: About 50% of alcoholic patients relapse within 3 months of treatment. Previous studies have suggested that acamprosate may help to prevent such relapse. The aim of our study was to assess the efficacy and safety of long-term acamprosate treatment in alcohol dependence. METHODS: In this multicentre, double-blind, placebo-controlled study, we recruited 455 patients, aged 18-65 years, with chronic or episodic alcohol dependence. Patients were randomly allocated treatment with acamprosate (1998 mg daily for bodyweight > 60 kg; 1332 mg daily for < or = kg) or placebo for 360 days. Patients were assessed on the day treatment started and on days 30, 90, 180, 270, and 360 by interview, self-report, questionnaire, and laboratory screening. Patients were classified as abstinent, relapsing, or non-attending. Time to first treatment failure (relapse or non-attendance) was the primary outcome measure. FINDINGS: Seven patients were excluded from the intention-to-treat analysis because they did not attend on the first treatment day and therefore received no medication. The acamprosate (n = 224) and placebo (n = 224) groups were well matched in terms of baseline demographic and alcohol-related variables. 94 acamprosate-treated and 85 placebo-treated patients completed the treatment phase: of those withdrawn, 104 (52 in each group) relapsed, 69 (33 vs 36, respectively) were lost to follow-up, 63 (31 vs 32) refused to continue treatment, 16 (15 vs 11) had concurrent illness, three (two vs one) died, ten (six vs four) had adverse side-effects, one (acamprosate treated) received the wrong medication, and three (placebo treated) were non-compliant. The proportion without treatment failure was higher in the acamprosate than in the placebo group throughout the treatment period (p < 0.001, Mantel-Cox). At the end of treatment, 41 (18.3%) acamprosate-treated and 16 (7.1%) placebo-treated patients had been continuously abstinent (p = 0.007). Mean cumulative abstinence duration was significantly greater in the acamprosate group than in the placebo group (138.8 [SD 137.5] vs 103.8 [119.0] days; p = 0.012). 148 patients (79 acamprosate, 69 placebo) completed 27 months follow-up: 27 (11.9%) acamprosate-treated and 11 (4.9%) placebo-treated patients remained continuously abstinent, and the mean cumulative abstinence duration was 230.8 days (259.1) and 183.0 days (235.2), respectively. Apart from occasional diarrhoea, there was no difference in side-effects between groups. INTERPRETATION: Acamprosate is an effective and well-tolerated pharmacological adjunct to psychosocial and behavioural treatment programmes for treatment of alcohol-dependent patients.

Characterising thematic role assignment in aphasic sentence production: procedures for elicited and spontaneous output.

This paper describes two assessment tools developed to assist in characterising certain anomias that may be best understood within a sentence-processing paradigm. Although sentence-processing models promise to contribute much to our understanding of a range of aphasic deficits, the lack of available tools to measure and monitor sentence behaviour has been a limiting factor both theoretically and clinically. Based on proposals that the process of thematic role assignment may be influential in some anomias, two tools were developed to profile thematic role realisation across elicited and spontaneous speech conditions. The first measure provides an opportunity to contrast word retrieval across elicited single-word and sentence contexts, whereas the second measure permits an examination of thematic role realisation in spontaneous output. The data from two case studies are presented to demonstrate application of the tools.