Stress accelerates neural degeneration and exaggerates motor symptoms in a rat model of Parkinson's disease

The causes of most cases of Parkinson's disease (PD) are still poorly understood. Here we show that chronic stress and elevated corticosterone levels exaggerate motor deficits and neurodegenerative events in a Parkinson's disease rat model. Animals were tested in skilled and non-skilled movement while being exposed to daily restraint stress or oral corticosterone treatment. Stress and corticosterone compromised normal motor function and exaggerated motor deficits caused by unilateral 6-hydroxydopamine lesion of the nigrostriatal bundle. Moreover, stress and corticosterone treatments diminished the ability to acquire compensatory strategies in limb use during skilled reaching and skilled walking. In contrast, lesion control animals were able to significantly improve in the ability of skilled limb use during the repeated test sessions. The exaggerated motor impairments in stress-treated animals were related to accelerated loss of midbrain dopamine-producing neurons during the first week postlesion. Correlation analysis revealed a significant connection between loss of tyrosine hydroxylase-positive cells and increase in Fluoro-Jade-positive cells only in stress- and corticosterone-treated animals. Furthermore, stress and elevated corticosterone levels caused greater permanent loss of midbrain neurons than found in non-treated lesion animals. These findings demonstrate that stress and elevated corticosterone levels can exaggerate nigral neuronal loss and motor symptoms in a rat analogue of PD. It is therefore possible that stress represents a key factor in the pathogenesis of human PD by impeding functional and structural compensation and exaggerating neurodegenerative processes.     

Advantages of a steady-state crossover design in assessment of bioequivalence of highly variable drugs: propafenone

Bioequivalence of highly variable drugs (i.e. high clearance drugs) is difficult to assess by means of conventional study designs. This paper reports a study on bioequivalence of two immediate release formulations of the antiarrhythmic drug propafenone in which a steady-state crossover design was used. The decision on bioequivalence was made with regard to the data of propafenone. Bioavailability data of the active metabolite, 5-hydroxypropafenone, and circadian pharmacokinetics of both analytes are also discussed. Following 5 days of administration (300 mg twice daily) to 20 volunteers, all parameters measured for estimating bioequivalence (AUC, C_max and PTF) were determined for both propafenone and 5-hydroxypropafenone during two consecutive dosage intervals. All target parameters obtained after administration of the test formulation were within the defined limits of bioequivalence when compared to reference for both parent compound and active metabolite for both dosage intervals. Basing on the calculated 90% confidence intervals it can be concluded that the two formulations are bioequivalent. Moreover, the steady-state study design may be applicable to other compounds with similar pharmacokinetic behaviour and seems to be generally advantageous for bioequivalence studies of highly variable drugs.     

A torque-controlled device to measure passive abduction of the thumb carpometacarpal joint.

The primary aim of this study was to design and then test the intrarater reliability of a torque-controlled method of measuring passive abduction of the thumb carpometacarpal (CMC) joint. A secondary aim was to quantify passive CMC abduction in patients with and without contracture. Initially, clinicians used subjective feel (without range of motion measurements) to identify 52 people with loss of passive thumb CMC abduction. All subjects had a neurological condition. Passive thumb CMC abduction was measured in both hands of these 52 people and the hands of another 20 healthy able-bodied individuals (total of 72 people and 144 hands). Passive thumb CMC abduction was measured using a newly designed torque-controlled device and the previously recommended caliper method. Repeat measurements were taken with both devices, two to three days later, by blinded assessors on a subgroup of 12 patients (24 hands). Median (interquartile range) CMC angle of thumbs deemed by clinicians to have contracture was 45 degrees (41-52 degrees) and that of subjects without contractures was 56 degrees (53-60 degrees). The intraclass correlation coefficient for the repeat measures attained with the torque-controlled device was 0.78 (95% confidence interval, 0.56-0.90). The torque-controlled device provides a way of standardizing torque when measuring passive thumb CMC abduction. The clear difference between passive CMC abduction of subjects with and without contracture confirms the ability of clinicians to use feel and subjective assessment to identify patients with contracture.     

Alcoholism and somatic comorbidity among homeless people in Mannheim,Germany

Aims  To assess the prevalence of alcoholism and somatic codisorders of homeless people.
Design  Epidemiological cross-sectional field study in a sample of the homeless in the area.
Setting  The study was conducted from 1997 to 1999 in the inner-city area of Mannheim, Germany (approximately 320 000 inhabitants).
Participants  One hundred and two single homeless people (15–16% of the estimated total population of single homeless people in the city).
Measurement  Alcoholism, substance abuse and mental disorders were diagnosed with the SCID. Medical examinations were performed by an experienced physician. Blood samples were taken and urine samples collected. Further assessments were conducted for factors potentially correlating with mental or physical state.
Findings  Of the study probands, 63.7% presented with the alcohol dependence syndrome or harmful use, 61.7% had current somatic problems or disorders. Probands with alcohol dependence had significantly more frequent somatic disorders in total, more cerebral degeneration, liver disease or alcoholic polyneuropathies. Multiple stepwise regression identified alcoholism, life-satisfaction, duration of homelessness and lacking social support as significant explanatory factors for having a somatic disorder. Alcoholism increased the risk of physical ill-health more than fourfold.
Conclusion  Alcoholism is a major contributor to the physical ill-health of homeless people. Treatment or rehabilitation of addictive behaviour among the homeless should be of major concern for adequate service planning or provision.     

The vast majority of bone-marrow-derived cells integrated into mdx muscle fibers are silent despite long-term engraftment

Bone-marrow-derived cells can contribute nuclei to skeletal muscle fibers. However, serial sectioning of muscle in mdx mice implanted with GFP-labeled bone marrow reveals that only 20% of the donor nuclei chronically incorporated in muscle fibers show dystrophin (or GFP) expression, which is still higher than the expected frequency of "revertant" fibers, but there is no overall increase above controls over time. Obviously, the vast majority of incorporated nuclei either never or only temporarily turn on myogenic genes; also, incorporated nuclei eventually loose the activation of the beta-actin::GFP transgene. Consequently, we attempted to enhance the expression of dystrophin. In vivo application of the chromatin-modifying agents 5-azadeoxycytidine and phenylbutyrate as well as local damage by cardiotoxin injections caused a small increase in dystrophin-positive fibers without abolishing the appearance of "silent" nuclei. The results thus confirm that endogenous repair processes and epigenetic modifications on a small-scale lead to dystrophin expression from donor nuclei. Both effects, however, remain below functionally significant levels.     

Empirical caspofungin therapy in clinical practice for suspected invasive fungal disease in adults with acute lymphoblastic leukaemia

Patients with acute lymphoblastic leukaemia (ALL) after cytotoxic chemotherapy or haematopoietic stem cell transplantation (HSCT) are at risk for life‐threatening invasive fungal disease (IFD). The aim was to evaluate the characteristics, antifungal therapy and outcome of adult patients with ALL after chemotherapy or HSCT receiving caspofungin empirically in a clinical setting. Retrospective chart reviews were conducted at nine large tertiary care centres in Germany. Adult patients with ALL treated empirically with caspofungin according to the product label between 2006 and 2012 were eligible. Data were extracted as case reports. In total, 25 patients (12 males, 13 females; median age 37 years; 19 with B‐ALL, 6 with T‐ALL) with 28 treatment episodes because of suspected IFD (18 episodes after chemotherapy, 10 episodes after allogeneic HSCT) were included in the analysis. Empirical caspofungin therapy (median duration: 19 days, range 1–105 days) was given as first‐line monotherapy in 20 (71.4%), second‐line monotherapy in five (17.9%) and combination therapy in three (10.7%) episodes respectively. Therapy rated successful according to the physician's overall assessment (inflammatory parameters, clinical symptoms): 20 (95%) of 21 evaluable episodes with therapy duration of at least 8 days. Empirical caspofungin appears to be an effective therapeutic option in critically ill adult ALL patients with suspected IFD in clinical practice.     

Urinary Dolichol—A Doubtful Marker of Alcoholism

The purpose of this study was to replicate the results of Pullarkat and Raguthu and Roine et al. who found elevated levels of urinary dolichol (long-chain 2,3-dihydropolyprenols) in chronic alcoholic patients. We investigated a sample of 21 alcohol-dependent inpatients voluntarily entering detoxification treatment. Urinary dolichol was only slightly increased as compared to 21 healthy controls. When dolichol was related to urinary creatinine no differences between alcoholic patients and controls could be found. Under conditions of confirmed abstinence the slightly elevated levels of dolichol returned to normal within 2 weeks. Compared with the sensitivity of gamma-glutamyltransferase which ranges from 72-85%, the value of urinary dolichol (sensitivity 9-19%) as a biochemical marker of alcoholism must be doubted.