Repeated l-DOPA treatment increases c-fos and BDNF mRNAs in the subthalamic nucleus in the 6-OHDA rat model of Parkinson's disease

The subthalamic nucleus and the striatum are input regions of the basal ganglia. This study used the unilateral 6-OHDA rat model of Parkinson's disease to examine effects of l-DOPA on the expression of c-fos and BDNF mRNAs in these nuclei. Dopamine depletion per se did not affect c-fos or BDNF. Both a single and repeated injections of l-DOPA induced c-fos, but not BDNF, in the dopamine-depleted striatum. However, repeated l-DOPA treatment increased c-fos and BDNF in the dopamine-depleted subthalamic nucleus. These molecular adaptations may reflect changes in neuronal plasticity that underlie some therapeutic actions and/or side effects of l-DOPA in Parkinson's disease.     

Risk of hepatitis A infection in sewage workers

OBJECTIVE: To evaluate the risk of hepatitis A virus (HAV) infection among sewage workers from occupational exposure to raw sewage. METHODS: An analytical cross sectional study of 241 company employees with possible occupational exposure to sewage in a large water and sewerage company was carried out. Previous exposure to hepatitis A virus infection was assessed, as were its associations with possible risk factors. RESULTS: Frequent occupational exposure to raw sewage was a significant risk factor for HAV infection, independently of other known risk factors (odds ratio 3.73, 95% confidence interval 1.48 to 9.37). Of 50 employees who reported occupational exposure to raw sewage most of the time, 30 (60%) had had HAV infection. CONCLUSION: Employees who are likely to be at risk of frequent exposure should have their immunity ensured. The salivary assay for IgG anti-HAV used in the study was highly specific and would be suitable for prevaccination testing of older employees, who are more likely to be immune.

 

     

Future technology insight: mass spectrometry imaging as a tool in drug research and development

In pharmaceutical research, understanding the biodistribution, accumulation and metabolism of drugs in tissue plays a key role during drug discovery and development. In particular, information regarding pharmacokinetics, pharmacodynamics and transport properties of compounds in tissues is crucial during early screening. Historically, the abundance and distribution of drugs have been assessed by well-established techniques such as quantitative whole-body autoradiography (WBA) or tissue homogenization with LC/MS analysis. However, WBA does not distinguish active drug from its metabolites and LC/MS, while highly sensitive, does not report spatial distribution. Mass spectrometry imaging (MSI) can discriminate drug and its metabolites and endogenous compounds, while simultaneously reporting their distribution. MSI data are influencing drug development and currently used in investigational studies in areas such as compound toxicity. In in vivo studies MSI results may soon be used to support new drug regulatory applications, although clinical trial MSI data will take longer to be validated for incorporation into submissions. We review the current and future applications of MSI, focussing on applications for drug discovery and development, with examples to highlight the impact of this promising technique in early drug screening. Recent sample preparation and analysis methods that enable effective MSI, including quantitative analysis of drugs from tissue sections will be summarized and key aspects of methodological protocols to increase the effectiveness of MSI analysis for previously undetectable targets addressed. These examples highlight how MSI has become a powerful tool in drug research and development and offers great potential in streamlining the drug discovery process.     

Clinical competence of interns

A clinical supervisors rating form addressing 13 competencies was used to assess the clinical competence of graduates one year after qualification in New South Wales (NSW), Australia. Data from 485 interns (97.2%) showed that graduates from the problem-based medical school were rated significantly better than their peers with respect to their interpersonal relationships, 'reliability' and 'self-directed learning'. Interns from one of the two traditional NSW medical schools had significantly higher ratings on 'teaching', 'diagnostic skills' and 'understanding of basic mechanisms'. Graduates from international medical schools performed worse than their peers on all competencies. These results were adjusted for age and gender. Additionally, women graduates and younger interns tended to have better ratings. Junior doctors have differing educational and other background experiences and their performance should be monitored.     

Risk stratification in unstable coronary artery disease: Additive value of troponin T determinations and pre-discharge exercise tests

In 963 patients, participating in a randomized study of lowmolecular weight heparin in unstable coronary artery diseaseand followed for 5 months, troponin T was determined. In the766 patients with a pre-discharge exercise test both troponinT level and exercise test response were independent predictorsof prognosis. Cardiac death or myocardial infarction occurredin 5, 9 and 13% of the patients with a maximal troponin T levelof <0·06 (n=154), 0·06–02 (n=175) and0·2 µg . 1^–1 (n=437), respectively. Basedon exercise tolerance and occurrence of ST depression, patientswith a low (n=361), intermediate (n=325) and high risk (n=80)exercise test response were identified. In these, death or myocardialinfarction occurred in 5, 13 and 29%, respectively. The combinationof troponin T and the exercise test response allowed an evenbetter categorization into low (n=84), intermediate (n=406)and high (n=276) risk groups with 1, 7 and 20% death or myocardialinfarction, respectively. Among those 197 patients unable toperform an exercise test the incidence was 3, 16 and 27% inpatients with troponin T <0·06, 0·06–0·2and 0·2 µg . 1^–1, respectively. Thus, troponin T determinations and pre-discharge exercise testsalone and combined are valuable for risk assessment in unstablecoronary artery disease.     

Neurokinin B/NK3 receptors exert feedback inhibition on L-DOPA actions in the 6-OHDA lesion rat model of Parkinson's disease

Neurokinin B (NKB) and substance P (SP) act via NK(3) and NK(1) receptors. Using the unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of Parkinson's disease (PD), it was found that chronic, but not acute, administration of L-DOPA increases striatal NKB expression in the dopamine-depleted hemisphere. In contrast, both acute and chronic administrations of L-DOPA restore reduced levels of SP mRNA. Co-treatment with the NK(3) receptor antagonist, SB222200, and L-DOPA increased contralateral rotations compared to L-DOPA alone in L-DOPA primed rats. The NK(3)R agonist, senktide, increased the phosphorylation of tyrosine hydroxylase (TH) at Ser(19)-TH, a CaMKII site, and of Thr(286)-CaMKII in striatal slices. Senktide had no effect on P-Ser(31)-TH, a MAPK site, but reduced P-Ser(217/221)-MEK. Amperometry demonstrated that senktide increased evoked dopamine release. SB222200 blocked the effects of senktide. In striatal slices prepared from 6-OHDA-lesioned rats repeatedly treated with L-DOPA, senktide no longer increased P-Thr(286)-CaMKII, suggesting a role of NK(3)R on dopamine terminals under normal conditions. SB222200 increased P-Ser(217/221)-MEK only in dopamine-depleted slices, indicating an increased NK(3)R tone under Parkinsonism conditions. Altogether, these data demonstrate a differential regulation of NKB and SP by L-DOPA in an animal model of PD and indicate a unique role of NKB in long-term effects of L-DOPA. Behavioural, biochemical and amperometric data indicate that NKB/NK(3)R signalling stimulates dopamine transmission at the presynaptic site, but inhibits it at the postsynaptic site. The inhibitory influence of NKB/NK(3)R on dopamine transmission dominates in an animal model of PD and provides a feedback inhibition on actions mediated via L-DOPA.     

The echogenicity of the intima–media complex in the common carotid artery is related to insulin resistance measured by the hyperinsulinemic clamp in elderly men

The echogenicity of the intima–media complex (IM‐GSM) has recently been shown to be related to the echogenicity in carotid artery plaque and to predict cardiovascular (CV) mortality. The present study aims to evaluate the relationship between metabolic CV risk factors, with special emphasis on insulin resistance, and IM‐GSM in the carotid artery. Carotid artery ultrasound with grey‐scale median analysis of the intima–media complex, IM‐GSM, was performed in a population sample of 480 men aged 75 years. In these subjects, a euglycemic hyperinsulinemic clamp to investigate insulin resistance was performed together with measurements of conventional CV risk factors at the age of 70. The metabolic syndrome (MetS) was defined by the NCEP/ATPIII‐criteria. In univariate analysis, IM‐GSM in the common carotid artery was inversely correlated with the intima–media thickness (IMT), body mass index (BMI), waist/hip ratio, fasting glucose, serum triglycerides, low HDL cholesterol and insulin resistance at the clamp (r = ?0·24, P<0·001). In multiple regression analysis, only insulin resistance at the clamp and BMI were independently related to IM‐GSM. Subjects with the MetS (22%) showed a reduced IM‐GSM when compared to those without (64 ± 20 SD versus 68 ± 19, P<0·05). Because the echogenicity of the intima–media complex in the carotid artery is related to obesity and insulin resistance at clamp independently of IMT, this new vascular characteristic would serve as a marker of vascular alterations induced by insulin resistance and the MetS and has the advantage to be obtainable in almost all subjects.     

L-DOPA produces strong induction of c-fos messenger RNA in dopamine-denervated cortical and striatal areas of the common marmoset

Common marmosets (Callithrix jacchus) with near-complete unilateral 6-hydroxydopamine denervation of the dopaminergic input received a single injection of saline or L-DOPA (15mg/kg plus 6.25mg/kg benserazide). Using in situ hybridization, the effects of these treatments on c-fos messenger RNA expression in the cerebral cortex, the striatal complex and the external layer of the pallidum were studied. Moreover, receptor autoradiography was used to determine the levels of dopamine D(1) and D(2) receptors in these areas. In the cerebral cortex, animals treated with L-DOPA displayed a high expression of c-fos messenger RNA restricted to the dopamine-denervated hemisphere. No changes in the levels of cortical D(1) and D(2) receptors were found in the dopamine-denervated hemisphere. L-DOPA treatment also induced a strong expression of c-fos messenger RNA in the striatal complex in the dopamine-denervated hemisphere. The levels of striatal D(2), but not D(1), receptors were increased in the dopamine-denervated hemisphere. In the external pallidum, the major terminal region for D(2) dopamine receptor-containing striatal projection neurons, L-DOPA treatment induced c-fos messenger RNA expression in both the intact and the dopamine-denervated hemispheres.Thus, using c-fos messenger RNA as a biochemical marker of postsynaptic neuronal activation, these results provide evidence that near-complete dopamine depletion causes a profound supersensitization to L-DOPA treatment in the cerebral cortex and in the striatal complex, but not in the external layer of the pallidum, of the primate brain. The cortical response may be unique to the primate brain, but c-fos messenger RNA activation within the striatum has also been reported in the rodent. The effects of L-DOPA probably depend both on a direct activation of supersensitized dopamine receptors by dopamine produced in the few remaining, but hyperactive, dopaminergic nerve terminals and in serotonergic nerve terminals, as well as on indirect actions of L-DOPA related to activation of circuitries connecting cerebral cortex and basal ganglia structures. These results provide novel information on the mechanisms underlying L-DOPA's action in the cerebral cortex, striatum and external pallidum in a primate model of Parkinson's disease.     

Depression Treatment Among Rural Older Adults: Preferences and Factors Influencing Future Service Use

The purpose of this study was to investigate depression treatment preferences and anticipated service use in a sample of adults aged 55 years or older who reside in rural Wyoming. Sixteen participants (mean age = 59) completed 30- to 60-minute, semi-structured interviews. Qualitative methods were used to characterize common themes. Social/provider support and community gatekeepers were perceived by participants as important potential facilitators for seeking depression treatment. In contrast, perceived stigma and the value placed on self-sufficiency emerged as key barriers to seeking treatment for depression in this rural, young-old sample. Participants anticipated presenting for treatment in the primary care sector and preferred a combination of medication and psychotherapy for treatment. Participants were, however, more willing to see mental health professionals if they were first referred by a clergy member or primary care physician.