Huntington disease: natural history, biomarkers and prospects for therapeutics

Huntington disease (HD) can be seen as a model neurodegenerative disorder, in that it is caused by a single genetic mutation and is amenable to predictive genetic testing, with estimation of years to predicted onset, enabling the entire range of disease natural history to be studied. Structural neuroimaging biomarkers show that progressive regional brain atrophy begins many years before the emergence of diagnosable signs and symptoms of HD, and continues steadily during the symptomatic or 'manifest' period. The continued development of functional, neurochemical and other biomarkers raises hopes that these biomarkers might be useful for future trials of disease-modifying therapeutics to delay the onset and slow the progression of HD. Such advances could herald a new era of personalized preventive therapeutics. We describe the natural history of HD, including the timing of emergence of motor, cognitive and emotional impairments, and the techniques that are used to assess these features. Building on this information, we review recent progress in the development of biomarkers for HD, and potential future roles of these biomarkers in clinical trials

Amblyopia and quality of life: a systematic review

Background/Aims Amblyopia is a common condition which can affect up to 5% of the general population. The health-related quality of life (HRQoL) implications of amblyopia and/or its treatment have been explored in the literature. Methods A systematic literature search was undertaken (16th-30th January 2007) to identify the HRQoL implications of amblyopia and/or its treatment. Results A total of 25 papers were included in the literature review. The HRQoL implications of amblyopia related specifically to amblyopia treatment, rather than the condition itself. These included the impact upon family life; social interactions; difficulties undertaking daily activities; and feelings and behaviour. The identified studies adopted a number of methodologies. The study populations included; children with the condition; parents of children with amblyopia; and adults who had undertaken amblyopia treatment as a child. Some studies developed their own measures of HRQoL, and others determined HRQoL through proxy measures. Conclusions The reported findings of the HRQoL implications are of importance when considering the management of cases of amblyopia. Further research is required to assess the immediate and long-term effects of amblyopia and/or its treatment upon HRQoL using a more standardised approach

Puzzle based teaching versus traditional instruction in electrocardiogram interpretation for medical students – a pilot study

<p>Abstract</p> <p>Background</p> <p>Most medical professionals are expected to possess basic electrocardiogram (EKG) interpretation skills. But, published data suggests that residents' and physicians' EKG interpretation skills are suboptimal. Learning styles differ among medical students; individualization of teaching methods has been shown to be viable and may result in improved learning. Puzzles have been shown to facilitate learning in a relaxed environment. The objective of this study was to assess efficacy of teaching puzzle in EKG interpretation skills among medical students.</p> <p>Methods</p> <p>This is a reader blinded crossover trial. Third year medical students from College of Human Medicine, Michigan State University participated in this study. Two groups (n = 9) received two traditional EKG interpretation skills lectures followed by a standardized exam and two extra sessions with the teaching puzzle and a different exam. Two other groups (n = 6) received identical courses and exams with the puzzle session first followed by the traditional teaching. EKG interpretation scores on final test were used as main outcome measure.</p> <p>Results</p> <p>The average score after only traditional teaching was 4.07 ± 2.08 while after only the puzzle session was 4.04 ± 2.36 (p = 0.97). The average improvement after the traditional session was followed up with a puzzle session was 2.53 ± 1.94 while the average improvement after the puzzle session was followed with the traditional session was 2.08 ± 1.73 (p = 0.67). The final EKG exam score for this cohort (n = 15) was 84.1 compared to 86.6 (p = 0.22) for a comparable sample of medical students (n = 15) at a different campus.</p> <p>Conclusion</p> <p>Teaching EKG interpretation with puzzles is comparable to traditional teaching and may be particularly useful for certain subgroups of students. Puzzle session are more interactive and relaxing, and warrant further investigations on larger scale.</p

Morphine activation of mu opioid receptors causes disinhibition of neurons in the ventral tegmental area mediated by β-arrestin2 and c-Src

Abstract The tyrosine kinase, c-Src, participates in mu opioid receptor (MOP) mediated inhibition in sensory neurons in which β-arrestin2 (β-arr2) is implicated in its recruitment. Mice lacking β-arr2 exhibit increased sensitivity to morphine reinforcement; however, whether β-arr2 and/or c-Src participate in the actions of opioids in neurons within the reward pathway is unknown. It is also unclear whether morphine acts exclusively through MOPs, or involves delta opioid receptors (DOPs). We examined the involvement of MOPs, DOPs, β-arr2 and c-Src in the inhibition by morphine of GABAergic inhibitory postsynaptic currents (IPSCs) recorded from neurons in the mouse ventral tegmental area. Morphine inhibited spontaneous IPSC frequency, mainly through MOPs, with only a negligible effect remaining in MOP−/− neurons. However, a reduction in the inhibition by morphine for DOP−/− c.f. WT neurons and a DPDPE-induced decrease of IPSC frequency revealed a role for DOPs. The application of the c-Src inhibitor, PP2, to WT neurons also reduced inhibition by morphine, while the inactive PP3, and the MEK inhibitor, SL327, had no effect. Inhibition of IPSC frequency by morphine was also reduced in β-arr2−/− neurons in which PP2 caused no further reduction. These data suggest that inhibition of IPSCs by morphine involves a β-arr2/c-Src mediated mechanism

Ca2+ Extrusion by NCX Is Compromised in Olfactory Sensory Neurons of OMP−/− Mice

The role of olfactory marker protein (OMP), a hallmark of mature olfactory sensory neurons (OSNs), has been poorly understood since its discovery. The electrophysiological and behavioral phenotypes of OMP knockout mice indicated that OMP influences olfactory signal transduction. However, the mechanism by which this occurs remained unknown.We used intact olfactory epithelium obtained from WT and OMP(-/-) mice to monitor the Ca(2+) dynamics induced by the activation of cyclic nucleotide-gated channels, voltage-operated Ca(2+) channels, or Ca(2+) stores in single dendritic knobs of OSNs. Our data suggested that OMP could act to modulate the Ca(2+)-homeostasis in these neurons by influencing the activity of the plasma membrane Na(+)/Ca(2+)-exchanger (NCX). Immunohistochemistry verifies colocalization of NCX1 and OMP in the cilia and knobs of OSNs. To test the role of NCX activity, we compared the kinetics of Ca(2+) elevation by stimulating the reverse mode of NCX in both WT and OMP(-/-) mice. The resulting Ca(2+) responses indicate that OMP facilitates NCX activity and allows rapid Ca(2+) extrusion from OSN knobs. To address the mechanism by which OMP influences NCX activity in OSNs we studied protein-peptide interactions in real-time using surface plasmon resonance technology. We demonstrate the direct interaction of the XIP regulatory-peptide of NCX with calmodulin (CaM).Since CaM also binds to the Bex protein, an interacting protein partner of OMP, these observations strongly suggest that OMP can influence CaM efficacy and thus alters NCX activity by a series of protein-protein interactions

Effects of supervised exercise training on lower-limb cutaneous microvascular reactivity in adults with venous ulcers

Purpose: To investigate the effects of a 12-week supervised exercise programme on lower-limb cutaneous microvascular reactivity in adults with venous leg ulceration. Methods: Thirty-eight adults with unilateral venous ulceration who were being treated with lower-limb compression therapy (58% male; mean age 65 years; median ulcer size 5 cm2) were randomly allocated to exercise or control groups. Exercise participants (n=18) were invited to attend thrice weekly sessions of lower-limb aerobic and resistance exercise for 12 weeks. Cutaneous microvascular reactivity was assessed in the gaiter region of ulcerated and non-ulcerated legs at baseline and 3 months using laser Doppler fluxmetry coupled with iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP). Cutaneous vascular conductance (CVC) was calculated as laser Doppler flux (AU)/mean arterial pressure (mmHg). Results: Thirty-seven participants completed follow-up assessments. Median class attendance was 36 (range 2 to 36). Analyses of covariance revealed greater peak CVC responses to ACh in the exercise group at 3 months in both the ulcerated (adjusted difference = 0.944 AU/mmHg; 95% CI 0.504 to 1.384) and non-ulcerated (adjusted difference = 0.596 AU/mmHg; 95% CI 0.028 to 1.164) legs. Peak CVC responses to SNP were also greater in the exercise group at 3 months in the ulcerated leg (adjusted difference = 0.882 AU/mmHg; 95% CI 0.274 to 1.491), but not the non-ulcerated leg (adjusted difference = 0.392 AU/mmHg; 95% CI -0.377 to 1.161). Conclusion: Supervised exercise training improves lower-limb cutaneous microvascular reactivity in adults with venous leg ulceration. Keywords Randomized controlled trial; Exercise; Ulceration; Vascular function; Laser Doppler fluxmetry; Iontophoresi

CD56 is a pathogen recognition receptor on human natural killer cells

Aspergillus (A.) fumigatus is an opportunistic fungal mold inducing invasive aspergillosis (IA) in immunocompromised patients. Although antifungal activity of human natural killer (NK) cells was shown in previous studies, the underlying cellular mechanisms and pathogen recognition receptors (PRRs) are still unknown. Using flow cytometry we were able to show that the fluorescence positivity of the surface receptor CD56 significantly decreased upon fungal contact. To visualize the interaction site of NK cells and A. fumigatus we used SEM, CLSM and dSTORM techniques, which clearly demonstrated that NK cells directly interact with A. fumigatus via CD56 and that CD56 is re-organized and accumulated at this interaction site time-dependently. The inhibition of the cytoskeleton showed that the receptor re-organization was an active process dependent on actin re-arrangements. Furthermore, we could show that CD56 plays a role in the fungus mediated NK cell activation, since blocking of CD56 surface receptor reduced fungal mediated NK cell activation and reduced cytokine secretion. These results confirmed the direct interaction of NK cells and A. fumigatus, leading to the conclusion that CD56 is a pathogen recognition receptor. These findings give new insights into the functional role of CD56 in the pathogen recognition during the innate immune response

A study of a culturally focused psychiatric consultation service for Asian American and Latino American primary care patients with depression

<p>Abstract</p> <p>Background</p> <p>Ethnic minorities with depression are more likely to seek mental health care through primary care providers (PCPs) than mental health specialists. However, both provider and patient-specific challenges exist. PCP-specific challenges include unfamiliarity with depressive symptom profiles in diverse patient populations, limited time to address mental health, and limited referral options for mental health care. Patient-specific challenges include stigma around mental health issues and reluctance to seek mental health treatment. To address these issues, we implemented a multi-component intervention for Asian American and Latino American primary care patients with depression at Massachusetts General Hospital (MGH).</p> <p>Methods/Design</p> <p>We propose a randomized controlled trial to evaluate a culturally appropriate intervention to improve the diagnosis and treatment of depression in our target population. Our goals are to facilitate a) primary care providers' ability to provide appropriate, culturally informed care of depression, and b) patients' knowledge of and resources for receiving treatment for depression. Our two-year long intervention targets Asian American and Latino American adult (18 years of age or older) primary care patients at MGH screening positive for symptoms of depression. All eligible patients in the intervention arm of the study who screen positive will be offered a culturally focused psychiatric (CFP) consultation. Patients will meet with a study clinician and receive toolkits that include psychoeducational booklets, worksheets and community resources. Within two weeks of the initial consultation, patients will attend a follow-up visit with the CFP clinicians. Primary outcomes will determine the feasibility and cost associated with implementation of the service, and evaluate patient and provider satisfaction with the CFP service. Exploratory aims will describe the study population at screening, recruitment, and enrollment and identify which variables influenced patient participation in the program.</p> <p>Discussion</p> <p>The study involves an innovative yet practical intervention that builds on existing resources and strives to improve quality of care for depression for minorities. Additionally, it complements the current movement in psychiatry to enhance the treatment of depression in primary care settings. If found beneficial, the intervention will serve as a model for care of Asian American and Latino American patients.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01239407">NCT01239407</a></p

Conjunctive Processing of Locomotor Signals by the Ventral Tegmental Area Neuronal Population

The ventral tegmental area (VTA) plays an essential role in reward and motivation. How the dopamine (DA) and non-DA neurons in the VTA engage in motivation-based locomotor behaviors is not well understood. We recorded activity of putative DA and non-DA neurons simultaneously in the VTA of awake mice engaged in motivated voluntary movements such as wheel running. Our results revealed that VTA non-DA neurons exhibited significant rhythmic activity that was correlated with the animal's running rhythms. Activity of putative DA neurons also correlated with the movement behavior, but to a lesser degree. More importantly, putative DA neurons exhibited significant burst activation at both onset and offset of voluntary movements. These findings suggest that VTA DA and non-DA neurons conjunctively process locomotor-related motivational signals that are associated with movement initiation, maintenance and termination