Activation of mGluR5 Induces Rapid and Long-Lasting Protein Kinase D Phosphorylation in Hippocampal Neurons

Metabotropic glutamate receptors (mGluRs), including mGluR5, play a central role in regulating the strength and plasticity of synaptic connections in the brain. However, the signaling pathways that connect mGluRs to their downstream effectors are not yet fully understood. Here, we report that stimulation of mGluR5 in hippocampal cultures and slices results in phosphorylation of protein kinase D (PKD) at the autophosphorylation site Ser-916. This phosphorylation event occurs within 30 s of stimulation, persists for at least 24 h, and is dependent on activation of phospholipase C and protein kinase C. Our data suggest that activation of PKD may represent a novel signaling pathway linking mGluR5 to its downstream targets. These findings have important implications for the study of the molecular mechanisms underlying mGluR-dependent synaptic plasticity.Howard Hughes Medical InstituteFRAXA Research FoundationNational Institute of Mental Health (U.S.)Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.

The Characterization of Varicella Zoster Virus-Specific T Cells in Skin and Blood during Aging

Reactivation of the varicella zoster virus (VZV) increases during aging. Although the effects of VZV reactivation are observed in the skin (shingles), the number and functional capacity of cutaneous VZV-specific T cells have not been investigated. The numbers of circulating IFN-γ-secreting VZV-specific CD4+ T cells are significantly decreased in old subjects. However, other measures of VZV-specific CD4+ T cells, including proliferative capacity to VZV antigen stimulation and identification of VZV-specific CD4+ T cells with an major histocompatibility complex class II tetramer (epitope of IE-63 protein), were similar in both age groups. The majority of T cells in the skin of both age groups expressed CD69, a characteristic of skin-resident T cells. VZV-specific CD4+ T cells were significantly increased in the skin compared with the blood in young and old subjects, and their function was similar in both age groups. In contrast, the number of Foxp3+ regulatory T cells and expression of the inhibitory receptor programmed cell death -1 PD-1 on CD4+ T cells were significantly increased in the skin of older humans. Therefore, VZV-specific CD4+ T cells in the skin of older individuals are functionally competent. However, their activity may be restricted by multiple inhibitory influences in situ

Impact of efalizumab on patient-reported outcomes in high-need psoriasis patients: results of the international, randomized, placebo-controlled Phase III Clinical Experience Acquired with Raptiva (CLEAR) trial [NCT00256139]

BACKGROUND: Chronic psoriasis can negatively affect patients' lives. Assessing the impact of treatment on different aspects of a patient's health-related quality of life (HRQOL) is therefore important and relevant in trials of anti-psoriasis agents. The recombinant humanized IgG(1 )monoclonal antibody efalizumab targets multiple T-cell-dependent steps in the immunopathogenesis of psoriasis. Efalizumab has demonstrated safety and efficacy in several clinical trials, and improves patients' quality of life. Objective: To evaluate the impact of efalizumab on HRQOL and other patient-reported outcomes in patients with moderate to severe plaque psoriasis, including a large cohort of High-Need patients for whom at least 2 other systemic therapies were unsuitable because of lack of efficacy, intolerance, or contraindication. METHODS: A total of 793 patients were randomized in a 2:1 ratio to receive efalizumab 1 mg/kg/wk (n = 529) or placebo (n = 264) for 12 weeks. The study population included 526 High-Need patients (342 efalizumab, 184 placebo). The treatment was evaluated by patients using the HRQOL assessment tools Short Form-36 (SF-36) and Dermatology Life Quality Index (DLQI). Other patient-reported assessments included the Psoriasis Symptom Assessment (PSA), a visual analog scale (VAS) for itching, and the Patient's Global Psoriasis Assessment (PGPA). RESULTS: Efalizumab was associated with improvements at Week 12 from baseline in patient-reported outcomes, both in the total study population and in the High-Need cohort. Among all efalizumab-treated patients, the DLQI improved by 5.7 points from baseline to Week 12, relative to an improvement of 2.3 points for placebo patients (P < .001). Corresponding improvements in DLQI in the High-Need cohort were 5.4 points for efalizumab compared to 2.3 for placebo (P < .001). Improvements from baseline on the SF-36, PSA, PGPA, and itching VAS at Week 12 were also significantly greater in efalizumab-treated patients than for placebo. CONCLUSION: A 12-week course of efalizumab improved HRQOL and other patient-reported outcomes in patients with moderate to severe plaque psoriasis. The benefits of efalizumab therapy in High-Need patients were similar to those observed in the total study population, indicating that the beneficial impact of efalizumab on QOL is consistent regardless of disease severity, prior therapy, or contraindications to previous therapies

Should a colon cancer screening decision aid include the option of no testing? A comparative trial of two decision aids

<p>Abstract</p> <p>Background</p> <p>An important question in the development of decision aids about colon cancer (CRC) screening is whether to include an explicit discussion of the option of not being screened. We examined the effect of including or not including an explicit discussion of the option of deciding not to be screened in a CRC screening decision aid on subjective measures of decision aid content; interest in screening; and knowledge.</p> <p>Methods</p> <p>Adults ages 50–85 were assigned to view one of two versions of the decision aid. The two versions differed only in the inclusion of video segments of two men, one of whom decided against being screened. Participants completed questionnaires before and after viewing the decision aid to compare subjective measures of content, screening interest and intent, and knowledge between groups. Likert response categories (5-point) were used for subjective measures of content (eg. clarity, balance in favor/against screening, and overall rating), and screening interest. Knowledge was measured with a three item index and individual questions. Higher scores indicated favorable responses for subjective measures, greater interest, and better knowledge. For the subjective balance, lower numbers were associated with the impression of the decision aid favoring CRC screening.</p> <p>Results</p> <p>57 viewed the "with" version which included the two segments and 49 viewed the "without" version. After viewing, participants found the "without" version to have better subjective clarity about benefits of screening ("with" 3.4, "without" 4.1, <it>p </it>< 0.01), and to have greater clarity about downsides of screening ("with" 3.2, "without" 3.6, <it>p </it>= 0.03). The "with" version was considered to be less strongly balanced in favor of screening. ("with" 1.8, "without" 1.6, <it>p </it>= 0.05); but the "without" version received a better overall rating ("with" 3.5, "without" 3.8, <it>p </it>= 0.03). Groups did not differ in screening interest after viewing a decision aid or knowledge.</p> <p>Conclusion</p> <p>A decision aid with the explicit discussion of the option of deciding not to be screened appears to increase the impression that the program was not as strongly in favor of screening, but decreases the impression of clarity and resulted in a lower overall rating. We did not observe clinically important or statistically significant differences in interest in screening or knowledge.</p

Self-Association of an Activating Natural Killer Cell Receptor, KIR2DS1

As a major component of the innate immune system, natural killer cells are responsible for activating the cytolytic killing of certain pathogen-infected or tumor cells. The self-recognition of natural killer cells is achieved in part by the killer cell immunoglobulin-like receptors (KIRs) protein family. In the current study, using a suite of biophysical methods, we investigate the self-association of an activating KIR, KIR2DS1. This KIR is of particular interest because when in the presence of the HLA-Cw6 protein, KIR2DS1 becomes a major risk factor for psoriasis, an autoimmune chronic skin disease. Using circular dichroism spectroscopy, dynamic light scattering, and atomic force microscopy, we reveal that KIR2DS1 self-associates in a well-defined fashion. Our novel results on an activating KIR allow us to suggest a working model for the KIR2DS1- HLA class I molecular mechanism

The impact of xerostomia on oral-health-related quality of life among younger adults

BACKGROUND: Recent research has suggested that chronic dry mouth affects the day-to-day lives of older people living in institutions. The condition has usually been considered to be a feature of old age, but recent work by our team produced the somewhat surprising finding that 10% of people in their early thirties are affected. This raises the issue of whether dry mouth is a trivial condition or a more substantial threat to quality of life among younger people. The objective of this study was to examine the association between xerostomia and oral-health-related quality of life among young adults while controlling for clinical oral health status and other potential confounding factors. METHODS: Cross-sectional analysis of data from a longstanding prospective observational study of a Dunedin (New Zealand) birth cohort: clinical dental examinations and questionnaires were used at age 32. The main measures were xerostomia (the subjective feeling of dry mouth, measured with a single question) and oral-health-related quality of life (OHRQoL) measured using the short-form Oral Health Impact Profile (OHIP-14). RESULTS: Of the 923 participants (48.9% female), one in ten were categorised as 'xerostomic', with no apparent gender difference. There was a strong association between xerostomia and OHRQoL (across all OHIP-14 domains) which persisted after multivariate analysis to control for clinical characteristics, gender, smoking status and personality characteristics (negative emotionality and positive emotionality). CONCLUSION: Xerostomia is not a trivial condition; it appears to have marked and consistent effects on sufferers' day-to-day lives

Mutation analysis of the LCE3B/LCE3C genes in Psoriasis

<p>Abstract</p> <p>Background</p> <p>An association between a common deletion comprising the late cornified envelope LCE3B and LCE3C genes (LCE3C_LCE3B-del) and Psoriasis (Ps) has been reported. The expression of these LCE genes was induced after skin barrier disruption and was also strong in psoriatic lesions. The damage to the skin barrier could trigger an epidermal response that includes the expression of genes involved in the formation of skin barrier.</p> <p>Methods</p> <p>We determined the LCE3C_LCE3B-del genotype in 405 Ps patients and 400 healthy controls from a Northern Spain region (Asturias). These patients and controls were also genotyped for the rs4112788 single nucleotide polymorphism, in strong linkage disequilibrium with the LCE3C_B cluster. The LCE3B and LCE3C gene variant was determined in the patients through SSCA, DHPLC, and direct sequencing.</p> <p>Results</p> <p>Allele and genotype frequencies did not differ between patients and controls for the rs4112788 and LCE3C_LCE3B-del polymorphisms. However, del/del homozygotes were significantly higher among patients with chronic plaque type Ps who did not develop arthritis (p = 0.03; OR = 1.4; 95%CI = 1.03-1.92). The analysis of the coding sequence of LCE3B and LCE3C in the patients who had at least one copy of this showed that only one patient has a no previously reported LCE3B variant (R68C).</p> <p>Conclusion</p> <p>Our work suggested that homozygosity for a common LCE3C_LCE3B deletion contributes to the risk of developing chronic plaque type Ps without psoriatic arthritis. Our work confirmed previous reports that described an association of this marker with only skin manifestations, and supported the concept of different genetic risk factors contributing to skin and joint disease.</p

Lymphocyte subsets in peripheral blood of patients with moderate-to-severe versus mild plaque psoriasis

In several studies peripheral blood T-cells have been quantified, yet few data are available on lymphocyte subsets in moderate-to-severe psoriasis (in terms of extent and activity of lesions) versus mild psoriasis. The objective is to compare lymphocyte subsets in peripheral blood of patients with moderate-to-severe disease (PASI-score ≥12) to patients with mild disease (PASI-score <12) and to healthy subjects. By means of flow cytometry method, lymphocytes in peripheral blood of 27 patients with psoriasis and 10 healthy controls were characterized. The absolute number of total lymphocytes was markedly decreased in patients with moderate-to-severe psoriasis as compared to patients with mild disease and normal subjects. Cellcounts of all analysed subsets were found to be increased in more severe psoriasis, except for CD8+CD45RO+ cells. The under-representation of CD8+CD45RO+ cells is compatible with the dynamics of acquired immunity, which requires a time log after the relapse of the lesions to differentiate from CD45RA+ naive cells