Toll-like receptor signaling adapter proteins govern spread of neuropathic pain and recovery following nerve injury in male mice.

BackgroundSpinal Toll-like receptors (TLRs) and signaling intermediaries have been implicated in persistent pain states. We examined the roles of two major TLR signaling pathways and selected TLRs in a mononeuropathic allodynia.MethodsL5 spinal nerve ligation (SNL) was performed in wild type (WT, C57BL/6) male and female mice and in male Tlr2-/-Tlr3-/-, Tlr4-/-, Tlr5-/-, Myd88-/-, Triflps2, Myd88/Triflps2, Tnf-/-, and Ifnar1-/- mice. We also examined L5 ligation in Tlr4-/- female mice. We examined tactile allodynia using von Frey hairs. Iba-1 (microglia) and GFAP (astrocytes) were assessed in spinal cords by immunostaining. Tactile thresholds were analyzed by 1- and 2-way ANOVA and the Bonferroni post hoc test was used.ResultsIn WT male and female mice, SNL lesions resulted in a persistent and robust ipsilateral, tactile allodynia. In males with TLR2, 3, 4, or 5 deficiencies, tactile allodynia was significantly, but incompletely, reversed (approximately 50%) as compared to WT. This effect was not seen in female Tlr4-/- mice. Increases in ipsilateral lumbar Iba-1 and GFAP were seen in mutant and WT mice. Mice deficient in MyD88, or MyD88 and TRIF, showed an approximately 50% reduction in withdrawal thresholds and reduced ipsilateral Iba-1. In contrast, TRIF and interferon receptor null mice developed a profound ipsilateral and contralateral tactile allodynia. In lumbar sections of the spinal cords, we observed a greater increase in Iba-1 immunoreactivity in the TRIF-signaling deficient mice as compared to WT, but no significant increase in GFAP. Removing MyD88 abrogated the contralateral allodynia in the TRIF signaling-deficient mice. Conversely, IFNβ, released downstream to TRIF signaling, administered intrathecally, temporarily reversed the tactile allodynia.ConclusionsThese observations suggest a critical role for the MyD88 pathway in initiating neuropathic pain, but a distinct role for the TRIF pathway and interferon in regulating neuropathic pain phenotypes in male mice

International travel and the risk of hospitalization with non-typhoidal Salmonella bacteremia. A Danish population-based cohort study, 1999-2008

<p>Abstract</p> <p>Background</p> <p>Information is sparse regarding the association between international travel and hospitalization with non-typhoidal <it>Salmonella </it>bacteremia. The aim of this study was to determine the proportion, risk factors and outcomes of travel-related non-typhoidal <it>Salmonella </it>bacteremia.</p> <p>Methods</p> <p>We conducted a 10-year population-based cohort study of all patients hospitalized with non-typhoidal <it>Salmonella </it>bacteremia in three Danish counties (population 1.6 million). We used denominator data on Danish travellers to assess the risk per 100,000 travellers according to age and travel destination. We used patients contemporaneously diagnosed with travel-related <it>Salmonella </it>gastroenteritis as reference patients to estimate the relative risk of presenting with travel-related bacteremia as compared with gastroenteritis. To evaluate clinical outcomes, we compared patients with travel-related bacteremia and patients with domestically acquired bacteremia in terms of length of hospital stay, number of extraintestinal focal infections and mortality after 30 and 90 days.</p> <p>Results</p> <p>We identified 311 patients hospitalized with non-typhoidal <it>Salmonella </it>bacteremia of whom 76 (24.4%) had a history of international travel. The risk of travel-related bacteremia per traveller was highest in the age groups 15-24 years (0.8/100,000 travellers) and 65 years and above (1.2/100,000 travellers). The sex- and age-adjusted relative risk of presenting with bacteremia was associated with travel to Sub-Saharan Africa (odds ratio 18.4; 95% confidence interval [6.9-49.5]), the Middle East (10.6; [2.1-53.2]) and South East Asia (4.0; [2.2-7.5]). We found high-risk countries in the same three regions when estimating the risk per traveller according to travel destination. Patients hospitalized with travel-related bacteremia had better clinical outcomes than patients with domestically acquired bacteremia, they had a shorter length of hospital stay (8 vs. 11 days), less extraintestinal focal infections (5 vs. 31 patients) and a lower risk of death within both 30 days (relative risk 0.2; [0.1-0.7]) and 90 days (0.3; [0.1-0.7]). A healthy traveller effect was a plausible explanation for the observed differences in outcomes.</p> <p>Conclusions</p> <p>International travel is a notable risk factor for being hospitalized with non-typhoidal <it>Salmonella </it>bacteremia and the risk differs between age groups and travel destinations. Healthy travellers hospitalized with bacteremia are less likely to have poor outcomes than patients with domestically acquired bacteremia.</p

Association and interaction of PPAR-complex gene variants with latent traits of left ventricular diastolic function

<p>Abstract</p> <p>Background</p> <p>Abnormalities in myocardial metabolism and/or regulatory genes have been implicated in left ventricular systolic dysfunction. However, the extent to which these modulate left ventricular diastolic function (LVDF) is uncertain.</p> <p>Methods</p> <p>Independent component analysis was applied to extract latent LVDF traits from 14 measured echocardiography-derived endophenotypes of LVDF in 403 Caucasians. Genetic association was assessed between measured and latent LVDF traits and 64 single nucleotide polymorphisms (SNPs) in three peroxisome proliferator-activated receptor <it>(PPAR)</it>-complex genes involved in the transcriptional regulation of fatty acid metabolism.</p> <p>Results</p> <p>By linear regression analysis, 7 SNPs (4 in <it>PPARA</it>, 2 in <it>PPARGC1A</it>, 1 in <it>PPARG</it>) were significantly associated with the latent LVDF trait, whereas a range of 0-4 SNPs were associated with each of the 14 measured echocardiography-derived endophenotypes. Frequency distribution of <it>P </it>values showed a greater proportion of significant associations with the latent LVDF trait than for the measured endophenotypes, suggesting that analyses of the latent trait improved detection of the genetic underpinnings of LVDF. Ridge regression was applied to investigate within-gene and gene-gene interactions. In the within-gene analysis, there were five significant pair-wise interactions in <it>PPARGC1A </it>and none in <it>PPARA </it>or <it>PPARG</it>. In the gene-gene analysis, significant interactions were found between rs4253655 in <it>PPARA </it>and rs1873532 (p = 0.02) and rs7672915 (p = 0.02), both in <it>PPARGC1A</it>, and between rs1151996 in <it>PPARG </it>and rs4697046 in <it>PPARGC1A </it>(p = 0.01).</p> <p>Conclusions</p> <p>Myocardial metabolism <it>PPAR</it>-complex genes, including within and between genes interactions, may play an important role modulating left ventricular diastolic function.</p

Symptoms in different severity degrees of bruxism: a cross-sectional study

Objective: The aim of the present study was to evaluate symptoms of the muscle pain, sleep quality, oral health, anxiety, stress and depression in individuals with different severity degrees of bruxism. Methods: Seventy-two individuals with bruxism were enrolled in the study, classified into: moderate (n=25) and severe (n=47) bruxism. Pain intensity was assessed using the Visual Analogical Scale, pain threshold with algometer, sleep quality by the Pittsburgh Sleep Quality Index, oral health by the Oral Health Impact Profile, anxiety by the State-Trait Anxiety Inventory, stress by the Perceived Stress Scale and depression using the Beck Depression Inventory. The significance level considered was 5%. Results: The results showed that individuals with severe bruxism presented greater muscle pain intensity, sleep disorder, worse oral health, high anxiety level and dysphoria with statistically significant differences (pObjetivo: Avaliar sintomas de dor muscular, qualidade de sono, saúde bucal, ansiedade, estresse e depressão em indivíduos com diferentes graus de severidade do bruxismo. Métodos: Setenta e dois indivíduos com bruxismo participaram do estudo e foram classificados com bruxismo moderado (n=25) e severo (n=47). A intensidade da dor foi avaliada pela Escala Visual Analógica, limiar de dor com o algômetro, qualidade de sono pelo Índice de Qualidade de Sono de Pittsburgh, saúde bucal pelo Perfil de Impacto de Saúde Bucal, ansiedade pelo Inventário de Ansiedade Traço-Estado, estresse pela Escala de Estresse Percebido e depressão pelo Inventário de Depressão de Beck. O nível de significância considerado foi 5%. Resultados: Os resultados demonstraram que indivíduos com bruxismo severo apresentaram maior intensidade de dor muscular, distúrbio do sono, pior qualidade de saúde bucal, elevado grau de ansiedade e disforia, com diferenças estatisticamente significantes (p;0,05). Conclusão: Os dados sugerem que indivíduos com bruxismo severo tem sintomas mais intensos. Eles apresentam maior intensidade de dor muscular, alterações na qualidade do sono e saúde bucal, ansiedade e depressão do que indivíduos com bruxismo moderado. Porém, ambos apresentam similaridade no estresse.Objetivo: Evaluar los síntomas dolor muscular, calidad de sueño, salud bucal, ansiedad, estrés y depresión en sujetos con diferentes niveles de gravedad del bruxismo. Método: Participaron del estudio 72 personas con bruxismo, clasificado según los niveles moderado (n=25) y grave (n=47). Se evaluaron la intensidad del dolor mediante la Escala Visual Analógica, umbral de dolor con algómetro, la calidad de sueño por el Índice de Calidad de Sueño de Pittsburgh, la salud bucal mediante el Perfil del Impacto de Salud Bucal, la ansiedad por el Inventario de Ansiedad Rasgo-Estado, el estrés mediante la Escala de Estrés Percibido y la depresión por el Inventario de Depresión de Beck. Se consideró el nivel de significación de 5%. Resultados: Los sujetos con bruxismo grave presentaron más intensamente dolor muscular, trastorno de sueño, peor calidad de salud bucal, alto grado de ansiedad y disforia, con diferencias estadísticamente significativas (p;0,05). Conclusión: Los datos mostraron que los sujetos con bruxismo grave sufren síntomas más intensos. A pesar de sufrir síntomas más intensos de dolor muscular, calidad de sueño y salud bucal alterada, ansiedad y depresión que los sujetos con bruxismo moderado, el estrés está presente en los dos niveles de bruxismo

CTGF is a central mediator of tissue remodeling and fibrosis and its inhibition can reverse the process of fibrosis

CTGF is a secreted matricellular protein with very complex biology. It has been shown to modulate many signaling pathways leading to cell adhesion and migration, angiogenesis, myofibroblast activation, and extracellular matrix deposition and remodeling, which together lead to tissue remodeling and fibrosis. It has been reported in the literature that inhibition of CTGF expression by siRNA prevents CCl4-induced liver fibrosis and can reverse fibrosis when administered after significant collagen deposition is observed. A monoclonal antibody to CTGF that is currently in clinical development (FG-3019) has demonstrated the ability to reverse vascular stiffening and improve cardiac function in a rat model of diabetic complications. FG-3019 has also exhibited activity in a murine radiation-induced pulmonary fibrosis model. When FG-3019 was administered to mice after a significant radiation-induced increase in lung density could be observed by CT imaging, the density of the lungs was observed to decrease over the period during which the antibody was administered and to remain stable after therapy had ceased. When considered together, these data indicate that inhibition of CTGF can prevent and reverse the process of fibrosis

A Re-conceptualization of Access for 21st Century Healthcare

Many e-health technologies are available to promote virtual patient–provider communication outside the context of face-to-face clinical encounters. Current digital communication modalities include cell phones, smartphones, interactive voice response, text messages, e-mails, clinic-based interactive video, home-based web-cams, mobile smartphone two-way cameras, personal monitoring devices, kiosks, dashboards, personal health records, web-based portals, social networking sites, secure chat rooms, and on-line forums. Improvements in digital access could drastically diminish the geographical, temporal, and cultural access problems faced by many patients. Conversely, a growing digital divide could create greater access disparities for some populations. As the paradigm of healthcare delivery evolves towards greater reliance on non-encounter-based digital communications between patients and their care teams, it is critical that our theoretical conceptualization of access undergoes a concurrent paradigm shift to make it more relevant for the digital age. The traditional conceptualizations and indicators of access are not well adapted to measure access to health services that are delivered digitally outside the context of face-to-face encounters with providers. This paper provides an overview of digital “encounterless” utilization, discusses the weaknesses of traditional conceptual frameworks of access, presents a new access framework, provides recommendations for how to measure access in the new framework, and discusses future directions for research on access

A Large-Scale Multi-ancestry Genome-wide Study Accounting for Smoking Behavior Identifies Multiple Significant Loci for Blood Pressure

Genome-wide association analysis advanced understanding of blood pressure (BP), a major risk factor for vascular conditions such as coronary heart disease and stroke. Accounting for smoking behavior may help identify BP loci and extend our knowledge of its genetic architecture. We performed genome-wide association meta-analyses of systolic and diastolic BP incorporating gene-smoking interactions in 610,091 individuals. Stage 1 analysis examined similar to 18.8 million SNPs and small insertion/deletion variants in 129,913 individuals from four ancestries (European, African, Asian, and Hispanic) with follow-up analysis of promising variants in 480,178 additional individuals from five ancestries. We identified 15 loci that were genome-wide significant (p <5 x 10(-8)) in stage 1 and formally replicated in stage 2. A combined stage 1 and 2 meta-analysis identified 66 additional genome-wide significant loci (13, 35, and 18 loci in European, African, and trans-ancestry, respectively). A total of 56 known BP loci were also identified by our results (p <5 x 10(-8)). Of the newly identified loci, ten showed significant interaction with smoking status, but none of them were replicated in stage 2. Several loci were identified in African ancestry, highlighting the importance of genetic studies in diverse populations. The identified loci show strong evidence for regulatory features and support shared pathophysiology with cardiometabolic and addiction traits. They also highlight a role in BP regulation for biological candidates such as modulators of vascular structure and function (CDKN1B, BCAR1-CFDP1, PXDN, EEA1), ciliopathies (SDCCAG8, RPGRIP1L), telomere maintenance (TNKS, PINX1, AKTIP), and central dopaminergic signaling MSRA, EBF2).Peer reviewe