by
Daniel A. Salmon;
William K. Y. Pan;
Saad B Omer;
William K. Y. Navar;
Walter Orenstein;
Edgar K. Marcuse;
James Taylor;
M. Patricia deHart;
Shannon Stokley;
Terrell Carter;
Neal A. Halsey
Objective: Compare vaccine knowledge, attitudes and practices of primary care providers for fully vaccinated children and children who are exempt from school immunization requirements. Methods: We conducted a mailed survey of parent-identified primary care providers from four states to measure perceived risks and benefits of vaccination and other key immunization beliefs. Frequencies of responses were stratified by type of provider, identified by exempt versus vaccinated children. Logistic regression was used to calculate odds ratios for responses by provider type. Results: 551 surveys were completed (84.3% response rate). Providers for exempt children had similar attitudes to providers for non-exempt children. However, there were statistically significant increased concerns among providers for exempt children regarding vaccine safety and lack of perceived individual and community benefits for vaccines compared to other providers. Conclusions: The great majority of providers for exempt children had similar attitudes about vaccine safety, effectiveness and benefits as providers of non-exempt children. Although providers for exempt children were more likely to believe that multiple vaccines weaken a child's immune system and were concerned about vaccine safety and less likely to consider vaccines were beneficial, a substantial proportion of providers of both exempt and vaccinated children have concerns about vaccine safety and believe that CDC underestimates the frequency of vaccine side effects. Effective continuing education of providers about the risks and benefits of immunization and including in vaccine recommendations more information on pre and post licensing vaccine safety evaluations may help address these concerns.
by
Alberto Albanese;
Francesca Del Sorbo;
Cynthia Comella;
Hyder Jinnah;
Jonathan W. Mink;
Bart Post;
Marie Vidailhet;
Jens Volkmann;
Thomas T. Warner;
Albert F. G. Leentjens;
Pablo Martinez-Martin;
Glenn T. Stebbins;
Christopher G. Goetz;
Anette Schrag
Many rating scales have been applied to the evaluation of dystonia, but only few have been assessed for clinimetric properties. The Movement Disorders Society commissioned this task force to critique existing dystonia rating scales and place them in the clinical and clinimetric context. A systematic literature review was conducted to identify rating scales that have either been validated or used in dystonia. Thirty-six potential scales were identified. Eight were excluded because they did not meet review criteria, leaving 28 scales that were critiqued and rated by the task force. Seven scales were found to meet criteria to be "recommended": the Blepharospasm Disability Index is recommended for rating blepharospasm; the Cervical Dystonia Impact Scale and the Toronto Western Spasmodic Torticollis Rating Scale for rating cervical dystonia; the Craniocervical Dystonia Questionnaire for blepharospasm and cervical dystonia; the Voice Handicap Index (VHI) and the Vocal Performance Questionnaire (VPQ) for laryngeal dystonia; and the Fahn-Marsden Dystonia Rating Scale for rating generalized dystonia. Two "recommended" scales (VHI and VPQ) are generic scales validated on few patients with laryngeal dystonia, whereas the others are disease-specific scales. Twelve scales met criteria for "suggested" and 7 scales met criteria for "listed." All the scales are individually reviewed in the online information. The task force recommends 5 specific dystonia scales and suggests to further validate 2 recommended generic voice-disorder scales in dystonia. Existing scales for oromandibular, arm, and task-specific dystonia should be refined and fully assessed. Scales should be developed for body regions for which no scales are available, such as lower limbs and trunk.
by
Weici Zhang;
Masanobu Tsuda;
Guo-Xiang Yang;
Koichi Tsuneyama;
Xiao-Song He;
Aftab Ansari;
William M. Ridgway;
Ross L. Coppel;
Zhe-Xiong Lian;
Patrick S.C. Leung;
M. Eric Gershwin
Hepatosplenic T cell lymphoma (HSTCL) is a distinct and lethal subtype of peripheral T cell lymphoma with an aggressive course and poor outcome despite multiagent chemotherapy. Contradictory literature, an unknown etiology, and poor response to treatment highlight the need to define the malignant process and identify molecular targets with potential for successful therapeutic interventions. Herein, we report that mice homozygously expressing a dominant negative TGFβRII (dnTGFβRII) under the control of the CD4 promoter spontaneously develop lymphoma-like T cell infiltration involving both spleen and liver. Splenomegaly, hepatomegaly and liver dysfunction were observed in homozygous dnTGFβRII mice between 10 weeks and 10 months of age associated with a predominant infiltration of CD4 - CD8 - TCRβ + NK1.1 + or CD8 + TCRβ + NK1.1 - T cell subsets. Notch 1 and c-Myc expression at the mRNA levels were significantly increased and positively correlated with the cell number of lymphoid infiltrates in the liver of dnTGFβRII homozygous compared to hemizygous mice. Further, 2×10 4 isolated lymphoma-like cells transplant disease by adoptive cell transfers. Collectively, our data demonstrate that increased copy number of dnTGFβRII is critical for development of lymphoma-like T cell infiltration.
The basal ganglia (BG) have long been considered to play an important role in the control of movement and the pathophysiology of movement disorders, such as Parkinson's disease (PD). Studies over the past decades have considerably broadened this view, indicating that the BG participate in multiple, parallel, largely segregated, cortico-subcortical reentrant pathways involving motor, associative and limbic functions. Research has shown that dysfunction within individual circuits is associated not only with movement disorders, but also with neuropsychiatric disorders. Accordingly, a number of movement disorders and neuropsychiatric disorders such as obsessive compulsive disorder and Tourette's syndrome are viewed as "circuit disorders." We here discuss the changes in our current understanding of the anatomic and functional organization of BG circuits and related circuit disorders.
by
Chie Sugimoto;
Shinichiro Nakamura;
Shoko I. Hagen;
Yasuko Tsunetsugu-Yokota;
Francois Villinger;
Aftab Ansari;
Yasuo Suzuki;
Naoki Yamamoto;
Yoshiyuki Nagai;
Louis J. Picker;
Kazuyasu Mori
Glycans of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) play pivotal roles in modulating virus-target cell interactions. We have previously reported that, whereas SIVmac239 is pathogenic, its deglycosylated essentially nonpathogenic mutant (Δ5G) serves as a live-attenuated vaccine, although both replicate similarly during primary infection. These findings prompted us to determine whether such a polarized clinical outcome was due to differences in the immune tissues targeted by these viruses, where functionally and phenotypically different memory CD4 + T cells reside. The results showed that Δ5G replicates in secondary lymphoid tissue (SLT) at 1- to 2-log-lower levels than SIVmac239, whereas SIVmac239-infected but not Δ5G-infected animals deplete CXCR3 + CCR5 + transitional memory (TrM) CD4 + T cells. An early robust Δ5G replication was localized to small intestinal tissue, especially the lamina propria (effector site) rather than isolated lymphoid follicles (inductive site) and was associated with the induction and depletion of CCR6 + CXCR3 - CCR5 + effector memory CD4 + T cells. These results suggest that differential glycosylation of Env dictates the type of tissue-resident CD4 + T cells that are targeted, which leads to pathogenic infection of TrM-Th1 cells in SLT and nonpathogenic infection of Th17 cells in the small intestine, respectively.
Purpose: HIV pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV transmission. Finding a PrEP provider, however, can be a barrier to accessing care. This study explores the distribution of publicly listed PrEP-providing clinics in the United States.
Methods: Data regarding 2094 PrEP-providing clinics come from PrEP Locator, a national database of PrEP-providing clinics. We compared the distribution of these PrEP clinics to the distribution of new HIV diagnoses within various geographical areas and by key populations.
Results: Most (43/50) states had less than one PrEP-providing clinic per 100,000 population. Among states, the median was two clinics per 1000 PrEP-eligible men who have sex with men. Differences between disease burden and service provision were seen for counties with higher proportions of their residents living in poverty, lacking health insurance, identifying as African American, or identifying as Hispanic/Latino. The Southern region accounted for over half of all new HIV diagnoses but only one-quarter of PrEP-providing clinics.
Conclusions: The current number of PrEP-providing clinics is not sufficient to meet needs. In addition, PrEP-providing clinics are unevenly distributed compared to disease burden, with poor coverage in the Southern divisions and areas with higher poverty, uninsured, and larger minority populations. PrEP services should be expanded and targeted to address disparities.
To understand how neurons control the expression of the AMPA receptor subunit GluR2, we cloned the 5' proximal region of the rat gene and investigated GluR2 promoter activity by transient transfection. RNase protection and primer extension of rat brain mRNA revealed multiple transcription initiation sites from -340 to -481 bases upstream of the GluR2 AUG codon. The relative use of 5' start sites was different in cortex and cerebellum, indicating complexity of GluR2 transcript expression among different sets of neurons. When GluR2 promoter activity was investigated by plasmid transfection into cultured cortical neurons, cortical gila, and C6 glioma cells, the promoter construct with the strongest activity, per transfected cell, was 29.4-fold (± 3.7) more active in neurons than in non- neural cells. Immunostaining of cortical cultures showed that >97% of the luciterase-positive cells also expressed the neuronal marker MAP-2. Evaluation of internal deletion and substitution mutations identified a functional repressor element 1 RE1-like silencer and functional Sp1 and nuclear respiratory factor-1 (NRF-1) elements within a GC-rich proximal GluR2 promoter region. The GluR2 silencer reduced promoter activity in gila and non-neuronal cell lines by two- to threefold, was without effect in cortical neurons, and could bind the RE1-silencing transcription factor (REST) because cotransfection of REST into neurons reduced GluR2 promoter activity in a silencer-dependent manner. Substitution of the GluR2 silencer by the homologous Nall RE1 silencer further reduced GluR2 promoter activity in non- neuronal cells by 30-47%. Maximal positive GluR2 promoter activity required both Sp1 and NRF-1 cis elements and an interelement nucleotide bridge sequence. These results indicate that GluR2 transcription initiates from multiple sites, is highly neuronal selective, and is regulated by three regulatory elements in the 5' proximal promoter region.
Irritable bowel syndrome (IBS) is a common gastrointestinal disorder characterized by chronic abdominal pain and alteration of bowel movements. The pathogenesis of visceral hypersensitivity in IBS patients remains largely unknown. Hydrogen sulfide (H 2 S) is reported to play an important role in development of visceral hyperalgesia. However, the role of H 2 S at spinal dorsal horn level remains elusive in visceral hypersensitivity. The aim of this study is designed to investigate how H 2 S takes part in visceral hypersensitivity of adult rats with neonatal colonic inflammation (NCI). Visceral hypersensitivity was induced by neonatal colonic injection of diluted acetic acid. Expression of an endogenous H2S synthesizing enzyme cystathionine ß-synthetase (CBS) was determined by Western blot. Excitability and synaptic transmission of neurons in the substantia gelatinosa (SG) of spinal cord was recorded by patch clamping. Here, we showed that expression of CBS in the spinal dorsal horn was significantly upregulated in NCI rats. The frequency of glutamatergic synaptic activities in SG was markedly enhanced in NCI rats when compared with control rats. Application of NaHS increased the frequency of both spontaneous and miniature excitatory post-synaptic currents of SG neurons in control rats through a presynaptic mechanism. In contrast, application of AOAA, an inhibitor of CBS, dramatically suppressed the frequency of glutamatergic synaptic activities of SG neurons of NCI rats. Importantly, intrathecal injection of AOAA remarkably attenuated visceral hypersensitivity of NCI rats. These results suggest that H2S modulates pain signaling likely through a presynaptic mechanism in SG of spinal dorsal horn, thus providing a potential therapeutic strategy for treatment for chronic visceral pain in patients with IBS.
Although many studies have documented that reduction of plasma cholesterol levels decreases the risk of coronary artery disease, it remains the most common cause of death in the Western world. Current therapeutic options are effective in lowering cholesterol, especially in clinical trials, but clinical application is not optimized for many reasons. Dietary restriction for long-term management of hypercholesterolemia is helpful but usually insufficient to reduce low-density lipoprotein cholesterol (LDL-C) to goal levels. Powerful drugs are available, but these are often insufficient to meet the clinical demands for cholesterol-lowering therapy. Phytosterols and phytostanols have been partially effective by providing some inhibition of absorption of cholesterol. Compounds that specifically and more effectively block intestinal absorption of dietary and biliary cholesterol should provide a significant new agent for altering lipoprotein concentrations favorably. Ezetimibe is the first of this class of compounds that act at the gut epithelium to reduce cholesterol absorption in the milligram dose range markedly. Clinical studies indicate that ezetimibe effectively decreases LDL-C by 15 to 20% as monotherapy, with a favorable safety profile. Moreover, results from preliminary clinical trials indicate that ezetimibe given concomitantly with a statin provides additive efficacy. The combination represents a new approach to lipid management, achieving greater LDL-C and triglyceride reductions and greater improvements in HDL-C than statin monotherapy. This could offer another important option in clinical practice for management of hypercholesterolemic patients.
The contribution of environmental toxicants to the etiology and risk of Parkinson's disease (PD) has been clearly established, with organochlorine insecticides routinely shown to damage the nigrostriatal dopamine pathway. Although PD is generally considered an adult onset disease, it has been postulated that exposure to environmental contaminants or other factors early in life during critical periods of neurodevelopment could alter the dopaminergic circuit and predispose individuals to developing PD. Recent epidemiological evidence has found exposure to the organochlorine insecticide endosulfan to be a risk factor for PD. However, the specific dopaminergic targets or vulnerable developmental time points related to endosulfan exposure have not been investigated. Thus, we sought to investigate dopaminergic neurotoxicity following developmental exposure to endosulfan as well as following an additional challenge with MPTP. Our in vitro findings demonstrate a reduction in SK-N-SH cells and ventral mesencephalic primary cultures after endosulfan treatment. Using an in vivo developmental model, exposure to endosulfan during gestation and lactation caused a reduction in DAT and TH in the striatum of male offspring. These alterations were exacerbated following subsequent treatment with MPTP. In contrast, exposure of adult mice to endosulfan did not elicit dopaminergic damage and did not appear to increase the vulnerability of the dopamine neurons to MPTP. These findings suggest that development during gestation and lactation represents a critical window of susceptibility to endosulfan exposure and development of the nigrostriatal dopamine system. Furthermore, these exposures appear to sensitize the dopamine neurons to additional insults that may occur later in life.