Showing papers by "University of Tennessee Health Science Center published in 2011"
Harvard University1, Cincinnati Children's Hospital Medical Center2, Duke University3, University of Arkansas for Medical Sciences4, Icahn School of Medicine at Mount Sinai5, Johns Hopkins University School of Medicine6, National Institutes of Health7, University of Southampton8, St Mary's Hospital9, LSU Health Sciences Center Shreveport10, University of Rochester Medical Center11, Rutgers University12, Boston Children's Hospital13, University of California, San Diego14, University of Colorado Denver15, Oregon Health & Science University16, University of Tennessee Health Science Center17, Food and Drug Administration18, University of California, Irvine19, Scripps Health20, University of Manitoba21, Children's National Medical Center22, University of Minnesota23, University of Rochester24
TL;DR: The National Institute of Allergy and Infectious Diseases, working with 34 professional organizations, federal agencies, and patient advocacy groups, led the development of clinical guidelines for the diagnosis and management of food allergy, which include a consensus definition for food allergy.
Abstract: Food allergy is an important public health problem that affects children and adults and may be increasing in prevalence. Despite the risk of severe allergic reactions and even death, there is no current treatment for food allergy: the disease can only be managed by allergen avoidance or treatment of symptoms. The diagnosis and management of food allergy also may vary from one clinical practice setting to another. Finally, because patients frequently confuse nonallergic food reactions, such as food intolerance, with food allergies, there is an unfounded belief among the public that food allergy prevalence is higher than it truly is. In response to these concerns, the National Institute of Allergy and Infectious Diseases, working with 34 professional organizations, federal agencies, and patient advocacy groups, led the development of clinical guidelines for the diagnosis and management of food allergy. These Guidelines are intended for use by a wide variety of health care professionals, including family practice physicians, clinical specialists, and nurse practitioners. The Guidelines include a consensus definition for food allergy, discuss comorbid conditions often associated with food allergy, and focus on both IgE-mediated and non-IgE-mediated reactions to food. Topics addressed include the epidemiology, natural history, diagnosis, and management of food allergy, as well as the management of severe symptoms and anaphylaxis. These Guidelines provide 43 concise clinical recommendations and additional guidance on points of current controversy in patient management. They also identify gaps in the current scientific knowledge to be addressed through future research.
2,014 citations
Harvard University1, Mayo Clinic2, University of Toronto3, University of California, Los Angeles4, University at Buffalo5, Fred Hutchinson Cancer Research Center6, University of California, Davis7, University of Tennessee Health Science Center8, George Washington University9, University of Western Ontario10, University of Wisconsin-Madison11, University of Kansas12, Laval University13, Queen's University14, University of British Columbia15
TL;DR: Exemestane significantly reduced invasive breast cancers in postmenopausal women who were at moderately increased risk for breast cancer and was associated with no serious toxic effects and only minimal changes in health-related quality of life.
Abstract: Background Tamoxifen and raloxifene have limited patient acceptance for primary prevention of breast cancer. Aromatase inhibitors prevent more contralateral breast cancers and cause fewer side effects than tamoxifen in patients with early-stage breast cancer. Methods In a randomized, placebo-controlled, double-blind trial of exemestane designed to detect a 65% relative reduction in invasive breast cancer, eligible postmenopausal women 35 years of age or older had at least one of the following risk factors: 60 years of age or older; Gail 5-year risk score greater than 1.66% (chances in 100 of invasive breast cancer developing within 5 years); prior atypical ductal or lobular hyperplasia or lobular carcinoma in situ; or ductal carcinoma in situ with mastectomy. Toxic effects and health-related and menopause-specific qualities of life were measured. Results A total of 4560 women for whom the median age was 62.5 years and the median Gail risk score was 2.3% were randomly assigned to either exemestane or placebo. At a median follow-up of 35 months, 11 invasive breast cancers were detected in those given exemestane and in 32 of those given placebo, with a 65% relative reduction in the annual incidence of invasive breast cancer (0.19% vs. 0.55%; hazard ratio, 0.35; 95% confidence interval [CI], 0.18 to 0.70; P = 0.002). The annual incidence of invasive plus noninvasive (ductal carcinoma in situ) breast cancers was 0.35% on exemestane and 0.77% on placebo (hazard ratio, 0.47; 95% CI, 0.27 to 0.79; P = 0.004). Adverse events occurred in 88% of the exemestane group and 85% of the placebo group (P = 0.003), with no significant differences between the two groups in terms of skeletal fractures, cardiovascular events, other cancers, or treatmentrelated deaths. Minimal quality-of-life differences were observed. Conclusions Exemestane significantly reduced invasive breast cancers in postmenopausal women who were at moderately increased risk for breast cancer. During a median follow-up period of 3 years, exemestane was associated with no serious toxic effects and only minimal changes in health-related quality of life. (Funded by Pfizer and others; NCIC CTG MAP.3 ClinicalTrials.gov number, NCT00083174.)
815 citations
Purdue University1, Kanazawa University2, Graduate University for Advanced Studies3, National Institutes of Natural Sciences, Japan4, Monash University5, University of California, Davis6, Pennsylvania State University7, University at Buffalo8, New York Botanical Garden9, University of Regina10, University of Arizona11, University of Georgia12, University of Potsdam13, Salk Institute for Biological Studies14, Charles University in Prague15, College of William & Mary16, University of California, San Diego17, École normale supérieure de Lyon18, Carnegie Institution for Science19, Hokkaido University20, University of Jena21, Martin Luther University of Halle-Wittenberg22, University of Copenhagen23, University of Tokyo24, Nagoya University25, Free University of Berlin26, University of Tsukuba27, University of Rostock28, University of Tübingen29, Nara Institute of Science and Technology30, Mayo Clinic31, University of California, Berkeley32, Rutgers University33, National Institute of Genetics34, Max Planck Society35, University of Tennessee Health Science Center36, University of Washington37, Dalhousie University38, University of Oxford39, University of Freiburg40, University of Los Andes41, University of Rhode Island42, Joint BioEnergy Institute43, Ruhr University Bochum44, Texas A&M University45, Osaka University46, Cornell University47, Cold Spring Harbor Laboratory48, University of Burgundy49, Utah State University50, United States Department of Energy51
TL;DR: The genome sequence of the lycophyte Selaginella moellendorffii (Selaginella), the first nonseed vascular plant genome reported, is reported, finding that the transition from a gametophytes- to a sporophyte-dominated life cycle required far fewer new genes than the Transition from a non Seed vascular to a flowering plant.
Abstract: Vascular plants appeared ~410 million years ago, then diverged into several lineages of which only two survive: the euphyllophytes (ferns and seed plants) and the lycophytes. We report here the genome sequence of the lycophyte Selaginella moellendorffii (Selaginella), the first nonseed vascular plant genome reported. By comparing gene content in evolutionarily diverse taxa, we found that the transition from a gametophyte- to a sporophyte-dominated life cycle required far fewer new genes than the transition from a nonseed vascular to a flowering plant, whereas secondary metabolic genes expanded extensively and in parallel in the lycophyte and angiosperm lineages. Selaginella differs in posttranscriptional gene regulation, including small RNA regulation of repetitive elements, an absence of the trans-acting small interfering RNA pathway, and extensive RNA editing of organellar genes.
750 citations
University of Texas Health Science Center at San Antonio1, Arizona State University2, Veterans Health Administration3, SUNY Downstate Medical Center4, Louisiana State University5, University of Southern California6, Georgetown University7, University of California, San Diego8, University of Tennessee Health Science Center9, Memorial Hospital of South Bend10
TL;DR: As compared with placebo, pioglitazone reduced the risk of conversion of impaired glucose tolerance to type 2 diabetes mellitus by 72% but was associated with significant weight gain and edema.
Abstract: RESULTS Annual incidence rates for type 2 diabetes mellitus were 2.1% in the pioglitazone group and 7.6% in the placebo group, and the hazard ratio for conversion to diabetes in the pioglitazone group was 0.28 (95% confidence interval, 0.16 to 0.49; P<0.001). Conversion to normal glucose tolerance occurred in 48% of the patients in the pioglitazone group and 28% of those in the placebo group (P<0.001). Treatment with pioglitazone as compared with placebo was associated with significantly reduced levels of fasting glucose (a decrease of 11.7 mg per deciliter vs. 8.1 mg per deciliter [0.7 mmol per liter vs. 0.5 mmol per liter], P<0.001), 2-hour glucose (a decrease of 30.5 mg per deciliter vs. 15.6 mg per deciliter [1.6 mmol per liter vs. 0.9 mmol per liter], P<0.001), and HbA1c (a decrease of 0.04 percentage points vs. an increase of 0.20 percentage points, P<0.001). Pioglitazone therapy was also associated with a decrease in diastolic blood pressure (by 2.0 mm Hg vs. 0.0 mm Hg, P = 0.03), a reduced rate of carotid intima–media thickening (31.5%, P = 0.047), and a greater increase in the level of high-density lipoprotein cholesterol (by 7.35 mg per deciliter vs. 4.5 mg per deciliter [0.4 mmol per liter vs. 0.3 mmol per liter], P = 0.008). Weight gain was greater with pioglitazone than with placebo (3.9 kg vs. 0.77 kg, P<0.001), and edema was more frequent (12.9% vs. 6.4%, P = 0.007). CONCLUSIONS As compared with placebo, pioglitazone reduced the risk of conversion of impaired glucose tolerance to type 2 diabetes mellitus by 72% but was associated with significant weight gain and edema. (Funded by Takeda Pharmaceuticals and others; ClinicalTrials.gov number, NCT00220961.)
644 citations
TL;DR: It is argued that sensitization remains a useful model for determining the neural basis of addiction, and an example is provided in which data from sensitization studies led to potential pharmacotherapies that have been tested in animal models of relapse and in human addicts.
Abstract: Repeated exposure to drugs of abuse enhances the motor-stimulant response to these drugs, a phenomenon termed behavioral sensitization. Animals that are extinguished from self-administration training readily relapse to drug, conditioned cue, or stress priming. The involvement of sensitization in reinstated drug-seeking behavior remains controversial. This review describes sensitization and reinstated drug seeking as behavioral events, and the neural circuitry, neurochemistry, and neuropharmacology underlying both behavioral models will be described, compared, and contrasted. It seems that although sensitization and reinstatement involve overlapping circuitry and neurotransmitter and receptor systems, the role of sensitization in reinstatement remains ill-defined. Nevertheless, it is argued that sensitization remains a useful model for determining the neural basis of addiction, and an example is provided in which data from sensitization studies led to potential pharmacotherapies that have been tested in animal models of relapse and in human addicts.
584 citations
TL;DR: Comparative analysis of the plant CYPomes provides information on the successive steps required for the evolution of land plants, and points to several cases of convergent evolution in plant metabolism.
Abstract: Being by far the largest family of enzymes to support plant metabolism, the cytochrome P450s (CYPs) constitute an excellent reporter of metabolism architecture and evolution. The huge superfamily of CYPs found in angiosperms is built on the successful evolution of 11 ancestral genes, with very different fates and progenies. Essential functions in the production of structural components (membrane sterols), light harvesting (carotenoids) or hormone biosynthesis kept some of them under purifying selection, limiting duplication and sub/neofunctionalization. One group (the CYP71 clan) after an early trigger to diversification, has kept growing, producing bursts of gene duplications at an accelerated rate. The CYP71 clan now represents more than half of all CYPs in higher plants. Such bursts of gene duplication are likely to contribute to adaptation to specific niches and to speciation. They also occur, although with lower frequency, in gene families under purifying selection. The CYP complement (CYPomes) of rice and the model grass weed Brachypodium distachyon have been compared to view evolution in a narrower time window. The results show that evolution of new functions in plant metabolism is a very long-term process. Comparative analysis of the plant CYPomes provides information on the successive steps required for the evolution of land plants, and points to several cases of convergent evolution in plant metabolism. It constitutes a very useful tool for spotting essential functions in plant metabolism and to guide investigations on gene function.
498 citations
TL;DR: There is an overview of available evidence for optimal use of Erwinia asparaginase in the treatment of ALL and debate on the optimal formulation and dosage of these agents continues.
Abstract: Asparaginases are a cornerstone of treatment protocols for acute lymphoblastic leukemia (ALL) and are used for remission induction and intensification treatment in all pediatric regimens and in the majority of adult treatment protocols. Extensive clinical data have shown that intensive asparaginase treatment improves clinical outcomes in childhood ALL. Three asparaginase preparations are available: the native asparaginase derived from Escherichia coli (E. coli asparaginase), a pegylated form of this enzyme (PEG-asparaginase), and a product isolated from Erwinia chrysanthemi, ie, Erwinia asparaginase. Clinical hypersensitivity reactions and silent inactivation due to antibodies against E. coli asparaginase, lead to inactivation of E. coli asparaginase in up to 60% of cases. Current treatment protocols include E. coli asparaginase or PEG-asparaginase for first-line treatment of ALL. Typically, patients exhibiting sensitivity to one formulation of asparaginase are switched to another to ensure they receive the most efficacious treatment regimen possible. Erwinia asparaginase is used as a second- or third-line treatment in European and US protocols. Despite the universal inclusion of asparaginase in such treatment protocols, debate on the optimal formulation and dosage of these agents continues. This article provides an overview of available evidence for optimal use of Erwinia asparaginase in the treatment of ALL.
486 citations
Fred Hutchinson Cancer Research Center1, University of California, Los Angeles2, Harvard University3, University of Tennessee Health Science Center4, George Washington University5, University of Minnesota6, Stanford University7, University of Texas at San Antonio8, Memorial Hospital of South Bend9, University of Alabama at Birmingham10
TL;DR: In this article, postmenopausal women with prior hysterectomy followed up for 10.7 years were associated with an increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality.
Abstract: Results The postintervention risk (annualized rate) for CHD among women assigned to CEE was 0.64% compared with 0.67% in the placebo group (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.75-1.25), 0.26% vs 0.34%, respectively, for breast cancer (HR, 0.75; 95% CI, 0.51-1.09), and 1.47% vs 1.48%, respectively, for total mortality (HR,1.00;95%CI,0.84-1.18).Theriskofstrokewasnolongerelevatedduringthepostintervention follow-up period and was 0.36% among women receiving CEE compared with 0.41% in the placebo group (HR, 0.89; 95% CI, 0.64-1.24), the risk of deep vein thrombosis was lower at 0.17% vs 0.27%, respectively (HR, 0.63; 95% CI, 0.41-0.98), and the risk of hip fracture did not differ significantly and was 0.36% vs 0.28%, respectively(HR,1.27;95%CI,0.88-1.82).Overtheentirefollow-up,lowerbreastcancerincidence in the CEE group persisted and was 0.27% compared with 0.35% in the placebo group(HR,0.77;95%CI,0.62-0.95).Healthoutcomesweremorefavorableforyounger comparedwitholderwomenforCHD(P=.05forinteraction),totalmyocardialinfarction (P=.007 for interaction), colorectal cancer (P=.04 for interaction), total mortality (P=.04 for interaction), and global index of chronic diseases (P=.009 for interaction). Conclusions Among postmenopausal women with prior hysterectomy followed up for 10.7 years, CEE use for a median of 5.9 years was not associated with an increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality. A decreased risk of breast cancer persisted.
459 citations
TL;DR: It is suggested that future studies of immunotherapeutic intervention with teplizumab might have increased success in prevention of a decline in β-cell function (measured by C-peptide) and provision of glycaemic control at reduced doses of insulin if they target patients early after diagnosis of diabetes and children.
405 citations
TL;DR: This article identified new regions showing association with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2.
Abstract: Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.
394 citations
TL;DR: A narrative review of osteonecrosis of the jaw in patients with low bone mass receiving treatment with antiresorptive agents is based on an appraisal of the literature as discussed by the authors.
Abstract: Background This narrative review of osteonecrosis of the jaw in patients with low bone mass receiving treatment with antiresorptive agents is based on an appraisal of the literature by an advisory committee of the American Dental Association Council on Scientific Affairs. It updates the committee's 2008 advisory statement. Methods The authors searched MEDLINE for literature published between May 2008 (the end date of the last search) and February 2011. Results This report contains recommendations based on the findings of the literature search and on expert opinion that relate to general dentistry; periodontal disease management; implant placement and maintenance; oral and maxillofacial surgery; endodontics; restorative dentistry and prosthodontics; orthodontics; and C-terminal telopeptide testing and drug holidays. Conclusions The highest reliable estimate of antiresorptive agent–induced osteonecrosis of the jaw (ARONJ) prevalence is approximately 0.10 percent. Osteoporosis is responsible for considerable morbidity and mortality. Therefore, the benefit provided by antiresorptive therapy outweighs the low risk of developing osteonecrosis of the jaw. Clinical Implications An oral health program consisting of sound hygiene practices and regular dental care may be the optimal approach for lowering ARONJ risk. No validated diagnostic technique exists to determine which patients are at increased risk of developing ARONJ. Discontinuing bisphosphonate therapy may not lower the risk but may have a negative effect on low-bone-mass–treatment outcomes.
Fred Hutchinson Cancer Research Center1, Yeshiva University2, Northwestern University3, Kaiser Permanente4, University of Wisconsin-Madison5, University of Cambridge6, Brown University7, University of Arizona8, University of Tennessee Health Science Center9, University of Massachusetts Medical School10, University of North Carolina at Chapel Hill11
TL;DR: Through comparison with biomarkers, the food record is shown to provide a stronger estimate of energy and protein than does the food frequency questionnaire, with 24-hour recalls mostly intermediate.
Abstract: The food frequency questionnaire approach to dietary assessment is ubiquitous in nutritional epidemiology research. Food records and recalls provide approaches that may also be adaptable for use in large epidemiologic cohorts, if warranted by better measurement properties. The authors collected (2007–2009) a 4-day food record, three 24-hour dietary recalls, and a food frequency questionnaire from 450 postmenopausal women in the Women’s Health Initiative prospective cohort study (enrollment, 1994–1998), along with biomarkers of energy and protein consumption. Through comparison with biomarkers, the food record is shown to provide a stronger estimate of energy and protein than does the food frequency questionnaire, with 24-hour recalls mostly intermediate. Differences were smaller and nonsignificant for protein density. Food frequencies, records, and recalls were, respectively, able to “explain” 3.8%, 7.8%, and 2.8% of biomarker variation for energy; 8.4%, 22.6%, and 16.2% of biomarker variation for protein; and 6.5%, 11.0%, and 7.0% of biomarker variation for protein density. However, calibration equations that include body mass index, age, and ethnicity substantially improve these numbers to 41.7%, 44.7%, and 42.1% for energy; 20.3%, 32.7%, and 28.4% for protein; and 8.7%, 14.4%, and 10.4% for protein density. Calibration equations using any of the assessment procedures may yield suitable consumption estimates for epidemiologic study purposes.
TL;DR: This narrative review explores the pathogenetic rationale for the treatment of type 2 diabetes, with the view of fostering better understanding of the evolving treatment modalities.
Abstract: The prevalence of type 2 diabetes continues to increase at an alarming rate around the world, with even more people being affected by prediabetes. Although the pathogenesis and long-term complications of type 2 diabetes are fairly well known, its treatment has remained challenging, with only half of the patients achieving the recommended hemoglobin A1c target. This narrative review explores the pathogenetic rationale for the treatment of type 2 diabetes, with the view of fostering better understanding of the evolving treatment modalities. The diagnostic criteria including the role of hemoglobin A1c in the diagnosis of diabetes are discussed. Due attention is given to the different therapeutic maneuvers and their utility in the management of the diabetic patient. The evidence supporting the role of exercise, medical nutrition therapy, glucose monitoring, and antiobesity measures including pharmacotherapy and bariatric surgery is discussed. The controversial subject of optimum glycemic control in hospitalized and ambulatory patients is discussed in detail. An update of the available pharmacologic options for the management of type 2 diabetes is provided with particular emphasis on newer and emerging modalities. Special attention has been given to the initiation of insulin therapy in patients with type 2 diabetes, with explanation of the pathophysiologic basis for insulin therapy in the ambulatory diabetic patient. A review of the evidence supporting the efficacy of the different preventive measures is also provided.
TL;DR: The long-term consequences of a single intravenous administration of a self-complementary AAV vector encoding a codon optimized human factor IX gene in 24 nonhuman primates revealed no toxicity, and data support further evaluation of this vector in hemophilia B patients.
TL;DR: Genomic studies suggest that targeted inhibition of receptor tyrosine kinases and RB regulatory proteins may be useful therapies for DIPG.
Abstract: Purpose Long-term survival for children with diffuse intrinsic pontine glioma (DIPG) is less than 10%, and new therapeutic targets are urgently required. We evaluated a large cohort of DIPGs to identify recurrent genomic abnormalities and gene expression signatures underlying DIPG. Patients and Methods Single-nucleotide polymorphism arrays were used to compare the frequencies of genomic copy number abnormalities in 43 DIPGs and eight low-grade brainstem gliomas with data from adult and pediatric (non-DIPG) glioblastomas, and expression profiles were evaluated using gene expression arrays for 27 DIPGs, six low-grade brainstem gliomas, and 66 nonbrainstem low-grade gliomas. Results Frequencies of specific large-scale and focal imbalances varied significantly between DIPGs and nonbrainstem pediatric glioblastomas. Focal amplifications of genes within the receptor tyrosine kinase–Ras–phosphoinositide 3-kinase signaling pathway were found in 47% of DIPGs, the most common of which involved PDGFRA and MET. Thirt...
TL;DR: These new markers should allow MRD studies in all B-lineage ALL patients, and substantially improve their sensitivity, when incorporated in 6-marker combinations.
TL;DR: These data provide the first large-scale demonstration of links between inflammatory markers and LTL in an older population and suggest that cumulative inflammatory load, as indexed by the combination of high levels of IL-6 and TNF-α, is associated with increased odds for short LTL.
Abstract: Background: Leukocyte telomere length (LTL) is an emerging marker of biological age. Chronic inflammatory activity is commonly proposed as a promoter of biological aging in general, and of leukocyte telomere shortening in particular. In addition, senescent cells with critically short telomeres produce pro-inflammatory factors. However, in spite of the proposed causal links between inflammatory activity and LTL, there is little clinical evidence in support of their covariation and interaction. Methodology/Principal Findings: To address this issue, we examined if individuals with high levels of the systemic inflammatory markers interleukin-6 (IL-6), tumor necrosis factor-a (TNF-a) and C-reactive protein (CRP) had increased odds for short LTL. Our sample included 1,962 high-functioning adults who participated in the Health, Aging and Body Composition Study (age range: 70–79 years). Logistic regression analyses indicated that individuals with high levels of either IL-6 or TNF-a had significantly higher odds for short LTL. Furthermore, individuals with high levels of both IL-6 and TNF-a had significantly higher odds for short LTL compared with those who had neither high (OR=0.52, CI=0.37–0.72), only IL-6 high (OR=0.57, CI=0.39–0.83) or only TNF-a high (OR=0.67, CI=0.46–0.99), adjusting for a wide variety of established risk factors and potential confounds. In contrast, CRP was not associated with LTL. Conclusions/Significance: Results suggest that cumulative inflammatory load, as indexed by the combination of high levels of IL-6 and TNF-a, is associated with increased odds for short LTL. In contrast, high levels of CRP were not accompanied by short LTL in this cohort of older adults. These data provide the first large-scale demonstration of links between inflammatory markers and LTL in an older population.
TL;DR: Soft tissue sarcomas are a heterogeneous group of mesenchymal malignancies that occur throughout the lifespan and the impact of age on disease features and outcome is unclear.
Abstract: Background
Soft tissue sarcomas (STS) are a heterogeneous group of mesenchymal malignancies that occur throughout the lifespan. The impact of age on disease features and outcome is unclear.
TL;DR: Prehospital SI>0.9 identifies patients at risk for MT who would otherwise be considered relatively normotensive under current prehospital triage protocols, and the risk forMT rises substantially with elevation of SI above this level.
Abstract: Background:In the prehospital environment, the failure of medical providers to recognize latent physiologic derangement in patients with compensated shock may risk undertriage. We hypothesized that the shock index (SI; heart rate divided by systolic blood pressure [SBP]), when used in the prehospita
TL;DR: Lower plasma β-amyloid 42/40 is associated with greater cognitive decline among elderly persons without dementia over 9 years, and this association is stronger among those with low measures of cognitive reserve.
Abstract: Context Lower plasma -amyloid 42 and 42/40 levels have been associated with incident dementia, but results are conflicting and few have investigated cognitive decline among elders without dementia. Objective To determine if plasma -amyloid is associated with cognitive decline and if this association is modified by measures of cognitive reserve. Design, Setting, and Participants We studied 997 black and white communitydwelling older adults from Memphis, Tennessee, and Pittsburgh, Pennsylvania, who were enrolled in the Health ABC Study, a prospective observational study begun in 1997-1998 with 10-year follow-up in 2006-2007. Participant mean age was 74.0 (SD, 3.0) years; 55.2% (n=550) were female; and 54.0% (n=538) were black. Main Outcome Measures Association of near-baseline plasma -amyloid levels (42 and 42/40 measured in 2010) and repeatedly measured Modified Mini-Mental State Examination (3MS) results. Results Low -amyloid 42/40 level was associated with greater 9-year 3MS cognitive decline (lowest -amyloid tertile: mean change in 3MS score, �6.59 [95% confidence interval [CI], �5.21 to �7.67] points; middle tertile: �6.16 [95% CI, �4.92 to �7.32] points; and highest tertile: �3.60 [95% CI, �2.27 to �4.73] points; P.001). Results were simi
University of Alabama at Birmingham1, Ohio State University2, University of Nebraska–Lincoln3, Johns Hopkins University4, University of California, San Francisco5, Seattle Cancer Care Alliance6, Memorial Sloan Kettering Cancer Center7, Roswell Park Cancer Institute8, Duke University9, University of Texas MD Anderson Cancer Center10, American Brain Tumor Association11, University of Tennessee Health Science Center12, Harvard University13, Vanderbilt University14, City of Hope National Medical Center15, Northwestern University16, Stanford University17, University of Utah18, Washington University in St. Louis19, University of South Florida20, University of Michigan21, Fox Chase Cancer Center22
TL;DR: These guidelines provide recommendations on the diagnosis and management of this group of diseases based on clinical evidence and panel consensus and include expert advice on the management of low-grade infiltrative astrocytomas, oligodendrogliomas, anaplastic gliomas, glioblastomas, medulloblastoma, supratentorial primitive neuroectodermal tumors, and brain metastases.
Abstract: Primary and metastatic tumors of the central nervous system are a heterogeneous group of neoplasms with varied outcomes and management strategies. Recently, improved survival observed in 2 randomized clinical trials established combined chemotherapy and radiation as the new standard for treating patients with pure or mixed anaplastic oligodendroglioma harboring the 1p/19q codeletion. For metastatic disease, increasing evidence supports the efficacy of stereotactic radiosurgery in treating patients with multiple metastatic lesions but low overall tumor volume. These guidelines provide recommendations on the diagnosis and management of this group of diseases based on clinical evidence and panel consensus. This version includes expert advice on the management of low-grade infiltrative astrocytomas, oligodendrogliomas, anaplastic gliomas, glioblastomas, medulloblastomas, supratentorial primitive neuroectodermal tumors, and brain metastases. The full online version, available at NCCN. org, contains recommendations on additional subtypes.
TL;DR: Use of once-daily grass AIT treatment effectively treats timothy grass (cross-reactive with Festucoideae grasses) pollen-induced ARC in North American children 5 years and older and might become an important addition to the North American ARC treatment armamentarium.
Abstract: Background Allergy immunotherapy tablet (AIT) treatment might be a safe and convenient form of specific immunotherapy but it has not been investigated in North American children and adolescents. Objective We sought to investigate the efficacy and safety of timothy grass AIT treatment in North American children/adolescents with grass pollen–induced allergic rhinoconjunctivitis (ARC) with or without asthma. Methods Three hundred forty-five subjects (5-17 years old) were randomized to once-daily grass AIT treatment (2,800 bioequivalent allergen units, 75,000 standardized quality tablet, approximately 15 μg of Phl p 5) or placebo approximately 16 weeks before the 2009 grass pollen season (GPS). Treatment continued through the GPS. Daily symptoms and allergy rescue medication use were recorded. The primary end point was the total combined score (TCS) of the daily symptom score (DSS) and daily medication score (DMS) for the entire GPS. DSS, DMS, Rhinoconjunctivitis Quality of Life Questionnaire score, and Phl p 5–specific IgG4 and IgE-blocking factor levels were secondary end points. Safety was assessed through adverse events. Results Eighty-nine percent of subjects were multisensitized. TCS, DSS, DMS, and Rhinoconjunctivitis Quality of Life Questionnaire score versus placebo improved 26% ( P = .001), 25% ( P = .005), 81% ( P = .006), and 18% ( P = .04). Phl p 5–specific IgG4 and IgE-blocking factor levels were significantly higher at the peak and end of the GPS ( P Conclusions Use of once-daily timothy grass AIT treatment effectively treats timothy grass (cross-reactive with Festucoideae grasses) pollen–induced ARC in North American children 5 years and older. Given its convenient administration, lack of dose build-up requirement, safety profile, and efficacy, AIT treatment might become an important addition to the North American ARC treatment armamentarium.
TL;DR: A new 30-valent vaccine containing M protein peptides from GAS serotypes prevalent in North America and Europe was immunogenic in rabbits and evoked bactericidal antibodies against all 30 vaccine serotypes of GAS.
TL;DR: Results suggest that, in the dopamine‐depleted state, glutamatergic inputs to the STN and reciprocal GPe–STN interconnections are both important for the generation and amplification of the oscillatory activity of STN neurons, which is subsequently transmitted to the GPi, thus contributing to the symptomatic expression of Parkinson’s disease.
Abstract: Parkinson's disease is characterized by degeneration of nigral dopaminergic neurons, leading to a wide variety of psychomotor dysfunctions. Accumulated evidence suggests that abnormally synchronized oscillations in the basal ganglia contribute to the expression of Parkinsonian motor symptoms. However, the mechanism that generates abnormal oscillations in a dopamine-depleted state remains poorly understood. We addressed this question by examining basal ganglia neuronal activity in two 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated Parkinsonian monkeys. We found that systemic administration of l-3,4-dihydroxyphenylalanine (l-DOPA; dopamine precursor) decreased abnormal neuronal oscillations (8-15 Hz) in the internal segment of the globus pallidus (GPi) and the subthalamic nucleus (STN) during the ON state when Parkinsonian signs were alleviated and during l-DOPA-induced dyskinesia. GPi oscillations and parkinsonian signs were suppressed by silencing of the STN with infusion of muscimol (GABA(A) receptor agonist). Intrapallidal microinjection of a mixture of 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP; N-methyl-d-aspartate receptor antagonist) and 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX; AMPA/kainate receptor antagonist) also decreased the oscillations in the GPi and the external segment of the globus pallidus (GPe). Neuronal oscillations in the STN were suppressed after intrasubthalamic microinjection of CPP/NBQX to block glutamatergic afferents of the STN. The STN oscillations were further reduced by muscimol inactivation of the GPe to block GABAergic inputs from the GPe. These results suggest that, in the dopamine-depleted state, glutamatergic inputs to the STN and reciprocal GPe-STN interconnections are both important for the generation and amplification of the oscillatory activity of STN neurons, which is subsequently transmitted to the GPi, thus contributing to the symptomatic expression of Parkinson's disease.
TL;DR: An association between low adaptive functioning in children with autism and increased parenting stress creates a need for additional family support as parents search for different coping strategies to assist the family with ongoing and new challenges.
Abstract: Background: As the number of children diagnosed with autism continues to rise, resources must be available to support parents of children with autism and their families. Parents need help as they assess their unique situations, reach out for help in their communities, and work to decrease their stress levels by using appropriate coping strategies that will benefit their entire family.Methods: A descriptive, correlational, cross-sectional study was conducted with 75 parents/primary caregivers of children with autism. Using the McCubbin and Patterson model of family behavior, adaptive behaviors of children with autism, family support networks, parenting stress, and parent coping were measured. Findings and Conclusions: An association between low adaptive functioning in children with autism and increased parenting stress creates a need for additional family support as parents search for different coping strategies to assist the family with ongoing and new challenges. Professionals should have up-to-date know...
TL;DR: It is found that GPRC6A is a candidate for mediating the response to Ocn in the bone‐pancreas endocrine loop regulating insulin signaling, and intraperitoneal injection of Ocn stimulated ERK activity in the pancreas and increased serum insulin levels in wild‐type mice, but these responses were markedly attenuated in Gprc6a−/− mice.
Abstract: A bone-pancreas endocrine loop has been identified recently that involves insulin secreted from β-cells in the pancreas stimulating insulin receptors in osteoblasts, leading to osteoblastic differentiation and increased secretion of osteocalcin (Ocn), a bone-derived hormone that regulates insulin secretion in β-cells. The identity of the Ocn-sensing receptor in β-cells is a missing component of this endocrine loop. The abnormalities in glucose homeostasis in Gprc6a null mice suggests that this pertussis toxin–sensitive G protein–coupled receptor is a candidate for mediating the effects of Ocn on insulin secretion in the pancreas. In support of this possibility, we found that transfection of non-Gprc6a-expressing HEK-293 cells with a full-length Gprc6a cDNA imparted a dose-dependent response to Ocn (5 to 60 ng/mL), as measured by PKD1 and ERK phosphorylation. In addition, Gprc6a is highly expressed in mouse pancreatic tissue and in the mouse TC-6 pancreatic β-cell line. Ocn also stimulated ERK activity in TC-6 pancreatic β-cells. Finally, intraperitoneal injection of Ocn stimulated ERK activity in the pancreas and increased serum insulin levels in wild-type mice, but these responses were markedly attenuated in Gprc6a−/− mice. These findings suggest that GPRC6A is a candidate for mediating the response to Ocn in the bone-pancreas endocrine loop regulating insulin signaling. © 2011 American Society for Bone and Mineral Research.
TL;DR: The molecular aspects involved in the activation of different inflammasomes by various pathogens are being rapidly elucidated, and their role during infections is being characterized.
Abstract: The inflammasome is an important innate immune pathway that regulates at least two host responses protective against infections: (1) secretion of the proinflammatory cytokines IL-1β and IL-18 and (2) induction of pyroptosis, a form of cell death. Inflammasomes, of which different types have been identified, are multiprotein complexes containing pattern recognition receptors belonging to the Nod-like receptor family or the PYHIN family and the protease caspase-1. The molecular aspects involved in the activation of different inflammasomes by various pathogens are being rapidly elucidated, and their role during infections is being characterized. Production of IL-1β and IL-18 and induction of pyroptosis of the infected cell have been shown to be protective against many infectious agents. Here, we review the recent literature concerning inflammasome activation in the context of bacterial infections and identify important questions to be answered in the future.
TL;DR: The capacity to activate or change the spatial distribution of the cutaneous HPA axis elements is dependent on highly energetic wavelengths (UVC and UVB), implying a dependence of a local stress response on their noxious activity with overlapping or alternative mechanisms activated by UVA.
Abstract: The hypothalamic-pituitary-adrenal (HPA) axis maintains basal and stress-related homeostasis in vertebrates. Skin expresses all elements of the HPA axis including corticotropin-releasing hormone (CRH), proopiomelanocortin (POMC), ACTH, β-endorphin (β-END) with corresponding receptors, the glucocorticoidogenic pathway, and the glucocorticoid receptor (GR). To test the hypothesis that cutaneous responses to environmental stressors follow the organizational structure of the central response to stress, the activity of the "cutaneous HPA" axis homolog was investigated after exposure to ultraviolet radiation (UVR) wavelengths of UVA (320-400 nm), UVB (280-320 nm), and UVC (100-280 nm) in human skin organ culture and in co-cultured keratinocytes/melanocytes. The level of stimulation of CRH, POMC, MC1R, MC2R, CYP11A1, and CYP11B1 genes was dependent on UV wavelengths and doses, with the highest effects observed for highly energetic UVC and UVB. ELISA and Western assays showed significant production of CRH, POMC, ACTH, and CYP11A1 proteins and of cortisol, with a decrease in GR expression only after UVB and UVC. However, β-END expression was also stimulated by UVA. Immunocytochemistry localized the deposition of the aforesaid antigens predominantly to the epidermis with additional accumulation of CRH, β-END, and ACTH in the dermis. UVR-stimulated CYP11A1 expression was seen in the basal layer of the epidermis and cells of adjacent dermis. Thus, the capacity to activate or change the spatial distribution of the cutaneous HPA axis elements is dependent on highly energetic wavelengths (UVC and UVB), implying a dependence of a local stress response on their noxious activity with overlapping or alternative mechanisms activated by UVA.
TL;DR: The value of synteny across genomes is emphasized as a tool for deep time evolutionary studies of P450s in animals and there is evidence that macrosynteny may be useful in tracing the origin of animal CYP clans.
TL;DR: It is proposed that viperin interacts with NS5A and the host factor, VAP‐A, to limit HCV replication at the replication complex, highlighting the complexity of the host control of viral replication by interferon‐stimulated gene expression.