Showing papers by "University of Tennessee Health Science Center published in 2012"

The tomato genome sequence provides insights into fleshy fruit evolution

Abstract: Tomato (Solanum lycopersicum) is a major crop plant and a model system for fruit development. Solanum is one of the largest angiosperm genera1 and includes annual and perennial plants from diverse habitats. Here we present a high-quality genome sequence of domesticated tomato, a draft sequence of its closest wild relative, Solanum pimpinellifolium2, and compare them to each other and to the potato genome (Solanum tuberosum). The two tomato genomes show only 0.6% nucleotide divergence and signs of recent admixture, but show more than 8% divergence from potato, with nine large and several smaller inversions. In contrast to Arabidopsis, but similar to soybean, tomato and potato small RNAs map predominantly to gene-rich chromosomal regions, including gene promoters. The Solanum lineage has experienced two consecutive genome triplications: one that is ancient and shared with rosids, and a more recent one. These triplications set the stage for the neofunctionalization of genes controlling fruit characteristics, such as colour and fleshiness.

Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

Abstract: Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

Thrombin-Receptor Antagonist Vorapaxar in Acute Coronary Syndromes

Abstract: In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.).

An Overview of Tubulin Inhibitors That Interact with the Colchicine Binding Site

Abstract: Tubulin dynamics is a promising target for new chemotherapeutic agents. The colchicine binding site is one of the most important pockets for potential tubulin polymerization destabilizers. Colchicine binding site inhibitors (CBSI) exert their biological effects by inhibiting tubulin assembly and suppressing microtubule formation. A large number of molecules interacting with the colchicine binding site have been designed and synthesized with significant structural diversity. CBSIs have been modified as to chemical structure as well as pharmacokinetic properties, and tested in order to find a highly potent, low toxicity agent for treatment of cancers. CBSIs are believed to act by a common mechanism via binding to the colchicine site on tubulin. The present review is a synopsis of compounds that have been reported in the past decade that have provided an increase in our understanding of the actions of CBSIs.

Consensus Paper: Pathological Role of the Cerebellum in Autism

Abstract: There has been significant advancement in various aspects of scientific knowledge concerning the role of cerebellum in the etiopathogenesis of autism. In the current consensus paper, we will observe the diversity of opinions regarding the involvement of this important site in the pathology of autism. Recent emergent findings in literature related to cerebellar involvement in autism are discussed, including: cerebellar pathology, cerebellar imaging and symptom expression in autism, cerebellar genetics, cerebellar immune function, oxidative stress and mitochondrial dysfunction, GABAergic and glutamatergic systems, cholinergic, dopaminergic, serotonergic, and oxytocin-related changes in autism, motor control and cognitive deficits, cerebellar coordination of movements and cognition, gene–environment interactions, therapeutics in autism, and relevant animal models of autism. Points of consensus include presence of abnormal cerebellar anatomy, abnormal neurotransmitter systems, oxidative stress, cerebellar motor and cognitive deficits, and neuroinflammation in subjects with autism. Undefined areas or areas requiring further investigation include lack of treatment options for core symptoms of autism, vermal hypoplasia, and other vermal abnormalities as a consistent feature of autism, mechanisms underlying cerebellar contributions to cognition, and unknown mechanisms underlying neuroinflammation.

Gene therapy for leber congenital amaurosis caused by RPE65 mutations: safety and efficacy in 15 children and adults followed up to 3 years

Abstract: Objective To determine the safety and efficacy of subretinal gene therapy in the RPE65 form of Leber congenital amaurosis using recombinant adeno-associated virus 2 (rAAV2) carrying the RPE65 gene. Design Open-label, dose-escalation phase I study of 15 patients (range, 11-30 years of age) evaluated after subretinal injection of the rAAV2- RPE65 vector into the worse-functioning eye. Five cohorts represented 4 dose levels and 2 different injection strategies. Main outcome measures Primary outcomes were systemic and ocular safety. Secondary outcomes assayed visual function with dark-adapted full-field sensitivity testing and visual acuity with Early Treatment Diabetic Retinopathy Study charts. Further assays included immune responses to the vector, static visual fields, pupillometry, mobility performance, and optical coherence tomography. Results No systemic toxicity was detected; ocular adverse events were related to surgery. Visual function improved in all patients to different degrees; improvements were localized to treated areas. Cone and rod sensitivities increased significantly in the study eyes but not in the control eyes. Minor acuity improvements were recorded in many study and control eyes. Major acuity improvements occurred in study eyes with the lowest entry acuities and parafoveal fixation loci treated with subretinal injections. Other patients with better foveal structure lost retinal thickness and acuity after subfoveal injections. Conclusions Gene therapy for Leber congenital amaurosis caused by RPE65 mutations is sufficiently safe and substantially efficacious in the extrafoveal retina. There is no benefit and some risk in treating the fovea. No evidence of age-dependent effects was found. Our results point to specific treatment strategies for subsequent phases. Application to clinical practice Gene therapy for inherited retinal disease has the potential to become a future part of clinical practice. Trial registration clinicaltrials.gov Identifier: NCT00481546.

Association of an intensive lifestyle intervention with remission of type 2 diabetes.

Abstract: Context The frequency of remission of type 2 diabetes achievable with lifestyle intervention is unclear. Objective To examine the association of a long-term intensive weight-loss intervention with the frequency of remission from type 2 diabetes to prediabetes or normoglycemia. Design, Setting, and Participants Ancillary observational analysis of a 4-year randomized controlled trial (baseline visit, August 2001–April 2004; last follow-up, April 2008) comparing an intensive lifestyle intervention (ILI) with a diabetes support and education control condition (DSE) among 4503 US adults with body mass index of 25 or higher and type 2 diabetes. Interventions Participants were randomly assigned to receive the ILI, which included weekly group and individual counseling in the first 6 months followed by 3 sessions per month for the second 6 months and twice-monthly contact and regular refresher group series and campaigns in years 2 to 4 (n=2241) or the DSE, which was an offer of 3 group sessions per year on diet, physical activity, and social support (n=2262). Main Outcome Measures Partial or complete remission of diabetes, defined as transition from meeting diabetes criteria to a prediabetes or nondiabetic level of glycemia (fasting plasma glucose 1c Results Intensive lifestyle intervention participants lost significantly more weight than DSE participants at year 1 (net difference, −7.9%; 95% CI, −8.3% to −7.6%) and at year 4 (−3.9%; 95% CI, −4.4% to −3.5%) and had greater fitness increases at year 1 (net difference, 15.4%; 95% CI, 13.7%-17.0%) and at year 4 (6.4%; 95% CI, 4.7%-8.1%) (P Conclusions In these exploratory analyses of overweight adults, an intensive lifestyle intervention was associated with a greater likelihood of partial remission of type 2 diabetes compared with diabetes support and education. However, the absolute remission rates were modest. Trial Registration clinicaltrials.gov Identifier: NCT00017953

Sensing the Environment: Regulation of Local and Global Homeostasis by the Skin's Neuroendocrine System

Abstract: 1.1. General overview The strategic location of the skin as the barrier between the environment and internal milieu determines its critical function in the preservation of body homeostasis, and ultimately organism survival (Slominski, 2005, Slominski and Wortsman, 2000, Slominski et al., 2000c, Zmijewski and Slominski, 2011). It also exposes skin to numerous pathological agents, processes, and events. Thus, the capability to locally recognize, discriminate and integrate various signals within a highly heterogeneous environment, and to immediately launch appropriate responses, is a vital property of skin (Slominski and Wortsman, 2000). These skin functions are integrated into the skin immune, pigmentary, epidermal and adnexal systems, and are in continuous communication with the systemic immune, neural and endocrine systems (Arck et al., 2006, Slominski, 2009c, Slominski et al., 2004c, Slominski and Wortsman, 2000, Slominski et al., 2007a, Stenn and Paus, 2001). These fundamental functions results from the location of the skin, which is the largest body’s organ, at the interphase between external and internal environment, requiring development of efficient sensory and effector capabilities to differentially react to changes in external environment. They are represented by inducible production of biologically active compounds (hormones, neurohormones and neurotransmitters) that act both locally and at the systemic levels (Fig. 1). Figure 1 Skin senses changes in the environment through cutaneous neuroendocrine system, which computes and translates the received information into chemical, physical and biological messengers that regulate global (A and B) and local (B) homeostasis. These signals ... The skin being continuously exposed to many external biological or environmental factors (acute transfers of solar, thermal or chemical energy), had to evolve optimal mechanism(s) to protect, restore or maintain local and global homeostasis in relation to hostile environment (Slominski et al., 1993b, Slominski and Pawelek, 1998, Slominski and Wortsman, 2000, Slominski et al., 2000c). We have proposed that precise coordination and execution of these responses are mediated by a cutaneous neuroendocrine system, which also is able to reset the body homeostatic adaptation mechanisms (Slominski and Wortsman, 2000). Superimposed on this is the impact of psychological stress on skin physiology and pathology, placed in the context of the bidirectional brain-skin communication (Arck et al., 2006, Slominski, 2005a, Slominski et al., 2008b). To summarize, in reaction to changing external and also internal environment, the skin can generate signals to produce rapid (neural) or slow (humoral or immune) responses at the local and systemic levels (Fig. 1). Coordination between these local and systemic responses is mediated by the skin neuroendocrine system (Slominski and Wortsman, 2000a), which employs local equivalents of the hypothalamo-pituitary-adrenal axis (HPA) (Slominski et al., 2007a), hypothalamo-pituitary-thyroid (HPT) axis (Pisarchik and Slominski, 2002, van Beek et al., 2008), catecholaminergic (Schallreuter et al., 1997), serotoninergic, melatoninergic (Slominski et al., 2008a, Slominski et al., 2005c), cholinergic (Grando, 2006, Grando et al., 2006), steroidogenic (Slominski et al., 2008b) and secosteroidogenic (Bikle, 2010, Holick, 2003, Slominski et al., 2010) systems (Fig. 2). Given their common embryonic origins, it is not surprising that skin shares numerous mediators with the CNS and endocrine system. Recent research has revealed that skin also harbors a complex opioidogenic (Grando et al., 1995, Slominski et al., 2011c) and canabinnoidogenic (Biro et al., 2009) systems, which role in the maintenance of cutaneous homeostasis is currently being intensively explored. Figure 2 Skin neuroendocrine system follows the algorithms of classical neuroendocrine or endocrine systems. It also forms a natural platform of signal exchange between internal organs and environment. For this purpose skin cells not only are subjected to neurohormonal ... In this monograph we will discuss the role of various components of the skin neuroendocrine system in sensing the environment with subsequent regulation of local and global homeostasis with a main focus on the algorithms of classical neuroendocrine axes.

Regulation and Function of the FGF23/Klotho Endocrine Pathways

Abstract: Calcium (Ca2+) and phosphate (PO43−) homeostasis are coordinated by systemic and local factors that regulate intestinal absorption, influx and efflux from bone, and kidney excretion and reabsorption of these ions through a complex hormonal network. Traditionally, the parathyroid hormone (PTH)/vitamin D axis provided the conceptual framework to understand mineral metabolism. PTH secreted by the parathyroid gland in response to hypocalcemia functions to maintain serum Ca2+ levels by increasing Ca2+ reabsorption and 1,25-dihydroxyvitamin D [1,25(OH)2D] production by the kidney, enhancing Ca2+ and PO43− intestinal absorption and increasing Ca2+ and PO43− efflux from bone, while maintaining neutral phosphate balance through phosphaturic effects. FGF23 is a recently discovered hormone, predominately produced by osteoblasts/osteocytes, whose major functions are to inhibit renal tubular phosphate reabsorption and suppress circulating 1,25(OH)2D levels by decreasing Cyp27b1-mediated formation and stimulating Cyp24-mediated catabolism of 1,25(OH)2D. FGF23 participates in a new bone/kidney axis that protects the organism from excess vitamin D and coordinates renal PO43− handling with bone mineralization/turnover. Abnormalities of FGF23 production underlie many inherited and acquired disorders of phosphate homeostasis. This review discusses the known and emerging functions of FGF23, its regulation in response to systemic and local signals, as well as the implications of FGF23 in different pathological and physiological contexts.

Allergic Rhinitis and its Impact on Asthma (ARIA): Achievements in 10 years and future needs

Abstract: Allergic rhinitis (AR) and asthma represent global health problems for all age groups. Asthma and rhinitis frequently coexist in the same subjects. Allergic Rhinitis and its Impact on Asthma (ARIA) was initiated during a World Health Organization workshop in 1999 (published in 2001). ARIA has reclassified AR as mild/moderate-severe and intermittent/persistent. This classification closely reflects patients' needs and underlines the close relationship between rhinitis and asthma. Patients, clinicians, and other health care professionals are confronted with various treatment choices for the management of AR. This contributes to considerable variation in clinical practice, and worldwide, patients, clinicians, and other health care professionals are faced with uncertainty about the relative merits and downsides of the various treatment options. In its 2010 Revision, ARIA developed clinical practice guidelines for the management of AR and asthma comorbidities based on the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) system. ARIA is disseminated and implemented in more than 50 countries of the world. Ten years after the publication of the ARIA World Health Organization workshop report, it is important to make a summary of its achievements and identify the still unmet clinical, research, and implementation needs to strengthen the 2011 European Union Priority on allergy and asthma in children.

The genome architecture of the collaborative cross mouse genetic reference population

Abstract: The Collaborative Cross Consortium reports here on the development of a unique genetic resource population. The Collaborative Cross (CC) is a multiparental recombinant inbred panel derived from eight laboratory mouse inbred strains. Breeding of the CC lines was initiated at multiple international sites using mice from The Jackson Laboratory. Currently, this innovative project is breeding independent CC lines at the University of North Carolina (UNC), at Tel Aviv University (TAU), and at Geniad in Western Australia (GND). These institutions aim to make publicly available the completed CC lines and their genotypes and sequence information. We genotyped, and report here, results from 458 extant lines from UNC, TAU, and GND using a custom genotyping array with 7500 SNPs designed to be maximally informative in the CC and used a novel algorithm to infer inherited haplotypes directly from hybridization intensity patterns. We identified lines with breeding errors and cousin lines generated by splitting incipient lines into two or more cousin lines at early generations of inbreeding. We then characterized the genome architecture of 350 genetically independent CC lines. Results showed that founder haplotypes are inherited at the expected frequency, although we also consistently observed highly significant transmission ratio distortion at specific loci across all three populations. On chromosome 2, there is significant overrepresentation of WSB/EiJ alleles, and on chromosome X, there is a large deficit of CC lines with CAST/EiJ alleles. Linkage disequilibrium decays as expected and we saw no evidence of gametic disequilibrium in the CC population as a whole or in random subsets of the population. Gametic equilibrium in the CC population is in marked contrast to the gametic disequilibrium present in a large panel of classical inbred strains. Finally, we discuss access to the CC population and to the associated raw data describing the genetic structure of individual lines. Integration of rich phenotypic and genomic data over time and across a wide variety of fields will be vital to delivering on one of the key attributes of the CC, a common genetic reference platform for identifying causative variants and genetic networks determining traits in mammals.

A novel retinoblastoma therapy from genomic and epigenetic analyses

Abstract: Retinoblastoma is an aggressive childhood cancer of the developing retina that is initiated by the biallelic loss of RB1. Tumours progress very quickly following RB1 inactivation but the underlying mechanism is not known. Here we show that the retinoblastoma genome is stable, but that multiple cancer pathways can be epigenetically deregulated. To identify the mutations that cooperate with RB1 loss, we performed whole-genome sequencing of retinoblastomas. The overall mutational rate was very low; RB1 was the only known cancer gene mutated. We then evaluated the role of RB1 in genome stability and considered non-genetic mechanisms of cancer pathway deregulation. For example, the proto-oncogene SYK is upregulated in retinoblastoma and is required for tumour cell survival. Targeting SYK with a small-molecule inhibitor induced retinoblastoma tumour cell death in vitro and in vivo. Thus, retinoblastomas may develop quickly as a result of the epigenetic deregulation of key cancer pathways as a direct or indirect result of RB1 loss.

Exploring mediators of food insecurity and obesity: a review of recent literature

Abstract: One in seven American households experience food insecurity at times during the year, lack of money and other resources hinder their ability to maintain consistent access to nutritious foods. Low-income, ethnic minority, and female-headed households exhibit the greatest risk for food insecurity, which often results in higher prevalence of diet-related disease. The food insecurity-obesity paradox is one that researchers have explored to understand the factors that influence food insecurity and its impact on weight change. The aim of this inquiry was to explore new evidence in associations of food insecurity and obesity in youth, adult, and elderly populations. A literature search of publication databases was conducted, using various criteria to identify relevant articles. Among 65 results, 19 studies conducted since 2005 were selected for review. Overall, the review confirmed that food insecurity and obesity continue to be strongly and positively associated in women. Growing evidence of this association was found in adolescents; but among children, results remain mixed. Few studies supported a linear relationship between food insecurity and weight outcomes, as suggested by an earlier review. New mediators were revealed (gender, marital status, stressors, and food stamp participation) that alter the association; in fact, newer studies suggest that food stamp participation may exacerbate obesity outcomes. Continued examination through longitudinal studies, development of tools to distinguish acute and chronic food insecurity, and greater inclusion of food security measurement tools in regional and local studies are warranted.

Genome sequence of the model medicinal mushroom Ganoderma lucidum

Abstract: Ganoderma lucidum is a widely used medicinal macrofungus in traditional Chinese medicine that creates a diverse set of bioactive compounds. Here we report its 43.3-Mb genome, encoding 16,113 predicted genes, obtained using next-generation sequencing and optical mapping approaches. The sequence analysis reveals an impressive array of genes encoding cytochrome P450s (CYPs), transporters and regulatory proteins that cooperate in secondary metabolism. The genome also encodes one of the richest sets of wood degradation enzymes among all of the sequenced basidiomycetes. In all, 24 physical CYP gene clusters are identified. Moreover, 78 CYP genes are coexpressed with lanosterol synthase, and 16 of these show high similarity to fungal CYPs that specifically hydroxylate testosterone, suggesting their possible roles in triterpenoid biosynthesis. The elucidation of the G. lucidum genome makes this organism a potential model system for the study of secondary metabolic pathways and their regulation in medicinal fungi. Ganoderma lucidumis a macrofungus in traditional Chinese medicine known to produce different bioactive compounds. In this study, the genome ofG. lucidumis sequenced, making this organism a potential model system for future studies of secondary metabolic pathways and their regulation in medicinal fungi.

Methylglyoxal modification of Na v 1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy

Abstract: Glucose and its metabolic derivatives are increased the plasma of patients with diabetes. Peter Nawroth and colleagues demonstrate that one such metabolite, methylglyoxal, is increased in patients with painful diabetic neuropathy, and find that it acts by modifying the excitability characteristics of a sodium channel protein.

Selective nonoperative management of blunt splenic injury: an Eastern Association for the Surgery of Trauma practice management guideline.

Abstract: BACKGROUNDDuring the last century, the management of blunt force trauma to the spleen has changed from observation and expectant management in the early part of the 1900s to mainly operative intervention, to the current practice of selective operative and nonoperative management. These issues were f

L-tyrosine and L-dihydroxyphenylalanine as hormone-like regulators of melanocyte functions.

Abstract: There is evidence that L-tyrosine and L-dihydroxyphenylalanine (L-DOPA), besides serving as substrates and intermediates of melanogenesis, are also bioregulatory agents acting not only as inducers and positive regulators of melanogenesis but also as regulators of other cellular functions. These can be mediated through action on specific receptors or through non-receptor-mediated mechanisms. The substrate induced (L-tyrosine and/or L-DOPA) melanogenic pathway would autoregulate itself as well as regulate the melanocyte functions through the activity of its structural or regulatory proteins and through intermediates of melanogenesis and melanin itself. Dissection of regulatory and autoregulatory elements of this process may elucidate how substrate-induced autoregulatory pathways have evolved from prokaryotic or simple eukaryotic organisms to complex systems in vertebrates. This could substantiate an older theory proposing that receptors for amino acid-derived hormones arose from the receptors for those amino acids, and that nuclear receptors evolved from primitive intracellular receptors binding nutritional factors or metabolic intermediates.

Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women's Health Initiative randomised placebo-controlled trial.

Abstract: Summary Background By contrast with many observational studies, women in the Women's Health Initiative (WHI) trial who were randomly allocated to receive oestrogen alone had a lower incidence of invasive breast cancer than did those who received placebo. We aimed to assess the influence of oestrogen use on longer term breast cancer incidence and mortality in extended follow-up of this cohort. Methods Between 1993 and 1998, the WHI enrolled 10 739 postmenopausal women from 40 US clinical centres into a randomised, double-masked, placebo-controlled trial. Women aged 50–79 years who had undergone hysterectomy and had expected 3-year survival and mammography clearance were randomly allocated by a computerised, permuted block algorithm, stratified by age group and centre, to receive oral conjugated equine oestrogen (0·625 mg per day; n=5310) or matched placebo (n=5429). The trial intervention was terminated early on Feb 29, 2004, because of an adverse effect on stroke. Follow-up continued until planned termination (March 31, 2005). Consent was sought for extended surveillance from the 9786 living participants in active follow-up, of whom 7645 agreed. Using data from this extended follow-up (to Aug 14, 2009), we assessed long-term effects of oestrogen use on invasive breast cancer incidence, tumour characteristics, and mortality. We used Cox regression models to estimate hazard ratios (HRs) in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00000611. Findings After a median follow-up of 11·8 years (IQR 9·1–12·9), the use of oestrogen for a median of 5·9 years (2·5–7·3) was associated with lower incidence of invasive breast cancer (151 cases, 0·27% per year) compared with placebo (199 cases, 0·35% per year; HR 0·77, 95% CI 0·62–0·95; p=0·02) with no difference (p=0·76) between intervention phase (0·79, 0·61–1·02) and post-intervention phase effects (0·75, 0·51–1·09). In subgroup analyses, we noted breast cancer risk reduction with oestrogen use was concentrated in women without benign breast disease (p=0·01) or a family history of breast cancer (p=0·02). In the oestrogen group, fewer women died from breast cancer (six deaths, 0·009% per year) compared with controls (16 deaths, 0·024% per year; HR 0·37, 95% CI 0·13–0·91; p=0·03). Fewer women in the oestrogen group died from any cause after a breast cancer diagnosis (30 deaths, 0·046% per year) than did controls (50 deaths, 0·076%; HR 0·62, 95% CI 0·39–0·97; p=0·04). Interpretation Our findings provide reassurance for women with hysterectomy seeking relief of climacteric symptoms in terms of the effects of oestrogen use for about 5 years on breast cancer incidence and mortality. However, our data do not support use of oestrogen for breast cancer risk reduction because any noted benefit probably does not apply to populations at increased risk of such cancer. Funding US National Heart, Lung, and Blood Institute; Wyeth.

Nonoperative management of blunt hepatic injury: An Eastern Association for the Surgery of Trauma practice management guideline

Abstract: BACKGROUND: During the last century, the management of blunt force trauma to the liver has changed from observation and expectant management in the early part of the 1900s to mainly operative intervention, to the current practice of selective operative and nonoperative management. These issues were first addressed by the Eastern Association for the Surgery of Trauma in the Practice Management Guidelines for Nonoperative Management of Blunt Injury to the Liver and Spleen published online in 2003. Since that time, a large volume of literature on these topics has been published requiring a reevaluation of the previous Eastern Association for the Surgery of Trauma guideline. METHODS: The National Library of Medicine and the National Institutes of Health MEDLINE database were searched using PubMed (www.pubmed.gov). The search was designed to identify English-language citations published after 1996 (the last year included in the previous guideline) using the keywords liver injury and blunt abdominal trauma. RESULTS: One hundred seventy-six articles were reviewed, of which 94 were used to create the current practice management guideline for the selective nonoperative management of blunt hepatic injury. CONCLUSION: Most original hepatic guidelines remained valid and were incorporated into the greatly expanded current guidelines as appropriate. Nonoperative management of blunt hepatic injuries currently is the treatment modality of choice in hemodynamically stable patients, irrespective of the grade of injury or patient age. Nonoperative management of blunt hepatic injuries should only be considered in an environment that provides capabilities for monitoring, serial clinical evaluations, and an operating room available for urgent laparotomy. Patients presenting with hemodynamic instability and peritonitis still warrant emergent operative intervention. Intravenous contrast enhanced computed tomographic scan is the diagnostic modality of choice for evaluating blunt hepatic injuries. Repeated imaging should be guided by a patient’s clinical status. Adjunctive therapies like angiography, percutaneous drainage, endoscopy/endoscopic retrograde cholangiopancreatography and laparoscopy remain important adjuncts to nonoperative management of hepatic injuries. Despite the explosion of literature on this topic, many questions regarding nonoperative management of blunt hepatic injuries remain without conclusive answers in the literature. (J Trauma Acute Care Surg. 2012;73: S288YS293.

Diabetes, Glucose Control, and 9-Year Cognitive Decline Among Older Adults Without Dementia

Abstract: Objectives: To determine if prevalent and incident diabetes mellitus (DM) increase risk of cognitive decline and if, among elderly adults with DM, poor glucose control is related to worse cognitive performance. Design: Prospective cohort study. Setting: Health, Aging, and Body Composition Study at 2 community clinics. Participants: A total of 3069 elderly adults (mean age, 74.2 years; 42% black; 52% female). Main Outcome Measures: Participants completed the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) at baseline and selected intervals over 10 years. Diabetes mellitus status was determined at baseline and during follow-up visits. Glycosylated hemoglobin A1c level was measured at years 1 (baseline), 4, 6, and 10 from fasting whole blood. Results: At baseline, 717 participants (23.4%) had prevalent DM and 2352 (76.6%) were without DM, 159 of whom developed incidentDMduring follow-up. Participants with prevalent DM had lower baseline test scores than participants withoutDM(3MS: 88.8 vs 90.9; DSST: 32.5 vs 36.3, respectively; t = 6.09; P = .001 for both tests). Results from mixed-effects models showed a similar pattern for 9-year decline (3MS: -6.0- vs -4.5-point decline; t = 2.66; P = .008; DSST: -7.9- vs -5.7-point decline; t = 3.69; P = .001, respectively). Participants with incident DM tended to have baseline and 9-year decline scores between the other 2 groups but were not statistically different from the group without DM. Multivariate adjustment for demographics and medical comorbidities produced similar results. Among participants with prevalent DM, glycosylated hemoglobin A1c level was associated with lower average mean cognitive scores (3MS: F = 8.2; P for overall = .003; DSST: F = 3.4; P for overall = .04), even after multivariate adjustment. Conclusion: Among well-functioning older adults, DM and poor glucose control among those with DM are associated with worse cognitive function and greater decline. This suggests that severity of DM may contribute to accelerated cognitive aging. ©2012 American Medical Association. All rights reserved.

Immunogenicity to Therapeutic Proteins: Impact on PK/PD and Efficacy

Abstract: The development of therapeutic proteins requires the understanding of the relationship between the dose, exposure, efficacy, and toxicity of these molecules. Several intrinsic and extrinsic factors contribute to the challenges for measuring therapeutic proteins in a precise and accurate manner. In addition, induction of an immune response to therapeutic protein results in additional complexities in the analysis of the pharmacokinetic profile, toxicity, safety, and efficacy of this class of molecules. Assessment of immunogenicity of therapeutic proteins is a required aspect of regulatory filings for a licensing application and for the safe and efficacious use of these compounds. A systematic strategy and well-defined criteria for measuring anti-drug antibodies (ADA) have been established, to a large extent, through coordinated efforts. These recommendations are based on risk assessment and include the determination of ADA content (concentration/titer), affinity, immunoglobulin isotype/subtype, and neutralization capacity. This manuscript reviews the requirements necessary for understanding the nature of an ADA response in order to discern the impact of immunogenicity on pharmacokinetics/pharmacodynamics and efficacy.

Genome-wide association for abdominal subcutaneous and visceral adipose reveals a novel locus for visceral fat in women.

Abstract: Body fat distribution, particularly centralized obesity, is associated with metabolic risk above and beyond total adiposity. We performed genome-wide association of abdominal adipose depots quantified using computed tomography (CT) to uncover novel loci for body fat distribution among participants of European ancestry. Subcutaneous and visceral fat were quantified in 5,560 women and 4,997 men from 4 population-based studies. Genome-wide genotyping was performed using standard arrays and imputed to ,2.5 million Hapmap SNPs. Each study performed a genome-wide association analysis of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), VAT adjusted for body mass index, and VAT/SAT ratio (a metric of the propensity to store fat viscerally as compared to subcutaneously) in the overall sample and in women and men separately. A weighted z-score meta-analysis was conducted. For the VAT/SAT ratio, our most significant p-value was rs11118316 at LYPLAL1 gene (p=3.1610E-09), previously identified in association with waist–hip ratio. For SAT, the most significant SNP was in the FTO gene (p=5.9610E-08). Given the known gender differences in body fat distribution, we performed sex-specific analyses. Our most significant finding was for VAT in women, rs1659258 near THNSL2 (p=1.661008), but not men (p=0.75). Validation of this SNP in the GIANT consortium data demonstrated a similar sex-specific pattern, with observed significance in women (p=0.006) but not men (p=0.24) for BMI and waist circumference (p=0.04 [women], p=0.49 [men]). Finally, we interrogated our data for the 14 recently published loci for body fat distribution (measured by waist–hip ratio adjusted for BMI); associations were observed at 7 of these loci. In contrast, we observed associations at only 7/32 loci previously identified in association with BMI; the majority of overlap was observed with SAT. Genome-wide association for visceral and subcutaneous fat revealed a SNP for VAT in women. More refined phenotypes for body composition and fat distribution can detect new loci not previously uncovered in large-scale GWAS of anthropometric traits. Citation: Fox CS, Liu Y, White CC, Feitosa M, Smith AV, et al. (2012) Genome-Wide Association for Abdominal Subcutaneous and Visceral Adipose Reveals a Novel

Screening Adult Survivors of Childhood Cancer for Cardiomyopathy: Comparison of Echocardiography and Cardiac Magnetic Resonance Imaging

Abstract: Purpose To compare two-dimensional (2D) echocardiography, the current method of screening for treatment-related cardiomyopathy recommended by the Children's Oncology Group Guidelines, to cardiac magnetic resonance (CMR) imaging, the reference standard for left ventricular (LV) function. Patients and Methods Cross-sectional, contemporaneous evaluation of LV structure and function by 2D and three-dimensional (3D) echocardiography and CMR imaging in 114 adult survivors of childhood cancer currently median age 39 years (range, 22 to 53 years) exposed to anthracycline chemotherapy and/or chest-directed radiation therapy. Results In this survivor population, 14% (n = 16) had an ejection fraction (EF) less than 50% by CMR. Survivors previously undiagnosed with cardiotoxicity (n = 108) had a high prevalence of EF (32%) and cardiac mass (48%) that were more than two standard deviations below the mean of normative CMR data. 2D echocardiography overestimated the mean EF of this population by 5%. Compared with CMR, 2...

Coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of STING-mediated signaling.

Abstract: Viruses have evolved elaborate mechanisms to evade or inactivate the complex system of sensors and signaling molecules that make up the host innate immune response. Here we show that human coronavirus (HCoV) NL63 and severe acute respiratory syndrome (SARS) CoV papain-like proteases (PLP) antagonize innate immune signaling mediated by STING (stimulator of interferon genes, also known as MITA/ERIS/MYPS). STING resides in the endoplasmic reticulum and upon activation, forms dimers which assemble with MAVS, TBK-1 and IKKe, leading to IRF-3 activation and subsequent induction of interferon (IFN). We found that expression of the membrane anchored PLP domain from human HCoV-NL63 (PLP2-TM) or SARS-CoV (PLpro-TM) inhibits STING-mediated activation of IRF-3 nuclear translocation and induction of IRF-3 dependent promoters. Both catalytically active and inactive forms of CoV PLPs co-immunoprecipitated with STING, and viral replicase proteins co-localize with STING in HCoV-NL63-infected cells. Ectopic expression of catalytically active PLP2-TM blocks STING dimer formation and negatively regulates assembly of STING-MAVS-TBK1/IKKe complexes required for activation of IRF-3. STING dimerization was also substantially reduced in cells infected with SARS-CoV. Furthermore, the level of ubiquitinated forms of STING, RIG-I, TBK1 and IRF-3 are reduced in cells expressing wild type or catalytic mutants of PLP2-TM, likely contributing to disruption of signaling required for IFN induction. These results describe a new mechanism used by CoVs in which CoV PLPs negatively regulate antiviral defenses by disrupting the STING-mediated IFN induction.