Endobronchial coils in treatment of advanced emphysema: A single center experience.
This study aims to present our experience with endobronchial coils in patients who underwent endobronchial lung volume reduction due to advanced emphysema. The study included 46 patients (45 males, 1 female; mean age 61.7±8 years; range, 43 to 80 years) who underwent endobronchial lung volume reduction with endobronchial coils for advanced emphysema. Patients" age, gender, pulmonary function tests, post-treatment morbidity, mortality, pre- and post-treatment (6 months) six-minute walking distance, modified Medical Research Council dyspnea scores, chronic obstructive pulmonary disease assessment test and Hospital Anxiety and Depression Scale scores were recorded. Patients had an average of 65 pack/year smoking history. An average of 11 (range, 9-15) coils were placed per lobe (right upper lobe=35, left upper lobe=19, right lower lobe=2, left lower lobe=4). Mean follow-up duration was 12.6 months (±5.6 months). Post-treatment forced expiratory volume in one second, residual volume and six-minute walking distance values were improved with statistical significance. Also, significant improvement was seen in quality of life, quantified by modified Medical Research Council, chronic obstructive pulmonary disease assessment test and Hospital Anxiety and Depression Scale scores. While no immediate major postoperative complications occurred, three patients developed chronic obstructive pulmonary disease exacerbation, two developed pneumonia, and one developed recurrence of previous neurologic disorder within 30 days. Endobronchial coil administration provides lower morbidity and mortality compared to lung volume reduction surgery as well as significant improvement in pulmonary functions and quality of life in selected patients with advanced emphysema.


Optimizing gallbladder stone lithotripsy: an international survey.
Rates of stone clearance with extracorporeal shock wave cholecystolithotripsy (biliary lithotripsy [BL]) initially reported by European groups were encouraging. An American multicenter BL study (the Dornier National Biliary Lithotripsy Study [DNBLS]) did not reproduce these results. The BL treatment strategies and 6-month stone clearance rates of six leading European and Japanese centers were compared with those of DNBLS. All foreign centers used adjuvant oral chemolitholysis and greater shock wave energies from the same lithotriptor as that in DNBLS. Six months after BL, the stone clearance rates at all six centers were higher than those of DNBLS. There were no significant differences in complication rates between centers. These findings suggest that the poor results of DNBLS were chiefly due to the use of low kilovoltage and few BL sessions. Increased energy levels and a fragment size end point of less than 5 mm optimize BL. Despite the popularity of laparoscopic cholecystectomy, BL can be recognized as a successful treatment alternative for patients with a low burden of radiolucent stones.


Impact of rurality on processes and outcomes in melanoma care: results from a whole-Scotland melanoma cohort in primary and secondary care.
Those living in rural areas have poorer cancer outcomes, but current evidence on how rurality impacts melanoma care and survival is contradictory. To investigate the impact of rurality on setting of melanoma excision and mortality in a whole-nation cohort. Analysis of linked routine healthcare data comprising every individual in Scotland diagnosed with melanoma, January 2005-December 2013, in primary and secondary care. Multivariate binary logistic regression was used to explore the relationship between rurality and setting of melanoma excision; Cox proportional hazards regression between rurality and mortality was used, with adjustments for key confounders. In total 9519 patients were included (54.3% [n = 5167] female, mean age 60.2 years [SD 17.5]). Of melanomas where setting of excision was known, 90.3% (n = 8598) were in secondary care and 8.1% (n = 771) in primary care. Odds of primary care excision increased with increasing rurality/remoteness. Compared with those in urban areas, those in the most remote rural locations had almost twice the odds of melanoma excision in primary care (adjusted odds ratio [aOR] 1.92; 95% confidence interval [CI] = 1.33 to 2.77). No significant association was found between urban or rural residency and all-cause mortality. Melanoma-specific mortality was significantly lower in individuals residing in accessible small towns than in large urban areas (adjusted hazards ratio [HR] 0.53; 95% CI = 0.33 to 0.87) with no trend towards poorer survival with increasing rurality. Patients in Scottish rural locations were more likely to have a melanoma excised in primary care. However, those in rural areas did not have significantly increased mortality from melanoma. Together these findings suggest that current UK melanoma management guidelines could be revised to be more realistic by recognising the role of primary care in the prompt diagnosis and treatment of those in rural locations.


CtBP2 modulates the androgen receptor to promote prostate cancer progression.
The androgen receptor (AR) is the key driver of both early and advanced prostate cancer, making a complete understanding of its regulation important. Here, we report the identification of multiple AR-binding sites in the gene encoding the transcription factor CtBP2 (carboxyl terminal-binding protein), genetic variations of which have been associated with prostate cancer susceptibility. Notably, we found that SNPs in the human CTBP2 gene that were associated with prostate cancer development were correlated with AR-enhancer activity. High CtBP2 expression levels correlated with poor prognosis in patients, whereas CtBP2 silencing reduced tumor growth in a mouse xenograft model of human prostate cancer. Consistent with its function as a transcriptional corepressor, CtBP2 repressed tumor-suppressor genes and AR corepressors in prostate cancer cells, such as NCOR and RIP140, by binding with AR to the promoter enhancers of these genes. Global gene-expression analyses revealed a positive effect on androgen-mediated gene expression, and CtBP2 silencing was found to increase AR interactions with corepressors that limit histone modification. Overall, our results show how CtBP2 contributes to prostate cancer progression by modulating AR and oncogenic signaling.


Novel therapeutic strategies targeting HIV integrase.
Integration of the viral genome into host cell chromatin is a pivotal and unique step in the replication cycle of retroviruses, including HIV. Inhibiting HIV replication by specifically blocking the viral integrase enzyme that mediates this step is an obvious and attractive therapeutic strategy. After concerted efforts, the first viable integrase inhibitors were developed in the early 2000s, ultimately leading to the clinical licensure of the first integrase strand transfer inhibitor, raltegravir. Similarly structured compounds and derivative second generation integrase strand transfer inhibitors, such as elvitegravir and dolutegravir, are now in various stages of clinical development. Furthermore, other mechanisms aimed at the inhibition of viral integration are being explored in numerous preclinical studies, which include inhibition of 3' processing and chromatin targeting. The development of new clinically useful compounds will be aided by the characterization of the retroviral intasome crystal structure. This review considers the history of the clinical development of HIV integrase inhibitors, the development of antiviral drug resistance and the need for new antiviral compounds.


Molecular Adaptations for Sensing and Securing Prey and Insight into Amniote Genome Diversity from the Garter Snake Genome.
Colubridae represents the most phenotypically diverse and speciose family of snakes, yet no well-assembled and annotated genome exists for this lineage. Here, we report and analyze the genome of the garter snake, Thamnophis sirtalis, a colubrid snake that is an important model species for research in evolutionary biology, physiology, genomics, behavior, and the evolution of toxin resistance. Using the garter snake genome, we show how snakes have evolved numerous adaptations for sensing and securing prey, and identify features of snake genome structure that provide insight into the evolution of amniote genomes. Analyses of the garter snake and other squamate reptile genomes highlight shifts in repeat element abundance and expansion within snakes, uncover evidence of genes under positive selection, and provide revised neutral substitution rate estimates for squamates. Our identification of Z and W sex chromosome-specific scaffolds provides evidence for multiple origins of sex chromosome systems in snakes and demonstrates the value of this genome for studying sex chromosome evolution. Analysis of gene duplication and loss in visual and olfactory gene families supports a dim-light ancestral condition in snakes and indicates that olfactory receptor repertoires underwent an expansion early in snake evolution. Additionally, we provide some of the first links between secreted venom proteins, the genes that encode them, and their evolutionary origins in a rear-fanged colubrid snake, together with new genomic insight into the coevolutionary arms race between garter snakes and highly toxic newt prey that led to toxin resistance in garter snakes.


Session 1: Public health nutrition. Breast-feeding practices in Ireland.
Breast-feeding is the superior infant feeding method from birth, with research consistently demonstrating its numerous short- and long-term health benefits for both mother and infant. As a global recommendation the WHO advises that mothers should exclusively breast-feed for the first 6-months of life, thus delaying the introduction of solids during this time. Historically, Irish breast-feeding initiation rates have remained strikingly low in comparison with international data and there has been little improvement in breast-feeding duration rates. There is wide geographical variation in terms of breast-feeding initiation both internationally and in Ireland. Some of these differences in breast-feeding rates may be associated with differing socio-economic characteristics. A recent cross-sectional prospective study of 561 pregnant women attending a Dublin hospital and followed from the antenatal period to 6 months post partum has found that 47% of the Irish-national mothers initiated breast-feeding, while only 24% were still offering 'any' breast milk to their infants at 6 weeks. Mothers' positive antenatal feeding intention to breast-feed is indicated as one of the most important independent determinants of initiation and 'any' breast-feeding at 6 weeks, suggesting that the antenatal period should be targeted as an effective time to influence and affect mothers' attitudes and beliefs pertaining to breast-feeding. These results suggest that the 'cultural' barrier towards breast-feeding appears to still prevail in Ireland and consequently an environment that enables women to breast-feed is far from being achieved. Undoubtedly, a shift towards a more positive and accepting breast-feeding culture is required if national breast-feeding rates are to improve.


Polarimetric laser radar target classification.
Imaging laser radar (ladar) systems have been developed for automatic target identification in surveillance systems. Ladar uses the range value at the target pixels to estimate the target's 3-D shape and identify the target. For targets in clutter and partially hidden targets, there are ambiguities in determining which pixels are on target that lead to uncertainties in determining the target's 3-D shape. An improvement is to use the polarization components of the reflected light. We describe the operation and preliminary evaluation of a polarization diverse imaging ladar system. Using a combination of intensity, range, and degree of polarization, we are better able to identify and distinguish the target from other objects of the same class.


Autologous bone marrow mononuclear cells therapy attenuates activated microglial/macrophage response and improves spatial learning after traumatic brain injury.
Autologous bone marrow-derived mononuclear cells (AMNCs) have shown therapeutic promise for central nervous system insults such as stroke and traumatic brain injury (TBI). We hypothesized that intravenous injection of AMNC provides neuroprotection, which leads to cognitive improvement after TBI. A controlled cortical impact (CCI) rodent TBI model was used to examine blood-brain barrier (BBB) permeability, neuronal and glial apoptosis, as well as cognitive behavior. Two groups of rats underwent CCI with AMNC treatment (CCI-autologous) or without AMNC treatment (CCI-alone), consisting of 2 million AMNC per kilogram body weight harvested from the tibia and intravenously injected 72 hours after injury. CCI-alone animals underwent sham harvests and received vehicle injections. Ninety-six hours after injury, AMNC significantly reduced the BBB permeability in injured animals, and there was an increase in apoptosis of proinflammatory activated microglia in the ipsilateral hippocampus. At 4 weeks after injury, we observed significant improvement in probe testing of CCI-Autologous group in comparison to CCI-Alone in the Morris Water Maze paradigm. Our data demonstrate that the intravenous injection of AMNC after TBI leads to neuroprotection by preserving early BBB integrity, increasing activated microglial apoptosis and improving cognitive function.


Reflections about bizarre mummification practices on mummies at Egypt's Dakhleh oasis: a review.
About 100 mummified human remains were excavated from the Dakhleh Oasis in Egypt's Western Desert. Of these, less than half were examined by dissection. These dated to the Late Ptolemaic and Roman Periods. Initially, a confusing pattern of mortuary mummification practices was encountered that was identified ultimately as a product of primarily initial spontaneous mummification by desiccation. This was followed by tomb robbing in antiquity with unwrapping; body disarticulation followed, in turn, by mummy body reconstruction with atypical use of resin applications. Some of the resin was shown to be contaminated by bitumen that was responsible for inappropriately old radiocarbon dates of mummy tissue samples. Chemical reconstruction of diet using stable isotope ratios of carbon and nitrogen characterized their diet to be primarily that of C3 plants, consistent with trading records excavated from that site. Analysis of the mummy coprolites also enabled the first finding of the intestinal parasite Enterobius vermicularis in either ancient or modern Egyptian human coprolites. The principal focus of this report is to demonstrate and verify the value of including visceral dissection as part of a mummy examination whenever possible.


CD164 monoclonal antibodies that block hemopoietic progenitor cell adhesion and proliferation interact with the first mucin domain of the CD164 receptor.
The novel sialomucin, CD164, functions as both an adhesion receptor on human CD34+ cell subsets in bone marrow and as a potent negative regulator of CD34+ hemopoietic progenitor cell proliferation. These diverse effects are mediated by at least two functional epitopes defined by the mAbs, 103B2/9E10 and 105A5. We report here the precise epitope mapping of these mAbs together with that of two other CD164 mAbs, N6B6 and 67D2. Using newly defined CD164 splice variants and a set of soluble recombinant chimeric proteins encoded by exons 1-6 of the CD164 gene, we demonstrate that the 105A5 and 103B2/9E10 functional epitopes map to distinct glycosylated regions within the first mucin domain of CD164. The N6B6 and 67D2 mAbs, in contrast, recognize closely associated and complex epitopes that rely on the conformational integrity of the CD164 molecule and encompass the cysteine-rich regions encoded by exons 2 and 3. On the basis of their sensitivities to reducing agents and to sialidase, O-sialoglycoprotease, and N-glycanase treatments, we have characterized CD164 epitopes and grouped them into three classes by analogy with CD34 epitope classification. The class I 105A5 epitope is sialidase, O-glycosidase, and O-sialoglycoprotease sensitive; the class II 103B2/9E10 epitope is N-glycanase, O-glycosidase, and O-sialoglycoprotease sensitive; and the class III N6B6 and 67D2 epitopes are not removed by such enzyme treatments. Collectively, this study indicates that the previously observed differential expression of CD164 epitopes in adult tissues is linked with cell type specific post-translational modifications and suggests a role for epitope-associated carbohydrate structures in CD164 function.


Enhanced apoptosis by pemetrexed and simvastatin in malignant mesothelioma and lung cancer cells by reactive oxygen species-dependent mitochondrial dysfunction and Bim induction.
Pemetrexed is a multitarget antifolate currently used for the treatment of malignant mesothelioma and non-small cell lung cancer (NSCLC). Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors used primarily for hyperlidpidemia, have been studied for their antiproliferative and pro-apoptotic effects. However, the effects of simvastatin on pemetrexed-induced apoptosis have not been investigated. In this study, we investigated whether combination treatment with pemetrexed and simvastatin potentiates the apoptotic activity above that is seen with either drug alone in malignant mesothelioma and NSCLC cells. We found that the combination of pemetrexed and simvastatin induced more extensive caspase-dependent apoptosis than either drug alone in malignant mesothelioma cells (MSTO-211) or NSCLC cells (A549). In addition, reactive oxygen species (ROS) generation in cells treated with both pemetrexed and simvastatin was markedly increased compared to cells treated with either pemetrexed or simvastatin alone. Combination treatment also increased the loss of mitochondrial membrane potential, increased cytosolic release of cytochrome c, and altered expression of inhibitor of apoptosis proteins (IAP) and B-cell lymphoma-2 (Bcl-2) families of apoptosis related proteins. On the other hand, pretreatment with N-acetylcysteine (NAC) prevented apoptosis and mitochondrial dysfunction by pemetrexed and simvastatin. In addition, Bim siRNA conferred protection against apoptosis induced by pemetrexed and simvastatin. These results suggest that combination of pemetrexed and simvastatin potentiates their apoptotic activity beyond that of either drug alone in malignant mesothelioma and lung cancer cells. This activity is mediated through ROS-dependent mitochondrial dysfunction and Bim induction.


Cognitive idiosyncrasies among children with the chronic fatigue syndrome: anomalies in self-reported activity levels.
The possibility that children with the chronic fatigue syndrome (CFS) and their parents tend to display idiosyncratic cognitive processing concerning levels of activity was examined by means of subjective and objective measures of current activity, together with subjective and objective measures of desired and expected future activity. The degree to which subjective reports of current activity level reflect objectively measured activity level was examined in a group of children with CFS and a healthy control group. All subjects were assessed over a 3-day period by means of ambulatory activity monitoring, and self-reports and parent-reports of current activity level were collected by means of visual analog scales. Analysis of variance revealed a significant interaction between the method of measurement (objective versus subjective) and the participant group (CFS versus Healthy) with the CFS children and their parents underestimating actual level of activity relative to the healthy group. Desired and expected levels of future activity were also assessed by means of subjective report. Child and parent expected levels of future activity were compared with their desired levels. Although expected levels of future activity were similar in the two groups, the divergence between expected levels and corresponding desired levels was significantly greater in the CFS group. These results are discussed in terms of idiosyncratic cognitive processes, which are hypothesized to be associated with CFS and which may play a role in the maintenance of the disorder.


Technical note: A muscle biopsy technique for stratifying cattle by skeletal muscle metabolic activity.
Tissue biopsy metabolic activity, assessed using the oxidation-reduction indicator resazurin, may serve as a proxy to assess energy expenditure associated with maintenance in nongrowing animals or growth rate in growing animals. Herein, we evaluate the repeatability, practicality, and sensitivity of a resazurin-based assay for ranking bovine skeletal muscle biopsies based on metabolic activity. Six yearling Holstein heifers (body weight = 330 ± 11.3 kg) were fed 4 dietary treatments consisting of high or low rumen-degradable starch and fiber arranged factorially in a partially replicated Latin square design. Periods were 18 d, consisting of 3 d for diet transition, 14 d for diet adaptation, and 1 d for sample collection. Semitendinosus biopsies were collected into ice-cold Dulbecco's modified Eagle medium (Fisher Scientific, Hampton, NH) from each heifer during each period. Analysis was initiated within an hour of sample collection. To assess tissue metabolic rate, biopsies were transferred to Dulbecco's modified Eagle medium with resazurin and incubated at 37°C. Fluorescence of each sample was read at time 0 and at 15-min intervals for 2 h. Change in fluorescence was representative of skeletal muscle reducing equivalent production. Fluorescent signal strength increased with time and relative rank of treatments did not change with time; accordingly, future studies may compare fluorescence at a single time point. Change in fluorescence at 120 min was used for analysis of the fixed effects of fiber, starch, and animal when accounting for a random effect of period. Samples collected when animals were on a high-ruminally degradable starch diet were more metabolically active than samples collected from animals on low-starch diets. Significant differences in metabolic activity among individual animals were also identified. Average relative fluorescence was correlated with dry matter intake, average daily gain, and feed-to-gain ratio. The relative fluorescence tended to correlate with average daily gain (r = 0.749) and feed-to-gain ratio (r = -0.783); change in fluorescence did not correlate with dry matter intake. Although evaluated on a small sample size, this technique shows promise as a potential means of ranking animals by growth or feed efficiency. Further work on a larger experimental population is needed to confirm the usefulness of this assay as a consistent and reliable predictor of these important phenotypic parameters.


B cell abnormalities in systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disease characterized by the differentiation of short- and long-lived immunoglobulin secreting plasma cells that secrete pathogenic autoantibodies. Ectopic germinal centers and plasma cells secreting autoantibodies have been observed in lupus nephritis kidneys. Candidate genetic susceptibility loci for SLE include genes that affect differentiation and survival of plasma cells, such as those that influence activation, proliferation, cytokine and chemokine secretion/responsiveness, and apoptosis of the T and B cells that are involved in humoral immunity generated in germinal centers, as well as genes that are involved in presentation and clearance of apoptotic material and autoantigens by antigen presenting cells and other phagocytes. Emerging data have demonstrated that B lymphocytes are active participants in humoral immune responses that lead to T-dependent and T-independent differentiation of immunoglobulin-secreting plasma cells by homotypic CD154-CD40 interactions as well as continued stimulation by B cell activating factor through B cell maturation antigen, B cell activating factor receptor and transmembrane activater.


Pre-conditioning induces the precocious differentiation of neonatal astrocytes to enhance their neuroprotective properties.
Hypoxic preconditioning reprogrammes the brain's response to subsequent H/I (hypoxia-ischaemia) injury by enhancing neuroprotective mechanisms. Given that astrocytes normally support neuronal survival and function, the purpose of the present study was to test the hypothesis that a hypoxic preconditioning stimulus would activate an adaptive astrocytic response. We analysed several functional parameters 24 h after exposing rat pups to 3 h of systemic hypoxia (8% O2). Hypoxia increased neocortical astrocyte maturation as evidenced by the loss of GFAP (glial fibrillary acidic protein)-positive cells with radial morphologies and the acquisition of multipolar GFAP-positive cells. Interestingly, many of these astrocytes had nuclear S100B. Accompanying their differentiation, there was increased expression of GFAP, GS (glutamine synthetase), EAAT-1 (excitatory amino acid transporter-1; also known as GLAST), MCT-1 (monocarboxylate transporter-1) and ceruloplasmin. A subsequent H/I insult did not result in any further astrocyte activation. Some responses were cell autonomous, as levels of GS and MCT-1 increased subsequent to hypoxia in cultured forebrain astrocytes. In contrast, the expression of GFAP, GLAST and ceruloplasmin remained unaltered. Additional experiments utilized astrocytes exposed to exogenous dbcAMP (dibutyryl-cAMP), which mimicked several aspects of the preconditioning response, to determine whether activated astrocytes could protect neurons from subsequent excitotoxic injury. dbcAMP treatment increased GS and glutamate transporter expression and function, and as hypothesized, protected neurons from glutamate excitotoxicity. Taken altogether, these results indicate that a preconditioning stimulus causes the precocious differentiation of astrocytes and increases the acquisition of multiple astrocytic functions that will contribute to the neuroprotection conferred by a sublethal preconditioning stress.


Outcomes of transcatheter tricuspid valve intervention by right ventricular function: a multicentre propensity-matched analysis.
Tricuspid regurgitation (TR) has a poor prognosis and limited treatment options and is frequently accompanied by right ventricular (RV) dysfunction. Transcatheter tricuspid valve interventions (TTVI) to reduce TR have been shown to be safe and feasible with encouraging early results. Patient selection for TTVI remains challenging, with the role of right ventricular (RV) function being unknown. The aims of this study were 1) to investigate survival in a TTVI-treated patient population and a conservatively treated TR population, and 2) to evaluate the outcome of TTVI as compared to conservative treatment stratified according to the degree of RV function. We studied 684 patients from the multicentre TriValve cohort (TTVI cohort) and compared them to 914 conservatively treated patients from two tertiary care centres. Propensity matching identified 213 pairs of patients with severe TR. As we observed a non-linear relationship of RV function and TTVI outcome, we stratified patients according to tricuspid annular plane systolic excursion (TAPSE) to preserved (TAPSE >17 mm), mid-range (TAPSE 13-17 mm) and reduced (TAPSE <13 mm) RV function. The primary outcome was one-year all-cause mortality. TTVI was associated with a survival benefit in patients with severe TR when compared to matched controls (one-year mortality rate: 13.1% vs 25.8%; p=0.031). Of the three RV subgroups, only in patients with mid-range RV function was TTVI associated with an improved survival (p log-rank 0.004). In these patients, procedural success was associated with a reduced hazard ratio for all-cause mortality (HR 0.22; 95% CI: 0.09, 0.57). TTVI is associated with reduced mortality compared to conservative therapy and might exert its highest treatment effect in patients with mid-range reduced RV function.


Functional interaction between Ssu72 and the Rpb2 subunit of RNA polymerase II in Saccharomyces cerevisiae.
SSU72 is an essential gene encoding a phylogenetically conserved protein of unknown function that interacts with the general transcription factor TFIIB. A recessive ssu72-1 allele was identified as a synthetic enhancer of a TFIIB (sua7-1) defect, resulting in a heat-sensitive (Ts(-)) phenotype and a dramatic downstream shift in transcription start site selection. Here we describe a new allele, ssu72-2, that confers a Ts(-) phenotype in a SUA7 wild-type background. In an effort to further define Ssu72, we isolated suppressors of the ssu72-2 mutation. One suppressor is allelic to RPB2, the gene encoding the second-largest subunit of RNA polymerase II (RNAP II). Sequence analysis of the rpb2-100 suppressor defined a cysteine replacement of the phylogenetically invariant arginine residue at position 512 (R512C), located within homology block D of Rpb2. The ssu72-2 and rpb2-100 mutations adversely affected noninduced gene expression, with no apparent effects on activated transcription in vivo. Although isolated as a suppressor of the ssu72-2 Ts(-) defect, rpb2-100 enhanced the transcriptional defects associated with ssu72-2. The Ssu72 protein interacts directly with purified RNAP II in a coimmunoprecipitation assay, suggesting that the genetic interactions between ssu72-2 and rpb2-100 are a consequence of physical interactions. These results define Ssu72 as a highly conserved factor that physically and functionally interacts with the RNAP II core machinery during transcription initiation.


Interaction between the helicases genetically linked to Fanconi anemia group J and Bloom's syndrome.
Bloom's syndrome (BS) and Fanconi anemia (FA) are autosomal recessive disorders characterized by cancer and chromosomal instability. BS and FA group J arise from mutations in the BLM and FANCJ genes, respectively, which encode DNA helicases. In this work, FANCJ and BLM were found to interact physically and functionally in human cells and co-localize to nuclear foci in response to replication stress. The cellular level of BLM is strongly dependent upon FANCJ, and BLM is degraded by a proteasome-mediated pathway when FANCJ is depleted. FANCJ-deficient cells display increased sister chromatid exchange and sensitivity to replication stress. Expression of a FANCJ C-terminal fragment that interacts with BLM exerted a dominant negative effect on hydroxyurea resistance by interfering with the FANCJ-BLM interaction. FANCJ and BLM synergistically unwound a DNA duplex substrate with sugar phosphate backbone discontinuity, but not an 'undamaged' duplex. Collectively, the results suggest that FANCJ catalytic activity and its effect on BLM protein stability contribute to preservation of genomic stability and a normal response to replication stress.


Unfolding the fullerene: nanotubes, graphene and poly-elemental varieties by simulations.
Recent research progress in nanostructured carbon has built upon and yet advanced far from the studies of more conventional carbon forms such as diamond, graphite, and perhaps coals. To some extent, the great attention to nano-carbons has been ignited by the discovery of the structurally least obvious, counterintuitive, small strained fullerene cages. Carbon nanotubes, discovered soon thereafter, and recently, the great interest in graphene, ignited by its extraordinary physics, are all interconnected in a blend of cross-fertilizing fields. Here we review the theoretical and computational models development in our group at Rice University, towards understanding the key structures and behaviors in the immense diversity of carbon allotropes. Our particular emphasis is on the role of certain transcending concepts (like elastic instabilities, dislocations, edges, etc.) which serve so well across the scales and for chemically various compositions.


Do Patients Hospitalized With COPD Have Airflow Obstruction?
Guidelines recommend the confirmation of a COPD diagnosis with spirometry. International Classification of Diseases, Ninth Revision, Clinical Modification, diagnostic codes are frequently used to identify patients with COPD for administrative purposes. However, coding the diagnosis of COPD does not require confirmation using spirometry. The purpose of this study was to determine how often the discharge diagnosis of COPD is supported by spirometric measurements in the Veterans Affairs (VA) health system. We reviewed records of patients hospitalized for COPD in a VA teaching hospital between 2005 and 2015. Individuals were counted once; rehospitalizations for COPD in the same time frame were excluded. Patient records were assessed for the presence of spirometric measurements and for spirometric evidence of COPD. There were 1,278 discharges with the principal diagnosis of COPD and allied conditions in the time frame. A total of 826 discharged patients were included. Among them, 21% had no spirometric measurements, 12% were unable to perform the breathing maneuvers correctly, 56% had spirometric evidence of airways obstruction, and 11% had normal prebronchodilator or postbronchodilator FEV1/FVC measurements. Older patients were more likely to fail the spirometry test or have no documented spirometry. Younger patients were more likely to have the first spirometry conducted after their COPD hospitalizations. Caution must be taken when using the discharge diagnosis database to measure health-care outcomes and determine resource management. Efforts are needed to assure that patients clinically suspected of having COPD are tested with spirometry to improve the accuracy of a COPD diagnosis.


Metropolitan-level racial residential segregation and black-white disparities in hypertension.
Few studies have examined geographic variation in hypertension disparities, but studies of other health outcomes indicate that racial residential segregation may help to explain these variations. The authors used data from 8,071 black and white participants in the National Health and Nutrition Examination Survey (1999-2006) who were aged 25 years or older to investigate whether black-white hypertension disparities varied by level of metropolitan-level racial residential segregation and whether this was explained by race differences in neighborhood poverty. Racial segregation was measured by using the black isolation index. After adjustment for demographics and individual-level socioeconomic position, blacks had 2.74 times higher odds of hypertension than whites (95% confidence interval (CI): 2.32, 3.25). However, race differences were significantly smaller in low- than in high-segregation areas (P(interaction) = 0.006). Race differences in neighborhood poverty did not explain this heterogeneity, but poverty further modified race disparities: Race differences were largest in segregated, low-poverty areas (odds ratio = 4.14, 95% CI: 3.18, 5.38) and smallest in nonsegregated, high-poverty areas (odds ratio = 1.24, 95% CI: 0.77, 2.01). These findings suggest that racial disparities in hypertension are not invariant and are modified by contextual levels of racial segregation and neighborhood poverty, highlighting the role of environmental factors in the genesis of disparities.


Odor composition of preferred (buffalo and ox) and nonpreferred (waterbuck) hosts of some Savanna tsetse flies.
A previous study on the feeding responses of tsetse flies, Glossina morsitans morsitans, implicated the existence of allomonal barriers, both volatile and nonvolatile, on the nonpreferred host, waterbuck, Kobus defassa. In the present study, electroantennogram-active compounds in odors from waterbuck were compared with those of two preferred hosts of tsetse flies, buffalo, Syncerus caffer, and ox, Bos indicus. Odors from the three bovids were trapped on activated charcoal and/or reverse-phase (octadecyl bonded) silica and analyzed with a gas chromatography-linked electroantennographic detector (GC-EAD) and, where possible, identified by using gas chromatography-linked mass spectrometry (GC-MS) and chromatographic comparisons with authentic samples. The GC-EAD profiles (with G. m. morsitans antennae) of the odors of the two preferred hosts were comparable, comprising medium-chain, saturated or unsaturated aldehydes and phenols, with buffalo emitting a few more EAG-active aldehydes. Waterbuck odor gave a richer profile, consisting of fewer aldehydes but more phenolic components and a series of 2-ketones (C-C13) and delta-octalactone. This bovid also emits moderate amounts of C5-C9 straight-chain fatty acids, some of which were detected in buffalo and ox only in trace amounts. However, these did not elicit significant GC-EAD responses. Waterbuck profiles from the antennae of G. pallidipes showed broad similarity to those from G. m. morsitans, although the composition of aldehydes and ketones was somewhat different, indicating species-specific difference in the detection of host odors. Certain waterbuck-specific EAG-active components, particularly the 2-ketones and lactone, constitute a candidate allomonal blend in waterbuck odor.


Structure and Characterization of a Covalent Inhibitor of Src Kinase.
Unregulated Src activity promotes malignant processes in cancer, but no Src-directed targeted therapies are used clinically, possibly because early Src inhibitors produce off-target effects leading to toxicity. Improved selective Src inhibitors may enable Src-directed therapies. Previously, we reported an irreversible Src inhibitor, DGY-06-116, based on the hybridization of dasatinib and a promiscuous covalent kinase probe SM1-71. Here, we report biochemical and biophysical characterization of this compound. An x-ray co-crystal structure of DGY-06-116: Src shows a covalent interaction with the kinase p-loop and occupancy of the back hydrophobic kinase pocket, explaining its high potency, and selectivity. However, a reversible analog also shows similar potency. Kinetic analysis shows a slow inactivation rate compared to other clinically approved covalent kinase inhibitors, consistent with a need for p-loop movement prior to covalent bond formation. Overall, these results suggest that a strong reversible interaction is required to allow sufficient time for the covalent reaction to occur. Further optimization of the covalent linker may improve the kinetics of covalent bond formation.


Electrical potential difference across the nasal epithelium is reduced in premature infants with chronic lung disease but is not associated with lower airway inflammation.
Airway liquid content and insufficient absorptive airway ion transport at birth are potentially important factors in the development and severity of neonatal respiratory disease. The role of deficient absorptive airway ion transport in the development of chronic lung disease of prematurity is unknown. Additionally, lung inflammatory mediators modulate airway ion transport. Their effect on preterm lung ion transport and absorptive capacity is not established. We performed serial nasal potential difference studies and broncho-alveolar lavage in preterm infants born less than 30 wk postmenstrual age over the first four postnatal weeks. Our study aims were to: 1) compare nasal potential difference between preterm infants developing chronic lung disease and babies of similar gestation who do not; and 2) examine for an association between airway inflammation and ion transport parameters. We found that potential difference across the nasal epithelium increased with gestation, remained low and unchanged in infants developing chronic lung disease over the first four postnatal weeks, was significantly lower at four weeks in chronic lung disease infants, and was not associated with lower airway inflammation at any time point. We conclude that infants with chronic lung disease postnatally have a persistently reduced absorptive airway ion transport capacity.


Discovery of Rab1 binding sites using an ensemble of clustering methods.
Targeting non-native-ligand binding sites for potential investigative and therapeutic applications is an attractive strategy in proteins that share common native ligands, as in Rab1 protein. Rab1 is a subfamily member of Rab proteins, which are members of Ras GTPase superfamily. All Ras GTPase superfamily members bind to native ligands GTP and GDP, that switch on and off the proteins, respectively. Rab1 is physiologically essential for autophagy and transport between endoplasmic reticulum and Golgi apparatus. Pathologically, Rab1 is implicated in human cancers, a neurodegenerative disease, cardiomyopathy, and bacteria-caused infectious diseases. We have performed structural analyses on Rab1 protein using a unique ensemble of clustering methods, including multi-step principal component analysis, non-negative matrix factorization, and independent component analysis, to better identify representative Rab1 proteins than the application of a single clustering method alone does. We then used the identified representative Rab1 structures, resolved in multiple ligand states, to map their known and novel binding sites. We report here at least a novel binding site on Rab1, involving Rab1-specific residues that could be further explored for the rational design and development of investigative probes and/or therapeutic small molecules against the Rab1 protein. Proteins 2017; 85:859-871. © 2016 Wiley Periodicals, Inc.


Influence of physiological phenology on the seasonal pattern of ecosystem respiration in deciduous forests.
Understanding the environmental and biotic drivers of respiration at the ecosystem level is a prerequisite to further improve scenarios of the global carbon cycle. In this study we investigated the relevance of physiological phenology, defined as seasonal changes in plant physiological properties, for explaining the temporal dynamics of ecosystem respiration (RECO) in deciduous forests. Previous studies showed that empirical RECO models can be substantially improved by considering the biotic dependency of RECO on the short-term productivity (e.g., daily gross primary production, GPP) in addition to the well-known environmental controls of temperature and water availability. Here, we use a model-data integration approach to investigate the added value of physiological phenology, represented by the first temporal derivative of GPP, or alternatively of the fraction of absorbed photosynthetically active radiation, for modeling RECO at 19 deciduous broadleaved forests in the FLUXNET La Thuile database. The new data-oriented semiempirical model leads to an 8% decrease in root mean square error (RMSE) and a 6% increase in the modeling efficiency (EF) of modeled RECO when compared to a version of the model that does not consider the physiological phenology. The reduction of the model-observation bias occurred mainly at the monthly time scale, and in spring and summer, while a smaller reduction was observed at the annual time scale. The proposed approach did not improve the model performance at several sites, and we identified as potential causes the plant canopy heterogeneity and the use of air temperature as a driver of ecosystem respiration instead of soil temperature. However, in the majority of sites the model-error remained unchanged regardless of the driving temperature. Overall, our results point toward the potential for improving current approaches for modeling RECO in deciduous forests by including the phenological cycle of the canopy.


Lessons from the past: evolutionary impacts of mass extinctions.
Mass extinctions have played many evolutionary roles, involving differential survivorship or selectivity of taxa and traits, the disruption or preservation of evolutionary trends and ecosystem organization, and the promotion of taxonomic and morphological diversifications-often along unexpected trajectories-after the destruction or marginalization of once-dominant clades. The fossil record suggests that survivorship during mass extinctions is not strictly random, but it often fails to coincide with factors promoting survival during times of low extinction intensity. Although of very serious concern, present-day extinctions have not yet achieved the intensities seen in the Big Five mass extinctions of the geologic past, which each removed > or =50% of the subset of relatively abundant marine invertebrate genera. The best comparisons for predictive purposes therefore will involve factors such as differential extinction intensities among regions, clades, and functional groups, rules governing postextinction biotic interchanges and evolutionary dynamics, and analyses of the factors that cause taxa and evolutionary trends to continue unabated, to suffer setbacks but resume along the same trajectory, to survive only to fall into a marginal role or disappear ("dead clade walking"), or to undergo a burst of diversification. These issues need to be addressed in a spatially explicit framework, because the fossil record suggests regional differences in postextinction diversification dynamics and biotic interchanges. Postextinction diversifications lag far behind the initial taxonomic and morphological impoverishment and homogenization; they do not simply reoccupy vacated adaptive peaks, but explore opportunities as opened and constrained by intrinsic biotic factors and the ecological and evolutionary context of the radiation.


Genomic sequencing of single microbial cells from environmental samples.
Recently developed techniques allow genomic DNA sequencing from single microbial cells [Lasken RS: Single-cell genomic sequencing using multiple displacement amplification. Curr Opin Microbiol 2007, 10:510-516]. Here, we focus on research strategies for putting these methods into practice in the laboratory setting. An immediate consequence of single-cell sequencing is that it provides an alternative to culturing organisms as a prerequisite for genomic sequencing. The microgram amounts of DNA required as template are amplified from a single bacterium by a method called multiple displacement amplification (MDA) avoiding the need to grow cells. The ability to sequence DNA from individual cells will likely have an immense impact on microbiology considering the vast numbers of novel organisms, which have been inaccessible unless culture-independent methods could be used. However, special approaches have been necessary to work with amplified DNA. MDA may not recover the entire genome from the single copy present in most bacteria. Also, some sequence rearrangements can occur during the DNA amplification reaction. Over the past two years many research groups have begun to use MDA, and some practical approaches to single-cell sequencing have been developed. We review the consensus that is emerging on optimum methods, reliability of amplified template, and the proper interpretation of 'composite' genomes which result from the necessity of combining data from several single-cell MDA reactions in order to complete the assembly. Preferred laboratory methods are considered on the basis of experience at several large sequencing centers where >70% of genomes are now often recovered from single cells. Methods are reviewed for preparation of bacterial fractions from environmental samples, single-cell isolation, DNA amplification by MDA, and DNA sequencing.


Succession patterns following soil disturbance in a sagebrush steppe community.
A study was begun in 1976 to measure succession patterns following soil disturbance within a sagebrush community in northwestern Colorado. The principal hypothesis was that type of disturbance affects the direction of succession, resulting in different plant communities over time. Successional dynamics were studied through 1988. Four types of soil disturbance resulted in 3 early seral communities: one dominated by grasses, one by annuals, and one intermediate. The annual-dominated communities were opportunistic on these sites, lasting 3-5 years and not determining the direction in which succession proceeded following their replacement. Twelve years after disturbance, 3 communities (one grass-dominated, one shrub-dominated, and one intermediate) occupied the site, the characteristics of which were functions of type of initial soil disturbance. For the period of time covered by this study (12 years), degree of disturbance was found to affect the direction of succession, resulting in different plant communities over time. There were, however, successional characteristics toward the end of the study that suggest that over a longer time period, succession might progress to a single community regardless of type of disturbance.


Early delayed language development in very preterm infants: evidence from the MacArthur-Bates CDI.
This study examined the effects of being born very preterm on children's early language development using prospective longitudinal data from a representative regional cohort of 90 children born very preterm (gestational age <33 weeks and/or birth weight <1,500 grams) and a comparison sample of 102 children born full term (gestational age 38-41 weeks). The MacArthur-Bates Communicative Development Inventory: Words and Sentences (CDI-WS) was used to assess children's language development at age 2;0 (corrected for gestational age at birth). Clear linear relationships were found between gestational age at birth and later language outcomes, with decreasing gestational age being associated with poorer parent-reported language skills. Specifically, children born extremely preterm (<28 weeks' gestation) tended to perform less well than those born very preterm (28-32 weeks' gestation), who in turn performed worse than children born full term (38-41 weeks' gestation). This pattern of findings was evident across a range of outcomes spanning vocabulary size and quality of word use, as well as morphological and syntactic complexity. Importantly, associations between gestational age at birth and language outcomes persisted after statistical control for child and family factors correlated with both preterm birth and language development. These findings demonstrate the presence of pervasive delays in the early language development of children born very preterm. They also highlight the importance of gestational age in predicting later language risk in this population of infants.


Assessment of clinical partner violence screening tools.
To compare the Women's Experience with Battering Scale (WEB) with the Index of Spouse Abuse-Physical Scale (ISA-P) as screening tools to identify intimate partner violence (IPV). We conducted a large cross-sectional survey of women age 18 to 65 attending one of two family practice clinics from 1997 to 1998. All women completed both the WEB and the ISA-P and a telephone interview. We figured agreement estimates between the two tools, used stratified analyses to evaluate attributes of those more likely to screen as battered or physically assaulted, and compared associations between the WEB and ISA-P and a range of mental and physical health indicators known to be associated with IPV. 18% of 1152 eligible women surveyed had experienced IPV in a current or most recent intimate relationship with a male partner; 17% had been battered (WEB+), and 10% had been physically assaulted (ISA-P+). Had we used the ISA-P alone to assess IPV, we would have missed almost 45% of IPV. As anticipated, the ISA-P was more strongly associated with IPV-associated injuries and number of physician visits in the last year. The WEB was more strongly associated with self-perceived mental health, anxiety, depression, drug abuse, and low social support. Clinicians need validated screening tools to rapidly and reliably screen patients for IPV. Most screening tools assess physical violence and injury without considering the more chronic experience of battering and the psychological terror associated with this violence. The WEB may identify more abused women than tools measuring physical assaults.


Nutrition and aging skin: sugar and glycation.
The effect of sugars on aging skin is governed by the simple act of covalently cross-linking two collagen fibers, which renders both of them incapable of easy repair. Glucose and fructose link the amino acids present in the collagen and elastin that support the dermis, producing advanced glycation end products or "AGEs." This process is accelerated in all body tissues when sugar is elevated and is further stimulated by ultraviolet light in the skin. The effect on vascular, renal, retinal, coronary, and cutaneous tissues is being defined, as are methods of reducing the glycation load through careful diet and use of supplements.


Prevalence of obesity among migrant Asian Indians: a systematic review and meta-analysis.
The objective of this review was to investigate the prevalence of obesity among migrant Asian Indians globally. The primary outcomes of interest included the incidence of obesity as measured objectively by body mass index (BMI), waist circumference, waist-to-hip ratio and body fat. All published studies that investigated obesity rates in migrant Asian Indians were considered for inclusion in the review. Studies were included if they had more than 100 participants and reported objective measures of obesity. A literature search was performed using the following databases Medline (2000-10), Cumulative Index to Nursing and Allied Health Literature (2000-11), Excerpta Medica Database (2000-current) and the Cochrane Controlled Studies Register (Issue 1, 2011 of Cochrane Library). In addition, the reference lists of relevant studies and conference proceedings were also scrutinised. Two reviewers independently assessed the eligibility of the studies for inclusion in the review, the methodological quality and then extracted details of eligible studies. Data were analysed using the Review Manager software. Ten studies investigating the obesity indices in Asian Indians were eligible for this review. All ten trials that reported on BMI values demonstrated significantly higher BMI values among migrant Asian Indians when compared with other migrants and the native population (standardised mean difference 0.36; 95% confidence interval 0.30, 0.41). A greater proportion of Asian Indians had BMIs greater than or equal to 30 when compared with other ethnic groups. Up to 80% of the Asian Indian women had a waist circumference greater than the recommended value of 88 cm. Based on the available evidence, the obesity indices among migrant Asian Indians are significantly greater when compared with the native population and those living in India, particularly among women. This is likely to contribute to the high levels of diabetes and coronary heart disease in this population. Culturally appropriate strategies to reduce obesity, particularly abdominal obesity, in this ethnic group are urgently needed.


Preventing nanoscale wear of atomic force microscopy tips through the use of monolithic ultrananocrystalline diamond probes.
Nanoscale wear is a key limitation of conventional atomic force microscopy (AFM) probes that results in decreased resolution, accuracy, and reproducibility in probe-based imaging, writing, measurement, and nanomanufacturing applications. Diamond is potentially an ideal probe material due to its unrivaled hardness and stiffness, its low friction and wear, and its chemical inertness. However, the manufacture of monolithic diamond probes with consistently shaped small-radius tips has not been previously achieved. The first wafer-level fabrication of monolithic ultrananocrystalline diamond (UNCD) probes with <5-nm grain sizes and smooth tips with radii of 30-40 nm is reported, which are obtained through a combination of microfabrication and hot-filament chemical vapor deposition. Their nanoscale wear resistance under contact-mode scanning conditions is compared with that of conventional silicon nitride (SiN(x)) probes of similar geometry at two different relative humidity levels (approximately 15 and approximately 70%). While SiN(x) probes exhibit significant wear that further increases with humidity, UNCD probes show little measurable wear. The only significant degradation of the UNCD probes observed in one case is associated with removal of the initial seed layer of the UNCD film. The results show the potential of a new material for AFM probes and demonstrate a systematic approach to studying wear at the nanoscale.


Risk of cancer-specific mortality following recurrence after radical nephroureterectomy.
To describe the natural history and identify predictors of cancer-specific survival in patients who experience disease recurrence after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). Of 2,494 UTUC patients treated with RNU without neoadjuvant chemotherapy, 597 patients experienced disease recurrence. A total of 148 patients (25 %) received adjuvant chemotherapy before disease recurrence. Multivariable Cox regression model addressed time to cancer-specific mortality after disease recurrence. The median time from RNU to disease recurrence was 12 months (interquartile range 5-22). A total of 491 (82 %) of 597 patients died from UTUC, and 8 patients (1.3 %) died from other causes. The median time from disease recurrence to death of UTUC was 10 months. Actuarial cancer-specific survival estimate at 12 months after disease recurrence was 35 %. On multivariable analysis that adjusted for the effects of standard clinicopathologic characteristics, higher tumor stages [hazard ratio (HR) pT3 vs. pT0-T1: 1.66, p = 0.001; HR pT4 vs. pT0-T1: 1.90, p = 0.002], absence of lymph node dissection (HR 1.28, p = 0.041), ureteral tumor location (HR 1.44, p < 0.0005) and a shorter interval from surgery to disease recurrence (p < 0.0005) were significantly associated with cancer-specific mortality. The adjusted 6-, 12- and 24-month postrecurrence cancer-specific mortality was 73, 60 and 57 %, respectively. Approximately 80 % of patients who experience disease recurrence after RNU die within 2 years after recurrence. Patients with non-organ-confined stage, absence of lymph node dissection, ureteral tumor location and/or shorter time to disease recurrence died of their tumor more quickly than their counterparts. These factors should be considered in patient counseling and risk stratification for salvage treatment decision making.


Risk factors for sudden cardiac death in childhood hypertrophic cardiomyopathy: A systematic review and meta-analysis.
Aims To perform a systematic literature review and meta-analysis of clinical risk factors for sudden cardiac death (SCD) in childhood hypertrophic cardiomyopathy. Methods Medline and PubMed databases were searched for original articles published in English from 1963 through to December 2015 that included patients under 18 years of age with a primary or secondary end-point of either SCD or SCD-equivalent events (aborted cardiac arrest or appropriate implantable cardioverter-defibrillator discharge) or cardiovascular death (CVD). Results Twenty-five studies (3394 patients) met the inclusion criteria. We identified four conventional major risk factors that were evaluated in at least four studies and that we found to be statistically associated with an increased risk of death in at least two studies: previous adverse cardiac event (pooled hazard ratio [HR] 5.4, 95% confidence interval [CI] 3.67-7.95, p < 0.001); non-sustained ventricular tachycardia (pooled HR 2.13, 95% CI 1.21-3.74, p = 0.009); unexplained syncope (pooled HR 1.89, 95% CI 0.69-5.16, p = 0.22); and extreme left ventricular hypertrophy (pooled HR 1.80, 95% CI 0.75-4.32, p = 0.19). Left atrial diameter did not meet the major risk factor criteria; however, this is likely to be an additional significant risk factor. 'Minor' risk factors included a family history of SCD, gender, age, symptoms, electrocardiogram changes, abnormal blood pressure response to exercise and left ventricular outflow tract obstruction. Conclusions A lack of well-designed, large, population-based studies in childhood hypertrophic cardiomyopathy means that the evidence base for individual risk factors is not robust. We have identified four clinical parameters that are likely to be associated with increased risk of SCD, SCD-equivalent events or CVD. Multi-centre prospective studies are needed in order to further determine the relevance of these factors in predicting SCD in childhood hypertrophic cardiomyopathy and to identify novel risk markers. Condensed abstract A systematic review and meta-analysis of clinical risk factors predicting sudden cardiac death in childhood hypertrophic cardiomyopathy was performed, identifying four 'major' factors: previous adverse cardiac event; non-sustained ventricular tachycardia; syncope; and extreme left ventricular hypertrophy. Well-designed multi-centre studies are required in the future in order to confirm these findings.


The diagnosis and management of subclinical hypothyroidism is assay-dependent- Implications for clinical practice.
We assessed the commutativity of Roche and Abbott thyroid assays in the diagnosis and management of subclinical hypothyroidism (SCH). The Roche and Abbott thyroid assays are used by approximately 75% of clinical laboratories in the UK. Consecutive samples received from primary care on patients with SCH who had a raised thyroid-stimulating hormone (TSH) <10 mIU/L and a normal free thyroxine (fT4) from two laboratories using either Roche or Abbott thyroid assays were identified over 10 working days. Following identification, samples were analysed at the other site within 24 hours. Diagnostic and management discordance were studied using the relevant manufacturer-provided reference ranges. We identified 93 patients with SCH (53 using the Roche assay). Roche TSH and fT4 results were respectively 40% ± 15% and 16% ± 7% higher (P < .001) compared to Abbott results. Of the 93 patients, 41 (44%) were concordant for SCH on both methods. Of the 53 patients with SCH on the Roche assays, 40 (75.5%) had normal thyroid function and 13 (24.5%) had SCH when analysed using the Abbott assays. Of the 40 patients with SCH on the Abbott assays, 28 (70%) had SCH and 12 (30%) had results indicative for levothyroxine replacement when analysed on the Roche assays. Of these 12 patients, four had TSH > 10 mIU/L, five had low fT4 and three had both. The diagnosis and management of SCH is strikingly different when using TSH and fT4 assays provided by Abbott Laboratories and Roche Diagnostics. Clinicians and laboratorians should be aware that between-assay differences and variations in reference ranges will directly impact the diagnosis and management of subclinical hypothyroidism.


Modulated speckle simulations based on the random-walk model.
The random-walk model is employed to simulate modulated speckle patterns. We demonstrate that the geometrical image approximation fails to describe the modulated speckle pattern. A new approach to analyzing this phenomenon is proposed. The validity of the approximations employed is verified by comparison of the simulation with the experimental results. Speckle metrological applications and phase measurement techniques could be improved by taking advantage of this model.


Zika Virus: Emergence, Phylogenetics, Challenges, and Opportunities.
Zika virus (ZIKV) is an emerging arthropod-borne pathogen that has recently gained notoriety due to its rapid and ongoing geographic expansion and its novel association with neurological complications. Reports of ZIKV-associated Guillain-Barré syndrome as well as fetal microcephaly place emphasis on the need to develop preventative measures and therapeutics to combat ZIKV infection. Thus, it is imperative that models to study ZIKV replication and pathogenesis and the immune response are developed in conjunction with integrated vector control strategies to mount an efficient response to the pandemic. This paper summarizes the current state of knowledge on ZIKV, including the clinical features, phylogenetic analyses, pathogenesis, and the immune response to infection. Potential challenges in developing diagnostic tools, treatment, and prevention strategies are also discussed.


The morphology of decorated amyloid fibers is controlled by the conformation and position of the displayed protein.
Self-assembled structures capable of mediating electron transfer are an attractive scientific and technological goal. Therefore, systematic variants of SH3-Cytochrome b(562) fusion proteins were designed to make amyloid fibers displaying heme-b(562) electron transfer complexes. TEM and AFM data show that fiber morphology responds systematically to placement of b(562) within the fusion proteins. UV-vis spectroscopy shows that, for the fusion proteins under test, only half the fiber-borne b(562) binds heme with high affinity. Cofactor binding also improves the AFM imaging properties and changes the fiber morphology through changes in cytochrome conformation. Systematic observations and measurements of fiber geometry suggest that longitudinal registry of subfilaments within the fiber, mediated by the interaction and conformation of the displayed proteins and their interaction with surfaces, gives rise to the observed morphologies, including defects and kinks. Of most interest is the role of small molecule modulation of fiber structure and mechanical stability. A minimum complexity model is proposed to capture and explain the fiber morphology in the light of these results. Understanding the complex interplay between these factors will enable a fiber design that supports longitudinal electron transfer.


Oxidative damage and myofiber degeneration in the gastrocnemius of patients with peripheral arterial disease.
Peripheral arterial disease (PAD), a manifestation of systemic atherosclerosis that produces blockages in arteries supplying the legs, affects an estimated 27 million people in Europe and North America. Increased production of reactive oxygen species by dysfunctional mitochondria in leg muscles of PAD patients is viewed as a key mechanism of initiation and progression of the disease. Previous studies demonstrated increased oxidative damage in homogenates of biopsy specimens from PAD gastrocnemius compared to controls, but did not address myofiber-specific damage. In this study, we investigated oxidative damage to myofibers as a possible cause of the myopathy of PAD. To achieve this, we developed and validated fluorescence microscopy procedures for quantitative analysis of carbonyl groups and 4-hydroxy-2-nonenal (HNE) adducts in myofibers of biopsy specimens from human gastrocnemius. PAD and control specimens were evaluated for differences in 1) myofiber content of these two forms of oxidative damage and 2) myofiber cross-sectional area. Furthermore, oxidative damage to PAD myofibers was tested for associations with clinical stage of disease, degree of ischemia in the affected leg, and myofiber cross-sectional area. Carbonyl groups and HNE adducts were increased 30% (p < 0.0001) and 40% (p < 0.0001), respectively, in the myofibers of PAD (N = 34) compared to control (N = 21) patients. Mean cross-sectional area of PAD myofibers was reduced 29.3% compared to controls (p < 0.0003). Both forms of oxidative damage increased with clinical stage of disease, blood flow limitation in the ischemic leg, and reduced myofiber cross-sectional area. The data establish oxidative damage to myofibers as a possible cause of PAD myopathy.


Efficacy and cost of a hepatocellular carcinoma screening program at an Australian teaching hospital.
Western countries are seeing an increasing prevalence of chronic viral hepatitis and a subsequent rise in the incidence of hepatocellular carcinoma (HCC). Screening patients at high risk of HCC has become standard practice. The aim of this study was to assess the efficacy and cost of screening high-risk individuals for HCC in an Australian tertiary hospital. A retrospective review was performed of all patients who underwent HCC screening at the Austin Hospital in Melbourne between 1 October 1998 and 31 August 2004. HCC screening was carried out in all cirrhotic patients and male non-cirrhotic patients with chronic hepatitis B virus. Screening consisted of 6-monthly alpha fetoprotein (AFP) measurements and ultrasounds (US). Outcomes of those who had HCC detected were followed up until 15 February 2007. Patients who had HCC satisfying the Milan criteria for liver transplantation were considered to have potentially curable tumor. Costs for the diagnostic tests were obtained from the 2004 Australian Medicare Benefits Schedule. A total of 268 patient records were reviewed as part of the study. Chronic viral hepatitis accounted for 63% of the patients (n = 167). US screening was carried out at a median of 6.5 months and AFP measurements at a median of 4.0 months. HCC was detected in 22 patients (8.2%) at an incidence of 2.7% per year. These patients had a mean follow up of approximately 5.0 years after tumor detection. At the time of diagnosis, 17 patients had potentially curable tumor and 10 were alive at the conclusion of follow up. Of these 10 patients, six were successfully transplanted, three were successfully treated with radiological therapies and one was awaiting transplantation. The total cost of the screening program over the study period, including secondary investigations, was $A300,568. The cost per HCC detected was $13,662 and cost per potentially curable HCC was $17,680. An effective HCC screening program can be provided through a multi-disciplinary outpatient facility in an Australian teaching hospital. Further stratification of the high risk patient cohort may improve the cost effectiveness of this screening program.


Allelic dimorphism in the merozoite surface protein-3alpha in Korean isolates of Plasmodium vivax.
To study the genetic diversity of re-emerging Plasmodium vivax in the Republic of Korea, nucleotide sequence variations at the merozoite surface protein-3alpha (PvMSP-3alpha) locus were analyzed using 24 re-emerging isolates and 4 isolates from imported cases. Compared with the well known Belem strain (Brazil), a large number of amino acid substitutions, deletions, and insertions were found at the locus of the isolates examined. The Korean isolates were divided into two allelic types; type I (15 isolates), similar to the Belem strain, and type II (9), similar to the Chess strain (New Guinea). Isolates from imported cases were classified into three types; type III (1 from Malaysia), similar to type B from western Thailand, type IV (1 each from Indonesia and India), and type V (1 from Pakistan), both being new types. Our results have shown that the MSP-3alpha locus of re-emerging Korean P. vivax is dimorphic with two allelic types coexisting in the endemic area.


Retinoblastoma in Great Britain 1963-2002.
This paper describes the epidemiology and family history status of 1601 children with retinoblastoma in Great Britain diagnosed 1963-2002 and summarises the practical consequences for diagnosis and counselling of developments in molecular genetics. Incidence rates were analysed according to year of diagnosis and tumour laterality. Cases were classified as heritable or non-heritable on the basis of laterality and family history of the disease. There were 998 unilateral cases, 581 bilateral and 22 of unknown laterality. Bilateral cases tended to be diagnosed at a younger age than unilateral. All bilateral cases are regarded as heritable, and 35% had a family history of the disease. 7% of the unilateral cases had a family history and are therefore heritable. Thus, at least (41%) of our cases are heritable. This is an underestimate, since these data on family history are incomplete. For unilateral cases aged below 1 year, the reported incidence rate increased significantly (p<0.0001) by about 2.5% per year; for the age group 1-4 years, the average increase was about 0.5% per year (not significant).


Single-molecule-magnet behavior in mononuclear homoleptic tetrahedral uranium(III) complexes.
The magnetic properties of the two uranium coordination compounds, [K(18c6)][U(OSi(O(t)Bu)3)4] and [K(18c6)][U(N(SiMe3)2)4], both presenting the U(III) ion in similar pseudotetrahedral coordination environments but with different O- or N-donor ligands, have been measured. The static magnetic susceptibility measurements and density functional theory studies suggest the presence of different ligand fields in the two compounds. Alternating-current susceptibility studies conducted at frequencies ranging from 95 to 9995 Hz and at temperatures in the 1.7-10 K range revealed for both compounds slow magnetic relaxation already at zero static magnetic field with similar energy barriers U ∼24 K.


Identifying, recruiting, and retaining seriously-ill patients and their caregivers in longitudinal research.
In order to improve the state of science in palliative care, we must increase our ability to document the real-time experience of patients and families as they traverse the end of life. Yet, frequently, prospective measurement is impeded by difficulty with patient identification, recruitment, enrollment, and retention. The palliative care literature is replete with descriptions of studies unable to meet enrollment goals, and that as a result, do not have adequate power to test hypotheses or draw conclusions. To review the literature describing difficulties associated with ascertainment, enrollment, and attrition. To outline the successful recruitment methods of a new longitudinal study of patients and their caregivers. A two-year longitudinal study of 240 patients with Stage IV cancer (breast, prostate, colorectal, lung), advanced congestive heart failure (CHF) LVEFB < 40 or advanced chronic obstructive pulmonary disease (COPD) pCO(2) > 46, and their caregivers, interviewed monthly for up to two years. Patients were identified using clinical and administrative databases from one geographic region. Representative and successful ascertainment was associated with use of clinical criteria and medical record review versus physician or other provider prognostication, use of recruitment letters from personal physician, recruitment letter content, brochure content, small monetary incentives, refined phone scripts, use of matched ethnicity interviewers, in-home and phone interview strategies, measure selection, patient and caregiver rapport, and on-going staff support (including grief and bereavement). Recruitment to prospective longitudinal studies at the end of life is difficult, but possible. The lessons learned from this study are applicable to future investigators conducting prospective research.


Determination of left ventricular mass in systemic hypertension: comparison of standard and signal averaged electrocardiography.
To investigate the quantitative relationship, if any, between signal averaged electrocardiographic variables and echocardiographically determined left ventricular mass in hypertensive subjects. Cohort analytic prospective study. University hospital. 50 hypertensive subjects selected consecutively from inpatients. Patients older than 75 years, with underlying cardiac disease, with inconclusive echocardiograms with bundle branch block, or in atrial fibrillation were excluded. Antihypertensive therapy involving 41 patients was continued. Left ventricular mass calculated in accordance with the standards of the Penn convention. Thirteen criteria derived from combinations of signal averaged electrocardiographic X, Y, and Z Frank orthogonal leads, including voltage criteria, duration, and time-voltage integrals of the QRS complex. Four widely used standard electrocardiographic criteria for detection of left ventricular hypertrophy. There was no difference in the values for any of the electrocardiographic variables between patients with (n = 29) and without left ventricular hypertrophy (n = 21). The time-voltage integral of QRS in the horizontal plane was the best signal averaged variable related to left ventricular mass (r = 0.33, P = 0.019); however, the correlation with Rodstein voltage was stronger (r = 0.46, P = 0.0009). A positive correlation was also found between left ventricular indexed mass and Rodstein voltage (r = 0.43, P = 0.0019). Stepwise regression analysis revealed Rodstein voltage as the only predictor of indexed mass (P = 0.0019), and Rodstein voltage (P = 0.0022) and body weight (P = 0.011) as the only independent correlates of left ventricular mass. The relation between electrocardiographic variables and left ventricular mass or indexed mass is of limited value; signal averaged orthogonal leads do not improve this assessment compared with standard electrocardiographic leads.


Low incidence of neoplasia in heart and heart-lung transplant recipients receiving triple-drug immunosuppression.
The risk of neoplasias developing after solid organ transplantation is markedly increased by immunosuppressive therapy. Lymphoma has been reported to develop in 13% of heart and in 33% of heart-lung transplant recipients treated with cyclosporine, and the incidence of skin carcinoma ranges between 6% and 16%. The incidence of posttransplant neoplasias with the use of lower loading and maintenance doses of cyclosporine as used in triple-drug immunosuppression is unknown. From December 1983 through August 1988, 134 heart and seven heart-lung transplants were performed at the University of Minnesota. All patients received a combination of cyclosporine, azathioprine, and prednisone. Survival was 94% at 1 and 90% at 3 years in heart recipients. Probability of acute rejection was 9% at 3 months and 12% at 1 and 3 years. B-cell lymphoma developed after heart transplant in only two patients for an incidence of 1.5%. Episodes of acute rejection and mean cyclosporine blood level did not predict the occurrence of posttransplant lymphoma. The incidence of skin carcinoma was 6.4%. No neoplasia occurred in heart-lung transplant recipients. All neoplasias were observed in patients older than 50 years. Our data indicate that the risk for developing lymphoproliferative disorders, but not for basal cell carcinoma, is reduced in heart and heart-lung transplant recipients receiving triple-drug immunosuppression. Older recipients may be at increased risk, suggesting that lower doses of immunosuppressive therapy should be considered in this group.


Effect of disorder on slow light velocity in optical slow-wave structures.
Slow-wave optical structures such as coupled photonic crystal cavities, coupled microresonators, and similar coupled-resonator optical waveguides are being proposed for slowing light because of the nature of their dispersion relationship. Since the group velocity becomes small, slow light and enhanced light-matter interaction may be observed at the edges of the waveguiding band. We derive a model of the effects of disorder on slow light in such structures, obtaining a relationship between the root-mean-square variation in the coupling coefficients and how slow the light is at the band edge.


Cost and health outcome of primary percutaneous coronary intervention versus thrombolysis in acute ST-segment elevation myocardial infarction-Results of the Swedish Early Decision reperfusion Study (SWEDES) trial.
In ST-elevation myocardial infarction, primary percutaneous coronary intervention (PCI) has a superior clinical outcome, but it may increase costs in comparison to thrombolysis. The aim of the study was to compare costs, clinical outcome, and quality-adjusted survival between primary PCI and thrombolysis. Patients with ST-elevation myocardial infarction were randomized to primary PCI with adjunctive enoxaparin and abciximab (n = 101), or to enoxaparin followed by reteplase (n = 104). Data on the use of health care resources, work loss, and health-related quality of life were collected during a 1-year period. Cost-effectiveness was determined by comparing costs and quality-adjusted survival. The joint distribution of incremental costs and quality-adjusted survival was analyzed using a nonparametric bootstrap approach. Clinical outcome did not differ significantly between the groups. Compared with the group treated with thrombolysis, the cost of interventions was higher in the PCI-treated group ($4,602 vs $3,807; P = .047), as well as the cost of drugs ($1,309 vs $1,202; P = .001), whereas the cost of hospitalization was lower ($7,344 vs $9,278; P = .025). The cost of investigations, outpatient care, and loss of production did not differ significantly between the 2 treatment arms. Total cost and quality-adjusted survival were $25,315 and 0.759 vs $27,819 and 0.728 (both not significant) for the primary PCI and thrombolysis groups, respectively. Based on the 1-year follow-up, bootstrap analysis revealed that in 80%, 88%, and 89% of the replications, the cost per health outcome gained for PCI will be <$0, $50,000, and $100,000 respectively. In a 1-year perspective, there was a tendency toward lower costs and better health outcome after primary PCI, resulting in costs for PCI in comparison to thrombolysis that will be below the conventional threshold for cost-effectiveness in 88% of bootstrap replications.


Level of evidence in anterior cruciate ligament reconstruction research: a systematic review.
There have been numerous studies on anterior cruciate ligament (ACL) reconstruction. Considering the vast number of studies, a quick assessment reveals rather few with a high level of evidence. The primary aim was to categorize the study type and level of evidence of studies on primary ACL reconstruction by applying the level of evidence rating system proposed by the Oxford Centre for Evidence-Based Medicine. The secondary aims were to correlate the level of evidence with the impact factor of the journal, to evaluate the level of evidence over time, and to evaluate the geographic distribution of the included studies. Systematic review. An electronic search was performed using the databases PubMed, EMBASE, and Cochrane Library. Studies published from January 1995 to August 2011 were included. Therapeutic studies written in English that report on isolated primary ACL reconstruction with clinical outcome measurements related to the reconstruction were included. Categorization and implementation of the level of evidence were performed. Correlation between the level of evidence and the impact factor of the journal was analyzed together with linear regression models to reveal any significant trends over time. A total of 7154 studies were analyzed, of which 1510 were included. Analysis of the study types revealed that case series (n = 494; 32.7%) was the most frequent study type. Randomized controlled trials represented 9.2% (n = 139) of the sample, whereas meta-analyses were rare. Single-bundle studies were the most common studies (n = 1333; 88.3%), followed by double-bundle (n = 98; 6.5%) and single- versus double-bundle (n = 79; 5.2%). The journals Arthroscopy, Knee Surgery Sports Traumatology Arthroscopy (KSSTA), and American Journal of Sports Medicine (AJSM) represented 43.5% (n = 657) of the included studies. Arthroscopy had the highest number of publications in general and in level 4 and 5 studies, whereas AJSM had the lowest number of the 3. AJSM had the highest number of level 1 and 2 studies in general. The mean level of evidence calculated without level 5 studies was 3.15 for Arthroscopy, 3.20 for KSSTA, and 2.9 for AJSM. There was a significant correlation (P < .05) between the impact factor of the journal and mean level of evidence of the journal and the proportion high level of evidence studies (levels 1 and 2). There was a significant (P < .05) trend toward higher mean level of evidence over time. Most therapeutic studies on primary ACL reconstruction were of low level of evidence, and there was a positive correlation between the journal's impact factor and the mean level of evidence and the proportion of high level of evidence studies. There was significant trend toward higher mean level of evidence over time.


Herpes simplex virus type 1 infection imposes a G(1)/S block in asynchronously growing cells and prevents G(1) entry in quiescent cells.
Herpes simplex virus type 1 (HSV-1) infection disrupted cell cycle regulation in at least two ways. First, infection of quiescent human embryonic lung cells simultaneously with readdition of serum caused inhibition of cyclin D/cyclin-dependent kinase (CDK) 4,6-specific and cyclin E/CDK2-specific phosphorylation of the retinoblastoma protein pRb. The inhibition of cyclin D/CDK4,6 kinase activity corresponded to a loss of cyclin D1 protein and a failure of CDK4 and CDK6 to translocate to the nucleus. Failure to detect cyclin E/CDK2 kinase activity was accompanied by a loss of cyclin E protein and a failure of CDK2 to translocate to the nucleus. Levels of pocket protein p130 persisted, whereas p107 did not accumulate. As a result of these effects on cyclin kinase, G(0)-infected cells failed to reenter the cell cycle. The second type of HSV-induced cell cycle dysregulation was observed in asynchronously dividing cell cultures. A rapid inhibition of preexisting cyclin E/CDK2 and cyclin A/CDK2 activities was observed in human embryonic lung cells, as well as two other human cell lines: C33 and U2OS. HSV-1 immediate-early gene expression was necessary for the inhibition of CDK2 kinase activity. Cyclin and CDK subunit protein levels, intracellular localization, and complex stability were unaffected by infection. In addition, levels of cyclin-dependent kinase inhibitors, p27 and p21, were not affected by HSV-1. Previous experiments demonstrated that in asynchronous infected cells, hypophosphorylated pRb and pocket protein-E2F complexes accumulated, and cellular DNA synthesis was rapidly inhibited. Coupled with the present results, this indicates that HSV-1 has evolved mechanisms for preventing cells in G(1) from proceeding through the restriction point and for cells in S from completing a round of DNA replication.


A COMPARISON OF ACADEMIC PERFORMANCE MEASURES OF HSTA PARTICIPANTS WITH NON-HSTA PARTICIPANTS: IS IT POSSIBLE TO NARROW THE AFRICAN AMERICAN-WHITE ACHIEVEMENT GAP?
Historically, African American and other underserved students encounter academic challenges in pursuit of a college degree-one of which is their performance on standardized tests. This paper analyzes College Grade Point Averages (CGPAs), ACT Composite (ACTC), and SAT Total (SATT) scores of students who participated in the Health Sciences and Technology Academy (HSTA), an out-of-school-time (OST) program, and Non-HSTA (NHSTA) students attending West Virginia University. Traditionally, OST programs provide academic enrichment to underserved youth to increase their chances for post-secondary entry and success. Two-Way Factorial ANOVA determined if HSTA participants performed better on academic measures than their NHSTA counterparts. The ANOVAs showed statistically significant differences based on Status (HSTA/NHSTA) and Race (African American/White) on the SATT and ACTC. Although not statistically significant, there are favorable outcomes on the CGPA for African American HSTA students comparable to their Non-HSTA counterparts.


Optimizing the parameters for measuring laser speckle and speckle contrast.
Evaluating the contrast in speckle patterns produced by laser projection displays can facilitate the development of methods to suppress such imperfection. Computer simulations were first conducted to characterize the contrast (C(gs)) of fully developed speckle patterns with spatial factor k and power factor r. Results showed that 0.1≤r≤2.0 and k≥4.0 were required to obtain a C(gs) with less than 5% error. Experimental results, however, revealed that a power factor within the range 0.5≤r≤2.0 was needed, meaning that the speckle dimension was at least four times the pixel pitch and the largest speckle intensity was of the order of magnitude of the saturation level of the camera. The method proposed here is that the spatial factor be determined by adjusting the distance between the object and the camera, and the power factor be determined by monitoring the real-time histogram representing the speckle pattern.


Threat assessment and locomotion: clinical applications of an integrated model of anxiety and postural control.
Interactions between anxiety and vestibular symptoms have been described since the late 1800s. Typically, they have been conceptualized as bidirectional effects of one condition on the other (i.e., anxiety disorders as a cause of vestibular symptoms and vestibular disorders as a cause of anxiety symptoms). Over the past 30 years, however, a steady progression of neurophysiological investigations of gait and stance under conditions of postural threat, neuroanatomical studies of connections between threat assessment and vestibular pathways in the brain, and clinical research on anxiety-related vestibular conditions has offered the building blocks of a more integrated model. In this newer concept, threat assessment is an integral component of spatial perception, postural control, and locomotion in health and disease. It is not imposed on the vestibular system from the outside or simply reactive to vestibular dysfunction, but an inherently necessary part of every aspect of mobility. In this article, the authors review evidence that supports this model and then use it to examine common neurotologic conditions in which anxiety-related processes play important roles-fear of falling, primary and secondary anxiety disorders in patients with vestibular symptoms, and chronic subjective dizziness.


Association of 3 Different Antihypertensive Medications With Hip and Pelvic Fracture Risk in Older Adults: Secondary Analysis of a Randomized Clinical Trial.
On the basis of observational studies, the use of thiazide diuretics for the treatment of hypertension is associated with reduced fracture risk compared with nonuse. Data from randomized clinical trials are lacking. To examine whether the use of thiazide diuretics for the treatment of hypertension is associated with reduced fracture risk compared with nonuse. Using Veterans Affairs and Medicare claims data, this study examined hip and pelvic fracture hospitalizations in Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial participants randomized to first-step therapy with a thiazide-type diuretic (chlorthalidone), a calcium channel blocker (amlodipine besylate), or an angiotensin-converting enzyme inhibitor (lisinopril). Recruitment was from February 1994 to January 1998; in-trial follow-up ended in March 2002. The mean follow-up was 4.9 years. Posttrial follow-up was conducted through the end of 2006, using passive surveillance via national databases. For this secondary analysis, which used an intention-to-treat approach, data were analyzed from February 1, 1994, through December 31, 2006. Hip and pelvic fracture hospitalizations. A total of 22 180 participants (mean [SD] age, 70.4 [6.7] years; 43.0% female; and 49.9% white non-Hispanic, 31.2% African American, and 19.1% other ethnic groups) were followed for up to 8 years (mean [SD], 4.9 [1.5] years) during masked therapy. After trial completion, 16 622 participants for whom claims data were available were followed for up to 5 additional years (mean [SD] total follow-up, 7.8 [3.1] years). During the trial, 338 fractures occurred. Participants randomized to receive chlorthalidone vs amlodipine or lisinopril had a lower risk of fracture on adjusted analyses (hazards ratio [HR], 0.79; 95% CI, 0.63-0.98; P = .04). Risk of fracture was significantly lower in participants randomized to receive chlorthalidone vs lisinopril (HR, 0.75; 95% CI, 0.58-0.98; P = .04) but not significantly different compared with those randomized to receive amlodipine (HR, 0.82; 95% CI, 0.63-1.08; P = .17). During the entire trial and posttrial period of follow-up, the cumulative incidence of fractures was nonsignificantly lower in participants randomized to receive chlorthalidone vs lisinopril or amlodipine (HR, 0.87; 95% CI, 0.74-1.03; P = .10) and vs each medication separately. In sensitivity analyses, when 1 year after randomization was used as the baseline (to allow for the effects of medications on bone to take effect), similar results were obtained for in-trial and in-trial plus posttrial follow-up. These findings from a large randomized clinical trial provide evidence of a beneficial effect of thiazide-type diuretic therapy in reducing hip and pelvic fracture risk compared with treatment with other antihypertensive medications. clinicaltrials.gov Identifier: NCT00000542.


Reactivity of a functional carbonyl moiety in bovine aortic lysyl oxidase. Evidence against pyridoxal 5'-phosphate.
Previous studies have pointed towards a cofactor role for pyridoxal 5'-phosphate (PLP) in lysyl oxidase, the enzyme that generates the peptidyl aldehyde precursor to the lysine-derived cross-linkages in elastin and collagen. The nature of a carbonyl moiety in purified bovine aortic lysyl oxidase was explored in the present study. A PLP dinitrophenylhydrazone could not be isolated from lysyl oxidase, although corresponding preparations of aspartate aminotransferase, a PLP-dependent enzyme, yielded this derivative, as revealed by h.p.l.c. Analysis of lysyl oxidase for PLP after reduction of the enzyme by NaBH4, a procedure that converts PLP-protein aldimines into stable 5'-phosphopyridoxyl functions, also proved negative in tests using monoclonal antibody specific for this epitope. Lysyl oxidase was competitively inhibited by phenylhydrazine, and inhibition became irreversible with time at 37 degrees C, displaying a first-order inactivation rate constant of 0.4 min-1 and KI of 1 microM. [14C]Phenylhydrazine was covalently incorporated into the enzyme in a manner that was prevented by prior modification of the enzyme with beta-aminopropionitrile, a specific active-site inhibitor, and which correlated with functional active-site content. The chemical stability of the enzyme-bound phenylhydrazine exceeded that expected of linkages between PLP and proteins. The absorption spectrum of the phenylhydrazine derivative of lysyl oxidase was clearly distinct from that of the phenylhydrazone of PLP. It is concluded that lysyl oxidase contains a carbonyl cofactor that is not identical with PLP and that is bound to the enzyme by a stable chemical bond.


Humanoid robots versus humans: How is emotional valence of facial expressions recognized by individuals with schizophrenia? An exploratory study.
The use of humanoid robots to play a therapeutic role in helping individuals with social disorders such as autism is a newly emerging field, but remains unexplored in schizophrenia. As the ability for robots to convey emotion appear of fundamental importance for human-robot interactions, we aimed to evaluate how schizophrenia patients recognize positive and negative facial emotions displayed by a humanoid robot. We included 21 schizophrenia outpatients and 17 healthy participants. In a reaction time task, they were shown photographs of human faces and of a humanoid robot (iCub) expressing either positive or negative emotions, as well as a non-social stimulus. Patients' symptomatology, mind perception, reaction time and number of correct answers were evaluated. Results indicated that patients and controls recognized better and faster the emotional valence of facial expressions expressed by humans than by the robot. Participants were faster when responding to positive compared to negative human faces and inversely were faster for negative compared to positive robot faces. Importantly, participants performed worse when they perceived iCub as being capable of experiencing things (experience subscale of the mind perception questionnaire). In schizophrenia patients, negative correlations emerged between negative symptoms and both robot's and human's negative face accuracy. Individuals do not respond similarly to human facial emotion and to non-anthropomorphic emotional signals. Humanoid robots have the potential to convey emotions to patients with schizophrenia, but their appearance seems of major importance for human-robot interactions.


Platelet activating factor and one-kidney, one clip hypertension.
The reduction in blood pressure to normotensive levels within 3 hours of unclipping the one-kidney, one clip Goldblatt hypertensive rat has been attributed to the release of potent blood pressure-lowering lipids, one of which is thought to be identical to platelet activating factor. The specific platelet activating factor receptor antagonist WEB 2086 was infused intravenously into hypertensive one-kidney, one clip rats, and the mean arterial blood pressure changes after unclipping were examined. Before infusion, blocking doses of WEB 2086 were confirmed to effectively abolish the fall in blood pressure induced by exogenous platelet activating factor. Serotonin release in response to exogenous platelet activating factor was also inhibited in platelets preincubated with plasma from rats infused with the antagonist. Hypertensive rats were given a bolus blocking dose of WEB 2086 (5 mg/kg i.v.) and the same dose by infusion (5 mg/kg/hr i.v.) before they were unclipped. A control group was given a bolus volume of saline and infused with saline before unclipping. In WEB 2086-treated rats, blood pressure fell from a baseline mean of 181 +/- 13.0 to 125 +/- 23 mm Hg after 4 hours, a fall of 28%. Saline-treated rats fell from a mean of 194 +/- 23 to 127 +/- 25 mm Hg (33%). There was no significant difference in the blood pressure fall between the two groups. Therefore, platelet activating factor is unlikely to be responsible for the restoration of normal blood pressure after unclipping the Goldblatt hypertensive rat. We attribute the fall in blood pressure to other presently unidentified renomedullary lipids.


Amino Acids in the Development of Prodrugs.
Although drugs currently used for the various types of diseases (e.g., antiparasitic, antiviral, antibacterial, etc.) are effective, they present several undesirable pharmacological and pharmaceutical properties. Most of the drugs have low bioavailability, lack of sensitivity, and do not target only the damaged cells, thus also affecting normal cells. Moreover, there is the risk of developing resistance against drugs upon chronic treatment. Consequently, their potential clinical applications might be limited and therefore, it is mandatory to find strategies that improve those properties of therapeutic agents. The development of prodrugs using amino acids as moieties has resulted in improvements in several properties, namely increased bioavailability, decreased toxicity of the parent drug, accurate delivery to target tissues or organs, and prevention of fast metabolism. Herein, we provide an overview of models currently in use of prodrug design with amino acids. Furthermore, we review the challenges related to the permeability of poorly absorbed drugs and transport and deliver on target organs.