Biochemical profiling of histone binding selectivity of the yeast bromodomain family.
It has been shown that molecular interactions between site-specific chemical modifications such as acetylation and methylation on DNA-packing histones and conserved structural modules present in transcriptional proteins are closely associated with chromatin structural changes and gene activation. Unlike methyl-lysine that can interact with different protein modules including chromodomains, Tudor and MBT domains, as well as PHD fingers, acetyl-lysine (Kac) is known thus far to be recognized only by bromodomains. While histone lysine acetylation plays a crucial role in regulation of chromatin-mediated gene transcription, a high degree of sequence variation of the acetyl-lysine binding site in the bromodomains has limited our understanding of histone binding selectivity of the bromodomain family. Here, we report a systematic family-wide analysis of 14 yeast bromodomains binding to 32 lysine-acetylated peptides derived from known major acetylation sites in four core histones that are conserved in eukaryotes. The histone binding selectivity of purified recombinant yeast bromodomains was assessed by using the native core histones in an overlay assay, as well as N-terminally biotinylated lysine-acetylated histone peptides spotted on streptavidin-coated nitrocellulose membrane in a dot blot assay. NMR binding analysis further validated the interactions between histones and selected bromodomain. Structural models of all yeast bromodomains were built using comparative modeling to provide insights into the molecular basis of their histone binding selectivity. Our study reveals that while not all members of the bromodomain family are privileged to interact with acetylated-lysine, identifiable sequence features from those that bind histone emerge. These include an asparagine residue at the C-terminus of the third helix in the 4-helix bundle, negatively charged residues around the ZA loop, and preponderance of aromatic amino acid residues in the binding pocket. Further, while bromodomains exhibit selectivity for different sites in histones, individual interactions are of modest affinity. Finally, electrostatic interactions appear to be a primary determining factor that guides productive association between a bromodomain and a lysine-acetylated histone.


Structural coloration and photonic pseudogap in natural random close-packing photonic structures.
Scales on the elytra of longhorn beetle Anoplophora graafi display diverse non-iridescent colors ranging from blue, green, yellow, and red to purple. By structural characterizations, optical measurements, and theoretical calculations, we found that the scale colors stem from an amorphous photonic structure possessing only short-range order: random close-packing of chitin nanoparticles. Our results showed that direction-independent photonic pseudogaps found in the photon density of states of the random close-packing photonic structure are the ultimate physical origin for non-iridescent coloration of scales. The color steering strategy of scales is ingenious, simply by varying the size of chitin nanoparticles. Revealed natural random close-packing photonic structures and the color steering strategy of scales could render valuable inspiration for the artificial fabrication and design of photonic structures and devices as well.


The impact of telemedicine intensivist support and a pediatric hospitalist program on a community hospital.
Because of centralization of care, pediatric patients often require transfer for subspecialty care. We evaluated the impact of telemedicine critical care consultation and a pediatric hospitalist program on enabling patients to remain at a community hospital. This is a retrospective chart review of pediatric patients at a community hospital receiving critical care consultation from a tertiary children's hospital from January 2006 to October 2009. Patient cohorts differed by modality of intensivist consultation (telephone versus telemedicine) and modality of inpatient ward care at the community hospital (primary care physician versus hospitalist). Patients were compared for differences in transfer rate and rate of diversion from the pediatric intensive care unit to the tertiary ward. One hundred fifty-three charts were analyzed: 41 from prior to hospitalist and telemedicine implementation (Cohort 1), 56 from post-implementation of telemedicine but pre-hospitalist program (Cohort 2), and 56 after implementation of both the telemedicine and hospitalist programs (Cohort 3). Baseline data did not differ among cohorts. Transfer rates after intensivist consultation were lower after implementation of telemedicine consultation (100%, 85.7%, and 87.5% in Cohorts 1-3, respectively; p=0.04). The proportion of transferred patients who were diverted to the tertiary ward decreased over time (19.5%, 14.5%, and 6.1% in Cohorts 1-3, respectively; p=0.003). Telemedicine consultation between pediatric intensivists and community hospital physicians combined with a pediatric hospitalist program at the community hospital has the potential to improve triage of pediatric patients and reduce the need to transfer patients.


A relationship between temperature and aggression in NFL football penalties.
Increased ambient temperature has been implicated in increased physical aggression, which has important practical consequences. The present study investigates this established relationship between aggressive behavior and ambient temperature in the highly aggressive context of professional football in the National Football League (NFL). Using a publicly available dataset, authors conducted multiple hierarchical regression analyses on game-level data (2326 games). The analysis revealed that temperature positively predicted aggressive penalties in football, and that this relationship was significant for teams playing at home but not for visiting teams. These results indicate that even in the aggressive context of football, warmer weather contributes to increased violence. Further, the presence of the heat-aggression relationship for the home team suggests that the characteristics of interacting groups may influence whether heat would have an adverse effect on the outcome of those interactions.


In vitro analysis of muscle activity illustrates mediolateral decoupling of hind and mid foot bone motion.
Activity of the extrinsic ankle-foot muscles is typically described for the whole foot. This study determines if this muscle activity is also confirmed for individual foot segments defined in multi-segment foot models used for clinical gait analysis. Analysis of the individual bone motion can identify functional complexes within the foot and evaluates the influence of an altered foot position on muscle activity. A custom designed and built gait simulator incorporating pneumatic actuators is used to control the muscle force of six muscle groups in cadaveric feet. Measurements were performed in three static postures in which individual muscle force was incrementally changed. The motion of four bone embedded LED-clusters was measured using a Krypton motion capture system and resulting motion of calcaneus, talus, navicular and cuboid was calculated. Results indicate that primary muscle activity at bone level corresponds with that described for the whole foot. Secondary activity is not always coherent for bones within one segment: decoupling of the movement of medial and lateral foot bones is documented. Furthermore, secondary muscle activity can alter according to foot position. The observed medio-lateral decoupling of the foot bones dictates the need to extend some of the multi-segment foot models currently used in clinical gait analysis.


Elimination of Taenia solium Transmission in Northern Peru.
Taeniasis and cysticercosis are major causes of seizures and epilepsy. Infection by the causative parasite Taenia solium requires transmission between humans and pigs. The disease is considered to be eradicable, but data on attempts at regional elimination are lacking. We conducted a three-phase control program in Tumbes, Peru, to determine whether regional elimination would be feasible. We systematically tested and compared elimination strategies to show the feasibility of interrupting the transmission of T. solium infection in a region of highly endemic disease in Peru. In phase 1, we assessed the effectiveness and feasibility of six intervention strategies that involved screening of humans and pigs, antiparasitic treatment, prevention education, and pig replacement in 42 villages. In phase 2, we compared mass treatment with mass screening (each either with or without vaccination of pigs) in 17 villages. In phase 3, we implemented the final strategy of mass treatment of humans along with the mass treatment and vaccination of pigs in the entire rural region of Tumbes (107 villages comprising 81,170 people and 55,638 pigs). The effect of the intervention was measured after phases 2 and 3 with the use of detailed necropsy to detect pigs with live, nondegenerated cysts capable of causing new infection. The necropsy sampling was weighted in that we preferentially included more samples from seropositive pigs than from seronegative pigs. Only two of the strategies implemented in phase 1 resulted in limited control over the transmission of T. solium infection, which highlighted the need to intensify the subsequent strategies. After the strategies in phase 2 were implemented, no cyst that was capable of further transmission of T. solium infection was found among 658 sampled pigs. One year later, without further intervention, 7 of 310 sampled pigs had live, nondegenerated cysts, but no infected pig was found in 11 of 17 villages, including all the villages in which mass antiparasitic treatment plus vaccination was implemented. After the final strategy was implemented in phase 3, a total of 3 of 342 pigs had live, nondegenerated cysts, but no infected pig was found in 105 of 107 villages. We showed that the transmission of T. solium infection was interrupted on a regional scale in a highly endemic region in Peru. (Funded by the Bill and Melinda Gates Foundation and others.).


Levels of serum fibronectin as a biomarker in gastric cancer patients: Correlation with clinical diagnosis and outcome.
Fibronectin is an important component of the extracellular matrix and serves a role in the pathogenesis of multiple malignancies. The expression of fibronectin also affects the outcome for patients with cancer. The objective of the present study was to determine the clinical significance of the serum fibronectin levels in patients with gastric cancer. A total of 63 patients with a pathologically confirmed diagnosis of gastric cancer were enrolled into the present study. Serum fibronectin concentrations were determined by the solid-phase sandwich enzyme-linked immunosorbent assay method. Age and sex matched healthy controls (n=30) were included in the analysis. The median age at diagnosis was 62 years (range 28-82 years). The baseline serum fibronectin levels of the patients with gastric cancer were significantly higher compared with those in the control group (median values, 606, vs. 193 ng/ml; P<0.001). The known clinical variables, including the age of the patient, gender, site of lesion, histology, histological grade, stage of disease and serum tumor markers, including lactate dehydrogenase, carcinoembryonic antigen and cancer antigen 19.9, were not found to be correlated with serum fibronectin concentrations (P>0.05). In addition, no correlation was observed in serum fibronectin level and response to chemotherapy (P=0.12). Serum fibronectin concentration demonstrated no prognostic role on survival (P=0.43). In conclusion, the serum levels of fibronectin may have a good diagnostic marker in patients with gastric cancer. However, its predictive and prognostic values remain to be elucidated.


B cell depletion reduces the number of autoreactive T helper cells and prevents glucose-6-phosphate isomerase-induced arthritis.
The therapeutic benefit of B cell depletion in patients with rheumatoid arthritis has provided proof of concept that B cells are relevant for the pathogenesis of arthritis. It remains unknown which B cell effector functions contribute to the induction or chronification of arthritis. We studied the clinical and immunological effects of B cell depletion in glucose-6-phosphate isomerase-induced arthritis. We targeted CD22 to deplete B cells. Mice were depleted of B cells before or after immunization with glucose-6-phosphate isomerase (G6PI). The clinical and histological effects were studied. G6PI-specific antibody responses were measured by ELISA. G6PI-specific T helper (Th) cell responses were assayed by polychromatic flow cytometry. B cell depletion prior to G6PI-immunization prevented arthritis. B cell depletion after immunization ameliorated arthritis, whereas B cell depletion in arthritic mice was ineffective. Transfer of antibodies from arthritic mice into B cell depleted recipients did not reconstitute arthritis. B cell depleted mice harbored much fewer G6PI-specific Th cells than control animals. B cell depletion prevents but does not cure G6PI-induced arthritis. Arthritis prevention upon B cell depletion is associated with a drastic reduction in the number of G6PI-specific effector Th cells.


Tracing the origins of midlife despair: association of psychopathology during adolescence with a syndrome of despair-related maladies at midlife.
Midlife adults are experiencing a crisis of deaths of despair (i.e. deaths from suicide, drug overdose, and alcohol-related liver disease). We tested the hypothesis that a syndrome of despair-related maladies at midlife is preceded by psychopathology during adolescence. Participants are members of a representative cohort of 1037 individuals born in Dunedin, New Zealand in 1972-73 and followed to age 45 years, with 94% retention. Adolescent mental disorders were assessed in three diagnostic assessments at ages 11, 13, and 15 years. Indicators of despair-related maladies across four domains - suicidality, substance misuse, sleep problems, and pain - were assessed at age 45 using multi-modal measures including self-report, informant-report, and national register data. We identified and validated a syndrome of despair-related maladies at midlife involving suicidality, substance misuse, sleep problems, and pain. Adults who exhibited a more severe syndrome of despair-related maladies at midlife tended to have had early-onset emotional and behavioral disorders [β = 0.23, 95% CI (0.16-0.30), p < 0.001], even after adjusting for sex, childhood SES, and childhood IQ. A more pronounced midlife despair syndrome was observed among adults who, as adolescents, were diagnosed with a greater number of mental disorders [β = 0.26, 95% CI (0.19-0.33), p < 0.001]. Tests of diagnostic specificity revealed that associations generalized across different adolescent mental disorders. Midlife adults who exhibited a more severe syndrome of despair-related maladies tended to have had psychopathology as adolescents. Prevention and treatment of adolescent psychopathology may mitigate despair-related maladies at midlife and ultimately reduce deaths of despair.


Relationships Among Performance Anxiety, Agari Experience, and Depressive Tendencies in Japanese Music Students.
The purpose of this study was to investigate the relationships among anxiety prior to actual performance (music performance anxiety, MPA), mental and physical negative responses during performance (agari), and depressive tendencies in Japanese college students majoring in music. Participants were 171 music majors (33 males, 138 females, 20.6±1.7 yrs). They rated the degree of self-perceived MPA before their performance on a scale ranging from 0-100%. The Features of Agari Experience Questionnaire was used to assess agari response levels during standard performances, and the Japanese version of the Center for Epidemiologic Studies Depression Scale (CESD) was used to measure depressive tendencies. Path analysis showed that MPA levels were positively related to agari scores, which were positively related to CES-D scores. Mediation analysis found a significant indirect effect of MPA scores on CES-D scores via the agari scores. These results suggest that MPA first occurs before an actual music performance and evokes agari, which in turn may cause an increase in depressive tendencies.


Targeted disruption of Plasmodium falciparum cysteine protease, falcipain 1, reduces oocyst production, not erythrocytic stage growth.
Cysteine proteases are currently targets for drug development in a number of parasitic diseases, including malaria. In Plasmodium falciparum, the parasite responsible for the most virulent form of human malaria, there are four members of the cathepsin L-like family of cysteine proteases. Three of these (falcipains 2A, 2B and 3) are thought to be primarily involved in haemoglobin digestion, whereas falcipain 1 has recently been linked to erythrocyte invasion. Neither their expression nor their role in P. falciparum gametocytogenesis, which is required for malaria transmission, has been evaluated. In this study, RNA transcripts for the falcipain family members were identified as the parasite developed through all five stages of gametocytogenesis. Falcipain 1 transcript was upregulated in gametocytes, while levels of falcipain 2A/2B decreased in late-stage gametocytes and gametes. To evaluate the function of falcipain 1, the gene was disrupted, and clones from independent transformations were isolated. The asexual growth of the falcipain 1 minus clones was not overtly affected, and they produced morphologically normal gametocytes and gametes. However, when falcipain 1 minus parasites were fed to a mosquito, oocyst production was reduced by 70-90%, suggesting an important role for falcipain 1 during parasite development in the mosquito midgut.


An Epidemiological Study of Burglary Offenders: Trends and Predictors of Self-Reported Arrests for Burglary in the United States, 2002-2013.
Burglary is serious property crime with a relatively high incidence and has been shown to be variously associated with other forms of criminal behavior. Unfortunately, an epidemiological understanding of burglary and its correlates is largely missing from the literature. Using public-use data collected between 2002 and 2013 as part of the National Survey on Drug Use and Health (NSDUH), the current study compared those who self-reported burglary arrest in the prior 12 months with and without criminal history. The unadjusted prevalence estimates of self-reported burglary arrest were statistically different for those with a prior arrest history (4.7%) compared with those without an arrest history (0.02%) which is a 235-fold difference. Those with an arrest history were more likely to report lower educational attainment, to have lower income, to have moved more than 3 times in the past 5 years, and to use alcohol, tobacco, illicit drugs, and engage in binge drinking. Moreover, those with prior arrest histories were younger and more likely to be male. There is considerable heterogeneity among burglars with criminal history indicating substantially greater behavioral risk.


Towards Real-time Metabolic Profiling of Cancer with Hyperpolarized Succinate.
The energy-yielding mitochondrial Krebs cycle has been shown in many cancers and other diseases to be inhibited or mutated. In most cells, the Krebs cycle with oxidative phosphorylation generates approximately 90% of the adenosine triphosphate in the cell. We designed and hyperpolarized carbon-13 labeled succinate (SUC) and its derivative diethyl succinate (DES) to interrogate the Krebs cycle in real-time in cancer animal models. Using Parahydrogen Induced Polarization (PHIP), we generated hyperpolarized SUC and DES by hydrogenating their respective fumarate precursors. DES and SUC metabolism was studied in five cancer allograft animal models: breast (4T1), Renal Cell Carcinoma (RENCA), colon (CT26), lymphoma NSO, and lymphoma A20. The extent of hyperpolarization was 8 ± 2% for SUC and 2.1 ± 0.6% for DES. The metabolism of DES and SUC in the Krebs cycle could be followed in animals 5 s after tail vein injection. The biodistribution of the compounds was observed using 13C FISP imaging. We observed significant differences in uptake and conversion of both compounds in different cell types both in vivo and in vitro. With hyperpolarized DES and SUC, we are able to meet many of the requirements for a useable in vivo metabolic imaging compound - high polarization, relatively long T1 values, low toxicity and high water solubility. However, succinate and its derivative DES are metabolized robustly by RENCA but not by the other cancer models. Our results underscore the heterogeneity of cancer cells and the role cellular uptake plays in hyperpolarized metabolic spectroscopy.


The use of medication for chronic pain in primary care, and the potential for intervention by a practice-based pharmacist.
The majority of people with chronic pain use analgesics regularly. Ensuring their safe and appropriate use is important. This study aimed to describe patterns of analgesic prescribing in one general practice, devise a method of identifying chronic pain patients from prescribing records, and assess prescribing recommendations made after a pharmacist-led review of analgesic prescribing and identify the proportion of these acted on by GPs. Prescribing records in a practice of 6720 patients were searched and 678 patients were identified as receiving prescriptions for analgesics. 230 were invited to participate and sent a questionnaire, including questions about chronic pain severity, general health and medications used. This was repeated after six months. The pharmacist completed a detailed medication review using information from medical records, questionnaires and personal interviews. Prescribing recommendations were made to GPs. 192 recommendations about safe or appropriate prescribing were made for 86% of participants after records review, 56% being directly related to analgesic use. After 6 months all recommendations had been implemented in 77% of the patients. Few additional recommendations were made after interview. There was little or no relationship with changes in chronic pain severity or general or psychological health. We have demonstrated a method of identifying patients with chronic pain in primary care, and the feasibility and acceptability of a pharmacist-led intervention. This is of potential value in primary care, as relevant prescribing recommendations were made for most patients although further research is required to assess these.


Basic fibroblast growth factor improves trabecular bone connectivity and bone strength in the lumbar vertebral body of osteopenic rats.
Recently, basic fibroblast growth factor (bFGF) has been found to increase trabecular bone mass and connectivity in the proximal tibial metaphyses (PTM) in osteopenic rats. The purpose of this study was to determine the bone anabolic effects of bFGF in the lumbar vertebral body (LVB), a less loaded skeletal site with a lower rate of bone turnover than the PTM. Six-month old female Sprague-Dawley rats were ovariectomized (OVX) or sham-operated and untreated for 8 weeks to induce osteopenia. Then group 1 (sham) and group 2 (OVX) were treated subcutaneously (s.c.) with vehicle, and OVXed groups 3 and 4 were treated s.c. with PTH [hPTH (1-34) at 40 microg/kg, 5x/week] and bFGF (1 mg/kg, 5x/week), respectively, for 8 weeks. At sacrifice, the fifth LVB was removed, subjected to micro-CT for determination of trabecular bone structure and then processed for histomorphometry to assess bone turnover. The sixth LVB was used for mechanical compression testing (MTS, Bionix 858). The data were analyzed with the Kruskal-Wallis test followed by post-hoc testing as needed. After 16 weeks of estrogen deficiency, there were significant reductions in vertebral trabecular bone volume and trabecular thickness. Treatment with either bFGF or hPTH (1-34) increased BV/TV in OVX animals. Human PTH (1-34)-treated animals had significant increases in trabecular (48%) and cortical thickness (30%) and bone strength [maximum load (53%) and work to failure (175%)] compared to OVX + Vehicle animals. Treatment of osteopenic rats with bFGF increased bone volume (15%), trabecular thickness (13%), maximum load (45%) and work to failure (140%) compared to OVX + Vehicle animals (all P <0.05). Basic FGF increased trabecular bone volume in the lumbar vertebral body of osteopenic rats by restoring trabecular number, thickness and connectivity density. Also, bFGF improved bone mechanical properties (maximum force and work to failure) compared to the OVX + Vehicle group. Therefore, increasing the number, thickness and connections of the trabeculae contributes to increased bone strength in this small animal model of osteoporosis.


Cigarette smoking blocks the protective expression of Nrf2/ARE pathway in peripheral mononuclear cells of young heavy smokers favouring inflammation.
Cigarette smoking is an important risk factor for atherosclerosis, a chronic inflammatory disease. However the underlying factors of this effect are unclear. It has been hypothesized that water-soluble components of cigarette smoke can directly promote oxidative stress in vasculature and blood cells. Aim of this study was to study the relationship between oxidative stress and inflammation in a group of young smokers. To do this we evaluated: 1) the oxidation products of phospholipids (oxPAPC) in peripheral blood mononuclear cells (PBMC); 2) their role in causing PBMC reactive oxygen species (ROS) generation and changes in GSH; 3) the expression of the transcription factor NF-E2-related factor 2 (Nrf2) and of related antioxidant genes (ARE); 4) the activation of NF-kB and C-reactive protein (CRP) values. We studied 90 healthy volunteers: 32 non-smokers, 32 moderate smokers (5-10 cigarettes/day) and 26 heavy smokers (25-40 cigarettes/day). OxPAPC and p47phox expression, that reasonably reflects NADPH oxidase activity, were higher in moderate smokers and heavy smokers than in non-smokers (p<0.01), the highest values being in heavy smokers (p<0.01). In in vitro studies oxPAPC increased ROS generation via NADPH oxidase activation. GSH in PBMC and plasma was lower in moderate smokers and heavy smokers than in non-smokers (p<0.01), the lowest values being in heavy smokers (p<0.01). Nrf2 expression in PBMC was higher in moderate smokers than in non-smokers (p<0.01), but not in heavy smokers, who had the highest levels of NF-kB and CRP (p<0.01). In in vitro studies oxPAPC dose-dependently increased NF-kB activation, whereas at the highest concentrations Nrf2 expression was repressed. The small interference (si) RNA-mediated knockdown of NF-kappaB/p65 increased about three times the expression of Nrf2 stimulated with oxPAPC. Cigarette smoke promotes oxPAPC formation and oxidative stress in PBMC. This may cause the activation of NF-kB that in turn may participate in the negative regulation of Nrf2/ARE pathway favouring inflammation.


Discrimination and psychological distress among recently released male prisoners.
Though theoretical perspectives suggest experiences of stigma and discrimination after release may be one pathway through which incarceration leads to poor mental health, little research considers the relationship between discrimination and mental health among former inmates. In this article, data from a sample of men recently released from prison to Oakland or San Francisco, California (N = 172), are used to consider how criminal record discrimination and racial/ethnic discrimination are independently and cumulatively associated with psychological distress. Results indicate that (a) the frequency of criminal record discrimination and racial/ethnic discrimination are similar; (b) both forms of discrimination are independently, negatively associated with psychological distress; and (c) the level of racial/ethnic discrimination does not alter the association between criminal record discrimination and psychological distress. The results highlight that criminal record discrimination is an important social stressor with negative implications for the mental health of previously incarcerated individuals.


Assignment of an essential role for the Neurospora frequency gene in circadian entrainment to temperature cycles.
Circadian systems include slave oscillators and central pacemakers, and the cores of eukaryotic circadian clocks described to date are composed of transcription and translation feedback loops (TTFLs). In the model system Neurospora, normal circadian rhythmicity requires a TTFL in which a White Collar complex (WCC) activates expression of the frequency (frq) gene, and the FRQ protein feeds back to attenuate that activation. To further test the centrality of this TTFL to the circadian mechanism in Neurospora, we used low-amplitude temperature cycles to compare WT and frq-null strains under conditions in which a banding rhythm was elicited. WT cultures were entrained to these temperature cycles. Unlike those normal strains, however, frq-null mutants did not truly entrain to the same cycles. Their peaks and troughs always occurred in the cold and warm periods, respectively, strongly suggesting that the rhythm in Neurospora lacking frq function simply is driven by the temperature cycles. Previous reports suggested that a FRQ-less oscillator (FLO) could be entrained to temperature cycles, rather than being driven, and speculated that the FLO was the underlying circadian-rhythm generator. These inferences appear to derive from the use of a phase reference point affected by both the changing waveform and the phase of the oscillation. Examination of several other phase markers as well as results of additional experimental tests indicate that the FLO is, at best, a slave oscillator to the TTFL, which underlies circadian rhythm generation in Neurospora.


The correlation between ventricular repolarization and clinical severity of spinal cord injuries.
Alteration in ventricular repolarization has been reported in patients with spinal cord injuries (SCIs). However, its clinical impact remains unclear. The purpose of this study was to investigate the correlation between SCIs and ventricular repolarization and the associated clinical impact. One hundred forty-four patients with an SCI were retrospectively reviewed and were divided into two groups (SCI level ≤ T6, n = 110; SCI level >T6, n = 34). The electrocardiograms were reviewed during acute phase (at emergency room) and chronic phase (>1 year). There were no differences in the underlying diseases or in ASIA score between the two groups, except there were more patients with tetraplegia among those with an SCI level ≤ T6. For the electrophysiological parameters from the electrocardiograms, the patients with an SCI level ≤ T6 had longer QTc and PR interval than those with an SCI level >T6 during acute phase. In the chronic phase, there were no differences in the electrophysiological parameters between the two groups. Only in patients with an SCI level ≤ T6 did a Kaplan-Meier analysis show that QTc prolongation could predict 30-day mortality after the acute injury. After multivariate Cox regression analysis, only tetraplegia and QTc prolongation were independent predictors of 30-day mortality (odds ratios 7.85 and 34.62, respectively). In patients with an SCI level ≤ T6, the QTc intervals were shorter in the chronic phase than those during the acute phase. QTc interval was associated with the level of acute SCI and predicted the 30-day mortality.


Treatment of spinal muscular atrophy by sodium butyrate.
Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by degeneration of the anterior horn cells of the spinal cord, leading to muscular paralysis with muscular atrophy. No effective treatment of this disorder is presently available. Studies of the correlation between disease severity and the amount of survival motor neuron (SMN) protein have shown an inverse relationship. We report that sodium butyrate effectively increases the amount of exon 7-containing SMN protein in SMA lymphoid cell lines by changing the alternative splicing pattern of exon 7 in the SMN2 gene. In vivo, sodium butyrate treatment of SMA-like mice resulted in increased expression of SMN protein in motor neurons of the spinal cord and resulted in significant improvement of SMA clinical symptoms. Oral administration of sodium butyrate to intercrosses of heterozygous pregnant knockout-transgenic SMA-like mice decreased the birth rate of severe types of SMA-like mice, and SMA symptoms were ameliorated for all three types of SMA-like mice. These results suggest that sodium butyrate may be an effective drug for the treatment of human SMA patients.


Would smokers with schizophrenia benefit from a more flexible approach to smoking treatment?
We evaluated literature that addresses the notion that flexible smoking treatment approaches are warranted for smokers with a diagnosis of schizophrenia. Understanding the biological and psychological mechanisms that increase the likelihood of smoking and decrease the motivation to quit for these individuals is addressed within the framework of a neurobiological model. We provide a brief overview of the limited smoking cessation treatment literature for patients with schizophrenia and compare abstinence-focused versus reduction-focused treatment modalities. The potential utility of the reduction-focused approach to tobacco treatment for these smokers is evaluated. Suggestions for future research to address the utility and efficacy of reduction-focused interventions for smokers with schizophrenia are put forth. We conclude with a consideration of the implications for the current understanding of smoking treatment among patients with co-morbid psychiatric diagnoses.


Highly localized sensitivity to climate forcing drives endemic cholera in a megacity.
The population dynamics of endemic cholera in urban environments--in particular interannual variation in the size and distribution of seasonal outbreaks--remain poorly understood and highly unpredictable. In part, this situation is due to the considerable demographic, socioeconomic, and environmental heterogeneity of large and growing urban centers. Despite this heterogeneity, the influence of climate variability on the population dynamics of infectious diseases is considered a large-scale, regional, phenomenon, and as such has been previously addressed for cholera only with temporal models that do not incorporate spatial structure. Here we show that a probabilistic spatial model can explain cholera dynamics in the megacity of Dhaka, Bangladesh, and afford a basis for cholera forecasts at lead times of 11 mo. Critically, we find that the action of climate variability (El Niño southern oscillation and flooding) is quite localized: There is a climate-sensitive urban core that acts to propagate risk to the rest of the city. The modeling framework presented here should be applicable to cholera in other cities, as well as to other infectious diseases in urban settings and other biological systems with spatiotemporal interactions.


A Transcriptional Program for Detecting TGFβ-Induced EMT in Cancer.
Most cancer deaths are due to metastasis, and epithelial-to-mesenchymal transition (EMT) plays a central role in driving cancer cell metastasis. EMT is induced by different stimuli, leading to different signaling patterns and therapeutic responses. TGFβ is one of the best-studied drivers of EMT, and many drugs are available to target this signaling pathway. A comprehensive bioinformatics approach was employed to derive a signature for TGFβ-induced EMT which can be used to score TGFβ-driven EMT in cells and clinical specimens. Considering this signature in pan-cancer cell and tumor datasets, a number of cell lines (including basal B breast cancer and cancers of the central nervous system) show evidence for TGFβ-driven EMT and carry a low mutational burden across the TGFβ signaling pathway. Furthermore, significant variation is observed in the response of high scoring cell lines to some common cancer drugs. Finally, this signature was applied to pan-cancer data from The Cancer Genome Atlas to identify tumor types with evidence of TGFβ-induced EMT. Tumor types with high scores showed significantly lower survival rates than those with low scores and also carry a lower mutational burden in the TGFβ pathway. The current transcriptomic signature demonstrates reproducible results across independent cell line and cancer datasets and identifies samples with strong mesenchymal phenotypes likely to be driven by TGFβ.Implications: The TGFβ-induced EMT signature may be useful to identify patients with mesenchymal-like tumors who could benefit from targeted therapeutics to inhibit promesenchymal TGFβ signaling and disrupt the metastatic cascade. Mol Cancer Res; 15(5); 619-31. ©2017 AACR.


Pneumothorax from subpleural blebs-a new association of sotos syndrome?
We describe two unrelated patients with molecularly confirmed Sotos syndrome with multiple subpleural blebs and pneumothorax. We propose this as a new association. Patient 1 is a 3-year-old boy with a 1.9 Mb interstitial deletion of the long arm of chromosome 5, with breakpoints at q35.2 and q35.3, encompassing NSD1 and Patient 2 is a 9-year-old girl with a de novo truncating mutation within NSD1. Both patients presented with sudden onset dyspnea due to a unilateral pneumothorax: Patient 1 at the age of 18 months and Patient 2 at 9 years. In both, the pneumothorax recurred following removal of the chest drain and, on further investigations, multiple subpleural blebs were identified necessitating a pleurodesis and tissue resection. This is the first report of multiple subpleural blebs leading to pneumothorax in association with Sotos syndrome. Given the similar and unusual presentation in the two affected patients, we suggest that this may be a real association, albeit a rare one. While screening would not be advocated for such a rare association, we recommend that clinicians consider pneumothorax in patients with Sotos syndrome and sudden onset of dyspnea and are aware that it may be refractory to first line treatment.


Restorative dentistry and oral rehabilitation: United Kingdom National Multidisciplinary Guidelines.
This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK and provides recommendations on the pre-treatment oral and dental assessment, during and after treatment and oral rehabilitation. Restorative dentists are core members of the multidisciplinary team treating head and neck cancer patients, involved from the treatment planning phase through to long-term rehabilitation. Recommendations • Preventative oral care must be delivered to patients whose cancer treatment will affect the oral cavity, jaws, salivary glands and oral accessibility. (G) • Close working and communication between the surgeons, oncologists and restorative dental specialists is important in ensuring optimal oral health outcomes. (G) • Intensity-modulated radiotherapy has been shown to reduce long-term xerostomia and should be offered to all appropriate patients. (R) • If patients are deemed at risk of trismus they should be warned and its progressive and potentially irreversible nature explained. (G) • Where it is known that adjuvant radiotherapy will be given, extractions should take place at primary surgery to maximise the time for healing and minimise the number of surgical events for patients. (G) • Osseointegrated implants should be considered for all patients having resection for head and neck cancer. (G).


High efficient blue emission of Ce3+ activated Ca4P2O9 phosphor for white LEDs.
Intense blue emission from Ca(4)P(2)O(9):Ce(3+) phosphor was observed with CIE chromaticity coordinates (0.157, 0.094) and a high external quantum yield up to 64.8%. Concentration quenching effect of Ca(4)P(2)O(9):xCe(3+) indicated that the optimal Ce(3+) concentration was at x = 0.005, and the energy transfer among the nearest neighbor ions accounted for this quenching. Good thermal stability of the optimal phosphor was also shown, since 90% of the initial intensity (at 300 K) remained as the temperature increased from 300 to 400 K. Ca(4)P(2)O(9):0.005Ce(3+) can act as a promising blue-emitting phosphor for white LEDs.


TLR signaling in human antigen-presenting cells regulates MR1-dependent activation of MAIT cells.
Mucosal-associated invariant T (MAIT) cells are an abundant innate-like T lymphocyte population that are enriched in liver and mucosal tissues. They are restricted by MR1, which presents antigens derived from a metabolic precursor of riboflavin synthesis, a pathway present in many microbial species, including commensals. Therefore, MR1-mediated MAIT cell activation must be tightly regulated to prevent inappropriate activation and immunopathology. Using an in vitro model of MR1-mediated activation of primary human MAIT cells, we investigated the mechanisms by which it is regulated. Uptake of intact bacteria by antigen presenting cells (APCs) into acidified endolysosomal compartments was required for efficient MR1-mediated MAIT cell activation, while stimulation with soluble ligand was inefficient. Consistent with this, little MR1 was seen at the surface of human monocytic (THP1) and B-cell lines. Activation with a TLR ligand increased the amount of MR1 at the surface of THP1 but not B-cell lines, suggesting differential regulation in different cell types. APC activation and NF-κB signaling were critical for MR1-mediated MAIT cell activation. In primary cells, however, prolonged TLR signaling led to downregulation of MR1-mediated MAIT cell activation. Overall, MR1-mediated MAIT cell activation is a tightly regulated process, dependent on integration of innate signals by APCs.


Preparation of enantiopure substituted piperidines containing 2-alkene or 2-alkyne chains: application to total syntheses of natural quinolizidine-alkaloids.
A general method for the preparation of enantiopure 2-alkene- or 2-alkyne-containing chain substituted piperidines was established by using nonracemic Betti base as a chiral auxiliary. The key step is that the auxiliary residue was removed by a novel base-catalyzed N-debenzylation via a formation of o-quinone methide mechanism in stead of the traditional hydrogenolysis, by which the alkene or alkyne groups survived. By this method, ten 2-alkene- or 2-alkyne-containing chain substituted piperidines were prepared on the gram scale within a few hours. To demonstrate the efficiency of the method and the versatility of the product, total syntheses of natural alkaloids (+)-pelletierine, (-)-lasubine II, and (+)-cermizine C were achieved by using (S)-2-allyl-N-Boc-piperidine as a versatile building block.


Acute ethanol administration reduces the cognitive deficits associated with traumatic brain injury in rats.
The present study was designed to determine whether a low dose of acute ethanol administration could attenuate cognitive deficits associated with traumatic brain injury. Adult male rats received oral administration of ethanol or drinking water 2 h prior to surgery to produce a blood ethanol concentration of 100 mg% and then received bilateral contusion injuries of the medial prefrontal cortex. Seven days after surgery, the rats began 10 days of testing for acquisition of spatial localization in the Morris water maze where they were required to find a hidden platform to escape from the water. The results indicate that the rats given ethanol at the time of injury later spent significantly less time searching for the hidden platform than their water-treated counterparts. On a memory probe test given on the final day of testing, in which the platform was removed from the pool, rats given the ethanol spent more time in the area where the platform had been located indicating that they learned its location better than the lesion/water controls. In addition, acute ethanol treatment reduced some of the histopathology that typically occurs following severe contusion of the medial frontal cortex but did not attenuate post-traumatic formation of edema. These results indicate that acute ethanol intoxication can reduce the severity of cognitive impairments caused by contusive traumatic brain injury and support the contention that there is a dose-response relationship of acute ethanol intoxication in the setting of traumatic brain injury.


Identifying patients at increased risk for unplanned readmission.
Reducing readmissions is a national priority, but many hospitals lack practical tools to identify patients at increased risk of unplanned readmission. To estimate the association between a composite measure of patient condition at discharge, the Rothman Index (RI), and unplanned readmission within 30 days of discharge. Adult medical and surgical patients in a major teaching hospital in 2011. The RI is a composite measure updated regularly from the electronic medical record based on changes in vital signs, nursing assessments, Braden score, cardiac rhythms, and laboratory test results. We developed 4 categories of RI and tested its association with readmission within 30 days, using logistic regression, adjusted for patient age, sex, insurance status, service assignment (medical or surgical), and primary discharge diagnosis. Sixteen percent of the sample patients (N=2730) had an unplanned readmission within 30 days of discharge. The risk of readmission for a patient in the highest risk category (RI<70) was >1 in 5 while the risk of readmission for patients in the lowest risk category was about 1 in 10. In multivariable analysis, patients with an RI<70 (the highest risk category) or 70-79 (medium risk category) had 2.65 (95% confidence interval, 1.72-4.07) and 2.40 (95% confidence interval, 1.57-3.67) times higher odds of unplanned readmission, respectively, compared with patients in the lowest risk category. Clinicians can use the RI to help target hospital programs and supports to patients at highest risk of readmission.


Conditional density estimation with dimensionality reduction via squared-loss conditional entropy minimization.
Regression aims at estimating the conditional mean of output given input. However, regression is not informative enough if the conditional density is multimodal, heteroskedastic, and asymmetric. In such a case, estimating the conditional density itself is preferable, but conditional density estimation (CDE) is challenging in high-dimensional space. A naive approach to coping with high dimensionality is to first perform dimensionality reduction (DR) and then execute CDE. However, a two-step process does not perform well in practice because the error incurred in the first DR step can be magnified in the second CDE step. In this letter, we propose a novel single-shot procedure that performs CDE and DR simultaneously in an integrated way. Our key idea is to formulate DR as the problem of minimizing a squared-loss variant of conditional entropy, and this is solved using CDE. Thus, an additional CDE step is not needed after DR. We demonstrate the usefulness of the proposed method through extensive experiments on various data sets, including humanoid robot transition and computer art.


Regulation of malate oxidation in plant mitochondria. Response to rotenone and exogenous NAD+.
Exogenous NAD+ stimulated the rotenone-resistant oxidation of all the NAD+-linked tricarboxylic acid-cycle substrates in mitochondria from Jerusalem artichoke (Helianthus tuberosus L.) tubers. The stimulation was not removed by the addition of EGTA, which is known to inhibit the oxidation of exogenous NADH. It is therefore concluded that added NAD+ gains access to the matrix space and stimulates oxidation by the rotenone-resistant NADH dehydrogenase located on the matrix surface of the inner membrane. Added NAD+ stimulated the activity of malic enzyme and displaced the equilibrium of malate dehydrogenase; both observations are consistent with entry of NAD+ into the matrix space. Analysis of products of malate oxidation showed that rotenone-resistant oxygen uptake only occurred when the concentration of oxaloacetate was low and that of NADH was high. Thus it is proposed that the concentration of NADH regulates the activity of the two internal NADH dehydrogenases. Evidence is presented to suggest that the rotenone-resistant NADH dehydrogenase is engaged under conditions of high phosphorylation potential, which restricts electron flux through the rotenone-sensitive dehydrogenase (coupled to ATP synthesis).


Comparative structural studies of two natural isoforms of ammodytoxin, phospholipases A2 from Vipera ammodytes ammodytes which differ in neurotoxicity and anticoagulant activity.
Ammodytoxin A (AtxA) and its natural isoform AtxC from the venom of Vipera ammodytes ammodytes belong to group IIA-secreted phospholipases A(2) which catalyze the hydrolysis of glycerophospholipids and exhibit strong neurotoxic and anticoagulant effects. The two isoforms, which differ in sequence by only two amino acid residues (Phe124>Ile and Lys128>Glu), display significant differences in toxicity and anticoagulant properties and act on protein targets including neurotoxic proteic receptors and coagulation factor Xa with significantly different strengths of binding. In order to characterize the structural basis of these functional differences, we have determined the crystal structures of the two isoforms. Comparison of the structures shows that the mutation Lys128>Glu in AtxC could perturb interactions with FXa, resulting in lower anticoagulant activity, since the side chain of Glu128 is partly buried, making a stabilizing hydrogen bond with the main-chain nitrogen atom of residue Thr35. This interaction leads to a displacement of the main polypeptide chain at positions 127 and 128 (identified by mutagenesis as important for interaction with FXa), and a different orientation of the side chain of unmutated Lys127. The mutation Phe124>Ile in AtxC induces no significant conformational changes, suggesting that the differences in toxicity of the two isoforms are due essentially to differences in surface complementarity in the interaction of the toxin with the neurotoxic protein receptor. The crystal structures also reveal a novel dimeric quaternary association involving significant hydrophobic interactions between the N-terminal alpha-helices of two molecules of ammodytoxin related by crystallographic symmetry. Interactions at the dimer interface include important contributions from Met7, which is unique to ammodytoxin. Equilibrium sedimentation experiments are consistent with the crystallographic model. Competition experiments using SPR technology show complete inhibition of AtxA binding to FXa by calmodulin (CaM). The crystal structure shows that the C-terminal region, important for binding to FXa and CaM, is fully exposed and accessible for interaction with proteic receptors in both the monomeric and dimeric forms of ammodytoxin described here.


Shear-Induced Changes of Electronic Properties in Gallium Nitride.
We show that sliding on the surface of GaN can permanently change the surface band structure, resulting in an increased degree of band bending by more than 0.5 eV. We hypothesize that shear and contact stresses introduce vacancies that cause a spatially variant band bending. Band bending is observed by shifts and broadening of core-level binding energies toward lower values in X-ray photoelectron spectroscopy. The extent of band bending is controlled by humidity, number of sliding cycles and applied load, presenting opportunities for scalable tuning of the degree of band bending on a GaN surface. Scanning transmission electron microscopy revealed that the epitaxy of GaN was preserved up to the surface with regions of defects near the surface. The hypothesized mechanism of band bending is shear-induced defect generation, which has been shown to affect the surface states. The ability to introduce band bending at the GaN surface is promising for applications in photovoltaics, photocatalysis, gas sensing, and photoelectrochemical processes.


Patient participation: A qualitative study of immigrant women and their experiences.
Patient participation in healthcare is a neglected area of interest in the rather extensive amount of research on immigrant so-called Selma patients in Swedish health care as well as worldwide. The aim is to explore the phenomenon "patient participation" in the context of the Swedish health care from the perspective of immigrants non-fluent in Swedish. A phenomenological lifeworld approach was chosen. Data were collected from patients within a municipal home care setting in Sweden. Eight women agreed to participate. In seven interviews, an interpreter was necessary for the translation of the interview. Five authorized interpreters were used. Data were analysed in accordance to a descriptive phenomenological method for caring research. The analysis led to an essence of the phenomenon with three constituents, "to experience participation," "to refrain from participation," and "to be deprived of participation." Patient participation from the perspective of immigrant women means that patients are involved and active in their own health and caring processes. For these women, it is particularly important to have the opportunity to express themselves. Patient participation presupposes professional caregivers who act in a way that increases the patients' opportunities to take part. A skilled interpreter is often necessary in order to enable the patient participation.


Socioeconomic status predicts objective and subjective sleep quality in aging women.
To test the hypothesis that socioeconomic status (SES) would be associated with sleep quality measured objectively, even after controlling for related covariates (health status, psychosocial characteristics). Epidemiological studies linking SES and sleep quality have traditionally relied on self-reported assessments of sleep. Ninety-four women, 61 to 90 years of age, participated in this study. SES was determined by pretax household income and years of education. Objective and subjective assessments of sleep quality were obtained using the NightCap sleep system and the Pittsburgh Sleep Quality Index (PSQI), respectively. Health status was determined by subjective health ratings and objective measures of recent and chronic illnesses. Depressive symptoms and neuroticism were quantified using the Center for Epidemiological Studies Depression Scale and the Neuroticism subscale of the NEO Personality Inventory, respectively. Household income significantly predicted sleep latency and sleep efficiency even after adjusting for demographic factors, health status, and psychosocial characteristics. Income also predicted PSQI scores, although this association was significantly attenuated by inclusion of neuroticism in multivariate analyses. Education predicted both sleep latency and sleep efficiency, but the latter association was partially reduced after health status and psychosocial measures were included in analyses. Education predicted PSQI sleep efficiency component scores, but not global scores. These results suggest that SES is robustly linked to both subjective and objective sleep quality, and that health status and psychosocial characteristics partially explain these associations.


Awake Craniotomy in Arteriovenous Malformation Surgery: The Usefulness of Cortical and Subcortical Mapping of Language Function in Selected Patients.
Awake craniotomy for removal of intra-axial lesions is a well-established procedure. Few studies, however, have investigated the usefulness of this approach for resection of arteriovenous malformations adjacent to eloquent language areas. We demonstrate our experience by using cortical stimulation mapping and report for the first time on the usefulness of subcortical stimulation with interrogation of language function during resection of arteriovenous malformations (AVMs) located near language zones. Patients undergoing awake craniotomy for AVMs located in language zones and at least 5 mm away from the closest functional magnetic resonance imaging activation were analyzed. During surgery, cortical bipolar stimulation at 50 Hz, with an intensity of 2 mA, increased to a maximum of 10 mA was performed in the region around the AVM before claiming it negative for language function. In positive language site, the area was restimulated 3 times to confirm the functional deficit. The AVM resection was started based on cortical mapping findings. Further subcortical stimulation performed in concert with speech interrogation by the neuropsychologist continued at key points throughout the resection as feasible. The usefulness of cortical and subcortical stimulation in addition to patient outcomes was analyzed. Between March 2009 and September 2014, 42 brain AVM resections were performed. Four patients with left-sided language zone AVMs underwent awake craniotomy. The AVM locations were fronto-opercular in 2 patients and posterior temporal in 2. The AVM Spetzler-Martin grades were II (2 patients) and III (2 patients). In 1 patient, complete speech arrest was noticed during mapping of the peri-malformation zone, which was not breached during resection. In a second patient who initially demonstrated negative cortical mapping, a speech deficit was noticed during resection and subcortical stimulation. This guided the approach to protect and avoid the sensitive zone. This patient experienced mild postoperative expressive dysphasia that improved to normal within 6 weeks. Complete resection was achieved in all 4 patients. There were no other complications and no permanent neurological morbidity, resulting in good outcome in all 4 patients. Language mapping, both cortical and subcortical during AVM resection, may be valuable in a very select group of AVMs in language zones. Defining safe margins and feedback to the surgeon may provide the highest chances of a surgical cure while minimizing the risk of incurring a language deficit.


Thickness of palatal masticatory mucosa and its relationship with different parameters in Turkish subjects.
The aim of the study was to clinically investigate the mucosal variations in different parts of hard palate subject to soft tissue harvesting and its relationship with selected parameters in patients with gingival recessions. Fifty periodontally healthy, dentate subjects (13 males) with gingival recessions were enrolled into the study. After initial periodontal therapy they were scheduled for surgical procedures. Palatal masticatory mucosa of five teeth was evaluated at five different points from the gingival margin and two points on the buccal gingival mucosa were evaluated on the day of surgical intervention via bone sounding method. Totally 27 assessments were performed for each patient. The overall mean thickness of palatal masticatory mucosa (PMM) was 2.55±0.49mm. The mean mid-facial gingival thickness was 1.11±0.39mm. The PMM showed an increase towards the posterior and raphe palatina. No difference was observed between genders, and no association of body mass index (BMI) and age with PMM was determined. An association was observed between the thicknesses of mid-facial gingival and palatal masticatory mucosa. The thickness of PMM in this study seems to be less than other reports possibly due to ethnicity or measurement design. Canine and premolar region reveals higher thickness values, and the increase in the tissue thickness towards the midline should also been taken into consideration. Clinicians planning soft tissue harvesting from the palate should take this variation into consideration. In this regard transmucosal probing of the donor site may provide valuable information where considerable variation exists.


Changes of liver-resident NK cells during liver regeneration in rats.
To determine the role of NK cells in regulation of tissue growth, the phenotype and function of liver-resident NK cells were studied after 70% partial hepatectomy in rats. The process of liver regeneration was generally completed by day 14. In contrast, the number of liver-resident NK cells (NKR-P1bright) was restored as early as day 3 after partial hepatectomy. However, spontaneous functions of liver-resident NK cells, including killing of YAC-1 and P815 targets, Ab-dependent cellular cytotoxicity, and redirected killing via NKR-P1, were continuously suppressed throughout the entire period of liver regeneration (from 3 h to 14 days). Augmentation of NK cytotoxicity against P815 targets and induction of NK cell adherence to plastic following 24 h of IL-2 stimulation showed a similar pattern of suppression. However, IL-2-induced augmentation of YAC-1 killing, proliferation and generation of adherent NK cells, and LAK activity in 5- to 7-day cultures were found to be suppressed only during the first 24 h and increased between days 2 and 7 after hepatectomy. Sorted NK cells (> or = NKR-P1bright) from liver-resident mononuclear leukocytes 24 h after partial hepatectomy showed the same pattern of suppression as unsorted mononuclear leukocytes. In contrast to liver-resident NK cells, no significant changes were detected in peripheral blood or spleen NK cells of rats following partial hepatectomy. Of particular interest, in normal liver, hepatocytes were resistant to NK lysis, while resident NK cells were cytotoxic for various NK-sensitive targets. In contrast, during the early period of liver regeneration, when hepatocytes were sensitive to lysis by liver-resident NK cells of normal rats, NK cells obtained from regenerating liver tissues were unable to mediate cytotoxicity. At the final phase of liver regeneration (days 7-14 after hepatectomy), both resistance of hepatocytes to killing by NK cells and cytotoxicity of liver-resident lymphocytes against hepatocytes from regenerating liver were simultaneously restored. In vivo depletion of NK cells by injection of rats with anti-NKR-P1 mAb resulted in a significant augmentation of liver regeneration subsequent to partial hepatectomy. Our data suggest that liver-resident NK cells may be involved in regulation of the extent of liver regeneration.


Biomechanical Loading Comparison between Titanium and Unsintered Hydroxyapatite/Poly-L-Lactide Plate System for Fixation of Mandibular Subcondylar Fractures.
Osteosynthesis absorbable materials made of uncalcined and unsintered hydroxyapatite (u-HA) particles, poly-l-lactide (PLLA), and u-HA/PLLA are bioresorbable, and these plate systems have feasible bioactive osteoconductive capacities. However, their strength and stability for fixation in mandibular subcondylar fractures remain unclear. This in vitro study aimed to assess the biomechanical strength of u-HA/PLLA bioresorbable plate systems after internal fixation of mandibular subcondylar fractures. Tensile and shear strength were measured for each u-HA/PLLA and titanium plate system. To evaluate biomechanical behavior, 20 hemimandible replicas were divided into 10 groups, each comprising a titanium plate and a bioresorbable plate. A linear load was applied anteroposteriorly and lateromedially to each group to simulate the muscular forces in mandibular condylar fractures. All samples were analyzed for each displacement load and the displacement obtained by the maximum load. Tensile and shear strength of the u-HA/PLLA plate were each approximately 45% of those of the titanium plates. Mechanical resistance was worst in the u-HA/PLLA plate initially loaded anteroposteriorly. Titanium plates showed the best mechanical resistance during lateromedial loading. Notably, both plates showed similar resistance when a lateromedially load was applied. In the biomechanical evaluation of mandibular condylar fracture treatment, the u-HA/PLLA plates had sufficiently high resistance in the two-plate fixation method.


Variability of child access prevention laws and pediatric firearm injuries.
State-level child access prevention (CAP) laws impose criminal liability on adults who negligently allow children access to firearms. The CAP laws can be further divided into strong CAP laws which impose criminal liability for negligently stored firearms and weak CAP laws that prohibit adults from intentionally, knowingly, and/or recklessly providing firearms to a minor. We hypothesized that strong CAP laws would be associated with a greater reduction in pediatric firearm injuries than weak CAP laws. We constructed a cross-sectional national study using the Healthcare Cost and Utilization Project-Kids Inpatient Database from 2006 and 2009 using weighted counts of firearm-related admissions among children younger than 18 years. Poisson regression was used to estimate the association of CAP laws with pediatric firearm injuries. After adjusting for race, sex, age, and socioeconomic income quartile, strong CAP laws were associated with a significant reduction in all (incidence rate ratio, 0.70; 95% confidence interval, 0.52-0.93), self-inflicted (incidence rate ratio, 0.46; 95% confidence interval, 0.26-0.79), and unintentional (incidence rate ratio, 0.56; 95% confidence interval, 0.43-0.74) pediatric firearm injuries. Weak CAP laws, which only impose liability for reckless endangerment, were associated with an increased risk of all pediatric firearm injuries. The association of CAP laws on hospitalizations for pediatric firearm injuries differed greatly depending on whether a state had adopted a strong CAP law or a weak CAP law. Implementation of strong CAP laws by each state, which require safe storage of firearms, has the potential to significantly reduce pediatric firearm injuries. Prognostic and epidemiology study, level III.


CHAL336 Benchmark Set: How Well Do Quantum-Chemical Methods Describe Chalcogen-Bonding Interactions?
We present the CHAL336 benchmark set-the most comprehensive database for the assessment of chalcogen-bonding (CB) interactions. After careful selection of suitable systems and identification of three high-level reference methods, the set comprises 336 dimers each consisting of up to 49 atoms and covers both σ- and π-hole interactions across four categories: chalcogen-chalcogen, chalcogen-π, chalcogen-halogen, and chalcogen-nitrogen interactions. In a subsequent study of DFT methods, we re-emphasize the need for using proper London dispersion corrections when treating noncovalent interactions. We also point out that the deterioration of results and systematic overestimation of interaction energies for some dispersion-corrected DFT methods does not hint at problems with the chosen dispersion correction but is a consequence of large density-driven errors. We conclude this work by performing the most detailed DFT benchmark study for CB interactions to date. We assess 109 variations of dispersion-corrected and dispersion-uncorrected DFT methods and carry out a detailed analysis of 80 of them. Double-hybrid functionals are the most reliable approaches for CB interactions, and they should be used whenever computationally feasible. The best three double hybrids are SOS0-PBE0-2-D3(BJ), revDSD-PBEP86-D3(BJ), and B2NCPLYP-D3(BJ). The best hybrids in this study are ωB97M-V, PW6B95-D3(0), and PW6B95-D3(BJ). We do not recommend using the popular B3LYP functional nor the MP2 approach, which have both been frequently used to describe CB interactions in the past. We hope to inspire a change in computational protocols surrounding CB interactions that leads away from the commonly used, popular methods to the more robust and accurate ones recommended herein. We would also like to encourage method developers to use our set for the investigation and reduction of density-driven errors in new density functional approximations.


Studies on antitumor polysaccharides, especially D-II, from mycelium of Coriolus versicolor.
A water-soluble polysaccharide, D-II with marked antitumor activity was isolated from the cultured mycelium of Coriolus versicolor by extraction with hot-water, fractional precipitation with ethanol and ion-exchange chromatography. D-II strongly inhibited the growth of Sarcoma-180 transplanted subcutaneously in mice by intraperitoneal, intravenous, subcutaneous or intra-muscular administration at a dose of 5 mg/kg. the molecular weight was estimated to be 2,000,000 by gel-filtration or 6,500,000 by light scattering analysis. The chemical structure of D-II was then investigated by periodate oxidation, methylation analysis, Smith degradation, and a combination of controlled Smith degradation and methylation analysis. These studies proposed that D-II is composed of a unit structure of four D-glucose residues, and is a glucan consisting of beta-D-1,3-linked main chain in which one for every three D-glucose residues is branched at C-6 with beta-D-1,6-linkage.


Effect of enhanced information, values clarification, and removal of financial barriers on use of prenatal genetic testing: a randomized clinical trial.
Prenatal genetic testing guidelines recommend providing patients with detailed information to allow informed, preference-based screening and diagnostic testing decisions. The effect of implementing these guidelines is not well understood. To analyze the effect of a decision-support guide and elimination of financial barriers to testing on use of prenatal genetic testing and decision making among pregnant women of varying literacy and numeracy levels. Randomized trial conducted from 2010-2013 at prenatal clinics at 3 county hospitals, 1 community clinic, 1 academic center, and 3 medical centers of an integrated health care delivery system in the San Francisco Bay area. Participants were English- or Spanish-speaking women who had not yet undergone screening or diagnostic testing and remained pregnant at 11 weeks' gestation (n = 710). A computerized, interactive decision-support guide and access to prenatal testing with no out-of-pocket expense (n = 357) or usual care as per current guidelines (n = 353). The primary outcome was invasive diagnostic test use, obtained via medical record review. Secondary outcomes included testing strategy undergone, and knowledge about testing, risk comprehension, and decisional conflict and regret at 24 to 36 weeks' gestation. Women randomized to the intervention group, compared with those randomized to the control group, were less likely to have invasive diagnostic testing (5.9% vs 12.3%; odds ratio [OR], 0.45 [95% CI, 0.25-0.80]) and more likely to forgo testing altogether (25.6% vs 20.4%; OR, 3.30 [95% CI, 1.43-7.64], reference group screening followed by invasive testing). Women randomized to the intervention group also had higher knowledge scores (9.4 vs 8.6 on a 15-point scale; mean group difference, 0.82 [95% CI, 0.34-1.31]) and were more likely to correctly estimate the amniocentesis-related miscarriage risk (73.8% vs 59.0%; OR, 1.95 [95% CI, 1.39-2.75]) and their estimated age-adjusted chance of carrying a fetus with trisomy 21 (58.7% vs 46.1%; OR, 1.66 [95% CI, 1.22-2.28]). Significant differences did not emerge in decisional conflict or regret. Full implementation of prenatal testing guidelines using a computerized, interactive decision-support guide in the absence of financial barriers to testing resulted in less test use and more informed choices. If validated in additional populations, this approach may result in more informed and preference-based prenatal testing decision making and fewer women undergoing testing. clinicaltrials.gov Identifier: NCT00505596.


New insights into prebiotic chemistry from Stanley Miller's spark discharge experiments.
1953 was a banner year for biological chemistry: The double helix structure of DNA was published by Watson and Crick, Sanger's group announced the first amino acid sequence of a protein (insulin) and the synthesis of key biomolecules using simulated primordial Earth conditions has demonstrated by Miller. Miller's studies in particular transformed the study of the origin of life into a respectable field of inquiry and established the basis of prebiotic chemistry, a field of research that investigates how the components of life as we know it can be formed in a variety of cosmogeochemical environments. In this review, I cover the continued advances in prebiotic syntheses that Miller's pioneering work has inspired. The main focus is on recent state-of-the-art analyses carried out on archived samples of Miller's original experiments, some of which had never before been analyzed, discovered in his laboratory material just before his death in May 2007. One experiment utilized a reducing gas mixture and an apparatus configuration (referred to here as the "volcanic" apparatus) that could represent a water-rich volcanic eruption accompanied by lightning. Another included H(2)S as a component of the reducing gas mixture. Compared to the limited number of amino acids Miller identified, these new analyses have found that over 40 different amino acids and amines were synthesized, demonstrating the potential robust formation of important biologic compounds under possible cosmogeochemical conditions. These experiments are suggested to simulate long-lived volcanic island arc systems, an environment that could have provided a stable environment for some of the processes thought to be involved in chemical evolution and the origin of life. Some of the alternatives to the Miller-based prebiotic synthesis and the "primordial soup" paradigm are evaluated in the context of their relevance under plausible planetary conditions.


Oral health related to demographic features in Bosnian children aged six.
The main aim of this paper is to present epidemiological indicators of oral health among six-year olds in Bosnia and Herzegovina (BH) and to analyze values of dmft index and dental treatment needs in order to identify differences in parts of the country. Another aim is to identify the needs from the public oral health care system in Bosnia and Herzegovina related to early permanent dentition by analyzing the condition of first permanent molars (FPM) as an indicator of oral health of permanent dentition. Survey was carried out in 2004 in 8 cantons of the Federation of BH (FBH) and in the Republic of Srpska (RS). Final sample included 560 participants aged six (mean 6.2, SD +/- 0.87). One dental team clinically examined all participants according to WHO methodology and criteria. The parameters used were: dmft index, DMFT index of first permanent molars (FPM), presence of sealants and treatment needs. A questionnaire about oral health habits had been administered. Dmft was 6.71 in that the d-component constituted the major part of the index. DMFT index of FPM was 0.61 (SD +/- 1.08). Percentage of caries free participants aged 6 was 6.8%. Average number of FPM with fissure sealants in BH was 0.25 (SD +/- 0.78). Significant demographic differences in dmft index, DMFT FPM and treatment needs were identified. Most participants (48.5%) had their first dental visit between the ages of five and seven. National oral health goal for Bosnia and Herzegovina should be to develop and implement disease prevention programs based on education of both parents and dental practitioners. It is necessary to improve access to dental care and shift focus from curative to preventive procedures. It is also necessary to set real goals for improvement of oral health which can be achieved within a desired time frame, as well as to precisely define measures to be taken.


Molecular therapies delaying cardiovascular aging: disease- or health-oriented approaches.
Regenerative medicine is a new therapeutic modality that aims to mend tissue damage by encouraging the reconstitution of physiological integrity. It represents an advancement over conventional therapies that allow reducing the damage but result in disease chronicization. Age-related decline in spontaneous capacity of repair, especially in organs like the heart that have very limited proliferative capacity, contributes in reducing the benefit of conventional therapy. ncRNAs are emerging as key epigenetic regulators of cardiovascular regeneration. Inhibition or replacement of miRNAs may offer reparative solutions to cardiovascular disease. The first part of this review article is devoted to illustrating novel therapies emerging from research on miRNAs. In the second part, we develop new therapeutic concepts emerging from genetics of longevity. Prolonged survival, as in supercentenarians, denotes an exceptional capacity to repair and cope with risk factors and diseases. These characteristics are shared with offspring, suggesting that the regenerative phenotype is heritable. New evidence indicates that genetic traits responsible for prolongation of health span in humans can be passed to and benefit the outcomes of animal models of cardiovascular disease. Genetic studies have also focused on determinants of accelerated senescence and related druggable targets. Evolutionary genetics assessing the genetic basis of adaptation and comparing successful and unsuccessful genetic changes in response to selection within populations represent a powerful basis to develop novel therapies aiming to prolong cardiovascular and whole organism health.


Behavioural effects of compounds co-consumed in dietary forms of caffeinated plants.
Research into the cognitive and mood effects of caffeine in human subjects has highlighted some fairly robust and well-accepted effects. However, the majority of these studies have focused on caffeine in isolation; whilst caffeine is normally consumed in the form of plant-derived products and extracts that invariably contain other potentially bioactive phytochemicals. The aim of the present review is to consider the possible mechanisms of action of co-occurring phytochemicals, and any epidemiological evidence suggesting that they contribute to potential health benefits ascribed to caffeine. Intervention studies to date that have been conducted to explore the effects on brain function of the non-caffeine components in caffeine-bearing plants (coffee, tea, cocoa, guaraná), either alone or in combination with caffeine, will also be summarised. Research is beginning to accumulate showing independent effects for several of the phytochemicals that co-occur with caffeine, and/or a modulation of the effects of caffeine when it is co-consumed with these naturally concomitant phytochemicals. The present review highlights that more research aimed at understanding the effects of these compounds is needed and, more importantly, the synergistic relationship that they may have with caffeine.


Current evidence and the evolving role of sunitinib in the management of renal cell carcinoma.
The development of targeted agents has expanded the anticancer arsenal available to oncologists and revolutionized the field of cancer treatment. In patients with advanced renal cell carcinoma (RCC), small molecule targeted therapies have improved clinical outcomes compared with cytokine-based treatments. Sunitinib malate is one such drug that has demonstrated clinical efficacy in patients with metastatic renal cell carcinoma (mRCC). This oral, multi-targeted tyrosine kinase inhibitor is approved for use in multiple countries for the treatment of advanced RCC and gastrointestinal stromal tumor patients who have progressed on imatinib therapy. In patients with advanced RCC, sunitinib significantly improves clinical outcomes with a favorable safety profile compared with conventional treatment with interferon-a. The clinically proven treatment and safety outcomes have led investigators to evaluate the merits of sunitinib therapy in the adjuvant and neoadjuvant setting in patients with mRCC. In the neoadjuvant setting, preliminary data suggest that sunitinib can effectively reduce the primary tumor and facilitate surgical resection in patients with locally advanced and mRCC. Post-operative complications were observed in some patients, but the overall safety profile and efficacy suggests that mRCC patients with surgically inoperable tumors may benefit from neoadjuvant sunitinib therapy. Ongoing clinical trials should provide insight into the value of sunitinib as adjuvant therapy.


Calcineurin inhibitor- and steroid-free immunosuppression in pancreas-kidney and solitary pancreas transplantation.
Calcineurin inhibitors and steroids are standard immunosuppressants in solid organ transplantation, but (long-term) side effects are harmful to the recipient and the graft. The authors present a novel strategy for posttransplant immunosuppression that combines a depleting antibody with an antimetabolite, avoiding calcineurin inhibitors and steroids. In a prospective, nonrandomized, observational cohort study, 75 pancreas-kidney and solitary pancreas recipients received alemtuzumab (4 doses for induction and up to 12 doses within the first year) and mycophenolate mofetil (> or = 2 g/day) for induction and maintenance therapy. Minimum follow-up was 6 months. We compared the results with a historical group of 266 consecutive pancreas recipients on Thymoglobulin (induction) and tacrolimus (maintenance). Differences in patient and graft survival rates between the study and control groups at 6 months were not statistically significant. However, the incidence of a first reversible rejection episode was significantly higher for simultaneous pancreas-kidney recipients in the study (vs. control) group. We noted a trend toward higher modification of renal disease levels at 6 months posttransplant in the study (vs. control) groups. The combination of alemtuzumab and mycophenolate mofetil was associated with an acceptable rejection rate, a good safety profile, and good (graft and native) kidney function; it eliminated undesired calcineurin inhibitor- and steroid-related side effects. Longer follow-up is warranted before expanded application can be recommended.


Is the mechanism of the [2+2] cycloaddition of cyclopentyne to ethylene concerted or biradical? A completely renormalized coupled cluster study.
The mechanism of the [2+2] cycloaddition reaction of cyclopentyne to ethylene has been studied using the completely renormalized coupled cluster method with singles, doubles, and noniterative triples (CR-CCSD(T)). In agreement with the experimentally observed stereochemistry, the CR-CCSD(T) method favors the concerted pathway involving a [2+1] transition state, whereas the popular CCSD(T) method, which is often regarded as the "gold standard" of electronic structure theory, and low-order multireference methods support the less probable biradical mechanism. In addition, the CCSD(T) approach produces an erroneous description of some transition states and intermediates, particularly those which have a significant biradical character. The CR-CCSD(T) calculations indicate that the reaction is a highly exothermic (deltaG(r)298 = -68 kcal/mol), predominantly concerted process with a relatively low activation barrier on the order of 13-16 kcal/mol which permits its thermal occurrence.


Preliminary Estimates of Mortality and Years of Life Lost Associated with the 2009 A/H1N1 Pandemic in the US and Comparison with Past Influenza Seasons.
The on-going debate about the health burden of the 2009 influenza pandemic and discussions about the usefulness of vaccine recommendations has been hampered by an absence of directly comparable measures of mortality impact. Here we set out to generate an "apples-to-apples" metric to compare pandemic and epidemic mortality. We estimated the mortality burden of the pandemic in the US using a methodology similar to that used to generate excess mortality burden for inter-pandemic influenza seasons. We also took into account the particularly young age distribution of deaths in the 2009 H1N1 pandemic, using the metric "Years of Life Lost" instead of numbers of deaths. Estimates are based on the timely pneumonia and influenza mortality surveillance data from 122 US cities, and the age distribution of laboratory-confirmed pandemic deaths, which has a mean of 37 years. We estimated that between 7,500 and 44,100 deaths are attributable to the A/H1N1 pandemic virus in the US during May-December 2009, and that between 334,000 and 1,973,000 years of life were lost. The range of years of life lost estimates includes in its lower part the impact of a typical influenza epidemic dominated by the more virulent A/H3N2 subtype, and the impact of the 1968 pandemic in its upper bound. We conclude that the 2009 A/H1N1 pandemic virus had a substantial health burden in the US over the first few months of circulation in terms of years of life lost, justifying the efforts to protect the population with vaccination programs. Analysis of historic records from three other pandemics over the last century suggests that the emerging pandemic virus will continue to circulate and cause excess mortality in unusually young populations for the next few years. Continuing surveillance for indicators of increased mortality is of key importance, as pandemics do not always cause the majority of associated deaths in the first season of circulation.


End-stage renal disease is associated with increased post endoscopic retrograde cholangiopancreatography adverse events in hospitalized patients.
To determine if end-stage renal disease (ESRD) is a risk factor for post endoscopic retrograde cholangiopancreatography (ERCP) adverse events (AEs). We performed a retrospective cohort study using the Nationwide Inpatient Sample (NIS) 2011-2013. We identified adult patients who underwent ERCP using the International Classification of Diseases 9th Revision (ICD-9-CM). Included patients were divided into three groups: ESRD, chronic kidney disease (CKD), and control. The primary outcome was post-ERCP AEs including pancreatitis, bleeding, and perforation determined based on specific ICD-9-CM codes. Secondary outcomes were length of hospital stay, in-hospital mortality, and admission cost. AEs and mortality were compared using multivariate logistic regression analysis. There were 492175 discharges that underwent ERCP during the 3 years. The ESRD and CKD groups contained 7347 and 39403 hospitalizations respectively, whereas the control group had 445424 hospitalizations. Post-ERCP pancreatitis (PEP) was significantly higher in the ESRD group (8.3%) compared to the control group (4.6%) with adjusted odd ratio (aOR) = 1.7 (95%CI: 1.4-2.1, a P < 0.001). ESRD was associated with significantly higher ERCP-related bleeding (5.1%) compared to the control group 1.5% (aOR = 1.86, 95%CI: 1.4-2.4, a P < 0.001). ESRD had increased hospital mortality 7.1% vs 1.15% in the control OR = 6.6 (95%CI: 5.3-8.2, a P < 0.001), longer hospital stay with adjusted mean difference (aMD) = 5.9 d (95%CI: 5.0-6.7 d, a P < 0.001) and higher hospitalization charges aMD = $+82064 (95%CI: $68221-$95906, a P < 0.001). ESRD is a risk factor for post-ERCP AEs and is associated with higher hospital mortality. Careful selection and close monitoring is warranted to improve outcomes.


Molecular and Histopathological Study on the Ameliorative Impacts of Petroselinum Crispum and Apium Graveolens against Experimental Hyperuricemia.
Hyperuricemia is an abnormal metabolic condition characterized by an increase in uric acid levels in the blood. It is the cause of gout, manifested by inflammatory arthritis, pain and disability. This study examined the possible ameliorative impacts of parsley (PAR) and celery (CEL) as hypouricemic agents at biochemical, molecular and cellular levels. PAR and CEL alone or in combination were orally administered to hyperuricemic (HU) mice and control mice for 10 consecutive days. Serum levels of uric acid and blood urea nitrogen (BUN), xanthine oxidase activity, antioxidants, inflammatory (IL-1β and TNF-α) and anti-inflammatory cytokines (IL-10) were measured. mRNA expression of urate transporters and uric acid excretion genes in renal tissues were examined using qRT-PCR (quantitative real time PCR). Normal histology and immunoreactivity of transforming growth factor-beta 1 (TGF-β1) in kidneys was examined. Administration of PAR and CEL significantly reduced serum BUN and uric acids in HU mice, ameliorated changes in malondialdehyde, catalase, and reduced glutathione, glutathione peroxidase (GPX), IL-1β, TNF-α and IL-10 in hyperuricemic mice. Both effectively normalized the alterations in mURAT-1, mGLUT-9, mOAT-1 and mOAT-3 expression, as well as changes in TGF-β1 immunoreactivity. Interestingly, combined administration of PAR and CEL mitigated all examined measurements synergistically, and improved renal dysfunction in the hyperuricemic mice. The study concluded that PAR and CEL can potentially reduce damaging cellular, molecular and biochemical effects of hyperuricemia both individually and in combination.


Pattern-specific role of the current orientation used to deliver Theta Burst Stimulation.
To evaluate the role of current direction on the after-effects of Theta Burst Stimulation (TBS) delivered with a biphasic Magstim 200(2) stimulator. Inhibitory (cTBS) and excitatory TBS (iTBS) were delivered over the motor cortex of healthy individuals using reversed and standard current orientations (initial current in the antero-posterior direction) at 80% and 100% of their respective active motor thresholds (AMT). The after-effects on the MEP amplitude were measured for 25 min. The effects of the most effective reversed cTBS paradigm on intracortical inhibition (SICI) and facilitation (ICF) were also tested. Reversing the current direction reduced AMT by 26%+/-2%. Compared to standard cTBS, reversed cTBS induced stronger and longer-lasting inhibition of corticospinal excitability when delivered at 100% AMTrev. SICI was reduced after cTBS100%revAMT while ICF was unchanged. The after-effects of reversed iTBS were quite variable regardless of the intensity. cTBS applied with antero-posterior current is more effective in suppressing subsequent MEPs than conventionally orientated cTBS when the absolute stimulation intensity is similar. On the contrary, posterior current orientation reduces the efficacy of iTBS. The current direction may affect the power of inhibitory and excitatory TBS in opposite ways; this should be considered in order to optimise the after-effects of biphasic RTMS.


Irreversible color vision losses in patients with chronic mercury vapor intoxication.
This longitudinal study addresses the reversibility of color vision losses in subjects who had been occupationally exposed to mercury vapor. Color discrimination was assessed in 20 Hg-exposed patients (mean age = 42.4 +/- 6.5 years; 6 females and 14 males) with exposure to Hg vapor during 10.5 +/- 5.3 years and away from the work place (relative to 2002) for 6.8 +/- 4.2 years. During the Hg exposure or up to one year after ceasing it, mean urinary Hg concentration was 47 +/- 35.4 mug/g creatinine. There was no information on Hg urinary concentration at the time of the first tests, in 2002 (Ventura et al., 2005), but at the time of the follow-up tests, in 2005, this value was 1.4 +/- 1.4 microg/g creatinine for patients compared with 0.5 +/- 0.5 microg/g creatinine for controls (different group from the one in Ventura et al. (2005)). Color vision was monocularly assessed using the Cambridge Colour Test (CCT). Hg-exposed patients had significantly worse color discrimination (p < 0.02) than controls, as evaluated by the size of MacAdam's color discrimination ellipses and color discrimination thresholds along protan, deutan, and tritan confusion axes. There were no significant differences between the results of the study in Ventura et al. (2005) and in the present follow-up measurements, in 2005, except for worsening of the tritan thresholds in the best eye in 2005. Both chromatic systems, blue-yellow and red-green, were affected in the first evaluation (Ventura et al., 2005) and remained impaired in the follow-up testing, in 2005. These findings indicate that following a long-term occupational exposure to Hg vapor, even several years away from the source of intoxication, color vision impairment remains irreversible.


An evolutionarily conserved PTEN-C/EBPalpha-CTNNA1 axis controls myeloid development and transformation.
Loss of function of tumor suppressor genes, such as PTEN, CEBPAlpha, and CTNNA1 (encoding the alpha-catenin protein), has been found to play an essential role in leukemogenesis. However, whether these genes genetically interact remains largely unknown. Here, we show that PTEN-mammalian target of rapamycin signaling acts upstream to dictate the ratio of wild-type p42 C/EBPalpha to its dominant-negative p30 isoform, which critically determines whether p30 C/EBPalpha (lower p42/p30 ratio) or p42 C/EBPalpha (higher p42/p30 ratio) binds to the proximal promoter of the retained CTNNA1 allele. Binding of p30 C/EBPalpha recruits the polycomb repressive complex 2 to suppress CTNNA1 transcription through repressive H3K27me3 modification, whereas binding of p42 C/EBPalpha relieves this repression and promotes CTNNA1 expression through activating H3K4me3 modification. Loss of Pten function in mice and zebrafish induces myelodysplasia with abnormal invasiveness of myeloid progenitors accompanied by significant reductions in both wild-type C/EBPalpha and alpha-catenin protein. Importantly, frame-shift mutations in either PTEN or CEBPA were detected exclusively in the primary LICs with low CTNNA1 expression. This study uncovers a novel molecular pathway, PTEN-C/EBPalpha-CTNNA1, which is evolutionarily conserved and might be therapeutically targeted to eradicate LICs with low CTNNA1 expression.


How practitioners integrate decision triggers with existing metrics in conservation monitoring.
Decision triggers are defined thresholds in the status of monitored variables that indicate when to undertake management, and avoid undesirable ecosystem change. Decision triggers are frequently recommended to conservation practitioners as a tool to facilitate evidence-based management practices, but there has been limited attention paid to how practitioners are integrating decision triggers into existing monitoring programs. We sought to understand whether conservation practitioners' use of decision triggers was influenced by the type of variables in their monitoring programs. We investigated this question using a practitioner-focused workshop involving a structured discussion and review of eight monitoring programs. Among our case studies, direct measures of biodiversity (e.g. native species) were more commonly monitored, but less likely to be linked to decision triggers (10% with triggers) than measures being used as surrogates (54% with triggers) for program objectives. This was because decision triggers were associated with management of threatening processes, which were often monitored as a surrogate for a biodiversity asset of interest. By contrast, direct measures of biodiversity were more commonly associated with informal decision processes that led to activities such as management reviews or external consultation. Workshop participants were in favor of including more formalized decision triggers in their programs, but were limited by incomplete ecological knowledge, lack of appropriately skilled staff, funding constraints, and/or uncertainty regarding intervention effectiveness. We recommend that practitioners consider including decision triggers for discussion activities (such as external consultation) in their programs as more than just early warning points for future interventions, particularly for direct measures. Decision triggers for discussions should be recognized as a critical feature of monitoring programs where information and operational limitations inhibit the use of decision triggers for interventions.


The bacterial contamination of allogeneic bone and emergence of multidrug-resistant bacteria in tissue bank.
Present study was carried out for the microbiological evaluation of allogeneic bone processed from femoral heads. A total 60 bacterial isolates comprising five different species including Streptococcus spp., Staphylococcus spp., Klebsiella spp., Bacillus spp., and Pseudomonas spp. were characterized based on their cultural and biochemical characteristics. Average bioburden was ranged from 5.7 × 10(1) to 3.9 × 10(4) cfu/gm. The majority (81.7%) of the microbial contaminants were detected as Gram positive with the predominant organism being skin commensal coagulase negative Staphylococci (43.3%). Antimicrobial resistance was evaluated by the activities of 14 broad and narrow spectrum antibiotic discs. Comparing the overall pattern, marked resistance was noted against Penicillin and Amoxicillin 100% (60/60). The most effective single antibiotics were Gentamicin, Tobramycin, and Ofloxacin which were bactericidal against 100% (60/60) isolates. Multidrug resistance (MDR) was confirmed in 70% (42/60) of the samples. Among them, the most prevalent antibiotypes were Penicillin, Amoxicillin, Oxacillin, Polymyxin, and Cefpodoxime (80% of total MDR). The study results revealed higher contamination rate on bone allografts and recommend the implementation of good tissue banking practices during tissue procurement, processing, and storage in order to minimize the chances of contamination.