Resistance exercise stimulates mixed muscle protein synthesis in lean and obese young adults.
Obese individuals exhibit a diminished muscle protein synthesis response to nutrient stimulation when compared with their lean counterparts. However, the effect of obesity on exercise-stimulated muscle protein synthesis remains unknown. Nine lean (23.5 ± 0.6 kg/m2 ) and 8 obese (33.6 ± 1.2 kg/m2 ) physically active young adults participated in a study that determined muscle protein synthesis and intracellular signaling at rest and following an acute bout of resistance exercise. Mixed muscle protein synthesis was determined by combining stable isotope tracer ([13 C6 ]phenylalanine) infusion with serial biopsies of the vastus lateralis. A unilateral leg resistance exercise model was adopted so that resting and postexercise measurements of muscle protein synthesis could be obtained simultaneously. Obesity was associated with higher basal levels of serum insulin (P < 0.05), plasma triacylglycerol (P < 0.01), plasma cholesterol (P < 0.01), and plasma CRP (P < 0.01), as well as increased insulin resistance determined by HOMA-IR (P < 0.05). However, resting and postexercise rates of muscle protein synthesis were not significantly different between lean and obese participants (P = 0.644). Furthermore, resistance exercise stimulated muscle protein synthesis (~50% increase) in both groups (P < 0.001), with no difference between lean and obese (P = 0.809). Temporal increases in the phosphorylation of intracellular signaling proteins (AKT/4EBP1/p70S6K) were observed within the exercised leg (P < 0.05), with no differences between lean and obese. These findings suggest a normal anabolic response to muscle loading in obese young adults.


Tumor necrosis factor (TNF) is induced in mice by Candida albicans: role of TNF in fibrinogen increase.
One intraperitoneal dose of Candida albicans (10(8) CFU) caused a chronic (longer than 2 months), significant elevation of plasma fibrinogen levels (Clauss method) in mice of strain C3H/HeN. Even a small dose (10(6) CFU) resulted in a significant increase in fibrinogen level for 5 days following injection, whereas other blood parameters (leukocytes, erythrocytes, platelets, hematocrit, hemoglobin, blood urea nitrogen, aspartate aminotransferase, albumin, alkaline phosphatase, antithrombin III, glucose, calcium, and total protein) measured by standard methods were normal. Blood taken during this period was negative for C. albicans. The role of tumor necrosis factor (TNF) in C. albicans infections was investigated by measuring the fibrinogen response after the administration of C. albicans or recombinant mouse TNF-alpha. Both challenges resulted in an elevated fibrinogen level. When polyclonal antibodies to mouse TNF-alpha were given prior to challenge with C. albicans or mouse TNF-alpha, the fibrinogen increase was significantly inhibited. C. albicans injections were found to significantly elevate endogenous TNF levels in mice (enzyme-linked immunosorbent assay). It was concluded that C. albicans induces TNF in the mouse. Furthermore, these data give evidence which supports a relationship between TNF and the fibrinogen increase induced by C. albicans.


Multitrait, Random Regression, or Simple Repeatability Model in High-Throughput Phenotyping Data Improve Genomic Prediction for Wheat Grain Yield.
High-throughput phenotyping (HTP) platforms can be used to measure traits that are genetically correlated with wheat ( L.) grain yield across time. Incorporating such secondary traits in the multivariate pedigree and genomic prediction models would be desirable to improve indirect selection for grain yield. In this study, we evaluated three statistical models, simple repeatability (SR), multitrait (MT), and random regression (RR), for the longitudinal data of secondary traits and compared the impact of the proposed models for secondary traits on their predictive abilities for grain yield. Grain yield and secondary traits, canopy temperature (CT) and normalized difference vegetation index (NDVI), were collected in five diverse environments for 557 wheat lines with available pedigree and genomic information. A two-stage analysis was applied for pedigree and genomic selection (GS). First, secondary traits were fitted by SR, MT, or RR models, separately, within each environment. Then, best linear unbiased predictions (BLUPs) of secondary traits from the above models were used in the multivariate prediction models to compare predictive abilities for grain yield. Predictive ability was substantially improved by 70%, on average, from multivariate pedigree and genomic models when including secondary traits in both training and test populations. Additionally, (i) predictive abilities slightly varied for MT, RR, or SR models in this data set, (ii) results indicated that including BLUPs of secondary traits from the MT model was the best in severe drought, and (iii) the RR model was slightly better than SR and MT models under drought environment.


Sleep onset insomnia, daytime sleepiness and sleep duration in relationship to Toxoplasma gondii IgG seropositivity and serointensity.
Toxoplasma gondii (T. gondii) infects central nervous tissue and is kept in relative dormancy by a healthy immune system. Sleep disturbances have been found to precipitate mental illness, suicidal behavior and car accidents, which have been previously linked to T. gondii as well. We speculated that if sleep disruption, particularly insomnia, would mediate, at least partly, the link between T. gondii infection and related behavioral dysregulation, then we would be able to identify significant associations between sleep disruption and T. gondii. The mechanisms for such an association may involve dopamine (DA) production by T. gondii, or collateral effects of immune activation necessary to keep T. gondii in check. Sleep questionnaires from 2031 Old Order Amish were analyzed in relationship to T. gondii-IgG antibodies measured by enzyme-linked immunosorbent assay (ELISA). Toxoplasma gondii seropositivity and serointensity were not associated with any of the sleep latency variables or Epworth Sleepiness Scale (ESS). A secondary analysis identified, after adjustment for age group, a statistical trend toward shorter sleep duration in seropositive men (p = 0.07). In conclusion, it is unlikely that sleep disruption mediates links between T. gondii and mental illness or behavioral dysregulation. Trending gender differences in associations between T. gondii and shorter sleep need further investigation.


Human conscious response to thermal input is adjusted to changes in mean body temperature.
To detect the dependable criteria of behavioural thermoregulation through modelling temperature fluctuations of individuals allowed to freely manipulate inlet water temperature of a liquid conditioning garment (LCG) during 130 min of passive exposure to -20 degrees C interspersed with a 10 min period of moderate exercise at the 65th minute using a double-blind experiment. Eleven volunteers (5 women; 23.40 (SD 2.09) years; BMI: 23.24 (SD 2.19)) who lacked previous experience with LCG and cold exposure experiments. Despite variations in core and skin temperatures, thermal comfort, thermal sensation, and mean body temperature did not fluctuate significantly over time. Participants were able to find a desired level of LCG inlet temperature within 25 minutes which was maintained at similar levels until the 65th minute of the cold exposure. During exercise, LCG inlet water temperature decreased significantly. Regression models demonstrated that mean skin temperature and change in mean body temperature were significantly associated with thermal comfort and thermal sensation. Subsequent models revealed that, although all temperature variables were associated with LCG inlet water temperature, the coefficient of determination mainly depended on mean skin temperature and change in mean body temperature. The involvement of skin temperature was anticipated as the liquid conditioning garment was in contact with the skin. Humans generate conscious thermoregulatory responses in resting and exercise conditions during exposures to cold environments that are aimed towards maintaining a threshold mean body temperature, rather than temperature changes in individual body regions.


Critical roles for the Bcl-3 oncoprotein in T cell-mediated immunity, splenic microarchitecture, and germinal center reactions.
Chromosomal translocations of bcl-3 are associated with chronic B cell lymphocytic leukemias. Previously, we have shown that Bcl-3, a distinct member of the I kappa B family, may function as a positive regulator of NF-kappa B activity, although its physiologic roles remained unknown. To uncover these roles, we generated Bcl-3-deficient mice. Mutant mice, but not their littermate controls, succumb to T. gondii owing to failure to mount a protective T helper 1 immune response. Bcl-3-deficient mice are also impaired in germinal center reactions and T-dependent antibody responses to influenza virus. The results reveal critical roles for Bcl-3 in antigen-specific priming of T and B cells. Altered microarchitecture of secondary lymphoid organs in mutant mice, including partial loss of B cells, may underlie the immunologic defects. The implied role of Bcl-3 in maintaining B cells in wild-type mice may related to its oncogenic potential.


Phasic dopamine release in the rat nucleus accumbens symmetrically encodes a reward prediction error term.
Making predictions about the rewards associated with environmental stimuli and updating those predictions through feedback is an essential aspect of adaptive behavior. Theorists have argued that dopamine encodes a reward prediction error (RPE) signal that is used in such a reinforcement learning process. Recent work with fMRI has demonstrated that the BOLD signal in dopaminergic target areas meets both necessary and sufficient conditions of an axiomatic model of the RPE hypothesis. However, there has been no direct evidence that dopamine release itself also meets necessary and sufficient criteria for encoding an RPE signal. Further, the fact that dopamine neurons have low tonic firing rates that yield a limited dynamic range for encoding negative RPEs has led to significant debate about whether positive and negative prediction errors are encoded on a similar scale. To address both of these issues, we used fast-scan cyclic voltammetry to measure reward-evoked dopamine release at carbon fiber electrodes chronically implanted in the nucleus accumbens core of rats trained on a probabilistic decision-making task. We demonstrate that dopamine concentrations transmit a bidirectional RPE signal with symmetrical encoding of positive and negative RPEs. Our findings strengthen the case that changes in dopamine concentration alone are sufficient to encode the full range of RPEs necessary for reinforcement learning.


Safety and potential efficacy of gemfibrozil as a supportive treatment for children with late infantile neuronal ceroid lipofuscinosis and other lipid storage disorders.
Neuronal Ceroid Lipofuscinosis (NCL), also known as Batten disease, is a group of genetically distinct lysosomal disorders that mainly affect the central nervous system, resulting in progressive motor and cognitive decline primarily in children. Multiple distinct genes involved in the metabolism of lipids have been identified to date with various mutations in this family of diseases. There is no cure for these diseases but some new therapeutic approaches have been tested that offer more hope than the standard palliative care. Many of the therapeutic advances require invasive procedures but some progress in slowing the disease has been found and more options can be expected in the future. We also review the literature on children with disease/conditions other than NCL for the non-invasive use, safety, and tolerability of a lipid-lowering drug, gemfibrozil, as a potential treatment for NCLs. Gemfibrozil has shown efficacy in an animal model of NCL known as CLN2 (late infantile classic juvenile) and has been shown to be safe for lowering lipids in children. Among the 200 non-NCL children found in the published literature who were treated with gemfibrozil for NCL-related problems, only 3 experienced adverse events, including 2 with muscle pain and 1 with localized linear IgA bullous dermatitis. We conclude that gemfibrozil is safe for long-term use in children, causes minimal adverse events, is well tolerated, and may delay the progression of NCLs. Gemfibrozil may potentially be an alternative to more invasive therapeutic approaches currently under investigation and has the potential to be used in combination with other therapeutic approaches.


The potential of metabolic and lipid profiling in inflammatory bowel diseases: A pilot study.
Inflammatory bowel diseases (IBDs) are conditions that still pose significant problems. A third of the patients are either misdiagnosed or a proper diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) cannot be made. We need new biomarkers, so that we can offer patients the best treatment and keep the disease in an inactive state for as long as possible. Alterations in metabolic profiles have been incriminated in the pathophysiology of IBD. The aim of the present study was to identify molecules that could serve as biomarkers for a positive diagnosis of IBD as well as to discriminate UC from colonic CD. Twenty-two patients with active colonic IBD (UC = 17, CD = 5) and 24 age- and gender-matched healthy controls were enrolled. Plasma lipid and metabolic profiles were quantified using ultra-high-performance liquid chromatography combined with mass spectrometry. Univariate and multivariate statistical tests were employed. Six lipid species and 7 metabolites were significantly altered in IBD patients compared to healthy controls, with the majority belonging to glycerophospholipid, linoleic acid, and sphingolipid metabolisms. Five lipid species and only 1 metabolite were significantly increased in UC compared to CD. This preliminary study suggests that lipid and metabolic profiling of serum can become diagnostic tools for IBD. In addition, they can be used to differentiate between CD and UC.


Association of enteric parasitic infections with intestinal inflammation and permeability in asymptomatic infants of São Tomé Island.
The cumulative effect of repeated asymptomatic enteric infections on intestinal barrier is not fully understood in infants. We aimed to evaluate the association between previous enteric parasitic infections and intestinal inflammation and permeability at 24-months of age, in asymptomatic infants of São Tomé Island. A subset of infants from a birth cohort, with intestinal parasite evaluations in at least four points of assessment, was eligible. Intestinal inflammatory response and permeability were assessed using fecal S100A12 and alpha-1-antitrypsin (A1AT), respectively. The cutoff <-1SD for weight-for-length and length-for-age was used to define wasting and stunting. Multivariable linear regression analysis explored if cumulative enteric parasitic infections explained variability of fecal biomarkers, after adjusting for potential confounders. Eighty infants were included. Giardia duodenalis and soil-transmitted helminths (STH) were the most frequent parasites. The median (interquartile range) levels were 2.87 μg/g (2.41-3.92) for S100A12 and 165.1 μg/g (66.0-275.6) for A1AT. Weak evidence of association was found between S100A12 levels and G. duodenalis (p = 0.080) and STH infections (p = 0.089), and between A1AT levels and parasitic infection of any etiology (p = 0.089), at 24-months of age. Significant associations between A1AT levels and wasting (p = 0.006) and stunting (p = 0.044) were found. Previous parasitic infections were not associated with fecal biomarkers at 24 months of age. To summarize, previous asymptomatic parasitic infections showed no association with intestinal barrier dysfunction. Notwithstanding, a tendency toward increased levels of the inflammatory biomarker was observed for current G. duodenalis and STH infections, and increased levels of the permeability biomarker were significantly associated with stunting and wasting.


Independent components of color natural scenes resemble V1 neurons in their spatial and color tuning.
It has been hypothesized that mammalian sensory systems are efficient because they reduce the redundancy of natural sensory input. If correct, this theory could unify our understanding of sensory coding; here, we test its predictions for color coding in the primate primary visual cortex (V1). We apply independent component analysis (ICA) to simulated cone responses to natural scenes, obtaining a set of colored independent component (IC) filters that form a redundancy-reducing visual code. We compare IC filters with physiologically measured V1 neurons, and find great spatial similarity between IC filters and V1 simple cells. On cursory inspection, there is little chromatic similarity; however, we find that many apparent differences result from biases in the physiological measurements and ICA analysis. After correcting these biases, we find that the chromatic tuning of IC filters does indeed resemble the population of V1 neurons, supporting the redundancy-reduction hypothesis.


Development of a method for personal, spatiotemporal exposure assessment.
This work describes the development and evaluation of a high resolution, space and time-referenced sampling method for personal exposure assessment to airborne particulate matter (PM). This method integrates continuous measures of personal PM levels with the corresponding location-activity (i.e. work/school, home, transit) of the subject. Monitoring equipment include a small, portable global positioning system (GPS) receiver, a miniature aerosol nephelometer, and an ambient temperature monitor to estimate the location, time, and magnitude of personal exposure to particulate matter air pollution. Precision and accuracy of each component, as well as the integrated method performance were tested in a combination of laboratory and field tests. Spatial data was apportioned into pre-determined location-activity categories (i.e. work/school, home, transit) with a simple, temporospatially-based algorithm. The apportioning algorithm was extremely effective with an overall accuracy of 99.6%. This method allows examination of an individual's estimated exposure through space and time, which may provide new insights into exposure-activity relationships not possible with traditional exposure assessment techniques (i.e., time-integrated, filter-based measurements). Furthermore, the method is applicable to any contaminant or stressor that can be measured on an individual with a direct-reading sensor.


Patterns of bidirectional communication between cortex and basal ganglia during movement in patients with Parkinson disease.
Cortico-basal ganglia networks are considered to comprise several parallel and mostly segregated loops, where segregation is achieved in space through topographic connectivity. Recently, it has been suggested that functional segregation may also be achieved in the frequency domain, by selective coupling of related activities at different frequencies. So far, however, any coupling across frequency in the human has only been modeled in terms of unidirectional influences, a misplaced assumption given the looped architecture of the basal ganglia, and has been considered in static terms. Here, we investigate the pattern of bidirectional coupling between mesial and lateral cortical areas and the subthalamic nucleus (STN) at rest and during movement, with and without pharmacological dopaminergic input, in patients with Parkinson's disease. We simultaneously recorded scalp electroencephalographic activity and local field potentials from depth electrodes and deduced patterns of directed coherence between cortical and STN levels across three frequency bands [sub-beta (3-13 Hz), beta (14-35 Hz), gamma (65-90 Hz)] in the different states. Our results show (1) asymmetric bidirectional coupling between STN and both mesial and lateral cortical areas with greater drives from cortex to STN at frequencies <35 Hz, (2) a drop of beta band coupling driven from mesial cortex to STN during movement, and (3) an increase in symmetrical bidirectional drives between STN and mesial cortex and in lateral cortical drive to STN in the gamma band after dopaminergic therapy. The results confirm a bidirectional pattern of cortico-basal ganglia communication that is differentially patterned across frequency bands and changes with movement and dopaminergic input.


Protein-mediated disproportionation of Au(i): insights from the structures of adducts of Au(iii) compounds bearing N,N-pyridylbenzimidazole derivatives with lysozyme.
Au(iii) compounds bearing N,N-pyridylbenzimidazole derivatives with the ethyl (1) or propyl sulfonate (2) appendage react with the model protein hen egg white lysozyme (HEWL), forming adducts with different gold-containing fragments. The conformation of the enzyme, the exact gold binding sites and the oxidation state of Au in the adducts are unknown. Here we report a structural study on the reaction of 1 and 2 with HEWL in solution and solid state. In agreement with previously reported electrospray ionization mass spectra, the compounds degrade in their interaction with the protein. In the structure derived from HEWL crystals exposed to 1 for less than one day, three Au binding sites were identified: Au(i) ions are bound to the side chain of His15 and to the side chains of His15 and Asn93. The third gold centre is buried in the hydrophobic pocket of the protein via the binding to the side chain of Met105 and the trapping between the side chains of Trp28, Trp108 and Trp111. In a second crystal fished three hours later from the same drop, only one Au ion, probably in the +1 oxidation state, is observed; it binds the protein close to the side chains of Asn93 and His15. After three days of soaking, the colour of HEWL crystals obtained in the presence of 1 turned violet. In these crystals, anomalous signals attributable to Au are found on the protein surface; gold atoms are not directly coordinated to residue side chains. Longer exposure of HEWL crystals to 1 produces gold-free crystals. In the adduct of HEWL exposed to 2 for one day, three Au(i) ions are detected close to the side chains of both Asn93 and His15, the side chain of His15 and that of Met105. Longer exposure of HEWL crystals to 2 affords gold-free crystals. These structural data and those of the other protein/gold adducts available at the Protein Data Bank suggest that the reduction of Au(iii) into Au(i) is the basis of the mechanism of action of the biologically active gold(iii) compounds. Besides, Au(i) ions can undergo disproportionation into Au(iii) and Au(0) that can diffuse away from the protein crystals.


Milk containing Mycobacterium bovis as a source of infection for white-tailed deer fawns (Odocoileus virginianus).
White-tailed deer represent the first wildlife reservoir of Mycobacterium bovis in the United States. The behavior of does with nursing fawns provides several potential mechanisms for disease transmission. Little information exists concerning transmission between doe and fawn, specifically transmammary transmission. Determine if fawns can become infected by ingestion of milk replacer containing M. bovis, thus simulating transmission from doe to fawn through contaminated milk. Seventeen, 21-day-old white-tailed deer fawns were inoculated orally with 2 x 10(8) CFU (high dose, n=5), 2.5 x 10(5) to 2.5 x 10(6) CFU (medium dose, n=5), and 1 x 10(4) CFU (low dose, n=5) of M. bovis in milk replacer. Dosages were divided equally and fed daily over a 5-day period. Positive control fawns (n=2) received 1 x 10(5) CFU of M. bovis instilled in the tonsillar crypts. Fawns were euthanized and examined 35-115 days after inoculation and various tissues collected for bacteriologic and microscopic analysis. All fawns in the tonsillar, high oral and medium oral dose groups developed generalized tuberculosis involving numerous organs and tissues by 35-84 days after inoculation. Three of five fawns in the low-dose oral group had tuberculous lesions in the mandibular lymph node, and one of five had lesions in the medial retropharyngeal lymph node when examined 115 days after inoculation. White-tailed deer fawns can become infected through oral exposure to M. bovis. Therefore, the potential exists for fawns to acquire M. bovis while nursing tuberculous does.


Seizure recurrence and remission after switching antiepileptic drugs.
Studies of seizure outcome in patients undergoing serial antiepileptic drug trials have all been uncontrolled, with no account made for the spontaneous changes in disease state that could confound the elucidation of drug effects. In addition, no study has ever looked at outcome following antiepileptic drug switch in seizure-free patients, despite the fact that this is done routinely in clinical practice. We aimed to address both of these issues using a matched case-cohort design. We followed patients taking phenytoin or carbamazepine in monotherapy for focal epilepsy who were being crossed over to a newer agent as part of studies on the metabolic effects of anticonvulsant therapy. Many had been seizure-free but were being switched nonetheless due to side effects or concerns about long-term adverse consequences. Each patient was matched with two controls of the same seizure status who were taking anticonvulsant monotherapy and whose drug was not switched. Seizure freedom over the ensuing 6 months was the primary end point. There were 43 cases and 86 matched controls. Twenty-three patients (cases) had been seizure-free on their old drug; 5 (21.7%) had seizure recurrence after drug switch compared to 2 (4.3%) of 46 matched controls. Twenty patients (cases) were having seizures on their old drug; 6 (30%) entered remission after drug switch, compared to 8 of 40 matched controls (20%). The two groups differed at baseline in number of anticonvulsants previously failed, which was the most important factor for prognosis. After statistical adjustment to account for this, seizure-free patients had 6.53 times higher odds of seizure recurrence if switched to a new drug (95% confidence interval [CI] 1.02-61.19; p = 0.06). Non-seizure-free patients had 1.66 times higher odds of remission if they remained on the same drug compared to switching, although this was not significant (95% CI 0.36-8.42; p = 0.532). Neither dose changes, nor drug mechanism, nor duration of seizure freedom had any bearing upon the results. Although the large majority of seizure-free patients remain so when switched to another agent, about one sixth have a recurrence attributable to the change. Conversely, our study design provides the first evidence to suggest that most improvements in drug-resistant patients are likely due to spontaneous remissions, not new drug introductions. These findings have conflicting implications for two competing models of comparative antiepileptic drug efficacy, which will require further study to elaborate.


A method for evaluating cocaine-induced social preference in rats.
Drug addicts are extremely sensitive to cues that predict drug availability and exposure to these cues can facilitate drug relapse. Cues vary in their nature but can include drug-associated paraphernalia, environmental contexts, and discrete conditioned stimuli (e.g., advertisements). One cue that has recently been heavily investigated is that of social interaction. To date, it has been demonstrated that when cocaine is conditioned with social interaction, place preference for cocaine significantly increases, suggesting that the presence of social interaction during a drug-associated "high" enhances the magnitude of drug reward. When social interaction is provided in a mutually exclusive, non-drug environment though, it can serve as a preventative stimulus towards cocaine seeking. What remains unknown is whether contact with rats associated with drug experience facilitates preferential social interactions for those rats. The first step in answering this question is to determine if rats can behaviorally discriminate between drug-associated and non-drug-associated conspecifics, much like humans can differentiate their "drug-friends" from their non-drug-using friends. Using a custom social interaction chamber, in which rats were able to interact with two distinct conspecifics via holes in a boundary wall, we demonstrate that rats exhibit more interactive and investigative behavior towards a partner that was consistently present during the drug-state, than a partner that was present when the rat was "sober". It is our hope that this protocol will contribute to the development of models designed to study social cue-induced reinstatement, and related neural substrates, and will ultimately contribute to the treatment of substance use disorders.


Effect of three indigenous food stains on resin-based, microhybrid-, and nanocomposites.
This study investigated the effects of three indigenous food stains (tea, tobacco, turmeric) on a nanocomposite (Ceram-X-Mono, Dentsply DeTery, Konstanz, Germany), a microhybrid posterior (P60, 3M ESPE, St. Paul, MN, USA), and a universal microhybrid (Z100, 3M ESPE) resin-based composite (RBC). Thirty-six disk-shaped specimens were fabricated (10 × 2 mm) for each type of RBC material, using a polytetraflouroethylene (PTFE) sheet. Specimens from each group were randomly distributed into three subgroups for each of the used stains. The baseline color values were measured using a spectrophotometer. The specimens were immersed in the staining solutions for a period of 3 hours per day for 15 days (3 hours/day × 15 days). Following this, the color change value (ΔE) was calculated. All the tested groups showed a clinically perceptible color change (ΔE values = 3.3 or >3.3), except for tea-stained P60 (ΔE = 3.15) and Z100 (ΔE = 1.63) groups. Turmeric caused the most significant color change for all the tested RBCs. The least amount of color change was observed with the Z100 (tea, ΔE = 1.63; tobacco, ΔE = 13.59; turmeric, ΔE = 38.77) group that was statistically significant from P60 (tea, ΔE = 3.15; tobacco, ΔE = 18.83; turmeric, ΔE = 57.72), and Ceram-X-Mono (tea, ΔE = 3.32; tobacco, ΔE = 18.83; turmeric, ΔE = 53.95) groups.


The 'cultural inflation of morbidity' during the English mortality decline: a new look.
This article contributes to the debate about using insurance records to reconstruct historical experiences of sickness during the Western mortality transition. Critics regard these sources as problematic as they measure morbidity indirectly through absences from work; these might be determined not by timeless biological criteria but by more contingent factors, notably shifting norms surrounding the sick role and responses to economic incentives (for which we adopt the generic term 'cultural inflation of morbidity'). We review historical demographers' contributions to this literature and discuss the concepts of moral hazard and the principal/agent problem as developed by health economists. This leads us to frame three empirical tests for 'cultural inflation' which allow us to assess the validity of insurance records for deriving morbidity trends: was there an increasing frequency of claims for complaints of diminishing severity; were unduly prolonged claims noticeable, particularly by older people for whom sickness benefit may have compensated for income insecurity; and did the insurer satisfactorily manage the agency problem to ensure reliable physician gatekeeping? We analyse records of the Hampshire Friendly Society, an exceptionally well-documented fund operational in Southern England, 1825-1989. Findings are based on a dataset of individual sickness histories of a sample of 5552 men and on qualitative documentary analysis of administrative records. On each count our results fail to demonstrate a cultural inflation of morbidity, except perhaps for those aged over 65. However, occasional discussion in the administrative records of economic incentives encouraging unnecessary prolongation of claims means we cannot rule it out entirely.


In situ synchrotron XRD analysis of the kinetics of spodumene phase transitions.
The phase transition by thermal activation of natural α-spodumene was followed by in situ synchrotron XRD in the temperature range 896 to 940 °C. We observed both β- and γ-spodumene as primary products in approximately equal proportions. The rate of the α-spodumene inversion is first order and highly sensitive to temperature (apparent activation energy ∼800 kJ mol-1). The γ-spodumene product is itself metastable, forming β-spodumene, with the total product mass fraction ratio fγ/fβ decreasing as the conversion of α-spodumene continues. We found the relationship between the product yields and the degree of conversion of α-spodumene to be the same at all temperatures in the range studied. A model incorporating first order kinetics of the α- and γ-phase inversions with invariant rate constant ratio describes the results accurately. Theoretical phonon analysis of the three phases indicates that the γ phase contains crystallographic instabilities, whilst the α and β phases do not.


Zinc(II) binding on human wild-type ISCU and Met140 variants modulates NFS1 desulfurase activity.
Human de novo iron-sulfur (Fe-S) assembly complex consists of cysteine desulfurase NFS1, accessory protein ISD11, acyl carrier protein ACP, scaffold protein ISCU, and allosteric activator frataxin (FXN). FXN binds the NFS1-ISD11-ACP-ISCU complex (SDAU), to activate the desulfurase activity and Fe-S cluster biosynthesis. In the absence of FXN, the NFS1-ISD11-ACP (SDA) complex was reportedly inhibited by binding of recombinant ISCU. Recent studies also reported a substitution at position Met141 on the yeast ISCU orthologue Isu, to Ile, Leu, Val, or Cys, could bypass the requirement of FXN for Fe-S cluster biosynthesis and cell viability. Here, we show that recombinant human ISCU binds zinc(II) ion, as previously demonstrated with the E. coli orthologue IscU. Surprisingly, the relative proportion between zinc-bound and zinc-depleted forms varies among purification batches. Importantly the presence of zinc in ISCU impacts SDAU desulfurase activity. Indeed, removal of zinc(II) ion from ISCU causes a moderate but significant increase in activity compared to SDA alone, and FXN can activate both zinc-depleted and zinc-bound forms of ISCU complexed to SDA. Taking into consideration the inhibition of desulfurase activity by zinc-bound ISCU, we characterized wild type ISCU and the M140I, M140L, and M140V variants under both zinc-bound and zinc-depleted conditions, and did not observe significant differences in the biochemical and biophysical properties between wild-type and variants. Importantly, in the absence of FXN, ISCU variants behaved like wild-type and did not stimulate the desulfurase activity of the SDA complex. This study therefore identifies an important regulatory role for zinc-bound ISCU in modulation of the human Fe-S assembly system in vitro and reports no 'FXN bypass' effect on mutations at position Met140 in human ISCU. Furthermore, this study also calls for caution in interpreting studies involving recombinant ISCU by taking into consideration the influence of the bound zinc(II) ion on SDAU complex activity.


Comparison of silver-coated dressing (Acticoat), chlorhexidine acetate 0.5% (Bactigrass), and silver sulfadiazine 1% (Silverdin) for topical antibacterial effect in Pseudomonas aeruginosa-contaminated, full-skin thickness burn wounds in rats.
Acticoat (Smith and Nephew, Istanbul, Turkey), chlorhexidine acetate 0.5%, and silver sulfadiazine 1% were compared to assess the antibacterial effect of their application on experimental burn wounds in contaminated with Pseudomonas aeruginosa in rats. All treatment modalities were effective against P. aeruginosa because there were significant differences between treatment groups and control groups. The mean eschar concentrations did not differ significantly between Acticoat and chlorhexidine acetate groups, but there were significant differences between the silver sulfadiazine group and the other treatment groups, indicating that silver sulfadiazine significantly eliminated P. aeruginosa more effectively in the tissues than did the other two agents. All treatment modalities were sufficient to prevent the P. aeruginosa from invading to the muscle and from causing systemic infection. In conclusion, silver sulfadiazine is the most effective agent in the treatment of the P. aeruginosa-contaminated burn wounds; Acticoat can be considered as a treatment choice because of its peculiar ability of limiting the frequency of replacing wound dressings.


Lamina-specific alterations in cortical GABA(A) receptor subunit expression in schizophrenia.
Dysfunction of the dorsolateral prefrontal cortex (DLPFC) in schizophrenia is associated with lamina-specific alterations in particular subpopulations of interneurons. In pyramidal cells, postsynaptic γ-aminobutyric acid (GABA(A)) receptors containing different α subunits are inserted preferentially in distinct subcellular locations targeted by inputs from specific interneuron subpopulations. We used in situ hybridization to quantify the laminar expression of α1, α2, α3, and α5 subunit, and of β1-3 subunit, mRNAs in the DLFPC of schizophrenia, and matched normal comparison subjects. In subjects with schizophrenia, mean GABA(A) α1 mRNA expression was 17% lower in layers 3 and 4, α2 expression was 14% higher in layer 2, α5 expression was 15% lower in layer 4, and α3 expression did not differ relative to comparison subjects. The mRNA expression of β2, which preferentially assembles with α1 subunits, was also 20% lower in layers 3 and 4, whereas β1 and β3 mRNA levels were not altered in schizophrenia. These expression differences were not attributable to medication effects or other potential confounds. These findings suggest that GABA neurotransmission in the DLPFC is altered at the postsynaptic level in a receptor subunit- and layer-specific manner in subjects with schizophrenia and support the hypothesis that GABA neurotransmission in this illness is predominantly impaired in certain cortical microcircuits.


Voice of the victims.
Over the past 10 years, I have been privileged to conduct educational forums for audiences containing many recovering alcoholics or otherwise chemically dependent persons. In these forums about the addictive diseases and their treatment and research possibilities, significant interaction with the audience members occurs. During these interactions, certain anecdotal phenomena seem to predominate. The repetitive nature of these reports suggests the need for systematic investigation. As with editorial comments in major medical journals, observed phenomena and unanswered questions from the victims can be valuable in the generation of testable hypotheses. Perhaps the ideas presented herein will be useful in the development of future research on alcohol abuse and alcoholism.


'Twisting the lion's tail': Manipulationist tests of causation for psychological mechanisms in the occurrence of delusions and hallucinations.
Over the past 20 years the importance of psychological processes in psychosis has gained increasing attention. However, it is key to determine the causal status of these processes in order to inform understanding and identify treatment targets. Studies that directly manipulate a psychological mechanism provide the most robust causal evidence. This review evaluates for the first time the extent of manipulationist causal evidence for the role of specific psychological mechanisms in delusions and hallucinations. A systematic search identified controlled experiments or targeted interventions that both manipulated a specific psychological mechanism and measured the effect on individual psychotic experiences. Forty-three manipulationist studies were found of which 40 measured paranoia, 11 measured hallucinations, and two measured grandiosity. Twenty-eight studies were experiments and 15 were targeted intervention trials. Only 18 used clinical samples. Manipulation of the specified psychological mechanism was demonstrated in 35 cases. Of these, 28 found a subsequent change in a psychotic experience. Negative affect and related psychological processing in relation to paranoia have been most tested. There is a small body of direct causal evidence for the role of psychological mechanisms in psychotic experiences - that highlight important novel treatment directions - but the manipulationist approach has been used too infrequently.


Local Injection of Triamcinolone Acetonide: A Forgotten Aetiology of Cushing's Syndrome.
Many different non systemic corticosteroid administrations can cause iatrogenic Cushing's Syndrome (CS). We herein report a case series of iatrogenic CS from keloid scars treatment and aesthetic regimen called mesotherapy. Our first patient developed CS after having exceeded recommended dose of intralesional injection of Triamcinolone Acetonide (TAC). Second case presented with CS followed by unidentified mesotherapy treatment for local fat reduction. Subcutaneous injections of dexamethasone were found to be the part of mesotherapy regimen in one case. Physicians should be insightful in prescribing TAC especially in those patients who have high predisposing factors for developing CS. In the same way, off-label mesotherapy combine with corticosteroid can lead to iatrogenic CS and Hypothalamic-Pituitary-Adrenal (HPA) axis suppression. Currently, there are no standard guidelines for mesotherapy treatment. Therefore, further clinical trials on dosage, duration and effective combination of mesotherapy regimens are needed to increase safety uses.


Evans Blue Reduces Neuropathic Pain Behavior by Inhibiting Spinal ATP Release.
Upon peripheral nerve injury, vesicular ATP is released from damaged primary afferent neurons. This extracellular ATP subsequently activates purinergic receptors of the spinal cord, which play a critical role in neuropathic pain. As an inhibitor of the vesicular nucleotide transporter (VNUT), Evans blue (EB) inhibits the vesicular storage and release of ATP in neurons. Thus, we tested whether EB could attenuate neuropathic pain behavior induced by spinal nerve ligation (SNL) in rats by targeting VNUT. An intrathecal injection of EB efficiently attenuated mechanical allodynia for five days in a dose-dependent manner and enhanced locomotive activity in an SNL rat model. Immunohistochemical analysis showed that EB was found in VNUT immunoreactivity on neurons in the dorsal root ganglion and the spinal dorsal horn. The level of ATP in cerebrospinal fluid in rats with SNL-induced neuropathic pain decreased upon administration of EB. Interestingly, EB blocked ATP release from neurons, but not glial cells in vitro. Eventually, the loss of ATP decreased microglial activity in the ipsilateral dorsal horn of the spinal cord, followed by a reduction in reactive oxygen species and proinflammatory mediators, such as interleukin (IL)-1β and IL-6. Finally, a similar analgesic effect of EB was demonstrated in rats with monoiodoacetate-induced osteoarthritis (OA) pain. Taken together, these data demonstrate that EB prevents ATP release in the spinal dorsal horn and reduces the ATP/purinergic receptor-induced activation of spinal microglia followed by a decline in algogenic substances, thereby relieving neuropathic pain in rats with SNL.


Co-Innervation of Triceps Brachii Muscle with Variant Branch of Ulnar Nerve.
To evaluate the existence of nerve innervation of the triceps brachii muscle via the ulnar nerve and its clinical importance in terms of nerve transfer or susceptibility to iatrogenic injuries during surgical procedures. Thirty-five skeletally mature upper extremities of adult cadavers were included in the present study. The ulnar nerve was revealed from the medial cord to the distal part of the cubital fossa. The existence of the branches of the ulnar nerve and communicant branch of the radial nerve was examined in the brachium. The diameter and length of the variant nerve branches were measured. A nerve branch from the ulnar nerve to the triceps brachii muscle was found in five of the dissected extremities (14.7%). The mean length and diameter of the variant nerve branch were 20.2 mm and 1.46 mm, respectively. The mean distance of the muscle entry point of the variant nerve branch from the bi-condylar line was 8.18 cm. A variant nerve branch via the ulnar nerve can innervate the medial head of the triceps brachii at the distal third of the brachium. This variant nerve branch will be under risk of iatrogenic injury during elbow surgery and it seems to be an option for nerve grafts.


Influence of the β-sheet content on the mechanical properties of aggregates during amyloid fibrillization.
Amyloid fibrils associated with neurodegenerative diseases, such as Parkinson's and Alzheimer's, consist of insoluble aggregates of α-synuclein and Aβ-42 proteins with a high β-sheet content. The aggregation of both proteins occurs by misfolding of the monomers and proceeds through the formation of intermediate oligomeric and protofibrillar species to give the final fibrillar cross-β-sheet structure. The morphological and mechanical properties of oligomers, protofibrils, and fibrils formed during the fibrillization process were investigated by thioflavin T fluorescence and circular dichroism in combination with AFM peak force quantitative nanomechanical technique. The results reveal an increase in the Young's modulus during the transformation from oligomers to mature fibrils, thus inferring that the difference in their mechanical properties is due to an internal structural change from a random coil to a structure with increased β-sheet content.


Rational design of a water-soluble NIR AIEgen, and its application in ultrafast wash-free cellular imaging and photodynamic cancer cell ablation.
The synthesis of water-soluble near-infrared (NIR)-emissive fluorescent molecules with aggregation-induced emission (AIE) characteristics and theranostic functions is highly desirable but remains challenging. In this work, we designed and readily prepared for the first time such a molecule with AIE features, good water-solubility and intense emission in the NIR region. This AIE luminogen (AIEgen) is able to specifically "light up" the cell membrane without the involvement of a washing procedure. Interestingly, the staining process can be performed by simply shaking the culture with cells at room temperature for only a few seconds after the addition of the AIEgen, indicating an ultrafast and easy-to-operate staining protocol. This is the first fluorescent "light-up" probe for cell-imaging that allows the combination of a short staining period (at the second-level) with a wash-free process. Additionally, the presented AIEgen has also been developed to serve as an excellent phototherapeutic agent for high efficiency generation of reactive oxygen species (ROS) upon visible light irradiation, which allows its effective application in the photodynamic ablation of cancer cells, demonstrating its dual role as an imaging and phototherapeutic agent.


Exploring the surfaceome of Ewing sarcoma identifies a new and unique therapeutic target.
The cell surface proteome of tumors mediates the interface between the transformed cells and the general microenvironment, including interactions with stromal cells in the tumor niche and immune cells such as T cells. In addition, the cell surface proteome of individual cancers defines biomarkers for that tumor type and potential proteins that can be the target of antibody-mediated therapy. We have used next-generation deep RNA sequencing (RNA-seq) coupled to an in-house database of genes encoding cell surface proteins (herein referred to as the surfaceome) as a tool to define a cell surface proteome of Ewing sarcoma compared with progenitor mesenchymal stem cells. This subtractive RNA-seq analysis revealed a specific surfaceome of Ewing and showed unexpectedly that the leucine-rich repeat and Ig domain protein 1 (LINGO1) is expressed in over 90% of Ewing sarcoma tumors, but not expressed in any other somatic tissue apart from the brain. We found that the LINGO1 protein acts as a gateway protein internalizing into the tumor cells when engaged by antibody and can carry antibody conjugated with drugs to kill Ewing sarcoma cells. Therefore, LINGO1 is a new, unique, and specific biomarker and drug target for the treatment of Ewing sarcoma.


Cefiderocol Antimicrobial Susceptibility Testing Considerations: the Achilles' Heel of the Trojan Horse?
Cefiderocol (formerly S-649266) is a novel siderophore-conjugated cephalosporin with activity against a broad array of multidrug-resistant (MDR), aerobic Gram-negative bacilli. The siderophore component binds iron and uses active iron transport for drug entry into the bacterial periplasmic space. The cephalosporin moiety is the active antimicrobial component, structurally resembling a hybrid between ceftazidime and cefepime. Like other β-lactam agents, the principal bactericidal activity of cefiderocol occurs via inhibition of bacterial cell wall synthesis by binding of penicillin-binding proteins (PBPs) and inhibiting peptidoglycan synthesis, leading to cell death. Iron concentrations need to be taken into consideration when in vitro antimicrobial susceptibility to cefiderocol is determined. Broth microdilution (BMD) and disk diffusion methods have been developed to determine in vitro activity of cefiderocol. For BMD, cation-adjusted Mueller-Hinton broth (CAMHB) requires iron depletion to provide MICs predictive of in vivo activity. A method to prepare iron-depleted CAMHB (ID-CAMHB) has been described by the Clinical and Laboratory Standards Institute (CLSI). For disk diffusion, standard Mueller-Hinton agar is recommended, presumably because iron is bound in the medium. Currently, clinical FDA and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints and investigational (research-use-only) CLSI breakpoints exist for interpreting cefiderocol susceptibility results for certain Gram-negative bacilli. Cefiderocol does not have clinically relevant activity against Gram-positive or anaerobic organisms. FDA or EUCAST breakpoints should be applied to interpret results for Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii complex for patient care until the investigational status has been removed from CLSI breakpoints. Further clinical outcome data are required to assess the effectiveness of cefiderocol for treatment of other Acinetobacter species (non-baumannii complex) and Stenotrophomonas maltophilia at this time, and, as such, antimicrobial susceptibility testing of these organisms should be limited to research use in the scenario of limited treatment options.


Differences in integrin expression during avian corneal stromal development.
The purpose of this study was to determine whether there are changes in integrin expression associated with the spatial and temporal variations in matrix expression that occur during specific stages in corneal stromal development. Immunofluorescence techniques were used to analyze beta 1-containing integrins and alpha v beta 3 localization both in situ and in cell cultures. In situ, beta 1 and alpha v beta 3 were present with different patterns of localization, and these varied with developmental stage. beta 1-containing integrins were present on most cells, whereas alpha v beta 3 was present on cells at the corneal-scleral epitheliomesenchymal interface during migration of keratocyte precursors; very little alpha v beta 3 was localized in keratocytes. Keratocytes and undifferentiated periocular mesenchyme cells grown in vitro also exhibited differences in localization of beta 1-containing integrins and alpha v beta 3. All focal adhesions contained beta 1, whereas a subset contained both beta 1 and alpha v beta 3, indicating potential functional differences in focal adhesions. In addition, most periocular mesenchyme cells exhibited alpha v beta 3-containing focal adhesions throughout, but the majority of keratocytes contained only peripherally located alpha v beta 3-positive focal adhesions. The localization of both beta 1-containing integrins and alpha v beta 3 was modulated by time allowed for attachment and spreading. Keratocytes and undifferentiated periocular mesenchyme cells exhibit developmental differences in integrin localization in situ. These two cell types also exhibit different patterns of alpha v beta 3 localization in vitro, possibly as a result of developmental differences in ligand-binding properties. beta 1-containing integrins and alpha v beta 3 define different types of focal adhesions, implying different functions. These differences in expression may be important in the initiation of cellular migration in the early stages of corneal development, as well as in the transition from the undifferentiated to the differentiated keratocyte phenotype.


Inflammatory Alteration of Human T Cells Exposed Continuously to Asbestos.
Asbestos is a known carcinogen and exposure can lead to lung cancer and malignant mesothelioma. To examine the effects of asbestos fibers on human immune cells, the human T cell leukemia/lymphoma virus (HTLV)-1 immortalized human T cell line MT-2 was employed. Following continuous exposure to asbestos fibers for more than eight months, MT-2 sublines showed acquisition of resistance to asbestos-induced apoptosis with decreased death signals and increased surviving signals. These sublines showed various characteristics that suggested a reduction in anti-tumor immunity. On the other hand, inflammatory changes such as expression of MMP7, CXCR5, CXCL13 and CD44 was found to be markedly higher in sublines continuously exposed to asbestos compared with original MT-2 cells. All of these molecules contribute to lung inflammation, T and B cell interactions and connections between mesothelial cells and T cells. Thus, further investigation focusing on these molecules may shed light on the role of chronic inflammation caused by asbestos exposure and the occurrence of malignant mesothelioma. Finally, regarding peripheral T cells from healthy donors (HD) and asbestos-exposed patients with pleural plaque (PP) or malignant pleural mesothelioma (MPM), following stimulation of CD4+ T cells, T cells from MPM patients showed reduced potential of interferon (IFN)-γ expression. Moreover, levels of interleukin (IL)-6, one of the most important cytokines in chronic inflammation, in cultured supernatants were higher in PP and MPM patients compared with HD. Overall, asbestos-induced chronic inflammation in the lung as well as the pleural cavity may facilitate the onset of asbestos-induced cancers due to alterations in the interactions among fibers, immune cells such as T and B cells and macrophages, and mesothelial and lung epithelial cells. Further investigations regarding chronic inflammation caused by asbestos fibers may assist in identifying molecular targets for preventive and therapeutic strategies related to the effects of asbestos exposure.


Development of real-time motion verification system using in-room optical images for respiratory-gated radiotherapy.
Phase-based respiratory-gated radiotherapy relies on the reproducibility of patient breathing during the treatment. To monitor the positional reproducibility of patient breathing against a 4D CT simulation, we developed a real-time motion verification system (RMVS) using an optical tracking technology. The system in the treatment room was integrated with a real-time position management system. To test the system, an anthropomorphic phantom that was mounted on a motion platform moved on a programmed breathing pattern and then underwent a 4D CT simulation with RPM. The phase-resolved anterior surface lines were extracted from the 4D CT data to constitute 4D reference lines. In the treatment room, three infrared reflective markers were attached on the superior, middle, and inferior parts of the phantom along with the body midline and then RMVS could track those markers using an optical camera system. The real-time phase information extracted from RPM was delivered to RMVS via in-house network software. Thus, the real-time anterior-posterior positions of the markers were simultaneously compared with the 4D reference lines. The technical feasibility of RMVS was evaluated by repeating the above procedure under several scenarios such as ideal case (with identical motion parameters between simulation and treatment), cycle change, baseline shift, displacement change, and breathing type changes (abdominal or chest breathing). The system capability for operating under irregular breathing was also investigated using real patient data. The evaluation results showed that RMVS has a competence to detect phase-matching errors between patient's motion during the treatment and 4D CT simulation. Thus, we concluded that RMVS could be used as an online quality assurance tool for phase-based gating treatments.


A highly sensitive and fast graphene nanoribbon/CsPbBr3 quantum dot phototransistor with enhanced vertical metal oxide heterostructures.
Although recent breakthroughs in reported graphene-based phototransistors with embedded quantum dots (QDs) have definitely been astonishing, there are still some obstacles in their practical use with regard to their electrical and optical performances. We show that through optimization of the vertical graphene nanoribbon (GNR)/QD/IGZO heterostructure and the ultrahigh efficiency of CsPbBr3 QDs, it is possible to significantly increase the on/off ratio (>103), the subthreshold slope (S.S., 0.9 V dec-1), the device's field effect mobility (μFET, 13 cm-1 V-1 S-1) and other electrical properties. Subsequently, on the basis of the extra optical-electrical characterization, we attribute the enhanced photosensitivity (800), the accelerated detecting speed (141 μs) and the high detectivity (7.5 × 1014 cm Hz1/2 W-1) to the vertical heterostructure associated with the optimized GNR component. To further demonstrate this enhancement phenomenon, the mechanism and theory mode of this vertical heterostructure are analyzed and exploited in this letter. This research indicates that a highly sensitive and fast phototransistor can be realized using the novel GNR/QD/IGZO vertical heterostructure and the long diffusion length of the perovskite QD photosensing component.


Transgenic Virus Resistance in Crop-Wild Cucurbita pepo Does Not Prevent Vertical Transmission of Zucchini yellow mosaic virus.
Zucchini yellow mosaic virus (ZYMV) is an economically important pathogen of cucurbits that is transmitted both horizontally and vertically. Although ZYMV is seed-transmitted in Cucurbita pepo, the potential for seed transmission in virus-resistant transgenic cultivars is not known. We crossed and backcrossed a transgenic squash cultivar with wild C. pepo, and determined whether seed-to-seedling transmission of ZYMV was possible in seeds harvested from transgenic backcrossed C. pepo. We then compared these transmission rates to those of non-transgenic (backcrossed and wild) C. pepo. The overall seed-to-seedling transmission rate in ZYMV was similar to those found in previous studies (1.37%), with no significant difference between transgenic backcrossed (2.48%) and non-transgenic (1.03%) backcrossed and wild squash. Fewer transgenic backcrossed plants had symptom development (7%) in comparison with all non-transgenic plants (26%) and may be instrumental in preventing yield reduction due to ZYMV. Our study shows that ZYMV is seed transmitted in transgenic backcrossed squash, which may affect the spread of ZYMV via the movement of ZYMV-infected seeds. Deep genome sequencing of the seed-transmitted viral populations revealed that 23% of the variants found in this study were present in other vertically transmitted ZYMV populations, suggesting that these variants may be necessary for seed transmission or are distributed geographically via seeds.


Critical appraisal of Chinese 2017 guideline on the management of hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is the fourth most common and the third most lethal cancer in China. An updated version of consensus-based recommendations on the management of HCC has been recently published by a multidisciplinary group of Chinese experts including liver surgeons, hepatic oncologists, radiologists and pathologists. Major changes have been made to the diagnostic criteria. In addition to dynamic multi-detector computed tomography (CT) and magnetic resonance imaging (MRI), gadoxetic acid-enhanced MRI and contrast-enhanced ultrasound (CEUS) are added to the diagnostic imaging tests. Meanwhile, positive alpha-fetoprotein (AFP) no longer functions as a confirmatory test in nodules of 1-2 cm in diameter. For patients with chronic hepatitis B/C or cirrhosis of any cause, nodules more than 2 cm can be diagnosed with HCC based on typical features on one of the four imaging techniques, whereas nodules ≤2 cm need two typical imaging findings for diagnosis. Based on the increased evidences and clinical practices, a new staging system and treatment algorithm has been developed to be more comprehensible and suitable for use in China. Surgical resection, transplantation and local regional therapies (LRTs) are indicated for more progressed HCC in terms of tumor burden and for more diseased patients in terms of liver function in China than in western centers. Laparoscopic liver resections (LLRs) are not restricted by intrahepatic tumor locations and the volume of resected liver, provided lesions generally ≤10 cm. Future efforts involving prospective studies are essential to confirm the validity of the current Chinese guidelines for HCC.


Tumor Necrosis Factor Alpha -308 G/A Single Nucleotide Polymorphism and Risk of Sperm Abnormalities in Iranian Males.
Signaling molecules such as cytokines regulate spermatogenesis during the maturation of germ cells and sperm apoptosis. Tumor necrosis factor alpha (TNFα) is one of the most-documented cytokines that is involved in spermatogenesis. We investigated the association of the TNFα -308 G/A single nucleotide polymorphism with sperm abnormalities in Iranian males. This case-control study included 180 infertile men who re- ferred to Yazd Research and Clinical Center for Infertility and 100 healthy normospermic controls. Infertile men were classified into four groups of azoospermia (n=91), oligospermia (n=26), teratospermia (n=30) and asthenoteratospermia (n=33). After sperm analysis, DNA was extracted from blood and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was carried out for the genotyping of TNFα- 308 G/A. The A allele was significantly associated with sperm abnormality in our population [(P<0.001, odds ratios (OR) 95% confidence interval (CI)=2.31]. In addition, the A allele was also associated with azoospermia (P<0.001, OR (95% CI)=2.484), oligospermia (P=0.005, OR (95% CI)=2.51) and teratospemia (P<0.001, OR (95% CI)=3.385) but not with asthenoteratospermia (P=0.623). Our data suggest that this single nucleotide polymorphism (SNP) maybe associated with the risk of sperm abnormality in infertile men of Iranian origin.


Long-term therapy in COPD: any evidence of adverse effect on bone?
Patients with COPD have high risk for osteoporosis and fractures. Hip and vertebral fractures might impair mobility, and vertebral fractures further reduce lung function. This review discusses the evidence of bone loss due to medical treatment opposed to disease severity and risk factors for COPD, and therapeutic options for the prevention and treatment of osteoporosis in these patients. A review of the English-language literature was conducted using the MEDLINE database until June 2009. Currently used bronchodilators probably lack adverse effect on bone. Oral corticosteroids (OCS) increase bone resorption and decrease bone formation in a dose response relationship, but the fracture risk is increased more than reflected by bone densitometry. Inhaled corticosteroids (ICS) have been associated with both increased bone loss and fracture risk. This might be a result of confounding by disease severity, but high doses of ICS have similar effects as equipotent doses of OCS. The life-style factors should be modified, use of regular OCS avoided and use of ICS restricted to those with evidenced effect and probably kept at moderate doses. The health care should actively reveal risk factors, include bone densitometry in fracture risk evaluation, and give adequate prevention and treatment for osteoporosis.


Evidence-based medicine: fifteen years later. Golem the good, the bad, and the ugly in need of a review?
Despite its well-deserved strengths, Evidence-Based Medicine (EBM)'s shell still remains half-full. Its strong points are clouded in persisting philosophical gaps and mostly ideological advancements of its concepts and rules. Further clarification of its logic and critical use of evidence is required. In this non-systematic essay and review, several present and future necessary achievements are outlined: Solid methodological tools were developed under the umbrella of surprisingly less-operational definition(s) of EBM and 'evidence' itself, incomplete classifications of various evidences and limited scope of original critical appraisal of evidence. The integration of the best evidence with clinical expertise, setting and circumstances, as well as patient expectations, values, and preferences and the application of evidence to a specific patient have only been conceptually traced so far and usable rules remain in waiting. The question of whether the practice of EBM produces better results than its alternatives also remains unanswered. Uses of the best evidence as a basis for the fundamental elements of modern argumentation and critical thinking applied to medicine may be one of the promising paths, but this approach still must be more widely applied and evaluated on its own merit. In other words, we do have a point, but it needs to be improved.


Hormonal control of cell form and number in the zebra finch song system.
Administration of testosterone (T), 17 beta-estradiol (E2), or 5 alpha-dihydrotestosterone (DHT) to female zebra finch chicks (Poephila guttata) at hatching exerts effects on brain sexual differentiation. Within a telencephalic station (the nucleus robustus archistriatalis, RA) of the neural pathway which participates in the efferent control of song, masculinization of several indices of neuronal size is induced by exposure to T or E2. Within RA, a sensitive assay of a single neuron's sexually differentiated state is the diameter of its soma. By this criteria, all of the neurons within RA can be masculinized with a sufficient dose of T. As the dose of T is progressively decreased, the proportion of RA neurons which undergo the transition from female to male falls, while the magnitude of the change in soma size remains basically unaltered. Administration of T or DHT masculinizes the number of neurons in RA.


Reprogramming the immunological microenvironment through radiation and targeting Axl.
Increasing evidence suggests that ionizing radiation therapy (RT) in combination with checkpoint immunotherapy is highly effective in treating a subset of cancers. To better understand the limited responses to this combination we analysed the genetic, microenvironmental, and immune factors in tumours derived from a transgenic breast cancer model. We identified two tumours with similar growth characteristics but different RT responses primarily due to an antitumour immune response. The combination of RT and checkpoint immunotherapy resulted in cures in the responsive but not the unresponsive tumours. Profiling the tumours revealed that the Axl receptor tyrosine kinase is overexpressed in the unresponsive tumours, and Axl knockout resulted in slower growth and increased radiosensitivity. These changes were associated with a CD8+ T-cell response, which was improved in combination with checkpoint immunotherapy. These results suggest a novel role for Axl in suppressing antigen presentation through MHCI, and enhancing cytokine release, which promotes a suppressive myeloid microenvironment.


Optical quantal analysis reveals a presynaptic component of LTP at hippocampal Schaffer-associational synapses.
The mechanisms by which long-term potentiation (LTP) is expressed are controversial, with evidence for both presynaptic and postsynaptic involvement. We have used confocal microscopy and Ca(2+)-sensitive dyes to study LTP at individual visualized synapses. Synaptically evoked Ca(2+) transients were imaged in distal dendritic spines of pyramidal cells in cultured hippocampal slices, before and after the induction of LTP. At most synapses, from as early as 10 min to at least 60 min after induction, LTP was associated with an increase in the probability of a single stimulus evoking a postsynaptic Ca(2+) response. These observations provide compelling evidence of a presynaptic component to the expression of early LTP at Schaffer-associational synapses. In most cases, the store-dependent evoked Ca(2+) transient in the spine was also increased after induction, a novel postsynaptic aspect of LTP.


Tra-2 Mediates Cross-Talk Between Sex Determination and Wing Polyphenism in Female Nilaparvata lugens.
Sexual dimorphism and wing polyphenism are important and evolutionarily conserved features of many insect species. In this article, we found a cross-talk linking sexual differentiation with wing polyphenism in the brown planthopper (BPH) Nilaparvata lugens (order: Hemiptera). Knockdown of the sex determination gene Transformer-2 in N. lugens (NlTra-2) in nymph caused females to develop into infertile pseudomales containing undeveloped ovaries. Whereas males treated with dsNlTra-2 exhibited normal morphology, but lost fertility. Knockdown of NlTra-2 in adult females (maternal RNAi) resulted in long-winged female offspring, indicating that maternal RNAi changed the wing morphs in female offspring. In addition, silencing of NlTra-2 down-regulated the expression of the forkhead transcription factor FoxO (NlFoxO), and simultaneously up-regulated the expression of phosphatidylinositol-3-OH kinase (PI(3)K)-protein kinase B (NlAkt), the two critical genes in the insulin signaling pathway. Furthermore, the long-winged effect caused by maternal dsNlTra-2 RNAi could be reversed by silencing of NlInR1 and NlAkt, leading to short-winged morphs. We propose that there is a cross-talk between the sexual differentiation and wing polyphenism pathways mediated by NlTra-2 during embryonic stages.


Frequency, predictors, and neurologic outcomes of vaso-occlusive strokes associated with cardiac surgery in children.
Our aim was to define the frequency, predictors, and outcomes of stroke associated with cardiac surgery in children with congenital heart disease. We performed a case-control study of children (term birth to 18 years) with congenital heart disease who underwent cardiac surgery at the Hospital for Sick Children between January 1, 1992, and March 1, 2001. Case subjects experienced stroke within 72 hours after cardiac surgery, and control subjects (2 for each case subjects) had cardiac surgery and no stroke. The frequency of arterial ischemic stroke/cerebral sinovenous thrombosis was calculated among children who underwent cardiac surgery during the study period. Predictors for stroke, including age, gender, simple versus complex procedure, reoperation, bypass duration, circulatory arrest, postoperative hematocrit level, and intraoperative activated clotting time, were tested. The presence of clinical and radiologically defined stroke was the main outcome. Neurologic outcomes were assessed in case subjects with the Pediatric Stroke Outcome Measure. During the study period, 30 children with stroke (28 with arterial ischemic stroke and 2 with cerebral sinovenous thrombosis) were identified among 5526 children undergoing cardiac surgery. This yielded a risk for arterial ischemic stroke/cerebral sinovenous thrombosis of 5.4 strokes per 1000 children undergoing a cardiac operation. Univariate analysis revealed that older age at the time of the procedure, longer duration of cardiopulmonary bypass, number of days in the hospital postoperatively, and reoperation were associated with stroke. In multivariate analyses, only reoperation was associated with stroke. The frequency of vaso-occlusive stroke in children with congenital heart disease undergoing cardiac surgery was 5.4 cases per 1000 children. Age, duration of bypass, and reoperation may be associated with stroke risk.


Targeting G protein-coupled receptor signaling at the G protein level with a selective nanobody inhibitor.
G protein-coupled receptors (GPCRs) activate heterotrimeric G proteins by mediating a GDP to GTP exchange in the Gα subunit. This leads to dissociation of the heterotrimer into Gα-GTP and Gβγ dimer. The Gα-GTP and Gβγ dimer each regulate a variety of downstream pathways to control various aspects of human physiology. Dysregulated Gβγ-signaling is a central element of various neurological and cancer-related anomalies. However, Gβγ also serves as a negative regulator of Gα that is essential for G protein inactivation, and thus has the potential for numerous side effects when targeted therapeutically. Here we report a llama-derived nanobody (Nb5) that binds tightly to the Gβγ dimer. Nb5 responds to all combinations of β-subtypes and γ-subtypes and competes with other Gβγ-regulatory proteins for a common binding site on the Gβγ dimer. Despite its inhibitory effect on Gβγ-mediated signaling, Nb5 has no effect on Gαq-mediated and Gαs-mediated signaling events in living cells.


Word add-in for ontology recognition: semantic enrichment of scientific literature.
In the current era of scientific research, efficient communication of information is paramount. As such, the nature of scholarly and scientific communication is changing; cyberinfrastructure is now absolutely necessary and new media are allowing information and knowledge to be more interactive and immediate. One approach to making knowledge more accessible is the addition of machine-readable semantic data to scholarly articles. The Word add-in presented here will assist authors in this effort by automatically recognizing and highlighting words or phrases that are likely information-rich, allowing authors to associate semantic data with those words or phrases, and to embed that data in the document as XML. The add-in and source code are publicly available at http://www.codeplex.com/UCSDBioLit. The Word add-in for ontology term recognition makes it possible for an author to add semantic data to a document as it is being written and it encodes these data using XML tags that are effectively a standard in life sciences literature. Allowing authors to mark-up their own work will help increase the amount and quality of machine-readable literature metadata.


Family history of suicide.
Among 243 patients with a family history of suicide, almost half (118 [48.6%]) had attempted suicide, more than half (137 [56.4%]) had a depressive disorder, and more than a third (84 [34.6%]) had recurrent affective disorder. These 243 patients with a family history of suicide were compared with 5,602 patients with no family history of suicide. A family history of suicide was found to significantly increase the risk for an attempt at suicide in patients with a wide variety of diagnoses: schizophrenia, unipolar and bipolar affective disorders, depressive neurosis, and personality disorders.


Endoscopic approach to cavernous sinus aneurysm.
Aneurysms protruding into sellae may mimic pituitary tumors by compressing adjacent cranial nerves. Carotid-Cavernous aneurysms are rarely associated with mortality, and surgical intervention is recommended especially for neuro-ophthalmologic progression. In this report we presented a 51-year-old woman who had severe headache and neuro-ophthalmologic signs with the initial diagnosis of pituitary apoplexy on MRI (Magnetic Resonanse Imaging). However preoperative CTA (Computed Tomography Angiography) revealed a carotid cavernous aneurysm protruding into sellae. The patient underwent endovascular intervention and endoscopic transphenoidal approach for the removal of the hematoma compressing the cranial nerves. The patient's neuro-ophthalmologic symptoms were improved during the follow-up, which may be related due to rapid evacuation of the hematoma.


Molecular genetic study of the frequency of monosomy 22q11 in DiGeorge syndrome.
It is well established that DiGeorge syndrome (DGS) may be associated with monosomy of 22q11-pter. More recently, DNA probes have been used to detect hemizygosity for this region in patients with no visible karyotypic abnormality. However, DGS has also been described in cases where the cytogenetic abnormality does not involve 22q11; for instance, four cases of 10p- have been reported. In this study we have prospectively analyzed patients, by using DNA markers from 22q11, to assess the frequency of 22q11 rearrangements in DGS. Twenty-one of 22 cases had demonstrable hemizygosity for 22q11. Cytogenetic analysis had identified interstitial deletion in 6 of 16 cases tested; in 6 other cases no karyotype was available. When these results are combined with those from our previous studies, 33 of 35 DGS patients had chromosome 22q11 deletions detectable by DNA probes.


Healing and Angiogenic Properties of Collagen/Chitosan Scaffolds Enriched with Hyperstable FGF2-STAB® Protein: In Vitro, Ex Ovo and In Vivo Comprehensive Evaluation.
Wound healing is a process regulated by a complex interaction of multiple growth factors including fibroblast growth factor 2 (FGF2). Although FGF2 appears in several tissue engineered studies, its applications are limited due to its low stability both in vitro and in vivo. Here, this shortcoming is overcome by a unique nine-point mutant of the low molecular weight isoform FGF2 retaining full biological activity even after twenty days at 37 °C. Crosslinked freeze-dried 3D porous collagen/chitosan scaffolds enriched with this hyper stable recombinant human protein named FGF2-STAB® were tested for in vitro biocompatibility and cytotoxicity using murine 3T3-A31 fibroblasts, for angiogenic potential using an ex ovo chick chorioallantoic membrane assay and for wound healing in vivo with 3-month old white New Zealand rabbits. Metabolic activity assays indicated the positive effect of FGF2-STAB® already at very low concentrations (0.01 µg/mL). The angiogenic properties examined ex ovo showed enhanced vascularization of the tested scaffolds. Histological evaluation and gene expression analysis by RT-qPCR proved newly formed granulation tissue at the place of a previous skin defect without significant inflammation infiltration in vivo. This work highlights the safety and biocompatibility of newly developed crosslinked collagen/chitosan scaffolds involving FGF2-STAB® protein. Moreover, these sponges could be used as scaffolds for growing cells for dermis replacement, where neovascularization is a crucial parameter for successful skin regeneration.


Cellular energy utilization and molecular origin of standard metabolic rate in mammals.
The molecular origin of standard metabolic rate and thermogenesis in mammals is examined. It is pointed out that there are important differences and distinctions between the cellular reactions that 1) couple to oxygen consumption, 2) uncouple metabolism, 3) hydrolyze ATP, 4) control metabolic rate, 5) regulate metabolic rate, 6) produce heat, and 7) dissipate free energy. The quantitative contribution of different cellular reactions to these processes is assessed in mammals. We estimate that approximately 90% of mammalian oxygen consumption in the standard state is mitochondrial, of which approximately 20% is uncoupled by the mitochondrial proton leak and 80% is coupled to ATP synthesis. The consequences of the significant contribution of proton leak to standard metabolic rate for tissue P-to-O ratio, heat production, and free energy dissipation by oxidative phosphorylation and the estimated contribution of ATP-consuming processes to tissue oxygen consumption rate are discussed. Of the 80% of oxygen consumption coupled to ATP synthesis, approximately 25-30% is used by protein synthesis, 19-28% by the Na(+)-K(+)-ATPase, 4-8% by the Ca2(+)-ATPase, 2-8% by the actinomyosin ATPase, 7-10% by gluconeogenesis, and 3% by ureagenesis, with mRNA synthesis and substrate cycling also making significant contributions. The main cellular reactions that uncouple standard energy metabolism are the Na+, K+, H+, and Ca2+ channels and leaks of cell membranes and protein breakdown. Cellular metabolic rate is controlled by a number of processes including metabolic demand and substrate supply. The differences in standard metabolic rate between animals of different body mass and phylogeny appear to be due to proportionate changes in the whole of energy metabolism. Heat is produced by some reactions and taken up by others but is mainly produced by the reactions of mitochondrial respiration, oxidative phosphorylation, and proton leak on the inner mitochondrial membrane. Free energy is dissipated by all cellular reactions, but the major contributions are by the ATP-utilizing reactions and the uncoupling reactions. The functions and evolutionary significance of standard metabolic rate are discussed.


Frequency fluctuations in silicon nanoresonators.
Frequency stability is key to the performance of nanoresonators. This stability is thought to reach a limit with the resonator's ability to resolve thermally induced vibrations. Although measurements and predictions of resonator stability usually disregard fluctuations in the mechanical frequency response, these fluctuations have recently attracted considerable theoretical interest. However, their existence is very difficult to demonstrate experimentally. Here, through a literature review, we show that all studies of frequency stability report values several orders of magnitude larger than the limit imposed by thermomechanical noise. We studied a monocrystalline silicon nanoresonator at room temperature and found a similar discrepancy. We propose a new method to show that this was due to the presence of frequency fluctuations, of unexpected level. The fluctuations were not due to the instrumentation system, or to any other of the known sources investigated. These results challenge our current understanding of frequency fluctuations and call for a change in practices.


Chromatin structure following UV-induced DNA damage-repair or death?
In eukaryotes, DNA is compacted into a complex structure known as chromatin. The unravelling of DNA is a crucial step in DNA repair, replication, transcription and recombination as this allows access to DNA for these processes. Failure to package DNA into the nucleosome, the individual unit of chromatin, can lead to genomic instability, driving a cell into apoptosis, senescence, or cellular proliferation. Ultraviolet (UV) radiation damage causes destabilisation of chromatin integrity. UV irradiation induces DNA damage such as photolesions and subjects the chromatin to substantial rearrangements, causing the arrest of transcription forks and cell cycle arrest. Highly conserved processes known as nucleotide and base excision repair (NER and BER) then begin to repair these lesions. However, if DNA repair fails, the cell may be forced into apoptosis. The modification of various histones as well as nucleosome remodelling via ATP-dependent chromatin remodelling complexes are required not only to repair these UV-induced DNA lesions, but also for apoptosis signalling. Histone modifications and nucleosome remodelling in response to UV also lead to the recruitment of various repair and pro-apoptotic proteins. Thus, the way in which a cell responds to UV irradiation via these modifications is important in determining its fate. Failure of these DNA damage response steps can lead to cellular proliferation and oncogenic development, causing skin cancer, hence these chromatin changes are critical for a proper response to UV-induced injury.


Developing the evidence base for adult social care practice: The NIHR School for Social Care Research.
In a foreword to Shaping the Future of Care Together, Prime Minister Gordon Brown says that a care and support system reflecting the needs of our times and meeting our rising aspirations is achievable, but 'only if we are prepared to rise to the challenge of radical reform'. A number of initiatives will be needed to meet the challenge of improving social care for the growing older population. Before the unveiling of the green paper, The National Institute for Health Research (NIHR) announced that it has provided £15m over a five-year period to establish the NIHR School for Social Care Research. The School's primary aim is to conduct or commission research that will help to improve adult social care practice in England. The School is seeking ideas for research topics, outline proposals for new studies and expert advice in developing research methods.


Anthelmintic efficacy on UK Thoroughbred stud farms.
Anthelmintic drugs have been applied indiscriminately to control horse nematodes for over 40 years. We undertook a comprehensive study to investigate efficacy of the four available broad-spectrum anthelmintic drugs on 16 Thoroughbred stud farms using the faecal egg count reduction test. Efficacy against strongyles was determined by calculating the percentage of reduction in faecal egg count between the group mean at Day 0 and Days 14-17 post-treatment and the 95% lower confidence intervals estimated by non-parametric bootstrapping. Individual strongyle faecal egg count reduction tests (n=429) were performed in which 179, 131, 89 and 30 horses were administered ivermectin, moxidectin, pyrantel and fenbendazole, respectively. Moxidectin was efficacious in all tests (faecal egg count reduction range: 99.8-100%; 95% lower confidence intervals range: 96.8-100%) and reduced efficacy of ivermectin (faecal egg count reduction range: 85.7-100%; 95% lower confidence intervals range: 65-100%) was observed in one group of yearlings. Reduced pyrantel efficacy was observed in five groups of yearlings (faecal egg count reduction range: 0-73%; 95% lower confidence intervals range: 0-59.5%), but pyrantel was found to be efficacious when administered to mares (faecal egg count reduction range: 98-99.4%; 95% lower confidence intervals range: 91.8-99.3%). Low efficacy of fenbendazole was always observed (faecal egg count reduction range: 0.4-41%; 95% lower confidence intervals not calculable). Two further methods for estimating efficacy were applied and outputs obtained using all methodologies were in agreement. Efficacy against Parascaris equorum was assessed on four farms: fenbendazole had acceptable efficacy (faecal egg count reduction range: 97.5-99.9%; 95% lower confidence intervals range: 96.3-99.1%), but reduced efficacy of ivermectin was observed (faecal egg count reduction range: 25.5-91.2%; 95% lower confidence intervals range: 6.7-82.4%). Strongyle faecal egg count were analysed at approximately 2 week intervals for up to 12 weeks after anthelmintic drug administration to determine the egg reappearance period for moxidectin, ivermectin and pyrantel. The egg reappearance period for all three anthelmintic drugs was shorter than previously observed. Overall, our results indicate that ivermectin and moxidectin administration provided acceptable efficacy at 14 days; however, egg reappearance period results suggest that these products are working less effectively than measured previously. As shortened egg reappearance period is believed to be an early indicator of resistance, this highlights the issue of impending multi-drug resistance in strongyles on stud farms.


Effect of smoking cessation and tobacco type on the risk of cancers of the upper aero-digestive tract in Brazil.
Tobacco smoking has long been identified as the most important risk factor for upper aero-digestive tract cancers. To investigate the effect of different tobacco types and the benefit of smoking cessation, we analyzed data from a case-control study of 784 cases of mouth, pharynx, and larynx cancers and 1,578 non-cancer controls in three metropolitan hospital areas in Brazil. Subjects were interviewed as to their smoking and drinking habits, demographics, environmental exposures, occupational history, health characteristics, and diet. Controlling for total tobacco and alcohol consumption, risks for ex-smokers compared with current smokers decreased substantially with time since cessation of the habit. Compared with never smokers, ex-smokers of >20 years had a relative risk (RR) of 1.98 [95% confidence interval (CI) = 1.0-3.8] for all upper aerodigestive tract cancers. RRs for long-term (>20 years) ex-smokers tended to be lower for mouth (RR = 1.61) and pharynx (RR = 1.52) than for larynx (RR = 3.63) cancers. The benefit of quitting was strongest for commercial cigarettes (RR = 1.45, 95% CI = 0.7-3.0) for ex-smokers of >10 years, as compared with smoking of black tobacco (RR = 2.57, 95% CI = 1.4-4.6), cigars (RR = 2.59, 95% CI = 0.6-11.6), and pipe tobacco (RR = 3.40, 95% CI = 1.3-8.8).


Absence of HBV Reactivation in Patients With Resolved HBV Infection Following DAA Therapy for Hepatitis C: A 1-Year Follow-up Study.
Patients with chronic hepatitis C virus (HCV) infection and active or previous hepatitis B virus (HBV) are at risk of HBV reactivation (HBV-R) during direct-acting antiviral (DAA) therapy. Recent reports suggest that HBV-R may even occur several months after completion of DAA therapy. The aim of this study was to assess the risk of HBV-R in patients with resolved HBV after successful DAA therapy during long-term follow-up (FU). Among 848 patients treated for chronic HCV, all patients with resolved HBV and long-term FU data were eligible for inclusion. Patients were HBV DNA/hepatitis B surface antigen (HBsAg)-negative at the end of therapy (EOT) and were followed for up to 52 weeks thereafter. Patients underwent regular alanine transaminase (ALT) testing, and additional HBV DNA/HBsAg testing was performed at FU week 12, end of FU, and in case of an ALT increase above the upper limit of normal (>ULN). A total of 108 patients were followed up for a mean (range) of 41.5 (24-52) weeks after EOT. None of the patients experienced reverse HBsAg seroconversion or reappearance of HBV DNA. One patient received a liver transplantation; 1 patient was diagnosed with de novo hepatocellular carcinoma, and 2 patients died. Eighteen patients (16.7%) had increased ALT levels (grade 0/1). Of those, the majority were male (72.2%) and significantly more patients had cirrhosis (66.7% vs 36.2%, P = .015) or received ribavirin as part of their treatment regimen (86.7% vs 46.8%, P = .041). None of these were associated with HBV-R. Our results indicate that the risk of HBV-R in patients with resolved HBV treated with DAAs for HCV is low during long-term follow-up.


Maternal behavior as an early modulator of neurobehavioral offspring responses by Sprague-Dawley rats.
Maternal care plays an important role as an early modeler of neurodevelopment and brain function, and its effects remain until adulthood. Such modeling or programming has shown to influence the stress response and represents a key susceptibility factor in the development of mood disorders. In order to characterize such process which is still not clear, male offspring were classified in animals with low, medium and high licking/grooming (LG) according to the maternal behavior. Juvenile animals were subjected to the open field test (OFT) and the forced swimming test (FST), and offspring of low and high LG mothers were compared. Seven days after the FST, neurochemical and gene expression analyses were carried out in order to identify possible changes on relevant targets. Maternal care did determine locomotor behaviors in the OFT, supporting an anxiogenic effect of low maternal investment. This effect seems to be associated with the serotonergic systems in both nucleus accumbens (NAc) and hippocampus (HPC), since offspring of low LG mothers showed decreased 5-HT neurotransmission in those brain regions compared with animals of high LG mothers. Furthermore, TrkB expression was higher in offspring of high LG compared to the group of low LG mothers, supporting its influence as a mechanistic intermediate of such effect, at least in the NAc. Taken together, these findings strongly support the influence of differential maternal care on the neurodevelopment and responsivity of juvenile rats.


Clostridium difficile infection is associated with poor outcomes in end-stage renal disease.
To investigate the association of Clostridium difficile infection (CDI) with the outcomes of hospitalized patients with end-stage renal disease (ESRD). We extracted all adult cases with a discharge diagnosis of ESRD or CDI from the United States Nationwide Inpatient Sample 2009 database. Outcome variables (mortality, length of hospital stay [LOS], and hospitalization charges), demographic information, and comorbidity data were collected. Data were evaluated by univariate and multiple regression analyses. We identified 184,139 cases with ESRD of which 2.8% had CDI. Comparison of patients with ESRD + CDI to those with only ESRD revealed in-hospital mortality (13.2% vs 5.3%; P < 0.001), LOS (17.3 vs 7.1 days; P < 0.001), and charges ($124,846 vs $56,663; P < 0.001) to be more than 2-fold greater. In the ESRD cohort (ESRD only and ESRD + CDI), CDI was independently associated with greater mortality (adjusted odds ratio, 2.15; 95% CI, 2.07-2.24; P < 0.001), longer LOS (mean difference, 9.4 days; 95% CI, 9.2-9.5; P < 0.001), and higher charges (mean difference, $62,824; 95% CI, 61,615-64,033; P < 0.001). Clostridium difficile infection is associated with significantly worse outcomes in hospitalized patients with ESRD.


Higher Frequency of Acute Occupational Therapy Services Is Associated With Reduced Hospital Readmissions.
Hospital readmissions are associated with poor patient outcomes, including higher risk for mortality, nutritional concerns, deconditioning, and higher costs. To evaluate how acute occupational therapy service delivery factors affect readmission risk. Cross-sectional, retrospective study. Single academic medical center. Medicare inpatients with a diagnosis included in the Hospital Readmissions Reduction Program (HRRP; N = 17,618). Data were collected from medical records at a large urban hospital in southeastern Wisconsin. Outcomes and Measures: Logistic regression models were estimated to examine the association between acute occupational therapy service delivery factors and odds of readmission. In addition, the types of acute occupational therapy services for readmitted versus not-readmitted patients were compared. Patients had significantly higher odds of readmission if they received occupational therapy services while hospitalized (odds ratio [OR] = 1.18, 95% confidence interval [CI] [1.07, 1.31]). However, patshients who received acute occupational therapy services had significantly lower odds of readmission if they received a higher frequency (OR = 0.99, 95% CI [0.99,1.00]) of acute occupational therapy services. A significantly higher proportion of patients who were not readmitted, compared with patients who were readmitted, received activities of daily living (ADL) or self-care training (p < .01). For patients with HRRP-qualifying diagnoses who received acute occupational therapy services, higher frequency of acute occupational therapy services was linked with lower odds of readmission. Readmitted patients were less likely to have received ADL or self-care training while hospitalized. What This Article Adds: Identifying factors of acute occupational therapy services that reduce the odds of readmission for Medicare patients may help to improve patient outcomes and further define occupational therapy's role in the U.S. quality-focused health care system.


Can homeopathy bring additional benefits to thalassemic patients on hydroxyurea therapy? Encouraging results of a preliminary study.
Several homeopathic remedies, namely, Pulsatilla Nigricans (30th potency), Ceanothus Americanus (both mother tincture and 6th potency) and Ferrum Metallicum (30th potency) selected as per similia principles were administered to 38 thalassemic patients receiving Hydroxyurea (HU) therapy for a varying period of time. Levels of serum ferritin (SF), fetal hemoglobin (HbF), hemoglobin (Hb), platelet count (PC), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular hemoglobin (MCH), white blood cell (WBC) count, bilirubin content, alanine amino transferase (ALT), aspartate amino transferase (AST) and serum total protein content of patients were determined before and 3 months after administration of the homeopathic remedies in combination with HU to evaluate additional benefits, if any, derived by the homeopathic remedies, by comparing the data with those of 38 subjects receiving only HU therapy. Preliminary results indicated that there was a significant decrease in the SF and increase in HbF levels in the combined, treated subjects. Although the changes in other parameters were not so significant, there was a significant decrease in size of spleen in most patients with spleenomegaly and improvement in general health conditions along with an increased gap between transfusions in most patients receiving the combined homeopathic treatment. The homeopathic remedies being inexpensive and without any known side-effects seem to have great potentials in bringing additional benefits to thalassemic patients; particularly in the developing world where blood transfusions suffer from inadequate screening and fall short of the stringent safety standards followed in the developed countries. Further independent studies are encouraged.