Ca(2+)-dependent Cl- conductance in taste cells from Necturus.
1. Taste responses adapt to a constant chemical stimulus. The present study describes a new ionic conductance in taste cells--a Ca(2+)-dependent anion conductance that may explain taste adaptation. 2. Patch-clamp recordings were made on isolated Necturus taste cells or on taste cells in lingual slices. When Na+ and K+ currents were eliminated with tetrodotoxin (TTX) and tetraethyl-ammonium (TEA) in the bath and replacing K+ with N-methyl-D-glucamine (NMDG+) in the pipette, Ca2+ currents were followed by prolonged outward currents. Outward current was abolished when Ca2+ was substituted with Ba2+ or when Cl- was replaced with large organic anions (methanesulfonate, isethionate, or ascorbate). 3. The outward, Ca-dependent current was reduced by certain agents that block Cl- conductances in other tissues, namely 4-acet-amido-4-isothiocyanostilbene-2,2-disulfonic acid (SITS) and 4,4-diisothiocyanostilbene-2,2-disulfonic acid (DIDS). However, other Cl- channel blockers--9-AC, furosemide and an antibody to Cl channels-had little or no specific effect on the Ca-dependent outward current in Necturus taste cells. 4. We postulate that the biological action of this Ca-dependent anion conductance in situ is to terminate depolarizing receptor potentials, even during maintained chemostimulation, thereby playing an important role in chemosensory adaptation and modulation of impulse discharge patterns in taste buds.


Immunochemical characterization of two surface polysaccharides of Bacteroides fragilis.
Immunochemical analysis of the capsular polysaccharide from Bacteroides fragilis NCTC 9343 revealed a novel structure composed of two distinct polysaccharides. Immunoelectrophoresis of an extract of purified surface polysaccharide from fermenter-grown organisms showed a complex precipitin profile with varying anodal mobility. DEAE-Sephacel anion-exchange chromatography of the polysaccharide extract failed to separate the majority of this aggregate. Disaggregation of this complex was accomplished by very mild acid treatment; purification was achieved by DEAE-Sephacel anion-exchange chromatography. Polysaccharide A had a neutral charge at pH 7.3, a net negative charge at pH 8.6, and an average Mr = 110,000; chemical analysis showed it to contain galactose, galactosamine, and an unidentified amino sugar. Polysaccharide B eluted from the anion-exchange column with increased salt concentration; it had a net negative charge and an average Mr = 200,000, and contained fucose, galactose, quinovosamine, galacturonic acid, and glucosamine. Neither of these polysaccharides contained detectable 3-deoxy-D-manno-octolusonic acid, and both were recognized as distinct antigens on the basis of their reactivity with monoclonal antibodies CE3 and F10, which reacted with the complex before acid treatment. These data indicate that the capsule of B. fragilis NCTC 9343 comprises two discrete, surface-exposed polysaccharides with differing physiochemical properties that are distinct from the lipopolysaccharide of this organism. The finding of two surface polysaccharides has not been described for other bacteria pathogenic to humans.


Density of tobacco retailers and its association with sociodemographic characteristics of communities across New York.
To examine the association of community median income, race/ethnicity and age with the availability of tobacco products in New York State and six subareas. Spatial regression analysis applied to licensed tobacco retailer and sociodemographic data in 2009 in New York. This study assessed the association between tobacco retailer density and four demographic correlates (percentage African American, percentage Hispanic, percentage aged <18 years and median household income) at the census tract level in New York in 2009. Associations were modelled for New York State and six subareas: Greater New York City/Long Island, New York minus Greater New York City/Long Island (rest of State), the Capital region (containing the city of Albany and surrounding areas), Erie County (containing the city of Buffalo), Monroe County (containing the city of Rochester) and Onondaga County (containing the city of Syracuse). In total, 19,420 licensed tobacco retailers were linked to 4795 residential census tracts. In New York State, residential census tracts with higher proportions of African Americans and Hispanics generally had a significantly higher density of tobacco retailers. Census tracts with a higher percentage of residents aged <18 years and higher median household income generally had a significantly lower density of tobacco retailers. However, these associations were not statistically significant in all areas studied. Tobacco retailers tend to be more densely distributed in areas characterized by high minority or low-income populations, but these associations were not found in all areas. This may suggest that policy measures to reduce the density of tobacco retailers may be more effective at reducing disparities in tobacco availability and exposure to point-of-sale advertising in some areas than in others.


Consistent and robust determination of border ownership based on asymmetric surrounding contrast.
Determination of the figure region in an image is a fundamental step toward surface construction, shape coding, and object representation. Localized, asymmetric surround modulation, reported neurophysiologically in early-to-intermediate-level visual areas, has been proposed as a mechanism for figure-ground segregation. We investigated, computationally, whether such surround modulation is capable of yielding consistent and robust determination of figure side for various stimuli. Our surround modulation model showed a surprisingly high consistency among pseudorandom block stimuli, with greater consistency for stimuli that yielded higher accuracy of, and shorter reaction times in, human perception. Our analyses revealed that the localized, asymmetric organization of surrounds is crucial in the detection of the contrast imbalance that leads to the determination of the direction of figure with respect to the border. The model also exhibited robustness for gray-scaled natural images, with a mean correct rate of 67%, which was similar to that of figure-side determination in human perception through a small window and of machine-vision algorithms based on local processing. These results suggest a crucial role of surround modulation in the local processing of figure-ground segregation.


An Inflammatory Story: Antibodies in Tuberculosis Comorbidities.
Mycobacterium tuberculosis (Mtb) resides in a quarter of the world's population and is the causative agent for tuberculosis (TB), the most common infectious reason of death in humans today. Although cellular immunity has been firmly established in the control of Mtb, there is growing evidence that antibodies may also modulate the infection. More specifically, certain antibody features are associated with inflammation and are divergent in different states of human infection and disease. Importantly, TB impacts not just the healthy but also those with chronic conditions. While HIV represents the quintessential comorbid condition for TB, recent epidemiological evidence shows that additional chronic conditions such as diabetes and kidney disease are rising. In fact, the prevalence of diabetes as a comorbid TB condition is now higher than that of HIV. These chronic diseases are themselves independently associated with pro-inflammatory immune states that encompass antibody profiles. This review discusses isotypes, subclasses, post-translational modifications and Fc-mediated functions of antibodies in TB infection and in the comorbid chronic conditions of HIV, diabetes, and kidney diseases. We propose that inflammatory antibody profiles, which are a marker of active TB, may be an important biomarker for detection of TB disease progression within comorbid individuals. We highlight the need for future studies to determine which inflammatory antibody profiles are the consequences of comorbidities and which may potentially contribute to TB reactivation.


Interleukin-21 receptor signalling is important for innate immune protection against HSV-2 infections.
Interleukin (IL) -21 is produced by Natural Killer T (NKT) cells and CD4(+) T cells and is produced in response to virus infections, where IL-21 has been shown to be essential in adaptive immune responses. Cells from the innate immune system such as Natural Killer (NK) cells and macrophages are also important in immune protection against virus. These cells express the IL-21 receptor (IL-21R) and respond to IL-21 with increased cytotoxicity and cytokine production. Currently, however it is not known whether IL-21 plays a significant role in innate immune responses to virus infections. The purpose of this study was to investigate the role of IL-21 and IL-21R in the innate immune response to a virus infection. We used C57BL/6 wild type (WT) and IL-21R knock out (KO) mice in a murine vaginal Herpes Simplex Virus type 2 (HSV-2) infection model to show that IL-21 - IL-21R signalling is indeed important in innate immune responses against HSV-2. We found that the IL-21R was expressed in the vaginal epithelium in uninfected (u.i) WT mice, and expression increased early after HSV-2 infection. IL-21R KO mice exhibited increased vaginal viral titers on day 2 and 3 post infection (p.i.) and subsequently developed significantly higher disease scores and a lower survival rate compared to WT mice. In addition, WT mice infected with HSV-2 receiving intra-vaginal pre-treatment with murine recombinant IL-21 (mIL-21) had decreased vaginal viral titers on day 2 p.i., significantly lower disease scores, and a higher survival rate compared to infected untreated WT controls. Collectively our data demonstrate the novel finding that the IL-21R plays a critical role in regulating innate immune responses against HSV-2 infection.


How to diagnose and manage antiphospholipid syndrome.
Antiphospholipid antibodies (aPL) are autoimmune antibodies directed toward phospholipids or phospholipid-protein complexes, particularly those containing β2-glycoprotein I (β2GPI). Persistently positive aPL accompanied by arterial or venous thrombosis, or recurrent pregnancy loss, constitutes the antiphospholipid syndrome (APS). Several types of aPL with different specificities have been defined and may be detected in the clinical lab, including lupus anticoagulants (detected using clotting assays) and anticardiolipin, anti-β2GPI and anti-prothrombin/phosphatidylserine antibodies (detected by ELISA); each of the last 3 aPL may be either IgG, IgM, or IgA, though IgA antibodies are not included in criteria for APS. Due to the relative rarity of APS and the heterogeneity of aPL, thrombosis risk stratification is challenging, and randomized clinical trials for thrombosis treatment and prevention have been limited. This lack of high-quality data has made the clinical management of APS difficult, and existing guidelines are few and could not possibly cover many of the scenarios encountered in managing patients with APS. In this review, we present 3 patients with aPL and/or APS who highlight treatment dilemmas, and we discuss background information that may help guide clinical judgment in developing individualized treatment plans for patients with these enigmatic antibodies.


Evaluating Candidacy for Hypofractionated Radiation Therapy, Accelerated Partial Breast Irradiation, and Endocrine Therapy After Breast Conserving Surgery: A Surveillance Epidemiology and End Results (SEER) Analysis.
After breast conserving surgery, adjuvant radiation therapy represents the standard of care for most patients. However, multiple options exist beyond standard fractionated whole breast irradiation including hypofractionated whole breast irradiation (HFRT), accelerated partial breast irradiation (APBI), and endocrine therapy (ET) alone, which can limit treatment duration, and potentially reduce morbidity and cost. Limited data are available on the percentage of patients eligible for these alternatives; therefore, a Surveillance Epidemiology and End Results (SEER) analysis was performed to assess candidacy for these alternative options in women with early stage breast cancer. Women treated for breast cancer between the years of 2010 and 2012 were identified in the SEER database. Patients with unknown staging, metastatic disease, T3/T4 disease, and ≥N1 disease were excluded. Patients were defined as eligible for HFRT based on the American Society for Radiation Oncology (ASTRO) consensus guidelines and randomised trial testing intensity modulated and partial organ radiotherapy following breast conservation surgery for early breast cancer (IMPORT LOW) trial criteria, APBI based on the ASTRO, American Brachytherapy Society and the Groupe Européen de Curiethérapie of European Society for Therapeutic Radiotherapy and Oncology (GEC-ESTRO) consensus guidelines, and GEC-ESTRO APBI and IMPORT LOW trial criteria, and ET alone based on the Cancer and Leukemia Group B 9343 and Post-operative Radiotherapy in Minimum Risk Elderly II inclusion criteria. A total of 108,484 women with early stage breast cancer who met the aforementioned inclusion criteria were identified. Of these patients, 86,896 (80.1%) were eligible for HFRT based on ASTRO consensus guidelines and 81,459 (75.0%) based on IMPORT LOW trial criteria. Regarding APBI, 44,797 (41.2%), 81,020 (74.6%), 81,020 (74.6%) were eligible according to ASTRO, ABS, GEC-ESTRO consensus guidelines, respectively, 97,301 (89.7%) patients according to the GEC-ESTRO trial criteria, and 81,459 (75.0%) patients according to the IMPORT LOW trial criteria. For ET alone, 23,006 (21.2%) were eligible according to Cancer and Leukemia Group B 9343 criteria and 42,104 (38.8%) according to Post-operative Radiotherapy in Minimum Risk Elderly II criteria. This SEER analysis demonstrates that a substantial proportion of women with early stage breast cancer are eligible for HFRT, APBI, or ET alone after breast conserving surgery according to consensus guidelines and prospective trial criteria. With incorporation of additional pathologic, dosimetric, and chemotherapy data, quality assurance pathways may use such data to help ensure patients are receiving appropriate risk stratified treatment recommendations.


Exogenous carbohydrases added to a starter diet reduced markers of systemic immune activation and decreased Lactobacillus in weaned pigs1.
Although the impact of carbohydrases on performance and nutrient utilization has been well studied, their effects on immune status and intestinal microbiota are less known in pigs. This study aimed to evaluate the impact of xylanase (X) and a carbohydrase enzyme blend (EB; cellulase, ß-glucanase, and xylanase) on the immune profile of the intestine and peripheral system as well as intestinal microbes and microbial metabolites of weaned pigs fed higher fiber diets. Pigs (n = 460; 6.43 ± 0.06 kg BW; F25 × 6.0 Genetiporc) were blocked by initial BW. Pens (n = 48; 12 per treatment; 9 or 10 pigs per pen) were randomly assigned to 1 of 4 dietary treatments, including a higher fiber control diet (CON) and the CON supplemented with 0.01% X, 0.01% EB, or both enzymes (X + EB), arranged in a 2 × 2 factorial. The diets were based on corn, soybean meal, corn distillers dried grains with solubles, and wheat middlings. After 7-d adaptation to the environment, pigs were fed experimental diets ad libitum for 28 d. Blood samples were collected from the same pig within each pen on days 0, 7, 14, and 28. Intestinal tissues and digesta were collected on day 28. Bacteria 16S rRNA gene copy numbers were quantified using qPCR. The mRNA levels of colonic IL-17, occludin (OCLN), and claudin 3 (CLDN3) were greater in pigs fed diets with X + EB, but not X or EB, compared with those fed CON (P < 0.05). The EB in the diet reduced plasma IL-8 over the 28-d trial compared with diets without EB (P < 0.05). There was an X × EB interaction on plasma tumor necrosis factor α and IL-1ß (P < 0.05); their levels were decreased when X and EB were added together, but not individually, compared with CON. The EB decreased cecal propionate, butyrate, and total volatile fatty acids (P < 0.05). Pigs fed X had lower ileal Lactobacillus and greater ileal and cecal Enterobacteriaceae compared with those fed unsupplemented diets (P < 0.05). The EB decreased Lactobacillus (P < 0.05) and tended to decrease (P = 0.065) Enterobacteriaceae in the colon compared with diets without EB. In conclusion, the addition of X and EB together decreased systemic markers of immune activation, potentially diverting energy and nutrients towards growth. The EB reduced colonic Lactobacillus and cecal total volatile fatty acids, probably due to improved prececal fiber and starch degradation and thus reduced substrate availability in the large intestine. These data corroborated previously observed enhanced growth in pigs fed EB-supplemented diets.


Replication of the correlation between natural mood states and working memory-related prefrontal activity measured by near-infrared spectroscopy in a German sample.
Previous studies have suggested complex interactions of mood and cognition in the lateral prefrontal cortex (PFC). Although such interactions might be influenced by various factors such as personality and cultural background, their reproducibility and generalizability have hardly been explored. In the present study, we focused on a previously found correlation between negative mood states and PFC activity during a verbal working memory (WM) task, which had been demonstrated by using near-infrared spectroscopy (NIRS) in a Japanese sample. To confirm and extend the generalizability of this finding, we conducted a similar experiment in a German sample, i.e., participants with a different language background. Here, PFC activity during verbal and spatial WM tasks was measured by NIRS using a delayed match-to-sample paradigm after the participants' natural mood states had been evaluated by a mood questionnaire (Profiles of Mood States: POMS). We also included control tasks to consider the general effect of visual/auditory inputs and motor responses. For the verbal WM task, the POMS total mood disturbance (TMD) score was negatively correlated with baseline-corrected NIRS data mainly over the left dorsolateral PFC (i.e., higher TMD scores were associated with reduced activation), which is consistent with previous studies. Moreover, this relationship was also present when verbal WM activation was contrasted with the control task. These results suggest that the mood-cognition interaction within the PFC is reproducible in a sample with a different language background and represents a general phenomenon.


Pro - inflammatory cytokines and metalloproteinase activation in polypropylene mesh implant in rat subcutaneous tissue.
Polypropylene meshes have been increasingly adopted for correction of pelvic organ prolapse due to its lower recurrence rate when compared to surgeries without meshes. The study of the interaction of these materials with the host tissue may contribute to the development of materials with best biocompatibility and, consequently, less complication rates. The present study compares the inflammatory reaction of standard-weight (SW) and lightweight (LW) meshes (72 g/m216g/m2 respectively), implanted in the abdomen of 20 adult rats, which were euthanized in four or 30 days. Quantification of pro-inflammatory markers, IL-1 and TNF-α, and of metalloproteinases, MMP2 and MMP3, were carried out through immunohistochemistry with AxioVision ® software. There were no significant differences in the quantification of IL-1 and TNF-α in LW versus SW meshes. However, IL-1 quantification increased along time (30 days >4 days, p=0.0269). Also, MMP-2 quantification was similar to SW and LW and both presented a significant increase along time (30 days >4 days, p < 0.0001). MMP-3 quantification also showed no difference between the SW and LW groups, but increased along time (30 days >4 days, p=0.02). Mesh's density did not influence the quantification of pro-inflammatory cytokines IL-1 and TNF-α and metalloproteinases 2 and 3. The increased expression of IL-1, MMP-2 and MMP-3 over time could represent a longstanding inflammatory response after PP mesh implantation. Possibly, the occurrence of adverse events following PP prosthetic implants can be influenced by other factors, not solely related to the amount of implanted material.


Structural and compositional mismatch between captive and wild Atlantic salmon (Salmo salar) parrs' gut microbiota highlights the relevance of integrating molecular ecology for management and conservation methods.
Stocking methods are used in the Province of Quebec to restore Salmo salar populations. However, Atlantic salmon stocked juveniles show higher mortality rates than wild ones when introduced into nature. Hatchery environment, which greatly differs from the natural environment, is identified as the main driver of the phenotypic mismatch between captive and wild parrs. The latter is also suspected to impact the gut microbiota composition, which can be associated with essential metabolic functions for their host. We hypothesized that hatchery-raised parrs potentially recruit gut microbial communities that are different from those recruited in the wild. This study evaluated the impacts of artificial rearing on gut microbiota composition in 0+ parrs meant for stocking in two distinct Canadian rivers: Rimouski and Malbaie (Quebec, Canada). Striking differences between hatchery and wild-born parrs' gut microbiota suggest that microbiota could be another factor that could impact their survival in the targeted river, because the microbiome is narrowly related to host physiology. For instance, major commensals belonging to Enterobacteriaceae and Clostridiacea from wild parrs' gut microbiota were substituted in captive parrs by lactic acid bacteria from the Lactobacillaceae family. Overall, captive parrs host a generalist bacterial community whereas wild parrs' microbiota is much more specialized. This is the very first study demonstrating extensive impact of captive rearing on intestinal microbiota composition in Atlantic salmon intended for wild population stocking. Our results strongly suggest the need to implement microbial ecology concepts into conservation management of endangered salmon stocks supplemented with hatchery-reared parrs.


Modeling the removal of VOC mixtures in biotrickling filters.
A mathematical model was derived for describing removal of mixed VOC vapors in biotrickling filters (BTFs). The model accounts for potential process rate limitation by the availability of oxygen as well as for potential kinetic interactions among pollutants during their biodegradation. Without using any fitted parameter, the model was found capable of predicting experimentally obtained removal rates of mono-chlorobenzene (m-CB) and ortho-dichlorobenzene (o-DCB) vapors. Experimental results reported here show that m-CB removal is better than that of o-DCB. The two compounds were known to be involved in a kinetic cross-inhibition interaction when degraded in suspended culture. However, model sensitivity studies showed that cross-inhibition does not affect BTF performance due to the low pollutant concentrations involved. For the same reason, the influence of oxygen on BTF performance was found to be minimal under the conditions tested. The model was found to predict experimentally obtained values with less than 10% error in the majority of cases. Computations with an earlier model describing VOC removal in conventional biofilters showed that, for the model mixture used in this study (m-CB/o-DCB), removal rates obtained with BTFs are one to more than two orders of magnitude higher than those obtained with conventional biofilters. This is attributed to the larger active specific biofilm surface area in BTFs, obtained through the creation of favorable growth conditions for the biomass, and better moisture control.


Changes in 5-HT1A receptor expression in the oculomotor nucleus in a rat model of post-traumatic stress disorder.
Post-traumatic stress disorder (PTSD) is an anxiety disorder that develops after exposure to a life-threatening traumatic experience. Mental disorder appears after the traumatic stress incident and affects the movement of the eye muscle dominated by the oculomotor nucleus, an important nuclear group of the brainstem. It has been reported that dysfunction of the neurotransmitter 5-hydroxytryptamine (5-HT) can lead to the instability of the internal environment in response to stress and plays an important role in the pathology of PTSD and that the 5-HT1A receptor (5-HT1AR) is critically involved in regulating mood and anxiety levels. In this study, the 5-HT1AR expression in the oculomotor nucleus was examined in rats with single-prolonged stress (SPS), a well established post-traumatic stress disorder animal model. Our results show that the expression of 5-HT1AR in the oculomotor nucleus neurons gradually increased 1, 4, and 7 days after exposure to SPS in comparison to the normal control group, measured by immunohistochemistry, western blotting, and reverse transcription polymerase chain reaction (RT-PCR). The expression of 5-HT1AR reached its peak 7 days after the SPS exposure and then decreased 14 days after. There is also a change in the ultrastructure in the oculomotor nucleus neuron upon SPS treatment which was observed by transmission electron microscopy. These results suggest that SPS can induce a change of the 5-HT1AR expression in the oculomotor nucleus, which may be one of the molecular mechanisms that lead to PTSD.


Left ventricular myocardial edema. Lymph flow, interstitial fibrosis, and cardiac function.
We hypothesized that both acute and chronic accumulation of myocardial interstitial edema (extravascular fluid [EVF]) would compromise cardiac function. We also postulated that excess fluid within the myocardial interstitial space would potentiate interstitial fibrosis, thus further compromising function. Dogs were divided into three groups: 1) control, 2) chronic pulmonary hypertensive with right heart failure, and 3) chronic arterial hypertensive. The quantity of EVF, expressed as the unitless blood-free (wet weight-dry weight)/dry weight ratio, and interstitial fibrosis (collagen content) were determined and correlated with cardiac function at baseline and after acute elevation of coronary venous pressure and reduction of cardiac lymph flow. Control EVF was 2.90 +/- 0.20 (mean +/- SD), which increased to 3.45 +/- 0.16 after acute (3-hour) elevation of coronary sinus pressure. This EVF significantly compromised cardiac function. The EVF in chronically hypertensive dogs and in dogs with chronic right heart pressure elevations was 3.50 +/- 0.30 and 3.50 +/- 0.08, respectively. End-diastolic left ventricular interstitial fluid pressure increased from a control value of 14.9 +/- 3.1 (at EVF = 2.9) to 24.8 +/- 3.7 (at EVF = 3.5). An EVF of 3.5 produced approximately 30% reduction of the heart's ability to maintain cardiac output at a left atrial pressure of 15 mm Hg. The compromised function in these chronic models is exacerbated after acute elevation of coronary venous pressure and reduction of cardiac lymph flow. Collagen levels were elevated by at least 20% in the chronic hypertensive dogs and in the nonhypertrophied left ventricles of dogs with chronic right heart pressure elevation.(ABSTRACT TRUNCATED AT 250 WORDS)


Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome.
The mechanisms underlying abdominal pain perception in irritable bowel syndrome (IBS) are poorly understood. Intestinal mast cell infiltration may perturb nerve function leading to symptom perception. We assessed colonic mast cell infiltration, mediator release, and spatial interactions with mucosal innervation and their correlation with abdominal pain in IBS patients. IBS patients were diagnosed according to Rome II criteria and abdominal pain quantified according to a validated questionnaire. Colonic mucosal mast cells were identified immunohistochemically and quantified with a computer-assisted counting method. Mast cell tryptase and histamine release were analyzed immunoenzymatically. Intestinal nerve to mast cell distance was assessed with electron microscopy. Thirty-four out of 44 IBS patients (77%) showed an increased area of mucosa occupied by mast cells as compared with controls (9.2% +/- 2.5% vs. 3.3 +/- 0.8%, respectively; P < 0.001). There was a 150% increase in the number of degranulating mast cells (4.76 +/- 3.18/field vs. 2.42 +/- 2.26/field, respectively; P = 0.026). Mucosal content of tryptase was increased in IBS and mast cells spontaneously released more tryptase (3.22 +/- 3.48 pmol/min/mg vs. 0.87 +/- 0.65 pmol/min/mg, respectively; P = 0.015) and histamine (339.7 +/- 59.0 ng/g vs. 169.3 +/- 130.6 ng/g, respectively; P = 0.015). Mast cells located within 5 microm of nerve fibers were 7.14 +/- 3.87/field vs. 2.27 +/- 1.63/field in IBS vs. controls (P < 0.001). Only mast cells in close proximity to nerves were significantly correlated with severity and frequency of abdominal pain/discomfort (P < 0.001 and P = 0.003, respectively). Colonic mast cell infiltration and mediator release in proximity to mucosal innervation may contribute to abdominal pain perception in IBS patients.


Sexual responsiveness of college students to rape depictions: inhibitory and disinhibitory effects.
Two experiments were conducted to identify the specific dimensions in portrayals of sexual violence that inhibit or disinhibit the sexual responsiveness of male and female college students. The first experiment replicated earlier findings that normals are less sexually aroused by portrayals of sexual assault than by depictions of mutually consenting sex. In the second experiment, it was shown that portraying the rape victim as experiencing an involuntary orgasm disinhibited subjects' sexual responsiveness and resulted in levels of arousal comparable to those elicited by depictions of mutually consenting sex. Surprisingly, however, it was found that although female subjects were most aroused when the rape victim was portrayed as experiencing an orgasm and no pain, males were most aroused when the victim experienced an orgasm and pain. The relevance of these data to pornography and to the common belief among rapists that their victims derive pleasure from being assaulted is discussed. Misattribution, identification, and power explanations of the findings are also discussed. Finally, it is suggested that arousing stimuli that fuse sexuality and violence may have antisocial effects.


Self-assembly of colloidal polymers via depletion-mediated lock and key binding.
We study the depletion-induced self-assembly of indented colloids. Using state-of-the-art Monte Carlo simulation techniques that treat the depletant particles explicitly, we demonstrate that colloids assemble by a lock-and-key mechanism, leading to colloidal polymerization. The morphology of the chains that are formed depends sensitively on the size of the colloidal indentation, with smaller values additionally permitting chain branching. In contrast to the case of spheres with attractive patches, Wertheim's thermodynamic perturbation theory fails to provide a fully quantitative description of the polymerization transition. We trace this failure to a neglect of packing effects and we introduce a modified theory that accounts better for the shape of the colloids, yielding improved agreement with simulation.


National interdisciplinary rhinoplasty.
Rhinoplasty is a complex and multifaceted operation. There are great differences in methodologies between practitioners. Examining the preoperative, operative, and postoperative techniques employed by different practitioners will provide rhinoplasty surgeons with benchmarks by which they can evaluate their own practice. To assess current trends in rhinoplasty surgery. A comprehensive questionnaire was sent to 7368 members of the following societies: the American Society of Plastic Surgeons (ASPS), the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS), and the American Academy of Facial Plastic and Reconstructive Surgery (AAFPRS). Subgroup statistical analysis was performed. The overall response rate was 26%. Plastic surgeons accounted for 68% of the response rate and ear, nose, and throat-affiliated physicians accounted for 28%, with a small minority (4%) being members of both groups. Sixty-five percent of respondents have been in practice 11 or more years. Fifty-two percent of respondents are in private practice, 19% are in academic practice, and the rest are in single- or multispecialty practices. The number of rhinoplasties performed per year is spread fairly evenly up to 50 per year; however, only 9% of respondents perform 50 to 100 rhinoplasties per year, and only 5% perform more than 100 rhinoplasties per year. Most prefer the open approach over the closed approach, with 33% performing open only and 42% using both approaches, but primarily open. There is no uniform consensus regarding general rhinoplasty trends. Subanalysis shows that, overall, there are statistically significant similarities and differences amongst different specialties.


Vitamin-D receptor genotype does not predict bone mineral density, bone turnover, and growth in prepubertal children.
We examined whether the polymorphism for BsmI restriction enzyme in the vitamin-D receptor (VDR) gene influenced radial (distal third) and lumbar (L2-L4) bone mineral density (BMD), phospho-calcium metabolism (calcium, phosphate, intact parathyroid hormone, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D), biochemical markers of bone formation (osteocalcin and carboxy-terminal propeptide of type-I procollagen) and bone resorption (carboxy-terminal telopeptide of type-I collagen and urinary cross-linked N-telopeptides of type I collagen), insulin-like growth factor I and insulin-like growth factor-binding protein 3, and growth in 209 healthy prepubertal children (112 males and 97 females) aged 7.1-10.0 years. Genotype frequencies were BB 19%, Bb 46%, and bb 35% in the pooled group of children. Clinical findings, dietary calcium intake, calcium density, and physical activity rate were not different (p NS) among the VDR genotypes. Radial BMD, lumbar BMDarea and lumbar BMD adjusted for the apparent bone volume (BMDvolume), and all the biochemical parameters did not differ (p NS) in relation to the VDR genotype. In conclusion, our data show that polymorphism for BsmI restriction enzyme in the VDR gene is not associated with radial and lumbar BMD, parameters of phospho-calcium metabolism and bone turnover, growth hormone-dependent growth factors, and growth in prepubertal children.


Measuring weight self-stigma: the weight self-stigma questionnaire.
Stigma associated with being overweight or obese is widespread. Given that weight loss is difficult to achieve and maintain, researchers have been calling for interventions that reduce the impact of weight stigma on life functioning. Sound measures that are sensitive to change are needed to help guide and inform intervention studies. This study presents the weight self-stigma questionnaire (WSSQ). The WSSQ has 12 items and is designed for use only with populations of overweight or obese persons. Two samples of participants--one treatment seeking, one nontreatment seeking--were used for validation (N = 169). Results indicate that the WSSQ has good reliability and validity, and contains two distinct subscales-self-devaluation and fear of enacted stigma. The WSSQ could be useful for identifying individuals who may benefit from a stigma reduction intervention and may also help evaluate programs designed to reduce stigma.


Use of metformin and outcome of patients with newly diagnosed glioblastoma: Pooled analysis.
Metformin has been linked to improve survival of patients with various cancers. There is little information on survival of glioblastoma patients after use of metformin. We assessed the association between metformin use and survival in a pooled analysis of patient data from 1,731 individuals from the randomized AVAglio, CENTRIC and CORE trials. We performed multivariate Cox analyses for overall survival (OS) and progression-free survival (PFS) comparing patients' use of metformin at baseline and/or during concomitant radiochemotherapy (TMZ/RT). Further exploratory analyses investigated the effect of metformin with a history of diabetes and nonfasting glucose levels in relation to OS or PFS of glioblastoma patients. Metformin alone or in any combination was not significantly associated with OS or PFS (at baseline, hazard ratio [HR] for OS = 0.87; 95% confidence interval [CI] = 0.65-1.16; HR for PFS = 0.84; 95% CI = 0.64-1.10; during TMZ/RT HR for OS = 0.97; 95% CI = 0.68-1.38; HR for PFS = 1.02; 95% CI = 0.74-1.41). We found a statistically nonsignificant association of metformin monotherapy with glioblastoma survival at baseline (HR for OS = 0.68; 95% CI = 0.42-1.10; HR for PFS = 0.57; 95% CI = 0.36-0.91), but not during the TMZ/RT period (HR for OS = 0.90; 95% CI = 0.51-1.56; HR for PFS = 1.05; 95% CI = 0.64-1.73). Diabetes mellitus or increased nonfasting glucose levels were not associated with a difference in OS or PFS in our selected study population. Metformin did not prolong survival of patients with newly diagnosed glioblastoma in our analysis. Additional studies may identify patients with specific tumor characteristics that are associated with potential benefit from treatment with metformin, possibly due to metabolic vulnerabilities.


Surgical practice kit. Ophthalmic suture simulator.
A practice surgery device used for training novice ophthalmic surgeons employs an inflatable bladder that supports a human bank scleral shell. The sclera is used for placement of sutures. A light source and universal joint to support a syringe are mounted on a 25 X 15-cm base. Glycerin-preserved sclera is available from many eye banks. Up to 100 practice sutures may be placed in each scleral shell. This device allows the beginning surgeon the opportunity to obtain a feel for needle passage through tissue. Technique for the use of loupe or microscope magnification can also be developed. In addition, a deflation of the scleral "globe" occurs when a needle is placed too deeply. This emphasizes the need of superficial suture placement.


The Potential of Artificial Intelligence to Detect Lymphovascular Invasion in Testicular Cancer.
Testicular cancer is the most common cancer in men aged from 15 to 34 years. Lymphovascular invasion refers to the presence of tumours within endothelial-lined lymphatic or vascular channels, and has been shown to have prognostic significance in testicular germ cell tumours. In non-seminomatous tumours, lymphovascular invasion is the most powerful prognostic factor for stage 1 disease. For the pathologist, searching multiple slides for lymphovascular invasion can be highly time-consuming. The aim of this retrospective study was to develop and assess an artificial intelligence algorithm that can identify areas suspicious for lymphovascular invasion in histological digital whole slide images. Areas of possible lymphovascular invasion were annotated in a total of 184 whole slide images of haematoxylin and eosin (H&E) stained tissue from 19 patients with testicular germ cell tumours, including a mixture of seminoma and non-seminomatous cases. Following consensus review by specialist uropathologists, we trained a deep learning classifier for automatic segmentation of areas suspicious for lymphovascular invasion. The classifier identified 34 areas within a validation set of 118 whole slide images from 10 patients, each of which was reviewed by three expert pathologists to form a majority consensus. The precision was 0.68 for areas which were considered to be appropriate to flag, and 0.56 for areas considered to be definite lymphovascular invasion. An artificial intelligence tool which highlights areas of possible lymphovascular invasion to reporting pathologists, who then make a final judgement on its presence or absence, has been demonstrated as feasible in this proof-of-concept study. Further development is required before clinical deployment.


Elevated serum neutrophil gelatinase-associated lipocalin is an early predictor of severity and outcome in acute pancreatitis.
About 210,000 new cases of acute pancreatitis (AP) involving reversible inflammation of the pancreas are reported in the United States every year. About one-fourth of all patients with AP go on to develop severe acute pancreatitis (SAP), which, unlike uncomplicated or mild acute pancreatitis (MAP, usually a self-limiting disease), constitutes a life-threatening condition with systemic complications, chiefly multiorgan dysfunction. An early prediction of the severity and outcome of patients with acute pancreatitis (AP) can lead to better treatment regimens for patients with SAP. There is currently no established biomarker for the early diagnosis of SAP. In this study, we investigated the potential of serum neutrophil gelatinase-associated lipocalin (NGAL) as an early marker to distinguish severe (SAP) from MAP and examine its ability to predict the prognosis of patients with SAP. To check the time kinetics of rise in NGAL during AP, we quantified NGAL levels in sera from mice with MAP or SAP at various time points (6, 12, 24 and 48 h) using sandwich enzyme-linked immunosorbent assay. NGAL levels were also quantified in serum from 28 MAP and 16 SAP cases and compared with 28 chronic pancreatitis and 30 healthy control samples. Samples collected within 5 days from onset of symptoms were included. The relationship of NGAL levels with survival and multiorgan failure (MOF) in SAP was also examined. Although NGAL levels were significantly higher in mice with both MAP and SAP 6 h after induction (compared to control animals), only mice with SAP exhibited a significant increase in NGAL levels at 24 h (P=0.003). NGAL levels declined at 48 h after induction in animals with both MAP and SAP but did not reach baseline levels. Among patients, mean (+/-s.e.) serum NGAL level was significantly higher in SAP (634+/-139 ng/ml) compared to MAP (84.7+/-7 ng/ml, P=0.0001). On subanalysis, the difference between MAP and SAP cases was significant in the first 48 h but not at 72, 96, or 120 h. NGAL was 100%, 96%, 97%, and 84% specific and 100%, 87.5%, 92%, and 94% sensitive in distinguishing SAP from MAP at 48, 72, 96, and 120 h, respectively, after the onset of symptoms. NGAL levels were significantly higher in SAP cases complicated by MOF (P=0.004), and high NGAL levels in SAP appeared to correlate with a fatal outcome. Our data provide the first evidence for the potential of serum NGAL as an early marker to distinguish MAP from SAP. Further, high NGAL levels predict MOF and fatal outcome in patients with SAP. This study provides sufficient evidence for multi-institutional randomized trials for estimating the potential of NGAL as early biomarker for SAP.


Graft-versus-host disease propagation depends on increased intestinal epithelial tight junction permeability.
Graft-versus-host disease (GVHD) is a complication of hematopoietic stem cell transplantation (HSCT) that affects multiple organs. GVHD-associated intestinal damage can be separated into two distinct phases, initiation and propagation, which correspond to conditioning-induced damage and effector T cell activation and infiltration, respectively. Substantial evidence indicates that intestinal damage induced by pretransplant conditioning is a key driver of GVHD initiation. Here, we aimed to determine the impact of dysregulated intestinal permeability on the subsequent GVHD propagation phase. The initiation phase of GVHD was unchanged in mice lacking long MLCK (MLCK210), an established regulator of epithelial tight junction permeability. However, MLCK210-deficient mice were protected from sustained barrier loss and exhibited limited GVHD propagation, as indicated by reduced histopathology, fewer CD8+ effector T cells in the gut, and improved overall survival. Consistent with these findings, intestinal epithelial MLCK210 expression and enzymatic activity were similarly increased in human and mouse GVHD biopsies. Intestinal epithelial barrier loss mediated by MLCK210 is therefore a key driver of the GVHD propagation. These data suggest that inhibition of MLCK210-dependent barrier regulation may be an effective approach to limiting GVHD progression.


Psychiatric and medical admissions observed among elderly patients with new-onset epilepsy.
Inpatient utilization associated with incidence of geriatric new-onset epilepsy has not been characterized in any large study, despite recognized high levels of risk factors (comorbidity). Retrospective study using administrative data (Oct '01-Sep '05) from the Veterans Health Administration from a nationwide sample of 824,483 patients over age 66 in the retrospective observational Treatment In Geriatric Epilepsy Research (TIGER) study. Psychiatric and medical hospital admissions were analyzed as a function of patient demographics, comorbid psychiatric, neurological, and other medical conditions, and new-onset epilepsy. Elderly patients experienced a 15% hospitalization rate in FY00 overall, but the subset of new-onset epilepsy patients (n = 1,610) had a 52% hospitalization rate. New-onset epilepsy was associated with three-fold increased relative odds of psychiatric admission and nearly five-fold increased relative odds of medical admission. Among new-onset epilepsy patients, alcohol dependence was most strongly associated with psychiatric admission during the first year after epilepsy onset (odds ratio = 5.2; 95% confidence interval 2.6-10.0), while for medical admissions the strongest factor was myocardial infarction (odds ratio = 4.7; 95% confidence interval 2.7-8.3). From the patient point of view, new-onset epilepsy was associated with an increased risk of medical admission as well as of psychiatric admission. From an analytic perspective, omitting epilepsy and other neurological conditions may lead to overestimation of the risk of admission attributable solely to psychiatric conditions. Finally, from a health systems perspective, the emerging picture of the epilepsy patient with considerable comorbidity and demand for healthcare resources may merit development of practice guidelines to improve coordinated delivery of care.


Decontamination of landfill leachate by soil infiltration.
A soil column study was conducted to evaluate the efficiency of soil to attenuate pollutants in landfill leachate. It was found that more than 60% of the initial alkalinity, COD, and total nitrogen was removed after the leachate had percolated through the soil column. Lower efficiencies were observed for the removal of dissolved cations, ammonia nitrogen, and nitrate nitrogen. When previously percolated leachate was recirculated through the soil column, significant removal (93.6%) of ammonia nitrogen was achieved. Moreover, a further reduction in COD, total nitrogen, nitrate nitrogen, and potassium was evident. Bioassay tests of seed germination and root growth of Brassica chinensis were performed to compare the phytotoxicities of untreated, percolated, and recirculated leachates. The phytotoxicity was reduced by both treatments, with the greatest detoxification observed in the leachate recirculation treatment. The values of pH and Olsen phosphorus were significantly reduced (P less than 0.01) in the treated column soil, whereas significant increases (P less than 0.05) in electrical conductivity (EC), various forms of nitrogen, exchangeable sodium percentage (ESP), potassium, magnesium, zinc, and iron were observed. EC, ESP, potassium, magnesium, sodium, iron, and various forms of nitrogen accumulated at the soil surface (10 cm). On the other hand, manganese was deposited at 20 to 50 cm below the soil surface of the treated column.


Anesthetic Neurotoxicity in Congenital Hand Surgery: An Overview of the Evidence and Advice for Counseling Parents.
Millions of children undergo general anesthesia for surgical procedures each year, the implications of which are not fully understood. Animal models demonstrate neurotoxicity and long-term cognitive impairment following exposure to common general anesthetic agents. However, it is unclear if human brains are affected in a similar fashion and what-if any-the implications on cognitive development may be. Furthermore, it is not known if these effects are additive and if they can be avoided by delaying reconstruction. Here, we explore reconstructive surgical timelines for common congenital hand differences in light of the available anesthetic neurotoxicity evidence, with an emphasis on preoperative counseling.


Substance P mobilizes intracellular calcium and activates a nonselective cation conductance in rat spiral ganglion neurons.
We demonstrate the expression of functional tachykinin receptors in rat spiral ganglion neurons (SGNs) using calcium signal measurement and whole-cell patch clamp recording. Substance P (SP; 10 microm, 1 s application) induced a transient increase in intracellular calcium. The SP dose-response study showed an EC50 of 18.8 microm and a Hill slope of 0.77. Comparison between specific agonists for the three tachykinin receptor (NKR) types showed the potency NKR3 > NKR1 > NKR2 at 10 microm. The Ca2+ response could be evoked in Ca2+-free medium and was blocked by N-ethylmaleimide and U-73122, indicating that Ca2+ was released from intracellular stores via a G-protein and phospholipase C pathway. Under whole-cell voltage clamp recording at a holding potential of -50 mV, SP (10 microm, 1 s) evoked a slowly developing transient inward current. The current reversed near to 0 mV and ionic permeability experiments revealed a cation nonselective conductance also permeable to large organic cations such as N-methyl-D-glucamine and tetraethylammonium. Neither removing extracellular calcium nor chelating intracellular calcium with 10 mm BAPTA could block the SP-evoked current. This conductance appeared coupled to G-protein activation as intracellular GDP-betaS blocked the SP-evoked current. Mutual desensitization and occlusion studies with acetylcholine and ATP showed that the SP-evoked conductance share effector channels and/or intracellular processes with the purinergic/cholinergic conductance. In SGNs, SP could have both a trophic action, via a calcium response, and a neuromodulatory role, by a depolarizing action through the activation of nonselective cation channels.


Response to COVID-19 in South Korea and implications for lifting stringent interventions.
After experiencing a sharp growth in COVID-19 cases early in the pandemic, South Korea rapidly controlled transmission while implementing less stringent national social distancing measures than countries in Europe and the USA. This has led to substantial interest in their "test, trace, isolate" strategy. However, it is important to understand the epidemiological peculiarities of South Korea's outbreak and characterise their response before attempting to emulate these measures elsewhere. We systematically extracted numbers of suspected cases tested, PCR-confirmed cases, deaths, isolated confirmed cases, and numbers of confirmed cases with an identified epidemiological link from publicly available data. We estimated the time-varying reproduction number, Rt, using an established Bayesian framework, and reviewed the package of interventions implemented by South Korea using our extracted data, plus published literature and government sources. We estimated that after the initial rapid growth in cases, Rt dropped below one in early April before increasing to a maximum of 1.94 (95%CrI, 1.64-2.27) in May following outbreaks in Seoul Metropolitan Region. By mid-June, Rt was back below one where it remained until the end of our study (July 13th). Despite less stringent "lockdown" measures, strong social distancing measures were implemented in high-incidence areas and studies measured a considerable national decrease in movement in late February. Testing the capacity was swiftly increased, and protocols were in place to isolate suspected and confirmed cases quickly; however, we could not estimate the delay to isolation using our data. Accounting for just 10% of cases, individual case-based contact tracing picked up a relatively minor proportion of total cases, with cluster investigations accounting for 66%. Whilst early adoption of testing and contact tracing is likely to be important for South Korea's successful outbreak control, other factors including regional implementation of strong social distancing measures likely also contributed. The high volume of testing and the low number of deaths suggest that South Korea experienced a small epidemic relative to other countries. Caution is needed in attempting to replicate the South Korean response in populations with larger more geographically widespread epidemics where finding, testing, and isolating cases that are linked to clusters may be more difficult.


A beta40 is a major form of beta-amyloid in nonhuman primates.
Because aged nonhuman primates show beta-amyloid (A beta) deposition in senile plaques and blood vessels similar to that seen in human aging and AD, we used C-terminal specific antibodies to A beta40 and A beta42 to investigate A beta peptide length in the brains of 11 aged rhesus monkeys and a 59-year-old chimpanzee. In contrast to AD, where the earliest and most prominent form of A beta in senile plaques is A beta42, in the monkey, A beta40-positive plaques predominated. The ratio of A beta40:A beta42-positive plaques averaged 2.08 in the monkey, as compared to a mean ratio of 0.37 in 68 human AD subjects (p < 0.001). A beta40 was also more prominent in the chimpanzee than in humans. Possible explanations for these findings include species differences in the cleavage of A beta from the amyloid precursor protein or in the activity of a putative carboxy peptidase forming A beta40 from A beta42 in situ.


Extrageniculate contributions to reflex visual orienting in normal humans: a temporal hemifield advantage.
Evidence is presented that the phylogenetically older retin-otectal pathway contributes to reflex orienting of visual attention in normal human subjects. The study exploited a lateralized neuroanatomic arrangement of retinotectal pathways that distinguishes them from those of the geniculostriate system; namely, more direct projections to the colliculus from the temporal hemifield. Subjects were tested under monocular viewing conditions and responded to the detection of a peripheral signal by making either a saccade to it or a choice reaction time manual keypress. Attention was summoned by noninformative peripheral precues, and the benefits and costs of attention were calculated relative to a central precue condition. Both the benefits and costs of orienting attention were greater when attention was summoned by signals in the temporal hemifield. This temporal hemifield advantage was present for both saccade and manual responses. These findings converge with observations in patients with occipital and midbrain lesions to show that the phylogenetically older retinotectal pathway retains an important role in controlling visually guided behavior; and they demonstrate the usefulness of temporal-nasal hemifield asymmetries as a marker for investigating extrageniculate vision in humans.


Voltammetric and Spectroscopic Studies of α- and β-[PW12O40]3- Polyoxometalates in Neutral and Acidic Media: Structural Characterization as Their [(n-Bu4N)3][PW12O40] Salts.
The structure of the Keggin-type β-[PW12O40]3- (PW12) polyoxometalate, with n-Bu4N+ as the countercation, has been determined for the first time by single-crystal X-ray analysis and compared to data obtained from a new determination of the structure of the α-PW12 isomer, having the same countercation. Analysis of cyclic voltammograms obtained in CH3CN (0.1 M [n-Bu4N][PF6]) reveals that the reversible potential for the β-PW12 isomer always remains ca. 100 mV more positive than that of the α-PW12 isomer on addition of the acid CF3SO3H. Simulations of the cyclic voltammetry as a function of acid concentration over the range 0-5 mM mimic experimental data exceptionally well. These simulation-experiment comparisons provide access to reversible potentials and acidity constants associated with α and β fully oxidized and one- and two-electron reduced systems and also explain how the two well-resolved one-electron W(VI)/W(V) processes converge into a single two-electron process if sufficient acid is present. 183W NMR spectra of the oxidized forms of the PW12 isomers are acid dependent and in the case of β-PW12 imply that the bridging oxygens between the WI and WII units are preferentially protonated in acidic media. EPR data on frozen solutions of one-electron reduced β-[PWVWVI11O40]4- indicate that either the WI or the WIII unit in β-PW12 is reduced in the β-[PWVI12O40]3-/β-[PWVWVI11O40]4- process. In the absence of acid, reversible potentials obtained from the α- and β-isomers of PW12 and [SiW12O40]4- exhibit a linear relationship with solvent properties such as Lewis acidity, acceptor number, and polarity index.


Genetics Evaluation Guidelines for the Etiologic Diagnosis of Congenital Hearing Loss. Genetic Evaluation of Congenital Hearing Loss Expert Panel. ACMG statement.
The advent of hearing screening in newborns in many states has led to an increase in the use of genetic testing and related genetic services in the follow-up of infants with hearing loss. A significant proportion of those with congenital hearing loss have genetic etiologies underlying their hearing loss. To ensure that those identified with congenital hearing loss receive the genetic services appropriate to their conditions, the Maternal and Child Health Bureau of the Health Resources and Services Administration funded the American College of Medical Genetics to convene an expert panel to develop guidelines for the genetic evaluation of congenital hearing loss. After a brief overview of the current knowledge of hearing loss, newborn screening, and newborn hearing screening, we provide an overview of genetic services and a guideline that describes how best to ensure that patients receive appropriate genetic services. The significant contribution of genetic factors to these conditions combined with the rapid evolution of knowledge about the genetics of these conditions overlaid with the inherently multidisciplinary nature of genetic services provides an example of a condition for which a well-integrated multidisciplinary approach to care is clearly needed.


Antibiotic interactions shape short-term evolution of resistance in E. faecalis.
Antibiotic combinations are increasingly used to combat bacterial infections. Multidrug therapies are a particularly important treatment option for E. faecalis, an opportunistic pathogen that contributes to high-inoculum infections such as infective endocarditis. While numerous synergistic drug combinations for E. faecalis have been identified, much less is known about how different combinations impact the rate of resistance evolution. In this work, we use high-throughput laboratory evolution experiments to quantify adaptation in growth rate and drug resistance of E. faecalis exposed to drug combinations exhibiting different classes of interactions, ranging from synergistic to suppressive. We identify a wide range of evolutionary behavior, including both increased and decreased rates of growth adaptation, depending on the specific interplay between drug interaction and drug resistance profiles. For example, selection in a dual β-lactam combination leads to accelerated growth adaptation compared to selection with the individual drugs, even though the resulting resistance profiles are nearly identical. On the other hand, populations evolved in an aminoglycoside and β-lactam combination exhibit decreased growth adaptation and resistant profiles that depend on the specific drug concentrations. We show that the main qualitative features of these evolutionary trajectories can be explained by simple rescaling arguments that correspond to geometric transformations of the two-drug growth response surfaces measured in ancestral cells. The analysis also reveals multiple examples where resistance profiles selected by drug combinations are nearly growth-optimized along a contour connecting profiles selected by the component drugs. Our results highlight trade-offs between drug interactions and resistance profiles during the evolution of multi-drug resistance and emphasize evolutionary benefits and disadvantages of particular drug pairs targeting enterococci.


Background and methodology of the Osteopathic Survey of Health Care in America 2010 (OSTEOSURV 2010).
The Osteopathic Survey of Health Care in America (OSTEOSURV) is a decennial national telephone survey. Its goals are to monitor longitudinal trends in awareness, beliefs, utilization, and patient satisfaction relating to osteopathic physicians and to assess beliefs and attitudes regarding contemporary health care issues in the United States. The questionnaire was validated during the administrations of OSTEOSURV-I and OSTEOSURV-II in 1998 and 2000, respectively. In OSTEOSURV 2010, the contemporary health care issues of interest are patient-centered care and the Patient Protection and Affordable Care Act of 2010. The target population was household residents of the United States aged 18 years or older. A total of 10,308 random landline telephone numbers were dialed using a computer-assisted telephone interviewing system to acquire 1000 completed interviews between July 23, 2010, and October 1, 2010. The response, cooperation, and contact rates as defined by the American Association for Public Opinion Research were comparable to those of other national telephone surveys. The survey provides an estimated margin of error no greater than 3% to 4% for both general items and for those relating to the subset of respondents claiming to be aware of osteopathic physicians. Because respondents were older and more likely to be female than referents in the general population, the observed responses will be weighted by age and sex to reflect the US Census estimates for persons aged 18 years or older in 2010. OSTEOSURV 2010 was successfully fielded as the latest national telephone survey relevant to osteopathic medicine and contemporary US health care issues. Data analysis should yield important new findings relating to osteopathic physicians, patient-centered care, and the Patient Protection and Affordable Care Act that may not be readily observed through other national health care data sets. While underrepresented in this survey, which excluded cell phone-only participants, young adult respondents were reflective of their national age referents with regard to health insurance coverage and general health status. Thus, it appears likely that statistical weighting by age and sex of the OSTEOSURV 2010 data will minimize potential bias in estimates of health-related items. Rapidly evolving technology and sociocultural transitions will necessitate changes in the design of OSTEOSURV 2020.


Suicide assisted by two Swiss right-to-die organisations.
In Switzerland, non-medical right-to-die organisations such as Exit Deutsche Schweiz and Dignitas offer suicide assistance to members suffering from incurable diseases. First, to determine whether differences exist between the members who received assistance in suicide from Exit Deutsche Schweiz and Dignitas. Second, to investigate whether the practices of Exit Deutsche Schweiz have changed since the 1990s. This study analysed all cases of assisted suicide facilitated by Exit Deutsche Schweiz (E) and Dignitas (D) between 2001 and 2004 and investigated by the University of Zurich's Institute of Legal Medicine (E: n = 147; D: n = 274, total: 421). Furthermore, data from the Exit Deutsche Schweiz study which investigated all cases of assisted suicide during the period 1990-2000 (n = 149) were compared with the data of the present study. More women than men were assisted in both organisations (D: 64%; E: 65%). Dignitas provided more assistance to non-residents (D: 91%; E: 3%; p = 0.000), younger persons (mean age in years (SD): D: 64.5 (14.1); E: 76.6 (13.3); p = 0.001), and people suffering from fatal diseases such as multiple sclerosis and amyotrophic lateral sclerosis (D: 79%; E: 67%; p = 0.013). Lethal medications were more often taken orally in cases assisted by Dignitas (D: 91%; E: 76%; p = 0.000). The number of women and the proportion of older people suffering from non-fatal diseases among suicides assisted by Exit Deutsche Schweiz has increased since the 1990s (women: 52% to 65%, p = 0.031; mean age in years (SD): 69.3 (17.0) to 76.9 (13.3), p = 0.000), non-fatal diseases: 22% to 34%, p = 0.026). Weariness of life rather than a fatal or hopeless medical condition may be a more common reason for older members of Exit Deutsche Schweiz to commit suicide. The strong over-representation of women in both Exit Deutsche Schweiz and Dignitas suicides is an important phenomenon so far largely overlooked and in need of further study.


The influence of role awareness, empathy induction and trait empathy on dictator game giving.
We ask how state empathy, trait empathy, and role awareness influence dictator game giving in a monetarily incentivized experiment. We manipulated two factors: role awareness (role certainty vs. role uncertainty) and state empathy induction (no empathy induction vs. empathy induction). Under role uncertainty, participants did not know their role as a dictator or a recipient when making their choices. State empathy was induced by asking the dictators to consider what the recipient would feel when learning about the decision. Each participant was randomly assigned into one of the four conditions, and in each condition, participants were randomly assigned into dictator and receiver roles. The role assignment took place before or after decisions were made, depending on the condition. We also studied the direct influence of trait empathy on dictator game giving as well as its interaction with the experimental manipulations. Trait empathy was measured by the Interpersonal Reactivity Index (IRI) and the Questionnaire of Cognitive and Affective Empathy (QCAE) before the experiment. Of our experimental manipulations, role awareness had an effect on dictator game giving; participants donated more under role uncertainty than under role certainty. Instead, we did not observe an effect of state empathy induction. Of trait empathy subscales, only affective empathy was positively associated with dictator game giving. Finally, role awareness did not influence all participants similarly but had a larger impact on those with low scores on trait empathic concern or trait affective empathy. Our results indicate that specific measures to induce altruistic sharing can be effective but their effect may vary depending on certain personal characteristics.


Close observation versus upfront treatment in hepatocellular carcinoma: are the exception points worth the risk?
To assess the outcomes of immediate LDT versus observation strategies for T1 hepatocellular carcinoma (HCC) with respect to progression beyond Milan and survival. T1 HCCs were retrospectively reviewed from a multidisciplinary tumour board database between September 2007 and May 2015. In the observation group, T1 lesions were observed until the tumour grew to meet T2 criteria (=2 cm). The treatment group consisted of T1 lesions treated at diagnosis with liver directed therapy (LDT). Kaplan-Meier plots were constructed for tumour progression beyond Milan and overall survival. 87 patients (observation n=56; LDT n=31) were included in the study. A total of 22% (n=19) of patients progressed beyond Milan with no difference in progression between treatment and observation groups (19% vs 23%, p=0.49). Median time to progression beyond Milan was 16 months. Overall transplantation rate was 22% (observation group n=16; treatment group n=3, p=0.04). Median survival was 55 months with LDT versus 36 months in the observation group (p=0.22). In patients who progressed to T2 (n=60), longer time to T2 progression was a predictor of improved survival (HR=0.94, 95% CI 0.88 to 0.99, p=0.03). Immediate LDT of T1 lesions was not associated with increased risk of progression beyond Milan criteria when compared with an observation approach. Longer time to T2 progression was associated with increased survival and may be a surrogate for favourable tumour biology.


Avoiding endotracheal ventilation to prevent bronchopulmonary dysplasia: a meta-analysis.
Mechanical ventilation via an endotracheal tube is a risk factor for bronchopulmonary dysplasia (BPD), one of the most common morbidities of very preterm infants. Our objective was to investigate the effect that strategies to avoid endotracheal mechanical ventilation (eMV) have on the incidence of BPD in preterm infants <30 weeks' gestational age (GA). In February 2013, we searched the databases Medline, Embase, and the Cochrane Central Register of Controlled Trials. Study selection criteria included randomized controlled trials published in peer-reviewed journals since the year 2000 that compared preterm infants <30 weeks' GA treated by using a strategy aimed at avoiding eMV with a control group in which mechanical ventilation via an endotracheal tube was performed at an earlier stage. Data were extracted and analyzed by using the standard methods of the Cochrane Neonatal Review Group. The authors independently assessed study eligibility and risk of bias, extracted data and calculated odds ratios and 95% confidence intervals, employing RevMan version 5.1.6. We identified 7 trials that included a total of 3289 infants. The combined odds ratio (95% confidence interval) of death or BPD was 0.83 (0.71-0.96). The number needed to treat was 35. The study results were remarkably homogeneous. Avoiding eMV had no influence on the incidence of severe intraventricular hemorrhage. Strategies aimed at avoiding eMV in infants <30 weeks' GA have a small but significant beneficial impact on preventing BPD.


Ideal observer analysis of the development of spatial contrast sensitivity in macaque monkeys.
To explore the factors limiting the development of visual sensitivity, we constructed an ideal observer model for the infant macaque visual system. We made measurements of retinal morphology in infant and adult macaque monkeys, and used the data in combination with published optical data to formulate the model. We compared the ideal observer's ability to detect low-contrast gratings presented either in isolation or in spatiotemporal noise with behavioral data obtained under matched conditions. The ideal observer showed some improvement in visual performance up to the age of 4 weeks, but little change thereafter. Behavioral data show extensive changes over the ages 5-50 wk, after the ideal observer's performance has become asymptotic. We conclude that the development of visual sensitivity in infant monkeys is not limited by changes in the front-end factors captured by the ideal observer model, at least after the age of 5 weeks. Using noise masking, we also estimated the variability of neural processing in comparison with the photon noise-limited ideal. We found that both additive and multiplicative components of this variability are elevated in infant monkeys, and improve (though not to ideal levels) during development. We believe that these changes all reflect maturation of visual processing in cortical circuits, and that no aspect of visual performance in the regime we studied is limited by the properties of the retina and photoreceptors, either in infant or in adult animals.


American Society of Maxillofacial Surgeons 2006 to 2016: Another Decade of Excellence in Education and Research.
Over the past 10 years, the American Society of Maxillofacial Surgeons (ASMS) has continued to advance to meet its mission of being the premier organization to represent maxillofacial and pediatric plastic surgery in the United States. These advances are focused on education of its members, to include the American Society of Maxillofacial Surgeons basic course, the preconference symposium, the annual meeting, two basic maxillofacial courses per year, advanced maxillofacial courses, a boot camp for craniofacial fellows, a cleft course, quarterly webinars, sponsored fellowships, a visiting professorship, and the ASMS journal. In addition, the ASMS has continued to advance as the premier national organization representing maxillofacial and pediatric plastic surgery in the United States, thereby positioning the organization as a primary advocate for these surgical specialties. Outreach of the ASMS has grown over the past decade and now includes representatives to the American Society of Plastic Surgeons/Plastic Surgery Foundation, the American Board of Plastic Surgeons, the American Medical Association, and most recently a seat as a governor with the American College of Surgeons. The ASMS has also initiated an annual Summer Leadership Seminar to explore topics of relevance in a changing health care environment. The present report outlines the major initiatives of the ASMS over the past 10 years.


Human papillomavirus in oropharyngeal cancer in Canada: analysis of 5 comprehensive cancer centres using multiple imputation.
The incidence of oropharyngeal cancer has risen over the past 2 decades. This rise has been attributed to human papillomavirus (HPV), but information on temporal trends in incidence of HPV-associated cancers across Canada is limited. We collected social, clinical and demographic characteristics and p16 protein status (p16-positive or p16-negative, using this immunohistochemistry variable as a surrogate marker of HPV status) for 3643 patients with oropharyngeal cancer diagnosed between 2000 and 2012 at comprehensive cancer centres in British Columbia (6 centres), Edmonton, Calgary, Toronto and Halifax. We used receiver operating characteristic curves and multiple imputation to estimate the p16 status for missing values. We chose a best-imputation probability cut point on the basis of accuracy in samples with known p16 status and through an independent relation between p16 status and overall survival. We used logistic and Cox proportional hazard regression. We found no temporal changes in p16-positive status initially, but there was significant selection bias, with p16 testing significantly more likely to be performed in males, lifetime never-smokers, patients with tonsillar or base-of-tongue tumours and those with nodal involvement (p < 0.05 for each variable). We used the following variables associated with p16-positive status for multiple imputation: male sex, tonsillar or base-of-tongue tumours, smaller tumours, nodal involvement, less smoking and lower alcohol consumption (p < 0.05 for each variable). Using sensitivity analyses, we showed that different imputation probability cut points for p16-positive status each identified a rise from 2000 to 2012, with the best-probability cut point identifying an increase from 47.3% in 2000 to 73.7% in 2012 (p < 0.001). Across multiple centres in Canada, there was a steady rise in the proportion of oropharyngeal cancers attributable to HPV from 2000 to 2012.


Trends in cigarette use behaviors among adolescents by region in Korea.
Understanding recent trends in cigarette smoking among adolescents is important in order to develop strategies to prevent cigarette smoking. The aim of this study was to compare recent trends in cigarette smoking for adolescents living in rural areas, small towns and metropolitan cities in Korea. The raw data from the Korea Youth Risk Behavior Web-based Survey (KYRBWS) from 2005 to 2009 were used. Data were analyzed by using the method of complex survey data analysis considering complex sampling design. Logistic regression models were used to evaluate significant linear time trends in cigarette smoking. The indicators of cigarette use behaviors were 'current smoking rate', 'frequent smoking rate', 'heavy smoking rate' and 'smoking experience rate before 13 years of age'. All analyses were conducted according to gender. Statistically significant increasing trends in current smoking rate and frequent smoking rate were observed and borderline significant increasing trends in heavy smoking rate were shown among rural boys. Among metropolitan city boys, statistically significant increasing trends were also seen for frequent smoking. Statistically significant decreasing trends in current smoking rate were observed among small town and metropolitan city girls. Smoking experience rate before 13 years of age for rural girls decreased significantly. Cigarette smoking prevalence among adolescents in the rural areas has increased in the last five years especially among boys. Our findings suggest that anti-tobacco program for adolescents should be conducted primarily for those in rural areas.


Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of an ongoing pandemic, with increasing deaths worldwide. To date, documentation of the histopathological features in fatal cases of the disease caused by SARS-CoV-2 (COVID-19) has been scarce due to sparse autopsy performance and incomplete organ sampling. We aimed to provide a clinicopathological report of severe COVID-19 cases by documenting histopathological changes and evidence of SARS-CoV-2 tissue tropism. In this case series, patients with a positive antemortem or post-mortem SARS-CoV-2 result were considered eligible for enrolment. Post-mortem examinations were done on 14 people who died with COVID-19 at the King County Medical Examiner's Office (Seattle, WA, USA) and Snohomish County Medical Examiner's Office (Everett, WA, USA) in negative-pressure isolation suites during February and March, 2020. Clinical and laboratory data were reviewed. Tissue examination was done by light microscopy, immunohistochemistry, electron microscopy, and quantitative RT-PCR. The median age of our cohort was 73·5 years (range 42-84; IQR 67·5-77·25). All patients had clinically significant comorbidities, the most common being hypertension, chronic kidney disease, obstructive sleep apnoea, and metabolic disease including diabetes and obesity. The major pulmonary finding was diffuse alveolar damage in the acute or organising phases, with five patients showing focal pulmonary microthrombi. Coronavirus-like particles were detected in the respiratory system, kidney, and gastrointestinal tract. Lymphocytic myocarditis was observed in one patient with viral RNA detected in the tissue. The primary pathology observed in our cohort was diffuse alveolar damage, with virus located in the pneumocytes and tracheal epithelium. Microthrombi, where observed, were scarce and endotheliitis was not identified. Although other non-pulmonary organs showed susceptibility to infection, their contribution to the pathogenesis of SARS-CoV-2 infection requires further examination. None.


Patterns of interval correlations in neural oscillators with adaptation.
Neural firing is often subject to negative feedback by adaptation currents. These currents can induce strong correlations among the time intervals between spikes. Here we study analytically the interval correlations of a broad class of noisy neural oscillators with spike-triggered adaptation of arbitrary strength and time scale. Our weak-noise theory provides a general relation between the correlations and the phase-response curve (PRC) of the oscillator, proves anti-correlations between neighboring intervals for adapting neurons with type I PRC and identifies a single order parameter that determines the qualitative pattern of correlations. Monotonically decaying or oscillating correlation structures can be related to qualitatively different voltage traces after spiking, which can be explained by the phase plane geometry. At high firing rates, the long-term variability of the spike train associated with the cumulative interval correlations becomes small, independent of model details. Our results are verified by comparison with stochastic simulations of the exponential, leaky, and generalized integrate-and-fire models with adaptation.


Surface Tensions of Picoliter Droplets with Sub-Millisecond Surface Age.
Aerosols are key components of the atmosphere and play important roles in many industrial processes. Because aerosol particles have high surface-to-volume ratios, their surface properties are especially important. However, direct measurement of the surface properties of aerosol particles is challenging. In this work, we describe an approach to measure the surface tension of picoliter volume droplets with surface age <1 ms by resolving their dynamic oscillations in shape immediately after ejection from a microdroplet dispenser. Droplet shape oscillations are monitored by highly time-resolved (500 ns) stroboscopic imaging, and droplet surface tension is accurately retrieved across a wide range of droplet sizes (10-25 μm radius) and surface ages (down to ∼100 μs). The approach is validated for droplets containing sodium chloride, glutaric acid, and water, which all show no variation in surface tension with surface age. Experimental results from the microdroplet dispenser approach are compared to complementary surface tension measurements of 5-10 μm radius droplets with aged surfaces using a holographic optical tweezers approach and predictions of surface tension using a statistical thermodynamic model. These approaches combined will allow investigation of droplet surface tension across a wide range of droplet sizes, compositions, and surface ages.


Complete genome sequence of Leuconostoc suionicum DSM 20241T provides insights into its functional and metabolic features.
The genome of Leuconostoc suionicum DSM 20241T (=ATCC 9135T = LMG 8159T = NCIMB 6992T) was completely sequenced and its fermentative metabolic pathways were reconstructed to investigate the fermentative properties and metabolites of strain DSM 20241T during fermentation. The genome of L. suionicum DSM 20241T consists of a circular chromosome (2026.8 Kb) and a circular plasmid (21.9 Kb) with 37.58% G + C content, encoding 997 proteins, 12 rRNAs, and 72 tRNAs. Analysis of the metabolic pathways of L. suionicum DSM 20241T revealed that strain DSM 20241T performs heterolactic acid fermentation and can metabolize diverse organic compounds including glucose, fructose, galactose, cellobiose, mannose, sucrose, trehalose, arbutin, salcin, xylose, arabinose and ribose.


Detection of circulating tumor cells in hepatocellular carcinoma using antibodies against asialoglycoprotein receptor, carbamoyl phosphate synthetase 1 and pan-cytokeratin.
Asialoglycoprotein receptor (ASGPR)-ligand-based separation combined with identification with Hep Par 1 or pan-cytokeratin (P-CK) antibody have been demonstrated to detect circulating tumor cells (CTCs) in hepatocellular carcinoma (HCC). The aim of this study was to develop an improved enrichment and identification system that allows the detection of all types of HCC CTCs. The specificity of the prepared anti-ASGPR monoclonal antibody was characterized. HCC cells were bound by ASGPR antibody and subsequently magnetically isolated by second antibody-coated magnetic beads. Isolated HCC cells were identified by immunofluorescence staining using a combination of anti-P-CK and anti-carbamoyl phosphate synthetase 1 (CPS1) antibodies. Blood samples spiked with HepG2 cells were used to determine recovery and sensitivity. CTCs were detected in blood samples from HCC patients and other patients. ASGPR was exclusively expressed in human hepatoma cell line, normal hepatocytes and HCC cells in tissue specimens detected by the ASGPR antibody staining. More HCC cells could be identified by the antibody cocktail for CPS1 and P-CK compared with a single antibody. The current approach obtained a higher recovery rate of HepG2 cells and more CTC detection from HCC patients than the previous method. Using the current method CTCs were detected in 89% of HCC patients and no CTCs were found in the other test subjects. Our anti-ASGPR antibody could be used for specific and efficient HCC CTC enrichment, and anti-P-CK combined with anti-CPS1 antibodies is superior to identification with one antibody alone in the sensitivity for HCC CTC detection.


Theoretical tuning of the singlet-triplet energy gap to achieve efficient long-wavelength thermally activated delayed fluorescence emitters: the impact of substituents.
Great progress has been made in developing highly efficient thermally activated delayed fluorescent (TADF) materials. However, developing highly efficient long-wavelength TADF emitters is still a challenge because a small energy gap (ΔEST) between the lowest singlet (S1) and triplet excited states (T1) and a relatively high fluorescence rate are difficult to achieve simultaneously in one molecule. Here, eleven donor-acceptor (D-A) type molecules using N3,N3,N6,N6-tetraphenyl-9H-carbazole-3,6-diamine (named DAC-II) as the electron donor and the 2-phenyl-quinoxaline-based electron acceptor are designed via introducing different electron-donating and electron-withdrawing groups into the acceptor and changing the connection position between the donor (D) and the acceptor (A). Quantum chemical calculations indicated that introducing the electron-donating groups (-OCH3, -CH3) into the phenyl ring of the acceptor, molecules 2 and 3, cannot change the emission property of molecule 1, thus molecules 2 and 3 could also be used as green TADF emitters like molecule 1. Introducing an electron-withdrawing unit (-CF3) into molecule 1, molecule 4, reduces the ΔEST value to 0.10 eV, while the radiative decay rate (kVE) is also reduced correspondingly. Changing the connection position between D and A, molecules 5 to 8, cannot reduce the ΔEST value and lowers the kVE value compared with molecules 1 to 4. However, introducing electron-withdrawing groups (-2F, -4F and -CN) into the quinoxaline moiety, molecules 9 to 11, contributes to both small ΔEST and large kVE for the emission process. The values of ΔEST of molecules 9 to 11 are in the range of 0.21 to 0.30 eV, and the maximum emission wavelengths of molecules 10 and 11 are 576 and 590 nm, respectively, which are promising to be used as efficient yellow and orange TADF emitters in organic light-emitting diodes.


Evolution of epitopes on human and nonhuman primate lymphocyte cell surface antigens.
The T- and B-cell surface polypeptides detected by an international workshop panel of 100 mouse monoclonal antibodies (M.Ab) were biochemically defined by radioimmunoprecipitation. Eight T-cell-associated molecules and eight B-cell-associated molecules were identified by multiple antibodies in the panel. Clusters of antibodies specific for the same polypeptide were then compared for their reactivity against peripheral blood mononuclear cells (PBMC) from 11 nonhuman primate species. All the major T- and B-cell antigens present in humans were also expressed in some nonhuman primates. M.Ab to the same antigen were found to react with distinct epitope groups that differed in their phylogenetic distribution. Some epitopes were highly conserved, while other epitopes on the same molecule were only expressed in hominoids and were not detected in old world and new world monkeys. Our detailed analysis of the phylogeny of 37 T-cell antigen epitopes on ten different molecules revealed there was no clear correspondence between the number of epitopes shared and evolutionary distance. Rather the data suggest that parallelism with back mutation may be a common mechanism in the evolution of T-cell antigens. The data also show that the tissue distribution of T-cell antigens can differ between primate species; for example, M.Ab to human Tp45 Tla-Qa-like antigens that did not react with human PBMC did react with PBMC from new world monkeys.


Clinical experience of baclofen in alcohol dependence: A chart review.
Craving is recognized as a formidable barrier in the management of patients with alcohol dependence. Among pharmacological agents that have been used in experimental studies for reduction in craving, baclofen appears to have a significant advantage over other agents. The study is retrospective chart review of patients (n = 113) who have been treated with baclofen for alcohol dependence in a tertiary hospital of North India. Baseline assessments included sociodemography, motivation, quantity-frequency of alcohol use, and other alcohol-related clinical parameters. Weekly assessments, for a period of 4 weeks, were extracted from records which included dose of baclofen, craving intensity, and alcohol consumption. The study sample was predominantly male, mean age of 41.49 (±9.75) years, most having a family history of substance use (70.97%), and many reporting binge use pattern in last year (49.46%). Baseline assessment revealed 48.7% of the sample was in precontemplation phase for alcohol use and 70% reported severe and persistent craving. This persistent craving was reported by only 15% of the sample by the end of 4 weeks treatment with baclofen (20-40 mg/day). Thirty-four percent of patients reported continued problematic use of alcohol by the end of 4 weeks. Our clinical experience suggests that baclofen reduces craving and alcohol consumption including in those with poor motivation. The drug causes few side effects and does not add to the intoxication effect of alcohol. Considering that baclofen is safe in those with liver cirrhosis and reduces withdrawal symptoms due to alcohol, a controlled trial comparing it with standard treatment is required.


Disc herniations in astronauts: What causes them, and what does it tell us about herniation on earth?
Recent work showed an increased risk of cervical and lumbar intervertebral disc (IVD) herniations in astronauts. The European Space Agency asked the authors to advise on the underlying pathophysiology of this increased risk, to identify predisposing factors and possible interventions and to suggest research priorities. The authors performed a narrative literature review of the possible mechanisms, and conducted a survey within the team to prioritize research and prevention approaches. Based on literature review the most likely cause for lumbar IVD herniations was concluded to be swelling of the IVD in the unloaded condition during spaceflight. For the cervical IVDs, the knowledge base is too limited to postulate a likely mechanism or recommend approaches for prevention. Basic research on the impact of (un)loading on the cervical IVD and translational research is needed. The highest priority prevention approach for the lumbar spine was post-flight care avoiding activities involving spinal flexion, followed by passive spinal loading in spaceflight and exercises to reduce IVD hyper-hydration post-flight.


Infectious tolerance.
Infectious tolerance can be induced in many ways, does not require a thymus or clonal deletion and can spread to third-party antigens linked on the same antigen-presenting cell-the process being variously described as linked-, bystanderor epitope-suppression. We here review the evidence concerning the mechanisms involved and attempt to make a consistent hypothesis, that during tolerance induction in the Th1-mediated autoimmune diseases and transplantation systems there would seem to be a phase of immune deviation towards Th2 cytokines, like IL-4 and IL-10; however, this may lead to an IL-10-induced form of anergy or nonresponsiveness and generation of the recently characterized Th3/T-regulatory-1 CD4+ T cell subset which is thought to downregulate the antigen-presenting cell, possibly via transforming growth factor beta.


Demonstration of functional oxytocin receptors in human breast Hs578T cells and their up-regulation through a protein kinase C-dependent pathway.
Oxytocin (OT) receptors (OTRs) have been demonstrated in a number of human breast tumors and tumor cells, but it was not clear whether the receptors were functional. We examined the regulation and function of OTR in a tumor cell line, Hs578T, derived from human breast. These cells expressed moderate levels of OTR when cultured in 10% FBS, as demonstrated by RT-PCR and binding analyses. Serum deprivation resulted in the loss of OTRs, with no effect on cell viability. Restoration of serum and addition of 1 microM dexamethasone (DEX) increased OTR levels by about 9-fold. Up-regulation was blocked by the addition of phospholipase C and PKC inhibitors. Serum/DEX treatment also increased steady state OTR messenger RNA levels. OT increased intracellular Ca2+ in a time- and dose-responsive manner, and the effects of OT were lost when OTRs were down-regulated by serum starvation. Serum/DEX up-regulation of OTR restored the responsiveness to OT. OT also stimulated ERK-2 (extracellular signal-regulated protein kinase) phosphorylation and PGE2 synthesis in Hs578T cells. In addition to showing that OTRs in the breast tumor cells are functional, these studies show that Hs578T cells can be used to study molecular regulation of OTR gene expression and intracellular signaling pathways stimulated by OT.


Alterations in conflict monitoring are related to functional connectivity in Parkinson's disease.
Patients with Parkinson's disease (PD) have difficulties in executive functions including conflict monitoring. The neural mechanisms underlying these difficulties are not yet fully understood. In order to examine the neural mechanisms related to conflict monitoring in PD, we evaluated 35 patients with PD and 20 healthy older adults while they performed a word-color Stroop paradigm in the MRI. Specifically, we focused on changes between the groups in task-related functional connectivity using psycho-physiological interaction (PPI) analysis. The anterior cingulate cortex (ACC), which is a brain node previously associated with the Stroop paradigm, was selected as the seed region for this analysis. Patients with PD, as compared to healthy controls, had reduced task-related functional connectivity between the ACC and parietal regions including the precuneus and inferior parietal lobe. This was seen only in the incongruent Stroop condition. A higher level of connectivity between the ACC and precuneus was correlated with a lower error rate in the conflicting, incongruent Stroop condition in the healthy controls, but not in the patients with PD. Furthermore, the patients also had reduced functional connectivity between the ACC and the superior frontal gyrus which was present in both the incongruent and congruent task condition. The present findings shed light on brain mechanisms that are apparently associated with specific cognitive difficulties in patients with PD. Among patients with PD, impaired conflict monitoring processing within the ACC-based fronto-parietal network may contribute to difficulties under increased executive demands.


Genome-wide analysis of the U-box E3 ubiquitin ligase family role in drought tolerance in sesame (Sesamum indicum L.).
Plant U-box (PUB) proteins belong to a class of ubiquitin ligases essential in various biological processes. Sesame (Sesamum indicum L.) is an important and worldwide cultivated oilseed crop. However few studies have been conducted to explore the role of PUBs in drought tolerance in sesame. This study identified a total of 56 members of the sesame PUB family (SiPUB) genes distributed unevenly across all 13 chromosomes. Based on phylogenetic analysis, all 56 SiPUB genes were classified into six groups with various structures and motifs. Cis-acting element analysis suggested that the SiPUB genes are involved in response to various stresses including drought. Based on RNA-seq analysis and quantitative real-time PCR, we identified nine SiPUB genes with significantly different expression profiles under drought stress. The expression patterns of six SiPUB genes in root, leaf and stem tissues corroborated the reliability of the RNA-seq datasets. These findings underscore the importance of SiPUB genes in enhancing drought tolerance in sesame plants. Our study provides novel insights into the evolutionary patterns and variations of PUB genes in sesame and lays the foundation for comprehending the functional characteristics of SiPUB genes under drought-induced stress conditions.


A pilot randomized control trial investigating the effect of mindfulness practice on pain tolerance, psychological well-being, and physiological activity.
To investigate the effect of mindfulness training on pain tolerance, psychological well-being, physiological activity, and the acquisition of mindfulness skills. Forty-two asymptomatic University students participated in a randomized, single-blind, active control pilot study. Participants in the experimental condition were offered six (1-h) mindfulness sessions; control participants were offered two (1-h) Guided Visual Imagery sessions. Both groups were provided with practice CDs and encouraged to practice daily. Pre-post pain tolerance (cold pressor test), mood, blood pressure, pulse, and mindfulness skills were obtained. Pain tolerance significantly increased in the mindfulness condition only. There was a strong trend indicating that mindfulness skills increased in the mindfulness condition, but this was not related to improved pain tolerance. Diastolic blood pressure significantly decreased in both conditions. Mindfulness training did increase pain tolerance, but this was not related to the acquisition of mindfulness skills.


Nutrient intakes and impact of fortified breakfast cereals in schoolchildren.
To report micronutrient intakes in Northern Ireland schoolchildren, and to establish the contribution of fortified breakfast cereal to overall nutrient intakes and achievement of current dietary recommendations. Analysis of dietary intakes and physical characteristics of participants in a randomly selected 2% population sample of 1015 schoolchildren aged 12 and 15 years in Northern Ireland during the 1990/1 school year. Dietary intakes, physical characteristics, and their association with consumption of fortified breakfast cereal. Mean micronutrient intakes were generally adequate with the exception of low intakes of folate (boys and girls) and iron (girls). Fortified breakfast cereals, consumed by a high proportion (94% boys; 83% girls) of the sample, were associated with higher daily intakes of most micronutrients and fibre and with a macronutrient profile consistent with current nutritional recommendations. Appreciable proportions of subjects who did not consume fortified breakfast cereals had daily intakes that fell below the lower reference nutrient intake for riboflavin, niacin, folate, vitamin B-12, and iron (girls). The results demonstrate the potential of fortification in contributing to micronutrient intakes of schoolchildren, particularly where requirements are high, or for those on marginal diets of low nutritional quality.