Antithrombotic management in patients with atrial fibrillation undergoing coronary stent implantation: What is the impact of guideline adherence?
Patients with atrial fibrillation (AF) who undergo percutaneous coronary intervention (PCI) and stenting require triple antithrombotic therapy according to current ESC guidelines. The purpose of this study was to assess guideline implementation and predictive factors of the prognosis related to ESC guideline adherence. We enrolled consecutive AF patients referred for PCI with stent from 2011 to 2014. Among 371 patients (72% male; mean age 76 ± 11) followed up for 505 ± 372 days (median 391, interquartile range 550 days), 118 (45%) undergoing elective coronary stenting and 41 (31%) among those with acute coronary syndrome were guideline adherent. Oral anticoagulation (OAC) before hospitalization was the only factor independently associated with guideline adherence (OR, 0.45; 95% CI 0.26-0.77; p=0.003). OAC underuse and antiplatelet therapy (APT) underuse were independently associated with increased risks of death (OR 5.55; 95% CI 2.42-13.47; p<0.0001 and OR 5.56; 95% CI, 2.17-14.65; p=0.0004, respectively) and major adverse cardiac events (MACE) (OR 4.18; 95% CI 2.05-8.79; p<0.0001 and OR 4.81; 95% CI, 2.09-11.18; p=0.0002, respectively). Guidelines for antithrombotic therapy in patients with AF who undergo PCI and stent implantation are still poorly followed in clinical practice. OAC and APT underuse were both associated with an increased risk of death and MACE in this population.


Genotype resistance profiles in patients failing an NNRTI-containing regimen, and modifications after stopping NNRTI therapy.
Resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) develops quickly and independently if they are used in combination with NRTIs or protease inhibitors (PIs) as rescue therapy, mainly due to the low genetic barrier of this class of drugs. In this study we examined clinical, therapeutic, and virologic characteristics in 88 patients with mutations conferring resistance to NNRTIs, and in 11 patients 1 year after stopping NNRTI therapy. Between patients administered Nevirapine (NVP) and those taking Efavirenz (EFV), no statistical differences were found in CD4 cell count, HIV viral load, time on NNRTI therapy, or number of PIs administered previously. A slow decline in the detectability of mutations encoding NNRTI resistance was found.


Facial features and head movements obtained with a webcam correlate with performance deterioration during prolonged wakefulness.
We have performed a direct comparison between facial features obtained from a webcam and vigilance-task performance during prolonged wakefulness. Prolonged wakefulness deteriorates working performance due to changes in cognition, emotion, and by delayed response. Facial features can be potentially collected everywhere using webcams located in the workplace. If this type of device can obtain relevant information to predict performance deterioration, this technology can potentially reduce serious accidents and fatality. We extracted 34 facial indices, including head movements, facial expressions, and perceived facial emotions from 20 participants undergoing the psychomotor vigilance task (PVT) over 25 hours. We studied the correlation between facial indices and the performance indices derived from PVT, and evaluated the feasibility of facial indices as detectors of diminished reaction time during the PVT. Furthermore, we tested the feasibility of classifying performance as normal or impaired using several machine learning algorithms with correlated facial indices. Twenty-one indices were found significantly correlated with PVT indices. Pitch, from the head movement indices, and four perceived facial emotions-anger, surprise, sadness, and disgust-exhibited significant correlations with indices of performance. The eye-related facial expression indices showed especially strong correlation and higher feasibility of facial indices as classifiers. Significantly correlated indices were shown to explain more variance than the other indices for most of the classifiers. The facial indices obtained from a webcam strongly correlate with working performance during 25 hours of prolonged wakefulness.


Autoantibodies in 16 patients with extensive burns and a review of the literature.
Serum samples were taken during the first 3 weeks and 1 year after discharge from hospital of 16 patients with burns covering more than 35 per cent of the body surface area. The sera were tested for the presence of antinuclear, antimitochondrial, anti smooth muscle, anti brush border and anti gastric parietal cell autoantibodies using the technique of indirect immunofluorescence. Compared with measurements for the same autoantibodies, in sera from 25 healthy blood donors, the burned patients' sera showed the presence of anti smooth muscle autoantibodies in 81.2 per cent, anti brush border autoantibodies in 56.2 per cent, antimitochondrial autoantibodies in 31.2 per cent and antinuclear autoantibodies in 12.5 per cent of the sera. Autoantibodies to gastric parietal cells were not detected. A correlation was noted between the presence of antimitochondrial autoantibodies and alterations in liver function. In contrast, no correlations were found between the raised levels of the various autoantibodies and resuscitative fluid or antibiotic therapy, intercurrent infections, serum immunoglobulin levels, surgical treatment or the duration of stay in hospital. The high titre of autoantibodies to anti smooth muscle could have arisen from tissue protein degradation associated with the raised requirements for energy by the hypermetabolic patients.


Effects of dilazep (Comelian) on the central purinergic system: inhibitory effects on clonidine-induced aggressive behavior.
Mice given clonidine (20-50 mg/kg i.p. and 5 micrograms i.c.v.) exhibited aggressive behavior. Dilazep as well as N6-(L-phenylisopropyl) adenosine (adenosine agonist) inhibited this behavior. Dilazep combined with N6-(L-phenylisopropyl) adenosine markedly inhibited the behavior at low doses that were without effect when given alone whereas the inhibitory effect of dilazep on the behavior was reversed by caffeine and 8-phenyltheophylline, which are adenosine antagonists. The results suggest that the inhibitory action of dilazep on clonidine-induced aggressive behavior can be substantially attributed to central purinoceptor stimulation.


Radiocarbon dating the late Middle Paleolithic and the Aurignacian of the Swabian Jura.
Many lines of evidence point to the period between roughly 40 and 30 ka BP as the period in which modern humans arrived in Europe and displaced the indigenous Neandertal populations. At the same time, many innovations associated with the Upper Paleolithic--including new stone and organic technologies, use of personal ornaments, figurative art, and musical instruments--are first documented in the European archaeological record. Dating the events of this period is challenging for several reasons. In the period about six to seven radiocarbon half-lives ago, variable preservation, pre-treatment, and sample preparation can easily lead to a lack of reproducibility between samples and laboratories. A range of biological, cultural, and geological processes can lead to mixing of archaeological strata and their contents. Additionally, some data sets point to this period as a time of significant spikes in levels of atmospheric radiocarbon. This paper assesses these questions in the context of the well-excavated and intensively studied caves of Geissenklösterle and Hohle Fels in the Swabian Jura of southwestern Germany. We conclude that variable atmospheric radiocarbon production contributes to the problems of dating the late Middle Paleolithic and the early Upper Paleolithic. To help establish a reliable chronology for the Swabian Aurignacian, we are beginning to focus our dating program on short-lived, stratigraphically secure features to see if they yield reproducible results. This approach may help to test competing explanations for the noisy and often non-reproducible results that arise when trying to date the transition from the Middle to the Upper Paleolithic.


Selenium Deficiency Induces Inflammation via the iNOS/NF-κB Pathway in the Brain of Pigs.
Selenium (Se) is an essential trace element to maintain homeostasis in humans and animals. The aim of the present study was to clarify the mechanism of Se deficiency-induced inflammation in the pig's brain. Twenty-four healthy pigs were randomly divided into two groups (n = 12/group): control group (group C) was fed diet with 0.3 mg/kg inorganic Se, and Se-deficient group (group L) was fed diet with 0.007 mg/kg inorganic Se. At the 90th day of the experiment, the histology in the pig's brain was observed by the microscope, the NO levels and iNOS activity were assayed, and the mRNA and protein expression levels of inflammatory cytokines (iNOS, COX-2, NF-κB, and PTGEs) and HSPs (HSP27, HSP40, HSP60, HSP70, and HSP90) were detected by real-time quantitative PCR and Western blot. Compared with group C, both of NO levels and iNOS activity were increased in group L, and the mRNA and protein expression levels of inflammatory cytokines (iNOS, COX-2, NF-κB, and PTGEs) and HSPs (HSP27, HSP40, HSP60, HSP70, and HSP90) were also upregulated; histological observation displayed inflammatory response in the brain of pig. In summary, diet with Se deficiency can activate the iNOS/NF-κB pathway to upregulate the expression of inflammatory cytokines, thereby leading to inflammatory lesions in the pig's brain, and HSPs are involved in the compensatory regulation of inflammation. This study provides a reference for the prevention of pig brain inflammation from the perspective of nutrition.


Factors Affecting Transfer of Pyrethroid Residues from Herbal Teas to Infusion and Influence of Physicochemical Properties of Pesticides.
The transfer of pesticide residues from herbal teas to their infusion is a subject of particular interest. In this study, a multi-residue analytical method for the determination of pyrethroids (fenpropathrin, beta-cypermethrin, lambda-cyhalothrin, and fenvalerate) in honeysuckle, chrysanthemum, wolfberry, and licorice and their infusion samples was validated. The transfer of pyrethroid residues from tea to infusion was investigated at different water temperatures, tea/water ratios, and infusion intervals/times. The results show that low amounts (0-6.70%) of pyrethroids were transferred under the different tea brewing conditions examined, indicating that the infusion process reduced the pyrethroid content in the extracted liquid by over 90%. Similar results were obtained for the different tea varieties, and pesticides with high water solubility and low octanol-water partition coefficients (log Kow) exhibited high transfer rates. Moreover, the estimated values of the exposure risk to the pyrethroids were in the range of 0.0022-0.33, indicating that the daily intake of the four pyrethroid residues from herbal tea can be regarded as safe. The present results can support the identification of suitable tea brewing conditions for significantly reducing the pesticide residue levels in the infusion.


[Sulfhydryl group distribution along the axis of the rod outer segment in the frog].
The existence of SH-group concentration axial gradient in frog's retinal rod outer segments has been shown. A diminution of SH-groups in the outer segment apical part points to a damage of the vision pigment during the life span of the rod disks.


Simple and quick repair of cardiac rupture due to blunt chest trauma.
Atrial rupture following blunt chest trauma carries a high mortality rate. It can be difficult to maintain hemodynamic stability and control massive bleeding due to poor visualization. We describe a case in which bleeding control was obtained simply and effectively using a Satinsky clamp, allowing repair of atrial rupture without the use of cardiopulmonary bypass.


Sphingomyelin synthase activity affects TRIF-dependent signaling of Toll-like receptor 4 in cells stimulated with lipopolysaccharide.
Bacterial lipopolysaccharide (LPS) is recognized by CD14 protein and the Toll-like receptor (TLR)4/MD2 complex localized in the plasma membrane of immune cells. TLR4 triggers two signaling pathways engaging the MyD88 and TRIF adaptor proteins which lead to production of various pro-inflammatory cytokines. These processes are likely to be modulated by sphingomyelin, as the CD14 - TLR4 interaction takes place in plasma membrane rafts enriched in this lipid. To verify this assumption, we analyzed the influence of tricyclodecane-9-yl xanthogenate (D609), which was proven here to be an SMS inhibitor, and silencing of sphingomyelin synthase (SMS) 1 and/or SMS2 on LPS-induced signaling in macrophages. LPS up-regulated the expression and activity of SMS while exposure to D609 or silencing of SMS1 and SMS2 counteracted this action and led (except for SMS2 silencing) to a depletion of sphingomyelin in cells. Concomitantly, the MyD88- and TRIF-dependent signaling pathways of TLR4 were inhibited with the latter being especially sensitive to the reduction of the SMS1 and/or SMS2 activity. The D609 treatment and SMS1 and/or SMS2 depletion all reduced the level of CD14 protein in cells, which likely was an important determinant of the reduction of the LPS-induced pro-inflammatory responses.


Subtype analysis of neuropathologically diagnosed patients in a Japanese geriatric hospital.
Dementia is a social problem in Japan, as it is in other countries. Recently, there has been an increase in the number of patients with Alzheimer-type dementia (ATD) in the population. We analyzed 239 cases of patients autopsied at Fukushimura Hospital over a 10-year period. Clinicopathologically, 66% of these cases (158 cases) presented with dementia symptoms. The predominant form of illness was ATD. We found dementia with Lewy bodies (DLB) to be as frequent as vascular dementia (VD). Although the numbers were small, limbic neurofibrillary tangle dementia (LNTD) and Pick's disease (PiD) followed a clinical course typical of these diseases. On the other hand, senile dementia of the Alzheimer's type (SDAT) and the common form of neocortical type DLB (diffuse Lewy body disease; DLBD) were difficult to distinguish from each other. We attempted to uncover differences between these dementias in terms of how they affect male and female patients. The clinical course of the male patients with the common form of neocortical type DLB was more or less typical, while that of the female patients was not.


Feasibility and applicability of Evenson sedentary behavior cut points applied to children with and without intellectual and developmental disabilities.
Sedentary behavior (SB) is widely studied as it is associated with cardiometabolic health and obesity issues. However, children with Intellectual and Developmental Disabilities (IDD) have been understudied. Accelerometers are commonly used to measure SB in typically developing populations but may be inappropriate for IDD populations due to differences in body movement and physiologic responses to the activity. The use of Evenson sedentary cut-points, created based on typically developing children, has yet to be applied and/or examined in children with IDD. A descriptive cross-sectional study was conducted to (1) Assess the feasibility of applying Evenson sedentary cut-points in children with IDD (2) Describe SB over a two-week period between diagnosis groups. The SB of 22 participants (8 children with Down syndrome, 6 children with spina bifida, 8 children with no chronic illness) was assessed on two separate occasions: (1) during a 7-minute sedentary protocol, and (2) over a two-week period. The study supports the preliminary efficacy of using Evenson cut-points for this population, with 100% of participants being within the Evenson counts per minute (0-100 cpm) during the 7-minute sedentary protocol. The total volume of SB over a two-week period was not significantly different between diagnosis groups (8.8 h, 8.6 h, and 7.1 h of SB for children with Down syndrome, spina bifida, or those with no chronic illness, respectively; p = 0.36). Evenson sedentary cut-points can be used for children with IDD. Preliminary data suggest that children with IDD do not engage in significantly different SB than children without a chronic illness. Further study is warranted.Implications for rehabilitationObjective measures of physical activity and sedentary behavior for children with Down syndrome or spina bifida are rarely used due to potential differences in body movement (e.g., gait) during ambulation compared to typically developing peers that may influence the accuracy of cut-points.This study supports that Evenson sedentary cut-points can be used in children with Down syndrome or spina bifida to assess sedentary activity.Preliminary findings from this study demonstrate similarities in patterns of sedentary behaviors exhibited by our sample of children with Down syndrome, spina bifida, or no chronic illness.


Embryonic and neonatal myosin heavy chain in denervated and paralyzed rat skeletal muscle.
Using immunofluorescence procedures with specific polyclonal and monoclonal antimyosin antibodies we have found that embryonic and neonatal myosin heavy chains (MHCs), which in rat skeletal muscle disappear during the first weeks after birth, are reexpressed in adult muscle after denervation. Reactivity for embryonic and neonatal MHCs was detected in some fibers as early as 3 days after denervation, became more evident by 7 days, and occurred exclusively in the type 2A fiber population. Paralysis of innervated muscles by tetrodotoxin block of the sciatic nerve also resulted in the reappearance of embryonic and neonatal MHCs in type 2A fibers. Significant variation in the degree of immunoreactivity was observed in different segments of the same muscle fiber, suggesting that coordination of muscle fiber nuclei in the control of myosin heavy chain gene expression is partially lost following denervation.


Automated generation of a finite element stent model.
Numerical simulations have proven to be a valuable tool to investigate the mechanical behavior of stents. These computer models require a considerable amount of preprocessing and computational effort and consequently there is a continuous need for accurate simplifications and automation. For example, it was recently shown that using beam elements instead of solid elements results in a significant speed up of stent simulations. However, the currently applied techniques to create a finite element mesh starting from stent samples remain time-consuming. We present a semi-automated strategy to obtain an accurate finite element beam mesh from a stent sample. The method consists of two steps: (1) A triangulated surface representation of the stent geometry is obtained from micro CT images. (2) Subsequently, a beam mesh is automatically generated by computing the centerline. The method is time-effective and results in an accurate 3D stent model as demonstrated for the MULTI-LINK Vision stent.


TWO-YEAR CLINICAL OUTCOMES AFTER PHOTODYNAMIC ACUTE EXUDATIVE MACULOPATHY IN PATIENTS WITH CHRONIC CENTRAL SEROUS CHORIORETINOPATHY.
To analyze the 2-year clinical outcomes after photodynamic therapy-induced acute exudative maculopathy (PAEM) in patients with chronic central serous chorioretinopathy. Prospective observational study that included 64 eyes of 64 patients with chronic central serous chorioretinopathy who received half-fluence photodynamic therapy and had a 2-year follow-up. Patients were classified into two groups based on whether they had had PAEM at 3 days after treatment (PAEM+, n = 22; ≥50 µ m) increase in subretinal fluid or not (PAEM-, n = 42). Best-corrected visual acuity and subretinal fluid changes evaluated with optical coherence tomography were registered at 3 days, 1 month, 3 months, 1 year, and 2 years after photodynamic therapy. The number of recurrences, the appearance of outer retinal atrophy, and choroidal neovascularization were analyzed. Best-corrected visual acuity was 75.9 ± 13.6 (20/32) and 82.0 ± 11.0 letters (20/25) at 2 years in the PAEM+ and PAEM- groups, respectively ( P = 0.055). There were no differences in the best-corrected visual acuity change (4.2 ± 7.7 vs. 3.3 ± 7.1 letters; P = 0.654) and the subretinal fluid decrease (-117.3 ± 74.2 vs. -138.5 ± 83.6 µ m; P = 0.323) at 2 years between patients with and without PAEM. No differences in the number of recurrences ( P = 0.267), the appearance of choroidal neovascularization ( P = 0.155), or outer retinal atrophy ( P = 0.273) between both groups were noted. Patients with chronic central serous chorioretinopathy with and without PAEM presented similar results at 2 years in best-corrected visual acuity gain, subretinal fluid reduction, and complication rate.


The association between an ultrabrief cognitive screening in older adults and hospital outcomes.
Though often recommended, hospital cognitive assessment is infrequently completed due to clinical and time constraints. This analysis aimed to evaluate the relationship between performance on ultrabrief cognitive screening instruments and hospital outcomes. This is a secondary data analysis of a quality improvement project. Tertiary Veterans Administration hospital in New England. Patients, ≥ 60 years old, admitted to the hospital. None. Upon admission, patients were administered 2 cognitive screening tools. The modified Richmond Agitation and Sedation Scale (mRASS) is a measure of arousal that can be completed in 15 seconds. The months of the year backward (MOYB) is a measure of attention that can be administered in ≤1 minute. In-hospital outcomes included restraints and mortality, whereas discharge outcomes included length of stay, discharge not home, and variable direct costs. Risk ratios were calculated for dichotomous outcomes and unadjusted Poisson regression for continuous outcomes. Patients (n = 3232) were screened. Altered arousal occurred in 15% of patients (n = 495); incorrect MOYB was recorded in 45% (n = 1457). Relative to those with normal arousal and attention, those with abnormal mRASS and incorrect MOYB had increased length of stay (incident rate ratio [IRR]: 1.23, 95% confidence interval [CI]: 1.17-1.30); restraint use (risk ratio [RR]: 5.05, 95% CI: 3.29-7.75), in-hospital mortality (RR: 3.46, 95% CI: 1.24-9.63), and decreased discharge home (RR: 2.97, 95% CI: 2.42-3.64). Hospital variable direct costs were slightly, but not significantly, higher (IRR: 1.02, 95% CI: 0.88-1.17). Impaired performance on ultrabrief cognitive assessments of arousal and attention provide valuable insights regarding hospital outcomes.


Bridging the gap between child mental health need and professional service utilisation: Examining the influence of mothers' parental attributions on professional help-seeking intentions.
There is a significant gap between the need for child mental health services and use of these services by families. Parental attributions may play a role in this. This study examined whether mothers' attributions about their child's problems influence professional help-seeking intentions in a general sample of community mothers. Secondary analysis re-examined this hypothesis in a subgroup of mothers of children with clinically elevated mental health symptoms. Cross-sectional survey data were collected from mothers (N = 184) of children aged between 2 and 12 years recruited from the community. Mothers completed self-report questionnaires measuring parental attributions: child-responsible attributions and parental self-efficacy; professional help-seeking intentions; and psychosocial covariates: child mental health, mothers' anxiety and depression, child age, gender, marital status, education, and professional help-seeking experience. Hierarchical regression modelling indicated that parental attributions explained professional help-seeking intentions after controlling for covariates in both the general sample (ΔF = 6.07; p = .003) and subgroup analysis (ΔF = 10.22, p = .000). Professional help-seeking intentions were positively associated with child-responsible attributions (β = .19, p = .002) but not parental self-efficacy (β = - .01, p = .865) in the general sample, while positively associated with child-responsible attributions (β = .20, p = .009) and negatively associated with parental self-efficacy (β = - .16, p = .034) in the subgroup analysis. Findings were independent of the presence of clinically elevated symptoms, problem type, and severity. Overall, the findings support models suggesting that parental attributions have a role in professional help-seeking for child mental health problems.


Clinical ethicists' perspectives on organisational ethics in healthcare organisations.
Demand for organisational ethics capacity is growing in health organisations, particularly among managers. The role of clinical ethicists in, and perspective on, organisational ethics has not been well described or documented in the literature. To describe clinical ethicists' perspectives on organisational ethics issues in their hospitals, their institutional role in relation to organisational ethics, and their perceived effectiveness in helping to address organisational ethics issues. Qualitative case study involving semi-structured interviews with 18 clinical ethicists across 13 health organisations in Toronto, Canada. From the clinical ethicists' perspective, the most pressing organisational ethics issues in their organisations are: resource allocation, staff moral distress linked to the organisation's moral climate, conflicts of interest, and clinical issues with a significant organisational dimension. Clinical ethicists were consulted in particular on issues related to staff moral distress and clinical issues with an organisational dimension. Some ethicists described being increasingly consulted on resource allocation, conflicts of interest, and other corporate decisions. Many clinical ethicists felt they lacked sufficient knowledge and understanding of organisational decision-making processes, training in organisational ethics, and access to organisational ethics tools to deal effectively with the increasing demand for organisational ethics support. Growing demand for organisational ethics expertise in healthcare institutions is reshaping the role of clinical ethicists. Effectiveness in organisational ethics entails a re-evaluation of clinical ethics training to include capacity building in organisational ethics and organisational decision-making processes as a complement to traditional clinical ethics education.


Presence of tetrahydroisoquinoline and 2-methyl-tetrahydroquinoline in parkinsonian and normal human brains.
1,2,3,4-Tetrahydroisoquinoline (TIQ) and 2-methyl-1,2,3,4-tetrahydroquinoline (2-Me-TQ) were identified for the first time by gas chromatography-mass spectrometry in the parkinsonian and normal human brains. TIQ, an analogue of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), was markedly increased in the parkinsonian brain and could be an endogenous neurotoxin to induce Parkinson's disease.


Is the knife-cut in the hypothalamus a permanent barrier to regrowth of nerve fibers? -an affirmative answer.
The regenerative capacity of nerve fibers was studied in adult female rats. Horseradish peroxidase was injected into the anterior hypothalamus lateral to the suprachiasmatic nucleus 4 days, 6 weeks and 4 months, respectively, following an archiform retrochiasmatic knife-cut. The trajectory of the stained fibers was examined on horizontal sections of the hypothalamus. No nerve fibers could be seen sprouting across the scar-tissue of the knife-cut regardless of the survival time. In one rat (6-week survival time) a bundle of fine nerve fibers turned in a medial direction at the caudal end of the knife-cut, suggesting that sprouting fibers were destined to reinnervate parts of the deafferented medial-basal hypothalamus.


Presence of atrial natriuretic factor and cyclic guanosine monophosphate in saliva. Comparison of plasma and salivary concentrations during a head-down tilt.
Using a specific and sensitive radio-immunoassay involving separation and extraction procedures, we measured the concentration of saliva and plasma atrial natriuric factor (ANF) and cyclic guanosine monophosphate (cGMP) in men before and during a 10 h head-down tilt at -6 degrees. Saliva values closely correlated with plasma for ANF (r = 0.7-0.95) and for cGMP (r = 0.65-1). During this dynamic test, the mean concentrations of ANF and cGMP were significantly higher after 15 and 45 min, respectively, this increase persisting for 3.5 h. We concluded that the concentration of ANF in saliva may be significantly affected by a marked fluid shift from the lower to the upper half of the body. This is the first time that the presence of ANF and cGMP has been demonstrated in saliva. The great advantage of studying saliva is that it can be obtained non-invasively in athletes or during space flight. This methodology will be used during the Soviet-French space flight (Antares Project) planned for 1992.


HLA-DRB1∗16 and -DQB1∗05 alleles are strongly associated with autoimmune pancreatitis in a cohort of hundred patients.
Autoimmune diseases are often associated with human leukocyte antigen (HLA) haplotypes, indicating that changes in major histocompatibility complex (MHC)-dependent self-peptide or antigen presentation contribute to autoimmunity. In our study, we aimed to investigate HLA alleles in a large European cohort of autoimmune pancreatitis (AIP) patients. Hundred patients with AIP, diagnosed and classified according to the International Consensus Diagnostic Criteria (ICDC), were prospectively enrolled in the study. Forty-four patients with chronic pancreatitis (CP) and 254 healthy subjects served as control groups. DNA was isolated from blood samples and two-digit HLA typing was performed with sequence-specific primer (SSP-) PCR. HLA allele association strength to AIP was calculated as odds ratio. We uncovered a strong enrichment of HLA-DQB1 homozygosity in type 1 and type 2 AIP patients. Moreover, a significantly increased incidence of the HLA-DRB1∗16 and HLA-DQB1∗05 alleles and a concomitant lack of the HLA-DRB1∗13 allele was detected in AIP type 1 and type 2 patients. In contrast, the HLA-DQB1∗02 allele was underrepresented in the 'not otherwise specified' (NOS) AIP subtype. We detected no significant difference in the HLA-DRB3, HLA-DRB4 and HLA-DRB5 allele frequency in our cohort. Although AIP type 1 and type 2 are characterized by distinct histopathological characteristics, both subtypes are associated with the same HLA alleles, indicating that the disease might rely on similar immunogenic mechanisms. However, AIP NOS represented another subclass of AIP.


Loss of hepatic Flcn protects against fibrosis and inflammation by activating autophagy pathways.
Non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease worldwide and can progress to non-alcoholic steatohepatitis (NASH), which is characterized by triglyceride accumulation, inflammation, and fibrosis. No pharmacological agents are currently approved to treat these conditions, but it is clear now that modulation of lipid synthesis and autophagy are key biological mechanisms that could help reduce or prevent these liver diseases. The folliculin (FLCN) protein has been recently identified as a central regulatory node governing whole body energy homeostasis, and we hypothesized that FLCN regulates highly metabolic tissues like the liver. We thus generated a liver specific Flcn knockout mouse model to study its role in liver disease progression. Using the methionine- and choline-deficient diet to mimic liver fibrosis, we demonstrate that loss of Flcn reduced triglyceride accumulation, fibrosis, and inflammation in mice. In this aggressive liver disease setting, loss of Flcn led to activation of transcription factors TFEB and TFE3 to promote autophagy, promoting the degradation of intracellular lipid stores, ultimately resulting in reduced hepatocellular damage and inflammation. Hence, the activity of FLCN could be a promising target for small molecule drugs to treat liver fibrosis by specifically activating autophagy. Collectively, these results show an unexpected role for Flcn in fatty liver disease progression and highlight new potential treatment strategies.


Interactions between prostaglandins and calcium: the importance of bell-shaped dose-response curves.
Biological responses to PGs show two basic forms of dose/response relationship, plateau and bell-types. Although bell-shaped dose/response curves are well documented their possible occurrence is almost always ignored in the design and interpretation of experiments on PGs and related substances. This may lead to serious errors, several types of which are described. The ignoring of a well-documented phenomenon may take place because there is no accepted hypothesis which attempts to explain the bell-type curves. A hypothesis is proposed which accounts for both plateau and bell type responses. It is developed primarily with respect to PG-calcium interactions but may be applicable to some PG-cyclic nucleotide interactions as well. The model leads to precise predictions which can be experimentally tested in many systems.


Comparison of Mathematics Problem-Solving Abilities in Autistic and Non-autistic Children: the Influence of Cognitive Profile.
This study examines relationships between mathematical problem-solving performance (in terms of strategies used and accuracy) and the main cognitive domains associated with mathematical learning (i.e. executive functions, verbal comprehension and social perception) of children with and without autism spectrum disorder (ASD and non-ASD resp.). The study involved 26 ASD and 26 non-ASD children without intellectual disabilities, between 6 and 12 years old, matched by sex, age and school (grade and classroom). The results show a higher percentage of ASD children with problem solving difficulties than non-ASD (57% vs. 23% resp.). Poor performing ASD children showed comparatively lower scores in inhibition, theory of mind and verbal comprehension. Implications for the design of mathematical interventions for ASD students are discussed.


The role of managed care in work-related injuries.
Many opportunities exist today for orthopedic surgeons in the treatment and management of work-related injuries. Physicians wishing to enter or participate in this market must realize that the role of the physician in the treatment of the injured worker has expanded from one of being solely the care giver to being a patient manager, a problem solver, and a communicator. A number of years ago, many orthopedic surgeons missed out on managed care contracting for health maintenance organizations because they thought they could survive without it. They soon learned the challenges of sitting on the sidelines. Whether we like it or not, managed care for work-related injuries is here and its likelihood for going away is about zero. If your state has not yet adopted utilization management standards or managed care for workers' compensation-enabling legislation, when you wake up tomorrow they may have done so. Because of its relative embryonic development, there are exceptional opportunities for practitioners to take active roles in shaping the models that will serve employees and employers in the year 2000. Physicians who are interested in the treatment of injured workers have a unique opportunity right now to develop relationships in the managed workers' compensation arena. Payment and patient referrals for workers' compensation may turn out to be more attractive financially than many of the contracts currently in place with health maintenance organizations and other general health plans. Physicians willing to partner with employers and other players in the workers' compensation arena currently face some challenging, rewarding, and exciting opportunities. In the immortal words of Hippocrates, "Healing is a matter of time, but it is sometimes a matter of opportunity."3 It is unclear whether Hippocrates ever imagined our current level of science, practice, and organization, but it is clear the opportunities to be an active participant in the changes occurring in workers' compensation are as real today as they were in 1973 when then President Nixon passed the Health Maintenance Organization Act.


Serologically active clinically quiescent systemic lupus erythematosus: a discordance between clinical and serologic features.
The significance of abnormal serologic tests in systemic lupus erythematosus (SLE) in the absence of active clinical disease is unclear. In this report we describe a group of 14 patients with SLE in whom a discordance between clinical and serologic features was apparent. These patients had persistently positive lupus erythematosus preparations and antinuclear antibody tests, low serum complement levels and high levels of DNA binding. Their lymphocyte response to concanavalin A (Con A) mitogen was suppressed. They have been asymptomatic and have remained untreated for a mean of four and a quarter years.


"Undisturbed by colors": photorealism and narrative bioethics in the poetry of William Carlos Williams.
Between 1917 and 1935, William Carlos Williams' poetic style shifted from a focus on color to a verbal grayscale of photorealism. Considering this shift alongside of the historical connection between photography and eugenics raises questions about Williams' status as a physician during an era when medical discourse was dominated by theories of scientific racism. While one might conclude that Williams move from color to grayscale represents a capitulation to public health anxieties regarding the pathologized bodies of the immigrant poor, I argue that it is precisely through his adoption of black-and-white photorealism that Williams overturns hereditary notions of degeneracy.


Clinical trial design for target specific anticancer agents.
Recently a large number of new anticancer agents targeting specifically one or more of the extracellular, transmembrane, or intracellular (but extranuclear) processes involved in malignant transformation of cells or carcinogenesis have been developed. These agents show target specificity, predominantly resulting in growth inhibition in tumor models and less frequently in tumor regression, acting in a cytostatic rather than a cytotoxic way. In addition, based on their specific mechanism of action, these target specific agents are expected to have a more favorable toxicity profile. In exploring new anticancer agents, phase I studies generally focus on toxicity and are primarily designed to describe dose limiting toxicity and to determine the maximum tolerated dose and the dose recommended for phase II studies. These phase II studies are subsequently performed in small groups of patients using the percentage tumor regression to screen for anticancer efficacy. Due to the anticipated low toxicity profile and the mainly growth inhibiting activity of target specific agents, the design of phase I and II studies involving these agents will have to be adapted in several ways. It is emphasized that, although it is helpful to distinguish cytotoxic from cytostatic anticancer agents, this dichotomy can be a simplification. In this paper, we will discuss important issues that will have to be faced when developing clinical trials with these agents and we will specifically translate this into the already known concepts of trial design exploring cytotoxic and cytostatic agents.


Direct evidence for the formation of a monolayer from a bilayer. An ellipsometric study at the nitrogen-water interface.
Direct evidence for the formation of a monolayer from a bilayer was measured by ellipsometry after spreading unilamellar vesicles of dioleoyl phosphatidylcholine (DOPC) at the nitrogen-water interface. The ellipsometric isotherms of DOPC vesicles and DOPC spread from an organic solvent were compared and found similar. From the observed ellipsometric angle (delta delta) in the plateau region (-1.04 degrees) and literature data for refractive indices of an anisotropic film similar to DOPC, we have calculated a thickness of 20 +/- 1 A. These results strongly suggest that, similarly to DOPC spread from an organic solvent, DOPC vesicles form a monolayer when spread at the nitrogen-water interface.


Investigating the electrical crosstalk effect between pixels in high-resolution organic light-emitting diode microdisplays.
Organic light-emitting diode (OLED) microdisplays have received great attention owing to their excellent performance for augmented reality/virtual reality devices applications. However, high pixel density of OLED microdisplay causes electrical crosstalk, resulting in color distortion. This study investigated the current crosstalk ratio and changes in the color gamut caused by electrical crosstalk between sub-pixels in high-resolution full-color OLED microdisplays. A pixel structure of 3147 pixels per inch (PPI) with four sub-pixels and a single-stack white OLED with red, green, and blue color filters were used for the electrical crosstalk simulation. The results showed that the sheet resistance of the top and bottom electrodes of OLEDs rarely affected the electrical crosstalk. However, the current crosstalk ratio increased dramatically and the color gamut decreased as the sheet resistance of the common organic layer decreased. Furthermore, the color gamut of the OLED microdisplay decreased as the pixel density of the panel increased from 200 to 5000 PPI. Additionally, we fabricated a sub-pixel circuit to measure the electrical crosstalk current using a 3147 PPI scale multi-finger-type pixel structure and compared it with the simulation result.


Epidemiological Study Regarding the Incidence of Venous Thromboembolism in Patients After Cancer Remission.
The time course of reduction in the risk of venous thromboembolism (VTE) in patients who were diagnosed with cancer, treated with anticancer therapy, and in remission is unclear. We hypothesized that the risk of VTE will decrease over time after cancer remission. We conducted a retrospective analysis using claims data for cancer remission in Japan. Background information of patients who developed VTE after cancer remission was collected, and the VTE incidence rate after cancer remission was analyzed. Subgroup analysis based on VTE history, cancer type, and the presence or absence of surgery during hospitalization was conducted. A total of 638,908 patients were eligible for the analysis. VTE occurred in 5533 of 638,908 cases, pulmonary embolism occurred in 779 cases, and deep vein thrombosis occurred in 5084 cases after cancer remission. The mean age of patients who developed VTE was 70.1 ± 12.5 years, and the proportion of men was 47.5%. All comorbidities and medications were higher in the VTE group (P < 0.001) than in the non-VTE group after cancer remission. The incidence of VTE was 2.4% per year in the first 30 days, 1.35% per year in 31-60 days, and gradually decreased to 0.48% per year in 181-360 days, becoming almost constant (annual rate 0.3%) 2 years after cancer remission. Risk of developing VTE decreased to the same level as that in patients without cancer 2 years after cancer remission. Although the guidelines do not specify the duration of anticoagulant prophylaxis for new onset or recurrent VTE after cancer remission and the appropriate duration of such prophylaxis may vary depending on VTE risk factors, determining the period of high risk of VTE for each patient and preventing VTE is considered important.


Gene expression profiling of adult female tissues in feeding Rhipicephalus microplus cattle ticks.
The southern cattle tick, Rhipicephalus microplus, is an economically important pest, especially for resource-poor countries, both as a highly adaptive invasive species and prominent vector of disease. The increasing prevalence of resistance to chemical acaricides and variable efficacy of current tick vaccine candidates highlight the need for more effective control methods. In the absence of a fully annotated genome, the wealth of available expressed sequence tag sequence data for this species presents a unique opportunity to study the genes that are expressed in tissues involved in blood meal acquisition, digestion and reproduction during feeding. Utilising a custom oligonucleotide microarray designed from available singletons (BmiGI Version 2.1) and expressed sequence tag sequences of R. microplus, the expression profiles in feeding adult female midgut, salivary glands and ovarian tissues were compared. From 13,456 assembled transcripts, 588 genes expressed in all three tissues were identified from fed adult females 20 days post infestation. The greatest complement of genes relate to translation and protein turnover. Additionally, a number of unique transcripts were identified for each tissue that relate well to their respective physiological/biological function/role(s). These transcripts include secreted anti-hemostatics and defense proteins from the salivary glands for acquisition of a blood meal, proteases as well as enzymes and transporters for digestion and nutrient acquisition from ingested blood in the midgut, and finally proteins and associated factors involved in DNA replication and cell-cycle control for oogenesis in the ovaries. Comparative analyses of adult female tissues during feeding enabled the identification of a catalogue of transcripts that may be essential for successful feeding and reproduction in the cattle tick, R. microplus. Future studies will increase our understanding of basic tick biology, allowing the identification of shared proteins/pathways among different tissues that may offer novel targets for the development of new tick control strategies.


Forum for Injection Technique (FIT), India: The Indian recommendations 2.0, for best practice in Insulin Injection Technique, 2015.
As injectable therapies such as human insulin, insulin analogs, and glucagon-like peptide-1 receptor agonists are used to manage diabetes, correct injection technique is vital for the achievement of glycemic control. The forum for injection technique India acknowledged this need for the first time in India and worked to develop evidence-based recommendations on insulin injection technique, to assist healthcare practitioners in their clinical practice.


Musings on track: creative use of multiple disciplines to evaluate client needs.
The author's concern about palliative care, the elderly and chronically ill is demonstrated by the creative utilization of a number of disciplines, Pastoral Counseling, Art Therapy, and Psychology in caring for clients. She shows how Maslow's Hierarchy can be used as a focused lens suggesting broader assessment of client needs that might enhance the interventional repertoire for mature students and more experienced creative clinicians in fields of Pastoral Counselling, CPE, Psychology, and Art Therapy.


Development of [18F]DASA-10 for enhanced imaging of pyruvate kinase M2.
The aim of this study was to develop a positron emission tomography (PET) radiotracer for measuring pyruvate kinase M2 (PKM2) with improved physicochemical and pharmacokinetic properties compared to [18F]DASA-23. First, we synthesized [18F]DASA-10 and tested its uptake and retention compared to [18F]DASA-23 in human and mouse glioma cell lines. We then confirmed the specificity of [18F]DASA-10 by transiently modulating the expression of PKM2 in DU145 and HeLa cells. Next, we determined [18F]DASA-10 pharmacokinetics in healthy nude mice using PET imaging and subsequently assessed the ability of [18F]DASA-10 versus [18F]DASA-23 to enable in vivo detection of intracranial gliomas in syngeneic C6 rat models of glioma. [18F]DASA-10 demonstrated excellent cellular uptake and retention with values significantly higher than [18F]DASA-23 in all cell lines and timepoints investigated. [18F]DASA-10 showed a 73 % and 65 % reduced uptake respectively in DU145 and HeLa cells treated with PKM2 siRNA as compared to control siRNA treated cells. [18F]DASA-10 showed favorable biodistribution and pharmacokinetic properties and a significantly improved tumor-to-brain ratio in rat C6 glioma models relative to [18F]DASA-23 (3.2 ± 0.8 versus 1.6 ± 0.3, p = 0.01). [18F]DASA-10 is a new PET radiotracer for molecular imaging of PKM2 with potential to overcome the prior limitations observed with [18F]DASA-23. [18F]DASA-10 shows promise for clinical translation to enable imaging of brain malignancies owing to its low background signal in the healthy brain.


Does upper airway deformation affect drug deposition?
Knowledge that enables the accurate simulation of drug deposition in the human upper airway is necessary to develop robust platforms for efficient drug delivery by inhalation devices. The human upper airway is deformable during inhalation but how it could affect the deposition of inhaled drugs is unknown. We aimed to determine whether pharyngeal deformation at the soft palate level would have any significant effects on throat deposition, in vitro lung dose and fine particle fraction. In this study, dry mannitol powders were delivered to the next-generation cascade impactor (NGI) through the United States Pharmacopeia (USP) throat, and a realistic upper airway cast (RUPAC) at flow rates of 40, 60 and 80 L min-1. Deformation of the upper airway at 25%, 50%, and 75% in the lateral and antero-posterior directions were experimentally simulated in the RUPAC. Throat deposition (p = 0.04) is significantly affected when the upper airway deforms laterally but not antero-posteriorly.


Is duration of preoperative anti-tuberculosis treatment a risk factor for postoperative relapse or non-healing of spinal tuberculosis?
This study evaluated the relationship between spinal TB postoperative recurrence or non-healing and duration of preoperative anti-TB treatment (ATT). From January 2004 to January 2013, patients who underwent surgery for spinal TB and met this study's inclusion criteria were retrospectively reviewed. Observed parameters were age, sex, initial ESR, preoperative ESR, degree of ESR change, initial CRP, preoperative CRP, degree of CRP change, duration of preoperative ATT, surgical approach, presence of internal fixation, location of spinal lesion, number of involved segments, duration of operation, and intraoperative blood loss. The data were analyzed by univariate and multivariate analyses for spinal TB recurrence or non-healing to determine related risk factors. A total of 223 patients met the inclusion criteria. There were 84 female and 139 male patients with a mean age of 42.2 years (range 2-85 years). The follow-up period was 18-72 months (average 28.7 months). Among 223 patients observed, 23 patients had postoperative relapse or non-healing (10.3 %) during the follow-up period. Statistical analysis indicated that the location of a spinal lesion was significantly associated with postoperative relapse or non-healing. Risk of postoperative relapse or non-healing in thoracolumbar TB was 2.524-fold (95 % CI 1.026-6.580) that of lumbosacral TB. Duration of preoperative ATT may not be a risk factor for postoperative recurrence or non-healing of spinal TB. Junctional zones such as the lumbosacral and thoracolumbar junction have a higher recurrence rate than non junctional.


Valorisation of pineapple peel waste as natural surimi gel enhancer and its optimization in Nile tilapia (Oreochromis niloticus) surimi gels.
This investigation explored the preparation of surimi gel enhancer from pineapple peel waste, hugely generated by industries and spreading serious environment pollutions. The peel extracted with 100% ethanol had higher bioactive and antioxidant attributes, which was subsequently fortified in tilapia surimi at levels of 0.20%-1.20%, w/w to improve its physiochemical, textural, protein structural and sensorial properties. Our finding demonstrated that surimi gels enriched with 0.80% ethanolic pineapple peel extract (PAPE) exhibited significant (p<0.05) improvement in water holding capacity, breaking force, gel strength, and other textural properties and sensory attributes. Furthermore, the surimi gels fortified with 0.80% PAPE exhibited the elevated levels of hydrogen and hydrophobic interactions, while sulfhydryl and free amino acid contents demonstrated a contrasting trend. The FTIR spectra displayed that the incorporation of PAPE influenced the secondary structure of the protein, as evidenced by shifts in the α-helix to β-sheet peaks. In addition, 0.80% PAPE added gels displayed a compact, uniform, and organized microstructure, featuring small cavities. In summary, the fortification of tilapia surimi gels with 0.80% PAPE could improve gelling and other technological properties with higher sensory scores. This study offers an effective approach to utilize the pineapple peel as a gel enhancer additive for the development of functional surimi and surimi-based products enriched with bioactive compounds.


Behavior of broilers and impacts occurring to them during mechanical loading under field conditions.
Mechanical loading has been used increasingly in recent years alongside the manual loading of broilers. The aim of this study was to analyze the influence of various factors on the behavior of broilers and the impacts occurring to broilers during loading with a loading machine in order to identify risk factors and thus improve animal welfare. During 32 loadings we assessed escape behavior, wing flapping, flip, bumping into an animal, and bumping against the machine or container by evaluation of video recordings. The parameters were analyzed for influences of rotation speed, container type (GP container vs. SmartStack container), husbandry system ("Indoor Plus" vs. "Outdoor Climate"), and season. In addition, the behavior and impact parameters were correlated with the loading-related injuries. The results showed that an increase in rotation and conveyor belt speed was associated with an elevated risk of all behaviors or impacts, except for a lower risk of escape behavior. The seasonal influence showed that the risk of wing flapping, bumping into an animal, and bumping against the machine or container was highest in fall. The comparison of the container types showed that the risk of escape behavior, wing flapping, and bumping into an animal was increased when loading with the SmartStack container, but the risk of bumping against the machine or container was reduced. For animals of the husbandry system "Outdoor Climate," the risk of bumping into an animal and bumping against the machine or container was reduced. In addition, we found an influence of the examined parameters on the loading-related injuries. Increased escape behavior reduced the risk of severe injuries (fractures, dislocations, epiphysiolyses). Wing flapping and bumping against the machine or container increased the risk of hematomas and abrasions. The risk of hematomas was increased if broilers bumped into conspecifics. In summary, our analysis revealed that the behavior and impacts on the animals during loading are influenced by each of the analyzed factors and that they in turn can affect loading-related injuries.


Hemodynamic effects of myocardial bridging in patients with hypertrophic cardiomyopathy.
Myocardial bridging (MB) is linked to angina and myocardial ischemia and may lead to sudden cardiac death in patients with hypertrophic cardiomyopathy (HCM). However, it remains unclear how MB affect the coronary blood flow in HCM patients. The aim of this study was to assess the effects of MB on coronary hemodynamics in HCM patients. Fifteen patients with MB (7 HCM and 8 non-HCM controls) in their left anterior descending (LAD) coronary artery were chosen. Transient computational fluid dynamics (CFD) simulations were conducted in anatomically realistic models of diseased (with MB) and virtually healthy (without MB) LAD from these patients, reconstructed from biplane angiograms. Our CFD simulation results demonstrated that dynamic compression of MB led to diastolic flow disturbances and could significantly reduce the coronary flow in HCM patients as compared with non-HCM group (P < 0.01). The pressure drop coefficient was remarkably higher (P < 0.05) in HCM patients. The flow rate change is strongly correlated with both upstream Reynolds number and MB compression ratio, while the MB length has less impact on coronary flow. The hemodynamic results and clinical outcomes revealed that HCM patients with an MB compression ratio higher than 65% required a surgical intervention. In conclusion, the transient MB compression can significantly alter the diastolic flow pattern and wall shear stress distribution in HCM patients. HCM patients with severe MB may need a surgical intervention.NEW & NOTEWORTHY In this study, the hemodynamic significance of myocardial bridging (MB) in patients with hypertrophic cardiomyopathy (HCM) was investigated to provide valuable information for surgical decision-making. Our results illustrated that the transient MB compression led to complex flow patterns, which can significantly alter the diastolic flow and wall shear stress distribution. The hemodynamic results and clinical outcomes demonstrated that patients with HCM and an MB compression ratio higher than 65% required a surgical intervention.


Enhanced Zika virus susceptibility of globally invasive Aedes aegypti populations.
The drivers and patterns of zoonotic virus emergence in the human population are poorly understood. The mosquito Aedes aegypti is a major arbovirus vector native to Africa that invaded most of the world's tropical belt over the past four centuries, after the evolution of a "domestic" form that specialized in biting humans and breeding in water storage containers. Here, we show that human specialization and subsequent spread of A. aegypti out of Africa were accompanied by an increase in its intrinsic ability to acquire and transmit the emerging human pathogen Zika virus. Thus, the recent evolution and global expansion of A. aegypti promoted arbovirus emergence not solely through increased vector-host contact but also as a result of enhanced vector susceptibility.


Knowledge and behaviors of primary care physicians on oral cancer in Italy.
We investigated the knowledge and behaviors of a random sample of 500 primary care physicians (PCPs) regarding oral cancer in Calabria (Italy). 87.6% and 64% indicated tobacco and alcohol use as risk factors, only 31.5% and 2.8% having a prior oral cancer lesion and older age. 60.9% knew that squamous-cell carcinoma is the most common form; 68.8% and 37.1% that the tongue and floor of the mouth were the two most common sites. Respectively 91.5% and 41.7% knew that leukoplakia and erythroplakia were the two conditions most likely to be associated with oral cancer. 17.6% of PCPs recognized that an early oral lesion usually is small and painless red area and 26.8% knew how to examine the tongue. PCPs who learned about oral cancer from scientific journals were more likely to indicate tobacco use as a risk factor for oral cancer and those who do not need additional information to indicate alcohol use as a risk factor. Oral examination was provided by 63.8% and 37.1% to those 40 years of age and older. Half of respondents asked about the personal patient's experience of oral cancer and about the patient's family, most about patients' tobacco and alcohol use. The odds of asking about patients' tobacco and alcohol use and of performing oral cancer examination were significantly higher for those who practiced medicine for a longer period. Additional training and continuing educational programs on prevention and early detection of oral cancer for PCPs are strongly needed.


Sonication of bacteria, phytoplankton and zooplankton: Application to treatment of ballast water.
We investigated the effect of high power ultrasound, at a frequency of 19 kHz, on the survival of bacteria, phytoplankton and zooplankton, in order to obtain estimates of effective exposure times and energy densities that could be applied to design of ultrasonic treatment systems for ballast water. Efficacy of ultrasonic treatment varied with the size of the test organism. Zooplankton required only 3-9s of exposure time and 6-19 J/mL of ultrasonic energy to realize a 90% reduction in survival. In contrast, decimal reduction times for bacteria and phytoplankton ranged from 1 to 22 min, and decimal reduction energy densities from 31 to 1240 J/mL. Our results suggest that stand-alone ultrasonic treatment systems for ballast water, operating at 19-20 kHz, may be effective for planktonic organisms >100 microm in size, but smaller planktonic organisms such as phytoplankton and bacteria will require treatment by an additional or alternative system.


Keratolytic winter erythema or 'oudtshoorn skin': a newly recognized inherited dermatosis prevalent in South Africa.
A hitherto undescribed inherited dermatosis, traceable to certain 19th-century inhabitants of Oudtshoorn, CP, has been transmitted as an autosomal dominant to a large number of their present-day descendants. The disease consists of intermittent and recurrent centrifugal peeling, with redness, of the palms and soles in particular. In more severe cases similar patches are found extending up the limbs to the buttocks and the trunk generally. The inconvenience is usually moderate, but it may be incapacitating. Some temporary relief, but so far nothing permanent, can be offered through treatment.


In Situ Raman Study of CO Electrooxidation on Pt(hkl) Single-Crystal Surfaces in Acidic Solution.
The adsorption and electrooxidation of CO molecules at well-defined Pt(hkl) single-crystal electrode surfaces is a key step towards addressing catalyst poisoning mechanisms in fuel cells. Herein, we employed in situ electrochemical shell-isolated nanoparticle-enhanced Raman spectroscopy (SHINERS) coupled with theoretical calculation to investigate CO electrooxidation on Pt(hkl) surfaces in acidic solution. We obtained the Raman signal of top- and bridge-site adsorbed CO* molecules on Pt(111) and Pt(100). In contrast, on Pt(110) surfaces only top-site adsorbed CO* was detected during the entire electrooxidation process. Direct spectroscopic evidence for OH* and COOH* species forming on Pt(100) and Pt(111) surfaces was afforded and confirmed subsequently via isotope substitution experiments and DFT calculations. In summary, the formation and adsorption of OH* and COOH* species plays a vital role in expediting the electrooxidation process, which relates with the pre-oxidation peak of CO electrooxidation. This work deepens knowledge of the CO electrooxidation process and provides new perspectives for the design of anti-poisoning and highly effective catalysts.


Potential application of heat shock proteins as therapeutic targets in Parkinson's disease.
Parkinson's disease (PD) is a common chronic neurodegenerative disease, and the heat shock proteins (HSPs) are proved to be of great value for PD. In addition, HSPs can maintain protein homeostasis, degrade and inhibit protein aggregation by properly folding and activating intracellular proteins in PD. This study mainly summarizes the important roles of HSPs in PD and explores their feasibility as targets. We introduced the structural and functional characteristics of HSPs and the physiological functions of HSPs in PD. HSPs can protect neurons from damage by degrading aggregates with three mechanisms, including the aggregation and removing α-Synuclein (α-Syn) aggregates, promotion the autophagy of abnormal proteins, and inhibition the apoptosis of degenerated neurons. This study underscores the importance of HSPs as targets in PD and helps to expand new mechanisms in PD treatment strategies.


Devices for monitoring intravesical pressure during transurethral resection of the prostate.
The importance of maintaining a low intravesical pressure during transurethral resection of the prostate has been demonstrated in studies of the relationship between bladder pressure and the amount of irrigating fluid absorbed during the procedure. Several methods of monitoring pressure are described, and the advantages and disadvantages of each are discussed.


A new interpretable belief rule base model with step-length convergence strategy for aerospace relay health state assessment.
Health state assessment is an important measure to maintain the safety of aerospace relays. Due to the uncertainty within the relay system, the accuracy of the model assessment is challenged. In addition, the opaqueness of the process and incomprehensibility of the results tend to lose trust in the model, especially in high security fields, so it is crucial to maintain the interpretability of the model. Thus, this paper proposes a new interpretable belief rule base model with step-length convergence strategy (IBRB-Sc) for aerospace relay health state assessment. First, general interpretability criteria for BRB are considered, and strategies for maintaining model interpretability are designed. Second, the evidential reasoning (ER) method is used as the inference machine. Then, optimization is performed based on the Interpretable Projection Covariance Matrix Adaptive Evolution Strategy (IP-CMA-ES). Finally, the validity of the model is verified using the JRC-7M aerospace relay as a case study. Comparative experiments show that the proposed model maintains high accuracy and achieves advantages in interpretability.


Sterol release in mammalian cells. The role of a liposomal-free albumin-phospholipid complex.
Human serum albumin, the purity of which was confirmed by two-dimensional gel electrophoresis and high-pressure liquid chromatography, is able to bind dipalmitoyl phosphatidylcholine and the resulting albumin-phospholipid complex can cause marked sterol release from animal and human cells in tissue culture. The complex-induced sterol release was synergistic, exceeding by 4--5-fold the sum of sterol release in the presence of albumin and phospholipid individually. Isolation of the albumin-phospholipid complex by gel permeation chromatography yielded a liposomal-free fraction which caused full sterol release. No synergistic release of sterol occurred when cells were incubated with human serum albumin and dilinoleoyl phosphatidylcholine.


Impulse perturbation reveals cross-modal access to sensory working memory through learned associations.
We investigated if learned associations between visual and auditory stimuli can afford full cross-modal access to working memory. Previous research using the impulse perturbation technique has shown that cross-modal access to working memory is one-sided; visual impulses reveal both auditory and visual memoranda, but auditory impulses do not seem to reveal visual memoranda (Wolff et al., 2020b). Our participants first learned to associate six auditory pure tones with six visual orientation gratings. Next, a delayed match-to-sample task for the orientations was completed, while EEG was recorded. Orientation memories were recalled either via their learned auditory counterpart, or were visually presented. We then decoded the orientation memories from the EEG responses to both auditory and visual impulses presented during the memory delay. Working memory content could always be decoded from visual impulses. Importantly, through recall of the learned associations, the auditory impulse also evoked a decodable response from the visual WM network, providing evidence for full cross-modal access. We also observed that after a brief initial dynamic period, the representational codes of the memory items generalized across time, as well as between perceptual maintenance and long-term recall conditions. Our results thus demonstrate that accessing learned associations in long-term memory provides a cross-modal pathway to working memory that seems to be based on a common coding scheme.


Esmolol-assisted balloon and stent angioplasty for aortic coarctation.
The objective of this study was to evaluate the effectiveness and safety of esmolol-induced negative ino- and chronotropism during stent/balloon angioplasty for aortic coarctation. Balloon angioplasty and stent placement have become widely accepted therapies for native and recurrent coarctation of the aorta (CoA). Trauma to the vessel wall and stent migration related to forward displacement of the balloon and/or stent by cardiac output, are the most common complications. Controlling stroke volume and heart rate may assist in balloon stability and accurate deployment of stents. All methods currently used to achieve this have significant limitations. We describe our experience using esmolol to control stroke volume and heart rate during balloon/stent angioplasty of CoA. We performed a retrospective review of all patients who had intravenous esmolol during percutaneous treatment of CoA. Six interventions were performed in six patients: coarctation stent angioplasty in five patients (two native coarctation) and balloon angioplasty alone in one patient. The median systolic blood pressure achieved during the procedure was 65 mmHg (range, 57-75) representing a median reduction of 40 mmHg (range, 20-80; p = 0.008) from baseline. The median heart achieved was 50 beats/min (range, 20-80), representing a median reduction of 20 beats/min (range, 15-90, p = 0.048) from baseline. Optimal stent position was obtained in all patients. Intravenous esmolol controls periprocedural hemodynamics effectively and safely during percutaneous therapy for aortic coarctation, thereby aiding accurate stent placement. Further evaluation of its use during other percutaneous left heart interventions is required.


What DKKtates where to metastasize.
Cancer cells preferentially metastasize to certain organs. A study in mouse models of breast cancer shows that the DKK1 negative regulator of WNT signalling inhibits tropism to the lung, but enhances tropism to the bone due to the differential regulation of canonical and non-canonical WNT signalling in the two microenvironments.


Cryoablation is associated with shorter length-of-stay and reduced opioid use after the Ravitch procedure.
The use of intercostal nerve cryoablation (INC) is becoming increasingly common in patients undergoing pectus repair. This study sought to evaluate the use of INC compared to traditional use of thoracic epidural (TE) in patients undergoing the modified Ravitch procedure. A retrospective review of 37 patients undergoing the modified Ravitch repair with either INC or TE from March 2009 to July 2021 was conducted. The operations were performed by four surgeons who worked together at four different hospitals and have the same standardized practice. The primary outcome measure was hospital length of stay (LOS). Secondary variables included surgical time, total operating room time, operating room time cost, total hospital cost, inpatient opioid use, long term opioid use after discharge, and post-operative complications. LOS decreased to 2.8 days in the INC group compared to 6 days in the TE group (p<0.0001). Surgical time and total OR time was increased in the INC group. The INC group experienced significantly lower hospital costs (p<0.01). Total hospital opioid administration was significantly lower in INC group, and there was a significant decrease in long term opioid use in the INC group (p<0.0001). INC is a newer modality that decreases LOS, controls pain, and results in overall cost savings for patients undergoing the modified Ravitch procedure. We recommend that INC be included in the current practice for postoperative pain control in pectus disorder patients undergoing the modified Ravitch procedure.


Sampling time effects on signal-to-noise and contrast-to-noise ratios in spin-echo MRI.
This work discusses the effect of sampling time on noise, signal-to-noise and contrast-to-noise ratios in magnetic resonance imaging. A simple imaging experiment is performed to demonstrate the effect of sampling time on noise, confirming theoretical expectations that doubling the sampling time while decreasing the read gradient strength by a factor of two reduces statistical noise to 1/square root 2 of its original level. This result suggests that sampling time should be maximized within the constraints of the pulse sequence: namely, that sampling time should be increased and read gradient strength decreased as TE is increased. Revised expressions for signal-to-noise and contrast-to-noise ratios are presented based on the assumption that sampling time increases linearly with echo delay time above a certain minimum TE value. The revised expressions are then used to derive new predictions of the interpulse delay times that maximize signal-to-noise and contrast-to-noise ratios in spin-echo imaging. It is demonstrated that sampling times are critical in determining whether T1-weighted or T2-weighted sequences produce superior tissue contrast in spin-echo imaging.


Cloning, genetic organization, and characterization of a structural gene encoding bacillopeptidase F from Bacillus subtilis.
Bacillopeptidase F is an extracellular serine protease that is expressed at the beginning of the stationary phase. To study its structure, regulation of expression, and physiological roles, we have cloned and characterized the structural gene (bpf) encoding this protease from Bacillus subtilis. DNA sequence analysis suggests this protease is synthesized as a preproenzyme (Mr = 92,000). Through processing at both the NH2 and COOH termini, it is gradually converted into various forms with molecular mass ranging from 80 to 48 kDa. Shortening the 3' end of bpf demonstrates that at least 290 amino acid residues from the COOH-terminus of bacillopeptidase F are not required for either catalytic activity or secretion. Bacillopeptidase F exhibits sequence similarity with several serine proteases. Its gene is found immediately downstream from the fts operon which was mapped at 135 degrees on the B. subtilis genetic linkage map. Inactivation of the chromosomal copy of bpf shows no effect on cell growth and sporulation. A triple protease-deficient strain (WB300 with the structural genes for bacillopeptidase F and two other major proteases inactivated) was constructed to serve as a better expression host for the production and secretion of foreign proteins.


Median Arcuate Ligament Syndrome Is Not a Vascular Disease.
Median arcuate ligament syndrome (MALS) is a rare disorder characterized by postprandial abdominal pain, weight loss, and celiac stenosis. Diagnosis can be challenging, leading to a delay in treatment. We report on our continued experience using a laparoscopic approach for this uncommon diagnosis. This is an Institutional Review Board-approved, prospectively collected retrospective analysis of patients treated with laparoscopic MAL release at our institution. Data collected included patient demographics, preoperative symptoms, operative approach, and postoperative outcomes. Patients were then contacted to complete a postoperative survey designed to assess the improvement of symptoms and overall patient satisfaction. A total of 39 patients (33 women and 6 men) underwent laparoscopic MAL release from March 2007 to July 2014. Mean age was 40.6 years (range, 17-77 years). Thirty of 39 patients had a postoperative celiac axis ultrasound. Twenty-three had a patent celiac axis on postoperative duplex. Of the remaining 7, 5 with residual celiac axis stenosis and 1 with occlusion, reported complete resolution of their symptoms. One remaining patient with occlusion remained symptomatic. Thirty-three of 39 (84.6%) reported symptom relief after surgery. Nine of 33 (27.3%) responders had cardiovascular risk factors versus 4 of 6 (67%) nonresponders. Five patients with atypical presentations underwent preoperative diagnostic celiac plexus block using local anesthetic, with 4 reporting symptom reliefs after block. These 4 patients also reported postoperative symptom relief. One patient of 39 received a postoperative celiac stent placement and remained symptomatic. There were 4 conversions to open surgery (10.3%) and no deaths. Laparoscopic MAL release continues to be a safe and effective means of managing MALS. Our data suggest that the symptoms associated with MALS are not related to vascular compromise, and atherosclerotic risk factors may predict poorer outcomes. Symptomatic relief is seen in the vast majority of patients undergoing this procedure. However, patient selection remains critically important in obtaining optimal results.


A review of biomechanical studies of intramedullary nails.
Fracture management is becoming less conservative, and more frequently surgical intervention is the treatment of choice. Intramedullary mailing is a modern surgical method of internal fracture used in long bones such as the femur, tibia and humerus. The nails' function is to stabilize the fracture fragments, allowing load transfer across the fracture site while maintaining anatomic alignment of the bone. There are a large number of different intramedullary nails available commercially but no universal guideline stating the conditions at which each nail will perform at its optimum. Numerous animal, biomechanical and clinical studies have documented the performance of the nails. Biomechanical studies have shown that in torsion, slotted nails have a considerably lower rigidity than non-slotted nails but that in bending, the slot makes little difference to the nails' behaviour and so the two nail types have similar stiffnesses. Studies also recommend that in unstable fractures an interlocked intramedullary nail is essential if limb shortening or malunion is to be avoided. It is the aim of this review to outline the work that has been published to date on the biomechanical testing of intramedullary nails and to highlight areas that require further investigation.


Potential impact of a nonavalent HPV vaccine on the occurrence of HPV-related diseases in France.
Human Papillomavirus (HPV) infection is known to be associated with a number of conditions including cervical, vaginal, vulvar, penile, anal neoplasias and cancers, oropharynx cancers and genitals warts (GW). Two prophylactic vaccines are currently available: a bivalent vaccine designed to prevent HPV type 16 and 18 infection and a quadrivalent vaccine targeting HPV 6, 11, 16, and 18. In France, HPV vaccination is recommended in 11-14 year-old girls with a catch-up for girls aged 15-19. The objective of this study was to assess the potential impact of an HPV 6/11/16/18/31/33/45/52/58 nonavalent vaccine on anogenital and oropharyngeal HPV-related diseases in France. HPV genotype distributions from 6 multicentric retrospective studies (EDiTH I to VI) were analyzed including 516 cases of invasive cervical cancers (ICC), 493 high-grade cervical neoplasias (CIN2/3), 397 low-grade squamous intraepithelial lesions (LSIL), 423 GW, 366 anal cancer and 314 oropharyngeal carcinomas. Low and high estimates of HPV vaccine impact were calculated as follows: low estimate: prevalence of HPV 6/11/16/18/31/33/45/52/58 genotypes alone or in association but excluding presence of another HPV type; high estimate: prevalence of HPV 6/11/16/18/31/33/45/52/58 genotypes alone or in association, possibly in presence of another HPV type. Estimates of potential impact varied from 85% (low estimate) to 92% (high estimate) for ICC, 77% to 90% for CIN2/3, 26% to 56% for LSIL, 69% to 90% for GW, 81% to 93% for anal cancer, and 41% to 44% for oropharyngeal carcinomas. Compared to the quadrivalent vaccine, the proportion of additional cases potentially prevented by the nonavalent vaccine was 9.9%-15.3% for ICC, 24.7%-33.3% for CIN2/3, 12.3%-22.7% for LSIL, 2.1%-5.4% for GW, 8.5%-10.4% for anal cancer, and 0.0%-1.6% for oropharyngeal carcinoma. The nonavalent HPV vaccine showed significant increased potential impact compared to the HPV 6/11/16/18 quadrivalent vaccine for ICC, CIN2/3 and LSIL. Considering a 100% vaccine efficacy and high vaccine coverage, about 90% of ICC, CIN2/3, GW or anal cancer cases could be prevented by a nonavalent HPV vaccine in France.


Gender differences in faculty rank among academic physicians: a systematic review and meta-analysis.
Many studies have analysed gender bias in academic medicine; however, no comprehensive synthesis of the literature has been performed. We conducted a pooled analysis of the difference in the proportion of men versus women with full professorship among academic physicians. Systematic review and meta-analysis. MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Education Resources Information Center and PsycINFO were searched from inception to 3 July 2020. All original studies reporting faculty rank stratified by gender worldwide were included. Study screening, data extraction and quality assessment were performed by two independent reviewers, with a third author resolving discrepancies. Meta-analysis was conducted using random-effects models. Our search yielded 5897 articles. 218 studies were included with 991 207 academic physician data points. Men were 2.77 times more likely to be full professors (182 271/643 790 men vs 30 349/251 501 women, OR 2.77, 95% CI 2.57 to 2.98). Although men practised for longer (median 18 vs 12 years, p<0.00002), the gender gap remained after pooling seven studies that adjusted for factors including time in practice, specialty, publications, h-index, additional PhD and institution (adjusted OR 1.83, 95% CI 1.04 to 3.20). Meta-regression by data collection year demonstrated improvement over time (p=0.0011); however, subgroup analysis showed that gender disparities remain significant in the 2010-2020 decade (OR 2.63, 95% CI 2.48 to 2.80). The gender gap was present across all specialties and both within and outside of North America. Men published more papers (mean difference 17.2, 95% CI 14.7 to 19.7), earned higher salaries (mean difference $33 256, 95% CI $25 969 to $40 542) and were more likely to be departmental chairs (OR 2.61, 95% CI 2.19 to 3.12). Gender inequity in academic medicine exists across all specialties, geographical regions and multiple measures of success, including academic rank, publications, salary and leadership. Men are more likely than women to be full professors after controlling for experience, academic productivity and specialty. Although there has been some improvement over time, the gender disparity in faculty rank persists. CRD42020197414.


Intraoral adenoid cystic carcinoma: prognostic factors and outcome.
Intraoral (oral cavity and oropharynx) adenoid cystic carcinomas are uncommon cancers characterized by slow evolution, protracted clinical course, multiple and/or delayed recurrences, and late distant metastases. The molecular biology behind this enigmatic disease remains poorly characterized. To analyze and correlate prognostic factors with outcome in intraoral adenoid cystic carcinoma. Medical records of 76 patients with intraoral adenoid cystic carcinoma treated with definitive loco-regional therapy at the institute between 1992 and 2004 were retrospectively reviewed and analyzed.Majority (85.5%) of the patients had advanced stage disease. Seventy-four patients underwent surgery, of which 51 (68.9%) received adjuvant radiotherapy. The median dose of radiation was 56 Gy (range 44-66 Gy). Two patients with medical co-morbidities received radical radiotherapy. Perineural invasion, margin positivity and nodal positivity were present in 24 (32.4%); 27 (36.4%); and 15 (19.7%) patients, respectively. Ten (13.1%) patients developed local recurrence and 6 (7.8%) distant metastases. With a median follow-up of 20 months (range 1-137 months), the 5-year Kaplan-Meier estimates of local control and disease-free survival were 57.9% and 47.1%, respectively. On uni-variate analysis, perineural invasion (p=0.003), oropharyngeal primary (p=0.033), and advanced T-stage (p=0.047) were associated with increased local recurrences. Perineural invasion (p=0.05) and primary site (p=0.042) also predicted disease-free survival. On multivariate analysis, both perineural invasion and primary site retained significance for local control (p=0.007, p=0.011) and disease-free survival (p=0.018, p=0.014), respectively. Intraoral adenoid cystic carcinoma is an uncommon disease with an enigmatic clinical course. Perineural invasion, site of primary, and T-stage significantly impact upon local control and disease-free survival. The role of adjuvant radiotherapy remains controversial. Larger prospective studies with mature follow-up are needed to define the optimal treatment of intraoral adenoid cystic carcinoma.


Anticonvulsant effects of Senna spectabilis on seizures induced by chemicals and maximal electroshock.
Senna spectabilis (Fabaceae) is one of the medicinal plants used in Cameroon by traditional healers to treat epilepsy, constipation, insomnia, anxiety. The present study aimed to investigate the anticonvulsant effects of Senna spectabilis decoction on seizures induced by maximal electroshock (MES), pentylenetetrazole (PTZ), pilocarpine (PC) and its possible action mechanisms in animal models using flumazenil (FLU), methyl-ß-carboline-3-carboxylate (BC) and bicuculline (BIC). Senna spectabilis decoction (106.5 and 213.0mg/kg) antagonized completely tonic-clonic hind limbs of mice induced by MES. The lowest plant dose (42.6mg/kg) provided 100% of protection against seizures induced by PTZ (70mg/kg). Administration of different doses of the plant decoction antagonized seizures induced by PC up to 75%, causing a dose dependent protection and reduced significantly the mortality rate induced by this convulsant. Both FLU and BC antagonize strongly the anticonvulsant effects of this plant and are unable to reverse totally diazepam or the plant decoction effects on inhibiting seizures. The animals did not present any sign of acute toxicity even at higher doses of the plant decoction. In conclusion, Senna spectabilis possesses an anticonvulsant activity. We showed that its decoction protects significantly mice against seizures induced by chemicals and MES, delays the onset time and reduces mortality rate in seizures-induced. It also appears that the oral administration of the decoction of S. spectabilis is more active than the intraperitoneal administration of the ethanolic extract on inhibiting seizures induced by MES and PTZ. Moreover, the plant decoction could interact with GABAA complex receptor probably on the GABA and benzodiazepines sites.


Sulforaphane regulates Nrf2-mediated antioxidant activity and downregulates TGF-β1/Smad pathways to prevent radiation-induced muscle fibrosis.
This study aimed to examine the efficacy of sulforaphane (SFN) in preventing radiation-induced muscle fibrosis (RIMF) and the potential role in nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant stress. The RIMF model was established by a single irradiation of the left thigh of C57BL/6 J mice, and the mice were then randomly divided into control, SFN, irradiation (IR), and IR + SFN (IR/SFN) groups. The serum and skeletal muscle were collected eight weeks after irradiation, and changes in oxidative stress and muscle fibrosis were detected. The IR group showed a more obvious skeletal muscle fiber atrophy, significantly higher number of collagen fibers, and higher inflammatory cell infiltration compared to control group. Compared to the IR group, the IR/SFN group had orderly arranged muscle fibers, decreased collagen fibers, and infiltration of inflammatory cells. In addition, compared with the control group, the expression of oxidative stress-related indexes was significantly increased, accompanied by activation of the transforming growth factor (TGF-β)/Smad pathway and its downstream fibrogenic molecules in the skeletal muscle of the IR group. After SFN intervention, the above indices were significantly restored. Furthermore, SFN induced the upregulation of Nrf2, activation of AKT, and inhibition of GSK-3β and Fyn accumulation. These results revealed that Nrf2 plays a central role in protecting against RIMF. Furthermore, SFN prevents RIMF by activating Nrf2 via the AKT/GSK-3β/Fyn pathway.


Antimycin inhibition as a probe of mitochondrial function in isolated rat hepatocytes. Effects of chronic ethanol consumption.
Previous studies have established that hepatic mitochondria and submitochondrial particles from rats, fed ethanol chronically, display diminished respiratory activities and alterations in the contents of specific electron transfer chain components. The latter include a decrease of about 50% in cytochrome b content. Titrations of respiratory activity in submitochondrial particles with antimycin, a stoichiometric inhibitor of electron flow through the cytochrome b-c1 region of the respiratory chain, indicated a comparable decrease (35%) in the amount of antimycin required to elicit maximal inhibition ('titer') after chronic ethanol treatment. Measurements of antimycin binding to submitochondrial particles by fluorescence quenching demonstrated a similar diminution in the number of tight binding sites per mg protein. By contrast, hepatocytes isolated from control and ethanol-fed rats exhibited nearly identical rates of oxygen utilization under a variety of conditions. However, antimycin titrations of respiratory activity in isolated hepatocytes revealed a 60% decrease in the antimycin titer, but no change in the maximal extent of inhibition after chronic ethanol treatment. Direct measurements of cytochrome b which could be reduced in the presence of antimycin in hepatocytes confirmed a comparable decrease (42%) after chronic ethanol treatment. The results demonstrate that molecular alterations in the cytochrome b region of the respiratory chain caused by ethanol feeding are present in intact liver cells, but suggest that substrate accessibility, rather than the respiratory chain, limits the rate of oxygen utilization in isolated hepatocytes. The data also suggest that mitochondria account for at least 80% of total oxygen utilization by liver cells from both control and ethanol-fed rats.


Clinicopathologic features, tumor immune microenvironment and genomic landscape of Epstein-Barr virus-associated intrahepatic cholangiocarcinoma.
Little is known about Epstein-Barr virus (EBV)-associated intrahepatic cholangiocarcinoma (EBVaICC) because of its rarity. We aimed to comprehensively investigate the clinicopathology, tumor immune microenvironment (TIME) and genomic landscape of this entity in southern China. We evaluated 303 intrahepatic cholangiocarcinomas (ICCs) using in situ hybridization for EBV. We compared clinicopathological parameters between EBVaICC and nonEBVaICC, and we analyzed EBV infection status, tumor-infiltrating lymphocytes (TILs) and genomic features of EBVaICC by immunohistochemistry, double staining, nested PCR, multiplex immunofluorescence staining, fluorescence in situ hybridization and whole-exome sequencing. EBVaICC accounted for 6.6% of ICCs and was associated with EBV latency type I infection and clonal EBV isolates. Patients with EBVaICC were more often female and younger, with solitary tumors, higher HBV infection rates and less frequent cirrhosis; the lymphoepithelioma-like (LEL) subtype was more common in EBVaICC. EBVaICC was associated with a significantly larger TIME component than nonEBVaICC. The LEL subtype of EBVaICC - associated with a significantly increased density and proportion of CD20+ B cells and CD8+ T cells - was associated with significantly higher 2-year survival rates than conventional EBVaICC and nonEBVaICC. Both PD-1 and PD-L1 in TILs, and PD-L1 in tumor cells, were overexpressed in EBVaICC. High PD-L1 expression in tumor cells and high CD8+ TIL densities were significantly more common in EBVaICC than in nonEBVaICC. Seven genes (MUC4, DNAH1, GLI2, LIPE, MYH7, RP11-766F14.2 and WDR36) were mutated in at least 3 patients. EBVaICC had a different mutational pattern to liver fluke-associated cholangiocarcinoma and HBV-associated ICC. EBVaICC, as a subset of ICC, has unique etiological, clinicopathological and genetic characteristics, with a significantly larger TIME component. Paradoxically, patients with EBVaICC could be candidates for immune checkpoint therapy. Epstein-Barr virus (EBV) is associated with a subtype of intrahepatic cholangiocarcinoma, with unique clinicopathological and genetic characteristics. The tumor immune microenvironment is also different in this tumor subtype and patients with EBV-associated intrahepatic cholangiocarcinoma may respond well to immune checkpoint inhibitors.


In vivo imaging of IFT in Chlamydomonas flagella.
Intraflagellar transport (IFT) is a specialized intracellular transport which is required for the assembly and maintenance of cilia and eukaryotic flagella. IFT protein particles move bidirectionally along the flagella in the space between the flagellar membrane and the axonemal doublets. The particles consist of more than 20 different polypeptides and are transported by kinesin-2 from the cell body to the flagellar tip and by cytoplasmic dynein back to the cell body. Chlamydomonas reinhardtii is unique in that IFT can be visualized by two distinct microscopic approaches: differential interference contrast (DIC) and tracking of fluorescently tagged IFT proteins. In vivo imaging of IFT is critical to determine, for example, the role of individual proteins in the IFT pathway and how flagellar proteins are transported by IFT. Here, the microscopic requirements and the procedures for the imaging of IFT by DIC and by total internal reflection fluorescence microscopy will be described. Kymograms, graphical representations of spatial position over time, provide a convenient way to analyze in vivo recordings of IFT. In the future, multicolor in vivo imaging of IFT and its cargoes will be used to understand how flagella are assembled, maintained, and repaired.


A DFT study on the adsorption and dissociation of N-Nitrosodimethylamine on a Ni8 nanocluster.
N-Nitrosodimethylamine (NDMA, ONN(CH3)2) is a highly potent carcinogenic investigated by health authorities in some countries. In this manuscript, density functional theory (DFT) is applied to study the NDMA molecular and dissociative adsorption on a Ni8 nanocluster. Molecular adsorption is two times stronger than the NDMA adsorption on the Ni{111} surface. NDMA dissociative adsorption is found more stable than molecular adsorption by ≈1 eV. To dissociate the NDMA molecule into O and NN(CH3)2 fragments, an activation energy is calculated in 0.954 and 0.810 eV from the two most stable molecular configurations. However, to dissociate the NDMA molecule into ON and N(CH3)2 fragments, a smaller activation energy of 0.654 eV is calculated. With the inclusion of the London dispersion forces (optB88-vdW functional), NDMA molecular interactions are a bit stronger. However, the activation energies are slightly smaller. Meta-GGA functional SCAN has also, been applied. The inclusion of the implicit solvation model displays a NDMA weaker interaction with the Ni8 nanocluster. Dissociative adsorption is more stable than molecular adsorption, but the energy difference is a bit smaller, ≈0.850 eV. Present results show that the Ni8 nanoclusters are promising catalysts to NDMA elimination from water.


Protracted febrile myalgia in a patient with Familial Mediterranean Fever and Ankylosing Spondylitis.
Protracted Febrile Myalgia is a rare form of vasculitis that is diagnosed in patients with Familial Mediterranean Fever. To present a case with Familial Mediterranean and Anklosing Spondylitis on anti-TNF therapy for three years, who developed protracted febrile myalgia syndrome. Case report. A 35-year-old woman with known Familial Mediterranean Fever and Anklosing Spondylitis for 3 years presented with fever, diarrhea, intermittent abdominal pain and severe diffuse muscular pain lasting for two weeks. The patient was investigated for any infection focus. The patient was diagnosed as having Protracted Febrile Myalgia four weeks after the onset of the symptoms. Prednisolone 1 mg/kg per day was applied. Her fever and muscle pain resolved within 48 hours. The coexisting Ankylosing Spondylitis disease and the use of anti-TNF treatment in patients with Familial Mediterranean Fever could be a confounding factor for the investigation of fever. Steroid therapy has a dramatic response.


Dose-response relationship of pulmonary disorders by inhalation exposure to cross-linked water-soluble acrylic acid polymers in F344 rats.
In Japan, six workers handling cross-linked water-soluble acrylic acid polymer (CWAAP) at a chemical plant suffered from lung diseases, including fibrosis, interstitial pneumonia, emphysema, and pneumothorax. We recently demonstrated that inhalation of CWAAP-A, one type of CWAAP, causes pulmonary disorders in rats. It is important to investigate dose-response relationships and recoverability from exposure to CWAAPs for establishing occupational health guidelines, such as setting threshold limit value for CWAAPs in the workplace. Male and female F344 rats were exposed to 0.3, 1, 3, or 10 mg/m3 CWAAP-A for 6 h/day, 5 days/week for 13 weeks using a whole-body inhalation exposure system. At 1 h, 4 weeks, and 13 weeks after the last exposure the rats were euthanized and blood, bronchoalveolar lavage fluid, and all tissues including lungs and mediastinal lymph nodes were collected and subjected to biological and histopathological analyses. In a second experiment, male rats were pre-treated with clodronate liposome or polymorphonuclear leukocyte-neutralizing antibody to deplete macrophages or neutrophils, respectively, and exposed to CWAAP-A for 6 h/day for 2 days. CWAAP-A exposure damaged only the alveoli. The lowest observed adverse effect concentration (LOAEC) was 1 mg/m3 and the no observed adverse effect concentration (NOAEC) was 0.3 mg/m3. Rats of both sexes were able to recover from the tissue damage caused by 13 weeks exposure to 1 mg/m3 CWAAP-A. In contrast, tissue damage caused by exposure to 3 and 10 mg/m3 was irreversible due to the development of interstitial lung lesions. There was a gender difference in the recovery from CWAAP-A induced pulmonary disorders, with females recovering less than males. Finally, acute lung effects caused by CWAAP-A were significantly reduced by depletion of alveolar macrophages. Pulmonary damage caused by inhalation exposure to CWAAP-A was dose-dependent, specific to the lung and lymph nodes, and acute lung damage was ameliorated by depleting macrophages in the lungs. CWAAP-A had both a LOAEC and a NOAEC, and tissue damage caused by exposure to 1 mg/m3 CWAAP-A was reversible: recovery in female rats was less than for males. These findings indicate that concentration limits for CWAAPs in the workplace can be determined.