An Echo of Consciousness: Brain Function During Preferred Music.
Background: Given its emotional and autobiographical properties, music appears as a potential aid in diagnostic assessment and therapeutics in patients with disorders of consciousness (DOCs). Several studies have shown boosting effects on behavior and brain functioning when patients were exposed to (their preferred) music. Objective: The aim of this study was to investigate if these effects on the brain's spontaneous activity are dependent on the level of consciousness. Methods: Nine postcomatose patients and eight healthy control subjects were assessed using functional magnetic resonance imaging in two conditions: rest (without stimulation) and music. All patients presented at least an auditory startle, thereby suggesting the presence of residual auditory function. A gradient of consciousness (from unresponsive wakefulness syndrome to healthy subjects) was formulated to evaluate consciousness-level-dependent increases in brain activity and connectivity. Network-based functional connectivity assessed auditory, default-mode, frontoparietal, and music-evoked emotion networks. Furthermore, exploratory voxel-to-voxel analyses were performed at the whole brain level using intrinsic connectivity contrast and (fractional) amplitude of low-frequency fluctuations. Results: Stronger consciousness-level-dependent increases within network-to-voxel analysis of connectivity were found in the frontoparietal network with the precuneus during music stimulation compared with rest. Voxel-to-voxel analyses showed stronger increases of intrinsic connectivity in the music condition compared with rest in regions previously related to music processing. There were consistently more regions with increased connectivity during the main effect of music compared with rest. These increases of connectivity during music were observed in brain regions involved in consciousness, language, emotion, and memory processing. Conclusions: Our results show that music seems to trigger more substantial connectivity changes compared with rest, pointing toward the potential ability of music to stimulate patients' brain function. Further research should focus on effects of music in general, its specific acoustical features, and the effects of simple auditory stimuli, as well as the possible therapeutic and diagnostic effects of music in well-controlled clinical trials. Impact statement Due to its emotional and autobiographical properties, music is a particularly salient stimulus. A few studies using musical stimuli have shown promising results in terms of behavioral responsiveness in patients with disorders of consciousness (Magee, 2005; Raglio et al., 2014; Verger et al., 2014). Our study confirms the presence of a beneficial effect of music on brain connectivity in these severely brain-injured patients, which moreover seems to be dependent on the level of consciousness. Our findings therefore strengthen the hypothesis that music could play a role from a diagnostic and therapeutic standpoint in this population, paving the way for future well-controlled clinical trials.


SLIPMAT: A pipeline for extracting tissue-specific spectral profiles from 1H MR spectroscopic imaging data.
1H Magnetic Resonance Spectroscopy (MRS) is an important non-invasive tool for measuring brain metabolism, with numerous applications in the neuroscientific and clinical domains. In this work we present a new analysis pipeline (SLIPMAT), designed to extract high-quality, tissue-specific, spectral profiles from MR spectroscopic imaging data (MRSI). Spectral decomposition is combined with spatially dependant frequency and phase correction to yield high SNR white and grey matter spectra without partial-volume contamination. A subsequent series of spectral processing steps are applied to reduce unwanted spectral variation, such as baseline correction and linewidth matching, before direct spectral analysis with machine learning and traditional statistical methods. The method is validated using a 2D semi-LASER MRSI sequence, with a 5-minute duration, from data acquired in triplicate across 8 healthy participants. Reliable spectral profiles are confirmed with principal component analysis, revealing the importance of total-choline and scyllo-inositol levels in distinguishing between individuals - in good agreement with our previous work. Furthermore, since the method allows the simultaneous measurement of metabolites in grey and white matter, we show the strong discriminative value of these metabolites in both tissue types for the first time. In conclusion, we present a novel and time efficient MRSI acquisition and processing pipeline, capable of detecting reliable neuro-metabolic differences between healthy individuals, and suitable for the sensitive neurometabolic profiling of in-vivo brain tissue.


Egg polymorphism of Schistosoma bovis.
A study of the egg morphology of Schistosoma bovis from Sudan and Spain revealed some differences in the size and shape of eggs depending on the method of their sampling. The size of eggs (especially the length) tended to increase in the following order: those recovered from the worm uterus smaller than those recovered from the liver and from the faeces of mice for both strains. The shape of eggs from the host faeces (the typical ones) and from the distal portion of the worm uterus for both strains tended to be homogeneous whereas those from the host liver were more heterogeneous. A comparison between the eggs of the two strains showed a great similarity in spite of their distant geographical origins; only the length of the eggs collected from the distal part of the worm uterus and those from the host faeces showed a significant difference at a 99% confidence limit.


Naringenin is a Potential Immunomodulator for Inhibiting Liver Fibrosis by Inhibiting the cGAS-STING Pathway.
Naringenin is an anti-inflammatory flavonoid that has been studied in chronic liver disease. The mechanism specific to its antifibrosis activity needs further investigation This study was to focused on the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) pathway in hepatic stellate cells and clarified the antifibrosis mechanism of naringenin. The relationship between the cGAS-stimulator of interferon genes (STING) pathway and liver fibrosis was analyzed using the Gene Expression Omnibus database. Histopathology, immunohistochemistry, fluorescence staining, Western blotting and polymerase chain reaction were performed to assess gene and protein expression levels associated with the cGAS pathway in clinical liver tissue samples and mouse livers. Molecular docking was performed to evaluate the relationship between naringenin and cGAS, and western blotting was performed to study the expression of inflammatory factors downstream of cGAS in vitro. Clinical database analyses showed that the cGAS-STING pathway is involved in the occurrence of chronic liver disease. Naringenin ameliorated liver injury and liver fibrosis, decreased collagen deposition and cGAS expression, and inhibited inflammation in carbon tetrachloride (CCl4)-treated mice. Molecular docking found that cGAS may be a direct target of naringenin. Consistent with the in vivo results, we verified the inhibitory effect of naringenin on activated hepatic stellate cells (HSCs). By using the cGAS-specific agonist double-stranded (ds)DNA, we showed that naringenin attenuated the activation of cGAS and its inflammatory factors affected by dsDNA. We verified that naringenin inhibited the cGAS-STING pathway, thereby reducing the secretion of inflammatory factors by HSCs to ameliorate liver fibrosis. Interrupting the cGAS-STING pathway helped reverse the fibrosis process. Naringenin has potential as an antihepatic fibrosis drug.


Brief Report: Potent clinical and radiological response to larotrectinib in TRK fusion-driven high-grade glioma.
Genes encoding TRK are oncogenic drivers in multiple tumour types including infantile fibrosarcoma, papillary thyroid cancer and high-grade gliomas (HGG). TRK fusions have a critical role in tumourigenesis in 40% of infant HGG. Here we report the first case of a TRK fusion-driven HGG treated with larotrectinib-the first selective pan-TRK inhibitor in clinical development. This 3-year-old girl had failed multiple therapies including chemotherapy and radiotherapy. Tumour profiling confirmed an ETV6-NTRK3 fusion. Treatment with larotrectinib led to rapid clinical improvement with near total resolution of primary and metastatic lesions on MRI imaging. This is the first report of a TRK fusion glioma successfully treated with a TRK inhibitor.


Development of a radioimmunoassay for [DES-ARG9]-bradykinin.
Antisera to [des-Arg9]-bradykinin were elicited in rabbits immunized with the peptide conjugated to thyroglobulin and/or ovalbumin. Sera were screened for the presence of antibody with three radioactive antigens, mono-125I-labeled derivatives of [Tyr1, des-Arg]-kallidin, [Tyr, des-Arg]-bradykinin, and [Tyr, des-Arg]-bradykinin that were prepared by treating mono-125I-labeled [Tyr]-kallidin, [Tyr]-bradykinin, and [Tyr]-bradykinin with carboxypeptidase B. Of the six animals immunized, five produced antibodies to [des-Arg]-bradykinin as evidenced by the ability of their sera to bind at least 33% of the added radioactivity at a final dilution of 1:500. Sensitivity and specificity studies were performed with each labeled antigen and a dilution of antiserum that bound 30-50% of the radioactivity. The best labeled antigen-antibody combination, with respect to titer, sensitivity, and specificity was obtained with [mono-125I-Tyr, des Arg]-bradykinin and serum from a rabbit immunized with [des-Arg]-bradykinin conjugated to ovalbumin with toluene diisocyanate. The lowest concentration of [des-Arg]-bradykinin inhibiting 50% of this radioactive antigen binding was 0.23 ng/ml and the lowest concentration which could be distinguished from no [des-Arg]-bradykinin added was 67 pg/ml. This antiserum cross-reacts with bradykinin and lysyl-bradykinin about 9% but not with methionyl-lysyl-bradykinin.


Palladium(II) catalyzed site-selective C-H olefination of imidazo[1,2-a]pyridines.
Herein, we disclose an efficient Pd(II)-catalyzed site selective C8 alkenylation of imidazo[1,2-a]pyridines with electronically biased olefinic substrates. Notably, besides the presence of four C-H sites available, selective mono-alkenylation was achieved by N-chelation overriding O-chelation. The versatility and scalability of the catalysis enabled the selective late-stage functionalization of a marketed drug, zolimidine. Various substituted heteroaryl alkenes can be afforded with moderate to good yields with high C8 regioselectivity.


Spontaneous healing of Mohs wounds of the cheek: a cosmetic assessment.
Facial defects after Mohs surgery may be closed at the time of surgery, shortly thereafter, or allowed to heal spontaneously. Selection of appropriate management options requires accurate prediction of the final cosmetic result. To determine the relative merits of treatment options for facial defects resulting from Mohs surgery. We prospectively and retrospectively analyzed outcomes for 132 wounds of the cheek resulting from Mohs surgery and allowed to heal spontaneously. The cheek was delineated into topographic areas and the wound location, size, and depth were recorded. Patients were observed intermittently, and a final evaluation of cosmesis was made after > or = 6 months. Most wounds in the nasolabial fold and preauricular areas healed with excellent results and half the wounds in the medial area of the cheek healed with good or excellent results. Central and mandibular areas of the cheek healed unpredictably, and results were unsatisfactory for most of these wounds. Final cosmetic results of Mohs surgery in the cheek area can be predicted on the basis of location, size, and depth of the wound, enabling physicians to knowledgeably select the most suitable treatment option.


Robust derivation of transplantable dopamine neurons from human pluripotent stem cells by timed retinoic acid delivery.
Stem cell therapies for Parkinson's disease (PD) have entered first-in-human clinical trials using a set of technically related methods to produce mesencephalic dopamine (mDA) neurons from human pluripotent stem cells (hPSCs). Here, we outline an approach for high-yield derivation of mDA neurons that principally differs from alternative technologies by utilizing retinoic acid (RA) signaling, instead of WNT and FGF8 signaling, to specify mesencephalic fate. Unlike most morphogen signals, where precise concentration determines cell fate, it is the duration of RA exposure that is the key-parameter for mesencephalic specification. This concentration-insensitive patterning approach provides robustness and reduces the need for protocol-adjustments between hPSC-lines. RA-specified progenitors promptly differentiate into functional mDA neurons in vitro, and successfully engraft and relieve motor deficits after transplantation in a rat PD model. Our study provides a potential alternative route for cell therapy and disease modelling that due to its robustness could be particularly expedient when use of autologous- or immunologically matched cells is considered.


An evaluation of the implementation of interventions to reduce postoperative infections and optimise antibiotic use across the surgical pathway in India: a mixed-methods exploratory study protocol.
Postoperative infections represent a significant burden of disease, demanding antibiotic prescriptions, and are contributing to antimicrobial resistance. The burden of infection as a surgical complication is greater in low- and middle-income countries (LMICs). We report the protocol of a pilot study for the co-design, implementation and evaluation of two infection prevention and control (IPC) and antimicrobial stewardship (AMS) interventions across the surgical pathway in a teaching hospital in India. The two interventions developed following in-depth qualitative enquiry are (i) surveillance and feedback of postoperative infections to optimise the use of antibiotics in two surgical departments (gastrointestinal and cardiovascular and thoracic surgery) and (ii) raising awareness amongst patients, carers and members of public about IPC and AMS. We will conduct a prospective study, formatively evaluating the implementation process of delivering the two co-designed interventions using implementation science frameworks. The study will systematically assess the context of intervention delivery, so that implementation support for the interventions may be adapted to the needs of stakeholders throughout the study. Analysis of implementation logs and interviews with stakeholders upon completion of the implementation period, will offer insights into the perceived acceptability, appropriateness, feasibility and sustainability of the interventions and their implementation support. Implementation costs will be captured descriptively. Feasibility of clinical data collection to investigate effectiveness of interventions will also be assessed for a future larger study. Thematic framework analysis and descriptive statistics will be used to report the qualitative and quantitative data, respectively. • The paired interventions have been co-designed from their inception with involvement of stakeholders at different stages in the surgical pathway. • Simultaneous evaluation of implementation and clinical outcomes will inform the development of a future larger study to enable/assess the scalability of interventions • The study offers a novel combination of implementation theory-informed, stakeholder-driven and clinically relevant evaluation, carried out in the context of a middle-income country hospital. • The project may not be applicable to every low-resource setting and surgical context due to differences in healthcare systems and cultures. However, the application of implementation science concepts may facilitate transferability and adaptation to other settings.


Long-term depot maintenance of chronic schizophrenic out-patients: the seven year follow-up of the Medical Research Council fluphenazine/placebo trial. II. The incidence of compliance problems, side-effects, neurotic symptoms and depression.
Seven years after the completion of the original trial, over 73% of patients were maintained on depot neuroleptics, and 70% had received such medication for over seven years. About 40% had presented with a problem of compliance at some time, and there was a significant correlation between poor compliance and in-patient admissions and schizophrenic relapses. The prevalence of parkinsonian side-effects, akathisia, and tardive dyskinesia was low. Non-psychotic symptoms were common, even in the absence of acute psychosis. Depression was found in a subgroup of patients; it was frequently reported as an indication for admission during follow-up period, and seemed to be part of the schizophrenic illness rather than a result of antipsychotic drug treatment.


Assessing the effect of the Queensland "Summer of Disasters" on perceptions of collective efficacy.
The collective efficacy literature suggests that neighborhoods with higher collective efficacy have fewer problems of disorder, increased volunteerism, and higher levels of life satisfaction and wellbeing, along with the increased potential for resilience in the face of a disaster. Although perceptions of collective efficacy typically remain stable over time, rapid or sudden social change, such as experiencing a natural disaster, has the potential to disrupt the neighborhood and the individuals within - including their perceptions of the regulatory mechanisms of collective efficacy. Still, the effect of a major disaster on perceptions of collective efficacy remains relatively unexamined. Longitudinal survey data collected before and after the Queensland flood and cyclone disasters permit a unique investigation of the impact of the disaster on perceptions of social control and social cohesion before and after the disaster. Results show that after this major natural disaster, respondents who were proximately affected reported decreased levels of collective efficacy. Also, persons who experienced the biggest decrease in perceived collective efficacy were those that had lower levels of collective efficacy prior to the disaster. We discuss the mechanisms surrounding disaster preparedness, response, and recovery that may contribute to changing perceptions of collective efficacy.


A pilot ontological model of public health indicators.
There are various public health databases in the world aiming to provide data to compare health conditions in different countries. Their data sets are more or less overlapping but data from different databases and different countries are hard to compare due to different definitions and interpretations. Our aim was to create a core ontological model that is able to represent public health indicators. We assumed, that by such representation comparability and quality of data could be improved. Three sets of indicators were taken, and a core ontology was built from information objects describing their top level entities. The Protégé ontology editor with RDF backend was used for building the ontology. The used indicator sets were the indicators of the Health for All Database of the World Health Organisation (HFA), the OECD Health Data, and the set of indicators proposed by the European Community Health Indicators (ECHI) European project. Then 19 indicators selected from HFA was represented using the core ontology. Strength and weaknesses of the descriptive capability of the model was studied. The drafted core model seems to be useful in representing many of the public health indicators. In some cases it really helps improve comparability. However, some of the semantic details cannot be sufficiently expressed by the used ontology representation language. There is a need of merging other domain ontologies to represent indicators related to other domains, such as economy, social and environmental sciences.


The Association of Soft Drink Consumption and the 24-Hour Movement Guidelines with Suicidality among Adolescents of the United States.
Evidence is lacking for the association of the behaviors of the 24 h movement guidelines including sleep duration, physical activity, screen time, and soft drink consumption with suicidality among adolescents. Data were extracted from a national representative sample of Youth Risk Behavior Surveys (YRBS) in the United States from 2011 to 2019. Binary logistic regression models with complex sampling designs were used to explore the association of the recommendations of the 24 h movement guidelines and soft drink consumption with suicidality. The total prevalence of suicidal ideation, suicide plan, suicide attempt, and suicide attempt with medical treatment was higher among adolescents who did not meet all the recommendations in the 24 h movement guidelines and had a higher level of soft drink consumption. Totally, not meeting all the recommendations of the 24 h movement guidelines was significantly associated with an increased risk of suicidal ideation (OR: 1.69, 95% CI: 1.30-2.19) and suicide plan (OR: 1.76, 95% CI: 1.34-2.33) compared with adolescents who meet all the recommendations. Soft drink consumption of ≥3 times/day was associated with an increased risk of suicidality including suicidal ideation, suicide plan, suicide attempt, and suicide attempt with medical treatment, regardless of sex. Soft drink consumption of ≥3 times/day was significantly associated with an increased risk of suicide attempt and suicide attempt with medical treatment, regardless of whether the recommendations of physical activity, screen time, and sleep duration were met. Age-appropriate sleep duration, no more than 2 h of screen time per day, at least 1 h of physical activity per day as contained in the 24 h movement guidelines and less than one soft drink consumption per day are good targets to prevent involvement in suicidality. More actions for intervening in the movement and dietary behaviors among adolescents are needed to maintain physical and mental health.


Giant cell tumor of the temporal bone--a case report.
Giant cell tumor is a benign but locally aggressive bone neoplasm which uncommonly involves the skull. The petrous portion of the temporal bone forms a rare location for this tumor. The authors report a case of a large giant cell tumor involving the petrous and squamous portions of the temporal bone in a 26 year old male patient. He presented with right side severe hearing loss and facial paresis. Radical excision of the tumor was achieved but facial palsy could not be avoided. Radical excision of skull base giant cell tumor may be hazardous but if achieved is the optimal treatment and may be curative.


Surgical treatment of thoracic aneurysm in a hemodialysis-dependent patient: a case report.
A 53-year-old woman who was on hemodialysis underwent the resection of an aneurysm of the descending thoracic aorta as well as graft replacement. The operation was performed with the aid of femoro-femoral bypass perfusion and an artificial kidney inserted on the venous side of bypass line. Although the perfusion time was short, the uremic metabolic substance was efficiently removed, resulting in easy management after surgery.


Development of immunity in early life.
The immune system in early life goes through rapid and radical changes. Early life is also the period with the highest risk of infections. The foetal immune system is programmed to coexist with foreign antigenic influences in utero, and postnatally to rapidly develop a functional system capable of distinguishing helpful microbes from harmful pathogens. Both host genetics and environmental influences shape this dramatic transition and direct the trajectory of the developing immune system into early childhood and beyond. Given the malleability of the immune system in early life, interventions aimed at modulating this trajectory thus have the potential to translate into considerable reductions in infectious disease burden with immediate as well as long-lasting benefit. However, an improved understanding of the underlying molecular drivers of early life immunity is prerequisite to optimise such interventions and transform the window of early life vulnerability into one of opportunity.


Cardiovascular risk in patients with bipolar disorder.
To date, little is known about cardiovascular risk (CVR) in terms of coronary heart disease (CHD) and cardiovascular mortality risk (CMR) in patients with bipolar disorder. This study provides data on the overall risk of any fatal or non-fatal coronary heart disease (CHD) and on the cardiovascular mortality risk (CMR) within 10 years in these patients. Naturalistic, cross-sectional, multicenter study conducted in Spain. Patients were evaluated for cardiovascular risk using the Framinghan function (CHD) and the Systematic COronary Risk Evaluation (SCORE) function (CMR). The mean age was 46.6 years and 49% were male. Forty-six percent were in remission. Ten-year CHD risk was 7.6% (males 10.2% versus females 4.7%, p<0.001) and 10-year CMR was 1.8% (males 2.2% versus females 1.3%, p 0.161). Fifty-one percent smoked and 34% was obese. Metabolic syndrome was present in 22.4% of the sample (35.6% according to AHA and NHLBI criteria). Cardiovascular risk significantly increases with age, body mass index and presence of metabolic syndrome. The cross-sectional design of the study. Cardiovascular risk is high in patients with bipolar disorder. It is associated with age, body mass index and metabolic syndrome. Psychiatrists should be aware of this issue and carefully monitor these patients for cardiovascular risk factors, including cigarette smoking, as part of the standard of care when treating them.


Intestinal immune activation in juvenile idiopathic arthritis and connective tissue disease.
To examine the prevalence of immune activation in gastrointestinal (GI) mucosa in children with juvenile idiopathic arthritis (JIA) or connective tissue disease (CTD). We studied 27 children (15 girls, mean age 9.8+/-4.8 years) with JIA/CTD and GI symptoms, including nine with oligoarthritis, nine with polyarthritis, two with systemic arthritis, three with enthesitis-related arthritis, and four with various CTDs. The control group consists of 54 children (31 girls, mean age 11.3+/-6.3 years) with GI symptoms but shown to have no significant GI or rheumatoid disorder. The subjects were examined by gastroduodenoscopy (22 patients, 50 controls) and colonoscopy (23 patients, 16 controls). Intraepithelial CD3+, alpha/beta+, and gamma/delta+ lymphocytes were counted from duodenal and ileal biopsies. Five patients with JIA/CTD (19%) had ulcerative colitis. Lymphoid nodular hyperplasia (LNH) was more common in the patients [74% (20/27)] than in the controls [16% (8/50), p = 0.001], as well in the duodenal bulb [29% (7/24) vs. 10% (5/50)], terminal ileum [74% (14/19) vs. 38% (5/13)], and the colon [50% (11/22) vs. 14% (2/14)]. In the duodenum, CD3, alpha/beta+, and gamma/delta+ lymphocytes counts were higher in JIA/CTD (p<0.05). In the ileum, gamma/delta+ cell numbers had increased in JIA/CTD (p<0.05). Either LNH, increased gamma/delta+ count, or both were more common in JIA/CTD [89% (24/27)] than in the controls [13% (7/54), p<0.0001]. The majority of children suffering from JIA or CTD with GI symptoms show abnormalities consistent with activation of the intestinal immune system. The aetiology of this reaction remains unknown, but similar features are seen in delayed-type food allergy.


Echinophilic proteins stomatin, sorcin, and synexin locate outside gangliosideM1 (GM1) patches in the erythrocyte membrane.
The detergent (Triton X-100, 4°C)-resistant membrane (DRM)-associated membrane proteins stomatin, sorcin, and synexin (anexin VII) exposed on the cytoplasmic side of membrane were investigated for their lateral distribution in relation to induced ganglioside(M1) (GM1) raft patches in flat (discocytic) and curved (echinocytic) human erythrocyte membrane. In discocytes, no accumulation of stomatin, sorcin, and synexin in cholera toxin subunit B (CTB) plus anti-CTB-induced GM1 patches was detected by fluorescence microscopy. In echinocytes, stomatin, sorcin, and synexin showed a similar curvature-dependent lateral distribution as GM1 patches by accumulating to spiculae induced by ionophore A23187 plus calcium. Stomatin was partly and synexin and sorcin were fully recruited to the spiculae. However, the DRM-associated proteins only partially co-localized with GM1 and were frequently distributed into different spiculae than GM1. The study indicates that stomatin, sorcin, and synexin are echinophilic membrane components that mainly locate outside GM1 rafts in the human erythrocyte membrane. Echinophilicity is suggested to contribute to the DRM association of a membrane component in general.


A role for cytokines in antigen presentation: IL-1 and IL-4 induce accessory functions of antigen-presenting cells.
Fixation of APC with 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide (ECDI) eliminates their ability to stimulate proliferation of alloreactive T cells or the D10 T cell clone, although a partial response, IL-4 production, was measured. However, if APC were activated before fixation, they could be ECDI-fixed and retain the ability to induce T cell proliferation. IL-1, IL-4 or LPS were capable of activating APC in this way, whereas IFN-gamma was not. This activation step occurred in 6 h, required protein synthesis, and was distinct from increases in Ia or IL-1. This suggests resting APC lack structures that are essential for inducing T cell proliferation.


Evaluation of a randomized controlled trial on the effect on return to work with coaching combined with light therapy and pulsed electromagnetic field therapy for workers with work-related chronic stress.
Chronic work-related stress is quite prevalent in the working population and is in some cases accompanied by long-term sick leave. These stress complaints highly impact employees and are costly due to lost productivity and medical expenses. A new treatment platform with light therapy plus Pulsed Electro Magnetic Fields (PEMF) in combination with coaching was used to assess whether more positive effects on return to work, stress, work-related fatigue, and quality of life could be induced compared to coaching alone. A placebo-controlled trial was executed after inclusion of 96 workers, aged 18-65 with work-related chronic stress complaints and who were on sick leave (either part-time or full-time). Participants were divided into three arms at random. Group 1 (n = 28) received the treatment and coaching (Intervention group), group 2 (n = 28) received the treatment with the device turned off and coaching (Placebo group) and group 3 (n = 28) received coaching only (Control group). The data were collected at baseline, and after 6, 12 and 24 weeks. The primary outcome was % return to work, and secondary outcomes were work-related fatigue (emotional exhaustion and need for recovery after work), stress (distress and hair cortisol), and quality of life (SF-36 dimensions: vitality, emotional role limitation, and social functioning). Eighty-four workers completed all measurements, 28 in each group. All groups improved significantly over time in the level of return to work, as well as on all secondary outcomes. No statistical differences between the three groups were found either on the primary outcome or on any of the secondary outcomes. Light therapy with Pulsed Electro Magnetic Fields PEMF therapy has no additional effect on return to work, stress, fatigue, and quality of live compared to coaching alone. NTR4794 , registration date: 18-sep-2014.


A comparative study of psychopathology in Greek adolescents in Germany and in Greece in 1980 and 1998--18 years apart.
In the 1980s, we assessed Greek adolescents living in Germany and Greek adolescents living in Greece. Data from this earlier study supported the hypothesis of selective migration with higher psychopathology self-rating scores in Greek adolescents in Greece as compared to Greek adolescents in Germany. The current study uses the same design and instruments so that the comparison of the mental health of populations in the same areas, almost two decades apart, becomes possible. In 1980, a total of 2631 Greek adolescents were assessed in Munich, Germany or Veria, Greece. In 1998, 2920 Greek adolescents were assessed in Munich, Germany and Veria, Greece. The General Health Questionnaire (GHQ-28) was used to assess mental health status at both times. 1) GHQ-28 scores showed a significant increase from 1980 to 1998 in both locations. 2) While in 1980, Greeks in Veria, Greece had higher psychopathology scores than Greek adolescents in Munich, Germany, this (with the exception of depression) was no longer true for 1998. 3) At both times and both locations adolescent girls scored higher in the GHQ-28 than adolescent boys. While the 1980 data supported the selective migration hypothesis, this was no longer true for the 1998 data. The increase in psychopathology in both locations is alarming and deserves further exploration.


Aurora kinase A inhibition induces synthetic lethality in SMAD4-deficient colorectal cancer cells via spindle assembly checkpoint activation.
SMAD4 loss-of-function mutations have been frequently observed in colorectal cancer (CRC) and are recognized as a drug target for therapeutic exploitation. In this study, we performed a synthetic lethal drug screening with SMAD4-isogenic CRC cells and found that aurora kinase A (AURKA) inhibition is synthetic lethal with SMAD4 loss. Inhibition of AURKA selectively inhibited the growth of SMAD4-/- CRC in vitro and in vivo. Mechanistically, SMAD4 negatively regulated AURKA level, resulting in the significant elevation of AURKA in SMAD4-/- CRC cells. Inhibition of AURKA induced G2/M cell cycle delay in SMAD4+/+ CRC cells, but induced apoptosis in SMAD4-/- CRC cells. We further observed that a high level of AURKA in SMAD4-/- CRC cells led to abnormal mitotic spindles, leading to cellular aneuploidy. Moreover, SMAD4-/- CRC cells expressed high levels of spindle assembly checkpoint (SAC) proteins, suggesting the hyperactivation of SAC. The silencing of key SAC proteins significantly rescued the AURKA inhibition-induced cell death in SMAD4-/- cells, suggesting that SMAD4-/- CRC cells are hyper-dependent on AURKA activity for mitotic exit and survival during SAC hyperactivation. This study presents a unique synthetic lethal interaction between SMAD4 and AURKA and suggests that AURKA could be a potential drug target in SMAD4-deficient CRC.


Drug regulators and ethics: which GCP issues are also ethical issues?
Within the European Union (EU), good clinical practice (GCP) provides an ethical mandate to regulators; however, it is unclear what the content of that mandate is. By looking at the correspondence between GCP and ethical imperatives, we identify that the mandate is within the following: principles; benefit-risk ratio; scientific validity; results publication; informed consent; respect for participants; and special populations. There are also cases when regulations were ethical but were not pairable to an imperative, and when the former were stricter than the latter. Hence, we suggest closer cooperation between ethics committees and regulators to ensure that future versions of ethics guidelines cover the ethically relevant regulations that were not directly pairable to any imperative, and cooperation between GCP legislative bodies and ethics guideline-making bodies to resolve the discordant areas.


The Surgical Lips Deformity Corrected with Hyaluronic Fillers: A Case Report.
Hyaluronic filler is a sterile, biodegradable, viscoelastic, isotonic, transparent injectable gel implant which was approved by Food and Drug Administration (FDA) 1996. It is used for face reconstruction and modelling. We report the case of a 40-year-old Serbian woman who presented after surgery of cleft lip, primary and secondary palate. We performed a biphasic therapy; in the first stage in the zone semimucosis lips is initially carried incision scar tissue. The second stage is placed hyaluronan implant. This case illustrates that, although hyaluronic fillers used mainly for correction of healthy tissue can be successfully used in the treatment of postoperative scars.


Potential for Screening for Pancreatic Exocrine Insufficiency Using the Fecal Elastase-1 Test.
The early diagnosis of pancreatic exocrine insufficiency (PEI) is hindered because many of the functional diagnostic techniques used are expensive and require specialized facilities, which prevent their widespread availability. We have reviewed current evidence in order to compare the utility of these functional diagnostic techniques with the fecal elastase-1 (FE-1) test in the following three scenarios: screening for PEI in patients presenting with symptoms suggestive of pancreatic disease, such as abdominal pain or diarrhea; determining the presence of PEI in patients with an established diagnosis of pancreatic disease, such as chronic pancreatitis or cystic fibrosis; determining exocrine status in disorders not commonly tested for PEI, but which have a known association with this disorder. Evidence suggests the FE-1 test is reliable for the evaluation of pancreatic function in many pancreatic and non-pancreatic disorders. It is non-invasive, is less time-consuming, and is unaffected by pancreatic enzyme replacement therapy. Although it cannot be considered the gold-standard method for the functional diagnosis of PEI, the advantages of the FE-1 test make it a very appropriate test for screening patients who may be at risk of this disorder.


Removal of nonspecific hemagglutination inhibitors, immunoglobulin G, and immunoglobulin A with streptococcal cells and its application to the rubella hemagglutination inhibition test.
A streptococcus, AW 43 strain, was found to bind nonspecific serum inhibitors of rubella virus hemagglutination (HA). This was demonstrated by titration of nonspecific HA inhibitors and by immunoelectrophoresis. Absorption of sera with the mixture of AW 43 cells, which bind IgA in addition to nonspecific HA inhibitors, and AR 1 cells, another strain of streptococci which bind IgG, removed nonspecific HA inhibitors, IgG, and IgA simultaneously, leaving behind IgM and a trace of IgA. Pretreatment of sera with those streptococcal cells prior to the rubella hemagglutination inhibition (HI) test enabled to circumvent kaolin treatment of sera, which partially removes IgM antibodies, and to determine exclusively the early-appearing antibodies. The rise and fall of the HI antibodies thus determined correlated well with that of the IgM antibodies determined by enzyme-linked immunosorbent assay (ELISA). Thus, this modified rubella HI test may be useful for serodiagnosis of recent rubella virus infection.


Protein structure prediction using a combination of sequence-based alignment, constrained energy minimization, and structural alignment.
We present a novel approach to protein structure prediction in which fold recognition techniques are combined with ab initio folding methods. Based on the predicted secondary structure, one of two different protocols is followed. For mostly alpha proteins, global optimization and sampling of a statistical energy function is used to generate many low-energy structures; these structures are then screened against a fold library. Any structural matches are then selected for further refinement. For proteins predicted to have significant beta-content, sequence and secondary structure-based alignment is used to identify candidate templates; spatial constraints are then extracted from these templates and used, along with the statistical energy function, in the global sampling and optimization program. Successes and failures of both protocols are discussed.


Clinical validation of a link between TNF-alpha and the glycosylation enzyme core 2 GlcNAc-T and the relationship of this link to diabetic retinopathy.
Increasing evidence suggests that chronic, subclinical inflammation plays an important role in the pathogenesis of diabetic retinopathy. We recently reported that a glycosylating enzyme, core 2 beta-1,6-N-acetylglucosaminyltransferase (core 2 GlcNAc-T), is implicated in increased leucocyte-endothelial cell adhesion in diabetic retinopathy via an upregulation mechanism controlled by TNF-alpha. We examined the functional link between circulating TNF-alpha and the activity and phosphorylation of core 2 GlcNAc-T in polymorphonuclear leucocytes of patients with type 1 and type 2 diabetes. Plasma levels of TNF-alpha, although similar in patients with type 1 and type 2 diabetes, were significantly higher than in age-matched healthy controls, and correlated well with the severity of retinopathy. Core 2 GlcNAc-T activity followed the same trend and was associated with phosphorylation of the enzyme. Finally, the observation that TNF-alpha levels are also linked to glycaemic values suggests that in patients, as well as in vitro, the glycosylation-mediated cell adhesion process that plays a role in diabetic retinopathy may involve glucose- and TNF-alpha-induced protein kinase beta2 activation, and subsequently raise activity of core 2 GlcNAc-T through increased enzyme phosphorylation. Our results reveal a novel rationale towards a specific treatment of diabetic retinopathy, based on the inhibition of core 2 GlcNAc-T activity and/or the blockage of cognate glycans.


Role of Tropomyosin-related kinase B receptor and brain-derived neurotrophic factor in cancer.
The tropomyosin-related kinase B (TrkB) receptor is a member of the neurotrophic tyrosine kinase receptors family and, together with the brain-derived neurotrophic factor (BDNF), plays an important role in the development of breast cancer, lung cancer, neuroblastoma, colorectal cancer, leukemia, cervical cancer, gallbladder cancer, gastric cancer, kidney cancer, Ewing's sarcoma, esophageal cancer, and head and neck cancer. Overexpression of these two factors has been associated with increased processes involved in carcinogenesis, such as invasion, migration, epithelial-mesenchymal transition (EMT), angiogenesis, metastasis, cell proliferation, resistance to apoptosis, resistance to cell death due to loss of adhesion (anoikis), activation of cell proliferation pathways, regulation of tumor suppressor genes, and drug resistance, and is related to advanced clinical stage. Inhibition of the TrkB/BDNF axis using drugs in phase 1 studies, approved drugs, and small interfering RNA (siRNA) are promising strategies for the treatment of various malignant tumors in addition to increasing the sensitivity of cells resistant to chemotherapy, improving the effectiveness of drugs without increasing toxicity. Another factor related to poor cancer prognosis is the presence of cancer stem cells, having effects similar to the high expression of the TrkB/BDNF axis, on cancer. This review aimed to show the role of the TrkB/BDNF axis in several types of cancer, its possible use as a prognostic biomarker, the effects of inhibiting this axis, and its role in the cancer stem cells.


Structural and fluctuational difference between two ends of Aβ amyloid fibril: MD simulations predict only one end has open conformations.
Aβ amyloid fibrils, which are related to Alzheimer's disease, have a cross-β structure consisting of two β-sheets: β1 and β2. The Aβ peptides are thought to be serially arranged in the same molecular conformation along the fibril axis. However, to understand the amyloid extension mechanism, we must understand the amyloid fibril structure and fluctuation at the fibril end, which has not been revealed to date. Here, we reveal these features by all-atom molecular dynamics (MD) simulations of Aβ42 and Aβ40 fibrils in explicit water. The structure and fluctuation were observed to differ between the two ends. At the even end, the Aβ peptide always took a closed form wherein β1 and β2 were closely spaced. The Aβ peptide fluctuated more at the odd end and took an open form wherein the two β-sheets were well separated. The differences are attributed to the stronger β-sheet formation by the β1 exposed at the even end than the β2 exposed at the odd end. Along with the small fluctuations at the even end, these results explain why the fibril extends from one end only, as observed in experiments. Our MD results agree well with recent observations by high-speed atomic force microscopy.


Rectal prolapse in children.
Rectal prolapse in children is an uncommon clinical entity in western countries. Treatment is generally supportive with surgery reserved for the intractable case. If operative intervention is advised, it should consist of one of several limited procedures that can be safely performed with low morbidity: anal encirclement, presacral packing, sclerosing injection, or linear rectal cauterization.


Lp(a), oxidized phospholipids and oxidation-specific epitopes are increased in subjects with keloid formation.
Keloid formation following trauma or surgery is common among darkly pigmented individuals. Since lipoprotein(a) [Lp(a)] has been postulated to have a putative role in wound healing, and also mediates atherosclerotic cardiovascular disease, it was assessed whether Lp(a), its associated oxidized phospholipids and other oxidation-specific biomarkers were associated with keloid formation. This case-control study included darkly pigmented individuals of African ancestry, 100 with keloid scarring and 100 non-keloid controls. The lipid panel, hsCRP, Lp(a), oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB), IgG and IgM apoB-immune complexes and IgG and IgM autoantibodies to a malondialdehyde mimotope (MDA-mimotope) were measured. Immunohistochemistry of keloid specimens was performed for both Lp(a) and OxPL staining. Cases and controls were well matched for age, sex and lipid profile. Mean Lp(a) (57.8 vs. 44.2 mg/dL; P = 0.01, OxPL-apoB 17.4 vs. 15.7 nmol/L; P = 0.009) and IgG and IgM apoB-immune complexes and IgG and IgM MDA-mimotope levels were significantly higher in keloid cases. Keloid tissue stained strongly for OxPL. Darkly pigmented individuals of African ancestry with keloids have higher plasma levels of Lp(a), OxPL-apoB and oxidation-specific epitopes. The commonality of excessive wound healing in keloids and chronic complications from coronary revascularization suggests avenues of investigation to define a common mechanism driven by Lp(a) and the innate response to oxidized lipids.


Models of integrated care.
This article describes the range of options for integrating medicine and psychiatry, with a focus on the advantages and limitations of each model. The models were developed in different countries with specific health care cultures. This article illustrates the range of in- and outpatient options as currently practiced, with case reports from practitioners when possible, and describes qualifications for practicing in each model, the settings, the patient populations, the relevant financial issues, and the advantages and disadvantages of practicing in each model. It closes with comments on the next steps for advancing integrated care and the barriers to be overcome.


The neuroprotective effects of transcranial direct current stimulation on global cerebral ischemia and reperfusion via modulating apoptotic pathways.
Cerebral ischemia-reperfusion, subsequent hyperthermia, and hyperglycemia lead to neural damage. This study aimed to investigate the effects of using cathodal and/or anodal transcranial direct current stimulation (tDCS) in different stages of ischemia-reperfusion on apoptosis and controlling hyperthermia and hyperglycemia. A total of 78 male Wistar rats were randomly assigned into six groups (n = 13), including sham, ischemia/reperfusion (I/R), anodal-tDCS (a-tDCS), cathodal-tDCS (c-tDCS), anodal/cathodal-tDCS (a/c-tDCS), and cathodal/anodal-tDCS (c/a-tDCS) groups. Global cerebral I/R was induced in all of the groups except for sham group. In a-tDCS and c-tDCS groups, the rats received anodal and cathodal currents in both I/R stages, respectively. In a/c-tDCS group, the rats received anodal current during the ischemia and cathodal current during the reperfusion. The c/a-tDCS group received the currents in the reverse order. The current intensity of 400 µA was applied in ischemia phase (15 min) and reperfusion phase (30 min, twice a day). Body temperature and plasma blood sugar were measured daily. Rats were also tested for novel object recognition and passive avoidance memory. The apoptosis of hippocampal tissue was evaluated by measuring Bax, Bcl-2, Caspase-3, and TUNEL staining. All tDCS significantly reduced hyperthermia and hyperglycemia, as well as Bax and Caspase-3 levels, it also increased Bcl-2 expression. The preliminary results from c/a-tDCS mode could improve the expression of apoptotic markers, memory function, hyperthermia, and hyperglycemia control and reduce DNA fragmentation compared to other stimulatory therapies. All tDCS modes could save neurons by suppressing apoptotic and enhancing anti-apoptotic pathways, especially in the c/a tDCS mode.


Declines in canopy greenness and tree growth are caused by combined climate extremes during drought-induced dieback.
Several dieback episodes triggered by droughts are revealing the high vulnerability of Mediterranean forests, manifested as declines in growth, increased defoliation, and rising mortality rates. Understanding forest responses to such climate extreme events is of high priority for predicting their future vegetation dynamics. We examined how remotely sensed measures of vegetation activity (NDVI, Normalized Difference Vegetation Index) and radial growth (BAI, basal area increment) responded to climate extreme events. We considered tree (Pinus sylvestris, Quercus pubescens, Quercus frainetto) and shrub (Juniperus phoenicea) populations from Italy and Spain showing recent dieback phenomena. Two components of drought, namely elevated atmospheric demand (VPD, vapor pressure deficit) and low soil moisture were analyzed in nearby stands showing or not showing dieback symptoms. Dieback stands exhibited lower NDVI values than non-dieback stands. NDVI and BAI were positively related in all sites except for the dieback stand of Q. frainetto that was negatively related. Such NDVI-BAI linkages were related to specific time windows, which could be useful for identifying when climatic conditions have the greatest influence on vegetation. Growth decline occurred in response to increasing VPD, but responses differed among species. J. phoenicea was the most negatively impacted by higher VPD, whereas oaks responded to soil moisture. A high VPD was related to stronger growth reduction in dieback P. sylvestris trees regardless of soil moisture changes. We highlighted that coupling between proxies of forest productivity (NDVI, BAI) allows better understanding and forecasting of drought-induced dieback phenomena in forests and shrublands. Scaling up from tree to stand levels might be feasible when using the maximum growing season NDVI, which can be applied for retrospective modeling of the impact of drought stress on forest productivity and tree growth.


Ex-Vivo Trans-Corneal and Trans-Scleral Diffusion Studies with Ocular Formulations of Glutathione as an Antioxidant Treatment for Ocular Diseases.
Exposure to sunlight and contact with atmospheric oxygen makes the eye particularly susceptible to oxidative stress, which can potentially produce cellular damage. In physiological conditions, there are several antioxidant defense mechanisms within the eye. Glutathione (GSH) is the most important antioxidant in the eye; GSH deficit has been linked to several ocular pathologies. The aim of this study was to explore the potential for newly developed formulations allowing controlled delivery of antioxidants such as GSH and vitamin C (Vit C) directly to the eye. We have investigated the stability of antioxidants in aqueous solution and assessed ex-vivo the diffusion of GSH through two ocular membranes, namely cornea and sclera, either in solution or included in a semisolid insert. We have also carried out the hen's egg-chlorioallantoic membrane test (HET-CAM) to evaluate the ocular irritancy of the different antioxidant solutions. Our results showed that GSH is stable for up to 30 days at 4 °C in darkness and it is not an irritant to the eye. The diffusion studies revealed that the manufactured formulation, a semisolid insert containing GSH, could deliver this tripeptide directly to the eye in a sustained manner.


Symptomatic adrenal suppression among children in Canada.
Adrenal suppression (AS) is an under-recognised side effect of glucocorticoid (GC) use. AS may go undetected until a physiological stress precipitates an adrenal crisis. The incidence of AS has not been established. We sought to estimate the minimum national incidence and presenting features of paediatric symptomatic AS. Through the established methodology of the Canadian Paediatric Surveillance Program, over 2500 paediatricians were surveyed monthly for 2 years (April 2010-March 2012) to report new cases of symptomatic AS. Forty-six cases of symptomatic AS were confirmed. The estimated annual incidence is 0.35/100 000 children aged 0-18 years (95% CI 0.26 to 0.47). The most common presentations were growth failure (35%), non-specific symptoms (28%) or both (13%). Adrenal crisis occurred in six cases (13%). Thirty-seven children (80%) had received inhaled corticosteroid (ICS) alone or in combination with other GC forms. Many children received high but commonly prescribed doses of ICS. AS is responsible for significant morbidity in children, including susceptibility to adrenal crisis. The minimal estimated incidence reported is for the entire paediatric population and would be much higher in the at-risk group (ie, children treated with GCs). Close monitoring of growth and possible symptoms of AS, which may be non-specific, are important in children on all forms of GC therapy including ICS. To reduce the risk of AS, physicians must be aware of the risk of AS, revisit GC doses frequently and use the lowest effective dose.


The novel HLA-B*53:01:30 allele characterised by two different sequencing-based typing techniques.
The novel allele HLA-B*53:01:30 differs from HLA-B*53:01:01:01 by one synonymous nucleotide substitution in exon 3.


Electrical microstimulation of primate posterior parietal cortex initiates orienting and alerting components of covert attention.
The posterior parietal cortex (PPC) is implicated in the control of visuospatial orienting, including both overt saccadic eye movements and covert shifts of attention (i.e., attention to a location other than at visual fixation). Some studies have suggested that the attentional system is part of the premotor processing in the brain, while others suggest they are separate. Here, we test how the PPC controls covert attention shifts in the absence of executed eye movements. Electrical microstimulation was applied to the right PPC while monkeys performed a spatial, cued target detection task, in which they were not allowed to move their gaze. At high currents, contralateral saccades were evoked. With currents below the thresholds for eliciting saccades, microstimulation produced a purely attentional shift (as indexed by decreased target reaction time) when a cue and target were presented in the contralateral visual field. This suggests that microstimulation can move attention specifically in the absence of any overt movements of the eyes or limbs. In addition, there was a reduction in reaction times in trials that did not evoke attentional orienting, suggesting a more general alerting effect of microstimulation These data provide direct evidence that the PPC may be a source of both attentional modulation of neuronal responses and saccadic eye movements to peripheral visual stimuli.


Acute chagasic myocardiopathy after orthotopic liver transplantation with donor and recipient serologically negative for Trypanosoma cruzi: a case report.
Chagas disease (American trypanosomiasis) is caused by the protozoan parasite Trypanosoma cruzi. Chagas disease following solid-organ transplantation has occurred in Latin America. This report presents the occurrence of Chagas disease despite negative serological tests in both the donor and the recipient, as well as the effectiveness of treatment. A 21-year-old woman from the state of Sao Paulo (Brazil) underwent cadaveric donor liver transplantation in November 2005, due to cirrhosis of autoimmune etiology. Ten months after liver transplantation, she developed signs and symptoms of congestive heart failure (New York Heart Association functional class IV). The echocardiogram, which was normal preoperatively, showed dilated cardiac chambers, depressed left ventricular systolic function (ejection fraction = 35%) and moderate pulmonary hypertension. Clinical investigation discarded ischemic heart disease and autoimmune and other causes for heart failure. Immuno fluorescence (immunoglobulin M and immunoglobulin G) and hemagglutination tests for T cruzi were positive, and abundant T cruzi amastigotes were readily identified in myocardial biopsy specimens. Treatment with benznidazole for 2 months yielded an excellent clinical response. At the moment of submission, the patient remains in functional class I. This case highlighted that more appropriate screening for T cruzi infection is mandatory in potential donors and recipients of solid-organ transplants in regions where Chagas disease is prevalent. Moreover, it stressed that this diagnosis should always be considered in recipients who develop cardiac complications, since negative serological tests do not completely discard the possibility of disease transmission and since good results can be achieved with prompt trypanocidal therapy.


Inhibition and superactivation of the calcium-stimulated isoforms of adenylyl cyclase: role of Gbetagamma dimers.
It was shown previously that chronic exposure to opiate agonists increases adenylyl cyclase (AC) activity, a phenomenon termed AC superactivation (or supersensitization). More recently, we showed that acute Gi/o- coupled receptor activation inhibits the activity of several AC isozymes, including Ca2+/calmodulin-stimulated AC-I and -VIII, whereas chronic receptor activation induces their superactivation. Here, we report that both acute Mu-opioid receptor-induced inhibition and chronic induced superactivation of AC-I and -VIII are pertussis toxin sensitive. In addition, we show that proteins that interfere with the activity of Gbetagamma subunits (Gbetagamma scavengers) strongly attenuate the acute inhibition of AC-I and -VIII and the superactivation of AC-I, and abolish the superactivation of AC-VIII. Based on these results, we suggest that Gbetagamma is involved in the acute inhibition and chronic agonist-induced superactivation of AC types I and VIII.


Analysis of indium (III) adsorption from leachates of LCD screens using artificial neural networks (ANN) and adaptive neuro-fuzzy inference systems (ANIFS).
Ten different adsorbent materials were tested to adsorb indium (III) from leachates of LCD screens, aiming to concentrate this valuable material. Artificial neural network (ANN) and adaptive neuro-fuzzy inference system (ANIFS) were applied to analyze the indium (III) adsorption. The input variables for the network models were: specific surface area, point of zero charge, adsorbent dosage and contact time. Adsorption capacity (q) was used as output variable. The adsorption capacity values ranged from 8.203 to 1000 mg g-1. The ANN modeling presented the best fit when the Levenberg-Marquardt algorithm was used. The ANFIS modeling presented the optimum performance when the hybrid method was used. Among the tested adsorbents, chitosan presented the best performance; attaining adsorption capacity of 1000 mg g-1 within 20 min. This is an excellent value since the maximum indium concentration in LCD screens is 0.613 mg g-1. This high capacity was attributed to the coordination ligation between chitosan and indium (III).


The SENECA study: Prognostic role of serum biomarkers in older patients with metastatic colorectal cancer.
Aging induces meaningful changes in the immune system and inflammation response with increase in monocyte-lymphocyte ratio (MLR) and serum lactate dehydrogenase (LDH) levels. Aim of this study was to explore the prognostic role of MLR and LDH levels in older patients (pts) with metastatic colorectal cancer (mCRC). We conducted a retrospective analysis of a consecutive cohort of 168 older (>70 years) patients with mCRC. The prognostic impact of MLR and LDH levels on overall survival (OS) was investigated through uni-and multivariate Cox regression analyses. Moreover, we categorized patients into three groups according to MLR and LDH levels (group 1: MLR-low and LDH-low; group 2: MLR-high or LDH-high; group 3: MLR-high and LDH-high). By univariate analysis, high LDH level (HR 1.74, 95% CI 1.05-2.90) and high MLR level (HR 2.19, 95% CI 1.48-3.44) were significantly associated with a worse OS. Conversely, primary tumor resection and left-sidedness were significantly associated with a longer OS. By multivariate analysis, high LDH level (HR 2.00, 95% CI 1.13-3.55) and high MLR level (HR 2.99, 95% CI 1.68-5.33) were independent prognostic factors of worse prognosis. Compared to group 1, a shorter survival was reported for patients included in group 2 (HR 1.97, 95% CI 1.21-3.23 in univariate; HR 2.54, 95% CI 1.43-4.51 in multivariate) or in group 3 (HR 2.42, 95% CI 24-4.74, p = .010 in univariate; HR 5.59, 95% CI 2.15-14.54 in multivariate) CONCLUSIONS: High baseline levels of LDH, MLR or both are independent unfavorable prognostic factors in older patients treated with first-line chemotherapy for mCRC.


Estimation of health state and physical efficiency of children from rural area of Lubin-Glogow copper-basin and lead levels in blood serum. Preliminary results.
The aim of the work was to estimate the health state and physical efficiency of children from rural area of Lubin-Głogów Copper-Basin in correlation with lead levels in blood. Lead concentration in blood showed increase tendency together with age of the children. In both sexes together with rise in lead concentration in blood enlargement of palatine tonsils was observed. In children with a higher lead concentration in blood lower values of physical fitness parameters are recorded.


WS-9659 A and B, novel testosterone 5 alpha-reductase inhibitors isolated from a Streptomyces. I. Taxonomy, fermentation, isolation, physico-chemical characteristics.
WS-9659 A and B, produced by Streptomyces sp. No. 9659, were extracted from cultured broth, purified by solvent extraction followed by chromatography on silica gel and then isolated as prisms (C22H24N2O, mp 161 approximately 162 degrees C, C22H23N2OCl, mp 152 approximately 153 degrees C). WS-9659 A and B have testosterone 5 alpha-reductase inhibitory activity. The IC50 values of WS-9659 A and B for partially purified rat prostate testosterone 5 alpha-reductase were 5.0 x 10(-7) M and 1.0 x 10(-5) M, respectively.


Differential Roles for the Coagulation Factors XI and XII in Regulating the Physical Biology of Fibrin.
In the contact activation pathway of the coagulation, zymogen factor XII (FXII) is converted to FXIIa, which triggers activation of FXI leading to the activation of FIX and subsequent thrombin generation and fibrin formation. Feedback activation of FXI by thrombin has been shown to promote thrombin generation in a FXII-independent manner and FXIIa can bypass FXI to directly activate FX and prothrombin in the presence of highly negatively charged molecules, such as long-chain polyphosphates (LC polyP). We sought to determine whether activation of FXII or FXI differentially regulate the physical biology of fibrin formation. Fibrin formation was initiated with tissue factor, ellagic acid (EA), or LC polyP in the presence of inhibitors of FXI and FXII. Our data demonstrated that inhibition of FXI decreased the rate of fibrin formation and fiber network density, and increased the fibrin network strength and rate of fibrinolysis when gelation was initiated via the contact activation pathway with EA. FXII inhibition decreased the fibrin formation and fibrin density, and increased the fibrinolysis rate only when fibrin formation was initiated via the contact activation pathway with LC polyP. Overall, we demonstrate that inhibition of FXI and FXII distinctly alter the biophysical properties of fibrin.


Examining the Relationship Between Neurosteroids, Cognition, and Menopause With Neuroimaging Methods.
Previous literature has shown inconsistent findings regarding the effects of neurosteroids on the brain in postmenopausal women. The goal of this paper is to examine how and whether advances in neuroimaging have helped elucidate the relationship between the withdrawal of and/or treatment with neurosteroids and cognition at menopause. Neuroimaging techniques such as structural and functional MRI have been used in recent studies to examine the relationship between neurosteroids and brain structure and functioning. However, the recent literature shows that different formulations of postmenopausal hormones given at different times, through different routes of administration, and in different combinations with progestins result in a variety of relationships with the brain outcomes. We suggest that still further research is needed to understand how the structural changes resulting from estrogen withdrawal or therapy at menopause can influence cognitive functioning. However, imaging studies are time-, resource-, and expertise-intensive. We believe that this information will help uncover the mechanisms and relationships that can aid in the explanation of the individual differences in the effects of menopause on the brain as well as how this menopause-related hormone change influences risk for pathological aging.


The role of MHC class I recycling and Arf6 in cross-presentation by murine dendritic cells.
Cross-presentation by MHC class I molecules (MHC-I) is critical for priming of cytotoxic T cells. Peptides derived from cross-presented antigens can be loaded on MHC-I in the endoplasmic reticulum and in endocytic or phagocytic compartments of murine DCs. However, the origin of MHC-I in the latter compartments is poorly understood. Recently, Rab22-dependent MHC-I recycling through a Rab11+ compartment has been suggested to be implicated in cross-presentation. We have examined the existence of MHC-I recycling and the role of Arf6, described to regulate recycling in nonprofessional antigen presenting cells, in murine DCs. We confirm folded MHC-I accumulation in a juxtanuclear Rab11+ compartment and partially localize Arf6 to this compartment. MHC-I undergo fast recycling, however, both folded and unfolded internalized MHC-I fail to recycle to the Rab11+Arf6+ compartment. Therefore, the source of MHC-I molecules in DC endocytic compartments remains to be identified. Functionally, depletion of Arf6 compromises cross-presentation of immune complexes but not of soluble, phagocytosed or mannose receptor-targeted antigen, suggesting a role of Fc receptor-regulated Arf6 trafficking in cross-presentation of immune complexes.


Fibroblast growth factor 2 regulates dopaminergic neuron development in vivo.
Fibroblast growth factor 2 (FGF-2) is a neurotrophic factor participating in regulation of proliferation, differentiation, apoptosis and neuroprotection in the central nervous system. With regard to dopaminergic (DA) neurons of substantia nigra pars compacta (SNpc), which degenerate in Parkinson's disease, FGF-2 improves survival of mature DA neurons in vivo and regulates expansion of DA progenitors in vitro. To address the physiological role of FGF-2 in SNpc development, embryonic (E14.5), newborn (P0) and juvenile (P28) FGF-2-deficient mice were investigated. Stereological quantification of DA neurons identified normal numbers in the ventral tegmental area, whereas the SNpc of FGF-2-deficient mice displayed a 35% increase of DA neurons at P0 and P28, but not at earlier stage E14.5. Examination of DA marker gene expression by quantitative RT-PCR and in situ hybridization revealed a normal patterning of embryonic ventral mesencephalon. However, an increase of proliferating Lmx1a DA progenitors in the subventricular zone of the ventral mesencephalon of FGF-2-deficient embryos indicated altered cell cycle progression of neuronal progenitors. Increased levels of nuclear FgfR1 in E14.5 FGF-2-deficient mice suggest alterations of integrative nuclear FgfR1 signaling (INFS). In summary, FGF-2 restricts SNpc DA neurogenesis in vivo during late stages of embryonic development.


Aging of mesenchymal stem cell: machinery, markers, and strategies of fighting.
Human mesenchymal stem cells (MSCs) are primary multipotent cells capable of differentiating into osteocytes, chondrocytes, and adipocytes when stimulated under appropriate conditions. The role of MSCs in tissue homeostasis, aging-related diseases, and cellular therapy is clinically suggested. As aging is a universal problem that has large socioeconomic effects, an improved understanding of the concepts of aging can direct public policies that reduce its adverse impacts on the healthcare system and humanity. Several studies of aging have been carried out over several years to understand the phenomenon and different factors affecting human aging. A reduced ability of adult stem cell populations to reproduce and regenerate is one of the main contributors to the human aging process. In this context, MSCs senescence is a major challenge in front of cellular therapy advancement. Many factors, ranging from genetic and metabolic pathways to extrinsic factors through various cellular signaling pathways, are involved in regulating the mechanism of MSC senescence. To better understand and reverse cellular senescence, this review highlights the underlying mechanisms and signs of MSC cellular senescence, and discusses the strategies to combat aging and cellular senescence.


A novel method for spine ultrasound and X-ray radiograph registration.
Ultrasound is a promising imaging method for scoliosis evaluation because it is radiation free and provide real-time images. However, it cannot provide bony details because ultrasound cannot penetrate the bony structure. Therefore, registration of real-time ultrasound images with the previous X-ray radiograph can help physicians understand the spinal deformity of patients. In this study, an improved free-from deformation registration method based on mutual registration and hierarchical adaptive grid (MRHA-FFD) was developed. The method first performed registration grid preprocessing and then optimized control points and conducted mutual registration. Finally, a Blur-aware Attention Network was adopted for image deblurring. The performance of each step was verified by ablation experiments. Comparison experiment between the proposed method and traditional registration methods was also conducted. The qualitative and quantitative results suggested that MRHA-FFD is a promising approach for registering spine ultrasound image and X-ray radiograph.


Optimization of graft fixation at the time of anterior cruciate ligament reconstruction. Part II: effect of knee flexion angle.
There is no consensus about flexion angle of the knee at the time of graft fixation in anterior cruciate ligament reconstruction. To evaluate the effect of flexion angle at the final graft fixation on the positional relationship as well as the load between femur and tibia. Controlled laboratory study. Six intact cadaveric knees were passively flexed and extended under 6 degrees of freedom with the robotic system developed in our laboratory, while their 3-dimensional paths were recorded. Anterior cruciate ligament reconstruction was performed with a single-socket technique using autogenous quadrupled hamstring tendons, while the graft was fixed at 0 degrees (group A), 20 degrees (group B), or 90 degrees (group C) with a constant initial tension of 44 N. The knees then repeated the same movement as before while the relative position between femur and tibia was recorded. The load in the femorotibial joint was also calculated based on the principle of superposition. Posterior displacement of the tibia compared with the normal knee was the smallest in group B at all flexion angles, while the load between tibia and femur in group B was also the smallest and the closest to the normal knee. As the positional relationship as well as the load between femur and tibia in group B was the closest to that in the normal knee, 20 degrees of flexion is the most desirable of the positions tested for graft tensioning and fixation at the time of anterior cruciate ligament reconstruction. The tibia-femur position is well retained when the graft was fixed at 20 degrees of flexion in anterior cruciate ligament reconstruction.


Calcium channel modulation as a target in chronic pain control.
Neuropathic pain remains poorly treated for large numbers of patients, and little progress has been made in developing novel classes of analgesics. To redress this issue, ziconotide (Prialt™) was developed and approved as a first-in-class synthetic version of ω-conotoxin MVIIA, a peptide blocker of Cav 2.2 channels. Unfortunately, the impracticalities of intrathecal delivery, low therapeutic index and severe neurological side effects associated with ziconotide have restricted its use to exceptional circumstances. Ziconotide exhibits no state or use-dependent block of Cav 2.2 channels; activation state-dependent blockers were hypothesized to circumvent the side effects of state-independent blockers by selectively targeting high-frequency firing of nociceptive neurones in chronic pain states, thus alleviating aberrant pain but not affecting normal sensory transduction. Unfortunately, numerous drugs, including state-dependent calcium channel blockers, have displayed efficacy in preclinical models but have subsequently been disappointing in clinical trials. In recent years, it has become more widely acknowledged that trans-aetiological sensory profiles exist amongst chronic pain patients and may indicate similar underlying mechanisms and drug sensitivities. Heterogeneity amongst patients, a reliance on stimulus-evoked endpoints in preclinical studies and a failure to utilize translatable endpoints, all are likely to have contributed to negative clinical trial results. We provide an overview of how electrophysiological and operant-based assays provide insight into sensory and affective aspects of pain in animal models and how these may relate to chronic pain patients in order to improve the bench-to-bedside translation of calcium channel modulators. This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.


Disinfection of gutta-percha cones with chlorhexidine and sodium hypochlorite.
To evaluate the effectiveness of chlorhexidine (CHX) or sodium hypochlorite (NaOCl) in disinfecting gutta-percha cones, to verify contamination of gutta-percha cones in their boxes, and to identify microorganisms after intentional contamination by handling cones. Gutta-percha cones contaminated in vitro with several microorganisms were left in contact with tested disinfecting solutions for different times, sterility of storage boxes was evaluated by immersing cones in broth medium, and the microorganisms most frequently found in handling cones were identified using biochemical tests. CHX was not effective in eliminating Bacillus subtilis spores on gutta-percha cones after 72 h of contact with the disinfecting substance. 5.25% NaOCl eliminated spores from gutta-percha after 1 min of disinfection. The cones evaluated from their boxes did not show contamination in 94.5% of the cases. The microbial genus most frequently found after intentional contamination with gloves was Staphylococcus. 5.25% NaOCl is an effective agent for a rapid disinfection of gutta-percha cones.


Corrigendum to: 'Mini-Max' knotless acetabular labrum repair: repair construct rationale and allocation in a consecutive case series with minimum 1-year clinical outcomes.
[This corrects the article DOI: 10.1093/jhps/hnab061.].


Gene-Specific Therapy With Mexiletine Reduces Arrhythmic Events in Patients With Long QT Syndrome Type 3.
Long QT syndrome type 3 (LQT3) is a lethal disease caused by gain-of-function mutations in the SCN5A gene, coding for the alpha-subunit of the sodium channel NaV1.5. Mexiletine is used to block late sodium current and to shorten QT interval in LQT3 patients. The aim of this study was to determine whether mexiletine prevents arrhythmic events (arrhythmic syncope, aborted cardiac arrest, or sudden cardiac death) in LQT3 patients. The endpoint of this retrospective cohort study, which studied consecutive LQT3 patients who were referred to our center and treated with mexiletine, was to evaluate the antiarrhythmic efficacy of mexiletine by comparing the number of arrhythmic events per patient and the annual rate of arrhythmic events during observation periods of equal duration before and after the beginning of therapy with mexiletine. The study population comprised 34 LQT3 patients, 19 (56%) of whom were male. The median age at beginning of treatment with mexiletine was 22 years, and median QTc interval before therapy 509 ms. The median duration of oral mexiletine therapy was 36 months, at an average daily dose of 8 ± 0.5 mg/kg. Mexiletine significantly shortened QTc (by 63 ± 6 ms; p < 0.0001) and reduced the percentage of patients with arrhythmic events (from 22% to 3%; p = 0.031), the mean number of arrhythmic events per patient (from 0.43 ± 0.17 to 0.03 ± 0.03; p = 0.027), and the annual rate of arrhythmic events (from 10.3% to 0.7%; p = 0.0097). Besides shortening QTc interval, mexiletine caused a major reduction of life-threatening arrhythmic events in LQT3 patients, thus representing an efficacious therapeutic strategy.


Recreational ketamine-induced cholangiopathy and ulcerative cystitis.
Ketamine is a versatile analgesic that has become an increasingly popular recreational drug. Chronic ketamine use has been found to cause biliary duct damage and bladder dysfunction. Ketamine-induced cholangiopathy and ulcerative cystitis are uncommon diagnoses presenting with nonspecific symptoms, creating diagnostic challenges for emergency physicians. We report a case of a teenage patient with the rare simultaneous presentation of ketamine-induced cholangiopathy and ulcerative cystitis. Due to increased recreational and chronic ketamine use, cases of ketamine-induced cholangiopathy and ulcerative cystitis are likely to rise with the increased knowledge, awareness, and reporting of these entities by radiologists and emergency physicians.


Early essential newborn care for cesarean section newborns in China: study protocol for a multi-centered randomized controlled trial.
Early essential newborn care (EENC) is a package of evidence-based and cost-effective interventions delivered around birth mainly including delayed cord clamping, immediate and sustained skin-to-skin contact, and early initiation of exclusive breastfeeding. EENC is proven effective in promoting breastfeeding and improving women's and newborns' health. However, there is little evidence on implementation of EENC on newborns born by cesarean section in China. Therefore, the objective of this study is to assess the effectiveness of EENC intervention on rates of exclusive breastfeeding and early initiation of breastfeeding for cesarean section newborns in China. This is a multi-centered, randomized controlled trial conducted in 4 tertiary hospitals in China. A total of 720 eligible women who will receive cesarean section are being randomized into four groups: control group (n=180), intervention group 1 (skin-to-skin contact for 30 min, n=180), intervention group 2 (skin-to-skin contact for 60 min, n=180), and intervention group 3 (skin-to-skin contact for 90 min, n=180). The control group will receive routine care, whereas the intervention groups will receive EENC with different duration of skin-to-skin contact. Demographic characteristics, clinical information, and breastfeeding outcomes will be collected. The primary outcome is rates of exclusive breastfeeding and early initiation of breastfeeding, and the secondary outcomes include maternal and neonatal morbidity and admissions. This study will provide evidence of the impact of EENC on improvement of breastfeeding outcomes and maternal and neonatal health for cesarean section newborns in China, and evidence-based recommendation to inform optimal duration of skin-to-skin contact for cesarean deliveries. The results of this study have potential to inform national-level guidelines and policy-making for optimizing EENC implementation for cesarean section newborns. Chinese Clinical Trial Registry ChiCTR2100048997. Retrospectively registered on 19 July 2021.


Increased Hospitalizations Involving Fungal Infections during COVID-19 Pandemic, United States, January 2020-December 2021.
Hospitalizations involving fungal infections increased 8.5% each year in the United States during 2019-2021. During 2020-2021, patients hospitalized with COVID-19-associated fungal infections had higher (48.5%) in-hospital mortality rates than those with non-COVID-19-associated fungal infections (12.3%). Improved fungal disease surveillance is needed, particularly during respiratory virus pandemics.


Management of strabismus with botulinum A toxin.
Three hundred eight patients with strabismus were treated with botulinum A toxin (Oculinum) chemodenervation; 153 were followed by the authors for at least 6 months. In this study group, 97 received botulinum A toxin injections as the primary method of treatment of their ocular deviation. Fifty-six received injections after traditional extraocular muscle surgery. Botulinum A toxin was useful for management of patients with recent surgical overcorrections and for management of some patients with sixth cranial nerve palsy. Chemodenervation of an extraocular muscle was not as successful as traditional strabismus surgery for treatment of infantile esotropia and other comitant deviations. Botulinum A toxin injection was ineffective in patients who had restrictive strabismus. This drug has limited application in the management of patients with strabismus.


Regulations of Free Fatty Acids and Diabetic Parameters in Drug Naïve Subjects with Type 2 Diabetes Treated with Canagliflozin Monotherapy.
The objective of this study is to investigate the regulations of FFA with canagliflozin in relation to metabolic parameters. Drug naïve subjects with T2DM were administered 50-100 mg/day canagliflozin monotherapy (n=70) for 3 months. Significant correlations between the changes of (Δ) FFA and Δadipo-IR (R=0.496), but no correlations between ΔFFA and ΔHOMA-R were observed. The subjects were divided into three groups with similar numbers according to Δ FFA: group A: highest tertile: (ΔFFA=38.7%, n=23); group B: intermediate tertile: (ΔFFA=2%, n=23); group C: lowest tertile: (ΔFFA=-36%, n=24). Metabolic parameters were compared between group A and group C. At baseline, FFA was higher in group C than group A (p<0.002). Greater degrees of HbA1c reduction and increases of insulin were observed in group C than group A (both p<0.05). In group A, significant reductions of BMI (-2.6%) and HOMA-R (-30%) were seen. In group C, significant reductions of non-HDL-C (-6.2%), UA (-7.6%) or adipo-IR (-28.7%), and increases of HOMA-B (+85.6%) were observed. Taken together, 1) certain population treated with canagliflozin showed decreased FFA. 2) beta-cell function increased while atherogenic cholesterol, UA and adipo-IR decreased in those with reduced FFA. Better glycemic efficacies were seen in these populations. 3) body weight and whole body insulin resistance (HOMA-R) significantly decreased in those with elevated FFA. 4) FFA is linked to adipose insulin resistance (adipo-IR), while it does not appear to impact whole body insulin resistance (HOMA-R).


Epidemiology of Group B Streptococcus in developing countries.
Group B Streptococcus (GBS) causes pneumonia, meningitis and sepsis in neonates. The current distribution pattern of GBS serotypes in developing countries such as India, China and Brazil is not clear. In order to appropriately plan for vaccination programs to address the burden of this disease in these countries, prospective population based studies are urgently needed. In our discussions, we focused on India, China and Brazil because of the membership of our workgroup, but data on other countries are also presented here. Further studies in developing countries are needed so as to better formulate appropriate public health interventions.


Retracted: Construction and Analysis of Indicators of the Labor Education System Based on the Gray Correlation Degree Model.
[This retracts the article DOI: 10.1155/2022/2281469.].


Spatial and Short-Temporal Variability of δ13C and δ15N and Water-Use Efficiency in Pine Needles of the Three Forests Along the Most Industrialized Part of Poland.
In this study, stable carbon and nitrogen isotope ratios in the samples of pine needles collected in 2013 and 2014 from heavily urbanized area in close proximity to point-source pollution emitters, such as a heat and power plant, nitrogen plant, and steelworks in Silesia (Poland), were analyzed as bio-indicators of contemporary environmental changes. The carbon isotope discrimination has been proposed as a method for evaluating water-use efficiency. The measurement of carbon and nitrogen isotopes was carried out using the continuous flow isotope ratio mass spectrometer. The isotope ratio mass spectrometer allows the precise measurement of mixtures of naturally occurring isotopes. The δ15N values were calibrated relative to the NO-3 and USGS34 international standards, whereas the δ13C values were calibrated relative to the C-3 and C-5 international standards. The strong year-to-year correlations between the δ13C in different sampling sites, and also the inter-annual correlation of δ15N values in the pine needles at each of the investigated sampling sites confirm that the measured δ13C and δ15N and also intrinsic water-use efficiency (iWUE) trends are representative of the sampling site. Diffuse air pollution caused the variation in δ 13C, δ15N, and iWUE dependent on type of emitter, the localization in the space (distance and direction) from factories and some local effect of other human activities. The complex short-term variation analysis can be helpful to distinguish isotopic fractionation, which is not an effect explainable by climatic conditions but by the anthropogenic effect. Between 2012 and 2014, an increase in iWUE is observed at leaf level.


Semantics and the chemotherapy of Hodgkin's disease--resistance is not relapse: alternative chemotherapy lacks effectiveness for disease not totally responsive to initial MOPP treatment.
Patients with advanced Hodgkin's disease not achieving a complete remission with initial MOPP therapy are significantly less responsive to adriamycin and nitrosourea-containing regimens than patients with relapsing disease following a complete remission with MOPP. Hodgkin's disease not responding completely to initial four-drug treatment represents resistant disease which, in most instances, may not be cured with existing alternative chemotherapy. These patients should receive innovative treatment.


The development of Coronavirus 3C-Like protease (3CLpro) inhibitors from 2010 to 2020.
This review fully describes the coronavirus 3CLpro peptidomimetic inhibitors and nonpeptidic small molecule inhibitors developed from 2010 to 2020. Specifically, the structural characteristics, binding modes and SARs of these 3CLpro inhibitors are expounded in detail by division into two categories: peptidomimetic inhibitors mainly utilize electrophilic warhead groups to covalently bind the 3CLpro Cys145 residue and thereby achieve irreversible inhibition effects, whereas nonpeptidic small molecule inhibitors mainly interact with residues in the S1', S1, S2 and S4 pockets via hydrogen bonds, hydrophobic bonds and van der Waals forces. Based on the emerging PROTAC technology and the existing 3CLpro inhibitors, 3CLpro PROTAC degraders are hypothesised to be next-generation anti-coronavirus drugs.


Positively charged silver nanoparticles and their effect on surface-enhanced Raman scattering of dye-labelled oligonucleotides.
Improved positively charged nanoparticles are described to provide a simplified SERS substrate for DNA detection. Complete flocculation of the nanoparticles is prevented due to the controlled analyte induced aggregation. This provides a stable aggregation state which significantly extends the analysis window simplifying DNA detection by SERS.


Bilateral idiopathic inflammation of the optic nerve sheaths. Light and electron microscopic findings.
Idiopathic perioptic neuritis is a term used to describe noninfectious inflammatory disorders of the optic nerve sheaths, the causes of which are unknown. In the following report, a 68-year-old woman with bilateral visual loss was found to have chronic inflammation with necrobiotic granulomas of her optic nerve sheaths. The patient, who had no systemic condition known to be associated with necrobiotic granuloma, lost vision from infarction of the optic nerve parenchyma and from compression due to thickened meninges. Although there are similarities between the inflammatory reaction in this case to the necrobiotic dermatoses, the pathogenesis of this condition remains obscure.


Meis1 regulates postnatal cardiomyocyte cell cycle arrest.
The neonatal mammalian heart is capable of substantial regeneration following injury through cardiomyocyte proliferation. However, this regenerative capacity is lost by postnatal day 7 and the mechanisms of cardiomyocyte cell cycle arrest remain unclear. The homeodomain transcription factor Meis1 is required for normal cardiac development but its role in cardiomyocytes is unknown. Here we identify Meis1 as a critical regulator of the cardiomyocyte cell cycle. Meis1 deletion in mouse cardiomyocytes was sufficient for extension of the postnatal proliferative window of cardiomyocytes, and for re-activation of cardiomyocyte mitosis in the adult heart with no deleterious effect on cardiac function. In contrast, overexpression of Meis1 in cardiomyocytes decreased neonatal myocyte proliferation and inhibited neonatal heart regeneration. Finally, we show that Meis1 is required for transcriptional activation of the synergistic CDK inhibitors p15, p16 and p21. These results identify Meis1 as a critical transcriptional regulator of cardiomyocyte proliferation and a potential therapeutic target for heart regeneration.


Association between a Rapid Reduction in Air Particle Pollution and Improved Lung Function in Adults.
Rationale: Lung function impairment is reportedly associated with elevated exposure to ambient fine particles (particulate matter ≤2.5 μm in aerodynamic diameter [PM2.5]). However, whether improvement of air quality prevents respiratory diseases is unclear.Objectives: To examine whether the policy-driven reduction in PM2.5 concentration after 2013 was associated with improved lung function among Chinese adults.Methods: We compared the longitudinal measurements of peak expiratory flow (PEF) before (2011) and after (2013 and 2015) China's clean air actions. Long-term exposure to ambient pollution was assessed using a state-of-the-art estimator of historical PM2.5 concentration, and its association with PEF was examined using a linear mixed-effects model. The robustness and homogeneity of the association were examined via sensitivity analyses.Results: We analyzed 35,055 repeated measurements from 13,959 adults. Mean of age at survey was 60.5 years (standard deviation = 9.7 yr). Compared with the reference in 2011, after the policy was implemented, the mean PEF was elevated by 9.19 (6.79-11.59) L/min and 36.64 (33.53-39.75) L/min in 2013 and 2015, respectively. According to the regression results, each 10-μg/m3 reduction of PM2.5 was associated with a 14.95 (12.62-17.28) L/min improvement of PEF. The significance of the association was not affected by adjustments for covariates, inclusion criteria, or the approach to control for the effects of age. Adults of lower socioeconomic status (e.g., those with an educational level of below middle school or rural residents) were more susceptible to the adverse effects of PM2.5 on PEF.Conclusions: We found a robust association between a reduction in PM2.5 and an increase in PEF among Chinese adults. The findings suggest that mitigation of air pollution can promote respiratory health.


Isolation and characterization of a novel monoacylated glucopyranosyl neutral lipid from the plasma membrane of Acholeplasma laidlawii B.
The level of a normally minor component of the membrane polar lipids of Acholeplasma laidlawii B was significantly increased when the glucose supplement in the growth medium was reduced. Under such glucose-limiting conditions the proportion of this component was found to be dependent upon the fatty acid supplement and could approach 55-60% of the total polar lipids when palmitic acid was used to supplement the growth medium. A number of physical measurements, along with specific chemical and enzymic degradation studies followed by a careful analysis of the degradation products, enabled us to tentatively identify this lipid as a polyprenyl-alpha-D-glucoside with a long-chain fatty acid esterified to the 2-hydroxyl group of the sugar moiety. This lipid exhibited some unusual thermotropic phase properties and our observations suggest that it may not be easily miscible with the other membrane lipid components. The structure and physical properties of this unusual glycolipid also suggest that it may be capable of forming non-bilayer phases under physiologically relevant conditions.


Why are Iraq and Afghanistan War veterans seeking PTSD disability compensation at unprecedented rates?
The wars in Iraq and Afghanistan have produced historically low rates of fatalities, injuries, and posttraumatic stress disorder (PTSD) among U.S. combatants. Yet they have also produced historically unprecedented rates of PTSD disability compensation seeking from the U.S. Department of Veterans Affairs. The purpose of this article is to consider hypotheses that might potentially resolve this paradox, including high rates of PTSD, delayed onset PTSD, malingered PTSD, and economic variables.


Lessons learned from two feasibility trials of a translated and minimally monitored iCBT program for young adults among community and university samples.
Young adults are less likely to use traditional mental health services than adults. iCBT may be more youth friendly, but its access remains limited in several countries. This study aims to evaluate the feasibility of a minimally monitored transdiagnostic iCBT program translated from English to French and offered in Canada for the treatment of anxiety and depression among young adults. The impact of the program on resilience was also assessed. Twenty-five participants from community and university samples were included in the analyses in two separate single-group feasibility trials with a 3-month follow-up. Feasibility outcomes were attrition, adherence, treatment acceptability and treatment gains. Outcome measures included the Patient Health Questionnaire 9-item (PHQ-9), Generalized Anxiety Disorder 7-item (GAD-7) and Connor-Davidson Resilience Scale (CD-RISC). In Trial 1 (N = 10), recruiting among the general population proved to be challenging. Low adherence (20%) and high attrition (80%) rates were observed. Methodological changes to recruitment were made and a second trial was conducted among university students using incentives (N = 15). About half of the participants completed treatment (55%, n = 8/15), 12/15 provided post-treatment data and 8/15 provided 3-month follow-up data. All study completers (100%; n = 14) reported they would recommend the program. Mixed effects model analyses revealed significant and large pre-post treatment reductions on the PHQ-9 and GAD-7 (Cohen's d = 1.09 and 1.64 respectively) with treatment gains maintained at follow-up. Moderate improvements were found on the CD-RISC post-treatment with further gains at follow-up (ds = 0.55 and 1.10 respectively). These finding suggest that future research on this French-Canadian version of the Mood Mechanic Course is feasible with appropriate attention to recruitment. Translating existing iCBT interventions and using minimal monitoring may be an optimal first step to initiate the cross-cultural dissemination of iCBT while increasing access to treatments among young adults. Lessons learned are discussed.


Reproducibility of left ventricular mass measurements by two-dimensional and M-mode echocardiography.
Both two-dimensional and M-mode echocardiography provide accurate estimates of left ventricular mass. However, their reproducibility in serial studies has not been compared, although this issue is critical to evaluation of regression of hypertrophy. To determine which technique provides more reproducible estimates of left ventricular mass, three serial studies were performed prospectively in each of eight normal adults over 5 months. Both two-dimensional and M-mode echocardiograms were obtained at each of these 24 studies. Measurements were performed by two independent observers who did not know patient identity. For the two-dimensional method, left ventricular mass was determined with use of a computer light-pen system and the truncated ellipsoid formula. For the M-mode method, mass was calculated from Penn convention measurements with use of the cube formula. At study 1 the group mean left ventricular mass by two-dimensional echocardiography (115 +/- 20 g) did not differ from that by M-mode study (127 +/- 37 g, p = NS). However, serial estimates of left ventricular mass were more reproducible by two-dimensional echocardiography. The mean difference among the three serial two-dimensional studies in each individual was 4.8 +/- 4 g (4.2 +/- 3%) by the two-dimensional method, but was 18.5 +/- 13 g (14.9 +/- 10%) by the M-mode method (p = 0.01). Interobserver results for left ventricular mass by two-dimensional echocardiography correlated closely (r = 0.95, n = 24, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)