Modular control of multiple pathways of Corynebacterium glutamicum for 5-aminolevulinic acid production.
5-aminolevulinic acid (ALA) has broad potential applications in the medical, agricultural and food industries. Several strategies have been implemented successfully to try to improve ALA synthesis. Nonetheless, the low yield has got in the way of large-scale bio-manufacture of 5-ALA. In this study, we explored strain engineering strategies for high-level 5-ALA production in Corynebacterium glutamicum F343 using the C4 pathway. Initially, the glutamate dehydrogenase-encoding gene gdhA was deleted to reduce glutamate yield. Then the C4 pathway was introduced in the gdhA mutant strain F2-A (∆gdhA + hemA), resulting in a 5-ALA yield of up to 3.2 g/L. Furthermore, the accumulations of downstream metabolites such as heme, porphobilinogen, and protoporphyrin IX, were decreased. After evaluating the mechanisms of this synthetic pathway by RNA-Seq, the results showed that genes involved in both the C5 pathway and heme pathways were down-regulated in strain F2-A (∆gdhA + hemA). Interestingly, upstream genes of succinyl-CoA in the tricarboxylic acid (TCA) cycle, such as icd, lpdA, were up-regulated, while its downstream genes, including sucC, sucD, sdhB, sdhA, sdhCD, were down-regulated. These changes amplify the sources of succinyl-CoA and reduce its expenditure, before pulling the carbon flux to produce 5-ALA. Furthermore, the down-regulation of most genes of the heme pathway could reduce the drainage of 5-ALA, which further enhance its accumulation. To alleviate competition between glyoxylate and the TCA cycle, the isocitrate dehydrogenase-encoding gene aceA was also knocked out, resulting in 3.86 g/L of 5-ALA. Finally, the fermentation conditions were optimized, resulting in a maximum 5-ALA yield of 5.6 g/L. Overall, the blocking of the glutamate synthesis pathway could be a powerful strategy to re-allocate the carbon flux to produce 5-ALA. It could also enable the efficient synthesis of other TCA derivatives in C. glutamicum.


Acute lung injury secondary to hydrochloric acid instillation induces small airway hyperresponsiveness.
Acute respiratory distress syndrome (ARDS) is a severe form of respiratory failure characterized by altered lung mechanics and poor oxygenation. Bronchial hyperresponsiveness has been reported in ARDS survivors and animal models of acute lung injury. Whether this hyperreactivity occurs at the small airways or not is unknown. To determine ex-vivo small airway reactivity in a rat model of acute lung injury (ALI) by hydrochloric acid (HCl) instillation. Twelve anesthetized rats were connected to mechanical ventilation for 4-hour, and randomly allocated to either ALI group (HCl intratracheal instillation; n=6) or Sham (intratracheal instillation of 0.9% NaCl; n=6). Oxygenation was assessed by arterial blood gases. After euthanasia, tissue samples from the right lung were harvested for histologic analysis and wet-dry weight ratio assessment. Precision cut lung slice technique (100-200 μm diameter) was applied in the left lung to evaluate ex vivo small airway constriction in response to histamine and carbachol stimulation, using phase-contrast video microscopy. Rats from the ALI group exhibited hypoxemia, worse histologic lung injury, and increased lung wet-dry weight ratio as compared with the sham group. The bronchoconstrictor responsiveness was significantly higher in the ALI group, both for carbachol (maximal contraction of 84.5±2.5% versus 61.4±4.2% in the Sham group, P<0.05), and for histamine (maximal contraction of 78.6±5.3% versus 49.6±5.3% in the Sham group, P<0.05). In an animal model of acute lung injury secondary to HCL instillation, small airway hyperresponsiveness to carbachol and histamine is present. These results may provide further insight into the pathophysiology of ARDS.


Effects of adenosine transport inhibitors on adenosine- and nerve-mediated relaxations of guinea pig taenia caeci.
Dipyridamole and 6-thiobenzyl derivatives of guanosine and inosine were studied in isolated guinea pig taenia caeci with respect to their direct relaxing effects and their influence on relaxations caused by adenosine and nonadrenergic inhibitory nerve stimulation. Direct inhibitory effects were noted with all drugs at 10 microM and these were usually reversible. All inhibitors potentiated the relaxant effects of a submaximal concentration of adenosine in a concentration dependent manner and the potentiating effects persisted for at least 2-3 h after washout of inhibitors. Among the nucleoside-type inhibitors 6-[(4-nitrobenzyl-thio]-purine riboside (NBMPR) was slightly more potent and longer lasting than the others and showed less direct depressant actions. Adenosine concentration-response curves were shifted to the left by all inhibitors but relaxations caused by 2-chloroadenosine remained unaffected. Frequency response curves (0.2-5 s-1), obtained under conditions of selective stimulation of nonadrenergic inhibitory nerves, were not affected by any of the nucleoside-type inhibitors while dipyridamole caused small but significant enhancement of relaxations at low frequencies only. All inhibitors shifted concentration-response curves of adenosine, but not of 2-chloroadenosine, to the left.


Dopamine D2 receptors: a potential pharmacological target for nomifensine and tranylcypromine but not other antidepressant treatments.
Treatment for 1 or 14 days by IP injection with the antidepressants, amitriptyline (10 mg/kg), bupropion (30 mg/kg), desipramine (10 mg/kg), GBR 12909 (10 mg/kg), sibutramine HCl (3 mg/kg), mianserin (5 mg/kg), and zimeldine (10 mg/kg), did not affect the number or affinity of dopamine D2 receptors determined by [3H]raclopride binding to rat striatal membranes. Similarly, neither did a single, nor repeated (five times over 10 days), electroconvulsive shock, given under halothane anaesthesia, have any effect on [3H]raclopride binding parameters. By contrast, the noradrenaline and dopamine reuptake inhibitor, nomifensine (5 mg/kg), and the monoamine oxidase inhibitor, tranylcypromine (5 mg/kg), decreased the number of dopamine D2 receptors by 12% and 11%, respectively, when given for 14 days. Administration of the D2 receptor antagonist, haloperidol (1 mg/kg), for 14 days increased the number of [3H]raclopride binding sites by 17%. Thus, the data demonstrate that although nomifensine and tranylcypromine decrease D2 receptor number after 14 days administration, this adaptive change is not observed with other antidepressant treatments. However, the findings do not preclude a contribution of altered dopamine D2 receptor function to the efficacy of those drugs with potent effects on dopaminergic neuronal function.


Expression microarray analysis identifies novel epithelial-derived protein markers in eosinophilic esophagitis.
Gene expression studies in eosinophilic esophagitis support an immune-mediated etiology associated with differential regulation of inflammatory and epithelial-derived genes. We aimed to further characterize epithelial gene expression alterations in eosinophilic esophagitis and to explore the use of immunohistochemistry to identify these alterations. Esophageal biopsies from pediatric patients with eosinophilic esophagitis before and after therapy with topical steroids (N=7) were screened by gene expression microarray and results were validated by RT-PCR. A larger group of eosinophilic esophagitis patients (N=42) was then used to evaluate protein expression by immunohistochemistry compared with reflux patients (N=15) and normal controls (N=17). Microarray and RT-PCR studies identified overexpression of ALOX15 and tumor necrosis factor alpha-induced factor 6 (TNFAIP6) and underexpression of filaggrin (FLG), SLURP1 and cysteine-rich secretory protein 3 (CRISP3) in eosinophilic esophagitis. Immunohistochemistry for ALOX15 was positive in 95% of eosinophilic esophagitis and negative in all controls, all eosinophilic esophagitis after therapy and all reflux biopsies (P<0.001). TNFAIP6 was positive in 88% of eosinophilic esophagitis samples versus 47% of controls, 29% of eosinophilic esophagitis after therapy and 40% of reflux samples (P=0.002). Overexpression of both ALOX15 and TNFAIP6 directly correlated with the degree of eosinophilic infiltration. FLG was positive in 88% of controls and 100% of reflux biopsies, but negative in all eosinophilic esophagitis samples, and its expression was regained in 86% of eosinophilic esophagitis after therapy patients (P<0.001). SLURP1 expression was positive in all controls and reflux samples, but only positive in 5% of eosinophilic esophagitis and was re-expressed to 100% positivity in eosinophilic esophagitis after therapy patients (P<0.001). The majority of controls (89%) and reflux biopsies (100%) were positive for CRISP3 while eosinophilic esophagitis before therapy were positive in 14% of samples (P<0.001) with partial recovery after treatment (43%, P=0.105). This study identified five epithelial-derived markers differentially expressed in eosinophilic esophagitis easily detectable by immunohistochemistry with potential diagnostic utility.


Chromatographic separation of enantiomers.
In this paper a review is presented on the chromatographic analysis of enantiomers with special attention to high pressure liquid chromatography. Also, some examples of resolution of racemates by thin layer chromatography and gas chromatography are given. The various procedures in the surveyed literature have been divided into three main classes: procedures with formation of diastereomeric compounds prior to the chromatographic separation, procedures in which a chiral mobile phase is used, and procedures with the use of a chiral stationary phase. These methods are subdivided and some examples of their application to drugs and related compounds are presented.


The development and feasibility of a group-based household-level intervention to improve preconception nutrition in Nawalparasi district of Nepal.
In a setting such as Nepal with malnutrition and persistent poor maternal and infant health outcomes, developing interventions to improve the nutrition of preconception and pregnant women is essential. The objectives of this paper are to describe the full design process of an intervention for newly married women, their husbands, and mothers-in-law to improve maternal nutrition and gender norms, and findings from the feasibility and acceptability pilot. In this paper we describe the three phases of the design of an intervention in rural Nepal. We first conducted a mixed methods formative phase which included in depth interviews with newly married women, their husbands and mothers-in-law (N=60) and a longitudinal study for 18 months with 200 newly married women. We then designed of a household level, group, intervention, in close partnership with community members. Finally, we conducted a pilot intervention with 90 participants and collected both pre/post survey data and in-depth qualitative interviews with a subset (N= 30). All participants from all phases of the study lived in Nawalparasi district of Nepal. Qualitative data was analyzed using a thematic analysis, with inductive and deductive themes and quantitative data was analyzed using descriptive statistics. Our formative work highlighted lack of awareness about nutrition, and how women eating last, limited mobility, household and community inequitable gender norms and poor household-level communication contributed to low quality diets. Thus we designed Sumadhur, an intervention that brought groups of households (newly married wife, husband, and mother-in-law) together weekly for four months to strengthen relationships and gain knowledge through interactive content. We found Sumadhur to be highly feasible and acceptable by all respondents, with most (83%) attending 80% of sessions or more and 99% reporting that they would like it to continue. Pre/post surveys showed a decrease in the proportion of women eating last and increase in knowledge about nutrition in preconception and pregnancy. Qualitative interviews suggested that respondents felt it made large impacts on their lives, in terms of strengthening relationships and trust, understanding each other, and changing behaviors. We show how a designing an intervention in close partnership with the target recipients and local stakeholders can lead to an intervention that is able to target complicated and culturally held practices and beliefs, positively benefit health and wellbeing, and that is very well received. ClinicalTrials.gov NCT04383847 , registered 05/12/2020.


Neural underpinning of Japanese particle processing in non-native speakers.
Grammar acquisition by non-native learners (L2) is typically less successful and may produce fundamentally different grammatical systems than that by native speakers (L1). The neural representation of grammatical processing between L1 and L2 speakers remains controversial. We hypothesized that working memory is the primary source of L1/L2 differences, by considering working memory within the predictive coding account, which models grammatical processes as higher-level neuronal representations of cortical hierarchies, generating predictions (forward model) of lower-level representations. A functional MRI study was conducted with L1 Japanese speakers and highly proficient Japanese learners requiring oral production of grammatically correct Japanese particles. We assumed selecting proper particles requires forward model-dependent processes of working memory as their functions are highly context-dependent. As a control, participants read out a visually designated mora indicated by underlining. Particle selection by L1/L2 groups commonly activated the bilateral inferior frontal gyrus/insula, pre-supplementary motor area, left caudate, middle temporal gyrus, and right cerebellum, which constituted the core linguistic production system. In contrast, the left inferior frontal sulcus, known as the neural substrate of verbal working memory, showed more prominent activation in L2 than in L1. Thus, the working memory process causes L1/L2 differences even in highly proficient L2 learners.


First experience with a supercharged pedicled jejunal interposition for esophageal replacement after caustic ingestion in a middle-income Latin American country.
Caustic or corrosive substance ingestion that results in severe esophageal and gastric lacerations frequently requires surgical management. The most common sequelae after an upper gastrointestinal tract caustic injury include non-responding luminal strictures, which are subject to esophageal replacement. Late corrective surgery may include esophagectomy with gastric pull-up and jejunal or colonic interpositions. Although long-segment esophageal reconstruction with jejunum is technically feasible and has demonstrated good outcomes, the complexity of the surgery has precluded the widespread use of this procedure in low- and middle-income countries. This document summarizes the most relevant aspects of caustic ingestion surgical management and describes the first Latin American experience in the reconstruction of an esophageal-gastric caustic injury using a pedicled jejunal interposition, as a viable and functional option in mid- and lower-income countries with well-established Thoracic Surgery departments and microsurgery access.


[Clinico-epidemiological characteristics of HIV-positive immigrants: study of 371 cases].
The number of HIV-positive immigrants have increased in Spain in the last few years, and now represent a significant proportion of the epidemic. Our objective is to describe the clinico-epidemiological characteristics of HIV-positive immigrants seen in a specialist unit in Madrid. Retrospective study. Every patient born in a country other than Spain and attended an HIV Unit in Madrid between 1992 and 2009 was included. Of the 371 patients included, 53.1% were Latin Americans, 24.5% Sub-Saharan Africans, and 22.4% others), and 60% were males. Immigrants represented 0.3% of new patients in 1992 and rose to 49.2% in 2009. The principal reason for HIV testing had been pregnancy/delivery among women (32.7%) and having a category-B disease among men (17.4%). Sexual transmission accounted for 92% of patients. Tuberculosis was the principal AIDS-diagnosing illness. Respectively 90%, 7.7%, 60%, 26.7%, 96% and 95% of patients had an IgG for HAV, HCV, Toxoplasma, Treponema, CMV and VZV. VHB-Ags+: 5.4%; PPD+: 17%. At least one syphilis episode was recorded in 62% of the men who have sex with men (MSM). Prevalence of HLA-B5701 was 6%, 0.9% and 3.8% in Caucasians, Amerindians and Afro-Americans, respectively. Immigrants represent a significant proportion of new HIV-positive patients. It is a very heterogeneous group according to their clinical and epidemiological characteristics.


Serotonin in nasal secretion.
The aim of this study was to investigate the serotonin content in nasal secretion. Histamine- and methacholine-induced nasal secretions were collected during a 5-min period after challenge in 33 normal subjects. Serotonin was determined radioenzymatically and was found in 66% of pure, blown secretions. The median concentration of serotonin in histamine- and methacholine-induced secretions was 6.3 nmol/l (range less than 1.6-52.0) and 2.3 nmol/l (range 1.6-140.0) (NS), respectively. The serotonin concentration in allergen-induced nasal secretions in 7 rhinitis patients was 0.8 to 159 nmol/l, median 10.4 nmol/l which did not differ from the serotonin levels in the normal subjects. The serotonin concentration in nasal lavage fluids in 5 subjects was low (below the detection limit in 78% of the samples). Further studies of serotonin in patients with nasal hypersecretion are indicated.


Decomposing intersectional inequalities in subjective physical and mental health by sex, gendered practices and immigration status in a representative panel study from Germany.
The mapping of immigration-related health inequalities remains challenging, since immigrant populations constitute a heterogenous socially constructed group whose health experiences differ by social determinants of health. In spite of the increasing awareness that population mobility and its effects on health are highly gendered, an explicit gender perspective in epidemiology is often lacking or limited. To map inequalities in self-reported physical and mental health in Germany at the intersections of sex, gendered practices and immigration status, we used data from the German Socioeconomic Panel (SOEP) and applied an intercategorical intersectional approach conducting multilevel linear regression models. We differentiated between sex (male/female) as reported in the survey and gendered social practices, quantified through a gender score (on a femininity-masculinity continuum). We included 20,897 participants in our analyses. We saw an intersectional gradient for physical and mental health. Compared to the reference group, i.e. non-immigrant males with masculine gendered practices, physical and mental health steadily decreased in the intersectional groups that did not embody one or more of these social positions. The highest decreases in health were observed in the intersectional group of immigrant females with feminine gendered practices for physical health (-1,36; 95% CI [-2,09; -0,64]) and among non-immigrant females with feminine practices for mental health (-2,51; 95% CI [-3,01; -2,01]). Patterns of physical and mental health vary along the intersectional axes of sex, gendered practices and immigration status. These findings highlight the relevance of intersections in describing population health statuses and emphasise the need to take them into account when designing public health policies aiming at effectively reducing health inequalities.


2-Aryl-8-aza-3-deazaadenosine analogues of 5'-O-[N-(salicyl)sulfamoyl]adenosine: Nucleoside antibiotics that block siderophore biosynthesis in Mycobacterium tuberculosis.
A series of 5'-O-[N-(salicyl)sulfamoyl]-2-aryl-8-aza-3-deazaadenosines were designed to block mycobactin biosynthesis in Mycobacterium tuberculosis (Mtb) through inhibition of the essential adenylating enzyme MbtA. The synthesis of the 2-aryl-8-aza-3-deazaadenosine nucleosides featured sequential copper-free palladium-catalyzed Sonogashira coupling of a precursor 4-cyano-5-iodo-1,2,3-triazolonucleoside with terminal alkynes and a Minakawa-Matsuda annulation reaction. These modified nucleosides were shown to inhibit MbtA with apparent Ki values ranging from 6.1 to 25nM and to inhibit Mtb growth under iron-deficient conditions with minimum inhibitory concentrations ranging from 12.5 to >50μM.


Improved accuracy in the assessment of vertebral cortical thickness by quantitative computed tomography using the Iterative Convolution OptimizatioN (ICON) method.
Vertebral whole bone strength is substantially affected by cortical bone properties. Disease and therapy may affect cancellous and cortical bone differently. Unlike Dual X-ray Absorptiometry (DXA), Quantitative Computed Tomography (QCT) permits selective assessment of cortical and cancellous bone, but image quality limits the accuracy. We present an image processing method specifically adopted to thin cortices that substantially improves accuracy. Ten human vertebrae embedded in epoxy resin were imaged using clinical QCT and High-Resolution QCT (HR-QCT) protocols, both acquired on a clinical whole body CT scanner, whereas high resolution peripheral QCT (HR-pQCT) was used as gold standard. Microstructural variables and BMD were calculated using in-house software StructuralInsight for QCT and HR-QCT and the manufacturer's μCT evaluation software for HR-pQCT. An adjusted measure, a deconvolved cortical thickness (dcCt.Th), corrected for partial volume effects, was derived applying the new Iterative Convolution OptimizatioN (ICON) method. Direct measurements of cortical thickness (Ct.Th) showed substantial overestimation with mean ± standard deviation of 1.8 ± 0.5 mm for QCT and 1.5 ± 0.3 mm for HR-QCT compared to 0.37 ± 0.07 mm using HR-pQCT. Correlations of both QCT (r2 = 0.05, p > 0.5.) and HR-QCT (r2 = 0.38, p = 0.060) with the gold standard HR-pQCT were not significant. Also QCT-based BMD and BMC as well as HR-QCT-based BMD did not show a significant correlation with the gold standard approach. Only HR-QCT-based BMC showed a modest correlation (r2 = 0.59, p = 0.01) After applying ICON corrections, dcCt.Th resulted in 0.52 ± 0.09 mm for QCT and 0.43 ± 0.07 mm for HR-QCT, both significantly correlated to HR-pQCT (r2 = 0.75, p = 0.0012 and r2 = 0.93, p < 0.0001, respectively). The average overestimation bias of Ct.Th was reduced from (402 ± 157)% to (45 ± 17)% for QCT and from (330 ± 69)% to (19 ± 8)% for HR-QCT. Due to inaccurate segmentation uncorrected QCT-based Ct.Th measures as well as BMD and BMC showed no correlation to HR-pQCT and thus such bias cortical data can be misleading. The application of ICON reduced random overestimation bias to about 50 μm and 20 μm for QCT and HR-QCT, respectively, leading to a recovery of a significant correlation with the reference data of HR-pQCT. This reveals the potential for fairly accurate assessment of cortical thickness, allowing to better characterize cortical mechanical competence. These results warrant testing of the performance in vivo.


Self-disgust in patients with borderline personality disorder. The associations with alexithymia, emotion dysregulation, and comorbid psychopathology.
Self-disgust is a negative self-conscious emotion, which has been linked with borderline personality disorder (BPD). However, it has not yet been investigated in relation to both emotion dysregulation and alexithymia, which are recognized as crucial to BPD. Therefore, the aim of our study was to measure these variables and examine the possible mediational role of emotional alterations and comorbid anxiety and depression symptoms in shaping self-disgust in patients with BPD and healthy controls (HCs). In total, the study included 100 inpatients with BPD and 104 HCs. Participants completed: the Self-Disgust Scale (SDS), Disgust Scale - Revised (DS-R), Toronto Alexithymia Scale (TAS-20), Emotion Dysregulation Scale short version (EDS-short), Borderline Personality Disorder Checklist (BPD Checklist), State-Trait Anxiety Inventory (STAI), and Center for Epidemiologic Studies Depression Scale (CESD-R). Inpatients with BPD showed higher self-disgust, alexithymia, emotion dysregulation, core and comorbid symptoms levels, and lower disgust sensitivity. Alexithymia, emotion dysregulation, and trait anxiety partially mediated between BPD diagnosis and self-disgust. The relationship between the severity of BPD symptoms and self-disgust was fully mediated by alexithymia, emotion dysregulation, depressive symptoms, and trait anxiety. The results of our study may imply the contribution of emotion dysregulation, alexithymia, and comorbid psychopathology to self-referenced disgust in BPD.


Association of pre-treatment lymphocyte-monocyte ratio with survival outcome in patients with head and neck cancer treated with chemoradiation.
Given the role of systematic inflammation in cancer progression, lymphocyte-monocyte ratio (LMR) from peripheral blood has been suggested as a biomarker to assess the extent of inflammation in several solid malignancies. However, the role of LMR as a prognostic factor in head and neck cancer was unclear in several meta-analyses, and there is a paucity of literature including patients in North America. We performed an observational cohort study to evaluate the association of LMR with survival outcomes in North American patients with head and neck cancer. A single-institution, retrospective database was queried for patients with non-metastatic head and neck cancer who underwent definitive chemoradiation from June 2007 to April 2021 at the Roswell Park Comprehensive Cancer Center. Primary endpoints were overall survival (OS) and cancer-specific survival (CSS). The association of LMR with OS and CSS was examined using nonlinear Cox proportional hazard model using restricted cubic splines (RCS). Cox multivariable analysis (MVA) and Kaplan-Meier method were used to analyze OS and CSS. Pre-radiation LMR was then stratified into high and low based on its median value. Propensity scored matching was used to reduce the selection bias. A total of 476 patients met our criteria. Median follow up was 45.3 months (interquartile range 22.8-74.0). The nonlinear Cox regression model showed that low LMR was associated with worse OS and CSS in a continuous fashion without plateau for both OS and CSS. On Cox MVA, higher LMR as a continuous variable was associated with improved OS (adjusted hazard ratio [aHR] 0,90, 95% confidence interval [CI] 0.82-0.99, p = 0.03) and CSS (aHR 0.83, 95% CI 0.72-0.95, p = 0.009). The median value of LMR was 3.8. After propensity score matching, a total of 186 pairs were matched. Lower LMR than 3.8 remained to be associated with worse OS (HR 1.59, 95% CI 1.12-2.26, p = 0.009) and CSS (HR 1.68, 95% CI 1.08-2.63, p = 0.02). Low LMR, both as a continuous variable and dichotomized variable, was associated with worse OS and CSS. Further studies would be warranted to evaluate the role of such prognostic marker to tailor interventions.


Association of COVID-19 outcomes with diabetes in the Veneto region (north-east italy): Epidemiological insights for the endemic phase?
Diabetes mellitus is a prevalent chronic disease in patients who die of COVID-19. The aim of this study was to investigate the clinical and metabolic characteristics of diabetic patients with COVID-19 during the pre-vaccination phase. A retrospective cohort study was conducted from February 2020 to February 2021 to examine the clinical and metabolic profiles of unvaccinated diabetic patients affected by COVID-19. Data were collected from claim databases, hospital discharge records, and clinical records within a healthcare district located in northeastern Italy with a population of 936,000. Potential prognostic indicators including sex, age, Body Mass Index (BMI), duration and type of diabetes, metabolic control, and the use of antidiabetic, antihypertensive, lipid-lowering, and antiplatelet therapies were investigated. For hospitalized patients, additional variables were recorded, such as length of hospital stay, blood pressure at admission, comorbidities, D-dimer levels, blood glucose (BG), in-hospital insulin and corticosteroid therapies, requirement for mechanical ventilation (i.e., orotracheal or tracheostomy), admission to the Intensive Care Unit (ICU), and mortality. Diabetic patients hospitalized for COVID-19 with a poorer prognosis were characterized by advanced age, longer diabetes duration, hypertension, higher usage of sulfonylureas, and lower usage of dietotherapy alone, metformin, Glucagon-Like Peptide-1 Receptor agonists (GLP1-Ra), and Renin-Angiotensin-Aldosterone System inhibitors (RAAS-i). Considering the potential for COVID-19 to become endemic, special care should be taken in managing older diabetic patients' treatments.


Roles of pyroptosis in atherosclerosis pathogenesis.
Pyroptosis is a pro-inflammatory type of regulated cell death (RCD) characterized by gasdermin protein-mediated membrane pore formation, cell swelling, and rapid lysis. Recent studies have suggested that pyroptosis is closely related to atherosclerosis (AS). Previous studies reported that pyroptosis involving endothelial cells (ECs), macrophages, and smooth muscle cells (SMCs) plays an important role in the formation and development of AS. Pyroptosis not only causes local inflammation but also amplifies the inflammatory response and it aggravates plaque instability, leading to plaque rupture and thrombosis, eventually resulting in acute cardiovascular events. In this review, we clarified some novel pathways and mechanics and presented some potential drugs.


Ion-imprinted thermosensitive chitosan derivative for heavy metal remediation.
Ion-imprinted thermosensitive chitosan derivative (ITC) was successfully synthesized through a novel gradient heating process towards applications in heavy metal remediation, using Cu2+ template paired with N-isopropylacrylamide (NIPAM) monomer. SEM, DSC, FTIR and Raman spectroscopy were used to characterize the structure and properties of ITC. The phase change temperature (PCT) of ITC was 35.31 °C in the heating cycle, whereas in the cooling cycle the PCT for ITC was 26.27 °C. The adsorption capacity of ITC for Cu2+ at 45 °C (> PCT) was 88.94 mg/g. Desorption rate of 98.90 % was achieved after washing with ultra-pure water at 20 °C (< PCT). An adsorption capacity of 85 mg/g and a desorption rate of 97 % sustained after five cycles reuse. The adsorption capacity for Cu2+ was measured at 80.23 mg/g under other seven interfering metal ions. The adsorption kinetics and adsorption isotherm fitted pseudo-second-order and Langmuir equation, respectively.


From Threat to Opportunity: Harnessing the Invasive Carpobrotus edulis (L.) N.E.Br for Nutritional and Phytotherapeutic Valorization Amid Seasonal and Spatial Variability.
Carpobrotus edulis (L.) N.E.Br. (Hottentot-fig) is a problematic invasive species found in coastal areas worldwide. Mechanical removal is a common control method, leaving the removed biomass available as a possible source of natural phytochemicals with prospective commercial applications. While the Hottentot-fig's vegetative organs have been studied previously, this work establishes for the first time a seasonal and spatial comparative analysis of its nutritional, chemical, and bioactivity profiles (in three locations over four seasons). Proximate and mineral contents were assessed, along with its phenolic composition and in vitro antioxidant and anti-inflammatory properties. Hottentot-fig's biomass offered a good supply of nutrients, mainly carbohydrates, proteins, and minerals, with a tendency for higher concentrations of the most relevant minerals and proteins in autumn and winter, and in plants from sites A (Ria de Alvor lagoon) and B (Ancão beach). The extracts were rich in polyphenolics, with higher levels in spring and summer, especially for luteolin-7-O-glucoside and salicylic and coumaric acids. The extracts were also effective antioxidants, with stronger radical scavenging activities in spring and summer, along with anti-inflammatory properties. Our results suggest that the usually discarded plant material of this invasive halophyte could be valuable as a source of natural products with potential biotechnological applications in the food and nutraceutical industries.


Preparing Map of Chromosome Territory Distribution Frequency.
The chromosomes in mammalian interphase nuclei are organized into domains called chromosome territories that play a major role in nuclear organization. Here we propose a methodology that combines the use of micro-patterning of adhesive molecules to impose single-cell geometry, with visualization of chromosome territories. This allows obtaining a representative statistical map of the absolute positions of chromosome territories relative to the geometry imposed to the cell population by combining the signal from each cell.


Can Type 2 Diabetes Sufferers Actually Estimate Serum Glucose Level From Interstitial Fluid Glucose Level: A Diabetes Patient's Experience.
The general assumption is that blood glucose (BG) and interstitial fluid glucose (IntFG) are practically the same. We aimed to determine whether the typical patient with type 2 diabetes can use IntFG to estimate BG. The study was conducted on an 83-year-old white male with type 2 diabetes. One hundred pairs of IntFG and BG observations mg/dL (n = 50 simultaneous; n = 50 with 15-minute lag) were made over a 10-day period. We used paired t tests, correlation coefficients, and linear regression to predict relationships between IntFG and BG. There were significant (P < .0001) mean differences between IntFG and BG (simultaneous: 53.8 mg/dL; 15-minute time lag: 46.4 mg/dL). There were significant (P < .0001) positive correlations between IntFG and BG (simultaneous: r = 0.641; 15-minute time lag: r = 0.712). Linear regression revealed that increased IntFG was significantly (P < .0001) associated with declines in mean predicted BG. The typical type 2 diabetes patient cannot use IntFG level to estimate BG.


Partial cystectomy: can it be incorporated into integrated therapy program?
A retrospective study of 23 partial cystectomies for bladder cancer performed during a twelve-year period revealed no operative deaths and a low morbidity. Bladder capacity was little affected by the use of preoperative radiotherapy, and complications were minimal. The results suggest that protracted radiotherapy can be used preoperatively without adversely influencing operative complications.


Monkey interferon: activity on human cells and chromatographic properties. Brief report.
Monkey interferon (MKIF) produced in monkey BSC-1 cells infected with Newcastle disease virus showed antiviral activity on human foreskin fibroblasts and RD114cells--a human line transformed by feline sarcoma virus. The titer of the monkey interferon in human cells was 10--30 fold greater than that found in several normal monkey (BSC-1, CV-1 or SV 40 transformed (C2, C6, T-22) monkey cell lines tested. Ten to fifteen-fold purification of MKIF without loss of activity could be achieved by chromatography on Phenyl-Sepharose CL-4B. Antiviral activity of MKIF was fully resistant to treatment with 1 per cent sodium dodecyl sulfate (SDS).


Plasminogen activator in chick embryo muscle cells: induction of enzyme by RSV, PMA and retinoic acid.
To explore the generality of the effects of sarcoma viruses, tumor-promoting phorbol esters and retinoic acid, we have studied plasminogen activator production in differentiating chick myogenic cultures. Although slightly higher than in chick fibroblast cultures, the level of spontaneously synthesized enzyme is low; it reaches a peak shortly after maximum cell fusion has been completed and then declines. Rous sarcoma virus (RSV) transformation of differentiating myotubes was accomplished by infecting myoblasts with a temperature-sensitive mutant, maintaining cultures at the nonpermissive temperature until completion of fusion and shifting to permissive temperatures at selected times thereafter. RSV transformation, phorbol myristate acetate (PMA) and retinoic acid all induced high levels of plasminogen activator production by differentiating myotubes in the absence of DNA synthesis. In comparison with fibroblasts, virus-induced enzyme synthesis by myogenic cultures proceeded more slowly but ultimately reached comparably high levels. Whereas cAMP strongly repressed RSV- and PMA-induced plasminogen activator production by chick fibroblasts, it weakly stimulated enzyme synthesis by myotubes. This suggests that enzyme induction by RSV and PMA is not mediated primarily through effects on cAMP metabolism.


Lipid profiles in patients with juvenile idiopathic arthritis: a systematic literature review and meta-analysis.
The purpose of this study was to comprehensively evaluate the lipid profiles in patients with juvenile idiopathic arthritis (JIA). The literature and relevant reviews were searched for published clinical studies on the relationship between JIA and blood lipid levels. The Newcastle-Ottawa scale (NOS) was applied to evaluate the risk and methodological value of the included case‒control and cohort studies. Standardized mean differences (SMDs) and 95% confidence intervals were derived for all variables with adequate unprocessed data. This meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. In total, 16 studies were incorporated through screening. The analysis findings revealed that the levels of very low-density lipoprotein cholesterol [SMD=-0.411, 95% CI (-0.774~-0.048), P = 0.026], high-density lipoprotein cholesterol [SMD=-0.528, 95% CI (-0.976~-0.079), P = 0.021], and apolipoprotein A1 [SMD=-1.050, 95% CI (-1.452~-0.647), P = 0.000] in JIA patients were statistically lower than those observed in healthy controls. The level of low-density lipoprotein cholesterol [SMD = 0.202, 95% CI (0.003 ~ 0.400), P = 0.046] was significantly higher in JIA patients than in healthy controls. In JIA patients, body mass index [SMD=-0.189, 95% CI (-0.690 ~ 0.311), P = 0.459], high-density lipoprotein [SMD =-1.235, 95% CI (-2.845 ~ 0.374), P = 0.133), low-density lipoprotein [SMD = 0.616, 95% CI (-0.813 ~ 2.046), P = 0.398), triglycerides (SMD = 0.278, 95% CI (-0.182 ~ 0.738), P = 0.236], total cholesterol [SMD=-0.073, 95% CI (-0.438 ~ 0.293), P = 0.696] and apolipoprotein B levels [SMD = 0.226, 95% CI (-0.133 ~ 0.585), P = 0.217] were not significantly different from those in healthy controls. The outcomes of this meta-analysis suggest that dyslipidemia is common in JIA patients compared to healthy controls. Patients with JIA have a significantly increased risk of atherosclerosis and cardiovascular disease later in life.


Effects of different doses of exercise in adjunct to diet-induced weight loss on the AGE-RAGE axis in patients with short standing type 2 diabetes: Secondary analysis of the DOSE-EX multi-arm, parallel-group, randomised trial.
These secondary analyses aimed to investigate the effects of different volumes of exercise in adjunct to diet-induced weight loss and standard care on advanced glycation end-products (AGEs) and receptor for AGE (RAGE). We hypothesized that exercise in adjunct to a diet-induced weight loss would dose-dependently increase the soluble decoy receptor for AGE (sRAGE) more than diet-induced weight loss and standard care alone. Secondarily, we expected changes in sRAGE to be associated with improved glycaemic control and inversely associated with low-grade inflammation. The DOSE-EX study was a 16-week parallel-group, 4-arm, single-centre, assessor-blinded, randomised, controlled trial (NCT03769883). We included persons living with T2D, duration ≤7 years, BMI >27 kg/m2 and <40 kg/m2, without severe diabetic complications. Participants were randomised (1:1:1:1) to either 1) standard care as control (CON), 2) standard care + diet (DCON), 3) standard care + diet + moderate exercise dose (MED) or 4) standard care + diet + high exercise dose (HED). Standard care included algorithm-guided pharmacological treatment. The diet intervention aimed at 25% reduced energy intake. The supervised exercise sessions included two aerobic sessions + one combined (aerobic and resistance training) session per week for the MED group, and four aerobic sessions + two combined sessions per week for the HED group. Primary outcome was the change in sRAGE from baseline to 16-week follow-up. Secondary outcomes encompassed changes in advanced glycation endproducts (AGE), glycaemic control and markers of low-grade inflammation. A total of 80 participants (CON: n = 20, DCON: n = 19, MED: n = 20, HED: n = 21) were included in this secondary analysis. The mean age was 58.3 years (SD 9.9), 53% males, and median T2D duration was 4.1 years (IQR 2.0-5.5). No change in sRAGE was observed in any of the groups from baseline to follow-up (p > 0.05). A 16-week intervention with either three or six exercise sessions per week in adjunct to diet-induced weight loss did not change the levels of sRAGE in persons living with well-regulated, short standing T2D.


Self-Report Data on Regular Consumption of Illicit Drugs and HIV Risk Behaviors after Kratom (Mitragyna Speciosa korth.) Initiation among Illicit Drug Users in Malaysia.
This study sought to determine the relationship between kratom (Mitragyna speciosa) initiation and regular consumption of illicit drugs and HIV risk behaviors in a cohort of illicit drug users in Malaysia. 260 illicit drug users with current kratom use were recruited through convenience sampling for this cross-sectional study. All were male, with the majority being Malays (95%, n = 246/260). Results suggest that kratom initiation was associated with significant decrease in the regular use of heroin (odds ratio (OR) = 0.50, 95% confidence interval (CI): 0.40- 0.72; p = .0001), methamphetamine (OR = 0.23, CI: 0.16- 0.35; p < .0001), and amphetamine (OR = 0.17, CI: 0.09- 0.34; p < .0001). Kratom initiation was also associated with reduction in regular HIV risk behaviors such as having sex with sex workers (OR = 0.20, CI: 0.12-0.32; p < .0001), using drugs before sexual intercourse (OR = 0.20, CI: 0.13- 0.31; p < .0001), injecting behaviors (OR = 0.10, CI: 0.04- 0.25; p < .0001), sharing of injection equipment (OR = 0.13, CI: 0.04- 0.43; p < .0001), and injecting with other injection drug users (IDUs) (OR = 0.07, CI: 0.02- 0.24; p < .0001).


Treatment of pancreatic cystic neoplasm: surgery or conservative?
Pancreatic cystic neoplasms (PCNs) are a heterogeneous group of tumors with distinct biological features. These neoplasms are now being recognized more frequently owing to advances in cross-sectional imaging and increasing awareness. Guidelines for treatment of the common and clinically important PCNs frequently have been revised in view of the continuing controversies and evolving clinical data. This review summarizes the management approaches of the common and clinically important PCNs based on current evidence and guidelines.


Malignant presacral teratoma in children.
Malignant presacral teratoma is a rare tumor seen predominantly in young female children. The introduction of planned multidisciplinary treatment has improved the outlook for patients with this once dismal disease. Six female children were seen at Memorial Hospital with the diagnosis of malignant presacral teratoma. Five children were age 17 mo to 3 yr and the sixth child was 13 yr old at diagnosis. Presenting symptoms included masses in the buttock or groin, constipation, difficulty voiding, and local pain. Pathological features were varied and complex but three had predominantly endodermal sinus features. One child had the malignant presacral teratoma develop 18 mo after successful resection of a benign sacrosoccygeal teratoma in the newborn period. Treatment varied in the six cases since all were referred after failure of treatment elsewhere. All children had surgery, irradiation, and multiple drug chemotherapy. Four of the six children are surviving disease-free, 3 more than 24 mo off treatment. Evolution of treatment up to the present protocol management is discussed.


QSAR modeling of blood:air and tissue:air partition coefficients using theoretical descriptors.
Human blood:air, human and rat tissue (fat, brain, liver, muscle, and kidney):air partition coefficients of a diverse set of organic compounds were correlated and predicted using structural descriptors by employing CODESSA-PRO and ISIDA programs. Four and five descriptor regression models developed using CODESSA-PRO were validated on three different test sets. Overall, these models have reasonable values of correlation coefficients (R(2)) and leave-one-out correlation coefficients (R(cv)(2)): R(2) = 0.881-0.983; R(cv)(2) = 0.826-0.962. Calculations with ISIDA resulted in models based on atom/bond sequences involving two to three atoms with statistical parameters that were similar to those of models obtained with CODESSA-PRO (R(2) = 0.911-0.974; R(cv)(2) = 0.831-0.936). A mixed pool of molecular and fragment descriptors did not lead to significant improvement of the models.


MR imaging of squamous cell carcinoma of the larynx and hypopharynx.
Despite recent diagnostic advances, the laryngopharynx remains an area where accurate assessment of tumor size and extent is difficult. Computed tomography has proven helpful in delineating lesions in these areas, yet significant limitations exist. In an attempt to more accurately evaluate laryngopharyngeal neoplasms, MR imaging was performed in 25 consecutive patients with squamous cell carcinoma of the larynx and hypopharynx. Mr imaging was analyzed for its utility in clinical staging, assistance in selection of candidates for conservation, Laryngeal surgery, and ability to reliably predict cartilage invasion. MR imaging improved the accuracy of tumor staging by 40% and was valuable in the selection of candidates for conservation surgery. In addition, MR imaging was able to predict cartilage invasion in 6 of 6 patients with pathologic confirmation with a single false-positive case. MR imaging appears to be a reliable indicator of tumor size and location and should be judiciously incorporated into the staging and pretreatment planning of patients presenting with laryngopharyngeal malignancies.


Elucidation of the bonding in Mn(eta2-SiH) complexes by charge density analysis and T1 NMR measurements: asymmetric oxidative addition and anomeric effects at silicon.
The bonding in Mn(eta2-SiH) complexes is interpreted in terms of an asymmetric oxidative addition whose extent is controlled by the substitution pattern at the hypercoordinate silicon centre, and especially by the ligand trans to the eta2-coordinating SiH moiety.


Single-Fiber Recordings of Nociceptive Fibers in Patients With HSAN Type V With Congenital Insensitivity to Pain.
Nerve growth factor (NGF) is a protein important for growth and survival, but also for modulation of sensitivity of nociceptors and sympathetic neurons. The purpose of the present study was to investigate the effects of reduced NGF signaling in patients with hereditary sensory and autonomic neuropathies type V, congenital insensitivity to pain, caused by a mutation of the NGFβ gene, including a characterization of single nociceptive fibers using microneurography (MNG). One homozygote and 2 heterozygote patients with this mutation were examined with electromyography/neurography, thermal testing, quantitative sudomotor axon reflex test, and electrically induced axon reflex erythema in addition to MNG. Low quantitative sudomotor axon reflex test measurements of 0.02 (left foot) and 0.03 (right foot) μL/cm and elevated thermal thresholds for warmth and cold detection testing showed clear impairment of small nerve fibers, both sudomotor efferent and somatic afferent fibers, in the patient homozygote for the mutation. MNG from one of the heterozygote patients revealed changes in the small nociceptive fibers in skin, including abnormally low conduction velocity, spontaneous activity in A-δ fibers and C-nociceptors and abnormal or lacking response to heat. The findings of grossly intact pain thresholds compared with anamnestic insensitivity of pain in deep somatic tissue such as bone suggest a gradient of impairment dependent on different NGF availability in various tissues. Even though these patients in some aspects report insensitivity to pain, they also report chronic spontaneous pain as their main symptom, strikingly highlighting differential mechanisms of insensitivity to evoked pain versus spontaneous pain.


Morphological study of the effects of ozone on rat lung. II. Long-term exposure.
To evaluate the morphological changes observed in animals after prolonged ozone exposure, 56 male rats were exposed to a high ambient level of ozone (0.5 ppm) 6 hr a day, 6 days a week, for 2, 3, 5, and 12 months and examined by light and electron microscopy. Bronchitis and peribronchitis were observed throughout the exposure periods, and connective tissue around the bronchi thickened as a result of fibrosis. Some bronchiolar ciliated cells were in a degenerated condition and others in a reparative phase. Hyperplastic nodules were not found in the bronchioles, but hyperplasia of the bronchiolar epithelium was observed. Hyperplasia of lymphoid nodules around small vessels was prominent after 2 months of exposure. After 3 months of exposure, alveolar ducts were lined by type 2 cells, and after 12 months, by the bronchiolar epithelium consisting of both ciliated and nonciliated cells. Alveolar macrophages accumulated in the centriacinar alveoli. Fibrous strands were seen to be deposited in alveolar ducts after 3 months, and in bronchioles after 5 months. This fibrosis was due to an increment in collagen fibers. The degree of fibrosis increased with the length of ozone exposure.


Characterization of increased synthesis of acute phase proteins from plasma concentration measurements: a system analysis of the ideal situation with use of computer simulation.
A method for characterizing the secretion of acute phase proteins in vivo from serial plasma concentration measurements is presented. By using a simple two-compartment model it was found that descriptive parameters could be derived from the time course of the increased plasma concentration of the protein. It was assumed that the secretion of an acute phase protein is adequately described by: (i) the start time t1; (ii) the end time t2; (iii) the magnitude of increased flux of the protein from synthetic sites to the extracellular space, described by a turnover index, S. The influence of sampling interval and analytical precision on the reliability of the estimated parameter values was investigated in the ideal situation by using computer simulation. It was found that informative estimates of the secretion rate of an acute phase protein could be obtained provided a fairly high analytical precision with a coefficient of variation less than or equal to 0.01 and using a sampling interval between 0.5--2 h.


Associations of depression score with metabolic dysfunction-associated fatty liver disease and liver fibrosis.
Growing evidence suggests a link between depression and nonalcoholic fatty liver disease (NAFLD). Recently, a change from NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed. The aim of this study was to determine whether depression scores are associated with newly defined MAFLD as well as liver fibrosis in the US general population. This cross-sectional study utilized data from the 2017-March 2020 cycle of the National Health and Nutrition Examination Survey (NHANES) in the US. The depression score was assessed with the Patient Health Questionnaire-9 (PHQ-9). Transient elastography was utilized to evaluate hepatic steatosis and fibrosis with controlled attenuation parameters and liver stiffness measurements, respectively. All the analyses accounted for the complex design parameters and sampling weights of the survey. A total of 3263 eligible subjects aged 20 years and older were included. The estimated prevalence of mild and major depression was 17.0 % (95 % confidence interval [CI]: 14.8-19.3 %) and 7.1 % (6.1-8.1 %), respectively. For every one-unit increase in depression score, a subject was 1.05 (1.02-1.08) times more likely to have MAFLD. Compared to the minimal depression group, those with mild depression had an odds ratio (OR) of 1.54 (1.06-2.25) for MAFLD. The depression score was not associated with clinically significant liver fibrosis. The depression score measured by PHQ-9 was independently associated with MAFLD among US adults. Causal relationship is not available due to the cross-sectional nature of the survey design.


Arsenic partitioning among particle-size fractions of mine wastes and stream sediments from cinnabar mining districts.
Tailings from abandoned mercury mines represent an important pollution source by metals and metalloids. Mercury mining in Asturias (north-western Spain) has been carried out since Roman times until the 1970s. Specific and non-specific arsenic minerals are present in the paragenesis of the Hg ore deposit. As a result of intensive mining operations, waste materials contain high concentrations of As, which can be geochemically dispersed throughout surrounding areas. Arsenic accumulation, mobility and availability in soils and sediments are strongly affected by the association of As with solid phases and granular size composition. The objective of this study was to examine phase associations of As in the fine grain size subsamples of mine wastes (La Soterraña mine site) and stream sediments heavily affected by acid mine drainage (Los Rueldos mine site). An arsenic-selective sequential procedure, which categorizes As content into seven phase associations, was applied. In spite of a higher As accumulation in the finest particle-size subsamples, As fractionation did not seem to depend on grain size since similar distribution profiles were obtained for the studied granulometric fractions. The presence of As was relatively low in the most mobile forms in both sites. As was predominantly linked to short-range ordered Fe oxyhydroxides, coprecipitated with Fe and partially with Al oxyhydroxides and associated with structural material in mine waste samples. As incorporated into short-range ordered Fe oxyhydroxides was the predominant fraction at sediment samples, representing more than 80% of total As.


Integrated testis transcriptome and whole genome analysis of sexual maturity in Large White and Tongcheng pigs.
Testicular development and spermatogenesis play critical roles in male fertility and sexual maturation. To explore the genetic basis and key genes related to sexual maturity, we measured serum testosterone content and analysed testis tissue sections of Large White (LW) and Tongcheng (TC) boars at an immature age. We then screened differentially expressed genes (DEGs) in testis development in both breeds using RNA-seq. Finally, we analysed the selection signatures of both breeds to investigate which DEGs were subjected to positive selection. Our findings showed that serum testosterone contents in TC pigs (~4 ng/mL) were much higher than those in LW pigs (<0.95 ng/mL). Haematoxylin and eosin staining of testicular sections showed that the cross-sectional areas and perimeters of the seminiferous tubules in TC testes were larger and longer than those in LW pigs. A total of 5068 DEGs were selected by filtering criteria of q value <0.05 and |log2 (fold change)| ≥ 1. Gene Ontology analysis revealed that 250 genes were enriched in 11 biological process categories involved in sexual maturity. Most candidate genes, including TRIP13, NR6A1, STRA8, PCSK4, ACRBP, TSSK1B and TSSK6, were under positive selection. These results provide a better understanding of the genetic basis for testicular maturation and are useful for enhancing boar reproductive traits through molecular breeding.


Random resampling numerical simulations applied to a SEIR compartmental model.
In this paper, we apply resampling techniques to a modified compartmental SEIR model which takes into account the existence of undetected infected people in an epidemic. In particular, we implement numerical simulations for the evolution of the first wave of the COVID-19 pandemic in Spain in 2020. We show, by using suitable measures of goodness, that the point estimates obtained by the bootstrap samples improve the ones of the original data. For example, the relative error of detected currently infected people is equal to 0.061 for the initial estimates, while it is reduced to 0.0538 for the mean over all bootstrap estimated series.


Attention-Deficit/Hyperactivity Disorder and Transitional Aged Youth.
Extensive research has been conducted on attention-deficit/hyperactivity disorder (ADHD) in children and adults; however, less is known about ADHD during the transition from childhood to adulthood. Transitional aged youth (TAY) with ADHD represents a particularly vulnerable population as their newfound independence and responsibility often coincides with the development of comorbid disorders. The purpose of this review is to provide an update on the evaluation, diagnosis, and treatment of TAY-ADHD. Recent studies discovering ADHD symptoms emerging in TAY call the classification of ADHD as a disorder necessarily developing in childhood into question. TAY-ADHD are also shown to be vulnerable to academic and social impairments, increased risky behavior, and comorbid psychiatric disorders. Due to the risk of stimulant diversion in TAY, providers are advised to take precaution when prescribing medication to this population. Recent studies demonstrating the efficacy of psychotherapy in conjunction with non-stimulant or extended release stimulant medication provide a feasible alternative. This review highlights research on the course and evaluation of ADHD, impairments and comorbidities specific to TAY, and treatments tailored to address the unique challenges associated with TAY-ADHD.


Synergistic effect of double Schottky potential well and oxygen vacancy for enhanced plasmonic photocatalytic U(VI) reduction.
Plasmonic photocatalysis is an effective strategy to solve radioactive uranium hazards in wastewater. A plasmonic photocatalyst Bi/Bi2O3-x@COFs was synthesized by in-situ growth of covalent organic frameworks (COFs) on Bi/Bi2O3-x surface for the U(VI) adsorption and plasmonic photoreduction in rare earth tailings wastewater. The presence of oxygen vacancy in Bi/Bi2O3-x and Schottky potential well formed by Bi and Bi2O3-x interface increased the number of free electrons, which induced localized surface plasmon resonance (LSPR) and enhanced the light absorption performance of composites. In addition, oxygen vacancy improved the Fermi level of Bi/Bi2O3-x, leading to another potential well between Bi2O3-x and COFs interface. The electron transport direction was reversed, thus increasing the electron density of COFs layer. COFs was an N-type semiconductor with specific binding U(VI) groups and suitable band structure, which could be used as an active reaction site. Bi/Bi2O3-x@COFs had 1411.5 mg g-1 removal capacity and high separation coefficient for U(VI) due to the synergistic action of photogenerated electrons and hot electrons. Moreover, the removal rate of uranium from rare earth tailings wastewater by regenerated Bi/Bi2O3-x@COFs was over 93.9%. The scheme of introducing LSPR and Schottky potential well provides another way to improve the photocatalytic effect.


Comparative study on effects of two different types of titanium dioxide nanoparticles on human neuronal cells.
Titanium dioxide (TiO2) are among most frequently used nanoparticles (NPs). They are present in a variety of consumer products, including food industry in which they are employed as an additive. The potential toxic effects of these NPs on mammal cells have been extensively studied. However, studies regarding neurotoxicity and specific effects on neuronal systems are very scarce and, to our knowledge, no studies on human neuronal cells have been reported so far. Therefore, the main objective of this work was to investigate the effects of two types of TiO₂ NPs, with different crystalline structure, on human SHSY5Y neuronal cells. After NPs characterization, a battery of assays was performed to evaluate the viability, cytotoxicity, genotoxicity and oxidative damage in TiO₂ NP-exposed SHSY5Y cells. Results obtained showed that the behaviour of both types of NPs resulted quite comparable. They did not reduce the viability of neuronal cells but were effectively internalized by the cells and induced dose-dependent cell cycle alterations, apoptosis by intrinsic pathway, and genotoxicity not related with double strand break production. Furthermore, all these effects were not associated with oxidative damage production and, consequently, further investigations on the specific mechanisms underlying the effects observed in this study are required.


Identifying the mediating role of socioeconomic status on the relationship between schizophrenia and major depressive disorder: a Mendelian randomisation analysis.
Depressive disorder prevalence in patients with schizophrenia has been reported to be 40%. People with low socioeconomic status (SES) are more likely to suffer from schizophrenia and major depressive disorder (MDD). However, the causal relationship between schizophrenia and depression and the potential mediating role of SES remains unclear. Two-sample Mendelian randomization (MR) analyses were conducted to explore the bidirectional causal relationship between schizophrenia and MDD with the largest sample size of European ancestry from public genome-wide association studies (sample size ranged from 130,644 to 480,359). Inverse variance weighted (IVW) method was used as the primary analysis, and several canonical MR methods were used as validation analyses. The mediating role of SES (educational years, household income, employment status, and Townsend deprivation index) was estimated by the two-step MR method. MR analyses showed that genetically predicted schizophrenia was associated with an increased risk of MDD (IVW odds ratio [OR] = 1.137 [95% CI 1.095, 1.181]). Reversely, MDD was also associated with an increased risk of schizophrenia (IVW OR = 1.323 [95% CI 1.118, 1.565]). The mediation analysis via the two-step MR method revealed that the causal effect of schizophrenia on MDD was partly mediated by the Townsend deprivation index with a proportion of 10.27%, but no significant mediation effect was found of SES on the causal effect of MDD on schizophrenia. These results suggest a robust bidirectional causal effect between schizophrenia and MDD. Patients with schizophrenia could benefit from the early and effective intervention of the Townsend deprivation index.


Announcing the winner of the John J. Sciarra IJGO Prize Paper Award for 2014.
The editors of the International Journal of Gynecology and Obstetrics (IJGO) are pleased to announce the winner of the prize paper award for the best clinical research paper from a low- or middle-income country published in the IJGO during 2014. The winning paper is: Dan K. Kaye, Othman Kakaire, Annettee Nakimuli, Scovia N. Mbalinda,Michael O. Osinde, Nelson Kakande. Survivors' understanding of vulnerability and resilience to maternal near-miss obstetric events in Uganda. Int J Gynecol Obstet 2014;127(3):265–8. It was published in the December 2014 issue of the IJGO.


Radiographic response to neoadjuvant therapy in pleural mesothelioma should serve as a guide for patient selection for cytoreductive operations.
Malignant pleural mesothelioma (MPM) is associated with poor prognosis despite advances in multimodal therapeutic strategies. While patients with resectable disease may benefit from added survival with oncologic resection, patient selection for mesothelioma operations often relies on both objective and subjective evaluation metrics. We sought to evaluate factors associated with improved overall survival (OS) in patients with mesothelioma who underwent macroscopic complete resection (MCR). Patients with MPM who received neoadjuvant therapy and underwent MCR were identified in a prospectively maintained departmental database. Clinicopathologic, blood-based, and radiographic variables were collected and included in a Cox regression analysis (CRA). Response to neoadjuvant therapy was characterized by a change in tumor thickness from pretherapy to preoperative scans using the modified RECIST criteria. In this study, 99 patients met the inclusion criteria. The median age of the included patients was 64.7 years, who were predominantly men, had smoking and asbestos exposure, and who received neoadjuvant therapy. The median change in tumor thickness following neoadjuvant therapy was -16.5% (interquartile range of -49.7% to +14.2%). CRA demonstrated reduced OS associated with non-epithelioid histology [hazard ratio (HR): 3.06, 95% confidence interval (CI): 1.62-5.78, p < 0.001] and a response to neoadjuvant therapy inferior to the median (HR: 2.70, CI: 1.55-4.72, p < 0.001). Patients who responded poorly (below median) to neoadjuvant therapy had lower median survival (15.8 months compared to 38.2 months, p < 0.001). Poor response to neoadjuvant therapy in patients with MPM is associated with poor outcomes even following maximum surgical cytoreduction and should warrant a patient-centered discussion regarding goals of care and may therefore help guide further therapeutic decisions.


[Liver metastasis in colorectal cancer and tumor angiogenesis].
To investigate the association between tumor angiogenetic activity and metastatic potential of colorectal cancer (CRC) retrospectively. The microvessel density (MVD) and the level of vascular endothelial growth factor (VEGF) expression were examined immunohistochemically from 61 specimens obtained by surgical resection of CRC. MVD was (27.0 +/- 8.4) and the expression of VEGF was (59.75 +/- 12.36)%. Both were significantly higher in the group of liver metastasis, and in the group of lymph node metastasis (P < 0.01, P < 0.05). Survival analysis indicated a significant difference between increasing MVD group and the control group (P < 0.01). VEGF-mediated angiogenesis plays an important role in liver metastasis of CRC, and MVD appears to be a new prognostic factor for the prediction of outcome in patients with CRC.


Structural characterization of NDH-1 complexes of Thermosynechococcus elongatus by single particle electron microscopy.
The structure of the multifunctional NAD(P)H dehydrogenase type 1 (NDH-1) complexes from cyanobacteria was investigated by growing the wild type and specific ndh His-tag mutants of Thermosynechococcus elongatus BP-1 under different CO(2) conditions, followed by an electron microscopy (EM) analysis of their purified membrane protein complexes. Single particle averaging showed that the complete NDH-1 complex (NDH-1L) is L-shaped, with a relatively short hydrophilic arm. Two smaller complexes were observed, differing only at the tip of the membrane-embedded arm. The smallest one is considered to be similar to NDH-1M, lacking the NdhD1 and NdhF1 subunits. The other fragment, named NDH-1I, is intermediate between NDH-1L and NDH-1M and only lacks a mass compatible with the size of the NdhF1 subunit. Both smaller complexes were observed under low- and high-CO(2) growth conditions, but were much more abundant under the latter conditions. EM characterization of cyanobacterial NDH-1 further showed small numbers of NDH-1 complexes with additional masses. One type of particle has a much longer peripheral arm, similar to the one of NADH: ubiquinone oxidoreductase (complex I) in E. coli and other organisms. This indicates that Thermosynechococcus elongatus must have protein(s) which are structurally homologous to the E. coli NuoE, -F, and -G subunits. Another low-abundance type of particle (NDH-1U) has a second labile hydrophilic arm at the tip of the membrane-embedded arm. This U-shaped particle has not been observed before by EM in a NDH-I preparation.


The effect of lithium chloride on tumour appearance and survival of melanoma-bearing mice.
The possible effect of lithium chloride, a compound which reduces the incidence of infection in cancer patients, was investigated on murine melanoma. C57 BL syngeneic mice were inoculated i.p. with B16 melanoma cells. The animals were divided into 4 groups, receiving daily i.p. treatment with saline--group 1, controls; lithium chloride--group 2, bleomycin and vinblastine--group 3, and lithium chloride with bleomycin and vinblastine--group 4. Animals in group 4 had a significant delay in tumour appearance, a higher degree of tumour necrosis, and a longer survival rate. In addition a significant reduction of serum lithium concentration was noted in animals of this group in comparison with animals in group 2, treated with lithium chloride alone. There was no lithium-induced leukocytosis.


Comparison of two DNA extraction methods from larvae, pupae, and adults of Aedes aegypti.
Mosquitoes are the most important arthropods from the point of view of public health, due to the fact that they can transmit a large number of pathogens which can cause diseases to humans and animals. Aedes aegypti (L.) is one of the most important vector species in the world, since it can transmit numerous pathogens such as dengue, Zika, and chikungunya. Therefore, studies involving the molecular aspects of this and other mosquitoes species are currently increasing. In this report, we describe the comparison between two DNA extraction techniques, Chelex and cetyltrimethylammonium bromide (CTAB), for carrying out DNA extraction in larvae, pupae and adult female of Ae. aegypti. The Chelex technique was superior in the amount and purity of DNA as compared to the CTAB technique in the three life stages we tested.


Screening mammography in the American elderly.
Substantial differences exist in estimates of the proportion of elderly women who undergo screening mammography and the impact of race and ethnicity on mammography usage. A representative 5% sample of elderly women living in 11 Surveillance, Epidemiology, and End Results areas from 1991 to 2001 was constructed using Medicare data. Biennial rates of screening mammography (at least one mammogram within each 2-year period) were calculated for overlapping 2-year periods, adjusting to a 2000-2001 age and race distribution. Multivariate repeated-measures logistic regression was used to examine predictors of screening usage. The sample included 146,669 women. Between 1991 and 2001 the age- and race-adjusted proportion of women aged 65 years and older who underwent at least biennial screening mammography increased from 35.8% to 47.9%. Mammography screening increased for all racial and ethnic groups, but remained significantly higher for non-Hispanic white women as compared with all other groups. The biennial screening rate in 2000-2001 was 50.6% for non-Hispanic white, 40.5% for African-American, 34.7% for Asian-American, 36.3% for Hispanic, and 12.5% for Native-American women. After controlling for age, site, physician access, comorbidities, education, and income, African Americans (odds ratio [OR] = 0.80, 95% confidence interval [CI] = 0.78-0.83), Asian Americans (OR=0.53, CI = 0.51-0.55), Hispanics (OR = 0.70, CI = 0.67-0.74), and Native Americans (OR=0.37, CI=0.29-0.46) were still all less likely than non-Hispanic white women to undergo screening. Elderly women undergo significantly less mammography screening than is suggested by self-reported surveys. All groups of non-white women undergo less screening than do white women. The magnitude of the difference in screening rates comparing Asian-American and Hispanic women with white women is especially large; however, other studies have questioned the sensitivity of Medicare data for identifying people of Asian and Hispanic ethnicity. For African-American women, the magnitude of the gap is smaller, but it is of concern that the gap in screening as compared with white women has grown over time.


African American Screening and Enrollment in (Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage III) CLEAR III.
Under-enrolling minority patients in clinical trials reduces generalizability. CLEAR III, a randomized controlled trial, presented an opportunity to assess African American (AA) participation. AA enrollment was compared to U.S. population and NINDS trial data then stratified by region; census data for 42 recruitment cities were compared to screening and randomization percentages, using simple linear regression. AAs were 25% of screens and 45.1% of enrollments (n=370), more than twice the 19.8% participation rate reported by the 2011 NINDS Advisory Panel on Health Disparities Research and triple the projected 13.9% 2014 U.S. population. Conversion rates were (AA vs. non-AA): overall (8.7% vs. 3.4%, p<0.001); Northeast (7.7% vs. 2.9%, p<0.001); South (8.2% vs. 4.0%, p<0.001); Midwest (10.3% vs. 3.6%, p<0.01); and West (8.9% vs. 3.8%, p=0.02). AA enrollments ranged from 0% to 100% (mean: 40.4%). AA screening ranged from 0% to 63.7% (mean: 23.2%). AA city census ranged from 1.3% to 82.7% (mean: 28.0%); higher census was associated with higher screening (p<0.0001) and enrollment (p=0.004). AAs were willing to enroll in an acute stroke trial. AA city census rates should be considered when selecting enrollment centers and setting recruitment goals. Factors leading to successful AA recruitment should be further investigated, as population-based participation is a goal in all trials.


Has hyperglycemia a different prognostic role in STEMI patients with or without diabetes?
Hyperglycemia at hospital admission is a common finding in patients with STEMI. However, whether elevated acute glycemia in these patients may have a direct impact on worsening prognosis or is just a marker of a greater neurohormonal activation in response to the infarction is still unsettled. We sought to investigate the prognostic impact of hyperglycemia at hospital admission in patients undergoing primary PCI (pPCI) for STEMI, and the influence of the presence of diabetes mellitus (DM) on its prognostic impact. and Results, We enrolled 2958 consecutive STEMI patients treated by pPCI. Hyperglycemia was defined as plasma glucose >198 mg/dL (or >11 mmol/L). Patients with hyperglycemia showed a greater risk-profile; they also experienced a higher mortality both at univariable (17.6% vs 5.2%, p < 0.001) and multivariable (HR 1.9, 95%IC 1.5-2.9, p = 0.001) analysis. However, after stratification for DM presence, hyperglycemia resulted as an independent predictor of mortality only in patients without DM (HR 2, 95%IC 1.2-3.4, p = 0.01). Hyperglycemia in the setting of myocardial infarction treated with primary PCI in an independent predictor of all-cause mortality in patients without diabetes; in patients with diabetes, its prognostic impact seems attenuated.


Phase alterations of spin echoes by motion along magnetic field gradients.
Using a Taylor series expansion of the phase shift of a moving isochromatic spin group in the presence of a magnetic field gradient, the refocusing effects of the Carr-Purcell-Meiboom-Gill pulse sequence on stationary nuclei and those with constant, rectilinear velocity are readily demonstrated. Continuing the analysis to higher orders of motion reveals that nuclei with a constant, rectilinear acceleration have a phase shift at the spin echoes which increases linearly with echo number. Constant, rectilinear jerk (the time rate of change of acceleration) leads to an increase in phase shift from echo to echo which is quadratic in nature with an overlying reduction of the odd-numbered echoes by a constant amount. Motion parameters may be measured by parameter identification techniques. These principles may be applied to phase-sensitive NMR imaging.


[Analysis of skin changes in outpatients bitten by a tick during a 1-year period].
Ninety-two patients with tick bites (Ixodes ricinus) visited Outpatient clinic for dermatovenerology of Military Medical Academy during a period od one year. Tick bites were generally localized on lower extremities and were seasonal in character. Most patients were 50-59 years old. Typical early skin manifestations in the form of Erythema migrans were diagnosed in 19.56%, and atypical forms of erythema in 8.69%. Late manifestations of illness were found on only two patients.


A Retrospective Statistical Validation Approach for Panel of Normal-Based Single-Nucleotide Variant Detection in Tumor Sequencing.
An important step of somatic variant calling algorithms for deep sequencing data is quantifying the errors. For targeted sequencing in which hotspot mutations are of interest, site-specific error estimation allows more accurate calling. The site-specific error rates are often estimated from a panel of normal samples, which has limited size and is subject to sampling bias and variance. We propose a novel statistical validation method for single-nucleotide variation (SNV) calling based on historical data. The validation method extracts the high-quality reads from the Binary Alignment/Map (BAM) files, finds the negative samples in the data, and builds a statistical model to call individual samples. It is particularly useful in detecting low-frequency variants that may be missed by traditional panel of normal-based SNV methods. The proposed method makes it possible to launch a simple and parallel validation pipeline for SNV calling and improve the detection limit.


Antioxidant and anti-α-glucosidase compounds from the rhizome of Peltiphyllum peltatum (Torr.) Engl.
The antioxidant, anti-α-glucosidase and anticholinesterase effects of the alcohol extract of fresh underground rhizomes of Peltiphyllum peltatum were studied. A potent antioxidant activity accompanied by a selective α-glucosidase effect was observed for the crude extract. Further activity-guided fractionation (petroleum ether, chloroform, ethyl acetate, n-butanol and water) resulted in the identification of the ethyl acetate fraction with the highest antioxidant effect. Gallic acid, methyl-3-O-methyl gallate, catechin, gallocatechin, bergenin and 11-O-galloylbergenin were isolated from the ethyl acetate fraction. While all the isolated compounds did show a variable degree of radical scavenging effect, 11-O-galloylbergenin was identified as the selective α-glucosidase inhibitor. The isolation, structural elucidation and biological effects of these compounds are discussed.


Extraction of PFOA from dilute wastewater using ionic liquids that are dissolved in N-octanol.
Polyfluoroalkyl Substances (PFAS) such as perfluorooctanoic acid (PFOA) are resistant to biodegradation leading to adverse health outcomes. Therefore, PFAS removal from drinking water is paramount. Liquid-liquid extraction processes can remove them from water; however, the hydrophobic and oleophobic properties of PFOA lead to the low extraction efficiency and severe emulsification, especially for the ppm-levels concentration of PFOA. Therefore, we introduced ionic liquid (IL) methyltrioctylammonium bis(trifluoromethylsulfonyl)imide ([A336][NTf2]) as extractant into octanol. We found that using hexadecyl trimethyl ammonium bromide (CTAB) as an extractant caused severe and stable emulsion. In comparison, [A336][NTf2] could suppress the emulsification with high extraction efficiency. The extraction performance of PFOA was examined as a function of various parameters. The results showed that the extraction efficiency was strongly dependent on the concentration of IL and aqueous pH. Further research revealed the extraction mechanisms at the molecular-level, and density functional theory (DFT) and molecular dynamic (MD) simulation agreed with the trends in the experiment. We determined that the extraction efficiency of PFOA from water could be up to 88.21 wt% for the optimized condition, indicating that the extraction system of [A336][NTf2] + octanol was efficient for separating PFOA from the diluted aqueous solution.


[Endoscopic removal of foreign bodies and intraoperative endoscopy (author's transl)].
Foreign bodies of the upper GIT are regularly extracted with endoscopes, provided, that they have neither left the pylorus, changed their form, nor perforated the wall. Endoscopic extraction is recommended when safe and spontaneous discharge is uncertain. Impacted rectal foreign bodies usually need proctologic or abdominal surgery. Intraoperative endoscopy should be limited to those organs that are not attainable by preoperative inspection like cholangioscopy and peroral jejunoileoscopy.


[General rules of the management of diabetes with psychiatric disorders].
Psychiatric disorders appear to be frequent in patients with diabetes mellitus. The presence of psychiatric co-morbidity may affect adherence to medication and self-care regimes. To establish rules of the management of diabetes among people with psychiatric disorders. Literature review on the PUBMED database using the following keywords: diabetes, psychiatric disorders, anti-psychotics, complications. Psychiatric disorders appear to be frequent in patients with diabetes mellitus. Their presence is associated with poor glycemic control and more diabetes complications. This negative effect may be increased by taking atypical antipsychotics which expose to several metabolic effects such as overweight, insulin resistance, hyperglycemia, Type 2 diabetes and dyslipidemia. The management of diabetes among people with psychiatric disorders should be multidisciplinary including internist, diabetologist, psychiatrist, and paramedical staff. This treatment includes medical (anti-diabetics, anti-psychotics) and psychotherapeutic interventions through which we can have better glycemic control and decreased rates of diabetes complications.


The ultrastructural localization of transport ATPase in the rat liver at non-bile canalicular plasma membranes.
Na,K-ATPase in rat livers was localized cytochemically at the ultrastructural level. The Ernst technique, a method using p-nitrophenylphosphate (pNPP) substrate, was used to demonstrate ouabain-sensitive, K-dependent phosphatase, an enzyme of the Na,K-ATPase reaction sequence. Reaction product was localized predominantly on the sinusoidal and non-bile canalicular (intercellular) surfaces. This localization contrasts with previous histo-chemical studies using ATP substrate and with models that have considered the transport enzyme to be localized at the canalicular surface. If Na,K-ATPase is of importance in bile salt independent flow, a significant presence of the enzyme at sites other than the canalicular membrane suggests that a paracellular movement of sodium and water into the canaliculus must be considered.


European Cancer Organisation Essential Requirements for Quality Cancer Care (ERQCC): Lung cancer.
European Cancer Organisation Essential Requirements for Quality Cancer Care (ERQCC) are written by experts representing all disciplines involved in cancer care in Europe. They give patients, health professionals, managers and policymakers a guide to essential care throughout the patient journey. Lung cancer is the leading cause of cancer mortality and has a wide variation in treatment and outcomes in Europe. It is a major healthcare burden and has complex diagnosis and treatment challenges. Care must only be carried out in lung cancer units or centres that have a core multidisciplinary team (MDT) and an extended team of health professionals detailed here. Such units are far from universal in European countries. To meet European aspirations for comprehensive cancer control, healthcare organisations must consider the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis, to treatment, to survivorship.


Glycolytic and Oxidative Phosphorylation Defects Precede the Development of Senescence in Primary Human Brain Microvascular Endothelial Cells.
Alterations of mitochondrial and glycolytic energy pathways related to aging could contribute to cerebrovascular dysfunction. We studied the impact of aging on energetics of primary human brain microvascular endothelial cells (HBMECs) by comparing the young (passages 7-9), pre-senescent (passages 13-15), and senescent (passages 20-21) cells. Pre-senescent HBMECs displayed decreased telomere length and undetectable telomerase activity although markers of senescence were unaffected. Bioenergetics in HBMECs were determined by measuring the oxygen consumption (OCR) and extracellular acidification (ECAR) rates. Cellular ATP production in young HBMECs was predominantly dependent on glycolysis with glutamine as the preferred fuel for mitochondrial oxidative phosphorylation (OXPHOS). In contrast, pre-senescent HBMECs displayed equal contribution to ATP production rate from glycolysis and OXPHOS with equal utilization of glutamine, glucose, and fatty acids as mitofuels. Compared to young, pre-senescent HBMECs showed a lower overall ATP production rate that was characterized by diminished contribution from glycolysis. Impairments of glycolysis displayed by pre-senescent cells included reduced basal glycolysis, compensatory glycolysis, and non-glycolytic acidification. Furthermore, impairments of mitochondrial respiration in pre-senescent cells involved the reduction of maximal respiration and spare respiratory capacity but intact basal and ATP production-related OCR. Proton leak and non-mitochondrial respiration, however, were unchanged in the pre-senescent HBMECs. HBMECS at passages 20-21 displayed expression of senescence markers and continued similar defects in glycolysis and worsened OXPHOS. Thus, for the first time, we characterized the bioenergetics of pre-senescent HBMECs comprehensively to identify the alterations of the energy pathways that could contribute to aging.


Mitochondrial CB₁ receptors regulate neuronal energy metabolism.
The mammalian brain is one of the organs with the highest energy demands, and mitochondria are key determinants of its functions. Here we show that the type-1 cannabinoid receptor (CB(1)) is present at the membranes of mouse neuronal mitochondria (mtCB(1)), where it directly controls cellular respiration and energy production. Through activation of mtCB(1) receptors, exogenous cannabinoids and in situ endocannabinoids decreased cyclic AMP concentration, protein kinase A activity, complex I enzymatic activity and respiration in neuronal mitochondria. In addition, intracellular CB(1) receptors and mitochondrial mechanisms contributed to endocannabinoid-dependent depolarization-induced suppression of inhibition in the hippocampus. Thus, mtCB(1) receptors directly modulate neuronal energy metabolism, revealing a new mechanism of action of G protein-coupled receptor signaling in the brain.


Sawadalepis prima n. g., n. sp. (Cestoda: Cyclophyllidea) from the Schreiber's bent-winged bat Miniopterus schreibersii Kuhl (Chiroptera: Vespertilionidae) from China.
Sawadalepis n. g. is erected for Sawadalepis prima n. sp. in Schreiber's bent-winged bat Miniopterus schreibersii Kuhl (Chiroptera: Vespertilionidae) from southern China. Diagnostic features of the currently monotypic genus include attributes of the osmoregulatory system and female genital organs. The dorsal osmoregulatory canals are shifted bilaterally towards the margins of proglottides in relation to the ventral canals. The genital pores are unilateral and sinistral. Among female attributes, the copulatory part of the vagina is covered externally by a dense layer of intensely stained cells; the conductive part of the vagina is clearly distinguishable from the seminal receptacle; the uterus has ventral and dorsal diverticula, extending bilaterally beyond the longitudinal osmoregulatory canals; and the eggs are spherical with thick outer coat.


Response to, "On the origins of the linear no-threshold (LNT) dogma by means of untruths, artful dodges and blind faith.".
It is not true that successive groups of researchers from academia and research institutions-scientists who served on panels of the US National Academy of Sciences (NAS)-were duped into supporting a linear no-threshold model (LNT) by the opinions expressed in the genetic panel section of the 1956 "BEAR I" report. Successor reports had their own views of the LNT model, relying on mouse and human data, not fruit fly data. Nor was the 1956 report biased and corrupted, as has been charged in an article by Edward J. Calabrese in this journal. With or without BEAR I, the LNT model would likely have been accepted in the US for radiation protection purposes in the 1950's.


Associations of Type 1 diabetes mellitus, maternal vascular disease and complications of pregnancy.
Maternal diabetes increases the risk of pre-eclampsia and abnormalities of fetal growth. We studied the additional impact of maternal vascular disease on these risks. The first viable (> 23 weeks) pregnancies of 138 women with Type 1 diabetes mellitus (Type 1 DM), delivered between 1994 and 2003 at the Queen's Medical Centre, Nottingham, UK were studied. Women were divided into groups with and without vascular disease (retinopathy and/or nephropathy and/or pre-existing hypertension). Primary outcomes were pre-eclampsia and fetal customized birthweight percentile (cbp) (adjusted for maternal weight, height, parity, ethnicity, gestational age and gender). Secondary outcomes were perinatal outcome (miscarriage, intrauterine or neonatal death), preterm birth, birth asphyxia, neonatal hypoglycaemia and delivery mode. Women with vascular disease were more likely to develop pre-eclampsia (OR 3.5; CI 1.28-9.53) and deliver infants with lower cbp (median 89.0, range 0-100 vs. 98.0, range 0-100; P < or = 0.005). Infants were less likely to be macrosomic (OR 0.46; CI 0.224-0.928) but more likely to have intrauterine growth restriction (IUGR; OR 6.0; CI 1.54-23.33). Women with vascular disease had higher Caesarean section rates (90 vs. 56%, P < or = 0.001). Women with Type 1 DM and vascular disease are at greater risk of pre-eclampsia and pathological fetal growth. This should influence counselling and merit increased pregnancy surveillance.


Computer simulation of the motoneuron pool-muscle complex. I. Input system and motoneuron pool.
The aim of the present study was to simulate the input system and the motoneuron (MN) pool of the MN pool-muscle complex (MNPMC). Input fibers, which can originate from command centers in the central nervous system or from sensory organs, activate the MN pool. They generate sequences of action potentials, the frequency of which is proportional to a time-dependent activation factor (which is an input to the model). Different connection patterns between the input fibers and motor units (MUs) are allowed. For simplicity and since no precise experimental data are available, 70 input fibers and 4 boutons per fiber and MN are simulated (this corresponds approximately to the monosynaptic group-Ia input of the cat medial gastrocnemius muscle). Each bouton generates the same conductance change in the postsynaptic membrane. The MNs are modeled with a single compartment and a homogeneous membrane. According to experimental data, the membrane leakage conductance and capacitance are MU dependent. Since the precise relation is unknown: (a) the computed relation between MU contraction force and the MN leakage conductance was taken from a steady-state MNPMC model, and (b) the capacitance was assumed to be proportional to the leakage conductance. The MN membrane includes time- and voltage-dependent ionic channels (fast and slow K(+) and low- and high-threshold Ca(2+) channels). The density and time constant of the slow K(+) channels and the density of the Ca(2+) channels were fitted to approximate afterhyperpolarization characteristics and frequency-injected current relations of type-identified cat MNs. If the membrane reaches a voltage threshold the MNs generate action potentials, which were simulated by voltage pulses. The activation of the MN pool of the human first dorsal interosseus muscle was simulated with injected and synaptic currents in order to illustrate the size principle, synaptic noise, and other features of muscle activation. It is concluded that the present model reproduces the main properties of the input-output relations of different MN types within a muscle. Together with the simulation of the muscle force and the surface EMG, which will be published in subsequent papers, it will be a powerful tool for reproducing experiments on the motor system and investigating functional mechanisms of motor control.


Effectiveness of negative pressure wound therapy for the wound of ileostomy closure: a multicenter, phase II randomized controlled trial.
The American Society of Surgery and American Society for Surgical Infections issued guidelines for surgical site infections (SSIs) in December 2016. These guidelines recommend a purse-string suture (PSS) for stoma closure as it facilitates granulation and enables open wound drainage. This study investigated the effect of using negative pressure wound therapy (NPWT) along with standard PSS and aimed to determine the optimal period of NPWT use. The patients were divided into three groups as follows: Group A, postoperative wound management alone with gauze exchange as the representative of conventional PSS; Group B, the performed management was similar to that of Group A plus NPWT for 1 week; and Group C, the performed management was similar to that of Group A plus NPWT for 2 weeks. Regarding objective measures, the wound reduction rate was the primary outcome, and the incidence of SSIs, length of hospital stay, and wound healing duration were the secondary outcomes. In total, 30 patients (male: 18, female: 12) were enrolled. The average age was 63 (range: 43-84) years. The wound reduction rate was significantly higher in Group B than in Group A on postoperative days (PODs) 7 (66.1 vs. 48.4%, p = 0.049) and 10 (78.6 vs. 58.2%, p = 0.011), whereas no significant difference was observed on POD 14. Compared with Group A, Group C (POD 7: 65.9%, POD 10: 69.2%) showed an increase in the wound reduction rate on POD 7, although the difference was not significant (p = 0.075). SSIs were observed in Groups B (n = 2) and C (n = 2) (20%) but not in Group A (0%). The most effective duration of NPWT use for ileostomy closure with PSS in terms of the maximum wound reduction rate was from PODs 3 to 10. However, NPWT did not shorten the wound healing duration. NPWT may reduce the wound size but should be used with precautions for SSIs. The small sample size (30 cases), the use of only one type of NPWT system, and the fact that wound assessment was subjective and not blinded were the limitations of this study. Further studies are needed to confirm our findings. UMIN Clinical Trials Registry; UMIN000032174 (10/04/2018).


Ventricular septal rupture following nonsurgical septal reduction for hypertrophic cardiomyopathy: treatment with percutaneous closure.
An 82-year-old woman with severe symptomatic hypertrophic obstructive cardiomyopathy undergoes nonsurgical septal reduction, leading to immediate hemodynamic and functional improvement. Five weeks later, she presents with severe biventricular failure due to a large septal rupture with marked left-to-right shunting. The rupture is closed with an Amplatzer post-MI ventricular septal defect occluding device. Residual shunting through the device and a small residual shunt at its superior rim lead to severe hemolysis, which resolves spontaneously after 10 days of supportive therapy. A further self-limiting episode of hemolysis recurred 3 months later following a period of excessive anticoagulation.


Arachidonic acid modulates hippocampal calcium current via protein kinase C and oxygen radicals.
Arachidonic acid (AA) is a second messenger liberated via receptor activation of phospholipase A2 or diacylglycerol-lipase. We used whole-cell voltage clamp of acutely isolated hippocampal CA1 pyramidal cells to investigate the hypothesis that AA modulates Ca2+ channel current (ICa) via activation of protein kinase C (PKC) and generation of free radicals. AA depressed ICa in a dose- and time-dependent manner similar to that previously reported for the action of phorbol esters on ICa. A similar depression was seen with a xanthine-based free radical generating system. The specific PKC inhibitor PKCI (19-36), the protein kinase inhibitor H-7, and the superoxide free radical scavenger SOD each blocked ICa depression by 70%-80%. Complete block of the AA response occurred when SOD was used simultaneously with a PKC inhibitor. These data suggest that PKC and free radicals play a role in AA-induced suppression of ICa.


Second-look surgery plus HIPEC for patients with colorectal cancer at high risk of peritoneal carcinomatosis: Should we resect the initial anastomosis? An observational study.
Cytoreductive surgery (CCRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) improves the overall survival in selected cases of peritoneal carcinomatosis (PC) of colorectal origin. Second-look surgery in asymptomatic patients at high risk of developing PC has shown encouraging results. This study aims at identifying cases in which initial anastomosis should be resected. Patients treated by second-look surgery and HIPEC were identified from a prospective database. High-risk was defined as synchronous resected and minimal PC, ovarian metastasis or perforated primary tumor. Patients were divided in two groups based on intra-operative evaluation of the anastomosis: possibly-invaded (PI) and unlikely-invaded (UI). PI was defined as 1) PC away from the anastomosis, 2) nodules resting on the anastomosis 3) anastomotic stenosis or anastomotic thickening. Anastomosis in the PI group were resected. Forty patients were included: 12 in the PI group and 28 in the UI group. Incidence of pathological anastomotic invasion was 42% (5 on 12 patients) in the PI group. In the UI group, 2 patients had anastomotic recurrence, both associated with peritoneal recurrence. Morbidity and mortality was not influenced by anastomosis resection. The presence of suspicious nodules on the anastomosis had a sensitivity of 100% and a specificity of 89% in predicting anastomotic invasion. In second-look surgery and HIPEC for colorectal cancer at high-risk of PC, anastomosis should be resected when overlying PC nodules are found. This attitude is supported by high sensitivity of this finding for anastomotic invasion and low morbidity related to anastomotic resection.