Oral bioaccessibility of potentially toxic elements (PTEs) and related health risk in urban playground soil from a medieval bell metal industrial town Khagra, India.
In vitro oral bioaccessibility assay (simple bioaccessibility extraction test) was used to assess bioaccessible PTEs (As, Cd, Co, Cu, Fe, Mn, Ni, Pb, Sn, and Zn) in 16 playground soils of Khagra, which is a medieval bell metal industrial town at Murshidabad district, West Bengal, India. The aim was also to establish levels of potentially toxic elements (PTEs) in soil, their origin, and human health risk, particularly on children. The average pseudo-total PTEs content in playground soil samples was in the decreasing order of Fe (18,988 mg kg-1) > Zn (1229 mg kg-1) > Cu (999 mg kg-1) > Mn (343 mg kg-1) > Pb (181 mg kg-1) > Sn (132 mg kg-1) > Co (8.63 mg kg-1) > As (5.21 mg kg-1) > Cd (0.88 mg kg-1). The pollution indices indicate significant enrichment of Cd, Cu, Pb, Zn, and Sn in the playground. The bioaccessible percentage of PTEs in the 16 playground soils ranged from 0 to 80.25%, where the range of percentage of bioaccessibility was 13.24-62.50, 0-61.46, 16.82-28.79, 5.05-73.06, 0.96-6.14, 2.28-38, and 0-80 for As, Cd, Co, Cu, Fe, Ni, and Zn, respectively. The order of percentage of bioaccessibility was As > Mn > Zn > Sn > Cu > Co > Pb > Cd > Ni > Fe. PCA extracted two major factors indicating the anthropogenic (Cd, Cu, Ni, Pb, Zn, and Sn) and geogenic (Co, Fe, and Mn) source. Stepwise multiple regression analysis exhibited that the oral bioaccessibility of PTEs did not correlate with physicochemical parameters like pH, EC. In contrast, Sn had a significant correlation with that of organic matter. The health risk for pseudo-total as well as bioavailable fraction in playground soil depicted that children were more vulnerable to ingestion of soil contaminated with PTEs, particularly for Cu and Pb. A risk management plan with the bioaccessible data involving detailed site-specific exposure factors to indicate the importance of the study in terms of child health safety is required.


Membrane potential, lipid regulation and adenylate energy charge in acyl chain modified Acholeplasma laidlawii.
In Acholeplasma laidlawii variations induced in the transmembrane electrical potential have been shown to affect the membrane lipid composition. Particularly the molar ratio between the predominant glucolipids, monoglucosyldiacylglycerol and diglucosyldiacylglycerol, decreases upon hyperpolarization and increases upon depolarization (Clementz et al. (1986) Biochemistry 25, 823-830). Upon variation of the degree of membrane fatty acyl chain unsaturation, known to affect the passive permeability for a number of small molecules, there was no significant correlation between acyl chain composition and the magnitude of the electrical potential. Hyperpolarization by valinomycin decreased the glucolipid ratio for all kinds of membranes, but the size of the decrease was not correlated to the acyl chain composition. However, a clear relationship, independent of acyl chain composition, was found between the extent of hyperpolarization and the size of the decrease in the glucolipid ratio. The adenylate energy charge value (Ec) of the cells was affected by the acyl chain composition, although not exclusively by the proportion of unsaturation. Furthermore, a larger hyperpolarization upon valinomycin addition was accompanied by a stronger reduction in Ec.


Transcriptome sequencing analysis reveals a potential role of lncRNA NONMMUT058932.2 and NONMMUT029203.2 in abnormal myelin development of male offspring following prenatal PM2.5 exposure.
Numerous epidemiological studies have shown that PM2.5 exposure in early life can influence brain development and increase the risk of neurodevelopmental disorders in boys, but the underlying molecular mechanisms remain unclear. In the current study, pregnant C57BL/6 J mice were oropharyngeally administered with PM2.5 suspension (3mg/kg/2 days) until the birth of offspring. Based on mRNA expression profiles, two-way analysis of variance (two-way ANOVA) and weighted gene co-expression network analysis (WGCNA) were conducted to explore the most impacted neurodevelopmental processes in male offspring and the most significantly associated gene modules. Gene Ontology (GO) enrichment and Encyclopedia of Genes and Genomes (KEGG) pathway analyses suggested that prenatal PM2.5 exposure significantly altered several biological processes (such as substrate adhesion-dependent cell spreading, myelination, and ensheathment of neurons) and KEGG pathways (such as tight junction and axon guidance). We further found that PM2.5 exposure significantly changed the expression of myelination-related genes in male offspring during postnatal development and impaired myelin ultrastructure on PNDs 14 and 21, as demonstrated by the decreased thickness of myelin sheaths in the optic nerves, and mild loss of myelin in the corpus callosum. Importantly, lncRNA NONMMUT058932.2 and NONMMUT029203.2 played key roles in abnormal myelination by regulating the expression of several myelination-related genes (Fa2h, Mal, Sh3tc2, Trf and Tppp) through the binding to transcription factor Ctcf. Our work provides genomic evidence for prenatal PM2.5 exposure-induced neurodevelopmental disorders in male offspring.


[Algorithm for the Classification of Type 1 and Type 2 Diabetes Mellitus for the Analysis of Routine Data].
Diabetes mellitus is a disease of high public health relevance. To estimate the temporal development of prevalence, routine data of statutory health insurances (SHI) are being increasingly used. However, these data are primarily collected for billing purposes and the case definition of specific diseases remains challenging. In this study, we present an algorithm for differentiation of diabetes types analyzing SHI routine data. The basis for the analysis was an age and sex-stratified random sample of persons of the Barmer SHI with a continuous insurance duration from 2010 to 2018 in the magnitude of 1% of the German population. Diabetes was defined in the reporting year 2018, as documentation of (1) a "confirmed" ICD diagnosis E10.- to E14.- in at least two quarters, (2) a "confirmed" ICD diagnosis E10.- to E14.- in one quarter with an additional prescription of an antidiabetic drug (ATC codes A10), or (3) an ICD diagnosis E10.- to E14.- in the inpatient sector, outpatient surgery, or work disability. Individuals were assigned to a diabetes type based on the specific ICD diagnosis E10.- to E14.- and prescribed medications, differentiated by insulin and other antidiabetics. Still unclear or conflicting constellations were assigned on the basis of the persons' age or the frequency and observation of the diagnosis documentation over more than one year. The participation in a disease management program was considered in a sensitivity analysis. The prevalence of documented diabetes in the Barmer sample was 8.8% in 2018. Applying the algorithm, 98.5% of individuals with diabetes could be classified as having type 1 diabetes (5.5%), type 2 diabetes (92.6%), or another specific form of diabetes (0.43%). Thus, the prevalence was 0.48% for type 1 diabetes and 8.1% for type 2 diabetes in 2018. The vast majority of people with diabetes can be classified by their diabetes type on the basis of just a few characteristics, such as diagnoses, drug prescription, and age. Further studies should assess the external validity by comparing the results with primary data. The algorithm enables the analysis of important epidemiological indicators and the frequency of comorbidities based on routine data differentiated by type 1 and type 2 diabetes, which should be considered in the surveillance of diabetes in the future.


Segmentation and classification of brain tumors using fuzzy 3D highlighting and machine learning.
Brain tumors are among the most lethal forms of cancer, so early diagnosis is crucial. As a result of machine learning algorithms, radiologists can now make accurate diagnoses of tumors without resorting to invasive procedures. There are, however, a number of obstacles to overcome. To begin, classifying brain tumors presents a significant difficulty in developing the most effective deep learning framework. Furthermore, physically dividing the brain tumor is a time-consuming and challenging process that requires the expertise of medical professionals. Here, we have discussed the use of a fuzzy 3D highlighting method for the segmentation of brain tumors and the selection of suspect tumor areas based on the geometric characteristics of MRI scans. After features were extracted from the brain tumor section, the images were classified using two machine learning methods: a support vector machine technique optimized with the grasshopper optimization algorithm (GOA-SVM), and a deep neural network technique based on features selected with the genetic algorithm (GA-DNN). This classifies brain tumors into benign and malignant. Implemented on the MATLAB platform, the proposed method is evaluated for effectiveness using performance metrics like sensitivity, accuracy, specificity, and Youden index. From these results, it is clear that the proposed strategy is significantly superior to the alternatives. The average classification accuracy was determined to be 97.53%, 97.65%, for GA-DNN and GOA-SVM, respectively. These findings may be a quick and important step to detect the presence of lesions at the same time as cancerous tumors in neurology diagnosis.


Emerging trends and research foci in gastrointestinal microbiome.
Gastrointestinal microbiome has drawn an increasing amount of attention over the past decades. There is emerging evidence that the gut flora plays a major role in the pathogenesis of certain diseases. We aimed to analyze the evolution of gastrointestinal microbiome research and evaluate publications qualitatively and quantitatively. We obtained a record of 2891 manuscripts published between 1998 and 2018 from the Web of Science Core Collection (WoSCC) of Thomson Reuters; this record was obtained on June 23, 2018. The WoSCC is the most frequently used source of scientific information. We used the term "Gastrointestinal Microbiomes" and all of its hyponyms to retrieve the record, and restricted the subjects to gastroenterology and hepatology. We then derived a clustered network from 70,169 references that were cited by the 2891 manuscripts, and identified 676 top co-cited articles. Next, we used the bibliometric method, CiteSpace V, and VOSviewer 1.6.8 to identify top authors, journals, institutions, countries, keywords, co-cited articles, and trends. We identified that the number of publications on gastrointestinal microbiome is increasing over time. 112 journals published articles on gastrointestinal microbiome. The United States of America was the leading country for publications, and the leading institution was the University of North Carolina. Co-cited reference analysis revealed the top landmark articles in the field. Gut microbiota, inflammatory bowel disease (IBD), probiotics, irritable bowel disease, and obesity are some of the high frequency keywords in co-occurrence cluster analysis and co-cited reference cluster analysis; indicating gut microbiota and related digestive diseases remain the hotspots in gut microbiome research. Burst detection analysis of top keywords showed that bile acid, obesity, and Akkermansia muciniphila were the new research foci. This study revealed that our understanding of the link between gastrointestinal microbiome and associated diseases has evolved dramatically over time. The emerging new therapeutic targets in gut microbiota would be the foci of future research.


Evolutionary Advantages of Stimulus-Driven EEG Phase Transitions in the Upper Cortical Layers.
Spatio-temporal brain activity monitored by EEG recordings in humans and other mammals has identified beta/gamma oscillations (20-80 Hz), which are self-organized into spatio-temporal structures recurring at theta/alpha rates (4-12 Hz). These structures have statistically significant correlations with sensory stimuli and reinforcement contingencies perceived by the subject. The repeated collapse of self-organized structures at theta/alpha rates generates laterally propagating phase gradients (phase cones), ignited at some specific location of the cortical sheet. Phase cones have been interpreted as neural signatures of transient perceptual experiences according to the cinematic theory of brain dynamics. The rapid expansion of essentially isotropic phase cones is consistent with the propagation of perceptual broadcasts postulated by Global Workspace Theory (GWT). What is the evolutionary advantage of brains operating with repeatedly collapsing dynamics? This question is answered using thermodynamic concepts. According to neuropercolation theory, waking brains are described as non-equilibrium thermodynamic systems operating at the edge of criticality, undergoing repeated phase transitions. This work analyzes the role of long-range axonal connections and metabolic processes in the regulation of critical brain dynamics. Historically, the near 10 Hz domain has been associated with conscious sensory integration, cortical "ignitions" linked to conscious visual perception, and conscious experiences. We can therefore combine a very large body of experimental evidence and theory, including graph theory, neuropercolation, and GWT. This cortical operating style may optimize a tradeoff between rapid adaptation to novelty vs. stable and widespread self-organization, therefore resulting in significant Darwinian benefits.


Association of Attention-Deficit/Hyperactivity Disorder and Depression Polygenic Scores with Lithium Response: A Consortium for Lithium Genetics Study.
Response to lithium varies widely between individuals with bipolar disorder (BD). Polygenic risk scores (PRSs) can uncover pharmacogenomics effects and may help predict drug response. Patients (N = 2,510) with BD were assessed for long-term lithium response in the Consortium on Lithium Genetics using the Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder score. PRSs for attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and schizophrenia (SCZ) were computed using lassosum and in a model including all three PRSs and other covariates, and the PRS of ADHD (β = -0.14; 95% confidence interval [CI]: -0.24 to -0.03; p value = 0.010) and MDD (β = -0.16; 95% CI: -0.27 to -0.04; p value = 0.005) predicted worse quantitative lithium response. A higher SCZ PRS was associated with higher rates of medication nonadherence (OR = 1.61; 95% CI: 1.34-1.93; p value = 2e-7). This study indicates that genetic risk for ADHD and depression may influence lithium treatment response. Interestingly, a higher SCZ PRS was associated with poor adherence, which can negatively impact treatment response. Incorporating genetic risk of ADHD, depression, and SCZ in combination with clinical risk may lead to better clinical care for patients with BD.


Thoracoscopic clipping of patent ductus arteriosus in premature infants.
Patent ductus arteriosus is a frequent indication for surgical intervention in preterm infants. Commonly this operation is performed through a dorsolateral thoracotomy. In an animal trial (piglets smaller than 1,400 g) instruments and technique for thoracoscopic clipping of patent ductus arteriosus were developed. Since January 1993, 3 premature infants have been treated with this new minimally invasive procedure. The instruments and the surgical technique are demonstrated.


Late complications of biliary atresia: hepatopulmonary syndrome and portopulmonary hypertension.
Children with biliary atresia (BA) following Kasai portoenterostomy have a high risk for portal hypertension, however, while variceal and hemorrhagic complications have been more commonly studied, less frequent but no less possibly devastating complications of hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPH) remain less well understood. HPS and PPH both occur in a setting of portal hypertension, however, paradoxically patients with HPS develop pulmonic vasculature dilation leading to shunting and hypoxia, while those with PPH develop an opposite progression of pulmonary vasoconstriction eventually leading to cor pulmonale and decompensation. Given the near diametric evolution of diseases, HPS and PPH differ widely in therapy, though liver transplantation can have a role for treatment in either disease state. We reviewed our series of 320 pediatric patients with biliary atresia treated at our institution over 44 years, highlighting two cases that developed HPS and PPH, respectively, using these cases in further discussion of hepatopulmonary syndrome and portopulmonary hypertension regarding disease etiology, diagnosis, management, and prognosis. The complicated nature of these processes demand a careful multidisciplinary approach to optimize patient outcomes, including mindful evaluation for when transplantation may offer benefit.


BOD-DO modeling and water quality analysis of a waste water outfall off Kochi, west coast of India.
Water quality scenarios around an offshore outfall off Kochi were simulated using MIKE21 water quality model, assuming a high Biochemical Oxygen Demand (BOD=50 mg l(-1)) effluent discharge. The discharge is introduced into the model through an outfall located at a distance of 6.8 km from the shore at a depth of 10 m. Three scenarios were simulated with different discharge rates such as 2, 5 and 10 m3 s(-1), with BOD load of 8640, 21,600 and 43,200 kg day(-1) respectively. Model simulations were carried out to estimate the assimilation capacity of the waters off Kochi for the three discharge rates. The results show that for 10 m3 s(-1) effluent discharge, the initial BOD of 50 mg l(-1) reduced to 3.33 mg l(-1) at the outfall after 48 h. High BOD values were confined to an elliptical area of approximately 8 km2 around the outfall. Based on this, the assimilative capacity of the waters off Kochi in terms of BOD can be estimated as 38,000 kg day(-1). It is suggested that offshore waters could be used as a feasible alternative to the Kochi backwaters for the disposal of treated effluent.


Lysyl hydroxylase 3-mediated post-translational modifications are required for proper biosynthesis of collagen α1α1α2(IV).
Collagens are the most abundant proteins in the body and among the most biosynthetically complex. A molecular ensemble of over 20 endoplasmic reticulum resident proteins participates in collagen biosynthesis and contributes to heterogeneous post-translational modifications. Pathogenic variants in genes encoding collagens cause connective tissue disorders, including osteogenesis imperfecta, Ehlers-Danlos syndrome, and Gould syndrome (caused by mutations in COL4A1 and COL4A2), and pathogenic variants in genes encoding proteins required for collagen biosynthesis can cause similar but overlapping clinical phenotypes. Notably, pathogenic variants in lysyl hydroxylase 3 (LH3) cause a multisystem connective tissue disorder that exhibits pathophysiological features of collagen-related disorders. LH3 is a multifunctional collagen-modifying enzyme; however, its precise role(s) and substrate specificity during collagen biosynthesis has not been defined. To address this critical gap in knowledge, we generated LH3 KO cells and performed detailed quantitative and molecular analyses of collagen substrates. We found that LH3 deficiency severely impaired secretion of collagen α1α1α2(IV) but not collagens α1α1α2(I) or α1α1α1(III). Amino acid analysis revealed that LH3 is a selective LH for collagen α1α1α2(IV) but a general glucosyltransferase for collagens α1α1α2(IV), α1α1α2(I), and α1α1α1(III). Importantly, we identified rare variants that are predicted to be pathogenic in the gene encoding LH3 in two of 113 fetuses with intracranial hemorrhage-a cardinal feature of Gould syndrome. Collectively, our findings highlight a critical role of LH3 in α1α1α2(IV) biosynthesis and suggest that LH3 pathogenic variants might contribute to Gould syndrome.


Molecular characterization of two Rhesus glycoproteins from the euryhaline freshwater white-rimmed stingray, Himantura signifer, and changes in their transcript levels and protein abundance in the gills, kidney, and liver during brackish water acclimation.
Himantura signifer is a freshwater stingray which inhabits rivers in Southeast Asia. It is ammonotelic in fresh water, but retains the capacities of urea synthesis and ureosmotic osmoregulation to survive in brackish water. This study aimed to elucidate the roles of Rhesus glycoproteins (Rhgp), which are known to transport ammonia, in conserving nitrogen (N) in H. signifer during brackish water acclimation when N became limited resulting from increased hepatic urea synthesis. The complete coding sequence of rhbg from H. signifer consisted of 1383 bp, encoding 460 amino acids with an estimated molecular mass of 50.5 kDa, while that of rhcg comprised 1395 bp, encoding for 464 amino acids with an estimated molecular mass of 50.8 kDa. The deduced amino sequences of Rhbg and Rhcg contained ammonia binding sites, which could recruit NH4+ to be deprotonated, and a hydrophobic pore with two histidine residues, which could mediate the transport of NH3. Our results indicated for the first time that brackish water acclimation resulted in significant decreases in the expression levels of rhbg/Rhbg and rhcg/Rhcg in the gills of H. signifer, which offered a mechanistic explanation of brackish water-related decreased ammonia excretion reported elsewhere. Furthermore, rhbg/Rhbg expression levels increased significantly in the liver of H. signifer during brackish water acclimation, indicating that the ammonia produced by extra-hepatic tissues and released into the blood could be channeled into the liver for increased urea synthesis. Overall, these results lend support to the proposition that H. signifer becomes N-limited upon utilizing urea as an osmolyte in brackish water.


Surface-induced aggregation of type I procollagen.
We have examined the state of aggregation of type I procollagen in the concentration range 5 to 800 micrograms/ml. Electron microscopy typically indicates a high proportion of aggregated material (greater than 50%), when a range of preparative techniques are used. Aggregates of in-register molecules (segment-long-spacing-like aggregates) are frequently observed, often with units of in-register molecules connected via the C-terminal propeptides. In contrast, studies using gel-filtration chromatography and density-gradient ultracentrifugation demonstrate only limited aggregation in solution (less than 5%) even at 800 micrograms/ml. The aggregated material is mainly dimeric and probably not segment-long-spacing-like. We conclude that aggregation of procollagen is strongly favoured by adsorption to a surface when samples are prepared for electron microscopy. The possible relevance of these observations to the fate of procollagen secreted by cells in vivo is discussed.


Natural size classes in DNA from Chinese hamster metaphase chromosomes.
DNA from isolated Chinese hamster ovary (CHO) metaphase chromosomes can be obtained in three different molecular weight classes. The two largest forms have sedimentation coefficients of 80 and 120 S at 7,500 rpm. Based on sedimentation and speed dependence analysis these have molecular weights of 220 million and above 5,000 million, and are thought to be analogs of DNA classes observed in a prior study of human metaphase chromosomes. An extract can be converted to primarily the 80 S form through alkaline pH treatment of metaphase DNA. The third class (45 S DNA) is formed as a result of metaphase chromosome exposure to the nuclease Bal31, and has a mass distribution analogous to the CHO replicon.


[Myeloradiculitis due to Schistosoma haematobium: about an observation in Dakar (Senegal)].
Nervous localisations of schistosomiasis are rare. We report the case of a 25 year-old Senegalese patient admitted for a progressive myeloradiculitis onset, over a one week period. The diagnosis of Schistosoma haematobium myeloradiculitis was made in front of a positive serum serology for S. haematobium, presence of S. haematobium eggs in urine, hyperproteinorachia, endemicity of S. haematobium in the region where the patient was originating and a past medical history of macroscopic hematuria in a context of river bathing. There was also no arguments for another cause to these neurological manifestations. Our patient was treated with praziquantel, prednisone and physiotherapy. Evolution was marked 6 weeks after the beginning of treatment by a significant improvement of motor deficit, enabling the patient to walk again. There was also a regression of genitosphincter dysfunction. Work-up for patients presenting with paraplegia in tropical countries, should also include search for S. heamatobium infection.


Bioinformatics analysis reveals immune prognostic markers for overall survival of colorectal cancer patients: a novel machine learning survival predictive system.
Immune microenvironment was closely related to the occurrence and progression of colorectal cancer (CRC). The objective of the current research was to develop and verify a Machine learning survival predictive system for CRC based on immune gene expression data and machine learning algorithms. The current study performed differentially expressed analyses between normal tissues and tumor tissues. Univariate Cox regression was used to screen prognostic markers for CRC. Prognostic immune genes and transcription factors were used to construct an immune-related regulatory network. Three machine learning algorithms were used to create an Machine learning survival predictive system for CRC. Concordance indexes, calibration curves, and Brier scores were used to evaluate the performance of prognostic model. Twenty immune genes (BCL2L12, FKBP10, XKRX, WFS1, TESC, CCR7, SPACA3, LY6G6C, L1CAM, OSM, EXTL1, LY6D, FCRL5, MYEOV, FOXD1, REG3G, HAPLN1, MAOB, TNFSF11, and AMIGO3) were recognized as independent risk factors for CRC. A prognostic nomogram was developed based on the previous immune genes. Concordance indexes were 0.852, 0.778, and 0.818 for 1-, 3- and 5-year survival. This prognostic model could discriminate high risk patients with poor prognosis from low risk patients with favorable prognosis. The current study identified twenty prognostic immune genes for CRC patients and constructed an immune-related regulatory network. Based on three machine learning algorithms, the current research provided three individual mortality predictive curves. The Machine learning survival predictive system was available at: https://zhangzhiqiao8.shinyapps.io/Artificial_Intelligence_Survival_Prediction_for_CRC_B1005_1/ , which was valuable for individualized treatment decision before surgery.


Effects of dietary inclusion of Radix Bupleuri extract on the growth performance, and ultrastructural changes and apoptosis of lung epithelial cells in broilers exposed to atmospheric ammonia.
To explore whether Radix Bupleuri extract (RBE) could protect lung injury of broilers under ammonia (NH3) exposure, 360 one-d-old male broilers were randomly allocated to four groups of six replicates each in a 2 × 2 factorial design with two diets (the basal diet [control; CON] and the basal diet supplemented with RBE [RB]) and two air conditions (normal condition [<2 ppm of NH3; NOR] and NH3 exposure [70 ppm of NH3; NH70]). The RB diet contained 80 mg saikosaponins/kg diet. On day 7, the lung tissues were collected and the lung epithelial cells (LEC) were isolated. Our experimental results showed that the NH3 exposure decreased body weight gain and feed intake irrespective of dietary treatments during days 1 to 7. However, the RBE addition decreased feed consumption to body weight gain ratio in broilers under NH70 conditions. In the LEC of CON-fed broilers under NH70 conditions, Golgi stacks showed the dilation of cisternaes and reduced secretory vesicles, mitochondria enlarged, the inner membrane of mitochondria became obscure, and the cristae of mitochondria ruptured, whereas only a mild enlargement of Golgi cisternaes and the part rupture of mitochondrial cristaes occurred in the LEC of RB-fed broilers under NH70 conditions. The NH3 exposure increased malondialdehyde (MDA) level, but decreased total antioxidant capacity (T-AOC) in the lungs of CON-fed broilers. However, the RBE addition decreased MDA level and increased T-AOC in the lungs of broilers under NH70 conditions. Simultaneously, the NH3 exposure increased apoptotic rate (AR), mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) level in the isolated LEC of CON-fed broilers. The RBE addition decreased AR, MMP, and ROS in the isolated LEC of broilers under NH70 condition. Besides, the NH3 exposure increased mRNA expression of B-cell lymphoma-2 associated X protein (BAX), caspase-3, and tumor necrosis factor α (TNF-α), but increased interferon γ (IFN-γ) mRNA abundance in the lungs of CON-fed broilers. The RBE supplement decreased mRNA levels of BAX, caspase-3, and TNF-α, but increased IFN-γ, interleukin (IL)-4, and IL-17 mRNA levels in the lungs of broilers under NH70 conditions. These results indicated that dietary RBE addition alleviated NH3 exposure-induced intercellular ultrastructural damage via mitochondrial apoptotic pathway, possibly due to RBE-induced increase of antioxidant capacity and immunomodulatory function in the lungs of broilers under NH3 exposure.


Multiple sclerosis: report of a case in a Papua New Guinean.
Multiple sclerosis is rare in equatorial countries and has not been diagnosed in the indigenous population of Papua New Guinea. We describe the clinical features of a young Papua New Guinean with optic neuritis and a myelopathy which we believe to be due to multiple sclerosis.


Assessing and managing agitation in a critically ill infant.
Agitation may be caused by respiratory insufficiency, pain, or environmental factors. Among its treatments are mechanical ventilation, comfort measures, and a variety of medications. Skillful intervention is essential to combine and monitor therapies and to wean infants from some medications.


Mild-intensity physical activity prevents cardiac and osseous iron deposition without affecting bone mechanical property or porosity in thalassemic mice.
Thalassemia causes anemia, ineffective erythropoiesis, bone loss and iron accumulation in several tissues, e.g., liver, bone and heart, the last of which leads to lethal cardiomyopathy and arrhythmia. Although exercise reportedly improves bone density in thalassemic mice, exercise performance is compromised and might pose risk of cardiovascular accident in thalassemic patients. Therefore, we sought to explore whether mild-intensity physical activity (MPA) with 30-50% of maximal oxygen consumption was sufficient to benefit the heart and bone. Herein, male hemizygous β-globin knockout (BKO) mice and wild-type littermates were subjected to voluntary wheel running 1 h/day, 5 days/week for 3 months (MPA group) or kept sedentary (SDN; control). As determined by atomic absorption spectroscopy, BKO-MPA mice had less iron accumulation in heart and bone tissues compared with BKO-SDN mice. Meanwhile, the circulating level of fibroblast growth factor-23-a factor known to reduce serum iron and intestinal calcium absorption-was increased early in young BKO-MPA mice. Nevertheless, MPA did not affect duodenal calcium transport or body calcium retention. Although MPA restored the aberrant bone calcium-phosphorus ratio to normal range, it did not change vertebral calcium content or femoral mechanical properties. Microstructural porosity in tibia of BKO-MPA mice remained unaltered as determined by synchrotron radiation X-ray tomographic microscopy. In conclusion, MPA prevents cardiac and bone iron accumulation, which is beneficial to thalassemic patients with limited physical fitness or deteriorated cardiac performance. However, in contrast to moderate-intensity exercise, MPA does not improve bone mechanical properties or reduce bone porosity.


One-Step Preparation of Competent E. coli: Transformation and Storage of Bacterial Cells in the Same Solution.
This protocol describes a convenient method for the preparation, use, and storage of competent Escherichia coli The reported transformation efficiency of this method is ∼5 × 107 transformants/µg of plasmid DNA.


The Price of Pre-adolescent Abuse: Effects of Sexual Abuse on Perinatal Depression and Anxiety.
Childhood abuse is a major public health concern and a risk factor for subsequent poor maternal mental health. This study of 176 racially diverse women explored the associations between the histories of childhood sexual abuse and depression and anxiety during pregnancy, at six weeks postpartum, and 12 weeks postpartum. Data on depressive and anxiety symptoms were gathered during pregnancy, at six weeks postpartum, and 12 weeks postpartum. Sociodemographic data were collected during pregnancy, while data on childhood sexual abuse were gathered during the 12-week postpartum period. Bivariate analyses and repeated mixed-effects linear regression with bootstrapping were used to assess the association between childhood sexual abuse and perinatal depressive and anxiety symptoms. Childhood sexual abuse was significantly associated with depressive symptoms (β = 2.52, 95% CI 1.72, 3.32, p < .001) and anxiety symptoms (β = 4.44, 95% CI 3.70, 5.81, p < .001) over time, while controlling for demographic characteristics and lifetime major depression and anxiety. Depressive and anxiety symptoms decreased over the perinatal period and were highest during pregnancy. Black women were more likely to report higher depressive symptoms (β = 1.35, 95% CI 0.51, 2.19, p = .002) and anxiety symptoms (β = 3.29 95% CI 1.72, 4.87, p < .001) over time compared to White women. The results highlight the importance of assessing the long-term effects of childhood sexual abuse on perinatal depressive and anxiety symptoms to help inform the development of interventions for women, particularly Black women.


Weight Loss and the Prevention and Treatment of Type 2 Diabetes Using Lifestyle Therapy, Pharmacotherapy, and Bariatric Surgery: Mechanisms of Action.
Weight loss, whether achieved by lifestyle intervention, pharmacotherapy, or bariatric surgery, is highly effective as a primary interventional strategy in both the prevention and treatment of type 2 diabetes. In high-risk patients with prediabetes and/or metabolic syndrome, weight loss effectively prevents progression to type 2 diabetes mellitus (T2DM) and improves cardiovascular risk factors. These benefits are the result of improvements in insulin resistance, which is central to the pathophysiology of cardiometabolic disease. In patients with T2DM, weight loss improves glycemia, while reducing the need for conventional glucose-lowering medicines, by affecting all three processes that produce and sustain the hyperglycemic state, namely via increments in peripheral insulin sensitivity with improvements in insulin signal transduction at the cellular level, more robust insulin secretory responses, and reduced rates of hepatic glucose production. In both nondiabetic and diabetic subjects, hypocaloric feeding (e.g., treatment with very low-calorie diet or bariatric surgery) produces a rapid improvement in insulin sensitivity due to mobilization of fat from the intramyocellular, intrahepatocellular, and intra-abdominal compartments, and via a more long-term mechanism that correlates with the loss of total body fat. In diabetes, by improving glycemia, weight loss also enhances glucose homeostasis by reversing the defects in insulin action and secretion attributable to glucose toxicity. Regardless of the therapeutic approach, weight loss of ∼ 10 % maximally prevents future diabetes in patients with prediabetes or metabolic syndrome. In T2DM, greater degrees of weight loss lead to progressive improvements in glucose homeostasis. Therefore, when accompanied by greater weight loss, the metabolic benefits following bariatric surgery are generally more pronounced than those achieved following lifestyle and medical treatment. In addition, the mechanisms by which bariatric operations improve diabetes may include both weight-dependent and weight-independent mechanisms, and the latter may involve changes in gut hormones, bile acids, or gut microflora.


Photoaffinity cross-linking of F1ATPase from spinach chloroplasts by 3'-arylazido-beta-alanyl-8-azido ATP.
UV irradiation of the ATPase (CF1) from spinach chloroplasts in the presence of 3'-arylazido-beta-alanyl-8-azido ATP (8,3'-DiN3ATP) results in a nucleotide-dependent inactivation of the enzyme and in a nucleotide-dependent formation of alpha-beta cross-links. The results demonstrate an interfacial localization of the nucleotide binding sites on CF1.


Apremilast Prolongs the Time to First Biologic Therapy in Japanese Patients with Psoriasis.
Biologic agents are used in patients with severe psoriasis who have not adequately responded to existing conventional systemic therapies. However, only a limited number of medical institutions in Japan are approved to use them, and their relatively high cost represents a substantial burden to patients. Apremilast is an oral phosphodiesterase-4 inhibitor approved in Japan for the treatment of psoriasis vulgaris in adult patients with an inadequate response to topical therapies and psoriatic arthritis in adult patients with active disease. To date, a large-scale real-world study of treatment patterns and costs associated with apremilast in Japan has not been conducted. The objective of this study was to assess whether apremilast can prolong time to first biologic therapy use and decrease total medical cost. Using the Medical Data Vision hospital-based claims database, 506 psoriasis patients were propensity score matched and analyzed (apremilast: n = 253; non-apremilast: n = 253). The incidence rate of first biologic therapy use per 1000 patient-years was significantly lower in the apremilast group than in the non-apremilast group (30.3 vs. 107.6; P < 0.001), and the total medical costs per month were significantly lower in the apremilast group than in the non-apremilast group (76,594 yen/month vs. 102,411 yen/month, P < 0.001). In a sensitivity analysis of a propensity-score-matched subset of eligible patients prescribed biologics during the follow-up period (apremilast: n = 14; non-apremilast: n = 14), the incidence of first biologic therapy use was 2,797.6 per 1000 patient-years (95% CI: 1,656.9, 4,723.6) in the non-apremilast group and 856.1 per 1000 patient-years (95% CI: 507.0, 1,445.5) in the apremilast group. These results suggest that apremilast prolongs the time to first biologic therapy use in patients with psoriasis, thereby reducing the total medical cost and decreasing the economic burden on patients.


Jak3 activation is significantly associated with ALK expression in anaplastic large cell lymphoma.
Janus kinase 3 (Jak3) is a tyrosine kinase that activates signal transducer and activator of transcription 3 (Stat3) in response to cytokine stimulation. Stat3 is an oncogene. In previous studies of anaplastic large cell lymphoma (ALCL), we showed that inhibition of Jak3 down-regulates activated/phosphorylated Stat3 (pStat3), decreases anaplastic lymphoma kinase (ALK) enzymatic activity, and induces cell-cycle arrest and apoptosis in ALK-positive ALCL. These findings implicate Jak3 as playing a significant role in the pathogenesis of ALK-positive ALCL; most likely via Stat3 and ALK activation. To assess this possibility, we used immunohistochemical staining to evaluate the frequency of expression of Jak3 and its activated/phosphorylated form (pJak3) in 48 systemic ALCL tumors included in a tissue microarray. pJak3 was detected in 17 (81%) of 21 ALK-positive tumors, compared with 3 (11%) of 27 ALK-negative tumors (P < .0001, Fisher exact test). pStat3 was present in 12 (86%) of 14 ALK-positive tumors and in 10 (40%) of 25 ALK-negative tumors assessed (P = .0078). Of 12 ALK-positive/pStat3-positive tumors, 8 (67%) expressed pJak3, but none of 10 ALK-negative/pStat3-positive tumors expressed pJak3. We conclude that Jak3 activation is predominantly restricted to ALK-positive ALCL tumors. Most likely, Jak3 collaborates with ALK in activating Stat3, leading to cell survival, cell-cycle progression, and tumor growth. In contrast, the mechanism of Stat3 activation in ALK-negative ALCL tumors appears to be independent of Jak3.


Electrolyte formulation strategies for potassium-based batteries.
Potassium (K)-based batteries are viewed as the most promising alternatives to lithium-based batteries, owing to their abundant potassium resource, lower redox potentials (-2.97 V vs. SHE), and low cost. Recently, significant achievements on electrode materials have boosted the development of potassium-based batteries. However, the poor interfacial compatibility between electrode and electrolyte hinders their practical. Hence, rational design of electrolyte/electrode interface by electrolytes is the key to develop K-based batteries. In this review, the principles for formulating organic electrolytes are comprehensively summarized. Then, recent progress of various liquid organic and solid-state K+ electrolytes for potassium-ion batteries and beyond are discussed. Finally, we offer the current challenges that need to be addressed for advanced K-based batteries.


Subjective voice change was associated with appendicular skeletal muscle mass in elderly men, but not in women: A cross-sectional study.
To investigate the relationship between subjective voice changes and appendicular skeletal muscle in the elderly in Korea. Retrospective cross-sectional study. Population-based survey data were collected by the Korean National Health and Nutrition Examination Survey between January 2009 and December 2011. A total of 2611 participants (1081 men and 1530 women) aged 65 to 80 years were enrolled in the Korean National Health and Nutrition Examination Survey from 2009 to 2011. A 70-degree laryngeal endoscopy was performed to check for abnormalities in the larynx, while dual-energy x-ray absorptiometry was utilised to measure appendicular skeletal muscle mass. The correlation between subjective voice change and appendicular skeletal muscle index (ASMI) was analysed using a linear-by-linear association test and logistic regression analysis. When comparing ASMI according to the presence or absence of subjective voice change, elderly men showed significantly lower ASMI values when subjective voice change was present (p = .021). However, in women, the ASMI was not significantly lower in the presence of subjective voice changes (p = .365). We confirmed that subjective voice change was significantly lower in the highest quintile of ASMI compared to lowest quintile of ASMI in the men using logistic regression analysis (B 0.281, 95% confident interval 0.082-0.964, p < .044). This study has shown that in Korean men aged >65 years, subjective voice abnormality significantly increased as skeletal muscle mass decreased. Further longitudinal studies are needed to determine whether a correlation exists between objective voice test results and ASMI.


Natural occurrence of fumonisins in corn puff in Argentina.
Maize presents a substantial contamination by fumonisins (FB) throughout the world. In particular, Argentina presents a high frequency of positive samples and levels of up to 10,000 μg/kg of total FB, depending on the harvest campaign studied. Corn puff, an extruded product of high consumption among children and adolescent populations, was analyzed with the aim of determining the presence and levels of fumonisins B1, B2 and B3. In the present study, 20 samples of different brands were collected from commercial stores. Two solvent systems, two types of agitation, and the number of extractions were tested in order to find the most suitable method to establish the level of fumonisins in corn puff. Extracts were analyzed by high performance liquid chromatography (HPLC) with fluorescence detection. A C18 column and precolumn derivatization with orthophtalaldialdehyde were utilized. The average of fumonisins found in 20 samples was 257.5 μg/kg (n = 19), 70.4 μg/kg (n = 14) and 73.3 μg/kg (n = 6) for FB1, FB2 and FB3, on positive samples, respectively. These are the first analyses in Argentina of this type of product, highlighting the need to continue the studies in the processing industries because, despite the extrusion process that the raw material suffers, a sample was found with a contamination of 1,649 μg/kg total fumonisins.


A critical test of infant pattern preference models.
Models of infant visual preferences with predictions based on the physical attributes of visual patterns were evaluated using pairs of schematic faces and abstract patterns that were identical except for contrast reversals. Preferences at 6 weeks were entirely consistent with the predictions of these models. However, at 12 weeks the preferences for facelike images were in clear violation of the predictions of these models. These results represent the first unambiguous demonstration of a face preference in young human infants. The results also allow rejection of all current stimulus-based models of visual preference and suggest that a fundamental change in the determinants of visual preference occurs between 6 and 12 weeks postnatally.


Effects of Campylobacter jejuni lipopolysaccharide on axonal injury in the spinal cord in rats.
To explore the effects of Campylobacter jejuni lipopolysaccharide (Cj-LPS) on axonal injury in the spinal cord. Wistar rats were divided into the control (NC) group, model group (Cj-LPS), and LPS antibody group (Anti-LPS). Rats in the NC group were injected with a mixture of normal saline and complete Freund's adjuvant (CFA) while those in Cj-LPS group were injected with Cj-LPS, composed of LPS, CFA, and saline. Rats were sacrificed at 4th week and 6th week after injection, and hematoxylin and eosin (HE) staining was performed on the spinal cord sections. Real time-reverse transcription(RT-PCR) was used to detect mRNA expression of the axonal nutrition factor neurotrophin-3 (NT-3) with its receptor tropomyosin receptor kinase C (TrkC) and axon inhibitory factor of NogoA/NgR (Nogo receptor). The results indicated that Cj-LPS induce axonal injury in the rat spinal cord, decreased the mRNA expression of the axonal nutrition factor NT-3/TrkC, and increased the mRNA expression of the inhibitory factor NogoA/NgR. However, anti-LPS ameliorated axonal injury in the rat spinal cord induced by Cj-LPS.


Resumption or persistence of menstruation after cytotoxic chemotherapy is a prognostic factor for poor disease-free survival in premenopausal patients with early breast cancer.
We investigated the relationship between resumption or persistence of menstruation after cytotoxic chemotherapy (RM) and disease-free survival (DFS) in premenopausal patients with early breast cancer. Medical records from 872 patients who received cytotoxic chemotherapy for stage I to III breast cancer were retrospectively reviewed. The median patient age was 41 years (range, 21-54) and the median follow-up duration was 6.2 years (range, 0.7-10.4). Six hundred ninety-two patients (79.4%) were hormone receptor (HR) positive and the majority of these received tamoxifen therapy after completing chemotherapy. The chemotherapy-induced amenorrhea (CIA) rate was 76.7% (n = 669), and 51.8% (n = 452) experienced RM during the follow-up period. One hundred twenty-one (13.9%) patients had persistent menstruation without CIA. DFS was significantly affected by younger age at diagnosis (≤35 years) (P = 0.013), tumor size > 2 cm (P < 0.001), node positivity (P < 0.001), HR negativity (P < 0.001), HER2 positivity (P = 0.010), and RM (P < 0.001). HR negativity [hazard ratio 1.7, 95% confidence interval (CI) 1.2-2.4, P = 0.006], tumor size > 2 cm (hazard ratio 2.1, 95% CI 1.4-3.0, P < 0.001), node positivity (hazard ratio 3.0, 95% CI 2.0-4.7, P < 0.001), and RM (hazard ratio 1.8, 95% CI 1.2-2.7, P = 0.004) remained significant factors for DFS on multivariate analysis. A considerable proportion of premenopausal patients treated with chemotherapy experienced RM after CIA. RM was a poor prognostic factor for DFS in premenopausal patients with early breast cancer.


Colonic carcinoma at the site of ureterosigmoidostomy: what is the risk?
A case of colonic carcinoma arising 27 years after urinary diversion by ureterosigmoidostomy is reported. This late complication is now well recognized and increasing numbers of cases are being reported. The implications of this patient and the 31 previously reported cases are considered.


Renal adenocarcinoma in an 8-year-old child, with a t(X;17)(p11.2;q25).
This report describes a chromosomal abnormality in an 8-year-old boy with renal adenocarcinoma. All tumor cells had the karyotype 46,XY, t(X;17)(p11.2;q25). This karyotype is compared with the cytogenetic descriptions of renal cell adenocarcinoma in two other pediatric patients and in adults.


Hematoma Progression Rates on Head Computed Tomography for Fluid Levels versus Mimics in Patients with Primary Intracerebral Hemorrhage.
Among stroke patients, primary intracerebral hemorrhage has the highest mortality rate. Expansion of hematoma plays a prognostic role in these patients. Although fluid levels have been shown to predict subsequent hematoma expansion, there are mimics of fluid levels that may confuse interpretation. We hypothesized that patients with true fluid levels on head computed tomography (CT) have higher hematoma progression rates and worse outcomes compared with patients who have fluid level mimics on CT. Adult patients presenting with intracerebral hemorrhage described as a fluid level on initial CT interpretation were included. Medical records were reviewed to extract relevant clinical variables. A CAQ-certified neuroradiologist retrospectively determined whether there was a true fluid level or mimic on CT and then evaluated follow-up CT scans for radiologic progression. We compared radiologic progression, mortality, and anticoagulation status between patients with true fluid levels and fluid level mimics. The study included 12 patients, 8 with true fluid levels and 4 with radiologic mimics. The patients with true fluid levels had a significantly higher likelihood of radiographic progression (P = 0.014). Differences in outcome, use of anticoagulation therapy, and average international normalized ratio were not significant. A fluid level within intraparenchymal hemorrhage on head CT scan is associated with higher likelihood of intracerebral hemorrhage progression. However, this applies only to true fluid levels, with mimics having a lower likelihood of progression. A careful analysis of potential fluid levels is necessary before assigning prognostic implications.


Ability of inactivated vaccines based on far-eastern tick-borne encephalitis virus strains to induce humoral immune response in originally seropositive and seronegative recipients.
Tick-borne encephalitis (TBE) remains one of the major public health concerns in northern Eurasia, and its' area is expanding. TBE virus (TBEV) includes three subtypes and several monophyletic groups, cocirculating in Russia. Five inactivated vaccines are used for TBE prophylaxis. The rising number of people subjected to vaccination brings up the issue of the impact of individual recipient characteristics on vaccination efficacy. The present work studies correlations among the vaccination scheme, sex, age, body mass index (BMI), chronic diseases, postvaccinal reaction, pre-existing anti-TBEV antibodies, and postvaccinal humoral immunity development. Sera were collected during clinical trials in the TBEV Siberian subtype endemic area. Adult recipients were vaccinated with Tick-E-Vac and EnceVir vaccines based on Far-Eastern TBEV strains. Vaccine ability to induce humoral immunity in different categories of recipients was estimated by seroconversion rates and the percentage of recipients with high neutralizing antibody titers (≥1:500). High immunogenicity of vaccines based on Far-Eastern TBEV strains in the TBEV Siberian subtype endemic area in all groups of recipients was demonstrated. Impact of pre-existing contact with the virus and high BMI on humoral immune response development 14 days after the first immunization was evidenced. Nevertheless, the difference was significantly less pronounced 30 days after the first vaccination and undetectable after the second one.


Energy flow analysis of grass carp pond system based on Ecopath model.
Grass carp (Ctenopharyngodon idellus) is the most productive freshwater fish in China, but its traditional aquaculture model still has problems, such as poor water quality and frequent diseases. We have taken monoculture and 80:20 polyculture grass carp ponds as the research object and used EwE software to build the Ecopath model of two ponds. We analyzed and compared the characteristics of ecological structure and energy flow in two ponds. The result showed the highest effective trophic level in the polyculture pond that was higher than that in the monoculture pond, and fish in polyculture had higher EE values which showed the production of fish in polyculture contributed more to the energy conversion efficiency of the ecosystem. Flows into detritus were the largest component of TST both in the two ponds, which accounted for 49.34% and 50.37%. And the average transfer efficiency in monoculture was 13.07%, while that in polyculture was 15.6%. The ascendency/total development capacity (A/TDC) and overhead/total development capacity (O/TDC) were 0.35 and 0.65 both in the two ponds, respectively, which indicated that both systems had a strong anti-perturbation ability, but the stability could be improved. Finn's cycling index (FCI) in polyculture was higher and showed that the polyculture pond was more mature and stable. Unused energy of functional groups will flow to detritus, and that in the monoculture pond was higher, the energy of C. idellus that flowed to detritus in monoculture was 48.17% higher than that in polyculture; unused energy of bacteria and phytoplankton were also high. The result showed that polyculture could improve energy utilization, increase transfer efficiency, and raise the stability of the ecosystem. Grass carp ponds still need to be improved in the aspects of mixed species and energy consumption. It is necessary to improve the ecological and economic benefits of grass carp ponds by optimizing the aquaculture structure and adjusting the aquaculture proportion.


Development of a polymerase chain reaction method for diagnosis of Babesia ovis infection in sheep and goats.
In this study, a pair of oligonucleotide primers were designed according to the nucleotide sequence of the small subunit ribosomal RNA (ssu rRNA) gene of Babesia ovis isolated from sheep in eastern Turkey. The primers were used to detect parasite DNA from blood samples of B. ovis-infected sheep and goats by polymerase chain reaction (PCR). A 549-bp DNA fragment was specifically amplified from blood samples from sheep and goats, naturally infected with B. ovis. No PCR products resulted from Babesia motasi, T. ovis, Theileria sp. OT1, Theileria sp. OT3, T. lestoquardi, B. canis, B. microti,T. annulata or normal sheep leucocytes DNA using these specific primers. B. ovis-infected erythrocytes with 1% parasitemia were subjected to 10-fold serial dilutions (from 10(-1) to 10(-9)) using an uninfected sheep erythrocytes, and DNA was extracted from each diluted sample for testing the sensitivity of the PCR. The PCR was sensitive enough to detect parasite DNA from the dilution of 10(-5) with 0.00001% parasitemia. This is more sensitive than examining 200 fields under light microscopy. In addition, 98 field samples collected from small ruminanats in eastern Turkey were tested for B. ovis infection. Four samples were positive Babesia spp. in blood smears, 21 samples were positive for B. ovis DNA by PCR. These results indicate that the PCR provides a useful diagnostic tool for the detection of B. ovis infection in sheep and goats.


[1,10-phenantroline europium complexes: their inclusion in liposomes and cytotoxicity].
For a series of 1,10-phenantroline tris-beta-diketonate europium complexes (EuC), cytotoxic activity on the HBL-100 human breast carcinoma cells was determined. Liposomal preparation of the most active EuC, V12, was also tested for cytotoxicity. Testing of this preparation in vivo on starting lethal murine model of T cell leukemic lymphoma ASF-LL showed that the inclusion of V12 in liposomes did not increase its antitumour activity in a local mode of administration.


Stage-dependent increase of orosomucoid and zinc-alpha2-glycoprotein in urinary bladder cancer.
Identification and characterization of biomarkers in body fluids such as serum or urine serve as a basis for early detection of diseases, particularly of cancer. Performing 2-DE with subsequent MS analyses, conventional immunoblotting and immunohistochemistry we identified two proteins, orosomucoid (ORM) and human zinc-alpha(2)-glycoprotein (ZAG), which were increased in the urine samples of patients with bladder cancer in comparison to the urine samples of healthy volunteers. The highest amount of both proteins was found in invasive bladder cancer stages such as pT2-3. Immunohistochemical studies showed ORM in inflammatory cells but also in endothelial cells of blood vessels within or adjacent to the tumor area and in part of the tumor cells. ZAG was prominent in tumor cells at the tumor invasion front. Additionally, ZAG was localized at the luminal surface of normal urothelium, which switches to the basal side when a superficial papillary tumor was observed. These results show that we have been able to identify two new proteins that may be related to the development of superficial bladder cancer and to its switch to an invasive phenotype.


Dissecting the high-resolution genetic architecture of complex phenotypes by accurately estimating gene-based conditional heritability.
Despite extensive research on global heritability estimation for complex traits, few methods accurately dissect local heritability. A precise local heritability estimate is crucial for high-resolution mapping in genetics. Here, we report the effective heritability estimator (EHE) that can use p values from genome-wide association studies (GWASs) for local heritability estimation by directly converting marginal heritability estimates of SNPs to a non-redundant heritability estimate of a gene or a small genomic region. EHE provides higher accuracy and precision for local heritability estimation among seven compared methods. Importantly, EHE can be applied to estimate the conditional heritability of nearby genes, where redundant heritability among the genes can also be removed further. The conditional estimation can be guided by tissue-specific expression profiles (or other functional scores) to prioritize and quantify more functionally important genes of complex phenotypes. Applying EHE to 42 complex phenotypes from the UK Biobank, we revealed the existence of two types of distinct genetic architectures for various complex phenotypes and found that highly pleiotropic genes are not enriched for more heritability compared to other candidate susceptibility genes. EHE provides an accurate and robust way to dissect the genetic architecture of complex phenotypes.


Morphologic Updates in Prostate Pathology.
In the past several years, modifications have been made to the original Gleason system with resultant therapeutic and prognostic implications. Several morphologic variants of prostatic adenocarcinoma have also been described. Prostate pathology has also evolved over the years with the discovery and utility of new immunohistochemical stains. The topics discussed in this update include the Gleason grading system, prognostic grade grouping, variants of prostatic adenocarcinoma, and the application of immunohistochemistry to prostate pathology.


Angelica Yinzi alleviates 1-chloro-2,4-dinitrobenzene-induced atopic dermatitis by inhibiting activation of NLRP3 inflammasome and down-regulating the MAPKs/NF-kB signaling pathway.
Atopic dermatitis (AD), characterized by eczema as a chronic pruritic inflammatory skin disease, has become a serious health problem with recurrent clinical episodes. However, current clinical treatments have limited relief and are accompanied by adverse effects. Therefore, there is a necessity to develop new effective drugs for AD treatment. Angelica Yinzi (AYZ) is a classic ancient prescription for nourishing blood, moistening dryness, dispelling wind, and relieving itching. However, its mechanism for alleviating atopic dermatitis remains unknown. Therefore, this study aimed at determining the effects of AYZ and its potential mechanism in alleviating AD-like symptoms. In the present study, we used 1-chloro-2,4-dinitrobenzene (DNCB) to establish a mouse model of atopic dermatitis, where DNCB readily penetrates the epidermis to cause inflammation. Histopathological analysis was performed to examine the thickening of dorsal skin and infiltration in the inflammatory and mast cells in C57BL/6 mice. Additionally, the immunoglobulin E (IgE) levels in serum were determined by enzyme-linked immunosorbent assay (ELISA) kits. The IL-1β and TNF-α expression were detected using qRT-PCR. Next, the Western blotting and immunohistochemistry assays were performed to assess the contribution of MAPKs/NF-κB signaling pathways and the NLRP3 inflammasome in AD responses. Histopathological examination revealed that AYZ reduced the epidermal thickness of AD-like lesioned skin and repressed the infiltration of mast cells into AD-like lesioned skin. AYZ significantly decreased the phosphorylation of p38 MAPK, JNK, ERK and NF-κB and downregulated serum IgE levels and IL-1β and TNF-α mRNA levels. Additionally, the NLRP3, ASC, Caspase-1, and IL-1β expression in dorsal skin were effectively down-regulated following AYZ treatment (p < 0.05 and p < 0.01). These findings revealed that AYZ effectively suppressed AD-induced skin inflammation by inhibiting the activation of the NLRP3 inflammasome and the MAPKs/NF-kB signaling. Therefore, AYZ is a potential therapeutic agent against AD in the clinical setting.


Do Histopathology and Clinical Outcomes of Breast Atypia Vary by Race/Ethnicity?
The clinical behavior of breast cancer varies by racial and ethnic makeup (REM), but the impact of REM on the clinical outcomes of breast atypia remains understudied. We examined the impact of REM on risk of underlying or subsequent carcinoma following a diagnosis of breast atypia. In this retrospective, single-institution chart review, adult women diagnosed with breast atypia (atypical ductal hyperplasia, atypical lobular hyperplasia, or lobular carcinoma in situ) were stratified by REM. Regression modeling was used to estimate risk of underlying or subsequent carcinoma. We identified 539 patients with breast atypia, including 15 Hispanic (2.8%), 127 non-Hispanic black (23.6%), and 397 non-Hispanic white women (73.7%). Diagnoses included 75.1% atypical ductal hyperplasia (n = 405), 4.6% atypical lobular hyperplasia (n = 25), and 20.2% lobular carcinoma in situ (n = 109). Rates for each type of atypia did not vary by REM (P = 0.33). Of those with atypia on needle biopsy, the rate of underlying carcinoma at excision was 17.3%. After adjustment, REM was not associated with greater risk for carcinoma at excision (P = 0.41). Of those with atypia alone on surgical excision, the rate of a subsequent carcinoma diagnosis was 15.4% (median follow-up 49 mo). REM was not associated with a long-term risk for carcinoma (P = 0.37) or differences in time to subsequent carcinoma (log-rank P = 0.52). Chemoprevention uptake rates were low (10.6%), especially among Hispanic (0%) and non-Hispanic black (3.8%) patients (P = 0.01). Among patients with atypia, REM does not appear to influence type of histologic atypia, risk for carcinoma, or clinical outcome, despite differences in chemoprevention rates.


Tissue regeneration in the reconstruction of lost bone and soft tissue in the lower limbs: a preliminary report.
Tissue regeneration obtained by using a limb lengthening apparatus has been used by the authors in five cases for the repair of traumatic loss of bone and soft tissue from the lower limbs. The principles of "regenerated tissue" introduced by Ilizarov for the lengthening of limbs were modified and applied to traumatological needs. Very encouraging results have been obtained.


Determination of left ventricular mass using single-photon emission computed tomography.
To test the hypothesis that single-photon emission computed tomography (SPECT) could actually determine left ventricular LV mass in humans, SPECT measurements of LV mass were compared with LV mass determined by cineangiography in 12 patients with normal coronary arteries and LV function. Repeat SPECT determinations of LV mass were carried out in 5 patients. Projection images of the left ventricle were acquired after intravenous injection of thallium-201 (TI-201) using a rotating gamma camera. Transverse sections were reconstructed by filtered backprojection. The boundary of LV uptake of TI-201 in each transverse section was defined using a 3-dimensional threshold detector. Scintigraphic LV mass (total number of voxels demonstrating LV TI-201 uptake X voxel volume X specific gravity of myocardium) was compared with angiographic LV mass. There was good correlation between LV mass determined by SPECT and that determined by cineangiography. Mean angiographic LV mass was 208 +/- 45 g (+/- standard deviation). Mean SPECT LV mass was 204 +/- 42 g. Linear regression analysis revealed the following relation: SPECT LV mass = 0.76 X angiographic LV mass + 46.1 (r = 0.82, root-mean-square deviation from regression = 24.7). The SPECT values of LV mass varied an average of 10.4 +/- 4.6% (+/- standard deviation) in the 5 patients in whom 2 determinations were made. Thus, SPECT of TI-201 can accurately measure LV mass in humans.


Transforming growth factor beta-producing Foxp3(+)CD8(+)CD25(+) T cells induced by iris pigment epithelial cells display regulatory phenotype and acquire regulatory functions.
The ocular pigment epithelial (PE) cells convert T cells into T regulators (Tregs) in vitro. The PE-induced Tregs fully suppress activation of bystander responder T cells. Iris PE (IPE) cells from anterior segment in the eye produce costimulatory molecules and transforming growth factor beta (TGFbeta) that is delivered to CD8(+) Tregs. We have now examined whether T cells exposed to cultured IPE express CD25 and Foxp3, and to determine if the CD25(+) IPE-exposed T cells display regulatory functions in vitro. We have found that cultured B7-2(+) IPE converted CTLA-4(+) T cells into CD25(+) Tregs that suppress the activation of bystander T cells. The CD8(+) IPE-induced Tregs constitutively expressed CD25. Through TGFbeta-TGFbeta receptor interactions, the IPE converted these T cells into CD25(+) Tregs that express Foxp3 transcripts. The CD8(+) IPE-induced Tregs produced immunoregulatory cytokines, e.g., interleukin-10 and TGFbeta. In addition, IPE-exposed T cells that downregulated Foxp3 mRNA failed to acquire the regulatory function. In conclusion, ocular pigment epithelial cells convert CD8(+) T cells into CD25(+) Tregs by inducing the transcription factor Foxp3. Thus, T cells that encounter ocular parenchymal cells participate in the T-cell suppression.


Triiodothyronine accelerates the synthesis of synapsin I in developing neurons from fetal rat brain cultured in a synthetic medium.
The effect of Triiodothyronine (T3) on Synapsin I appearance in rat cortical neurons has been investigated in vitro. Neuronal cultures from 16-day-old fetal rat brain grown in the absence of T3, express immunohistochemically detectable Synapsin I at the 14th day in vitro. The addition of the hormone to the culture medium determines an early (at the 7th day in vitro) appearance of fluorescent dots specific for Synapsin I.


Impact of the COVID-19 Pandemic on Sports Medicine Patient Care.
The COVID-19 pandemic has necessitated new practices in sports medicine patient care. Telehealth has been validated as a reliable tool for consultations and physical examinations and increases access to care in a cost-efficient manner. Social distancing and avoiding team members who have tested positive are the most effective ways to reduce spread. For screening, daily self-reported symptom checklists and fever monitoring help identify potentially infected athletes who should be instructed to isolate and seek care. Polymerase chain-reaction (PCR) testing for the virus via nasopharyngeal swab is not recommended for screening and should be reserved for symptomatic individuals with fever, cough, or shortness of breath. Face masks and personal protective equipment (PPE) may be beneficial in high-risk settings, but there is little evidence to support use in athletic populations. Median return to play after COVID-19 in elite athletes has been reported as 18 days (range: 12 to 30), with 27% not fully available at 28 days. Chest pain at diagnosis was the only symptom associated with time loss longer than 28 days. Finally, canceled competitions or time loss results in grief, stress, and frustration for athletes, as well as loss of a social support network and routine training regimens. Mental health support services may be indicated.


Muscle regeneration. The effect of hypophysectomy on cell proliferation and expression of insulin-like growth factor-I.
Against the background of the importance of growth hormone (GH) for normal muscle growth, a study was performed to investigate whether lack of GH after hypophysectomy affects the cell proliferation and the local production of insulin-like growth factor-I (IGF-I) in the early stages of muscle regeneration in adult rats. The level of IGF-I in the serum of hypophysectomised rats was reduced to about 30% of that of controls. The incorporation of [methyl-3H]thymidine into the regenerating muscle showed a peak 6 days after the operation and then gradually declined to the end of the period of study 30 days after initiation of regeneration by ischemic necrosis. The DNA content rose to a maximum level after 6-8 days, and remained high after 30 days. There was no major difference in the incorporation of [3H]thymidine in regenerating muscle of hypophysectomised and control rats, but the DNA concentration in the regenerating muscles of hypophysectomised rats was significantly reduced after 30 days. There was a corresponding reduction in the number of nuclei per muscle fibre, indicating that hypophysectomy has a small effect on the cell proliferation during the early stages of muscle regeneration. Immunohistochemical demonstration of IGF-I in the regenerating muscle revealed the transient presence of immunoreactive material in satellite cells and myotubes after 6 to 8 days of regeneration but no immunoreactivity after 30 days. No obvious difference was observed between hypophysectomised and control rats, indicating that the endogenous production of IGF-I in regenerating skeletal muscle can occur independently of GH.


A randomized clinical trial of a coping improvement group intervention for HIV-infected older adults.
This research tested if a 12-session coping improvement group intervention (n = 104) reduced depressive symptoms in HIV-infected older adults compared to an interpersonal support group intervention (n = 105) and an individual therapy upon request (ITUR) control condition (n = 86). Participants were 295 HIV-infected men and women 50-plus years of age living in New York City, Cincinnati, OH, and Columbus, OH. Using A-CASI assessment methodology, participants provided data on their depressive symptoms using the Geriatric Depression Screening Scale (GDS) at pre-intervention, post-intervention, and 4- and 8-month follow-up. Whether conducted with all participants (N = 295) or only a subset of participants diagnosed with mild, moderate, or severe depressive symptoms (N = 171), mixed models analyses of repeated measures found that both coping improvement and interpersonal support group intervention participants reported fewer depressive symptoms than ITUR controls at post-intervention, 4-month follow-up, and 8-month follow-up. The effect sizes of the differences between the two active interventions and the control group were greater when outcome analyses were limited to those participants with mild, moderate, or severe depressive symptoms. At no assessment period did coping improvement and interpersonal support group intervention participants differ in depressive symptoms.


2,5-hexanedione induces NLRP3 inflammasome activation and neurotoxicity through NADPH oxidase-dependent pathway.
Chronic exposure to n-hexane causes sensorimotor neuropathy, which is mediated by 2,5-hexanedione (HD), a toxic metabolite of n-hexane. Activation of the nucleotide-binding and oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) inflammasome is involved in multiple neurodegenerative diseases. However, whether the NLRP3 inflammasome contributes to HD-induced neurotoxicity remains unclear. In this study, the effects of HD on NLRP3 inflammasome activation and the underlying mechanisms were determined by using HD-treated rat and cell culture models. Increased NLRP3 expression, caspase-1 activation and interleukin-1β production were observed in both the brain and spinal cord of HD-treated rats. Double-immunofluorescence staining showed that ASC speck formation and caspase-1 expression were mainly localized in microglia. HD-induced activation of the NLRP3 inflammasome was further mirrored in BV2 microglial cells and was associated with NADPH oxidase activation. Interestingly, inhibition of NADPH oxidase by apocynin or specific siRNAs significantly mitigated HD-induced NLRP3 inflammasome activation. Furthermore, apocynin suppressed activation of the MAPK and NF-κB signaling pathways. Blocking activation of p38-MAPK and NF-κB significantly reduced HD-induced capase-1 activation and interleukin-1β maturation, indicating a critical role of NADPH oxidase and downstream MAPK and NF-κB pathways in regulating activation of NLRP3 inflammasome, in HD-treated microglia. Finally, we found that inhibition of microglial NLRP3 inflammasome and NADPH oxidase activation abrogated HD-induced microglial activation and neurodegeneration in both SHSY5Y neuronal cells and primary cortical neuron-glia cultures. Altogether, our findings suggest that NADPH oxidase-dependent activation of microglial NLRP3 inflammasome contributes to HD-induced neurotoxicity, providing novel insight into the mechanisms of this solvent-induced neuropathy.


Emergency surgery for appendectomy and incidental diagnosis of superficial peritoneal endometriosis in fertile age women.
This study aimed to evaluate the presence of superficial peritoneal endometriosis (SUP) in women referred to emergency surgery for right iliac fossa (RIF) pain and undergoing an appendectomy, considering which factors may be useful to suspect and identify endometriosis. An observational case-control study was conducted on a group (n = 149) of fertile age women. After surgery, Group A was selected upon the diagnosis of endometriosis (n = 34); Group B (n = 115) represented the controls. Demographics, comorbidities and clinical findings were registered and analysed. Appendicitis of various grades of severity was diagnosed in all patients, but SUP was also identified in 23%, of which 14.7% also presented with endometriosis of the appendix. Women in Group A reported chronic pelvic pain, dysmenorrhoea, dyspareunia and oral contraceptive use more frequently. At multivariate analysis, factors associated with endometriosis were: age <40 years, autoimmune disorders, multiple allergies, abdominal chronic pain, associated gynaecological pain symptoms, Alvarado score ≤6, and inconclusive ultrasound findings. The incidental finding of SUP in fertile age women presenting with an acute RIF pain and undergoing emergency surgery is a relevant observation. Clinical history and symptoms should guide surgeons in performing a correct diagnosis and in referring the patient to the gynaecology specialist.


A rapid and simple method for efficient capture and accurate discrimination of circulating tumor cells using aptamer conjugated magnetic beads and surface-enhanced Raman scattering imaging.
The efficient isolation and the accurate phenotype discrimination of circulating tumor cells (CTCs) are expected to provide much valuable information for the understanding of tumor metastasis and to play an important role in personalized treatment of cancer patients in the future. In this study, we developed a novel, rapid, and simple method for efficient capture and accurate identification of CTCs using aptamer conjugated magnetic beads and surface-enhanced Raman scattering (SERS) imaging technique. Using aptamer conjugated magnetic beads, rare target cancer cells can be captured efficiently from buffer and whole blood sample with capture efficiency of 73 % and 55 %, respectively. Meanwhile, captured cancer cells were labeled by specific SERS probes and can be identified readily and accurately by SERS imaging technique. Results of our experiment demonstrate the potential feasibility of aptamer conjugated magnetic beads coupled with SERS imaging technique for the efficient capture and accurate discrimination of CTCs in clinical whole blood sample. Graphical Abstract Schematic Representation of CTCs Capture and Identification Using Apt-MBs and SERS Imaging.


Clinical simulation strategies for knowledge integration relating to initial critical recognition and management of COVID-19 for use within continuing education and health-related academia in Brazil: a descriptive study.
The COVID-19 pandemic has led to an immense need to develop training on case recognition and management, with a focus on patients' and health professionals' safety at several levels of healthcare settings in Brazil. Different simulation strategies can be included in the diverse clinical care phases for these patients. To suggest a complete simulation-based training program for Brazilian hospitals and/or academic institutions at this moment of the pandemic. Descriptive analysis on possible simulated clinical cases using different methodologies, thereby supporting suspected or confirmed COVID-19 patients. This was a reflective theoretical descriptive study on an educational program based on clinical simulation, with four practical phases at different performance and complexity levels. Wearing, handling and adequately disposing of personal protective equipment, along with specific respiratory procedures in different healthcare settings up to intensive care for seriously infected patients were addressed. This program was designed for application at different Brazilian healthcare levels through different clinical simulation strategies. Summaries of expected performance were suggested in order to standardize technical capacity within these simulation settings, so as to serve these levels. Developing training programs for situations such as the current COVID-19 pandemic promotes safety not only for patients but also for healthcare workers. In the present context, clear definition of which patients need hospital outpatient or inpatient care will avoid collapse of the Brazilian healthcare system. Institutions that do not have simulated environments can, through the examples described, adopt procedures to promote didactic information in order to help healthcare professionals during this time.


Splenic size determination in sickle cell anaemia: an ultrasonographic study.
To examine the generally accepted concept of autosplenectomy in patients with sickle cell anaemia, and determine the relationship between age, the steady state PCV and splenic size. Case-control study. Sickle Cell Clinic, University of Ilorin Teaching Hospital, Ilorin, Nigeria. Sickle cell anaemia patients aged three to 47 years, while the controls included age and sex matched patients attending the General Outpatient Department for minor ailments. Longitudinal and coronal sizes of the spleen were measured antemortem, by ultrasonographic method, in 98 adult sickle cell anaemia patients and 48 control subjects and compared. The splenic size was correlated with age and PCV among sickle cell anaemia patients. Determination of longitudinal and coronal sizes of the spleen, comparison of mean splenic sizes of patients with those of controls by Student's t test, and correlation of age and PCV with splenic sizes. Both mean longitudinal and coronal diameters, and surface area were found to be higher in the sickle cell anaemia patients compared to the controls. While the longitudinal diameter increased with age continuously, the coronal diameter decreased after the age of 30 years. There were no significant correlations between the splenic sizes and PCV and number of crises per year. The general belief that sickle cell anaemia patients suffer anatomical autosplenectomy was not confirmed. This could be due to the effect of malaria and improved clinical care.


Reduced COVID-19 hospitalizations among New York City residents following age-based SARS-CoV-2 vaccine eligibility: Evidence from a regression discontinuity design.
In clinical trials, several SARS-CoV-2 vaccines were shown to reduce risk of severe COVID-19 illness. Local, population-level, real-world evidence of vaccine effectiveness is accumulating. We assessed vaccine effectiveness for community-dwelling New York City (NYC) residents using a quasi-experimental, regression discontinuity design, leveraging a period (January 12-March 9, 2021) when ≥ 65-year-olds were vaccine-eligible but younger persons, excluding essential workers, were not. We constructed segmented, negative binomial regression models of age-specific COVID-19 hospitalization rates among 45-84-year-old NYC residents during a post-vaccination program implementation period (February 21-April 17, 2021), with a discontinuity at age 65 years. The relationship between age and hospitalization rates in an unvaccinated population was incorporated using a pre-implementation period (December 20, 2020-February 13, 2021). We calculated the rate ratio (RR) and 95% confidence interval (CI) for the interaction between implementation period (pre or post) and age-based eligibility (45-64 or 65-84 years). Analyses were stratified by race/ethnicity and borough of residence. Similar analyses were conducted for COVID-19 deaths. Hospitalization rates among 65-84-year-olds decreased from pre- to post-implementation periods (RR 0.85, 95% CI: 0.74-0.97), controlling for trends among 45-64-year-olds. Accordingly, an estimated 721 (95% CI: 126-1,241) hospitalizations were averted. Residents just above the eligibility threshold (65-66-year-olds) had lower hospitalization rates than those below (63-64-year-olds). Racial/ethnic groups and boroughs with higher vaccine coverage generally experienced greater reductions in RR point estimates. Uncertainty was greater for the decrease in COVID-19 death rates (RR 0.85, 95% CI: 0.66-1.10). The vaccination program in NYC reduced COVID-19 hospitalizations among the initially age-eligible ≥ 65-year-old population by approximately 15% in the first eight weeks. The real-world evidence of vaccine effectiveness makes it more imperative to improve vaccine access and uptake to reduce inequities in COVID-19 outcomes.


Distilling complexity to advance cardiac tissue engineering.
The promise of cardiac tissue engineering is in the ability to recapitulate in vitro the functional aspects of a healthy heart and disease pathology as well as to design replacement muscle for clinical therapy. Parts of this promise have been realized; others have not. In a meeting of scientists in this field, five central challenges or "big questions" were articulated that, if addressed, could substantially advance the current state of the art in modeling heart disease and realizing heart repair.


A needle-catheter kit in knee arthrography.
Use of a sheathed Teflon needle in knee arthrography facilitates removal of synovial effusion and eliminates trauma due to a rigid needle.


[Advantages and difficulties of an erythrocytapheresis program for sickle-cell patients: a pediatric experience].
Transfusion programs are sometimes necessary to take care of severe sickle-cell patients. Treatment of cerebrovascular disease in sickle-cell disease is the most common indication. Periodic automated red blood cell exchange (erythrocytapheresis) is an alternative treatment. Sixteen patients less than 20 years old have been treated with chronic erythrocytapheresis since 2004 in the pediatric hematology and oncology department of the University Hospital of Rouen, 10 patients for cerebrovascular disease (1 was on secondary prevention and 9 were on primary prevention), 5 patients for pain crisis recurrence, and the last one for mild psychocognitive deficit disorder. This treatment was unsuccessful for 4 patients, 3 on primary prevention and 1 treated for pain crisis recurrence. These failures were caused by alloimmunization for 2 patients and venous access problems for 2 patients. For the other 12 patients, 5 of the 6 patients on primary prevention showed clear improvement (normalization of transcranial Doppler ultrasound or improvement on magnetic resonance angiography), the patient on secondary prevention had stability on cerebral MRI after 2 years of treatment, the 5 patients with pain crisis recurrence had good improvement, and psychocognitive abilities improved for the last patient. One hundred and ninety-nine erythroexchange sessions were performed for the 9 patients treated over a period of 10 to 30 months. Erythrocytapheresis sessions ran on average less than 1.5h. Three patients showed high ferritin levels at the beginning of erythroexchange, which normalized 2 to 10 months later. All patients reported better quality of life. Periodic erythroexchanges are an effective treatment for complicated sickle-cell anemia and iron overload. It requires human, material, and financial support, but not as much as simple transfusion or manual erythroexchange. Practical experience shows problems of venous access because of coagulation when sampling.


[Septicemia secondary to an infected pacemaker system: removal of the endocardial lead with the aid of extracorporeal circulation (author's transl)].
Right ventriculotomy with extracorporeal circulation was used for removal of an infected transvenous pacemaker electrode which was firmly attached to the myocardium in a patient with septicemia. Alternative methods and suggestions to prohibit electrode incarceration are discussed.


Integrated pharmacokinetics and pharmacodynamics of the novel calcium sensitizer levosimendan as assessed by systolic time intervals.
Levosimendan is a new calcium sensitizer, acting calcium-dependently on cardiac troponin C. In the present study pharmacokinetic-pharmacodynamic interrelations of levosimendan were assessed. Ten healthy subjects (22-27 years) were given single doses of 2 mg of levosimendan in 4 different formulations: intravenous (i.v.), conventional tablet (CT), conventional capsule (CC), and slow-release tablet (SR) on different days. Systolic time intervals and impedance cardiography were recorded up to 4 hours post drug. Plasma concentrations of levosimendan and its metabolite OR-1855 were analyzed using HPLC. Hysteresis loops were constructed by connecting the effect-concentration points in time order. In addition, pharmacokinetic-pharmacodynamic modelling was performed with the i.v. data. The i.v. administration, giving a maximal levosimendan concentration of 180 ng x ml(-1), increased heart rate by 8 beats min(-1) and cardiac output by 18%. It shortened heart rate corrected electromechanical systole QS2i by 23 ms, indicating a fairly strong positive inotropic effect. The conventional oral formulations (giving maximal drug concentrations of about 70-80 ng x ml(-1)) increased heart rate by 4-5 beats min(-1) and cardiac output by 5-8%, while QS2i shortened by 9-13 ms. The SR formulation resulted in low drug concentrations and generally weaker effects than the other formulations. The bioavailability of CT and CC was 83 and 87%, while that of SR was only 31%. QS2i showed counter-clockwise hysteresis after all formulations (p < 0.01). The mean equilibration half-time (ln(2)/k(e0)) after i.v. administration was 9.6 min. Only after SR, OR-1855 was detected in appreciable amounts in plasma, the highest value being 2.2 ng x ml(-1) which occurred 24 hours after drug intake. In conclusion, the pharmacokinetic-dynamic behavior of the inotropy index QS2i indicates an equilibration delay of levosimendan, which most probably reflects the time the drug requires to distribute from plasma to its cardiac site of action. The deviant kinetic-dynamic profile of the oral slow-release formulation suggests a different absorption pattern of levosimendan from this formulation.


Treatment of Unruptured Brain Arteriovenous Malformations: A Single-Center Experience of 86 Patients and a Critique of the A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) Trial.
The A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) trial has received fierce criticism, including considerable selection bias, poor generalizability, questionable clinical practices (only 15.8% underwent surgical resection, the gold standard for arteriovenous malformation [AVM] treatment), and short follow-up (33 months) for a disease process that carries a life-long risk. In this study, we sought to present our own experience treating unruptured brain AVMs to provide supporting evidence of the ARUBA trial criticism. All cases of treated brain AVMs from 2004 to 2017 at our institution were retrospectively reviewed and included in the analysis if they met ARUBA trial inclusion criteria. The primary outcome was symptomatic stroke or death. Secondary outcomes included AVM obliteration, long-term clinical impairment (modified Rankin Scale score >1), and new major or minor postoperative deficit. Of the 245 reviewed cases, 86 met the ARUBA trial criteria. Treatment included microsurgical resection alone (2.3%), preoperative embolization followed by microsurgical resection (62.8%), stereotactic radiosurgery alone (10.5%), embolization followed by stereotactic radiosurgery (15.1%), and embolization alone (9.3%). The primary outcome was met in 8.3%, new perioperative major and minor complications occurred in 5.8% and 12.8%, and long-term clinical impairment in 4.5%. AVM obliteration was observed in 92.4% overall and in 100% of patients who underwent surgical resection. The criticism of the ARUBA trial is warranted, as our study found that treatment of unruptured brain AVMs has an acceptable safety profile when approached in a multidisciplinary manner at an experienced institution, using surgical resection as the primary treatment modality when applicable.


Evaluation of biodegradation kinetic constants for aromatic compounds by means of aerobic batch experiments.
Kinetics of aerobic biodegradation have been investigated for twenty aromatic species using sludges collected from the aeration basin of municipal sewage treatment plants. The reproducibility of the results is tested with respect to the sludges period of collection and the wastewater treatment plant where they are taken. The comparison of kinetic constants, estimated for the investigated chemicals, allows to evaluate the reactivity effect of single groups (i.e., -OH, -CH3, -Cl, -NO2) into the aromatic structures. The search for easy structure-reactivity relationships is also attempted by means of contributing group methods.


Variability of postural orthostatic tachycardia in patients with myalgic encephalomyelitis and orthostatic intolerance.
Central nervous system dysfunction with myalgic encephalomyelitis (ME) has been suggested as the main cause of chronic fatigue syndrome. Fluctuation of the symptom severity and hierarchy is a characteristic feature in ME patients. The characteristics of the sympathetic activation may differ between the "good days" and "bad days" in them. Twenty-four ME patients with orthostatic intolerance underwent a conventional 10-min active standing test and echocardiography both on a "good day" and a "bad day", defined according to the severity of their symptoms. The mean heart rate at rest was significantly higher on the "bad days" than on the "good days". During the standing test on a "bad day", 5 patients (21 %) failed to maintain an upright posture for 10 min, whereas on a "good day" all the 24 patients maintained it. Postural orthostatic tachycardia (POT) (increase in heart rate ≥30 beats/min) or severe POT (heart rate ≥120 beats/min) was observed on the "bad days" in 10 patients (43 %) who did not suffer from the severe tachycardia on the "good days", suggesting the exaggerated sympathetic nervous activation. In contrast, POT did not occur or severe POT was attenuated on the "bad days" in 5 patients (21 %) who developed POT or severe POT on the "good days", suggesting the impaired sympathetic activation. Echocardiography revealed significantly lower mean values of both the left ventricular end-diastolic diameter and stroke volume index on the "bad days" compared with the "good days". In conclusion, in ME patients with orthostatic intolerance, the exaggerated activation of the sympathetic nervous system while standing appears to switch to the impaired sympathetic activation after the system is loaded with the additional accentuated stimuli associated with the preload reduction.


Regional variation in distal esophagus distensibility assessed using the functional luminal imaging probe (FLIP).
This study aimed to evaluate the spatial variation in esophageal distensibility in normal subjects using a novel multichannel functional luminal imaging probe (FLIP). Ten healthy subjects (four men, age 21-49 years) were evaluated during endoscopy with a high-resolution impedance planimetry probe (FLIP) positioned through the esophagogastric junction (EGJ) and distal 10 cm of the esophageal body. Stepwise bag distensions using 5-mL increments from 0 to 60 mL were conducted, and simultaneous measurements of cross-sectional area (CSA) and the associated intrabag pressure from each subject were analyzed using a customized MATLAB™ program. The distensibility along the esophagus was determined and compared between the EGJ and interval locations at 2-5 cm and 6-10 cm above the EGJ. The pressure-CSA relationship was nearly linear among sites at lower pressures (0 to 7.5 mmHg) and reached a distension plateau at pressures ranging from 8 to 24 mmHg. The location of greatest distensibility was 4 cm above the EGJ. Although the CSAs of individual recording loci were not significantly different, there was a significant difference between the mean CSAs when comparing the region 2 to 5 cm proximal to EGJ with that 6 to 10 cm proximal to the EGJ. There were significant regional differences in distensibility along the distal esophagus with lower values in the proximal part compared with more distal part. The greatest distensibility was noted to occur at about 4 cm above the EGJ in close proximity to the location of the contractile deceleration point and phrenic ampulla.


The Burden of Pruritus Associated With CKD: A Mixed Methods Analysis Among Patients Undergoing Dialysis.
Despite its prevalence and distress to patients, chronic kidney disease-associated pruritus (CKD-aP) is poorly characterized, which may contribute to the condition's underdiagnosis and inadequate management. This study aimed to understand the symptom experience of patients with CKD-aP and the extent to which pruritus impacts their lives. Mixed methods study including one-on-one qualitative interviews and completion of the Skindex-10 Questionnaire (measuring itch-related quality of life). A total of 23 patients undergoing hemodialysis and reporting pruritus at 4 dialysis centers in the United States. Interviews followed a semistructured guide that included targeted and follow-up questions to elicit discussion of patients' symptoms of pruritus, including frequency and variability, impact on activities of daily living, and emotional and social functioning. Interviews were digitally audio-recorded. A coding dictionary was developed from transcripts to analyze themes and concepts. Participants described their itch with various terms, including "numbness," "pain," and "tingling" on their skin. Itch affected multiple areas but especially the back, usually occurred daily, and was often worse at night. For some, itching was a constant experience. Patients relieved their itch through scratching and various off-label treatments; some reported skin damage from excessive scratching and most indicated treatments provided limited relief. Pruritus considerably disrupted physical function, including sleep, daily activities, social functioning and relationships, and emotional and psychological wellbeing. All participants reported being bothered by their itching during the past week on the Skindex-10 Questionnaire. All participants were from the United States, so the findings may not be generalizable to other countries. Although symptom experience varies considerably, CKD-aP causes severe distress for many patients undergoing hemodialysis and can profoundly impair their quality of life. The results of this study show the impact of itch from patients' perspectives and highlight the need for greater awareness and better management of this condition. Patients with chronic kidney disease often experience itching, or pruritus, but its importance to patients is regularly overlooked. This study used one-on-one interviews to investigate patients' experiences of chronic kidney disease-associated pruritus and how it impacts their lives. We found that participants experienced itch on various body areas and used different words to describe their itch (eg, "numbness" and "pain"). Some reported skin damage from excessive scratching, and many used off-label treatments and other interventions (eg, rubbing alcohol and multiple showers daily), which provided limited relief. For many, itching was experienced daily and severely disrupted sleep, daily activities, interactions with others, and mental wellbeing. These findings reveal chronic kidney disease-associated pruritus severely impacts patients and highlights the need for improved management of this condition.


The function debate in philosophy.
This paper reviews the debate on the notion of biological function and on functional explanation as this takes place in philosophy. It describes the different perspectives, issues, intuitions, theories and arguments that have emerged. The author shows that the debate has been too heavily influenced by the concerns of a naturalistic philosophy of mind and argues that in order to improve our understanding of biology the attention should be shifted from the study of intuitions to the study of the actual practice of biological inquiry.