Depletion of the AMPAR reserve pool impairs synaptic plasticity in a model of hepatic encephalopathy.
Hepatic encephalopathy (HE) is the most common neuropsychiatric complication of acute or chronic liver failure. Clinical symptoms include cognitive and intellectual dysfunction as well as impaired motor activity and coordination. There is general consensus that increased levels of ammonia play a central role in the pathogenesis of HE. However, it is still elusive how cognitive performance including the ability to learn and memorize information is affected by ammonia at molecular levels. In the present study, we have employed a neuroglial co-culture model, which preserves neuroglial interplay but allows for cell-type specific molecular and functional analyses, to investigate glutamatergic neurotransmission under conditions of high ammonia. Chronic exposure to ammonia significantly reduced neuronal mRNA and protein expression of AMPA-subtype glutamate receptors (AMPARs), which mediate most fast excitatory neurotransmission in the brain. Surprisingly, neurons were able to fully maintain basal glutamatergic neurotransmission as recorded by AMPAR-mediated miniature excitatory postsynaptic currents (mEPSCs) even when >50% of total AMPARs were lost. However, long-lasting, activity-dependent changes in the efficacy of synaptic communication, which model the capability of the brain to learn and store information, were severely constrained. Whereas synaptic efficacy could still be depressed, an increase in synaptic strength was abolished. We conclude that neurons retain basal glutamatergic transmission at the expense of the extrasynaptic population of AMPARs, which is revealed when the extrasynaptic reserve pool is recruited in vain for synaptic potentiation. Our findings thus offer a molecular model, which might not only explain impaired synaptic plasticity in HE but also in other neurological diseases accompanied by a decrease in extrasynaptic AMPAR expression.


Quantification of MYCN, DDX1, and NAG gene copy number in neuroblastoma using a real-time quantitative PCR assay.
Amplification of the proto-oncogene MYCN is a strong adverse prognostic factor in neuroblastoma patients in all tumor stages. The status of the MYCN gene has become an important factor in clinical decision making and therapy stratification. Consequently, fast and accurate assessment of MYCN gene copy number is of the utmost importance and the use of two independent methods to determine MYCN status is recommended. For these reasons we have developed and evaluated a real-time quantitative PCR (Q-PCR) assay as an alternative for time-consuming Southern blot analysis (SB), and as a second independent technique in parallel with fluorescence in situ hybridization (FISH) analysis. Advantages of Q-PCR are a large dynamic range of quantification, no requirement for post-PCR sample handling and the need for very small amounts of starting material. The accuracy of the assay was illustrated by measurement of MYCN single gene copy changes in DNA samples of two patients with 2p deletion and duplication, respectively. Two different detection chemistries i.e., a sequence specific TaqMan probe and a generic DNA binding dye SYBR Green I were evaluated and shown to yield similar results. Also, two different calculation methods for copy number determination were used i.e., the kinetic method and the comparative C(T) method, and shown to be equivalent. In total, 175 neuroblastoma samples with known MYCN status, as determined by FISH and/or SB, were examined. Q-PCR data were highly concordant with FISH and SB data. In addition to MYCN copy number evaluation, DDX1 and NAG gene copy numbers were determined using a similar Q-PCR strategy. Survival analysis pointed out that DDX1 and/or NAG amplification has no additional adverse effect on prognosis.


Social isolation increases the density of [125I]omega-conotoxin GVIA binding sites in the rat frontal cortex and caudate nucleus.
Rats were reared from weaning either in isolation or in social groups for 12 weeks. Potential isolation-related changes in L- and N-type voltage-sensitive calcium channels (VSCCs) were assessed by the in vitro binding of [3H]isradipine (100 pM) and [125I]omega-conotoxin GVIA (4 pM) to membranes prepared from three discrete central nervous system regions: frontal cortex, caudate nucleus and hippocampus. The [3H]isradipine binding was generally not affected by isolation. However, [125I]omega-conotoxin GVIA binding was significantly higher in frontal cortex (52%) and caudate nucleus (75%) of isolated rats when compared with socially reared controls. The increased [125I]omega-conotoxin GVIA binding reflected an elevated density of binding sites without an alteration of receptor affinity. The possible contribution of an increased density of neuronal N-VSCCs (as labeled with [125I]omega-conotoxin GVIA) to the behavioral and neurochemical changes observed in 'isolation syndrome' is discussed.


Regional cortical thinning in preclinical Huntington disease and its relationship to cognition.
The authors studied presymptomatic individuals with the Huntington disease (HD) mutation to determine whether cortical thinning was present. They found thinning that was regionally selective, semi-independent of striatal volume loss, and correlated with cognitive performance. Early, extensive cortical involvement occurs during the preclinical stages of HD.


Development and Validation of a Deep Neural Network for Accurate Identification of Endoscopic Images From Patients With Ulcerative Colitis and Crohn's Disease.
The identification of ulcerative colitis (UC) and Crohn's disease (CD) is a key element interfering with therapeutic response, but it is often difficult for less experienced endoscopists to identify UC and CD. Therefore, we aimed to develop and validate a deep learning diagnostic system trained on a large number of colonoscopy images to distinguish UC and CD. This multicenter, diagnostic study was performed in 5 hospitals in China. Normal individuals and active patients with inflammatory bowel disease (IBD) were enrolled. A dataset of 1,772 participants with 49,154 colonoscopy images was obtained between January 2018 and November 2020. We developed a deep learning model based on a deep convolutional neural network (CNN) in the examination. To generalize the applicability of the deep learning model in clinical practice, we compared the deep model with 10 endoscopists and applied it in 3 hospitals across China. The identification accuracy obtained by the deep model was superior to that of experienced endoscopists per patient (deep model vs. trainee endoscopist, 99.1% vs. 78.0%; deep model vs. competent endoscopist, 99.1% vs. 92.2%, P < 0.001) and per lesion (deep model vs. trainee endoscopist, 90.4% vs. 59.7%; deep model vs. competent endoscopist 90.4% vs. 69.9%, P < 0.001). In addition, the mean reading time was reduced by the deep model (deep model vs. endoscopists, 6.20 s vs. 2,425.00 s, P < 0.001). We developed a deep model to assist with the clinical diagnosis of IBD. This provides a diagnostic device for medical education and clinicians to improve the efficiency of diagnosis and treatment.


Selection on ancestral genetic variation fuels repeated ecotype formation in bottlenose dolphins.
Studying repeated adaptation can provide insights into the mechanisms allowing species to adapt to novel environments. Here, we investigate repeated evolution driven by habitat specialization in the common bottlenose dolphin. Parapatric pelagic and coastal ecotypes of common bottlenose dolphins have repeatedly formed across the oceans. Analyzing whole genomes of 57 individuals, we find that ecotype evolution involved a complex reticulated evolutionary history. We find parallel linked selection acted upon ancient alleles in geographically distant coastal populations, which were present as standing genetic variation in the pelagic populations. Candidate loci evolving under parallel linked selection were found in ancient tracts, suggesting recurrent bouts of selection through time. Therefore, despite the constraints of small effective population size and long generation time on the efficacy of selection, repeated adaptation in long-lived social species can be driven by a combination of ecological opportunities and selection acting on ancestral standing genetic variation.


Distributions of diluted bitumen and conventional crude oil in a range of water types.
Concern about the impacts that accidental discharge of under-investigated, heavy petroleum products may have on aquatic environments has prompted a comparative examination of the behaviours of diluted bitumen (DB) and light conventional crude (CC) oil in different water types. Distributions of oil among the water column and floating water-in-oil (w/o) emulsion are evaluated by a novel, reproducible procedure involving mixing oil with water, then separating, extracting, and quantifying the total absolute oil content of the water column via gravimetric and gas-chromatographic (high-temperature simulated distillation) analyses. The CC contents of water columns tend to be significantly greater than those of DB under comparable conditions, while the fraction of oil remaining afloat at the water's surface is greater for DB than for CC. The elucidated phase distribution patterns have important implications pertaining to the recoverability of these oils in the event of their release into aquatic environments, which serves to inform best practices for oil spill response. For both DB and CC, oil contents within water columns are the highest in waters of low salinity and high pH. Water contents of buoyant w/DB emulsions are significantly greater than those of w/CC emulsions after 60 min at rest, and are the highest in waters of low salinity and low pH. The effect of crude oil on the pH of water is also studied, and DB is found to have a greater effect than CC on water samples of varying initial pH.


A simple method for isolating and culturing the rat brain microvascular endothelial cells.
Brain microvascular endothelial cells (BMECs), a main component of the blood-brain barrier, play a critical role in the pathogenesis of many brain diseases. The primary culture of BMECs has been used in various models for studying cerebrovascular diseases in vitro. However, there are still several problems existing in the isolation and cultivation of primary rat BMECs, such as low yield, contamination with other cell types, and requirement of a large number of animals and expensive growth factor. In this study, we describe a simple, economical (without any growth factor) and repeatable method to obtain endothelial cells with high purity (>99%) and yield (about 2.2×10(7) per rat) from cerebral cortexes of neonatal rat, mainly from gray matter. In vitro examinations determined that the isolated cells expressed typical phenotypic markers of differentiated brain endothelium such as multiple drug resistant protein, von Willebrand factor, platelet endothelial cell adhesion molecule 1 (PECAM-1/CD31), and intercellular adhesion molecule (ICAM). These cells also possessed morphological and ultra-structural characteristics that were observed by phase contrast microscope and electric microscope. Then GFAP and α-SMA were used, respectively, to identify astrocyte and pericyte which were potential to contaminate primary culturing of BMECs. And specific reaction of endothelial cells to external stimulation was tested by culture with TNF-α for 24h. All these results of our experiments supply that our protocol provides an effective and reliable method to obtain high purity and yield of rat BMECs and offers a useful tool for studying cellular physiology, cerebrovascular diseases, brain tumors, blood-brain barrier and neurovascular units, etc.


Can we improve clinical prediction of at-risk older drivers?
To conduct a pilot study to evaluate the predictive value of the Montreal Cognitive Assessment test (MoCA) and a brief test of multiple object tracking (MOT) relative to other tests of cognition and attention in identifying at-risk older drivers, and to determine which combination of tests provided the best overall prediction. Forty-seven currently licensed drivers (58-95 years), primarily from a clinical driving evaluation program, participated. Their performance was measured on: (1) a screening test battery, comprising MoCA, MOT, Mini-Mental State Examination (MMSE), Trail-Making Test, visual acuity, contrast sensitivity, and Useful Field of View (UFOV) and (2) a standardized road test. Eighteen participants were rated at-risk on the road test. UFOV subtest 2 was the best single predictor with an area under the curve (AUC) of .84. Neither MoCA nor MOT was a better predictor of the at-risk outcome than either MMSE or UFOV, respectively. The best four-test combination (MMSE, UFOV subtest 2, visual acuity and contrast sensitivity) was able to identify at-risk drivers with 95% specificity and 80% sensitivity (.91 AUC). Although the best four-test combination was much better than a single test in identifying at-risk drivers, there is still much work to do in this field to establish test batteries that have both high sensitivity and specificity.


The use of betamethasone to manage the trapped penis following neonatal circumcision.
The trapped penis results from cicatricial scar formation over the glans after circumcision. Management of this problem has been surgical either by incision of the cicatrix or formal surgical reconstruction. We report a series of neonates with trapped penises which were effectively managed primarily with topical steroid cream with operative intervention reserved for failed cases. A retrospective study of 14 neonates who presented with a trapped penis treated with topical betamethasone cream was performed. Each child underwent topical application of 0.05% betamethasone 3 times daily for 3 weeks in conjunction with manual retraction that continued after the steroid course. The need for surgical intervention was assessed during and after the treatment period. All 14 boys were evaluated by the pediatric urologist within 4 weeks of circumcision. Each child had a trapped penis with a dense cicatrix of the residual foreskin distal to the glans. All parents were compliant with the regimen. There were no untoward effects of topical steroid application. Following therapy 11 boys (79%) demonstrated softening of the cicatrix with easy exposure of the glans in 2 and mild persistence of the cicatrix amenable to vertical relaxation incision in 2. The cicatrix persisted in 3 boys (14%) who required formal operative repair at ages 5 to 8 months. The combination of topical betamethasone and manual retraction is effective in managing the trapped penis. This combination may affect complete resolution of the condition in the majority of patients. Otherwise, this regimen may release the closing cicatrix and allow for simple incision of the constricting phimotic ring, thus reducing the need for formal surgical repair.


Proximal tubule dopamine histofluorescence in renal slices incubated with L-dopa.
Renal cortex slices were incubated with amine precursors L-dopa, or L-5-HTP. Localization of synthesized amines, dopamine or serotonin, was examined by means of histofluorescence methods. Formaldehyde-induced fluorescence was present in the proximal convoluted tubule and not in the pars recta or other segments of the tubules after incubation in the presence of 10(-3) to 10(-7) M L-dopa. Tubule-induced fluorescence was not seen in the presence of an inhibitor of dopa-decarboxylase or in the absence of sodium. It was independent of innervation. It is concluded that dopamine and serotonin are accumulated and likely formed within proximal convoluted tubular cells.


Comparative study of the Jordan left-right reversal test, the reversals frequency test, and teachers' observations.
The intertest pass/fail reliability of the Jordan left-right reversal test (JRT) and reversals frequency test (RFT) was compared on 510 "regular classroom" and 126 "learning handicapped" children. Children were divided into two age groups, 5 to 8 years and 9 to 13 years. Teachers completed a questionnaire assessing whether they felt a reversal problem existed. Statistical analysis showed low to moderate agreement between the pass/fail rate of the two tests (p less than 0.001) for both age groups of normal children; however, no statistical agreement was found for either age group of learning handicapped children. There was only very low agreement between the teacher's assessment of reversals and the pass/fail rates for both age groups of normals and the 9- to 13-year-old learning handicapped group. No agreement was found for the 5- to 8-year-old learning handicapped group. The effect of test design and recommendations for the clinical investigation of reversals are discussed.


Effect of treatment with inhaled corticosteroid on serum periostin levels in asthma.
Periostin is a biomarker of eosinophilic airway inflammation and may contribute to airway remodeling in asthma. The anti-inflammatory activity of inhaled corticosteroids (ICS) for asthma control is widely recognized. The aim of this study was to assess the effects of ICS on serum periostin levels and its relationships to inflammation and airway geometry. Forty-two healthy controls and 20 patients with steroid-naïve asthma before and after treatment with fluticasone propionate (800 μg/day for 16 weeks) were examined. Serum periostin, lung function and inflammatory cell counts in sputum were measured. Airway dimensions were determined by quantitative computed tomography (total area of the airway (Ao), wall area (WA), wall thickness (T) and percentage wall area (WA%) ). Serum periostin concentrations were significantly higher in patients with asthma than in controls. Periostin levels were correlated with airway wall thickness and sputum eosinophilia and inversely correlated with airflow limitation in asthma. ICS significantly decreased serum periostin (P < 0.01), decreased WA corrected for body surface area (WA/BSA, P < 0.05), T/√BSA (P < 0.01) and WA% (P < 0.01), reduced the percentage of sputum eosinophils (P < 0.01) and improved airflow limitation. The decrease in serum periostin levels was associated with an increased per cent predicted forced expiratory volume in 1 s (r = -0.64, P < 0.01), decreased WA/BSA (r = 0.46, P < 0.05) and decreased sputum eosinophils (r = 0.71, P < 0.01). Serum periostin levels respond partially to ICS and may reflect a reduction in airway inflammation and wall thickening in asthma.


Adult onset xanthogranuloma presenting as laryngeal mass.
Histiocytic disorders can be classified according to the distribution pattern of the lesions and the organs involved. Non-Langerhans-cell histiocytosis is a rare group of diseases that have varied clinical presentations ranging from isolated masses to diffuse systemic eruptions. We discuss a patient who initially presented with a vocal cord lesion and was ultimately diagnosed with adult onset xanthogranuloma.


Acute bulbar, neck and limb weakness with monospecific anti-GT1a antibody: A rare localized subtype of Guillain-Barré syndrome.
Acute bulbar, neck, and limb weakness carries several potential differential diagnoses. Although a diagnosis can often be established clinically, investigations such as electrodiagnostic and antibody testing can provide support for the clinical diagnosis and may aid in understanding the pathogenesis. A 65-year-old woman presented with acute bulbar, neck, and rapidly progressive bilateral upper limb weakness. Clinical evaluation, electrophysiological, and serological studies were undertaken. Neurophysiology demonstrated proximal conduction block. A clinical diagnosis of pharyngeal-cervical-brachial weakness, a localized variant of Guillain-Barré syndrome, was made. The patient received treatment with intravenous immunoglobulin and made a remarkable recovery over the next month. She was found to have serum monospecific anti-GT1a antibodies. We report a case of pharyngeal-cervical-brachial weakness with monospecific anti-GT1a antibodies and discuss the differential diagnosis of acute bulbar, neck, and limb weakness.


A short chain (pro)collagen from aged endochondral chondrocytes. Biochemical characterization.
After 5 weeks in secondary culture, chondrocytes derived from specific regions of the embryonic chick tibiotarsus secrete greater than 90% of their culture medium collagen as a short chain (SC) collagen. Quantities of the molecule, sufficient for biochemical characterization, were isolated without proteolytic treatment from the medium of such mass cell cultures. The chains, Mr = 59,000, of SC collagen are cleaved to Mr = 45,000 by limited pepsin digestion of the native molecule. These two forms of SC collagen are referred to as the 59K form and the 45K form. The CD spectrum of the 59K form confirms the presence of a triple helical domain within the molecule. The amino acid composition of the two forms of SC collagen show it to be different from any other known collagen, including the short chain collagens that have been isolated by the proteolytic extraction of cartilages. The most characteristic features of SC collagen are its high content of methionine, low level of arginine, and a lack of cysteine. The amino acid composition of the 45K form shows it to be the collagenous domain, while the differences between the 45K and 59K form presumably reflect the composition of the nonhelical domain of the 59K form. The nonhelical domain contains greatly elevated levels of aromatic amino acids which contribute to the hydrophobic character of this domain.


Metabolic pathway engineering using the central signal processor PII.
PII signal processor proteins are wide spread in prokaryotes and plants where they control a multitude of anabolic reactions. Efficient overproduction of metabolites requires relaxing the tight cellular control circuits. Here we demonstrate that a single point mutation in the PII signaling protein from the cyanobacterium Synechocystis sp. PCC 6803 is sufficient to unlock the arginine pathway causing over accumulation of the biopolymer cyanophycin (multi-L-arginyl-poly-L-aspartate). This product is of biotechnological interest as a source of amino acids and polyaspartic acid. This work exemplifies a novel approach of pathway engineering by designing custom-tailored PII signaling proteins. Here, the engineered Synechocystis sp. PCC6803 strain with a PII-I86N mutation over-accumulated arginine through constitutive activation of the key enzyme N-acetylglutamate kinase (NAGK). In the engineered strain BW86, in vivo NAGK activity was strongly increased and led to a more than tenfold higher arginine content than in the wild-type. As a consequence, strain BW86 accumulated up to 57 % cyanophycin per cell dry mass under the tested conditions, which is the highest yield of cyanophycin reported to date. Strain BW86 produced cyanophycin in a molecular mass range of 25 to >100 kDa; the wild-type produced the polymer in a range of 30 to >100 kDa. The high yield and high molecular mass of cyanophycin produced by strain BW86 along with the low nutrient requirements of cyanobacteria make it a promising means for the biotechnological production of cyanophycin. This study furthermore demonstrates the feasibility of metabolic pathway engineering using the PII signaling protein, which occurs in numerous bacterial species.


It is not only the empty vials that go into the garbage can during chemotherapy drugs preparation: a cost analysis of unused chemotherapy drugs in cancer treatment.
Cancer therapy is a costly treatment. Costs of drugs used in cancer therapy are gradually increasing with the addition of new and expensive drugs. This fact imposes obligation on reasonable drug usage. Occasionally, all of the prescribed drugs are not used for various reasons, and a number of drugs can be left over. In this study, we aimed to calculate the costs of unused chemotherapeutic drugs in our oncology clinics. A total of 117 patients with 17 different types of cancer were administered 32 cancer therapy protocols during 2 months. After administration of ideal doses of the prescribed drugs calculated on an individual basis, the number of unused drug doses in the packages was recorded and the costs of the unused drugs were calculated based on current prices of the drugs. The cumulative cost of the unused drugs calculated for all patients was US dollars (USD) 6406.93, and average cost of the drug per capita was USD 54.76. Minimal and maximal unused drug costs per drug were USD 0.29 for 5-fluorouracil, and USD 247.12 for bevacizumab, respectively. Minimal increase in drug costs per recipe was USD 0.50 for a prescription containing cyclophosphamide and 5-fluorouracil, while the total cost of bevacizumab plus irinotecan combination increased tremendously to USD 309.12. Among chemotherapeutic protocols the cheapest one was AC (adriamycin, cyclophosphamide) with USD 4.77, while the most expensive one (USD 116.02) was FOLFIRI-B (5-fluorouracil, calcium folinate, irinotecan, and bevacizumab). The important financial burden of unused drugs goes unrecognized among routine chemotherapeutic applications. In order to be able to avoid this extravagance, drug industry, prescribing physicians, and practice nurses must assume important roles.


Significance of Malignant Peritoneal Cytology on the Survival of Women with Early-Stage Cervical Cancer: A Japanese Gynecologic Oncology Group Study.
This study examined the association between peritoneal cytology and survival in early-stage cervical cancer. This is a nationwide multicenter retrospective study, examining consecutive women with clinical stage IB1-IIB cervical cancer who underwent radical hysterectomy with available peritoneal cytology results from 2004-2008. Propensity score inverse probability of treatment weighting was used to assess the impact of malignant peritoneal cytology on survival. Among 1409 analyzed cases, 88 (6.2%) had malignant peritoneal cytology. On weighted models, malignant peritoneal cytology was associated with decreased disease-free survival (hazard ratio (HR) 1.78, 95% confidence interval (CI) 1.36-2.32) and overall survival (OS, HR 1.93, 95% CI 1.44-2.59). On sensitivity analyses, malignant peritoneal cytology was associated with decreased OS in adenocarcinoma/adenosquamous carcinoma, high-risk early-stage disease and those who received concurrent chemo-radiotherapy. However, among women who received postoperative systemic chemotherapy, malignant peritoneal cytology was not associated with OS (HR 1.21, 95% CI 0.72-2.04). A systematic review, including our results, showed that malignant peritoneal cytology was associated with decreased OS (HR 4.03, 95% CI 1.81-8.99) and increased recurrence in squamous carcinoma (odds ratio 1.89, 95% CI 1.05-3.39) and adenocarcinoma (odds ratio 4.30, 95% CI 2.30-8.02). In conclusion, the presence of malignant cells in peritoneal cytology is associated with decreased survival in early-stage cervical cancer. The possible benefit of systemic chemotherapy in this subgroup merits further investigation.


LncRNA polymorphisms and upper gastrointestinal cancer risk.
Upper gastrointestinal (GI) cancers such as oral (OC), esophageal (EC), and gastric (GC) cancers affect the digestive system, with a high mortality rate. Clinical symptoms are, however, not recognizable at early stages, and most patients are diagnosed in advanced stages. Therefore, the mechanism underlying the origin and development of upper GI cancer must be evaluated and also new therapeutic targets and effective methods should be identified and established to control GI cancers. Genome-wide approaches have introduced many long non-coding RNAs (lncRNAs) transcribed in various manners in malignant and normal tissues. It is found that the aberrant expression of specific lncRNAs is closely associated with the diagnosis or prognosis of the patients with upper GI cancers and involved in targeted therapy, which may improve the development of prevention strategies and advanced therapies. lncRNA-associated SNPs show amazing variations in interfering with the lncRNA function of regulating genes which contribute to important signaling pathways and carcinogenesis. Most data on genetic variations in lncRNAs have considered polymorphisms in focal amplifications and regulatory regions, which influence the levels of expression rather than lncRNA functionalities. The present study attempted to summarize lncRNA-related polymorphisms effective in the development of upper GI cancers. It is proposed that the individual and combined genotypes of lncRNA-related polymorphisms may predict cancer risk, and in some cases the clinical and therapeutic outcomes.


Forensic medicine in The Netherlands.
In this paper a review is given of the evolution of the Dutch Forensic Medical Association (Forensisch Medisch Genootschap, FMG): post-graduate education and the position of the police surgeon today in the Dutch legal and medical society. In just a couple of years forensic medicine has grown into a respected form of social health with worldwide contacts.


The Needs and Utilization of Long-Term Care Service Resources by Dementia Family Caregivers and the Affecting Factors.
This study was to evaluate the utilization of long-term care service resources by caregivers of patients with dementia (PWD) and to determine affecting factors. In this cross-sectional study, a total of 100 dyads were enrolled and caregivers responded to the questionnaires. We found 40% of caregivers not using any care resources. Between those caregivers using and not-using care resources, we found differences (p < 0.05) in their health status and living conditions; the difference (p < 0.05) was also found in patients' behavior and psychological symptoms of dementia (BPSD). The frequency of BPSD (OR = 1.045, p = 0.016, 95% CI = 1.001-1.083) and the living conditions (OR = 3.519, p = 0.007, 95% CI = 1.414-8.759) were related to their use of care resources. Particular BPSDs, such as anxiety or restlessness, throwaway food, aggressive behavior, tearing of clothes, and sexual harassment of patients were related to the caregivers' use of care resources (p < 0.01). Health professionals have to evaluate the patients' BPSD and identify the caregivers' essential needs. Individualized medical care and BPSD-related care resources should be provided for patients and caregivers for taking off their care burden and improving patient care.


Determinants of diarrhea in viral enteritis. The role of ion transport and epithelial changes in the ileum in transmissible gastroenteritis in piglets.
To understand mechanisms of viral diarrhea further, we studied ileal ion transport in vitro in relation to mucosal changes and epithelial differentiation in transmissible gastroenteritis in piglets, an invasive viral enteritis thought to involve mainly proximal intestine. In infected pigs, at the height of diarrhea, short-circuited ileal epithelium failed actively to transport Na+ and Cl-, and there was a defect of glucose-mediated Na+ transport. The Cl- secretory response to theophylline remained intact. Conductance measurements indicate that paracellular permeability may be reduced and transcellular transport may be altered. A mucosal lesion was observed at the time of the transport changes, characterized by villus blunting, crypt hyperplasia, and immature crypt-type enterocytes on the villus epithelium, deficient in disaccharidase and (Na+, K+)ATPase activity but rich in thymidine kinase. Consideration of the major determinants of diarrhea in this invasive enteritis must take into account not only altered mucosal function and differentiation but also the extent of intestinal involvement, including the ileum, a major site of fluid absorption in the intestine.


Molecular detection of Torque teno sus virus from tissues samples of sick pigs in China.
In the present study, Torque teno sus virus (TTSuV) was detected from different tissues, stool and serum samples of 25 sick pigs. The total prevalence of TTSuV1 and TTSuV2 were 64% (16/25) and 28% (7/25), 24% (6/25) were co-infected with both TTSuV1 and TTSuV2. The prevalence of TTSuV infection in spleen is a slightly higher, with positive rates of 52% (13/25) for TTSuV1 and 24% (6/25) for TTSuV2. Phylogenetic analysis of TTSuV1 showed that 21 isolates were distributed into two clusters (genotype TTSuV1a and TTSuV1b), with genotype TTSuV1b was the dominant genotype. Phylogenetic analysis of TTSuV2 showed that the nine isolates shared 80.9-99.2% nucleotide homology with each other, and were distributed in different genotypes (TTSuV2a-TTSuV2f). TTSuV2d was the most prevalent genotype in this study, which contained five Spanish strains and nine Chinese strains, and shared 94.2-96.8% homology.


MicroRNA-10a Regulation of Proinflammatory Mediators: An Important Component of Untreated Juvenile Dermatomyositis.
To identify differentially expressed microRNA (miRNA) in muscle biopsies (MBx) from 15 untreated children with juvenile dermatomyositis (JDM) compared with 5 controls. Following MBx miRNA profiling, differentially expressed miRNA and their protein targets were validated by quantitative real-time PCR (qRT-PCR) and immunological assay. The association of miRNA-10a and miRNA-10b with clinical data was evaluated, including Disease Activity Score (DAS), von Willebrand factor antigen (vWF:Ag), nailfold capillary end row loops, duration of untreated disease, and tumor necrosis factor (TNF)-α-308A allele. In JDM, 16/362 miRNA were significantly differentially expressed [false discovery rate (FDR) < 0.05]. Among these, miRNA-10a was the most downregulated miRNA in both FDR and ranking of fold change: miRNA-10a = -2.27-fold, miRNA-10b = -1.80-fold. Decreased miRNA-10a and miRNA-10b expressions were confirmed using q -4.16 and -2.59 fold, respectively. The qRT-PCR documented that decreased miRNA-10a expression was related to increased vascular cell adhesion molecule 1 in 13 of these JDM cases (correlation -0.67, p = 0.012), unlike miRNA-10b data (not significant). Concurrent JDM plasma contained increased levels of interleukin (IL) 6 (p = 0.0363), IL-8 (p = 0.0005), TNF-α (p = 0.0011), and monocyte chemoattractant proteins 1 (p = 0.0139). Decreased miRNA-10a, but not miRNA-10b, was associated with the TNF-α-308A allele (p = 0.015). In the 15 JDM, a trend of association of miRNA-10a (but not miRNA-10b) with vWF:Ag and DAS was observed. MiRNA-10a downregulation is an important element in untreated JDM muscle pathophysiology. We speculate that muscle miRNA expression in adult dermatomyositis differs from muscle miRNA expression in untreated childhood JDM.


Left ventricular remodeling after myocardial infarction impairs early diastolic, but not systolic, function in the radial direction in the remote normal region.
It is acknowledged that expansion of the remote normal region of the left ventricle causes remodeling after myocardial infarction (MI). However, the characteristics of that region have not been fully elucidated. We studied 13 patients with atypical chest pain (controls) and 15 patients with a prior anterior MI who underwent cardiac catheterization. With Doppler strain imaging, we measured the peak radial myocardial systolic strain and peak radial early diastolic strain rate at the posterior wall of the left ventricle. None of the patients with atypical chest pain exhibited significant stenosis of the three major coronary arteries or left ventricular (LV) wall motion abnormality in cardiac catheterization. The patients with a prior anterior MI had single anterior descending artery disease without wall motion abnormality in the LV inferoposterior wall. LV ejection fraction and the LV relaxation time constant were also measured. The LV ejection fraction was significantly smaller in patients with a prior MI compared to controls. The peak radial systolic strain in the LV posterior wall was not significantly different between the patients with a prior MI and controls (125 ± 49 vs. 122 ± 29%). In contrast, the peak radial early diastolic strain rate in the same area was significantly lower in the patients with a prior MI than in controls (-7.4 ± 2.7 vs. -13.2 ± 4.0 s(-1), p < 0.001). Peak early diastolic radial strain rate was significantly correlated with the LV relaxation time constant in all patients (r = 0.69, p < 0.001). LV remodeling after an MI impairs local early diastolic myocardial function in the remote normal region and it is related to global LV diastolic dysfunction.


No significant post-operative limb length difference following medial opening wedge high tibial osteotomy in a multi-ethnic Southeast Asian population.
This study aims to assess the significance of post-operative change in limb length in medial opening wedge high tibial osteotomy (MOWHTO), and evaluate the correlation between correction angles and changes in limb length. We hypothesize that opening wedge height and correction angles directly correlate to changes in limb length. The medical records and radiographs of 91 MOWHTO patients were retrospectively evaluated for relevant radiographical parameters both pre- and post-operatively. The exclusion criteria are: (i) concurrent distal femur osteotomy in the same setting, (ii) other previous unilateral lower limb surgeries prior to MOWHTO and (iii) failure to follow-up with post-operative radiographs. A linear regression model was performed and a line of best fit, Pearson's correlation coefficient (r) and coefficient of determination (R2) were computed. Chi-squared test was also performed, and results with P < 0.05 were considered statistically significant. There is a statistically significant increase in post-MOWHTO limb length (Absolute Δ = 4.3 ± 2.86 mm, % Δ = 0.652% ± 0.434%, p < 0.001). There was no significant difference in the limb length change between patients with larger (> 8 mm) and smaller (< 8 mm) opening widths. There was a weakly positive correlation between limb length change versus actual (R2 = 0.140, 95%CI [-0.068, 0.336]) and planned correction angles (R2 = 0.196, 95%CI [-0.012, 0.387]). In conclusion, post-MOWHTO change in limb length is statistically significant, but the clinical significance is minimal. Further studies are required to assess other factors. Development of a reliable mathematical model that predicts post-MOWHTO limb length change would be useful in predicting the anatomical outcomes. Level III. Retrospective Cohort Study.


The Pot1a-associated proteins Tpt1 and Pat1 coordinate telomere protection and length regulation in Tetrahymena.
We have identified two new telomere proteins, Tpt1 and Pat1, from the ciliate Tetrahymena thermophila. Although Tetrahymena telomerase is well characterized, only one telomere protein had previously been identified. This was the G-overhang binding-protein Pot1a. Tpt1 and Pat1 were isolated as Pot1a binding partners and shown to localize to telomeres. As Tpt1 and Pat1 were both found to be essential, conditional cell lines were generated to explore their function. Tpt1 depletion caused a rapid growth arrest and telomere elongation in the absence of cell division. The phenotype was similar to that seen after Pot1a depletion suggesting that Tpt1 and Pot1a function together to regulate telomere length and prevent telomere deprotection. In contrast, Pat1 depletion had a modest effect on cell growth but caused progressive telomere shortening similar to that observed upon TERT depletion. Thus Pat1 appears to be needed for telomerase to maintain the chromosome terminus. Analysis of Pot1a-Tpt1-Pat1 complex formation using purified proteins indicated that Tpt1 interacts directly with Pot1a while Pat1 interacts with Tpt1. Our results indicate that Tpt1 is the Tetrahymena equivalent of mammalian TPP1, Schizosaccharomyces pombe Tpz1, and Oxytricha nova TEBPβ.


Delayed presentation and sub-optimal outcomes of pediatric patients with acute appendicitis during the COVID-19 pandemic.
Early presentation and prompt diagnosis of acute appendicitis are necessary to prevent progression of disease leading to complicated appendicitis. We hypothesize that patients had a delayed presentation of acute appendicitis during the COVID-19 pandemic, which affected severity of disease on presentation and outcomes. We conducted a retrospective review of all patients who were treated for acute appendicitis at Morgan Stanley Children's Hospital (MSCH) between March 1, 2020 and May 31, 2020 when the COVID-19 pandemic was at its peak in New York City (NYC). For comparison, we reviewed patients treated from March 1, 2019 to May 31, 2019, prior to the pandemic. Demographics and baseline patient characteristics were analyzed for potential confounding variables. Outcomes were collected and grouped into those quantifying severity of illness on presentation to our ED, type of treatment, and associated post-treatment outcomes. Fisher's Exact Test and Kruskal-Wallis Test were used for univariate analysis while cox regression with calculation of hazard ratios was used for multivariate analysis. A total of 89 patients were included in this study, 41 patients were treated for appendicitis from March 1 to May 31 of 2019 (non-pandemic) and 48 were treated during the same time period in 2020 (pandemic). Duration of symptoms prior to presentation to the ED was significantly longer in patients treated in 2020, with a median of 2 days compared to 1 day (p = 0.003). Additionally, these patients were more likely to present with reported fever (52.1% vs 24.4%, p = 0.009) and had a higher heart rate on presentation with a median of 101 beats per minute (bpm) compared to 91 bpm (p = 0.040). Findings of complicated appendicitis on radiographic imaging including suspicion of perforation (41.7% vs 9.8%, p < 0.001) and intra-abdominal abscess (27.1% vs 7.3%, p = 0.025) were higher in patients presenting in 2020. Patients treated during the pandemic had higher rates of non-operative treatment (25.0% vs 7.3%, p = 0.044) requiring increased antibiotic use and image-guided percutaneous drain placement. They also had longer hospital length of stay by a median of 1 day (p = 0.001) and longer duration until symptom resolution by a median of 1 day (p = 0.004). Type of treatment was not a predictor of LOS (HR = 0.565, 95% CI = 0.357-0.894, p = 0.015) or duration until symptom resolution (HR = 0.630, 95% CI = 0.405-0.979, p = 0.040). Patients treated for acute appendicitis at our children's hospital during the peak of the COVID-19 pandemic presented with more severe disease and experienced suboptimal outcomes compared to those who presented during the same time period in 2019. III.


Post-exposure prophylaxis with SA58 (anti-SARS-COV-2 monoclonal antibody) nasal spray for the prevention of symptomatic COVID-19 in healthy adult workers: a randomized, single-blind, placebo-controlled clinical study.
Monoclonal antibodies (mAbs) and the post-exposure prophylaxis (PEP) with mAbs represent a very important public health strategy against coronavirus disease 2019 (COVID-19). This study has assessed a new Anti-SARS-COV-2 mAb (SA58) Nasal Spray for PEP against COVID-19 in healthy adults aged 18 years and older within three days of exposure to a SARS-CoV-2 infected individual. Recruited participants were randomized in a ratio of 3:1 to receive SA58 or placebo. Primary endpoints were laboratory-confirmed symptomatic COVID-19 within the study period. A total of 1222 participants were randomized and dosed (SA58, n = 901; placebo, n = 321). Median of follow-up was 2.25 and 2.79 days for SA58 and placebo, respectively. Adverse events occurred in 221 of 901 (25%) and 72 of 321 (22%) participants with SA58 and placebo, respectively. All adverse events were mild in severity. Laboratory-confirmed symptomatic COVID-19 developed in 7 of 824 participants (0.22 per 100 person-days) in the SA58 group vs. 14 of 299 (1.17 per 100 person-days) in the placebo group, resulting in an estimated efficacy of 80.82% (95%CI 52.41%-92.27%). There were 32 SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT-PCR) positives (1.04 per 100 person-days) in the SA58 group vs. 32 (2.80 per 100 person-days) in the placebo group, resulting in an estimated efficacy of 61.83% (95%CI 37.50%-76.69%). A total of 21 RT-PCR positive samples were sequenced and all were the Omicron variant BF.7. In conclusion, SA58 Nasal Spray showed favourable efficacy and safety in preventing symptomatic COVID-19 or SARS-CoV-2 infection in adults who had exposure to SARS-CoV-2 within 72 h.


[Effect of Salvia miltiorrhizae Composita on erythrocyte membrane phospholipid in patients with coronary heart disease].
To investigate the function of phospholipid metabolism in pathogenesis of coronary heart disease (CHD) and the effect of Salvia miltiorrhizae Composita (SMC) on it. The levels of erythrocyte membrane phospholipid, blood lipid peroxide (LPO), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were determined in the patients with CHD by Thinlayer chromatography and fluorimetry during the treatment of SMC. Sphingomyelins (SM), phosphatidyl serine (PS), phosphatidyl ethanolamine (PE) and lysophosphatide (LL) of erythrocyte membrane phospholipid were increased in patients with CHD. Phosphatidyl cholines (PC) was lower than control group. Among them, the ratios of SM/PC and PS/PC were significantly higher. In the patients with CHD, LPO was significantly increased and ratios of SOD/LPO and GSH-Px/LPO significantly decreased. After the treatment with SMC, LL, SM, PS and PE of erythrocyte phospholipid and the ratios of SM/PC and PS/PC and LPO were decreased. PC and SOD/LPO were increased. The abnormality of erythrocyte membrane phospholipid participate the occurrence and development of CHD. SMC might improve the abnormality of erythrocyte phospholipid and lipid peroxide and possess the effect of regulating phospholipid metabolism.


The ENDS of assumptions: an online tool for the epistemic non-parametric drug-response scoring.
The drug sensitivity analysis is often elucidated from drug dose-response curves. These curves capture the degree of cell viability (or inhibition) over a range of induced drugs, often with parametric assumptions that are rarely validated. We present a class of non-parametric models for the curve fitting and scoring of drug dose-responses. To allow a more objective representation of the drug sensitivity, these epistemic models devoid of any parametric assumptions attached to the linear fit, allow the parallel indexing such as half-maximal inhibitory concentration and area under curve. Specifically, three non-parametric models including spline (npS), monotonic and Bayesian and the parametric logistic are implemented. Other indices including maximum effective dose and drug-response span gradient pertinent to the npS are also provided to facilitate the interpretation of the fit. The collection of these models is implemented in an online app, standing as useful resource for drug dose-response curve fitting and analysis. The ENDS is freely available online at https://irscope.shinyapps.io/ENDS/ and source codes can be obtained from https://github.com/AmiryousefiLab/ENDS. Supplementary data are available at Bioinformatics online.


GLUT1 expression in human papillomavirus-positive anogenital lesions.
GLUT1, an ubiquitous glucose transporter in the mammalian cells, is upregulated in many tumours, including human papillomavirus (HPV)-induced head and neck or cervical cancer. To study in anogenital lesions whether or not GLUT1 expression correlates with genomic high-risk HPV integration, the first step in neoplastic transformation. Forty-three HPV-positive biopsies positive for either low-risk or high-risk HPV were selected. Paraffin sections adjacent to those tested for the presence of HPV were processed for GLUT1 immunocytochemistry. GLUT1 expression was analysed by two histologists, blinded to HPV type and status and then compared with HPV typing results. Two main staining patterns were observed, either staining from the basal to the granular layer or staining of superficial layers only. The first staining pattern corresponded to lesions with high number of episomal HPV-positive nuclei. Superficial staining was observed in lesions with low number of episomal HPV nuclei or when high-risk HPV was integrated in the cell genome. Our results show that GLUT1 overexpression correlates with the number of episomally infected cells in the lesion, but not with the type (low or high risk) of HPV.


Pneumatoceles in postpneumonic empyema: an algorithmic approach.
The aim of the study was to determine the natural course and select appropriate therapy for pneumatocele (PC) in children with postpneumonic empyema. Records of 134 children treated for postpneumonic empyema between October 1997 and June 2003 were reviewed retrospectively, and 58 (43%) of them were found to have PC. Their chest x-rays and computed tomography scans as well as patient profiles were evaluated to assess the size, location, course, and complications. Clinical course, treatment indications, and results were also reviewed. The patients were aged from 14 months to 15 years (mean 3.8 years). There were 36 boys and 22 girls. The PC was located on the right hemithorax in 34 patients and on the left in 24. Staphylococcus aureus was the most common isolated infective agent. Of the 58 children, 37 (63.7%) showed complete resolution with improvement of the infection within 2 months. Thirteen PCs had evidences of gradual decrease in size without any indication for invasive approaches, and they resolved completely, with a mean time of 6.1 (ranging from 1-13) months. One tension PC, 3 large PCs (>50% of hemithorax), 1 case with bad tolerance to follow-up, and 2 persistent PCs had no reduction in size on follow-up; a total of 7 patients underwent image-guided catheter drainage procedure, and 5 of them resolved completely. In the last 2 cases, surgical excision was required because of persistent cystic cavity caused by thickened PC wall. One patient whose PC had not been decreasing in size developed findings of severe lung abscess with thickened wall and directly underwent surgery. In none of these patients recurrences or complaints related to PC were noted on their control visits. Most of these PCs are simple PC and show spontaneous resolution with improvement of the infection within the first 2 months. However, some decrease gradually by time, and close follow-up should be continued in case of complicated PC. Persistent features of chest infection, more than 50% involvement of hemithorax and severe atelectasis, development of broncopleural fistulae (tension PC), and bad tolerance to follow-up remind complicated PC, and they are indications of image-guided catheter drainage procedure. Its failure occurs in PC with thickened wall that does not collapse, as was in our cases with persistent PC and severe infected PC, and thus, this is an indication for surgical excision.


Biological potential of marine macroalgae of the genus Cystoseira.
In the present investigation the acetone extracts of three macroalgae, Cystoseira amentacea, Cystoseira barbata and Cystoseira compressa, were tested for antioxidant, antimicrobial and cytotoxic potential. As a result of the study, C. amentacea extract had more potent free radical scavenging activity (IC50 = 409.81 μg/mL) than C. barbata and C. compressa extracts. For reducing power, measured values of absorbance varied from 0.0352 to 0.8873. The IC50 values for superoxide anion scavenging activity for different extracts were 521.45-976.62 μg/mL. Total phenol and flavonoid contents in extracts were 39.96-81.28 μg PE/mg and 20.85-64.58 μg RE/mg respectively. Further, all three Cystoseira species exhibited a similar antimicrobial activity. The lowest MIC value (0.312 mg/mL) was shown in the extract obtained from C. compressa against Bacillus subtilis. Finally, extract of C. amentacea expressed the strongest cytotoxic activity toward tested cell lines with IC50 values ranging from 94.72 to 186.55 μg/mL. Based on these results, it can be stated that the tested macroalgae can be used as potential natural antioxidants and antimicrobial and cytotoxic agents.


Oral Immune-Related Adverse Events Caused by Immune Checkpoint Inhibitors: Salivary Gland Dysfunction and Mucosal Diseases.
Conventional chemotherapy and targeted therapies have limited efficacy against advanced head and neck squamous cell carcinoma (HNSCC). The immune checkpoint inhibitors (ICIs) such as antibodies against CTLA-4, PD-1, and PD-L1 interrupt the co-inhibitory pathway of T cells and enhance the ability of CD8+ T cells to destroy tumors. Even in advanced HNSCC patients with recurrent diseases and distant metastasis, ICI therapy shows efficiency and become an effective alternative to conventional chemotherapy. However, as this therapy releases the immune tolerance state, cytotoxic CD8+ T cells can also attack organs and tissues expressing self-antigens that cross-react with tumor antigens and induce immune-related adverse events (irAEs). When patients with HNSCC are treated with ICIs, autoimmune diseases occur in multiple organs including the skin, digestive tract, endocrine system, liver, and respiratory tract. Treatment of various malignancies, including HNSCC, with ICIs may result in the appearance of oral irAEs. In the oral cavity, an oral lichenoid reaction (OLR) and pemphigoid develop. Sicca syndrome also occurs in association with ICIs, affecting the salivary glands to induce xerostomia. It is necessary to elucidate the pathogenic mechanisms of these intractable diseases that are not seen with conventional therapy. Early diagnosis and appropriate approaches to irAEs are needed for efficient treatment of advanced HNSCC by ICIs.


[Colonic Lipomatosis: report of a case and review of the literature].
Colonic lipomas are a rare entity, even lessfrequent colonic lipomatosis (lipohyperplasia) of which we only found very few reports in literature (five cases). We report a case of colonic lipomatosis in a young adult that manifested as acute diverticulitis with perforation and rectalpolyposis requiring surgical resolution.


Characterization of phenothiazine-induced apoptosis in neuroblastoma and glioma cell lines: clinical relevance and possible application for brain-derived tumors.
In this study we aimed to (1). screen phenothiazines for cytotoxic activity in glioma, neuroblastoma, and primary mouse brain tissue; and (2). determine the mechanism of the cytotoxic effect (apoptosis, necrosis) and the roles of calmodulin inhibition and sigma receptor modulation. Rat glioma (C6) and human neuroblastoma (SHSY-5Y) cell lines were treated with different phenothiazines. All agents induced a dose-dependent decrease in viability and proliferation, with the highest activity elicited by thioridazine. Sensitivity to thioridazine of glioma and neuroblastoma cells was significantly higher (p < 0.05) than that of primary mouse brain culture (IC50 11.2 and 15.1 microM vs 41.3 microM, respectively). The N-mustard fluphenazine induced significantly lower cytotoxicity in glioma cells, compared to fluphenazine. The sigma receptor selective ligand (+)-SK&F10047 increased viability slightly while combined with fluphenazine; SK&F10047 did not alter fluphenazine activity. Flow cytometry of propidium iodide (PI)-stained glioma cells treated with thioridazine, fluphenazine, or perphenazine (6-50 microM) resulted in a concentration-dependent increase of fragmented DNA up to 94% vs 3% in controls by all agents. Thioridazine (12.5 microM)-treated glioma cells costained with PI and Hoechst 33342 revealed a red fluorescence of fragmented nuclei in treated cells and a blue fluorescence of intact control nuclei. After 4-h exposure to thioridazine (25 and 50 microM), a 25- to 30-fold increase in caspase-3 activity in neuroblastoma cells was noted. Overall, the marked apoptotic effect of phenothiazines in brain-derived cancer cells, and the low sensitivity of primary brain tissue suggest the potential use of selected agents as therapeutic modalities in brain cancer.


Network-based Drug Repurposing: A Critical Review.
New drug development for a disease is a tedious, time-consuming, complex, and expensive process. Even if it is done, the chances for success of newly developed drugs are still very low. Modern reports state that repurposing the pre-existing drugs will have more efficient functioning than newly developed drugs. This repurposing process will save time, reduce expenses and provide more success rate. The only limitation for this repurposing is getting a desired pharmacological and characteristic parameter of various drugs from vast data about medications, their effects, and target mechanisms. This drawback can be avoided by introducing computational methods of analysis. This includes various network analysis types that use various biological processes and relationships with various drugs to simplify data interpretation. Some of the data sets now available in standard, and simplified forms include gene expression, drug-target interactions, protein networks, electronic health records, clinical trial results, and drug adverse event reports. Integrating various data sets and interpretation methods allows a more efficient and easy way to repurpose an exact drug for the desired target and effect. In this review, we are going to discuss briefly various computational biological network analysis methods like gene regulatory networks, metabolic networks, protein-protein interaction networks, drug-target interaction networks, drugdisease association networks, drug-drug interaction networks, drug-side effects networks, integrated network-based methods, semantic link networks, and isoform-isoform networks. Along with this, we briefly discussed the drug's limitations, prediction methodologies, and data sets utilised in various biological networks for drug repurposing.


Assessment of organic contamination along the coast of Laizhou Bay, China: chemical analysis and integrated biomarker responses in the clam Ruditapes philippinarum.
An investigative biomonitoring study was conducted along the coastal area of Laizhou Bay (China) to evaluate the impact of organic pollution on the clam Ruditapes philippinarum using bioaccumulation and multi-biomarker measurements. In addition, the polychlorinated biphenyls (PCBs), total petroleum hydrocarbons (TPHs) and nonylphenol (NP) content in surface sediment at the study sites were also analyzed. Concentrations of PCBs, TPHs and NP in the sediments of the study area were 1.90 ± 0.10 μg kg-1, 39.55 ± 2.42 mg kg-1, 9.23 ± 0.41 μg kg-1 dry weight, respectively, while the organic contaminants in the soft tissues of R. philippinarum were 14.81 ± 0.96 μg kg-1 for PCBs, 165.87 ± 5.03 mg kg-1 for TPHs and 86.16 ± 5.29 μg kg-1 for NP. Linear regression analysis on the levels of organic pollutants accumulated in R. philippinarum and in sediments showed no significant correlation. Multi-biomarkers including superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase, total glutathione and lipid peroxidation were assayed in gills and digestive glands of R. philippinarum. Finally, the biomarkers in gills were selected to calculate the Integrated Biomarker Response (IBR) index and to evaluate the impact of the three organic contaminants on R. philippinarum collected from different sites. According to IBR results, the western coast and eastern coast exhibited higher environmental stress than the sampling sites along the southern coast of Laizhou Bay. Significant correlation was found between the level of organic contaminants in the sediments and IBR whereas no dependence was found between pollutants' concentrations in sediments and separate biomarker responses. The results showed that PCBs and NP were the main organic pollutants among the three studied which have caused pollution pressure on R. philippinarum in Laizhou Bay coastal area.


Acanthocytosis and cholesterol enrichment decrease lipid fluidity of only the outer human erythrocyte membrane leaflet.
The structure and functions of the human erythrocyte are influenced by the composition and organization of the membrane lipids. The outer (exofacial) and inner (endofacial) leaflets of the erythrocyte membrane differ in lipid composition, and recent studies using a group of membrane-impermeant pyrene fluorophores have demonstrated that the lipid fluidity of the outer leaflet exceeds that of the inner. Using one of these probes, pyrene butyryl hydrazide linked to the tetrasaccharide stachyose (SPBH), we have compared the lipid fluidity of the outer and inner leaflets in normal human erythrocytes treated experimentally to alter membrane cholesterol content and in acanthocytes, erythrocytes of altered morphology found in individuals with the genetic disorder abetalipoproteinaemia. The results, reported here, demonstrate that hemileaflet fluidity can be altered selectively: acanthocytosis and experimental cholesterol enrichment decrease the lipid fluidity of the outer but not the inner hemileaflet.


Evolution of changes in the computed tomography scans of the brain of a patient with left middle cerebral artery infarction: a case report.
Stroke is a common and important condition in medicine. Effective early management of acute stroke can reduce morbidity and mortality. A 63-year-old man presented to the Accident and Emergency department with a history of collapse and progressive right-sided weakness. Clinically this was a cerebrovascular accident affecting the left hemisphere of the brain causing right hemiplegia. Computed tomography scans, performed 3 days apart, showed the evolution of infarction in the brain caused by the thrombus in the left middle cerebral artery. This is one of the early signs for stroke seen on computed tomography imaging and it is called the hyperdense middle cerebral artery sign. Patients admitted with a stroke, undergo CT brain within 24 hours. The scan usually takes place at admission into the hospital and is done to rule out a bleed or a space occupying lesion within the brain. A normal CT brain does not confirm a stroke has not taken place. When scanned early, the changes seen on the CT due to an infarction from a thrombus may not have taken place yet. This paper highlights the early changes that can be seen on the CT brain following a stroke caused by infarction due to a thrombus in the middle cerebral artery.


Grip strength cut-points from the Swiss DO-HEALTH population.
While grip strength (GS) is commonly assessed using a Dynamometer, the Martin Vigorimeter was proposed as an alternative method especially in older adults. However, its reference values for Swiss older adults are missing. We therefore aimed to derive sex- and age-specific GS cut-points for the dominant and non-dominant hand (DH; NDH) using the Martin Vigorimeter. Additionally, we aimed to identify clinically relevant weakness and assess convergent validity with key markers of physical function and sarcopenia in generally healthy Swiss older adults. This cross-sectional analysis includes baseline data from Swiss participants enrolled in DO-HEALTH, a 3-year randomized controlled trial in community-dwelling adults age 70 + . For both DH and NDH, 4 different definitions of weakness to derive GS cut-points by sex and age category (≤ 75 vs. > 75 years) were used: i) GS below the median of the 1st quintile, ii) GS below the upper limit of the 1st quintile, iii) GS below 2-standard deviation (SD) of the sex- and age-specific mean in DO-HEALTH Swiss healthy agers (i.e. individuals without major chronic diseases, disabilities, cognitive impairment or mental health issues) and iv) GS below 2.5-SD of the sex- and age-specific mean in DO-HEALTH Swiss healthy agers. To assess the proposed cut-points' convergent validity, we assessed their association with gait speed, time to complete the 5 Times Sit-To-Stand (5TSTS) test, and present sarcopenia. In total, 976 participants had available GS at the DH (mean age 75.2, 62% women). According to the 4 weakness definitions, GS cut-points at the DH ranged from 29-42 and 25-39 kPa in younger and older women respectively, and from 51-69 and 31-50 kPa in younger and older men respectively. Overall, weakness prevalence ranged from 2.0% to 19.3%. Definitions of weakness using the median and the upper limit of the 1st GS quintile were most consistently associated with markers of physical performance. Weak participants were more likely to have lower gait speed, longer time to complete the 5TSTS, and sarcopenia, compared to participants without weakness. In generally healthy Swiss older adults, weakness defined by the median or the upper limit of the 1st GS quintile may serve as reference to identify clinically relevant weakness. Additional research is needed in less healthy populations in order to derive representative population-based cut-points. ClinicalTrials.gov Identifier: NCT01745263.


Herbivory and the cycling of nitrogen and phosphorus in isolated California oak trees.
Nitrogen and phosphorus flow in litterfall and throughfall were studied in two California Quercus species (the evergreen Q. agrifolia and deciduous Q. lobata) before, during, and after an outbreak of the California oak moth, Phryganidia californica. All of the foliage of both oak species was removed by the herbivore during the course of this outbreak. During the outbreak, total N and P flow to the ground more than doubled from Q. agrifolia and increased to a lesser extent from Q. lobata over the previous year. The composition of the litter during the outbreak year shifted so that in Q. agrifolia, almost 70% of the total N and P flow to the ground moved through frass and insect remains, while in Q. lobata, approximately 60% of the N and 40% of the P moved through frass and insect remains. Short-term leaching experiments showed that nitrogen was far more rapidly lost from Phryganidia frass than from leaf litter of either species. These results and the relative frequency of Phryganidia outbreaks suggest that this herbivore has significant effects on the nutrient cycling beneath these trees.


Reversible capsulo-tegmental locked-in state as first manifestation of multiple sclerosis.
An 18-year-old girl developed a reversible locked-in state with bilateral ptosis and almost complete ophthalmoplegia. She later presented with a relapsing and remitting course suggestive of multiple sclerosis. Autopsy findings demonstrated bilateral capsular and tegmental demyelinating lesions. In addition to this unusual aetiology, this is the first report with pathological evidence of a locked-in syndrome due to lesions outside the ventral brainstem.


Cytotoxicity and antihyperglycemic effect of minor constituents from Rhizoma Coptis in HepG2 cells.
Generally, berberine, coptisine, palmatine, and jatrorrhizine were considered as the main bio-active compounds in Rhizoma Coptis (RC). Little attention was paid to investigate the pharmacological activity of minor constituents in RC. The present study was designed to separate the minor compounds, and the cytotoxicity and antihyperglycemic effect of these compounds in HepG2 cells were also studied. Palmatine (1), berberine (2), coptisine (3), epiberberine (4), columbamine (5), and jatrorrhizine (6) from RC ethanol extract were isolated by high speed counter current chromatography (HSCCC) in one run. The remaining fraction (about 50% of extract in HSCCC) was further isolated by traditional column chromatography methods to yield magnoflorine (7), ferulic acid (8), and choline (9). Another four alkaloids, namely groenlandicine (10), berberrubine (11), oxyberberine (12), 8-oxo-coptisine (13), also were obtained from CHCl(3) extracts. Especially, choline was first isolated from RC. Cell assay indicated that the minor fractions excluding compounds 1-6 showed obvious glucose lowering activity. In addition, the minor monomers also exhibited moderate glucose lowering activity. The combination of berberine and ferulic acid showed synergistic effect on antihyperglycemic. The combination of alkaloids 1-6 was same so. All compounds had different cytotoxicity in HepG2 cells within the test concentration. Of them, berberrubine showed the strongest cytotoxicity. The results suggested that combined action of variety constituents contributed to the antihyperglycemic effects and low cytotoxicity of RC extract in HepG2 cells.


Retraction: a descriptive study of a manual therapy intervention within a randomised controlled trial for hamstring and lower limb injury prevention.
The journal has been informed by its publisher BioMed Central that contrary to the statement in this article [Wayne Hoskins, Henry Pollard, Chiropractic & Osteopathy 2010, 18:23], they have been advised by the authors' institution Macquarie University, that its Human Research Ethics Committee did not approve this study. Because the study was conducted without institutional ethics committee approval it has been retracted.


[Analysis of ethnogeographic groups of Kazakhs based on nuclear genome DNA polymorphism].
Eight nuclear DNA loci, including six Alu insertions (ACE, APOA1, PV92, TPA25, Ya5NBC27, and Ya5NBC148), 32-bp deletion in the CCR5 gene, and VNTR locus at the eNOS gene, were examined in three ethnogeographic groups of Kazakhs (342 individuals). The individuals examined lived in southeastern, central, and southwestern regions of Kazakhstan, and according to their tribal attribution, belonged to the Senior, Middle, and Junior Zhuzes. The Alu insertions appeared to be polymorphic in all populations examined: the insertion frequency varied from 0.264 in the populations of the Senior and Middle Zhuzes at the Ya5NBC27 and Ya5NBC148 loci, to 0.827 in Kazakhs of the Middle Zhuz at the APOA1 locus. In Kazakh groups examined only two alleles of the eNOS VNTR locus were detected with the number of repeats constituting four (A) and five (B) copies. The highest frequency of A allele was found in Kazakhs from the Junior Zhuz (0.113), while the highest frequency of B allele was detected in population of the Senior Zhuz (0.893). The frequency of the 32-bp deletion in the chemokine receptor CCR5 gene varied from 0.027 in the Junior Zhuz to 0.045 in the Senior Zhuz. Kazakhs showed high genetic diversity (Hex = 0.376). In general, in three ethnogeographic groups of Kazakhs, the coefficient of gene differentiation (G(ST)) over eight diallelic markers of nuclear genome constituted 1.1%. The differences in the Alu insertions made the highest contribution to the among-population diversity (G(ST) = 1.2%).


Do environmental factors influence the occurrence of acute meningitis in industrialized countries? An epidemic of varying aetiology in Northern Italy.
Environmental and atmospheric factors have been associated with meningitis epidemics in sub-Saharan Africa but not in the northern hemisphere. An epidemic of meningitis caused by different agents occurred in a health district in northern Italy during the first quarter of 2003: there were 50 cases compared to the expected number of 19, with an incidence rate ratio of 2.7 (95% C.I. = 1.8-3.8). The epidemic occurred concurrently with unusual atmospheric and environmental conditions, such as low temperature, low humidity and elevated PM10. These conditions may have affected local immunity of the pharynx, increasing host vulnerability to acute meningitis. We propose a cumulative index combining temperature, humidity and pollution (THP index), and we set a threshold beyond which an increased risk of acute meningitis may be predicted.


Targeting MYCN-Driven Transcription By BET-Bromodomain Inhibition.
Targeting BET proteins was previously shown to have specific antitumoral efficacy against MYCN-amplified neuroblastoma. We here assess the therapeutic efficacy of the BET inhibitor, OTX015, in preclinical neuroblastoma models and extend the knowledge on the role of BRD4 in MYCN-driven neuroblastoma. The efficacy of OTX015 was assessed in in vitro and in vivo models of human and murine MYCN-driven neuroblastoma. To study the effects of BET inhibition in the context of high MYCN levels, MYCN was ectopically expressed in human and murine cells. The effect of OTX015 on BRD4-regulated transcriptional pause release was analyzed using BRD4 and H3K27Ac chromatin immunoprecipitation coupled with DNA sequencing (ChIP-Seq) and gene expression analysis in neuroblastoma cells treated with OTX015 compared with vehicle control. OTX015 showed therapeutic efficacy against preclinical MYCN-driven neuroblastoma models. Similar to previously described BET inhibitors, concurrent MYCN repression was observed in OTX015-treated samples. Ectopic MYCN expression, however, did not abrogate effects of OTX015, indicating that MYCN repression is not the only target of BET proteins in neuroblastoma. When MYCN was ectopically expressed, BET inhibition still disrupted MYCN target gene transcription without affecting MYCN expression. We found that BRD4 binds to super-enhancers and MYCN target genes, and that OTX015 specifically disrupts BRD4 binding and transcription of these genes. We show that OTX015 is effective against mouse and human MYCN-driven tumor models and that BRD4 not only targets MYCN, but specifically occupies MYCN target gene enhancers as well as other genes associated with super-enhancers. Clin Cancer Res; 22(10); 2470-81. ©2015 AACR.


Structure deformation and curvature sensing of PIEZO1 in lipid membranes.
PIEZO channels respond to piconewton-scale forces to mediate critical physiological and pathophysiological processes1-5. Detergent-solubilized PIEZO channels form bowl-shaped trimers comprising a central ion-conducting pore with an extracellular cap and three curved and non-planar blades with intracellular beams6-10, which may undergo force-induced deformation within lipid membranes11. However, the structures and mechanisms underlying the gating dynamics of PIEZO channels in lipid membranes remain unresolved. Here we determine the curved and flattened structures of PIEZO1 reconstituted in liposome vesicles, directly visualizing the substantial deformability of the PIEZO1-lipid bilayer system and an in-plane areal expansion of approximately 300 nm2 in the flattened structure. The curved structure of PIEZO1 resembles the structure determined from detergent micelles, but has numerous bound phospholipids. By contrast, the flattened structure exhibits membrane tension-induced flattening of the blade, bending of the beam and detaching and rotating of the cap, which could collectively lead to gating of the ion-conducting pathway. On the basis of the measured in-plane membrane area expansion and stiffness constant of PIEZO1 (ref. 11), we calculate a half maximal activation tension of about 1.9 pN nm-1, matching experimentally measured values. Thus, our studies provide a fundamental understanding of how the notable deformability and structural rearrangement of PIEZO1 achieve exquisite mechanosensitivity and unique curvature-based gating in lipid membranes.


Phasic genioglossus and palatoglossus muscle activity during recovery from sevoflurane anesthesia: a prospective observational study in children.
Inhalational anesthetic effects on upper airway muscle activity in children are largely unknown. The authors tested the hypothesis that phasic inspiratory genioglossus and palatoglossus activity increases during recovery from sevoflurane anesthesia in a dose-dependent manner in children. Sixteen children, aged 2.0 to 6.9 yr, scheduled for elective urological surgery were studied. Electromyogram recordings were acquired using intramuscular needle electrodes during spontaneous ventilation. After a 15-min period of equilibration, electromyogram activity was recorded over 30 s at each of three end-tidal concentrations, 1.5, 1.0, and 0.5 minimum alveolar concentration (MAC), administered in sequence. Phasic genioglossus activity was noted in four children at 1.5 MAC, five at 1.0 MAC, and six children at 0.5 MAC sevoflurane. Phasic palatoglossus activity was noted in 4 children at 1.5 MAC, 6 at 1.0 MAC, and 10 children at 0.5 MAC sevoflurane. Both the proportion of children exhibiting phasic activity, and the magnitude of phasic activity increased during recovery from anesthesia. For the genioglossus, decreasing the depth of sevoflurane anesthesia from 1.5 to 1.0 MAC increased phasic activity by approximately 35% and a further decrease to 0.5 MAC more than doubled activity (median [range] at 1.5 and 0.5 MAC: 2.7 μV [0 to 4.0 μV] and 8.6 μV [3.2 to 17.6], respectively; P = 0.029). A similar dose-related increase was recorded at the palatoglossus (P = 0.0002). Genioglossus and palatoglossus activity increases during recovery from sevoflurane anesthesia in a dose-dependent manner over the clinical range of sevoflurane concentrations in children.


Process-induced formation of imidazoles in selected foods.
The presence of 4-methylimidazole (4-MEI), 2-methylimidazole (2-MEI) and 2-acetyl-4-tetrahydroxybutylimidazole (THI) in some foods may result from the usage of caramel colorants E150c and E150d as food additives. This study demonstrates that alkylimidazoles are also byproducts formed from natural constituents in foods during thermal processes. A range of heat-processed foods that are known not to contain caramel colorants were analyzed by isotope dilution LC-MS/MS to determine the contamination levels. Highest 4-MEI concentrations (up to 466µg/kg) were observed in roasted barley, roasted malt and cocoa powders, with the concomitant presence of 2-MEI and/or THI in some cases, albeit at significantly lower levels. Low amounts of 4-MEI (<20µg/kg) were also detected in cereal-based foods such as breakfast cereals and bread toasted to a brown color (medium toasted). The occurrence of 4-MEI in certain processed foods is therefore not a reliable indicator of the presence of the additives E150c or E150d.


Cross-species analysis of thyroperoxidase inhibition by xenobiotics demonstrates conservation of response between pig and rat.
Thyroperoxidase (TPO), the enzyme that catalyzes the synthesis of thyroid hormone, is a known target for thyroid-disrupting chemicals. In vivo toxicological evidence supporting TPO-inhibition as one molecular-initiating event that leads to thyroid disruption is derived largely from rat models; however, a significant fraction of research on the inhibition of TPO by xenobiotics has been conducted using porcine TPO. The current work tested the hypothesis that porcine and rat thyroid microsomes exposed to TPO-inhibiting chemicals would demonstrate different responses in a guaiacol oxidation assay. A primary objective of this work is to establish the degree of concordance between rat and porcine TPO inhibition data. Microsomes were isolated from both rat and pig thyroid glands, and the guaiacol oxidation assay was performed for a training set of 12 chemicals, including previously reported TPO inhibitors, thyroid-disrupting chemicals thought to perturb other targets, and several previously untested chemicals, to determine the relative TPO inhibition responses across species. Concentration-response curves were derived for methimazole (MMI), dibutylphthalate (DBP), diethylhexylphthalate (DEHP), diethylphthalate (DEP), 3,5-dimethylpyrazole-1-methanol (DPM), iopanoic acid (IOA), 2-mercaptobenzothiazole (MBT), sodium perchlorate (PERC), p-nonylphenol (PNP), 4-propoxyphenol (4POP), 6-propylthiouracil (PTU), and triclosan (TCS). MMI, PTU, MBT, DPM, 4POP, and at extremely high concentrations, PERC, inhibited TPO activity. Results demonstrated a strong qualitative concordance of response between the two species. All chemicals that inhibited TPO in porcine microsomes also inhibited TPO in rat microsomes. Hill model-derived IC50 values revealed approximate 1.5- to 50-fold differences in relative potency to MMI between species for positive chemicals. DPM, MBT, 4POP, and PTU exhibited greater relative potency to MMI using rat TPO versus porcine TPO, but rank order potency for inhibition was similar for the other test chemicals, with: PTU>MBT>DPM>4POP>PERC for rat TPO and MBT>PTU>DPM>4POP>PERC for porcine TPO. These data support the extrapolation of porcine TPO data to potential thyroid-disrupting activity in rodent models to evaluate TPO-inhibiting chemicals.


The strap-electrode: a stimulating and recording electrode for small nerves.
A method is described for the construction of a strap-electrode that can be used for stimulation as well as recording of small nerves. The electrode can be applied to nerves of various diameters by adjusting the strap diameter with a teflon sleeve. Shunting is minimized by using dental rubber-dam placed under the nerve and enveloping the electrode and nerve with a silicon polymer. The arrangement is very resistant against straining forces. Stable nerve recordings and stimulus thresholds were obtained for several hours.


Premature chromosome condensation as a predictive indicator of relapse in children and adolescents with acute leukemia: initial observations.
Premature chromosome condensation has been used to determine a proliferative potential index (PPI) in a study of children in leukemia remission at varying times during the disease. Values 35% and greater were considered predictive of relapse. Such values preceded relapse with a mean of 5 months in acute lymphoblastic leukemia (ALL) patients who had previously relapsed and in myeloid leukemia patients. ALL patients followed from diagnosis and children off therapy had fluctuating and false predictive PPI values preceding long courses of continued remission. This study suggests that the PPI as a predictive indicator for relapse may be useful for patients with ALL who have previously relapsed and for patients with myeloid leukemias. Future exploration to further evaluate this mechanism of prediction is to be attempted by investigating the ability to obtain similar and more detailed information through the use of peripheral blood rather than bone marrow samples.


A NF-ĸB-Activin A signaling axis enhances prostate cancer metastasis.
Metastasis is a main cause of death in prostate cancer (PCa). To dissect the molecular cues from cancer cell-microenvironment interaction that drive metastatic cascade, bone metastatic PCa cells were intravenously implanted into zebrafish embryos and mice tibia forming metastatic lesions. Transcriptomic analysis showed an elevated expression of stemness genes, pro-inflammatory cytokines and TGF-β family member Activin A in the cancer cells at metastatic onset in both animal models. Consistently, analysis of clinical datasets revealed that the expression of Activin A is specifically elevated in metastases and correlates with poor prognosis in stratified high-risk PCa patients. It is further unveiled that the microenvironment induced Activin A expression by NF-κB activation. The elevated level of Activin A enhanced the invasive ALDHhi CSC-like phenotypes and PCa proliferation by activation of Smad and ERK1/2 signaling driving metastasis. Suppression of Activin A or Activin receptor significantly reduced the CSC-like subpopulation, invasion, metastatic growth, and bone lesion formation in zebrafish and mice xenografts, suggesting a functional role of NF-κB-dependent Activin A in PCa metastasis. Overall, our study demonstrates that human PCa cells can display a comparable response with the microenvironment in zebrafish and mice xenografts. Combining both animal models, we uncovered the microenvironment-dependent activin signaling as an essential driver in PCa metastasis with therapeutic potential.


An assessment of the reliability of 52 enhanced preliminary embryofetal development studies to detect developmental toxicity.
Preliminary embryofetal development (pEFD) data from two species are currently recommended before inclusion of women of child-bearing potential (WOCBP) in clinical trials in Europe or Japan, but not before trials in the United States. The ICH S5(R3) guideline advises an "enhanced" study design for this purpose. The reliability of pEFD studies was assessed by comparing the outcome of 52 enhanced pEFD studies (25 rat, 23 rabbit, and 4 mouse) with the results of the definitive nonclinical EFD assessment. Four pEFD studies revealed severe developmental hazard without the need for a main EFD study. Only one pEFD study failed to detect drug-related teratogenicity or pregnancy failure subsequently detected in the main study. There were, however, some false positive and some equivocal pEFD study results. Of the 48 pEFD studies for which a main EFD study was performed, 16 (33%) failed to accurately predict (within two-fold) the no adverse effect level (NOAEL) for developmental toxicity subsequently defined in the main EFD study. Skeletal examination of fetuses in the pEFD study was necessary was to detect drug-induced malformations. One quarter (23%) of EFD investigations revealed malformations and/or pregnancy failure at one dose level or more. pEFD studies are effective for the detection of serious or irreversible effects on embryofetal development, provided that full fetal examinations are completed. They are not, however, sufficiently powered to reliably define the NOAEL for developmental toxicity. The regulatory impact of pEFD studies remains obscure since maximum pregnancy prevention precautions are required in clinical trials in all regions until the results of the main EFD studies are available.


Functional hearing loss and developmental imbalances.
Functional hearing loss (FHL) is a disorder in which there are abnormal values on a hearing test, despite the absence of organic abnormalities in the peripheral and central auditory pathways. Here, we examined the developmental characteristics of FHL and the importance of intervention by analyzing the clinical characteristics of children with this disorder. We retrospectively examined 16 patients assessed under a diagnosis of FHL. After interventions such as psychological counseling by our pediatrics and psychiatry departments, we compared the clinical profiles of patients in which hearing was "improved/normalized" and "unimproved". Fourteen patients visited a pediatrician and two chose not to do so. A discrepancy between the maximum and minimum values of the four index scores was observed in all patients in which WISC-IV (the fourth version of the Wechsler Intelligence Scale for Children) was performed (n = 12). The discrepancy between the verbal comprehension index (VCI) and perceptual reasoning index (PRI) was significantly greater in "unimproved" patients than in "improved/normalized" patients. Hearing improved, or was normalized, after intervention in six of 16 patients. Developmental imbalances were suspected in all 12 children who visited a pediatrician and completed the WISC-IV. Cooperation with pediatricians, psychiatrists, and other health professionals is desirable in supporting patients diagnosed with FHL.


Increase in adrenomedullin gene expression in the left atrium and ventricle in the two-kidney one-clip renovascular hypertensive rats.
The 2-kidney 1-clip rat model was set up by clipping the left renal artery. At 5 weeks after clipping, there was an increase in preproadrenomedullin mRNA levels in both the left atria and the left ventricle. Adrenomedullin (AM) contents, however, increased in the left ventricle but decreased in the left atrium. These changes were not observed at 2 weeks after clipping. There were no changes in AM or preproadrenomedullin mRNA levels in the thoracic aorta and the mesenteric artery, and in plasma AM levels at 2 weeks or 5 weeks after clipping. We concluded that there was an increase in the secretion of AM in the left ventricle and the left atria in the 5 week renovascular hypertensive rat. The lack of change in plasma AM level suggests a paracrine function for the peptide in this setting.


A dual-emissive supramolecular sensor for fast and ratiometric determination of carprofen in meat.
Carprofen (CPF) is a non-steroidal anti-inflammatory drug that has been widely used in livestock for the treatment of fever and inflammation. Yet the massive use of CPF comes at the cost of its residue ubiquitous in the environment thus leading to a huge risk to human health. Therefore, development of a convenient analytical method for monitoring CPF is of considerable importance. In this study, a dual-emissive supramolecular sensor was facilely constructed using bovine serum albumin as the host and an environmentally sensitive dye as the guest. This sensor, for the first time, successfully realized the fluorescent detection of CPF with a rapid response, high sensitivity and selectivity. More importantly, this sensor exhibited a very unique ratiometric response to CPF, which endowed this method with satisfactory detection accuracy for food analysis. To the best of our knowledge, this is the first fluorescent method for fast determination of CPF in food.


Measurement agreement between a new biometer based on partial coherence interferometry and a validated biometer based on optical low-coherence reflectometry.
To evaluate the agreement of ocular measurements obtained with a new optical biometer (AL-Scan) and a previously validated optical biometer (Lenstar). Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China. Prospective observational cross-sectional study. For a comprehensive comparison between the partial coherence interferometry (PCI) device and the optical low-coherence reflectometry (OLCR) device, the axial length (AL), central corneal thickness (CCT), anterior chamber depth (ACD), aqueous depth, mean keratometry (K), astigmatism, white-to-white (WTW), and pupil diameter were measured 3 times per device in eyes with cataract. The sequence of the device was in random order. The mean values were compared and 95% limits of agreement (LoA) were assessed. Ninety-two eyes of 92 cataract patients were included. Bland-Altman analysis showed excellent agreement between the PCI device and the OLCR device for AL, CCT, ACD and aqueous depth measurements with narrow 95% LoA (-0.05 to 0.06 mm, -13.39 to 15.61 μm, -0.11 to 0.10 mm, and -0.12 to 0.10 mm, respectively), and the P values were more than 0.05. The mean K, astigmatism, and WTW values provided by the PCI device were in good agreement with the OLCR device, although statistically significant differences were detected. A major difference was observed in the pupil diameter measurement, with a 95% LoA of -0.73 to 1.21 mm. The PCI device biometer provided ocular measurements similar to those provided by the OLCR device for most parameters, especially for AL, CCT, and ACD. The pupil diameter values obtained with the PCI device were in poor agreement with the OLCR device, and these measurements should be interpreted with necessary adjustment. None of the authors has a proprietary or financial interest in any material or method mentioned.


Dual-layer transposon repression in heads of Drosophila melanogaster.
piRNA-mediated repression of transposable elements (TE) in the germline limits the accumulation of mutations caused by their transposition. It is not clear whether the piRNA pathway plays a role in adult, nongonadal tissues in Drosophila melanogaster. To address this question, we analyzed the small RNA content of adult Drosophila melanogaster heads. We found that the varying amount of piRNA-sized, ping-pong positive molecules in heads correlates with contamination by gonadal tissue during RNA extraction, suggesting that most of the piRNAs detected in heads originate from gonads. We next sequenced the heads of wild-type and piwi mutants to address whether piwi loss of function would affect the low amount of piRNA-sized, ping-pong negative molecules that are still detected in heads hand-checked to avoid gonadal contamination. We find that loss of piwi does not significantly affect these 24-28 nt RNAs. Instead, we observe increased siRNA levels against the majority of Drosophila TE families. To determine the effect of this siRNA level change on transposon expression, we sequenced the transcriptome of wild-type, piwi, dicer-2 and piwi, dicer-2 double-mutant heads. We find that RNA expression levels of the majority of TE in piwi or dicer-2 mutants remain unchanged and that TE transcripts increase only in piwi, dicer-2 double-mutants. These results lead us to suggest a dual-layer model for TE repression in adult somatic tissues. Piwi-mediated gene silencing established during embryogenesis constitutes the first layer of TE repression whereas Dicer-2-dependent siRNA-mediated silencing provides a backup mechanism to repress TEs that escape silencing by Piwi.


Modeled Early Longitudinal PSA Kinetics Prognostic Value in Rising PSA Prostate Cancer Patients after Local Therapy Treated with ADT +/- Docetaxel.
In metastatic prostate cancer (PCa) patients, androgen-deprivation therapy (ADT) combined with chemotherapy or next-generation androgen receptor targeted agents is a new standard treatment. The objective of the present study is to assess longitudinal PSA kinetics during treatment using mathematical modeling, to identify the modeled PSA kinetic parameters able to exhibit early prognostic/predictive values. Phase III clinical trial dataset (NCT00764166) comparing ADT +/- docetaxel in 250 locally treated patients for PCa with rising PSA levels, who were at high risk of metastatic disease was assessed. A kinetic-pharmacodynamic (K-PD) model was used to fit PSA kinetics during the first 100 treatment days, to estimate the modeled PSA production rate K (KPROD) and elimination constant rate K (KELIM). The prognostic value of these parameters, considered as categorized (favorable vs. unfavorable) covariates regarding PSA progression-free survival (PSA-PFS) and overall survival (OS), was assessed using univariate/multivariate analyses. Data from 177/250 patients was assessed. KELIM exhibited a significant prognostic value regarding PSA-PFS and KPROD regarding OS (univariate analysis). In the PSA-PFS final multivariate model, KELIM and the primary therapy type were significant. The OS multivariate model integrated both KPROD and baseline PSA doubling-time. In this first study assessing the modeled PSA kinetics prognostic value in PCa patients treated with systemic treatments, KELIM and KPROD exhibited respective prognostic values regarding PSA-PFS and OS.


Carnitine palmitoyltransferase 2 gene polymorphism is a genetic risk factor for sudden unexpected death in infancy.
Carnitine palmitoyltransferase (CPT) II is one of a pivotal enzyme in mitochondrial fatty acid oxidation, which is essential for energy production during simultaneous glucose sparing and a requirement for major energy supply, such as prolonged fasting or exercise. When infants require more energy than provided by the glycolytic system, they rely on the mitochondrial fatty acid oxidation pathway. Mutations of the CPT2 gene have been reported to cause sudden unexpected death in infancy (SUDI). A thermolabile phenotype of a CPT2 polymorphism (F352C) has been recently reported to reduce CPT II enzyme activity. The F352C variant results in energy crisis at high temperature and is suspected as a risk factor for acute encephalopathy. However, a relationship between CPT2 gene polymorphism and SUDI has not been described. Single nucleotide polymorphisms of the CPT2 gene were investigated among 54 SUDI cases and 200 healthy volunteers. The frequency of the C allele was significantly higher in the SUDI group than in the control group [25.0% vs 16.0%, odds ratio (OR)=1.75, 95% confidence interval (CI)=1.05-2.92, p=0.030). The frequency of the F352C homozygote was significantly higher in the SUDI group than in control group (11.1% vs 3.5%, OR=3.45, 95% CI=1.11-10.73, p=0.036). The F352C CPT2 variant might be a genetic risk factor for SUDI.


Factors Affecting Hospitalization Length and in-Hospital Death Due to COVID-19 Infection in Saudi Arabia: A Single-Center Retrospective Analysis.
The emerging COVID-19 coronavirus disease has widely spread, causing a serious worldwide pandemic. Disease severity and mortality risk can be predicted using an analysis of COVID-19 clinical characteristics. Finding out what influences patients' hospitalization length and in-hospital mortality is crucial for decision-making and planning for emergencies. The goal of this study is to identify the factors that influence hospital stay length and in-hospital death due to COVID-19 infection. This cross-sectional study was conducted from August to October 2020 and included 630 patients with a confirmed diagnosis of COVID-19 infection. Using odds ratios (OR) and 95% confidence intervals (CI), a multivariable logistic regression model was used to assess the variables that are linked to longer hospital stays and in-hospital deaths. Most patients were male (64.3%), and most were older than 40 years (81.4%). The mean length of hospital stay (LoHS) was 10.4±11.6 days. The overall death rate among these COVID-19 cases was 14.3%. Non-survivors were older, had more comorbidities, had prolonged LoHS with increased ICU admission rates and mechanical ventilation usage, and had a more severe condition than survivors. ICU admission, low serum albumin, and elevated LDH levels were associated with longer LoHS, while ICU admission, DM, and respiratory diseases as comorbidities, total leukocytic count, and serum albumin were predictors of mortality. Longer LoHS due to COVID-19 infection was linked to ICU admission, low serum albumin, and elevated LDH levels, while the independent predictors of in-hospital death were ICU admission, DM, and respiratory diseases as comorbidities, total leukocytic count, and serum albumin.


[Level of Binocular Pseudoaccommodation in Patients Implanted with an Apodised, Diffractive and Trifocal Multifocal Intraocular Lens].
The aim of this study was to make an evaluation of the pseudoaccommodation span and clinical results after implantation of a diffractive, apodised and trifocal multifocal intraocular lens (MIOL). In a prospective, single-centre study 28 eyes of 14 patients were evaluated after in the bag implantation of the Micro-F MIOL (PhysIOL, Belgium) during routine microsurgical cataract surgery. Two to four months postoperatively the final examinations were performed. Refraction, visual acuity monocular and binocular (near in 40 cm, intermediate in 80 cm and distance) as well as binocular defocus curves were evaluated. Mean monocular UDVA (uncorrected distance visual acuity) increased significantly (p < 0.0001) from 0.471 ± 0.22 logMAR to 0.144 ± 0.14 logMAR. For the monocular UNVA (uncorrected near visual acuity) and UIVA (uncorrected intermediate visual acuity) postoperative values of 0.127 ± 0.117 and 0.158 ± 0.20 logMAR compared to binocular results of 0.057 ± 0.137 and 0.094 ± 0.181 logMAR were found. In the analysis of the binocular defocus curve two peaks could be found between 0.0 and - 0.5 D with a visual acuity of 0.0 logMAR and at - 3.0 D with a visual acuity of 0.068 logMAR. In the intermediate range a constant pseudoaccommodation of 0.2 logMAR could be found. The trifocal, diffractive MIOL shows good functional results in all distances with a span of pseudoaccommodation of 3D and a mean visual acuity of 0.2 logMAR and better. Indeed it is offering a high level of spectacle independency without the typical intermediate gap of bifocal diffractive MIOLs.