Deep Learning-based MSMS Spectra Reduction in Support of Running Multiple Protein Search Engines on Cloud.
The diversity of the available protein search engines with respect to the utilized matching algorithms, the low overlap ratios among their results and the disparity of their coverage encourage the community of proteomics to utilize ensemble solutions of different search engines. The advancing in cloud computing technology and the availability of distributed processing clusters can also provide support to this task. However, data transferring and results' combining, in this case, could be the major bottleneck. The flood of billions of observed mass spectra, hundreds of Gigabytes or potentially Terabytes of data, could easily cause the congestions, increase the risk of failure, poor performance, add more computations' cost, and waste available resources. Therefore, in this study, we propose a deep learning model in order to mitigate the traffic over cloud network and, thus reduce the cost of cloud computing. The model, which depends on the top 50 intensities and their m/z values of each spectrum, removes any spectrum which is predicted not to pass the majority voting of the participated search engines. Our results using three search engines namely: pFind, Comet and X!Tandem, and four different datasets are promising and promote the investment in deep learning to solve such type of Big data problems.


[Anesthesia in craniofacial interventions in childhood].
Nine children with severe craniofacial malformations underwent eleven major reconstructive craniofacial osteotomies; in two children, cranio-orbito-facial reconstructions were performed. Anaesthesia lasted from seven to eleven hours. The anaesthetic technique consisted of inhalation anaesthetics and supplementation with narcotics. Intraoperative problems were seen mainly regarding the protection of airways, the body temperature, and the extensive blood loss. At the end of anaesthesia all children were awake, three were extubated in the operating room. In children with mid-face advancement the nasotracheal tube was left in place for at least 48 hours.


Dynamical splayed ferromagnetic ground state in the quantum spin ice Yb(2)Sn(2)O(7).
From magnetic, specific heat, (170)Yb Mössbauer effect, neutron diffraction, and muon spin relaxation measurements on polycrystalline Yb(2)Sn(2)O(7), we show that below the first order transition at 0.15 K all of the Yb(3+) ions are long-range magnetically ordered and each has a moment of 1.1 μ(B) which lies at ≃ 10° to a common fourfold cubic axis. The four sublattice moments have four different directions away from this axis and are therefore noncoplanar. We term this arrangement splayed ferromagnetism. This ground state has a dynamical component with a fluctuation rate in the megahertz range. The net ferromagnetic exchange interaction has an anisotropy that favors the local threefold axis. We discuss our results in terms of the phase diagram proposed by Savary and Balents [Phys. Rev. Lett. 108, 037202 (2012)] for a pyrochlore lattice of Kramers 1/2 effective spins.


Are hepatic and soleus lipid content, assessed by magnetic resonance spectroscopy, associated with low birth weight or insulin resistance in a rural Indian population of healthy young men?
To assess young healthy men from rural India, who had normal or low birth weights, using magnetic resonance spectroscopy to determine the potential differences in ectopic fat storage between birth weight groups, and to determine if ectopic fat storage was associated with insulin resistance in this population. A total of 54 lean men with normal birth weight and 49 lean men with low birth weight (age range 18-22 years) from rural India were recruited. All the men underwent anthropometry, magnetic resonance spectroscopy, a hyperinsulinaemic-euglycaemic clamp and a dual-energy X-ray absorptiometry. The median (interquartile range) values for hepatic cellular lipids, intramyocellular lipids and extramyocellular lipids, measured using magnetic resonance spectroscopy were 0.76 (0.1-1.8)%, 1.27 (1.0-2.3)% and 1.89 (1.3-3.2)%, respectively, for the normal birth weight group and 0.4 (0.1-1.3)%, 1.38 (0.9-2.2)% and 2.07 (1.2-2.8)%, respectively, for the low birth weight group (P > 0.05). No difference in ectopic fat storage was observed between the low and normal birth weight groups, with or without adjustment for age and total fat percentage. Homeostatic model assessment of insulin resistance values were not associated with hepatic cellular, intramyocellular or extramyocellular lipid content in any of the groups. Total fat percentage was the only independent predictor of intramyocellular and extramyocellular lipid content. Young and lean men from rural India with low birth weight were not observed to have ectopic fat storage in the liver or muscle, and the amount of liver and muscle fat was unrelated to insulin resistance. Older age and/or an urban affluent lifestyle may be required to show a potential role of ectopic fat storage on insulin resistance in Indian people with low or normal birth weight.


Fungemia in a Spanish hospital: the role of Candida parapsilosis over a 15-year period.
Candida parapsilosis is one of the main causes of fungemia in tertiary-care hospitals. Few studies have analysed the changes in its distribution over a long period. We compared the distribution of C. parapsilosis with that of other fungi over a 15-y period in a tertiary hospital. The susceptibility of C. parapsilosis was analysed using the new species-specific clinical breakpoints. The C. parapsilosis complex species were differentiated molecularly. From January 1997 to December 2011, 360 isolates causing 350 episodes of fungemia were isolated. C. parapsilosis was the second most frequently isolated species (20%); only 1 C. orthopsilosis was identified and there were no C. metapsilosis. The remaining episodes were caused by C. albicans (43.1%), C. tropicalis (14.4%), C. glabrata (11.7%), and other fungal species (10.8%). The incidence of candidemia increased more than two-fold between 2009 and 2011 (from 3.3 to 7.4 cases/100,000 population), and C. parapsilosis and C. glabrata fungemia increased throughout the period. C. parapsilosis was the most frequent species in children under 15 y (57.1%). All C. parapsilosis isolates were susceptible to anidulafungin, micafungin, flucytosine, amphotericin B, and posaconazole, while 98.5% were susceptible to caspofungin, 97.1% to voriconazole, 95.6% to fluconazole, and 76.5% to itraconazole. This long-term study showed a slight increase in the incidence of candidemia during the years of the study and a trend towards an increase in C. parapsilosis. Because of its high frequency and intrinsic low susceptibility to echinocandins, the prevalence and susceptibility of C. parapsilosis should be monitored, especially in children.


Effectiveness of Helicobacter pylori eradication in chronic urticaria: evidence-based analysis using the Grading of Recommendations Assessment, Development, and Evaluation system.
Chronic urticaria is a common and often frustrating condition that physicians encounter in the outpatient setting. Its management continues to be a challenge, and an exogenous cause for chronic urticaria is only found rarely. Helicobacter pylori has been implicated as a factor for many disorders and proposed as an etiologic factor for chronic urticaria. We aim to provide a comprehensive review of the data on H. pylori eradication for treatment of chronic urticaria by utilizing the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to analyze and determine the quality of evidence for this proposed therapy. Although H. pylori eradication has been recommended as part of routine chronic urticaria management by multiple authors, the trials of H. pylori eradication in the treatment of chronic urticaria have yielded conflicting results and suffer from substantial methodological limitations. Our critical appraisal of the 10 trials showing the benefit of H. pylori eradication in patients with chronic urticaria leads to an overall very low grade for this intervention. Appraisal of nine studies in which H. pylori eradication showed no benefit in the course of chronic urticaria also leads to an overall very low grade. The evidence that H. pylori eradication leads to improvement of chronic urticaria outcomes is weak and conflicting; this leads to a weak recommendation for routine H. pylori eradication for patients with chronic urticaria. For this reason, a decision to proceed with this management should be considered carefully in the context of relative harms/burdens and benefits, as well as patient values and preferences.


The Effect of Computerized Cognitive Training on Body Function and Activity Participation of Patient with Schizophrenia.
Schizophrenia spectrum disorder (SSD) is a neurobiological illness that causes considerable deficits in body functions and activity participation. This study examined the effects of a computerized cognitive training (CCT) on cognition, motor functions and activity participation with a quasi-experimental, pretest-posttest design. A total of 14 patients participated. All participants underwent two stages of CCT but one did not complete the posttest. The training was 3 times a week, 40 minutes each time and lasted for 12 weeks. Cognition, upper extremity motor, postural control performance, and activity participation (work behavior) were measured at three times: before and after 6 and 12 weeks of training. CCT improved participant's cognition and work behavior significantly and have the tendency to improve motor function. The training dosage might be insufficient for motor function improvement.Clinical Relevance- SSD patients benefit from the CCT in cognition and work behavior significantly but Motor function slightly.


[Human erythrocyte lipid peroxidation in different pathologic states].
Various capacity to reactions of peroxidative oxidation was found in lipids from erythrocytes of patients with impairments of inflammatory and tumoral nature. The most reactive were lipids from erythrocytes of patients with inflammation; lower capacity of lipids to peroxidative oixidation was observed in the blood cells of patients with tumors. The intensity of reactions of lipid peroxidation had a reverse correlation with the stability of erythrocyte membranes in isotonic buffer pH 3.0.


Core Hairpin Structure of SpCas9 sgRNA Functions in a Sequence- and Spatial Conformation-Dependent Manner.
The clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system is a widely used genome-editing tool with great clinical potential. However, its application is limited because of low editing efficiency of some target sequences and off-target effects. As this system contains only the Cas9 protein and a single-guide RNA (sgRNA; engineered from crRNA and tracrRNA), the structure and function of these components should be studied in detail to address the current clinical needs. Consequently, we investigated the structural and sequence features of the core hairpin (the first stem loop of sgRNA) of SpCas9 sgRNA. We showed that the core hairpin structure of sgRNA is essential for SpCas9/sgRNA-mediated DNA cleavage and that the internal loop structure in the core hairpin plays a vital role in target DNA cleavage. We observed that the root stem structure within the core hairpin preferentially forms Watson-Crick base pairs and should be of a specific length to maintain an appropriate spatial conformation for Cas9 binding. However, the length of the leaf stem structure of the core hairpin is flexible, having a variable nucleotide composition. Furthermore, extension of the leaf stem structure enhances the DNA cleavage activity of the Cas9/sgRNA complex, and this could be used to enhance the efficiency of gene editing. These observations provide insight into the sgRNA/Cas9 interaction, indicating that sgRNA modification could be a strategy for improved DNA editing efficiency, and optimized sgRNA can be further used for genome-wide functional screening and clinical application.


Prophylaxis and treatment of HIV-1 infection in pregnancy: Swedish recommendations 2013.
Prophylaxis and treatment with antiretroviral drugs and elective caesarean section delivery have resulted in very low mother-to-child transmission of HIV during recent years. Updated general treatment guidelines and increasing knowledge about mother-to-child transmission have necessitated regular revisions of the recommendations for the prophylaxis and treatment of HIV-1 infection in pregnancy. The Swedish Reference Group for Antiviral Therapy (RAV) updated the recommendations from 2010 at an expert meeting on 11 September 2013. The most important revisions are the following: (1) ongoing efficient treatment at confirmed pregnancy may, with a few exceptions, be continued; (2) if treatment is initiated during pregnancy, the recommended first-line therapy is essentially the same as for non-pregnant women; (3) raltegravir may be added to achieve rapid reduction in HIV RNA; (4) vaginal delivery is recommended if at > 34 gestational weeks and HIV RNA is < 50 copies/ml and no obstetric contraindications exist; (5) if HIV RNA is < 50 copies/ml and delivery is at > 34 gestational weeks, intravenous zidovudine is not recommended regardless of the delivery mode; (6) if HIV RNA is > 50 copies/ml close to delivery, it is recommended that the mother should undergo a planned caesarean section, intravenous zidovudine, and oral nevirapine, and the infant should receive single-dose nevirapine at 48-72 h of age and post-exposure prophylaxis with 2 drugs; (7) if delivery is preterm at < 34 gestational weeks, a caesarean section delivery should if possible be performed, with intravenous zidovudine and oral nevirapine given to the mother, and single-dose nevirapine given to the infant at 48-72 h of age, as well as post-exposure prophylaxis with 2 additional drugs.


Sizes of components in frog skeletal muscle measured by methods of stereology.
Stereological techniques of point and intersection counting were used to measure morphological parameters from light and electron micrographs of frog skeletal muscle. Results for sartorius muscle are as follows: myofibrils comprise 83% of fiber volume; their surface to volume ratio is 3.8 mum-1. Mitochondria comprise 1.6% of fiber volume. Transverse tubules comprise 0.32% of fiber volume, and their surface area per volume of fiber is 0.22 mum-1. Terminal cisternae of the sarcoplasmic reticulum comprise 4.1% of fiber volume; their surface area per volume of fiber is 0.54 mum-1. Longitudinal sarcoplasmic reticullum comprises 5.0% of fiber volume, and its surface area per volume of fiber is 1.48 mum-1. Longitudinal bridges between terminal cisternae on either side of a Z disk were observed infrequently; they make up only 0.035% of fiber volume and their surface area per volume of fiber is 0.009 mum-1. T-SR junction occurs over 67% of the surface of transverse tubules and over 27% of the surface of terminal cisternae. The surface to volume ratio of the caveolae is 48 mum-1; caveolae may increase the sarcolemmal surface area by 47%. Essentially the same results were obtained from semitendinosus fibers.


Prostate brachytherapy seed embolization to the right renal artery.
We report three cases of seed embolization to the right renal artery after iodine-125 (I-125) transperineal interstitial permanent prostate brachytherapy. Case 1: A 65-year-old man presented with right flank and back pain less than 4 months after prostatic seed implantation. CT evaluation for renal stone showed a seed embedded in the lower aspect of the right kidney. Case 2: A 73-year-old man complained of painless hematuria 3 years after prostatic seed brachytherapy. CT and subsequent abdominal angiography showed a seed embolization to a lower branch of the right renal artery. Case 3: An 84-year-old man presented with gross hematuria 7 months after prostatic seed implantation. Excretory urogram and subsequent CT demonstrated the right lower renal seed migration. Prostatic seed embolization to the right renal artery may cause pain and hematuria. This pattern of seed migration may be easily overlooked by imagers because it mimics renal lithiasis on cross-sectional imaging. Knowledge of prior history of permanent interstitial prostate brachytherapy and careful radiologic interpretation may help to achieve the correct diagnosis of rare renal seed migration. We present an additional atypical site of brachytherapy seed relocation in the right renal artery in 3 patients. This type of migration is probably secondary to pulmonary arteriovenous malformation or right-to-left cardiac shunts. Awareness of the propensity of seeds to dislodge and vigilance in imaging interpretation of prostatic brachytherapy recipients are necessary for the correct diagnosis of seed embolization.


Environmental risk factors of type 2 diabetes-an exposome approach.
Type 2 diabetes is one of the major chronic diseases accounting for a substantial proportion of disease burden in Western countries. The majority of the burden of type 2 diabetes is attributed to environmental risks and modifiable risk factors such as lifestyle. The environment we live in, and changes to it, can thus contribute substantially to the prevention of type 2 diabetes at a population level. The 'exposome' represents the (measurable) totality of environmental, i.e. nongenetic, drivers of health and disease. The external exposome comprises aspects of the built environment, the social environment, the physico-chemical environment and the lifestyle/food environment. The internal exposome comprises measurements at the epigenetic, transcript, proteome, microbiome or metabolome level to study either the exposures directly, the imprints these exposures leave in the biological system, the potential of the body to combat environmental insults and/or the biology itself. In this review, we describe the evidence for environmental risk factors of type 2 diabetes, focusing on both the general external exposome and imprints of this on the internal exposome. Studies provided established associations of air pollution, residential noise and area-level socioeconomic deprivation with an increased risk of type 2 diabetes, while neighbourhood walkability and green space are consistently associated with a reduced risk of type 2 diabetes. There is little or inconsistent evidence on the contribution of the food environment, other aspects of the social environment and outdoor temperature. These environmental factors are thought to affect type 2 diabetes risk mainly through mechanisms incorporating lifestyle factors such as physical activity or diet, the microbiome, inflammation or chronic stress. To further assess causality of these associations, future studies should focus on investigating the longitudinal effects of our environment (and changes to it) in relation to type 2 diabetes risk and whether these associations are explained by these proposed mechanisms.


Trends in life expectancy by income from 1988 to 2007: decomposition by age and cause of death.
Less attention has been paid to mortality trends across income groups than those measured by other socioeconomic indicators. This study assessed the change in life expectancy by income over 20 years in the Finnish general population. Life expectancy among 35-year-olds by household income quintiles was studied. Change in life expectancy from 1988-92 to 2003-7 was decomposed by age and cause of death. The dataset contained 754,087 deaths by oversample of 80% of all deaths during the period. The gap in life expectancy between the highest and the lowest income quintiles widened during the study period by 5.1 years among men and 2.9 years among women, and in 2007 it stood at 12.5 years and 6.8 years, respectively. Stagnation in the lowest income group was the main reason for the increased disparity for both sexes. Increasing mortality attributable to alcohol-related diseases and increasing or stagnating mortality for many cancers, as well as a slower decline in mortality due to ischaemic heart disease among men in the lowest income quintile, were the most significant factors increasing the gap. The increasing gap in life expectancy was mostly due to the stagnation of mortality in the lowest income quintile and especially because of the increasing mortality in alcohol-related diseases. The increase in disparity may be more extreme when using income instead of occupational class or education, possibly because income identifies a lower and economically more deprived segment on a social hierarchy more clearly. The results identify a clear need to tackle the specific health problems of the poorest.


Effect of carbon coating on the physico-chemical properties and toxicity of copper and nickel nanoparticles.
The primary aim of these interdisciplinary studies is to investigate the effect of surface carbon coating on the physico-chemical properties and toxicity of carbon-coated and noncoated copper and nickel nanoparticles (C-Cu, Cu, C-Ni, Ni NPs) in A549 alveolar epithelial cells. Compared to Cu NPs, C-Cu NPs exhibit protection against surface oxidation, tenfold higher cellular uptake, and fourfold lower release of soluble Cu. The toxicity of C-Cu NPs and Cu NPs is associated with pronounced damage to mitochondrial function and plasma membrane integrity, respectively. Compared to Cu and C-Cu NPs, Ni and C-Ni NPs are less toxic. These studies demonstrate that correlations can be drawn between physico-chemical properties and resultant toxicity of NPs as a function of surface carbon coating.


Carotid endarterectomy: a perspective.
Carotid endarterectomies have been performed for over a decade now. To review the knowledge derived from this surgical experience, i studied 18 reports on the subject, giving attention to four specific phases of patient care: the diagnostic, preoperative, intraoperative, and postoperative periods. Emphasis was placed on studying the causes of postoperative morbidity and mortality and how they are approached through radiologic, surgical, and medical technics.


[Chest pain and ST segment abnormalities in patients with accessory atrioventricular pathways. Report of three cases].
We report three patients with pre-excitation syndrome that resembled an acute coronary syndrome. A 65 years old woman, consulting in the emergency room for palpitations and retrosternal pain. EKG showed regular tachycardia and ST depression that reverted spontaneously after an episode of vomiting. A subsequent EKG demonstrated a pre-excitation syndrome and the accessory pathway was fulgurated. A 18 years old male presenting with tachycardia and chest pain elicited during exercise. An EKG showed a pre-excitation syndrome and ST segment elevation in V2 and V3. A coronary angiogram was normal. The accessory pathway successfully fulgurated. A 63 years old woman that presented tachycardia while exercising. She was subjected to an electrical cardioversion. An electrophysiological study showed an accessory pathway that was successfully fulgurated.


Neuroimaging findings in children with rare or novel de novo chromosomal anomalies.
De novo constitutional chromosomal anomalies provide important insights into the genetic loci responsible for congenital neurological disorders. However, most phenotypic descriptions of patients with rare chromosomal abnormalities are published as individual case reports or small group studies, making genotype-phenotype correlations unclear. Moreover, many clinical genetic reports do not include neuroimaging. We conducted a retrospective case series study of all children who had genetic testing done at Children's Memorial Hospital in Chicago, Illinois between 1985 and 2006. The case series was selected from a database containing all chromosomal testing results, clinical data, and neuroimaging. Clinical examination results were assigned by board certified geneticists and/or neurologists and neuroimages were reviewed by both a neurologist or neuroradiologist and a blinded neurologist. Of the 28,108 children in the series, we identified 34 children with novel or apparently novel de novo chromosomal abnormalities. Several of the cases represent potentially new genetic loci for neurological malformations and novel syndromic conditions. This study demonstrates the utility of large clinical databases in assessing genotype-phenotype correlations and mapping loci for congenital neurological disorders. We describe a case-series strategy to analyze existing databases to reveal new genotype-phenotype correlations.


Maternal Anemia and BMI as Determinants of Pregnancy Outcomes: A Hospital-Based Study.
Malnutrition is a serious underlying cause of child and maternal deaths around the world. The objective of this study evaluates maternal anemia and body mass index as determinants of pregnancy outcomes. Undernourishment during pregnancy can occurs Intra Uterine Growth Retardation. Contributing to about 80,0000 new-borns, 40,0000 infant deaths and 20% under 2 years children have stunted, 20% of maternal deaths during labor and early postpartum. This study Hospital-based cross-sectional study. The study comprised laboring women admitted for delivery in selected tertiary care hospital in South India from 10th November 2021 to 20th January 2022. Structured interview schedule for demographic information, patient's case sheet for information about the 'Body Mass Index as a determinants of pregnancy outcomes' and anthropometric measurement for body mass index (weight and height). All registered deliveries in the study period have been included, comprising of 101 sample size Bivariate logistic regressions were used to determine the factors associated with outcome variables. A significant level of 5% was used to decide the significance of statistical tests. Body Mass Index in the 1st antenatal visit of the women who came for delivery in tertiary care hospital, underweight 36.6%, normal body mass index 52.5%, and overweight 10.9%. During 1st antenatal visit 58.4% had anemia, while 53.5% had mild anemia during the last antenatal visit. Respectively 39.6% of antenatal women had normal Hb% during 1st antenatal care visit, whereas 46.5% had normal Hb%, during their last antenatal visit. The mode of delivery; spontaneous vaginal delivery 45.5%, vacuum delivery 3.0%, emergency caesarean section delivery 50.5%. Preterm delivery was statistically significant among whose first antenatal care visit was after 11th weeks of gestation. Whereas, emergency caesarean section delivery was statistically significant among underweight. Increasing maternal weight body mass index was associated with maternal and neonatal health outcomes. Which was risk of pregnancy induced hypertension, preeclampsia, eclampsia, gestational diabetes mellitus and caesarean section delivery. Every 2nd women was anemic, every 3rd pregnant women was underweight (BMI >18.5), every 2nd baby was born with caesarean section delivery. Preterm delivery was statically significant of weeks of gestation during first antenatal care visit with more than 11th weeks of gestation. Whereas, emergency cesarean section was significant with low body mass index.


SRPX2 Promotes Cell Proliferation and Invasion in Osteosarcoma Through Regulating Hippo Signaling Pathway.
Osteosarcoma (OS), a primary bone malignancy, is characterized by a high rate of metastasis. It has been found that Sushi repeat containing protein X-linked 2 (SRPX2) is involved in tumor cell proliferation, adhesion, invasion and migration. The current work aimed to explore the effect of SRPX2 on OS cell invasion and proliferation. Immunohistochemistry (IHC), Western blotting and reverse transcription-polymerase chain reaction (RT-PCR) were used to detect the expression of the associated protein in OS tissues and cell lines. Cell counting kit-8 (CCK8), transwell and colony formation assays were used to determine cell viability, invasion, and proliferation, respectively. The in vivo tumorigenic ability of SRPX2 gene was determined using nude mouse tumorigenesis test. SRPX2 knockdown suppressed the viability, while SRPX2 overexpression increased the invasion and colony formation ability of the cells in vitro. In vivo experiments demonstrated that SRPX2 knockdown inhibited tumor growth and invasion as evidenced by decreased Ki67 and N-cadherin levels, and increased E-cadherin level. Downregulation of SRPX2 increased YAP phosphorylation resulting in reduced nuclear translocation to activate Hippo signaling pathway. The promotion of cell viability, colony-forming ability, and invasion, and the inhibition of CTGF, Cyr61, and Birc5 levels promoted by SRPX2 overexpression were reversed by YAP inhibition. SRPX2 increased cell proliferation and invasion in osteosarcoma by activating Hippo signaling pathway.


[Specific modification of the alpha-subunit of Escherichia coli Rna polymerase by monomercuric derivative of fluorescein mercuric acetate].
The method for specific modification of Escherichia coli RNA polymerase by a monomercuric derivative of fluorescein--fluoresceinmonomercuracetate (FMMA)--a specific reagent for SH-groups of proteins is suggested. It is shown, that in conditions of equimolar FMMA/enzyme ratio the fluorescent label interacts preferantially with a single sulfhydryl group in alpha-subunit of RNA polymerase. The mercaptide bonding formation is followed by significant alterations of all spectral parameters of FMMA, but has no effect on the kinetic parameters (KB and k2) of RNA synthesis initiation nor does it lead to inhibition of the total RNA synthesis. The modification presented may be used in structural and topological investigations of RNA polymerase functioning.


The epidemiology of vitamin D and cancer incidence and mortality: a review (United States).
In vitro and animal studies indicate that vitamin D may have anti-cancer benefits, including against progression and metastasis, against a wide spectrum of cancers. Supporting an anti-cancer effect of vitamin D is the ability of many cells to convert 25(OH)D, the primary circulating form of vitamin D, into 1,25(OH)2D, the most active form of this vitamin. No epidemiologic studies have directly measured vitamin D concentrations or intakes on risk of total cancer incidence or mortality. However, higher rates of total cancer mortality in regions with less UV-B radiation, and among African-Americans and overweight and obese people, each associated with lower circulating vitamin D, are compatible with a benefit of vitamin D on mortality. In addition, poorer survival from cancer in individuals diagnosed in the months when vitamin D levels are lowest suggests a benefit of vitamin D against late stages of carcinogenesis. The only individual cancer sites that have been examined directly in relation to vitamin D status are colorectal, prostate and breast cancers. For breast cancer, some data are promising for a benefit from vitamin D but are far too sparse to support a conclusion. The evidence that higher 25(OH)D levels through increased sunlight exposure or dietary or supplement intake inhibit colorectal carcinogenesis is substantial. The biologic evidence for an anti-cancer role of 25(OH)D is also strong for prostate cancer, but the epidemiologic data have not been supportive. Although not entirely consistent, some studies suggest that higher circulating 1,25(OH)2D may be more important than 25(OH)D for protection against aggressive, poorly-differentiated prostate cancer. A possible explanation for these divergent results is that unlike colorectal tumors, prostate cancers lose the ability to hydroxylate 25(OH)D to 1,25(OH)2D, and thus may rely on the circulation as the main source of 1,25(OH)2D. The suppression of circulating 1,25(OH)2D levels by calcium intake could explain why higher calcium and milk intakes appear to increase risk of advanced prostate cancer. Given the potential benefits from vitamin D, further research should be a priority.


The cost-effectiveness of infliximab (Remicade) in the treatment of ankylosing spondylitis in Canada.
To estimate the cost-effectiveness of the treatment of ankylosing spondylitis (AS) with infliximab (Remicade) in Canada over the long term, with both international and Canadian treatment regimens. A previously published disease model based on functional capacity and disease activity was adapted to the Canadian setting. Current resource consumption from a cross-sectional bottom-up burden-of-illness study in 545 patients at different levels of severity of AS in 4 Canadian provinces was incorporated into the model. Cost-effectiveness estimates were based on a 3-month placebo-controlled clinical trial with 2-year open extension as well as a 4-year followup study of clinical practice in Canada. In the cost-effectiveness model, patients with insufficient response to treatment at 12 weeks (> or = 50% reduction in Bath Ankylosing Spondylitis Disease Activity Index) discontinue treatment. In view of the long disease duration, simulations over a 30-year timeframe were performed, incorporating disease progression from cohort studies and assumptions about treatment continuation beyond the clinical trial from the trial extension period. Results are presented in Canadian dollars, from the societal and healthcare payer perspectives, with both costs and effects discounted at 5%. Over a 30-year timeframe, with the assumption that patients' disease would remain stable while on treatment, the cost per quality-adjusted life-year (QALY) gained in the societal perspective is $37,491, using the treatment regimen in the clinical trial (5 mg/kg every 6 weeks). Using the dosing regimen of the Canadian study (75% at 3 mg/kg every 8 weeks, 15% at 3 mg/kg every 6 weeks, and 10% at 5 mg/kg every 8 weeks) the cost per QALY is dollar 10,264. Assuming that patients on treatment progress at half the rate of untreated patients, the cost-effectiveness ratios are dollar 45,121 and dollar 13,883, respectively, while the most conservative assumption that progression is the same in both arms, the ratios are dollar 54,137 and dollar 18,712, respectively. The results are sensitive to the dosing regimen adopted, the discontinuation rate, and assumptions concerning disease progression while on treatment. Our results indicate that infliximab therapy for patients with active AS would be cost-effective (ranges dollar 10,264-dollar 54,137 per QALY) in a Canadian setting.


Litchi-like Fe3O4@Fe-MOF capped with HAp gatekeepers for pH-triggered drug release and anticancer effect.
A novel litchi-like porous composite composed of a magnetic core, a tunable metal-organic framework (MOF) shell and a pH-sensitive hydroxyapatite (HAp) gatekeeper was successfully fabricated in this work. The anticancer drug doxorubicin (DOX) was effectively loaded on the Fe3O4@Fe-MOF@HAp nanocomposite with a loading capacity of 75.38 mg g-1. The nanocomposite had a saturation magnetization of 34 emu g-1 and thus possessed magnetic targeting function. In addition, the HAp gate, which had favorable biocompatibility and pH response characteristics, could be used to control the release of loaded DOX from the Fe3O4@Fe-MOF@HAp nanocomposite microspheres in a simulated acidic tumor cell environment, effectively killing tumor cells and reducing the toxic side effects to normal tissue. The smart design presented in this study, which incorporates a tunable shell and gate-controlled architecture, allows the sensitive release of drugs for efficient antitumor activity.


Reading DNA at single-nucleotide resolution with a mutant MspA nanopore and phi29 DNA polymerase.
Nanopore technologies are being developed for fast and direct sequencing of single DNA molecules through detection of ionic current modulations as DNA passes through a pore's constriction. Here we demonstrate the ability to resolve changes in current that correspond to a known DNA sequence by combining the high sensitivity of a mutated form of the protein pore Mycobacterium smegmatis porin A (MspA) with phi29 DNA polymerase (DNAP), which controls the rate of DNA translocation through the pore. As phi29 DNAP synthesizes DNA and functions like a motor to pull a single-stranded template through MspA, we observe well-resolved and reproducible ionic current levels with median durations of ∼28 ms and ionic current differences of up to 40 pA. Using six different DNA sequences with readable regions 42-53 nucleotides long, we record current traces that map to the known DNA sequences. With single-nucleotide resolution and DNA translocation control, this system integrates solutions to two long-standing hurdles to nanopore sequencing.


Review and Hypothesis: A Potential Common Link Between Glial Cells, Calcium Changes, Modulation of Synaptic Transmission, Spreading Depression, Migraine, and Epilepsy-H.
There is significant evidence to support the notion that glial cells can modulate the strength of synaptic connections between nerve cells, and it has further been suggested that alterations in intracellular calcium are likely to play a key role in this process. However, the molecular mechanism(s) by which glial cells modulate neuronal signaling remains contentiously debated. Recent experiments have suggested that alterations in extracellular H+ efflux initiated by extracellular ATP may play a key role in the modulation of synaptic strength by radial glial cells in the retina and astrocytes throughout the brain. ATP-elicited alterations in H+ flux from radial glial cells were first detected from Müller cells enzymatically dissociated from the retina of tiger salamander using self-referencing H+-selective microelectrodes. The ATP-elicited alteration in H+ efflux was further found to be highly evolutionarily conserved, extending to Müller cells isolated from species as diverse as lamprey, skate, rat, mouse, monkey and human. More recently, self-referencing H+-selective electrodes have been used to detect ATP-elicited alterations in H+ efflux around individual mammalian astrocytes from the cortex and hippocampus. Tied to increases in intracellular calcium, these ATP-induced extracellular acidifications are well-positioned to be key mediators of synaptic modulation. In this article, we examine the evidence supporting H+ as a key modulator of neurotransmission, review data showing that extracellular ATP elicits an increase in H+ efflux from glial cells, and describe the potential signal transduction pathways involved in glial cell-mediated H+ efflux. We then examine the potential role that extracellular H+ released by glia might play in regulating synaptic transmission within the vertebrate retina, and then expand the focus to discuss potential roles in spreading depression, migraine, epilepsy, and alterations in brain rhythms, and suggest that alterations in extracellular H+ may be a unifying feature linking these disparate phenomena.


Aortic valve homografts in adults: a clinical perspective.
Aortic valve replacement is a lifesaving measure in patients with severe aortic valve disease. In the United States, the most commonly used prostheses are the mechanical and bioprosthetic valves. With mechanical valves, long-term anticoagulation is necessary because of high thrombogenic potential. Bioprosthetic valves have a relatively high incidence of structural failure, especially in younger patients. Aortic valve homografts, derived from human heart donors or autopsy material, provide an alternative to mechanical or animal valves. The advantages of the homograft in comparison with the mechanical prostheses are the low incidence of thromboembolism without anticoagulation and lower valvular gradients in smaller sizes. Homografts are relatively resistant to endocarditis and are the valve of choice during active endocarditis. Their major mode of failure has been aortic regurgitation; however, recent advances in preservation and operative techniques have decreased this problem. Whether implantation of an aortic valve homograft should be the procedure of choice in subsets of patients remains controversial. Herein we review the history, techniques, results, complications, and current indications for aortic valve homografts.


Age estimation by amino acid racemization in teeth--a comparison of aspartic acid with glutamic acid and alanine as indicators.
On the age estimation by the amino acid racemization analysis of dentine, besides the utilization of aspartic acid (Asp) as described in earlier reports, we further studied relationships between the D/L ratios based on glutamic acid (Glu) as well as alanine (Ala) and actual ages. The study was followed up by comparing racemization velocities of the three amino acids under some heating experiments. At four steps (6, 24, 48 and 72 hours) of hydrolysis, the coefficient values of D/L ratio of each amino acid and actual age were calculated as 0.986 to 0.994 for Asp, 0.522 to 0.806 for Glu, and 0.577 to 0.737 for Ala. The data indicate that Asp gives an extremely good result. Glu and Ala do provide reliable D/L ratios, however they are not in proportion to actual ages. Consequently, Glu and Ala seem to be much less suitable for utilization in age estimation. Reaction rate constants (k.yr-1) of racemization of Asp, Glu and Ala in antemortem teeth were 5.3825 X 10(-4), 5.1000 X 10(-5) and 2.3875 X 10(-5), respectively. Those in teeth left drying at 15 degrees C were 2.4850 X 10(-8), 1.9119 X 10(-9), and 1.1450 X 10(-9), respectively. Assuming that the reaction velocity of Asp be 1 in both living and dried states, that of Glu were calculated as 0.09 and 0.08, that of Ala, 0.04 and 0.05, indicating very similar rates. The result confirmed that both Glu and Ala gave considerably slow racemization velocities as compared with Asp.


The best of tendon and nerve transfers in the upper extremity.
After reading this article, the participant should be able to: 1. Identify the prerequisite conditions to perform a tendon or a nerve transfer. 2. Detail some of the current nerve and tendon transfer options in upper extremity peripheral nerve injuries. 3. Understand the advantages and disadvantages of tendon and nerve transfers used in isolation and in combination. 4. Appreciate the controversies that surround the nerve/tendon transfers. 5. Realize the treatment outcomes of peripheral nerve injuries. Traditional treatment of a Sunderland fourth- or fifth-degree peripheral nerve injury has been direct neurorrhaphy, nerve grafting, or tendon transfers. With increasing knowledge of nerve pathophysiology, additional treatment options such as nerve transfers have become increasingly popular. With an array of choices for treating peripheral nerve injuries, there is debate as to whether tendon transfers and/or nerve transfers should be performed to restore upper extremity function. Often, tendon and nerve transfers are used in combination as opposed to one in isolation to obtain the most normal functioning extremity without unacceptable donor deficits. The authors tend to prefer reconstructive techniques that have proven long-term efficacy to restore function. Nerve transfers are becoming more common practice, with excellent results; however, the authors are wary of using nerve transfers that sacrifice possible secondary tendon reconstruction should the nerve transfer fail.


Carbonic anhydrase I is an early specific marker of normal human erythroid differentiation.
The expression of carbonic anhydrase (CA) as a marker of erythroid differentiation was investigated by immunologic and enzymatic procedures. A polyclonal anti-CA antibody was obtained by immunizing rabbits with purified CA I isozyme. This antibody is reactive with CA I but not with CA II. Within blood cells, CA I was only present in erythrocytes, whereas CA II was also detected in platelet lysates by enzymatic assay. Concerning marrow cells, identifiable erythroblasts and some blast cells expressed CA I. Most of the glycophorin A-positive marrow cells were clearly labeled by the anti-CA I antibody. However, rare CA I-positive cells were not reactive with anti-glycophorin A antibodies. We therefore investigated whether these cells were erythroid precursors or progenitors. In cell sorting experiments of marrow cells with the FA6 152 monoclonal antibody, which among hematopoietic progenitors is reactive only with CFU-E and a part of BFU-E, was performed, CA I+ cells were found mainly in the positive fraction. The percentage of CA I+ cells nonreactive with anti-glycophorin A antibodies contained in the two fractions was in the same range as the percentage of erythroid progenitors identified by their capacity to form colonies. In addition, the anti-CA I antibody labeled blood BFU-E-derived colonies as early as day 6 of culture, whereas in similar experiments with the anti-glycophorin A antibodies, they were stained three or four days later. No labeling was observed in CFU-GM- or CFU-MK-derived colonies. The phenotype of the day 6 cells expressing CA I was similar to that of erythroid progenitors (CFU-E or BFU-E): negative for glycophorin A and hemoglobin, and positive for HLA-DR antigen, the antigen identified by FA6 152, and blood group A antigen. Among the cell lines tested, only HEL cells expressed CA I, while K562 was unlabeled by the anti-CA I antibody. In contrast, HEL and K562 cells expressed CA II as detected by a biochemical technique. Synthesis of CA I, as with other erythroid markers such as glycophorin A and hemoglobin, was almost abolished after 12-O-tetradecanoyl-phorbol-13 acetate treatment of HEL cells. In conclusion, CA I appears to be an early specific marker of the erythroid differentiation, expressed by a cell with a similar phenotype as an erythroid progenitor.


Xenopus: An emerging model for studying congenital heart disease.
Congenital heart defects affect nearly 1% of all newborns and are a significant cause of infant death. Clinical studies have identified a number of congenital heart syndromes associated with mutations in genes that are involved in the complex process of cardiogenesis. The African clawed frog, Xenopus, has been instrumental in studies of vertebrate heart development and provides a valuable tool to investigate the molecular mechanisms underlying human congenital heart diseases. In this review, we discuss the methodologies that make Xenopus an ideal model system to investigate heart development and disease. We also outline congenital heart conditions linked to cardiac genes that have been well studied in Xenopus and describe some emerging technologies that will further aid in the study of these complex syndromes.


Defecography: a practical approach.
The purpose of this pictorial essay is to describe the main morpho- functional imaging features, physiological and pathological, of the recto-anal region and pelvic floor as depicted with conventional video defecography. Defecography has dramatically improved our knowledge of dysfunctions of evacuation. The most frequent indications and related disorders are presented from a database of more than 2500 examinations conducted in two radiology departments over a period of 15 years. Imaging features of the common recto-anal and pelvic floor disorders are described: rectal prolapse, rectocele, intussusception, descending pelvic floor syndrome, puborectalis muscle syndrome, enterocele, and sigmoidocele. Conventional video defecography still represents the gold standard examination for the identification and staging of morphological and functional disorders of the recto-anal region and pelvic floor in evacuation dysfunctions.


Limits to the differential avidity model of T cell selection in the thymus.
It has been postulated that the critical feature that determines the developmental fate of an immature thymocyte is the avidity of interaction between thymocyte TCR and peptide/MHC molecules on thymic stromal cells. However, it is possible that certain innate properties of peptides predispose them to triggering only positive or negative selection irrespective of their density on thymic stromal cells. To distinguish between these hypotheses, we examined the ability of several different peptides to induce the positive and negative selection of TCR transgenic (P14) antilymphocytic choriomeningitis virus (LCMV) CTLs in fetal thymus organ cultures (FTOC) from TAP1+ and TAP1- mice. We found that only relatively weak agonist peptides could induce the positive selection of anti-LCMV CTLs. A nonagonist peptide could induce positive selection but not negative selection; however, a weak agonist peptide could induce the positive selection of anti-LCMV CTLs in P14 TAP1- FTOC and negative selection in P14 TAP1+ FTOC. These data imply that there are upper and lower limits for the affinity of a peptide in triggering positive or negative selection, but that for peptides of intermediate affinity the overall avidity of interaction with the P14 TCR is the critical parameter in determining the developmental fate of thymocytes. Our observations also suggest a prominent role for low affinity self peptides in selecting a function repertoire of CD8+ T cells.


Robust Sparse Representation and Multiclass Support Matrix Machines for the Classification of Motor Imagery EEG Signals.
EEG signals are extremely complex in comparison to other biomedical signals, thus require an efficient feature selection as well as classification approach. Traditional feature extraction and classification methods require to reshape the data into vectors that results in losing the structural information exist in the original featured matrix. The aim of this work is to design an efficient approach for robust feature extraction and classification for the classification of EEG signals. In order to extract robust feature matrix and reduce the dimensionality of from original epileptic EEG data, in this paper, we have applied robust joint sparse PCA (RJSPCA), Outliers Robust PCA (ORPCA) and compare their performance with different matrix base feature extraction methods, followed by classification through support matrix machine. The combination of joint sparse PCA with robust support matrix machine showed good generalization performance for classification of EEG data due to their convex optimization. A comprehensive experimental study on the publicly available EEG datasets is carried out to validate the robustness of the proposed approach against outliers. The experiment results, supported by the theoretical analysis and statistical test, show the effectiveness of the proposed framework for solving classification of EEG signals.


Modification of suction-induced hemolysis during cell salvage.
The efficiency of red blood cell collection during cell salvage is dictated by multiple variables, including suction pressure. In this study, we attempted to determine the influence of suction pressure on the efficiency of cell salvage and to identify methods for minimizing the impact of suction on salvaged blood. Whole blood was placed in 60-mL aliquots either in a beaker or on a flat surface and suctioned at 100 and 300 mm Hg. The amount of hemolysis was measured and compared under the varying conditions. The experiments were repeated with the blood diluted with normal saline solution in a 1:1 mix. Hemolysis ranged from 0.21% to 2.29%. Hemolysis was greatest when whole blood was suctioned from a flat surface at 300 mm Hg. It was reduced when the blood was diluted with saline. Blood suctioned from a surgical field during cell salvage should be done with minimal suction pressures and with the goal of minimizing blood-air interfaces. Significant reduction of blood damage can be obtained by diluting blood with normal saline while suctioning it from the surgical field. Although immediate hemolysis due to suctioning was not very high, the red blood cell damage from suctioning produced by a dynamic blood-air interface might adversely affect the efficiency of cell salvage.


High serum levels of secretory IgA in liver disease: possible liver origin of the circulating secretory component.
Patients with liver disease frequently display unexplained elevations of serum secretory IgA (sIgA). The sIgA levels in various liver diseases were compared to various biochemical or clinical parameters. Patients with primary biliary cirrhosis, biliary tract obstruction, or acute hepatitis displayed highest sIgA levels. In chronic parenchymal liver disease sIgA levels correlated strongly with serum alkaline phosphatase (r = 0.79), leucine aminopeptidase (r = 0.83), and direct bilirubin levels (r = 0.63), but not with prothrombin time, aminopyrine breath test, or presence of portacaval shunting. In acute hepatitis sIgA correlated best with serum glutamic oxaloacetic transaminase (r = 0.69) but not with bilirubin; in four patients with fulminant hepatitis, sIgA fell rapidly together with all liver enzymes and prothrombin time; it rose quickly again in one patient when parenchymal regeneration occurred. These results suggest a hepatobiliary origin of the serum sIgA in liver disease. In acute hepatitis the persistence of hepatocytes seems necessary for maintaining high serum sIgA levels, suggesting a possible hepatocyte origin of the secretory component.


Elevated 1,25(OH)2D3, intestinal absorption, and renal mineral conservation in male rats.
We studied the physiological importance of elevated serum 1,25-dihydroxy-vitamin D3 [1,25(OH)2D3] in male rats. Male and female rats of equal weight consumed either a high calcium diet (1.20% calcium; HCD), a low calcium diet (0.02% calcium; LCD), or a normal calcium diet (0.60% calcium; NCD). With all three diets, serum 1,25(OH)2D3 was higher in males than females and rose in both sexes with decreasing diet calcium. There was a direct correlation between serum 1,25(OH)2D3 and proximal duodenal 45Ca uptake (r = 0.667; P less than 0.001). With NCD, we performed a balance study and found a direct correlation between serum 1,25(OH)2D3 and both 5-day fractional calcium absorption (r = 0.703; P less than 0.01) and fractional phosphorus absorption (r = 0.679; P less than 0.01). In addition, serum 1,25(OH)2D3 was directly correlated with 5-day calcium retention (r = 0.772; P less than 0.001) and phosphorus retention (r = 0.830; P less than 0.001). Males grew faster than females (F ratio = 1,194; P less than 0.001). Elevated 1,25(OH)2D3 in males appears to be of biological significance and may help satisfy a greater, growth-related, need for calcium.


Photoredox-Catalyzed Tandem Cyclization of Enaminones with N-Sulfonylaminopyridinium Salts toward the Synthesis of 3-Sulfonaminated Chromones.
A photoredox-catalyzed intermolecular tandem sulfonamination/cyclization of enaminones was realized by using N-aminopyridinium salts as the sulfonaminated reagents without transition-metal catalysts or bases. The reaction exhibits a broad scope and good functional group tolerance, good yields, and regioselectivity. Preliminary mechanistic studies support the radical property of the reaction and the involvement of N-centered radical intermediates.


Rings of membrane sterols surround the openings of vesicles and fenestrae, in capillary endothelium.
We investigated the distribution of sterols in the cell membrane of microvascular endothelium (mouse pancreas, diaphragm, brain, heart, lung, kidney, thyroid, adrenal, and liver) with the polyene antibiotic filipin, which reportedly has binding specificity for free 3-beta-hydroxysterols. In some experiments, concomitantly, cell-surface anionic sites were detected with cationized ferritin. Vessels were perfused in situ with PBS, followed by light fixation and filipin administration for 10 to 60 min. Tissues were further processed for thin-section and freeze-fracture electron microscopy. Short exposure (10 min) to filipin-glutaraldehyde solution resulted in the initial appearance, on many areas, of rings of characteristic filipin-sterol complexes within the rim surrounding stomata of most plasmalemmal vesicles, transendothelial channels, and fenestrae. Such rings were absent from the rims of the large openings of the sinusoid endothelium (liver, adrenal), coated pits and phagocytic vacuoles. After longer exposure (30-60 min), filipin-sterol complexes labeled randomly the rest of plasma membrane (except for coated pits, and partially the interstrand areas of junctions), and also marked most plasmalemmal vesicles. These peristomal rings of sterols were displayed mostly on the P face, and, at their full development, consisted of 6-8 units around a vesicle stoma, and 10-12 units around a fenestra. At their level, the intramembranous particles and the cell surface anionic sites were virtually excluded. Peristomal rings of sterols were also detected on the plasma membrane of pericytes and smooth muscle cells of the microvascular wall, which otherwise were poorly labeled with filipin-sterol complexes as compared to endothelial plasmalemma. It is presumed that the peristomal rings of cholesterol may represent important contributors to the local transient stabilization of plasma membrane and to the phase separation between cell membrane and vesicle membrane at a certain stage of their fusion/fission process.


PCR in Helicobacter spp. diagnostic in extragastric malignancies of digestive system.
Recognition of Helicobacter pylori as an important factor in genesis of gastric adenocarcinoma lead to a large number of studies concerning potential role of Helicobacter spp. in the development of extragastric digestive malignancies. The serological studies indicated possible localizations in the digestive system being from interest in enlightening Helicobacter spp. carcinogenic potential. The PCR obtruded itself as a gold standard in proving existence of actual correlation. In this review, the authors have examined studies conducted in the last 10 years examining Helicobacter spp. correlation with extragastric digestive carcinogenesis. Studies have been observed in four groups referring to hepatic carcinoma, bile duct cancer, pancreatic cancer, and colon cancer. The results of these researches have shown that there is a strong correlation between Helicobacter spp. colonization and primary liver tumors as well as bile duct tumors, whereas conclusions made by authors examining pancreatic cancer are contradictory and demands further investigation. No correlation between Helicobacter spp. and colon cancer have been proven. The PCR subtype most widely used in studies included in this review was nested PCR, whereas genes targeted most frequently for amplification are 16S rDNA of Helicobacter spp. and UreA gene or cagA gene of H. pylori. During the last 10 years PCR has proven itself as a sovereign method for Helicobacter spp. diagnostic in extragastric organs in the digestive system. Knowledge and experiences obtained in this domain could be encouraging for researchers in analogous fields of interest.


The effect of clozapine on premature mortality: an assessment of clinical monitoring and other potential confounders.
Clozapine can cause severe adverse effects yet it is associated with reduced mortality risk. We test the hypothesis this association is due to increased clinical monitoring and investigate risk of premature mortality from natural causes. We identified 14 754 individuals (879 deaths) with serious mental illness (SMI) including schizophrenia, schizoaffective and bipolar disorders aged ≥ 15 years in a large specialist mental healthcare case register linked to national mortality tracing. In this cohort study we modeled the effect of clozapine on mortality over a 5-year period (2007-2011) using Cox regression. Individuals prescribed clozapine had more severe psychopathology and poorer functional status. Many of the exposures associated with clozapine use were themselves risk factors for increased mortality. However, we identified a strong association between being prescribed clozapine and lower mortality which persisted after controlling for a broad range of potential confounders including clinical monitoring and markers of disease severity (adjusted hazard ratio 0.4; 95% CI 0.2-0.7; p = .001). This association remained after restricting the sample to those with a diagnosis of schizophrenia or those taking antipsychotics and after using propensity scores to reduce the impact of confounding by indication. Among individuals with SMI, those prescribed clozapine had a reduced risk of mortality due to both natural and unnatural causes. We found no evidence to indicate that lower mortality associated with clozapine in SMI was due to increased clinical monitoring or confounding factors. This is the first study to report an association between clozapine and reduced risk of mortality from natural causes.


The hepatic WASH complex is required for efficient plasma LDL and HDL cholesterol clearance.
The evolutionary conserved Wiskott-Aldrich syndrome protein and SCAR homolog (WASH) complex is one of the crucial multiprotein complexes that facilitates endosomal recycling of transmembrane proteins. Defects in WASH components have been associated with inherited developmental and neurological disorders in humans. Here, we show that hepatic ablation of the WASH component Washc1 in chow-fed mice increases plasma concentrations of cholesterol in both LDLs and HDLs, without affecting hepatic cholesterol content, hepatic cholesterol synthesis, biliary cholesterol excretion, or hepatic bile acid metabolism. Elevated plasma LDL cholesterol was related to reduced hepatocytic surface levels of the LDL receptor (LDLR) and the LDLR-related protein LRP1. Hepatic WASH ablation also reduced the surface levels of scavenger receptor class B type I and, concomitantly, selective uptake of HDL cholesterol into the liver. Furthermore, we found that WASHC1 deficiency increases LDLR proteolysis by the inducible degrader of LDLR, but does not affect proprotein convertase subtilisin/kexin type 9-mediated LDLR degradation. Remarkably, however, loss of hepatic WASHC1 may sensitize LDLR for proprotein convertase subtilisin/kexin type 9-induced degradation. Altogether, these findings identify the WASH complex as a regulator of LDL as well as HDL metabolism and provide in vivo evidence for endosomal trafficking of scavenger receptor class B type I in hepatocytes.


Comment on: Polarity effects and apparent ion recombination in microionization chambers Med. Phys. 43(5), 2141-2152 (2016).
In a recent paper of Miller et al. (Med. Phys. 43(5), 2141-2152 (2016), the voltage dependence polarity effect of microionization chambers was studied. It was identified that polarity effect arises from the difference in electric potential between the collecting electrode and the guard electrode, which in turn deforms the electric field and affects the charge collection. Nevertheless, the cause of such potential difference has not been identified. In this letter, we explain that the electric potential perturbation arises from the work function difference of the disparate materials electrodes (collecting vs guard electrodes in the particular case).


Inhibition Effects of Some Bioactive Peroxovanadium Complexes on the Tyrosine Phosphatase.
In order to study the structure-activity relationship and molecular mechanism of insulin-mimetic peroxovanadium complexes, the low-molecular-weight BHPTPase from bovine heart has been purified mainly by chromatography of DEAE-cellulose and Sephadex G-75, which was showed homogenicity on SDS-PAGE. Four bioactive peroxovanadium(pV) complexes bpV(ox), bpV(bipy), bpV(phen) and bpV(pic), [VO(O(2))(2)L](n-), where L = oxalic acid dianion(ox), bipyridine(bipy), 1,10-phenanthroline(phen), pyridine-2-carboxylic acid(pic) have been synthesized the bonding properties of center metal and its ligand were characterized by (51)V NMR, (13)C NMR, IR and elemental analysis. The complexes displayed remarkable inhibitory effects on the bovine heart tyrosine phosphatase. Their IC(50) were 0.22, 0.36 and 0.90 and 0.28 &mgr;mol/L, respectively. The structure-activity relationship of the complexes were discussed by their oxidizing ability and through the steric space hindrance of the organic ligands.


Efficacy and tolerability of adapalene 0.3% gel compared to tazarotene 0.1% gel in the treatment of acne vulgaris.
Treatment of acne vulgaris can be challenging for both patients and physicians. Topical retinoids are often considered first-line therapy for the treatment of all but the most severe forms of acne. A variety of formulations of topical retinoids, including adapalene and tazarotene, are available but tazarotene 0.1% gel is widely perceived to be the most efficacious. The goal of this study was to evaluate the efficacy and tolerability of a new, higher concentration of adapalene, adapalene 0.3% gel, compared to tazarotene 0.1% gel in the treatment of acne vulgaris. The primary efficacy outcome was the percent reduction in total lesion count at week 12. Subjects 12 to 35 years of age with acne vulgaris (N=172) participated in a 12-week, randomized, evaluator-blinded, noninferiority study of once-daily therapy with adapalene 0.3% gel or tazarotene 0.1% gel. Subjects in each group achieved clinically significant reductions in total lesion counts at week 12 (61% and 57% median reductions for adapalene and tazarotene, respectively); adapalene 0.3% gel was noninferior to tazarotene 0.1% gel (95% confidence interval [CI]: -5.2-9.6). The adapalene arm was also therapeutically similar to the tazarotene arm in terms of the percent reduction in inflammatory and noninflammatory lesion counts at week 12, as well as in the assessments of acne severity and improvement. Mean tolerability scores for erythema, dryness, scaling, and stinging/burning were consistently lower in the adapalene arm compared to patients treated with tazarotene (P<.014 at week 12, Cochran-Mantel-Haenszel [CMH] test). The worst score for any tolerability parameter in the treatment phase in the adapalene arm was less than 1 (mild). Adapalene was also associated with a lower incidence of treatment-related adverse events when compared to tazarotene (3.5% versus 14%, respectively). Once daily therapy with adapalene 0.3% gel provided similar efficacy (noninferior) to tazarotene 0.1% gel in the treatment of acne vulgaris, but demonstrated a superior tolerability profile.


Beliefs, attitudes, and activities of healthcare personnel about influenza and pneumococcal vaccines.
Vaccination of healthcare personnel (HCP) is an effective measure for preventing the spread of influenza among at-risk patients. This study was conducted to determine influenza vaccination rates and activities among HCP working at a tertiary healthcare setting. This study included 470 HCP (85 physicians, 134 nurses, 53 healthcare assistants, 44 paramedics, 47 medical secretaries, and 107 auxillary staff members) working at the emergency, cardiology, chest diseases, and internal medicine departments with the largest volume of patients with vaccination indication of two large university hospitals with similar medical practices and work environment. Each participant completed an anonymous questionnaire form. A total of 470 HCP participated in the survey. The compliance rate of the HCP to participate in the survey was 93.6%. Of these, 26.7% had been vaccinated against influenza. Vaccination in the survey year was significantly associated with having regular influenza vaccinations (OR 48.66; 95% CI:[25.09-94.369]; P<.01); having an educational level of college or higher (OR 2.07; 95% CI:[1.03-4.15]; P<.05); being a physician (OR 4.25; 95% CI:[1.28-14.07]; P< .05); and a professional experience of more than 5 years (OR 2.02; 95%CI:[1.13-5.62]; P< .05). Physicians recommended and prescribed the influenza vaccine significantly more frequently than the pneumococcal vaccine (37.6% vs 30.6%, P = .03, 25.9% vs 17.6%, P = .001, respectively). Among all HCP, the reasons for vaccination included having the opinion that the vaccine provides a partial protection against the infection (75.2%), reduces work force loss (48.8%), reduces the rates of death and severe conditions like pneumonia (43.2%), and reduces hospitalization (40.8%). The HCP had been vaccinated to protect family members (81.6%), people around (51.2%), herself/himself (47.2%), and patients (28%) fom infection. The reasons of not getting vaccinated against influenza among HCP included fear of vaccine's adverse effects (31.0%), doubts about its efficacy (28.9%) and safety (22.3%), and lack of adequate knowledge about vaccination (16.2%). Our results indicated that influenza vaccination rates are low in our whole HCP sample, with physicians having a slightly better rate than other HCP. Getting regularly vaccinated, having an educational level of college or higher, being a physician, and having a professional experience of more than 5 years positively affects the rate of future vaccinations. Physicians significantly more commonly recommended and prescribed the influenza vaccine than the pneumococcal vaccine. The most important reasons for getting vaccinated included having the opinion that the vaccine provided partial protection and intending to protect family members from infection. In our whole HCP sample, the reasons of not getting vaccinated against influenza included fear of vaccine's adverse effects and doubts about its efficacy and safety. Training meetings should be held for HCPs to underscore the importance of the influenza vaccine for protection of patients against the influenza.


[Pertussis seroprevalence and vaccination status in three selected provinces of Turkey].
The aim of this community-based seroepidemiological survey was to assess the immune status against pertussis among the healthy population in three selected provinces with different geographical and socioeconomical status (Antalya, Diyarbakir and Samsun, located at Mediterrenean, Southeast Anatolia and Black Sea regions of Turkey, respectively) in relation with DwPT (whole cell pertussis vaccine combined with diphtheria and tetanus toxoids) vaccination status. A total of randomly selected 2085 subjects ages between 6 months to > 50 years were included to the study. Serum samples have been screened for the presence of pertussis antibodies by an in house ELISA method with the use of pertussis toxin (PT) and filamentous hemagglutinin (FHA) antigens. The levels of > or = 10 EU/mL was accepted as positive for anti-PT and anti-FHA. Vaccination rate with 3-4 doses among children under 15 years old was significantly lower in Diyarbakir compared to the other two provinces (p< 0.05). The antibody positivity was increased with age up to the 10-14 year group and was maintained among older groups. There was no statistically significant relationship between the vaccination rate and antibody prevalence (p> 0.05). Adult females showed a significantly higher antibody-positivity rate for anti-PT than the males (p< 0.05). Our study pointed out a high prevalence of pertussis infection in those selected provinces, suggesting that the adults play a role as potential reservoirs for B. pertussis. It can be concluded that adult immunization, especially of those who are likely to have close contact with infants, should be considered.


Genetic Factors of the Disease Course After Sepsis: Rare Deleterious Variants Are Predictive.
Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection. For its clinical course, host genetic factors are important and rare genomic variants are suspected to contribute. We sequenced the exomes of 59 Greek and 15 German patients with bacterial sepsis divided into two groups with extremely different disease courses. Variant analysis was focusing on rare deleterious single nucleotide variants (SNVs). We identified significant differences in the number of rare deleterious SNVs per patient between the ethnic groups. Classification experiments based on the data of the Greek patients allowed discrimination between the disease courses with estimated sensitivity and specificity>75%. By application of the trained model to the German patients we observed comparable discriminatory properties despite lower population-specific rare SNV load. Furthermore, rare SNVs in genes of cell signaling and innate immunity related pathways were identified as classifiers discriminating between the sepsis courses. Sepsis patients with favorable disease course after sepsis, even in the case of unfavorable preconditions, seem to be affected more often by rare deleterious SNVs in cell signaling and innate immunity related pathways, suggesting a protective role of impairments in these processes against a poor disease course.


Preservation of chicken breast meat treated with thyme and balm essential oils.
The present study evaluated the effects of thyme and balm essential oils on the 3-wk storage of fresh chicken breast meat at 4 °C. Thyme and, to a lesser extent, balm essential oils reduced DPPH (2,2-diphenyl-1-picrylhydrazyl) radical formation in the meat (25% to 30% and 20%, respectively). Treatment with the 2 essential oils also limited lipid peroxidation and the deterioration of sarcoplasmic proteins, helping to preserve the meat even after 2 wk of storage. Thyme and balm essential oils decreased the natural microflora present in the meat; total microbial content decreased down to 50% in comparison to the control samples. In addition, a clear effect on lactic acid bacterial growth was recorded. Balm essential oil significantly limited the growth of Salmonella sp., whereas thyme essential oil effectively inhibited the growth of Escherichia coli. Our data demonstrate that these 2 essential oils effectively reduced deteriorative processes in chicken meat and extended the shelf life of this fresh product. Practical Application: The essential oils of thyme and balm can protect the chicken meat from decomposition during the storage time.


Association of Common Genetic Variants in the CPSF7 and SDHAF2 Genes with Canine Idiopathic Pulmonary Fibrosis in the West Highland White Terrier.
Canine idiopathic pulmonary fibrosis (CIPF) is a chronic fibrotic lung disease that is observed at a higher frequency in the West Highland White Terrier dog breed (WHWT) and may have molecular pathological overlap with human lung fibrotic disease. We conducted a genome-wide association study (GWAS) in the WHWT using whole genome sequencing (WGS) to discover genetic variants associated with CIPF. Saliva-derived DNA samples were sequenced using the Riptide DNA library prep kit. After quality controls, 28 affected, 44 unaffected, and 1,843,695 informative single nucleotide polymorphisms (SNPs) were included in the GWAS. Data were analyzed both at the single SNP and gene levels using the GEMMA and GATES methods, respectively. We detected significant signals at the gene level in both the cleavage and polyadenylation specific factor 7 (CPSF7) and succinate dehydrogenase complex assembly factor 2 (SDHAF2) genes (adjusted p = 0.016 and 0.024, respectively), two overlapping genes located on chromosome 18. The top SNP for both genes was rs22669389; however, it did not reach genome-wide significance in the GWAS (adjusted p = 0.078). Our studies provide, for the first time, candidate loci for CIPF in the WHWT. CPSF7 was recently associated with lung adenocarcinoma, further highlighting the potential relevance of our results because IPF and lung cancer share several pathological mechanisms.


Shaping the dynamics of a bidirectional neural interface.
Progress in decoding neural signals has enabled the development of interfaces that translate cortical brain activities into commands for operating robotic arms and other devices. The electrical stimulation of sensory areas provides a means to create artificial sensory information about the state of a device. Taken together, neural activity recording and microstimulation techniques allow us to embed a portion of the central nervous system within a closed-loop system, whose behavior emerges from the combined dynamical properties of its neural and artificial components. In this study we asked if it is possible to concurrently regulate this bidirectional brain-machine interaction so as to shape a desired dynamical behavior of the combined system. To this end, we followed a well-known biological pathway. In vertebrates, the communications between brain and limb mechanics are mediated by the spinal cord, which combines brain instructions with sensory information and organizes coordinated patterns of muscle forces driving the limbs along dynamically stable trajectories. We report the creation and testing of the first neural interface that emulates this sensory-motor interaction. The interface organizes a bidirectional communication between sensory and motor areas of the brain of anaesthetized rats and an external dynamical object with programmable properties. The system includes (a) a motor interface decoding signals from a motor cortical area, and (b) a sensory interface encoding the state of the external object into electrical stimuli to a somatosensory area. The interactions between brain activities and the state of the external object generate a family of trajectories converging upon a selected equilibrium point from arbitrary starting locations. Thus, the bidirectional interface establishes the possibility to specify not only a particular movement trajectory but an entire family of motions, which includes the prescribed reactions to unexpected perturbations.


Revelation of candidate genes and molecular mechanism of reproductive seasonality in female rohu (Labeo rohita Ham.) by RNA sequencing.
Carp fish, rohu (Labeo rohita Ham.) is important freshwater aquaculture species of South-East Asia having seasonal reproductive rhythm. There is no holistic study at transcriptome level revealing key candidate genes involved in such circannual rhythm regulated by biological clock genes (BCGs). Seasonality manifestation has two contrasting phases of reproduction, i.e., post-spawning resting and initiation of gonadal activity appropriate for revealing the associated candidate genes. It can be deciphered by RNA sequencing of tissues involved in BPGL (Brain-Pituitary-Gonad-Liver) axis controlling seasonality. How far such BCGs of this fish are evolutionarily conserved across different phyla is unknown. Such study can be of further use to enhance fish productivity as seasonality restricts seed production beyond monsoon season. A total of ~ 150 Gb of transcriptomic data of four tissues viz., BPGL were generated using Illumina TruSeq. De-novo assembled BPGL tissues revealed 75,554 differentially expressed transcripts, 115,534 SSRs, 65,584 SNPs, 514 pathways, 5379 transcription factors, 187 mature miRNA which regulates candidate genes represented by 1576 differentially expressed transcripts are available in the form of web-genomic resources. Findings were validated by qPCR. This is the first report in carp fish having 32 BCGs, found widely conserved in fish, amphibian, reptile, birds, prototheria, marsupials and placental mammals. This is due to universal mechanism of rhythmicity in response to environment and earth rotation having adaptive and reproductive significance. This study elucidates evolutionary conserved mechanism of photo-periodism sensing, neuroendocrine secretion, metabolism and yolk synthesis in liver, gonadal maturation, muscular growth with sensory and auditory perception in this fish. Study reveals fish as a good model for research on biological clock besides its relevance in reproductive efficiency enhancement.


Computed tomography features of small bowel obstruction due to mesodiverticular band.
Meckel's diverticulum is the most common congenital anomaly of the small intestine. Common complications related to a Meckel's diverticulum include hemorrhage, intestinal obstruction, and inflammation. Small bowel obstruction due to mesodiverticular band of Meckel's diverticulum is a rare complication. Herein, we report a case of small bowel obstruction occurring due to mesodiverticular band of a Meckel's diverticulum. The important aspect of our case is clear demonstration of the mesodiverticular band adjacent to the Meckel's diverticulum on pre-operative computed tomography (CT).


School Choice at a Cost? Academic Achievement, School Satisfaction and Psychological Complaints among Students in Disadvantaged Areas of Stockholm.
School choice allows students from more disadvantaged district areas in metropolitan Swedish cities to commute to more prestigious schools outside of their residential area. This study examined how such students fare compared to their peers who attend more deprived schools in their own district area. Multilevel analysis was applied, estimating 2-level random intercept linear regression models based on cross-sectional survey data collected among ninth grade students in 2014 and 2016 (n = 2105). Analyses showed that students living in relatively disadvantaged district areas of Stockholm who chose to attend more prestigious schools outside of their residential area performed better academically compared to students who opted to remain at more deprived schools in their catchment area, an association that was partly mediated by school quality in terms of teacher-rated school ethos. Yet, commuting students reported lower school satisfaction and more psychological complaints than students who stayed behind, even when taking academic achievement and school ethos into account. The association with psychological complaints was partly mediated by school satisfaction. Thus, the academic gain associated with having chosen to commute from a disadvantaged area to a more prestigious school does not appear to translate into higher school satisfaction and better psychological well-being.


Time-integrated blood lead concentration is a valid surrogate for estimating the cumulative lead dose assessed by tibial lead measurement.
The concentration of lead in tibia (Pb-T) was measured in vivo by a 109Cd K-shell X-ray fluorescence technique in 123 workers from a primary lead smelter (age: mean, 45 years; range, 30-61; duration of employment: mean, 20 years; range, 7-45). Their cumulative blood lead index (CBLI) was also calculated on the basis of the blood lead (Pb-B) records available from the company's medical files. Geometric mean for Pb-T was 49 micrograms Pb/g bone mineral (range, 15-167). The company's health surveillance programs, implemented since 1945, resulted in Pb-B values which rarely exceeded 70 micrograms Pb/dl whole blood. Pb-B at the time of Pb-T measurement averaged 31 micrograms Pb/dl (range, 6-62) and the geometric mean for CBLI amounted to 803 micrograms Pb/dl x year (range, 220-2130). Despite various assumptions and uncertainties inherent in the assessment of the cumulative lead dose through Pb-T measurement or CBLI calculation, the relation between both variables in the present lead smelter populations is very strong (rpearson = 0.80, P < 0.0001; age explained at the most 9.5% of the variance). The slope of the regression equation of log Pb-T vs log CBLI showed that a doubling of CBLI also corresponds to doubling of Pb-T. It may be concluded that a sound calculation of CBLI represents a valid surrogate for estimating the life time integrated dose of lead as assessed by the measurement of cortical bone lead (e.g., in tibia).


Control of venom production and secretion by sympathetic outflow in the snake Bothrops jararaca.
Many studies have examined the morphological and biochemical changes in the secretory epithelium of snake venom glands after a bite or milking. However, the mechanisms of venom production and secretion are not yet well understood. The present study was undertaken to evaluate the role of the sympathetic nervous system in the control of venom production and secretion. Venom glands were obtained from Bothrops jararaca (Viperidae) snakes, either unmilked previously or milked 4, 7 or 15 days before they were killed. Levels of tyrosine-hydroxylase-like immunoreactivity were higher in venom glands collected 4 days after milking, coinciding with the maximal synthetic activity of the secretory cells. The only catecholamine detected by high-performance liquid chromatography was noradrenaline, indicating the presence of noradrenergic fibres in these glands. In reserpine-treated milked snakes, no venom could be collected, and electron microscopic analysis showed narrow rough endoplasmic reticulum cisternae, instead of wide cisternae, and less well-developed Golgi apparatus compared with milked untreated snakes, indicating impairment of protein synthesis and secretion. The administration of isoprenaline or phenylephrine (beta- and alpha-adrenoceptor agonists, respectively) to reserpine-treated milked snakes promoted the widening of the rough endoplasmic reticulum and restored venom production, but only phenylephrine restored the development of the Golgi apparatus and the formation of many secretory vesicles. These results provide the first evidence that the sympathetic nervous system plays an important role in venom production and secretion in the venom glands of Bothrops jararaca. Understanding the importance of noradrenergic stimulation in venom production may provide new insights for research into the treatment of snakebites.


Species conservation profiles of a random sample of world spiders IV: Scytodidae to Zoropsidae.
The IUCN Red List of Threatened Species is the most widely used information source on the extinction risk of species. One of the uses of the Red List is to evaluate and monitor the state of biodiversity and a possible approach for this purpose is the Red List Index (RLI). For many taxa, mainly hyperdiverse groups, it is not possible within available resources to assess all known species. In such cases, a random sample of species might be selected for assessment and the results derived from it extrapolated for the entire group - the Sampled Red List Index (SRLI). The current contribution is the final in four papers that will constitute the baseline of a future spider SRLI encompassing 200 species distributed across the world. A sample of 200 species of spiders were randomly selected from the World Spider Catalogue, an updated global database containing all recognised species names for the group. The selected species were classified taxonomically at the family level and the familes were ordered alphabetically. In this publication, we present the conservation profiles of 50 species belonging to the families alphabetically arranged between Scytodidae and Zoropsidae, which encompassed Scytodidae, Selenopidae, Sicariidae, Sparassidae, Tetrablemmidae, Tetragnathidae, Theraphosidae, Theridiidae, Theridiosomatidae, Thomisidae, Trochanteriidae, Zodariidae and Zoropsidae.


Determination of coefficient of friction for self-expanding stent-grafts.
Migration of stent-grafts (SGs) after endovascular aneurysm repair of abdominal aortic aneurysms is a serious complication that may require secondary intervention. Experimental, analytical, and computational studies have been carried out in the past to understand the factors responsible for migration. In an experimental setting, it can be very challenging to correctly capture and understand the interaction between a SG and an artery. Quantities such as coefficient of friction (COF) and contact pressures that characterize this interaction are difficult to measure using an experimental approach. This behavior can be investigated with good accuracy using finite element modeling. Although finite element models are able to incorporate frictional behavior of SGs, the absence of reliable values of coefficient of friction make these simulations unreliable. The aim of this paper is to demonstrate a method for determining the coefficients of friction of a self-expanding endovascular stent-graft. The methodology is demonstrated by considering three commercially available self-expanding SGs, labeled as A, B, and C. The SGs were compressed, expanded, and pulled out of polymeric cylinders of varying diameters and the pullout force was recorded in each case. The SG geometries were recreated using computer-aided design modeling and the entire experiment was simulated in ABAQUS 6.8/STANDARD. An optimization procedure was carried out for each SG oversize configuration to determine the COF that generated a frictional force corresponding to that measured in the experiment. The experimental pullout force and analytically determined COF for SGs A, B, and C were in the range of 6-9 N, 3-12 N, and 3-9 N and 0.08-0.16, 0.22-0.46, and 0.012-0.018, respectively. The computational model predicted COFs in the range of 0.00025-0.0055, 0.025-0.07, and 0.00025-0.006 for SGs A, B, and C, respectively. Our results suggest that for SGs A and B, which are exoskeleton based devices, the pullout forces increase upto a particular oversize beyond which they plateau, while pullout forces showed a continuous increase with oversize for SG C, which is an endoskeleton based device. The COF decreased with oversizing for both types of SGs. The proposed methodology will be useful for determining the COF between self-expanding stent-grafts from pullout tests on human arterial tissue.


Tranexamic acid reduces blood loss and transfusion requirements in primary simultaneous bilateral total knee arthroplasty: a meta-analysis of randomized controlled trials.
: The aim of this meta-analysis is to assess the effectiveness and safety of intravenous application tranexamic acid (TXA) in primary simultaneous bilateral total knee arthroplasty (TKA). We searched electronic databases including PubMed, Embase, the Web of Science, the Cochrane Library and the Google Scholar, for published studies involving the intravenous application TXA in primary simultaneous bilateral TKA. All randomized controlled trials were included. The focus of the meta-analysis was on the outcomes of total blood loss, drainage volume, transfusion requirements and deep venous thrombosis (DVT) and/or pulmonary embolism. The relevant data were analyzed using RevMan 5.2. Six high randomized controlled trials were included, with a total sample size of 394 patients. The intravenous application of TXA significantly reduced total blood loss [95% confidence interval (CI), -519.52 to -126.40; P = 0.001], drainage volume (95% CI, -551.76 to -138.57; P = 0.001) and transfusion requirements (risk ratio, 0.38; 95% CI, 0.21-0.68; P = 0.001) compared with the control group. In addition, there were no significant differences in the rate of DVT (P = 1.00) and/or pulmonary embolism between the two groups. Based on the current evidence, this meta-analysis showed that intravenous application of TXA is effective and a well tolerated treatment to reduce total blood loss, drainage volume and transfusion requirements without increasing the risk of DVT and/or pulmonary embolism in primary simultaneous bilateral TKA.


Magnetic Resonance Imaging (MRI) and Digital Subtraction Angiography Investigation of Childhood Moyamoya Disease.
Because digital subtraction angiography (DSA) is not an ideal angiographic examination for moyamoya disease in the pediatric population, magnetic resonance angiography (MRA) provides a noninvasive contrast-free angiographic examination; whereas magnetic resonance imaging (MRI) provides superior spatial resolution and soft-tissue contrast for lesion assessment. Ninety patients with moyamoya disease were examined by MRI and DSA to assess the distribution of lesions and their diagnostic agreement between modalities. MRI examination revealed 439 lesions. Punctate lesions were the most abundant, followed by patchy lesions. These lesions generally covered a smaller area than the abnormal-vascular corresponding brain parenchyma. Steno-occlusive changes at bilateral anterior, medial, and posterior cerebral arteries were identified by MRA and DSA. MRI showed moderate agreement in identifying lesions after steno-occlusive changes in anterior and medial cerebral arteries, and good agreement in posterior cerebral arteries; 6% to 11% of cases were misdiagnosed by MRA.


Transcriptomic changes in oligodendrocytes and precursor cells predicts clinical outcomes of Parkinson's disease.
Several prior studies have proposed the involvement of various brain regions and cell types in Parkinson's disease (PD) pathology. Here, we performed snRNA-seq on the prefrontal cortex and anterior cingulate regions from post-mortem control and PD brain tissue. We found a significant association of oligodendrocytes (ODCs) and oligodendrocyte precursor cells (OPCs) with PD-linked risk loci and report several dysregulated genes and pathways, including regulation of tau-protein kinase activity, regulation of inclusion body assembly and protein processing involved in protein targeting to mitochondria. In an independent PD cohort with clinical measures (681 cases and 549 controls), polygenic risk scores derived from the dysregulated genes significantly predicted Montreal Cognitive Assessment (MoCA)-, and Beck Depression Inventory-II (BDI-II)-scores but not motor impairment (UPDRS-III). We extended our analysis of clinical outcome prediction by incorporating three separate datasets that were previously published by different laboratories. In the first dataset from the anterior cingulate cortex, we identified a correlation between ODCs and BDI-II. In the second dataset obtained from the substantia nigra (SN), OPCs displayed notable predictive ability for UPDRS-III. In the third dataset from the SN region, a distinct subtype of OPCs, labeled OPC_ADM, exhibited predictive ability for UPDRS-III. Intriguingly, the OPC_ADM cluster also demonstrated a significant increase in PD samples. These results suggest that by expanding our focus to glial cells, we can uncover region-specific molecular pathways associated with PD symptoms.


Mepolizumab in Patients With Severe Asthma and Comorbidities: 1-Year REALITI-A Analysis.
Severe asthma is complex; comorbidities may influence disease outcomes. To assess mepolizumab effectiveness in patients with severe asthma and comorbidities. REALITI-A was a 2-year international, prospective study enrolling adults with asthma newly prescribed mepolizumab (100 mg subcutaneously) at physician's discretion. This post hoc analysis assessed 1-year outcomes stratified by comorbidities at enrollment: chronic rhinosinusitis with nasal polyps (CRSwNP), gastroesophageal reflux disease (GERD), depression/anxiety, and chronic obstructive pulmonary disease (COPD). Outcomes included the rate of clinically significant asthma exacerbations (CSEs; requiring systemic corticosteroids and/or hospital/emergency room admission) between the 12 months pre- and post-mepolizumab treatment and changes from baseline in daily maintenance oral corticosteroid dose (mo 12), Asthma Control Questionnaire-5 score (mo 12) and forced expiratory volume in 1 second (FEV1; mo 9-12). At enrollment (n = 822), 321 of 822 (39%), 309 of 801 (39%), 203 of 785 (26%), and 81 of 808 (10%) patients had comorbid CRSwNP, GERD, depression/anxiety, and COPD, respectively. Post- versus pre-treatment across all comorbidity subgroups: the rate of CSEs decreased by 63% or more; among 298 (39%) patients on maintenance oral corticosteroids at baseline, median dose decreased by 50% or more; Asthma Control Questionnaire-5 score decreased by 0.63 or more points; FEV1 increased by 74 mL or more. Patients with versus without CRSwNP had the greatest improvements (eg, rate of CSEs decreased by 75%). Patients without GERD, depression/anxiety, or COPD had greater improvements than those with the respective comorbidities, except for FEV1 in patients with COPD. Mepolizumab improved disease outcomes in patients with severe asthma irrespective of comorbidities, with additional benefit for patients with CRSwNP.


Myocardial infarction in rats. Infarct size, myocyte hypertrophy, and capillary growth.
To determine the compensatory reserve capacity of the ventricular myocardium following infarction, the left coronary artery in rats was ligated, and the animals were killed 40 days later. Infarcts affecting an average 23% of the left ventricle were characterized by a 27% hypertrophic growth of the remaining myocardium that produced a complete replacement of the necrotic tissue. In contrast, infarcts with an average 50% loss of mass resulted in 83% expansion of the spared myocardium that was inadequate for a complete restoration of ventricular tissue. Myocyte hypertrophy was 26% and 78% in small and large infarcts, respectively. Cellular hypertrophy in both cases involved significant increases in myocyte transverse area and myocyte length. After large infarcts, there was an 18% reduction in capillary surface and a 16% increase in the diffusion distance. Corresponding values for small infarcts were -10% and 9%. These alterations combined with the deficient reconstitution of myocardial mass following large infarcts resulted in 25%, 29%, and 30% deficits in the absolute amounts of capillary lumen, surface, and length per ventricle respectively. Even with small infarcts, a deficit was seen in capillary luminal surface (-16%), and length (-19%). In conclusion, we have demonstrated that cardiac hypertrophy following myocardial infarction is consistent with cellular shape changes characteristic of a combination of concentric and eccentric hypertrophic growth. However, cardiac muscle cells appear to be unable to compensate for the loss of mass induced by a 50% infarct. The inadequate adaptation of the capillary vasculature in the infarcted hearts suggests that the injured ventricle is more vulnerable to additional ischemic episodes.


The trinucleotide repeat sequence d(GTC)15 adopts a hairpin conformation.
The structure of a single-stranded (ss) oligonucleotide containing (GTC)15 [ss(GTC)15] was examined. As a control, parallel studies were performed with ss(CTG)15, an oligonucleotide that forms a hairpin. Electrophoretic mobility, KMnO4 oxidation and P1 nuclease studies demonstrate that, similar to ss(CTG)15, ss(GTC)15 forms a hairpin containing base paired and/or stacked thymines in the stem. Electrophoretic mobility melting profiles performed in approximately 1 mM Na+ revealed that the melting temperature of ss(GTC)15 and ss(CTG)15 were 38 and 48 degrees C respectively. The loop regions of ss(GTC)15 and ss(CTG)15 were cleaved by single-strand-specific P1 nuclease at the T25-C29 and G26-C27 phosphodiester bonds respectively (where the loop apex of the DNAs is T28). Molecular dynamics simulations suggested that in ss(GTC)15 the loop was bent towards the major groove of the stem, apparently causing an increased exposure of the T25-C29 region to solvent. In ss(CTG)15 guanine--guanine stacking caused a separation of the G26 and C27 bases, resulting in exposure of the intervening phosphodiester to solvent. The results suggest that ss(GTC)15 and ss(CTG)15 form similar, but distinguishable, hairpin structures.