Retest reliability of measuring hip extensor muscle strength in different testing positions in young people with cerebral palsy.
In young people with spastic diplegic cerebral palsy weakness of the hip extensor muscles are associated with limitations in activity. It is important that clinicians can reliably measure hip extensor muscle strength to monitor changes over time and the effects of any interventions. Previous research has demonstrated high reliability for measuring strength of all muscles of the lower limb, with the exception of the hip extensors. Therefore the aim of this study was to examine the retest reliability of measuring hip extensor strength in young people with cerebral palsy. Using a test-retest reliability research design, 19 participants with spastic diplegic cerebral palsy (Gross Motor Function Classification System Levels II and III) (mean 19 y 2 mo [S D 2 y 5 mo]) attended two testing sessions held 12 weeks apart. Three trials with a hand-held dynamometer were taken at each testing session in supine, prone and standing. Retest reliability was calculated with Intraclass Correlation Coefficients (ICC(2,1)) and with units of measurement (kilograms) converted to a percentage strength change. ICC values ranged from .74 to .78 in supine, .75 to .80 in prone, and .73 to .75 in standing. To be 95% confident that real change had occurred, an individual's strength would need to increase 55 to 60% in supine, 86 to 102% in prone, and 102 to 105% in standing. To be 95% confident that real change had occurred across groups, strength would need to increase 4 to 8% in supine, 22 to 31% in prone, and 32% to 34% in standing. Higher ICC values were observed when three trials were used for testing. The supine testing position was more reliable than the prone or standing testing positions. It is possible to measure hip extensor strength with sufficient reliability to be able monitor change within groups using the supine position provided three trials are used during testing. However, there is insufficient reliability to monitor changes in hip extensor strength in individuals with cerebral palsy unless they exhibit very large strength increases.


A study of litter and waste management policies at (primary) eco-schools in Istanbul.
In addition to environmental and economic benefits, systematic application of sustainable waste management in elementary education buildings also makes a positive contribution to the education of future generations. This study examines elementary schools in Istanbul, which are part of the Eco-Schools International Programme. This programme was established in 1994 with European Union support and it aims to introduce environmental management systems into primary schools within the scope of ISO 14001/EMAS. A questionnaire study was administered on the theme of litter management and sustainable waste management within elementary schools located in the Asian and European parts of Istanbul city, and the findings of a field survey were examined. Questionnaire findings were gathered under five themes: litter management, composting of organic waste, re-use of school materials, reducing consumption-selection of recycled products, waste management and sorting of recyclable materials.


[Health status determinants among river-dwelling children under two years of age in Pará State, Brazil: a cross-sectional study].
The aim of this study was to identify predictors of poor health in children less than two years of age from river-dwelling families in Pará State, Brazil. A total of 202 children were evaluated, considering poor health as the outcome variable, consisting of the combination of nutritional status, psychomotor development, and intercurrent illnesses in the previous month. The data were analyzed with a multilevel hierarchical model, and predictors of poor health were defined as variables with p < 0.05 after adjustment. According to the crude odds ratio, poor health is associated with families that own their own homes, are older, and present exclusive breastfeeding at two, three, four, and five months. After adjustment, children with families that own their homes showed 2.76 greater odds of having poor health; poor health also increased with age, and was 5.04 higher among children from 18 to 23 months, as compared to infants less than 7 months of age. In these communities, home owning and higher age represent longer exposure to the risk of poor health.


Hybrid optical-electronic convolutional neural networks with optimized diffractive optics for image classification.
Convolutional neural networks (CNNs) excel in a wide variety of computer vision applications, but their high performance also comes at a high computational cost. Despite efforts to increase efficiency both algorithmically and with specialized hardware, it remains difficult to deploy CNNs in embedded systems due to tight power budgets. Here we explore a complementary strategy that incorporates a layer of optical computing prior to electronic computing, improving performance on image classification tasks while adding minimal electronic computational cost or processing time. We propose a design for an optical convolutional layer based on an optimized diffractive optical element and test our design in two simulations: a learned optical correlator and an optoelectronic two-layer CNN. We demonstrate in simulation and with an optical prototype that the classification accuracies of our optical systems rival those of the analogous electronic implementations, while providing substantial savings on computational cost.


Autobiographical memory compromise in individuals with alcohol use disorders: Towards implications for psychotherapy research.
It has been found that Autobiographical memory (i.e., memory for personal experiences and facts about the self) are not properly maintained in people with alcohol-use disorders (AUD). The present paper offers a comprehensive overview of findings regarding the consequences of AUD on autobiographical memory. More specifically, we offer a theoretical model (the AMAUD Autobiographical Memory and Alcohol Use Disorders model) according to which chronic alcohol consumption compromises emotion regulation as well as executive control, which maintains the construction of autobiographical memory. Compromises in emotional regulation and executive functioning can be linked to a weak aspiration to construct detailed memories (i.e., autobiographical overgenerality), compromises of subjective reliving, anterograde amnesia, negative self-defining memories, and a difficulty to mentally project oneself forward in time to generate complex autobiographical representations and self-images. By gathering cognitive and clinical aspects of autobiographical decline in AUD, this model constitutes a theoretical foundation that may lead to a better understanding of this decline. Different clinical perspectives are proposed for developing personalized autobiographical memory rehabilitation programs for individuals with AUD.


Polyimide tubing: dispelling the myths.
The capabilities and potential of polyimide and polyimide tubing are gaining popularity in the medical design market place as a result of the increasing need for minimally invasive surgical devices. This article looks at the myths surrounding the tubing to better understand its advantages for medical applications.


[Multiplication of Listeria in milk products].
The results of the evaluation of the multiplication dynamics of Listeria cells in milk and Bifidok, a lactic acid product, are presented. The samples were inoculated on thioglycol agar and studied at different exposure time after incubation at 37 degrees C, 20 degrees C and 4 degrees C. The study revealed the intensive multiplication of Listeria cells in milk, also during storage in a household refrigerator. The presence of bifidobacteria mixed with kefir-producing culture in dairy products was shown to essentially inhibit the growth of Listeria cells which were not detected by bacteriological techniques on day 7.


Serum 5alpha-dihydrotestosterone and testosterone changes with age in man.
Serum 5alpha-dihydrotestosterone (DHT) and testosterone (T) were measured in 98 normal adult men aged between 20-80 years, separating T and DHT by thin layer chromatography and using a sensitive and reliable radio-immunoassay. In three age groups between 20-40, 40-60 and 60-80, the means +/- SEM for serum DHT were 84 +/- 4, 79 +/- 3 and 67 +/- 3 (ng/100 ml) respectively. The corresponding values for testosterone were 559 +/- 25, 491 +/- 25 and 475 +/- 28 (ng/100 ml). A significant decrease was observed in the DHT level of the 60-80 years age group compared to either the 20-40 (P less than 0.01) or the 40-60 (P less than 0.02) age groups. There was a moderate decline in the testosterone level of the 60-80 years age group compared to 20-40 years (P less than 0.05) but there were no significant changes in the testosterone levels between other groups.


Arcobacter cibarius sp. nov., isolated from broiler carcasses.
Twenty Gram-negative, rod-shaped, slightly curved, non-spore-forming bacteria that gave a negative result in Arcobacter species-specific PCR tests but that yielded an amplicon in an Arcobacter genus-specific PCR test were isolated from 13 unrelated broiler carcasses. Numerical analysis of the profiles obtained by SDS-PAGE of whole-cell proteins clustered all isolates in a single group distinct from the other Arcobacter species. DNA-DNA hybridization among four representative strains exhibited DNA binding values above 91 %. DNA-DNA hybridization with reference strains of the current four Arcobacter species revealed binding levels below 47 %. The G+C contents ranged between 26.8 and 27.3 mol%. Pairwise comparison of 16S rRNA gene sequences revealed the mean values for similarity to the type strain of Arcobacter cryaerophilus (97.5 %), Arcobacter butzleri (96.5 %), Arcobacter skirrowii (96.0 %) and Arcobacter nitrofigilis (95.0 %). The levels of similarity to Campylobacter and Helicobacter species were below 88 and 87 %, respectively. The isolates could be distinguished from other Arcobacter species by the following biochemical tests: catalase, oxidase and urease activities; reduction of nitrate; growth at 25 and 37 degrees C under aerobic conditions; growth on 2-4 % (w/v) NaCl media; and susceptibility to cephalothin. These data demonstrate that the 20 isolates represent a single novel Arcobacter species, for which the name Arcobacter cibarius sp. nov. is proposed, with LMG 21996(T) (=CCUG 48482(T)) as the type strain.


MicroRNAs and ectodermal specification I. Identification of miRs and miR-targeted mRNAs in early anterior neural and epidermal ectoderm.
The establishment of cell lineages occurs via a dynamic progression of gene regulatory networks (GRNs) that underlie developmental commitment and differentiation. To investigate how microRNAs (miRs) function in this process, we compared miRs and miR targets at the initiation of the two major ectodermal lineages in Xenopus. We used next-generation sequencing to identify over 170 miRs expressed in midgastrula ectoderm expressing either noggin or a constitutively active BMP receptor, reflecting anterior neural or epidermal ectoderm, respectively; 125 had not previously been identified in Xenopus. We identified the locations of the pre-miR sequences in the X. laevis genome. Neural and epidermal ectoderm express broadly similar sets of miRs. To identify targets of miR-dependent translational control, we co-immunoprecipitated Argonaute-Ribonucleoprotein (Ago-RNP) complexes from early neural and epidermal ectoderm and sequenced the associated RNA. The Ago-RNP RNAs from these tissues represent overlapping, yet distinct, subsets of genes. Moreover, the profile of Ago-RNP associated genes differs substantially from the profile of total RNAs in these tissues. We generated target predictions for the "high confidence" Ago-RNP RNAs using the identified ectodermal miRs; These RNAs generally had target sites for multiple miRs. Oct4 orthologues, as well as many of their previously identified transcriptional targets, are represented in the Ago-RNP pool in both tissues, suggesting that miR-dependent regulation contributes to the downregulation of the oct4 gene regulatory network and the reduction in ectodermal pluripotency.


Demystified molecular pathology of NUT midline carcinomas.
NUT midline carcinoma (NMC) is a rare, highly lethal cancer that occurs in children and adults of all ages. NMCs uniformly present in the midline, most commonly in the head, neck or mediastinum, as poorly differentiated carcinomas with variable degrees of squamous differentiation. This tumour is defined by rearrangement of the nuclear protein in testis (NUT) gene on chromosome 15q14. In most cases, NUT is involved in a balanced translocation with the BRD4 gene on chromosome 19p13.1, an event that creates a BRD4-NUT fusion gene. Variant rearrangements, some involving the BRD3 gene, occur in the remaining cases. NMC is diagnosed by detection of NUT rearrangement by fluorescence in situ hybridisation or reverse transcriptase PCR. Due its rarity and lack of characteristic histological features, most cases of NMC currently go unrecognised.


Expression of the TAL1/SCL transcription factor in physiological and pathological vascular processes.
The TAL1/SCL transcription factor is essential for haematopoietic commitment and vascular remodelling during embryonic development. To help clarify its role in postnatal vascular processes, we characterized the expression of mouse Tal1 protein by immunocytochemistry in several experimental models of blood vessel formation. In adult mice, Tal1 protein was expressed in rare microvascular endothelial cells and in extravascular cells provisionally identified as endothelial progenitors from their morphology, proximity to vessels and expression of vascular endothelial growth factor receptor-2. The number of Tal1-expressing endothelial cells increased significantly but transiently in all the models-hormone-induced ovulation, wound healing and tumour development. Finally, Tal1 protein was detected in the nuclei of newly formed lymphatic endothelial cells in tumour-bearing animals. These results show that TAL1 is expressed by vascular endothelial cells and endothelial progenitors at sites of physiological and pathological neovascularization and suggest a role for this transcription factor in adult vasculogenesis. This work also provides the first evidence for TAL1 expression in lymphangiogenesis.


Leptospirosis.
Leptospirosis is a worldwide zoonotic infection with a much greater incidence in tropical regions and has now been identified as one of the emerging infectious diseases. The epidemiology of leptospirosis has been modified by changes in animal husbandry, climate, and human behavior. Resurgent interest in leptospirosis has resulted from large outbreaks that have received significant publicity. The development of simpler, rapid assays for diagnosis has been based largely on the recognition that early initiation of antibiotic therapy is important in acute disease but also on the need for assays which can be used more widely. In this review, the complex taxonomy of leptospires, previously based on serology and recently modified by a genotypic classification, is discussed, and the clinical and epidemiological value of molecular diagnosis and typing is also evaluated.


A Bacterial Cell Shape-Determining Inhibitor.
Helicobacter pylori and Campylobacter jejuni are human pathogens and causative agents of gastric ulcers/cancer and gastroenteritis, respectively. Recent studies have uncovered a series of proteases that are responsible for maintaining the helical shape of these organisms. The H. pylori metalloprotease Csd4 and its C. jejuni homologue Pgp1 cleave the amide bond between meso-diaminopimelate and iso-d-glutamic acid in truncated peptidoglycan side chains. Deletion of either csd4 or pgp1 results in bacteria with a straight rod phenotype, a reduced ability to move in viscous media, and reduced pathogenicity. In this work, a phosphinic acid-based pseudodipeptide inhibitor was designed to act as a tetrahedral intermediate analog against the Csd4 enzyme. The phosphinic acid was shown to inhibit the cleavage of the alternate substrate, Ac-l-Ala-iso-d-Glu-meso-Dap, with a Ki value of 1.5 μM. Structural analysis of the Csd4-inhibitor complex shows that the phosphinic acid displaces the zinc-bound water and chelates the metal in a bidentate fashion. The phosphinate oxygens also interact with the key acid/base residue, Glu222, and the oxyanion-stabilizing residue, Arg86. The results are consistent with the "promoted-water pathway" mechanism for carboxypeptidase A catalysis. Studies on cultured bacteria showed that the inhibitor causes significant cell straightening when incubated with H. pylori at millimolar concentrations. A diminished, yet observable, effect on the morphology of C. jejuni was also apparent. Cell straightening was more pronounced with an acapsular C. jejuni mutant strain compared to the wild type, suggesting that the capsule impaired inhibitor accessibility. These studies demonstrate that a highly polar compound is capable of crossing the outer membrane and altering cell shape, presumably by inhibiting cell shape determinant proteases. Peptidoglycan proteases acting as cell shape determinants represent novel targets for the development of antimicrobials against these human pathogens.


Polar decomposition of 3 x 3 Mueller matrix: a tool for quantitative tissue polarimetry.
The polarization properties of any medium are completely described by the sixteen element Mueller matrix that relates the polarization parameters of the light incident on the medium to that emerging from it. Measurement of all the elements of the matrix requires a minimum of sixteen measurements involving both linear and circularly polarized light. However, for many diagnostic applications, it would be useful if the polarization parameters can be quantified with linear polarization measurements alone. In this paper, we present a method based on polar decomposition of Mueller matrix for quantification of the polarization parameters of a scattering medium using the nine element (3 x 3) Mueller matrix that requires linear polarization measurements only. The methodology for decomposition of the 3 x 3 Mueller matrix is based on the previously developed decomposition process for sixteen element (4 x 4) Mueller matrix but with an assumption that the depolarization of linearly polarized light due to scattering is independent of the orientation angle of the incident linear polarization vector. Studies conducted on various scattering samples demonstrated that this assumption is valid for a turbid medium like biological tissue where the depolarization of linearly polarized light primarily arises due to the randomization of the field vector's direction as a result of multiple scattering. For such medium, polar decomposition of 3 x 3 Mueller matrix can be used to quantify the four independent polarization parameters namely, the linear retardance (delta ), the circular retardance (psi), the linear depolarization coefficient (Delta) and the linear diattenuation (d) with reasonable accuracy. Since this approach requires measurements using linear polarizers only, it considerably simplifies measurement procedure and might find useful applications in tissue diagnosis using the retrieved polarization parameters.


Colonizing multidrug-resistant bacteria and the longitudinal evolution of the intestinal microbiome after liver transplantation.
Infections by multidrug-resistant bacteria (MDRB) remain a leading cause of morbidity and mortality after liver transplantation (LT). Gut dysbiosis characteristic of end-stage liver disease may predispose patients to intestinal MDRB colonization and infection, in turn exacerbating dysbiosis. However, relationships between MDRB colonization and dysbiosis after LT remain unclear. We prospectively recruited 177 adult patients undergoing LT at a single tertiary care center. 16 S V3-V4 rRNA sequencing was performed on 723 fecal samples collected pre-LT and periodically until one-year post-LT to test whether MDRB colonization was associated with decreased microbiome diversity. In multivariate linear mixed-effect models, MDRB colonization predicts reduced Shannon α-diversity, after controlling for underlying liver disease, antibiotic exposures, and clinical complications. Importantly, pre-LT microbial markers predict subsequent colonization by MDRB. Our results suggest MDRB colonization as a major, previously unrecognized, marker of persistent dysbiosis. Therapeutic approaches accounting for microbial and clinical factors are needed to address post-transplant microbiome health.


Ultrasound findings in AL musculoskeletal amyloidosis.
Systemic AL amyloidosis is one of the differential diagnosis of chronic musculoskeletal disease, especially when swollen and painful joints is associated with claw hands. Ultrasound evaluation is a good diagnosis tool, showing a characteristic joint and tendon involvement and assisting in guided biopsy procedure. We report a 55 year old caucasian woman, diagnosed for two years with RA without improvement under different DMARDs, admitted for fixed flexion contractures of both hands ("claw hands"), worsening pain and swelling of small joints of hands and feet, elbows and shoulders. Pad shoulder sign and bilateral anterior wrist and elbow pads, macroglossia, thickened skin of fingers and ecchymotic rashes on forearm and around eyes were observed. Ultrasound examinations showed subdeltoid and bicipitoradial bursitis, presence of inhomogeneous hypoechoic material around bicipital tendons and tenosinovitis of the extensor tendons of the hand, and synovial thickening of elbow and shoulder joints. Complete analysis of the bone marrow biopsy and biopsy specimens from subacromial bursa were positive for AL amyloidosis.


Quantitative shotgun proteomics of enriched heterocysts from Nostoc sp. PCC 7120 using 8-plex isobaric peptide tags.
The filamentous cyanobacterium Nostoc sp. strain PCC 7120 is capable of fixing atmospheric nitrogen. The labile nature of the core process requires the terminal differentiation of vegetative cells to form heterocysts, specialized cells with altered cellular and metabolic infrastructure to mediate the N2-fixing process. We present an investigation targeting the cellular proteomic expression of the heterocysts compared to vegetative cells of a population cultured under N2-fixing conditions. New 8-plex iTRAQ reagents were used on enriched replicate heterocyst and vegetative cells, and replicate N2-fixing and non-N2-fixing filaments to achieve accurate measurements. With this approach, we successfully identified 506 proteins, where 402 had confident quantifications. Observations provided by purified heterocyst analysis enabled the elucidation of the dominant metabolic processes between the respective cell types, while emphasis on the filaments enabled an overall comparison. The level of analysis provided by this investigation presents various tools and knowledge that are important for future development of cyanobacterial biohydrogen production.


Effect of a comprehensive lifestyle modification program on the bone density of male heavy drinkers.
Heavy alcohol drinking is implicated in osteoporosis. Although abstinence is rapidly followed by a restoration of osteoblastic activity, little is known about the contributions of alcohol-related factors or the effectiveness of a lifestyle modification program (LMP) on bone density. We conducted a study of 138 male alcoholic patients to investigate whether drinking history and concurrent factors were associated with the bone density of the calcaneus. A 2.5-months LMP in an institutionalized setting was completed by 20 of them, and its effect on bone density, serum parathyroid hormone (PTH), and 1.25-(OH)(2) vitamin D levels were assessed. The patients had a high prevalence of daytime drinking (93.5%), continuous drinking (84.1%), and current smoking (82.0%) with mean duration of alcohol abuse of 30.0 +/- 12.8 years. The patients had lower bone density than a reference control group (Z-scores: -0.45 +/- 1.02). Multiple stepwise regression analysis identified age, poor activities of daily living (ADL), continuous drinking, absence of liver cirrhosis, depression, and dementia as determinants of low bone density. The bone density of the 20 participants in the LMP improved 2.3% (p = 0.0003) with a more ameliorating effect on bone density than a conventional abstinence therapy (p = 0.014 for interventional effect). The upper normal range of PTH levels at baseline were significantly decreased, and 1.25-(OH)(2) vitamin D levels also had a trend toward decrease during the abstinence. Alcoholic patients may have many complications such as poor ADL and dementia, which are independently associated with decreased bone density. The results of this study support the idea that comprehensive approach to lifestyle factors to minimize risk of osteoporosis is the best way to improve bone density.


Development of a small-molecule serum- and glucocorticoid-regulated kinase-1 antagonist and its evaluation as a prostate cancer therapeutic.
Androgens, through their actions on the androgen receptor (AR), are required for the development of the prostate and contribute to the pathologic growth dysregulation observed in prostate cancers. Consequently, androgen ablation has become an essential component of the pharmacotherapy of prostate cancer. In this study, we explored the utility of targeting processes downstream of AR as an alternate approach for therapy. Specifically, we show that the serum and glucocorticoid-regulated kinase 1 (SGK1) gene is an androgen-regulated target gene in cellular models of prostate cancer. Furthermore, functional serum- and glucocorticoid-regulated kinase 1 (SGK1) protein, as determined by the phosphorylation of its target Nedd4-2, was also increased with androgen treatment. Importantly, we determined that RNA interference-mediated knockdown of SGK1 expression attenuates the androgen-mediated growth of the prostate cancer cell line LNCaP. Given these findings, we explored the utility of SGK1 as a therapeutic target in prostate cancer by developing and evaluating a small-molecule inhibitor of this enzyme. From these studies emerged GSK650394, a competitive inhibitor that quantitatively blocks the effect of androgens on LNCaP cell growth. Thus, in addition to androgen ablation, inhibition of pathways downstream of AR is likely to have therapeutic utility in prostate cancer.


Differential Effects of Adult Salmon Lice Lepeophtheirus salmonis on Physiological Responses of Sockeye Salmon and Atlantic Salmon.
The salmon louse Lepeophtheirus salmonis, a type of sea lice (family Caligidae), is enzootic in marine waters of British Columbia and poses a health risk to both farmed Atlantic Salmon Salmo salar and wild Pacific salmon Oncorhynchus spp. At the adult stage, sea lice infections can often result in severe cutaneous lesions in their salmonid hosts. To evaluate and compare the physiological consequences of adult L. salmonis infections, smolts of Atlantic Salmon and Sockeye Salmon O. nerka were exposed to 2 (low), 6 (medium), or 10 (high) adult female lice/fish. Mean lice abundance decreased over time in all groups. Skin disruption due to parasite infection was observed in both species. Plasma samples were collected from infected fish and uninfected controls at 1, 3, 5, and 7 d postinfection and measured for indicators of osmoregulatory function and stress. Sockeye Salmon, regardless of L. salmonis exposure level, showed a rapid onset of elevated osmolality and sodium and chloride ion concentrations which were sustained until 7 d postinfection when values returned to levels comparable with the unexposed controls. Conversely, these effects were not measured in Atlantic Salmon. Additionally, differential host effects in blood glucose levels were observed, with Sockeye Salmon displaying immediate elevation in glucose. Relative to Atlantic Salmon, infection with L. salmonis caused a profound physiological impact to Sockeye Salmon characterized by loss of osmoregulatory integrity and a stress response. This work provides the first comprehensive report of the physiological consequences of infections with adult L. salmonis in Sockeye Salmon smolts and helps to further define the mechanisms of susceptibility in this species.


Dentist Related Factors Associated with Implementation of COVID-19 Protective Measures: A National Survey.
Little is known about the extent to which dentists have implemented COVID-19 infection control guidelines and the factors influencing this process in daily practice. This national online survey assessed the implementation of enhanced infection control guidelines in daily practice, and explored dentist related factors influencing their application, more specifically dentist infection status and their perceived risk of cross-infection in the dental setting. The survey was validated, pretested and carried out in 2020. A total of 1436 dentists participated, of whom 9.1% presumably had COVID-19 infection experience. At least 75% of dentists complied with the core part of the recommended protective measures protocol. For each patient treated during the pandemic, an additional cost of 10-30 EUR (86.7%) and an extra time of 10-30 min (70.7%) was estimated. A stepwise binary logistic regression analysis revealed that dentists assumed to have experienced COVID-19 reported a higher self-perceived risk of virus acquisition (β = 2.090; p = 0.011), lower concern of getting infected (β = 0.576; p = 0.027), and lower confidence in being able to prevent disease transmission in the dental setting (β = 0.535; p = 0.022). Some parts of the protective measures were more difficult to apply than others; however, there was no indication of increased disease acquisition in the dental setting.


Application of pseudo amino acid composition for predicting protein subcellular location: stochastic signal processing approach.
The function of a protein is closely correlated with its subcellular location. With the success of human genome project and the rapid increase in the number of newly found protein sequences entering into data banks, it is highly desirable to develop an automated method for predicting the subcellular location of proteins. The establishment of such a predictor will no doubt expedite the functionality determination of newly found proteins and the process of prioritizing genes and proteins identified by genomics efforts as potential molecular targets for drug design. Based on the concept of pseudo amino acid composition originally proposed by K. C. Chou (Proteins: Struct. Funct. Genet. 43: 246-255, 2001), the digital signal processing approach has been introduced to partially incorporate the sequence order effect. One of the remarkable merits by doing so is that many existing tools in mathematics and engineering can be straightforwardly used in predicting protein subcellular location. The results thus obtained are quite encouraging. It is anticipated that the digital signal processing may serve as a useful vehicle for many other protein science areas as well.


Temporal changes in appropriateness of cardiac imaging.
Appropriate use criteria (AUC) for cardiac imaging have been available for almost 10 years. The extent to which there has been a reported improvement in appropriate use is undefined. This study systematically reviewed published evidence to identify whether the promulgation of AUC has led to an improvement in the proportion of appropriate cardiac imaging requests. Electronic databases were systematically searched for English-language papers related to AUC and cardiovascular imaging. We found 59 reports involving 103,567 tests that were published from 2000 to 2012. The rate of appropriate testing over time was analyzed in a meta-regression. New AUC were associated with apparent improvements in appropriateness for transthoracic echocardiography (TTE) (80% [95% confidence interval (CI): 0.75 to 0.84] vs. 85% [95% CI: 0.81 to 0.89]), transesophageal echocardiography (TEE) (89% [95% CI: 0.81 to 0.94] vs. 95% [95% CI: 0.93 to 0.96]) and computed tomography angiography (CTA) (37% [95% CI: 0.21 to 0.55] vs. 55% [95% CI: 0.44 to 0.65]) but not stress echocardiography (53% [95% CI: 0.45 to 0.61] vs. 52% [95% CI: 0.42 to 0.61]) or single-photon emission computed tomography (72% [95% CI: 0.66 to 0.77] vs. 68% [95% CI: 0.60 to 0.74]). Although there were no correlations between the proportion of appropriate TTEs and published year (p = 0.36) for 2007 AUC, there was a positive correlation between proportion of appropriateness and the year of publication (p = 0.01) for 2011 AUC. There was a significant decrease in the proportion of appropriateness over time using the 2007 TEE AUC (p = 0.03) and 2006 CT AUC (p = 0.02). There were no meaningful associations between appropriateness and publication year for stress echocardiography, CTA, or single-photon emission computed tomography. Rates of reported appropriate use in imaging show improvements for TTE and CTA but not for stress imaging and TEE. The observed reductions in imaging studies are not matched by reported rates of appropriate use.


1 alpha,25(OH)2D3 inhibits not only Th1 but also Th2 differentiation in human cord blood T cells.
Human naive CD4+ T helper (Th) and CD8+ cytotoxic (Tc) T cells, which only produce IL-2, may differentiate into Th1/Tc1- or Th2/Tc2-like lymphocytes, characterized by their cytokine production profile. 1 alpha,25-dihydroxyvitamin D3 (1 alpha, 25(OH)2D3) has been reported to inhibit Th1/Tc1-related, but increase Th2/Tc2-associated cytokines in T cells from adults. In industrialized countries, vitamin D supplementation for prevention of rickets is initiated within the first days of life and continued throughout the entire first year. Epidemiologic studies suggest an association of vitamin D exposure in newborns with the incidence of allergic diseases in later life. This study addresses the effects of 1 alpha, 25(OH)2D3 on Th1/Tc1 versus Th2/Tc2 differentiation in long term cell cultures of (naive) cord blood T lymphocytes. Our results show that in CD4+ as well as CD8+ cord blood cells, 1 alpha, 25(OH)2D3 inhibits not only IL-12-generated IFN-gamma production, but also suppresses IL-4 and IL-13 expression induced by IL-4. Thus, in cord blood 1 alpha, 25(OH)2D3 induces a T cell population without predominance of Th2 related cytokines.


BRD4 inhibition and FXR activation, individually beneficial in cholestasis, are antagonistic in combination.
Activation of farnesoid X receptor (FXR) by obeticholic acid (OCA) reduces hepatic inflammation and fibrosis in patients with primary biliary cholangitis (PBC), a life-threatening cholestatic liver failure. Inhibition of bromodomain-containing protein 4 (BRD4) also has antiinflammatory, antifibrotic effects in mice. We determined the role of BRD4 in FXR function in bile acid (BA) regulation and examined whether the known beneficial effects of OCA are enhanced by inhibiting BRD4 in cholestatic mice. Liver-specific downregulation of BRD4 disrupted BA homeostasis in mice, and FXR-mediated regulation of BA-related genes, including small heterodimer partner and cholesterol 7 alpha-hydroxylase, was BRD4 dependent. In cholestatic mice, JQ1 or OCA treatment ameliorated hepatotoxicity, inflammation, and fibrosis, but surprisingly, was antagonistic in combination. Mechanistically, OCA increased binding of FXR, and the corepressor silencing mediator of retinoid and thyroid hormone receptor (SMRT) decreased NF-κB binding at inflammatory genes and repressed the genes in a BRD4-dependent manner. In patients with PBC, hepatic expression of FXR and BRD4 was significantly reduced. In conclusion, BRD4 is a potentially novel cofactor of FXR for maintaining BA homeostasis and hepatoprotection. Although BRD4 promotes hepatic inflammation and fibrosis in cholestasis, paradoxically, BRD4 is required for the antiinflammatory, antifibrotic actions of OCA-activated FXR. Cotreatment with OCA and JQ1, individually beneficial, may be antagonistic in treatment of liver disease patients with inflammation and fibrosis complications.


[Nutritional status by social stratification in Venezuelan school children].
This study assessed nutritional status of 590 children from Naguanagua, Valencia, attending school, aged between 4 and 14 years and its relation to social stratification, age and gender. Body dimension indicators were used for nutritional diagnosis. NCHS/OMS and Frisancho references were used for height/age (HA) weight/height (WH) cut-off points, and body mass index (BMI). Graffar modified by Mendez was used to establish socioeconomic status. Statistical analyses included descriptives, x2 and student-test. 91% of the children were in poverty, (71% relative and 20% critical). For HA, 6.4% classified as short, 27.6% in risk, and 4.9% tall for age without significative differences between sex. For WH, 0.6% were in nutritional deficit, 10.2% in risk and 22.1% in excess. For BMI, 12.9% had nutritional deficit, 7.3% excess but no significative differences for sex. Stunting and deficit were present in all age groups, but more significantly in those older than 10 years (12%; 23.9% respectively). Social stratification was associated with WH and BMI being deficit more prevalent in III and V class, predominating excess in IV class. The high prevalence of obesity makes this group as a high risk one for chronic degenerative diseases.


Emergency readmission criterion: a technique for determining the emergency readmission time window.
A frequently chosen time window in defining readmission is 28 days after discharge. Yet in the literature, shorter and longer periods such as 14 days or 90-180 days have also been suggested. In this paper, we develop a modeling approach that systematically tackles the issue surrounding the appropriate choice of a time window as a definition of readmission. The approach is based on the intuitive idea that patients who are discharged from hospital can be broadly divided in to two groups-a group that is at high risk of readmission and a group that is at low risk. Using the national data (England), we demonstrate the usefulness of the approach in the case of chronic obstructive pulmonary disease (COPD), stroke, and congestive heart failure (CHF) patients, which are known to be the leading causes of early readmission. Our findings suggest that there are marked differences in the optimal width of the time window for COPD, stroke, and CHF patients. Furthermore, time windows and the probabilities of being in the high-risk group for COPD, stroke, and CHF patients for each of the 29 acute and specialist trusts in the London area indicate wide variability between hospitals. The novelty of this modeling approach lies in its ability to define an appropriate time window based on evidence objectively derived from operational data. Therefore, it can separately provide a unique approach in examining variability between hospitals, and potentially contribute to a better definition of readmission as a performance indicator.


Selection and characterization of a mutant T7 RNA polymerase that recognizes an expanded range of T7 promoter-like sequences.
The compatible plasmids pKGP1-1 and pCM-X# will confer chloramphenicol resistance to Escherichia coli harboring the two plasmids if the T7 RNA polymerase produced from pKGP1-1 can recognize the T7 promoter carried on pCM-X# and transcribe the CAT gene that is cloned behind the promoter [Ikeda et al. (1992) Biochemistry 31, 9073-9080]. When E. coli harbor pKGP1-1 and a pCM-X# plasmid that carries a point mutation in the T7 promoter that destroys promoter activity (an inactive pCM-X#), the T7 RNA polymerase will not utilize the T7 promoter point mutant, will not produce CAT, and will not induce chloramphenicol resistance. The selection of mutants of T7 RNA polymerase that exhibit altered promoter recognition was pursued by randomly mutagenizing pKGP1-1 with aqueous hydroxylamine, cotransforming E. coli with the mutagenized pKGP1-1 and a mixture of seven different inactive pCM-X# plasmids, and isolating and characterizing the RNA polymerase that was present in those colonies that exhibited chloramphenicol resistance. It was established that E. coli harboring the mutant plasmid pKGP-HA1mut4 and an inactive pCM-X# are chloramphenicol-resistant and that the mutation responsible for the expression of CAT from the inactive pCM-X# plasmid is a G to A transition at nucleotide 664 of T7 gene 1 that converts glutamic acid (222) to lysine. Apparently this mutation expands the range of T7 promoter sequences that can be utilized by the enzyme. The mutant T7 RNA polymerase, GP1(Lys222), utilizes all seven inactive T7 promoter point mutants more efficiently than wild-type T7 RNA polymerase both in vivo and in vitro. Furthermore, the correlation of in vivo and in vitro promoter utilization suggests that the restoration of chloramphenicol resistance in the cotransformed E. coli results from the ability of GP1(Lys222) to initiate transcription from T7 promoter point mutants that are normally inactive.


Acute effects of growth hormone in alcohol-fed rats.
The present study examined whether administration in vivo of a maximally stimulating dose of growth hormone (GH) was capable of modulating selected aspects of the GH-insulin-like growth factor (IGF) system to the same extent in alcohol-fed and control animals. Rats were maintained on an alcohol-containing diet for 14 weeks, while control animals were fed isocalorically. After surgical implantation of a catheter in the carotid artery, rats were starved overnight. The next morning, rats were injected with recombinant human GH (500 microg/kg, s.c.) or an equal volume of saline at time 0 and 12 h. Blood samples were collected prior to GH and at 6, 12 and 24 h thereafter; tissues were collected at the end of the study. Time-matched control and alcohol-fed rats not receiving GH were also included. Although the plasma concentrations of both total and free IGF-I were decreased 30-40% in alcohol-fed rats, the ability of GH to elevate circulating IGF-I was not diminished. GH was equally effective at increasing IGF-I peptide levels in both liver and skeletal muscle. GH also produced comparable increases in IGF-I mRNA in muscle in both groups. Hepatic GH receptor (GHR) peptide levels were not significantly altered by either alcohol or GH. Alcohol feeding decreased plasma levels of IGF binding protein (IGFBP)-3 and increased IGFBP-1, and GH did not significantly alter this profile. Hepatic expression of suppressor of cytokine signalling (SOCS-3) mRNA was not different between the groups. However, SOCS-3 mRNA was increased by approximately 50% in control animals in response to GH, but remained unchanged in alcohol-fed rats. These data indicate that the decrease in hepatic IGF-I synthesis and plasma IGF-I observed in alcohol-fed rats was independent of a change in GHR levels. In contrast, the ability of a maximally stimulating dose of GH to modulate selected biological responses in vivo was not impaired by chronic alcohol consumption and was associated with a lack of a GH-induced increase in SOCS-3 mRNA.


Media matters: culture medium-dependent hypervariable phenotype of mesenchymal stromal cells.
Despite a long history of investigation and sustained efforts in clinical testing, the number of market authorisations for mesenchymal stromal cell (MSC) therapies remains limited, with none approved by the United States Food and Drug Administration. Several barriers are impeding the clinical progression of MSC therapies, to the forefront of these is a lack of standardised manufacturing protocols which is further compounded by an absence of biologically meaningful characterisation and release assays. A look at clinical trial registries demonstrates the diversity of MSC expansion protocols with variabilities in cell source, isolation method and expansion medium, among other culture variables, making it extraordinarily difficult to compare study outcomes. Current identification and characterisation standards are insufficient; they are not specific to MSCs and do not indicate cell function or therapeutic action. This work analysed the influence of five widely used culture media formulations on the colony-forming potential, proliferation kinetics, trilineage differentiation potential and immunomodulatory potential of human bone marrow-derived MSCs (BM-MSCs). The surface marker expression profiles were also characterised using a high-content flow cytometry screening panel of 243 markers. Significant differences in the biological attributes of BM-MSCs including clonogenicity, proliferation, differentiation propensity and immunomodulatory capacity were revealed in response to the composition of the culture medium. Despite their biological differences, all cell preparations uniformly and strongly expressed the standard positive markers proposed for BM-MSCs: CD73, CD90 and CD105. Immunophenotypic profiling revealed that the culture medium also had a significant influence on the surface proteome, with one-third of tested markers exhibiting variable expression profiles. Principal component analysis demonstrated that BM-MSCs isolated and expanded in a proprietary xeno- and serum-free medium displayed the most consistent cell phenotypes with little variability between donors compared to platelet lysate and foetal bovine serum-containing media. These data suggest that media composition has a highly significant impact on the biological attributes of MSCs, but standard surface marker tests conceal these differences. The results indicate a need for (1) standardised approaches to manufacturing, with an essential focus on defined media and (2) new biologically relevant tests for MSC characterisation and product release.


[Ruthenium red inhibits energy-dependent and passive Ca2+ transport in permeabilized smooth muscle cells].
The effects of ruthenium red, pH, and sodium ions on active and passive Ca2+ transport were studied in digitonin-treated (0.1 mg/ml) suspension of myometrial cells using radiolabeled 45Ca2+. The inhibitor of mitochondrial Ca2+ accumulation ruthenium red (10 microM) suppressed active accumulation of the cation in permeabilized myocytes by 78-85%. Ruthenium red-sensitive Ca2+ accumulation significantly (10-fold, mean) exceeds ruthenium red-resistant Mg2+, ATP-dependent Ca2+ accumulation assayed in the absence of oxalate and inhibited by 50 nM tapsigargin (blocker of endo/sarcoplasmic reticulum calcium pump). Acidification of incubation medium (pH 8.0-6.0, Tris-malcate/KOH buffer) inhibits ruthenium red-sensitive active Ca2+ accumulation in permeabilized myocytes and passive release of this cation in the dilution medium after blockage of mitochondrial Ca2+ accumulation by ruthenium red. Partial isotonic substitution of KCl (135-95 mM) with NaCl (15-55 mM) in incubation medium did not affect the initial rate of active ruthenium red-sensitive Ca2+ accumulation and the kinetics of passive Ca2+ release from permeabilized cells after blockade of active Ca2+ accumulation by ruthenium red. Mechanism of Ca2+ exchange in myometrial mitochondria is discussed.


Tracheopulmonary myiasis caused by a mature third-instar Cuterebra larva: case report and review.
Myiasis is the infestation of vertebrate tissues with fly larvae (Diptera). Most human cases in North America are subcutaneous forms due to Dermatobia hominis imported from Central and South America. Human cases of myiasis acquired in North America are rare and are primarily subdermal or ophthalmologic forms of infestation caused by early stages of Cuterebra larvae. We report an unusual case of tracheopulmonary myiasis, resulting from the in situ development of a mature cuterebrine larva associated with high eosinophilia. Only two other cases of tracheopulmonary cuterebrid myiasis have been reported in humans, and they are reviewed herein. Cuterebra myiasis (cuterebrosis) remains a rare and aberrant cause of tracheopulmonary disease and is a newly described cause of eosinophilia in humans.


EEG patterns and epileptic seizures in acute phase stroke.
The rate of early post-stroke epileptic seizures ranges from 2 to 33%. This wide range is likely due to differences in study design, patient selection and type of neurophysiological monitoring. Electroencephalography (EEG), which is not used in the routine work-up of acute stroke, is the best neurodiagnostic technique for detecting epileptic activity, especially in patients with non-convulsive post-stroke epileptic activity. The aim of this study was to analyze patterns on EEGs performed within 24 h of stroke onset, and to investigate correlations between these patterns and the occurrence of early epileptic seizures and status epilepticus (SE), vascular risk factors, stroke subtypes and short-term outcome. We prospectively studied 232 patients (mean age 71 ± 12 years; 177 ischemic strokes and 55 hemorrhagic). EEG recording was performed within 24 h from hospitalization. The follow-up lasted 1 week. Fifteen patients (6.5%) had early seizures within 24 h; 10 of these patients had focal SE with or without secondary generalization. EEG revealed sporadic epileptiform focal abnormalities in 10% and periodic lateralized epileptiform discharges (PLEDs) in 6%. SE was recorded in 71.4% of patients with PLEDs. At the multivariate analysis, only early epileptic manifestations (p < 0.001) were independently associated with PLEDs. Our study confirms that seizures are not frequent in the early phase of acute stroke and occur prevalently as focal SE at onset. EEG may help to detect specific patterns, such as PLEDs, that are closely related to early seizures. EEG monitoring should be performed in order to detect purely electrographic seizures.


Behavioural effects of high fat diet in a mutant mouse model for the schizophrenia risk gene neuregulin 1.
Schizophrenia patients are often obese or overweight and poor dietary choices appear to be a factor in this phenomenon. Poor diet has been found to have complex consequences for the mental state of patients. Thus, this study investigated whether an unhealthy diet [i.e. high fat diet (HFD)] impacts on the behaviour of a genetic mouse model for the schizophrenia risk gene neuregulin 1 (i.e. transmembrane domain Nrg1 mutant mice: Nrg1 HET). Female Nrg1 HET and wild-type-like littermates (WT) were fed with either HFD or a control chow diet. The mice were tested for baseline (e.g. anxiety) and schizophrenia-relevant behaviours after 7 weeks of diet exposure. HFD increased body weight and impaired glucose tolerance in all mice. Only Nrg1 females on HFD displayed a hyper-locomotive phenotype as locomotion-suppressive effects of HFD were only evident in WT mice. HFD also induced an anxiety-like response and increased freezing in the context and the cued version of the fear conditioning task. Importantly, CHOW-fed Nrg1 females displayed impaired social recognition memory, which was absent in HFD-fed mutants. Sensorimotor gating deficits of Nrg1 females were not affected by diet. In summary, HFD had complex effects on the behavioural phenotype of test mice and attenuated particular cognitive deficits of Nrg1 mutant females. This topic requires further investigations thereby also considering other dietary factors of relevance for schizophrenia as well as interactive effects of diet with medication and sex.


Interaction of α-synuclein with biomembranes in Parkinson's disease--role of cardiolipin.
One of the key molecular events underlying the pathogenesis of Parkinson's disease (PD) is the aberrant misfolding and aggregation of the α-synuclein (αS) protein into higher-order oligomers that play a key role in neuronal dysfunction and degeneration. A wealth of experimental data supports the hypothesis that the neurotoxicity of αS oligomers is intrinsically linked with their ability to interact with, and disrupt, biological membranes; especially those membranes having negatively-charged surfaces and/or lipid packing defects. Consequences of αS-lipid interaction include increased membrane tension, permeation by pore formation, membrane lysis and/or leakage due to the extraction of lipids from the bilayer. Moreover, we assert that the interaction of αS with a liquid-disordering phospholipid uniquely enriched in mitochondrial membranes, namely cardiolipin (1,3-diphosphatidyl-sn-glycerol, CL), helps target the αS oligomeric complexes intracellularly to mitochondria. Binding mediated by CL may thus represent an important pathomechanism by which cytosolic αS could physically associate with mitochondrial membranes and disrupt their integrity. Impaired mitochondrial function culminates in a cellular bioenergetic crisis and apoptotic death. To conclude, we advocate the accelerated discovery of new drugs targeting this pathway in order to restore mitochondrial function in PD.


Antipsychotic drugs versus cognitive behavioural therapy versus a combination of both in people with psychosis: a randomised controlled pilot and feasibility study.
Little evidence is available for head-to-head comparisons of psychosocial interventions and pharmacological interventions in psychosis. We aimed to establish whether a randomised controlled trial of cognitive behavioural therapy (CBT) versus antipsychotic drugs versus a combination of both would be feasible in people with psychosis. We did a single-site, single-blind pilot randomised controlled trial in people with psychosis who used services in National Health Service trusts across Greater Manchester, UK. Eligible participants were aged 16 years or older; met ICD-10 criteria for schizophrenia, schizoaffective disorder, or delusional disorder, or met the entry criteria for an early intervention for psychosis service; were in contact with mental health services, under the care of a consultant psychiatrist; scored at least 4 on delusions or hallucinations items, or at least 5 on suspiciousness, persecution, or grandiosity items on the Positive and Negative Syndrome Scale (PANSS); had capacity to consent; and were help-seeking. Participants were assigned (1:1:1) to antipsychotics, CBT, or antipsychotics plus CBT. Randomisation was done via a secure web-based randomisation system (Sealed Envelope), with randomised permuted blocks of 4 and 6, stratified by gender and first episode status. CBT incorporated up to 26 sessions over 6 months plus up to four booster sessions. Choice and dose of antipsychotic were at the discretion of the treating consultant. Participants were followed up for 1 year. The primary outcome was feasibility (ie, data about recruitment, retention, and acceptability), and the primary efficacy outcome was the PANSS total score (assessed at baseline, 6, 12, 24, and 52 weeks). Non-neurological side-effects were assessed systemically with the Antipsychotic Non-neurological Side Effects Rating Scale. Primary analyses were done by intention to treat; safety analyses were done on an as-treated basis. The study was prospectively registered with ISRCTN, number ISRCTN06022197. Of 138 patients referred to the study, 75 were recruited and randomly assigned-26 to CBT, 24 to antipsychotics, and 25 to antipsychotics plus CBT. Attrition was low, and retention high, with only four withdrawals across all groups. 40 (78%) of 51 participants allocated to CBT attended six or more sessions. Of the 49 participants randomised to antipsychotics, 11 (22%) were not prescribed a regular antipsychotic. Median duration of total antipsychotic treatment was 44·5 weeks (IQR 26-51). PANSS total score was significantly reduced in the combined intervention group compared with the CBT group (-5·65 [95% CI -10·37 to -0·93]; p=0·019). PANSS total scores did not differ significantly between the combined group and the antipsychotics group (-4·52 [95% CI -9·30 to 0·26]; p=0·064) or between the antipsychotics and CBT groups (-1·13 [95% CI -5·81 to 3·55]; p=0·637). Significantly fewer side-effects, as measured with the Antipsychotic Non-neurological Side Effects Rating Scale, were noted in the CBT group than in the antipsychotics (3·22 [95% CI 0·58 to 5·87]; p=0·017) or antipsychotics plus CBT (3·99 [95% CI 1·36 to 6·64]; p=0·003) groups. Only one serious adverse event was thought to be related to the trial (an overdose of three paracetamol tablets in the CBT group). A head-to-head clinical trial of CBT versus antipsychotics versus the combination of the two is feasible and safe in people with first-episode psychosis. National Institute for Health Research.


Genetic Analysis and Characterization of a Bacteriophage ØCJ19 Active against Enterotoxigenic Escherichia coli.
Enterotoxigenic Escherichia coli (ETEC) is the major pathogenic E. coli that causes diarrhea and edema in post-weaning piglets. In this study, we describe the morphology and characteristics of ØCJ19, a bacteriophage that infects ETEC, and performed genetic analysis. Phage ØCJ19 belongs to the family Myoviridae. One-step growth curve showed a latent phase of 5 min and burst size of approximately 20 phage particles/infected cell. Phage infectivity was stable for 2 h between 4°C and 55°C, and the phage was stable between pH 3 and 11. Genetic analysis revealed that phage ØCJ19 has a total of 49,567 bases and 79 open reading frames (ORFs). The full genomic sequence of phage ØCJ19 showed the most similarity to an Escherichia phage, vB_EcoS_ESCO41. There were no genes encoding lysogeny, toxins, virulence factors, or antibiotic resistance in this phage, suggesting that this phage can be used safely as a biological agent to control ETEC. Comparative genomic analysis in terms of the tail fiber proteins could provide genetic insight into host recognition and the relationship with other coliphages. These results showed the possibility to improve food safety by applying phage ØCJ19 to foods of animal origin contaminated with ETEC and suggests that it could be the basis for establishing a safety management system in the animal husbandry.


Implantable cardioverter defibrillators for the treatment of arrhythmias and cardiac resynchronisation therapy for the treatment of heart failure: systematic review and economic evaluation.
This assessment updates and expands on two previous technology assessments that evaluated implantable cardioverter defibrillators (ICDs) for arrhythmias and cardiac resynchronisation therapy (CRT) for heart failure (HF). To assess the clinical effectiveness and cost-effectiveness of ICDs in addition to optimal pharmacological therapy (OPT) for people at increased risk of sudden cardiac death (SCD) as a result of ventricular arrhythmias despite receiving OPT; to assess CRT with or without a defibrillator (CRT-D or CRT-P) in addition to OPT for people with HF as a result of left ventricular systolic dysfunction (LVSD) and cardiac dyssynchrony despite receiving OPT; and to assess CRT-D in addition to OPT for people with both conditions. Electronic resources including MEDLINE, EMBASE and The Cochrane Library were searched from inception to November 2012. Additional studies were sought from reference lists, clinical experts and manufacturers' submissions to the National Institute for Health and Care Excellence. Inclusion criteria were applied by two reviewers independently. Data extraction and quality assessment were undertaken by one reviewer and checked by a second. Data were synthesised through narrative review and meta-analyses. For the three populations above, randomised controlled trials (RCTs) comparing (1) ICD with standard therapy, (2) CRT-P or CRT-D with each other or with OPT and (3) CRT-D with OPT, CRT-P or ICD were eligible. Outcomes included mortality, adverse events and quality of life. A previously developed Markov model was adapted to estimate the cost-effectiveness of OPT, ICDs, CRT-P and CRT-D in the three populations by simulating disease progression calculated at 4-weekly cycles over a lifetime horizon. A total of 4556 references were identified, of which 26 RCTs were included in the review: 13 compared ICD with medical therapy, four compared CRT-P/CRT-D with OPT and nine compared CRT-D with ICD. ICDs reduced all-cause mortality in people at increased risk of SCD, defined in trials as those with previous ventricular arrhythmias/cardiac arrest, myocardial infarction (MI) > 3 weeks previously, non-ischaemic cardiomyopathy (depending on data included) or ischaemic/non-ischaemic HF and left ventricular ejection fraction ≤ 35%. There was no benefit in people scheduled for coronary artery bypass graft. A reduction in SCD but not all-cause mortality was found in people with recent MI. Incremental cost-effectiveness ratios (ICERs) ranged from £14,231 per quality-adjusted life-year (QALY) to £29,756 per QALY for the scenarios modelled. CRT-P and CRT-D reduced mortality and HF hospitalisations, and improved other outcomes, in people with HF as a result of LVSD and cardiac dyssynchrony when compared with OPT. The rate of SCD was lower with CRT-D than with CRT-P but other outcomes were similar. CRT-P and CRT-D compared with OPT produced ICERs of £27,584 per QALY and £27,899 per QALY respectively. The ICER for CRT-D compared with CRT-P was £28,420 per QALY. In people with both conditions, CRT-D reduced the risk of all-cause mortality and HF hospitalisation, and improved other outcomes, compared with ICDs. Complications were more common with CRT-D. Initial management with OPT alone was most cost-effective (ICER £2824 per QALY compared with ICD) when health-related quality of life was kept constant over time. Costs and QALYs for CRT-D and CRT-P were similar. The ICER for CRT-D compared with ICD was £27,195 per QALY and that for CRT-D compared with OPT was £35,193 per QALY. Limitations of the model include the structural assumptions made about disease progression and treatment provision, the extrapolation of trial survival estimates over time and the assumptions made around parameter values when evidence was not available for specific patient groups. In people at risk of SCD as a result of ventricular arrhythmias and in those with HF as a result of LVSD and cardiac dyssynchrony, the interventions modelled produced ICERs of < £30,000 per QALY gained. In people with both conditions, the ICER for CRT-D compared with ICD, but not CRT-D compared with OPT, was < £30,000 per QALY, and the costs and QALYs for CRT-D and CRT-P were similar. A RCT comparing CRT-D and CRT-P in people with HF as a result of LVSD and cardiac dyssynchrony is required, for both those with and those without an ICD indication. A RCT is also needed into the benefits of ICD in non-ischaemic cardiomyopathy in the absence of dyssynchrony. This study is registered as PROSPERO number CRD42012002062. The National Institute for Health Research Health Technology Assessment programme.


Prevalence and factors associated with early initiation of breastfeeding among Bangladeshi mothers: A nationwide cross-sectional study.
Early initiation of breastfeeding (EIBF) is associated with better health of the mothers and reduced risk of neonatal mortality. The objective of this study was to determine the prevalence of EIBF and associated factors among Bangladeshi mothers. The data was extracted from the Bangladesh Demographic and Health Survey (BDHS)-2014. A total of 4,092 married non-pregnant Bangladeshi mothers who had at least one child aged 2 years or younger were included in this study. A two-level logistic regression model was used to remove the clustering effect for finding the impact of socio-economic and demographic factors on EIBF. The prevalence of EIBF among Bangladeshi mothers was 51.4% (urban: 47.1% and rural: 53.4%). A two -level logistic regression model showed that mothers living in the Sylhet division (p<0.01) and rural environment (p<0.05) were more likely to practice EIBF. Mothers who were obese or overweight (p<0.01), had secondary (p<0.05) or higher education (p<0.01) were less likely to provide early breastfeeding to their newborn babies compared to their counterparts. Those who delivered by caesarian-section (p<0.01) were less likely to perform EIBF while those who attended an antenatal care clinic more than 3 times (p<0.05) were more likely to do so. About half of the Bangladeshi mothers did not start breast-feeding within one hour after birth. This study identified several geographical and socio-demographic factors that were associated with EIBF, and hope that this information will help the government to focus their resources to promote early breastfeeding.


Interfacial strength between molded UHMWPE and PMMA-MMA monomer treated UHMWPE.
To solve aseptic loosening of cemented acetabular cup and tibial plateaus of hips and knee joint prostheses in total joint replacement, adhesion between the polymeric prostheses made of ultra-high molecular weight polyethylene (UHMWPE) and bone cement made of polymethyl-methacrylate (PMMA) has been investigated. Previous studies using xylene, PMMA, and MMA monomer solution to treat bulk surfaces of UHMWPE resulted in 11.5 +/- 0.65 MPa as the maximum interfacial strength between the treated UHMWPE and bone cement. The present study eliminates the use of xylene; instead, UHMWPE powders were treated with MMA monomer and PMMA-MMA solution, dried, and then compression-molded with untreated UHMWPE powders. The interfacial tensile strengths were measured and the best molding conditions investigated by varying temperature, pressure, and time. Temperature was the predominant factor when compared to that of pressure or time. The maximum interfacial strength between the treated UHMWPE and untreated UHMWPE was 16.3 +/- 0.94 MPa with the molding conditions of 166.5 degrees C, 38.7 MPa, and 1 h. Scanning electron microscopic (SEM) pictures show the coating of the nodules and fibrils of UHMWPE powder with PMMA. Pulled out aggregated nodular space and coated PMMA after fracture could be seen easily from PMMA-MMA treated UHMWPE powder.


Synovial cysts of the lumbar spine: surgery-related results and outcome.
The authors conducted a study to determine the surgery-related results and outcomes in patients with synovial cysts of the lumbar spine. They emphasize several specific characteristics useful in clinical management. Forty-six consecutive patients with 54 lumbar synovial cysts underwent surgery between 1990 and 2001. A retrospective analysis of the clinical presentation and follow-up data, radiological findings, and surgical techniques was performed. Clinical presentation was dominated by acute or subacute sciatic pain. No specific symptom allowed differentiation of synovial cyst from a lumbar disc herniation. Computerized tomography scanning aided in establishing the correct diagnosis in 19 of 30 cases and magnetic resonance (MR) imaging did so in all cases. Three of the 46 patients presented with bilateral lumbar synovial cysts. The L4-5 level was affected in 61%, and radiological signs of disc degeneration/spondylosis were observed in 54% of the patients. Immediate symptom relief without local recurrence was obtained by complete microsurgical excision in which bipolar coagulation was used to remove the synovial membrane and in which the interapophysial joint was preserved. During the 1st postoperative year, a newly formed symptomatic synovial cyst developed on the contralateral side or at a superior vertebral level in five patients. They underwent surgery; results were good and there was no recurrence. The findings in this series suggest that synovial cysts can occur at multiple lumbar sites within a short period of time and could be predisposed to developing in certain individuals, predominantly in women older than 40 years of age. Postoperative follow up is recommended and MR imaging mandatory in cases of recurrent sciatica.


XoRehab: IoT Enabled Wheelchair based Lower Limb Rehabilitation System.
IoT in healthcare brought a technological revolution in rehabilitation, enabling the patients to get rehabilitation in the comfort of their home, while being supervised remotely by the professionals. IoT enabled rehabilitation ensures a best possible way towards recovery, without inflicting further injuries. It also allows customization of rehabilitation plan based on the patient profile and progress, while helping in defining their personalised milestones. The main contribution of this paper is a novel wheelchair based IoT enabled 'XoRehab", exoskeleton for rehabilitation; a device for lower limb, with a backrest mechanism. This involves development of a well-trained robot based on electromechanical actuation with micro-controller and feedback system, which can replace the physical trainer or physiotherapist. This autonomous device will control speed of flexion and extension on patient's limbs to improve efficiency of the treatment. It also provides repetitive motion of flexion and extension. The edge system design to upload local rehabilitation data and logs to the cloud server is presented. We propose an opensource Elasticsearch Logstash Kibana (ELK) stack for providing the cloud services, which is a scalable solution. The design of the developed prototype has been discussed in detail along with the functional test results.Clinical Relevance- The introduction of well-trained exoskeleton in the rehabilitation process, gives a high level of performance in patient recovery, and it contributes to expeditious restoration of their joints and improvement in muscle and nerve system.


Ketoconazole and fluconazole drug interactions.
This article reviews potential drug interactions that exist between ketoconazole or fluconazole and other drugs. English-language data sources included human subjects' computerized databases and published indexes. Case reports and studies demonstrate decreased dosage requirements of cyclosporine sodium, methylprednisolone sodium succinate, and possibly anticoagulants and phenytoin after ketoconazole or fluconazole administration, suggesting hepatic enzyme inhibition. Increased dosage requirements of ketoconazole are necessary after rifampin administration, suggesting rifampin's induction of hepatic microsomal enzymes. Possibly a similar effect may occur with concomitant fluconazole and rifampin. The effect of ketoconazole administration on prednisolone sodium phosphate and theophylline warrants further study. Fluconazole, a more selective agent for fungal P-450, seems to be of less concern regarding the potential for drug interactions than ketoconazole.


Hematopoietic stem cell tracking in vivo: a comparison of short-term and long-term repopulating cells.
We have previously demonstrated that we could separate long-term repopulating stem cells from cells that provided radioprotection (short-term repopulating cells) on the basis of size and suggested that this might be due to the quiescent nature of long-term repopulating cells. To further define the activity of these populations, we used a dye (PKH26), which incorporates into the membrane of cells and is equally distributed to daughter cells when they divide. We developed an assay, which allowed us to retrieve PKH26(+) long-term and short-term repopulating cells in the hematopoietic tissues of the recipients posttransplant. We were able to recover the labeled cells and determine their cell cycle activity, as well as their ability to reconstitute secondary lethally irradiated hosts in limiting dilution. The results of our assay suggest that long-term repopulating cells are quiescent in the bone marrow (BM) 48 hours after transplant. We were able to detect only a few labeled cells in the peripheral blood posttransplant and even though cells homed to both the spleen and BM, more long-term repopulating cells homed to the marrow and only these cells, which homed to the marrow, were capable of reconstituting lethally irradiated secondary hosts long-term.


Out-of-field doses in pediatric craniospinal irradiations with 3D-CRT, VMAT, and scanning proton radiotherapy: A phantom study.
Craniospinal irradiation (CSI) has greatly increased survival rates for patients with a diagnosis of medulloblastoma and other primitive neuroectodermal tumors. However, as it includes exposure of a large volume of healthy tissue to unwanted doses, there is a strong concern about the complications of the treatment, especially for the children. To estimate the risk of second cancers and other unwanted effects, out-of-field dose assessment is necessary. The purpose of this study is to evaluate and compare out-of-field doses in pediatric CSI treatment using conventional and advanced photon radiotherapy (RT) and advanced proton therapy. To our knowledge, it is the first such comparison based on in-phantom measurements. Additionally, for out-of-field doses during photon RT in this and other studies, comparisons were made using analytical modeling. In order to describe the out-of-field doses absorbed in a pediatric patient during actual clinical treatment, an anthropomorphic phantom, which mimics the 10-year-old child, was used. Photon 3D-conformal RT (3D-CRT) and two advanced, highly conformal techniques: photon volumetric-modulated arc therapy (VMAT) and active pencil beam scanning (PBS) proton RT were used for CSI treatment. Radiophotoluminescent and poly-allyl-diglycol-carbonate nuclear track detectors were used for photon and neutron dosimetry in the phantom, respectively. Out-of-field doses from neutrons were expressed in terms of dose equivalent. A two-Gaussian model was implemented for out-of-field doses during photon RT. The mean VMAT photon doses per target dose to all organs in this study were under 50% of the target dose (i.e., <500 mGy/Gy), while the mean 3D-CRT photon dose to oesophagus, gall bladder, and thyroid, exceeded that value. However, for 3D-CRT, better sparing was achieved for eyes and lungs. The mean PBS photon doses for all organs were up to three orders of magnitude lower compared to VMAT and 3D-CRT and exceeded 10 mGy/Gy only for the oesophagus, intestine, and lungs. The mean neutron dose equivalent during PBS for eight organs of interest (thyroid, breasts, lungs, liver, stomach, gall bladder, bladder, prostate) ranged from 1.2 mSv/Gy for bladder to 23.1 mSv/Gy for breasts. Comparison of out-of-field doses in this and other phantom studies found in the literature showed that a simple and fast two-Gaussian model for out-of-field doses as a function of distance from the field edge can be applied in a CSI using photon RT techniques. PBS is the most promising technique for out-of-field dose reduction in comparison to photon techniques. Among photon techniques, VMAT is a preferred choice for most of out-of-field organs and especially for the thyroid, while doses for eyes, breasts, and lungs are lower for 3D-CRT. For organs outside the field edge, a simple analytical model can be helpful for clinicians involved in treatment planning using photon RT but also for retrospective data analysis for cancer risk estimates and epidemiology in general.


A disease-related rheumatoid factor autoantibody is not tolerized in a normal mouse: implications for the origins of autoantibodies in autoimmune disease.
We have analyzed B cell tolerance in a rheumatoid factor (RF) transgenic mouse model. The model is based on AM14, a hybridoma, originally isolated from an autoimmune MRL/lpr mouse that has an affinity and specificity typical of disease-related RFs from this strain. AM14 binds to immunoglobulin (Ig)G2a of the "a" allotype (IgG2aa) and not to IgG2ab. Thus, by crossing the transgenes onto an IgHa (BALB/c) background or to a congenic IgHb (CB.17) background, we could study the RF-expressing B cells when they were self-specific (IgHa) or when they were not self-specific (IgHb). These features make the AM14 model unique in focusing on a true autoantibody specificity while at the same time allowing comparison of autoreactive and nonautoreactive transgenic B cells, as was possible in model autoantibody systems such as anti-hen egg lysozyme. Studies showed that AM14 RF B cells can make primary immune responses and do not downregulate sIgM, indicating that the presence of self-antigen does not induce anergy of these cells. In fact, IgHa AM14 transgenic mice have higher serum levels of transgene-encoded RF than their IgHb counterparts, suggesting that self-antigen-specific activation occurs even in the normal mouse background. Since AM14 B cells made primary responses, we had the opportunity to test for potential blocks to self-reactive cells entering the memory compartment. We did not find evidence of this, as AM14 B cells made secondary immune responses as well. These data demonstrate that a precursor of a disease-specific autoantibody can be present in the preimmune repertoire and functional even to the point of memory cell development of normal mice. Therefore, immunoregulatory mechanisms that normally prevent autoantibody production must exert their effects later in B cell development or through T cell tolerance. Conversely, the data suggest that it is not necessary to break central tolerance, even in an autoimmune mouse, to generate pathologic, disease-associated autoantibodies.


Trends in Homicide Rates for US Children Aged 0 to 17 Years, 1999 to 2020.
Homicide is a leading cause of death among children in the US. To examine trends in child homicide rates and characteristics most commonly associated with these deaths. In this cross-sectional study, the study team used National Vital Statistics System WONDER mortality data for 38 362 homicide victims aged 0 to 17 years for 1999 to 2020 and National Violent Death Reporting System data for child homicide victims for 2003 to 2019 in 45 states, Washington, DC, and Puerto Rico. WONDER data are based on death certificates for US residents. National Violent Death Reporting System data include characteristics of violent deaths, linking information from death certificates, and law enforcement, coroner, and medical examiner reports. Child homicide was defined using underlying cause-of-death codes U01 to U02, X85 to Y09, and Y87.1 from the International Classification of Diseases, Tenth Revision, Clinical Modification. Trends in homicide rates per 100 000 children were tested using joinpoint regression analysis; differences in rates from 2019 to 2020 were evaluated using z tests. Circumstances of child homicides were described. This study included 38 362 homicide victims (69.4% male). The overall child homicide rate (per 100 000 children) has increased annually, on average 4.3% since 2013, with a precipitous rise from 2019 to 2020 (2019 rate, 2.2; 2020 rate, 2.8; overall increase of 27.7%). Homicide rates recently increased significantly for boys (2018 rate, 2.9; 2020 rate, 4.1; overall increase of 16.1%), 6- to 10-year-olds (2014 rate, 0.5; 2020 rate, 0.8; overall increase of 5.6%), 11- to 15-year-olds (2018 rate, 1.3; 2020 rate, 2.2; overall increase of 26.9%), 16- to 17-year-olds (2018 rate, 6.6; 2020 rate, 10.0; overall increase of 19.0%), Black children (2012 rate, 5.9; 2018 rate, 6.8; 2020 rate, 9.9; overall increase of 16.6% from 2018 to 2020), Hispanic children (2014 rate, 1.6; 2020 rate, 2.2; overall increase of 4.7%), children in the South (2013 rate, 2.1; 2020 rate, 3.5; overall increase of 6.4%), and in rural (2011 rate, 1.8; 2020 rate, 2.4; overall increase of 3.2%) and urban areas (2013 rate, 1.9; 2020 rate, 2.9; overall increase of 4.4%). Since 1999, homicide rates have decreased for girls (1999 rate, 1.9; 2020 rate, 1.5; overall decrease of 1.4%), infants (1999 rate, 8.7; 2020 rate, 6.6; overall decrease of 1.3%), 1- to 5-year-olds (1999 rate, 2.1; 2020 rate, 1.8; overall decrease of 1.0%), Asian or Pacific Islander children (1999 rate, 2.0; 2020 rate, 0.5; overall decrease of 4.4%), White children (1999 rate, 1.5; 2020 rate, 1.3; overall decrease of 0.7%), and children in the Northeast (1999 rate, 2.0; 2020 rate, 1.7; overall decrease of 1.4%). Homicides of children 10 years or younger were most commonly precipitated by abuse/neglect, perpetrated by parents/caregivers. Homicides of 11- to 17-year-olds were most commonly precipitated by crime and arguments and perpetrated by someone known to them, especially friends and acquaintances. The decline in homicide rates for some geographic and child demographic groups is encouraging; however, rates recently increased across several subpopulations, with some racial and ethnic disparities persisting for more than 20 years. More targeted strategies are needed to (1) protect 6- to 10-year-olds, 11- to 17-year-olds, and children in certain geographic areas and (2) urgently address firearm violence, racism, and inequities at the root of youth violence.


Depressive and anxiety disorders and risk of subclinical atherosclerosis Findings from the Netherlands Study of Depression and Anxiety (NESDA).
Current evidence regarding the association between psychopathology and subclinical atherosclerosis show inconsistent results. The present study examined whether subclinical atherosclerosis was more prevalent in a large cohort of persons with depressive or anxiety disorders as compared to non-depressed and non-anxious controls. Baseline data from the Netherlands Study of Depression and Anxiety were used, including 2717 persons, free of clinical cardiovascular disease. Participants had a DSM-IV-based current or remitted depressive (major depressive disorder, dysthymia) or anxiety (social phobia, generalized anxiety disorder, panic disorder, agoraphobia) disorder (n=2115) or were healthy controls (n=602). Additional clinical characteristics (severity, duration, age of onset and medication) were assessed. Ankle-brachial index (ABI) was used as a measure of vascular risk and was categorized as low (<or=0.90) and mildly low ABI (0.90-1.11) indicating subclinical atherosclerosis, and high ABI (>1.40), which was previously designated as a cardiovascular risk factor, reflecting arterial stiffness and wall calcification. As compared to normal controls, persons with current (i.e., past year) depressive, anxiety or comorbid depressive and anxiety disorders showed a two- to threefold increased odds of low ABI (OR=2.78, 95% CI=1.05-7.35; OR=3.14, 95% CI=1.25-7.85; OR=2.67, 95% CI=1.09-6.51, respectively). No associations were found with mildly low or high ABI. Also, we did not further find a differential role for symptoms severity, duration, age of onset, and use of psychotropic medication in the link between psychopathology and subclinical atherosclerosis. Persons with current depressive or anxiety disorders were more likely to have subclinical atherosclerosis compared to healthy controls.


Health behaviours of teachers and other education professionals in France: can we do better?
Education professionals play a critical role in health education, both as knowledge providers and as role-models. Drawing on the CONSTANCES French cohort (baseline 2012-19) and adjusting for important confounders, we compared education professionals (n = 14 730) with a random sample of non-education sector employees (n = 34 244) on three indicators of high-risk behaviour (at-risk drinking, current smoking, past-year cannabis use) and three indicators of unhealthy lifestyle (low physical activity, poor adherence to nutritional guidelines, overweight/obesity). Among education professionals, we distinguished between teachers (n = 12 820), school principals (n = 372), senior education advisers (n = 189), school health professionals (n = 128) and school service staff (n = 1221). Compared with non-education sector employees with similar demographic and socioeconomic profiles, teachers were less likely to be at-risk drinkers, to smoke, to have used cannabis in the past year and to be overweight/obese. Other non-teaching education professionals were also less involved in high-risk behaviours than non-education employees, but results were more mixed concerning some lifestyle indicators, with certain non-teaching education professional groups showing a higher likelihood of being physically inactive or overweight/obese. In this nationwide French study, our results suggest a window of opportunity to promote school staff health but also indirectly, that of the youth with whom they interact daily. We suggest that school staff should be supported in health matters not only through the provision of health information but also most importantly, through the development of a favourable and supportive environment enabling them to put health knowledge into practice.


Reservoirs for repair? Damage-responsive stem cells and adult tissue regeneration in Drosophila.
Adult stem cells in mammals are important for normal tissue renewal (homeostasis) and regeneration after injury. In the past ten years, different types of homeostatic adult stem cells have also been identified in the genetically accessible fruit fly (Drosophila melanogaster), among which intestinal stem cells have taken centre stage. Recent studies provide evidence that adult fly tissues may also harbor quiescent stem cells, which can enter cell cycle upon injury to regenerate compromised tissue. Such damage-responsive stem cells have been described in flight muscles, the adult brain and in a narrow region of the fly hindgut. Strikingly, many mammalian tissues have also been shown to maintain quiescent, but regeneration-competent, stem cells. However, little is known about the injury-induced signals that lead to their activation. Here, we provide a brief overview of active and damage-responsive adult stem cells in the fruit fly and focus on injury-dependent signalling events. We highlight the potential of Drosophila to model damage-induced stem cell activation to deepen our molecular understanding of how dormant stem cells can be efficiently recruited for tissue repair after injury.


Why Authors Don't Visualize Uncertainty.
Clear presentation of uncertainty is an exception rather than rule in media articles, data-driven reports, and consumer applications, despite proposed techniques for communicating sources of uncertainty in data. This work considers, Why do so many visualization authors choose not to visualize uncertainty? I contribute a detailed characterization of practices, associations, and attitudes related to uncertainty communication among visualization authors, derived from the results of surveying 90 authors who regularly create visualizations for others as part of their work, and interviewing thirteen influential visualization designers. My results highlight challenges that authors face and expose assumptions and inconsistencies in beliefs about the role of uncertainty in visualization. In particular, a clear contradiction arises between authors' acknowledgment of the value of depicting uncertainty and the norm of omitting direct depiction of uncertainty. To help explain this contradiction, I present a rhetorical model of uncertainty omission in visualization-based communication. I also adapt a formal statistical model of how viewers judge the strength of a signal in a visualization to visualization-based communication, to argue that uncertainty communication necessarily reduces degrees of freedom in viewers' statistical inferences. I conclude with recommendations for how visualization research on uncertainty communication could better serve practitioners' current needs and values while deepening understanding of assumptions that reinforce uncertainty omission.


A Robust Bimodal Index Reflecting Relative Dynamics of EEG and HRV With Application in Monitoring Depth of Anesthesia.
Supplemental information captured from HRV can provide deeper insight into nervous system function and consequently improve evaluation of brain function. Therefore, it is of interest to combine both EEG and HRV. However, irregular nature of time spans between adjacent heartbeats makes the HRV hard to be directly fused with EEG timeseries. Current study performed a pioneering work in integrating EEG-HRV information in a single marker called cumulant ratio, quantifying how far EEG dynamics deviate from self-similarity compared to HRV dynamics. Experimental data recorded using BrainStatus device with single ECG and 10 EEG channels from healthy-brain patients undergoing operation (N = 20) were used for the validation of the proposed method. Our analyses show that the EEG to HRV ratio of first, second and third cumulants gets systematically closer to zero with increase in depth of anesthesia, respectively 29.09%, 65.0% and 98.41%. Furthermore, extracting multifractality properties of both heart and brain activities and encoding them into a 3-sample numeric code of relative cumulants does not only encapsulates the comparison of two evenly and unevenly spaced variables of EEG and HRV into a concise unitless quantity, but also reduces the impact of outlying data points.


Expression of messenger RNA for ADAMTS subtypes changes in the periovulatory follicle after the gonadotropin surge and during luteal development and regression in cattle.
Extensive remodeling of the extracellular matrix occurs in the ovary during the periovulatory period. Matrix metalloproteinases and their endogenous inhibitors, tissue inhibitors of metalloproteinases, are believed to play integral roles in this highly regulated series of cellular events, but their specific roles remain unclear. Recent cloning studies have identified a novel family of metalloproteinases, the ADAMTS (A Disintegrin And Metalloproteinase with ThromboSpondin motifs) family. The regulated expression of distinct ADAMTS subtypes has been shown to be required for tissue morphogenesis during embryonic development and for maintaining the integrity of tissues in the adult. In the present studies, we have determined that multiple ADAMTS subtypes are present in the bovine ovary using a reverse transcription-polymerase chain reaction strategy. In particular, ADAMTS-1, -2, -3, -4, -5 (also known as ADAMTS-11), -7, -8, and -9, but not ADAMTS-6, -10, or -12, mRNA transcripts were detected in granulosa cells of nonatretic ovarian follicles and corpora lutea. The levels of mRNA for these ovarian ADAMTS were up- or down-regulated or remained unchanged in the granulosa and/or theca cells of the dominant follicle following the preovulatory surge of gonadotropins, depending on the subtype and/or the cell compartment, and in the corpus luteum during the luteal phase of the estrous cycle. The complex expression patterns observed for the distinct ADAMTS subtypes in the granulosa and theca cells of the periovulatory follicle and in the luteal tissues of the bovine ovary suggest that these novel proteases mediate, at least in part, the remodeling events underlying folliculogenesis and ovulation and the formation, maintenance, and regression of the corpus luteum.


Catalytic wet air oxidation of 2-chlorophenol over sewage sludge-derived carbon-based catalysts.
A sewage sludge derived carbon-supported iron oxide catalyst (FeSC) was prepared and used in the Catalytic Wet Air Oxidation (CWAO) of 2-chlorophenol (2-CP). The catalysts were characterized in terms of elemental composition, surface area, pHPZC, XRD and SEM. The performances of the FeSC catalyst in the CWAO of 2-CP was assessed in a batch reactor operated at 120°C under 0.9MPa oxygen partial pressure. Complete decomposition of 2-CP was achieved within 5h and 90% Total Organic Carbon (TOC) was removed after 24h of reaction. Quite a straight correlation was observed between the 2-CP conversion, the amount of iron leached in solution and the pH of the reaction mixture at a given reaction time, indicating a strong predominance of the homogeneous catalysis contribution. The iron leaching could be efficiently prevented when the pH of the solution was maintained at values higher than 4.5, while the catalytic activity was only slightly reduced. Upon four successive batch CWAO experiments, using the same FeSC catalyst recovered by filtration after pH adjustment, only a very minor catalyst deactivation was observed. Finally, based on all the identified intermediates, a simplified reaction pathway was proposed for the CWAO of 2-CP over the FeSC catalyst.


[Causes of myoglobinemia in surgery with artificial circulation].
Release of myoglobin (Mg) into the plasma and increase of its concentration during perfusion are a result of muscle cell injury during artificial circulation. High values of oxygen tension and hypothermia during cardiosurgery are sources of active oxygen forms damaging the biomembranes. We investigated release of Mg into the blood and relationship of this parameter with oxygen tension and depth of cooling. 95 patients were tested during open-heart surgery and operations on the main vessels: 25 perfusions at 30-32 degrees C, 41 at 26-29 degrees C, and 20 at 12-14 degrees C. The patients were divided into subgroups depending on arterial blood oxygen pressure. Myoglobin release into the blood was minimum under mild hypothermia and moderate PaO2. The degree of myoglobinemia increased with elevation in PaO2. As body temperature decreased, the concentration of Mg increased and differences between the groups with different PaO2 leveled. Critical myoglobinemia (30-fold vs. the initial value) was observed in the group with the deepest hypothermia (14 degrees C). Since the myocardium contains high amounts of Mg, it is clear that loss of this heme-containing protein impairs the feeding of the myocardium and, hence, decreases its contractility.


Influence in rats of dietary fats during the perinatal period: effects upon development and behavior of dams and offspring.
Female rats were fed purified rations containing 20% fat during gestation and lactation. The fat content was butter oil, an equal mixture of butter oil and lard, or safflower oil. Each litter size was reduced (at random) to 2 male and 2 female pups 1 day postpartum, and these offspring were feed a commercial ration after weaning and until they were 20 weeks of age. When dams were fed safflower oil, fewer of them produced litters after mating, and their behavior during lactation was less than optimal. Litter size and birth weights were similar in all dams producing litters. The type of fat fed to the dam in the perinatal period did not influence the growth, development, and spontaneous activity of the offspring. However, the offspring from the dams fed safflower oil exhibited poorer learning performance in a T-maze and sometimes had a longer time of inactivity following auditory stimulation than did the offspring from dams fed the other types of fats.


Genotypic characterization of Toxoplasma gondii strains associated with human toxoplasmosis in Spain: direct analysis from clinical samples.
Genetic analysis of the SAG2 locus was performed to determine the prevalence of the different genotypes of Toxoplasma gondii (strain types I, II, and III) associated with human toxoplasmosis in Spain. This determination was made directly from primary clinical samples, obviating the previous process of isolation in mice or cell culture. A total of 34 isolates of T. gondii, collected from immunocompromised patients and congenital infection cases, were analyzed. Restriction fragment length polymorphism in PCR-amplified SAG2 products was used to group strains into one of the three genotypes of T. gondii. Complete characterization of the SAG2 gene was successful in 76.5% of the cases, demonstrating the feasibility of direct genotype analysis from clinical samples of different origins. Strains of T. gondii type II were the most prevalent in immunocompromised patients, with 52% of cases, while strains of type I were present in 75% of the congenital infection cases. These data differ from previous reports that show type II strains to be mostly associated with all kinds of human toxoplasmosis. These differences might be an effect of selection in the process of culture and isolation of the samples performed by other researchers prior to strain characterization.


Antiproliferative, Antiangiogenic, and Antimetastatic Therapy Response by Mangiferin in a Syngeneic Immunocompetent Colorectal Cancer Mouse Model Involves Changes in Mitochondrial Energy Metabolism.
In spite of the current advances and achievements in cancer treatments, colorectal cancer (CRC) persists as one of the most prevalent and deadly tumor types in both men and women worldwide. Drug resistance, adverse side effects and high rate of angiogenesis, metastasis and tumor relapse remain one of the greatest challenges in long-term management of CRC and urges need for new leads of anticancer drugs. We demonstrate that CRC treatment with the phytopharmaceutical mangiferin (MGF), a glucosylxanthone present in Mango tree stem bark and leaves (Mangifera Indica L.), induces dose-dependent tumor regression and decreases lung metastasis in a syngeneic immunocompetent allograft mouse model of murine CT26 colon carcinoma, which increases overall survival of mice. Antimetastatic and antiangiogenic MGF effects could be further validated in a wound healing in vitro model in human HT29 cells and in a matrigel plug implant mouse model. Interestingly, transcriptome pathway enrichment analysis demonstrates that MGF inhibits tumor growth, metastasis and angiogenesis by multi-targeting of mitochondrial oxidoreductase and fatty acid β-oxidation metabolism, PPAR, SIRT, NFκB, Stat3, HIF, Wnt and GP6 signaling pathways. MGF effects on fatty acid β-oxidation metabolism and carnitine palmitoyltransferase 1 (CPT1) protein expression could be further confirmed in vitro in human HT29 colon cells. In conclusion, antitumor, antiangiogenic and antimetastatic effects of MGF treatment hold promise to reduce adverse toxicity and to mitigate therapeutic outcome of colorectal cancer treatment by targeting mitochondrial energy metabolism in the tumor microenvironment.


Studying the morphology of lyophilized protein solids using X-ray micro-CT: effect of post-freeze annealing and controlled nucleation.
The objective of this study was to determine how different techniques used during the freezing step of lyophilization affect morphology of the dried protein solids. Aqueous solutions containing recombinant human albumin, trehalose, and sodium phosphate buffer were dried after their freezing by shelf-ramp cooling, immersion in liquid nitrogen, or controlled ice nucleation. Some shelf-frozen solutions were heat treated (annealed) before the vacuum drying. We used three-dimensional (3D) X-ray micro-computed tomography (micro-CT) and scanning electron microscopy (SEM) to study the morphology of solids. The X-ray micro-CT images of the lyophilized microporous solids showed traces of varied size and structure ice crystals that were comparable to corresponding SEM images. A post-freeze heat treatment and a controlled nucleation both induced larger ice crystal ghosts in the solids. The variations in the structure of walls surrounding ice crystals, formed by the different freezing procedures, should affect the water vapor transition during the primary and secondary drying. Some solids also showed higher-density layer in the upper surface. Overall, the simple sample preparation procedures and the ample morphological information make the X-ray micro-CT appropriate for analyzing lyophilized pharmaceuticals.