Mitochondrial membrane fusion.
Mitochondrial fusion has been observed in a great variety of organisms from yeast to man. It serves to mix and unify the mitochondrial compartment and plays roles in cellular aging, cell development, energy dissipation and mitochondrial DNA inheritance. Large GTPases in the mitochondrial outer membrane, termed Fzo or mitofusins, have been identified as key components of the mitochondrial fusion machinery in yeast, flies and mammalian cells. Recent studies in yeast suggest an involvement of a dynamin-related protein in the intermembrane space. Additional components have been identified by genetic screens. These findings suggest a unique and evolutionarily conserved mechanism for mitochondrial membrane fusion.


Common UCP2 variants contribute to serum urate concentrations and the risk of hyperuricemia.
Elevated serum urate, which is regulated at multiple levels including genetic variants, is a risk factor for gout and other metabolic diseases. This study aimed to investigate the association between UCP2 variants and serum urate as well as hyperuricemia in a Chinese population. In total, 4332 individuals were genotyped for two common UCP2 variants, -866G/A and Ala55Val. These loci were not associated either serum urate level or with a risk of hyperuricemia in the total group of subjects. However, in females, -866G/A and Ala55Val were associated with a lower serum urate (P = 0.006 and 0.014, seperately) and played a protective role against hyperuricemia (OR = 0.80, P = 0.018; OR = 0.79, P = 0.016). These associations were not observed in the males. After further stratification, the two loci were associated with serum urate in overweight, but not underweight females. The haplotype A-T (-866G/A-Ala55Val) was a protective factor for hyperuricemia in the female subgroup (OR = 0.80, P = 0.017). This present study identified a novel gene, UCP2, that influences the serum urate concentration and the risk of hyperuricemia, and the degree of association varies with gender and BMI levels.


[Impact of fusarium toxins on growth and slaughter performance of broilers and turkeys].
In two broiler and two turkey trials the influence of Fusarium toxins in maize on growth and slaughter performance, on residues of toxins in carcass and litters and blood parameters were investigated. In one broiler and turkey trial with naturally contaminated maize the main contaminants were deoxynivalenol (DON), moniliformin (MON and beauvericin (BEA). In one further broiler and turkey trial with inoculated maize (Fusarium subglutinans) the main contaminants were MON and BEA. The level of contamination of mycotoxins in the diets was free, low, medium and high. For every broiler trial 180 and for the turkey trials 60 and 100 one day old chicken were used. The result of these investigations shows that broiler and turkeys are not very sensitive to Fusarium toxins. Growth and slaughter performance and also blood parameters were not negative influenced by higher mycotoxin dosages in the diets.


Mitochondrial pyruvate carrier function and cancer metabolism.
Metabolic reprogramming in cancer supports the increased biosynthesis required for unchecked proliferation. Increased glucose utilization is a defining feature of many cancers that is accompanied by altered pyruvate partitioning and mitochondrial metabolism. Cancer cells also require mitochondrial tricarboxylic acid cycle activity and electron transport chain function for biosynthetic competency and proliferation. Recent evidence demonstrates that mitochondrial pyruvate carrier (MPC) function is abnormal in some cancers and that increasing MPC activity may decrease cancer proliferation. Here we examine recent findings on MPC function and cancer metabolism. Special emphasis is placed on the compartmentalization of pyruvate metabolism and the alternative routes of metabolism that maintain the cellular biosynthetic pools required for unrestrained proliferation in cancer.


The Impact of Social Determinants of Health on Vestibular Schwannoma Management: A Single Institution Review.
To evaluate social determinants of health and their effect on the management of vestibular schwannoma (VS). Retrospective chart review. Tertiary referral center. Patients >18 years old with sporadic VS newly diagnosed between January 1, 2010, and December 31, 2020. Magnetic resonance imaging; audiogram; treatment recommendations. Differences in treatment recommendations for patients based on their social determinants of health, including race, ethnicity, and socioeconomic status. A total of 811 patients were included in analysis. Patients with a higher area deprivation index (ADI) presented with larger tumors. A higher ADI was associated with a higher likelihood of recommending radiation (or the option of surgery or radiation) compared with a recommendation of surgery alone. Tumor grade and patient age were significantly associated with treatment recommendation. Older age was associated with a recommendation of observation alone or a recommendation of radiation. Higher tumor grade was associated with a recommendation of surgery. There was a trend for higher hearing class to be associated with a recommendation of surgery, but this did not reach statistical significance. Race, ethnicity, and gender were not significantly associated with treatment recommendation. Patients with higher levels of disadvantage presented with higher tumor grade, suggesting that access to care influences diagnosis. Factors including age, ADI, and tumor grade were associated with treatment recommendation.


Regulation of apicomplexan actin-based motility.
Apicomplexan parasites are an ancient group of protozoan parasites that includes several significant pathogens of humans and animals. To target and invade host cells they use a unique form of actin-based motility, called gliding motility. At the centre of the molecular motor that underlies this unique mode of locomotion are short, highly dynamic actin filaments. Recent molecular work, along with the availability of completed genomes for several Apicomplexa, has highlighted unique features of parasite actin and its regulation - features that might provide new ways to block motility and, consequently, prevent infection and disease.


t-boc synthesis of huwentoxin-i through native chemical ligation incorporating a trifluoromethanesulfonic acid cleavage strategy.
Tert-butyloxycarbonyl (t-Boc)-based native chemical ligation (NCL) techniques commonly employ hydrogen fluoride (HF) to create the thioester fragment required for the ligation process. Our research aimed to assess the replacement of HF with Trifluoromethanesulfonic acid (TFMSA). Here we examined a 33 amino acid test peptide, Huwentoxin-I (HwTx-I) as a novel candidate for our TFMSA cleavage protocol. Structurally HwTx-I has an X-Cys(16) -Cys(17) -X sequence mid-region, which makes it an ideal candidate for NCL. Experiments determined that the best yields (16.8%) obtained for 50 mg of a thioester support resin were achieved with a TFMSA volume of 100 μL with a 0.5-h incubation on ice, followed by 2.0 h at room temperature. RP-HPLC/UV and mass spectra indicated the appropriate parent mass and retention of the cleaved HwTx-I N-terminal thioester fragment (Ala(1) -Cys(16) ), which was used in preparation for NCL. The resulting chemically ligated HwTx-I was oxidized/folded, purified, and then assessed for pharmacological target selectivity. Native-like HwTx-I produced by this method yielded an EC50 value of 340.5 ± 26.8 nM for Nav 1.2 and an EC50 value of 504.1 ± 81.3 nM for Nav 1.3, this being similar to previous literature results using native material. This article represents the first NCL based synthesis of this potent sodium channel blocker. Our illustrated approach removes potential restrictions in the advancement of NCL as a common peptide laboratory technique with minimal investment, and removes the hazards associated with HF usage. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 737-745, 2016.


Differential effects on natural reward processing in rats after repeated heroin.
Heroin users report reward deficits as well as reward enhancements (to drug stimuli). To better understand the causal relation between chronic heroin and alterations in natural reward processing, we used experimental techniques in animal models. Separate groups of rats were trained in several food reward paradigms: conditioned place preference (CPP), food-reinforced lever pressing under a progressive ratio schedule of reinforcement, free feeding, and lever pressing with conditioned reinforcement. After training, the rats were subjected to 10 daily heroin (2 mg/kg) or saline vehicle injections and tested at 3, 15, and 30 days post-treatment. Repeated heroin treatment abolished the CPP and significantly reduced break points for food reward at 3, 15, and 30 days post-treatment. Repeated heroin did not affect free feeding. Finally, repeated heroin significantly enhanced responding for a food-based conditioned reinforcer. Repeated heroin decreases the attractiveness of food-associated cues and reduces motivation to work for natural reward. However, it appears to enhance natural conditioned reward processes that involve the acquisition of novel responding. Thus, repeated heroin appears to produce differential effects on natural reward processing depending on the nature of the reward-directed behavior.


Functional characteristics of the stratum corneum in photoaged skin in comparison with those found in intrinsic aging.
Among various functions of the skin, the most vital one is carried out by the stratum corneum (SC), because the SC effectively protects our body from desiccation even in a dry environment as well as from external invasion of injurious agents. Despite the general decline of various bodily functions in advanced age, the barrier function of the SC does not deteriorate but rather improves with aging, reflecting the reduced epidermal proliferation associated with slower desquamation of the SC. Although the intercellular lipid production that is crucial for the SC barrier is reduced in aged epidermis, it is compensated by the thicker SC, consisting of larger corneocytes covering the aged skin surface due to the retardation of the desquamating process. However, such SC is deficient in water-binding capacity, another important function of the SC that keeps the skin surface soft and smooth, due to decreased amounts of water-binding substances in the SC. Thus, large portions of the covered skin begin to develop xerotic changes in a dry environment of winter, being frequently accompanied by pruritus. In contrast, most elderly individuals display the unique features of photoaging on their exposed skin such as the face and hands due to chronic exposure to the ultraviolet light (UV) of sunlight. However, functional derangements of the SC are rather mild in the photoaged skin. Our functional analyses of the SC of the chronically sun-exposed skin found in the symmetrical located areas, i.e., the dorsa of the hands in middle-aged Japanese golf players who always wore a glove only on the one of the hands demonstrated significant impairment in SC water-binding capacity in the sun-exposed side, while its barrier function was well retained. Despite the decreased water content of the SC, elderly people can live without any inconvenience even when they expose the facial skin to the dry environment of winter, because there take place sebum excretion and non-apparent sweating by comparison with the skin of the sun-protected areas such as the trunk and limbs that easily develop xerotic changes in cold seasons.


Location and Number of Astrocytes Determine Dopaminergic Neuron Survival and Function Under 6-OHDA Stress Mediated Through Differential BDNF Release.
While astrocytes throughout the CNS share many common traits, they exhibit significant differences in function and number among brain regions. The aim of the present study is to assess the effect of region-specificity and number of astrocytes on the survival of dopaminergic neurons under stress, and to understand the possible mechanism by which these astrocytes extend neuroprotection to dopaminergic neurons. Purified astrocytes obtained from forebrain, midbrain, and hindbrain region were characterized through FACS and immunofluorescence. Co-culture experiments (using trans-wells) were then performed to measure the effect of region-specificities and numbers of astrocytes on primary midbrain culture under 6-OHDA stress. Cell survival augmented with an increase in astrocyte seeding number and total cell survival was comparable among the different region-specific astrocytes for all numbers. However, striking differences were observed in dopaminergic neuronal (TH) cell survival in the presence of midbrain astrocytes in comparison to forebrain and hindbrain astrocytes at all seeding numbers. At 75 μM 6-OHDA insult, while cell survival was comparable in purified astrocytes from the different brain regions, a distinct increase in BDNF secretion (significantly higher than its constitutive release) was noted for midbrain astrocytes compared to forebrain and hindbrain astrocytes. The TH immunopositive population decreased when TrkB inhibitor was added to the co-culture under 6-OHDA toxicity, suggesting that BDNF released by co-cultured astrocytes plays a key role in the survival of dopaminergic neurons. This BDNF release decreased in presence of NO inhibitor and increased in the presence of NO donor (DETA/NO). We conclude that the BDNF released from astrocytes under 6-OHDA toxicity is mediated through NO release through both autocrine and paracrine signaling, and this BDNF release is primarily responsible for the differential effect of region-specific astrocytes on TH neuron survival under these conditions.


Oligomerization of the Tetraspanin CD81 via the Flexibility of Its δ-Loop.
Tetraspanins are master organizers in the plasma membrane, forming tetraspanin-enriched microdomains with one another and other surface molecules. Their rod-shaped structure includes a large extracellular loop (LEL) that plays a pivotal role in tetraspanin network formation. We performed comparative atomistic and coarse-grain molecular-dynamics simulations of the LEL in isolation and full-length CD81, and reproduced LEL flexibility patterns known from wet-lab experiments in which the LEL δ-loop region showed a pronounced flexibility. In a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine lipid bilayer and a plasma membrane environment, the conformational flexibility of the δ-loop initiates CD81-CD81 contacts for oligomerization. Furthermore, in the plasma membrane, CD81-ganglioside bridges arising from preformed glycolipid patches cross-link the complexes. The data suggest that exposing a flexible domain enables binding to interaction partners by circumventing the restriction of orientation and conformational freedom of membrane proteins.


Telomere length and human hippocampal neurogenesis.
Short telomere length is a risk factor for age-related disease, but it is also associated with reduced hippocampal volumes, age-related cognitive decline and psychiatric disorder risk. The current study explored whether telomere shortening might have an influence on cognitive function and psychiatric disorder pathophysiology, via its hypothesised effects on adult hippocampal neurogenesis. We modelled telomere shortening in human hippocampal progenitor cells in vitro using a serial passaging protocol that mimics the end-replication problem. Serially passaged progenitors demonstrated shorter telomeres (P ≤ 0.05), and reduced rates of cell proliferation (P ≤ 0.001), with no changes in the ability of cells to differentiate into neurons or glia. RNA-sequencing and gene-set enrichment analyses revealed an effect of cell ageing on gene networks related to neurogenesis, telomere maintenance, cell senescence and cytokine production. Downregulated transcripts in our model showed a significant overlap with genes regulating cognitive function (P ≤ 1 × 10-5), and risk for schizophrenia (P ≤ 1 × 10-10) and bipolar disorder (P ≤ 0.005). Collectively, our results suggest that telomere shortening could represent a mechanism that moderates the proliferative capacity of human hippocampal progenitors, which may subsequently impact on human cognitive function and psychiatric disorder pathophysiology.


Development of a maxillofacial virtual surgical system based on biomechanical parameters of facial soft tissue.
Lack of biomechanical force model of soft tissue hinders the development of virtual surgical simulation in maxillofacial surgery. In this study, a physical model of facial soft tissue based on real biomechanical parameters was constructed, and a haptics-enabled virtual surgical system was developed to simulate incision-making process on facial soft tissue and to help maxillofacial surgery training. CT data of a 25-year-old female patient were imported into Mimics software to reconstruct 3D models of maxillofacial soft and skeletal tissues. 3dMD stereo-photo of the patient was fused on facial surface to include texture information. Insertion and cutting parameters of facial soft tissue measured on fresh cadavers were integrated, and a maxillofacial biomechanical force model was established. Rapid deformation and force feedback were realized through localized deformation algorithm and axis aligned bounding box (AABB)-based collision detection. The virtual model was validated quantitatively and qualitatively. A patient-specific physical model composed of skeletal and facial soft tissue was constructed and embedded in the virtual surgical system. Insertion and cutting in different regions of facial soft tissue were simulated using omega 6, and real-time feedback force was recorded. The feedback force was consistent with acquired force data of experiments conducted on tissue specimen. Real-time graphic and haptic feedback were realized. The mean score of the system performance was 3.71 given by surgeons in evaluation questionnaires. The maxillofacial physical model enabled operators to simulate insertion and cutting on facial soft tissue with realization of realistic deformation and haptic feedback. The combination of localized deformation algorithm and AABB-based collision detection improved computational efficiency. The proposed virtual surgical system demonstrated excellent performance in simulation and training of incision-making process.


Development of C2-Symmetric Chiral Diphosphine Ligands for Highly Enantioselective Hydrogenation Assisted by Ion Pairing.
A new series of C2-symmetrical chiral ferrocene-based diphosphino-ethane ligands termed as f-DPE were developed. Assisted by the ion pairing interaction with the ligand, a wide scope of 2-substituted acrylic acids was hydrogenated to obtain chiral propanoic acids with high yields and enantioselectivities. The well-known anti-inflammatory drugs ibuprofen, naproxen, and flurbiprofen could be synthesized efficiently. In addition, the synthetic utilities of the current method were demonstrated by gram-scale experiments.


[Biotechnical increase of litter size in early pregnant sows using steroid application. 1. The effect of a single application of hydroxyprogesterone capronate on fertility response in ovulation-synchronized gilts and old sows].
One single intramuscular injection of hydropyrogesteroncapronate was given in an experiment to 199 gilts and 239 old sows on the 13th or 15th or 17th day after insemination to test various fertility performance parameters. Doses were 50 mg, 75 mg or 100 mg. Positive effects on litter size were established from the majority of nine compared experimental variants. The number of live-born piglets was increased up to two. Several groups of gilts had higher mean litter weights. More studies are necessary to prepare an adequate therapeutic regime by which to reduce loss of embryos in swine.


Apatinib plus paclitaxel versus paclitaxel monotherapy for platinum-resistant recurrent ovarian cancer treatment: A retrospective cohort study.
Apatinib, an oral antiangiogenic drug, exerts potential anti-tumour effects on platinum-resistant recurrent ovarian cancer (PROC). This study intended to evaluate the efficacy and safety of apatinib plus paclitaxel compared to paclitaxel monotherapy in PROC patients. This retrospective cohort study reviewed 70 PROC patients who received apatinib plus paclitaxel (apatinib plus paclitaxel group) (N = 32) or paclitaxel monotherapy (paclitaxel monotherapy group) (N = 38). The recommended regimens were as follows: paclitaxel (60 mg/m2 ) administrated once a week with a maximum of 18 weeks; apatinib (250-375 mg/day) administrated until disease progression or patient intolerance. Disease control rate was elevated (84.4% vs. 60.5%, P = 0.028), whereas objective response rate only disclosed an increasing trend (lacked statistical significance) (37.5% vs. 18.4%, P = 0.074) in apatinib plus paclitaxel group compared with paclitaxel monotherapy group. Progression-free survival (median [95% confidence interval (CI)]: 5.0 [2.5-7.5] months vs. 3.8 [2.4-5.2] months, P = 0.033) and overall survival (median [95% CI]: 21.1 [13.2-29.0] months vs. 14.8 [11.4-18.2] months, P = 0.032) were both prolonged in apatinib plus paclitaxel group compared to paclitaxel monotherapy group, which were further verified in the multivariate Cox's proportional hazard regression analyses (both P < 0.050). Additionally, the incidence of each adverse event was not different between the two groups (all P > 0.050). Apatinib plus paclitaxel exhibits better efficacy and acceptable toxicity compared with paclitaxel monotherapy in PROC patients.


[Hormonal function of adrenal glands and gonads in patients with leukemia].
The steroid hormone patterns were investigated in peripheral blood of healthy subjects and patients with chronic lympholeukemia, chronic myeloleukemia and acute leukemia. In all types of leukemia, the plasma levels of dehydroepiandrosterone were relatively lower, while testosterone concentration changes appeared to be sex-dependent: testosterone levels were lower in males and markedly higher in females.


Exosome-mediated small interfering RNA delivery inhibits aberrant osteoblast differentiation in Apert syndrome model mice.
Apert syndrome, an autosomal dominant congenital disorder characterized by craniosynostosis, is caused by a missense mutation (S252W or P253R) in fibroblast growth factor receptor 2 (FGFR2). Exosomes are naturally occurring carriers that deliver nucleic acids, including small interfering RNA (siRNA), to induce gene silencing. This study aimed to develop siRNA-loaded exosomes (Ex-siRNAFgfr2S252W) to silence the Fgfr2S252W gain-of-function mutation, thereby inhibiting the increased osteoblastic differentiation caused by the constitutive activation of FGFR2 signaling in calvarial osteoblastic cells isolated from Apert syndrome model mice. Primary calvarial osteoblast-like cells were isolated from the embryonic calvarial sutures of the Apert syndrome model (Fgfr2S252W/+) and littermate wild-type mice (Ap-Ob and Wt-Ob, respectively). Exosomes were extracted from the serum of wild-type mice, validated using biomarkers, and used to encapsulate siRNAs. After exosome-mediated siRNA transfection, cells were analyzed under a fluorescence microscope to validate the delivery of Ex-siRNAFgfr2S252W, followed by western blot and real-time reverse transcription polymerase chain reaction analyses. After 24 h of Ex-siRNAFgfr2S252W delivery in both Ap-Ob and Wt-Ob, siRNA-loaded exosome delivery was validated. Moreover, p44/42 mitogen-activated protein kinase (MAPK) phosphorylation, runt-related transcription factor 2 (Runx2), and collagen type 1 alpha 1 (Col1a1) mRNA expression, and alkaline phosphatase (ALP) activity were significantly increased in Ap-Ob. The levels of phospho-p44/42 protein, Runx2, Col1a1, and ALP were significantly decreased after Ex-siRNAFgfr2S252W transfection but did not affect Wt-Ob. These results indicate that exosome-mediated delivery of siRNA targeting Fgfr2S252W is a potential non-invasive treatment for aberrant FGF/FGFR signaling.


SONAR enables cell type deconvolution with spatially weighted Poisson-Gamma model for spatial transcriptomics.
Recent advancements in spatial transcriptomic technologies have enabled the measurement of whole transcriptome profiles with preserved spatial context. However, limited by spatial resolution, the measured expressions at each spot are often from a mixture of multiple cells. Computational deconvolution methods designed for spatial transcriptomic data rarely make use of the valuable spatial information as well as the neighboring similarity information. Here, we propose SONAR, a Spatially weighted pOissoN-gAmma Regression model for cell-type deconvolution with spatial transcriptomic data. SONAR directly models the raw counts of spatial transcriptomic data and applies a geographically weighted regression framework that incorporates neighboring information to enhance local estimation of regional cell type composition. In addition, SONAR applies an additional elastic weighting step to adaptively filter dissimilar neighbors, which effectively prevents the introduction of local estimation bias in transition regions with sharp boundaries. We demonstrate the performance of SONAR over other state-of-the-art methods on synthetic data with various spatial patterns. We find that SONAR can accurately map region-specific cell types in real spatial transcriptomic data including mouse brain, human heart and human pancreatic ductal adenocarcinoma. We further show that SONAR can reveal the detailed distributions and fine-grained co-localization of immune cells within the microenvironment at the tumor-normal tissue margin in human liver cancer.


Predictive modeling of an azo metal complex dye sorption by pumpkin husk.
Effective disposal of pumpkin husk (PH) as a redundant waste is a significant work for environmental protection and full utilization of resource. Predictive modeling of sorption of Lanaset Red (LR) G on PH was investigated in a batch system as functions of particle size, adsorbent dose, pH, temperature, and initial dye concentration. Fourier transform infrared spectroscopy attenuated total reflectance spectra of PH powders before and after the sorption of LR G were determined. Sorption process was found to be dependent on particle size, adsorbent dose, pH, temperature, initial dye concentration, and contact time. Amine and amide groups of PH had significant effect on the sorption process. The pHzpc of PH was found as 6.4. Sorption process was very fast initially and reached equilibrium within 60 min. Dynamic behavior of sorption was well represented by logistic and Avrami models. The sorption of LR G on PH was excellently described by Langmuir model, indicating a homogeneous phenomenon. Monolayer sorption capacity decreased from 440.78 to 436.28 mg g(-1) with increasing temperature. Activation energy, thermodynamic, and desorption studies showed that this process was physical character, exothermic, and spontaneous. This study confirmed that PH as an effective and low-cost adsorbent had a great potential for the removal of LR G as an alternative eco-friendly process.


Reconstructing a sense of self in patients with chronic mental illness.
The loss and reconstruction of self in patients with a chronic mental illness. To describe the loss of self and its reconstruction. The authors' own clinical work and review of the literature. Nurses can help patients who have undergone a loss of self to discover a more active sense of self, take stock of the self, put the self into action, and use the enhanced self as a refuge. This process involves the fostering of hope.


Intramuscular lesions in musculoskeletal MRI as a favourable prognostic sign in patients with anti-MDA5 antibody-positive dermatomyositis.
Anti-differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis, which has been described as clinically amyopathic dermatomyositis, complicates rapidly progressive interstitial lung disease (ILD). Owing to the absence of significant muscle symptoms, musculoskeletal MRI is often not performed. In this study, we aimed to devise a simple evaluation method using musculoskeletal MRI findings to elucidate the relationship between MRI findings and ILD prognosis and development. The medical records and MRI scans of the proximal muscles at the time of diagnosis were retrospectively reviewed for 28 patients with anti-MDA5 antibody-positive dermatomyositis who were admitted to The Jikei University Hospital and The Jikei University Kashiwa Hospital between January 2008 and March 2022. Three observers evaluated nine proximal muscles for high signals on either short-tau inversion recovery images and/or fat-saturated gadolinium-enhanced T1-weighted images in the fascia and/or in the margins of the muscles in contact with the fascia (fascial pattern), and/or high signals in the muscles away from the fascia (intramuscular pattern), and a consensus was reached. Of the 28 patients, 15 presented with 'radiological myositis', where an intramuscular pattern was observed at any site. Patients with radiological myositis had significantly higher survival rates than those without radiological myositis, despite the lower rate of triple therapy with prednisolone, calcineurin inhibitors and cyclophosphamide. The spread of ILD on chest CT negatively and significantly correlated with the proportion of intramuscular lesions. The detection of intramuscular lesions on musculoskeletal MRI using our novel evaluation method could be clinically useful as a favourable prognostic marker.


Reorganization of cytoskeletal proteins and prolonged life expectancy caused by hepatocyte growth factor in a hamster model of late-phase dilated cardiomyopathy.
It has been postulated recently that changes in cytoskeletal and sarcolemmal proteins initiate a final common pathway for contractile dysfunction in dilated cardiomyopathy. In ischemic cardiomyopathy, hepatocyte growth factor plays an important role in reorganizing the impaired cytoskeletal proteins in several cell types. We have tested the hypothesis that hepatocyte growth factor might improve life expectancy through modification of the molecular process that contributes to impairment in dilated cardiomyopathy. Adult male 27-week-old BIO TO-2 hamsters, which show moderate cardiac remodeling, were divided into treatment groups that received (1) hemagglutinating virus of Japan liposomes containing human hepatocyte growth factor cDNA (H group), (2) culture medium (C group), or (3) sham operation (S group). After the operation, echocardiography demonstrated that the enlarged left ventricular end-systolic dimension and decreased fractional shortening were significantly attenuated in the H group compared with the C group. There was significantly less myocardial fibrosis in the H group compared with the C group. Immunohistochemical analysis showed alpha-dystroglycan and alpha- and beta-sarcoglycan expression in the basement membrane beneath the cardiomyocytes in the H group, whereas no expression of these proteins was seen in the C group. The 40-week survival was significantly better in the H group than in the C and S groups. An improved survival associated with transient reorganization of the cytoskeletal proteins and reduction in myocardial fibrosis was achieved by hepatocyte growth factor treatment in an adult hamster model of dilated cardiomyopathy. The results suggest a therapeutic potential of hepatocyte growth factor in the treatment of dilated cardiomyopathy.


Views of healthcare professionals on gender roles: A qualitative study.
Gender equality is one of the most important determinants of health. Discriminatory interventions, values, beliefs, and prejudices of healthcare professionals during their service affect health adversely. There is not adequate information about the views of healthcare professionals on gender roles. This study was conducted to understand and define the views of healthcare professionals involved in the health system on gender roles. This study was performed using the "phenomenological method," one of the qualitative research methods. A total of 28 healthcare professionals - 10 midwives, 12 nurses, and 6 doctors - were included in the research. Individual in-depth interviews were held with the healthcare professionals included in the study. As a result of the descriptive analysis performed after the individual interviews about the views of healthcare professionals on gender roles, 6 main themes were determined. These themes are (1) the neglect of women by society, (2) using force on women, (3) seeing women as sexual objects, (4) having a say in society, (5) glorified masculinity and femininity roles, and (6) gender equality. In this study, healthcare professionals expressed that women were neglected by societies since gender roles were determined by patriarchal societies. This situation adversely influences the health of individuals. Importance should be attached to equality between women and men to improve health. Healthcare professionals who support equality will improve the quality of care. Healthcare professionals should provide equitable services without discrimination. This equitable care they provide will positively affect the health of individuals.


Polymer-Stabilized Liquid Crystal Films Containing Dithienyldicyanoethene-Based Chiral Photoswitch: Multi-Modulation for Environment-Adaptative Smart Windows.
A polymer-stabilized liquid crystal (PSLC)-based environment-adaptative smart window with multi-modulations is demonstrated. This PSLC system contains a right-handed dithienyldicyanoethene-based chiral photoswitch and a chiral dopant, S811, with opposite handedness, of which the reversible cis-trans photoisomerization of the switch can drive self-shading of the smart window under UV light stimulus because of the transition from nematic phase to cholesteric one. With the assistance of solar heat, the opacity of the smart window can be deepened because the heat promotes the isomerization conversion rate of the switch. This switch has no thermal relaxation at room temperature, therefore, the smart window exhibits dual stabilization: transparent state (cis-isomer) and opaque state (trans-isomer). Moreover, the incident intensity of sunlight can be regulated by an electric field, which allows the smart window to adapt to some specific situations. Such an energy-saving device can be used in buildings and vehicles to control indoor temperature and adapt to the required ambiance.


Clinical response of antilymphocyte globulin-based treatment in patients in taiwan with aplastic anemia: positive hepatitis C antibody may represent a response predictor.
Immunosuppression (IS) therapy with antilymphocyte globulin (ALG) is currently the treatment of choice for patients with aplastic anemia who do not have histocompatible sibling donors or who are not candidates for allogeneic bone marrow transplantation. Thirty-eight patients with aplastic anemia who received ALG-based therapy at a single institute in Taiwan were analyzed, and 28 were followed up for more than 6 months. Four patients (10.5%) had a complete response, and 11 (28.9%) had a partial response. The overall response rate was 39.4%. The significant prognostic factor that affected the response to IS therapy was a positive test result for antibodies to the hepatitis C virus. The rate of early mortality (death within 90 days after initiation of ALG-based therapy) was 15.8%, and most deaths were secondary to infection. Factors influencing the risk of early mortality were old age, hypotension, and bacteremia. In conclusion, ALG-based IS therapy was effective for aplastic anemia in Chinese patients. The role of hepatitis C associated with aplastic anemia and its relationship to IS need to be clarified by further investigations.


Lung cancer near an industrial site in Lithuania with major emissions of airway irritants.
To assess the relation between air pollution with airway irritants, including sulfuric acid and lung cancer, a case-control study was performed near an industry producing sulfuric acid and fertilizers in Kedainiai county, central Lithuania. The county had the highest lung cancer rates of the country among men. Between 1967 and 1973, the levels of sulfuric acid exceeded 500 microg/m(3) within 2 km of the industry and 100 microg/m(3) more than 5 km away. A total of 277 men who were diagnosed as having lung cancer during 1981-1991 in Kedainiai county were included as well as 1,108 population controls. Information on residential history since 1960, smoking habits, occupations and workplaces during lifetime was obtained from questionnaires mailed to next-of-kin. The relative risk of lung cancer associated with living within approximately 5 km from the plant was 1.02 (95% CI: 0.76-1.38) compared to those who had never lived in this area. No relation with distance or duration of residence was observed. Furthermore, workers at the plant did not have an increased lung cancer risk. The relative risk of lung cancer associated with smoking was 21.2 (95% CI: 7.51; 60.1) for current smokers and 14.0 (95% CI: 4.88; 40.3) for exsmokers. The duration of smoking, a low age at start and amount of cigarettes smoked daily were positively associated with lung cancer risk. Smoking levels appeared more pronounced among study controls than in the rest of the country. Our study could not confirm earlier evidence of an association between exposure to airway irritants, such as sulfuric acid and lung cancer. Smoking is the major determinant of the risk of lung cancer in men in Kedainiai county. It is probable that higher smoking rates constitute the main reason for the increased lung cancer risk among men in this area.


Long term follow up of mucous membrane grafting for cicatricial ectropion in Ichthyosis: A case report.
Ichthyosis is a group of keratinizing diseases characterized by scaly and dry skin. One of the ocular complications associated with ichthyosis is cicatricial ectropion which often results in exposure keratopathy and eventually corneal scarring. In this report we are presenting a 21-year-old female who is known to have ichthyosis-related bilateral lower lid cicatricial ectropion, which was managed with Mucous Membrane Grafting (MMG) six years ago. Despite the serious complications of ichthyosis-related eyelid malposition such as cicatricial ectropion, until present no single way has been standardized to treat the ectropion in these patients. MMG has been previously described, but up to our knowledge this is the first reported long term follow up of MMG offered for ichthyosis-related cicatricial ectropion. We strongly recommend MMG as a promising surgical treatment option offered for ichthyosis patients with cicatricial ectropion providing good outcome and acceptable cosmetic results.


[De novo sarcoidosis after kidney transplantation].
A 39-year-old man complained of unspecific chest pains four years after kidney transplantation. Laboratory tests revealed a slow increase of retentions values; the value of soluble IL-2 receptor was slightly elevated. Computed tomography of the chest confirmed mediastinal and bilateral hilar masses. The broncho-alveolar lavage (BAL) showed a marked increase of the CD4/CD8 T-lymphocyte ratio and the aspiration cytology of these lymphadenopathies revealed the cytopathological characteristics of sarcoidosis. An asymptomatic stage I sarcoidosis was diagnosed, and the immunosuppressive treatment with cyclosporine, mycophenolatmofetil and prednisone was retained. The patient has remained asymptomatic for now six months. When bilateral hilar / mediastinal lymphadenopathies occur after organ transplantation with immunosuppression de novo sarcoidosis should be taken into account.


Assessing the effect of pruning and thinning on crown fire hazard in young Atlantic maritime pine forests.
Management of fuel to minimize crown fire hazard is a key challenge in Atlantic forests, particularly for pine species. However, a better understanding of effectiveness of silvicultural treatments, especially forest pruning, for hazard reduction is required. Here we evaluate pruning and thinning as two essential silvicultural treatments for timber pine forests. Data came from a network of permanent plots of young maritime pine stands in northwestern Spain. Vertical profiles of canopy bulk density were estimated for field data and simulated scenarios of pruning and thinning using individual tree biomass equations. Analyses of variance were conducted to establish the influence of each silvicultural treatment on canopy fuel variables. Results confirm the important role of both pruning and thinning in the mitigation of crown fire hazard, and that the effectiveness of the treatments is related to their intensity. Finally, models to directly estimate the vertical profile of canopy bulk density (CBD) were fitted using the Weibull probability density function and usual stand variables as regressors. The models developed include variables sensitive to pruning and thinning interventions and provide useful information to prevent extreme fire behavior through effective silviculture.


A randomized trial of endoscopy vs no endoscopy in the management of seronegative Helicobacter pylori dyspepsia.
It is unclear whether endoscopy influences the management of Helicobacter pylori negative dyspepsia. To determine whether endoscopy alters health-care resource utilization, quality of life and symptom outcome in H. pylori seronegative dyspeptic patients aged under 45 years; and to determine which factors predict outcome of symptoms. One hundred and fifty-four H. pylori seronegative subjects were randomized to have an endoscopy or no endoscopy before subsequent management by their GPs. Assessment was carried out at 6 months and supplementary information obtained at 12 months. There was no significant difference between the two groups for progression of dyspeptic symptoms (better, same and worse) at 6 months (47%, 46%, 7% vs 43%, 52%, 5%), and at 12 months (55%, 34%, 11% vs 57%, 28%, 15%). Prescriptions were lower in both groups at 6 and 12 months than on entry into the study, independent of endoscopy. Endoscopy did not influence quality of life, visits to GPs and days lost from work. Prognostic factors for symptom resolution at 6 months were lower severity of initial symptoms, non-smoking, non-Caucasians, less anxious patients and those not on acid suppressants. H. pylori negative dyspeptic patients aged under 45 years without sinister symptoms could be managed without the need of an endoscopy.


Adsorption of toluene on various natural soils: Influences of soil properties, mechanisms, and model.
This study investigated toluene adsorption on natural soils. The linear partition model was found to represent the adsorption isotherm well (R2 = 0.958-0.994), compared with the Freundlich model (R2 = 0.901-0.991). Therefore, the coefficient, Kd, of the linear model indicated the adsorption capacity of soils A to F. Traditionally, Kd and the total organic carbon (TOC) content have a good linear relationship. However, this relationship was weak (correlation coefficient (r) = 0.689) when TOC values (8.43-12.9 mg/g) were low and close. To correct this deviation, this study investigated the influences of physicochemical properties, such as special surface area, mineral composition, functional groups, pH, and potentials. As soils B and C consisted of a large amount of active clayey minerals (69.4% kaolinite and 79.3% nacrite, respectively) and rich functional groups, they demonstrated the strongest adsorption capacity. Additionally, the r for pH-Kd, zeta potential-Kd, and redox potential-Kd were high, at 0.806, 0.914, and 0.932, respectively. To explore adsorption mechanisms, the adsorption thermodynamic parameter (enthalpy) was used initially to determine the forces. Combined with the analysis of soil properties, the mechanisms identified were hydrophobic interaction and hydrogen-pi bonding, involving co-adsorption with water molecules. Based on all studies, the properties were quantified and simplified by the plastic limit (PL), and TOC was simplified by soil organic matter (SOM). Then, PL and SOM were weighted by the entropy-weight method to obtain the determination factor, DF, a logarithmic parameter to replace TOC. Finally, a new model describing toluene adsorption on natural soils was established and expressed as Kd = 4.80 + 3.53DF. This new model had significantly improved the correlation between Kd and TOC (r = 0.933) and expanded the engineering adaptability.


Interaction of lactoferrin with Escherichia coli cells and correlation with antibacterial activity.
It has been established that the antimicrobial activity of lactoferrin towards Escherichia coli is enhanced by a direct contact between the protein and the microbial cell and that, in the case of E. coli K-12 strains, an antibacterial activity of lactoferrin unrelated to iron withdrawal is present. Evidence is now reported that lactoferrin binds to surface structures expressed in E. coli K-12 strains grown in either an "excess" or "stress" of iron. Under the experimental conditions used, lactoferrin binding both in the apo and in the iron-saturated form yields a maximum of 1.6 X 10(5) bound molecules/E. coli K-12 cell; the amount of lactoferrin bound does not depend on the expression of the iron-regulated outer membrane proteins. In contrast, lactoferrin does not bind to E. coli clinical isolates. Apo-lactoferrin (at 500 micrograms/ml in a chemically defined medium) inhibits the growth of E. coli K-12 strains but not of clinical isolates. These findings suggest that the antibacterial activity of the protein could be associated to its binding to the cell surface.


MatVPC: A User-Friendly MATLAB-Based Tool for the Simulation and Evaluation of Systems Pharmacology Models.
Quantitative systems pharmacology (QSP) models are progressively entering the arena of contemporary pharmacology. The efficient implementation and evaluation of complex QSP models necessitates the development of flexible computational tools that are built into QSP mainstream software. To this end, we present MatVPC, a versatile MATLAB-based tool that accommodates QSP models of any complexity level. MatVPC executes Monte Carlo simulations as well as automatic construction of visual predictive checks (VPCs) and quantified VPCs (QVPCs).


Prevalence of depression in patients with type 2 diabetes mellitus in Irish primary care and the impact of depression on the control of diabetes.
As the Irish population ages, the management of chronic conditions in primary care is emerging as a challenge. The presence of co-morbid depression is common among such patients and may affect their response to treatment. This study sought to determine whether the prevalence of depression is higher in patients with type 2 diabetes mellitus than in the population aged >50 in the West of Ireland, and whether depression is an independent predictor of diabetes control. We used a cross-sectional design to examine an anonymized database of 9,698 patients aged >50 years whose medical data were collected as part of NUI Galway's CLARITY study. Glycosylated HbA1c levels were used to estimate type 2 DM control; depression was assessed using the Hospital Anxiety and Depression Scale. We found that while there is a higher prevalence of severe depression in patients with type 2 DM, there is no association between their diabetes control and depression after controlling for age, gender, comorbidity and GMS status. Multimorbidity is a significant predictor of depression in both diabetic and non-diabetic populations, with the odds of depression increasing as the number of co-morbidities increased. Patients with type 2 DM are more likely to suffer from severe depression than those without. Depression itself is not an independent predictor of diabetes control. However, it may be that the increased rates of depression observed in patients with type 2 DM are at least partially attributable to the burden of additional illnesses seen in these patients.


Combination of obesity with hyperglycemia is a risk factor for the presence of vertebral fractures in type 2 diabetic men.
Although patients with type 2 diabetes show no bone mineral density (BMD) reduction, fracture risks are known to increase. It is unclear why the patients have an increased risk of fracture despite sufficient BMD. We investigated the relationships of body mass index (BMI), HbA(1c), and urinary C-peptide (uC-peptide) versus BMD, bone metabolic markers, serum adiponectin, and prevalent vertebral fracture (VF). A total of 163 Japanese type 2 diabetic men were consecutively recruited, and radiographic and biochemical data were collected. BMI was positively correlated with BMD at the whole body, lumbar spine, and femoral neck (P < 0.05) and negatively correlated with osteocalcin and urinary N-terminal cross-linked telopeptide of type-I collagen (uNTX) (P < 0.01). HbA(1c) was negatively correlated with osteocalcin (P < 0.01) but not BMD at any site. Subjects were classified into four groups based on BMI and HbA(1c) (group LL BMI < 24 and HbA(1c) < 9, group LH BMI < 24 and HbA(1c) > or = 9, group HL BMI > or = 24 and HbA(1c) < 9, group HH BMI > or = 24 and HbA(1c) > or = 9). Serum adiponectin, osteocalcin, and uNTX were lower and the incidence of VF was higher despite sufficient BMD in the HH group. Multivariate logistic regression analysis adjusted for age, duration of diabetes, uC-peptide, and estimated glomerular filtration rate showed that the HH group was associated with the presence of a VF and multiple VFs (odds ratio [OR] = 3.056, 95% confidence interval [CI] 1.031-9.056, P = 0.0439, and OR = 5.415, 95% CI 1.126-26.040, P = 0.0350, respectively). Combination of obesity with hyperglycemia was a risk factor for VF despite sufficient BMD in diabetic men.


Prevalence of pelvic floor dysfunction in recreational athletes: a cross-sectional survey.
Pelvic floor dysfunction (PFD) affects many women and participation in elite sport and high-impact exercise has been reported as a potential risk. However, few studies have investigated the effects of exercising at recreational levels on PFD. Our aim was to investigate levels of PFD in women exercising at, or above, UK guidelines for health and compare them with levels in non-exercisers. Data on levels of PFD and potential risk factors (age, hormonal status, body mass index, constipation, parity, forceps delivery, and recreational exercise) were collected using a cross-sectional survey distributed via social media. The International Consultation Incontinence Questionnaire (ICIQ) Urinary Incontinence Short Form was used to estimate prevalence of urinary incontinence (UI). Selected questions from the ICIQ vaginal symptom and bowel symptom questionnaires were used to estimate prevalence of anal incontinence (AI) and pelvic organ prolapse (POP). Logistic regression analysis was used to compare exercisers and non-exercisers after adjusting for potential confounders. We recruited 1,598 adult women (1,141 exercisers and 457 non-exercisers). The majority were parous. High prevalence of UI (70%), AI (52%) and POP (18%) was reported. No significant association was found between recreational exercise and PFD despite adjustment for confounders, or further investigation regarding exercise involving impact, although some increased reporting of AI was seen in those exercising for over 10 hours per week. High levels of all PFD were reported but no significant association was found between recreational exercise and symptoms. However, data suggest that women modify their exercise regimes as required. Few symptomatic women sought professional help.


Clinical outcomes of stage-IV non-small-cell lung cancer in young patients and the impact of tumor markers.
Non-Small Cell Lung Cancer (NSCLC) diagnosed at a younger age have patterns of care, responses to treatment, and outcomes not entirely clear. A particular feature includes more advanced stages at diagnosis. Our objective was to characterize these young patients with advanced disease and evaluate the impact of targeted therapies. Analyzing our cohort of 18,252 newly diagnosed NSCLC patients, we defined Young-age versus Norm-age based on the age distribution at the time of diagnosis. Stage-IV patients were investigated on their clinical information and outcomes; deaths were considered lung cancer-related. Primary outcome was overall survival (OS). Multivariate Cox models were built to evaluate independent prognostic factors in comparative age groups. We found 4,267 patients with stage-IV NSCLC (359 Young-age; 3,908 Norm-age). Young patients had predominance of females (52.6% vs. 43.3%, P = 0.001), never-smokers (43.2% vs. 14.8%, P < 0.001), and adenocarcinoma (73.5% vs. 62.5%, P < 0.001). Mean OS was 21.1 months in the Young and 15.1 months in Norm, respectively (P < 0.001). Young patients were more often treated with surgery (6.7% vs. 5.0%), chemotherapy (53.2% vs. 44.1%), and targeted therapy (10.6% vs. 5.7%). Molecular studies were assessed in patients when the mutation tests became clinically available (93 Young, 875 Norm) and revealed a critical role of targeted therapy in the improved survival of both age groups. Young patients with stage-IV NSCLC have a specific profile and benefit more when treated with surgery and targeted therapy. Molecular testing is critical in this population, where improved survival was identified. A more aggressive approach to this population needs to be considered.


EEG mapping for surgery of epilepsy.
This report describes the objectives, problems, and current techniques associated with using EEG maps in the management of surgery of epilepsy. The purpose of EEG mapping in epilepsy is to precisely identify and characterize epileptogenic zones of the brain. Such zones may be single or multiple, pointlike or diffuse, and may be near or distant from the recording electrodes. The resulting measured electric fields are used to obtain information which, when analyzed in light of all the complementary clinical information, can frequently help to localize and describe the epileptic foci with more precision.


A 1,8-naphthimide-based Fluorescent Probe for Analyzing DMF/H2O Composition.
A novel 1,8-naphthalimide fluorescent probe (BNAS) containing 2-thiopheneethylamine moiety was designed and synthesized for analyzing the composition of N,N-dimethylformamide (DMF)/deionized water (H2O) mixtures. With the increase of DMF content, the fluorescence of the system was enhanced from dark to bright yellow-green. Taking 15% (volume) DMF content as the dividing point, the fluorescence intensity of the system at 535 nm showed two good linear relationships with the DMF content 1-15% and 15-99%, based on which the composition of the DMF/H2O mixtures with a volume ratio of 1/99-99/1 could be quickly and efficiently analyzed with high selectivity and sensitivity. BNAS can be applied in real sample assay and further be loaded onto filter paper to make a portable sensor. The mechanism of BNAS response to DMF/H2O composition was also explored.


Comparison of tobramycin pharmacokinetics after administration by CRIS and a traditional intravenous piggyback infusion.
To compare the administration pharmacokinetics of a 30-minute intravenous piggyback (ivpb) infusion of tobramycin with those of controlled-release infusion system (CRIS) using a 20-mL vial at rates of 60 and 120 mL/h. Randomized, controlled, crossover, prospective, open-label trial. Medical college-affiliated hospital. Eight healthy volunteer men between the ages of 22 and 24 years weighing between 60 and 90 kg. Volunteers received, in random order, tobramycin sulfate 2 mg/kg i.v. on 3 occasions separated by 1 week. The drug was administered using a 50-mL ivpb infusion at 100 mL/h for 30 minutes, and with the CRIS using a 20-mL vial with flow rates of 60 mL/h for 1 hour (slow) and 120 mL/h for 1 hour (fast). Primary endpoints were area under the time-concentration curve (AUC), time to reach maximum concentration (tmax), and maximum concentration (Cmax). Secondary endpoints were elimination rate constant (ke), clearance (Cl), and half-life (t1/2). Six volunteers successfully completed the trial. The tmax values observed following fast CRIS and ivpb were 28 +/- 8 and 32 +/- 4 minutes, respectively, and not significantly different from each other. Both occurred significantly earlier than the tmax associated with slow CRIS (44 +/- 7 min). The Cmax values observed following ivpb (11.2 +/- 1.5 mg/L) and slow CRIS (10.9 +/- 0.9 mg/L) administration were not significantly different from each other, but both were significantly lower than that of fast CRIS (13.4 +/- 1.5 mg/L). The AUCs of slow and fast CRIS were 29.8 +/- 4.8 and 31.2 +/- 3.8 mg/L.h, respectively, and were not significantly different from each other. The AUC of fast CRIS was significantly greater than that observed with ivpb (27.4 +/- 4.3 mg/L.h). No significant difference in ke (fast CRIS 0.32 +/- 0.03 h-1; slow CRIS 0.33 +/- 0.04 h-1; ivpb 0.34 +/- 0.0 h-1) was observed among any of the methods. CRIS administration of tobramycin resulted in higher AUCs than did ivpb administration. Compared with ivpb, fast CRIS resulted in a higher Cmax, but the tmax values of fast CRIS and ivpb administration were not statistically different. Compared with ivpb, slow CRIS resulted in a more delayed tmax, but the Cmax values of slow CRIS and ivpb were not statistically different.


Complete amino acid sequence of bovine colostrum low-Mr cysteine proteinase inhibitor.
The complete amino acid sequence of bovine colostrum cysteine proteinase inhibitor was determined by sequencing native inhibitor and peptides obtained by cyanogen bromide degradation, Achromobacter lysylendopeptidase digestion and partial acid hydrolysis of reduced and S-carboxymethylated protein. Achromobacter peptidase digestion was successfully used to isolate two disulfide-containing peptides. The inhibitor consists of 112 amino acids with an Mr of 12787. Two disulfide bonds were established between Cys 66 and Cys 77 and between Cys 90 and Cys 110. A high degree of homology in the sequence was found between the colostrum inhibitor and human gamma-trace, human salivary acidic protein and chicken egg-white cystatin.


A new method for long-term home monitoring of fetal movement by pregnant women themselves.
Fetal movement is one index of fetal well-being. We designed and built a new recorder based on fetal movement acceleration measurement (FMAM). The FMAM recorder has a newly developed, capacitive acceleration sensor that can detect the oscillations of the maternal abdominal wall caused by fetal movements. In this study, the recorder was examined for its suitability for long-term home monitoring of fetal movement by pregnant women themselves. Experiment I: Fourteen pregnant women underwent 45 examinations in the laboratory at gestational 20-39 weeks. We simultaneously recorded fetal movement as detected by the recorder, ultrasonography, and maternal perception, and then calculated agreement among the three methods. We evaluated agreement using prevalence-adjusted bias-adjusted kappa (PABAK). Agreement for gross fetal movement as detected by FMAM and ultrasonography was substantial or almost perfect, while agreement between maternal perception and ultrasonography was moderate or substantial. Experiment II: Six pregnant women undertook 53 experiments at home by themselves. Fetal movement during maternal nocturnal sleep was successfully recorded 50 out of 53 times at home. In conclusion, there was high agreement for gross fetal movement between FMAM and ultrasonography. The recorder is promising for objective, accurate, and long-term home monitoring of gross fetal movement by pregnant women themselves.


Functional interactions of cytoplasmic domains of the skeletal muscle Ca2+ release channel.
The skeletal muscle Ca(2+) release channel (RYR1) is a homotetramer with subunits of 565 kD. Although the channel part of this protein is probably formed by the C-terminal one fifth of the protein, most of the regulation of channel activity is likely to arise from intermolecular and intramolecular interactions of its large cytoplasmic domain. This cytoplasmic region of the protein is thought to contain binding sites for a variety of modulators, including the t-tubule voltage sensor, and mutations in some cases of malignant hyperthermia and central core disease. Regulation of channel activity must, therefore, involve long-distance allosteric modulation arising from changes in both intersubunit and intrasubunit interactions within the cytoplasmic domain of the RYR1 tetramer. Biochemical studies are beginning to elucidate some of the sites within the cytoplasmic domains important for modulting channel activity in the membrane-spanning domain. This review summarizes these findings and presents a working model for the regulation of the channel by the interactions of its cytoplasmic domains.


Protecting and respecting the vulnerable: existing regulations or further protections?
Scholars and policymakers continue to struggle over the meaning of the word "vulnerable" in the context of research ethics. One major reason for the stymied discussions regarding vulnerable populations is that there is no clear distinction between accounts of research vulnerabilities that exist for certain populations and discussions of research vulnerabilities that require special regulations in the context of research ethics policies. I suggest an analytic process by which to ascertain whether particular vulnerable populations should be contenders for additional regulatory protections. I apply this process to two vulnerable populations: the cognitively vulnerable and the economically vulnerable. I conclude that a subset of the cognitively vulnerable require extra protections while the economically vulnerable should be protected by implementing existing regulations more appropriately and rigorously. Unless or until the informed consent process is more adequately implemented and the distributive justice requirement of the Belmont Report is emphasized and operationalized, the economically disadvantaged will remain particularly vulnerable to the harm of exploitation in research.


Cystic Fibrosis-related cirrhosis.
While liver involvement is common in cystic fibrosis, the major liver disorder with impact on the clinical outcome of individuals with CF is the development of multilobular cirrhosis with progression to portal hypertension. Interestingly, this is a disorder primarily of children and adolescents. We review the proposed pathogenesis, clinical presentation, diagnostic work-up, medical and surgical management, and complications of CF cirrhosis.


Perfusion assessed by real-time contrast echocardiography correlates with clinical and echocardiographic parameters in patients with first STEMI treated with PCI - 6-month follow-up.
Angiographic flow in an epicardial artery does not define perfusion at a microvascular level in patients with acute myocardial infarction (AMI). The aim of the study was assessing microvascular reperfusion by myocardial contrast echocardiography (MCE) and left ventricular (LV) functional recovery by echocardiographic methods in patients treated with primary PTCA. 100 consecutive patients with first ST-elevation AMI with single vessel disease treated successfully with primary PCI were enrolled. Regional contrast score index (RCSI), ejection fraction (EF), wall motion score index (WMSI), and end-systolic and end-diastolic volume (ESV, EDV) were evaluated during hospitalization and at 6-month follow-up. The patients were divided into 2 groups according to the absence (Group 1) or presence (Group 2) of perfusion defects on MCE. Group 1 had lower WMSI (p = 0.0009), higher EF than Group 2 (44.7 and 55.9% respectively, p = 0.000067), and lower ESV (66.0 and 52.6 ml respectively, p = 0.003185). In Group 1 LVEF increased significantly on 6-month follow-up (p = 0.026), while in Group 2 it decreased (p = 0.0175). Both EDV and ESV were significantly lower in Group 1 (p = 0.0106 and p = 0.002882, respectively). There was a correlation between the presence of perfusion defects in the initial contrast echo and unfavourable change in ejection fraction during the follow-up (ANOVA for repeated measures, F[1.91] = 5.85, p = 0.0175). The combined clinical end-point (death and reinfarction) was significantly lower in patients without perfusion defect (p = 0.039). Myocardial contrast echocardiography results correlated with clinical outcome and recovery of systolic left ventricular function at 6-month follow-up.


Super-refractory status epilepticus: an approach to therapy in this difficult clinical situation.
Super-refractory status epilepticus (SE) is a stage of refractory SE characterized by unresponsiveness to initial anesthetic therapy. It is a new concept that has been the focus of recent basic and therapeutic work, and is defined as "SE that continues or recurs 24 hours or more after the onset of anesthesia, including those cases in which SE recurs on the reduction or withdrawl of anesthesia." It is encountered typically, but not exclusively, in two quite distinctive clinical situations: (1) in patients with severe acute brain injury, and (2) in patients with no history of epilepsy in whom status epilepticus develops out of the blue with no overt cause. There are a variety of treatments used, almost entirely based on open observational studies or case reports. Therapy includes anesthesia, antiepileptic drug therapy, hypothermia and ICU therapy, other medical, immunological, and physical therapies. In this review, the range of possible therapies is outlined and an approach to therapy is discussed.


Projected benefits of universal or scheduled antepartum corticosteroids to prevent neonatal morbidity: a decision analysis.
The purpose of this study was to compare strategies of corticosteroid administration for the prevention of neonatal morbidity and death. A Markov decision model compared 3 strategies of antepartum corticosteroid administration: (1) to all pregnant women (universal), (2) to all pregnant women with a previous preterm delivery (high risk), and (3) to women who had preterm labor symptoms that placed them at risk for delivery within 7 days (current). A second model with addition of a "rescue" arm to capture women who remained undelivered was also created. Compared with the current strategy, the universal strategy would result in roughly 1000 fewer cases of respiratory distress syndrome and > 3 million more women would receive corticosteroids annually. The addition of a rescue arm further reduces morbidity and mortality rates. A universal strategy of corticosteroid administration confers potential benefit for the prevention neonatal morbidity or death over the current strategy but requires that a large number of women be treated.


Predictors of high functional capacity and mortality in elderly Finnish men.
Factors predicting high functional capacity in old age and 25-year mortality were studied in 1711 men aged 40 to 59 years. The study population was that of the East-West Study, i.e. the Finnish part of the Seven Countries Study. After the 25-year follow-up (in 1984) 766 men were still alive. Nonsmoking and good pulmonary function in earlier middle-age and the absence of coronary heart disease, cerebrovascular disease or emphysema in later middle-age predicted high functional capacity in old age. High systolic blood pressure, low forced vital capacity, smoking, and the presence of coronary heart disease predicted mortality in the next 10 to 25 years. Although mortality rates were higher in eastern Finland, the predictors were similar in both the eastern and the southwestern parts of the country.


Geographic tracing of cereals from South Tyrol (Italy) and neighboring regions via 87Sr/86Sr isotope analysis.
The protection and promotion of agricultural niche products can be supported by the application of analytical techniques able to link food to its territory. This study aimed at exploring the possibility to discriminate between cereal samples from South Tyrol (Italy) and the neighboring regions (Trentino, East Tyrol, and North Tyrol) by their 87Sr/86Sr ratios. Soil and grain (different species) samples were collected from around 100 fields in two sampling campaigns. No difference in the 87Sr/86Sr ratios among different cereal species (p < 0.05) was found when cultivated on the same field. A high correlation between 87Sr/86Sr ratios in cereal grains and soil samples was found, with results in line with the local geology characteristics. Cereal samples from South Tyrol showed relatively high 87Sr/86Sr values (0.716 - 0.721, mean 50%), separating them from the other regions investigated and many cereal production areas of global importance.


Hemarthrosis and synovitis associated with hemophilia: clinical use of P-32 chromic phosphate synoviorthesis for treatment.
To evaluate the clinical usefulness of phosphorus-32 chromic phosphate synoviorthesis in patients with hemophilia, recurrent hemarthrosis, and synovitis. Forty-four P-32 colloid synoviorthesis procedures were performed in 38 patients with these abnormalities. P-32 colloid was injected intramuscularly in a dose of 1.0 mCi (37.0 MBq) in adult knees and 0.5 mCi (18.5 MBq) in adult elbows. A thin-window Geiger-Müller counter was used to survey treated joints, lymph nodes, and liver in order to detect leakage from the joint. Follow-up extended to a maximum of 4 years after treatment. No evidence of clinically significant leakage was seen. Twenty-two of 28 treatments (78%) with longer than 6 months follow-up were associated with improvement in range of motion and frequency of hemorrhage. Of 15 treatments with longer than 2 years follow-up, 10 (67%) were associated with improvement in range of motion; 12 (80%), with improvement in frequency of hemorrhage; and 12 (80%) with improvement in quality-of-life activities. P-32 colloid synoviorthesis is a clinically useful out-patient procedure in patients with hemophilia, recurrent hemarthrosis, and synovitis in whom hemostatic therapy has failed.


The early negative bias of social semantics: evidence from behavioral and ERP studies.
Compared to nonsocial information, the human brain is more highly sensitive to social information. As a kind of typical social semantic information, the words describing person traits differ from the nonsocial semantic information describing inanimate objects in many ways. It remains to be seen whether the processing of trait words has a valence asymmetric and whether it differs from the processing of nonsocial semantic information in terms of behavioral responses and neural temporal processes. Taking person and object names as priming stimuli and adjective words only used for describing humans or objects as target stimuli, the present study aimed to investigate the processing characteristics of social and nonsocial semantic information by recording both behavioral and ERP data. Behavioral results showed that the response times for negative words were significantly slower than those for positive words whether for social or nonsocial semantic information. The accuracy rates of negative words were significantly lower than those of positive words when the targets were social words which is contrary to the nonsocial words. The ERP results indicated that there was a negative bias effect on the processing of both types of information during the whole time course of brain neural activity; that is, the P2, N400, and LPP amplitudes elicited by negative words were larger than those elicited by positive words; However, the negative bias effect of social semantic information started at the early perceptual stage which was significantly earlier than the onset of negative bias of nonsocial semantic information, and was significantly affected by the prime type. In addition, there was a significant semantic conflict N400 effect only for nonsocial semantic information. Overall, the present study revealed the existence of an early negative bias of social information and provided evidence for the specificity of social information.


Age-specific behavioral responses to psychostimulants in mice.
This study investigated the influence of age on the behavioral responses elicited by psychostimulants in male CD-1 mice. Behavioral activity including locomotion and stereotypy was measured following acute or repeated administration of cocaine, methylphenidate, amphetamine or saline to postweanling (24 days old), periadolescent (33 days old) and adult (60 days old) mice. Postweanling mice exhibited less total and ambulatory activity than periadolescent mice following a single acute injection of cocaine (20 or 30 and 30 mg/kg, respectively). Further, postweanling mice showed less total activity than both periadolescent and adult mice at a dose of 10 mg/kg methylphenidate. Less stereotypy was also seen in postweanling mice when compared to adolescent mice after 30 mg/kg amphetamine. Seven daily injections of cocaine resulted in a heightened behavioral response on day 7 as compared to day 1, indicative of behavioral sensitization in adult and periadolescent, but not postweanling mice. Repeated methylphenidate resulted in increased total activity in adult, but not periadolescent or postweanling mice. None of the animals were sensitized to the behavioral activating effects of amphetamine. The magnitude of behavioral response and the development of sensitization were dependent upon the age of the animal and the agent tested.


Long-term outcome of cases of fetal pleural effusion: A study at a single perinatal center in Japan.
To analyze the long-term prognosis of primary and secondary fetal pleural effusion (FPE). We investigated all cases of FPE in a single University hospital (2005-2020). Cases were classified as primary (cases with only pleural effusion) and secondary (cases with other abnormalities such as chromosomal abnormalities or fetal cardiac failure). We retrospectively reviewed the medical records from the time of diagnosis, to assess medical procedures performed, chromosomal test results, and clinical outcomes. Among 18 027 deliveries, 17 FPEs were identified (primary FPE: 8, secondary FPE: 9). Most primary FPEs were diagnosed in the second trimester of pregnancy, while all secondary FPEs were diagnosed in the third trimester. Secondary FPE was often associated with chromosomal abnormalities, including trisomy 21. The prognosis of pleural effusion caused by trisomy 21 was relatively good, except for cases with TAM. Cases of secondary FPE without trisomy 21 were of cardiac origin, and the neonatal prognosis was poor. The short-term prognosis was better in the primary FPE group, but long-term follow-up identified conditions such as acute encephalitis with refractory, repetitive partial seizures, developmental delay and attention deficit hyperactivity disorder. Fetal pleural effusion without the presence of chromosomal abnormalities or morphologies has a good short-term prognosis, but the long-term prognosis is poor. Thus, long-term follow-up is necessary for all cases of fetal pleural effusion.


Learning to Inhabit the Forest: Autonomy and Interdependence of Lives from a Mbya-Guarani Perspective.
This chapter examines the ideas of reciprocity, respect, autonomy, and interdependence of lives and the impact of these on children's learning. Using an ecological perspective that recognizes humans' relationship with other living beings that inhabit the forest, this chapter is based on ethnographic research conducted in two Mbya-Guarani communities (Argentina). Respect and reciprocity are key for children to develop as part of the community and the forest and they are related to children's well-being and health. I describe Mbya perspectives on children's growth and development, emphasizing the balance between interdependence and autonomy as complementary goals and values, providing examples of environmentally relevant skills to grow up in the forest. These skills are associated with particular ways of inhabiting the forest, including learning how to walk in it and developing entendimiento (understanding). These make possible children's integration in community life through their participation and collaboration in daily activities. I attempt to articulate these ideas with the theoretical framework of Learning by Observing and Pitching In, especially concerning ways of organizing and supporting children's learning processes in the context of their engagement with multiaged and more experienced group of people.


Role of tactic response on the mobilization of motile bacteria through micrometer-sized pores.
A major cause of high bioremediation endpoints is the limited bioaccessibility to residual contaminants resting in soil pores with diameters close to the size exclusion limit of bacterial cells. Under nongrowing conditions and in the absence of hydraulic flow, we examined how the tactic behavior of motile, contaminant-degrading Pseudomonas putida G7 cells (2 × 1 μm) influenced passage through membranes with pores ranging in size from 1 μm to 12 μm. The bacteria were spontaneously retained by the membranes - even those with the largest pore size. However, the cells were mobilized through 5 μm and 12 μm pores after the application of an attractant (salicylate). Mobilization also occurred by attraction to the common root exudate constituents γ-aminobutyric acid and citrate and repellence (or negative taxis) to zero-valent iron nanoparticles. The observed pore size threshold for tactic mobilization (5 μm) and unaltered cell fluxes and effective cell diffusion against different chemoeffector strengths and concentrations suggest that there is a physical constraint on the gradient sensing mechanism at the pores that drives the tactic response. Our results indicate that chemically mediated, small-scale tactic reactions of motile bacteria may become relevant to enhance the bioaccessibility of the residual contaminants present in micrometer-sized soil pores.


Commentary: death certificate reporting needs to be fixed.
Something is wrong with the death reporting when there is a fivefold difference in the reported rates of fall mortality between Alabama and Vermont, two states in the United States. The problem is not unique here, as even the Swedish have trouble with their death certificate data. We understand that some of the reason is poor reporting, but how do we figure out how to do it right?


Syringe-dispensed omega-3 lipid injectable emulsions should be stored under airtight refrigeration: A proposal for the efficient supply of unapproved precious lipid resources.
Both fish-oil lipid injectable emulsion (FO-ILE) and mixed-oil lipid injectable emulsion (MO-ILE) are key components of parenteral nutrition and require importation into Japan, and they are easily oxidized after opening. Given the small daily volumes of these lipids dispensed in infants and children with intestinal failure (IF), the purpose of the study was to identify the optimal storage method. Lipids were prepared in polypropylene syringes in the following manner: air-sealing and photoprotection, air-sealing only, photoprotection only, and uncovered. Samples were stored for 14 days at 4°C or 26°C. The degree of oxidative degradation was evaluated by measuring malondialdehyde (MDA) concentration and pH and comparing them to the values measured immediately after opening. For FO-ILE, the increase in MDA concentration for 14 days was insignificant in air-sealed samples, regardless of photoprotection (+0.45 μM, P = 1.0) or no photoprotection (+0.52 μM, P = 1.0). This trend was more pronounced at 4°C than at 26°C (P < 0.01). The maximum pH decrease was 0.08 at 4°C. MO-ILE exhibited an insignificant increase in MDA concentration for 14 days with air-sealed samples, regardless of photoprotection (+0.36 μM, P = 0.11) or no photoprotection (+0.33 μM, P = 0.76). This trend was more pronounced at 4°C than at 26°C (P < 0.01). The maximum pH decrease was 0.12 at 4°C. For soybean-oil lipid injectable emulsion, the trend was similar with no considerable deterioration. Syringe-dispensed FO-ILE and MO-ILE stored under airtight refrigeration remained undeteriorated for 14 days. Our results are considered clinically valuable when supplying these expensive resources for infants with IF.


The gnotobiotic brine shrimp (Artemia franciscana) model system reveals that the phenolic compound pyrogallol protects against infection through its prooxidant activity.
The phenolic compound pyrogallol is the functional unit of many polyphenols and currently there has been a growing interest in using this compound in human and animal health owing to its health-promoting effects. The biological actions of pyrogallol moiety (and polyphenols) in inducing health benefitting effects have been studied; however, the mechanisms of action remain unclear yet. Here, we aimed at unravelling the underlying mechanism of action behind the protective effects of pyrogallol against bacterial infection by using the gnotobiotically-cultured brine shrimp Artemia franciscana and pathogenic bacteria Vibrio harveyi as host-pathogen model system. The gnotobiotic test system represents an exceptional system for carrying out such studies because it eliminates any possible interference of microbial communities (naturally present in the experimental system) in mechanistic studies and furthermore facilitates the interpretation of the results in terms of a cause effect relationship. We provided clear evidences suggesting that pyrogallol pretreament, at an optimum concentration, induced protective effects in the brine shrimp against V. harveyi infection. By pretreating brine shrimp with pyrogallol in the presence or absence of an antioxidant enzyme mixture (catalase and superoxide dismutase), we showed that the Vibrio-protective effect of the compound was caused by its prooxidant action (e.g. generation of hydrogen peroxide, H2O2). We showed further that generation of prooxidant is linked to the induction of heat shock protein Hsp70, which is involved in eliciting the prophenoloxidase and transglutaminase immune responses. The ability of pyrogallol to induce protective immunity makes it a potential natural protective agent that might be a potential preventive modality for different host-pathogen systems.


Supercooling Pretreatment Improves the Shelf-Life of Freeze-Dried Leuconostoc mesenteroides WiKim32.
Storage stability of freeze-dried lactic acid bacteria is a critical factor for their cost-effectiveness. Long-term storage of lactic acid bacteria enables microbial industry to reduce distribution costs. Herein, we investigated the effect of cold adaptation under supercooling conditions at -5°C on the viability of Leuconostoc mesenteroides WiKim32 during the freeze-drying process and subsequent storage. Cold adaptation increased the thickness of exopolysaccharides (EPS) and improved the viability of freeze-dried Leu. mesenteroides WiKim32. Compared to non-adapted cells, cold-adapted cells showed a 35.4% increase in EPS thickness under supercooling conditions. The viability of EPS-hydrolyzed cells was lower than that of untreated cells, implying that EPS plays a role in protection during the freeze-drying process. Cold adaptation increased the storage stability of freeze-dried Leu. mesenteroides WiKim32. Fifty-six days after storage, the highest viability (71.3%) was achieved with cold adaptation at -5°C. When EPS-containing broth was added prior to the freeze-drying process, the viability further increased to 82.7%. These results imply that cold adaptation by supercooling pretreatment would be a good strategy for the long-term storage of Leu. mesenteroides WiKim32.


Comparative efficacy of ramosetron and ondansetron in preventing postoperative nausea and vomiting: An updated systematic review and meta-analysis with trial sequential analysis.
Postoperative nausea and vomiting is a distressing complication of surgery, and 5-HT3 receptor antagonists are often prescribed to prevent it. Ondansetron is the agent typically administered to prevent postoperative nausea and vomiting. Although ramosetron has a longer duration of action than ondansetron, it remains unclear whether ramosetron is the more effective medication. We performed an updated meta-analysis on the comparative efficacy of ramosetron and ondansetron in preventing postoperative nausea and vomiting. We searched six databases for all trials that randomly assigned patients to ramosetron or ondansetron groups. The primary outcome was postoperative nausea or vomiting in the early, late, and next-day periods. The secondary outcomes were side effects of the medications. We used the random-effects model to combine the results. Trial sequential analyses were performed to correct for repetitive testing in the updated meta-analysis. Twenty-seven randomized controlled trials with 3,811 patients were included in the meta-analysis. The combined results of ramosetron vs. ondansetron efficacy in preventing postoperative nausea and vomiting were as follows: Risk ratio [95% confidence interval] = 0.82 [0.69-0.98] for early postoperative nausea, 0.76 [0.65-0.89] for late postoperative nausea, 0.69 [0.57-0.84] for next-day postoperative nausea, 0.78 [0.63-0.98] for early postoperative vomiting, 0.57 [0.45-0.72] for late postoperative vomiting, and 0.61 [0.43-0.86] for next-day postoperative vomiting. Dizziness was significantly lower in ramosetron groups than in ondansetron groups (risk ratio [95% confidence interval] = 0.81 [0.66-0.98]). Trial sequential analysis revealed that the results for late postoperative nausea, late postoperative vomiting, and next-day postoperative nausea were conclusive. Ramosetron is more effective in preventing late postoperative nausea, late postoperative vomiting, and next-day postoperative nausea than ondansetron. The incidence of dizziness may be lower in patients receiving ramosetron than in patients receiving ondansetron. University hospital Medical Information Network Clinical Trials Registry: UMIN000022980.


Bivariate Metal-Organic Frameworks with Tunable Spin-Crossover Properties.
In this work, pyrazine (A), aminopyrazine (B), quinoxaline (C), and 5,6,7,8-tetrahydroquinoxaline (D) have been screened out among a large number of pyrazine derivatives to construct Hofmann-type metal-organic frameworks (MOFs) Fe(L)[M(CN)4 ] (M=Pt, Pd) with similar 3D pillared-layer structures. X-ray single-crystal diffraction reveals that the alternate linkage between M and FeII ions through cyano bridges forms the 2D extended metal cyanide sheets, and ligands A-D acted as vertical columns to connect the 2D sheets to give 3D pillared-layer structures. Subsequently, a series of bivariate MOFs were constructed by pairwise combination of the four ligands A-D, which were confirmed by 1 H NMR, PXRD, FTIR, and Raman spectroscopy. The results demonstrated that ligand size and crystallization rate play a dominant role in constructing bivariate Hofmann-type MOFs. More importantly, the spin-crossover (SCO) properties of the bivariate MOFs can be finely tuned by adjusting the proportion of the two pillared ligands in the 3D Hofmann-type structures. Remarkably, the spin transition temperatures, Tc ↑ and Tc ↓ of Fe(A)x (B)1-x [Pt(CN)4 ] (x=0 to 1) can be adjusted from 239 to 254 K and from 248 to 284 K, respectively. Meanwhile, the width of the hysteresis loops can be widened from 9 to 30 K. Changing Pt to Pd, the hysteresis loops of Fe(A)x (B)1-x [Pd(CN)4 ] can be tuned from 9 (Tc ↑=215 K, Tc ↓=206 K) to 24 K (Tc ↑=300 K, Tc ↓=276 K). This research provides wider implications in the development of advanced bistable materials, especially in precisely regulating SCO properties.


The origins of radical mastectomy.
William halsted is the 19th century surgeon whose name is most frequently associated with the radical mastectomy procedure; however, this type of surgery actually has been performed since the 16th century. The development of radical mastectomy was a long process, and many surgeons over time have contributed valuable insights and alterations to this fundamental treatment for breast cancer. This procedure may be most commonly associated with Halsted because he promoted a meticulous operative technique, synthesized the best points in the techniques suggested by the most famous surgeons of the 19th century, and provided a scientific basis for the performance of radical mastectomy.


Clinical, neuroimaging, and behavioural risk factors for neurocognitive impairment in Chinese patients with haemophilia: A multicentre study.
Few studies have evaluated the impact of subclinical microstructural changes and psychosocial factors on cognitive function in patients with haemophilia. To determine the prevalence and characteristics of cognitive impairment in patients with haemophilia, and identify associated risk factors. We recruited haemophilia A or B patients who were aged ≥10 years old from three public hospitals in Hong Kong. A neurocognitive battery was administered to evaluate their attention, memory, processing speed and cognitive flexibility performances. They also underwent magnetic resonance imaging to identify cerebral microbleeds. Validated self-reported questionnaires were administered to assess their mental health status and adherence to prophylactic treatment. General linear modelling was used to investigate the association of neurocognitive outcomes with risks factors, adjusting for age and education attainment. Forty-two patients were recruited (median age 32.0 years; 78.6% haemophilia A; 80.9% moderate-to-severe disease). Six patients (14.3%) had developed cerebral microbleeds. A subgroup of patients demonstrated impairments in cognitive flexibility (30.9%) and motor processing speed (26.2%). Hemarthrosis in the previous year was associated with worse attention (Estimate = 7.62, 95% CI: 1.92-15.33; p = .049) and cognitive flexibility (Estimate = 8.64, 95% CI: 2.52-13.29; p = .043). Depressive (Estimate = 0.22, 95% CI: 0.10-0.55; p = .023) and anxiety (Estimate = 0.26, 95% CI: 0.19-0.41; p = .0069) symptoms were associated with inattentiveness. Among patients receiving prophylactic treatment (71.4%), medication adherence was positively correlated with cognitive flexibility (p = .037). A substantial proportion of patients with haemophilia demonstrated cognitive impairment, particularly higher-order thinking skills. Screening for cognitive deficits should be incorporated into routine care. Future studies should evaluate the association of neurocognitive outcomes with occupational/vocational outcomes.


Preserved antibacterial activity of ribosomal protein S15 during evolution.
Conventional role of ribosomal proteins is ribosome assembly and protein translation, but some ribosomal proteins also show antimicrobial peptide (AMP) activity, though their mode of action remains ill-defined. Here we demonstrated for the first time that amphioxus RPS15, BjRPS15, was a previously uncharacterized AMP, which was not only capable of identifying Gram-negative and -positive bacteria via interaction with LPS and LTA but also capable of killing the bacteria. We also showed that both the sequence and 3D structure of RPS15 and its prokaryotic homologs were highly conserved, suggesting its antibacterial activity is universal across widely separated taxa. Actually this was supported by the facts that the residues positioned at 45-67 formed the core region for the antimicrobial activity of BjRPS15, and its prokaryotic counterparts, including Nitrospirae RPS1933-55, Aquificae RPS1933-55 and P. syringae RPS1950-72, similarly displayed antibacterial activities. BjRPS15 functioned by both interaction with bacterial surface via LPS and LTA and membrane depolarization as well as induction of intracellular ROS. Moreover, we showed that RPS15 existed extracellularly in amphioxus, shrimp, zebrafish and mice, hinting it may play a critical role in systematic immunity in different animals. In addition, we found that neither BjRPS15 nor its truncated form BjRPS1545-67 were toxic to mammalian cells, making them promising lead molecules for the design of novel AMPs against bacteria. Collectively, these indicate that RPS15 is a new member of AMP with ancient origin and high conservation throughout evolution.


Press Releases of Drug-Related Randomized Trial Results Prior to Publication in High-Impact Journals: an Observational Study.
Results from high-profile randomized controlled trials (RCTs) are routinely reported through press release months prior to peer-reviewed publication. There are potential benefits to press releases (e.g., knowledge dissemination, ensuring regulatory compliance), but also potential drawbacks (e.g., selective reporting, positive "spin"). To characterize the practice of press release predating the publication of a drug-related RCT in a peer-reviewed journal ("preemptive press release"), including factors associated with this practice. We systematically reviewed all RCTs of medications published between 2015 and 2019 in the New England Journal of Medicine (NEJM), Journal of the American Medical Association (JAMA), and Lancet. Press releases were identified using a systematic search of the grey literature (e.g., press release databases, study sponsor websites). An RCT was considered to have a preemptive press release if the press release was published at least three months (90 days) prior to the date of publication in a peer-reviewed journal. Presence of preemptive press release, defined as a press-release at least 90 days prior to the date of publication in a peer-reviewed journal. As secondary measures for dissemination, we also assessed citation count and Altmetric score. We identified 988 RCTs, of which 172 (17%) had a press release published at least 90 days before the date of peer-reviewed publication. Press releases were published a median of 246 days (interquartile range [IQR] 169-366 days) before publication in a peer-reviewed journal. In the multivariable logistic regression model, the strongest predictor of having a preemptive press release was funding by a pharmaceutical company (odds ratio 13, 95% CI 7, 25). Approximately 85% of RCTs with preemptive press releases had a positive primary outcome and, concordantly, 81% of the corresponding press releases had a positive headline. Multivariable regression models identified studies with a preemptive press release had a similar Altmetric score (median - 15, 95% CI - 33, 12) and higher median citation count (median 22 [95% CI 10 to 33] compared to studies without a preemptive press release. Preemptive press releases were common, most often issued for trials funded by a pharmaceutical company, and typically preceded publication in a peer-reviewed journal by approximately eight months.


[Not Available].
Following an experiment feeding Deoxynivalenol to growing pigs histological studies have been carried out to evaluate tissue damaging effects of DON. Pigs were fed with naturally contaminated wheat containing 4000 and 6000 µg DON/kg feed. A number of two animals was chosen from control and high exposed group, respectively. Samples of the gastrointestinal tract, liver and kidney were examined. Although, clear effects in feed consumption and weight gain could be realized, only one animal from the high exposed group showed focal alterations in tissues of the gastrointestinal tract.


Fusarium toxins in cereals grown in Switzerland.
770 cereal samples of Swiss origin which were collected in various feed mills and cereal collection centres in the years 2000 - 2002 were assayed for Deoxynivalenol (DON) and zearalenone (ZEA). 137 samples were also assayed for T-2 toxin. The prevalence of DON and ZEA contamination was higher in cereals harvested in the rainy summer 2002 than in the previous years. T-2 toxin levels exceeding 100 µg/kg were found only in three oats samples. High levels ofFusarium toxins do not frequently occur in Swiss cereals.


Development of a Risk Assessment Model for Early Grade ≥ 3 Infection During the First 3 Months in Patients Newly Diagnosed With Multiple Myeloma Based on a Multicenter, Real-World Analysis in China.
The study aimed to assess factors associated with early infection and identify patients at high risk of developing infection in multiple myeloma. The study retrospectively analyzed patients with MM seen at two medical centers between January 2013 and June 2019. One medical center reported 745 cases, of which 540 of the cases were available for analysis and were further subdivided into training cohort and internal validation cohort. 169 cases from the other medical center served as an external validation cohort. The least absolute shrinkage and selection operator (Lasso) regression model was used for data dimension reduction, feature selection, and model building. Bacteria and the respiratory tract were the most common pathogen and localization of infection, respectively. In the training cohort, PS≥2, HGB<35g/L of the lower limit of normal range, β2MG≥6.0mg/L, and GLB≥2.1 times the upper limit of normal range were identified as factors associated with early grade ≥ 3 infections by Lasso regression. An infection risk model of MM (IRMM) was established to define high-, moderate- and low-risk groups, which showed significantly different rates of infection in the training cohort (46.5% vs. 22.1% vs. 8.8%, p<0.0001), internal validation cohort (37.9% vs. 24.1% vs. 13.0%, p=0.009) and external validation cohort (40.0% vs. 29.2% vs. 8.5%, p=0.0003). IRMM displayed good calibration (p<0.05) and discrimination with AUC values of 0.76, 0.67 and 0.71 in the three cohorts, respectively. Furthermore, IRMM still showed good classification ability in immunomodulatory (IMiD) based regimens, proteasome-inhibitors (PI) based regimens and combined IMiD and PI regimens. In this study, we determined risk factors for early grade ≥ 3 infection and established a predictive model to help clinicians identify MM patients with high-risk infection.