Plasma Cytokine Levels in Fibromyalgia and Their Response to 15 Weeks of Progressive Resistance Exercise or Relaxation Therapy.
The aims of this study were to compare circulating cytokines between FM and healthy controls and to investigate the effect on cytokine levels by 15 weeks of progressive resistance exercise or relaxation therapy in FM. Baseline plasma cytokine levels and clinical data were analyzed in 125 women with FM and 130 age-matched healthy women. The FM women were then randomized to progressive resistance exercise (n = 49) or relaxation (n = 43). Baseline IL-2, IL-6, TNF-α, IP-10, and eotaxin were higher in FM than in healthy controls (P < 0.041), whereas IL-1β was lower (P < 0.001). There were weak correlations between cytokine levels and clinical variables. After both interventions, IL-1ra had increased (P = 0.004), while IL-1β had increased in the relaxation group (P = 0.002). Changes of IFN-γ, IL-2, IL-4, IL-6, IL-8, and IL-17A were weakly correlated with changes of PPT, but there were no significant correlations between changes of cytokine and changes in other clinical variables. The elevated plasma levels of several cytokines supports the hypothesis that chronic systemic inflammation may underlie the pathophysiology of FM even if the relation to clinical variables was weak. However, 15 weeks of resistance exercise, as performed in this study, did not show any anti-inflammatory effect on neither FM symptoms nor clinical and functional variables. This trial is registered with ClinicalTrials.gov NCT01226784, registered October 21, 2010. The first patient was recruited October 28, 2010.


Management of Clinically and Mammographically Occult Benign Papillary Lesions Diagnosed at Ultrasound-Guided 14-Gauge Breast Core Needle Biopsy.
To determine how to manage clinically and mammographically occult benign papillary lesions diagnosed at ultrasound (US)-guided 14-gauge breast core needle biopsy (CNB) by evaluating their upgrade rates. From our pathologic database of US-guided 14-gauge breast CNB, 69 benign papillomas and 9 atypical papillomas with available subsequent excisional findings (surgery or vacuum-assisted removal with additional US follow-up for ≥2 years) or US follow-up alone (≥2 years) were included in this study. We analyzed their upgrade rates by using excisional or US follow-up findings, with no change at 2 years as the reference standard. Patient age, lesion size, lesion distance from the nipple, multiplicity, imaging-histologic concordance, and histologic findings were compared between groups with and without upgrades by statistical analysis. Surgical excision was performed in 53 (67.9%) of 78 benign papillary lesions and revealed 5 upgrades (11.4%) to atypical papillomas in 44 benign papillomas and 2 upgrades (22.2%) to ductal carcinomas in situ in 9 atypical papillomas. Among 12 benign papillomas (15.4%) with vacuum-assisted removal and US follow-up (≥2 years), 1 (8.3%) was upgraded to atypical papilloma. The remaining 13 benign papillomas (16.7%) were followed with US and were stable after a 2-year follow-up period. There were no significant differences in the variables between the groups. Uniform surgical excision is not a reasonable management strategy for clinically and mammographically occult benign papillary lesions diagnosed at US-guided 14-gauge breast CNB. Clinically and mammographically occult benign papillary lesions may be subsequently managed by vacuum-assisted removal or imaging follow-up if atypia is not found.


Low Cycle Fatigue Life Prediction Using Unified Mechanics Theory in Ti-6Al-4V Alloys.
Fatigue in any material is a result of continuous irreversible degradation process. Traditionally, fatigue life is predicted by extrapolating experimentally curve fitted empirical models. In the current study, unified mechanics theory is used to predict life of Ti-6Al-4V under monotonic tensile, compressive and cyclic load conditions. The unified mechanics theory is used to derive a constitutive model for fatigue life prediction using a three-dimensional computational model. The proposed analytical and computational models have been used to predict the low cycle fatigue life of Ti-6Al-4V alloys. It is shown that the unified mechanics theory can be used to predict fatigue life of Ti-6Al-4V alloys by using simple predictive models that are based on fundamental equation of the material, which is based on thermodynamics associated with degradation of materials.


A comparison of memory and attention in Turner syndrome and learning disability.
Compared short-term verbal memory, sustained attention, and impulsivity in 13 children with Turner syndrome to 13 females and 14 males with learning disability who had neuropsychological patterns similar to the children with Turner syndrome. Similar patterns of short-term memory deficits were found in all three groups. There were no significant differences among the groups on computer measures of sustained attention and impulsivity. However, extreme variability of the attention and impulsivity scores for the Turner syndrome group may reflect atypical attention deficit disorder in some of these children.


Recent developments in trace element metabolism and function: newer roles of selenium in nutrition.
Until recently, studies of the function of selenium focused on the selenoenzyme, glutathione peroxidase. However, the recognition that several metabolic effects of selenium are not associated with glutathione peroxidase has forced a re-evaluation of the function of this enzyme and the element. Hepatic glutathione peroxidase contains a significant percentage of the regulated selenium in the rat and is more sensitive to selenium deficiency than other selenoproteins. Thus, in addition to its enzymatic activity, it might have a storage function for the element. Another selenoprotein, designated selenoprotein P, has been found in rat plasma and has been quantitated. Its function is not yet known, but it has been postulated to be a transport protein for selenium and a defense against oxidant stress. Understanding the nutritional effects of selenium will require better characterization of glutathione peroxidase, selenoprotein P and other selenoproteins.


Kinetic and thermodynamic resolution of the interactions between sulfite and the pentahaem cytochrome NrfA from Escherichia coli.
NrfA is a pentahaem cytochrome present in a wide-range of γ-, δ- and ε-proteobacteria. Its nitrite and nitric oxide reductase activities have been studied extensively and contribute to respiratory nitrite ammonification and nitric oxide detoxification respectively. Sulfite is a third substrate for NrfA that may be encountered in the micro-oxic environments where nrfA is expressed. Consequently, we have performed quantitative kinetic and thermodynamic studies of the interactions between sulfite and Escherichia coli NrfA to provide a biochemical framework from which to consider their possible cellular consequences. A combination of voltammetric, spectroscopic and crystallographic analyses define dissociation constants for sulfite binding to NrfA in oxidized (~54 μM), semi-reduced (~145 μM) and reduced (~180 μM) states that are comparable with each other, and the Km (~70 μM) for sulfite reduction at pH 7. Under comparable conditions Km values of ~22 and ~300 μM describe nitrite and nitric oxide reduction respectively, whereas the affinities of nitrate and thiocyanate for NrfA fall more than 50-fold on enzyme reduction. These results are discussed in terms of the nature of sulfite co-ordination within the active site of NrfA and their implications for the cellular activity of NrfA.


Aging and caloric restriction: effects on Leydig cell steroidogenesis.
We have shown previously that testosterone concentration in the blood serum of Brown Norway rat becomes reduced with aging, and that this results from reduced testosterone production by individual Leydig cells. Herein we examine the effects of caloric restriction (CR), an intervention shown to delay or inhibit age-associated pathologic and biologic changes in a number of systems and organisms, on Leydig cell steroidogenic function. CR (40%) was initiated in 4 month-old Brown Norway rats, and continued through age 34 months. Serum testosterone concentration in the ad libitum (AL)-fed controls was reduced by 30% from 5 to 13 months, by another 67% through 25 months, and then was sustained through 34 months. For the CR rats, the serum testosterone level was reduced to 45% of AL controls by 5 months, only 6 weeks after the initiation of the CR regimen. There was no further reduction through 25 months, at which time serum testosterone concentration in CR animals was significantly higher than in AL controls. By age 28-34 months, there was no significant difference between the two diets. The weights of prostate and seminal vesicle, two biomarkers of serum androgen levels, were consistent with the changes in serum testosterone concentration in both AL and CR animals. The ability of isolated Leydig cells to produce testosterone in vitro also paralleled the age- and CR-related changes in serum testosterone concentration. CR resulted in a rapid, 36% reduction in testosterone production from control by age 5 months. In contrast to cells from the AL rats, there were no further decreases in testosterone production through age 25 months. Indeed, Leydig cells from the 25 month-old CR rats produced significantly greater amounts of testosterone than cells from the 25 month-old AL rats. These results indicate that short-term CR results in the suppression of Leydig cell function and in reduction in serum testosterone levels. The significantly higher concentrations of serum testosterone concentration, and increased Leydig cell testosterone production, elicited by CR in 25 month-old rats compared to AL controls suggest that long-term CR can transiently suppress the reductions in steroidogenesis that are characteristic of aging.


Sono-activated materials for enhancing focused ultrasound ablation: Design and application in biomedicine.
The ablation effect of focused ultrasound (FUS) has played an increasingly important role in the biomedical field over the past decades, and its non-invasive features have great advantages, especially for clinical diseases where surgical treatment is not available or appropriate. Recently, rapid advances in the adjustable morphology, enzyme-mimetic activity, and biostability of sono-activated materials have significantly promoted the medical application of FUS ablation. However, a systematic review of sono-activated materials based on FUS ablation is not yet available. This progress review focuses on the recent design, fundamental principles, and applications of sono-activated materials in the FUS ablation biomedical field. First, the different ablation mechanisms and the key factors affecting ablation are carefully determined. Then, the design of sono-activated materials with high FUS ablation efficiencies is comprehensively discussed. Subsequently, the representative biological applications are summarized in detail. Finally, the primary challenges and future perspectives are also outlined. We believe this timely review will provide key information and insights for further exploration of focused ultrasound ablation and new inspiration for designing future sono-activated materials. STATEMENT OF SIGNIFICANCE: The ablation effect of focused ultrasound (FUS) has played an increasingly important role in the biomedical field over the past decades. However, there are also some challenges of FUS ablation, such as skin burns, tumour recurrence after thermal ablation, and difficulty in controlling cavitation ablation. The rapid advance in adjustable morphology, enzyme-mimetic activity, and biostability of sono-activated materials has significantly promoted the medical application of FUS ablation. However, the systematic review of sono-activated materials based on FUS ablation is not yet available. This progress review focuses on the recent design, fundamental principles, and applications in the FUS ablation biomedical field of sono-activated materials. We believe this timely review will provide key information and insights for further exploration of FUS ablation.


Serotonergic neurosecretory synapse targeting is controlled by netrin-releasing guidepost neurons in Caenorhabditis elegans.
Neurosecretory release sites lack distinct postsynaptic partners, yet target to specific circuits. This targeting specificity regulates local release of neurotransmitters and modulation of adjacent circuits. How neurosecretory release sites target to specific regions is not understood. Here we identify a molecular mechanism that governs the spatial specificity of extrasynaptic neurosecretory terminal (ENT) formation in the serotonergic neurosecretory-motor (NSM) neurons of Caenorhabditis elegans. We show that postembryonic arborization and neurosecretory terminal targeting of the C. elegans NSM neuron is dependent on the Netrin receptor UNC-40/DCC. We observe that UNC-40 localizes to specific neurosecretory terminals at the time of axon arbor formation. This localization is dependent on UNC-6/Netrin, which is expressed by nerve ring neurons that act as guideposts to instruct local arbor and release site formation. We find that both UNC-34/Enabled and MIG-10/Lamellipodin are required downstream of UNC-40 to link the sites of ENT formation to nascent axon arbor extensions. Our findings provide a molecular link between release site development and axon arborization and introduce a novel mechanism that governs the spatial specificity of serotonergic ENTs in vivo.


Development of a novel ReaxFF reactive potential for organochloride molecules.
This article presents a new reactive potential in the ReaxFF formalism. It aims to include the chlorine element and opens up the fields of use of ReaxFF to the whole class of organochloride compounds including conjugated or aromatic groups. Numerous compounds in this family raise global awareness due to their environmental impact, and such a reactive potential will help investigate their degradation pathways. The new force field, named CHONCl-2022_weak, belongs to the aqueous branch. The force field parameters were fitted against high-level quantum chemistry calculations, including complete active space self-consistent field/NEVPT2 calculations and density functional theory calculations, and their accuracy was evaluated using a validation set. The root means square deviation against quantum mechanics energies is 0.38 eV (8.91 kcal mol-1). From a structural point of view, the root means square deviation is about 0.06 Å for the bond lengths, 11.86° for the angles, and 4.12° for the dihedral angles. With CHONCl-2022_weak new force field, we successfully investigated the regioselectivity for nucleophilic or electrophilic attacks on polychlorinated biphenyls, which are toxic and permanent pollutants. The rotation barriers along the bond linking the two benzene rings, which is crucial in the toxicity of these compounds, are well reproduced by CHONCl-2022_weak. Then, our new reactive potential is used to investigate the chlorobenzene reactivity in the presence of hydroxyl radicals in atmospheric condition or in aqueous solution. The reaction pathways computed with ReaxFF agree with the quantum mechanics results. We showed that, in the presence of dioxygen molecules, in atmospheric condition, the oxidation of chlorobenzene likely leads to the formation of highly oxygenated compounds after the abstraction of hydrogen radicals. In water, the addition of a hydroxyl radical leads to the formation of chlorophenol or phenol molecules, as already predicted from plasma-induced degradation experiments.


Scale, distribution and variations of global greenhouse gas emissions driven by U.S. households.
The U.S. household consumption, a key engine for the global economy, has significant carbon footprints across the world. Understanding how the U.S. household consumption on specific goods or services drives global greenhouse gas (GHG) emissions is important to guide consumption-side strategies for climate mitigation. Here we examined global GHG emissions driven by the U.S. household consumption from 1995 to 2014 using an environmentally extended multi-regional input-output model and detailed U.S. consumer expenditure survey data. The results show that the annual carbon footprint of the U.S. households ranged from 17.7 to 20.6 tCO2eq/capita with an expanding proportion occurring overseas. Housing and transportation contributed 53-66% of the domestic carbon footprint. Overseas carbon footprint shows an overall increasing trajectory, from 16.4% of the total carbon footprint in 1995 to the peak of 20.4% in 2006. These findings provide valuable insights on the scale, distribution, and variations of the global GHG emissions driven by the U.S. household consumption for developing consumption-side strategies in the U.S. for climate mitigation.


Intracellular amplification of proviral DNA in tissue sections using the polymerase chain reaction.
We developed a new method to amplify cell DNA in situ using the polymerase chain reaction (PCR). Proviral sequences of mouse mammary tumor virus (MMTV) contained in cultured cells and tissue sections were amplified intracellularly using a thermal cycler. Two techniques were employed to maintain the localization of the amplified DNA. First, complementary tails at the 5' ends of the oligonucleotide primers resulted in the synthesis of high molecular weight concatamers containing the target sequences. Second, the PCR was carried out in a thin film of agarose solidified over the tissue sections. The specifically amplified and localized DNA was then detected by in situ hybridization (ISH). Our results demonstrate that (a) DNA in tissue sections can serve as the target for the polymerase chain reaction in situ, (b) cell morphology is maintained, and (c) a target of 167 BP can be specifically detected in individual cells. This technique should be generally applicable to amplifying cellular DNA targets in tissue sections for detection in situ.


Accelerating Inference of Convolutional Neural Networks Using In-memory Computing.
In-memory computing (IMC) is a non-von Neumann paradigm that has recently established itself as a promising approach for energy-efficient, high throughput hardware for deep learning applications. One prominent application of IMC is that of performing matrix-vector multiplication in O ( 1 ) time complexity by mapping the synaptic weights of a neural-network layer to the devices of an IMC core. However, because of the significantly different pattern of execution compared to previous computational paradigms, IMC requires a rethinking of the architectural design choices made when designing deep-learning hardware. In this work, we focus on application-specific, IMC hardware for inference of Convolution Neural Networks (CNNs), and provide methodologies for implementing the various architectural components of the IMC core. Specifically, we present methods for mapping synaptic weights and activations on the memory structures and give evidence of the various trade-offs therein, such as the one between on-chip memory requirements and execution latency. Lastly, we show how to employ these methods to implement a pipelined dataflow that offers throughput and latency beyond state-of-the-art for image classification tasks.


Site-directed mutagenesis reveals the thermodynamic requirements for single-stranded DNA recognition by the telomere-binding protein Cdc13.
The essential Saccharomyces cerevisiae protein Cdc13 binds the conserved single-stranded overhang at the end of telomeres and mediates access of protein complexes involved in both end-capping and telomerase activity. The single-stranded DNA-binding domain (ssDBD) of Cdc13 exhibits both high affinity (K(d) of 3 pM) and sequence specificity for the GT-rich sequences present at yeast telomeres. We have used the ssDBD of Cdc13 to understand the sequence-specific recognition of extended single-stranded DNA (ssDNA). The recent structure of the Cdc13 DNA-binding domain revealed that ssDNA is recognized by a large protein surface containing an oligonucleotide/oligosaccharide-binding fold (OB-fold) augmented by an extended 30-amino acid loop. Contacts to ssDNA occur via a contiguous surface of aromatic, hydrophobic, and basic residues. A complete alanine scan of the binding interface has been used to determine the contribution of each contacting side chain to binding affinity. Substitution of any aromatic or hydrophobic residue at the interface was deleterious to binding (20 to >700-fold decrease in binding affinity), while tolerance for replacement of basic residues was observed. The important aromatic and hydrophobic contacts are spread throughout the extended interface, indicating that the entire surface is both structurally and thermodynamically required for binding. While all of these contacts are important, several of the individual alanine substitutions that abolish binding cluster to one region of the protein surface. This region is vital for recognition of four bases at the 5' end of the DNA and constitutes a "hotspot" of binding affinity.


Speech recognition and temporal amplitude modulation processing by Mandarin-speaking cochlear implant users.
Fundamental frequency (F0) information is important to Chinese tone and speech recognition. Cochlear implant (CI) speech processors typically provide limited F0 information via temporal envelopes delivered to stimulating electrodes. Previous studies have shown that English-speaking CI users' speech performance is correlated with amplitude modulation detection thresholds (AMDTs). The present study investigated whether Chinese-speaking CI users' speech performance (especially tone recognition) is correlated with temporal processing capabilities. Chinese tone, vowel, consonant, and sentence recognition were measured in 10 native Mandarin-speaking CI users via clinically assigned speech processors. AMDTs were measured in the same subjects for 20- and 100-Hz amplitude modulated (AM) stimuli presented to a middle electrode at five stimulation levels that spanned the dynamic range. To further investigate the CI users' sensitivity to temporal envelope cues, AM frequency discrimination thresholds (AMFDTs) were measured for two standard AM frequencies (50 and 100 Hz), presented to the same middle electrode at 30% and 70% dynamic range with a fixed modulation depth (50%). Results showed that AMDTs significantly improved with increasing stimulation level and that individual subjects exhibited markedly different AMDT functions. AMFDTs also improved with increasing stimulation level and were better with the 100-Hz standard AM frequency than with the 50-Hz standard AM frequency. Statistical analyses revealed that both mean AMDTs (averaged for 20- or 100-Hz AM across all stimulation levels) and mean AMFDTs (averaged for the 50-Hz standard AM frequency across both stimulation levels) were significantly correlated with tone, consonant, and sentence recognition scores, but not with vowel recognition scores. Mean AMDTs were also significantly correlated with mean AMFDTs. These preliminary results, obtained from a limited number of subjects, demonstrate the importance of temporal processing to CI speech recognition. The results further suggest that CI users' Chinese tone and speech recognition may be improved by enhancing temporal envelope cues delivered by speech processing algorithms.


Recurrent deletion of 3p13 targets multiple tumour suppressor genes and defines a distinct subgroup of aggressive ERG fusion-positive prostate cancers.
Deletion of 3p13 has been reported from about 20% of prostate cancers. The clinical significance of this alteration and the tumour suppressor gene(s) driving the deletion remain to be identified. We have mapped the 3p13 deletion locus using SNP array analysis and performed fluorescence in situ hybridization (FISH) analysis to search for associations between 3p13 deletion, prostate cancer phenotype and patient prognosis in a tissue microarray containing more than 3200 prostate cancers. SNP array analysis of 72 prostate cancers revealed a small deletion at 3p13 in 14 (19%) of the tumours, including the putative tumour suppressors FOXP1, RYBP and SHQ1. FISH analysis using FOXP1-specific probes revealed deletions in 16.5% and translocations in 1.2% of 1828 interpretable cancers. 3p13 deletions were linked to adverse features of prostate cancer, including advanced stage (p < 0.0001), high Gleason grade (p = 0.0125), and early PSA recurrence (p = 0.0015). In addition, 3p13 deletions were linked to ERG(+) cancers and to PTEN deletions (p < 0.0001 each). A subset analysis of ERG(+) tumours revealed that 3p13 deletions occurred independently from PTEN deletions (p = 0.3126), identifying tumours with 3p13 deletion as a distinct molecular subset of ERG(+) cancers. mRNA expression analysis confirmed that all 3p13 genes were down regulated by the deletion. Ectopic over-expression of FOXP1, RYBP and SHQ1 resulted in decreased colony-formation capabilities, corroborating a tumour suppressor function for all three genes. In summary, our data show that deletion of 3p13 defines a distinct and aggressive molecular subset of ERG(+) prostate cancers, which is possibly driven by inactivation of multiple tumour suppressors.


In silico study of the impact of oxidation on pyruvate transmission across the hVDAC1 protein channel.
The overexpression of voltage dependent anion channels (VDACs), particularly VDAC1, in cancer cells compared to normal cells, plays a crucial role in cancer cell metabolism, apoptosis regulation, and energy homeostasis. In this study, we used molecular dynamics (MD) simulations to investigate the effect of a low level of VDAC1 oxidation (induced e.g., by cold atmospheric plasma (CAP)) on the pyruvate (Pyr) uptake by VDAC1. Inhibiting Pyr uptake through VDAC1 can suppress cancer cell proliferation. Our primary target was to study the translocation of Pyr across the native and oxidized forms of hVDAC1, the human VDAC1. Specifically, we employed MD simulations to analyze the hVDAC1 structure by modifying certain cysteine residues to cysteic acids and methionine residues to methionine sulfoxides, which allowed us to investigate the effect of oxidation. Our results showed that the free energy barrier for Pyr translocation through the native and oxidized channel was approximately 4.3 ± 0.7 kJ mol-1 and 10.8 ± 1.8 kJ mol-1, respectively. An increase in barrier results in a decrease in rate of Pyr permeation through the oxidized channel. Thus, our results indicate that low levels of CAP oxidation reduce Pyr translocation, resulting in decreased cancer cell proliferation. Therefore, low levels of oxidation are likely sufficient to treat cancer cells given the inhibition of Pyr uptake.


Immunophenotypic analysis of the transformation zone of human cervix.
The immunocompetent cell population of the cervical transformation zone of 18 uteri removed for noncervical disease, has been investigated with monoclonal antibodies. The panel included Leu 2a, 3a, 4, 14, and IL II receptor for lymphocytes and T cell subsets, Leu 7 for NK cells, Leu M5, Leu 10, HLA-DR, DRC 1 for dendritic cells, and Leu 6 for Langerhans' cells (LC). In ectocervical epithelium HLA-DR, Leu 6 and Leu 10 antibodies identified subpopulations of dendritic cells which differed in number and in topographic distribution. Furthermore, a strong HLA-DR epithelial positivity was constantly observed in endocervical columnar cells as well as in keratinocytes of squamous metaplasia. Leu 2a+ cells (T suppressor/cytotoxic) prevailed in the stromal and epithelial compartments of ecto/endocervix; in 6 cases, however, Leu 3a+ cells (T helper/inducer) represented the main T cell subset in the ectocervical stroma. B lymphocytes were occasionally noticed in the subepithelial stroma while NK and DRC-1 cells were never observed. Finally, only few lymphocytes displayed a positivity for IL II receptor. This study suggests that several phenotypes of intraepithelial dendritic cells are present in the transformation zone and that endocervical columnar cells and keratinocytes of squamous metaplasia express HLA-DR products; the latter finding may be related to the presence of intraepithelial and stromal T lymphocytes.


A human cytomegalovirus glycoprotein complex designated gC-II is a major heparin-binding component of the envelope.
The purposes of this study were to determine whether heparin would block human cytomegalovirus (HCMV) infection of skin fibroblast (SF) cells and to identify HCMV envelope glycoproteins which might have affinity for heparin. It was determined that soluble heparin in concentrations of 5 to 20 micrograms/ml was capable of blocking HCMV infection of SF cells. However, after virus had adsorbed to the SF cells, heparin lost its ability to block infection. It was also determined that treatment of SF cells with heparinase to remove cell surface heparinlike moieties prevented HCMV infection of SF cells. These data showed that HCMV, like other herpesviruses, adsorbed to cells by binding cell surface heparin. Heparin affinity chromatography was done to determine which HCMV envelope glycoproteins bound heparin. HCMV envelope glycoproteins were solubilized in a nonionic detergent and applied to a heparin affinity column. An HCMV glycoprotein complex designated gC-II was the major component to bind to immobilized heparin and elute in the presence of soluble heparin.


Calcineurin Co-regulates contractile and metabolic components of slow muscle phenotype.
Activation of the transcription factor nuclear factor of activated T cells by the calcium-sensitive serine/threonine phosphatase calcineurin has been proposed as one of the molecular mechanisms by which motor nerve activity establishes the slow muscle phenotype. To investigate whether the calcineurin pathway can regulate the large spectrum of slow muscle characteristics in vivo, we treated rats for three weeks with cyclosporin A (an inhibitor of calcineurin). In soleus (slow muscle), but not in plantaris (fast muscle), the proportion of slow myosin heavy chain (MHC-1) and slow sarcoplasmic reticulum ATPase (SERCA2a) was decreased, whereas that of fast MHC (MHC-2A) and fast SERCA1 increased, indicating a slow to fast contractile phenotype transition. Cytosolic isoforms of creatine kinase and lactate dehydrogenase (most abundant in fast fibers), as well as mitochondrial creatine kinase and citrate synthase activities (elevated in fast/oxidative fibers) were dose dependently increased by cyclosporin A treatment in soleus muscle, with no change in plantaris. Calcineurin catalytic subunit was more abundant in soleus muscle fibers compared with plantaris. Taken together these results suggest that the calcineurin pathway co-regulates a set of multigenic protein families involved in the transition between slow oxidative (type I) to fast oxidative (type IIa) phenotype in soleus muscle.


Opening the Doors for Health: School Administrators' Perceived Benefits, Barriers, and Needs Related to Shared Use of School Recreational Facilities for Physical Activity.
Shared use agreements (SUA) that allow the use of public school facilities by the community are recommended as a key public health strategy for increasing physical activity (PA). The purpose of this study was to examine the current nature and extent of SUA in Ohio, as well as school administrators' perceived benefits, barriers and needs. School administrators were recruited to respond to an e-mail survey through the predominant state-level professional membership organization's listserv in September 2013. Respondents (n = 96) were mostly superintendents who reported a lower prevalence of formal SUA (38.5%) than informal (65.6%), with a total of 9.3% reporting neither formal nor informal SUA. The most commonly perceived benefits included improved relationships with taxpayers and community organizations and increased PA options. Top barriers were costs and liability concerns. According to this sample of school administrators, their doors are open to some extent, but the majority SUA were informal agreements. Advocacy efforts for SUA should include the passage of a state-level law that provides reasonable immunity from liability. Outreach to the school community should include examples of written formal agreements, innovative cost management examples, and updated research on the connection of PA to learning and academic performance.


Microsatellite instability status in gastric cancer: a reappraisal of its clinical significance and relationship with mucin phenotypes.
Gastric cancers with microsatellite instabilities (MSI) have been reported to be associated with favorable prognosis. However, the significance of the effect of MSI on the clinicopathological features, as well as its association with mucin phenotype, remains unclear. MSI status was assessed in 414 cases of gastric cancer using polymerase chain reaction analysis of five microsatellite loci, as recommended by National Cancer Institution criteria. The expression of mucins (MUC5AC, MUC6, MUC2, and CD10) was assessed. Out of 414 total cases of gastric cancer, 380 (91.7%), 11 (2.7%), and 23 (5.6%) were microsatellite stable (MSS), low-level MSI (MSI-L), and high-level MSI (MSI-H), respectively. Compared to MSS/MSI-L, MSI-H gastric cancers were associated with older age (p=0.010), tumor size (p=0.014), excavated gross (p=0.042), intestinal type (p=0.028), aggressive behaviors (increase of T stage [p=0.009]), perineural invasion [p=0.022], and lymphovascular emboli [p=0.027]). MSI-H gastric cancers were associated with tumor necrosis (p=0.041), tumor-infiltrating lymphocytes (≥2/high power field, p<0.001), expanding growth patterns (p=0.038), gastric predominant mucin phenotypes (p=0.028), and MUC6 expression (p=0.016). Tumor necrosis (≥10% of mass, p=0.031), tumor-infiltrating lymphocytes (p<0.001), intestinal type (p=0.014), and gastric mucin phenotypes (p=0.020) could represent independent features associated with MSI-H gastric cancers. MSI-H intestinal type gastric cancers had a tendency for poor prognosis in univariate analysis (p=0.054) but no association in Cox multivariate analysis (p=0.197). Our data suggest that MSI-H gastric cancers exhibit distinct aggressive biologic behaviors and a gastric mucin phenotype. This contradicts previous reports that describe MSI-H gastric cancer as being associated with favorable prognosis.


Reactivity and mass transfer of low-dimensional catalysts.
Understanding the mechanisms governing chemical and morphological changes induced by an ambient-pressure gas and how such changes influence the activity of heterogeneous catalysts is central to the formation of a predictive capability for structure-reactivity relationships. With techniques such as ambient-pressure photoelectron spectroscopy, scanning tunneling microscopy, and surface X-ray diffraction, active phases and reaction intermediates can be probed in situ on relevant samples to form a comprehensive picture of this dynamic interplay between gases and surfaces. Of particular interest is the interaction of oxygen and carbon monoxide with catalysts. We will describe how model systems of increased complexity can be used to investigate gas-mediated mass transfer processes that may occur even at relatively modest temperatures. Furthermore, we will discuss how the morphology may be tailored to study specific contributions from defect sites and charge transfer to catalytic activity.


Macular Telangiectasia Type 2: Visual Acuity, Disease End Stage, and the MacTel Area: MacTel Project Report Number 8.
To report the visual acuity measures from the macular telangiectasia type 2 (MacTel) registry and to investigate and describe phenotypic findings in eyes with substantial vision loss resulting from MacTel. Cross-sectional multicenter study. Participants in the MacTel Natural History Observation Registration Study. Best-corrected visual acuity (BCVA) data, retinal imaging data, and clinical data were accessed from the MacTel Study databases in May 2019. Frequency distribution of BCVA and its relationship to age; morphologic changes in eyes with very late disease stages, defined by a BCVA of 20/200 or worse; average retinal thickness of macular subfields on OCT; and dimensions of the area affected by MacTel (i.e., the MacTel area). Best-corrected visual acuity was 20/50 or worse in 37.3% and 20/200 or worse in 3.8% of 4449 eyes of 2248 patients; 18.4% and 0.7% of all patients showed bilateral BCVA of 20/50 or worse and 20/200 or worse, respectively. Asymmetry between right and left eyes was present (median BCVA, 71 letters vs. 74 letters), a finding supported by more advanced morphologic changes in right eyes. Participant age correlated with BCVA, but the effect size was small. If a neovascularization or macular hole were present, bilateral occurrence was frequent (33% or 17%, respectively), and BCVA was better than 20/200 (79% or 78%, respectively) or 20/50 or better (26% or 13%, respectively). Eyes with advanced disease (BCVA, ≤20/200) showed the following characteristics: (1) atrophy of the foveal photoreceptor layer with or without associated subretinal fibrosis; (2) an affected area, termed MacTel area, limited to a horizontal diameter not exceeding the distance between the temporal optic disc margin and foveal center, and the vertical diameter not exceeding approximately 0.8 times this distance (exceptions were eyes with large active or inactive neovascular membranes); (3) reduced retinal thickness measures within the MacTel area; and (4) less frequent retinal greying and more frequent hyperpigmentations compared with eyes that have better BCVA. Severe vision loss is rare in MacTel and is related to photoreceptor atrophy in most people. Results indicate disease asymmetry with slightly worse vision and more advanced disease manifestation in right eyes. MacTel-related neurodegeneration does not spread beyond the limits of the MacTel area.


Development and measurement of guideline-based indicators for patients with non-Hodgkin's lymphoma.
Patients with cancer are not always treated according to available guidelines. Factors such as age and comorbidities are frequently used as arguments for nonadherence. The aim of this study was to measure guideline adherence with guideline-based indicators for patients with non-Hodgkin's lymphoma (NHL) and to examine the need for improvement, considering relevant arguments. A RAND-modified Delphi procedure was used to systematically develop NHL indicators. We evaluated their improvement potential (defined as < 90% score) in a random sample of patients with NHL (N = 431) diagnosed in 2006-2007 in 22 hospitals in the Netherlands with data from medical records. Multilevel logistic regression analyses were used to estimate the relationship between indicator scores and factors: comorbidity index (combined with age), stage, patient's objections, and lymphoma type. Scores were adjusted for significant factors. Of the 20 indicators developed, 16 had improvement potential. Scores were lowest for assessment of International Prognostic Index, 21%; imaging of neck, thorax, and abdomen and bone marrow examination during the diagnostic process, 23%, and after chemotherapy, 37%; adequate pathology reporting, 11%; and multidisciplinary discussion of patients, 21%. Scores for eight indicators were better for patients with a low Charlson index, stage III or IV disease, no objections to care, and aggressive lymphoma. After adjustments, adherence to all but one indicator (administration of the combination of rituximab and cyclophosphamide-doxorubicin-vincristine-prednisone) remained < 90%. In the Netherlands, almost all indicators for NHL needed improvement. This should be evaluated in other countries as well. International efforts should be undertaken to improve the quality of care of this often curable malignancy.


HmuY haemophore and gingipain proteases constitute a unique syntrophic system of haem acquisition by Porphyromonas gingivalis.
Haem (iron protoporphyrin IX) is both an essential growth factor and virulence regulator for the periodontal pathogen Porphyromonas gingivalis, which acquires it mainly from haemoglobin via the sequential actions of the R- and K-specific gingipain proteases. The haem-binding lipoprotein haemophore HmuY and its cognate receptor HmuR of P. gingivalis, are responsible for capture and internalisation of haem. This study examined the role of the HmuY in acquisition of haem from haemoglobin and the cooperation between HmuY and gingipain proteases in this process. Using UV-visible spectroscopy and polyacrylamide gel electrophoresis, HmuY was demonstrated to wrest haem from immobilised methaemoglobin and deoxyhaemoglobin. Haem extraction from oxyhaemoglobin was facilitated after oxidation to methaemoglobin by pre-treatment with the P. gingivalis R-gingipain A (HRgpA). HmuY was also capable of scavenging haem from oxyhaemoglobin pre-treated with the K-gingipain (Kgp). This is the first demonstration of a haemophore working in conjunction with proteases to acquire haem from haemoglobin. In addition, HmuY was able to extract haem from methaemalbumin, and could bind haem, either free in solution or from methaemoglobin, even in the presence of serum albumin.


SIRT1-mediated deacetylation of CRABPII regulates cellular retinoic acid signaling and modulates embryonic stem cell differentiation.
Retinoid homeostasis is critical for normal embryonic development. Both the deficiency and excess of these compounds are associated with congenital malformations. Here we demonstrate that SIRT1, the most conserved mammalian NAD⁺-dependent protein deacetylase, contributes to homeostatic retinoic acid (RA) signaling and modulates mouse embryonic stem cell (mESC) differentiation in part through deacetylation of cellular retinoic acid binding protein II (CRABPII). We show that RA-mediated acetylation of CRABPII at K102 is essential for its nuclear accumulation and subsequent activation of RA signaling. SIRT1 interacts with and deacetylates CRABPII, regulating its subcellular localization. Consequently, SIRT1 deficiency induces hyperacetylation and nuclear accumulation of CRABPII, enhancing RA signaling and accelerating mESC differentiation in response to RA. Consistently, SIRT1 deficiency is associated with elevated RA signaling and development defects in mice. Our findings reveal a molecular mechanism that regulates RA signaling and highlight the importance of SIRT1 in regulation of ESC pluripotency and embryogenesis.


[Type 2 diabetes mellitus in the pediatric age group].
In the past two decades, type 2 diabetes mellitus has increased in children and adolescents, especially within certain ethnic groups. This increase has been parallel to the rising prevalence of obesity. Because of the overlap between some clinical characteristics, the differential diagnosis between type 1 and 2 diabetes is difficult. Of 300 diabetic patients in our diabetes section, only three (1 %) had type 2 diabetes. Two patients were obese adolescents with a positive family history of type 2 diabetes mellitus; the third patient was a prepubertal, overweight girl with no family history of this disorder. The diagnosis was incidental in two patients and one patient presented with ketoacidosis. The differences between the three patients reveal the great clinical variability of this disorder and suggest that various underlying factors are involved in the pathophysiology of type 2 diabetes.


Grand canonical validation of the bipartite international trade network.
Devising strategies for economic development in a globally competitive landscape requires a solid and unbiased understanding of countries' technological advancements and similarities among export products. Both can be addressed through the bipartite representation of the International Trade Network. In this paper, we apply the recently proposed grand canonical projection algorithm to uncover country and product communities. Contrary to past endeavors, our methodology, based on information theory, creates monopartite projections in an unbiased and analytically tractable way. Single links between countries or products represent statistically significant signals, which are not accounted for by null models such as the bipartite configuration model. We find stable country communities reflecting the socioeconomic distinction in developed, newly industrialized, and developing countries. Furthermore, we observe product clusters based on the aforementioned country groups. Our analysis reveals the existence of a complicated structure in the bipartite International Trade Network: apart from the diversification of export baskets from the most basic to the most exclusive products, we observe a statistically significant signal of an export specialization mechanism towards more sophisticated products.


Impact of metabolic syndrome-related factors on the development of benign prostatic hyperplasia and lower urinary tract symptoms in Asian population.
This study aimed to investigate the metabolic syndrome-related risk factors for the development of benign prostatic hyperplasia (BPH) with lower urinary tract symptoms (LUTS) in healthy men.A total of 4880 healthy men who underwent transrectal ultrasonography at our hospital during routine health examinations were included in this study. Those who had undergone a prior biopsy or surgery for prostate disease, were suspected of having urinary tract infection, or were taking BPH/LUTS or metabolic syndrome medications were excluded. BPH/LUTS was defined as an International Prostate Symptom Score (IPSS) of ≥8 and a prostate volume (PV) of ≥30 cm.The subjects had a mean age of 54.1 years, PV of 29.2 cm, prostate-specific antigen (PSA) level of 1.20 ng/mL, and IPSS of 9.2. The annual PV growth rate was 0.48 cm/year. Age, body mass index (BMI), PSA, basal metabolic rate, apolipoprotein A-1, fasting blood glucose, high-density lipoprotein (HDL) cholesterol levels were significant predictive factors for PV. Age, PSA, apolipoprotein B, fasting blood glucose, cholesterol, HDL, and low-density lipoprotein (LDL) levels were predictors of BPH/LUTS at the initial health examination. A decreased fat mass and LDL level were a significant risk factor for the development of BPH/LUTS within 5 years in men without a BPH/LUTS diagnosis at the initial examination.Metabolic syndrome-related variables were strongly associated with BPH/LUTS and by decreasing fat mass and LDL levels, development of BPH/LUTS could be prevented within 5 years in healthy Korean men.


Adjusting the timing of left-ventricular pacing using electrocardiogram and device electrograms.
Left-ventricular (LV) pacing with optimized atrio-ventricular (AV) timing may provide similar or greater benefit in comparison with bi-ventricular (BiV) pacing in a subset of cardiac resynchronization therapy (CRT) patients with sinus rhythm and preserved AV conduction. We hypothesized that the optimal device AV delays during LV pacing can be predicted using electrocardiogram (ECG) and device electrograms. METHODS AND RESULTS PATIENTS: (n= 55) with sinus rhythm and PR interval < 300 ms had their CRT devices programmed to atrial and LV pacing with a range of AVs as well as to echocardiographically optimized BiV and no ventricular pacing. At each setting, LV function was evaluated using echocardiography and AVs corresponding to the highest LV ejection fraction (LVEF), lowest LV end-systolic volume (LVESV), and the average of the two (by EF and ESV) were determined. Correlation between the optimal AVs and the following intervals was investigated: intrinsic QRS duration (QRSs), intervals from atrial pacing (Ap) to right-ventricular (RV) sensing (Ap-RVs), from RV sensing to LV activation (RVs-LVs), and from LV pacing to RV sensing (LVp-RVs). Optimal AVs moderately correlated with intrinsic Ap-RVs interval, whereas other parameters showed weak or no correlation. The best correlation (R = 0.66, P< 0.0001) was between the optimal AV delay according to EF and ESV, and Ap-RVs interval. Programming of AVs during LV pacing to the shortest of 70% of the intrinsic Ap-RVs interval, or Ap-RVs--40 ms resulted in significant improvement in LV function similar to that in case of BiV. Optimal AV during LV pacing can be approximated from the intrinsic AV conduction time.


Respiratory effects of household exposures to tobacco smoke and gas cooking.
The records of 1,724 residents of Washington County, Maryland, who had participated in 2 studies of respiratory symptoms and ventilatory function were analyzed to evaluate the effects of exposures at home to tobacco smoke generated by other members of their households and to fumes from the use of gas as a cooking fuel. Currently smoking subjects showed the highest frequency of respiratory symptoms and impaired ventilatory function; former smokers showed a lower frequency of these findings; and persons who had never smoked had the lowest prevalence of abnormal respiratory findings. The presence of a smoker in the household other than the subject was not associated with the frequency of respiratory symptoms, and only suggestively associated with evidence of impaired ventilatory function. The use of gas for cooking was related to an increased frequency of respiratory symptoms and impaired ventilatory function among men, being most marked among men who had never smoked. There was no evidence that cooking with gas was harmful to women.


Management of regurgitation in patients with gastroesophageal reflux disease.
Precision treatment of medically-refractory regurgitation differs from that of heartburn. Regurgitation is an often-overlooked symptom characterized as a bitter taste in the mouth or a sense of fluid moving up from the stomach occurring in approximately 80% of gastroesophageal reflux disease (GERD) patients with varying severity. Its response to standard medical therapy is significantly less than heartburn while significantly lessening quality of life in 10-20% of GERD patients. The therapeutic gain of proton pump inhibitors (PPIs) above placebo averages 17% for regurgitation compared with 41% for heartburn. Increased dosing of medication is commonly, yet futilely, used. The symptom is probably mediated more by fluid volume than by the acidity of the refluxate. PPIs significantly decrease gastric acid secretion and to some extent volume of gastric juice. Significantly, doubling the PPI dose does not incrementally decrease gastric juice volume though it may decrease gastric acid secretion further. Studies on refractory regurgitation using some of the newer antireflux procedures (magnetic sphincter augmentation and transoral fundoplication) demonstrated success in over 85% of patients whereas increased PPI dosing helped in approximately 15%. Precision care of regurgitation should recognize the low-therapeutic impact of acid control, while antireflux procedures are very successful.


Secretion of the chemokine interleukin-8 during Japanese encephalitis virus infection.
Japanese encephalitis (JE) virus infection induces infiltration of neutrophils in neural as well as extraneural tissues in patients. As interleukin-8 (IL-8) has inflammatory properties, the present study was undertaken to investigate the IL-8 concentrations in cerebrospinal fluid (CSF) and serum from patients with JE and correlate them with neutrophil counts. IL-8 was measured in the CSF or serum of 30 patients with confirmed JE. The majority (92%) of the acute CSF samples showed raised levels of IL-8 with raised numbers of polymorphonuclear leucocytes. Similarly, significantly higher serum IL-8 concentrations were detected in the acute phase of illness than in convalescent JE patients or normal healthy controls. Twenty-one of 25 patients with high concentrations of IL-8 showed significantly increased neutrophil counts in acute phase sera. A gradual decline in neutrophil counts was observed in the convalescent phase of patients who recovered. There was a significant correlation between IL-8 level and the severity of illness, as all severely ill and fatal cases showed higher levels of IL-8 in acute CSF or serum than the levels found in those who recovered. IL-8 concentrations remained high for a longer period in patients with prolonged severe illness than in those who made a complete recovery.


In Vitro Investigation of an Electrically Actuated Antireflux Valve for a Multiuse Contrast Agent Injection System.
OBJECTIVE. The purpose of this study was to determine the capability of a newly developed antireflux valve for a multiuse contrast agent injection system. MATERIALS AND METHODS. Multiuse contrast agent injection systems require an antireflux valve to eliminate the risk of cross-patient blood contamination. An electrically actuated antireflux valve developed for this purpose can control risk of contamination because it is under forced control and surveillance. In this study, the injection system was connected to a pulsatile circulation system that reproduced an aortic flow environment in vitro. The transvalvular pressure difference was measured, and flow dynamics during valve opening and closing were visualized by high-speed flow visualization. A total of 30 injection conditions were tested, which included two catheters (6- and 2-French diameter), five contrast agent concentrations (100%, 90%, 50%, 10%, and 0%), and a wide range of flow rates (0.1-25.0 mL/s). RESULTS. The transvalvular pressure difference and flow dynamics during valve opening and closing were characterized. Just before valve opening, a minimum transvalvular pressure difference of 0.20 MPa (1500 mm Hg) was confirmed. The positive pressure difference prevented regurgitation during valve opening. During valve closing, the front of the backflow was monitored continuously, and we confirmed that the front failed to reach the valve before complete closure. CONCLUSION. This study provided proof of concept for an electrically actuated antireflux valve to be used in a multiuse contrast agent injection system.


Nutrient intake, digestibility, growth performance, and carcass of sheep fed urea-based diet supplemented with natural clinoptilolite.
Forty-five male Barki lambs (30.62 ± 4.54 kg BW) were allocated into three treatments designed to evaluate the effect of replacing soybean meal nitrogen with urea supplemented with natural clinoptilolite on performance and carcass characteristics. Lambs were randomly assigned to nine pens blocked according to age and initial BW into three blocks of three pens each assigned to one of three treatments: Control diet: animals received only a basal diet ad libitum, UR diet: urea replaced 68% of SBM nitrogen in the control diet or UR-Z diet: UR diet supplemented with 20-g zeolite for 141 days. Lambs fed on UR-Z diet increased (p < 0.05) total intakes of DM, crude protein digestibility, ADG, FCR, blood glucose and cholesterol concentration. Lambs fed on UR-Z diet decreased (p < 0.05) ruminal NH3 -N concentration compared to the UR diet. Carcasses from lambs fed on UR diet had greater (p < 0.05) ether extract content, fat thickness, meat yellowness and saturation attributes than those fed on UR-Z and control diets. Sheep fed on UR-Z diet made higher economic profit than UR and control diets. Partial replacement of soybean meal with urea supplemented with zeolite seemed to be economically efficient, with comparable performance and carcass attributes in growing lambs diet.


[Hyperinsulinemia and B-cell proliferation in rats treated postnatally with L-glutamate].
Development of hyperinsulinemia was investigated which appeared late in the obese state in rats postnatally treated with L-glutamate. Insulin concentrations were estimated in the blood plasma of the caval and portal vein, and morphometric and immunohistochemical measurements of cells in the islets of Langerhans were performed, and also glucose tolerance tests. Not earlier than at 3 months hyperinsulinemia is shown in glutamate obese rats (GOR) in the peripheral blood plasma. Also in the portal blood plasma the insulin concentration is higher (167%) in GOR relative to controls. The insulin concentrations in the portal vein rise further in both animal groups whereas insulin concentration in the peripheral blood remains at the different levels in both animal groups. Impaired glucose tolerance was observed for GOR only. Islets of Langerhans in the Pancreas show enlargement and increased proliferation of B-cells in GOR. In contrast the number of D-cells is diminished. The hyperplasia of islets differs remarkably to hypoplasia of other organs in GOR. We conclude that the peripheral hyperinsulinemia is caused by a permanent hypersecretion of insulin.


Glucosamine use, smoking and risk of incident chronic obstructive pulmonary disease: a large prospective cohort study.
Chronic inflammation exerts pleiotropic effects in the aetiology and progression of chronic obstructive pulmonary disease (COPD). Glucosamine is widely used in many countries and may have anti-inflammatory properties. We aimed to prospectively evaluate the association of regular glucosamine use with incident COPD risk and explore whether such association could be modified by smoking in the UK Biobank cohort, which recruited more than half a million participants aged 40-69 years from across the UK between 2006 and 2010. Cox proportional hazards models with adjustment for potential confounding factors were used to calculate hazard ratios (HR) as well as 95 % CI for the risk of incident COPD. During a median follow-up of 8·96 years (interquartile range 8·29-9·53 years), 9016 new-onset events of COPD were documented. We found that the regular use of glucosamine was associated with a significantly lower risk of incident COPD with multivariable adjusted HR of 0·80 (95 % CI, 0·75, 0·85; P < 0·001). When subgroup analyses were performed by smoking status, the adjusted HR for the association of regular glucosamine use with incident COPD were 0·84 (0·73, 0·96), 0·84 (0·77, 0·92) and 0·71 (0·62, 0·80) among never smokers, former smokers and current smokers, respectively. No significant interaction was observed between glucosamine use and smoking status (Pfor interaction = 0·078). Incident COPD could be reduced by 14 % to 84 % through a combination of regular glucosamine use and smoking cessation.


Durable complete response to early immunotherapy discontinuation in a kidney transplant recipient with advanced cutaneous squamous cell carcinoma: A case report and review of literature.
The usage of immunotherapy to treat skin malignancies in transplant patients requires weighing the risk of acute organ transplant rejection with the potential reduction of antitumor efficacy by transplant immunosuppression. Reducing the duration of immune checkpoint inhibitor treatment may help prevent acute transplant rejection and late immune-related adverse events. An allogenic kidney transplant patient who developed regionally metastatic cutaneous squamous cell carcinoma received four cycles of pembrolizumab with complete response to therapy. Therapy was discontinued due to fatigue, significant cancer response, and to reduce the risk of acute graft rejection. His renal function remained stable, and he achieved subsequent durable response after treatment discontinuation. Organ transplant recipients with complete response to immunotherapy for cutaneous squamous cell carcinoma may continue to respond despite early treatment cessation. This may reduce the risks of late immune-related adverse events and acute graft rejection.


[Na-Dis disc electrophoresis of mitochondrial membrane of cereals].
Na-DS disc electrophoresis of mitochondrial membrane proteins of cereals on polyacrylamide plates resulted in 37 to 44 subunits with molecular weights ranging from 10 000 to 300 000. The high affinity of electrophoretic patterns of the mitochondrial membranes of rye, oats and two selectively different wheat varieties and their identicity in 3- and 10-day-old sprouts and roots are indicative of evolutionary and functional stability of this protein group.


Scleral fixation of Ahmed glaucoma valve tube tip for adjustment of cornea-touching malposition.
Tube-corneal touch occurring after Ahmed glaucoma valve (AGV) implantation is conventionally treated by tube cutting or tube transposition from the original pathway. However, in some cases, tube cutting is insufficient, and rearranging the pathway of the tube through a new sclera tunnel, ciliary sulcus, or pars plana is not feasible, as the conjunctiva and sclera covering the tube are difficult to be redissected. So, we propose a novel technique that repositions malpositioned AGV tube using scleral fixation and its successful applications in two patients with tube-corneal touch. (A) A scleral flap is made at the point for scleral fixation. (B) The anterior chamber is maintained using an anterior chamber maintainer. The incision is made immediately above the tube entering the anterior chamber and the tube end is flipped out using a Sinskey. (C) A double-armed 10/0 prolene straight needle is penetrated through the tube end. The leading needle enters the anterior chamber through the previously made incision and is pulled through the scleral flap. (D) The tube tip and the second needle of the double-armed 10/0 prolene straight needle also enter the anterior chamber through the previously made incision and the second needle is pulled through the scleral flap. The tube end is extended to be parallel to the cornea surface. Patients maintained good tube positioning without any serious complications during average of 15 months of follow-up after operation. We believe that our method is a simple and minimally invasive surgical method for treating AGV tube touching of the corneal endothelium. However, considering the limited number of cases studied and the short follow-up period, a larger group with a longer follow-up period is necessary.


Investigating tumor-host response dynamics in preclinical immunotherapy experiments using a stepwise mathematical modeling strategy.
Immunotherapies such as checkpoint blockade to PD1 and CTLA4 can have varied effects on individual tumors. To quantify the successes and failures of these therapeutics, we developed a stepwise mathematical modeling strategy and applied it to mouse models of colorectal and breast cancer that displayed a range of therapeutic responses. Using longitudinal tumor volume data, an exponential growth model was utilized to designate response groups for each tumor type. The exponential growth model was then extended to describe the dynamics of the quality of vasculature in the tumors via [18F] fluoromisonidazole (FMISO)-positron emission tomography (PET) data estimating tumor hypoxia over time. By calibrating the mathematical system to the PET data, several biological drivers of the observed deterioration of the vasculature were quantified. The mathematical model was then further expanded to explicitly include both the immune response and drug dosing, so that model simulations are able to systematically investigate biological hypotheses about immunotherapy failure and to generate experimentally testable predictions of immune response. The modeling results suggest elevated immune response fractions (> 30 %) in tumors unresponsive to immunotherapy is due to a functional immune response that wanes over time. This experimental-mathematical approach provides a means to evaluate dynamics of the system that could not have been explored using the data alone, including tumor aggressiveness, immune exhaustion, and immune cell functionality.


Cloning of human Ca2+ homoeostasis endoplasmic reticulum protein (CHERP): regulated expression of antisense cDNA depletes CHERP, inhibits intracellular Ca2+ mobilization and decreases cell proliferation.
A monoclonal antibody which blocks InsP(3)-induced Ca(2+) release from isolated endoplasmic reticulum was used to isolate a novel 4.0 kb cDNA from a human erythroleukaemia (HEL) cell cDNA expression library. A corresponding mRNA transcript of approx. 4.2 kb was present in all human cell lines and tissues examined, but cardiac and skeletal muscle had an additional transcript of 6.4 kb. The identification in GenBank(R) of homologous expressed sequence tags from many tissues and organisms suggests that the gene is ubiquitously expressed in higher eukaryotes. The gene was mapped to human chromosome 19p13.1. The cDNA predicts a 100 kDa protein, designated Ca(2+) homoeostasis endoplasmic reticulum protein (CHERP), with two putative transmembrane domains, multiple consensus phosphorylation sites, a polyglutamine tract of 12 repeats and regions of imperfect tryptophan and histadine octa- and nona-peptide repeats. In vitro translation of the full-length cDNA produced proteins of M(r) 128000 and 100000, corresponding to protein bands detected by Western blotting of many cell types. CHERP was co-localized in HEL cells with the InsP(3) receptor by two-colour immunofluorescence. Transfection of HEL cells with antisense cDNA led to an 80% decline in CHERP within 5 days of antisense induction, with markedly decreased intracellular Ca(2+) mobilization by thrombin, decreased DNA synthesis and growth arrest, indicating that the protein has an important function in Ca(2+) homoeostasis, growth and proliferation.


Metabolomic identification of biochemical changes induced by fluoxetine and imipramine in a chronic mild stress mouse model of depression.
Metabolomics was applied to a C57BL/6N mouse model of chronic unpredictable mild stress (CMS). Such mice were treated with two antidepressants from different categories: fluoxetine and imipramine. Metabolic profiling of the hippocampus was performed using gas chromatography-mass spectrometry analysis on samples prepared under optimized conditions, followed by principal component analysis, partial least squares-discriminant analysis, and pair-wise orthogonal projections to latent structures discriminant analyses. Body weight measurement and behavior tests including an open field test and the forced swimming test were completed with the mice as a measure of the phenotypes of depression and antidepressive effects. As a result, 23 metabolites that had been differentially expressed among the control, CMS, and antidepressant-treated groups demonstrated that amino acid metabolism, energy metabolism, adenosine receptors, and neurotransmitters are commonly perturbed by drug treatment. Potential predictive markers for treatment effect were identified: myo-inositol for fluoxetine and lysine and oleic acid for imipramine. Collectively, the current study provides insights into the molecular mechanisms of the antidepressant effects of two widely used medications.


Paper-based lateral flow assay for the point-of-care detection of neurofilament light chain.
Neurofilament light chain (NF-L) is a protein found in neurons of the nervous system and is widely used as a biomarker for neurological disorders. However, the current methods for detecting NF-L levels are complicated, expensive, and require specialized equipment, making it challenging to implement in a point-of-care (POC) setting. In this study, we developed a gold nanoshell (AuNS)-assisted lateral flow assay (LFA) based test strip for the POC detection of NF-L at a low ng/mL level (8 ng/mL = 117.65 pM). The test strip is a simple, rapid, and cost-effective method for detecting NF-L, making it suitable for use in a POC setting for the diagnosis and treatment of various neurological disorders. With its ease of use and reliability, the paper-based LFA is a valuable tool for the diagnosis and management of neurological conditions.Clinical Relevance- The AuNS-assisted LFA test strip developed in this study offers a rapid, cost-effective, and simple method for detecting NF-L levels, making it of great interest to practicing clinicians for the diagnosis of various neurological diseases such as HIV-associated dementia (HID), Amyotrophic Lateral Sclerosis (ALS), and Creutzfeldt-Jakob disease (CJD).


Developing a neonatal workforce: role evolution and retention of advanced neonatal nurse practitioners.
Over the past decade more than 120 advanced neonatal nurse practitioners (ANNPs) have graduated from the Southampton based ANNP programme. To determine the scope of practice and evolving role of ANNPs and to identify factors that may affect future recruitment and retention. An open ended structured questionnaire on clinical role, working arrangements, retention and attrition, continuing education, and professional development was sent to 95 ANNPs. A response rate of 83% was achieved. There was an attrition rate of 14%, with most ANNPs remaining in their original seconding unit. Factors considered to be important for role satisfaction included a well defined role, working within a team of ANNPs, appropriate remuneration, and evidence of unit support for both role definition and continuing professional development. Although ANNPs are expensive to both train and employ, this evidence suggests that there is a good return on the investment in terms of retention to the unit and the specialty. Their role incorporates many features of advanced nursing practice as well as providing "value added" neonatal care by merging traditional medical and nursing roles and crossing professional boundaries. In 2004 the manpower challenges for neonatal units will be even more acute; these data confirm that there are effective options available but they require long term strategic planning and investment.


[Application of morcellator in transurethral bipolar plasmakinetic anatomical enucleation of the prostate].
To assess the safety and therapeutic effect of morcellator in transurethral bipolar plasmakinetic anatomical enucleation (TUPKAEP) of benign prostate hyperplasia (BPH). The clinical data of 47 patients with BPH receiving TUPKAEP between January and July, 2015 were analyzed. During the operation, morcellator was used to smash the enucleated BPH which was aspirated with subatmospheric pressure in 29 cases, and the tissue was smashed with bipolar electrosurgical loop slicing from top to bottom and aspirated by ellic suction in 18 cases. s The procedures were completed successfully in all the 47 cases. The time used for adenoma dissociation was 2.24∓1.09 with morcellator at the speed of 18.43∓6.01 g/min, and was 17.19∓11.74 min with bipolar electrosurgical loop at the speed of 1.91∓0.65 g/min; the mean total operation time was significantly shorter in morcellator group (28.13∓14.71 vs 43.22∓25.39 min). The 2 groups showed no significant difference in postoperative continuous bladder irrigation time, postoperative indwelling time of urinary catheter or postoperative hospital stay. s Morcellator is safe and feasible for application in TUPKAEP and helps to shorten the operation time.


Management of ionizing radiation injuries and illnesses, part 4: acute radiation syndrome.
To provide proper medical care for patients after a radiation incident, it is necessary to make the correct diagnosis in a timely manner and to ascertain the relative magnitude of the incident. The present article addresses the clinical diagnosis and management of high-dose radiation injuries and illnesses in the first 24 to 72 hours after a radiologic or nuclear incident. To evaluate the magnitude of a high-dose incident, it is important for the health physicist, physician, and radiobiologist to work together and to assess many variables, including medical history and physical examination results; the timing of prodromal signs and symptoms (eg, nausea, vomiting, diarrhea, transient incapacitation, hypotension, and other signs and symptoms suggestive of high-level exposure); and the incident history, including system geometry, source-patient distance, and the suspected radiation dose distribution.


DLC1 interaction with S100A10 mediates inhibition of in vitro cell invasion and tumorigenicity of lung cancer cells through a RhoGAP-independent mechanism.
The DLC1 gene encodes a Rho GTPase-activating protein (RhoGAP) that functions as a tumor suppressor in several common human cancers. The multidomain structure of DLC1 enables interaction with a number of other proteins. Here we report that the proinflammatory protein S100A10 (also known as p11), a key cell surface receptor for plasminogen which regulates pericellular proteolysis and tumor cell invasion, is a new binding partner of DLC1 in human cells. We determined that the 2 proteins colocalize in the cell cytoplasm and that their binding is mediated by central sequences in the central domain of DLC1 and the C-terminus of S100A10. Because the same S100A10 sequence also mediates binding to Annexin 2, we found that DLC1 competed with Annexin 2 for interaction with S100A10. DLC1 binding to S100A10 did not affect DLC1's RhoGAP activity, but it decreased the steady-state level of S100A10 expression in a dose-dependent manner by displacing it from Annexin 2 and making it accessible to ubiquitin-dependent degradation. This process attenuated plasminogen activation and resulted in inhibition of in vitro cell migration, invasion, colony formation, and anchorage-independent growth of aggressive lung cancer cells. These results suggest that a novel GAP-independent mechanism contributes to the tumor suppressive activity of DLC1, and highlight the importance and complexity of protein-protein interactions involving DLC1 in certain cancers.


The rise and fall of excess winter mortality in New Zealand from 1876 to 2020.
Excess winter mortality (EWM) has been used as a measure of how well populations and policy moderate the health effects of cold weather. We aimed to investigate long-term changes in the EWM of Aotearoa New Zealand (NZ), and potential drivers of change, and to test for structural breaks in trends. We calculated NZ EWM indices from 1876 (4,698 deaths) to 2020 (33,310 deaths), total and by age-group and sex, comparing deaths from June to September (the coldest months) to deaths from February to May and October to January. The mean age and sex-standardised EWM Index (EWMI) for the full study period, excluding 1918, was 1.22. However, mean EWMI increased from 1.20 for 1886 to 1917, to 1.34 for the 1920s, then reduced over time to 1.14 in the 2010s, with excess winter deaths averaging 4.5% of annual deaths (1,450 deaths per year) in the 2010s, compared to 7.9% in the 1920s. Children under 5 years transitioned from a summer to winter excess between 1886 and 1911. Otherwise, the EWMI age-distribution was J-shaped in all time periods. Structural break testing showed the 1918 influenza pandemic strain had a significant impact on trends in winter and non-winter mortality and winter excess for subsequent decades. It was not possible to attribute the post-1918 reduction in EWM to any single factor among improved living standards, reduced severe respiratory infections, or climate change.


[Submicroscopic surface organization of Candida lipolytica cells growing on hexadecane].
The ultrastructure of the cell wall surface was studied in two Candida lipolytica strains, IBPhM-160 (704) and 1, during their growth on hexadecane, using the technique of ultrathin sections. Linear three-layer membranes, membrane vesicles and complicated membrane complexes were shown to appear on the surface of the cell walls when the yeast strains were grown on hexadecane. The rate of membrane formation was greater in the cells of strain 1, and increased in the both strains by the stationary growth phase. Since no cells underwent lysis at any of the growth phases studied, the formation of membrane complexes on the yeast cell wall should reflect the reconstruction of the surface of morphologically intact cells grown on hexadecane.


Asymmetric synthesis of polyhydroxylated pyrrolizidines via transannular iodoamination with concomitant N-debenzylation.
The doubly diastereoselective "matched" conjugate addition of lithium (R)-N-but-3-enyl-N-(α-methyl-p-methoxybenzyl)amide to tert-butyl (4S,5R,E)-4,5-O-isopropylidene-2,7-dienoate (derived from d-ribose in 3 steps) and in situ enolate oxidation with (-)-camphorsulfonyloxaziridine was followed by ring-closing metathesis with Grubbs I to give a hexahydroazocine scaffold. Subsequent treatment with I(2) resulted in transannular iodoamination accompanied by loss of the α-methyl-p-methoxybenzyl group to give the corresponding pyrrolizidine scaffold as a single diastereoisomer upon direct crystallization from the crude reaction mixture. Further functional group manipulations enabled the preparation of (-)-7a-epi-hyacinthacine A1.


[Some problems for dosage form based on questionnaire surveying compliance in patients taking tamsulosin hydrochloride].
After the dosage form of tamsulosin hydrochloride was changed from a capsule to on orally disintegrating tablet (ODT, Harnal D), we often received patient complaints and noted an increase in noncompliance with medication regimens. The change in dosage form appeared to cause poor compliance by patients who had become accustomed to the light pink/white capsule over many years. Therefore, we carried out a questionnaire survey of patients taking the ODT form to determine the effects of changing the dosage form and the usefulness of the ODT. Most (92%) of respondents took the ODT with water. In addition, 16% missed taking the medicine after the change in dosage form. ODT is a dosage form that is easy to take for patient with dysphagia, or those on restricted water intake. However, it appears that elderly men and patients with visual disorders cannot distinguish the ODT from other medicines and this affects patient compliance. In conclusion, all pharmaceutical companies should consider the design of medications in terms of coloration, indications, or shape in anticipation of the aging society in future, so that patients can distinguish them. Furthermore, sufficient pharmaceutical care is needed to improve both compliance and safety management for the elderly.


Unorthodox alternative therapies marketed to treat Lyme disease.
Some patients with medically unexplained symptoms or alternative medical diagnoses suspect that they chronically suffer from the tick-borne infection Lyme disease. These patients are commonly targeted by providers of alternative therapies. This study was designed to identify and characterize the range of unorthodox alternative therapies advertised to patients with a diagnosis of Lyme disease. Internet searches using the Google search engine were performed to identify the websites of clinics and services that marketed nonantimicrobial therapies for Lyme disease. We subsequently used the PubMed search engine to identify any scientific studies evaluating such treatments for Lyme disease. Websites were included in our review so long as they advertised a commercial, nonantimicrobial product or service that specifically mentioned utility for Lyme disease. Websites with patient testimonials (such as discussion groups) were excluded unless the testimonial appeared as marketing on a commercial site. More than 30 alternative treatments were identified, which fell into several broad categories: these included oxygen and reactive oxygen therapy; energy and radiation-based therapies; nutritional therapy; chelation and heavy metal therapy; and biological and pharmacological therapies ranging from certain medications without recognized therapeutic effects on Borrelia burgdorgeri to stem cell transplantation. Review of the medical literature did not substantiate efficacy or, in most cases, any rationale for the advertised treatments. Providers of alternative therapies commonly target patients who believe they have Lyme disease. The efficacy of these unconventional treatments for Lyme disease is not supported by scientific evidence, and in many cases they are potentially harmful.


Structural analysis of Arabidopsis thaliana chromosome 5. IV. Sequence features of the regions of 1,456,315 bp covered by nineteen physically assigned P1 and TAC clones.
Nineteen P1 and TAC clones, which have been precisely localized to the fine physical map of Arabidopsis thaliana chromosome 5, were newly sequenced, and their sequence features were analysed. The total length of the clones sequenced was 1,456,315 bp. Together with the previously reported sequences, the regions of chromosome 5 that have been sequenced to date is now 5,310,105 bp. When the sequences determined in this study were subjected to similarity search against protein and expressed sequence tag (EST) databases and analysis with computer programs for gene modeling, a total of 354 potential protein-coding genes and/or gene segments were identified. The average density of the assigned genes and/or gene segments was one gene per 4,114 bp. Introns were identified in 75% of the potential protein genes, and the average number per gene and the average length of the introns were 3.7 and 194 bp, respectively. These sequence features are essentially identical to those in the previously reported sequences. The numbers of the Arabidopsis ESTs matched to each of the predicted genes have been counted to monitor the transcription level. The sequence data and gene information are available on the World Wide Web database KAOS (the Kazusa Arabidopsis data Opening Site) at http://www.kazusa.or.jp/arabi/.


Bad mood--bad activation? : The influence of emotions on the BOLD signal during finger tapping.
The aim of this study was to investigate the influence of the subject's emotional state on the BOLD signal during simple finger tapping. Twenty-nine healthy subjects participated in three functional magnetic resonance imaging (fMRI) sessions each. The sessions differed regarding emotional states, which were induced by standardized pleasant (positive condition, POS), unpleasant (negative condition, NEG), or neutral (neutral condition, NEU) pictures taken from the International Affective Picture System (IAPS) while the subjects performed a finger-tapping task (right index-to-thumb opposition). After each session, the subjects had to rate their actual mood and the pleasantness of the presented pictures. Furthermore, their state anxiety was assessed. Behavioral data were evaluated with SPSS. Functional imaging data were processed using statistical parametric mapping (SPM2) and were analyzed for main effects of emotional stimulation using an analysis of variance (ANOVA). The local maximum of interest was analyzed by a signal change analysis. Compared to the neutral emotional state, the positive and the negative emotional states caused a reduction of signal intensity changes within the primary sensorimotor hand area during simple finger tapping. The behavioral data indicated that the unpleasant pictures had a stronger effect on the emotional state than the pleasant images. According to these data the decrease in signal intensity change was more pronounced (significant; p < 0.001) in the negative condition than in the positive condition. This study showed that the emotional state of a test person is indeed influencing fMRI results and that well-balanced subjects in a neutral mood achieve the best fMRI results.


Correlation between the Aging Males' Symptoms Scale and sex steroids, gonadotropins, dehydroepiandrosterone sulfate, and growth hormone levels in ambulatory men.
Partial androgen deficiency of the aging male (PADAM) is defined as a biochemical syndrome associated with advancing age that is characterized by a deficiency in serum androgen levels. The Aging Males' Symptoms (AMS) Scale was developed to evaluate PADAM-related symptoms and is currently used worldwide; however, it has been reported that PADAM-related symptoms evaluated by this scale are not related to serum testosterone levels. In addition to testosterone, the levels of other hormones also decrease with age; therefore, multihormone alterations may influence PADAM-related symptoms. To investigate the relationship between PADAM-related symptoms evaluated by the AMS Scale and serum levels of testosterone, estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH), dehydroepiandrosterone sulfate (DHEA-S), and growth hormone (GH) in men. A total of 141 ambulatory men were recruited after excluding men with endocrine and other related diseases. All participants completed the AMS questionnaire and an analysis of serum levels of total and free testosterone (TT and FT), E2, LH, FSH, DHEA-S, and GH. The relationship between AMS scores (total and subscores) and serum hormone levels was determined. There were significant negative correlations between age and serum FT and DHEA-S levels, as well as positive correlations between age and serum LH and FSH levels, but no correlation between age and AMS scores. None of the three AMS domain scale scores and total scores significantly correlated with serum levels of TT, FT, E2, LH, FSH, DHEA-S, or GH. The results of the present study suggest that PADAM-related symptoms as evaluated by the AMS Scale are not significantly related to serum levels of TT, FT, E2, LH, FSH, DHEA-S, or GH. Because many factors related to aging are thought to contribute to the occurrence of PADAM-related symptoms, the AMS Scale may not be able to predict serum hormone levels.


Multi-scale study of condensation in water jets using ellipsoidal-statistical Bhatnagar-Gross-Krook and molecular dynamics modeling.
Homogeneous water condensation and ice formation in supersonic expansions to vacuum for stagnation pressures from 12 to 1000 mbar are studied using the particle-based Ellipsoidal-Statistical Bhatnagar-Gross-Krook (ES-BGK) method. We find that when condensation starts to occur, at a stagnation pressure of 96 mbar, the increase in the degree of condensation causes an increase in the rotational temperature due to the latent heat of vaporization. The simulated rotational temperature profiles along the plume expansion agree well with measurements confirming the kinetic homogeneous condensation models and the method of simulation. Comparisons of the simulated gas and cluster number densities, cluster size for different stagnation pressures along the plume centerline were made and it is found that the cluster size increase linearly with respect to stagnation pressure, consistent with classical nucleation theory. The sensitivity of our results to cluster nucleation model and latent heat values based on bulk water, specific cluster size, or bulk ice are examined. In particular, the ES-BGK simulations are found to be too coarse-grained to provide information on the phase or structure of the clusters formed. For this reason, molecular dynamics simulations of water condensation in a one-dimensional free expansion to simulate the conditions in the core of a plume are performed. We find that the internal structure of the clusters formed depends on the stagnation temperature. A larger cluster of average size 21 was tracked down the expansion, and a calculation of its average internal temperature as well as a comparison of its radial distribution functions (RDFs) with values measured for solid amorphous ice clusters lead us to conclude that this cluster is in a solid-like rather than liquid form. In another molecular-dynamics simulation at a much lower stagnation temperature, a larger cluster of size 324 and internal temperature 200 K was extracted from an expansion plume and equilibrated to determine its RDF and self-diffusion coefficient. The value of the latter shows that this cluster is formed in a supercooled liquid state rather than in an amorphous solid state.


[Early carcinoma of the stomach in Europe (author's transl)].
In a retrospective study of 317 816 gastroscopies between 1968 and 1973, the incidence of early carcinoma of the stomach was assessed. Among 18 887 gastric carcinomas there were 1170 early carcinomas. The most frequent kind was one of mucosal changes with defect (types II c and III according to the Japanese classification). 47% of early carcinomas were located in the lesser curvature. The diagnosis was made by biopsy in 90% of cases. The correctness of biopsy was proportional to the number of biopsies per lesion. Adding cytological examination to biopsy decreased the number of false-negative results by 30%. In most cases the history was non-specific. But in 70 patients (16%) over 40 years gastro-intestinal bleedings were the reason for endoscopic examination and led to the diagnosis of early carcinoma.


Public health and vector-borne diseases - a new concept for risk governance.
Public Health is defined as an interdisciplinary multilevel approach that deals with questions of preventing diseases at the population level. In this context, this paper focuses on vector-borne diseases as an important threat with an increasing impact on human and animal health. Emphasis is laid on an integrated health approach ('One-Health' initiative) as it recognizes the interrelated nature of both human and animal health. The importance of vector-borne diseases to new and emerging diseases in Europe was demonstrated, for example, by the recent outbreak of West Nile virus infections in Greece, Northern Italy and Hungary; the spread of Crimean-Congo haemorrhagic fever virus across Turkey, south-western countries of the former USSR and the Balkans; the dramatic increase in hantavirus infections in Germany in 2012; and the dengue virus outbreak in Portugal in the same year. This paper provides a systematic approach for the analysis, assessment and governance of emerging health risks attributed to vector-borne diseases by using a holistic approach developed by the International Risk Governance Council (IRGC), called the 'IRGC Risk Governance Framework'. It can be used by decision-makers and general Public Health authorities in order to evaluate the situation regarding any specific pathogen or Public Health risk and to decide if additional measures should be implemented.


High flow nasal cannula versus noninvasive ventilation in the treatment of acute hypercapnic respiratory failure: A systematic review and meta-analysis.
Chronic obstructive pulmonary disease can lead to acute hypercapnic respiratory failure (AHRF), often treated using noninvasive ventilation (NIV). Emerging research suggests the potential utility of high flow nasal cannula (HFNC) for AHRF. This systematic review and meta-analysis aimed to determine the effect of HFNC versus NIV on AHRF management. A search of electronic databases (CINAHL, MEDLINE, and Academic Search Complete), web sources, and trial registries was last conducted on 9 February 2023. Quality and risk of bias assessments were conducted. Meta-analyses were used to synthesise data. Seven randomised controlled trials were included. No statistically significant differences between HFNC and NIV were found within the following outcomes of interest: (i) correction of pCO2: standardised mean difference (SMD) = -0.16, 95% confidence interval (CI) (-0.34 to 0.02), p = 0.08; (ii) correction of pH: SMD = -0.05, 95% CI (-0.25 to 0.14), p = 0.59; (iii) correction of pO2: SMD = -0.15, 95% CI (-0.40 to 0.09), p = 0.22; (iv) intubation rates: risk ratio (RR) = 0.87, 95% CI (0.41 to 1.82), p = 0.71; (v) mortality rates: RR = 0.85, 95% CI (0.47 to 1.56), p = 0.61; and (vi) treatment switch: RR = 1.30, 95% CI (0.43 to 3.94), p = 0.64. More controlled trials with large sample sizes are required to investigate the management of AHRF of various aetiologies. HFNC may be used as a final exhaustive measure for COPD-related AHRF where NIV is not tolerated, and when it is not clinically indicated to extend to endotracheal intubation.


Characterization of the antifungal functions of a WGA-Fc (IgG2a) fusion protein binding to cell wall chitin oligomers.
The majority of therapeutic strategies for mycosis require the protracted administration of antifungals, which can result in significant toxicities and have unacceptable failure rates. Hence, there is an urgent need for the development of improved therapeutic approaches, and monoclonal antibody-based drugs are potentially a powerful alternative to standard antifungals. To develop a broad antibody-like reagent against mycosis, wheat germ agglutinin (WGA) was linked to the effector Fc region of murine IgG2a. The resultant WGA-Fc displayed high affinity to purified chitin and bound efficiently to fungal cell walls, co-localizing with chitin, in patterns ranging from circular (Histoplasma capsulatum) to punctate (Cryptococcus neoformans) to labeling at the bud sites (Candida albicans and Saccharomyces cerevisiae). WGA-Fc directly inhibited fungal growth in standard cultures. WGA-Fc opsonization increased fungal phagocytosis, as well augmented the antifungal functions by macrophages. Prophylactic administration of WGA-Fc fully protected mice against H. capsulatum, correlating with a reduction in lung, spleen and liver fungal burdens. Administration of WGA-Fc also dramatically diminished pulmonary inflammation. Hence, the opsonic activity of WGA-Fc effectively modulates fungal cell recognition and promotes the elimination of fungal pathogens. Therefore, we propose WGA-Fc as a potential "pan-fungal" therapeutic that should be further developed for use against invasive mycoses.


Day-to-day variability of post-concussion-like symptoms reported over time by a non-concussed cohort.
To explore the change (trend) in post-concussion-like symptoms reported over time. Longitudinal study. University students aged 18-30 years self-reported their symptoms experienced on a daily basis. Each participant was contacted via a text message each day during one of three pre-defined time zones to complete the Sport Concussion Assessment Tool 2 (SCAT2) post-concussion symptom scale on 7 consecutive days. One hundred and ten (26 males and 84 females) students completed the study on all 7 days. Only two meaningful clusters emerged and comprised of a total of 105 participants. The primary cluster included 85 participants who showed a relatively stable pattern in their symptoms reported over time. Meanwhile, a second cluster comprised of 20 participants who demonstrated a decreasing trend in the reported symptom scores. The data indicated that non-concussed participants exhibited considerable individual variability in the symptom scores reported over time. However, some participants showed a systematic decreasing trend in their symptom scores reported over the 7 days. Caution must be exercised in interpreting the serial symptom scores that are obtained following a concussion, given that this study was conducted in a non-concussed cohort.


Understanding the health risks in basic science medical students: a cross sectional survey.
This article was migrated. The article was marked as recommended. Background Medical students are usually subjected to a high workload environment and stress is one of the most important health risks that medical students encounter. The negative impact of stress on the student's mental and general health in basic science has often been under reported. Methods and Materials A cross-sectional questionnaire survey was performed in Avalon University School of Medicine (AUSOM), Curacao, amongst the first to fourth semester basic science students with an objective to explore and understand their perspectives on different health risks. ResultsMore than ⅔ of the students (79.61%, n=82) were feeling stressed out during their basic sciences. The mean stress level among the basic science students was 7.42 ± 2.13 (scale:1-10). Common health issues encountered by the students were: sleep problems, impaired concentration, low mood, mood swings, difficulty in making decisions, emotional distress, anxiety, substance abuse, and abnormal weight gain. Conclusion Although lack of sleep and behavioral problems are the most common health issues encountered by the pre-clinical medical students. There is an urgent need to implement health promotion strategies in medical curriculum for mental and physical well-being of the students.


Cytokine-mediated down-regulation of the transcription factor cAMP-response element-binding protein in pancreatic beta-cells.
Cytokines are known to induce apoptosis of pancreatic beta-cells. Impaired expression of the anti-apoptotic gene bcl-2 is one of the mechanisms involved. In this study, we identified a defect involving transcription factor cAMP-response element-binding protein (CREB) in the expression of bcl-2. Exposure of mouse pancreatic beta-cell line, MIN6 cells, to cytokines (interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma) led to a significant (p < 0.01) decrease in Bcl-2 protein and mRNA levels. Cytokines decreased (56%) the activity of the bcl-2 promoter that contains a cAMP-response element (CRE) site. Similar decreases were seen with a luciferase reporter gene driven by tandem repeats of CRE and a CREB-specific Gal4-luciferase reporter, suggesting a defect at the level of CREB. The active phospho form (serine 133) of CREB diminished significantly (p < 0.01) in cells exposed to cytokines. Examination of signaling pathways upstream of CREB revealed a reduction in the active form of Akt. Cytokine-induced decrease of bcl-2 promoter activity was partially restored when cells were cotransfected with a constitutively active form of Akt. Several end points of cytokine action including decreases in phospho-CREB, phospho-Akt, and BCl-2 levels and activation of caspase-9 were observed in isolated mouse islets. Overexpression of wild-type CREB in MIN6 cells by plasmid transfection and adenoviral infection led to protection against cytokine-induced apoptosis. Adenoviral transfer of dominant-negative forms of CREB, on the other hand, resulted in activation of caspase-9 and exaggeration of cytokine-induced beta-cell apoptosis. Together, these results point to CREB as a novel target for strategies aimed at improving the survival of beta-cells.