Metabolomic signatures of cardiac remodelling and heart failure risk in the community.
Heart failure (HF) is associated with several metabolic changes, but it is unknown whether distinct components of the circulating metabolome may be related to cardiac structure and function, and with incident HF in the community. We assayed 217 circulating metabolites in 2336 Framingham Study participants (mean age 55 ± 10 years, 53% women) without HF at baseline. We used linear and Cox regression to relate concentrations of metabolites to left ventricular (LV) diastolic dimension, LV wall thickness, LV ejection fraction, left atrial dimension, LV ventricular mass, and aortic root size cross-sectionally and to incident HF prospectively. Bonferroni-adjusted P-values <0.05 denoted statistical significance. Circulating concentrations of kynurenine [β = -0.12 cm per standard deviation (SD) increment in normalized residual of metabolite, P = 7.3 × 10-8 ] and aminoadipate (-0.11 cm per SD increment, P = 2.61 × 10-5 ) were associated with left ventricular diastolic dimension, phosphatidylcholine (carbon:double bound = 38:6) with left atrial dimension (0.10 cm per SD increment, P = 9.7 × 10-6 ), and cholesterol ester (carbon:double bound = 20:5) with left atrial dimension (0.10 cm per SD increment, P = 1.4 × 10-5 ) in multivariable-adjusted models. During an average follow-up of 15.8 (range 0.02-23.2) years, 113 participants (5%) were diagnosed with HF with reduced ejection fraction and 106 individuals (5%) with HF with preserved ejection fraction. In multivariable analyses, concentrations of phosphatidylcholine (hazard ratio 0.63, P = 1.3 × 10-5 ) and ornithine (hazard ratio 1.44, P = 0.00014) were associated with HF with reduced ejection fraction. Several metabolites, including the vasoactive metabolite kynurenine, were related to cardiac structure and function in our sample. Additional research is warranted to confirm our observations and investigate if these metabolites can risk stratify ambulatory individuals.


Outcome of surgical management of concealed penis.
To review the etiological factors, clinical presentations and outcome of our surgical technique to correct the anomaly of concealed penis. Thirty consecutive patients were treated in 2000-2004. Mean age at operation was 6.7 years (range 13 months-15.4 years). They underwent penoplasty alone (22 patients) or penoplasty with liposuction of prominent prepubic fat pad (eight patients). The medical records of all the patients were retrospectively reviewed, and 23 patients were interviewed, examined clinically and questioned about their initial complaint and the results of our technique. Mean follow up was 28 months (range 6 months-5 years). The patients most commonly presented with cosmetic (60.0%), voiding (56.6%) and psychosocial (50.5%) concerns. Three underlying anatomic defects contributing to concealment were observed: fibrotic dartos fascia with poor skin attachment at the base of the penis (93%), prominent prepubic fat pad (40%) and postoperative phimosis leading to trapped penis (26%). Early postoperative complications occurred in 4 patients (13.3%) and all were treated conservatively and successfully. Fourteen patients (46.6%) underwent secondary minor day-case operations, the majority for excision of redundant subcoronal preputial collar. Clinical examination of 23 patients showed very good results in terms of general appearance and accessibility. The older boys were generally more satisfied with the results of surgery than the parents of younger children, whose main source of dissatisfaction was the final circumcised appearance of the penis. The surgical approach used to correct concealed penis alleviates the initial complaint and provides good cosmetic and functional results with greater satisfaction in older patients. Our technique had a low early complication rate but a significant number of patients needed a secondary procedure to improve the final cosmetic results.


Palladium Nanoparticles Hardwired in Carbon Nanoreactors Enable Continually Increasing Electrocatalytic Activity During the Hydrogen Evolution Reaction.
Invited for this month's cover is the group of Maria Gimenez-Lopez at the University of Santiago de Compostela. The image shows the self-improving electrochemical activity of palladium nanoparticles hardwired into a graphitic step-edge for hydrogen production. The Full Paper itself is available at 10.1002/cssc.202101236.


Mechanism of effector cell blockade--IV. Induction by monoclonal anti-mu or anti-idiotypic antibody, role of secreted IgM and mechanism of decreased secretion.
Effector cell blockade (ECB), the inhibition of antibody synthesis by antigen or antigen-antibody complexes, was shown to be induced by monoclonal anti-mu or anti-idiotypic antibodies. An initial event in the induction of blockade was demonstrated to be the build up on the cell surface of a complex of membrane Ig, and either antigen or anti-mu or anti-Id antibody, together with secreted IgM. Trapping of secreted IgM in this complex was not, however, sufficient to account for the overall reduction in antibody secretion. This reduction was not due to reduced translation of mu mRNA, but rather to blockade of the normal process of assembly of the IgM molecule which was followed by increased intracellular degradation of intermediate precursor molecules. These findings have shown ECB to be a rapidly induced negative feedback control of IgM secretion which, at least initially, could be reversed. ECB may act in vivo as a flexible first-line mechanism for prevention of overproduction of IgM antibodies.


[Metabonomic study of the urine of rat acute gouty arthritis model].
[ To analysis the metabonome characteristics of the urine of MSU crystal-induced acute gouty arthritis rats by the method of metabolomics. Based on the method of metabolomics, which applies LC/MS as data acquisition platform, incorporating with the means of stoechiometry such as principal component analysis, we analyzed the metabonome difference between the urine of acute gouty arthritis rats and that of normal rats. Compare with control group, the metabolism status of acute gouty arthritis model group deviated. After that, with the time lapsed, it retrieved gradually to the incipient metabolism status. The variation of metabolism locus of rats measured by the methods of metabolomics properly reflects the genesis, development, and recuperation course of acute gouty arthritis. The whole metabolism status of rat model is able to be presented finely with the method of metabolomics. The metabolomics study could offer a satisfactory research approach to acute gouty arthritis.


Tailoring surface carboxyl groups of mesoporous carbon boosts electrochemical H2O2 production.
Oxygen-doped porous carbon materials have been shown promising performance for electrochemical two-electron oxygen reduction reaction (2e- ORR), an efficient approach for the safe and continuous on-site generation of H2O2. The regulation and mechanism understanding of active oxygen-containing functional groups (OFGs) remain great challenges. Here, OFGs modified porous carbon were prepared by thermal oxidation (MC-12-Air), HNO3 oxidation (MC-12-HNO3) and H2O2 solution hydrothermal treatment (MC-12-H2O2), respectively. Structural characterization showed that the oxygen doping content of three catalysts reached about 20%, with the almost completely maintained specific surface area (exception of MC-12- HNO3). Spectroscopic characterization further revealed that hydroxyl groups are mainly introduced into MC-12-Air, while carboxyl groups are mainly introduced into MC-12- HNO3 and MC-12- H2O2. Compared with the pristine catalyst, three oxygen-functionalized catalysts showed enhanced activity and H2O2 selectivity in 2e- ORR. Among them, MC-12-H2O2 exhibited the highest catalytic activity and selectivity of 94 %, as well as a considerable HO2- accumulation of 46.2 mmol L-1 and excellent stability in an extended test over 36 h in a H-cell. Electrochemical characterization demonstrated the promotion of OFGs on ORR kinetics and the greater contribution of carboxyl groups to the intrinsically catalytic activity. DFT calculations confirmed that the electrons are transferred from carboxyl groups to adjacent carbon and the enhanced adsorption strength toward *OOH intermediate, leading to a lower energy barrier for forming *OOH on carboxyl terminated carbon atoms.


14-3-3ζ interacts with hepatocyte nuclear factor 1α and enhances its DNA binding and transcriptional activation.
14-3-3 proteins regulate numerous cellular processes through interaction with a variety of proteins, and have been identified as HNF1α binding partner by mass spectrometry analysis in our previous study. In the present study, the interaction between 14-3-3ζ and HNF1α has been further validated by in vivo and in vitro assays. Moreover, we have found that overexpression of 14-3-3ζ potentiated the transcriptional activity of HNF1α in cultured cells, and silencing of 14-3-3ζ by RNA interference in HepG2 cells specifically affected the HNF1α-dependent gene expression. Furthermore, we have demonstrated that 14-3-3ζ is recruited to endogenous HNF1α responsive promoters and enhances HNF1α binding to its cognate DNA sequences. In addition, we have also provided evidence that the association between HNF1α and 14-3-3ζ is phosphorylation-dependent. Taken together, these results suggest that 14-3-3ζ may be an endogenous physiologic regulator of HNF1α.


A Comprehensive Review of Nanoparticles for Oral Delivery in Food: Biological Fate, Evaluation Models, and Gut Microbiota Influences.
Edible nanoparticles are being developed for the oral delivery of nutrients to improve human health and well-being. Because of the extremely demanding conditions foods experience within the gastrointestinal tract, fundamental knowledge about the biological fate of encapsulated nutrients must be constantly revised. In this review, we first provide an overview of the fundamental absorption pathways of ingested foods and then discuss the evaluation models available to test and predict the biological fate of nutrient-loaded nanoparticles. Then, owing to their importance for human health, the impacts of nanoparticles on the gut microbiota are evaluated. Lastly, the limitations of current evaluation methods are highlighted and future research directions on the study and application of edible nanoparticles for the oral delivery of bioactive food compounds are discussed.


Multiplex gene knockout raises Ala-Gln production by Escherichia coli expressing amino acid ester acyltransferase.
L-Alanyl-L-Glutamine (Ala-Gln) is a common parenteral nutritional supplement. In our previous study, the recombinant whole-cell catalyst Escherichia coli BL21(DE3) overexpressing α-amino acid ester acyltransferase (BPA) to produce Ala-Gln has high activity and has been applied to large-scale production experiments. However, the degradation of Ala-Gln is detected under prolonged incubation, and endogenous broad-spectrum dipeptidase may be the primary cause. In this study, a CRISPR-Cas9 method was used to target pepA, pepB, pepD, pepN, dpp, and dtp to knock out one or more target genes. The deletion combination was optimized, and a triple knockout strain BL21(DE3)-ΔpepADN was constructed. The degradation performance of the knockout chassis was measured, and the results showed that the degradation rate of Ala-Gln was alleviated by 48% compared with the control. On this basis, BpADNPA (BPA-ΔpepADN) was built, and the production of Ala-Gln was 129% of the BPA's accumulation, proving that the ΔpepADN knockout conducive to the accumulation of dipeptide. This study will push forward the industrialization process of Ala-Gln production by whole-cell catalyst Escherichia coli expressing α-amino acid ester acyltransferase. KEY POINTS: • Endogenous dipeptidase knockout alleviates the degradation of Ala-Gln by the chassis • The balanced gene knockout combination is pepA, pepD, and pepN • The accumulation of Ala-Gln with BpADNPA was 129% of the control.


Differentiation of respiratory epithelium in a 3-dimensional co-culture with fibroblasts embedded in fibrin gel.
Tracheal tissue engineering is a promising option for the treatment of tracheal defects. In a previous study we proved the suitability of fibrin gel as a scaffold for tracheal tissue engineering. This study investigates whether the differentiation of respiratory epithelium can be increased by culturing epithelial cells in a three dimensional system containing fibroblasts embedded into fibrin gel. Respiratory epithelial cells were isolated from porcine trachea, seeded onto a fibrin gel and kept in air-liquid-interface culture for 33 days. Morphology as well as pan-cytokeratin, MUC5AC and claudin-1 expression of cells cultured on pure fibrin gel were compared to culture on gels containing fibroblasts. After two weeks, cells seeded on pure fibrin gel were multilayered, showed hyperproliferation and dedifferentiation. Co-cultured cells built up a pseudostratified epithelium. The differentiation and organization of epithelial structure improved with respect to time. After four weeks, morphology of the co-cultured respiratory epithelium resembled native tracheal epithelium. Immunohistochemistry showed that respiratory epithelium co-cultured with fibroblasts had an increasing similarity of pan-cytokeratin expression compared to native trachea. Cells cultured without fibroblasts differed in pan-cytokeratin expression from native trachea and did not show any improvement of differentiation. Immunohistochemical staining of MUC5AC and claudin-1 proved seeded cells being respiratory epithelial cells. This study indicates that adding fibroblasts to fibrin gel positively influences the differentiation of respiratory epithelium.


A hypothalamomedullary network for physiological responses to environmental stresses.
Various environmental stressors, such as extreme temperatures (hot and cold), pathogens, predators and insufficient food, can threaten life. Remarkable progress has recently been made in understanding the central circuit mechanisms of physiological responses to such stressors. A hypothalamomedullary neural pathway from the dorsomedial hypothalamus (DMH) to the rostral medullary raphe region (rMR) regulates sympathetic outflows to effector organs for homeostasis. Thermal and infection stress inputs to the preoptic area dynamically alter the DMH → rMR transmission to elicit thermoregulatory, febrile and cardiovascular responses. Psychological stress signalling from a ventromedial prefrontal cortical area to the DMH drives sympathetic and behavioural responses for stress coping, representing a psychosomatic connection from the corticolimbic emotion circuit to the autonomic and somatic motor systems. Under starvation stress, medullary reticular neurons activated by hunger signalling from the hypothalamus suppress thermogenic drive from the rMR for energy saving and prime mastication to promote food intake. This Perspective presents a combined neural network for environmental stress responses, providing insights into the central circuit mechanism for the integrative regulation of systemic organs.


Nanodentistry: A Paradigm Shift-from Fiction to Reality.
Nanodentistry is an emerging field with significant potential to yield new generation of technologically advanced clinical tools and devices for oral healthcare. Nanoscale topology and quantitative biomechanical or biophysical analysis of dental surfaces are of significant interest. In particular, using Atomic force microscopy techniques-diseases such as dental caries, tooth hypersensitivity, and oral cancer can be quantified based on morphological, biophysical and biochemical nanoscale properties of tooth surface itself and dental materials or oral fluids such as saliva. An outlook on future "nanodentistry" developments such as saliva exosomes based diagnostics, designing biocompatible, antimicrobial dental implants and personalized dental healthcare is presented. This article examines current applications of nanotechnology alongside proposed applications in the future and aims to demonstrate that, as well as a good deal of science fiction, there is some tangible science fact emerging from this novel multidisciplinary science.


The use of a retroviral vector to identify foetal striatal neurones transplanted into the adult striatum.
A retrovirus which encodes beta-galactosidase was used to infect embryonic rat striatal cells before grafting these cells into the lesioned adult rat striatum. Examination of the grafts after long term survival (8 months) revealed that a few small and large cells expressed large amounts of bacterial beta-galactosidase activity. The larger diameter cells were identified as neurones by their size, shape and presence of neuronal processes. The identity of the small diameter cell types was not established.


Methodological approaches for conducting follow-up research with clinical trial participants: a scoping review and expert interviews.
Evidence-based establishment and implementation of best principles, laws and ordinances that regulate clinical research depend on the consultation and involvement of trial participants. Yet, guidance on methodological approaches to obtain trial participants' perspectives is currently missing. This scoping review therefore aimed at identifying, describing and evaluating research approaches to obtain trial participants' feedback on their views and experiences. We searched the electronic databases Medline and PsycInfo via Ovid and the Web of Science Core Collection. Clinical trials were included that involved adult participants that were conducted in selected high-income countries and that were published in peer-reviewed journals between 1985 and 2018. In addition, 29 expert interviews were conducted between March and May 2019. Out of 5994 identified records, 23 articles were included in this review. Twelve studies used a qualitative approach, 10 were quantitative and one study used a mixed-method design. More than 75% of all work was conducted in the USA and the UK. The scoping review and the expert interviews highlighted that recruitment of participants was generally done through direct contact by principal investigators and/or study nurses or through searches in de-identified patient databases. Authors used surveys, interviews or focus group discussions. The tools used were either based on existing validated ones or developed and verified de novo with the support of experts and/or patient representatives. To our knowledge, this is the first methodological literature review of approaches to researching experiences of clinical trial participants where findings were triangulated with expert interviews. Covering a range of indications, trial phases and study settings, it demonstrates that clinical trial participant perspectives and experience is heavily under-researched. This casts doubt on the overall robustness of available insight into trial participants' views and experiences. Our results demonstrate that the methodology for studying participant opinion, perception and experience should be adapted to the measure of interest and conform to the study population. Using valid patient experience data is the basis to evaluate existing legal and regulatory human subject research frameworks for their appropriateness from a patient perspective. Such an evaluation will be critical to empower research participants.


Anti-androgenic activities of Ganoderma lucidum.
The inhibitory effects of methanol extracts of 19 edible and medicinal mushrooms on 5alpha-reductase activity were examined. The extract of Ganoderma lucidum Fr. Krast (Ganodermataceae) showed the strongest 5alpha-reductase inhibitory activity. The treatment of the fruit body of Ganoderma lucidum or the extract prepared from it significantly inhibited the testosterone-induced growth of the ventral prostate in castrated rats. These results showed that Ganoderma lucidum might be a useful ingredient for the treatment of benign prostatic hyperplasia (BPH).


STAT5a promotes the transcription of mature mmu-miR-135a in 3T3-L1 cells by binding to both miR-135a-1 and miR-135a-2 promoter elements.
Despite extensive research on the role of miR-135a in biological processes, very little attention has been paid to the regulation of its transcription. We have previously reported that miR-135a suppresses 3T3-L1 preadipocyte differentiation and adipogenesis by directly targeting the adenomatous polyposis coli (APC) gene and activating the canonical Wnt/β-catenin signaling pathway, but the regulatory elements that regulate the expression of the two isoforms of miR-135a (miR-135a-1 and miR-135a-2) remain poorly understood. Here, by using deletion analysis, we predicted two binding sites (-874/-856 and -2020/-2002) for the transcription factor Signal Transducers and Activators of Transcription 5a (STAT5a) within the core promoters of miR-135a-1 and miR-135a-2 (-1128/-556 and -2264/-1773), and the subsequent site-directed mutagenesis indicated that the two STAT5a binding sites regulated the activity of the miR-135a-1 and miR-135a-2 promoters. The binding of STAT5a to the miR-135a-1/2 core promoters in vitro and in cell culture was identified by electrophoretic mobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) assays. Overexpression and RNAi knockdown of STAT5a showed that the transcription factor regulated the endogenous miR-135a expression. Additionally, The expression time frame of STAT5a and APC indicated a potential negative feedback between them. In sum, the overall results from this study indicate that STAT5a regulates miR-135a transcription by binding to both miR-135a-1 and miR135a-2 promoter elements and the findings provide novel insights into the molecular regulatory mechanisms of miR-135a during adipogenesis.


A rapid assessment of stimulus properties of morphine.
The difficulty in assessing stimulus properties of drugs becomes apparent when the test drug, like morphine, carries both aversive and reinforcing effects at certain doses. Mice (ICR Crj strain) were trained in a passive avoidance conditioning using a two-compartment shuttle-box. On alternate days, morphine (3.0 mg/kg) was paired with shock in one compartment and saline with shock in the other compartment. A total of 3 morphine/saline pairings were given. Animals were then tested 7 times, one test per day, with saline and different doses of morphine (0.75, 1.12, 1.32, 0.93, 1.50, 3.0 mg/kg) to reveal the stimulus properties of morphine. The preference for the morphine-conditioned safe compartment after morphine injections was used to indicate that the animals associated some "stimulus" or "motivational" properties of morphine with the cues of the safe compartment. The animals discriminated very well between saline and low doses of morphine on the one hand, and higher doses of morphine (close to that given during conditioning) on the other. The discontinuity between injections responded to as saline and those responded to as morphine was virtually complete between 1.12 and 1.32 mg/kg of morphine. These findings demonstrate that the present method can be used to establish an association between some stimulus properties of morphine and avoidance of shock. Accordingly, the successful discrimination of the animals between the two compartments revealed some stimulus properties of morphine.


Differential effect of IL-15 and IL-2 on survival of phytohemagglutinin-activated umbilical cord blood T cells.
Cytokine immunotherapy using interleukin (IL)-2 and IL-15 may be beneficial for patients receiving umbilical cord blood (CB) transplantation by ameliorating post-transplant T-cell apoptosis. The present study compares the differential effect of IL-15 and IL-2 on survival of phytohemagglutinin (PHA)-activated CB and adult peripheral blood (APB) T lymphocytes. In comparison with IL-2, IL-15 preferentially enhanced the survival of CB PHA-activated T cells by decreasing the caspase-3+ population and by increasing the Bcl-2+ population. Activated CB T cells were more susceptible to TNF-alpha-induced apoptosis compared to their adult counterparts. However, the susceptibility could be abrogated by IL-15 but not by IL-2. IL-15 but not IL-2 down-regulated CD28 expression on both activated CB and APB CD8+ T cells, with a much greater effect seen with CB. Western-blot analysis shows that IL-15 Ralpha is deficient in CB compared to APB immediately after PHA stimulation, while culturing with IL-15 significantly enhanced CB IL-15 Ralpha expression to levels comparable to that of adults. Thus, IL-15 may provide a better therapeutic choice for immune reconstitution than IL-2 post-CB transplantation due to its preferential survival enhancing effect on CB T cells.


Hyaluronan increases glomerular cyclooxygenase-2 protein expression in a p38 MAP-kinase-dependent process.
Accumulation of the matrix glycosaminoglycan hyaluronan occurs in many types of renal injury but could follow any provision of hyaluronan substrate to the kidney, for example, through widespread use of supplementary glucosamine in osteoarthritic conditions. Hyaluronan can increase cyclooxygenase-2 (COX-2) protein and prostaglandin production. This effect was characterized in rat renal glomeruli to determine the cellular mechanism of activation. Isolated glomeruli were treated with purified hyaluronan (molecular mass 2 x 105 D) for up to 24 hours. An increase in cyclooxygenase capacity and COX-2 protein was shown to follow the activation of p38-mitogen-activated protein (MAP) kinase and to be inhibited by a specific pyridinyl imadazole inhibitor (SB 202190). Hyaluronan-induced activation of cytosolic phospholipase A2 also was shown to be a p38 MAP kinase effect in these preparations. Prostaglandin production was inhibited by COX-2-specific non-steroidal anti-inflammatory compounds (NS-398 and celecoxib) but, as shown for many non-steroidal anti-inflammatory drugs (NSAIDs), an increase in COX-2 protein accompanied this inhibition. We propose that these findings have clinical relevance. Prostaglandins have a number of important intrarenal regulatory effects leading to some debate over renal function with the use of NSAIDs. Where hyaluronan is increased, p38 MAP-kinase-dependent provision of prostaglandin substrate, via activation of cytosolic phospholipase A2, and a concomitant increase in cyclooxygenase-2 protein would raise renal prostaglandin levels. While NSAID treatment can prevent a rise in prostaglandin levels, it needs to be maintained to avoid possible exacerbation of pro-inflammatory conditions due to increased COX-2 protein levels.


Multiple trypanosome infections in wild tsetse in Côte d'Ivoire detected by PCR analysis and DNA probes.
Trypanosomes were isolated from the midguts of Glossina palpalis palpalis, G. pallicera pallicera and G. nigrofusca nigrofusca captured around the village of Guediboua, South West of Daloa in Côte d'Ivoire. Seventy of the 124 isolates, obtained from 688 flies, were examined for four different kinds of trypanosome using the Polymerase Chain Reaction (PCR). Prevalences were: Trypanozoon 46%, riverine-forest T. congolense 86% and savannah T. congolense 54%. Only 29 samples were examined for T. simiae but it was not detected. Just 30% of the infections involved a single kind of trypanosome; the remainder were mixtures either of two (37%) or all three (27%) of the target organisms. 30 of the 70 isolates examined by PCR were successfully amplified to provide material for DNA probe hybridization. To a large extent, DNA probes confirmed the PCR results; all (28/28) of the riverine-forest and 82% (18/22) of the savannah T. congolense infections were identified. However, only 8% (1/13) of the PCR positives for Trypanozoon hybridized with the appropriate DNA probe. No T. simiae or T. godfreyi infections were identified using DNA probes but a large proportion (97%) (29/30) of the probed midguts were shown to contain Kilifi T. congolense. Four isolates out of 70 could not be identified by any method. There was no obvious association between the different species of flies and the infecting trypanosomes.


Correction to: Genome-wide identifcation and characterization of the C2 domain family in Sorghum bicolor (L.) and expression profles in response to saline-alkali stress.
[This corrects the article DOI: 10.1007/s12298-022-01222-3.].


Caloric restriction counteracts age-related changes in the activities of sorbitol metabolizing enzymes from mouse liver.
The influence of caloric restriction (CR) on hepatic sorbitol-metabolizing enzyme activities was investigated in young and old mice. Aldose reductase and sorbitol dehydrogenase activities were significantly lower in old CR mice than in old controls. Young CR mice showed decreased aldose reductase activity and a trend towards decreased sorbitol dehydrogenase when compared to controls. Metabolites of the pathway, namely sorbitol, glucose and fructose were decreased by CR in young and old mice. Pyruvate levels were decreased by CR in both young and old mice, while lactate decreased only in old CR. Malate levels increased in old CR but remained unchanged in young CR, when compared with controls. Accordingly, the lactate/pyruvate and malate/pyruvate ratios in young and old CR mice were increased, indicating increased NADH/NAD and NADPH/NADP redox couples, respectively. The results indicate that decreased glucose levels under CR conditions lead to decreased sorbitol pathway enzyme activities and metabolite levels, and could contribute to the beneficial effects of long-term CR through decreased sorbitol levels and NADPH sparing.


Identification of third stage larval types of cyathostomins of equids: An improved perspective.
Cyathostomins comprise around 50 parasite species of equids, offering a great challenge regarding their individual identification. The objective of our work was to improve identification of infective third stage larvae (L3) with a morphological key supplemented with detailed scientific illustrations based on our research and available literature. The highlighted features were; the number, arrangement, and shape of intestinal cells (IC), general features and the total body length of the eight different Cyathostomin sensu latum types (Type A, B, C, D, E, F, G, H), Gyalocephalus capitatus, and Posteriostomum spp. Due to variability, we were unable to define final body length measurements to differentiate L3 of cyathostomins. However, IC characteristics displayed a higher difference between L3 types than total body length. Through the number and arrangement of IC, 14 species were classified within three larval types. The classification of L3 into distinct larval types sensu latum gives us the advantage of reducing the number of probable species presented in equine faecal samples using a low-cost technique when monitoring the parasite fauna present in individual horses or on the farm level. The present improved identification key shall increase the diagnostic capabilities of classical equine parasitology techniques, using general L3 morphology thereby pragmatically improving regional and transnational epidemiological and biodiversity studies. The present key may also assist in defining the cyathostomin community in cyathostominosis clinical cases and within drug resistant populations across different management systems and geographical locations.


Unprovoked Venous Thromboembolism: The Search for the Cause.
Venous thromboembolism (VTE) is a common vascular disorder encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE). There is no data on global estimates of VTE prevalence and incidence. Most patients with unprovoked VTE require secondary thromboprophylaxis upon the completion of the primary treatment phase if they have no high bleeding risk. Risk prediction models can help identify patients at low VTE recurrence risk who may discontinue anticoagulation upon the completion of the primary treatment phase.


Associations between psychological distress and hair cortisol during pregnancy and the early postpartum: A meta-analysis.
Pregnancy and the early postpartum signify a period of high stress. Perinatal stress can include psychological distress (PD), such as anxiety, depression, and stress, as well as neuroendocrine stress, indexed by activation of the hypothalamic-pituitary-adrenal (HPA) axis and the production of the hormone cortisol. Elevated PD and cortisol levels during the perinatal period can have long-term implications for the mother and child. Methodological advances have enabled the sampling of cortisol from hair, to provide a retrospective marker of HPA axis activity over several months. Despite knowing that maternal PD and HPA activity during the perinatal period independently impact health and development, research to date is unclear as to the association between maternal PD and hair cortisol. The present meta-analysis included 29 studies to assess the strength of the relation between maternal PD and hair cortisol levels during pregnancy and the early postpartum period. Several sample and methodological factors were assessed as moderators of this effect. Analyses were conducted using multilevel meta-analysis. Results of the multilevel meta-analysis indicated that the overall effect size between PD and HCC was small but not significant z = 0.039, 95% CI [- 0.001, 0.079]. Moderator analyses indicated that the strength of the association between PD and hair cortisol was moderated by pregnancy status (i.e., effects were stronger in pregnant compared to postpartum samples), timing of HCC and PD measurements (i.e., effects were larger when PD was measured before HCC) and geographic location (i.e., effects were larger in North American studies). The findings advance our understanding of the link between PD and HPA activity during the perinatal period, a time of critical impact to child development.


Comparative analysis of sequence variation in gp116 and gp55 components of glycoprotein B of human cytomegalovirus.
Sequence variation in the gp116 component of cytomegalovirus envelope glycoprotein B was examined in 11 clinical strains and compared with variation in gp55. The peptide variation in gp116 was found to be strongly clustered at codons 27-67, 440-460, and to a lesser extent at codons 181-194, 311-317, and 387-397. Strains adopted one of three to four peptide configurations at these loci, usually consistent with their gp55 sequence configuration. Two instances were observed of a sequence variation arising from recombination within gB. The limited, largely group-specific nature of variation in both gp116 and gp55 facilitates functional and immunologic analyses.


Differential antimitogenic effectiveness of atrial natriuretic peptides in primary versus subcultured rat aortic smooth muscle cells: relationship to expression of ANF-C receptors.
Previous studies have shown that atrial natriuretic peptides inhibit mitogenesis in subcultured aortic smooth muscle cells by a mechanism that appears to be mediated via the C-type or "clearance" receptor. In the current study, we have compared the antimitogenic effect of these peptides in serum-stimulated primary aortic smooth muscle cell cultures and in subcultured cells. A series of atrial peptides, including rANF99-126, rANF103-126, and rANF103-125, were only poorly antimitogenic in serum-stimulated primary cultures, whereas des[Cys105,Cys121] rANF104-126 which binds selectively to the ANF-C receptors had no antimitogenic activity. In contrast, in subcultured cells (between subcultures 3 and 25), rANF99-126, rANF103-126, rANF103-126, Cys116rANF102-116, and des[Cys105,Cys121] rANF104-126 inhibited serum-induced [3H]thymidine incorporation (IC50 in the range of 10-50 nM), with maximal inhibition of 40-70%. The lack of antimitogenic activity in primary cultures did not appear to be related to the lack of cGMP elevation elicited by atrial peptides or to an inherent insensitivity to the action of antimitogens, because primary cultures were responsive to the cGMP-elevating effect of atrial peptides and the cells were more rather than less sensitive to the antimitogenic effect of the nitric-oxide-generating vasodilator, SNAP, as compared to subcultured cells. Analysis of the affinity and binding capacity of freshly isolated aortic membranes, and primary or secondary cultures for [125I]rANF99-126, revealed that the number of ANF receptors increased by tenfold, following subculture. Moreover, subcultured cells contained receptors with increased binding affinity for peptide analogues selective for the ANF-C-type receptor. Covalent cross-linking studies with (125I)rANF99-126 confirmed that membranes prepared from fresh aortae predominantly expressed the ANF-A/guanylate cyclase receptor, whereas in subcultured cells the predominantly cross-linked protein was the ANF-C-type receptor, with receptors in primary cultures occupying an intermediate position. These results suggest that the binding and antimitogenic activity of atrial peptides in aortic smooth muscle cells depends on the phenotypic state of these cells. Moreover, the increased antimitogenic potency of atrial peptides in secondary cultures may reflect increased expression of the ANF-C-type receptors.


Investigation of certain physical-chemical features of oil recovery by an optimized alkali-surfactant-foam (ASF) system.
The objective of this study is to discover a synergistic effect between foam stability in bulk and micro-emulsion phase behaviour to design a high-performance chemical system for an optimized alkaline-surfactant-foam (ASF) flooding for enhanced oil recovery (EOR). The focus is on the interaction of ASF chemical agents with oil in the presence and absence of a naphthenic acid component and in situ soap generation under bulk conditions. To do so, the impact of alkalinity, salinity, interfacial tension (IFT) reduction and in situ soap generation was systematically studied by a comprehensive measurement of (1) micro-emulsion phase behaviour using a glass tube test method, (2) interfacial tension and (3) foam stability analysis. The presented alkali-surfactant (AS) formulation in this study lowered IFT between the oil and aqueous phases from nearly 30 to 10-1-10-3 mN/m. This allows the chemical formulation to create considerably low IFT foam flooding with a higher capillary number than conventional foam for displacing trapped oil from porous media. Bulk foam stability tests demonstrated that the stability of foam diminishes in the presence of oil with large volumes of in situ soap generation. At lower surface tensions (i.e. larger in situ soap generation), the capillary suction at the plateau border is smaller, thus uneven thinning and instabilities of the film might happen, which will cause acceleration of film drainage and lamellae rupture. This observation could also be interpreted by the rapid spreading of oil droplets that have a low surface tension over the lamella. The spreading oil, by augmenting the curvature radius of the bubbles, decreases the surface elasticity and surface viscosity. Furthermore, the results obtained for foam stability in presence of oil were interpreted in terms of phenomenological theories of entering/spreading/bridging coefficients and lamella number.


OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY BIOMARKERS AND MICROPERIMETRY FEATURES IN BEHÇET'S UVEITIS.
To evaluate the parafoveal macular microvasculature and the macular function in patients with retinal vasculitis associated with Behçet's uveitis. In 14 patients with inactive Behçet's uveitis and 26 control individuals (13 with nonocular Behçet's syndrome and 13 healthy subjects), we analyzed the retinal nerve fiber layer, ganglion cell layer, full retinal thickness, foveal avascular zone area and sectorial parafoveal vascular density in the superficial vascular plexus, intermediate capillary plexus, and deep capillary plexus using SPECTRALIS optical coherence tomography (OCT) 2 and OCT angiography. Macular sensitivity was analyzed using an MP-3 microperimeter. Eighteen eyes (78%) had a best-corrected visual acuity ≥ 20/25. Significant differences were found in Behçet's uveitis in comparison with the controls on the OCT and OCT angiography: 14.8%, 22.4%, and 14.9% ganglion cell layer thinning in the global, nasal, and inferior sectors, respectively; 6%, 13.2%, and 7.5% full retinal thickness thinning in the superior, nasal, and inferior sectors; and 16.8%, 14.9%, 23.6%, 15.8%, and 12.6% mean deep capillary plexus density reduction in the global, superior, nasal, inferior, and temporal sectors. Microperimetry data demonstrated significant mean reductions of 21% and 23.6% in central and average macular sensitivities and 28.8%, 40.4%, 27.7%, and 24.2% in the superior, nasal, inferior, and temporal sectors, respectively. Outer plexiform layer elevations were observed in Behçet's uveitis (69.6%). Behçet's uveitis presented structural and functional macular damage despite good best-corrected visual acuity, mainly affecting the nasal sector and the deep capillary plexus. On OCT and OCT angiography, quantitative and qualitative changes can be valuable biomarkers of ocular involvement in Behçet's syndrome.


Arachidonate 5-lipoxygenase (ALOX5) gene polymorphism is associated with Alzheimer's disease and body mass index.
Dementias of old age, in particular Alzheimer's disease (AD), pose a growing threat to the longevity and quality of life of individuals as well as whole societies world-wide. The risk factors are both genetic and environmental (life-style) and there is an overlap with similar factors predisposing to cardiovascular diseases (CVD). Using a case-control genetic approach, we have identified a SNP (rs10507391) in ALOX5 gene, previously associated with an increased risk of stroke, as a novel genetic risk factor for AD. ALOX5 gene encodes a 5'-lipoxygenase (5'-LO) activating protein (FLAP), a crucial component of the arachidonic acid/leukotriene inflammatory cascade. A-allele of rs4769874 polymorphism increases the risk of AD 1.41-fold (p<0.0001), while AA genotype does so 1.79-fold (p<0.0001). In addition, GG genotype of rs4769874 polymorphism is associated with a modest increase in body mass index (BMI). We discuss potential biochemical mechanisms linking the SNP to AD and suggest possible preventive pharmacotherapies some of which are based on commonly available natural products. Finally, we set the newly identified AD risk factors into a broader context of similar CVD risk factors to generate a more comprehensive picture of interacting genetics and life-style habits potentially leading to the deteriorating mental health in the old age.


Scarlett Letter: A study based on experience of stigma by COVID-19 patients in quarantine.
Stigma around COVID-19 is a major barrier in global efforts to control the COVID 19 pandemic. Limited data is available regarding stigma faced by COVID-19 patients in low- and middle-income countries (LMIC). The aim of the current study was to explore the stigma experienced by hospitalized patients with COVID-19 illness in Lahore, Pakistan. Following Institutional Review Board approval and informed consent, patients were assessed using modified HIV short form stigma scale and open-ended questions. Questions focused on experiences, feelings, and opinions as to how patients feel and how they were treated prior to and during the hospitalization. Data analysis for quantitative data was performed using SPSS-20, while qualitative responses were interpreted by content analysis method. One hundred and fourteen patients were interviewed (Mean age 38.8 years + 15.3) with 53.5% being males. Widespread experience of stigma was reported by patients particularly for concerns about public attitudes (7.43 + 1.43) & disclosure (6.89 + 1.45). Main themes which emerged from the qualitative responses were social stigma and rejection, humiliating behaviour of others, breach of confidentiality, loss of trust/ respect, and impact of COVID-19 diagnosis on their business. Existence of significant stigma among COVID-19 patients isolated in a tertiary care hospital in a LMIC highlights the need for culturally sensitive strategies to address it.


A global assessment of the mixed layer in coastal sediments and implications for carbon storage.
The sediment-water interface in the coastal ocean is a highly dynamic zone controlling biogeochemical fluxes of greenhouse gases, nutrients, and metals. Processes in the sediment mixed layer (SML) control the transfer and reactivity of both particulate and dissolved matter in coastal interfaces. Here we map the global distribution of the coastal SML based on excess 210Pb (210Pbex) profiles and then use a neural network model to upscale these observations. We show that highly dynamic regions such as large estuaries have thicker SMLs than most oceanic sediments. Organic carbon preservation and SMLs are inversely related as mixing stimulates oxidation in sediments which enhances organic matter decomposition. Sites with SML thickness >60 cm usually have lower organic carbon accumulation rates (<50 g C m-2 yr-1) and total organic carbon/specific surface area ratios (<0.4 mg m-2). Our global scale observations reveal that reworking can accelerate organic matter degradation and reduce carbon storage in coastal sediments.


Examining the validity of autism spectrum disorder subtypes.
The classification of autism spectrum disorders (ASDs) is a topic of debate among clinicians and researchers with many questioning the validity of the distinction among subtypes. This manuscript examines the validity of three ASD subtypes (Autism, Asperger's, and PDDNOS) by reviewing 22 studies published between 1994 and 2006. We reviewed studies that examined differences between the subtypes in terms of clinical and demographic characteristics, neuropsychological profiles, comorbidity, and prognosis. Results largely did not support differences between autism and Asperger's disorder based on current diagnostic criteria. Overall, the most salient group differences were noted when samples were categorized on IQ. Drawing definitive conclusions is difficult due to the inconsistent application of diagnostic criteria and circularity in methods.


Ensuring privacy protection in the era of big laparoscopic video data: development and validation of an inside outside discrimination algorithm (IODA).
Laparoscopic videos are increasingly being used for surgical artificial intelligence (AI) and big data analysis. The purpose of this study was to ensure data privacy in video recordings of laparoscopic surgery by censoring extraabdominal parts. An inside-outside-discrimination algorithm (IODA) was developed to ensure privacy protection while maximizing the remaining video data. IODAs neural network architecture was based on a pretrained AlexNet augmented with a long-short-term-memory. The data set for algorithm training and testing contained a total of 100 laparoscopic surgery videos of 23 different operations with a total video length of 207 h (124 min ± 100 min per video) resulting in 18,507,217 frames (185,965 ± 149,718 frames per video). Each video frame was tagged either as abdominal cavity, trocar, operation site, outside for cleaning, or translucent trocar. For algorithm testing, a stratified fivefold cross-validation was used. The distribution of annotated classes were abdominal cavity 81.39%, trocar 1.39%, outside operation site 16.07%, outside for cleaning 1.08%, and translucent trocar 0.07%. Algorithm training on binary or all five classes showed similar excellent results for classifying outside frames with a mean F1-score of 0.96 ± 0.01 and 0.97 ± 0.01, sensitivity of 0.97 ± 0.02 and 0.0.97 ± 0.01, and a false positive rate of 0.99 ± 0.01 and 0.99 ± 0.01, respectively. IODA is able to discriminate between inside and outside with a high certainty. In particular, only a few outside frames are misclassified as inside and therefore at risk for privacy breach. The anonymized videos can be used for multi-centric development of surgical AI, quality management or educational purposes. In contrast to expensive commercial solutions, IODA is made open source and can be improved by the scientific community.


Role of lipoprotein(a) concentrations in bioprosthetic aortic valve degeneration.
Lipoprotein(a) (Lp(a)) is associated with an increased incidence of native aortic stenosis, which shares similar pathological mechanisms with bioprosthetic aortic valve (bAV) degeneration. However, evidence regarding the role of Lp(a) concentrations in bAV degeneration is lacking. This study aims to evaluate the association between Lp(a) concentrations and bAV degeneration. In this retrospective multicentre study, patients who underwent a bAV replacement between 1 January 2010 and 31 December 2020 and had a Lp(a) measurement were included. Echocardiography follow-up was performed to determine the presence of bioprosthetic valve degeneration, which was defined as an increase >10 mm Hg in mean gradient from baseline with concomitant decrease in effective orifice area and Doppler Velocity Index, or new moderate/severe prosthetic regurgitation. Levels of Lp(a) were compared between patients with and without degeneration and Cox regression analysis was performed to investigate the association between Lp(a) levels and bioprosthetic valve degeneration. In total, 210 cases were included (mean age 74.1±9.4 years, 72.4% males). Median time between baseline and follow-up echocardiography was 4.4 (IQR 3.7) years. Bioprostheses degeneration was observed in 33 (15.7%) patients at follow-up. Median serum levels of Lp(a) were significantly higher in patients affected by degeneration versus non-affected cases: 50.0 (IQR 72.0) vs 15.6 (IQR 48.6) mg/dL, p=0.002. In the regression analysis, high Lp(a) levels (≥30 mg/dL) were associated with degeneration both in a univariable analysis (HR 3.6, 95% CI 1.7 to 7.6, p=0.001) and multivariable analysis adjusted by other risk factors for bioprostheses degeneration (HR 4.4, 95% CI 1.9 to 10.4, p=0.001). High serum Lp(a) is associated with bAV degeneration. Prospective studies are needed to confirm these findings and to investigate whether lowering Lp(a) levels could slow bioprostheses degradation.


Role of estrogen receptors in thyroid toxicity induced by mono (2-ethylhexyl) phthalate via endoplasmic reticulum stress: An in vitro mechanistic investigation.
Mono(2-ethylhexyl) phthalate (MEHP) can influence the expression of estrogen receptors (ERs) and induce thyroid injury. The expression of ERs can be related to thyroid disease and abnormal expression of ERs has been associated with activation of endoplasmic reticulum stress. This study aimed to clarify the role of ERs in MEHP-induced thyroid damage via endoplasmic reticulum stress. We exposed Nthy-ori 3-1 cells to different doses of MEHP. We found that after the exposure, the cell viability and the expression levels of thyroid hormone metabolism-related proteins decreased, while the apoptosis level and the expression levels of ERs (ERα and GPR30) increased. Three endoplasmic reticulum stress-related signaling pathways were activated by MEHP. After ERα and GPR30 were knocked down, these three pathways were inhibited and the thyroid toxicity was alleviated. Taken together, our results indicate that MEHP can induce thyroid toxicity by upregulating the expression of ERs, further activating endoplasmic reticulum stress.


Isoelectric focusing of phosphorylated cattle rhodopsin.
32P-rhodopsin was partially separated by isoelectric focusing into several fractions of different phosphorylation extent. It was found that the incorporated phosphate is not uniformly distributed in a population of rhodopsin molecules. In a preparation with an average phosphorylation extent of 2.4 moles of phosphate per mole of rhodopsin, most of the 32P-phosphate was found in fractions where 4-5 phosphates are bound per rhodopsin, whereas a large fraction of the total rhodopsin was not phosphorylated at all. The maximum number os phosphate binding sites in rhodopsin appears to be at least five.


Diabetic foot infections: Current treatment and delaying the 'post-antibiotic era'.
Treatment for diabetic foot infections requires properly diagnosing infection, obtaining an appropriate specimen for culture, assessing for any needed surgical procedures and selecting an empiric antibiotic regimen. Therapy will often need to be modified based on results of culture and sensitivity testing. Because of excessive and inappropriate use of antibiotics for treating diabetic foot infections, resistance to the usually employed bacteria has been increasing to alarming levels. This article reviews recommendations from evidence-based guidelines, informed by results of systematic reviews, on treating diabetic foot infections. Data from the pre-antibiotic era reported rates of mortality of about 9% and of high-level leg amputations of about 70%. Outcomes have greatly improved with appropriate antibiotic therapy. While there are now many oral and parenteral antibiotic agents that have demonstrated efficacy in treating diabetic foot infections, the rate of infection with multidrug-resistant pathogens is growing. This problem requires a multi-focal approach, including providing education to both clinicians and patients, developing robust antimicrobial stewardship programmes and using new diagnostic and therapeutic technologies. Recently, new methods have been developed to find novel antibiotic agents and to resurrect old treatments, like bacteriophages, for treating these difficult infections. Medical and political leaders have recognized the serious global threat posed by the growing problem of antibiotic resistance. By a multipronged approach that includes exerting administrative pressure on clinicians to do the right thing, investing in new technologies and encouraging the profitable development of new antimicrobials, we may be able to stave off the coming 'post-antibiotic era'.


A claims analysis comparing citalopram with sertraline as initial pharmacotherapy for a new episode of depression: impact on depression-related treatment charges.
Citalopram, a selective serotonin reuptake inhibitor (SSRI) recently approved in the United States for treatment of depression, has similar efficacy to and a lower acquisition cost than other SSRIs. The impact of using citalopram (instead of other SSRIs) on total treatment costs has not been studied extensively. The aim of this study was to compare depression-related treatment charges for the first 6 months of treatment among patients with newly diagnosed depression who received sertraline or citalopram. This was a retrospective analysis of medical and pharmaceutical claims from 20 managed care organizations across the United States. This study population can be considered representative of a commercially insured US population. Patients aged >or= 18 years with newly diagnosed depression (ie, major depressive disorder, dysthymia, or depressive disorder not otherwise specified) who had a prescription claim for sertraline or citalopram (within 30 days of initial diagnosis) from July 1, 1998, through June 30, 1999, were included in the study. Patients with previous mental disorders and/or treatment with an SSRI (including patients diagnosed with an anxiety disorder before the first SSRI prescription) were excluded from the analysis. Log-transformed depression-related treatment charges for the first 6 months of therapy were compared across the 2 treatment cohorts with use of multivariate regression. Other outcomes measures included medication compliance and use of other antidepressant medications during the 6-month study period. Costs were measured in year-1999 US dollars. A total of 15222 sertraline and 3175 citalopram patients met the inclusion criteria. Mean disease-related medical charges were US dollars 931 per patient in the setraline group and US dollars 1035 in the citalopram group ( [P<0.001). The difference between groups may have been due to higher mean outpatient charges in the citalopram group (US dollars 414 vs US dollars 360; P<0.001). Citalopram patients had lower mean pharmacy charges than did sertraline patients (US dollars 255 vs Us dollars 267; 0.036). After the data were controlled for differences in age, sex, managed care plan, pretreatment history of resource use, physician specialty type, index prescription year, and switching/augmentation of the treatment drug, depression-related charges for the citalopram patients were 22% higher than those for the sertraline cohort (beta coefficient, -0.21925; P<0.001). Despite potential cost savings due to a lower acquisition cost, initial treatment of depression with citalopram was associated with higher depression-related charges than was sertraline in the population studied.


Cysteine thiol oxidation on SIRT2 regulates inflammation in obese mice with sepsis.
Obesity increases morbidity and mortality in acute illnesses such as sepsis and septic shock. We showed previously that the early/hyper-inflammatory phase of sepsis is exaggerated in obese mice with sepsis; sirtuin 2 (SIRT2) modulates sepsis inflammation in obesity. Evidence suggests that obesity with sepsis is associated with increased oxidative stress. It is unknown whether exaggerated hyper-inflammation of obesity with sepsis modulates the SIRT2 function in return. We showed recently that SIRT6 oxidation during hyper-inflammation of sepsis modulates its glycolytic function. This study tested the hypothesis that increased oxidative stress and direct SIRT2 oxidation exaggerate hyper-inflammation in obesity with sepsis. Using spleen and liver tissue from mice with diet-induced obesity (DIO) we studied oxidized vs. total SIRT2 expression during hyper- and hypo-inflammation of sepsis. To elucidate the mechanism of SIRT2 oxidation (specific modifications of redox-sensitive cysteines) and its effect on inflammation, we performed site-directed mutations of redox-sensitive cysteines Cys221 and Cys224 on SIRT2 to serine (C221S and C224S), transfected HEK293 cells with mutants or WT SIRT2, and studied SIRT2 enzymatic activity and NFĸBp65 deacetylation. Finally, we studied the effect of SIRT2 mutation on LPS-induced inflammation using RAW 264.7 macrophages. In an inverse relationship, total SIRT2 decreased while oxidized SIRT2 expression increased during hyper-inflammation and SIRT2 was unable to deacetylate NFĸBp65 with increased oxidative stress of obesity with sepsis. Mechanistically, both the mutants (C221S and C224S) show decreased (1) SIRT2 enzymatic activity, (2) deacetylation of NFĸBp65, and (3) anti-inflammatory activity in response to LPS vs. WT SIRT2. Direct oxidation modulates SIRT2 function during hyper-inflammatory phase of obesity with sepsis via redox sensitive cysteines.


C-Reactive Protein and Frailty in Heart Failure.
Frailty commonly coexists with heart failure and although both have been associated with neurohormonal dysregulation, inflammation, catabolism, and skeletal muscle dysfunction, there are still no defined biomarkers to assess frailty, especially from the perspective of populations with cardiovascular diseases. This is a cross-sectional study with 106 outpatients with heart failure, aged ≥60 years, which aimed to assess frailty through a physical (frailty phenotype) and multidimensional (Tilburg Frailty Indicator) approach and to analyze its association with inflammatory and humoral biomarkers (high sensitivity C-reactive protein [hs-CRP], interleukin 6, tumor necrosis factor-α, insulin-like growth factor-1, and total testosterone), clinical characteristics, and functional capacity. In univariate analysis, hs-CRP was associated with frailty in both phenotype and Tilburg Frailty Indicator assessment (PR = 1.005, 95% confidence interval [CI] 1.001 to 1.009, p = 0.027 and PR = 1.015, 95% CI 1.006 to 1.024, p = 0.001, respectively), which remained significant in the final multivariate model in the frailty assessment by the phenotype (PR = 1.004, 95% CI 1.001 to 1.008, p = 0.025). There was no statistically significant difference between the groups for other biomarkers analyzed. Frailty was also associated with worse functional capacity, nonoptimized pharmacological treatment and a greater number of drugs in use, age, female gender, and a greater number of comorbidities. In conclusion, frailty is associated with higher levels of hs-CRP, which can indicate it is a promising frailty biomarker.


Primitive neuroectodermal tumors after prophylactic central nervous system irradiation in children. Association with an activated K-ras gene.
Three patients had supratentorial malignant brain tumors 7 to 9 years after prophylactic central nervous system (CNS) treatment for acute lymphocytic leukemia or malignant T-cell lymphoma. Therapy was administered at the age of 3 to 8 years and included cranial irradiation (total dose, 1800 to 2400 cGy) and intrathecal methotrexate. The brain tumors had histologic and immunohistochemical features of primitive neuroectodermal tumors (PNET), including neuroblastic rosettes, rhythmic arrangement of tumor cells, and immunohistochemical expression of glial, and in one patient neuronal, marker proteins. Using polymerase chain reaction-mediated DNA amplification from paraffin-embedded tissues and subsequent DNA sequence analysis, an activating point mutation was detected in the K-ras protooncogene in one tumor. This mutation was a G to A transition in position 2 of codon 12, substituting aspartate (GAT) for glycine (GGT). This type of mutation has not been observed before in human brain tumors, but it is frequent in radiation-induced murine lymphomas. These observations suggest that PNET can be induced after completion of the embryonal and fetal development of the human CNS. Oncogene-activating point mutations may represent a pathogenetic mechanism involved in the genesis of radiation-induced brain tumors.


Crescerin uses a TOG domain array to regulate microtubules in the primary cilium.
Eukaryotic cilia are cell-surface projections critical for sensing the extracellular environment. Defects in cilia structure and function result in a broad range of developmental and sensory disorders. However, mechanisms that regulate the microtubule (MT)-based scaffold forming the cilia core are poorly understood. TOG domain array-containing proteins ch-TOG and CLASP are key regulators of cytoplasmic MTs. Whether TOG array proteins also regulate ciliary MTs is unknown. Here we identify the conserved Crescerin protein family as a cilia-specific, TOG array-containing MT regulator. We present the crystal structure of mammalian Crescerin1 TOG2, revealing a canonical TOG fold with conserved tubulin-binding determinants. Crescerin1's TOG domains possess inherent MT-binding activity and promote MT polymerization in vitro. Using Cas9-triggered homologous recombination in Caenorhabditis elegans, we demonstrate that the worm Crescerin family member CHE-12 requires TOG domain-dependent tubulin-binding activity for sensory cilia development. Thus, Crescerin expands the TOG domain array-based MT regulatory paradigm beyond ch-TOG and CLASP, representing a distinct regulator of cilia structure.


Quantitative assessment of nerve echogenicity as an additional tool for evaluation of common fibular neuropathy.
Quantitative assessment of nerve echogenicity using the MaxEntropy, RenyiEntropy and Yen methods has shown promise in the assessment of ulnar neuropathy at the elbow. The purpose of this study was to determine the clinical usefulness of quantitative echogenicity measurement when using these three automatic thresholding methods in the evaluation of patients with common fibular (CF) neuropathy. High-resolution ultrasonography (HRUS) images of the CF nerve from 45 patients with CF neuropathy were compared to 42 healthy controls. With all three methods patients with CF neuropathy had significantly higher mean hypoechoic fraction than healthy controls at the level of the fibular head (FH): MaxEntropy 87.4% versus 71.9% (p<0.001), RenyiEntropy 84.7% versus 68% (p<0.001) and Yen 87.6% versus 68.2% (p<0.001). Patients with CF neuropathy could be differentiated from healthy controls at a hypoechoic fraction cut-off point of 82% (MaxEntropy), 80% (RenyiEntropy) and 80% (Yen) with a sensitivity of 82%, 82% and 84% respectively, and a specificity of 93%, 95% and 83% respectively. Similar results were found for sonographic measurements above the FH. Quantitative assessment of nerve echogenicity using the MaxEntropy, RenyiEntropy and Yen methods can be used to distinguish between patients with CF neuropathy and healthy controls with high sensitivity and specificity. These three proven automatic thresholding methods can be used to assess nerve echogenicity in future studies. Quantitative echogenicity assessment with HRUS shows promise for the future as a potential diagnostic tool in daily clinical practice.


Relationship between work engagement and healthy work environment among Chinese ICU nurses: The mediating role of psychological capital.
To evaluate the relationship between healthy work environment and work engagement considering the effect of psychological capital among ICU nurses. The study was cross-sectional design. The subjects were 671 registered nurses from 20 ICUs in 18 general hospitals in Shandong province between October 2021 and December 2021. The questionnaires testing nurses' perception of healthy work environment, their work engagement, and psychological capital were used. Structural equation modeling was used to explore their relationship. Work engagement was positively affected by a healthy work environment and psychological capital. The structural equation modeling showed psychological capital mediated the relationship between healthy work environment and their work engagement. There were 681 clinical nurses reported at public contribution for responding to the questionnaires and providing valuable data for the study and there was no patient contribution in this study.


Bioaccumulation of heavy metals in marine organisms and sediments from Admiralty Bay, King George Island, Antarctica.
The Antarctic continent is considered a low-impact environment; however, there is a tendency to increase the contaminants' levels due to human activities in the research stations. In this study, As, Cd, Cr, Cu, Hg, Ni, Pb and Zn levels in sediment and biota were determined in the environmental samples from Admiralty Bay (King George Island, Antarctica) collected in 2003. The results demonstrated high concentrations of Cu and Zn in the sediments. There was bioaccumulation of As in the biota from Admiralty Bay and bioaccumulation of Zn specifically in the biota from Martel Inlet. In addition, the results were useful in order to understand the heavy metal levels for the pre-accident condition of Comandante Ferraz Antarctic Station, where an accident occurred in 2012, and also for the comparison with current conditions within the monitoring work developed by INCT-APA (National Institute of Science and Technology for Environmental Research Antarctic).


Drug treatment combined with BCG vaccination reduces disease reactivation in guinea pigs infected with Mycobacterium tuberculosis.
Bacillus-Calmette-Guerin (BCG), the only human tuberculosis vaccine, primes a partially protective immune response against Mycobacterium tuberculosis infection in humans and animals. In guinea pigs, BCG vaccination slows the progression of disease and reduces the severity of necrotic granulomas, which harbor a population of drug-tolerant bacilli. The objective of this study was to determine if reducing disease severity by BCG vaccination of guinea pigs prior to M. tuberculosis challenge enhanced the efficacy of combination drug therapy. At 20 days of infection, treatment of vaccinated and non-vaccinated animals with rifampin, isoniazid, and pyrizinamide (RHZ) was initiated for 4 or 8 weeks. On days 50, 80 and 190 of infection (10 weeks after drug were withdrawn), treatment efficacy was evaluated by quantifying clinical condition, bacterial loads, lesion severity, and dynamic changes in peripheral blood and lung leukocyte numbers by flow cytometry. In a separate, long-term survival study, treatment efficacy was evaluated by determining disease reactivation frequency post-mortem. BCG vaccination alone delayed pulmonary and extra-pulmonary disease progression, but failed to prevent dissemination of bacilli and the formation of necrotic granulomas. Drug therapy either alone or in combination with BCG, was more effective at lessening clinical disease and lesion severity compared to control animals or those receiving BCG alone. Fewer residual lesions in BCG vaccinated and drug treated animals, equated to a reduced frequency of reactivation disease and improvement in survival even out to 500 days of infection. The combining of BCG vaccination and drug therapy was more effective at resolving granulomas such that fewer animals had evidence of residual infection and thus less reactivation disease.


[Update on mechanisms of pituitary tumorigenesis.]
Pituitary adenomas are intracranial neoplasms that originate from the adeno-pituitary cells, are mostly benign and slow growing. However, a small percentage can be aggressive and spread locally and / or remotely as malignancies. In recent years, progress has been made in understanding the biology of pituitary tumors, identifying mutations in the germline, somatic lines, and epigenetic mechanisms. Objective: review the updated bibliography on the mechanisms of pituitary tumorigenesis. Data source: bibliographic search was performed using the MEDLINE (PubMed), LILACS and Google Scholar databases since 2010 to April 2020. Conclusion: Knowledge and information on pituitary tumorogenesis mechanisms increased in recent decades, and new neoplastic pathways are recognized. However, there are currently few therapeutic approaches to act specifically on the underlying tumor genesis pathway identified in each case.


Immune response to virus-infection-associated (VIA) antigen in cattle repeatedly vaccinated with foot-and-mouth disease virus inactivated by formalin or acetylethyleneimine.
The results of experiments to investigate antibody to 'virus infection associated' (VIA) antigen in cattle repeatedly vaccinated with formalin- or acetylethyleneimine- (AEI) inactivated foot-and-mouth disease (FMD) vaccines under laboratory conditions are reported. Results are also presented from some vaccinated animals subsequently exposed to FMD infection. Antibody against VIA was not detected before and after the first vaccination with formalin or AEI-inactivated vaccine but did develop in all animals after the second formalin vaccination and persisted throughout the experiment. After the second AEI vaccination, 4 of 12 animals developed antibody which persisted for at least 37 days. This transient response in some cattle was repeated after successive vaccinations but, in general, more animals responded as the number of vaccinations increased. After exposure to infection a transient VIA antibody response was occasionally observed in immune AEI-vaccinated animals. Some immune repeatedly AEI-vaccinated cattle did not develop detectable VIA antibody after challenge despite the persistence of virus in oesophageal-pharyngeal (O/P) fluid. The presence of antibody to VIA antigen is not conclusive proof that vaccinated animals have been exposed to infection and field data must be interpreted with caution.


Bfa1 can regulate Tem1 function independently of Bub2 in the mitotic exit network of Saccharomyces cerevisiae.
In budding yeast, exit from mitosis is achieved by inactivation of Cdc28/Clb2 activity. Although it is not clear at present how mitotic exit is triggered, a growing body of evidence suggests that the Tem1 GTPase plays a critical role in mediating this pathway and that Bfa1 and Bub2 constitute a two-component GTPase-activating protein to negatively regulate Tem1. Here, we have demonstrated that introduction of bfa1 Delta suppresses the growth defects associated with the cdc5-1 mutation significantly better than that of bub2 Delta, suggesting that Bfa1 may have a previously uncharacterized role in this pathway. Overexpression of BFA1 efficiently arrested the cell cycle at postanaphase even in the absence of BUB2, whereas overexpression of BUB2 weakly induced mitotic arrest only in the presence of BFA1. Coimmunoprecipitation and in vitro binding studies indicate that Bfa1 binds strongly to Tem1 independently of Bub2. Provision of GDP+AlF(4)(-), which mimics the GTPase transition state, enhanced the Bub2-Tem1 interaction both in vitro and in vivo. Interestingly, introduction of bfa1 Delta, but not bub2 Delta, greatly increased the interaction between Tem1 and Cdc15, a step that is thought to be critical for activating the mitotic exit network. Our data suggest that, in addition to its role as a putative, two-component GTPase-activating protein with Bub2, Bfa1 also can play a role in the regulation of mitotic exit by directly inhibiting the interaction between Tem1 and Cdc15 even in the absence of Bub2.


Simultaneous quantitation of volatile compounds in citrus beverage through stir bar sorptive extraction coupled with thermal desorption-programmed temperature vaporization.
Due to disparate concentrations and physiochemical properties of analytes, difficulties in terms of sensitivity and reproducibility are commonly encountered in flavour analysis. In this study, we attempted to improve the performance of stir bar sorptive extraction coupled with thermal desorption and programmed temperature vaporization (SBSE-TD-PTV) based on a model citrus beverage. Through response surface methodology, thermal desorption conditions (i.e. desorption flow, thermal desorption time and cryofocusing temperature) were optimised based on constrained optimisation. Solute discrimination during injection was alleviated by normalising the variability of peak responses of different analytes. In addition, the effects of extraction conditions (i.e. ionic strength, stirring speed, extraction time, temperature and pH) were also investigated using partial factorial design. The obtained method showed high precision and good linearity over the concentration ranged from 0.10 to 20.00 μg L(-1) with the correlation coefficients higher than 0.991 for most of the selected chemicals, except indole. The limit of detection ranged from 0.03 to 3.89 μg L(-1). Hence, our results indicated that through the systematic study, SBSE-TD-PTV method became much less solute discriminative and more reliable to quantitate complex analytes.


Trichloroethanol enhances the activity of recombinant human TREK-1 and TRAAK channels.
Human TREK-1 and TRAAK (hTREK-1 and hTRAAK) are the recently cloned tandem pore-domain potassium channels that are highly expressed in the central nervous system (CNS). The roles of 2P domain K+ channels in general anesthesia and neuroprotection have been proposed recently. We have investigated the ability of 2,2,2-trichloroethanol (an active metabolite of the general anesthetic chloral hydrate (CH)) to modulate the activity of hTREK-1 and hTRAAK channels expressed heterologously in Chinese hamster ovary cells by using whole-cell patch-clamp recording. Trichloroethanol potentiated hTREK-1 and hTRAAK channel activity in a reversible, concentration-dependent manner. The parent compound CH also augmented the activity of both the channels reversibly. CH activation of hTREK-1 was transient followed by a rapid inhibition, whereas hTRAAK activation was not followed by inhibition. Deletions of the carboxy terminal domain (Delta89, Delta100 and Delta119) of hTREK-1 did not abolish sensitivity to TCE (20 mM) suggesting that C-terminal tail is not essential for the activation of hTREK-1 by TCE. The hTREK-1 currents consisted of an instantaneous and a time-dependent component. The time-dependent current was reduced by trichloroethanol (20 mM). Our findings identify TREK-1 and TRAAK channels as molecular targets for trichloroethanol and suggest that activation of these channels might contribute to the CNS depressant effects of CH.


[Change in nitric oxide contents of knee joint fluid in patients with degenerative osteoarthritis].
The degenerative osteoarthritis (DOA) is a common disease of aged people. But its pathogenesis and mechanism are not very clear. We compared the Nitric Oxide content in knee fluid of DOA with the normal people as matched age. The results indicated that the Nitric oxide has a high concentration in DOA. This suggested that the Nitric Oxide may play an important role in the mechanism of this disease.


Cutaneous lesions associated with coronavirus-induced vasculitis in a cat with feline infectious peritonitis and concurrent feline immunodeficiency virus infection.
This report describes a clinical case of feline infectious peritonitis (FIP) with multisystemic involvement, including multiple nodular cutaneous lesions, in a cat that was co-infected with feline coronavirus and feline immunodeficiency virus. The skin lesions were caused by a pyogranulomatous-necrotising dermal phlebitis and periphlebitis. Immunohistology demonstrated the presence of coronavirus antigen in macrophages within these lesions. The pathogenesis of FIP involves a viral associated, disseminated phlebitis and periphlebitis which can arise at many sites. Target organs frequently include the eyes, abdominal organs, pleural and peritoneal membranes, and central nervous tissues, but cutaneous lesions have not previously been reported.


Outcomes and Prognosis of Neurological Decompression and Stabilization for Spinal Metastasis: Is Assessment with the Spinal Instability Neoplastic Score Useful for Predicting Surgical Results?
Retrospective study. To evaluate the efficacy of the Spinal Instability Neoplastic Score (SINS) in predicting surgical outcomes and survival. Patients were categorized into two groups according to the SINS, and their surgical outcomes and survival following decompression and stabilization were assessed. Palliative surgery in patients with a life expectancy ≥3 months may effectively improve their overall condition in the long term. Currently, the effectiveness of the SINS for predicting surgical results and survival remains controversial. This study included 44 patients who underwent decompression and stabilization for spinal metastases at Yokosuka Kyosai Hospital between 2008 and 2017. The patients were divided into two groups: stable (SINS ≤12) and unstable (SINS ≥13). Changes in the Frankel score and Eastern Cooperative Oncology Group Performance Status (ECOG-PS) were compared between the two groups, and patient survival was evaluated according to the SINS, Tokuhashi score, and Katagiri score. The stable group (SINS range, 7-12) included 24 patients while the unstable group (SINS range, 13-16) included 20 patients. The Frankel score significantly improved from 2.8 to 3.6 in the stable group (p <0.001) and from 2.7 to 3.9 in the unstable group (p <0.001). The ECOG-PS significantly improved from 3.2 to 2.1 in the stable group (p <0.001) and from 3.0 to 1.8 in the unstable group (p <0.001). There was a statistically significant difference in median survival between the two groups. All patients treated with palliative surgery showed favorable outcomes, as indicated by improved the Frankel score and ECOG-PS following surgery. However, median survival was significantly better in the stable group. The results of this study indicate that the SINS is appropriate for surgical decision making and may be used to predict survival.


Dicarboxylate transport in the inner membrane matrix fraction obtained from rat liver mitochondria.
Dicarboxylate transport was studied in the inner membrane matrix fraction (mitoplasts) and compared to that in intact rat-liver mitochondria from which the former was obtained. It is concluded that, kinetics of dicarboxylate exchange measured in mitoplasts, are very similar to those observed with mitochondria. These results would indicate that the preparation technique preserves the integrity of the inner membrane and that neither the outer membrane nor the components of the peripheral space affect these results.


Postspace pretreatment with 17% ethylenediamine tetraacetic acid, 7% maleic acid, and 1% phytic acid on bond strength of fiber posts luted with a self-adhesive resin cement.
Pretreatment of radicular dentin with chelating agents improves the bond strength of fiber-posts luted with a self-adhesive resin cement. The aim of this study was to assess the effects of the three chelating agents as final rinse of the postspace on bond strength of fiber posts luted with a self-adhesive resin cement. This is an in vitro laboratory study. Forty-five mandibular premolars were prepared using MTwo rotary system and irrigation was done with 2.5% sodium hypochlorite. Three groups of teeth samples were considered for postspace preparation and irrigated with different solutions: Group 1: 17% ethylenediamine tetraacetic acid (EDTA); Group 2: 7% Maleic acid; Group 3: 1% Phytic acid. This was followed by the luting the posts with RelyX U200. After a week, from each sample, 2 mm thick slices were obtained from each third of the root and subjected to push-out bond strength testing. One-way analysis of variance and Bonferroni's Post hoc analysis was used for assessing the results. The statistical significance level was set at P < 0.05. Bond strength values were improved with maleic acid and phytic acid pretreatment with slight or no significant difference between these groups. A final rinse of postspace with EDTA significantly reduced the bond strength. Maleic acid (7%) pretreatment of postspace improved the adhesion of fiber posts luted with a self-adhesive resin cement.


Models for mature T-cell lymphomas--a critical appraisal of experimental systems and their contribution to current T-cell tumorigenic concepts.
Mature T-cell lymphomas/leukemias (MTCL) have been understudied lymphoid neoplasms that currently receive growing attention. Our historically rudimentary molecular understanding and dissatisfactory interventional success in this complex and for the most part poor-prognostic group of tumors is only slightly improving. A major limiting aspect in further progress in these rare neoplasms is the lack of suitable model systems that would substantially facilitate pathogenic studies and pre-clinical drug evaluations. Such representations of MTCL have thus far not been systematically appraised. We therefore provide an overview on existing models and point out their particular advantages and limitations in the context of the specific scientific questions. After addressing issues of species-specific differences and classifications, we summarize data on MTCL cell lines of human as well as murine origin, on murine strain predispositions to MTCL, on available models of genetically engineered mice, and on transplant systems. From an in-silico meta-analysis of available primary data of gene expression profiles on human MTCL we cross-reference genes reported to transform T-cells in mice and reflect on their general vs entity-restricted relevance and on target-promoter influences. Overall, we identify the urgent need for new models of higher fidelity to human MTCL with respect to their increasingly recognized diversity and to predictions of drug response.


Phosphatidylinositol-3-kinase-gamma is integral to homing functions of progenitor cells.
Endothelial progenitor cells (EPCs) and hematopoietic progenitor cells are recruited to ischemic regions, improving neovascularization. beta1 and beta2 integrins play a crucial role for progenitor cell homing to ischemic tissues. Integrin activity is regulated by chemokines and their respective G protein-coupled receptors. The phosphatidylinositol-3-kinase catalytic subunit gamma (PI3Kgamma) is the PI3K isoform that selectively transduces signals from G protein-coupled receptors. Here, we investigated the role of PI3Kgamma as a signaling intermediate in the chemokine-induced integrin-dependent homing functions of progenitor cells. A pharmacological PI3Kgamma inhibitor significantly reduced chemokine-induced chemotaxis and stromal cell-derived factor (SDF)1alpha-induced transmigration of human EPCs. Moreover, the PI3Kgamma inhibitor significantly reduced SDF1alpha-induced adhesion of EPCs to intercellular adhesion molecule-1 and human umbilical vein endothelial cell monolayers. These findings were corroborated with Lin(-) bone marrow-derived progenitor cells from PI3Kgamma-deficient mice that displayed reduced SDF1alpha-induced migration and intercellular adhesion molecule-1 adhesion as compared with wild-type cells. Pharmacological inhibition or genetic ablation of PI3Kgamma reduced SDF1alpha-induced integrin activation in human EPCs and in murine Lin(-) BM-derived progenitor cells, respectively. In vivo, the homing of PI3Kgamma-deficient Lin(-) progenitor cells to ischemic muscles after intravenous infusion in the model of hindlimb ischemia and their neovascularization-promoting capacity was reduced as compared with wild-type cells. In conclusion, PI3Kgamma is integral to the integrin-dependent homing of progenitor cells.


Current treatment guidelines of chronic hepatitis B: The role of nucleos(t)ide analogues and peginterferon.
Chronic hepatitis B is prevalent worldwide and is a major contributor to death from cirrhosis and hepatocellular carcinoma. Thus, the goals of therapy are to prevent the development of cirrhosis, hepatocellular carcinoma and liver-related death. Safe and effective therapy is available but complete cure is not yet possible. The decision to treat is complex and must be individualized. Each of the three major liver societies, the American Association for the Study of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL) and the Asian Pacific Association for the Study of the Liver (APASL) have developed treatment guidelines to provide healthcare professionals guidance on management of chronic HBV infection. This review will cover the specific, evidence-based or expert opinion guideline recommendations on who should be treated, what to treat with, how to monitor, when to stop therapy and management of treatment failure.


Influence of coadministration on the pharmacokinetics of mezlocillin and cefotaxime in healthy volunteers and in patients with renal failure.
The pharmacokinetic disposition of cefotaxime, desacetyl cefotaxime, and mezlocillin after the administration of each drug singly and in combination was examined in eight healthy volunteers and in five anuric patients with end-stage renal disease (ESRD). In the presence of ESRD, the total body clearance of cefotaxime decreased from 256.7 +/- 41.5 to 65.4 +/- 42.0 ml/min, and its elimination half-life (t1/2) increased from 1.1 to 3.6 hours as compared with healthy volunteers. Concomitant administration of mezlocillin in healthy volunteers decreased the total body clearance of cefotaxime by 42% and increased its steady-state volume of distribution. This reduction in clearance was reflected by a decrease in both renal and nonrenal clearances. In the presence of ESRD, coadministration of mezlocillin increased the t1/2 of cefotaxime to 5.8 hours. Desacetyl cefotaxime accumulated in ESRD with a prolongation of its elimination t1/2 to 18.7 hours from 1.7 hours in healthy volunteers. Desacetyl cefotaxime peak plasma concentrations occurred later with the combination regimen in the presence of ESRD. The clearance of mezlocillin was reduced and t1/2 prolonged in ESRD from 194.6 +/- 31.9 to 76.4 +/- 38.8 ml/min and 1.4 to 2.3 hours, respectively. Concomitant administration of cefotaxime did not alter the pharmacokinetics of mezlocillin. These data suggest that in the presence of normal renal function, lower doses of cefotaxime may be adequate to maintain similar cefotaxime plasma concentrations when mezlocillin is coadministered compared to when cefotaxime is given alone. Additional pharmacodynamic and clinical studies with this combination are warranted to further elucidate the clinical impact of this pharmacokinetic interaction.


Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers Are Associated With Improved Outcome but Do Not Prevent New-Onset Atrial Fibrillation After Acute Myocardial Infarction.
Treatment with renin-angiotensin system (RAS) inhibitors might restrain the structural/electrical remodeling associated with atrial fibrillation (AF). Limited evidence exists regarding the potential benefits of RAS inhibition post-acute myocardial infarction (AMI) in patients with AF. This study sought to assess the association between RAS inhibition and all-cause mortality and new-onset AF in patients with/without congestive heart failure (CHF) post-AMI. Patients hospitalized for AMI between 2006 and 2012 were identified in Swedish registries. Patients were stratified in 4 subgroups; patients with CHF and AF (n=11 489); patients with CHF without AF (n=31 676); patients with AF without CHF (n=10 066); and patients without both CHF and AF (n=59 417). Patients exposed to RAS inhibition were compared to nontreated. Three-year risk of all-cause mortality and new-onset AF was assessed using adjusted Cox regression analyses. At discharge, 83 291 (73.9%) patients received RAS inhibition. RAS inhibition was associated with lower 3-year risk of all-cause mortality in CHF patients with AF, adjusted hazard ratio (HR) with 95% CI 0.75 (0.70-0.81), CHF patients without AF, HR 0.65 (0.60-0.69), AF patients without CHF, HR 0.82 (0.75-0.90), and in patients without CHF and AF, HR 0.76 (0.72-0.81), respectively. RAS inhibition was not associated with lower 3-year risk of new-onset AF in patients without AF but with/without CHF; HR 0.96 (0.84-1.10) and 1.12 (1.02-1.22), respectively. RAS inhibition post-AMI was associated with lower risk of all-cause mortality. In patients with/without CHF, RAS inhibition was not associated with lower incidence of new-onset AF.


A case of placental fusion in a Sprague Dawley rat.
Placental fusion was observed in one of 62 Sprague Dawley rats examined on the 20th day of gestation. The associated fetuses were smaller than usual, but were not otherwise abnormal.


Effectiveness and Safety of Ureteroscopic Lithotripsy in Young, Old-Old, and Oldest Old Patients.
Objectives: To investigate the efficacy and safety of ureteroscopic lithotripsy (URSL) in young, old-old, and oldest old patients. Materials and Methods: We enrolled 157 patients who underwent URSL. We divided the patients into young (<65 years), old-old (65-84 years), and oldest old (≥85 years) groups and compared the safety of surgery between young vs old-old and young vs oldest old, separately. Results: In the <65 group, 65 to 85 group, and ≥85 group, respectively, the mean stone diameters were 8.9 ± 4.9, 10.8 ± 7.7, and 11.4 ± 6.3 mm; mean operative time was 76.6 ± 33.1, 86.7 ± 44.7, and 84.0 ± 44.5 min; the stone-free rates were 95.9%, 94.4%, and 96.3%; and the complication rates were 8.2%, 9.8%, and 3.7%. Conclusions: In this study, we showed the feasibility and safety of URSL for elderly people. Although oldest old (≥85 years) people had multiple comorbidities with low performance status, URSL could be performed with acceptable complication rates. Clinical Trial Registration Number: 1809-1.


Association Between Sunlight Exposure and Mental Health: Evidence from a Special Population Without Sunlight in Work.
In recent years, mental health problems have become the most serious social problems worldwide. Past studies have proposed that some links exist between sunlight and mental health; however, relevant studies examining low-dose sunlight exposure populations are lacking. We conducted a study among a group of operating room nurses (ORNs) who work long hours in operating rooms and have limited sunlight exposure. We aim to add to and refine previous researches on the association between mental health and sunlight exposure in community population. A total of 787 ORNs were interviewed and analyzed. Mental health, sunlight exposure duration, sociodemographic and work-related variables, and chronic diseases were evaluated. The Kessler 10 scale (K10) was used to assess participants' mental health status, and their sunlight exposure duration was assessed using their self-reports. Multiple linear regression analysis was adopted to examine the association between sunlight exposure and mental health. The average K10 score of ORNs was 25.41. ORNs exhibit poorer mental health than other populations. Poor mental health was negatively associated with greater sunlight exposure hours per day (β=-0.378) and sleep regularity (β=-3.341). Poor mental health was positively associated with chronic disease (β=3.514). This study indicated that the positive association between sunlight exposure and mental health existed. Appropriate enhancement of sunlight exposure will be beneficial to mental health. Hospitals, related organizations and individuals should pay greater attention to ORNs' mental health and sunlight exposure conditions. More policy recommendations as well as building structure recommendations should be proposed.


Effect of processing methods on colouration of human serum albumin preparations.
Human serum albumin is a well tolerated therapeutic for the treatment of hypovolemia. Despite all commercial human albumin preparations being derived from plasma, these products can have a highly variable colour. Albumin samples derived from ethanol precipitation and chromatographic fractionation procedures were evaluated for bilirubin and biliverdin levels and by spectrophotometry. It was shown that albumin derived from a chromatographic process, which had a bilirubin:albumin ratio similar to that observed in plasma, had a vibrant yellow appearance. The albumin derived from ethanol precipitation had undetectable levels of bilirubin, and the amber colour of this product was attributed mainly to residual haem. The presence of bilirubin during pasteurisation led to oxidation to biliverdin, with a resultant colour change from yellow to yellow/green. Given that the antioxidant properties of bilirubin are well established, it is possible that bilirubin helps protect albumin from oxidation during the pasteurisation step.


The antipruritic effect of a sedative and a non-sedative antihistamine in atopic dermatitis.
A double-blind, randomized, cross-over study was carried out on the effect of a sedative and a non-sedative antihistamine on 25 adults with atopic dermatitis. Intensity of itch was recorded using a computerized method for self-assessment (Pain-Track) and using conventional visual analogue scales. The antipruritic effect of 3 days of treatment with the non-sedative H1 antagonist terfenadine (60 mg b.i.d.) and with the sedative antihistamine, clemastine (2 mg b.i.d.) did not differ from that found with the placebo. Our findings support the view that histamine is not of importance in the pathogenesis of itch in atopic dermatitis.


The performance of the Finnish Diabetes Risk Score, a modified Finnish Diabetes Risk Score and a simplified Finnish Diabetes Risk Score in community-based cross-sectional screening of undiagnosed type 2 diabetes in the Philippines.
The performance of the Finnish Diabetes Risk Score (FINDRISC) and 2 modifications in community screening for undiagnosed type 2 diabetes (UDD) in the Philippines was evaluated. Active community-based screening for diabetes was conducted where FINDRISC assessment was done. Modified (modFINDRISC) and simplified (simpFINDRISC) versions were rendered based on Asian standards, study results, and local context. Diabetes was diagnosed through 2 separate blood glucose tests. Areas under the receiver operating characteristic curve (ROC-AUC) and statistics for diagnostic tests for FINDRISC and the modifications were analyzed. Complete data was collected from 1752 people aged 20-92; 8.6% tested positive for diabetes. ROC-AUC for UDD were 0.738 (FINDRISC), 0.743 (modFINDRISC) and 0.752 (simpFINDRISC). The differences between the FINDRISC and the modifications were not statistically significant (p=0.172). The performance of all 3 risk score calculators in the screening for UDD in the Philippines was good and may be useful in populations having similar characteristics. Considering the setting and resource constraints, the simpFINDRISC is preferred.


Studies on brain cytosol neuraminadase. I. Isolation and partial characterization of two forms of the enzyme from pig brain.
1. Two forms of cytosol neuraminidase (EC 126.96.36.199) (neuraminidase A and neuraminidase B) were isolated and purified from pig brain homogenate, by proceeding through the following steps: centrifugation of brain homogenate at 105 000 X g (1h); ammonium sulphate fractionation (35-55% saturated fraction); column chromatography on Biogel A 5 m; column chromatography on hydroxy apatite/cellulose gel; affinity chromatography on Affinose-tyrosyl-p-nitrophenyloxamic acid. The separation of the two forms of neuraminidase was provided by chromatography on hydroxylapatite/cellulose gel. Neuraminidase A was purified about 500-fold; neuraminidase B about 400-fold. 2. The pH optima and the maximum activities in various buffers were different for neuraminidase A and B (for instance the pH optimum was in sodium acetate/acetic acid buffer, 4.7 for neuraminidase A and 4.9 for neuraminidase B). Ions affected in a different way the two enzymes: K+ activated neuraminidase A but not neuraminidase B; Na+ and Li+ inhibited neuraminidase A at a higher degree than neuraminidase B. Neuraminidase B seemed to be moderately activated by some bivalent cations (Ca2+; Mg2+; Zn2+); neuraminidase A did not. The Km values for sialyllactose were different: 2.2-10(-3) M for neuramindase A; 0.46-10(-3) M for neuraminidase B.