A new adaptable computerized system for the measurement of specific airways conductance.
We have developed an automated system for the measurement of specific airways conductance (SGaw) which differs in several aspects from other reported automated systems. In seven subjects this system was used to measure baseline SGaw and the provocation concentration (PC) of histamine producing a 35% fall in SGaw. The results produced were compared with those obtained by manual analysis using both one limb and two limbs of the inspiratory part of the flow/box pressure curve. Using the automated system, baseline SGaw and PC35SGaw results were similar to those obtained by the two limbs method of manual analysis, but the analysis time was considerably reduced. A single measurement of SGaw was obtained within 2-3 seconds. Both the automated and two limbs manual methods of analysis were more reproducible than the one limb method of manual analysis.


Current perspectives and challenges in understanding the role of nitrite as an integral player in nitric oxide biology and therapy.
Beyond an inert oxidation product of nitric oxide (NO) metabolism, current thinking posits a key role for nitrite as a mediator of NO signaling, especially during hypoxia. This concept has been discussed in the context of nitrite serving a role as an endogenous modulator of NO homeostasis, but also from a novel clinical perspective whereby nitrite therapy may replenish NO signaling and prevent ischemic tissue injury. Indeed, the relatively rapid translation of studies delineating mechanisms of action to ongoing and planned clinical trials has been critical in fuelling interest in nitrite biology, and several excellent reviews have been written on this topic. In this article we limit our discussions to current concepts and what we feel are questions that remain unanswered within the paradigm of nitrite being a mediator of NO biology.


Role of serum interleukin-6 in comparing surgical stress after laparoscopic-assisted vaginal hysterectomy and non-descent vaginal hysterectomy for large uteri.
To compare the perioperative inflammatory response using interleukin-6 (IL-6) in patients of laparoscopic-assisted vaginal hysterectomy (LAVH) and non-descent vaginal hysterectomy (NDVH) for large uteri with benign disease. Twenty women with benign uterine disease and failed medical management with size of uterus ranging from 300 to 1,500 g (12-24 weeks) were randomized into two equal groups for either technique of hysterectomy, LAVH and NDVH. Venous blood levels of IL-6 were measured preoperatively and 3, 24 and 72 h after beginning of surgery. Statistical analysis was done using SPSS15 software. No statistically significant difference was present in demographic characteristics, operating time, and uterine weight between the two groups. No major complications were encountered. The increase in serum interleukin 6 levels from preoperative value to the value at 3 h postoperatively was found to be significantly higher in LAVH group when compared with NDVH group indicating greater tissue handling and trauma in LAVH group. Non-descent vaginal hysterectomy appears to be better than laparoscopic-assisted vaginal hysterectomy for large uteri in terms of inflammatory response.


Comparison of cardio-focal and chest reconstruction of technetium-99m pyrophosphate scintigraphy for diagnosis of transthyretin cardiac amyloidosis: a quality assurance study.
SPECT improves diagnostic specificity of Technetium-99m pyrophosphate (PYP) scintigraphy. Diagnostic performance of PYP data, reconstructed as either chest or cardio-focal SPECT is not known. In this quality assurance study, blinded evaluation of PYP SPECT/CT data from 102 Caucasian patients (mean age 76 ± 11 years, 67% men) was performed by two readers. Reader 1 reviewed planar and PYP chest SPECT, while reader 2 reviewed planar and cardio-focal PYP SPECT. Demographic, clinical, and other testing data were obtained from the electronic medical records. A total of 41 patients (40%) were considered positive based on myocardial uptake on chest PYP SPECT. Of these, 98% of the patients had a Perugini score ≥ 2 on planar imaging. There was good agreement between the two readers for visual score ≥ 2 (k = .88, P < .001) and excellent agreement for myocardial uptake on tomographic imaging (98%, P < .001). Only one study was categorized as false negative by cardio-focal SPECT reconstruction. Non-diffuse myocardial uptake was identified in 22% of those with a positive PYP SPECT. When read by experienced readers, chest and cardio-focal reconstruction of PYP SPECT have comparable diagnostic performance. A substantial proportion of patients with a positive PYP SPECT have a non-diffuse distribution of PYP. Given the possibility of misclassification of non-diffuse myocardial uptake on cardio-focal reconstruction alone, chest reconstruction of PYP scintigraphy should be strongly considered.


Feasibility of in vitro culturing of lesional psoriatic keratinocytes in medium containing high calcium concentrations.
Lesional psoriatic keratinocyte (LPK) culture is considered to be difficult under high-Ca2+ conditions in the absence of special proliferative agents. Using a permeable collagen membrane, we obtained a culture of LPKs under high-Ca2+ conditions without any special proliferative agents. Single-cell suspensions were prepared from the epidermis of chronic psoriatic plaques. Cells were inoculated on the collagen membrane suspended slightly above the bottom of a Petri dish. We used a culture medium of Eagle's MEM containing 10% fetal calf serum. LPKs attached to the membrane 12 h after inoculation and gradually spread. They reached a confluent state by the 10th day of culture. We measured the concentrations of TGF alpha and IL-6 in the medium of LPKs, and compared these with the concentrations in normal keratinocyte (NK) cultures. Significantly increased secretion of TGF alpha by LPKs was observed during the initial phase but this secretion subsequently decreased. Concentrations of IL-6 were below the detectable level in both of NKs and LPKs throughout the observation period. Our results demonstrate that cultured LPKs under high-Ca2+ conditions secrete a larger amount of TGF alpha but not IL-6. Our cell culture system, which allows LPKs to spread and stratify, contributes to the study of the pathogenesis of psoriasis.


The Emergency Surgery Score is a powerful predictor of outcomes across multiple surgical specialties: Results of a retrospective nationwide analysis.
The Emergency Surgery Score was recently validated in a prospective multicenter study as an accurate predictor of mortality in emergency general surgery patients. The Emergency Surgery Score is easily calculated using multiple demographic, comorbidity, laboratory, and acuity of disease variables. We aimed to investigate whether the Emergency Surgery Score can predict 30-day postoperative mortality across patients undergoing emergency surgery in multiple surgical specialties. Our study is a retrospective cohort study using data from the national American College of Surgeons National Surgical Quality Improvement Program database (2007-2017). We included patients that underwent emergency gynecologic, urologic, thoracic, neurosurgical, orthopedic, vascular, cardiac, and general surgical procedures. The Emergency Surgery Score was calculated for each patient, and the correlation between the Emergency Surgery Score and 30-day mortality was assessed for each specialty using the c-statistics methodology. Of 6,485,915 patients, 173,890 patients were included. The mean age was 60 years, 50.6% were female patients, and the overall mortality was 9.7%. The Emergency Surgery Score predicted mortality best in emergency gynecologic, general, and urologic surgery (c-statistics: 0.97, 0.87, 0.81, respectively). The Emergency Surgery Score predicted mortality moderately well in emergency thoracic, neurosurgical, orthopedic, and vascular surgery (c-statistics 0.73-0.79). For example, the mortality of gynecology patients with an Emergency Surgery Score of 5, 9, and 13 was 2%, 27%, and 50%, respectively. The Emergency Surgery Score performed poorly in cardiac surgery. The Emergency Surgery Score accurately predicts mortality across patients undergoing emergency surgery in multiple surgical specialties, especially general, gynecologic, and urologic surgery. The Emergency Surgery Score can prove useful for perioperative patient counseling and for benchmarking the quality of surgical care.


Applications of yoga in oral oncology: A systematic scoping review.
Yoga is well-thought-out as an all-inclusive approach globally and can be administered in clinical care as an integrative or alternate approach to regular treatment. Yoga exercise has been disclosed to influence remission from cancer cells over a long period of time and also reverses epigenetic alterations. Applications of Yoga in the management of oral oncology patients are scarce, hence the need for a scoping review of the literature. Hence, this study aimed to conduct a scoping review of the existing empirical evidence on the applications of yoga in oral oncology. The review methodology was informed by Joanna Brigg's Institute guidelines for systematic scoping reviews, and the review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. Ten databases were searched. The records of all the literature retrieved from the search were imported into the Rayyan software for deduplication. After the full-text screening, only two were found eligible for inclusion in the scoping review. Data obtained in the included literature were extracted and synthesized. This review found that Yoga was not significantly effective in the management of stress among oral cancer patients (p-values > 0.04). However, it was found that Yoga significantly reduced anxiety, saliva stickiness, and episodes of falling ill (p-values < 0.05) while it improved mental well-being, cognitive functioning, emotional functioning, and head and neck pain of those oral cancer patients that received it (p-values < 0.05). An integrative care approach that considers nonpharmaceutical techniques such as yoga could help to reduce care cost while improving care outcomes and quality of life of oral cancer patients. Hence, it is imperative to consider yoga along with its potential benefits, and we recommend gradual incorporation of yoga into oral cancer care.


COVID-19 vaccine acceptance among high-risk populations in Uganda.
Immunization is an important strategy for controlling the COVID-19 pandemic. COVID-19 vaccination was recently launched in Uganda, with prioritization to healthcare workers and high-risk individuals. In this study, we aimed to determine the acceptability of COVID-19 vaccine among persons at high risk of COVID-19 morbidity and mortality in Uganda. Between 29 March and 14 April 2021, we conducted a cross-sectional survey consecutively recruiting persons at high risk of severe COVID-19 (diabetes mellitus, HIV and cardiovascular disease) attending Kiruddu National Referral Hospital outpatient clinics. A trained research nurse administered a semi-structured questionnaire assessing demographics, COVID-19 vaccine related attitudes and acceptability. Descriptive statistics, bivariate and multivariable analyses were performed using STATA 16. A total of 317 participants with a mean age 51.5 ± 14.1 years were recruited. Of this, 184 (60.5%) were female. Overall, 216 (70.1%) participants were willing to accept the COVID-19 vaccine. The odds of willingness to accept COVID-19 vaccination were four times greater if a participant was male compared with if a participant was female [adjusted odds ratio (AOR): 4.1, 95% confidence interval (CI): 1.8-9.4, p = 0.00]. Participants who agreed (AOR: 0.04, 95% CI: 0.01-0.38, p = 0.003) or strongly agreed (AOR: 0.04, 95% CI: 0.01-0.59, p = 0.005) that they have some immunity against COVID-19 were also significantly less likely to accept the vaccine. Participants who had a history of vaccination hesitancy for their children were also significantly less likely to accept the COVID-19 vaccine (AOR: 0.1, 95% CI: 0.01-0.58, p = 0.016). The willingness to receive a COVID-19 vaccine in this group of high-risk individuals was comparable to the global COVID-19 vaccine acceptance rate. Increased sensitization, myth busting and utilization of opinion leaders to encourage vaccine acceptability is recommended.


STUB1 is an intracellular checkpoint for interferon gamma sensing.
Immune checkpoint blockade (ICB) leads to durable and complete tumour regression in some patients but in others gives temporary, partial or no response. Accordingly, significant efforts are underway to identify tumour-intrinsic mechanisms underlying ICB resistance. Results from a published CRISPR screen in a mouse model suggested that targeting STUB1, an E3 ligase involved in protein homeostasis, may overcome ICB resistance but the molecular basis of this effect remains unclear. Herein, we report an under-appreciated role of STUB1 to dampen the interferon gamma (IFNγ) response. Genetic deletion of STUB1 increased IFNGR1 abundance on the cell surface and thus enhanced the downstream IFNγ response as showed by multiple approaches including Western blotting, flow cytometry, qPCR, phospho-STAT1 assay, immunopeptidomics, proteomics, and gene expression profiling. Human prostate and breast cancer cells with STUB1 deletion were also susceptible to cytokine-induced growth inhibition. Furthermore, blockade of STUB1 protein function recapitulated the STUB1-null phenotypes. Despite these encouraging in vitro data and positive implications from clinical datasets, we did not observe in vivo benefits of inactivating Stub1 in mouse syngeneic tumour models-with or without combination with anti-PD-1 therapy. However, our findings elucidate STUB1 as a barrier to IFNγ sensing, prompting further investigations to assess if broader inactivation of human STUB1 in both tumors and immune cells could overcome ICB resistance.


Towards a Better Understanding of the Post-Gastric Behavior of Enteric-Coated Formulations.
The aim of our work was to develop a biorelevant dissolution method for a better understanding of the in vivo performance of delayed-release tablet formulations. The typical pH profile and residence times in the stomach and small intestine were determined in fasted conditions based on the published results of swallowable monitoring devices. Then, a multi-stage pH shift dissolution method was developed by adding different amounts of phosphate-based buffer solutions to the initial hydrochloric acid solution. Because of the highly variable in vivo residence times in the stomach, two alternatives of the method were applied, modeling rapid and slow gastric emptying as well. This approach provided an opportunity to study the effect of the acidic treatment on post gastric release. Six enteric-coated low-dose acetylsalicylic acid (ASA) formulations including the reference Aspirin Protect were tested as a model compound. Moreover, the thickness of the coating of each formulation was investigated by scanning electron microscope. Comparing the in vitro results to the known properties of the formulations, the new method was found to be more discriminative than the USP dissolution method. Ingredients affecting the in vitro dissolution, and thus probably the in vivo performance, were identified in both the tablet core and the coating of the tested formulations. The limited available in vivo data also indicated an increased predictivity. Overall, the presented method may be an efficient tool to support the development of enteric coated generic formulations.


The Need for Local, Multidisciplinary Collaborations to Promote Advances in Physical Activity Research and Policy Change: The Creation of the Boston Physical Activity Resource Collaborative (BPARC).
This commentary describes the development, vision, and initial progress of the newly-founded Boston Physical Activity Resource Collaborative (BPARC). Our aims are to move the field of physical activity forward, with broader dissemination and translation, by creating a local Boston and Massachusetts hub for researchers, practitioners, advocates, and policymakers. Participants come from multiple academic and medical centers, local advocacy groups, and government agencies, all of whom are working on components of physical activity promotion. We have had initial success in collaborating on study design, methodology, and grant applications. Future endeavors aim to produce streamlined methods and products with maximal impact for the field of physical activity research, policy, and practice.


Discovery of a Series of 5-Azaquinazolines as Orally Efficacious IRAK4 Inhibitors Targeting MyD88L265P Mutant Diffuse Large B Cell Lymphoma.
In this article, we report the discovery of a series of 5-azaquinazolines as selective IRAK4 inhibitors. From modestly potent quinazoline 4, we introduced a 5-aza substitution to mask the 4-NH hydrogen bond donor (HBD). This allowed us to substitute the core with a 2-aminopyrazole, which showed large gains in cellular potency despite the additional formal HBD. Further optimization led to 6-cyanomethyl-5-azaquinazoline 13, a selective IRAK4 inhibitor, which proved efficacious in combination with ibrutinib, while showing very little activity as a single agent up to 100 mg/kg. This contrasted to previously reported IRAK4 inhibitors that exhibited efficacy in the same model as single agents and was attributed to the enhanced specificity of 13 toward IRAK4.


[Electrochemical immunoanalysis of cardiac myoglobin].
Method targeting the direct monitoring of myoglobin based on analysis of electrochemical parameters of modified electrodes were proposed. Method of direct detection is based on interaction of myoglobin with anti-myoglobin with subsequent electrochemical registration of hemeprotein. Myocardial infarction biomarker myoglobin was quantified at biological level using screen printed electrodes modified with gold nanoparticles stabilized with didodecyldimethylammonium bromide (DDAB) and antibodies. Proposed method did not require signal enhancement and amplification and also labeled secondary antibodies. Electro analysis has high specificity and sensitivity. Myoglobin -antibodies interaction was studied also with electrochemical impedance spectroscopy. Sensor has low detection limit and broad diapason of working concentrations (17.8 ng/ml-1780 ng/ml; 1 nM-10 nM). Method based on gold nanoparticles detection on the surface of electrodes was treated for myoglobin identification. AuNP worked as an electrochemical sensing platform: the oxidation of gold surface (resulted in gold oxide formation) upon polarization served as a basis for analytical response. The difference of cathodic peak area and peak high of gold oxide reduction in the case of electrodes with antibodies and electrodes with antibodies-myoglobin complex, was registered.


Reactive oxygen species and transcript analysis upon excess light treatment in wild-type Arabidopsis thaliana vs a photosensitive mutant lacking zeaxanthin and lutein.
Reactive oxygen species (ROS) are unavoidable by-products of oxygenic photosynthesis, causing progressive oxidative damage and ultimately cell death. Despite their destructive activity they are also signalling molecules, priming the acclimatory response to stress stimuli. To investigate this role further, we exposed wild type Arabidopsis thaliana plants and the double mutant npq1lut2 to excess light. The mutant does not produce the xanthophylls lutein and zeaxanthin, whose key roles include ROS scavenging and prevention of ROS synthesis. Biochemical analysis revealed that singlet oxygen (1O2) accumulated to higher levels in the mutant while other ROS were unaffected, allowing to define the transcriptomic signature of the acclimatory response mediated by 1O2 which is enhanced by the lack of these xanthophylls species. The group of genes differentially regulated in npq1lut2 is enriched in sequences encoding chloroplast proteins involved in cell protection against the damaging effect of ROS. Among the early fine-tuned components, are proteins involved in tetrapyrrole biosynthesis, chlorophyll catabolism, protein import, folding and turnover, synthesis and membrane insertion of photosynthetic subunits. Up to now, the flu mutant was the only biological system adopted to define the regulation of gene expression by 1O2. In this work, we propose the use of mutants accumulating 1O2 by mechanisms different from those activated in flu to better identify ROS signalling. We propose that the lack of zeaxanthin and lutein leads to 1O2 accumulation and this represents a signalling pathway in the early stages of stress acclimation, beside the response to ADP/ATP ratio and to the redox state of both plastoquinone pool. Chloroplasts respond to 1O2 accumulation by undergoing a significant change in composition and function towards a fast acclimatory response. The physiological implications of this signalling specificity are discussed.


Margination of red blood cells infected by Plasmodium falciparum in a microvessel.
We investigated numerically the mechanism of margination of Plasmodium falciparum malaria-infected red blood cells (Pf-IRBCs) in micro-scale blood flow. Our model illustrates that continuous hydrodynamic interaction between a Pf-IRBC in the trophozoite stage (Pf-T-IRBC) and healthy red blood cells (HRBCs) results in the margination of the Pf-T-IRBC and, thus, a longer duration of contact with endothelial cells. The Pf-T-IRBC and HRBCs first form a "train". The volume fraction of RBCs is then locally increased, to approximately 40%, and this value is maintained for a long period of time due to the formation of a long train in high-hematocrit conditions. Even in low-hematocrit conditions, the local volume fraction is instantaneously elevated to 40% and the Pf-T-IRBC can migrate to the wall. However, the short train formed in low-hematocrit conditions does not provide continuous interaction, and the Pf-T-IRBC moves back to the center of the channel.


Does brightness contrast really affect the Mueller-Lyer illusion.
Several writers have hypothesized that the Mueller-Lyer illusion is influenced by brightness contrast between figure and background. According to them, lateral inhibition in the retina causes displacement in Mueller-Lyer figures at the intersections of lines. They argue that the strength of the displacement varies with brightness contrast between the background and the figure, and they cite research by Pollack and others for support. The experiments reported here show that the Mueller-Lyer illusion is no more affected by changes in contrast than are judgment of single straight lines. These results are not consistent with the view that lateral inhibition in the retina has an effect on the illusion.


Palladium-Catalyzed Cross-Coupling of gem-Bis(boronates) with Aryl Halides: An Alternative To Access Quaternary α-Aryl Aldehydes.
The compounds with a quaternary α-aryl aldehyde skeleton are important units in organic chemistry. Previously, the aryl group and carbonyl group are introduced in a stepwise manner. Herein, a novel route is developed to construct the quaternary α-aryl aldehydes with gem-bis(boronates) as precursors, in which the two groups are installed simultaneously. The gem-bis(boronates) are readily available from ketones; as a result, this methodology provides a more general strategy to produce the quaternary α-aryl aldehydes with broad scopes and synthetic convenience.


Paracetamol use prior to and in early pregnancy: Prevalence and patterns among women with and without chronic medical diseases.
Paracetamol is commonly consumed by pregnant women, even though recent data have questioned its safety. Having chronic medical diseases (CMDs) may influence the prevalence of use during pregnancy. We aimed to assess the prevalence and patterns of use 3 months prior to pregnancy and in the first trimester among women with and without CMDs and the potential influence of CMDs on frequent use in the first trimester. We used patient-reported data from the Copenhagen Pregnancy Cohort from 1 October 2013 to 23 May 2019 with information on CMDs and paracetamol use. Prevalence and patterns of use were assessed descriptively and by multivariable logistic regression models. We included 24 019 pregnancies. Use of paracetamol prior to and in early pregnancy was significantly higher among women with CMDs compared to women without (40.7% vs. 35.8% and 9.1% vs. 5.1%, respectively). Women with CMDs were 2.7 times more likely to have a frequent intake compared to women without [aOR 2.69 (95% CI 2.05-3.32)]. Migraine, rheumatoid arthritis and mental disease were associated with a higher use of paracetamol [aOR 4.39 (3.20-6.02), aOR 4.32 (2.41-7.72) and aOR 2.74 (1.67-4.49), respectively]. Women with CMDs had a higher paracetamol use before and during pregnancy than women without CMDs. Women with migraine, rheumatoid arthritis and mental disease showed the highest risk of frequent use. This study highlights the importance of discussing pain relief in pregnancy and evaluating the influence of maternal CMDs when assessing adverse effects of paracetamol use during pregnancy.


The Twin-Flex clasp: an esthetic alternative.
In removable partial denture fabrication, the patient's interest usually lies in the improvement of his or her esthetic appearance. Unsightly facial clasps have always been a cosmetic problem with traditional options either expensive or technically difficult. This article describes an alternative for anterior retention that maintains excellent esthetics with a simple approach.


Consumers' Expectations about Meat from Surgical Castrated or Immunocastrated Male and Female Iberian Pigs.
A common practice in Iberian pigs is the castration of both males and females, and it can be carried out surgically or by immunization against gonadotropin-releasing factor (GnRF). The aim of this work was to determine consumers' overall liking and expectations towards Iberian pork from five different sex types (castrated females, entire females, GnRF-vaccinated females, castrated males and GnRF-vaccinated males), as well as to know the attitudes and beliefs of consumers towards castration and immunocastration. Loins from 83 Iberian pigs were collected and evaluated by 252 consumers in Barcelona and Madrid. Consumers evaluated the five types of meat in three situations: blind condition (tasting the product), expectations (without tasting) and informed condition. Finally, attitudes and beliefs towards castration and immunocastration were also determined. Results distinguished three segments of consumers labeled as "Indifferent", "Against castration and immunocastration" and "Against immunocastration". Meat from castrated males had higher overall liking scores in the blind condition. Expectations towards pork depending on its sex type affect consumer-informed acceptability; thus, it is important to consider marketing strategies to avoid or direct the effect of the information provided on the acceptability of the pork.


Hairpin structures in synthetic oligodeoxynucleotides: sequence effects on the duplex-to-hairpin transition.
We have synthesized and examined a number of fully and partly self-complementary palindromic oligodeoxynucleotides for their ability to assume in solution a unimolecular hairpin structure. The main results obtained by a combined optical and electrophoresis investigation show that: (i) DNA folding needs not be driven by mismatched base pairings over the dyad; fully self-complementary palindromic duplexes, comprising regular (CG)n DNA fragments, possess a considerable intrinsic propensity to make intramolecular base pairings; (ii) The duplex-hairpin interconversion is, in general, a slow process independent of the length and base composition of the palindrome; (iii) The palindromic sequences energetically least favored to form hairpin structures consist of C:G base pairs around the dyad axis and of T:A blocks in the arms of the inverted repeat; (IV) The base composition of the stem strongly influences the hairpin thermal stability. For instance, the substitution of one C:G with one A:T base pair in the stem helix of d(CG)7 diminishes the stability of the hairpin by 9 degrees C. It is found that the stability of the stem helix, in hairpins of defined sequence and with the same loop length, decreases in the order alternating-CG greater than homo-CG greater than AC(GT) greater than alternating-AT, i.e. as in polynucleotides. The thermodynamic parameters for the hairpin-coil transition are reported.


NosA, a transcription factor important in Aspergillus fumigatus stress and developmental response, rescues the germination defect of a laeA deletion.
Aspergillus fumigatus is an increasingly serious pathogen of immunocompromised patients, causing the often fatal disease invasive aspergillosis (IA). One A. fumigatus virulence determinant of IA is LaeA, a conserved virulence factor in pathogenic fungi. To further understand the role of LaeA in IA, the expression profile of ΔlaeA was compared to wild type, and several transcription factors were found significantly misregulated by LaeA loss. One of the transcription factors up-regulated over 4-fold in the ΔlaeA strain was Afu4g09710, similar in sequence to Aspergillus nidulans NosA, which is involved in sexual development. Here we assessed loss of nosA (ΔnosA) and overexpression of nosA (OE::nosA) on A. fumigatus in both a wild type and ΔlaeA background. Based on the multiple alterations of physiological development of single and double mutants, we suggest that NosA mediates the decreased radial growth and delayed conidial germination observed in ΔlaeA strains, the former in a light dependent manner. The ΔnosA mutant showed increased virulence in the Galleria mellonella larvae model of disseminated aspergillosis, potentially due to its increased growth and germination rate. Furthermore, the A. fumigatus nosA allele was able to partially remediate sexual development in an A. nidulans ΔnosA background. Likewise, the A. nidulans nosA allele was able to restore the menadione sensitivity defect of the A. fumigatus ΔnosA strain, suggesting conservation of function of the NosA protein in these two species.


Increased somatic mutation burdens in normal human cells due to defective DNA polymerases.
Mutation accumulation in somatic cells contributes to cancer development and is proposed as a cause of aging. DNA polymerases Pol ε and Pol δ replicate DNA during cell division. However, in some cancers, defective proofreading due to acquired POLE/POLD1 exonuclease domain mutations causes markedly elevated somatic mutation burdens with distinctive mutational signatures. Germline POLE/POLD1 mutations cause familial cancer predisposition. Here, we sequenced normal tissue and tumor DNA from individuals with germline POLE/POLD1 mutations. Increased mutation burdens with characteristic mutational signatures were found in normal adult somatic cell types, during early embryogenesis and in sperm. Thus human physiology can tolerate ubiquitously elevated mutation burdens. Except for increased cancer risk, individuals with germline POLE/POLD1 mutations do not exhibit overt features of premature aging. These results do not support a model in which all features of aging are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.


NIR-emitting styryl dyes with large Stokes' shifts for imaging application: From cellular plasma membrane, mitochondria to Zebrafish neuromast.
Near-infrared (NIR) emitting probes with very large Stokes' shifts play a crucial role in bioimaging applications, as the optical signals in this region exhibit high signal to background ratio and allow deeper tissue penetration. Herein we illustrate NIR-emitting probe 2 with very large Stokes' shifts (Δλ ≈ 260 - 272 nm) by integrating the excited-state intramolecular proton transfer (ESIPT) unit 2-(2'-hydroxyphenyl)benzoxazole (HBO) into a pyridinium derived cyanine. The ESIPT not only enhances the Stokes' shifts but also improves the quantum efficiency of the probe 2 (фfl = 0.27 - 0.40 in DCM). The application of 2 in live cells imaging reveals that compound 2 stains mitochondria in eukaryotic cells, normal human lungs fibroblast (NHLF), Zebrafish's neuromast hair cells, and support cells, and inner plasma membrane in prokaryotic cells, Escherichia coli (E. coli).


Characterization of phosphopeptide derived from bovine beta-casein: an inhibitor to intra-intestinal precipitation of calcium phosphate.
Casein phosphopeptide (CPP), a highly phosphorylated peptide fragment which inhibits the formation of hydroxyapatite crystal was isolated from pooled ileal contents of rats fed a semi-synthetic diet containing bovine beta-casein. The estimated amino acid sequence of the CPP was shorter than that of the trypsin-digested beta-casein but the core region consisting of consecutive bindings of phosphoserine was fully conserved. A moderate and exchangeable binding to Ca2+ of the CPP molecule well substantiates the high absorbability of calcium from milk and dairy products.


The pleiotropic effects of α-thalassemia on HbSS and HbSC sickle cell disease: Reduced erythrocyte cation co-transport activity, serum erythropoietin, and transfusion burden, do not translate into increased survival.
α-Thalassemia is one of the most important genetic modulators of sickle cell disease (SCD). Both beneficial and detrimental effects have been described previously. We use a 12-year data set on a large cohort of patients with HbSS (n = 411) and HbSC (n = 146) to examine a wide range of these clinical and laboratory associations. Our novel findings are that α-thalassemia strongly reduces erythrocyte potassium chloride co-transporter (KCC) activity in both HbSS and HbSC (p = .035 and p = .00045 respectively), suggesting a novel mechanism through which α-thalassemia induces a milder phenotype by reducing red cell cation loss. This may be particularly important in HbSC where reduction in mean cell hemoglobin concentration is not seen and where KCC activity has previously been found to correlate with disease severity. Additionally, we show that α-thalassemia not only increases hemoglobin in patients with HbSS (p = .0009) but also reduces erythropoietin values (p = .0005), demonstrating a measurable response to improved tissue oxygenation. We confirm the reno-protective effect of α-thalassemia in patients with HbSS, with reduced proteinuria (p = .003) and demonstrate a novel association with increased serum sodium (p = .0004) and reduced serum potassium values (p = 5.74 × 10-10 ). We found patients with α-thalassemia had a reduced annualized transfusion burden in both HbSS and HbSC, but α-thalassemia had no impact on annualized admission rates in either group. Finally, in a larger cohort, we report a median survival of 62 years in patients with HbSS (n = 899) and 80 years in those with HbSC (n = 240). α-thalassemia did not influence survival in HbSS, but a nonsignificant trend was seen in those with HbSC.


Mussel-inspired alkaline phosphatase-specific coating on orthopedic implants for spatiotemporal modulating local osteoimmune microenvironment to facilitate osseointegration.
Inadequate initial osseointegration and consequent prosthesis loosening are the most severe complications after artificial arthroplasty. Proper immune responses are crucial for the successful implantation of artificial prostheses. Macrophages are central in osteoimmunomodulation because they exert distinct functions with highly plasticity. Herein, we developed an alkaline phosphatase (ALP) sensitive mussel-inspired coating on orthopedic implants for promoting osseointegration. First, the resveratrol-alendronate complexes were deposited on titanium implant surface through mussel-inspired interfacial interactions. Upon prosthesis implantation, macrophages first polarized towards M1 type to initiate inflammatory responses and bone regeneration. As osteogenesis progresses, increasing amounts of ALP secreted by osteoblasts was cleaved the resveratrol-alendronate complexes. Then, the released resveratrol further promoted osteogenic differentiation of BMSCs and induced locoregional macrophages M2 polarization. Our results demonstrated that the bioinspired osteoimmunomodulation coating remarkably facilitated the prosthesis-bone integration by spatiotemporally modulating macrophages switching from M1 to M2 polarization in response to a real-time healing signal during osteogenesis. In summary, the mussel-inspired osteoimmunomodulation coating technology may provide a new approach for promoting osseointegration after artificial arthroplasty.


Quantitation of Long Noncoding RNA Using Digital PCR.
Long noncoding RNAs (lncRNAs) are implicated in many physiological or disease processes and alterations in their expression may contribute to the development of various diseases. Accurate quantitation of lncRNA can be useful in measuring changes in expression in different settings such as in the circulation where the measurement of lncRNA may be useful as a biomarker of disease. However, the low levels of lncRNA expression require the use of highly sensitive detection technologies for accurate quantitation. Digital polymerase chain reaction (dPCR) is a sensitive method for absolute quantification of lncRNA and can be useful for measurement of gene expression when transcript levels are low. By providing a direct measurement without normalization, the use of dPCR may provide advantages for quantitation of low-abundance targets.


Fluorescent protein fusions in Candida guilliermondii.
Candida guilliermondii is an emerging fungal agent of candidiasis often associated with oncology patients. This yeast also remains a promising biotechnological model for the industrial production of value-added metabolites. In the present study, we developed a recipient strain as well as a set of plasmids for construction of fluorescent protein (FP) fusions in this species. We demonstrated that C. guilliermondii phosphoglycerate kinase transcription-regulating sequences allow a constitutive expression of codon-optimized green, cyan, yellow and mCherry FP genes in C. guilliermondii cells and the fluorescence signal could be directly observed at the colony and blastospore level by epifluorescence microcopy. To illustrate differential targeting of the FPs into specified cellular compartments, we studied and validated the expected subcellular localization of various C. guilliermondii predicted proteins fused to FPs. Furthermore, co-expression experiments of various couples of FP-tagged C. guilliermondii predicted proteins in the same cell showed that the fluorescence of each FP could be detected independently, providing firm evidences that YFP/CFP and GFP/mCherry pairs can be used for dual labeling in C. guilliermondii cells. This technical advance will facilitate future studies of protein co-expression and co-localization in C. guilliermondii and will give precious help for elucidating new molecular events supporting pathogenicity, antifungal resistance and for exploring the potential of yeast metabolic engineering.


[Treatment of tuberculosis].
The aim of this article is to give practicing physicians a practical approach to the treatment of latent and active tuberculosis. Most patients follow TB standard treatment recommended by WHO that depend on category of patient. It is a combination of four essential tuberculosis drugs of the first group: isoniazid, rifampicin, pyrazinamid and ethambutol; in some cases streptomycin can replace ethambutol. This initial phase of intensive treatment is followed by a consolidation phase. Drugs should be administered in the morning on an empty stomach one hour before meals. Treatment of latent tuberculosis (TB) infection is an important component of TB control programs. Preventive treatment can reduce the risk of developing active TB.


Redesigning value-based hospital structures: a qualitative study on value-based health care in the Netherlands.
A crucial component of value-based health care concerns the redesign of organizational structures. In theory, hospital structures should follow value creation: addressing medical conditions for specific groups of patients over full cycles of care. In practice, however, it remains unclear how hospitals can reorganize themselves into value-based structures. The purpose of this study is to explore the ways in which Dutch hospitals are currently implementing and pursuing value-based redesign. This qualitative exploratory study used semi-structured interviews and a focus group for data collection. Transcripts were analyzed through deductive coding, for which we used Mintzberg's theory on organizational structures, particularly his work on design parameters. In their efforts to create more value-based structures, Dutch hospitals often employ a variety of liaison devices, such as project teams and committees. By contrast, the actual formation of units around medical conditions is much rarer. Outcome data are widely used within planning and control systems, and some hospitals partake in external benchmarking. Not all hospitals use cost indicators for monitoring performance. Value-based redesign is not necessarily a matter of radical changes or binary choices. Instead, as Dutch hospitals show, it can be an incremental process, with a variety of potential knobs to turn to various degrees. Health care executives, managers, and professionals thus have a wide range of options when they aim for more value-based structures. Our conceptualization of "value-based design parameters" can help guide the selection and implementation of strategies and mechanisms for further coordination around medical conditions over full cycles of care.


Enhanced protein delivery by multi-ion containing eggshell derived apatitic-alginate composite nanocarriers.
Eggshell is an attractive natural source of calcium for the synthesis of hydroxyapatite (HA) as it contains minor amounts of biologically relevant elements such as Mg, Sr, and Si. The mineral phase of the human bone is essentially a calcium deficient hydroxyapatite (CDHA) which shows more bioactivities and absorbance than stoichiometric HA does. Hence, we have attempted to develop a protein delivery system based on eggshell derived CDHA (ECDHA) nanoparticles for bone tissue engineering. Nanoparticles with Ca/P molar ratio of 1.67, 1.61 and 1.51 to form CDHAs with compositions covering the properties of stable HA phase (Ca/P=1.67) to degradable tricalcium phosphate (TCP) phase (Ca/P=1.5) were synthesized by microwave-accelerated wet chemical synthesis using eggshell as well as synthetic calcium hydroxide as calcium precursors. The delivery profiles of bovine serum albumin (BSA), a model protein by the nanocarriers, were studied. Both eggshells derived and synthetic CDHA samples showed maximum amount of loading of 57% and 37%, respectively at a Ca/P ratio of 1.51, comparing to stoichiometric HA. ECDHA also showed a much more BSA release (25%) than synthetically derived CDHA (6.5%) did. To further improve the release profile, alginate coating was carried out on CDHA nanoparticles and the BSA release profiles were evaluated. A maximum release of 65% was observed for alginate coated ECDHA at a Ca/P ratio of 1.51 for a period of 2 days. The ECDHA nanoparticle with a Ca/P ratio similar to degradable TCP and with alginate coating seems to be an ideal protein delivery agent.


Vitamin D Status Among Children With Juvenile Idiopathic Arthritis: A Multicenter Prospective, Non-randomized, Comparative Study.
Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disease characterized by destructive and inflammatory damage to the joints. The aim in this study was to compare vitamin D levels between children and adolescents, 1-18 years of age, with juvenile idiopathic arthritis (JIA) and a health control group of peers. We considered effects of endogenous, exogenous, and genetic factors on measured differences in vitamin D levels among children with JIA. Our findings are based on a study sample of 150 patients with various variants of JIA and 277 healthy children. The blood level of vitamin D was assessed by calcidiol level. The following factors were included in our analysis: age and sex; level of insolation in three regions of country (center, south, north); assessment of dietary intake of vitamin D; effect of prophylactic doses of cholecalciferol; a relationship between the TaqI, FokI, and BsmI polymorphisms of the VDR gene and serum 25(OH)D concentration. We identified a high frequency of low vitamin D among children with JIA, prevalence of 66%, with the medial level of vitamin D being within the range of "insufficient" vitamin D. We also show that the dietary intake of vitamin D by children with JIA is well below expected norms, and that prophylactic doses of vitamin D supplementation (cholecalciferol) at a dose of 500-1,000 IU/day and 1,500-2,000 IU/day do not meet the vitamin D needs of children with JIA. Of importance, we show that vitamin D levels among children with JIA are not affected by clinical therapies to manage the disease nor by the present of VDR genetic variants. Prophylactic administration of cholecalciferol and season of year play a determining role in the development of vitamin D deficiency and insufficiency.


Treatment and prognosis of type B2 thymoma.
Because of the rarity of thymoma, no randomized trials have prospectively detected the prognosis and optimal treatment for type B2 thymoma. The aim of this study is to investigate the treatment and prognosis for patients with type B2 thymoma. We retrospectively evaluated the outcome of 42 patients with type B2 thymoma who were treated between 1995 and 2010 in Zhejiang Cancer Hospital. Survival curves were plotted using the Kaplan-Meier method. The Cox proportional hazard model was used for multivariate analysis. The current study included 42 patients. The 5-year disease-free survival and overall survival rates were 62.8% and 84.9%, respectively. There were significant differences in disease-free survival and overall survival among different Masaoka stages (both P<0.001). Univariate and multivariate analysis revealed that Masaoka stage was associated with disease-free survival and overall survival (P=0.00 and 0.001, respectively). Our results indicate that Masaoka stage affects disease-free survival and overall survival of patients with type B2 thymoma.


Aquaporins and (in)fertility: More than just water transport.
Aquaporins (AQPs) are a family of channel proteins that facilitate the transport of water and small solutes across biological membranes. They are widely distributed throughout the organism, having a number of key functions, some of them unexpected, both in health and disease. Among the various diseases in which AQPs are involved, infertility has been overlooked. According to the World Health Organization (WHO) infertility is a global public health problem with one third of the couples suffering from subfertility or even infertility due to male or female factors alone or combined. Thus, there is an urgent need to unveil the molecular mechanisms that control gametes production, maturation and fertilization-related events, to more specifically determine infertility causes. In addition, as more couples seek for fertility treatment through assisted reproductive technologies (ART), it is pivotal to understand how these techniques can be improved. AQPs are heterogeneously expressed throughout the male and female reproductive tracts, highlighting a possible regulatory role for these proteins in conception. In fact, their function, far beyond water transport, highlights potential intervention points to enhance ART. In this review we discuss AQPs distribution and structural organization, functions, and modulation throughout the male and female reproductive tracts and their relevance to the reproductive success. We also highlight the most recent advances and research trends regarding how the different AQPs are involved and regulated in specific mechanisms underlying (in)fertility. Finally, we discuss the involvement of AQPs in ART-related processes and how their handling can lead to improvement of infertility treatment.


Randomised equivalency trial comparing 2.5% povidone-iodine eye drops and ophthalmic chloramphenicol for preventing neonatal conjunctivitis in a trachoma endemic area in southern Mexico.
To evaluate the effectiveness of 2.5% povidone-iodine eye drops (PIED) compared with ophthalmic chloramphenicol (OC) for preventing neonatal conjunctivitis. 2004 neonates were enrolled from three rural hospitals in a trachoma endemic area. They were randomly assigned to receive either PIED (n = 1024) or OC (n = 974). Infectious conjunctivitis was confirmed by laboratory methods, including specific search for Chlamydia trachomatis by polymerase chain reaction assay. During the first 48 hours after birth, PIED and OC had similar efficacy against bacterial conjunctivitis (95% confidence interval (CI), -0.031 to -0.004; p = 0.01); from day 3 to day 15, PIED was 6% less effective than OC (95% CI, -0.058 to -0.006; p = 0.01); after day 16 there was no significant difference between the groups (95% CI, -0.022 to 0.041; p = 0.57). However, the risk of C trachomatis conjunctivitis was increased in neonates receiving PIED prophylaxis (relative risk = 1.99 (95% CI, 1.07 to 3.71), log-rank p = 0.029). Ocular side effects were rare and self limiting in both groups (p = 0.223). PIED seems to increase the risk of acquiring chlamydial conjunctivitis in neonates. Additional measures are required to prevent mother to fetus transmission of chlamydial infection during pregnancy, delivery, and after birth.


Community-based appraisal of menopause-specific health problems and quality of life among women of rural Western Maharashtra.
Menopause is an important hormonal transition of women's lifespan which can strike as early as 30-35 years of age. Menopause-specific quality of life (MENQoL) mainly depends upon awareness, frequency, and intensity of menopausal symptoms; sociocultural, lifestyle, and dietary factors; and availability of health services specifically focusing on these issues. As life expectancy increases, women have to spend more years after menopause. So menopause specific quality of life will be a major issue of concern in the near future. The aim of this study was to assess the post-menopausal symptoms and quality of life (QoL) amongst post-menopausal women and their association with various sociodemographic factors. A community-based, descriptive, cross-sectional study was undertaken at Sakuri village among 100 postmenopausal women. Information was collected using MENQoL questionnaire. Unpaired t-test and Chi-squared test were used. The mean age of participants and menopause was 51.8 ± 4.54 years and 46.42 ± 4.13 years, respectively. The major symptoms reported were hot flushes (70%), under accomplishment (100%), bloating (100%), decrease in physical strength (95%), and change in sexual desire (78%). Statistically significant association was found between age and psychosocial domain. QoL was associated with age and educational level. More than half of the participants had poor QoL for all four domains. Awareness about post-menopausal changes and available treatment modalities can improve QoL. Accessible and affordable gynaecological and psychiatric health services through channel of primary health care are necessary to alleviate these complaints.


[WHO Guideline: Physical Activity, Sedentary Behavior and Sleep for Children under 5 Years of Age].
Early childhood is a time during which a child's habits are formed and family lifestyle habits are open to changes and adaptations. This guideline provides recommendations on the amount of time during the 24 hours of a day that young children, under 5 years of age, should spend being physically active or sleeping for their health and wellbeing. The guideline was developed by the World Health Organization (WHO) in accordance with WHO standards. The summary was translated into German by employees of the WHO Collaborating Center at Danube University Krems (Austria). A day consists of sleep time, sedentary time and physical activity of light, moderate or vigorous intensity. Young children should have opportunities to participate in a range of developmentally appropriate, safe, enjoyable play-based physical activities.


Altered resting-state functional connectivity of the default mode and central executive networks following cognitive processing therapy for PTSD.
Psychotherapy research is increasingly targeting both psychological and neurobiological mechanisms of therapeutic change. This trend is evident in and applicable to post-traumatic stress disorder (PTSD) treatment research given the high nonresponse rate of individuals with PTSD who undergo cognitive-behavioral therapy (CBT). Functional connectivity analyses investigating disrupted brain networks across mental disorders have been employed to understand both mental disorder symptoms and therapeutic mechanisms. However, few studies have examined pre-post CBT brain changes in PTSD using functional connectivity analyses. The current study investigated a) whether brain networks commonly implicated in psychopathology (e.g., default mode network [DMN], central executive network [CEN], and salience network [SN]) changed following Cognitive Processing Therapy (CPT) for PTSD and b) whether change in these networks was associated with PTSD and/or transdiagnostic symptom change. Independent components analysis was implemented to investigate resting-state functional connectivity in DMN, CEN, and SN in 42 women with PTSD and 18 trauma-exposed controls (TEC). Results indicated decreased CEN-cerebellum connectivity in PTSD participants versus TEC prior to CPT and decreased DMN connectivity in PTSD participants after CPT. Additionally, DMN and SN connectivity was related to change in positive and negative affectivity, while exploratory analyses at a cluster threshold of pFDR < .10 indicated DMN and SN connectivity was also related to change in PTSD symptoms and rumination. These findings provide evidence for normalization of CEN connectivity with treatment and implicate the DMN and SN in clinical symptom change following CPT.


Eosin-Y-Catalyzed Photoredox C-S Bond Formation: Easy Access to Thioethers.
An operationally simple Eosin Y catalyzed sulfenylation of hydrazones has been realized to afford a range of thioethers under visible light. The methodology provides high yields of thioethers under ambient conditions employing readily available and inexpensive starting materials. The reaction has broad substrate scope and is compatible with various functional groups.


Metallic Nanoalloys on Vertical GaAs Nanowires: Growth Mechanisms and Shape Control of Ni-GaAs Compounds.
GaAs nanowires are promising candidates for emerging devices in a broad field of applications (e.g., nanoelectronics, photodetection, or photoconversion). These nanostructures benefit greatly from a vertical integration, as it allows for the exhibition of the entire nanowire surface. However, one of the main challenges related to vertical integration is the conception of an efficient method to create low resistive contacts at nanoscale without degrading the device performance. In this article, we propose a complementary metal-oxide-semiconductor (CMOS)-compatible approach to form alloyed contacts at the extremities of vertical GaAs nanowires. Ni-based and Pd-based alloys on different vertical GaAs nanostructures have been characterized by structural and chemical analyses to identify the phase and to study the growth mechanisms involved at the nanoscale. It is shown that the formation of the Ni3GaAs alloy on top of nanowires following the epitaxial relation Ni3GaAs(0001)∥GaAs(111) leads to a pyramidal shape with four faces. Finally, guidelines are presented to tune the shape of this alloy by varying the initial metal thickness and nanowire diameters. It will facilitate the fabrication of a nanoalloy structure with tailored shape characteristics to precisely align with a designated application.


Impact of inpatient mental health rehabilitation on psychiatric readmissions: a propensity score matched case control study.
Background: Examination of readmission data is a standard method for evaluating health service outcomes. Limited work has evaluated the efficacy of mental health rehabilitation, despite the need for evidence-based approaches.Aims: To evaluate the impact of inpatient mental health rehabilitation using metrics of psychiatric readmissions routinely collected at occasions of service.Methods: Consumers (n = 252) of a nonacute inpatient mental health rehabilitation unit were case matched with normative clients from community mental health services. The impact of inpatient care was measured on: (1) the occurrence of a psychiatric readmission within 12 months of discharge; (2) the total number of psychiatric readmissions within 12 months of discharge; and (3) the number of days to a psychiatric readmission after discharge.Results: The proportion of consumers experiencing a readmission significantly decreased following inpatient care, comparable to the normative group. The number of readmissions also significantly decreased, approaching normative group levels, except in consumers with comorbid bipolar, substance use, or personality disorder. Time to a readmission significantly increased following inpatient care, approximating normative group values, and was related to the number of previous admissions.Conclusion: Routinely collected service data demonstrated nonacute inpatient mental health rehabilitation reduces re-hospitalization, which will have benefits for both consumers and health services.


IVth International Symposium on Neural Transplantation.
IVth International Symposium on Neural TransplantationEdited by William J. Freed and Jeffrey M. RosensteinThe George Washington University, Washington, DC, USAJuly 12-16, 1992.


Arsenic disrupts neuronal insulin signaling through increasing free PI3K-p85 and decreasing PI3K activity.
Previously, we reported that prolonged arsenic exposure impaired neuronal insulin signaling. Here we have further identified novel molecular mechanisms underlying neuronal insulin signaling impairment by arsenic. Arsenic treatment altered insulin dose-response curve and reduced maximum insulin response in differentiated human neuroblastoma SH-SY5Y cells, suggesting that arsenic hindered neuronal insulin signaling in a non-competitive like manner. Mechanistically, arsenic suppressed insulin receptor (IR) kinase activity, as witnessed by a decreased insulin-activated autophosphorylation of IR at Y1150/1151. Arsenic decreased the level of insulin receptor substrate 1 (IRS1) but increased the protein ratio between PI3K regulatory subunit, p85, and PI3K catalytic subunit, p110. Interestingly, co-immunoprecipitation demonstrated that arsenic did not alter a level of PI3K-p110/PI3K-p85 complex while increased PI3K-p85 levels in a PI3K-p110 depletion supernatant resulted from PI3K-p110 immunoprecipitation. These results indicated that arsenic increased PI3K-p85 which was free from PI3K-p110 binding. In addition, arsenic significantly increased interaction between IRS1 and PI3K-p85 but not PI3K-p110, suggesting that there may be a fraction of free PI3K-p85 interacting with IRS1. In vitro PI3K activity demonstrated that arsenic lowered PI3K activity in both basal and insulin-stimulated conditions. These results suggested that the increase in free PI3K-p85 by arsenic might compete with PI3K heterodimer for the same IRS1 binding site, in turn blocking the activation of its catalytic subunit, PI3K-p110. Taken together, our results provide additional insights into mechanisms underlying the impairment of neuronal insulin signaling by arsenic through the reduction of IR autophosphorylation, the increase in free PI3K-p85, and the impeding of PI3K activity.


Combined approach for intrapelvic abscess drainage among adults.
Obturator internus muscle (OIM) and adductor brevis (AB) abscess occurs rarely in adults. This condition mainly affects children experiencing trauma. This paper presents and discusses a unique case of OIM and AB abscess in an adult male that was treated operatively with a combined surgical approach (modified Stoppa and Smith-Peterson) after multiple failed drainage procedures. A 23-year-old male underwent reduction and fixation of his right tibiae shaft fracture with an intramedullary nail. After several referrals to the emergency room due to recurrent symptoms of fever and groin pain, he was finally admitted and diagnosed with OIM and AB abscess and fulminant MRSA sepsis. The operative treatment was performed by addressing the abscess with an unusual combined surgical approach (Smith-Peterson and modified Stoppa) for abscess drainage. Using PubMed, Google scholar and Hadassah Hebrew University search engines, we conducted a literature search using the following keywords: 'pyomyositis', 'obturator abscess', 'pelvic abscess', and 'pelvic osteomyelitis among children and adults'. Twenty case studies were found (14 children and 6 adults). No cases of combined OIM and AB abscess were found and only one OIM case was reported with methicillin-resistant Staphylococcus (MRSA).


The effect of membrane potential on the development of chemical osmotic pressure in compacted clay.
When clay soils are subjected to salt concentration gradients, various interrelated processes come into play. It is known that chemical osmosis induces a water flow and that a membrane potential difference develops that counteracts diffusive flow of solutes and osmotic flow of water. In this paper, we present the results of experiments on the influence of membrane potential on chemical osmotic flow and diffusion of solutes and we show how we are able to derive the membrane potential value from theory. Moreover, the simultaneous development of water pressure, salt concentration and membrane potential difference are simulated using a model for combined chemico-electroosmosis in clays. A new method for short-circuiting the clay sample is employed to assess the influence of electrical effects on flow of water and transport of solutes.


Responses to a spino-olivo-cerebellar pathway in the cat.
1. Surface potentials, similar to those found by earlier workers, have been recorded from the vermis of the anterior lobe of the cerebellum following stimulation of muscular, cutaneous and articular nerves of the ipsilateral hind limb. The most conspicuous component of the response consisted of a positive potential succeeded by a smaller negative potential.2. Micro-electrode recordings showed that this component coincided both with climbing fibre responses in individual Purkinje cells, and with extracellular field potentials within the cerebellar cortex which closely resembled those found by Eccles, Llinás & Sasaki (1966) following electrical stimulation of the inferior olive.3. Stimulation of the cerebellar surface, in the region where the responses to limb nerve stimulation were largest, led to antidromic invasion of neurones of the contralateral inferior olive. The antidromic action potentials were sometimes followed by up to three orthodromic spikes. Histological techniques were used to show that these neurones were located in the caudal parts of the dorsal and medial accessory olives.4. Stimulation of nerves of the hind limb evoked discharges of the same neurones of the dorsal accessory olive which were antidromically invaded from the vermis of the anterior lobe. The nerves used (quadriceps, gastrocnemius-soleus, sural and the posterior nerve to the knee joint) were shown to excite heavily overlapping populations of neurones.5. Those neurones of the medial accessory olive, which were identified antidromically from the anterior lobe vermis, were not discharged by stimulation of hind limb nerves.6. Simultaneous recording from the surface of the anterior lobe and from the dorsal accessory olive showed that the onset of olive cell discharges occurred about 5 msec before the onset of the positive potential at the cerebellar surface.


SNPbox: web-based high-throughput primer design with an eye for repetitive sequences.
In this omics era, researchers in biosciences need more than ever user-friendly, fast, and straightforward computational tools for high-throughput research. In this chapter, we present SNPbox and explain the general primer design strategy. We also show how the four modules, Exon, Single-Nucleotide Polymorphism (SNP), Saturation, and Exon + Saturation, exactly apply the primer design strategy, give clear guidance for users of the Web interface at http://www.SNPbox.org, and explain how pre-designed primers for Ensembl genes can be visualized and retrieved.


Metallic Glass-Fiber Fabrics: A New Type of Flexible, Super-Lightweight, and 3D Current Collector for Lithium Batteries.
Current collectors are indispensable parts that provide electron transport and mechanical support of electrode materials in a battery. Nowadays, thin metal foils made of Cu and Al are used as current collectors of lithium batteries, but they do not contribute to the storage capacity. Therefore, decreasing the weight of current collectors can directly enhance the energy density of a battery. However, limited by the requirements of mechanical strength, it is difficult to reduce the weight of metal foils any further. Herein, a new type of current collectors made of 3D metallic glass-fiber fabrics (MGFs), which shows advantages of super-lightweight (2.9-3.2 mg cm⁻2 ), outstanding electrochemical stability for cathodes and anodes of lithium-ion and lithium-metal batteries (LMBs), fire resistance, high strength, and flexibility suitable for roll-to-roll electrode fabrication is reported. The gravimetric energy densities of lithium batteries exhibit improvements of 9-18% by only replacing the metal foils with the MGFs. In addition, MGFs are suitable for the fabrication of flexible batteries. A high-energy-density flexible lithium battery with an outstanding figure of merit of flexible battery (fbFOM ) and flexing stability is demonstrated.


S100A8 and S100A9 in Cancer.
S100A8 and S100A9 are Ca2+ binding proteins that belong to the S100 family. Primarily expressed in neutrophils and monocytes, S100A8 and S100A9 play critical roles in modulating various inflammatory responses and inflammation-associated diseases. Forming a common heterodimer structure S100A8/A9, S100A8 and S100A9 are widely reported to participate in multiple signaling pathways in tumor cells. Meanwhile, S100A8/A9, S100A8, and S100A9, mainly as promoters, contribute to tumor development, growth and metastasis by interfering with tumor metabolism and the microenvironment. In recent years, the potential of S100A8/A9, S100A9, and S100A8 as tumor diagnostic or prognostic biomarkers has also been demonstrated. In addition, an increasing number of potential therapies targeting S100A8/A9 and related signaling pathways have emerged. In this review, we will first expound on the characteristics of S100A8/A9, S100A9, and S100A8 in-depth, focus on their interactions with tumor cells and microenvironments, and then discuss their clinical applications as biomarkers and therapeutic targets. We also highlight current limitations and look into the future of S100A8/A9 targeted anti-cancer therapy.


Multiple benign lichenoid keratoses simulating photodermatoses: evolution from senile lentigines and their spontaneous regression.
Evidence from several studies has established that a solitary benign lichenoid keratosis evolves from a senile lentigo. This lesion tends to resolve spontaneously with partial or complete regression of the original senile lentigo. In a 2-year period we studied fourteen patients with multiple benign lichenoid keratoses simulating photodermatoses. The original two patients were thought initially to have either cutaneous lupus erythematosus or a drug-induced photodermatitis. All fourteen patients were found to have multiple benign lichenoid keratoses distributed primarily in sun-exposed skin and arising from preexisting senile lentigines. The lichenoid lesions disappear either with topical corticosteroid treatment or spontaneously and are followed by partial or complete regression of the original senile lentigines. This disease entity seems to be fairly common and may be easily confused with photodermatoses.


Effect of chronic dietary zinc deficiency on cadmium toxicity and carcinogenesis in the male Wistar [Hsd: (WI)BR] rat.
Though it is known that excess zinc will prevent cadmium carcinogenesis, the impact of zinc deficiency on cadmium carcinogenesis has not been defined. This study assessed the effect of dietary zinc deficiency on the carcinogenic potential of cadmium in rats. Groups (n = 28 each) of male Wistar [Hsd: (WI)BR] rats were fed diets adequate (60 ppm) or deficient (7 ppm) in zinc and received a single sc dose of cadmium (5, 10, or 30 mumol Cd/kg). Lesions were assessed over the next 92 weeks. All cadmium doses increased the incidence of testicular interstitial cell tumors. The incidence of cadmium-induced testicular tumors was unaffected by dietary zinc status. However, when multiplicity of testicular lesions was considered, zinc-deficient diets markedly increased the number of testicular interstitial cell adenomas generated by cadmium exposure while significantly reducing the number of preneoplastic lesions (interstitial cell hyperplasias). The combined total number of neoplastic and preneoplastic lesions of the testes was independent of zinc status clearly indicating a shift from hyperplasia to neoplasia within the testes of zinc-deficient rats. The highest cadmium dose (30 mumol/kg) increased injection site sarcomas in zinc-deficient rats (7 tumors/27 rats at risk) but not zinc-adequate rats (3/26) when compared to control (0/49). Chronic progressive renal nephropathy was accelerated by cadmium in zinc-deficient rats. Results indicate that dietary zinc deficiency enhances carcinogenic response at the injection site of cadmium, promotes the neoplastic progression of cadmium-induced testicular lesions, and enhances chronic progressive nephropathy. Thus, dietary zinc deficiency appears to cause a generalized increase in the chronic toxic effects of cadmium.


GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers.
We describe methods with enhanced power and specificity to identify genes targeted by somatic copy-number alterations (SCNAs) that drive cancer growth. By separating SCNA profiles into underlying arm-level and focal alterations, we improve the estimation of background rates for each category. We additionally describe a probabilistic method for defining the boundaries of selected-for SCNA regions with user-defined confidence. Here we detail this revised computational approach, GISTIC2.0, and validate its performance in real and simulated datasets.


Rate of blood loss and timing of exsanguination on prevalence of ecchymosis in fallow deer (Dama dama).
Blood loss associated with four combinations of stunning and exsanguination methods was determined as part of studying prevalence of ecchymosis in slaughtered fallow deer (Dama dama). A fifth treatment simulated incomplete severance of the extended neck after captive bolt stunning. Predicted mean weights of blood collected from the five slaughter treatments, including electrical stunning followed by the thoracic stick method of exsanguination, captive bolt stunning followed by the thoracic stick, captive bolt stunning followed by the gash cut method of exsanguination, electrical stunning followed by the gash cut, and captive bolt stunning followed by incomplete severance of the extended neck, were 1458.7, 1072.7, 684.5, 463.7, and 228.5 g, respectively. The overall effect of exsanguination method was highly significant (p<0.001) with the thoracic stick resulting in the greatest weight of blood collection in the 10s period immediately after initiation. The overall effect of stunning method on blood loss was not significant, although there was a significant (p<0.05) stunning method by exsanguination method interaction. Ecchymosis of varying severity occurred in some carcases from all treatment groups. Using the total loin and round ecchymosis scores, when little or no ecchymosis (grades 0 or 1) was compared with some ecchymosis (grade 2) by logistic regression, castrated bucks were 9.8 times more likely (p=0.002) and does 4.2 times more likely (p=0.06) to have some ecchymosis than entire bucks. The results indicate that ecchymosis can be reduced in fallow deer carcases by thoracic stick exsanguination incorporated less than 10s after stunning.


K63-linked ubiquitylation induces global sequestration of mitochondria.
Even though K63-linked polyubiquitin chains do not target proteins for proteasomal degradation, they play nevertheless a complementary protective role in maintaining protein homeostasis by directing malfunctioning proteins and organelles to inclusion bodies or autophagosomes. A paradigm for this process is the sequestration and autophagic degradation of dysfunctional mitochondria. Although studies have shown that K63-ubiquitylation of mitochondrial proteins by the ubiquitin ligase Parkin is important in this process, it is presently not clear if this modification also suffices to initiate this cascade of events. To address this question, we have engineered the ubiquitin ligase ProxE3, which in an inducible manner synthesizes K63-linked ubiquitin chains on the surface of mitochondria. We found that the presence of K63-linked ubiquitin chains on mitochondria resulted in the recruitment of the ubiquitin adaptor p62 and induced a dramatic redistribution of mitochondria, which was reminiscent to the Parkin-facilitated sequestration in response to mitochondrial uncoupler. However, ProxE3 did not induce autophagic degradation of mitochondria. Our data show that K63-linked ubiquitin chains at the mitochondrial membrane are sufficient for the induction of mitochondrial sequestration, but not mitophagy, without the need of extrinsically inflicting mitochondrial dysfunction.


A hermeneutic phenomenological explorations of living in old age.
Although there have been some studies that explore the meaning of aging and give voice to older people, the impact that the aging experience can have on them justifies continued research in this area. In this study, with a hermeneutic phenomenological design and an interpretation method inspired by the philosophy of Ricoeur, we conducted in-depth interviews with 14 elderly people at a social day center in Rome (Italy). The analysis revealed three central themes associated with the experience of being old: changes and limitations related with being aged, the experience that comes from having lived a long life, and an awareness of death. The findings could help health professionals, families and caregivers to achieve a deeper understanding of what old age entails, and may also serve as a platform for interventions that seek to enable older people to experience aging as a meaningful and positive process.


Pitfalls of Minimally Invasive Fracture Repair.
Minimally invasive fracture repair (MIFR) is the ultimate culmination of current osteosynthesis concepts that emphasize the preservation and enhancement of the biologic components of fracture healing. Although the "less is more" approach to tissue dissection and fracture exposure and handling that defines MIFR has numerous reported advantages over more traditional open surgical treatments, it does present some unique challenges and important considerations for the surgeon. This article describes some of the general MIFR challenges a surgeon may encounter.


Pediatric overtriage as a consequence of the tachycardia responses of children upon ED admission.
Overtriage has been observed among pediatric patients in emergency departments (EDs) under 5-level acuity pediatric triage systems. This study aimed to investigate the causes of overtriage and to provide suggestions for future amendments to such systems. This study has a retrospective follow-up design in which 42000 pediatric patients who were admitted to the ED of the largest medical center in Taiwan between January and December of 2010 were recruited. The study variables included patient demographics, chief concerns, individual vital signs (ie, blood pressure, heart rate, body temperature, respiratory rate, and O2 saturation), triage level, ED final disposition, ED expenses, and total medical expenses. A logistic regression model was applied to explore the causes of overtriage and the effectiveness of a modified acuity system. Approximately 13.6% of the pediatric ED visits were upgraded to acuity level 1 based on vital signs that included heart rate (97.3%). The strength of the trend association (odds ratio) between decreasing acuity urgency (from levels 1 to 5) and hospitalization increased from 0.73 (95% confidence interval, 0.72-0.75) with the Pediatric Triage and Acuity System (Ped-TTAS) to 0.57 (95% confidence interval, 0.55-0.59) with the modified Ped-TTAS, which downgraded acuity levels by excluding the weighting of vital signs. Further validation was accomplished by comparing the trend association between decreasing acuity urgency and total medical expenses (Ped-TTAS: β = -0.13; modified Ped-TTAS: β = -0.18). Heart rate is prone to be affected by emotional responses among pediatric patients in certain specific age groups. Appropriate revisions of the pediatric triage system are suggested.


Demonstrating core molecular biology principles using GST-GFP in a semester-long laboratory course.
Undergraduate laboratory courses are essential to teaching core principles in STEM. This course, Quantitative Biological Methods, provides a unique approach to teaching molecular biology research techniques to students, in a laboratory that is delivered in a sequence that parallels standard biomedical research laboratory protocols. Students attend a lecture where they are taught the essential principles of biomedical research, and a lab where they learn to use laboratory equipment, perform experiments, and purify and quantify DNA and proteins. The course begins with an introduction to laboratory safety, pipetting, centrifugation, spectrophotometry, and other basic laboratory techniques. Next, the lab focuses on the purification and analysis of glutathione S-transferase (GST) fused to green fluorescent protein (GFP) from an Escherichia coli lysate. Students study this GST-GFP fusion protein and perform protein quantification, enzyme assays, chromatography, fluorescent detection, normalization, SDS-PAGE, and western blotting. Students then learn recombinant DNA technology using the GST-GFP vector that was the source of the fusion protein in the prior labs, and perform ligation, transformation of E. coli cells, blue/white screening, DNA purification via a miniprep, PCR, DNA quantification, restriction enzyme digestion, and agarose gel electrophoresis. Students write laboratory reports to demonstrate an understanding of the principles of the laboratory methods, and they must present and critically analyze their data. The lab methods described herein aim to emphasize the core molecular biology principles and techniques, prepare students for work in a biomedical research laboratory, and introduce students to both GST and GFP, two versatile laboratory proteins.


Long-term edaravone efficacy in amyotrophic lateral sclerosis: Post-hoc analyses of Study 19 (MCI186-19).
In a Phase 3 study, amyotrophic lateral sclerosis (ALS) patients experienced significantly less physical functional decline with 24-week edaravone vs placebo, followed by open-label treatment for an additional 24 weeks. Outcome (the change in ALS Functional Rating Scale-Revised, ALSFRS-R, from baseline) was projected for placebo patients through 48 weeks and compared with 48-week edaravone or 24-week edaravone after switching from placebo. A total of 123 patients received open-label treatment (65 edaravone-edaravone; 58 placebo-edaravone). The projected ALSFRS-R decline for placebo from baseline through week 48 was greater than for 48-week edaravone (P < .0001). For patients switching from placebo to edaravone, ALSFRS-R slope approached that of continued edaravone for 48 weeks. ALSFRS-R decline did not differ between actual and projected edaravone through week 48. Compared with placebo, these analyses suggest that edaravone is beneficial in ALS patients even after 6 mo of receiving placebo, and efficacy is maintained for up to 1 year.


Dentistry and aviation engineering - behind the scenes at operations in a UK-based airline.
The healthcare industry is commonly compared to the aviation industry with emphasis on human factors and the decision-making processes undertaken by pilots and clinicians alike. The authors have been given exclusive access to meet the head of the maintenance team behind one of the UK's most popular airlines. An open-ended interview took place which was audio-transcribed for thematic analysis. Data were initially coded to identify basic patterns in the transcript. Once this was completed, themes were identified and agreed between the authors which could be compared to healthcare and dentistry. These themes were: regulation, occupational health, maintenance of equipment, use of checklists, reporting, just culture, burnout and disturbances.The aviation engineering industry requires the combination of a skilled workforce working under time pressure often in a financially restricted environment in a similar way to healthcare, especially dentistry. The two industries share common risks, although introduction of risk management tools such as checklists have been prevalent in aviation since the 1930s. Recognition of said risks and themes can lead to shared learning opportunities to benefit both sectors.


Management of long-standing mandibular dislocation.
Long-standing dislocation of the temporomandibular joint (TMJ) is rare. The management of this disorder is still controversial. This paper presents the authors' experience of managing long-standing dislocation of the TMJ, and their attempt to develop guidelines for the management of this problem. They also show magnetic resonance images of two patients with long-standing dislocation of the TMJ.


Combination of reduced folates with methotrexate or 5-fluorouracil. Comparison between 5-formyltetrahydrofolate (folinic acid) and 5-methyltetrahydrofolate in vitro activities.
Folinic acid (dlFA) is increasingly used in clinical oncology. The active isomer lFA is intensively metabolized into l5-methyltetrahydrofolate (l5MTHF), the relative proportions of lFA, dFA and l5MTHF in blood varying considerably between oral and i.v. FA administration. The purpose of the study was to compare the in vitro activities of pure lFA and pure l5MTHF at equivalent drug exposure [area under curve (AUC)], taking into account their respective chemical stability in the culture medium. The in vitro growth inhibition [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) test] was evaluated on five human tumor cell lines after methotrexate (MTX)-folate or 5-fluorouracil (5FU)-folate exposures. Not only were the activities of lFA and l5MTHF compared, but also clinically relevant mixtures of lFA + dFA + l5MTHF corresponding to the proportions found at steady state during oral (PO mixture, 4, 39 and 57%, respectively) and i.v. administrations (i.v. mixture, 7, 81 and 12%, respectively). Measurement of folates demonstrated the marked lability of l5MTHF (65.8% loss over 5 days in the culture medium) as compared to lFA (2.6% loss). Whatever the pharmacological model tested (MTX-folate or 5FU-folate), comparison of the folate effects at equivalent drug exposure taking into account their relative stability showed that l5MTHF was never more potent than lFA. Moreover, a higher efficiency of lFA was demonstrated for the cell line most sensitive to 5FU; in this case, as expected, the i.v. mixture was more potent than the PO mixture. This study shows that depending on the tumor, lFA can be more potent than its main circulating metabolite l5MTHF. Along with the limited capacity of oral absorption, the choice between oral and i.v. route for FA administration in patients should take into consideration the different pharmacological activities between lFA and l5MTHF which suggest that the oral route is potentially detrimental to the optimal activity of the 5FU-FA combination as compared to i.v. administration.


Imaging of diaphragmatic rupture after trauma.
Traumatic rupture of the diaphragm usually results from blunt or penetrating injuries, or iatrogenic causes. Most cases are initially overlooked in the acute phase because they present with variable clinical and radiological signs. An overlooked diaphragmatic injury presents as a hernia many years later with potentially serious complications, therefore selection of the most appropriate radiological technique and accurate diagnosis of traumatic diaphragmatic hernias (DH) on the first admission is important. Although the diagnosis of diaphragmatic injuries is problematic, various investigations may be used for diagnosis. We describe the imaging findings of 19 traumatic DH cases with various imaging techniques. The patients were acute trauma cases or cases with prior trauma or thoraco-abdominal surgery with clinical suspicion of DH. An evaluation of the imaging techniques used in the diagnosis of DH is presented.


Mast cell apoptosis.
Apoptosis is a physiological form of cell death. Cells undergoing apoptosis execute a genetically controlled program that leads to organized breakdown of cellular structures and ends in phagocytosis of their remains. In mast cells, several mechanisms regulating apoptosis have been identified including growth factors, tumor necrosis factor-alpha receptors, monomeric IgE, Toll-like receptors, and proteins of the bcl-2 family. Methods used to characterize apoptosis of mast cells are reviewed, with special attention to flow cytometric analysis of annexin V staining, analysis of deoxyribonucleic acid fragmentation by gel electrophoresis and end-labeling techniques, measurement of caspase activity by enzymatic assays, and characterization of pro- and anti-apoptotic proteins by immunoblotting.


Char and tar formation during hydrothermal gasification of dewatered sewage sludge in subcritical and supercritical water: Influence of reaction parameters and lumped reaction kinetics.
The hydrothermal gasification of dewatered sewage sludge converts waste into syngas fuel (gas containing H2, CH4, CO, and CO2), but the formation of char and tar by a side reaction restricts practical applications. In this study, the formation of char/tar by the hydrothermal gasification of dewatered sewage sludge at 300-400 °C for 5-90 min with a heating rate of 8-50 °C/min is investigated. The results showed that the formation of tar/char reached equilibrium after 30 min, and an increase in the temperature and heating rate reduced the char yield. However, a higher tar yield was achieved at the highest temperature. Experiments on sludge with different moisture contents were also conducted, and the formation of char/tar was inhibited at a higher moisture content. The addition of NaOH and H2O2 can effectively reduce the char and tar yields, respectively. A lumped kinetic model for describing carbon conversion during the hydrothermal gasification of sewage sludge was developed to elucidate the char/tar formation mechanism. The experimental data were used to determine the model parameters, and the fitting results showed that solid-solid conversion from organic matter in sludge was the predominant char/tar formation pathway, with an activation energy of 7.1 kJ/mol. The experiments using the model compounds indicated that humus and protein are the main precursors of char and tar, respectively. This study provides insights for understanding the formation of char/tar from sewage sludge following hydrothermal gasification, which is vital for controlling the formation of char and tar to improve the gasification efficiency.


Pre-treatment sarcopenic assessments as a prognostic factor for gynaecology cancer outcomes: systematic review and meta-analysis.
Gynaecology cancers, including ovarian (OC), endometrial (EC), and cervical (CC), are prevalent with high mortality. Sarcopenia is found in 38.7% of cancer patients, adversely affecting prognosis. Computed tomography (CT) is performed routinely in oncology, yet CT assessments of sarcopenia are not commonly used to measure prognosis. This systematic review and meta-analysis aimed to evaluate the prognostic potential of pre-treatment sarcopenia assessments on overall survival (OS) and progression free survival (PFS) in gynaecology cancer. Four electronic databases were systematically searched from 2000 to May 2020 in English: Ovid Medline, EMBASE, Web of Science, and CINAHL plus. Titles and abstracts were screened, eligible full-texts were reviewed, and data from included studies was extracted. Meta-analyses were conducted on homogenous survival data, heterogenous data were narratively reported. The initial search yielded 767 results; 27 studies were included in the systematic review (n = 4286), all published between 2015 and 2020. Meta-analysis of unadjusted results revealed a negative effect of pre-treatment sarcopenia on OS in OC (HR: 1.40, 1.20-1.64, p < 0.0001) (n = 10), EC (HR: 1.42, 0.97-2.10, p = 0.07) (n = 4) and CC (HR: 1.10, 0.93-1.31, p = 0.28) (n = 5), and a negative effect on PFS in OC (HR: 1.28, 1.11-1.46, p = 0.0005) (n = 8), EC (HR: 1.51, 1.03-2.20, p = 0.03) (n = 2) and CC (HR: 1.14, 0.85-1.53, p = 0.37) (n = 2). Longitudinal analysis indicated negative effects of muscle loss on survival. Overall, there was a high risk of bias. Pre-treatment sarcopenia negatively affected survival in gynaecology cancers. Incorporating such assessments into cancer management may be beneficial. Heterogeneity in sarcopenia assessments makes data interpretation challenging. Further research in prospective studies is required.


Using response surface models to analyze drug combinations.
Quantitative evaluation of how drugs combine to elicit a biological response is crucial for drug development. Evaluations of drug combinations are often performed using index-based methods, which are known to be biased and unstable. We examine how these methods can produce misleadingly structured patterns of bias, leading to erroneous judgments of synergy or antagonism. By contrast, response surface models are less prone to these defects and can be applied to a wide range of data that have appeared in recent literature, including the measurement of combination therapeutic windows and the analysis of discrete experimental measures, three-way drug combinations, and atypical response behaviors.


Association of small, dense low-density lipoprotein cholesterol and galectin-3 in patients with chronic kidney disease.
Dyslipidemia is a common feature of chronic kidney disease (CKD). Although it has been observed that the pattern of lipid abnormalities can vary according to the stage of CKD, there is lack of data concerning the distribution of lipoprotein subclasses at various stages of the disease. In addition, association of proatherogenic small, dense low-density lipoprotein (sdLDL) subclasses with markers of inflammation, such is galectin-3, is not sufficiently explored. The aim of this study was to analyze concentrations and relative proportions of sdLDL-cholesterol (sdLDL-C) and galectin-3 in patients with CKD, with respect to the stage of the disease. Also, we sought possible independent associations of galectin-3 and sdLDL-C. The study involved 100 hemodialysis (HD) and 50 pre-dialysis patients, together with 94 healthy individuals. SdLDL-C was measured by heparin-magnesium precipitation method. Galectin-3 was measured by ELISA technique. Galectin-3 levels were higher in pre-dialysis and HD patients than in the control group (p < 0.01). The concentration of sdLDL-C was highest in the pre-dialysis group and lowest in HD patients (p < 0.01). CKD patients with increased galectin-3 concentrations had significantly higher relative proportions of cholesterol in sdLDL (% sdLDL-C) than their counterparts with lower galectin-3 levels (p < 0.05). Relative proportion of sdLDL-C was shown to be an independent determinant of galectin-3 concentration. Our results demonstrated alterations in concentrations and proportions of sdLDL-C according to the stages of CKD. The observed independent associations of % sdLDL-C and galectin-3 provide further insight into their complex interaction during the progression of atherosclerosis in CKD.


Irreversible inactivation of pyruvate decarboxylase in the presence of substrate and an oxidant. An example of paracatalytic enzyme inactivation.
Pyruvate decarboxylase from yeast is progressively inactivated in the presence of pyruvate and an extrinsic oxidant such as 2,6-dichloroindophenol or hexacyanoferrate(III). The inactivation is linked to the oxidation of the hydroxyethylthiamine diphosphate intermediate to acetate. Removal of low-molecular compounds by gel filtration does not reactivate the enzyme. The rate of inactivation obeys saturation kinetics with respect to substrate concentration and is independent of enzyme concentration. In analogy to the paracatalytic inactivation of other enzymes forming oxidizable carbanion intermediates [Christen, P. (1977) Methods Enzymol.46, 48--54], the oxidation of enzyme-bound hydroxyethylthiamine diphosphate is thought to generate a transiently reactive intermediate which, without being released from the enzyme, covalently modifies a group at or near the active site. Reconstitution experiments indicate that the protein rather than the coenzyme moiety is modified.


Lactate dehydrogenase isoenzyme patterns upon chronic exposure to cigarette smoke: Protective effect of bacoside A.
Despite a strong association between cigarette smoking and alarming increase in mortality rate from smoking-related diseases, around 35-40% of the world's population continues to smoke and many more are being exposed to environmental tobacco smoke. Since the role of free radicals and oxidative damage in the pathogenesis of smoking-related diseases has been suggested, bacoside A, a potent antioxidant was tested for its ability to protect against cigarette smoking-induced toxicity in terms of lactate dehydrogenase (LDH) and its isoenzymes. Rats were exposed to cigarette smoke and simultaneously administered with bacoside A, for a period of 12 weeks. Total LDH activity was assayed in serum, lung, heart, brain, liver and kidney, and serum LDH isoforms were separated electrophoretically. Cigarette smoke exposure resulted in significant increase in serum LDH and its isoenzymes with a concomitant decrease in these organs. These alterations were prevented by administration of bacoside A. Excessive oxidants from cigarette smoke is known to cause peroxidation of membrane lipids leading to cellular damage, thereby resulting in the leakage of LDH into the circulation. Bacoside A could have rendered protection to the organs by stabilizing their cell membranes and prevented the release of LDH, probably through its free radical scavenging and anti-lipid peroxidative effect.


Oscillatory behavior in inferior olive neurons: mechanism, modulation, cell aggregates.
Inferior olive neurons, in brain slices maintained in vitro, display spontaneous, continuous oscillations of their membrane potential which are consonant with olivary rhythmic activity seen in vivo. This oscillatory behavior was studied with intracellular electrophysiological techniques. The 3-10 Hz rhythmicity of these cells from guinea pigs is tetrodotoxin resistant and dependent on a somatic calcium conductance. The oscillatory behavior can exhibit intrinsic frequency modulation and can be altered by synaptic processes. Synaptic alteration of the oscillatory behavior by afferent sources and extensive electrotonic coupling between cells in local aggregates (shown by Lucifer yellow dye-coupling) provide the substrate for a potent central pattern generator with a well established efferent pathway for control of motor functions.


Duration of Antiplatelet Therapy Following Transcatheter Aortic Valve Replacement: Systematic Review and Network Meta-Analysis.
Background Although current guidelines recommend dual antiplatelet therapy (DAPT) for 3 to 6 months following transcatheter aortic valve replacement (TAVR), there are no studies directly comparing outcomes of different durations of DAPT following TAVR. Methods and Results PubMed, EMBASE, and Cochrane Database were searched through November 2020 to identify clinical studies that investigated single antiplatelet therapy versus DAPT use following TAVR. Studies using oral anticoagulants and antiplatelet therapy concomitantly were excluded. The DAPT group was subdivided by the duration of DAPT. We extracted the risk ratios (RRs) of major or life-threatening bleeding, stroke, and all-cause mortality. Four randomized controlled trials, 2 propensity-score matched studies, and 1 observational study were identified, yielding a total of 2498 patients who underwent TAVR assigned to the single antiplatelet therapy group (n=1249), 3-month DAPT group (n=485), or 6-month DAPT group (n=764). Pooled analyses demonstrated that when compared with the single antiplatelet therapy group, the rates of major or life-threatening bleeding were significantly higher in the 3- and 6-month DAPT groups (RR [95% CI]=2.13 [1.33-3.40], P=0.016; RR [95% CI]=2.54 [1.49-4.33], P=0.007, respectively) with no difference between the 3-month DAPT versus 6-month DAPT groups. The rates of stroke and all-cause mortality were similar among the 3 groups. Conclusions In this network meta-analysis of antiplatelet therapy following TAVR, single antiplatelet therapy with aspirin had lower bleeding without increasing stroke or death when compared with either 3- or 6-month DAPT.