IGF1R expression by adult oligodendrocytes is not required in the steady-state but supports neuroinflammation.
In the central nervous system (CNS), insulin-like growth factor 1 (IGF-1) regulates myelination by oligodendrocyte (ODC) precursor cells and shows anti-apoptotic properties in neuronal cells in different in vitro and in vivo systems. Previous work also suggests that IGF-1 protects ODCs from cell death and enhances remyelination in models of toxin-induced and autoimmune demyelination. However, since evidence remains controversial, the therapeutic potential of IGF-1 in demyelinating CNS conditions is unclear. To finally shed light on the function of IGF1-signaling for ODCs, we deleted insulin-like growth factor 1 receptor (IGF1R) specifically in mature ODCs of the mouse. We found that ODC survival and myelin status were unaffected by the absence of IGF1R until 15 months of age, indicating that IGF-1 signaling does not play a major role in post-mitotic ODCs during homeostasis. Notably, the absence of IGF1R did neither affect ODC survival nor myelin status upon cuprizone intoxication or induction of experimental autoimmune encephalomyelitis (EAE), models for toxic and autoimmune demyelination, respectively. Surprisingly, however, the absence of IGF1R from ODCs protected against clinical neuroinflammation in the EAE model. Together, our data indicate that IGF-1 signaling is not required for the function and survival of mature ODCs in steady-state and disease.


Influence of suicidality on adult perceptions of COVID-19 risk and guideline adherence.
Suicide rates have been increasing for decades, and the challenges of a global pandemic seem to have worsened suicide risk factors. The relationship between suicidality, COVID-19 risk perceptions, and guideline adherence was examined to inform potential barriers to the implementation of behavioral interventions aimed at preventing future pandemics. A national sample of 159 MTurk participants (Mage = 37.64 years, SD = 11.92; 48.4% female) completed an online survey containing the following: demographics, Suicidal Ideation Attributes Scale, Broadly Applicable Measure of Risk Perception of COVID-19, and Adherence to COVID-19 Guidelines and Perceived Risk Scale. Multiple linear regressions assessed how suicidality related to perceived risk subscales and each adherence indicator while controlling for biological sex, age, and essential worker status. Over 25% of participants reported suicidality over the past month, and 19% were at high risk of suicidal behavior. Greater suicidality was associated with lower general COVID-19 risk perceptions (β = -0.326, p < .001), decreased handwashing (β = -0.423, p < .001), lower likelihood of planning to self-quarantine if infected with COVID-19 (β = -0.400, p < .001), less social distancing (β = -0.457, p < .001), and increased attendance of large gatherings (β = 0.405, p < .001). Temporal relationships were unable to be assessed due to the cross-sectional nature of the data used. The low internal reliability of the risk probability subscale precluded its inclusion in analyses. Given suicidality's associations with decreased risk perceptions and low adherence, it may present as a barrier to the sustained behavior change that will be necessary in preventing the occurrence of future pandemics.


Identification of Putative Mitochondrial Protease Substrates.
Mitochondrial proteases constitute a fundamental part of the organellar protein quality control system to ensure the timely removal of damaged or obsolete proteins. The analysis of proteases is often limited to the identification of bona fide substrates that are degraded in the presence and become more abundant in the absence of the respective protease. However, proteases in numerous organisms from bacteria to humans can process specific substrates to release shortened proteins with potentially altered activities. Here, we describe an adaptation of the substrate-trapping approach, as well as the N-terminal profiling protocol Terminal Amine Isotope Labeling of Substrates (TAILS) for the identification of bona fide substrates and mitochondrial proteins that undergo complete or partial proteolysis.


Impedance studies of a nano-structured conducting polymer and its application to the design of reliable scaffolds for impedimetric biosensors.
Electrochemical impedance spectroscopy (EIS) as a powerful, non-invasive and informative technique was used to obtain important information about kinetics of doping process in conducting polymers. Polypyrrole (PPy) and its derivatives can form conducting polymer films which represent excellent charge transfer behaviors during doping processes. It can also have a wide range of applications in bioelectrochemistry. In the present study the conducting polymer of alpha-carboxy pyrrole (alpha-COOH-PPy), appended onto the underlying film of PPy, was prepared by electrochemical methods and its behavior was analyzed using EIS. From highly accurate fitting of impedance results it was found that the charging mechanism is governed by the diffusion process. In addition, the impedance analyses provided values for the bulk polymer parameters including diffusion coefficient (D), equilibrium capacitance (C(0)) and diffusion resistance (R(0)). The surface morphology of the polymeric film was characterized using scanning electron microscopy (SEM). The film was then used to immobilize the cytochrome C (cyt-C) and to perform its electrochemical studies. The modified cyt-C/alpha-COOH-PPy electrode was used for electrocatalytic reduction of H(2)O(2) in solution and its viability as a new impedimetric biosensor was examined. Based on the calibration curve obtained for the proposed impedimetric biosensor, the limit of detection and relative standard deviation were evaluated as 0.25 micromolL(-1) and 7%, respectively. Finally, the prolonged stability test was performed and high stability and reproducibility of the new biosensor was confirmed.


The efficacy and mechanism of salmeterol against influenza A virus in vitro and in vivo.
Influenza A virus (IAV) is the most harmful pathogen to human beings among the various subtypes of influenza virus, which can lead to immune response, cause serious inflammation and damage to the lung. Salmeterol is a candidate compound with anti-IAV activity screened by virtual network proximity predication. In this paper, we further evaluated the pharmacodynamics of salmeterol against IAV in vivo and in vitro. The results showed that salmeterol could inhibit the activity of three IAV strains (H1N1, H3N2 and H1N1 strain resistant to oseltamivir and amantadine) in the MDCK cells. In vivo, salmeterol could improve the survival state of infected mice, and further mechanism studies shown that salmeterol could improve the pathological characteristics of the lungs, reduce the loads of virus and the expression of M2 and IFITM3 proteins in the lungs of mice. In addition, salmeterol could inhibit the formation of NLRP3 inflammasome, thus reducing the production of the TNF-α, IL-6 and MCP-1 and alleviating inflammatory symptoms. Further results showed that salmeterol can protect A549 cells from cytopathic effect caused by IAV and reduce the production of inflammasome by decreasing the expression of RIG-1 in A549 cells. Finally, salmeterol could improve the spleen morphology and significantly increase the ratio of lymphocyte CD4+/CD8+ to improve immune function of infected mice. In our study, it is confirmed that salmeterol has certain anti-IAV activity through pharmacodynamic study in vivo and in vitro, which lays an important research foundation for the new indication of salmeterol and discovery of new drug against IAV.


Regulation of angiogenesis: apoptotic cues from the ECM.
The extracellular matrix (ECM) acts both as a physical scaffold for cells and as a repository for growth factors. Moreover, ECM structure and physical-chemical properties convey precise information to cells that profoundly influences their biology by interactions with cell surface receptors termed integrins. During angiogenesis, the perivascular ECM plays a critical role in determining the proliferative, invasive and survival responses of the local vascular cells to the angiogenic growth factors. Dynamic changes in both the ECM and the local vascular cells act in concert to regulate new blood vessel growth. The digestion of ECM components by proteolysis is critical for the invasive capacity of endothelial cells, but also creates ECM fragments, which antagonize the mechanosensory function of integrins, and can be apoptogenic. Here, we discuss the roles of integrins in modulating cellular responses to a changing ECM, in particular the regulation of survival and invasion among invasive endothelial cells.


Distinct racial and ethnic metabolic syndrome characteristics: A comparative assessment in low-income children 7-10 years of age.
Pediatric MetS prevalence varies due to lack of consensus on evaluative criteria and associated thresholds, with most not recommending a diagnosis <10 years. However, MetS risk components are becoming evident earlier in life and affect races and ethnicities disproportionately. To compare the prevalence of MetS based on existing definitions and elucidate racial- and ethnic-specific characteristics associated with MetS prevalence. The baseline and follow-up samples included 900 and 557 children 7-10 years, respectively. Waist circumference, BMI percentile, blood pressure, fasting plasma glucose (FPG), insulin, triglycerides, and high-density lipoprotein cholesterol (HDL-C) were measured. Agreement between MetS definitions was quantified via kappa statistics. MetS and risk factor prevalence and the predictability of metabolic parameters on MetS eight months later was evaluated via logistic regression. McFadden pseudo-R2 was reported as a measure of predictive ability, and the Akaike information criterion evaluated fit of each model. The baseline sample was 55.0% male and 71.6% Hispanic, followed by non-Hispanic White (NHW) (17.3%) and non-Hispanic Black (NHB) (11.1%), with an average age of 9.2 years. MetS prevalence ranged from 7.6% to 21.4%, highest in Hispanic (9.0%-24.0%) and lowest in NHB children (4.0%-14.0%). Highest agreement was between Ford et al. and Cook et al. definitions (K = 0.88) and lowest agreements were consistently with the International Diabetes Federation criteria (K ≤ 0.57). Compared to NHW children, Hispanic children had higher odds for MetS (OR: 1.7; p = 0.03) and waist circumference, HDL-C, and FPG risk factors (p < 0.05), while NHB children had higher odds for the FPG risk factor (p ≤ 0.007) and lower odds for the plasma triglycerides risk factor (p = 0.002), across multiple MetS definitions. In longitudinal analyses, HDL-C was the strongest independent predictor of MetS in Hispanic and NHW children (p < 0.001 and p < 0.01, respectively), while plasma triglycerides was the strongest independent predictor of MetS in NHB children (p < 0.05). MetS prevalence was high in children ≤10 years, and proposed criteria are susceptible to racial and ethnic bias, diagnosing some populations more than other populations with high cardiovascular risk. Earlier preventative measures should be imposed in clinical settings, accounting for racial and ethnic differences, to mitigate disease onset.


Estradiol affects calcium transport across mitochondrial membrane in different brain regions.
The in vitro effect of estradiol on flux of Ca(2+) in the synaptosomal mitochondria from nucleus caudatus and hippocampus of chronically ovariectomized female rats was examined. No effect of estradiol on Ca(2+) influx through ruthenium red-sensitive channels was found. Estradiol, at a concentration of 0.05-5 nmol/L for nucleus caudatus and 0.5-5 nmol/L for the hippocampus, decreased Na-dependent Ca(2+) efflux about 25%.


Antimicrobial resistance heterogeneity among multidrug-resistant Gram-negative pathogens: Phenotypic, genotypic, and proteomic analysis.
Microbes evolve rapidly by modifying their genomes through mutations or through the horizontal acquisition of mobile genetic elements (MGEs) linked with fitness traits such as antimicrobial resistance (AMR), virulence, and metabolic functions. We conducted a multicentric study in India and collected different clinical samples for decoding the genome sequences of bacterial pathogens associated with sepsis, urinary tract infections, and respiratory infections to understand the functional potency associated with AMR and its dynamics. Genomic analysis identified several acquired AMR genes (ARGs) that have a pathogen-specific signature. We observed that blaCTX-M-15, blaCMY-42, blaNDM-5, and aadA(2) were prevalent in Escherichia coli, and blaTEM-1B, blaOXA-232, blaNDM-1, rmtB, and rmtC were dominant in Klebsiella pneumoniae. In contrast, Pseudomonas aeruginosa and Acinetobacter baumannii harbored blaVEB, blaVIM-2, aph(3'), strA/B, blaOXA-23, aph(3') variants, and amrA, respectively. Regardless of the type of ARG, the MGEs linked with ARGs were also pathogen-specific. The sequence type of these pathogens was identified as high-risk international clones, with only a few lineages being predominant and region-specific. Whole-cell proteome analysis of extensively drug-resistant K. pneumoniae, A. baumannii, E. coli, and P. aeruginosa strains revealed differential abundances of resistance-associated proteins in the presence and absence of different classes of antibiotics. The pathogen-specific resistance signatures and differential abundance of AMR-associated proteins identified in this study should add value to AMR diagnostics and the choice of appropriate drug combinations for successful antimicrobial therapy.


Return to play following ACL reconstruction: survey among experienced arthroscopic surgeons (AGA instructors).
There is a lack of consensus regarding appropriate criteria attesting patient's unrestricted sports activities after ACL reconstruction. The purpose of this study was to perform a survey among experienced arthroscopic surgeons regarding their return to play guidelines in these patients. A six-item questionnaire was distributed among experienced arthroscopic surgeons (instructors of the German speaking society of arthroscopy, AGA). Study participants were asked to choose from multiple choice answers and had the possibility answering in an open discussion field. The response rate of the survey was 85.7 %. A total of 83.5 % used autologous hamstring grafts for ACL reconstruction in athletes followed by BPTB (37.2 %) and quadriceps tendon graft (12 %). Approximately 63.5 % recommended a time point later than 6 months allowing return to play after ACL reconstruction in the athlete (after 4 and 6 months 2.3 and 35.3 %, respectively). 76.6 % recommended starting with sports specific rehabilitation after 4 months (21.6 % after 6 months). The most frequent criterion (multiple answers) to allow return to play was negative Lachman test (81.7 % positive answers) followed by free range of motion (78.4 %), negative pivot shift (60.1 %), anterior drawer (45.4 %), proprioception test (43.1 %), muscular strength analysis (40.8 %), single-leg hop jump test (39.0 %), KT 1000 measurement (16.1 %), and MRI (4.1 %). Of the surgeons 85.8 % did not use any of the given scores as criterion to allow return to competitive sports (subjective IKDC score 10.6 %, Lysholm score 8.3 %, objective IKDC score 7.4 %, Tegner activity scale 3.7 %). In conclusion, the majority of surgeons do not consider muscle function, jump tests, alignment tests, and proprioception as relevant return to sports criterion. However, these are two crucial parameters for return to sports.


Allocation of kidney transplants in the UK.
Live and donation after cardiac death has increased markedly recently. The allocation system for donation after brain death reserves the least mismatched organs for young people. Live donors most often donate to relatives but a scheme tries to 'exchange' live donor kidneys when direct transplantation is not possible.


Coping strategy for work-family conflict and burnout in construction industrial adult workers: A philosophical highlight.
The work environment in Nigeria is demanding and could lead to psychological disturbances. Evidentially, construction workers have confirmed the horrible job stress and work-family conflict they experience in the workplace. This has led to work-related burnout. As a matter of importance, this study was conducted. A pure experimental design was used, which helped to randomly assigned recruited 98 construction industry adult workers to 2 arms (treatment and waitlisted control groups). Two dependent measures were distributed before, immediately after, and 4 weeks after completion of intervention with 12 sessions that were given to the treatment group. This study found that cognitive behavior therapy is beneficial in the management of work-family conflict and work burnout among construction industry workers. Therefore, there is a need for advancement and adequate implementation of cognitive behavior therapy in industries for psychological functioning of workers.


Pharmacological aspects of chiral nonsteroidal anti-inflammatory drugs.
Most NSAIDs are chiral molecules: they exist under 2 configurations of non-superimposable mirror images which are termed enantiomers or optical isomers or optical antipodes. Direct or indirect (resolution) methods are used to separate this equal mixture of compounds. Some of the enantiomers of the NSAIDs are able to undergo chiral inversion from the inactive R(-) to the active S(+) form. The pharmacokinetics in terms of absorption, distribution, metabolism, protein binding and elimination may be different for the 2 enantiomers, leading to interindividual variability in clinical response and drug toxicity.


Antioxidant PDA-PEG nanoparticles alleviate early osteoarthritis by inhibiting osteoclastogenesis and angiogenesis in subchondral bone.
Accumulating evidence suggests that osteoclastogenesis and angiogenesis in subchondral bone are critical destructive factors in the initiation and progression of osteoarthritis (OA). Herein, methoxypolyethylene glycol amine (mPEG-NH2) modified polydopamine nanoparticles (PDA-PEG NPs) were synthesized for treating early OA. The cytotoxicity and reactive oxygen species (ROS) scavenging ability of PDA-PEG NPs were evaluated. The effects of PDA-PEG NPs on osteoclast differentiation and vessel formation were then evaluated. Further, PDA-PEG NPs were administrated to anterior cruciate ligament transection (ACLT)-induced OA mice. Results demonstrated that PDA-PEG NPs had low toxicity both in vitro and in vivo. PDA-PEG NPs could inhibit osteoclastogenesis via regulating nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Moreover, PDA-PEG NPs suppressed osteoclast-related angiogenesis via down-regulating platelet-derived growth factor-BB (PDGF-BB). In vivo, PDA-PEG NPs inhibited subchondral bone resorption and angiogenesis, further rescuing cartilage degradation in OA mice. In conclusion, we demonstrated that PDA-PEG NPs deployment could be a potential therapy for OA.


Relationship between coracoacromial arch and rotator cuff analysed by a computer-assisted method.
In this paper we describe and assess the feasibility of a computer-assisted method which could be useful to investigate the mechanism of subacromial impingment of the shoulder. The relationship between the infraspinatus and supraspinatus and the coracoacromial (CA) arch during passive elevation and abduction are described. The methodology is based on the use of a tracker for recording surfaces and passive movements and data elaboration using dedicated software. In four cadavers, we observed that the minimal distances between the rotator cuff insertions and CA arch were realized at 45 degrees abduction between the acromion and infraspinatus, at 50-90 degrees elevation between the acromion and supraspinatus and also at 45-70 degrees abduction between the CA ligament and supraspinatus. This study showed that the proposed method is able to provide repeatable kinematic data (ICC > or = 0.90), numerical anatomical data comparable with the literature and, moreover, individual measurements on the shoulder joint. This preliminary results support the extension of the methodology to an in vivo protocol to be used during computer-assisted arthroscopic surgery.


Photocatalytic removal of toxic dyes, liquorice and tetracycline wastewaters by a mesoporous photocatalyst under irradiation of different lamps and sunlight.
Simple recyclable K5CoW12O40/TiO2 was synthesized and used to remove methyl orange, rhodamine B, direct red 16 and crystal violet toxic organic dyes, liquorice industrial wastewater and tetracycline (TC) as an antibiotic. Photoactivity of the catalyst was checked out under irradiation of various lamps (such as 18 W fluorescent, 300 W Xenon, LED and IR lamps). The best efficiency was obtained by fluorescent lamp at catalyst loading of 3 g/L, initial pH of 5, initial dye concentration of 5 ppm, complete degradation was achieved after 30 min contact time. Mechanistic investigation showed that·O2 radicals and h+ are majorly responsible for photodegradation in this process. Electrochemical investigation, Nyquist, Bode, Mott-Schottky, Tauc plots and photoluminescence proved that using this photocatalyst delay the electron-hole recombination, increase the lifetime of excited electron, extend light absorption to visible region and improve the light absorption capacity. This photocatalyst work well under winter sunlight. Also 97% and 84% dye removal was obtained for liquorice with 300 and 1000 COD at optimal condition. This catalyst showed similar activity for TC wastewater. Photocatalyst was characterized by FE-SEM, EDX, AFM, FT-IR, XRD, PL, DRS, EIS, BJH and BET.


A national survey of lead and other metal(loids) in residential drinking water in the United States.
Exposure to lead (Pb), arsenic (As) and copper (Cu) may cause significant health issues including harmful neurological effects, cancer or organ damage. Determination of human exposure-relevant concentrations of these metal(loids) in drinking water, therefore, is critical. We sought to characterize exposure-relevant Pb, As, and Cu concentrations in drinking water collected from homes participating in the American Healthy Homes Survey II, a national survey that monitors the prevalence of Pb and related hazards in United States homes. Drinking water samples were collected from a national survey of 678 U.S. homes where children may live using an exposure-based composite sampling protocol. Relationships between metal(loid) concentration, water source and house age were evaluated. 18 of 678 (2.6%) of samples analyzed exceeded 5 µg Pb L-1 (Mean = 1.0 µg L-1). 1.5% of samples exceeded 10 µg As L-1 (Mean = 1.7 µg L-1) and 1,300 µg Cu L-1 (Mean = 125 µg L-1). Private well samples were more likely to exceed metal(loid) concentration thresholds than public water samples. Pb concentrations were correlated with Cu and Zn, indicative of brass as a common Pb source is samples analyzed. Results represent the largest national-scale effort to date to inform exposure risks to Pb, As, and Cu in drinking water in U.S. homes using an exposure-based composite sampling approach. To date, there are no national-level estimates of Pb, As and Cu in US drinking water collected from household taps using an exposure-based sampling protocol. Therefore, assessing public health impacts from metal(loids) in drinking water remains challenging. Results presented in this study represent the largest effort to date to test for exposure-relevant concentrations of Pb, As and Cu in US household drinking water, providing a critical step toward improved understanding of metal(loid) exposure risk.


Multi-component adsorption model for pellicle formation: the influence of salivary proteins and non-salivary phospho proteins on the binding of histatin 5 onto hydroxyapatite.
The acquired enamel pellicle formed by selective adsorption of proteins in whole saliva is a protective integument on the tooth surface. The purpose of the present study was to investigate the formation of human acquired enamel pellicle using an in vitro hydroxyapatite (HA) model and 3H-histatin 5 to allow accurate measurement of histatin 5 binding in a multi-component experimental system. A binary system was employed by mixing 3H-histatin 5 with one unlabeled protein prior to incubation with HA or by first incubating 3H-histatin 5 with the HA which had been pre-coated with one of a panel of unlabeled proteins (human albumin, salivary amylase, lysozyme, acidic PIFs, statherin, the N-terminal fragment of statherin, and egg yolk phosvitin). A ternary system was employed by mixing 3H-histatin 5 with HA sequentially pre-coated with two different unlabeled proteins, including recombinant histatin 1. The results showed that only salivary statherin and egg yolk phosvitin promote histatin 5 adsorption significantly. The amount of histatin 5 adsorbed was also found to increase as a function of the amount of phosvitin and statherin used to pre-coat HA up to a maximum level that was two- to four-fold greater than that observed on untreated HA. These data suggest that specific protein-protein interactions may play important roles in pellicle formation in vivo.


Ruptured heterotopic pregnancy: a rare cause for hemoperitoneum; report of three cases from kashmir, India.
Heterotopic pregnancy has been found in various forms but is still a rare event in the natural conception cycles, occurring in less than 1:30000 pregnancies with the incidence rising to 1:100 to 1:500 pregnancies duo to assisted reproductive technologies. Delay in diagnosing the condition can be fatal for both the mother and the fetus. Three patients aged 28, 31 and 26 years presented with amenorrhea of ten, eight and twelve weeks duration respectively with signs of peritonism and shock. Investigations revealed intra and extra uterine pregnancies in all the three cases with the rupture of the extra uterine pregnancies. All the cases were operated and first two cases were followed up postoperatively till the delivery of the term live babies. The third case is still under our follow up. A high index of suspicion by a general surgeon is needed in arriving at a prompt diagnosis of ruptured heterotopic pregnancy so that rapid resuscitation, heart sparing anesthesia and expeditious surgery is carried out for both maternal and intrauterine fetal wellbeing.


Gastric cancer may share genetic predisposition with esophageal squamous cell carcinoma in Chinese populations.
Many features are shared between esophageal cancer (EC) and gastric cancer (GC). This study aimed to explore whether known EC susceptibility loci are also important in the development of GC. A total of 21 genetic variants associated with EC in genome-wide association studies were evaluated with association of GC risk in 2631 cases and 4373 controls of Chinese ancestry. Single variant and weighted genetic scores (WGS) for esophageal squamous cell carcinoma (ESCC), esophageal adenocarcinoma (EAC), and overall EC were analyzed with GC risk, respectively. Genetic variants of rs2274223 in PLCE1 at 10q23.33 (per G allele: odds ratio (OR) = 1.26, 95% confidence interval (CI): 1.16-1.38, P = 6.51 × 10-8), rs10052657 in PDE4D at 5q11.2 (per C allele: OR = 1.12, 95% CI: 1.01-1.25, P = 3.28 × 10-2) and rs671 in ALDH2 at 12q24.12 (per A-allele: OR = 0.83, 95% CI: 0.75-0.91, P = 1.14 × 10-4) were significantly associated with GC risk. The combined effect of those three variants had stronger influence on GC risk (OR = 1.31, 95% CI: 1.19-1.44, P = 2.34 × 10-8). High WGS of ESCC was also associated with increased risk of GC (P = 5.52 × 10-4 as a continuous variable) (trend test P = 2.71 × 10-4), whereas no statistically significant associations were observed between the WGS of EAC and GC risk (P = 0.66 as a continuous variable) (trend test P = 0.70). ESCC rather than EAC may share genetic susceptibility with GC. Genetic variants at 10q23.33, 5q11.2, and 12q24.12 may be useful as biomarkers to identify individuals with high risk for both ESCC and GC.


The Prognosis of Small Cell Lung Cancer in Patients with Pulmonary Fibrosis.
The purpose of this study was to assess the prognosis of small cell lung cancer (SCLC) based on the underlying pulmonary disease. A total of 204 patients with SCLC were reviewed and categorized into three groups: normal, emphysema and fibrosis. The median overall survival duration (OS) in patients with normal lungs (n=57), with emphysema (n=105) and fibrosis (n=42) was 21.3, 16.4 and 10.8 months (p=0.063). In limited-stage disease (LD), the median OS in patients with fibrosis (7.4 months) was shorter than normal (52.7 months) or emphysema patients (26.4 months) (p=0.034). In extensive-stage disease (ED), the median OS in patients with fibrosis (12.7 months) was not significantly different from normal (11.4 months) or emphysema patients (13.5 months) (p=0.600). Patients with fibrosis had a poorer prognosis than normal or emphysema patients in LD-SCLC, but the coexistence of pulmonary fibrosis did not affect the prognostic outcomes in ED-SCLC.


Pieiotropic effect of two cell wall mutants on the activity of some cell wall enzymes in the yeast Saccharomyces cerevisiae.
The two mutants (abs) and (wal) affecting the cell morphology of yeast lead also to higher in vivo activities of the cell wall enzymes acid phosphatase, invertase and melibiase.


Identification and validation of reference genes for normalization of gene expression analysis using qRT-PCR in Megalurothrips usitatus (thysanoptera: thripidae).
Introduction: Gene expression analysis by reverse transcription quantitative polymerase chain reaction (qRT-PCR) has been widely used in research including insects. The selection of appropriate reference genes is the key to obtaining accurate and reliable results from qRT-PCR. However, studies on the expression stability of reference genes in Megalurothrips usitatus remain lacking. Methods: In this study, qRT-PCR was used to analyze the expression stability of candidate reference genes in M. usitatus. The expression levels of six candidate reference gene transcription of M. usitatus were analyzed. GeNorm, NormFinder, BestKeeper, and ΔCt were used to analyze the expression stability of M. usitatus treated with biological factors (developmental period treatment) and abiotic factors (light, temperature, insecticide treatment, respectively). Comprehensive stability ranking of candidate reference genes was recommended by RefFinder. Results and Discussion: Results showed that ribosomal protein S (RPS) was the most suitable expression in insecticide treatment. Ribosomal protein L (RPL) was the most suitable expression at developmental stage and light treatment, whereas elongation factor was the most suitable expression in temperature treatment. RefFinder was used to comprehensively analyze the above four treatments, and the results showed that RPL and actin (ACT) showed high stability in each treatment. Therefore, this study identified these two genes as reference genes in the qRT-PCR analysis of different treatment conditions of M. usitatus. Ourfindings will be beneficial for improving the accuracy of qRT-PCR analysis for future functional analysis of the target gene expression in M. usitatus.


Normative Data for Brainstem Structures, the Midbrain-to-Pons Ratio, and the Magnetic Resonance Parkinsonism Index.
Imaging biomarkers derived from different brainstem structures are suggested to differentiate among parkinsonian disorders, but clinical implementation requires normative data. The main objective was to establish high-quality, sex-specific data for relevant brainstem structures derived from MR imaging in healthy subjects from the general population in their sixth and seventh decades of life. 3D T1WI acquired on the same 1.5T scanner of 996 individuals (527 women) between 50 and 66 years of age from a prospective population study was used. The area of the midbrain and pons and the widths of the middle cerebellar peduncles and superior cerebellar peduncles were measured, from which the midbrain-to-pons ratio and Magnetic Resonance Parkinsonism Index [MRPI = (Pons Area / Midbrain Area) × (Middle Cerebellar Peduncles / Superior Cerebellar Peduncles)] were calculated. Sex differences in brainstem measures and correlations to age, height, weight, and body mass index were investigated. Inter- and intrareliability for measuring the different brainstem structures showed good-to-excellent reliability (intraclass correlation coefficient = 0.785-0.988). There were significant sex differences for the pons area, width of the middle cerebellar peduncles and superior cerebellar peduncles, midbrain-to-pons ratio, and MRPI (all, P < .001; Cohen D = 0.44-0.98), but not for the midbrain area (P = .985). There were significant very weak-to-weak correlations between several of the brainstem measures and age, height, weight, and body mass index in both sexes. However, no systematic difference in distribution caused by these variables was found, and because age had the highest and most consistent correlations, age-/sex-specific percentiles for the brainstem measures were created. We present high-quality, sex-specific data and age-/sex-specific percentiles for the mentioned brainstem measures. These normative data can be implemented in the neuroradiologic work-up of patients with suspected brainstem atrophy to avoid the risk of misdiagnosis.


The primary structure of elongation factor EF-1 alpha from the brine shrimp Artemia.
cDNA as well as amino acid sequencing has revealed the complete primary structure of elongation factor EF-1 alpha from the brine shrimp Artemia. A comparison with the published sequences of bacterial EF-Tu, mitochondrial EF-Tu and chloroplastic EF-Tu shows that distinct areas of these polypeptide chains are conserved in evolution. The evolutionary distance between prokaryotic and eukaryotic types of EF-Tu is larger than among bacterial and organellar EF- Tus . A number of regions present in both EF-Tu and EF-G from Escherichia coli are also found in EF-1 alpha from Artemia.


Emerging Treatments for Insomnia, Sleep Apnea, and Restless Leg Syndrome Among Dialysis Patients.
Sleep disturbances are highly prevalent in patients with predialysis chronic kidney disease, end-stage kidney disease, and after a kidney transplant. They contribute to impairment in daily function and are associated with a high burden of physical and psychiatric symptoms, decreased quality of life, and increased morbidity and mortality. Sleep disturbances also may precipitate and accelerate kidney disease progression. They often evolve across the spectrum of kidney dysfunction and may persist or re-emerge in kidney transplant recipients. Investigation into the multifaceted and dynamic relationships between sleep disturbance and chronic kidney disease requires consideration of myriad contributors including the progression of kidney disease itself, the role of treatment via dialysis and kidney transplant, psychosocial factors, and underlying sleep disorders. Despite sleep disturbance being identified as a priority to address by patients and caregivers, sleep disorders including insomnia, sleep apnea, and restless leg syndrome remain under-recognized and undertreated, and innovation in their management remains modest. In this article, we review the relationships between sleep disturbance and kidney disease, the impact of sleep disturbance and sleep disorders on symptom burden and mental health, and treatment opportunities that may address overlapping symptoms across the spectrum of kidney disease and that could improve patient-related and clinical outcomes.


Androgen receptor directed therapies in castration-resistant metastatic prostate cancer.
Recent results of phase III randomized studies confirm that targeting the androgen receptor (AR)-through inhibition of androgen synthesis or through AR targeting directly-can improve survival for patients with metastatic castration-resistant prostate cancer (mCRPC), a condition previously considered to be "refractory" to further hormonal manipulation. These data validate in the clinical setting much of the scientific work of the previous decade that has demonstrated the extent of and mechanisms behind retained AR signaling in advanced prostate cancer. The convergence of these observations effectively changes the perspective with which androgen deprivation is utilized in prostate cancer, and forms the basis for further expansion of systemic therapy in the disease. In this review, the rationale for and clinical results with these new therapies will be discussed as will the future directions required to fully leverage these therapeutic modalities to the maximum clinical benefit for patients.


Collaboration Leading to Addiction Treatment and Recovery from Other Stresses (CLARO): process of adapting collaborative care for co-occurring opioid use and mental disorders.
Opioid use disorders (OUD), co-occurring with either depression and/or PTSD, are prevalent, burdensome, and often receive little or low-quality care. Collaborative care is a service delivery intervention that uses a team-based model to improve treatment access, quality, and outcomes in primary care patients, but has not been evaluated for co-occurring OUD and mental health disorders. To address this treatment and quality gap, we adapted collaborative care for co-occurring OUD and mental health disorders. Our adapted model is called Collaboration Leading to Addiction Treatment and Recovery from Other Stresses (CLARO). We used the five-step Map of Adaptation Process (McKleroy in AIDS Educ Prev 18:59-73, 2006) to develop the model. For each step, our stakeholder team of research and clinical experts, primary care partners, and patients provided input into adaptation processes (e.g., adaptation team meetings, clinic partner feedback, patient interviews and beta-testing). To document each adaptation and our decision-making process, we used the Framework for Reporting Adaptations and Modifications-Enhanced (Wiltsey Stirman in Implement Sci 14:1-10, 2019). We documented 12 planned fidelity-consistent adaptations to collaborative care, including a mix of content, context, and training/evaluation modifications intended to improve fit with the patient population (co-occurring disorders) or the New Mexico setting (low-resource clinics in health professional shortage areas). Examples of documented adaptations include use of community health workers as care coordinators; an expanded consultant team to support task-shifting to community health workers; modified training protocols for Problem-Solving Therapy and Written Exposure Therapy to incorporate examples of treating patients for depression or PTSD with co-occurring OUD; and having care coordinators screen for patients' social needs. We completed the first three steps of the Map of Adaptation Process, resulting in a variety of adaptations that we believe will make collaborative care more acceptable and feasible in treating co-occurring OUD and mental health disorders. Future steps include evaluating the effectiveness of CLARO and documenting reactive and/or planned adaptations to the model that occur during its implementation and delivery. Trial registration NCT04559893, NCT04634279. Registered 08 September 2020, https://clinicaltrials.gov/ct2/show/NCT04559893.


Seasonal changes of fine root density in the Southern Californian chaparral.
Fine root extractions from soil cores of a south facing slope in the Southern Californian chaparral were used to study the dynamics of feeder root growth in a summer-dry area. The studies were concentrated on the root systems of Adenostoma fasciculatum, Arctostaphylos glauca, Ceanothus greggii, and Rhus ovata. The total fine root biomass of Adenostoma fasciculatum increased from 0.6 g dm-3 in early spring to 3.6 g dm-3 in late summer. Considering the specific soil conditions at this site and earlier gained information on fine root distribution with depth, the value of 3.6 g dm-3 converts to 1.58 kg m-2 of ground shaded by the shrub canopy. The observed seasonal biomass increase is mainly due to the accumulation of dead root material in the soil when low soil moisture contents presumably inhibited decomposition processes. The total length of living fine roots also increased during the season, e.g. from 0.8 m dm-3 to more than 5 m dm-3 (0.35 km m-2 to 2.2 km m-2) in A. fasciculatum. Unusual summer rains in the research year stimulated vigorous fine root growth at a time when the normally low soil moisture would prohibit further fine root growth. The average fine root diameters and total lengths of fine roots beneath one square meter of ground surface allowed an estimate of root area indices (RAI) analogous to the leaf area indices (LAI). The data provide evidence for a significant fine root turnover in the chaparral.


Pattern-reversal visual evoked potentials in patients with newly diagnosed epilepsy.
The possible occurrence of evoked potential (EP) abnormalities in patients with newly diagnosed epilepsy has been little investigated. The main purpose of the present study was to investigate possible changes in pattern-reversal visual evoked potential (P-VEP) responses in newly diagnosed epilepsy patients. By using P-VEPs, latency values of the N75 and P100 together with amplitude values of P100 were recorded in newly diagnosed idiopathic epilepsy patients. The patients comprised two groups; nonphotosensitive (non-PS), and photosensitive (PS) patients. Shortened N75 and normal P100 latencies of the P-VEP with higher than normal P100 amplitudes were detected in PS patients. In non-PS patients, N75 latencies of the P-VEPs were unaffected; however, P100 latencies were prolonged, and P100 amplitudes were unchanged. P-VEPs are different from those of controls in previously untreated idiopathic epilepsy patients. Results also indicate different P-VEP features in patients with and without photoparoxysmal responses. The changes might be the result of a disorder of one or more neurotransmitters or subtle morphologic damage such as microdysgenesis.


A Stress Test of Artificial Intelligence: Can Deep Learning Models Trained From Formal Echocardiography Accurately Interpret Point-of-Care Ultrasound?
To test if a deep learning (DL) model trained on echocardiography images could accurately segment the left ventricle (LV) and predict ejection fraction on apical 4-chamber images acquired by point-of-care ultrasound (POCUS). We created a dataset of 333 videos from cardiac POCUS exams acquired in the emergency department. For each video we derived two ground-truth labels. First, we segmented the LV from one image frame and second, we classified the EF as normal, reduced, or severely reduced. We then classified the media's quality as optimal, adequate, or inadequate. With this dataset we tested the accuracy of automated LV segmentation and EF classification by the best-in-class echocardiography trained DL model EchoNet-Dynamic. The mean Dice similarity coefficient for LV segmentation was 0.72 (N = 333; 95% CI 0.70-0.74). Cohen's kappa coefficient for agreement between predicted and ground-truth EF classification was 0.16 (N = 333). The area under the receiver-operating curve for the diagnosis of heart failure was 0.74 (N = 333). Model performance improved with video quality for the tasks of LV segmentation and diagnosis of heart failure, but was unchanged with EF classification. For all tasks the model was less accurate than the published benchmarks for EchoNet-Dynamic. Performance of a DL model trained on formal echocardiography worsened when challenged with images captured during resuscitations. DL models intended for assessing bedside ultrasound should be trained on datasets composed of POCUS images. Such datasets have yet to be made publicly available.


The impact of future summer temperature on public health in Barcelona and Catalonia, Spain.
Several epidemiological studies have reported associations between increases in summer temperatures and risks of premature mortality. The quantitative implications of predicted future increases in summer temperature, however, have not been extensively characterized. We have quantified these effects for the four main cities in Catalonia, Spain (Barcelona, Tarragona, Lleida, Girona). We first used case-crossover analysis to estimate the association between temperature and mortality for each of these cities for the period 1983 to 2006. These exposure-response (ER) functions were then combined with local measures of current and projected changes in population, mortality and temperature for the years 2025 and 2050. Predicted daily mean temperatures were based on the A1B greenhouse gas emission, "business-as-usual" scenario simulations derived from the ENSEMBLES project. Several different ER functions were examined and significant associations between temperature and mortality were observed for all four cities. For these four cities, the age-specific piecewise linear model predicts 520 (95%CI 340, 720) additional annual deaths attributable to the change in temperature in 2025 relative to the average from the baseline period of 1960-1990. For 2050, the estimate increases to 1,610 deaths per year during the warm season. For Catalonia as a whole, the point estimates for those two years are 720 and 2,330 deaths per year, respectively, or about 2 and 3% of the warm season. In comparing these predicted impacts with current causes of mortality, they clearly represent significant burdens to public health in Catalonia.


Clinical research informatics: survey of recent advances and trends in a maturing field.
To provide a survey of the field of clinical research informatics (CRI), focusing in particular on significant developments over the past 3 years and the insights they provide about the progress and state of the field. An iterative "scoping review" of the literature published in scientific journals and conference proceedings that are relevant to CRI, from late 2009 to early 2013. 212 articles were identified, and 64 were selected to illustrate recent advances in the field. Based on those, six categories of CRI activity were identified: Data and Knowledge Management, Discovery and Standards; Clinical Data Re-Use for Research; Researcher Support and Resources; Participant Recruitment; Patients/Consumers and CRI; Policy, Regulatory and Fiscal Matters. This survey demonstrates that the field of CRI has matured and is now well established. The ongoing work is essential to overcome many of the challenges the clinical research enterprise is facing and more work is needed. Even as work continues to establish necessary infrastructure, methods, and best practices, CRI researchers should strive for more rigorous study designs to evaluate the impacts of the work in the field. There is little doubt that the field is poised for rapid growth, and that the CRI literature will continue to reflect that growth in years to come.


A Refined Method for Studying Foraging Behaviour and Body Mass in Group-Housed European Starlings.
Laboratory experiments on passerine birds have been important for testing hypotheses regarding the effects of environmental variables on the adaptive regulation of body mass. However, previous work in this area has suffered from poor ecological validity and animal welfare due to the requirement to house birds individually in small cages to facilitate behavioural measurement and frequent catching for weighing. Here, we describe the social foraging system, a novel technology that permits continuous collection of individual-level data on operant foraging behaviour and body mass from group-housed European starlings (Sturnus vulgaris). We report on the rapid acquisition of operant key pecking, followed by foraging and body mass data from two groups of six birds maintained on a fixed-ratio operant schedule under closed economy for 11 consecutive days. Birds gained 6.0 ± 1.2 g (mean ± sd) between dawn and dusk each day and lost an equal amount overnight. Individual daily mass gain trajectories were non-linear, with the rate of gain decelerating between dawn and dusk. Within-bird variation in daily foraging effort (key pecks) positively predicted within-bird variation in dusk mass. However, between-bird variation in mean foraging effort was uncorrelated with between-bird variation in mean mass, potentially indicative of individual differences in daily energy requirements. We conclude that the social foraging system delivers refined data collection and offers potential for improving our understanding of mass regulation in starlings and other species.


Impact of planned movement direction on judgments of visual locations.
The present study examined if and how the direction of planned hand movements affects the perceived direction of visual stimuli. In three experiments participants prepared hand movements that deviated regarding direction ("Experiment 1" and "2") or distance relative to a visual target position ("Experiment 3"). Before actual execution of the movement, the direction of the visual stimulus had to be estimated by means of a method of adjustment. The perception of stimulus direction was biased away from planned movement direction, such that with leftward movements stimuli appeared somewhat more rightward than with rightward movements. Control conditions revealed that this effect was neither a mere response bias, nor a result of processing or memorizing movement cues. Also, shifting the focus of attention toward a cued location in space was not sufficient to induce the perceptual bias observed under conditions of movement preparation ("Experiment 4"). These results confirm that characteristics of planned actions bias visual perception, with the direction of bias (contrast or assimilation) possibly depending on the type of the representations (categorical or metric) involved.


Parvalbumin immunoreactivity in the central auditory system of the gerbil: a developmental study.
Changes in parvalbumin-like immunoreactivity were studied during ontogenetic development of the central auditory system of the Mongolian gerbil (Meriones unguiculatus). The nucleus of the trapezoid body contained cells that could be stained on the day of birth while in the superior olivary complex, prominent staining of cell somata was only found at P15 (postnatal day 15). Neurons located in the ventral nucleus, in the dorsal nucleus of the lateral lemniscus and in the inferior colliculus developed parvalbumin immunoreactivity mostly between P11-P15 (ventral nucleus), P15-P19 (dorsal nucleus) and P15-P19 (inferior colliculus), respectively. The accumulation of PV correlates reasonably well with the functional maturation of the neurons in these areas.


Prevalence and predictors of low bone mineral density in males with ulcerative colitis.
Low bone mineral density (BMD) is common in patients with inflammatory bowel diseases. The objective of the study was to assess the prevalence and the predictors of low BMD (osteoporosis or osteopenia) and fragility fractures among men with ulcerative colitis. This was a retrospective database analysis. The study was conducted at a nationwide Veterans Affairs health care system. Male ulcerative colitis patients who were followed up in the Veterans Affairs system between 2001 and 2011 were identified using the International Classification of Diseases, ninth revision (ICD-9). We identified patients with low BMD and fragility fractures using ICD-9 codes. Steroid exposure was assessed using pharmacy data. A multivariate analysis was used to identify the independent effect of systemic steroids on the risk of low BMD and fragility fractures. We identified 34 665 patients. Among them, 31% used steroids. The prevalence of low BMD was 15.8% and 7.1% among those who used and did not use steroids, respectively (P < .001). Prevalence of fragility fractures was 7.9%, 4.4%, and 1.1% for those with osteoporosis and osteopenia and those without low BMD, respectively (P < .001). Steroid exposure showed a dose-response pattern, patients who had cumulative prednisone exposure of greater than 11 136 mg (10th decile) were more likely to develop low BMD (odds ratio 8.9, P < .001) and fragility fractures (odds ratio 1.8, P < .001) as compared with non-steroid users after controlling for other possible predictors. In this nationwide cohort, the prevalence of low BMD was higher than what was reported for the general male population. There was a strong correlation between the cumulative steroid use and the risk of low BMD. Both steroids and low BMD were independent risk factors for fragility fractures.


Prmt5 deficiency inhibits CD4+ T-cell Klf2/S1pr1 expression and ameliorates EAE disease.
Protein arginine methyltransferase 5 (Prmt5) is the main type II methyltransferase, catalyzes protein arginine residue symmetric dimethylation, and modulates normal cellular physiology and disease progression. Prmt5 inhibition or deletion in CD4+ T cells has been reported to ameliorate experimental autoimmune encephalomyelitis (EAE), but the detailed molecular mechanisms have not yet been elucidated. EAE was induced by administration of myelin oligodendrocyte glycoprotein (MOG35-55) in T cells Prmt5 conditional knockout (CD4-cre-Prmt5fl/fl, Prmt5cko) and Prmt5fl/fl (WT) mice. Flow cytometry, single-cell RNA sequencing, ATAC sequencing and chromatin immunoprecipitation assay (ChIP) approaches were used to explore the detail mechanisms. We find that Prmt5cko mice are resistant to EAE; infiltrating inflammatory CD4+ T cells in the central nervous system (CNS) are greatly reduced. However, in Prmt5cko mice, T cells in the spleen show much more proliferation and activation properties, the total number of CD4+ T cells in the spleen is not reduced, and the percentage of Rora+ CD4+ T cells is elevated. Also, CD4+ T cells express lower levels of S1pr1 and Klf2 than WT mice, which may influence pathogenic CD4+ T-cell egress from the spleen and migration to the CNS. Moreover, the single-cell ATAC sequence and ChIP assay reveal that the transcription factor Klf2 is enriched at the S1pr1 promoter and that Klf2 motif activity is reduced in Prmt5cko mice. Our study delineates the undiscovered role of Prmt5 in T-cell biology in which Prmt5 may inhibit Klf2-S1pr1 pathway to ameliorate EAE disease. Controlling T-cell Prmt5 expression may be helpful for the treatment of autoimmune diseases.


Rationale for (-)deprenyl (selegiline) medication in Parkinson's disease and in prevention of age-related nigral changes.
(-)Deprenyl (selegiline, jumex, eldepryl, movergan), a close structural relative to phenylethylamine (PEA), is a drug with a unique pharmacological spectrum. It is a highly potent and selective, irreversible inhibitor of B-type monoamine oxidase (MAO), a predominantly glial enzyme in the brain. The activity of this enzyme significantly increases with age. (-)deprenyl, the first selective inhibitor of MAO-B described in literature, has become the universally used research tool for selectively blocking B-type MAO. It is the only selective MAO-B inhibitor in clinical use. (-)Deprenyl interferes with the uptake of catecholamines and indirectly acting sympathomimetics because it is handled by the catecholaminergic neuron in a way similar to the physiological substances transported through the axonal end organ and vesicular membrane. The unique behavior of (-)deprenyl is that, in striking contrast to PEA and its relatives it does not displace the transmitter from storage, ie it is not a releaser. The net result is that (-)deprenyl inhibits the releasing effect of tyramine, and at present, is the only safe MAO inhibitor that can be administered without dietary precautions. Maintenance on (-)deprenyl selectively enhances superoxide dismutase (SOD) and catalase activity in the striatum. This effect is unrelated to its effect on MAO-B and the inhibitory effects of the drug on neurotransmitter uptake. Maintenance on (-)deprenyl facilitates the activity of the catecholaminergic system in the brain, and this effect, too, is unrelated to either its effects on MAO or on neurotransmitter uptake. (-)Deprenyl protects the nigrostriatal dopaminergic neurons against selective neurotoxins (6-hydroxydopamine, MPTP, DSP-4).(ABSTRACT TRUNCATED AT 250 WORDS)


Current comprehensive assessment and management of women at increased risk for breast cancer.
The potential for reducing the risk of breast cancer through selective estrogen receptor modulators, aromatase inhibitors, and surgery has generated interest in the use of quantitative models of risk assessment. With the addition of ductal lavage cytology to traditional epidemiologic risk factors, a discovery of cellular atypia can result in refinement of assigned risk values, while simultaneously optimizing patient selection for selective estrogen receptor modulators utilization. In view of increasing complexity in this arena, a Risk Assessment Working Group was formed to outline management strategies for the patient at an elevated risk for the development of breast cancer. No longer a statistical exercise, quantitative risk assessment is part of basic breast care and comprehensive management includes a discussion of the following: ductal lavage for improved risk stratification, multiple options for risk reduction, and high risk surveillance strategies that might incorporate investigational imaging protocols.


Effects of single or concurrent infections with Eimeria alabamensis and gastrointestinal nematodes on the performance of calves on pasture.
Twenty-four calves unexposed to pasture were allocated to four groups and inoculated with either two doses of 5 million Eimeria alabamensis oocysts at turn-out (E), 90,000 L3 of Ostertagia ostertagi and Cooperia oncophora divided on six occasions (N) or both oocysts and larvae as above (E + N). A control group was left uninoculated (C). For 10 weeks, the groups grazed in separate uniform paddocks not previously grazed by cattle. By day 5, most calves in groups E and E + N developed clinical coccidiosis that resulted in reduced weight gain compared to C and N. Mean trichostrongylid faecal egg counts in groups N and E + N never exceeded 300 eggs per gram of faeces, and average serum pepsinogen levels were less than 3.8 U tyrosine. This experiment demonstrates the potential impact of E. alabamensis on the performance of previously unexposed calves, whereas no aggravated effects were observed due to concurrent infections with gastrointestinal nematodes.


The Injury Distress Index: development and validation.
To develop and validate a new measurement tool designed to assess self-reported distress responses after traumatic physical injury. A mixed-methods study design was used. Development of the Injury Distress Index (IDI) included input from patients and experts and a comprehensive literature review. The IDI and validity measures were administered by a trained research assistant at bedside within 1 week of admission. The internal structure (exploratory factor analyses [EFAs]), reliability (internal consistency), and associations with other variables (construct and criterion validity) were examined. Hand, multiple trauma, and burn services at a large southeastern level-1 trauma center. Multicultural cohort of 169 traumatically injured adults (31% hand, 21% burn, 48% multiple trauma). Not applicable. IDI, Trauma Symptom Checklist-40, Short-Form McGill Pain Questionnaire, Perceived Stress Scale-10, Life Orientation Test-Revised, General Perceived Self-Efficacy Scale, Drug Abuse Screening Test-10, Brief Michigan Alcoholism Screening Test, Abbreviated Injury Scale, hospital length of stay (LOS), postdischarge emergency department visits, and days readmitted to hospital postdischarge. An item pool was developed from patient, expert, and literature review data. EFAs extracted 3 separate factors for posttraumatic stress (avoidance and numbing, re-experience, and hyperarousal: coefficient range, .31-.98), which is consistent with conceptual and diagnostic criteria. EFAs also produced single factors of depression (coefficient range, .44-.72), anxiety (coefficient range, .50-.75), and pain (coefficient range, .57-.79). Most IDI scales (except anxiety) could be differentiated between different levels of injury severity. IDI scales and subscales correlated highly and in a convergent pattern with validity measures of posttraumatic stress (r range, .18-.50), depression (r range, .24-.52), anxiety (r range, .30-.57), and pain (r range, .10-.42), as well as theoretically related variables, such as general distress (r range, .32-.56), self-efficacy (r range, -.15 to -.39), and optimism (r range, -.21 to -.45). IDI scales correlated in a discriminant pattern with measures of drug and alcohol abuse (r range, .02-.07; r range, .09-.21, respectfully). Concurrent and predictive validity evidence was also supported with small associations with injury severity (r range, .16-.30), hospital LOS (r range, .05-.21), number of emergency department visits postdischarge (r range, -.05 to .27), and number of days readmitted to the hospital postdischarge (r range, .05-.21). Cronbach alpha coefficients were within the acceptable range (alpha range, .75-.92). A new tool to examine injury-related distress after traumatic physical injury has been developed. Results suggest that IDI scores showed acceptable reliability and validity coefficients with this multicultural sample. Additional validation studies are recommended with larger sample sizes using similar populations to confirm these findings.


Imbalance of p75(NTR)/TrkB protein expression in Huntington's disease: implication for neuroprotective therapies.
Neuroprotective therapies based on brain-derived neurotrophic factor (BDNF) administration have been proposed for Huntington's disease (HD) treatment. However, our group has recently reported reduced levels of TrkB in HD mouse models and HD human brain suggesting that besides a decrease on BDNF levels a reduction of TrkB expression could also contribute to diminished neurotrophic support in HD. BDNF can also bind to p75 neurotrophin receptor (p75(NTR)) modulating TrkB signaling. Therefore, in this study we have analyzed the levels of p75(NTR) in several HD models, as well as in HD human brain. Our data demonstrates a p75(NTR)/TrkB imbalance in the striatum of two different HD mouse models, Hdh(Q111/111) homozygous knockin mice and R6/1 mice that was also manifested in the putamen of HD patients. The imbalance between TrkB and p75(NTR) levels in a HD cellular model did not affect BDNF-mediated TrkB activation of prosurvival pathways but induced activation of apoptotic cascades as demonstrated by increased JNK phosphorylation. Moreover, BDNF failed to protect mutant huntingtin striatal cells transfected with p75(NTR) against NMDA-mediated excitotoxicity, which was associated with decreased Akt phosphorylation. Interestingly, lack of Akt activation following BDNF and NMDA treatment correlated with increased PP1 levels. Accordingly, pharmacological inhibition of PP1 by okadaic acid (OA) prevented mutant huntingtin striatal cell death induced by NMDA and BDNF. Altogether, our findings demonstrate that the p75(NTR)/TrkB imbalance induced by mutant huntingtin in striatal cells associated with the aberrant activity of PP1 disturbs BDNF neuroprotection likely contributing to increasing striatal vulnerability in HD. On the basis of this data we hypothesize that normalization of p75(NTR) and/or TrkB expression or their signaling will improve BDNF neuroprotective therapies in HD.


Temperature induced modulation of resonant Raman scattering in bilayer 2H-MoS2.
The temperature evolution of the resonant Raman scattering from high-quality bilayer 2H-MoS[Formula: see text] encapsulated in hexagonal BN flakes is presented. The observed resonant Raman scattering spectrum as initiated by the laser energy of 1.96 eV, close to the A excitonic resonance, shows rich and distinct vibrational features that are otherwise not observed in non-resonant scattering. The appearance of 1st and 2nd order phonon modes is unambiguously observed in a broad range of temperatures from 5 to 320 K. The spectrum includes the Raman-active modes, i.e. E[Formula: see text]([Formula: see text]) and A[Formula: see text]([Formula: see text]) along with their Davydov-split counterparts, i.e. E[Formula: see text]([Formula: see text]) and B[Formula: see text]([Formula: see text]). The temperature evolution of the Raman scattering spectrum brings forward key observations, as the integrated intensity profiles of different phonon modes show diverse trends. The Raman-active A[Formula: see text]([Formula: see text]) mode, which dominates the Raman scattering spectrum at T = 5 K quenches with increasing temperature. Surprisingly, at room temperature the B[Formula: see text]([Formula: see text]) mode, which is infrared-active in the bilayer, is substantially stronger than its nominally Raman-active A[Formula: see text]([Formula: see text]) counterpart.


Cough reflex and oral chemesthesis induced by capsaicin and capsiate in healthy never-smokers.
Many tussive agents are components of foods, but little is known about the relationship between cough reflex and oral chemesthesis sensitivities. We investigated the relationships between cough reflex and oral chemesthesis in individuals using two transient receptor potential vanilloid 1 (TRPV1) agonists with different potencies: capsaicin and capsiate. Twenty-eight healthy never-smokers were allocated to evaluate cough and oral chemesthesis of capsinoids. Cough reflex sensitivities are estimated by the lowest concentrations generating five coughs by each TRPV1 agonist inhalation. Oral chemesthesis sensitivities are estimated by the lowest concentrations which generate a hot sensation when filter paper loaded with each TRPV1 agonist is placed on the tongue. There were strong correlations between capsaicin- and capsiate-induced cough reflex sensitivities, and between capsaicin- and capsiate-induced oral chemesthesis sensitivities. However, there were no significant correlations between cough reflex and oral chemesthesis sensitivities induced by both capsaicin and capsiate. The cough reflex sensitivities are significantly greater in females than in males whereas there were no gender differences in oral chemesthesis. The results showed that the sensitivities of sensory afferents were different between cough reflex and oral chemesthesis, suggesting that TRPV1 sensitivities differ between organs within healthy individuals. Capsiate could be a tussigen for the cough challenge test.


Changes of tumor vascularity during gene therapy monitored with color Doppler US.
Using contrast-enhanced color Doppler (CD) sonography, we assessed alterations of tumor blood flow induced in 25 murine Morris hepatomas transfected with a gancyclovir- (GCV-)sensitizing Herpes simplex virus thymidine kinase (HSVtk) suicide gene in combination with systemic GCV treatment and compared findings with a control tumor. CD measurements were quantified by the color pixel density (CPD) and the mean encoded flow velocity (mean color value, MCV), using computer-assisted image analysis, and compared with histologic arteriole counts. During 5 days, the tumor volume remained constant. In HSVtk-expressing tumors, the median CPD dropped from 16% at baseline to 5% on day 5 (p = 0.001), remaining constant in controls. The MCV decreased from 1.9 cm/s to 1.6 cm/s in the HSVtk-expressing tumors (p = 0.001) and rose from 1.8 cm/s to 2.0 cm/s in the controls (p = 0.002). In an accompanying histologic arteriole assay, we found no alterations attributable to treatment.


Neurodegenerative diseases among miners in Ontario, Canada, using a linked cohort.
We examined employment in mining occupations and industries and its association with neurological disease incidence in a linkage cohort from Ontario, Canada. Outcomes included Alzheimer's disease (alone and with other dementias), Parkinson's disease, parkinsonism, motor neuron disease and amyotrophic lateral sclerosis (ALS). The Occupational Disease Surveillance System cohort was created by linking workers' compensation data and healthcare usage records. This analysis included over 1.1 million male workers, followed between 1999 and 2016. Neurological diseases were ascertained using physician billing and hospital discharge records. Adjusted Poisson regression models were used to estimate incidence rate ratios (RR) comparing mining to non-mining workers overall and by ore (industry) and occupation group. Suggested elevations in incidence rates were observed for ALS among workers of metal mines (RR 2.21, 95% CI 1.04 to 4.69) and for motor neuron disease among those employed in mining occupations within metal mining industries (RR 1.96, 95% CI 1.01 to 3.79), though these were based on relatively few cases. In miscellaneous metal mines, workers who held mining occupations had an elevated rate of Alzheimer's disease (RR 1.27, 95% CI 0.92 to 1.77). Parkinson's disease rate was elevated among workers with rock and soil drilling occupations (RR 1.60, 95% CI 1.04 to 2.45). Mining hazards may be associated with elevated rates of neurodegenerative diseases among workers in mining occupations and industries. More work is needed to better understand mining exposures and their associations with neurodegenerative diseases.


Speciation measurements of uranium in alkaline waters using diffusive gradients in thin films technique.
This work investigated the application of diffusive gradients in thin films technique (DGT) to uranium speciation measurements in natural water. Two binding phases were examined, a commercially available affinity membrane, Whatman DE 81 (DE 81), with amino binding functional groups and the conventionally used Chelex 100 beads imbedded polyacrylamide hydrogel (Chelex) with iminodiacetate functional groups. The DGT devices assembled with the binding phases of DE 81 (DE 81 DGT) and Chelex gel (Chelex DGT) were tested both in synthetic river water solutions and in local river water. DE 81 DGT and Chelex DGT measured 80% and 75% of the total uranium in synthetic river water solution, respectively, and measured 73% and 60% of the total uranium in St. Lawrence River, Canada, respectively. The binding properties of the DE 81 membrane and Chelex gel for uranium, and the diffusion of uranyl complexes in the polyacrylamide gel (PAM) were also studied.


Long-term Trends in Open vs Endoscopic Carpal Tunnel Release Among the Medicare Population in the United States.
Carpal tunnel release (CTR) surgery is the most common surgery billed to Medicare by hand surgeons. As such, the purpose of this study was to evaluate trends for CTR surgeries billed to Medicare from 2000 to 2020. The publicly available Medicare Part B National Summary File from 2000 to 2020 was queried. For both open carpal tunnel release (OCTR) and endoscopic carpal tunnel release (ECTR), the number of procedures and total Medicare reimbursement were extracted. For year 2020, the specialty of the performing surgeon was recorded. Descriptive statistics were reported. A total of 3 429 471 CTR surgeries were performed in the Medicare population from 2000 to 2020. For these procedures, Medicare paid surgeons over $1.23 billion. During this period, there was a 101.8% increase in annual CTR procedures (91 130 in 2000, 183 911 in 2020). Further, annual volume of ECTR increased by 456.2%, and accounted for an increasing percentage of total CTR procedures (9.1% in 2012, 25.2% in 2020). The average adjusted Medicare reimbursement per procedure decreased by 1.5% for OCTR, and decreased by 11.6% for ECTR. In 2020, orthopedic surgeons performed 85.1% of CTR procedures. The volume of CTR surgeries among the Medicare population has increased from 2000 to 2020, and ECTR is accounting for a growing proportion of surgeries. When adjusted for inflation, average reimbursement has decreased, with a greater decrease among ECTR. Orthopedic surgeons perform most of such surgeries. These trends are important to assure adequate resource allocation as treating carpal tunnel becomes more common among the aging Medicare population.


Tuning the Baird aromatic triplet-state energy of cyclooctatetraene to maximize the self-healing mechanism in organic fluorophores.
Bright, photostable, and nontoxic fluorescent contrast agents are critical for biological imaging. "Self-healing" dyes, in which triplet states are intramolecularly quenched, enable fluorescence imaging by increasing fluorophore brightness and longevity, while simultaneously reducing the generation of reactive oxygen species that promote phototoxicity. Here, we systematically examine the self-healing mechanism in cyanine-class organic fluorophores spanning the visible spectrum. We show that the Baird aromatic triplet-state energy of cyclooctatetraene can be physically altered to achieve order of magnitude enhancements in fluorophore brightness and signal-to-noise ratio in both the presence and absence of oxygen. We leverage these advances to achieve direct measurements of large-scale conformational dynamics within single molecules at submillisecond resolution using wide-field illumination and camera-based detection methods. These findings demonstrate the capacity to image functionally relevant conformational processes in biological systems in the kilohertz regime at physiological oxygen concentrations and shed important light on the multivariate parameters critical to self-healing organic fluorophore design.


Non-homogeneous stereological properties of the rat hippocampus from high-resolution 3D serial reconstruction of thin histological sections.
Integrating hippocampal anatomy from neuronal dendrites to whole system may help elucidate its relation to function. Toward this aim, we digitally traced the cytoarchitectonic boundaries of the dentate gyrus (DG) and areas CA3/CA1 throughout their entire longitudinal extent from high-resolution images of thin cryostatic sections of adult rat brain. The 3D computational reconstruction identified all isotropic 16 μm voxels with appropriate subregions and layers (http://krasnow1.gmu.edu/cn3/hippocampus3d). Overall, DG, CA3, and CA1 occupied comparable volumes (15.3, 12.2, and 18.8 mm(3), respectively), but displayed substantial rostrocaudal volumetric gradients: CA1 made up more than half of the posterior hippocampus, whereas CA3 and DG were more prominent in the anterior regions. The CA3/CA1 ratio increased from ∼0.4 to ∼1 septo-temporally because of a specific change in stratum radiatum volume. Next we virtually embedded 1.8 million neuronal morphologies stochastically resampled from 244 digital reconstructions, emulating the dense packing of granular and pyramidal layers, and appropriately orienting the principal dendritic axes relative to local curvature. The resulting neuropil occupancy reproduced recent electron microscopy data measured in a restricted location. Extension of this analysis across each layer and subregion over the whole hippocampus revealed highly non-homogeneous dendritic density. In CA1, dendritic occupancy was >60% higher temporally than septally (0.46 vs. 0.28, s.e.m. ∼0.05). CA3 values varied both across subfields (from 0.35 in CA3b/CA3c to 0.50 in CA3a) and layers (0.48, 0.34, and 0.27 in oriens, radiatum, and lacunosum-moleculare, respectively). Dendritic occupancy was substantially lower in DG, especially in the supra-pyramidal blade (0.18). The computed probability of dendrodendritic collision significantly correlated with expression of the membrane repulsion signal Down syndrome cell adhesion molecule (DSCAM). These heterogeneous stereological properties reflect and complement the non-uniform molecular composition, circuit connectivity, and computational function of the hippocampus across its transverse, longitudinal, and laminar organization.


Persistence of colonization of human colonic mucosa by a probiotic strain, Lactobacillus rhamnosus GG, after oral consumption.
Lactobacillus rhamnosus GG is one of the most thoroughly studied probiotic strains. Its advantages in the treatment of gastrointestinal disorders are well documented. The aim of the present study was to demonstrate with colonic biopsies the attachment of strain GG to human intestinal mucosae and the persistence of the attachment after discontinuation of GG administration. A whey drink fermented with strain GG was fed to human volunteers for 12 days. Fecal samples were collected before, during, and after consumption. L. rhamnosus GG-like colonies were detected in both fecal and colonic biopsy samples. Strain GG was identified by its characteristic colony morphology, a lactose fermentation test, and PCR. This study showed that strain GG was able to attach in vivo to colonic mucosae and, although the attachment was temporary, to remain for more than a week after discontinuation of GG administration. The results demonstrate that the study of fecal samples alone is not sufficient in evaluating colonization by a probiotic strain.


Penetrating thoracoabdominal injuries from multiple-spiked spear stabbing: Case report and literature review.
Penetrating thoracoabdominal injuries carry high morbidity and mortality. Concurrent clinical evaluation and resuscitation followed by early surgery are associated with good outcome. In a resource-limited setting, plain X-rays are valuable in surgery planning. Impalement objects must only be removed at surgery.


The influence of the type of sulphate bond and degree of sulphation of glycosaminoglycans on their interaction with lysosomal enzymes.
Significant differences occur between the interaction of several sulphated glycosaminoglycans with a particular lysosomal protein, leading to inhibition in the case of lysosomal enzymes. The order of strength of inhibition at pH4 was: heparin greater than chondroitin 4-sulphate = chondroitin 6-sulphate greater than dermatan sulphate.


Enhancers as non-coding RNA transcription units: recent insights and future perspectives.
Networks of regulatory enhancers dictate distinct cell identities and cellular responses to diverse signals by instructing precise spatiotemporal patterns of gene expression. However, 35 years after their discovery, enhancer functions and mechanisms remain incompletely understood. Intriguingly, recent evidence suggests that many, if not all, functional enhancers are themselves transcription units, generating non-coding enhancer RNAs. This observation provides a fundamental insight into the inter-regulation between enhancers and promoters, which can both act as transcription units; it also raises crucial questions regarding the potential biological roles of the enhancer transcription process and non-coding enhancer RNAs. Here, we review research progress in this field and discuss several important, unresolved questions regarding the roles and mechanisms of enhancers in gene regulation.


Substrate specificity of the SpCCE1 holliday junction resolvase of Schizosaccharomyces pombe.
SpCCE1 from Schizosaccharomyces pombe is an endonuclease that resolves Holliday junctions in vitro. SpCCE1 also binds and cleaves a range of other DNAs (Y-junction; flap; and flayed, nicked, and partial duplexes) with varying efficiency. Cleavage sites are always 3' of thymine nucleotides positioned at or close to the branch point or strand interruption. SpCCE1's favored substrate is the X-junction. Up to two dimers of SpCCE1 can bind concurrently to the same X-junction at its crossover point. From mixing experiments of SpCCE1 and the Escherichia coli RuvA protein, we show that each dimer of SpCCE1 binds to a different face of the X-junction and that both are seemingly competent for strand cleavage. We propose that this provides a mechanism whereby SpCCE1 can scrutinize all four junction strands simultaneously for cleavable thymine nucleotides. SpCCE1 appears to resolve X-junctions by a nick and counter-nick mechanism. Therefore, to ensure a high probability of bilateral strand cleavage, SpCCE1 has a relatively long lifetime on X-junctions. This mechanism has the drawback of limiting dissociation from noncleavable junctions. We discuss why this might not be a problem in vivo.


Cumulative genetic defects in carcinogen metabolism may increase breast cancer risk (The Netherlands).
Variants in the metabolic genes NAT1, NAT2, GSTM1 or GSTT1, may cause differences in individual detoxifying capacity of possible carcinogens. We examined the cumulative effect of putative at risk genotypes on breast cancer risk and we examined the extent to which these polymorphisms modify the association between smoking and breast cancer. A case cohort study was conducted in the DOM cohort with 676 breast cancer cases and a random sample of 669 individuals. No effect of the NAT1, NAT2 or GSTM1 genotypes on breast cancer risk was observed. However, women with GSTT1 null genotype had a 30% increased breast cancer risk compared to women with GSTT1 present (RR = 1.30 (95% confidence interval (CI) 1.04-1.64)). Smoking did not influence breast cancer risk nor did genetic variations in NAT1, NAT2 or GSTM1 in combination with smoking. Compared to women who never smoked with GSTT1 present, women with GSTT1 null genotype and who formerly smoked showed an increased breast cancer risk (RR = 2.55 (95% CI 1.10-5.90)), but current smokers who smoked 20 cigarettes or more per day did not (RR = 1.06 (95% CI 0.51-2.18)). Increasing numbers of putative at risk genotypes increased breast cancer risk in a dose dependent manner (p for trend 0.01). The risk was more than doubled in women with all four risk genotypes, RR = 2.45 (95% CI 1.24-4.86), compared to women with zero putative at risk genotypes. In conclusion, the results of this study suggest that presence of three or more putative at risk genotypes increases breast cancer risk.


Long-term potentiation in the hippocampal CA1 region of mice lacking cGMP-dependent kinases is normal and susceptible to inhibition of nitric oxide synthase.
Long-term potentiation (LTP) is a potential cellular mechanism for learning and memory. The retrograde messenger nitric oxide (NO) is thought to induce LTP in the CA1 region of the hippocampus via activation of soluble guanylyl cyclase (sGC) and, ultimately, cGMP-dependent protein kinase (cGK). Two genes code for the isozymes cGKI and cGKII in vertebrates. The functional role of cGKs in LTP was analyzed using mice lacking the gene(s) for cGKI, cGKII, or both. LTP was not altered in the mutant mice lineages. However, LTP was reduced by inhibition of NO synthase and NMDA receptor antagonists, respectively. The reduced LTP was not recovered by the cGK-activator 8-(4 chlorophenylthio)-cGMP. Moreover, LTP was not affected by the sGC inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]-quiloxalin-1-one. In contrast, it was effectively suppressed by nicotinamide, a blocker of the ADP-ribosyltransferase. These results show that cGKs are not involved in LTP in mice and that NO induces LTP through an alternative cGMP-independent pathway, possibly ADP-ribosylation.


Evaluation of transport pathways for Na+ across frog skin epithelium by means of presteady-state flux ratio.
A method is described that makes it possible to separate the sodium fluxes through the isolated frog skin into sets characteristic of the cellular and the paracellular pathway, respectively. If there are two significant pathways for the ion, and if they differ with respect to flux ratio as well as mean passage time, the flux ratios for the individual pathways can be obtained from a set of inward and outward tracer fluxes, covering the time from the addition of the tracers until the achievement of constant fluxes in both directions.


Internal stabilization after external fixation of fractures of the shaft of the tibia: sense or nonsense?
A series of 95 patients with fresh fractures of the shaft of the tibia, treated primarily with a Vidal-Adrey transfixation frame, was studied retrospectively. Only 20 fractures (21.0 per cent) attained clinical and radiological consolidation within 4 months after injury. Pseudoarthrosis was seen in 12 patients (12.9 per cent). The external fixator was attached for an average time of 25.0 weeks. Pin loosening was seen in seven patients (7.3 per cent), minor pin track infection in nine (9.4 per cent) and major pin track infection in three (3.1 per cent). In 31 patients (32.6 per cent) a second operative procedure was necessary to accelerate fracture healing. In 17 patients an autologous bone graft was carried out with the external fixator in place. Internal stabilization was performed after removal of the external fixator frame in 14 cases, at an average time of 9.4 months after injury. In difficult fractures we feel that change from external to internal fixation should be performed earlier; it makes early removal of the fixator pins possible and prevents the problems associated with prolonged use of fixator frames. The internal fixation, eventually combined with a transplantation of cancellous autografts, creates a mechanical and biological stimulus for bone consolidation. Functional recovery may also be improved because of a shorter healing time.


Individual male perception of female genitalia.
Australian Medicare data show that the rates of cosmetic labiaplasty have tripled over the last decade; however, there is little understanding about the social factors that contribute to the popularity of female genital cosmetic surgeries (FGCS). The aim of this study was to investigate male perception of female genitalia and to assess men's awareness of FGCS and whether these surgeries are viewed as a positive and acceptable option. A cross-sectional study of male adults in the Townsville region was conducted via an online questionnaire. A total of 500 online surveys were sent out and 248 respondents were included in the study; 49.2 % of participants do not have a preferred appearance of labia minora and 70.4 % of men are aware of FGCS, but 53.8 % do not believe that FGCS is a good option for women. Only 14 % of men supported genital cosmetic surgery, while 29.6 % are undecided about the practice. The most common preferred pubic hair appearance is completely hairless (45 %). This study indicates that the majority of men do not have a preferred appearance for female genitalia, nor do they support FGCS or consider discussing genital surgery with their partner. The major limitation of the study is that the participants' age distribution was skewed heavily towards the younger demographic, with 18- to 24-year-old men comprising 81.5 % of respondents.


A survey of simian Plasmodium infections in humans in West Kalimantan, Indonesia.
The simian parasite Plasmodium knowlesi is the predominant species causing human malaria infection, including hospitalisations for severe disease and death, in Malaysian Borneo. By contrast, there have been only a few case reports of knowlesi malaria from Indonesian Borneo. This situation seems paradoxical since both regions share the same natural macaque hosts and Anopheles mosquito vectors, and therefore have a similar epidemiologically estimated risk of infection. To determine whether there is a true cross-border disparity in P. knowlesi prevalence, we conducted a community-based malaria screening study using PCR in Kapuas Hulu District, West Kalimantan. Blood samples were taken between April and September 2019 from 1000 people aged 6 months to 85 years attending health care facilities at 27 study sites within or close to jungle areas. There were 16 Plasmodium positive samples by PCR, five human malarias (two Plasmodium vivax, two Plasmodium ovale and one Plasmodium malariae) and 11 in which no species could be definitively identified. These data suggest that, if present, simian malarias including P. knowlesi are rare in the Kapuas Hulu District of West Kalimantan, Indonesian Borneo compared to geographically adjacent areas of Malaysian Borneo. The reason for this discrepancy, if confirmed in other epidemiologically similar regions of Indonesian Borneo, warrants further studies targeting possible cross-border differences in human activities in forested areas, together with more detailed surveys to complement the limited data relating to monkey hosts and Anopheles mosquito vectors in Indonesian Borneo.


p62/SQSTM1 interacts with vimentin to enhance breast cancer metastasis.
The signalling adaptor p62 is frequently overexpressed in numerous cancer types. Here, we found that p62 expression was elevated in metastatic breast cancer and its overexpression correlated with reduced metastasis- and relapse-free survival times. Analysis of p62 expression in breast cancer cell lines demonstrated that high p62 expression was associated with the invasive phenotypes of breast cancer. Indeed, silencing p62 expression attenuated the invasive phenotypes of highly metastatic cells, whereas overexpressing p62 promoted the invasion of non-metastatic cells in in vitro microfluidic model. Moreover, MDA-MB-231 cells with p62 depletion which were grown in a three-dimensional culture system exhibited a loss of invasive protrusions. Consistently, genetic ablation of p62 suppressed breast cancer metastasis in both zebrafish embryo and immunodeficient mouse models, as well as decreased tumourigenicity in vivo. To explore the molecular mechanism by which p62 promotes breast cancer invasion, we performed a co-immunoprecipitation-mass spectrometry analysis and revealed that p62 interacted with vimentin, which mediated the function of p62 in promoting breast cancer invasion. Vimentin protein expression was downregulated upon p62 suppression and upregulated with p62 overexpression in breast cancer cells. Linear regression analysis of clinical breast cancer specimens showed a positive correlation between p62 and vimentin protein expression. Together, our findings provide strong evidence that p62 functions as a tumour metastasis promoter by binding vimentin and promoting its expression. This finding might help to develop novel molecular therapeutic strategies for breast cancer metastasis treatment.


Robust dynamic susceptibility contrast MR perfusion using 4D nonlinear noise filters.
To investigate if 4D (simultaneous space and time) nonlinear filtering techniques can produce more robust cerebral blood flow (CBF) estimates by reducing noise in acquired dynamic susceptibility contrast (DSC) MR perfusion data. A digital anthropomorphic brain perfusion phantom was constructed to analyze filter performance by: 1) deriving anthropomorphic tissue volume fractions from a human subject and 2) simulating DSC-MR perfusion signals for voxels with mixed tissue for various signal-to-noise ratios (SNRs). DSC-MR data for 11 acute ischemic stroke patients were also acquired at 3T. CBF maps cross-calibrated so that normal white matter CBF was 22 mL/minute/100 g were produced from DSC-MR data without filtering and from 4D-Gaussian and 4D-bilateral noise-filtered DSC-MR data. The nonlinear 4D-bilateral filter yielded the lowest CBF root-mean square error (RMSE) in the phantom experiments with noise (average RMSE across all tissues regions for no filtering, 4D-Gaussian, and 4D-bilateral was 5.3 mL/minute/100 g, 6.2 mL/minute/100 g, and 4.0 mL/minute/100 g, respectively) and had the best image quality in both the phantom and patient data. Nonlinear 4D noise filters are better suited to the 4D nature of DSC-MR data. Linear spatial filters are not appropriate and can produce larger CBF errors than without filtering.


Wound Matrix Stiffness Imposes on Macrophage Activation.
The immune system depends on two major paths-the innate and the adaptive immunity. Macrophage, with its unique features as the first line of immune defense to engulf and digest invaders, serves as the key effector cells integrating those two paths. The dynamic plasticity of macrophage activation during wound repair, inflammation resolution, and tissue remodeling are emerging biomedical and bioengineering hot topics in immune function studies such as the various secretions of cytokines and chemokines and the signaling pathways with ligands and their cognate receptors. Better knowledge on how physical/mechanical and multicellular microenvironment on the modulation of macrophage functions will create innovative therapies to boost host defense mechanism and assist wound healing. In this, we describe an easy method to measure functions (gene expressions) of human and mouse macrophages in response to mechanical microenvironment changes by embedding isolated macrophages in polymerized hyaluronan gel with different wound matrix stiffness.


Coblation Versus Conventional Tonsillectomy: A Double Blind Randomized Controlled Trial.
Post tonsillectomy bleeding and pain are two main problems following traditional tonsillectomy. Coblation therapy (controlled ablation) was first used in tonsillectomy in 2001. A great amount of literature debated around its use with controversial opinions regarding its benefits, efficacy, and cost. This is a prospective double-blind randomized controlled study that compares between coblation tonsillectomy and conventional tonsillectomy as regard operative time, operative blood loss, time needed to return back to the normal activity and diet, and incidence of postoperative hemorrhage whether primary or secondary. The study included 1004 patients with mean age of 10.4 years (range from 4 to 35 years). The first group (coblation tonsillectomy group) included 507 patients, age ranging from 4 to 35 years with mean age 15.1 year. This group included 277 female (54.6%) and 230 male (45.4%). The second group (conventional tonsillectomy group) included 497 patients, age ranging from 4 to 24 years and mean age 14.7 years. This group included 274 female (55.1%) and 223 male (44.9%). Coblation tonsillectomy offers significant advantages over dissection method with less operative time, decreased intraoperative blood loss, early restoration of daily activities and normal diet. However coblation tonsillectomy is associated with a higher incidence of secondary hemorrhage.


Intelligent Micro-/Nanorobots for Cancer Theragnostic.
Cancer is one of the most intractable diseases owing to its high mortality rate and lack of effective diagnostic and treatment tools. Advancements in micro-/nanorobot (MNR)-assisted sensing, imaging, and therapeutics offer unprecedented opportunities to develop MNR-based cancer theragnostic platforms. Unlike ordinary nanoparticles, which exhibit Brownian motion in biofluids, MNRs overcome viscous resistance in an ultralow Reynolds number (Re << 1) environment by effective self-propulsion. This unique locomotion property has motivated the advanced design and functionalization of MNRs as a basis for next-generation cancer-therapy platforms, which offer the potential for precise distribution and improved permeation of therapeutic agents. Enhanced barrier penetration, imaging-guided operation, and biosensing are additionally studied to enable the promising cancer-related applications of MNRs. Herein, the recent advances in MNR-based cancer therapy are comprehensively addresses, including actuation engines, diagnostics, medical imaging, and targeted drug delivery; promising research opportunities that can have a profound impact on cancer therapy over the next decade is highlighted.


Up-regulation of cyclin-E(1) via proline-mTOR pathway is responsible for HGF-mediated G(1)/S progression in the primary culture of rat hepatocytes.
Hepatocyte growth factor (HGF) is a key ligand that elicits G1/S progression of epithelial cells, including hepatocytes. Proline is also required for DNA synthesis that is induced by growth factors in primary culture of hepatocytes. However, it remains unknown how proline contributes to the G1/S progression of hepatocytes. The primary culture of rat hepatocytes using HGF plus proline can be a conceptual model for elucidating the molecular linkage of amino acids and growth factors during G1/S progression. Using this in vitro model, we provide evidence that not only induction of cyclin-D1 by HGF but also up-regulation of cyclin-E1 by proline is required for hepatocytes to enter the S-phase. Proline-enhanced cyclin-E1 induction, without changing its mRNA level, is associated with the activation of mammalian target of rapamycin (mTOR)-dependent pathways. Indeed, proline enhanced the ribosomal protein S6 phosphorylations (i.e., mTOR target), concomitantly with an increase in cyclin-E1. Inversely, mTOR-inhibitor, rapamycin suppressed the proline-mediated induction of cyclin-E1. As a result, DNA synthesis of hepatocytes, which was induced by HGF in the presence of proline, was largely abolished by mTOR-inhibitor treatment. Such a co-mitogenic effect of proline was also dependent on collagen synthesis: collagen synthesis inhibitors, such as cis-OH-proline, diminished the proline-induced cyclin-E1, and then the G1/S progression of hepatocytes was also suppressed. Overall, proline-mediated mTOR activation and collagen synthesis were found critical for HGF-induced DNA synthesis, partly via the sufficient accumulation of cyclin-E1. This is the first report to demonstrate the molecular bridge between amino acids and growth factors that drive mitogenic outcomes.


Concentric needle single fiber electromyography: comparative jitter on voluntary-activated and stimulated Extensor Digitorum Communis.
To compare the jitter values in voluntarily activated (v-CNE) and stimulated (s-CNE) techniques for Extensor Digitorum Communis muscle using a disposable concentric needle electrode (CNE). Quantifying jitter using a CNE in conjunction with a stimulated technique has not been reported previously. Forty-one normal subjects were studied, 15 male and 26 female with a mean age of 34.1+/-10.7 years (19-55). The jitter values were expressed as the mean consecutive difference (MCD) of 20 analyzed potential pairs using v-CNE and 30 isolated potentials using s-CNE. The mean MCD (n=41) was 23.0+/-2.8 micros for v-CNE and 18.2+/-2.2 micros for s-CNE. The mean jitter of all recorded potentials was 22.9+/-6.7 micros for v-CNE (n=820) and 18.3+/-5.2 micros for s-CNE (n=1230). Upper limits for the 18th (v-CNE) and 27th highest (s-CNE) MCD were 38.9 and 30 micros, respectively (95% confidence limit). The jitter decrease in s-CNE compared to v-CNE was 1:0.79. Our findings of the jitter values using CNE were similar to other published reports using the voluntarily activated technique; however, these are the first described for the stimulated technique using CNE. The present study confirms that CNE can be used for the stimulated jitter acquisition and measurement, although certain precautions must be taken regarding signal quality, e.g., observing minimal summation.