Radiographic grading system for usual interstitial pneumonia correlates with mortality and may serve as a surrogate endpoint in clinical trials.
Usual interstitial pneumonia (UIP)/ idiopathic pulmonary fibrosis (IFP) is a relentlessly progressive lung disease with outcomes similar to cancer. We have previously established a radiologic grading system for UIP and demonstrated that it correlates with pulmonary function tests; here we test the hypothesis that it correlates with mortality. Validating a correlation with mortality will demonstrate the utility of this system for monitoring progression over time clinically and in trials of anti-fibrotic agents. We searched the radiology record system "Catalyst" to identify cases and reviewed each case to confirm the diagnosis. 94 patients met the inclusion criteria for further assessment. Chest CT grade was determined by consensus of two cardiothoracic radiologists. Data was analyzed to identify the interval between chest CT and death. This interval was correlated with CT grade using Spearman correlation analysis. For all cases, chest CT grade and mortality demonstrated a positive correlation of rs = 0.37732, 2-tailed p = 0.00018. We also employed subgroup analysis; for the subgroup with intervals less than or equal to 100 days, there was a positive correlation, rs = 0.48339, 2-tailed p = 0.03602; for the subgroup with an interval greater than 100 days between imaging and death there was a positive correlation, rs = 0.302, 2-tailed p = 0.00846. These data support use of this system for monitoring clinical progression and as a surrogate endpoint for clinical trials. Future work building upon the data presented here will evaluate its utility in clinical trials and develop automated grading.


Protection from septic peritonitis by rapid neutrophil recruitment through omental high endothelial venules.
Acute peritonitis is a frequent medical condition that can trigger severe sepsis as a life-threatening complication. Neutrophils are first-responders in infection but recruitment mechanisms to the abdominal cavity remain poorly defined. Here, we demonstrate that high endothelial venules (HEVs) of the greater omentum constitute a main entry pathway in TNFα-, Escherichia coli (E. coli)- and caecal ligation and puncture-induced models of inflammation. Neutrophil transmigration across HEVs is faster than across conventional postcapillary venules and requires a unique set of adhesion receptors including peripheral node addressin, E-, L-selectin and Mac-1 but not P-selectin or LFA-1. Omental milky spots readily concentrate intra-abdominal E. coli where macrophages and recruited neutrophils collaborate in phagocytosis and killing. Inhibition of the omental neutrophil response exacerbates septic progression of peritonitis. This data identifies HEVs as a clinically relevant vascular recruitment site for neutrophils in acute peritonitis that is indispensable for host defence against early systemic bacterial spread and sepsis.


Actigraphy correctly predicts sleep behavior in infants who are younger than six months, when compared with polysomnography.
Actigraphy has been widely used in adults and children. In infants, validation of actigraphy has typically used a comparison with behaviorally determined sleep state classification rather than polysomnography (PSG). This study validated actigraphy against PSG for determining sleep and waking states in infants who were younger than 6 mo. Twenty-two healthy infants, 13 term and 9 preterm, were studied at three different matched postconceptional ages. Actigraph data were compared with PSG recordings in 1-min epochs. Agreement rate (AR), predictive value for sleep, predictive value for wake, sensitivity. and specificity were calculated and compared between activity thresholds and across ages with two-way ANOVA for repeated measures. Thirty-two validation studies were analyzed. Overall AR with PSG of 93.7 +/- 1.3 and 91.6 +/- 1.8 were obtained at 2-4 wk and 5-6 mo, respectively, at the low activity threshold setting, whereas the auto activity threshold gave the best agreement with PSG at 2-4 mo (AR 89.3 +/- 1.3%). Sensitivity values of 96.2 +/- 1.1% at 2-4 wk, 91.2 +/- 1.5% at 2-4 mo, and 94.0 +/- 1.9% were obtained at these same settings. There was no difference across ages in AR or sensitivity. PVW and specificity values were low in this study. We conclude that actigraphy is a valid method for monitoring sleep in infants who are younger than 6 mo.


Effects of a regional-rural immersion program in Northland, New Zealand, on returning to work in that region.
It is well established that rural workforce outcomes are more likely among medical graduates who spend time training in non-urban areas; however, fewer studies have assessed whether graduates are more likely to return to the specific area where they undertook rural training. This study aimed to determine whether graduates who had undertaken a regional-rural immersion program in Northland, NZ, were more likely to have returned to work in Northland as of mid-2021, relative to peers who did not participate. This prospective cohort study used longitudinal tracking survey responses, medical school administrative data and workforce outcome information. A multinomial model, accounting for other covariates, was built to determine the association between graduates practising in Northland (population ⟨ 100 000), which encompasses both rural (population ⟨ 25 000) and regional (25 000 ⟩ population ⟨ 100 000) areas, and having participated in a Northland-based immersion program during medical school. The study population was University of Auckland domestic medical students graduating between 2009 and 2018, inclusive. Immersion program participants who responded to longitudinal career tracking surveys were included in the study sample. The final sample size was 1320 students (80% of population of interest). Graduates who undertook the Northland immersion program (n = 169) were more likely than non-participants (n = 1151) to be working in Northland as of 2020-2021 (relative risk: 3.2). Regional-rural immersion programs might preferentially build workforces in that specific region; however, further research is required to understand whether these findings are generalizable, and the main reasons for this effect.


Single-unit responses of serotonergic dorsal raphe nucleus neurons to environmental heating and pyrogen administration in freely moving cats.
Single-unit activity of serotonergic neurons in the dorsal raphe nucleus was examined in response to environmental heating and pyrogen-induced fever in freely moving cats. In the heating study, ambient temperature was rapidly raised from a baseline of 25 degrees to 43 +/- 1 degrees C and maintained at this level for 2 h. Cats displayed hyperthermia, intense panting, and signs of heat stress, however, the discharge rate of serotonergic neurons of the dorsal raphe nucleus was not significantly different from baseline at any time during heat exposure. Similarly, the activity of these neurons was not significantly altered at any time during an approximately 6-h long febrile response induced by the synthetic pyrogen muramyl dipeptide (50 micrograms/kg, i.v.). These results indicate that serotonergic unit activity in the dorsal raphe nucleus is not related to either the activation of behavioral or physiological mechanisms underlying heat defense, or to alterations in thermoregulatory mechanisms during the febrile response to exogenous pyrogen. Furthermore, because these neurons do not respond to an elevation in body temperature induced by either ambient heating or pyrogen, they do not appear to be directly temperature-sensitive. These results do not support a specific role for serotonergic neurons of the dorsal raphe nucleus in thermoregulation.


Obstruction of the large and small intestine.
This article provides an overview of mechanical small and large bowel obstruction with emphasis on newer diagnostic and therapeutic surgical techniques. Small and large intestinal pseudo-obstruction is discussed with reference to its diagnosis and appropriate treatment.


Serial MRI of extrapontine myelinolysis of the basal ganglia: a case report.
We study a patient with extrapontine myelinolysis (EPM), without central pontine myelinolysis (CPM), who exhibited changes in abnormalities observed with MRI. MRI in the acute stage of the bilateral basal ganglia showed a high signal intensity on T2-weighted images, and a low signal on T1-weighted images. The low signal on T1-weighted images of the lesion in the acute stage changed to a high signal in the subacute stage. This change may reflect the involvement of microhemorrhagic lesions caused by vascular endothelial injury associated with EPM. We propose that vascular endothelial injury due to rapid osmotic change and subsequent demyelination is involved in the patho-etiology of EPM.


miRNA-382-5p Suppresses the Expression of Farnesoid X Receptor to Promote Progression of Liver Cancer.
The dysregulation of microRNAs (miRNAs) and hepatotoxicity due to the aberrant accumulation of bile acids (BAs) are notorious causes that predispose an individual to the development of hepatocellular carcinoma (HCC). Farnesoid X receptor (FXR), encoded by NR1H4 gene, has been identified as a crucial BA receptor to maintain the homeostasis of BA pool and its expression is decreased in HCC. miR-382-5p plays an important role in the pathogenesis of many human malignancies and was reported to promote the proliferation and differentiation of normal liver cells and liver regeneration. However, there is still some controversy about its role in HCC microenvironment. This study aims to explore the expression pattern of miR-382-5p in HCC and its role in regulating FXR during the development of HCC. Tissues collected from 30 HCC patients were subjected to extraction of total RNA and quantitative real-time PCR (qRT-PCR) for the analyses of miR-382-5p expression and NR1H4 mRNA levels, and their expressions were verified by analyzing the online HCC-related GSE datasets. The role of miR-382-5p in regulating cellular proliferation and expression of FXR in different HCC cell lines was analyzed by qRT-PCR, Western Blot, real-time cellular analysis (RTCA) and luciferase reporter assays. The role of miR-382-5p in regulating downstream genes of FXR in HCC cells was also analyzed. miR-382-5p was upregulated in HCC tissues and inversely associated with the downregulation of NR1H4 mRNA levels. The luciferase reporter assay proved that miR-382-5p directly targeted the 3'-untranslated region (3'-UTR) of human NR1H4 mRNA. Overexpression of miR-382-5p led to a malignant proliferation of HCC cells by suppressing the expression of FXR. In contrast, blocking the endogenous miR-382-5p was sufficient to suppress the cellular proliferation rate of HCC through increasing FXR expression. Additionally, miR-382-5p inhibited the expression of some target genes of FXR, including SHP, FGF19 and SLC51A, and this inhibitory effect was FXR-dependent. Therefore, miR-382-5p promotes the progression of HCC in vitro by suppressing FXR and could serve as a valuable therapeutic target for HCC treatment.


The crosstalk between Nrf2 and NF-κB pathways in coronary artery disease: Can it be regulated by SIRT6?
Coronary artery disease (CAD) is the leading cause of death worldwide. Oxidative stress and inflammation are major mechanisms responsible for the progression of CAD. Nuclear transcription factor erythroid-2 related factor 2 (Nrf2) is a transcription factor that modulates the cellular redox status. Nrf2 upregulation increases the expression of antioxidant genes, decreases the expression of Nuclear factor-kappa B (NF-kB), and increases free radical metabolism. Activated NF-kB increases the production of inflammatory cytokines causing endothelial dysfunction. The two pathways of Nrf2 and NF-kB can regulate the expression of each other. Foremost, the Nrf2 pathway can decrease the level of active NF-κB by increasing the level of antioxidants and cytoprotective enzymes. Furthermore, the Nrf2 pathway prevents IκB-α degradation, an inhibitor of NF-kB, and thus inhibits NF-κB mediated transcription. Also, NF-kB transcription inhibits Nrf2 activation by reducing the antioxidant response element (ARE) transcription. Sirtuin 6 (SIRT6) is a member of the Sirtuins family that was found to protect against cardiovascular diseases. SIRT6 can suppress the production of Reactive oxygen species (ROS) through deacetylation of NRF2 which results in NRF2 activation. Furthermore, SIRT6 can inhibit the inflammatory process through the downregulation of NF-kB transcription. Therefore, targeting sirtuins could be a therapeutic strategy to treat CAD. This review describes the potential role of SIRT6 in regulating the crosstalk between NRF2 and NF-kB signaling pathways in CAD.


Exercise as a non-pharmacological intervention to protect pancreatic beta cells in individuals with type 1 and type 2 diabetes.
Diabetes is characterised by progressive loss of functional pancreatic beta cells. None of the therapeutic agents used to treat diabetes arrest this process; preventing beta cell loss remains a major unmet need. We have previously shown that serum from eight young healthy male participants who exercised for 8 weeks protected human islets and insulin-producing EndoC-βH1 cells from apoptosis induced by proinflammatory cytokines or the endoplasmic reticulum (ER) stressor thapsigargin. Whether this protective effect is influenced by sex, age, training modality, ancestry or diabetes is unknown. We enrolled 82 individuals, male or female, non-diabetic or diabetic, from different origins, in different supervised training protocols for 8-12 weeks (including training at home during the COVID-19 pandemic). EndoC-βH1 cells were treated with 'exercised' serum or with the exerkine clusterin to ascertain cytoprotection from ER stress. The exercise interventions were effective and improved [Formula: see text] values in both younger and older, non-obese and obese, non-diabetic and diabetic participants. Serum obtained after training conferred significant beta cell protection (28% to 35% protection after 4 and 8 weeks of training, respectively) from severe ER stress-induced apoptosis. Cytoprotection was not affected by the type of exercise training or participant age, sex, BMI or ancestry, and persisted for up to 2 months after the end of the training programme. Serum from exercised participants with type 1 or type 2 diabetes was similarly protective. Clusterin reproduced the beneficial effects of exercised sera. These data uncover the unexpected potential to preserve beta cell health by exercise training, opening a new avenue to prevent or slow diabetes progression through humoral muscle-beta cell crosstalk.


Small molecule activator of the human epithelial sodium channel.
The epithelial sodium channel (ENaC), a heterotrimeric complex composed of alpha, beta, and gamma subunits, belongs to the ENaC/degenerin family of ion channels and forms the principal route for apical Na(+) entry in many reabsorbing epithelia. Although high affinity ENaC blockers, including amiloride and derivatives, have been described, potent and specific small molecule ENaC activators have not been reported. Here we describe compound S3969 that fully and reversibly activates human ENaC (hENaC) in an amiloride-sensitive and dose-dependent manner in heterologous cells. Mechanistically, S3969 increases hENaC open probability through interactions requiring the extracellular domain of the beta subunit. hENaC activation by S3969 did not require cleavage by the furin protease, indicating that nonproteolyzed channels can be opened. Function of alphabetaG37Sgamma hENaC, a channel defective in gating that leads to the salt-wasting disease pseudohypoaldosteronism type I, was rescued by S3969. Small molecule activation of hENaC may find application in alleviating human disease, including pseudohypoaldosteronism type I, hypotension, and neonatal respiratory distress syndrome, when improved Na(+) flux across epithelial membranes is clinically desirable.


Chemical inhibition of DNA-PKcs impairs the activation and cytotoxicity of CD4+ helper and CD8+ effector T cells.
Modulation of T cell activity is an effective strategy for the treatment of autoimmune diseases, immune-related disorders and cancer. This highlights a critical need for the identification of proteins that regulate T cell function. The kinase DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is emerging as a potent regulator of the immune system, spurring interest in its use as a therapeutic target. In murine models of immune-related diseases including asthma and rheumatoid arthritis, treatment with small-molecule DNA-PKcs inhibitors decreased the disease severity. Additionally, DNA-PKcs inhibitors reduced T cell-mediated graft rejection in a murine allogenic skin graft model. These in vivo studies suggest the use of DNA-PKcs inhibitors as immunotherapy for autoimmune and T cell-mediated disorders. In this study, we sought to characterize further the effects of DNA-PKcs inhibitors on T cells to better understand their clinical potential. We determined that inhibition of DNA-PKcs using inhibitor NU7441 and the inhibitors currently in clinical trials for cancer therapy, M3184 and AZD7648, abrogated the activation of murine and human CD4+ and CD8+ T cells as evidenced by the reduced expression of the activation markers CD69 and CD25. Furthermore, inhibition of DNA-PKcs impeded metabolic pathways and the proliferation of activated T cells. This reduced the ability of OTI-CD8+ T cells to kill cancer cells and the expression of IFNγ and cytotoxic genes. These results highlight a critical role for DNA-PKcs in T cells and validate future studies using DNA-PKcs inhibitors as immune modulation therapy for the treatment of immune-related diseases.


EZ-IO in the ED: an observational, prospective study comparing flow rates with proximal and distal tibia intraosseous access in adults.
Intraosseous (IO) access is an important alternative to conventional intravenous access when intravenous access is difficult. A nonrandomized, prospective, observational study comparing flow rates with distal and proximal tibia IO access in adults using the EZ-IO-powered drill device. The proximal tibia was the first site of insertion, and a second IO was inserted in the distal tibia if clinically indicated. Intravenous saline infusion was started for all patients, initially without, then with a pressure bag device applied. From September 19, 2008 to November 3, 2010, 22 patients were recruited, with 20 proximal tibial and 22 distal tibia insertions. Two patients had only distal tibia IO insertions. Five distal tibia and 3 proximal tibia insertions had no flow when initiating normal saline infusion without pressure. Upon comparing the mean flow rates without pressure bag, it is significantly faster in the proximal tibia, 4.96 mL/min, compared with distal tibia, 2.07 ml/min, difference of 2.89 ml/min (95% CI 1.20-4.58). Flow rates with pressure bags also revealed a similar result. Flow rates in the proximal tibia were significantly faster, 7.70 ml/min to that of distal tibia, 3.80 ml/min, difference of 3.89 ml/min (95% CI 1.68-6.10). In both proximal and distal tibia groups, the flow rates are also significantly faster with pressure bags compared with without. Flow rates are significantly faster in the proximal tibia compared with the distal tibia. In addition, flow rates with pressure bags are significantly faster than without pressure bags in both groups.


A promising hypothesis of c-KIT methylation/ expression paradox in c-KIT (+) squamous cell carcinoma of uterine cervix ----- CTCF transcriptional repressor regulates c-KIT proto-oncogene expression.
We recently reported one interesting case showing mutation-free c-KIT proto-oncogene overexpression and paradoxical hypermethylation in 54 cases of primary squamous cell carcinoma of uterine cervix (SCC). However, its molecular mechanisms still remain unknown. We propose the hypothesis that increased methylation at the CpG islands on the promoter near the first exon region might interfere with the binding of CTCF repressor with c-KIT promoter that regulates c-KIT proto-oncogene expression in such case. Further studies focusing on the status of epigenetic modifications of mutation-free c-KIT (+) tumors are encouraged.


Leishmania braziliensis panamensis: increased infectivity resulting from heat shock.
Promastigotes of Leishmania braziliensis panamensis were subjected to a heat shock transformation yielding an amastigote-like stage. During the process of conversion, the heat-induced differentiating form displayed an increase in infectivity (as determined by lesion size) accompanied by a total protein composition unlike that of the promastigote and a morphology resembling that of the amastigote. These biological/functional changes may be related to an involvement of a heat shock response in the differentiation of leishmania, thus having important implications in the development of prevention and treatment stratagems.


Telomere length assessment and molecular characterization of TERT gene promoter in periampullary carcinomas.
Genetic and epigenetic alterations of the telomere maintenance machinery like telomere length and telomerase reverse transcriptase (encoded by TERT gene) are reported in several human malignancies. However, there is limited knowledge on the status of the telomere machinery in periampullary carcinomas (PAC) which are rare and heterogeneous groups of cancers arising from different anatomic sites around the ampulla of Vater. In the current study, we investigated the relative telomere length (RTL) and the most frequent genetic and epigenetic alterations in the TERT promoter in PAC and compared it with tumor-adjacent nonpathological duodenum (NDu). We found shorter RTLs (1.27 vs 1.33, P = 0.01) and lower TERT protein expression (p = 0.04) in PAC tissues as compared to the NDu. Although we did not find any mutation at two reactivating hotspot mutation sites of the TERT promoter, we detected polymorphism in 45% (9/20) of the cases at rs2853669 (T > C). Also, we found a hypermethylated region in the TERT promoter of PACs consisting of four CpGs (cg10896616 with Δβ 7%; cg02545192 with Δβ 9%; cg03323598 with Δβ 19%; and cg07285213 with Δβ 15%). In conclusion, we identified shorter telomeres with DNA hypermethylation in the TERT promoter region and lower TERT protein expression in PAC tissues. These results could be used further to investigate molecular pathology and develop theranostics for PAC.


Parameter and observation importance in modelling virus transport in saturated porous media-investigations in a homogenous system.
This paper evaluates the importance of seven types of parameters to virus transport: hydraulic conductivity, porosity, dispersivity, sorption rate and distribution coefficient (representing physical-chemical filtration), and in-solution and adsorbed inactivation (representing virus inactivation). The first three parameters relate to subsurface transport in general while the last four, the sorption rate, distribution coefficient, and in-solution and adsorbed inactivation rates, represent the interaction of viruses with the porous medium and their ability to persist. The importance of four types of observations to estimate the virus-transport parameters are evaluated: hydraulic heads, flow, temporal moments of conservative-transport concentrations, and virus concentrations. The evaluations are conducted using one- and two-dimensional homogeneous simulations, designed from published field experiments, and recently developed sensitivity-analysis methods. Sensitivity to the transport-simulation time-step size is used to evaluate the importance of numerical solution difficulties. Results suggest that hydraulic conductivity, porosity, and sorption are most important to virus-transport predictions. Most observation types provide substantial information about hydraulic conductivity and porosity; only virus-concentration observations provide information about sorption and inactivation. The observations are not sufficient to estimate these important parameters uniquely. Even with all observation types, there is extreme parameter correlation between porosity and hydraulic conductivity and between the sorption rate and in-solution inactivation. Parameter estimation was accomplished by fixing values of porosity and in-solution inactivation.


A rare case of partial absence of the right ventricular musculature in asymptomatic adult man: partial Uhl's anomaly.
Uhl's anomaly is a myocardial disorder of unknown cause that is characterized by complete or partial absence of the myocardium of the right ventricle. The disease may represent a cause of right heart dilatation and failure. Although most cases of Uhl's anomaly end fatally in infancy or childhood, an initial presentation during adulthood has been reported in rare cases. We report a very rare case of partial absence of the right ventricular musculature or partial Uhl's anomaly that incidentally found in asymptomatic adult man.


Pedicled external spermatic fascia flap for urethroplasty in hypospadias and closure of urethrocutaneous fistula.
To prevent the development of urethrocutaneous fistula after urethroplasty for hypospadias or recurrence after closure of a urethrocutaneous fistula, the authors developed a new simple technique wherein the readily available external spermatic fascia (ESF) surrounding the testis and cord is used as a pedicled blanket flap to cover the neourethra or the site of closure of a urethrocutaneous fistula. In three patients who had urethroplasty for hypospadias incorporating our ESF flap procedure, no urethrocutaneous fistula developed. It was also effective for closure of urethrocutaneous fistula in five patients, some of whom had had recurrent fistula formation.


'Unite and conquer': enhanced prediction of protein subcellular localization by integrating multiple specialized tools.
Knowing the subcellular location of proteins provides clues to their function as well as the interconnectivity of biological processes. Dozens of tools are available for predicting protein location in the eukaryotic cell. Each tool performs well on certain data sets, but their predictions often disagree for a given protein. Since the individual tools each have particular strengths, we set out to integrate them in a way that optimally exploits their potential. The method we present here is applicable to various subcellular locations, but tailored for predicting whether or not a protein is localized in mitochondria. Knowledge of the mitochondrial proteome is relevant to understanding the role of this organelle in global cellular processes. In order to develop a method for enhanced prediction of subcellular localization, we integrated the outputs of available localization prediction tools by several strategies, and tested the performance of each strategy with known mitochondrial proteins. The accuracy obtained (up to 92%) surpasses by far the individual tools. The method of integration proved crucial to the performance. For the prediction of mitochondrion-located proteins, integration via a two-layer decision tree clearly outperforms simpler methods, as it allows emphasis of biologically relevant features such as the mitochondrial targeting peptide and transmembrane domains. We developed an approach that enhances the prediction accuracy of mitochondrial proteins by uniting the strength of specialized tools. The combination of machine-learning based integration with biological expert knowledge leads to improved performance. This approach also alleviates the conundrum of how to choose between conflicting predictions. Our approach is easy to implement, and applicable to predicting subcellular locations other than mitochondria, as well as other biological features. For a trial of our approach, we provide a webservice for mitochondrial protein prediction (named YimLOC), which can be accessed through the AnaBench suite at http://anabench.bcm.umontreal.ca/anabench/. The source code is provided in the Additional File 2.


Influence of Hempseed Meal on Fresh Goat Meat Characteristics Stored in Vacuum Packaging.
The objective of this study was to determine the influence of hempseed meal (HSM) on goat meat characteristics. Goats (N = 10/treatment) were allocated to a diet concentration (0, 10, 20, or 30%) of HSM, fed for 60 days, and harvested. Carcass measurements were collected after chilling, and subsequently fabricated into wholesale subprimals. From the subprimals of the shoulder and leg, steaks were cut 2.54 cm thick, vacuum packaged, and assigned to laboratory methods: cook yield, instrumental color, lipid oxidation, microbial spoilage, and instrumental tenderness. HSM did not alter (p > 0.05) carcass characteristics, microbial spoilage, cook loss, or the thiobarbituric acid reactive substance (TBARS). However, a decrease in objective tenderness measurements (p < 0.05) was observed with greater concentrations of HSM supplementation in the diet. Instrumental surface color values for lightness (L*) indicated that steaks became lighter and less red (a*) as storage time increased (p < 0.05). Results suggest that HSM and storage time do not alter some goat meat traits, but HSM or storage time separately may influence goat meat quality. HSM may be an effective feed ingredient that does not alter carcass quality or meat yield.


Non-HDL-cholesterol to HDL-cholesterol ratio is a better predictor of new-onset non-alcoholic fatty liver disease than non-HDL-cholesterol: a cohort study.
The nonHDLc/HDLc ratio (in which nonHDLc is defined as total cholesterol minus HDLc) is positively associated with multiple dyslipidemia-related disorders. This study aimed to determine whether the nonHDLc/HDLc ratio is an independent predictor of new-onset NAFLD (non-alcoholic fatty liver disease) in Chinese population. A perspective cohort study consisting of 3374 Chinese adults without liver diseases or metabolic disturbances was performed. Anthropometric parameters and data of metabolic and plasma lipid profile were collected. Univariate and multivariate Cox proportional analyses were carried out to evaluate the association of the nonHDLc/HDLc ratio with incident NAFLD. ROC curve analysis was preformed to compare the predictive value between the nonHDLc/HDLc and the nonHDLc for NAFLD. Two thousand seven hundred seventeen participants were included in the final analysis. During a median follow-up period of 1.6 years, 264 participants (9.71%) developed NAFLD. After adjustment for potential confounders, a high nonHDLc/HDLc ratio (highest tertile) was associated with elevated risk of NAFLD (HR = 2.66; 95% CI, 1.13-6.24; P = 0.025 in female and HR = 2.11; 95% CI, 1.15-3.90; P = 0.016 in male). A nonlinear relationship was observed when the nonHDLc/HDLc ratio was ≤3.5. AUC values for nonHDLc/HDLc ratios (0.717 in female and 0.682 in male) were significantly higher than nonHDLc (0.675 in female and 0.653 in male) (P = 0.049 in female and P = 0.037 in male). In addition, the optimal cut-off value of nonHDLc/HDLc ratio for detection of NAFLD was 2.4 in female and 2.3 in male. The nonHDLc/HDLc ratio is an independent predictor of NAFLD and a stronger predictor than nonHDLc in Chinese population, which might be expected to better guide early identification of individuals at risk of NAFLD.


Molecular Mechanisms of Neuroplasticity: An Expanding Universe.
Biochemical processes in synapses and other neuronal compartments underlie neuroplasticity (functional and structural alterations in the brain enabling adaptation to the environment, learning, memory, as well as rehabilitation after brain injury). This basic molecular level of brain plasticity covers numerous specific proteins (enzymes, receptors, structural proteins, etc.) participating in many coordinated and interacting signal and metabolic processes, their modulation forming a molecular basis for brain plasticity. The articles in this issue are focused on different "hot points" in the research area of biochemical mechanisms supporting neuroplasticity.


The contribution of focus groups in the evaluation of hearing conservation program (HCP) effectiveness.
Exclusive reliance on such practices as policy review, audiometric testing audits, and noise surveillance to evaluate the effectiveness of workplace hearing conservation programs (HCP) fails to capture the impact of these programs as experienced by workers at the "shop floor" and offers little insight into the reasons and potential remedies for noted deficiencies. A qualitative approach for evaluating industrial HCPs (and their various components) is discussed using three industrial populations as case studies. For each study population, this paper illustrates how focus groups, comprised of line workers and supervisors, were used to clarify and augment information gathered through more traditional program assessments to provide a more enriched picture of hearing conservation practices. Descriptive data on plant hearing conservation program practices at each plant are presented with a comparison of proactive elements of each program relative to the Occupational Safety and Health Administration (OSHA) Hearing Conservation Amendment (HCA) requirement and to internal plant policy. Yearly program evaluation with input from all end-users is important in the process of hearing loss prevention. The qualitative assessment outlined in this paper serves as a basis for future quantitative assessments of HCP effectiveness using hearing threshold data and noise exposure assessments to examine changes in hearing levels as a function of noise exposure and other risk factors for hearing loss.


Radiation-induced lung injury.
Radiation therapy (RT) for thoracic-region tumors often causes lung injury. The incidence of lung toxicity depends on the method of assessment (eg, radiographs, patient's symptoms, or functional endpoints such as pulmonary function tests). Three-dimensional (3D) treatment planning tools provide dosimetric predictors for the risk of symptomatic RT-induced lung injury and allow for beams to be selected to minimize these risks. A variety of cytokines have been implicated as indicators/mediators of lung injury. Recent work suggests that injury-associated tissue hypoxia perpetuates further injury. Sophisticated planning/delivery methods, such as intensity modulation, plus radioprotectors such as amifostine, hold promise to reduce the incidence of RT-induced lung injury.


DEVELOPING AN OPERATIONAL DECISION RULE FOR IDENTIFYING THE FATAL CASE DOCUMENTS AT RISK OF BEING RETURNED THROUGH MATHEMATICAL MODELLING.
Incomplete or inaccurately filled fatal case documents are often returned to the hospital by higher headquarters, causing delay in the completion of procedural formalities. A mathematical model was developed to identify those fatal case documents which are at an increased risk of being returned so that the corrective action may be taken a priori. The data was subjected to a multiple logistic regression analysis. Diagnostic test characteristics were worked out and a Receiver Operating Curve analysis was done to find out optimum operating points on the slope, and the following mathematical rule was developed: 7.06=1 (if age > 50 years) - 4.5 (if age <= 12 years) + 9.88 (if serving person) + 2.75 (if ex-serviceman) + 4.5 (if dependent son or daughter) + 6.38 (if time lag > 10 days). This rule carries a sensitivity of 53 per cent and specificity of 75 per cent.


Long-term results after total wrist fusion.
Sixty-eight patients with seventy-one total wrist fusions were retrospectively reviewed with a mean follow-up of 11.7 years. The main purpose of this study was to determine long-term functional results and define possible reasons for remaining pain. Except one asymptomatic non-union, all wrist fusions united. The long-term functional result averaged 30 points using the DASH score and appears to be more favorable compared to midterm results in another publication from this department. Only 15 patients were completely free of pain. Most patients complained about remaining pain during strong activities with a mean VAS of 4/10 that could not further been defined on clinical or radiological examinations. Patients with more than two previous operations had a significant worse outcome concerning the modified Mayo wrist score [≤ 1 operation mean 61 points vs. ≥ 2 operations mean 56 points (Mann-Whitney U test: p = 0.009)] and PRWE-G [≤ 1 operation mean 27 points vs. ≥ 2 operations mean 37 points (t test: p = 0.047)] and furthermore a downward trend for worse DASH [≤ 1 operation mean 265 points vs. ≥ 2 operations mean 35 points (t test: p = 0.086)] results. Despite the loss of wrist motion and remaining pain, patients were highly satisfied with the long-term result and 93% would undergo the operation again.


Precise quantitation of 5alpha-reductase type 1 mRNA by RT-PCR in rat liver and its positive regulation by testosterone and dihydrotestosterone.
The liver is a multifunctional organ responsible for steroid hormones catabolism. Thus, the enzymes responsible for steroid catabolism are located in the liver, including the steroid 5alpha-Reductase (5alpha-R) (EC 220.127.116.11) which catalyzes the conversion of compounds with Delta(4,5) double bonds such as testosterone (T) into their respective reduced derivatives such as dihydrotestosterone (DHT), which are more hydrosoluble, therefore facilitating their excretion. We present precise measurements of mRNA levels of steroid 5alpha-Reductase type 1 isozyme (5alpha-R1) in the liver of male rats with different androgen status, using a quantitative RT-PCR coupled to laser-induced fluorescence capillary electrophoresis (LIF-CE). By means of this technique, we demonstrate a high level of expression of the gene that encodes 5alpha-R1 isozyme in male rat liver, and both T and DHT exert a positive control on the genetic expression of liver 5alpha-R1 isozyme. Since DHT does not contain a Delta(4,5) double bond, our results raise the possibility that hepatic 5alpha-R type 1 not only participates in the catabolism of steroids with Delta(4,5) double bonds, but also in other physiological functions, perhaps in the masculinization of the external genitalia in males with 5alpha-R type 2 gene deficiency.


[The influence of aconitum preparations on the development of chronic inflammation].
Experiments show that ethanol extracts prepared from the above-ground parts of Aconitum baicalensis and the above-ground parts and roots of Aconitum septentrionale L. suppressed the exudative and proliferative stages of model chronic inflammation. Both phytopreparations normalized some biochemical indices of the blood (total protein, seromucoids, firbinogen) altered by the inflammation.


[Polyethylene particles in synovial fluid after knee arthroplasty with a conventional or highly cross-linked polyethylene. Preliminary study].
In recent years cross-linked polyethylenes have been developed in an attempt to reduce the wear, as has been demonstrated in knee simulators. The aim is to assess, by counting particles of polyethylene in synovial fluid, whether the reduction in wear is confirmed in patients with a highly crosslinked polyethylene prosthesis. A prospective randomised study was designed. During the implantation of a knee prosthesis, one group of patients was assigned the use of a conventional polyethylene (group A), and the other group a highly crosslinked polyethylene (X3, Stryker Orthopaedics) (group B). At 12 months after surgery a knee arthrocentesis was performed, and the number of polyethylene particles was counted in a scanning electron microscopy. Fourteen samples from each group were studied. Both groups were comparable in all study variables. We found no significant differences in the concentration of polyethylene particles/ml (1.49 ± 0.85 million in group A vs 1.42 ± 0.91 million in group B, P=.60) or the total number of isolated particles. We found no differences either in size or morphology of particles between both groups. Although several in vitro studies in vitro using different types of highly crosslinked polyethylene found a significant reduction, we did not find that that wear was reduced in the knees of these patients. The great variability in the number of particles between individuals suggests that polyethylene wear in vivo depends on many factors, so perhaps the type of polyethylene is not the most significant factor.


CD4+ TIL to the Rescue of Anti-PD-1 Failure by Targeting MHC-II.
In this CCR Translations, we discuss the potential for tumor-infiltrating lymphocyte therapy to overcome immune checkpoint inhibitor resistance through CD4+-mediated and MHC-II-dependent killing. Validating these results from human tumors has potential to improve the clinical application of adoptive cellular transfer in advanced cancers. See related article by Draghi et al., p. 3937.


Accuracy of neck circumference for diagnosing overweight in six- and seven-year-old children.
To estimate the accuracy of neck circumference measurement as a method of diagnosing excess weight of six and seven-year-old children. 1026 six and seven-year-old children were included and anthropometric data were collected using cut-off points for the Body Mass Index (BMI) Z-score, in addition to the measurement of their neck circumference in centimeters. Pearson's correlation coefficient was used to assess the correlation between neck circumference and BMI. Sensitivity, specificity, positive and negative predictive values were calculated. The Receiver Operating Characteristic curve was used to measure the accuracy of neck circumference as a diagnostic method for excess weight. A positive linear correlation value was observed between neck circumference and BMI 0.572 (p<0.001). The accuracy value of the global ROC curve was 0.772 (p<0.001). Sensitivity and specificity showed low values, but high positive predictive values were observed, especially between measures of 30 and 31cm. Neck circumference showed accuracy of 77.2% as a diagnostic method for overweightness in six and seven-year-old children.


A pro-drug of zidovudine with enhanced efficacy against human immunodeficiency virus.
In an attempt to alleviate the drug-related toxicity of zidovudine in patients with AIDS, a pro-drug of zidovudine, 5'-[(1,4-dihydro-1-methyl-3-pyridinylcarbonyl)oxy]-3'-azido-2',3'- dideoxythymidine (DP-AZT), has been evaluated. Cellular uptake by H9 cells and peripheral blood lymphocytes (PBL) with zidovudine and DP-AZT showed at least a 50% greater intracellular concentration of DP-AZT within 2 hr. DP-AZT was significantly less toxic to murine bone marrow cells as measured by CFU-E assay. The ED50 concentration to inhibit the production of HIV specific p24 antigen was 0.05 microM for DP-AZT whereas zidovudine required 0.125 microM. These results demonstrated that DP-AZT has a higher therapeutic ratio than zidovudine as an anti-HIV-1 agent.


A logical framework to ballpoint ink dating interpretation.
Since its beginnings, the forensic field of questioned documents has been concerned with the dating of inks. Ink ageing processes follow complex paths. Disagreements about the feasibility of current methods have been voiced worldwide among the scientific and legal communities, This controversy has been the starting point of the present work. Its aim was that of evaluating the interpretation processes of such evidence, Subjective statistical data have been assigned from earlier works and illustrate the kind of data necessary to date ballpoint ink, and how to use it for this purpose. This work also suggests that the court and scientific requirements for standards of reliability are not yet fulfilled by actual ink dating methods for regulatory use in expert testimony.


Seminal Fluid and Mate Choice: New Predictions.
Recent evidence shows that seminal fluid can affect females and offspring independently of fertilisation in species lacking conventional 'nuptial gifts'. We argue that a hypothesis from paternal investment systems - that selection can favour changing female preferences that maximise both sperm-borne and seminal fluid-borne benefits - could therefore apply much more broadly.


Predictors of positive angiography in pelvic fractures: a prospective study.
Severe pelvic fractures continue to be a major problem for trauma surgeons. Early identification of patients who would benefit from therapeutic angiographic embolization (AE) of pelvic bleeding would be beneficial. We hope to identify simple risk factors that would pinpoint patients who would benefit from therapeutic AE. This is a prospective observational study at an academic Level I trauma center. All blunt trauma patients with a pelvic fracture admitted from December 2003 to February 2007 were included. AE was performed for hemodynamic instability (systolic blood pressure < 100 mmHg), fracture pattern (sacroiliac joint [SIJ] disruption, butterfly, open book), or CT demonstrating a large pelvic hematoma. AE was considered therapeutic if contrast extravasation was noted and addressed with embolization. Main outcomes measures were positive angiography and mortality. Stepwise logistic regression was performed to identify predictors of therapeutic AE. A predictive model was built based on these independent risk factors to estimate the probability of a therapeutic AE. One hundred thirty-seven (23%) of 603 patients with pelvic fractures had angiography. Therapeutic AE was performed in 85 patients (62%). Indications for angiography included hemodynamic instability (58%), fracture pattern (26%), and CT findings (9%). Nineteen patients (22%) with therapeutic AE had no hypotension or tachycardia. Independent predictors for therapeutic AE were SIJ disruption (odds ratio [OR]: 4.5; 95% CI, 1.6 to 12.6; p = 0.005), female gender (OR: 3.9; 95% CI, 1.5 to 10.0; p = 0.005), and duration (in minutes) of systolic blood pressure < 100 mmHg (OR: 1.4; 95% CI, 1.1 to 1.9; p = 0.007). Presence of SIJ disruption, female gender, and duration of hypotension can reliably predict patients who would benefit from AE. This predictive model can help early identification of patients who would benefit from pelvic angiography.


Studying the S-nitrosylation of model peptides and eNOS protein by mass spectrometry.
Oxidative addition of a nitric oxide (NO) molecule to the thiol group of cysteine residues is a physiologically important post-translational modification that has been implicated in several metabolic and pathophysiological events. Our previous studies have indicated that S-nitrosylation can result in the disruption of the endothelial NO synthase (eNOS) dimer. It has been suggested that for S-nitrosylation to occur, the cysteine residue must be flanked by hydrophilic residues either in the primary structure or in the spatial proximity through appropriate conformation. However, this hypothesis has not been confirmed. Thus, the objective of this study was to determine if the nature of the amino acid residues that flank the cysteine in the primary structure has a significant effect on the rate and/or specificity of S-nitrosylation. To accomplish this, we utilized several model peptides based on the eNOS protein sequence. Some of these peptides contained point mutations to allow for different combinations of amino acid properties (acidic, basic, and hydrophobic) around the cysteine residue. To ensure that the results obtained were not dependent on the nitrosylation procedure, several common S-nitrosylation techniques were used and S-nitrosylation followed by mass spectrometric detection. Our data indicated that all peptides independent of the amino acids surrounding the cysteine residue underwent rapid S-nitrosylation. Thus, there does not appear to be a profound effect of the primary sequence of adjacent amino acid residues on the rate of cysteine S-nitrosylation at least at the peptide levels. Finally, our studies using recombinant human eNOS confirm that Cys98 undergoes S-nitrosylation. Thus, our data validate the importance of Cys98 in regulating eNOS dimerization and activity, and the utility of mass spectroscopy to identify cysteine residues susceptible to S-nitrosoylation.


Flash spectroscopy of purple membrane.
Flash spectroscopy data were obtained for purple membrane fragments at pH 5, 7, and 9 for seven temperatures from 5 degrees to 35 degrees C, at the magic angle for actinic versus measuring beam polarizations, at fifteen wavelengths from 380 to 700 nm, and for about five decades of time from 1 microsecond to completion of the photocycle. Signal-to-noise ratios are as high as 500. Systematic errors involving beam geometries, light scattering, absorption flattening, photoselection, temperature fluctuations, partial dark adaptation of the sample, unwanted actinic effects, and cooperativity were eliminated, compensated for, or are shown to be irrelevant for the conclusions. Using nonlinear least squares techniques, all data at one temperature and one pH were fitted to sums of exponential decays, which is the form required if the system obeys conventional first-order kinetics. The rate constants obtained have well behaved Arrhenius plots. Analysis of the residual errors of the fitting shows that seven exponentials are required to fit the data to the accuracy of the noise level.


The SINTART 2 Study. A phase II non-randomised controlled trial of induction chemotherapy, photon-, proton- and carbon-ion-based radiotherapy integration in patients with locally advanced unresectable sinonasal tumours.
Unresectable, locally advanced sinonasal epithelial tumours are rare diseases with poor prognosis. Multimodal approach is widely used, although no standard therapy has been established in prospective trials. This study assessed activity and safety of an innovative integration of multimodality treatment-induction chemotherapy (ICT), surgery and radiotherapy (RT)-modulated by histology and response to ICT. Patients with untreated, unresectable sinonasal epithelial tumours with selected histotypes (squamous cell carcinoma, intestinal-type adenocarcinoma, sinonasal undifferentiated and neuroendocrine carcinoma, olfactory neuroblastoma) were enroled in a single-arm, open-label, phase II, multicentre clinical trial. Patients were treated with up to 5 ICT cycles, whose regimen was selected according to histotype. Photon and/or proton/carbon-ion-based RT was employed according to disease site, stage and ICT response. Primary end-point was 5-years progression-free survival (PFS), secondary end-points were overall survival (OS), ICT objective response rate per RECIST 1.1 and safety. Twenty-five patients were evaluable for primary end-point. Five-year PFS was 26.8% (95% confidence interval [CI]: 12.6-57.1), with a median PFS of 18 months. Five-year OS was 23.8% (95% CI: 9.5-59.3), with a median OS of 27 months. The overall response rate to ICT was 40%. Three-year PFS for patients achieving major volumetric partial response (mPRv) versus non-mPRv was 40% (95% CI: 13.7-100%) versus 23.1% (95% CI: 8.3-64.7%) (P = 0.318) and 3-year OS was 53.3% (95% CI: 21.4-100%) versus 37.7% (95% CI: 20.0-71.0%) (P = 0.114). Multimodal combination of ICT and innovative RT did not provide a significant improvement in survival rates with respect to previous experiences. This finding underscores the need for future research in this rare disease, still characterised by a heavy burden and poor prognosis. We observed longer survival in subjects achieving response to ICT. The overall treatment safety is acceptable.


Considerations for employing intersectionality in qualitative health research.
Intersectionality theory has recently emerged in the health sciences as a critical theoretical and methodical approach. Though some scholars have outlined explicit guidelines for applying intersectionality in research using quantitative methods, others have cited epistemological concerns and additive thinking to advocate for the analysis of intersectionality with qualitative methods. Thus, there remains a need for additional guidance and support for utilizing and applying intersectionality theory throughout the qualitative research process. With the goal of demystifying the process of utilizing intersectionality as a methodological approach in qualitative research in the health sciences, this paper provides researchers with recommendations, specific examples, and important considerations for incorporating intersectional approaches into study conceptualization, participant recruitment, data collection, and data analysis. Additionally, this paper reviews challenges that researchers may experience in conducting research using intersectional approaches and offers suggestions for overcoming challenges. This paper offers timely and relevant information that can be used to strengthen the theoretical and methodological rigor of qualitative health research, especially studies that seek to advance health equity.


ICU family support group sessions: family members' perceived benefits.
The purpose of this research was to identify the relationship between attending an ICU family support group and the family's appraisal of stress, social support, and hope. In addition, the family members' perceived benefits of attending an ICU family support family support group session does not significantly change stress levels, feelings of hope, and social support. Analysis of data reconfirms that family members of critically ill patients have a tremendous need for information. Although findings revealed that the majority of the family members who attended the support session would recommend attending again, it is unclear whether the support session method is the most beneficial and cost-effective means to support families of critically ill patients.


Treatment of Ipsilateral Distal Humerus and Diaphyseal Ulna Fractures by Using an Olecranon Osteotomy and Intramedullary Nail.
To evaluate the results of treatment of an osteotomy of the olecranon and an ulnar diaphyseal fracture with a single nail, in cases with an ipsilateral ulnar diaphyseal fracture and a comminuted fracture of the distal humerus. Retrospective clinical study. University-affiliated teaching hospital. Eight patients with comminuted fractures of the distal humerus and ipsilateral ulnar diaphyseal fractures were included. Using a transolecranon approach, internal fixation of the distal humeral fracture with medial and lateral plates was performed. The ulnar diaphyseal fracture and additional osteotomy were fixed using a locked intramedullary nail. Subjective pain assessment was performed by using a visual analog scale (VAS). There were 6 (75%) male and 2 (25%) female patients, with a mean age of 40.9 (range, 32-56) years. The mean follow-up period was 24.6 (range, 12-36) months. All patients achieved union of the ulnar diaphyseal fracture and olecranon osteotomy. Union of the distal humeral fracture was observed in 7 (87.5%) patients. The mean time to union was 16.3 (range, 12-22) weeks, mean visual analog scale score was 1.8 (range, 0-3), median elbow performance score was 85 (range, 70-95), and median disabilities of the arm, shoulder, and hand score was 17.9 (range, 5-45.8). Osteotomy of the olecranon and ulnar diaphyseal fracture using an intramedullary nail was a cosmetically advantageous and safe technique that enabled rehabilitation during the early postoperative period. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Cell surface glycoproteins of rabbit lymphocytes: characterization with monoclonal antibodies.
The structural characteristics of antigens recognized by a panel of monoclonal antibodies prepared against a rabbit T-lymphocyte cell line have been investigated. Those antigens which could be isolated using immunoadsorbents prepared from the monoclonal antibodies had mol. wts of 42,000, 90,000 and 120,000. The 42,000 mol. wt molecule is similar or identical to a rabbit class I major histocompatibility complex antigen and its characterization has been reported elsewhere. Three different 90,000 mol. wt proteins can be distinguished by their reactivity with lectins and by sequential immunoprecipitation. The 120,000 mol. wt protein is a very abundant surface glycoprotein that appears to be a specific marker for T-cells in the rabbit. It is the immunodominant antigen in a lentil lectin bound glycoprotein pool. Over half of the antibodies were directed against this antigen. All antigens detected by the panel of monoclonal antibodies have been detected on normal lymphoid cells.


Measuring informal workplace learning outcomes in residency training: a validation study.
Informal workplace learning (WPL) has no concrete learning objective and takes place without a responsible supervisor, which makes it difficult to assess its learning outcomes. Formal learning situations, as they are known from universities or schools, do not exist in this context and make a conventional assessment of learning goals and achievements impossible. Informal learning in the workplace is of central importance, and the assessment of informal learning outcomes in medical education is an under-researched area. The aim of our study was to adapt and validate an informal WPL questionnaire (originally developed for social workers) to assess learning outcomes due to informal WPL in residency training. A total of 528 residents (n = 339 female; age: M = 29.79; SD = 3.37 years) completed an adapted questionnaire on informal WPL outcomes and the Freiburg Questionnaire to Assess Competencies in Medicine (i.e. medical knowledge, communication, and scholarship). Exploratory factor analysis was used to determine the underlying factor structure. The reliability of the factors was tested using McDonald's omega, and the correlation between the factors and the three subscales of the Freiburg questionnaire was tested using Spearman's rho correlation coefficient. To investigate construct validity, a structural equation model was calculated to examine the relationships between medical competencies and informal learning outcomes. The exploratory factor analysis yielded a four-factor solution that best fit the data. The scores of all four factors (GLO-CD: generic learning outcomes-competence development, GLO-R: generic learning outcomes-reflection, JSLO: job-specific learning outcomes, and OLLO: organisational learning outcomes) showed good internal consistency (Ω ≥ .69). The structural equation model showed that "medical expertise" had an impact on all four factors of informal learning at work. "Scholarship" seemed to predict GLO-CD and GLO-R. Our four-factor model reveals meaningful determinants of informal WPL in relation to residency training. The instrument is therefore the first promising attempt to assess informal WPL in the broader context of medical education during residency, thus supporting its construct validity.


The effect of hyperglycemia and hypoglycemia on glucose transport and expression of glucose transporters in human lymphocytes B and T: an in vitro study.
Glucose transport in lymphocytes is regulated by many agents. It is interesting if only changing glucose concentrations in environment involves the impact on glucose uptake. The aims of this study were to investigate the impact of changing glucose concentrations in medium on deoxy-d-glucose uptake and what these conditions impact on the percent of cells with expression of chosen glucose transporters in human lymphocytes B and T. Isolated lymphocytes B and T obtained from healthy subject were cultivated in different concentrations of glucose. The experiments were carried out using tritium labeled deoxy-d-glucose and flow cytometry. In comparison to normoglycemia, hyperglycemia impairs the uptake of deoxy-d-glucose more than hypoglycemia. Lymphocytes B manifest significantly lower uptake of deoxy-d-glucose than lymphocytes T. Lymphocytes incubated in hyperglycemic and hypoglycemic medium show lower percent cells with expression of GLUT 1 and GLUT 3, and higher percent cells with expression of GLUT 4. The incubation of lymphocytes in hyperglycemic and hypoglycemic medium does not stimulate translocation of glucose transporters 3 and 4 to plasma membrane. Study shows that a change in concentration of glucose in incubation environment influence intracellular expression of glucose transporters in a significant part of lymphocytes B and T.


Clonal heterogeneity in curetted human epidermal cancers and precancers analysed by flow cytometry and compared with histology.
DNA frequency distributions analysed by single nuclei flow cytometry were studied in sixty-five curetted human epidermal tumours, i.e. five actinic keratoses (AK), seven Bowen's diseases (BO), nine squamous cell carcinomas (SCC), forty-three basal cell carcinomas (BCC) and one baso-squamous carcinoma (BSC). Seventy-five per cent (16/21) of the samples with squamous cell differentiation (AK, BO and SCC) showed features suggestive of more than one stem cell population, against 24% of the pure BCC samples (11/43). The DNA indices for the tumours, i.e. the ratio between the DNA content of the tumour stem cell line G1 cells and normal epidermis G1 cells were calculated. For BCC and SCC a preponderance was found for near-diploid and near-tetraploid cell clones. The precancerous lesions contained clones with more broadly scattered DNA indices. The fractions of cells in S and G2M and S + G2M phases were calculated for the samples with only one detectable stem cell population. For the squamous cell tumours and the nodular (but not the superficial) BCC, these fractions were significantly different from the unaffected skin of patients with multiple epidermal cancers. The usefulness of cell cycle fraction determinations for curetted tumours is discussed.


Cleavage of Ig-Hepta at a "SEA" module and at a conserved G protein-coupled receptor proteolytic site.
Ig-Hepta is a member of a new subfamily of the heptahelical receptors and has an unusually long N terminus extending toward the extracellular side of the plasma membrane. Pulse-chase experiments in 293T cells using antisera specifically recognizing its N- and C-terminal regions demonstrated that Ig-Hepta is core-glycosylated cotranslationally and proteolytically processed into a two-chain form in the endoplasmic reticulum, followed by maturation of oligosaccharide chains and dimerization. The cleavage occurs at two highly conserved sites: one in a "SEA" module (a module first identified in sperm protein, enterokinase, and agrin) near the N terminus and the other in the stalk region preceding the first transmembrane span, generating approximately 20-, 130-, and 32-kDa fragments. The latter two remain tightly associated non-covalently even after cleavage as revealed by immunoprecipitation of native and myc-tagged Ig-Hepta constructs that were transiently expressed in 293T cells. The dimer consisting of four chains, (130 kDa + 32 kDa)(2), is linked by disulfide bonds. A fusion protein of the extracellular domain of Ig-Hepta and the Fc domain of immunoglobulin was found to be a good substrate of the processing enzymes and used for determining the exact cleavage sites in the SEA module and juxtamembrane stalk region.


Efficacy of MER immunotherapy when added to a regimen of 5-fluorouracil and methyl-CCNU following resection for carcinoma of the large bowel. A Veterans Administration Surgical Oncology Group report.
Two hundred four patients with a microscopically incomplete resection for carcinoma of the colon or rectum were accepted for study. All patients were treated with 5-fluorouracil and methyl-CCNU beginning about the second postoperative week. Concurrent immunotherapy with the methanol extraction residue of bacillus Calmette-Guérin (MER) was randomly assigned to 103 patients. Treatment was continued as long as acceptable to the patient, and until clinical recurrence. Toxic reactions to the drug were not increased by the addition of MER, and seldom were severe enough to require the discrimination of therapy. No evidence of improved survival was seen in treated patients. On the contrary, survival in patients who experienced severe reactions to treatment may have been impaired by MER, with the period of impairment continuing after all adjuvant therapy was stopped. Similar proportions of treated and control deaths were attributable to residual or recurrent disease.


Myeloperoxidase-catalyzed iodination and coupling.
Myeloperoxidase (MPO), which displays considerable amino acid sequence homology with thyroid peroxidase (TPO) and lactoperoxidase (LPO), was tested for its ability to catalyze iodination of thyroglobulin and coupling of two diiodotyrosyl residues within thyroglobulin to form thyroxine. After 1 min of incubation in a system containing goiter thyroglobulin, I-, and H2O2, the pH optimum of MPO-catalyzed iodination was markedly acidic (approximately 4.0), compared to LPO (approximately 5.4) and TPO (approximately 6.6). The presence of 0.1 N Cl- or Br- shifted the pH optimum for MPO to about 5.4 but had little or no effect on TPO- or LPO-catalyzed iodination. At pH 5.4, 0.1 N Cl- and 0.1 N Br- had a marked stimulatory effect on MPO-catalyzed iodination. At pH 4.0, however, iodinating activity of MPO was almost completely inhibited by 0.1 N Cl- or Br-. Inhibition of chlorinating activity of MPO by Cl- at pH 4.0 has been previously described. When iodination of goiter thyroglobulin was performed with MPO plus the H2O2 generating system, glucose-glucose oxidase, at pH 7.0, the iodinating activity was markedly increased by 0.1 N Cl-. Under these conditions iodination and thyroxine formation were comparable to values observed with TPO. MPO and TPO were also compared for coupling activity in a system that measures coupling of diiodotyrosyl residues in thyroglobulin in the absence of iodination. MPO displayed very significant coupling activity, and, like TPO, this activity was stimulated by a low concentration of free diiodotyrosine (1 microM). The thioureylene drugs, propylthiouracil and methimazole, inhibited MPO-catalyzed iodination both reversibly and irreversibly, in a manner similar to that previously described for TPO-catalyzed iodination.


Movement of developmentally disabled individuals among out-of-home residential facilities.
This paper reported on the movement of a large (N = 2271) probability sample of the nation's residents of public (PRF) and community (CRF) residential facilities for developmentally disabled children and adults. Estimates placed the national population at 217,410 in all facilities--73,709 in CRFs and 143,701 in PRFs--in the fall of 1978, when the sample was selected, although extrapolation from subsequent surveys suggest that the CRF numbers should be about 100,000. In the winter of 1979 direct care staff and administrators completed detailed information about each resident sampled, about themselves, and about their facilities. In 1980 they were asked if their residents had moved exactly one year later. Most residents (91%) had not moved; 1.3% had died; and about 8.5% had moved. Most moves featured greater integration into the community. Multivariate analyses indicated very little difference between moved and unmoved residents. Among moved subjects, three dimensions accounted for 62% of the common variance in placement status: (a) ability, (b) age, and (c) autonomy.


A convenient method for synthesis of cyclic peptide libraries.
Cyclic peptides have been reported to bind to multiple, unrelated classes of receptor with high affinity. Owing to the robustness of amide bond chemistry, the ability to explore extensive chemical diversity by incorporation of unnatural and natural amino acids, and the ability to explore conformational diversity, through the incorporation of various constraints, arrays of cyclic peptides can be tailored to broadly sample chemical diversity. We describe the combination of a safety catch linker with a directed-sorted procedure for the synthesis of large arrays of diverse cyclic peptides for high-throughput screening.


Elongated styloid process: an overview.
Stylalgia is a condition that causes a dull, nagging pain in the oropharynx, often referred to the ear and the mastoid region. The clinical diagnosis is certain if the elongated styloid process is palpated through the tonsillar area. Radiological investigations, such as orthopantomograms, give information about the medial angulation. The treatment of choice is surgical shortening of the process. Trans-tonsillar fossa excision is a simple technique and does not involve greater morbidity than a routine tonsillectomy.


Molecular diagnosis of X-linked chronic granulomatous disease in Iran.
Chronic granulomatous disease (CGD) is an inherited disorder of pathogen killing by phagocytic leukocytes caused by mutations in NADPH oxidase subunits. Patients with CGD have life-threatening bacterial and fungal infections. Children's Medical Center at Tehran University is the referral center for immunodeficiency in Iran. During 2 years of study, 11 non-consanguineous families with clinically diagnosed CGD were referred to this center. In functional assays performed on neutrophils from affected children and their mothers; no activity or strongly decreased oxidase activity was detected in the patients' cells. In oxidase tests that scored this activity on a per-cell basis, a mosaic pattern was detected in the neutrophils from all 11 mothers. Western blot analysis revealed an X91 degrees phenotype in all patients. Mutation screening in the CYBB gene encoding gp91(phox) by SSCP analysis followed by sequencing showed nine different mutations, including two novel mutations. The present survey is the first study aimed to analyze the clinical features and the molecular diagnosis of X-CGD in Iranian patients.


Targeted rapid amplification of cDNA ends (T-RACE)--an improved RACE reaction through degradation of non-target sequences.
Amplification of the 5' ends of cDNA, although simple in theory, can often be difficult to achieve. We describe a novel method for the specific amplification of cDNA ends. An oligo-dT adapter incorporating a dUTP-containing PCR primer primes first-strand cDNA synthesis incorporating dUTP. Using the Cap finder approach, another distinct dUTP containing adapter is added to the 3' end of the newly synthesized cDNA. Second-strand synthesis incorporating dUTP is achieved by PCR, using dUTP-containing primers complimentary to the adapter sequences incorporated in the cDNA ends. The double-stranded cDNA-containing dUTP serves as a universal template for the specific amplification of the 3' or 5' end of any gene. To amplify the ends of cDNA, asymmetric PCR is performed using a single gene-specific primer and standard dNTPs. The asymmetric PCR product is purified and non-target transcripts containing dUTP degraded by Uracil DNA glycosylase, leaving only those transcripts produced during the asymmetric PCR. Subsequent PCR using a nested gene-specific primer and the 3' or 5' T-RACE primer results in specific amplification of cDNA ends. This method can be used to specifically amplify the 3' and 5' ends of numerous cDNAs from a single cDNA synthesis reaction.


Prediction of coronary heart disease based on combined reinforcement multitask progressive time-series networks.
Coronary heart disease is the first killer of human health. At present, the most widely used approach of coronary heart disease diagnosis is coronary angiography, a surgery that could potentially cause some physical damage to the patients, together with some complications and adverse reactions. Furthermore, coronary angiography is expensive thus cannot be widely used in under development country. On the other hand, the heart color Doppler echocardiography report, blood biochemical indicators and personal information, such as gender, age and diabetes, can reflect the degree of heart damage in patients to some extent. This paper proposes a combined reinforcement multitask progressive time-series networks (CRMPTN) model to predict the grade of coronary heart disease through heart color Doppler echocardiography report, blood biochemical indicators and ten basic body information items about the patients. In this model, the first step is to perform deep reinforcement learning (DRL) pre-training through asynchronous advantage actor-critic (A3C). Training data is adopted to optimize the recurrent neural network (RNN) that parameterizes the stochastic policy. In the second step, soft parameter sharing module, hard parameter sharing module and progressive time-series networks are used to predict the status of coronary heart disease. The experimental results show that after DRL pre-training, the multiple tasks in the model interact with each other and learn together to achieve satisfactory results and outperform other state-of-the-art methods.


One hundred years of cancer immunotherapy: a critical appraisal.
First attempts of cancer immunotherapy were made approximately 100 years ago on the assumption that tumor cells are recognized as 'foreign' by the immune system. Later on, a whole series of experimental animal tumor models were developed. They included the use of syngeneic tumors, spontaneously arising tumors and human tumor xenografts in immunodeficient mice. The experimental data contributed to our understanding of the interaction between immunocompetent cells and their products on the one hand and tumor cells on the other. On this basis, various immunotherapeutic protocols have been devised which included the use of 'nonspecific' components such as bacterial adjuvants, cytokines, NK cells and macrophages and attempts were made to raise specific T and B cell responses against tumor cells. Many human tumor-associated antigens have been characterized, and various ways of increasing the immunogenicity of human tumor cells have been described. Moreover, more insight has been achieved in defining 'high risk' populations on the basis of genetic background, the role of environmental factors and the characterization of 'precancerous' cells. Some cancer vaccines have been used in clinical trials which have resulted in partially beneficial therapeutic effects but have not provided a full solution for a rational use of immunotherapy against human neoplasia.


Comparison of human papillomavirus infection and cervical cytology in women using copper-containing and levonorgestrel-containing intrauterine devices.
To investigate whether there is a difference in cervical cytology and high-risk human papillomavirus (HPV) infection clearance between levonorgestrel- and copper-containing intrauterine device (IUD) users. The electronic medical record system was searched by the appropriate procedural code for IUD insertion for all patients undergoing IUD placement during the study period (January 31, 2005 to January 31, 2012). Patients who received treatment for cervical dysplasia, had their IUDs removed, or conceived during the study period were excluded. High-risk HPV and cervical cytology results immediately preceding and after IUD placement were obtained. One hundred fifty patients had a copper-containing and 152 patients a levonorgestrel-containing IUD placed. The groups were comparable in terms of age, body mass index, duration of follow-up, and percentage of smokers. Sixty-six patients were high-risk HPV-positive before IUD insertion (30 in copper compared with 36 in the levonorgestrel IUD group, P=.4), and the groups had similar follow-up times (364.1±26.3 compared with 357.2±29.7 days, respectively, between the IUD placement and a repeat Pap test with high-risk HPV cotesting, P=.2). Of those, 21 (70%; 95% confidence interval [CI] 53.6-86.4%) cleared the infection after copper-containing IUD placement compared with 15 (42%; 95% CI 25.6-57.8%) in the levonorgestrel group (P=.04). There were only two (1.7%) new high-risk HPV infections in the copper compared with eight (6.9%) in the levonorgestrel group (P=.056). Our data suggest that levonorgestrel-containing IUD could be associated with decreased high-risk HPV infection clearance and possibly increased acquisition compared with the copper-containing IUD. II.


Arterial spin labelling: final steps to make it a clinical reality.
Since its inception in the early 1990s, arterial spin labelling (ASL) has been developed in numerous variants. Tremendous improvements in both pulse sequences and hardware have allowed improved image quality and reduced scan time, to the point where the technique might be ready for clinical application. However, although now routinely used in research centres and universities, its application in daily clinical routine remains restricted to a few centres. Its popularity in magnetic resonance imaging (MRI) research centres and among physicists may have contributed to the lack of enthusiasm from the clinical community, as the variety of possible sequences available might deter even the most die-hard technology-driven neuroradiologist from using this technique. Therefore, a joint action directed towards the harmonisation of all the existing ASL pulse sequences and the development of a reliable and common post-processing pipeline to provide guidance for the major MRI manufacturers was recently endeavoured and dubbed the 'ASL Network' ( http://www.asl-network.org ). This network was established to provide a communication platform among physicists, engineers and clinicians who are keen to see this technique finally make it to daily clinical practice. Finally, a networking European Grant from the COST Office was secured to help fund some of the activities of the ASL Network, in particular as they pertain to the application of ASL in dementia ( http://www.cost.eu/domains_actions/bmbs/Actions/BM1103 ). Here, both the ASL Network and the COST Action are described, with their respective goals and aspirations.


Predictive Value of [18F]ML-10 PET/CT in Early Response Evaluation of Combination Radiotherapy with Cetuximab on Nasopharyngeal Carcinoma.
Apoptosis may be an indication of success therapy, and precise detection of apoptosis can provide instructional suggestions in the therapy management of malignant tumors. We used CNE-1 cell lines for in vitro experiments, and colony formation assay, CCK-8 assay, cell apoptosis analysis, and western blotting were performed. For in vivo experiments, subcutaneous xenotransplanted tumor models of CNE-1 in nude mice were established. Then, small animal positron emission tomography/X-ray computed tomography (PET/CT) images were acquired by tail intravenous injection of 2-(5-[18F]fluoropentyl)-2-methyl-malonic acid ([18F]ML-10) or 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) before and 24 h and 48 h after treatment. Moreover, expression of epidermal growth factor receptor (EGFR), Ki-67, Glut-1, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) was examined by immunohistochemical examination. Tumor volumes of mice were recorded every 2 days. In the presence of Cetuximab, the number of colonies of CNE-1 cells decreased significantly after irradiation at 1 and 2 Gy. In addition, Cetuximab increased the radiation-induced cytotoxicity and apoptosis of CNE-1 cells. Mechanistic studies demonstrated that Cetuximab enhanced radiosensitivity by suppressing the EGFR/PI3-K/AKT pathway. In PET/CT imaging, the tumors showed clear uptake of [18F]ML-10 at 24 h and 48 h after combined treatment, and the value of tumor/muscle (T/M) and SUVmax (the max of standard uptake value) was significantly higher than those of the other three groups. The T/M of [18F]ML-10 uptake showed a positive correlation of 0.926 with the apoptosis index (P < 0.001). However, the uptake of [18F]FDG in tumors exhibited no trend among the four groups. The T/M of [18F]FDG revealed a positive correlation of 0.926 with Glut-1 intensity (P < 0.001). Our work revealed that Cetuximab could increase the radiosensitivity of CNE-1 cells both in vitro and in vivo. Apoptosis imaging with [18F]ML-10 PET/CT is a promising modality for application in the response prediction of nasopharyngeal carcinoma.


Weak observer-level correlation and strong stimulus-level correlation between the McGurk effect and audiovisual speech-in-noise: A causal inference explanation.
The McGurk effect is a widely used measure of multisensory integration during speech perception. Two observations have raised questions about the validity of the effect as a tool for understanding speech perception. First, there is high variability in perception of the McGurk effect across different stimuli and observers. Second, across observers there is low correlation between McGurk susceptibility and recognition of visual speech paired with auditory speech-in-noise, another common measure of multisensory integration. Using the framework of the causal inference of multisensory speech (CIMS) model, we explored the relationship between the McGurk effect, syllable perception, and sentence perception in seven experiments with a total of 296 different participants. Perceptual reports revealed a relationship between the efficacy of different McGurk stimuli created from the same talker and perception of the auditory component of the McGurk stimuli presented in isolation, both with and without added noise. The CIMS model explained this strong stimulus-level correlation using the principles of noisy sensory encoding followed by optimal cue combination within a common representational space across speech types. Because the McGurk effect (but not speech-in-noise) requires the resolution of conflicting cues between modalities, there is an additional source of individual variability that can explain the weak observer-level correlation between McGurk and noisy speech. Power calculations show that detecting this weak correlation requires studies with many more participants than those conducted to-date. Perception of the McGurk effect and other types of speech can be explained by a common theoretical framework that includes causal inference, suggesting that the McGurk effect is a valid and useful experimental tool.


Carboxyhemoglobin levels in medical intensive care patients: a retrospective, observational study.
Critical illness leads to increased endogenous production of carbon monoxide (CO) due to the induction of the stress-response enzyme, heme oxygenase-1 (HO-1). There is evidence for the cytoprotective and anti-inflammatory effects of CO based on animal studies. In critically ill patients after cardiothoracic surgery, low minimum and high maximum carboxyhemoglobin (COHb) levels were shown to be associated with increased mortality, which suggests that there is an 'optimal range' for HO-1 activity. Our study aimed to test whether this relationship between COHb and outcome exists in non-surgical ICU patients. We conducted a retrospective, observational study in a medical ICU at a university hospital in Vienna, Austria involving 868 critically ill patients. No interventions were undertaken. Arterial COHb was measured on admission and during the course of treatment in the ICU. The association between arterial COHb levels and ICU mortality was evaluated using bivariate tests and a logistic regression model. Minimum COHb levels were slightly lower in non-survivors compared to survivors (0.9%, 0.7% to 1.2% versus 1.2%, 0.9% to 1.5%; P=0.0001), and the average COHb levels were marginally lower in non-survivors compared to survivors (1.5%, 1.2% to 1.8% versus 1.6%, 1.4% to 1.9%, P=0.003). The multivariate logistic regression analysis revealed that the association between a low minimum COHb level and increased mortality was independent of the severity of illness and the type of organ failure. Critically ill patients surviving the admission to a medical ICU had slightly higher minimum and marginally higher average COHb levels when compared to non-survivors. Even though the observed differences are statistically significant, the minute margins would not qualify COHb as a predictive marker for ICU mortality.


Trends, Predictors, and Outcomes Associated With 30-Day Hospital Readmissions After Percutaneous Coronary Intervention in a High-Volume Center Predominantly Using Radial Vascular Access.
Patients undergoing percutaneous coronary intervention (PCI) are at high-risk for hospital readmission. We examined the rate, factors associated with, and outcomes of 30-day readmissions for patients who underwent a PCI. We reviewed medical records of all patients who underwent PCI between 2011 and 2014 at a central New England radial first, tertiary care center. Data was collected on occurrence and cause of readmission as well as patients' bleeding events and survival at one year. Logistic regression was used to examine factors associated with 30-day readmission as well as its association with bleeding and all-cause mortality. A total of 3858 patients were studied (mean age = 62.8 years with 26.1% women), among whom 348 (9.5%) patients were readmitted within 30-days. Cardiac causes of readmission represented 62% of all readmissions. In the multi-variable adjusted regression model, factors that were significantly associated with 30-day readmission included female gender, prior coronary bypass surgery, acute coronary syndrome, anemia, length of stay, and delay in initial presentation. Patients who were readmitted had more than twice the risk of bleeding and mortality at one year as compared to those who were not readmitted within 30 days. In conclusion, our results suggest that early hospital readmission after undergoing PCI is common and has not changed in recent years. Efforts should be made to identify and closely monitor patients who are at risk for readmission after PCI.


Extracellular Hsp90α Clinically Correlates with Tumor Malignancy and Promotes Migration and Invasion in Esophageal Squamous Cell Carcinoma [Retraction].
[This retracts the article DOI: 10.2147/OTT.S195529.].


Health literacy in dietary supplement use among working-age groups: systematic review and meta-analysis.
Globally, dietary supplement use (DSU) is very popular against COVID19. This study aims to investigate the characteristics of research on health literacy (HL) in DSU and compare HL among working-age groups by reviewing related research between 2011 and 2021 in PubMed, SCOPUS, ClinicalKey, Google Scholar and ThaiJO. Twenty-five articles that met the inclusion criteria were selected for study and analyzed using Cohen's d. The results showed that HL affected dietary supplement (DS) consumption behavior among working-age groups with an average effect size of 0.423 (95% CI = 0.249-0.598), followed by disclosure of DSU with an average effect size of 0.220 (95% CI = 0.087-0.353). No effect was found on awareness of dietary supplement advertisements. The discovery of such knowledge is a significant contribution to public health, leading to the development of interventions and policies for enhancing HL in DSU e.g. organizing knowledge-sharing workshops on DSU and building support networks across all sectors.


Enhanced apoptosis by a novel gene, Bak-like, that lacks the BH3 domain.
In a variety of physiological settings, cells are eliminated by apoptosis-a genetically encoded process of cellular suicide. Bak, a member of the Bcl-2 protein family, accelerates apoptosis by an unknown mechanism. We have found a novel cDNA encoding a 101-amino acid protein that possesses a Bak-like sequence in our full-length cDNA bank and termed it Bak-like. This protein shares the conserved domains BH1 and BH2 with other pro-apoptotic proteins, but lacks the BH3 domain. Database searches identified this gene on chromosome 6, which could account for the cloned bak and bak-like transcripts by alternative splicing. Bak-like is expressed in a wide variety of tissues. Bak-like is different from bak by Southern blots using probes with or without homology to bak. Despite the loss of the BH3 sequence, bak-like did enhance apoptosis, but was less potent than bak. Confocal microscopy of HeLa cells revealed that EGFP-Bak-like was located diffusely throughout the cytosol. However, upon induction of apoptosis, EGFP-Bak-like redistributed into a punctuate pattern, colocalizing with mitochondria. Like bak, the bak-like gene product directly enhanced apoptotic cell death following an appropriate stimulus.


A systematic review of upper extremity responses during reactive balance perturbations in aging.
Balance responses to perturbations often involve the arms in an attempt to either restore balance or protect against impact. Although a majority of research has been dedicated to understanding age-related changes in lower limb balance responses, there is a growing body of evidence supporting age-related changes in arm responses. This systematic review aimed to summarize differences in arm responses between older and younger adults under conditions requiring counterbalancing, reaching to grasping, and protection against impact. Following a systematic review and critical appraisal of the literature, data regarding the arm response in studies comparing young and older adults was extracted. The resulting articles were also assessed for quality to determine risk of bias. Fifteen high quality studies were identified. The majority of these studies reported delayed onsets in muscle activation, differences in arm movement strategies, delayed movement timing, increased impact forces, and greater grasp errors in older compared to young adults. These differences were also identified under varied visual and cognitive conditions. The studies included in this review demonstrate age-related differences in arm responses regardless of the direction and nature of the perturbation. These differences could provide insight into developing more targeted rehabilitation and fall prevention strategies. More research is needed to assess whether the identified age-related differences are a necessary compensation or a contributory factor to balance impairments and fall risk in older adults.


Effects of age on noninvasive assessments of vascular function in nonhuman primates: implications for translational drug discovery.
Endothelium-dependent flow mediated dilation (FMD) and pulse-wave velocity (PWV), are used as measures of vascular health and predictors of cardiovascular risk in clinical studies, and both are age-dependent. Numbers of circulating endothelial microparticles (EMPs) and endothelial progenitor cells (EPCs) are also associated with cardiovascular risk, but independent of age in humans. The use of these measurements for pre-clinical assessment of drug cardiovascular safety and efficacy in non-human primates (NHPs) may promote the translation of drug-induced effects on vascular function to clinic outcomes. However, in NHPs, the age effects on the non-invasive measurements of FMD and PWV and the relationship of EMPs/EPCs with FMD are unknown. A non-invasive, clinically-relevant approach to assess FMD and PWV was used to examine their relationship with age and with EMPs/EPCs in NHPs. The effects on FMD of nicotine and rosiglitazone were evaluated in senescent primates in an effort to validate our FMD method for pre-clinical assessment of vascular function. FMD and PWV methods were established in a colony (n = 25) of metabolically healthy, cynomolgus monkeys ranging in age from 6 to 26 years. FMD, defined as the percent change, at 1 min of cuff release, from baseline vascular diameter (0.15 ± 0.03 cm), had a strong, negative correlation with age (r = -0.892, p < 0.0001), ranging from 6% to 33%. PWV positively correlated with age (r = 0.622, p < 0.002) in the same healthy monkeys. Nicotine and rosiglitazone, were evaluated in subsets of senescent primates (mean age 16.3 ± 1.5[SEM] years). Rosiglitazone significantly improved FMD (21.0 ± 1.6% vs. vehicle 16.3 ± 1.6%, p < 0.01) without changing baseline diameters, and coincided with a significant increase in circulating numbers of endothelial progenitor cells (CD45-CD31 + CD34 + VEGFR2+ 7.1 ± 1.3 vs. 4.8 ± 1.1 counts/μl) and a decrease in endothelial microparticles (CD45-CD42a-CD54+ 26.7 ± 11.1 vs. 62.2 ± 9.8 counts/μl)(p < 0.05). Conversely, FMD was significantly reduced with nicotine (8.7 ± 1.4% vs. vehicle 20.1 ± 2.2%, p < 0.05). Adult NHPs demonstrate the characteristic linear relationship between age and vascular function using the non-invasive clinically-related measurements of FMD and PWV. However, numbers of circulating EMPs and EPCs did not correlate with age. Endothelial function assessed with FMD, together with EMPs/EPCs assessment, may serve as a novel approach for translational research and therapeutic discovery. Age should be considered in the study design or data analyses when FMD or PWV is used in NHPs.


A disposable gold foil paper-based aptasensor for detection of enteropathogenic Escherichia coli with SERS analysis and magnetic separation technology.
Rapid and sensitive detection of enteropathogenic Escherichia coli (EPEC) in fluids with complex background is an important task for safety quality control in the field of medicine, environment, and food. In this study, a gold foil paper-based aptasensor was developed for the detection of enteropathogenic EPEC O26:K60 with surface-enhanced Raman spectroscopy (SERS) and magnetic separation technology mediated by Fe3O4@Au composite. The gold foil paper was firstly modified with thiolated capture probe and SERS tag. The thiolated aptamer probe for EPEC was immobilized onto a Fe3O4@Au composite. In the presence of EPEC, highly specific recognition between the aptamer probe and EPEC made the Fe3O4@Au composite partially dissociated from the gold foil paper. This led to a decreased Raman intensity response, which showed an obvious negative linear correlation with increasing concentration of EPEC over a wide concentration range from 10 to 107 CFU/mL under an excitation wavelength of 633 nm. The detection limit was about 2.86 CFU/mL in a buffer solution and a licorice extractum and the detection time was only 2.5 h. The results demonstrate that the gold foil paper-based aptasensor can be an excellent biosensing platform that offers a reliable, rapid, and sensitive alternative for EPEC detection.


Complete response of esophageal cancer achieved by combination therapy with 5-fluorouracil, low-dose cisplatin, and radiation: report of a case.
To improve the survival rate of patients with esophageal cancer, several protocols of a preoperative combination of chemotherapy and radiotherapy, known as chemoradiation therapy, have been developed, recently characterized by the combination of 5-fluorouracil (5-FU), cisplatin, and radiation. Although some of these combinations have been demonstrated to be effective, the optimal chemoradiation dose and schedule are not yet precisely established. Recent investigations have elucidated that the radiosensitizing effects of cisplatin are able to be achieved more effectively by the daily administration of cisplatin before each fraction of radiation. Based on these investigations, we report herein the case of a patient with esophageal cancer with direct invasion to the trachea, in whom a complete response was achieved by the continuous administration of 5-FU, 600 mg/m2 per day, from days 1-5 combined with the daily administration of low-dose cisplatin, 10 mg/m2 per day before each fraction of radiation, given as 2Gy each time, throughout the entire treatment period of 3 weeks beginning on day 1. The benefits of our preoperative chemoradiation therapy included no severe side effects, down-staging and resectability of the tumor, as well as a pathological complete response, which could prolong the survival time. Our experience of this case prompts us to recommend the concurrent daily preoperative chemoradiation therapy for patients with locally advanced esophageal cancer.


Reproductive investiment in the scorpion Centruroides vittatus.
Among invertebrates, scorpions possess a relatively unique set of reproductive traits. The interrelationships of these traits may have important implications for life history theory, yet there have been few studies of these traits in scorpions. Our data indicate that larger female Centruroides vittatus produce more offspring and have a higher total litter mass than smaller females. There was, however, no significant relationship between offspring size and female or litter size. Mean offspring mass increased with increases in total litter mass and within litter variation in offspring size (coefficients of variation) decreased with increasing total litter mass. These results suggest that large female scorpions with a larger investment in reproduction produced more offspring that were more uniform in size, but not significantly larger, than small females with less investment. The fractional clutch principle and physiological and functional constraints on size and number of offspring are suggested as possible explanations for the relationships we found among offspring size, variation in offspring size and total investment in offspring in C. vittatus.


Thymus gland involution induced by lithium chloride.
Chronic treatment with lithium chloride produced significant involution of the thymus gland with histological evidence of reduced cellularity due to loss of thymic lymphocytes and a significant reduction in the weight of the gland in normal and adrenalectomized mice. Lithium also increased corticosterone levels in normal mice without changes in adrenal weights. The involution of the thymus gland is most likely due to an effect of lithium on the gland, and it is not mediated by adrenocortical mechanisms or stress.


Colorectal Cancer in Octogenarian and Nonagenarian Patients: Clinicopathological Features and Survivals.
Elderly population will comprise a substantial proportion of colorectal cancer (CRC) patients. We examined patients older than 80 years according to their clinical and pathological characteristics to fully understand the elderly patients. CRC patients, 60 years or older at diagnosis, admitted between 2009 and 2014 at our hospital were enrolled. The patients were divided into 2 groups: elderly (aged > 80 years, n = 133), and controls (aged 60 to 79 years, n = 596). Patient's demographics, risk factors for prognosis of CRC, Clinicopathological parameters, treatment, and survival rates were compared. The mean ages were 83.9 and 64.8 years, respectively. Male-to-female ratio and tumor sidedness were comparable in both groups. Prognostic factors found in univariate analysis; differentiation, stage, lymphovascular invasion, and carcinoembryonic antigen showed no statistical difference. The microsatellite instability status and number of retrieved lymph nodes were also similar (17.2 vs 21.6, P = 0.505). A significant difference was found in the treatment approach for chemotherapy as the elderly patients with stage III and IV tend to have omitted adjuvant (43.6% vs. 92.8%, P < 0.001) or palliative (35.8% vs. 89.4%, P = 0.016) chemotherapy. Except in stage I, elderly patients showed significantly lower overall survival rates. Current study shows far-elderly patients with CRC were less likely to receive standard treatments, which might have resulted in an inferior outcome. As the number of elderly patients with CRC increase, our results provide a basis for further clinical and molecular investigations of elderly CRC patients.