Facile synthesis of ultrathin Ni-MOF nanobelts for high-efficiency determination of glucose in human serum.
Ultrathin Ni-MOF nanobelts, [Ni20(C5H6O4)20(H2O)8]·40H2O(Ni-MIL-77 NBs), were synthesized by a facile one-pot solution process and can be used as an efficient catalyst electrode for glucose oxidation under alkaline conditions. Electrochemical measurements demonstrate that the NB/GCE, when used as a non-enzymatic glucose sensor, offers superior analytical performances with a wide linear range (from 1 μM to 500 μM), a low detection limit (0.25 μM, signal-to-noise = 3), and a response sensitivity of 1.542 μA mM-1 cm-2. Moreover, it can also be applied for glucose detection in human blood serum with the relative standard deviation (RSD) of 7.41%, showing the high precision of the sensor in measuring real samples.


Advances in Candida detection platforms for clinical and point-of-care applications.
Invasive candidiasis remains one of the most serious community and healthcare-acquired infections worldwide. Conventional Candida detection methods based on blood and plate culture are time-consuming and require at least 2-4 days to identify various Candida species. Despite considerable advances for candidiasis detection, the development of simple, compact and portable point-of-care diagnostics for rapid and precise testing that automatically performs cell lysis, nucleic acid extraction, purification and detection still remains a challenge. Here, we systematically review most prominent conventional and nonconventional techniques for the detection of various Candida species, including Candida staining, blood culture, serological testing and nucleic acid-based analysis. We also discuss the most advanced lab on a chip devices for candida detection.


Hypertension and incident cardiovascular events following ibrutinib initiation.
Ibrutinib is associated with dramatic efficacy against B-cell malignancies. Yet, it has been linked with potentially limiting cardiotoxicity, including emerging reports of profound hypertension (HTN). The long-term incidence, severity, and impact of HTN development with ibrutinib are unknown. Therefore, in 562 consecutive patients treated with ibrutinib for B-cell malignancies from 2009 through 2016, we assessed the new/incident or worsened HTN (systolic blood pressure [BP] cutoff, 130 mm Hg). Observed incident HTN rates were compared with Framingham-heart-predicted incident HTN rates. We also evaluated the relationship of HTN to the development of other major adverse cardiovascular events (MACEs), including arrhythmia, myocardial infarction, stroke, heart failure, and cardiovascular death. Further, we assessed the effects of different antihypertensive classes on ibrutinib-related HTN. Overall, 78.3% of ibrutinib users developed new or worsened HTN over a median of 30 months. New HTN developed in 71.6% of ibrutinib users, with a time to 50% cumulative incidence of 4.2 months. Among those without preceding HTN, 17.7% developed high-grade HTN (BP >160/100 mm Hg). In multivariate regression, new or worsened HTN was associated with increased MACEs (hazard ratio [HR], 2.17; 95% confidence interval [CI], 1.08-4.38). No single antihypertensive class was associated with prevention or control of ibrutinib-related HTN. However, antihypertensive initiation was associated with a lower risk of a MACE (HR, 0.40; 95% CI, 0.24-0.66). Collectively, these data suggest that ibrutinib is associated with a substantial increase in the incidence and severity of HTN, and that HTN development carries a higher risk of subsequent cardiotoxic events.


Stroke Incidence in Victoria, Australia-Emerging Improvements.
Evidence of a decline in the incidence of stroke has emerged from population-based studies. These have included retrospective and prospective cohorts. However, in Australia and other countries, government bodies and stroke foundations predict a rise in the prevalence of stroke that is anticipated to increase the burden of stroke across the entire domain of care. This increase in prevalence must be viewed as different from the decline in incidence being observed, a measure of new stroke cases. In Victoria, all public emergency department visits and public and private hospital admissions are reported to the Department of Health and Human Services and include demographic, diagnostic, and procedural/treatment information. We obtained data from financial years 1997/1998 to 2007/2008 inclusive, for all cases with a primary stroke diagnosis (ICD-10-AM categories) with associated data fields. Incident cases were established by using a 5-year clearance period. From 2003/2004 to 2007/2008 inclusive, there were 53,425 patients with a primary stroke or TIA diagnosis. The crude incident stroke rate for first ever stroke was 211 per 100,000 per year (95% CI 205-217) [females-205 per 100,000 per year (95% CI 196-214) and males-217 per 100,000 per year (95% CI 210-224)]. The overall stroke rates were seen to significantly decline over the period [males (per 100,000 per year) 227 in 2003/2004 to 202 in 2007/2008 (p = 0.0157) and females (per 100,000 per year) 214 in 2003/2004 to 188 in 2007/2008 (p = 0.0482)]. Ischemic stroke rates also appeared to decline; however, this change was not significant. These results demonstrate a significant decline in stroke incidence during the study period and may suggest evidence for effectiveness of primary and secondary prevention strategies in cerebrovascular risk factor management.


Isoflurane favorably modulates guanosine triphosphate cyclohydrolase-1 and endothelial nitric oxide synthase during myocardial ischemia and reperfusion injury in rats.
The authors investigated the hypothesis that isoflurane modulates nitric oxide (NO) synthesis and protection against myocardial infarction through time-dependent changes in expression of key NO regulatory proteins, guanosine triphosphate cyclohydrolase (GTPCH)-1, the rate-limiting enzyme involved in the biosynthesis of tetrahydrobiopterin and endothelial nitric oxide synthase (eNOS). Myocardial infarct size, NO production (ozone-mediated chemiluminescence), GTPCH-1, and eNOS expression (real-time reverse transcriptase polymerase chain reaction and western blotting) were measured in male Wistar rats with or without anesthetic preconditioning (APC; 1.0 minimum alveolar concentration isoflurane for 30 min) and in the presence or absence of an inhibitor of GTPCH-1, 2,4-diamino-6-hydroxypyrimidine. NO2 production (158 ± 16 and 150 ± 13 pmol/mg protein at baseline in control and APC groups, respectively) was significantly (P < 0.05) increased 1.5 ± 0.1 and 1.4 ± 0.1 fold by APC (n = 4) at 60 and 90 min of reperfusion, respectively, concomitantly, with increased expression of GTPCH-1 (1.3 ± 0.3 fold; n = 5) and eNOS (1.3 ± 0.2 fold; n = 5). In contrast, total NO (NO2 and NO3) was decreased after reperfusion in control experiments. Myocardial infarct size was decreased (43 ± 2% of the area at risk for infarction; n = 6) by APC compared with control experiments (57 ± 1%; n = 6). 2, 4-Diamino-6-hydroxypyrimidine decreased total NO production at baseline (221 ± 25 and 175 ± 31 pmol/mg protein at baseline in control and APC groups, respectively), abolished isoflurane-induced increases in NO at reperfusion, and prevented reductions of myocardial infarct size by APC (60 ± 2%; n = 6). APC favorably modulated a NO biosynthetic pathway by up-regulating GTPCH-1 and eNOS, and this action contributed to protection of myocardium against ischemia and reperfusion injury.


Effects of Sanhujori and Menopausal Adaptation on Health-related QOL in Middle-aged Women.
This study investigated the effects of menopausal adaptation and Sanhujori (Korean traditional postnatal care) on the Health-related quality of life in middle-aged women. Women aged from 45 to 60 completed questionnaires consisting of SF-36 ver. 2 and menopausal adaptation scale between July to Aug, 2013. Two hundred and eighteen participants' data were analyzed using descriptive statistics, t-test, ANOVA, Pearson's correlation coefficient and multiple regression. Physical health (69.5+/-15.1) was better than mental health (68.8+/-17.1), and bodily pain and social functioning were the same results as 2009 general U.S. population, with the sub-variables of quality of life being lower. Menopausal adaptation was at moderate level, and correlation of its sub-variables with quality of life were significant: fatigue (r=.60, p<.001), accomplishing feeling (r=.55, p<.001), confidence (r=.54, p<.001), dryness (r=.51, p<.001), flush (r=.38, p<.001), dominance (r=-.36, p<.001), stability (r=.26, p<.001). Fatigue, confidence, stability, period of sanhujori, and dryness revealed as influencing quality of life, while the total variation explained by these components was at 52%. To improve quality of life of middle aged women, health care providers need to provide nursing intervention to relieve fatigue and dryness; and address psychosocial concerns with developing nursing strategies to improve stability and confidence. For post-partum women, enough periods of sanhujori needs to be recommended.


Identifying Frailty and its Outcomes in Older People in Rural Tanzania.
Background/Study Context: Interest in frailty is growing in low- and middle-income countries, due to demographic aging and resource limitations. However, there is a paucity of data on the nature of frailty in Africa. The study collected frailty data from people aged 70 years and over living in six villages in the rural Hai District of northern Tanzania. At baseline, a limited data set was collected for 1198 people and a more comprehensive data set for a stratified sample of 296 people. A 40-item frailty index was constructed. Data regarding mortality and dependency were collected at 3-year follow-up. A higher frailty index score was significantly correlated with greater age, never having attended school, falls, mortality, and dependency in activities of daily living. Logistic regression modeling revealed functional disability and cognitive function to be significant independent predictors of the outcome "mortality or dependency." In resource-poor settings, brief frailty screening assessments may be a useful way of identifying those most in need of support.


An assessment of the management of acute bleeding varices: a multicenter prospective member-based study.
Bleeding from esophagogastric varices is a major complication of portal hypertension. Despite recent practice guidelines for the management of bleeding esophageal or gastric varices, the widespread application of these measures by gastroenterologists has not been evaluated. The purpose of this study was to continue the concept of membership-based research within diverse practice settings by expanding the American College of Gastroenterology (ACG) GI Bleeding Registry to assess the management and outcome of acute variceal bleeding. All ACG members (domestic and foreign) were invited to participate during the 1997 Annual Fall meeting and by mail. Data were collected over 12 months. Information obtained included physician training, practice demographics, patient demographics, disease etiology and severity, clinical presentation, medications, transfusion needs, therapy, complications, and rebleeding within 2 wk. A total of 93 physicians/centers (79.6% domestic, 26.9% university and affiliated, 3.2% Veterans Affairs) participated. Complete demographic data were available for 725 of the 741 patients enrolled with index bleeding. The median age of these 725 patients was 52 yr and 73.3% were male. The most common single etiology for portal hypertension was cirrhosis (94.3%). The most common causes of cirrhosis were alcohol (56.7%), hepatitis C virus (30.3%), and hepatitis B virus (10.0%). Hemodynamic instability was noted in 60.7% of the patients (22.3% tachycardic, 9.7% orthostatic, 28.7% hypotensive). Index interventions included banding (40.8%; median five bands), sclerotherapy (36.3%), combination banding/sclerotherapy (6.2%), octreotide (52.6%; median 3 days), balloon tamponade (5.5%), transjugular intrahepatic portosystemic shunt (TIPS) (6.6%), liver transplantation (1.1%), surgical shunt (0.7%), and embolization (0.1%). Transfusion of packed red blood cells, fresh frozen plasma, and platelets was given in 83.4%, 44.7%, and 24.6% of the patients with index bleeding, respectively. Median transfusion was four units of packed red blood cells, three units of fresh frozen plasma, and 1.5 units of platelets. Rebleeding occurred in 92 of the 741 patients (12.6%) at a median of 7 days (mean 11 days) and was treated by banding (18.5%; median six bands), sclerotherapy (30.4%), octreotide (63%; median 2 days), balloon tamponade (17.4%), TIPS (15.2%), and surgical shunt (3.3%). Complications from the index bleeding and rebleeding within 2 wk included ulceration (2.6%, 2.2%), aspiration (2.4%, 3.3%), medication side effects (0.8%, 0%), dysphagia (2.3%, 0%), odynophagia (2.2%,0%), encephalopathy (13%,17.4%), and hepatorenal syndrome (2.4%, 2.2%), respectively. After the index bleeding, 46.2% of patients were treated with beta-blockers and 8.2% with nitrates. The majority of patients with index bleeding had Child's B cirrhosis (61.5%). Patients presenting with recurrent bleeding had mostly Child's B (46.7%) or Child's C cirrhosis (44.6%). The overall short-term mortality after index bleeding was 12.9%. Acute variceal hemorrhage occurs more often in patients with Child's B and C cirrhosis. Endoscopic banding is the most common single endoscopic intervention. Adjunctive pharmacotherapy is prevalent acutely and after stabilization. Both morbidity and mortality may be lower than reported in previous studies.


Improved air quality and attenuated lung function decline: modification by obesity in the SAPALDIA cohort.
Air pollution and obesity are hypothesized to contribute to accelerated decline in lung function with age through their inflammatory properties. We investigated whether the previously reported association between improved air quality and lung health in the population-based SAPALDIA cohort is modified by obesity. We used adjusted mixed-model analyses to estimate the association of average body mass index (BMI) and changes in particulate matter with aerodynamic diameter ≤ 10 µm (PM10; ΔPM10) with lung function decline over a 10-year follow-up period. Lung function data and complete information were available for 4,664 participants. Age-related declines in lung function among participants with high average BMI were more rapid for FVC (forced vital capacity), but slower for FEV1/FVC (forced expiratory volume in 1 sec/FVC) and FEF25-75 (forced expiratory flow at 25-75%) than declines among those with low or normal average BMI. Improved air quality was associated with attenuated reductions in FEV1/FVC, FEF25-75, and FEF25-75/FVC over time among low- and normal-BMI participants, but not overweight or obese participants. The attenuation was most pronounced for ΔFEF25-75/FVC (30% and 22% attenuation in association with a 10-μg/m3 decrease in PM10 among low- and normal-weight participants, respectively.) Our results point to the importance of considering health effects of air pollution exposure and obesity in parallel. Further research must address the mechanisms underlying the observed interaction.


Snake venom derived molecules in tumor angiogenesis and its application in cancer therapy; an overview.
Snake venom is a complex mixture of biologically and pharmacologically active components, comprising hydrolytic enzymes, non-enzymatic proteins/peptides, and small amounts of organic and inorganic molecules. The venom components are known to vary with geographic location, season, species and age of the snakes. The role of the venom in the snake is not primarily for self-defense, but in prey immobilization and its subsequent digestion. Hence, several digestive enzymes in venoms, in addition to their hydrolytic activity have evolved to interfere in diverse physiological processes that help in the immobilization of prey/victim. As snake components are capable of modulating the physiological response of envenomated prey/victim, they show promise as potential pharmacological tools, as drug leads and in diagnostic applications. This, in a practical sense to be a reality has to be linked to the advances in toxinology that provide investigators with an understanding of the pharmacodynamics of toxins together with improved understanding of the etiology of many human diseases and identification of potential sites for therapeutic intervention. This review aims at providing an overview on snake venom toxins and their derivatives that have potential anti-angiogenic effects for cancer treatment. Some of the anti-angiogenic components of snake venom like Snake venom metalloproteinases (SVMPs), Disintegrins, Phospholipases A2 (PLA2), CType Lectins (CLP), Vascular Apoptosis inducing Proteins (VAP) and L-Amino Acid Oxidases (LAAO) are discussed. This review aims at giving an overall view of these molecules and their mechanism of action as an effective antiangiogenic agent towards the treatment of cancer.


Radiation dosimetry assessment of routine CT scanning protocols used in Western Australia.
Technical data on local CT practice in Western Australia were collected for five major CT providers using a self-completed questionnaire. The CTDIvol DLP and effective dose for each protocol were obtained and providers were ranked according to radiation burden for each clinical scenario. The mean, median, 75th percentile and standard deviation were calculated for both effective dose and DLP for each scenario and these values were compared with published data. CT utilisation data were used to estimate the attributable radiation dose to the WA population and the potential change in population annual effective dose according to the protocol used was estimated. We found that wide variations in technique and radiation dose exist across providers for similar examinations, producing a higher radiation burden than reported internationally. As expected, the CT protocol used dramatically affects the radiation dose received, and this has a significant effect on annual population dose. This study highlights the need for recognition and understanding of both the degree of variation in radiation dose across providers and the relatively high radiation burden afforded by protocols in use in Western Australia so that necessary dialogue can be launched for practitioner consensus on appropriate diagnostic reference levels in CT scanning.


Differential development of learning strategies on a Pictorial Verbal Learning Test (PVLT) in primary-school children.
The aim of this study was to test the hypothesis that developmental differences exist in the use of learning strategies in primary school children. Serial and subjective clustering in a multitrial Pictorial Verbal Learning Test (PVLT) were compared in 79 children aged 6-12. Correlation analyses indicated that serial clustering yielded better performance when information was presented on the initial trials of the test. Subjective clustering was superior when information was presented repeatedly, i.e., after three or more trials. Analyses of variance indicated that subjective clustering was used more often in older children with repeated presentations. On the other hand, there was no increase in the use of serial clustering with age and with repeated presentations. The findings imply that training in the use of proper strategies could have benefit for children who use an inefficient learning strategy and/or have a learning problem. In addition, they point to the importance of the factor "age" in relation to the way information is presented to children.


Can repeated plasma donation by asymptomatic HIV-infected individuals delay the onset of AIDS?
Healthy HIV-positive regular donors of plasma in a programme of passive immunotherapy for AIDS patients were studied over a period of about two years. None developed symptoms of clinical progression; most seemed to make substantial gains of CD4 cells by comparison with asymptomatic individuals who were not donating. The effects of donation did not seem to diminish with repetition, and donor CD4 counts tended towards stabilizing within normal limits. Asymptomatic HIV-positive individuals were compared immunologically with 'normals' and people with AIDS, using a battery of 25 measurements on peripheral blood. The immunological profiles of donor and non-donor asymptomatics, indistinguishable at the start, became dissimilar: donors' profiles resembled AIDS less, non-donors became less like 'normal' and a few non-donor results could not be distinguished from AIDS. Improvement in the CD4 counts and amelioration of the immunological profile in donors provide prima facie evidence that plasmapheresis may be therapeutic for asymptomatic HIV-positive people. Further studies are justified.


Effect of a glucosidase inhibitor on the bioactivity and immunoreactivity of human immunodeficiency virus type 1 envelope glycoprotein.
Apparently conflicting results have been reported regarding the role of env glycoprotein glycans in human immunodeficiency virus type 1 (HIV-1) infectivity and cytopathogenicity. Whereas we have shown that enzymic removal of carbohydrates from mature envelope glycoproteins has only limited effect on the ability of HIV-1 to bind to CD4 and to infect target cells, sugar analogues that interfere with the glycosylation process of the nascent molecule markedly reduce virus infectivity. Here we have investigated the effect of a glucosidase inhibitor, 1-deoxynojirimycin (dNM), on the bioactivity and immunoreactivity of precursor gp160 produced by recombinant vaccinia virus-infected BHK-21 cells (rgp160). dNM (4 mM) did not affect the amount of rgp160 recovered nor its secretion from the cells. As described by other authors the effect of dNM was incomplete, resulting in the production of rgp160, the glycosylation of which was heterogeneous with respect to apparent Mr distribution and to sensitivity to endoglycosidase H and endoglycosidase F, all the species being susceptible to N-glycanase. A major reduction of the binding to CD4+ cells was noted with rgp 160 produced by dNM-treated cells using a quantitative indirect immunofluorescence assay and labelling with polyclonal human anti-HIV IgG. Similarly, dNM treatment altered the accessibility to murine monoclonal antibody 110-4 of the exposed V3 loop of HIV-1 gp120 by at least 10-fold, as determined by either ELISA capture assay or immunoaffinity purification. Such bioactivity and conformation modifications, which result from the abnormal folding of the nascent glycoprotein due to aberrant glycosylation, may account for the impaired HIV-1 infectivity elicited by dNM.


Prognostic Factors for Pediatric Living Donor Liver Transplantation: Impact of Zero-mortality Transplant for Cholestatic Diseases.
Living donor liver transplantation (LDLT) is the final therapeutic arm for pediatric end-stage liver diseases. Toward the goal of achieving further improvement in LDLT survival, we investigated factors affecting recipient survival. We evaluated the prognostic factors of 60 pediatric recipients (< 16 years old) who underwent LDLT between 1997 and 2015. In a univariate analysis, non-cholestatic (NCS) disease, graft/recipient body weight ratio, cold and warm ischemic times, and intraoperative blood loss were significant factors impacting survival. In a multivariate analysis, NCS disease was the only significant factor worsening survival (p=0.0021). One-and 5-year survival rates for the cholestatic disease (CS, n=43) and NCS (n=17) groups were 100% vs. 70.6% and 97.4% vs. 58.8% (p=0.004, log-rank). Intergroup comparisons revealed that CS was significantly associated with operation time, cold ischemia, hepatomegaly of the native liver, and portal plasty. These data suggest that a cirrhotic, swollen, artery-dominant liver did not increase graft size-related risks despite the surgical complexity of preceding operations. The NCS group's poorer survival originated from recurrence of the primary disease and liver manifestation of systemic disease untreatable by transplantation. Improving the survival of pediatric recipients requires intensive efforts to prevent primary disease relapse and more rapid diagnoses to exclude contraindications from NCS disease.


Diabetic Retinopathy in Patients with Dyslipidemia: Development and Progression.
To investigate the association of dyslipidemia with the development of diabetic retinopathy (DR). A prospective cohort from the Longitudinal Health Insurance Database in Taiwan. Patients with diabetes mellitus (DM) aged ≥18 years from this cohort. A logistic regression model considering age, sex, and adapted Diabetes Complication Severity Index (aDCSI) including diabetic retinopathy, diabetic neuropathy, diabetic nephropathy cardiovascular disease, cerebrovascular disease, peripheral arteriolar disease, and metabolic disease. We estimated the propensity score for disease assignment probability for each included patient with DM and dyslipidemia. For each patient, a comparison patient without dyslipidemia was matched with a propensity score using a greedy algorithm. The standardized mean differences method was used to measure the difference in means or proportions divided by the pooled standard deviation of a variable. We calculated the incidence densities of nonproliferative DR (NPDR), diabetic macular edema (DME), and proliferative DR (PDR) as total events divided by the sum of follow-up duration, and the incidence curves were measured using the Kaplan-Meier method. The log-rank test was applied to test the differences of incidence curves. Hazard ratios (HRs) for DR. Our results demonstrated that the cumulative incidence of NPDR, DME, and PDR significantly increased in patients with DM and dyslipidemia compared with those without before adjustment for covariates (P < 0.001). Adjusted HRs for NPDR, DME, and PDR in patients with dyslipidemia were 1.77 (95% confidence interval [CI] = 1.63-1.92), 2.34 (95% CI = 1.24-4.41), and 1.07 (95% CI = 0.91-1.27), respectively. The risks of NPDR, DME, and PDR increased in patients who had underlying complications according to the aDCSI. Only statin use had a protective effect against the development of NPDR (HR = 0.83; 95% CI = 0.76-0.90), but it had no effect on DME and PDR. The protective effect was not significantly different between patients with and without dyslipidemia. Dyslipidemia is involved in the development of DR at an earlier stage, but the role of lipid-modulating agents in DR requires additional study.


[Quantitative analysis of mechanical characteristics of pathologically altered soft biological tissues].
The diagnostic importance of the mechanical properties of pathologically altered soft biological tissues is substantiated. The data on elastic properties of prostate and mammary gland obtained on postoperational material are presented. The methods of treating the experimental data used to determine these characteristics are described.


[Leu2]Gramicidin S preserves the structural properties of its parent peptide and forms helically aligned β-sheets.
For crystallographic analysis, Leu was substituted for Orn in Gramicidin S (LGS) to suppress interactions with hydrophilic solvent molecules, which increased the flexibility of the Orn side chains, leading to disorder within the crystals. The asymmetric unit (C62H94N10O10·1.296C3H8O·1.403H2O) contains three LGS molecules (A, B and C) forming β-turn and intramolecular β-sheet structures. With the exception of one motif in molecule C, D-Phe-Pro turn motifs (Phe is phenylalanine and Pro is proline) were classed as type II' β-turns. The peptide backbones twist slightly to the right along the long axis of the molecule. The puckering of Pro is in a Cγ-endo or twisted Cγ-endo-Cβ-exo form. Flanking molecules are arranged such that the angles (A...B = 104°, B...C = 139° and C...A = 117°) form helical β-sheets. Solvent molecules interact with the peptide backbones supporting the β-sheets. The forms of the replacement Leu side chains are consistent with the e-form of the Orn side chain in GS analogues. No hydrophilic region composed of solvent molecules, such as that observed in Gramicidin S hydrochloride (GS·HCl) crystals, was found. The perturbation of αH chemical shifts and coupling constants of CONH showed that the structural properties of GS·HCl and LGS are similar to each other in solution. CD spectra also supported the structural similarity. With the sequence cyclo(-Val-Leu-Leu-D-Phe-Pro-)2 (Val is valine and Leu is leucine), LGS lacks the amphiphilicity and antimicrobial activity of parental Gramicidin S (GS). However, the structure of LGS reflects the structural characteristics of GS and no disordering inconvenient for structural analysis was found. Thus, LGS could be a novel scaffold useful for studying β-turn and sheet structures.


Dissonance of Choice: Biomedical and Lived Perspectives on HIV Treatment-Taking.
Treat-all recommends prompt treatment initiation for those diagnosed HIV positive, requiring adaptations to individuals' behavior and practice. Drawing on data from a longitudinal qualitative study in Eswatini, we examine the choice to initiate treatment when asymptomatic, the dissonance between the biomedical logic surrounding Treat-all and individuals' conceptions of treatment necessity, and the navigation over time of ongoing engagement with care. We reflect on the perspectives of healthcare workers, responsible for implementing Treat-all and holding a duty of care for their patients. We explore how the potentially differing needs and priorities of individuals and the public health agenda are navigated and reconciled. Rationalities regarding treatment-taking extend beyond the biomedical realm, requiring adjustments to sense of self and identity, and decision-making that is situated and socially embedded. Sense of choice and ownership for this process is important for individuals' engagement with treatment and care.


Impact of CYP2D6*10 on recurrence-free survival in breast cancer patients receiving adjuvant tamoxifen therapy.
The clinical outcomes of breast cancer patients treated with tamoxifen may be influenced by the activity of cytochrome P450 2D6 (CYP2D6) enzyme because tamixifen is metabolized by CYP2D6 to its active forms of antiestrogenic metabolite, 4-hydroxytamoxifen and endoxifen. We investigated the predictive value of the CYP2D6*10 allele, which decreased CYP2D6 activity, for clinical outcomes of patients that received adjuvant tamoxifen monotherapy after surgical operation on breast cancer. Among 67 patients examined, those homozygous for the CYP2D6*10 alleles revealed a significantly higher incidence of recurrence within 10 years after the operation (P = 0.0057; odds ratio, 16.63; 95% confidence interval, 1.75-158.12), compared with those homozygous for the wild-type CYP2D6*1 alleles. The elevated risk of recurrence seemed to be dependent on the number of CYP2D6*10 alleles (P = 0.0031 for trend). Cox proportional hazard analysis demonstrated that the CYP2D6 genotype and tumor size were independent factors affecting recurrence-free survival. Patients with the CYP2D6*10/*10 genotype showed a significantly shorter recurrence-free survival period (P = 0.036; adjusted hazard ratio, 10.04; 95% confidence interval, 1.17-86.27) compared to patients with CYP2D6*1/*1 after adjustment of other prognosis factors. The present study suggests that the CYP2D6 genotype should be considered when selecting adjuvant hormonal therapy for breast cancer patients.


Emerging Trends in Cryo-EM-based Structural Studies of Neuropathological Amyloids.
Tauopathies, synucleinopathies, Aβ amyloidosis, TDP-43 proteinopathies, and prion diseases- these neurodegenerative diseases have in common the formation of amyloid filaments rich in cross-β sheets. Cryo-electron microscopy now permits the visualization of amyloid assemblies at atomic resolution, ushering a wide range of structural studies on several of these poorly understood amyloidogenic proteins. Amyloids are polymorphic with minor modulations in reaction environment affecting the overall architecture of their assembly, making amyloids an extremely challenging venture for structure-based therapeutic intervention. In 2017, the first cryo-EM structure of tau filaments from an Alzheimer's disease-affected brain established that in vitro assemblies might not necessarily reflect the native amyloid fold. Since then, brain-derived amyloid structures for several proteins across many neurodegenerative diseases have uncovered the disease-relevant amyloid folds. It has now been shown for tauopathies, synucleinopathies and TDP-43 proteinopathies, that distinct amyloid folds of the same protein might be related to different diseases. Salient features of each of these brain-derived folds are discussed in detail. It was also recently observed that seeded aggregation does not necessarily replicate the brain-derived structural fold. Owing to high throughput structure determination, some of these native amyloid folds have also been successfully replicated in vitro. In vitro replication of disease-relevant filaments will aid development of imaging ligands and defibrillating drugs. Towards this direction, recent high-resolution structures of tau filaments with positron emission tomography tracers and a defibrillating drug are also discussed. This review summarizes and celebrates the recent advancements in structural understanding of neuropathological amyloid filaments using cryo-EM.


Sensitivity of magnetic properties to chemical pressure in lanthanide garnets Ln 3 A 2 X 3O12, Ln = Gd, Tb, Dy, Ho, A = Ga, Sc, In, Te, X = Ga, Al, Li.
A systematic study of the structural and magnetic properties of three-dimensionally frustrated lanthanide garnets Ln 3 A 2 X 3O12, Ln = Gd, Tb, Dy, Ho, A = Ga, Sc, In, Te, X = Ga, Al, Li is presented. Garnets with Ln = Gd show magnetic behaviour consistent with isotropic Gd3+ spins; no magnetic ordering is observed for T ⩾ 0.4 K. Magnetic ordering features are seen for garnets with Ln = Tb, Dy, Ho in the temperature range 0.4 < T < 2.5 K, however the nature of the magnetic ordering varies for the different Ln as well as for different combinations of A and X. The magnetic behaviour can be explained by tuning of the magnetic interactions and changes in the single-ion anisotropy. The change in magnetic entropy is evaluated from isothermal magnetisation measurements to characterise the magnetocaloric effect in these materials. Among the Gd garnets, the maximum change in magnetic entropy per mole (15.45 J K-1 [Formula: see text]) is observed for Gd3Sc2Ga3O12 at 2 K, in a field of 9 T. The performance of Dy3Ga5O12 as a magnetocaloric material surpasses the other garnets with Ln = Tb, Dy, Ho.


Mining for recurrent long-range interactions in RNA structures reveals embedded hierarchies in network families.
The wealth of the combinatorics of nucleotide base pairs enables RNA molecules to assemble into sophisticated interaction networks, which are used to create complex 3D substructures. These interaction networks are essential to shape the 3D architecture of the molecule, and also to provide the key elements to carry molecular functions such as protein or ligand binding. They are made of organised sets of long-range tertiary interactions which connect distinct secondary structure elements in 3D structures. Here, we present a de novo data-driven approach to extract automatically from large data sets of full RNA 3D structures the recurrent interaction networks (RINs). Our methodology enables us for the first time to detect the interaction networks connecting distinct components of the RNA structure, highlighting their diversity and conservation through non-related functional RNAs. We use a graphical model to perform pairwise comparisons of all RNA structures available and to extract RINs and modules. Our analysis yields a complete catalog of RNA 3D structures available in the Protein Data Bank and reveals the intricate hierarchical organization of the RNA interaction networks and modules. We assembled our results in an online database (http://carnaval.lri.fr) which will be regularly updated. Within the site, a tool allows users with a novel RNA structure to detect automatically whether the novel structure contains previously observed RINs.


[Clinical Analysis of Infants with Acute Lymphoblastic Leukemia (18 cases)].
To investigate the clinical features and outcomes of infants (<1 year old) with acute lymphoblastic leukemia (IALL). The clinical manifestations, laboratory examination results, treatment and prognosis of 18 infants diagnosed with ALL at our department between January 1, 2014 and August 31, 2022 were retrospectively analyzed. Among the 18 cases of IALL, there were 10 males and 8 females. The median age of patients was 6.5 months old (3 months-11 months old). The median white blood cell count (WBC) was 33.63×109/L [(3.92-470)×109/L] at initial diagnosis, including 2 patients with WBC≥300×109/L. Flow cytometric immunophenotyping showed a B-lineage infant ALL in all the 18 patients. Eight of the 18 children had abnormal chromosome karyotype analysis. Fusion gene detection showed 12 KMT2A-rearrangement of 18 patients. 15 patients underwent leukemia related mutation gene screening, among which KRAS, NRAS and FLT3 were the most common mutation genes. 4 patients underwent allogeneic hematopoietic stem cell transplantation and two survived. 14 patients received chemotherapy only and ten survived. The 3-year OS rate was (65.5±11.5)%, while the EFS rate was (46.9±12.3)%. B-cell ALL and KMT2A rearrangement are prevalent in IALL. The therapeutic effect of IALL with standard childhood ALL protocal is similer to international infant specific protocal.


The influence of surgery on survival of patients with angina.
Myocardial revascularization surgery has proved most effective in relieving angina pectoris. Its influence on the survival of patients with coronary atherosclerosis, however, remains a contentious subject and one which may not be finally settled for years. The follow-up results of the first 196 patients to undergo direct coronary artery surgery at the Prince Henry Hospital support those who claim increased longevity as one of its benefits.


Oral selective serotonin reuptake inhibitors activate vagus nerve dependent gut-brain signalling.
The vagus nerve can transmit signals to the brain resulting in a reduction in depressive behavior as evidenced by the long-term beneficial effects of electrical stimulation of the vagus in patients with intractable depression. The vagus is the major neural connection between gut and brain, and we have previously shown that ingestion of beneficial bacteria modulates behaviour and brain neurochemistry via this pathway. Given the high levels of serotonin in the gut, we considered if gut-brain signaling, and specifically the vagal pathway, might contribute to the therapeutic effect of oral selective serotonin reuptake inhibitors (SSRI). Mesenteric nerve recordings were conducted in mice after treatment with SSRI to ascertain if this class of drugs resulted in increased vagal excitability. Patch clamp recordings of enteric neurons were carried out to measure activity of primary afferent neurons in the gut in response to SSRI and to assess the importance of gut epithelium in transducing signal. The tail suspension test (TST) was used following 14d feeding of SSRI in vagotomised and surgical sham mice to measure depressive-like behaviour. Brain mRNA expression was examined via PCR and the intestinal microbiome was assessed. Mesenteric nerve recordings in BALB/c mice demonstrated that oral treatment with SSRI leads to a significant increase in vagal activity. This effect was not observed in mice treated with a representative noradrenaline-dopamine reuptake inhibitor. It is known that signals from the gut can be transmitted to the vagus via the enteric nervous system. Exposure of the gut to SSRI increased the excitability of intrinsic primary afferent neurons in the myenteric plexus, through an intestinal epithelium dependent mechanism, and alpha-diversity of gut microbiota was altered. Critically, blocking vagal signaling from gut to brain, via subdiaphragmatic vagotomy, abolished the antidepressive effects of oral SSRI treatment as determined by the tail suspension test. This work suggests that vagus nerve dependent gut-brain signaling contributes to the effects of oral SSRI and further, highlights the potential for pharmacological approaches to treatment of mood disorders that focus on vagal stimulation and may not even require therapeutic agents to enter the circulation.


Innovations in three-dimensional treatment planning and quality assurance.
Radiation therapy treatment planning and treatment delivery are in the process of changing dramatically over the next several years. This change has been driven in large part by continued advances in computer hardware and software and in medical imaging. Three-dimensional radiation treatment planning systems are rapidly being implemented in clinics around the world. These developments in turn have prompted manufacturers to employ advanced microcircuitry and computer technology to produce treatment delivery systems capable of precise shaping of dose distributions via computer-controlled multileaf collimators which cause the beam intensity to be varied across the beam. Image-based 3D planning and beam intensity modulated delivery systems show significant potential for improving the quality of radiotherapy and improving the efficiency with which radiation therapy can be planned and delivered. However, significant research and development work on these systems and their clinical use remains to be performed. The techniques used for the treatment planning and the methods used for quality assurance procedures and testing must all be revised and/or redesigned to allow efficient clinical use of these technological advances. Although much of the current 3D radiation therapy process requires interactive tasks (and some still very laborious) the path is clear toward solving the technological obstacles so that a nearly automated planning, delivery, and verification system will become a reality over the next decade. Such systems will allow radiation oncologists to significantly increase dose to many tumor sites while concomitantly lowering doses to critical organs-at-risk. Most of the tasks will be automated, thus lowering the overall costs currently needed to provide high-quality external beam radiation therapy.


Utilization of alkaline hydrogen peroxide-treated wheat straw in cattle growing and finishing diets.
Two experiments were conducted to evaluate alkaline hydrogen peroxide-treated wheat straw (AHPWS) in cattle growing (Exp. 1) and finishing (Exp. 2) diets. In Exp. 1, 162 crossbred steers (257 kg) were fed 66% roughage diets in an 84-d growth trial to compare AHPWS to corn silage (CS) and to evaluate different supplemental CP sources and levels. A completely randomized design with a 3 x 3 factorial arrangement of treatments was used. Factors were roughage source (CS, a 1:1 mixture of CS:AHPWS [MIX] and AHPWS) and CP treatment (13 and 11% CP with supplemental CP provided by soybean meal [13-SBM] and [11-SBM] and 11% CP with a combination of urea, corn gluten meal, and fish meal [UGF]). Lasalocid was fed at the rate of 200 mg per steer daily. Steers fed AHPWS had decreased (P less than .01) DMI compared with steers fed MIX and CS. This may be due to increased dietary Na from residual Na in AHPWS. With each incremental increase in AHPWS, ADG and gain/feed decreased (P less than .01). Dry matter intakes (kg/d), ADG (kg), and gain/feed for CS, MIX, and AHPWS were 8.0, 1.56, and .19; 8.2, 1.33, and .16; and 7.5, 1.08, and .14, respectively. Decreased performance by steers fed AHPWS may be due, in part, to a negative interaction between the lasalocid and dietary minerals. There were no differences in performance due to CP supplementation. In Exp. 2, AHPWS was compared to alfalfa hay (AH) and CS at 10 and 20% of dietary DM (2 x 3 factorial) in a 127-d finishing trial with 108 crossbred steers (341 kg).(ABSTRACT TRUNCATED AT 250 WORDS)


Lactobacillus salivarius and L. gasseri down-regulate Aggregatibacter actinomycetemcomitans exotoxins expression.
Beneficial microbes, such as lactobacilli establish a symbiosis with the host and confer health-associated effects, by limiting the growth of indigenous pathogens and challenging microbes introduced by altered foods. Nevertheless, there is scarce information on the effects of beneficial microbes on the virulence properties of bacterial species associated with oral diseases, such as periodontitis. Aggregatibacter actinomycetemcomitans is a Gram-negative species highly implicated in the etiology of localized aggressive periodontitis. The objective of this study was to investigate the effect of lactobacilli on the expression of the two major virulence factors of A. actinomycetemcomitans. Lactobacillus salivarius and L. gasseri were selected as beneficial species. The gene expressions of leukotoxin (LtxA) and cytolethal distending toxin (CdtB) by A. actinomycetemcomitans were analyzed in response to challenge by lactobacilli cell-free supernatants. Neither lactobacilli affected the growth, but strongly attenuated the expressions of both CdtB and LtxA in the two A. actinomycetemcomitans strains tested. This reduction of the expression of these two exotoxins was time-dependent. These fundamental findings may indicate that lactobacilli can reduce the virulence of putative opportunistic oral pathogens, and may provide insights to future therapeutic approaches for the respective diseases.


Does alleviating poverty increase cognitive performance? Short- and long-term evidence from a randomized controlled trial.
In this Registered Report, we investigated the impact of a cash transfer based poverty alleviation program on cognitive performance. We analyzed data from a randomized controlled trial conducted on low-income, high-risk individuals in Liberia where a random half of the participants (n = 251) received a $200 lump-sum unconditional cash transfer - equivalent approximately to 300% of their monthly income - while the other half (n = 222) did not. We tested both the short-term (2-5 weeks) and the long-term (12-13 months) impact of the treatment via several executive function measures. The observed effect sizes of cash transfers on cognitive performance (b = .13 for the short- and b = .08 for the long-term) were roughly three and four times smaller than suggested by prior non-randomized research. Bayesian analyses revealed that the overall evidence supporting the existence of these effects is inconclusive. A multiverse analysis showed that neither alternative analytical specifications nor alternative processing of the dataset changed the results consistently. However cognitive performance varied between the executive function measures, suggesting that cash transfers may affect the subcomponents of executive function differently.


Cellular and viral specificities of human immunodeficiency virus type 1 vif protein.
The vif gene of human immunodeficiency virus type 1 (HIV-1) greatly enhances the infectivity of HIV-1 virions that are released from cells classified as nonpermissive (e.g., lymphocytes, macrophages, and H9 leukemic T cells) but is irrelevant in permissive cells (e.g., HeLa or COS cells). Recently, it was reported that vif expression in nonpermissive cells dramatically increases infectivity not only of HIV-1 but also of other enveloped viruses, including murine leukemia viruses (MLVs). This was surprising in part because MLVs and other murine retroviruses lack vif genes yet replicate efficiently in T lymphocytes. To investigate these issues, we first developed improved methods for producing substantial quantities of HIV-1 virions with vif deletions from healthy H9 cells. These virions had approximately the same amounts of major core proteins and envelope glycoproteins as the control wild-type virions but were only approximately 1% as infectious. We then produced H9 cells that contained wild-type or vif deletion HIV-gpt proviruses, which lack a functional env gene. After superinfection with either xenotropic or amphotropic MLVs, these cells released HIV-gpt virions pseudotyped with an MLV envelope plus replication-competent MLV. Interestingly, the pseudotyped HIV-gpt (vif deletion) virions were noninfectious, whereas the MLV virions simultaneously released from the same H9 cells were fully infectious. These results strongly suggest that the Vif protein functions in a manner that is both cell specific and at least substantially specific for HIV-1 and related lentiviruses. In addition, these results confirm that vif deletion HIV-1 virions from nonpermissive cells are blocked at a postpenetration stage of the infection pathway.


A Genome-Wide Association Study of Nausea Incidence in Varenicline-Treated Cigarette Smokers.
Varenicline is the most efficacious smoking cessation treatment; however, long-term cessation rates tend to be <25%. Nausea, the most common side effect of varenicline, observed in ~28% of individuals treated, peaks early following treatment initiation and reduces cessation success. Genetic variation influences treatment response, however genetic contributors to individual differences in side effects are less understood. We conducted a genome-wide association study of nausea incidence at 1 week following the initiation of varenicline treatment (corresponding to the target quit date) in 189 cigarette smokers of European ancestry (NCT01314001). Additive genetic models examining the likelihood of experiencing any versus no nausea controlled for population substructure, age, and sex. Variants with minor allele frequencies (MAF)≥10% were considered. Fifty-seven (30.2%) out of 189 participants reported nausea. The top variant associated with nausea was rs1568209 (odds ratio [OR] = 2.61 for A vs. G allele; 95% confidence interval [CI] = 1.65,4.15; p = 2.1e-7; MAF = 48.7%), mapping to the SLCO3A1 drug transporter gene on chromosome 15. In the same trial, rs1568209 was not associated with nausea in either the nicotine patch (p = .56; n = 181) or placebo (p = .59; n = 174) arms. In varenicline-treated smokers, the incidence of nausea was higher in females (44.6%; n = 74) versus males (20.9%; n = 115) (p = .001), however there was no evidence of a difference in the influence of rs1568209 on nausea between the sexes (p for sex*genotype interaction = .36). Future studies in larger samples are required to test the robustness of this finding. Variation in SLCO3A1 may influence the risk for developing nausea in varenicline-treated smokers, which may alter adherence and cessation. Varenicline-associated nausea reduces adherence and limits cessation success. Previous candidate gene association studies showed genetic factors influence nausea on varenicline. This pilot genome-wide investigation of nausea, the most common side effect associated with varenicline treatment and an important cause of treatment discontinuation, suggests the potential involvement of common variation in the SLCO3A1 drug transporter gene.


Impact on the composition of the faecal flora by a new probiotic preparation: preliminary data on maintenance treatment of patients with ulcerative colitis.
Although 5-aminosalicylic acid (5-ASA) oral compounds are the standard maintenance treatment for ulcerative colitis in remission, some patients cannot use them because of side-effects. Clinical and experimental observations have suggested the potential role of probiotics in inflammatory bowel disease therapy. To evaluate the effects on intestinal microflora and the clinical efficacy of a new probiotic preparation in patients with ulcerative colitis in remission. Twenty patients with ulcerative colitis, intolerant or allergic to 5-ASA, have been treated with a new probiotic preparation (VSL#3, CSL, Milan, Italy) containing 5x10(11) cells/g of 3 strains of bifidobacteria, 4 strains of lactobacilli and 1 strain of Streptococcus salivarius ssp. thermophilus. Two doses of 3 g were administered o.d. for 12 months. Faecal samples for stool culture were obtained from the patients at the beginning of the trial and after 10, 20, 40, 60, 75, 90 days, 12 months and at 15 days after the end of the treatment. The following bacterial groups have been evaluated in the faeces: total aerobic and anaerobic bacteria, enterococci, Streptococcus thermophilus, lactobacilli, bifidobacteria, Bacteroides, clostridia, coliforms. Patients were assessed clinically every two months, and assessed endoscopically at 6 and 12 months or in relapse. Faecal concentrations of Streptococcus salivarius ssp. thermophilus, lactobacilli and bifidobacteria increased significantly in all patients, compared to their basal level, from the 20th day of treatment (P<0.05) and remained stable throughout the study. Concentrations of Bacteroides, clostridia, coliforms, total aerobic and anaerobic bacteria did not change significantly during treatment (P = N.S.). Fifteen of 20 treated patients remained in remission during the study, one patient was lost to follow up, while the remaining relapsed. No significant side-effects have been reported. These results show that this probiotic preparation is able to colonize the intestine, and suggest that it may be useful in maintaining the remission in ulcerative colitis patients intolerant or allergic to 5-ASA. Controlled trials are warranted to confirm these preliminary results.


COVID-19 DEATHS AND VACCINATION IN NIGERIA: AN APPRAISAL.
Some estimates indicates that by 2021 ending, more people as a share of the vulnerable population in Africa, Nigeria inclusive, have died than elsewhere due to late and inadequate vaccination. With the pandemic phase of high daily deaths formally declared over, COVID-19 deaths before and after vaccination commenced were compared to observe how vaccination impacted COVID-19 deaths. COVID-19 cases, deaths and vaccination rates in World Health Organization databases up to 07 June 2023 and other variables of interest unavailable there but found in other open- sources were all extracted and examined. Case fatality rate (CFR) per 1,000 for the period prior to vaccination (CFR1) and the period after vaccination commenced (CFR2) was computed. Simple statistics were used in data analysis. Between when the first case was documented and 05 June 2023, Nigeria recorded 3,155 COVID-19 deaths and majority (61.84%) occurred between 19 March 2020 and March 5, 2021 when vaccination commenced. COVID-19 deaths declined to 61.7% of pre-vaccination figure coinciding with vaccination that delivered partial, primary and booster rates of 39.94%, 33.86% and 5.97% respectively. The cumulative COVID-19 deaths by population size was 8.94/106 pre-vaccination while COVID-19 deaths in vaccination era added 5.510/106mortalities to the final mortality figure of 14. 44/106. The calculated CFR1 and CFR2 rebased were 1.24% and 1.04% respectively. More COVID-19 deaths occurred before vaccination commenced than in over two years of ongoing vaccination.


α2 Adrenergic receptor-mediated inhibition of thermogenesis.
α2 adrenergic receptor (α2-AR) agonists have been used as antihypertensive agents, in the management of drug withdrawal, and as sedative analgesics. Since α2-AR agonists also influence the regulation of body temperature, we explored their potential as antipyretic agents. This study delineates the central neural substrate for the inhibition of rat brown adipose tissue (BAT) and shivering thermogenesis by α2-AR agonists. Nanoinjection of the α2-AR agonist clonidine (1.2 nmol) into the rostral raphe pallidus area (rRPa) inhibited BAT sympathetic nerve activity (SNA) and BAT thermogenesis. Subsequent nanoinjection of the α2-AR antagonist idazoxan (6 nmol) into the rRPa reversed the clonidine-evoked inhibition of BAT SNA and BAT thermogenesis. Systemic administration of the α2-AR agonists dexmedetomidine (25 μg/kg, i.v.) and clonidine (100 μg/kg, i.v.) inhibited shivering EMGs, BAT SNA, and BAT thermogenesis, effects that were reversed by nanoinjection of idazoxan (6 nmol) into the rRPa. Dexmedetomidine (100 μg/kg, i.p.) prevented and reversed lipopolysaccharide-evoked (10 μg/kg, i.p.) thermogenesis in free-behaving rats. Cholera toxin subunit b retrograde tracing from rRPa and pseudorabies virus transynaptic retrograde tracing from BAT combined with immunohistochemistry for catecholaminergic biosynthetic enzymes revealed the ventrolateral medulla as the source of catecholaminergic input to the rRPa and demonstrated that these catecholaminergic neurons are synaptically connected to BAT. Photostimulation of ventrolateral medulla neurons expressing the PRSx8-ChR2-mCherry lentiviral vector inhibited BAT SNA via activation of α2-ARs in the rRPa. These results indicate a potent inhibition of BAT and shivering thermogenesis by α2-AR activation in the rRPa, and suggest a therapeutic potential of α2-AR agonists for reducing potentially lethal elevations in body temperature during excessive fever.


Innervation of cat visual areas 17 and 18 by physiologically identified X- and Y- type thalamic afferents. I. Arborization patterns and quantitative distribution of postsynaptic elements.
Specific thalamic afferents to visual areas 17 and 18 were physiologically classified as X or Y type and injected with horseradish peroxidase (HRP). The axons were examined under the light microscope and were then processed for correlated electron microscopy. X axons arborized in area 17 and in the border between area 17 and 18. The X axons all formed terminals throughout layer 6, but were heterogeneous in their distribution in layer 4. They either occupied the entire width of sublayers 4A and 4B or were strongly biased toward layer 4A. Y axons also arborized in layers 4 and 6, but in area 17 they did not form boutons in sublamina 4B. Some Y axons projected only to area 18; others branched and arborized in both areas 17 and 18. Only the collaterals of one X axons were found to enter area 18; all the others were restricted to area 17. Y axons formed three to four separate patches of boutons about 300-400 microns in diameter, while all but one X axon formed a single elongated patch. Y axons had thicker main branches (3-4 microns) than X axons (1.5-2.5 microns) at their point of entry to the cortex. The main axon trunks and their medium-calibre collaterals were myelinated, but the preterminal segments were unmyelinated and studded with boutons. Each X or Y axon contacted about seven to ten somata, but Y axons made more contacts per soma (three to six) than did X axons (two to three). In addition to somatic synapses, both X and Y axons formed asymmetric (type 1) synapses on dendritic spines and shafts, with spines forming the most frequent targets (80%). Each Y bouton made, on average, 1.64 synapses in area 17 and 1.79 synapses in area 18, whereas each X bouton made only 1.27 synapses on average. Although there are proportionally fewer Y axons than X axons entering area 17, the Y axons provide as many synapses as the X axons because of their larger arbors and multisynaptic boutons.


Elevated dietary sugar and the heart: experimental models and myocardial remodeling.
A dramatic rise in the prevalence of insulin resistance has been paralleled by increasing dietary consumption of sugar. The use of added sweeteners containing fructose (sucrose and high-fructose corn syrup) has increased by 25% over the past 3 decades. High fructose intake has the potential to adversely influence systemic and cellular metabolism via insulin resistance and glycolytic dysregulation. As a tissue that is both insulin sensitive and glycolysis dependent, the heart may be especially vulnerable to fructose over-consumption. In this review, experimental studies of elevated dietary sugar intake are evaluated, including sucrose and fructose dietary manipulation models. The possible role of the GLUT5 transporter as a mediator of cardiomyocyte fructose uptake is considered. The impact of dietary sucrose and fructose on cardiac insulin-dependent signaling in the context of perturbed systemic metabolic response is detailed. Myocardial dysfunction, modified growth, and oxidative stress responses associated with high dietary sugar intake are discussed. Finally, the involvement of the renin-angiotensin system in mediating fructose cardiopathology is considered. This review highlights the importance of obtaining new mechanistic data that can contribute to a more developed understanding of how high sugar intake directly contributes to structural and functional cardiomyopathy.


Late effects on the health-related quality of life in a cohort population decades after environmental radiation exposure.
To evaluate the late effects on the quality of life (QOL) of individual years after protracting low-dose radiation exposure. We assessed 1,818 subjects using the World Health Organization Questionnaire on Quality of Life--Brief Version (WHOQOL-BREF) in several Health-Related Quality of Life (HRQoL) domains. After adjusting for demographic characteristics and comorbidities, we examined the HRQoL differences at various levels of exposure and ages at disclosure. We also evaluated the potential effect modification by gender. After adjusting for potential confounders, girls aged 12 years or younger at the disclosure of exposure had lower HRQoL scores in physical, psychological, and environmental domains compared to those with later age at disclosure. The differences in the HRQoL scores between different exposure subgroups were not significant in physical, psychological, and social relationship domains, and only appeared in the environmental domain. Being female and less than 12 years of age at disclosure were more significant predictors of HRQoL scores than the levels of radiation exposure among people exposed to protracted low-dose radiation. Further studies are needed to determine the psychological distresses, such as depression and anxiety, and their relationships in this case, especially for the most vulnerable young females.


Signatures of cochlear processing in neuronal coding of auditory information.
The vertebrate ear is endowed with remarkable perceptual capabilities. The faintest sounds produce vibrations of magnitudes comparable to those generated by thermal noise and can nonetheless be detected through efficient amplification of small acoustic stimuli. Two mechanisms have been proposed to underlie such sound amplification in the mammalian cochlea: somatic electromotility and active hair-bundle motility. These biomechanical mechanisms may work in concert to tune auditory sensitivity. In addition to amplitude sensitivity, the hearing system shows exceptional frequency discrimination allowing mammals to distinguish complex sounds with great accuracy. For instance, although the wide hearing range of humans encompasses frequencies from 20 Hz to 20 kHz, our frequency resolution extends to one-thirtieth of the interval between successive keys on a piano. In this article, we review the different cochlear mechanisms underlying sound encoding in the auditory system, with a particular focus on the frequency decomposition of sounds. The relation between peak frequency of activation and location along the cochlea - known as tonotopy - arises from multiple gradients in biophysical properties of the sensory epithelium. Tonotopic mapping represents a major organizational principle both in the peripheral hearing system and in higher processing levels and permits the spectral decomposition of complex tones. The ribbon synapses connecting sensory hair cells to auditory afferents and the downstream spiral ganglion neurons are also tuned to process periodic stimuli according to their preferred frequency. Though sensory hair cells and neurons necessarily filter signals beyond a few kHz, many animals can hear well beyond this range. We finally describe how the cochlear structure shapes the neural code for further processing in order to send meaningful information to the brain. Both the phase-locked response of auditory nerve fibers and tonotopy are key to decode sound frequency information and place specific constraints on the downstream neuronal network.


Changes in anti-heat shock protein 27 antibody and C-reactive protein levels following cardiac surgery and their association with cardiac function in patients with cardiovascular disease.
The relationship between serum anti-heat shock protein (Hsp)27 antibody and high sensitive C-reactive protein (hs-CRP) levels and indices of cardiac function were investigated in patients undergoing coronary artery bypass grafting (CABG) or heart valve replacement. The changes in anti-Hsp27 antibody titers and hs-CRP levels were compared among patients undergoing off-pump and on-pump CABG or valvular heart replacement. Fifty-three patients underwent off-pump, on-pump CABG, and heart valvular replacement in each group. Serum anti-Hsp27 titers and hs-CRP values were measured 24 h before and after the operation and at discharge. Echocardiography was performed before surgery and before discharge. The results were compared with values from 83 healthy controls. hs-CRP levels increased and anti-Hsp27 antibody decreased following surgery (P < 0.001 and P < 0.05, respectively), although these changes were independent of operative procedure (P = 0.361 and P = 0.120, respectively). Anti-Hsp27 antibody levels were higher at the time of discharge (P = 0.016). Only in coronary patients were anti-Hsp27 antibody levels negatively associated with E/E' (r = -0.268, P = 0.022), a marker of pulmonary capillary wedge pressure. In conclusions, anti-Hsp27 antibody levels are associated with indices of cardiac function in coronary patients. Cardiopulmonary bypass had no significant effect on the induction of changes in anti-Hsp27 levels. Moreover, anti-Hsp27 antibody levels fell in all groups postoperatively; this may be due to the formation of immune complexes of antigen-antibody, and antibody levels were higher at the time of discharge.


Automatic target segmentation by locally adaptive image thresholding.
A locally adaptive thresholding algorithm, concerning the extraction of targets from a given field of background, is proposed. Conventional histogram-based or global-type methods are deficient in detecting small targets of possibly low contrast as well. The present research is notable for solving the mentioned problems by introducing (1) shape connectivity measure based on co-occurrence statistics for threshold evaluation; and (2) no-target identification procedure for modeling a local-processing paradigm. In this manner, thresholds are determined adaptively even in the presence of space-varying noise or clutter. Experiments show that the results are reliable and even outperform those that manual operations can achieve for global thresholding.


Addressing the support needs of families during the acute hospitalization of a parent with mental illness: A narrative literature review.
Hospitalisation of a parent with acute mental health problems impacts the consumer, their extended family/carers and children. Mental health nurses are at the forefront of promoting recovery for consumers in an acute inpatient setting. Recovery-oriented care can include provision of family-focused care which supports recovery of the parent-consumer and their family members and contributes to prevention of intergenerational mental illness. The aim of this narrative literature review was to explore existing knowledge regarding the experiences, care and support needs of parent-consumers, their family members/carers and children during the parent's acute mental health hospitalisation. It also aims to explore existing knowledge about the practices of mental health nurses providing care to this consumer group, to inform future healthcare practice and strengthen parent, child and family outcomes. Nineteen published studies addressed the review questions. In the context of hospitalisation, the majority of research regarding parenting with a mental illness is focused on mothers. Parents reported experiencing stigma during their hospitalisation. Separation from children was a concern for parents and their extended family, but admission provided an opportunity for the parent to receive treatment and for the family to receive support. Mental health nurses did not always identify parental status on admission. When parental status was identified, nurses reported issues regarding logistics and practicalities of using family rooms, children visiting the unit, and their own professional knowledge and organisational support regarding familyfocused care. Implications for practice are identified, highlighting how mental health nurses can develop their practice to support the recovery of parent-consumers.


Climate change, precipitation and impacts on an estuarine refuge from disease.
Oysters play important roles in estuarine ecosystems but have suffered recently due to overfishing, pollution, and habitat loss. A tradeoff between growth rate and disease prevalence as a function of salinity makes the estuarine salinity transition of special concern for oyster survival and restoration. Estuarine salinity varies with discharge, so increases or decreases in precipitation with climate change may shift regions of low salinity and disease refuge away from optimal oyster bottom habitat, negatively impacting reproduction and survival. Temperature is an additional factor for oyster survival, and recent temperature increases have increased vulnerability to disease in higher salinity regions. We examined growth, reproduction, and survival of oysters in the New York Harbor-Hudson River region, focusing on a low-salinity refuge in the estuary. Observations were during two years when rainfall was above average and comparable to projected future increases in precipitation in the region and a past period of about 15 years with high precipitation. We found a clear tradeoff between oyster growth and vulnerability to disease. Oysters survived well when exposed to intermediate salinities during two summers (2008, 2010) with moderate discharge conditions. However, increased precipitation and discharge in 2009 reduced salinities in the region with suitable benthic habitat, greatly increasing oyster mortality. To evaluate the estuarine conditions over longer periods, we applied a numerical model of the Hudson to simulate salinities over the past century. Model results suggest that much of the region with suitable benthic habitat that historically had been a low salinity refuge region may be vulnerable to higher mortality under projected increases in precipitation and discharge. Predicted increases in precipitation in the northeastern United States due to climate change may lower salinities past important thresholds for oyster survival in estuarine regions with appropriate substrate, potentially disrupting metapopulation dynamics and impeding oyster restoration efforts, especially in the Hudson estuary where a large basin constitutes an excellent refuge from disease.


Structural analysis and transcriptional mapping of the Marek's disease virus gene encoding pp38, an antigen associated with transformed cells.
The gene encoding a Marek's disease virus (MDV) pp38 phosphoprotein has been identified, sequenced, and localized to the BamHI H fragment to the left of the putative MDV origin of replication. The open reading frame was defined by sequencing of a lacZ-pp38 fusion protein gene from a lambda gt11 expression library. The entire open reading frame is 290 amino acids long and codes for a protein with a calculated molecular weight of 31,169, compared with the size of 38 kDa of the phosphorylated form estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. S1 nuclease protection analysis showed that the pp38 gene is transcribed leftward as an unspliced mRNA. On the basis of transcriptional mapping studies, the pp38 transcript is predicted to be about 1.8 kb in length without a poly(A) sequence. Its promoter-enhancer region overlaps that of the major rightward BamHI H 1.8-kb transcript implicated in tumor induction. This region contains Oct-1, Sp1, and CCAAT motifs as well as the putative origin of replication. The pp38 protein is the only presently known antigen that is consistently associated with the transformation state. It may play a significant role in MDV transformation.


Optimal control in microgrid using multi-agent reinforcement learning.
This paper presents an improved reinforcement learning method to minimize electricity costs on the premise of satisfying the power balance and generation limit of units in a microgrid with grid-connected mode. Firstly, the microgrid control requirements are analyzed and the objective function of optimal control for microgrid is proposed. Then, a state variable "Average Electricity Price Trend" which is used to express the most possible transitions of the system is developed so as to reduce the complexity and randomicity of the microgrid, and a multi-agent architecture including agents, state variables, action variables and reward function is formulated. Furthermore, dynamic hierarchical reinforcement learning, based on change rate of key state variable, is established to carry out optimal policy exploration. The analysis shows that the proposed method is beneficial to handle the problem of "curse of dimensionality" and speed up learning in the unknown large-scale world. Finally, the simulation results under JADE (Java Agent Development Framework) demonstrate the validity of the presented method in optimal control for a microgrid with grid-connected mode.


New bacterial strain of the genus Ochrobactrum with glyphosate-degrading activity.
Thirty bacterial strains with various abilities to utilize glyphosate as the sole phosphorus source were isolated from farm soils using the glyphosate enrichment cultivation technique. Among them, a strain showing a remarkable glyphosate-degrading activity was identified by biochemical features and 16S rRNA sequence analysis as Ochrobactrum sp. (GDOS). Herbicide (3 mM) degradation was induced by phosphate starvation, and was completed within 60 h. Aminomethylphosphonic acid was detected in the exhausted medium, suggesting glyphosate oxidoreductase as the enzyme responsible for herbicide breakdown. As it grew even in the presence of glyphosate concentrations as high as 200 mM, Ochrobactrum sp. could be used for bioremediation purposes and treatment of heavily contaminated soils.


Reliability and validity of the Korean version of the Penn State Worry Questionnaire in primary school children.
Worry is a generalized psychological phenomenon seen among most people. When worry is excessive and nearly uncontrollable, people usually suffer psychological pain. The Penn State Worry Questionnaire for Children (PSWQ-C) was developed to measure worry objectively. It comprises 14 items for measuring excessive, generalized, and uncontrollable worry in children. This study, conducted with a large group of elementary children (3rd through 6th graders, ages 8-12 yr; N=973), investigated the reliability and validity of the Korean version of the Penn State Worry Questionnaire for Children (PSWQ-CK). The PSWQ-CK showed high reliability by test-retest and also excellent internal consistency results. To examine the validity of the PSWQ-CK, we calculated its correlation with the Revised Children's Manifest Anxiety Scale (RCMAS). The PSWQ-CK had a higher correlation with the worry/oversensitivity factor than with other subscales of the RCMAS, and it showed no correlation with the lie factor. When 3 reversed PSWQ-CK items were eliminated, the instrument showed higher internal consistency. However, this did not improve its correlation with other anxiety-measuring tools. In conclusion, the PSWQ-CK's reliability and validity were satisfactory, and it is a useful tool for objectively measuring the worry of Korean children of this age group.


Reconstruction of putative DNA virus from endogenous rice tungro bacilliform virus-like sequences in the rice genome: implications for integration and evolution.
Plant genomes contain various kinds of repetitive sequences such as transposable elements, microsatellites, tandem repeats and virus-like sequences. Most of them, with the exception of virus-like sequences, do not allow us to trace their origins nor to follow the process of their integration into the host genome. Recent discoveries of virus-like sequences in plant genomes led us to set the objective of elucidating the origin of the repetitive sequences. Endogenous rice tungro bacilliform virus (RTBV)-like sequences (ERTBVs) have been found throughout the rice genome. Here, we reconstructed putative virus structures from RTBV-like sequences in the rice genome and characterized to understand evolutionary implication, integration manner and involvements of endogenous virus segments in the corresponding disease response. We have collected ERTBVs from the rice genomes. They contain rearranged structures and no intact ORFs. The identified ERTBV segments were shown to be phylogenetically divided into three clusters. For each phylogenetic cluster, we were able to make a consensus alignment for a circular virus-like structure carrying two complete ORFs. Comparisons of DNA and amino acid sequences suggested the closely relationship between ERTBV and RTBV. The Oryza AA-genome species vary in the ERTBV copy number. The species carrying low-copy-number of ERTBV segments have been reported to be extremely susceptible to RTBV. The DNA methylation state of the ERTBV sequences was correlated with their copy number in the genome. These ERTBV segments are unlikely to have functional potential as a virus. However, these sequences facilitate to establish putative virus that provided information underlying virus integration and evolutionary relationship with existing virus. Comparison of ERTBV among the Oryza AA-genome species allowed us to speculate a possible role of endogenous virus segments against its related disease.


[Activity of bovine colostral IgG in the human digestive tract].
The biological activity of cow IgG administered orally to 11 volunteers in the colostrum of cows vaccinated with Sh. sonnei was studied. At the same time the degree of immunologic protection was determined on the experimental model of pepsin fragments of this IgG active against Sh. sonnei. IgG, introduced orally, could be regularly found in gastric and intestinal juices, as well as in coprofiltrates. A decrease in the concentration of IgG and related antibodies was observed as this IgG moved down along the digestive tract: the maximum loss of biological activity occurred in the lower sections of the intestine. The products of pepsin hydrolysis of immune cow IgG ensure pronounced protection against Sh. sonnei. The preservation of the biological activity of IgG in the digestive secretions of adults receiving immune colostrum orally indicates the expediency of further studies in the field of passive enteral immunization for the prevention and treatment of acute intestinal diseases.


Association of calponin with desmin intermediate filaments.
Our previous immunoelectron microscopy studies of chicken gizzard smooth muscle cells showed that in certain areas the distribution of anti-calponin exhibits a high degree of overlap with beta-actin, filamin, and in particular, desmin, suggesting that in situ a fraction of calponin may be associated with intermediate filaments of the cytoskeleton. In this work we further explore this idea by studying the interaction between calponin and desmin. We found that at physiological salt concentrations, calponin bound only weakly to synthetic desmin intermediate filaments. On the other hand, calponin bound strongly to nonfilamentous desmin tetramers and was incorporated into intermediate filaments when the two proteins were mixed in a buffer containing 6 M urea and dialyzed into a buffer containing 0.15 M NaCl. Anti-calponin was found to label a portion of intermediate filaments and dense bodies isolated from gizzard tissues. Our findings suggest that in chicken gizzard smooth muscle cells, calponin may be an integral component of desmin intermediate filaments in the vicinity of dense bodies. Since calponin is also known to bind actin, we hypothesize that one of the functions of calponin might be to bridge intermediate filaments with actin in dense bodies.


Biological properties of the encapsulated Staphylococcus aureus M.
Strain M, classified as a Staphylococcus aureus, behaves like the other rare encapsulated staphylococcal strains. It was clumping-factor negative, grew in diffuse-type colonies in serum-soft agar, and produced rapidly fatal disease in mice. Strain M was highly resistant to phagocytosis by human or mouse leukocytes and required both specific antibody and heat-labile serum factor(s) for efficient ingestion by human polymorphonuclear leukocytes. Electron micrographs confirmed the presence of a large capsule. Agglutination studies, active or passive mouse protection experiments, and opsonic studies revealed that strain M represents a new, immunologically distinct strain of encapsulated staphylococcus. Strain M differs from other known encapsulated staphylococci in several other respects: its cellular and colonial morphology is atypical; its LD(50) in the mouse peritoneal model is 100 times less than that of other mouse lethal strains; it is poorly opsonized by normal human serum; and, finally, it possesses an unusually large capsule as seen in electron micrographs.


Height-specific blood pressure cutoffs for screening elevated and high blood pressure in children and adolescents: an International Study.
Pediatric blood pressure (BP) reference tables are generally based on sex, age, and height and tend to be cumbersome to use in routine clinical practice. In this study, we aimed to develop a new, height-specific simple BP table according to the international child BP reference table based on sex, age and height and to evaluate its performance using international data. We validated the simple table in a derivation cohort that included 58,899 children and adolescents aged 6-17 years from surveys in 7 countries (China, India, Iran, Korea, Poland, Tunisia, and the United States) and in a validation cohort that included 70,072 participants from three other surveys (China, Poland and Seychelles). The BP cutoff values for the simple table were calculated for eight height categories for both the 90th ("elevated BP") and 95th ("high BP") percentiles of BP. The simple table had a high performance to predict high BP compared to the reference table, with high values (boys/girls) of area under the curve (0.94/0.91), sensitivity (88.5%/82.9%), specificity (99.3%/99.7%), positive predictive values (93.9%/97.3%), and negative predictive values (98.5%/97.8%) in the pooled data from 10 studies. The simple table performed similarly well for predicting elevated BP. A simple table based on height only predicts elevated BP and high BP in children and adolescents nearly as well as the international table based on sex, age, and height. This has important implications for simplifying the detection of pediatric high BP in clinical practice.


Analysis of the Effects on Time Between Divorce Decree and Suicide.
Background: Divorced individuals carry unique suicide risks, from both acute and chronic exposure to stressors from divorce. Aims: Several statewide data sets were linked to assess the relationship between divorce and suicide. Method: Divorced suicide decedents in the Colorado Violent Death Reporting System, 2004-2015, were matched with divorce decree, using multiple identifiers. Statistically significant differences between the linked cohort and all divorced suicide decedents were assessed using chi-square statistics. Kaplan-Meier survival analyses were conducted assessing which demographics and circumstances had a significant effect on the time between divorce and death. Results: The linkage resulted in 381 divorced suicide decedents linked to a divorce decree. Time between divorce and death ranged from less than 1 year to more than 10 years. Age and intimate partner problems both had significant effects on reducing the survival probability at 1 year and beyond. Limitations: Only 14% of divorced suicide decedents were linked to a Colorado divorce decree. There were noted significant differences between the linked cohort and the total divorced suicide population. Conclusion: Better understanding the relationship between divorce and suicide is imperative to design effective prevention programs for this specific population.


Is there a rationale for eradication of Helicobacter pylori? Cost-benefit: the case for.
Screening and treating the community for Helicobacter pylori would have seemed inconceivable 5 years ago. This has now become a real possibility given that H. pylori is a major risk factor for gastric carcinoma. Screening should not be introduced, however, before the costs and benefits of the programme are established. It has been estimated that 1:30-1:60 of the UK population die from an H. pylori related disease. If treating H. pylori were to reduce premature mortality, then this would be a persuasive argument for a screening strategy. The financial costs of screening and treating H. pylori are significant but this would be partially offset by savings that would accrue from reducing dyspepsia in the community. Indeed, decision analysis models suggest H. pylori screening is cost-effective. The potential benefits are enormous and prospective randomised trials are urgently required to establish whether such a programme is worthwhile.


Synthesis and Characterization of Poly(RGD) Proteinoid Polymers and NIR Fluorescent Nanoparticles of Optimal d,l-Configuration for Drug-Delivery Applications-In Vitro Study.
RGD sequence is a tripeptide composed of three amino acids: arginine (R), glycine (G), and aspartic acid (D). The RGD peptide has a high affinity to the integrin alpha v beta 3, which is overexpressed on the membrane of many cancer cells and is attracted to areas of angiogenesis. Proteinoids are biodegradable polymers based on amino acids which are formed by bulk thermal step-growth polymerization mechanism. Hollow proteinoid nanoparticles (NPs) may be formed via self-assembly process of the proteinoid polymers. We propose using novel RGD-based proteinoid polymers to manufacture NPs in which the RGD motif is self-incorporated in the proteinoid backbone. Such P(RGD) NPs can act both as a drug carrier (by encapsulation of a desired drug) and as a targeting delivery system. This article presents the synthesis of four RGD proteinoids with different RGD optical configurations, (d) or (l) arginine, glycine, and (d) or (l) aspartic acid, in order to determine which configuration is optimal as a drug-targeting carrier. These new RGD proteinoid polymers possess high molecular weights and molecular weight monodispersity. Homonuclear nuclear magnetic resonance methods were employed to predict the expected concentration of RGD tripeptide sequence in the polymer. Near infrared fluorescent NPs have been prepared by the encapsulation of indocyanine green (ICG) dye within the different P(RGD) NPs. The dry diameters of the hollow P(RdGDd), P(RdGD), P(RGD), and P(RGDd) NPs are 55 ± 13, 48 ± 9, 45 ± 11, and 42 ± 9 nm, respectively, whereas those of the ICG-encapsulated NPs were significantly higher, 141 ± 24, 95 ± 13, 86 ± 11, and 87 ± 12 nm, respectively. The ICG-encapsulated P(RdGD) NPs exhibited higher selectivity toward epithelial injury, as demonstrated using an in vitro scratch assay, because the P(RdGD) NPs accumulated in the injured area at higher concentrations when compared to other P(RGD) NPs with different chiralities. Therefore, the P(RdGD) polymer configuration is the polymer of choice for use as a targeted drug carrier to areas of angiogenesis, such as in tumors, wounds, or cuts.


[New approaches to dosimetry of ions in air].
The authors considered contemporary methods of air ions dosimetry, suggested new approaches to dosimetry of ions in air, set new concepts for exposure and absorbed dose rate. The article covers experimental results and method determining absorbed dose rate under exposure to air ions.


Towards a better understanding of physical activity in people with COPD: predicting physical activity after pulmonary rehabilitation using an integrative competence model.
The integrative Physical Activity-related Health Competence (PAHCO) model specifies competences (movement competence, control competence, and self-regulation competence) that enable people to lead a physically active lifestyle. This longitudinal study analyses the predictive quality of a multidimensional PAHCO assessment for levels of physical activity (PA) and their relevance for quality of life in COPD patients after pulmonary rehabilitation. At the end of an inpatient pulmonary rehabilitation (T2), 350 COPD patients participating in the Stay Active after Rehabilitation (STAR) study underwent assessments, including a six-factor measurement of PAHCO. PA (triaxial accelerometry) and quality of life (Saint George's Respiratory Questionnaire) were recorded 6 weeks (T3) and 6 months (T4) after rehabilitation. Structural equation modelling (SEM) was used to regress the PAHCO assessment on PA, which should, in turn, influence quality of life. In univariable analysis, five and six factors of the PAHCO model were related to PA and quality of life, respectively. Multivariate modelling showed that the predictive analyses for the PA level were dominated by the 6-minute walking test representing movement competence (0.562 ≤ |β| ≤ 0.599). Affect regulation as an indicator of control competence co-predicted quality of life at T3 and levels of PA at T4. The PA level was, in turn, significantly associated with patients' quality of life (0.306 ≤ |β| ≤ 0.388). The integrative PAHCO model may be used as a theoretical framework for predicting PA in COPD patients following pulmonary rehabilitation. The results improve our understanding of PA behaviour in COPD patients and bear implications for person-oriented PA promotion.


HMGB1 promotes differentiation syndrome by inducing hyperinflammation via MEK/ERK signaling in acute promyelocytic leukemia cells.
Differentiation therapy based on all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) for the treatment of acute promyelocytic leukemia (APL) is complicated by the development of differentiation syndrome (DS), which can be fatal. We examined the role of HMGB1 (high-mobility group box 1) in DS using both in vitro and in vivo models. HMGB1 and the pro-inflammatory cytokines IL-1β and TNF-α were gradually released from NB4 and HL-60 cells treated with ATRA and/or ATO. Similarly, higher serum HMGB1 levels positively correlated with the clinical status of DS patients. Exogenous HMGB1 promoted rapid release of IL-1β and TNF-α as well as elevated expression of ICAM-1, without altering cell differentiation. Exogenous HMGB1 also enhanced pulmonary infiltration and up-regulated ICAM-1 expression in the ATRA-treated DS mouse. Pharmacological inhibition or depletion of MEK1/2 reduced the cytokine levels and suppressed expression of ICAM-1 and the adhesion of HMGB1-treated NB4 cells to endothelial cells, implicating MEK/ERK signaling in the response to HMGB1 during DS. Treatment with a HMGB1-neutralizing antibody reduced secretion of TNF-α and IL-1β, arrested the elevation of ICAM-1 and blunted the activation of ERK1/2 in ATRA-induced NB4 cells. The HMGB1-neutralizing antibody also decreased ICAM-1 expression and reduced mortality in ATRA-treated DS model mice. These findings demonstrate that released HMGB1 is central to DS, and that targeting HMGB1 may be of therapeutic value in the treatment of DS.


Sixteen-Week Physical Activity Intervention in Subjects With Increased Cardiometabolic Risk Shifts Innate Immune Function Towards a Less Proinflammatory State.
Background Low-grade inflammation, largely mediated by monocyte-derived macrophages, contributes to atherosclerosis. Sedentary behavior is associated with atherosclerosis and cardiovascular diseases (CVD). We examined whether reducing sedentary behavior and improving walking time improves monocyte inflammatory phenotype in subjects with increased cardiovascular risk. Methods and Results Across 2 waves, 16 individuals with increased cardiovascular risk performed a 16-week intervention study (age 64±6 years, body mass index 29.9±4.3 kg/m2), using a device with vibration feedback to promote physical activity. Before and after intervention, we objectively examined physical activity (ActivPAL), cytokine production capacity after ex vivo stimulation in peripheral blood mononuclear cells, metabolism of peripheral blood mononuclear cells, circulating cytokine concentrations, and monocyte immunophenotype. Overall, no significant increase in walking time was found (1.9±0.7 to 2.2±1.2 h/day, P=0.07). However, strong, inverse correlations were observed between the change in walking time and the change in production of interleukin (IL)-1β, IL-6, IL-8, and IL-10 after lipopolysaccharide stimulation (rs=-0.655, -0.844, -0.672, and -0.781, respectively, all P<0.05). After intervention optimization based on feedback from wave 1, participants in wave 2 (n=8) showed an increase in walking time (2.2±0.8 to 3.0±1.3 h/day, P=0.001) and attenuated cytokine production of IL-6, IL-8, and IL-10 (all P<0.05). Glycolysis (P=0.08) and maximal OXPHOS (P=0.04) of peripheral blood mononuclear cells decreased after intervention. Lower IL-6 concentrations (P=0.06) and monocyte percentages (P<0.05), but no changes in monocyte subsets were found. Conclusions Successfully improving walking time shifts innate immune function towards a less proinflammatory state, characterized by a lower capacity to produce inflammatory cytokines, in individuals with increased cardiovascular risk. Clinical Trial Registration Information URL: http://www.trialregister.nl. Unique identifier: NTR6387.


Metabolomic study of fatty livers in ducks: Identification by 1H-NMR of metabolic markers associated with technological quality.
The control of fatty liver fat loss during cooking is a major issue. Previous studies showed that fat loss was influenced by bird production factors and liver technological treatments. However, part of the variability in fat loss remained uncontrolled. To provide enhanced insights into the determinism of fatty liver quality, liver hydrophilic metabolite profiles were measured by nuclear magnetic resonance of the proton ((1)H-NMR). The study aimed at i) comparing fatty livers with extreme fat loss values and ii) at characterizing the effect of postmortem evolution of livers during chilling. A group of 240 male mule ducks (Cairina moschata × Anas platyrhynchos) was reared and overfed. Their livers were sampled at 20 min and 6 h postmortem. Of these birds, 2 groups of ducks were built with extreme values on the technological yield (TY; TY = 100 - % fat loss; the low-fat-loss group, TY = 89.9%, n = 13; and the high-fat-loss group, TY = 68.3%, n = 12, P < 0.001). The (1)H-NMR analyses showed that the high-fat-loss livers were more advanced in postmortem biochemical and structural changes than low-fat-loss livers early postmortem. The high-fat-loss livers were characterized by hydrolysis of glycogen into glucose, worse integrity of cell membrane with diminution of compounds of phospholipids, and higher catabolic processes. The accelerated postmortem processes may be the origin of the differences in fat loss during cooking. During the early postmortem period, the adenosine triphosphate amount in liver cells was strongly reduced and lipolysis of triglycerides seemed to be enhanced. The glycogen stored in liver was first converted into glucose, but contrary to what happens in postmortem muscles, glucose was not converted into lactate.


One Health as a moral dilemma: Towards a socially responsible zoonotic disease control.
During the last decade, the concept of One Health has become the international standard for zoonotic disease control. This call for transdisciplinary collaboration between professionals in human, animal and environmental health has produced several successes in zoonotic disease control, surveillance and research. Despite the lack of a clear definition, a shared agenda or institutional governance, One Health has proven to be a fruitful idea. Due to its ambiguity, the One Health concept functions as a boundary object: by leaving room for interpretation to fit different purposes, it facilitates cooperation. In many cases, this results in the promotion of health of humans, animals and the environment. However, there are also situations in which this mutual benefit of a One Health approach is not that evident, for instance, when healthy animals are culled to protect public health. Although such a strategy could well be part of a One Health approach, it is hard to understand how this contributes to the health of concerning animals. Consequently, these practices often lead to public debate. This raises questions on how we should understand the One Health concept in zoonotic disease control. Is it really about equally improving the health of humans, animals and the environment and is this even possible? Or is it ultimately just public health that counts? In cases of conflict between different values, the lack of a universal definition of the One Health concept contributes to this complexity. Although boundary objects have many positive aspects, in the context of One Health and zoonotic disease control, this conception seems to conceal underlying normative differences. To address moral dilemmas related to a One Health approach in zoonotic disease control, it is important to reflect on moral status and the meaning of health for humans, animals and the environment.