Cadmium sulfide nanoparticles-assisted intimate coupling of microbial and photoelectrochemical processes: Mechanisms and environmental applications.
Intimate coupling of microbial extracellular electron transfer (EET) and photoelectrochemical processes is an emerging research area with great potential to circumvent many disadvantages associated with traditional techniques that depend on independent microbial or photocatalysis treatment. Microbial EET processes involve microorganism oxidation of extracellular electron donors for respiration and synchronous reduction of extracellular electron acceptors to form an integrated respiratory chain. Coupled microbial EET-photoelectrochemical technologies greatly improve energy conversion efficiency providing both economic and environmental benefits. Among substitutes for semiconductor photocatalysts, cadmium sulfide nanoparticles (CdS NPs) possess several attractive properties. Specifically, CdS NPs have suitable electrical conductivity, large specific surface area, visible light-driven photocatalysis capability and robust biocompatibility, enabling them to promote hybrid microbial-photoelectrochemical processes. This review highlights recent advances in intimately coupled CdS NPs-microbial extracellular electron transfer systems and examines the mechanistic pathways involved in photoelectrochemical transformations. Finally, the prospects for emerging applications utilizing hybrid CdS NPs-based microbial-photoelectrochemical technologies are assessed. As such, this review provides a rigorous fundamental analysis of electron transport dynamics for hybrid CdS NPs-microbial photoelectrochemical processes and explores the applicability of engineered CdS NPs-biohybrids for future applications, such as in environmental remediation and clean-energy production.


A trusted node-free eight-user metropolitan quantum communication network.
Quantum communication is rapidly gaining popularity due to its high security and technological maturity. However, most implementations are limited to just two communicating parties (users). Quantum communication networks aim to connect a multitude of users. Here, we present a fully connected quantum communication network on a city-wide scale without active switching or trusted nodes. We demonstrate simultaneous and secure connections between all 28 pairings of eight users. Our novel network topology is easily scalable to many users, allows traffic management features, and minimizes the infrastructure as well as the user hardware needed.


Polybrominated diphenyl ethers in thirteen shark species from offshore and coastal waters of Korea.
Limited reports are available on polybrominated diphenyl ethers (PBDEs) in sharks. In this study, PBDEs were measured in dorsal muscles (n=105) from 13 shark species collected from offshore and coastal waters of Korea. The PBDE concentrations varied greatly not only among species but also within species of sharks. The major PBDE congeners detected in our samples were BDEs 47, 28, 99, 153, 100, and 154. Concentrations of PBDEs in sharks in this study were lower than those reported for previous studies. The high PBDE concentrations were found for aggressive shark species. Inter-species differences in the concentrations and accumulation profiles of PBDEs are explained by differences in feeding habits and sampling locations. Several contributing factors such as growth velocity, trophic level, and local contamination may affect the bioaccumulation of PBDEs in sharks. The present study provides baselines for the occurrence and accumulation status of PBDEs in various shark species.


Organotypic Culture of the Mouse Cochlea from Embryonic Day 12 to the Neonate.
The development of the mammalian cochlea is a complex process involving several intersecting signaling pathways to ultimately generate its highly organized cellular architecture. In humans, and in the mouse, there is one row of inner hair cells aligned next to three rows of outer hair cells. The support cells intercalate between the hair cells to create a cellular mosaic across the organ of Corti (OC). Organotypic culture of the cochlea is a valuable technique for investigating the early stages of OC development. Cultures can be established at proliferative stages and maintained in vitro until cellular differentiation commences. It is straightforward to monitor differentiation in response to perturbations of key signaling pathways using pharmacological agents. While postnatal cochlea organ cultures have already been adapted for in vitro studies, it is more challenging to establish cultures at early embryonic stages due to the small size of the organ primordium. The protocol described in this chapter is permissive for all stages of development from E12 cochleas to day 5 neonatal murine cochleas, allowing culture survival up to 2 weeks in vitro.


Acquisition behaviours for nutrition-related information based on a health promotion model for older adults in a long-term care facility.
To explore the acquisition behaviours for nutrition-related information of older adults in a long-term care facility. A qualitative descriptive design was used in this study. Sixteen older adults in a long-term care facility were recruited using purposive sampling between March and May 2021. Data were collected via face-to-face semi-structured interviews, based on open questions regarding acquisition behaviours for nutrition-related information and flexible question formulation, and the data were analysed using an inductive-deductive method. A health promotion model was used as a conceptual framework to regulate the refinement of themes. Three themes were identified in this study. The first theme discussed the individual characteristics and experiences of older adults that contributed to their acquisition behaviours for nutrition-related information. The second theme described behaviour-specific cognitions of and the effects on the participants regarding the influencing factors involving various internal individual elements and external physical environment. The third theme explored the positive behavioural outcomes of the participants resulting from these acquisition behaviours. Acquisition behaviours for nutrition-related information of older adults in long-term care facilities were affected by both individual characteristics and external physical environment factors. Access to nutritional information can help older adults cultivate a healthy diet. Although they exhibited a significant interest in nutrition, the participants still encountered several difficulties. Based on the actual care needs of the older people, appropriate nutritional information interventions should be provided by healthcare providers working in long-term care facilities so as to improve the ability of the older people to acquire information independently. All 16 participants actively participated in the interview process and the preliminary preparation of the article.


Nanocrystals: comparison of the size reduction effectiveness of a novel combinative method with conventional top-down approaches.
Nanosizing is a non-specific approach to improve the oral bioavailability of poorly soluble drugs. The decreased particle size of these compounds results in an increase in surface area. The outcome is an increased rate of dissolution, which can lead to a better oral absorption. Standard approaches are bottom-up and top-down techniques. Combinative technologies are relatively new approaches, and they can be described as a combination of a bottom-up process followed by a top-down step. The work presented in this paper can be described as a combination of a non-aqueous freeze drying step (bottom-up), followed by wet ball milling or high pressure homogenization (top-down) to produce fine drug nanocrystals. The crystal habit of the model drug glibenclamide was modified by freeze drying from dimethyl sulfoxide (DMSO)/tert-butanol (TBA) solvent mixtures using different ratios. The resulting drug powders were characterized by scanning electron microscopy (SEM) as well as by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC). It was shown that the combinative approach can significantly improve the particle size reduction effectiveness of both top-down methods over conventional approaches. Drug lyophilization using DMSO:TBA in 25:75 and 10:90 v/v ratios resulted in a highly porous and breakable material. The milling time to achieve nanosuspensions was reduced from 24h with the jet-milled glibenclamide to only 1h with the modified starting material. The number of homogenization cycles was decreased from 20 with unmodified API to only 5 with the modified drug. The smallest particle size, achieved on modified samples, was 160nm by wet ball milling after 24h and 355nm by high pressure homogenization after 20 homogenization cycles at 1500bar.


The study on the characteristics of carbon pressure agglomeration and the dynamic evolution of heterogeneity in China from a regional perspective.
Provinces (cities and districts) with identifiable boundaries are under intense pressure to reduce emissions as a fundamental unit and research object of carbon peaking and carbon-neutrality goals. Due to the significant variability of regional development, achieving equilibrium between carbon emissions and carbon absorption is challenging, contributing to the difficulty of developing carbon emission reduction and relevant green strategic initiatives in China. Therefore, this paper explored the spatial effect of carbon balance with carbon pressure as the starting point. First, this paper defined the "carbon pressure index" (CPI) of 30 provinces (cities and districts) in China from 2000 to 2019. Second, this paper validated the CPI agglomeration evolutionary characteristics in global and local aspects based on the Moran's index. Third, this paper identified and decomposed the spatial heterogeneity of CPI using the kernel density estimation method and the Theil index, then extracted typical cities to analyze the specific causes. Finally, this paper classified the seven regions in China into four types according to a comprehensive analysis of CPI. The results indicated that China's ecological carbon cycle system was in a serious "carbon overload" state. Thirty provinces (cities and districts) showed significant spatial agglomeration characteristics. The spatial gap of CPI was gradually decreasing nationwide, and the intra-regional differences were the leading cause of CPI levels in China. This can provide policy basis for the improvement of China's balanced development system of regional carbon emission reduction.


Stability analysis of Hadamard and Caputo-Hadamard fractional nonlinear systems without and with delay.
This paper handles with the Hadamard and the Caputo-Hadamard fractional derivative and stability of related systems without and with delay. Firstly, the derivative inequalities are obtained, which is indispensable in applying the theorems derived in this paper. Then, for systems without delay, we get the stability results by using the Lyapunov direct method and for systems with delay, we explore two useful inequalities to verify the stability. Examples are presented with numerical simulations to illustrate the effectiveness of our results.


4-hydroxynonenal from pathology to physiology.
4-hydroxynonenal is a major product of lipid peroxidation. It was firstly studied under the point of view of its toxicity, as it is an easily diffusable substance, thought to be able to explain the "far damages" seen in conditions of increased lipid peroxidation. Really, when used at concentration from 10 microM to 1 mM, usually referred to as high concentrations, the aldehyde is able to produce strong inhibitions of several enzymatic activities. When used, however, at concentration of 1 microM or lower, it displays a lot of activities regarding especially cell multiplication and differentiation. As the concentrations indicated above are usually found in normal tissues, these effects may be considered as physiological. As a low level of lipid peroxidation exists in normal tissues, the aldehyde displays signalling activities in normal cells. Among them, it is to consider the stimulation of neutrophil chemotaxis, the strong activation of plasmamembrane adenylate kinase, the strong activation of membrane phospholipase C, both in hepatocytes and neutrophils, the block in the expression of the oncogene c-myc in human leukemic cells, accompanied by differentiation of the same cells, the effects on the cyclins and the activity of E2F transcription factor, the strong increase of the expression of the gene for procollagen alfa1(I), occurring due to the activation of the c-jun/junkinases/AP-1 pathway. Moreover, it is able to block the activity of the PDGF-beta receptor. The last facts allow to think that a hydroxynonenal pathway works in the production of fibrosis.


Computerized model of cost-utility analysis for treatment of age-related macular degeneration.
To present a computerized model assessing individualized cost utility for current treatments for neovascular age-related macular degeneration (AMD) to enhance discussion regarding treatment options. Case- and eye-specific cost-utility analysis using individual case scenarios. Visual acuity data from published randomized controlled trials are incorporated into this analysis. Computerized model (Microsoft Visual Basic 6.0 programming) to establish preference-based cost-utility analysis in association with individual cost of treatment and blindness for neovascular AMD for both the better and worst seeing eye, with extrapolation of results over a 5-year term. Cost per quality-adjusted life-year (QALY) and cost per QALY gained for comparison of treatments for specific visual acuities. All treatments show an increase in utility in comparison with best supportive care (BSC) if the better-seeing eye is treated. Ranibizumab, using the Phase IIIb, Multicenter, Randomized, Double-Masked, Sham Injection-Controlled Study of the Efficacy and Safety of Ranibizumab in Subjects with Subfoveal Choroidal Neovascularisation (CNV) with or without Classic CNV Secondary to AMD (PIER) regimen, is the most cost effective at $626 938 per QALY gained for treatment of the better seeing eye. To increase utility value when treating the worst seeing eye, the vision must improve to such a degree that it becomes the better seeing eye. This level of improvement is only possible if there is <9 letters difference between the 2 eyes and treated with ranibizumab. Over 5 years, increasing influence from the cost of blindness results in increasing costs for those treatments unable to stabilize vision. Within 5 years, the cost per QALY for the BSC is greater than all treatments except monthly ranibizumab injections. Assessment of cost of treatment incorporates both effectiveness of treatment, cost of treatment, and cost of blindness. Cost analysis enables incorporation of these aspects of treatment with the quality of life data to provide a better comparison of treatments over time. This analysis has provided a method for individual analysis and therefore can provide the structure for resource allocation. The authors have no proprietary or commercial interest in any materials discussed in this article.


Breathing pattern affects respiratory heat loss but not bronchoconstrictor response in asthma.
To determine whether changes in breathing pattern alone affect respiratory heat loss (RHL) and the constrictor response to cold dry gas hyperpnea in asthmatic subjects, we performed the following 2 part study: first we measured RHL in 8 asthmatic and 8 normal subjects during controlled eucapnic hyperpnea while they breathed at inspiratory to expiratory ratios (I/E) of 1:3, 3:1, and 2:2, and we recorded postchallenge forced expiratory volume in 1 sec (FEV1) in the asthmatic group; we then performed the same measurements in 8 asthmatic and 8 normal subjects at fixed target minute ventilation (VE) for tidal volumes of 0.2 X Forced vital capacity (FVC), 0.4 X FVC, and 0.6 X FVC by varying the target respiratory rate appropriately. Our results show that (1) increasing I/E ratio or tidal volume-frequency ratio (VT/f) at fixed VE produced small but statistically significant increases (p less than 0.05) in overall heat loss per unit volume of respired gas (RHL/VE) in both asthmatic and nonasthmatic subjects of 1-4 cal/L; (2) changes in breathing pattern alone did not affect bronchoconstrictor response as assessed by lack of change in slopes and intercepts of % delta FEV1 vs. RHL dose-response curves; and (3) the increase in RHL per unit volume of respired gas resulting from increasing VT/f ratios during cold gas hyperpnea was significantly greater in asthmatic than in nonasthmatic subjects. We conclude that changes in breathing pattern may affect overall RHL measured at the mouth, although the maximum effect of such changes in both asthmatic and nonasthmatic subjects is small (10-15%); that such changes do not significantly alter airway constrictor response in asthmatic persons; and (3) that the effects of changing breathing pattern on RHL may be more pronounced in asthmatic than nonasthmatic subjects, which suggests that the asthmatic group may be less able to adapt to factors that alter the magnitude and site of RHL.


Distinct distribution of GLUT4 and insulin regulated aminopeptidase in the mouse kidney.
The physiological importance of the insulin responsive glucose transporter GLUT4 in adipocytes and muscle in maintaining glucose homeostasis is well established. A key protein associated with this process is the aminopeptidase IRAP which co-localizes with GLUT4 in specialized vesicles, where it plays a tethering role. In this study, we investigated the distribution of both GLUT4 and IRAP in the kidney to gain insights into the potential roles of these proteins in this organ. Both IRAP and GLUT4 immunostaining was observed in the epithelial cells of the proximal and distal tubules and thick ascending limbs in the cortex, but very little overlap between GLUT4 and IRAP immunoreactivity was observed. GLUT4 staining was consistent with a vesicular localization, whereas IRAP staining was predominantly on the luminal surface. In the principal cells of the inner medulla collecting duct (IMCD), IRAP immunoreactivity was detected throughout the cell, with limited overlap with the vasopressin responsive water channel aquaporin-2 (AQP-2). AQP-2 levels were observed to be two-fold higher in IRAP knockout mice. Based on our results, we propose that GLUT4 plays a role in shunting glucose across epithelial cells. In the kidney cortex, IRAP, in concert with other peptidases, may be important in the generation of free amino acids for uptake, whereas in the principal cells of the inner medulla IRAP may play a localized role in the regulation of vasopressin bioactivity.


Smooth muscle caldesmon is an extended flexible monomeric protein in solution that can readily undergo reversible intra- and intermolecular sulfhydryl cross-linking. A mechanism for caldesmon's F-actin bundling activity.
Caldesmon is a major F-actin binding protein of smooth muscle that has been implicated as a component of a thin filament regulatory system. Chicken gizzard caldesmon consists of polypeptides of Mr-135,000 and 140,000 which are closely related as determined by analysis of cyanogen bromide cleavage fragments. It is a highly extended flexible protein having a contour length of about 146 nm and a secondary structure composed primarily of random coil. Physical and chemical cross-linking data suggest that caldesmon exists as a monomer in solution. The cysteine content of caldesmon was determined to be 2 residues/polypeptide. Remarkably, in solution it readily undergoes sulfhydryl oxidation to form either an internal disulfide bridge in the protein or cross-links between individual polypeptides to form dimers, trimers, tetramers, etc. The internally cross-linked species have a smaller Stokes radius than the reduced molecules, indicating that the cross-link "trapped" the molecule in a compact conformation. Oxidized protein containing caldesmon oligomers is a potent F-actin bundling protein. Complete reduction of caldesmon abolishes the F-actin bundling activity. Since a vast excess of reducing agent is required to convert caldesmon from an oxidized to reduced state, it may exist in either state in vivo. Thus, the ability of caldesmon to undergo reversible sulfhydryl cross-linking, and thereby reversible F-actin cross-linking, may be of physiological significance.


Endothelial dysfunction following thrombolysis in vitro.
Thrombolytic therapy is frequently used to manage vascular graft thrombosis. However, long-term patency after thrombolysis remains poor. The purpose of this study was to characterise the morphological and functional response of endothelial cells (EC) exposed to a thrombus and subsequently lytic therapy. Human EC were exposed to human whole blood thrombus for 2, 6, 12, and 24 h. The thrombus was lysed with urokinase. Cell morphology was studied with electron microscopy. Northern blot analyses were performed with human c-DNA probes for endothelin-1, thrombomodulin, tissue factor, tissue plasminogen activator, plasminogen activator inhibitor, and triose phosphate isomerase. EC retraction occurred for each period of incubation. Thrombomodulin expression was increased 2.2-fold at 6 h and 2.4-fold at 24 h. t-PA expression was depressed proportionally to the duration of thrombus exposure. PAI and TF expression transiently increased 1.5-fold at 2 h of exposure and returned to baseline at 6 h. Endothelin expression remained unchanged. Except for a transient increase in TF expression and reversal of the tPA/PAI ratio, EC exposed to thrombus do not appear to become actively procoagulant. The increase in TM expression may reflect enhanced thromboresistance. However, EC retraction may be responsible for an increase thrombogenicity of saphenous vein graft after thrombosis and Urokinase therapy.


The role of insulin resistance in the relation of visceral, abdominal subcutaneous and total body fat to cardiovascular function.
The separate cardiovascular effects of type 2 diabetes and adiposity remain to be examined. This study aimed to investigate the role of insulin resistance in the relations of visceral (VAT), abdominal subcutaneous (aSAT) adipose tissue and total body fat (TBF) to cardiovascular remodeling. In this cross-sectional analysis of the population-based Netherlands Epidemiology of Obesity study, 914 middle-aged individuals (46% men) were included. Participants underwent magnetic resonance imaging. Standardized linear regression coefficients (95%CI) were calculated, adjusted for potential confounding factors. All fat depots and insulin resistance (HOMA-IR), separate from VAT and TBF, were associated with lower mitral early and late peak filling rate ratios (E/A): -0.04 (-0.09;0.01) per SD (54 cm2) VAT; -0.05 (-0.10;0.00) per SD (94 cm2) aSAT; -0.09 (-0.16;-0.02) per SD (8%) TBF; -0.11 (-0.17;-0.05) per 10-fold increase in HOMA-IR, whereas VAT and TBF were differently associated with left ventricular (LV) end-diastolic volume: -8.9 (-11.7;-6.1) mL per SD VAT; +5.4 (1.1;9.7) mL per SD TBF. After adding HOMA-IR to the model to evaluate the mediating role of insulin resistance, change in E/A was -0.02 (-0.07;0.04) per SD VAT; -0.03 (-0.08;0.02) per SD aSAT; -0.06 (-0.13;0.01) per SD TBF, and change in LV end-diastolic volume was -7.0 (-9.7;-4.3) mL per SD VAT. In women, adiposity but not HOMA-IR was related to higher aortic arch pulse wave velocity. Insulin resistance was associated with reduced diastolic function, separately from VAT and TBF, and partly mediated the associations between adiposity depots and lower diastolic function.


Evaluation of knowledge and behavior of and attitudes towards smoking cigarettes and using smokeless tobacco in patients with chronic renal failure.
Smoking can have negative effects on renal function in healthy individuals, which may result in kidney disease. To determine knowledge, behavior, and attitudes toward smoking cigarettes and using smokeless tobacco among patients with chronic renal failure, we sought to provide evidence for appropriate precautions and guidance for further research. The study included 86.7% of 390 patients undergoing treatment for chronic renal failure who completed a 30-question instrument. Of the participants, 7.9% were smokers and 12.6% ex-smokers. Among the smokers, 61% said they wanted to quit and 45% said they needed help to quit. Of the participants, 9.5% were using Maras powder, a type of smokeless tobacco. Of the smokeless tobacco users, 55.6% noted that they wanted to give it up. The rate of the participants smoking cigarettes and/or using smokeless tobacco was 17.4%. In addition, 38.9% of the participants said that they started to use smokeless tobacco to quit smoking cigarettes. Of the participants, 62.6% thought smoking was harmful to the kidneys. The rate of the passive smokers was 30.2%. Of the participants, 66.3% explained that they were exposed to smoke at home. Appropriate interventions should begin to help patients with chronic renal failure stop smoking and to prevent them from exposure to cigarette smoke. Smokers should be informed that using smokeless tobacco is not a way to stop smoking cigarettes. Education programs should be conducted to prevent people from using smokeless tobacco and to help smokeless tobacco users to quit their habit.


Herbs as old potential treatments for lymphedema management: A systematic review.
Herbs have been reported to be effective in reducing lymphedema burden. This paper aimed to review literature reporting on herbs for lymphedema treatment. A systematic review was performed using the PRISMA guideline. Clinical studies on herbal intervention and lymphedema were included. Evidence on the effectiveness of herbal interventions for desired outcomes including reduction of edema volume, other symptoms, quality of life and inflammation were collected and assessed in detail. In all twenty studies were included in this review. Of these 14 studies were randomized clinical trials and the rest were prospective pilot studies. Herbal treatment was reported for breast cancer-related lymphedema in most studies and coumarin was the most reported herb that used for lymphedema management. Edema volume reduction (17 out of 20) and symptoms improvement (15 out of 20) were the outcomes reported in most studies. Phytochemicals can be a promising pharmacotherapy for lymphedema management. However, further evidence is needed to establish definite effectiveness for the use of herbal remedies for lymphedema management.


[Pain within the healthcare team, a source of dyscommunication].
The subjective nature and complexity of the pain phenomenon make it a difficult symptom to take into consideration, regardless of where the patient is being cared for, leading to multiple sources of dyscommunication between professionals. Despite the undeniable progress that has been made, this recurring theme has received little attention in the professional literature. It is therefore worthwhile analyzing the causes of these relational problems and proposing avenues of reflection and work that could help remedy them.


Predictors and outcomes of disseminated tuberculosis in an intermediate burden setting.
University-affiliated hospital located in Porto, North Portugal, an area with a low to intermediate incidence of tuberculosis (TB). To identify predictors and outcomes of disseminated TB (dTB). A cohort of patients diagnosed with TB between 2007 and 2013 was retrospectively analysed. Patients with dTB criteria were characterized and compared to single organ TB cases. Factors independently associated with dTB were determined by multivariate logistic regression analysis. A total of 744 patients were analysed, including 145 with dTB. Independent risk factors for dTB were pharmacological immunosuppression (OR 5.6, 95% CI 2.8-11.3), HIV infection (OR 5.1, 95% CI 3.1-8.3), chronic liver failure or cirrhosis (OR 2.3, 95% CI 1.4-4.1) and duration of symptoms (OR 2.3, 95% CI 1.4-3.8). Compared to single organ TB, the clinical presentation of dTB patients differed by the absence of haemoptysis (OR 3.2, 95% CI 1.3-8.4) and of dyspnoea (OR 1.9, 95% CI 1.2-3.1), presence of weight loss (OR 1.8, 95% CI 1.1-2.9), night sweats (OR 1.7, 95% CI 1.1-2.7) and bilateral lung involvement (OR 4.4, 95% CI 2.8-7.1). Mortality and time until culture conversion were higher for dTB patients, although not reaching statistical significance. Immunosuppressive conditions and chronic liver failure or cirrhosis were associated with increased risk of dTB. The haematogenous spread may be dependent on longer symptomatic disease and usually progresses with bilateral lung involvement.


Design, synthesis and biological evaluation of diamino substituted cyclobut-3-ene-1,2-dione derivatives for the treatment of drug-resistant tuberculosis.
Mycobacterium tuberculosis (Mtb) ATP synthase is an important target for treating drug-resistant infections and sterilizing the bacteria, spurring intensive efforts to develop new TB therapeutics based on this target. In this work, four novel series including furan-2(5H)-ketone (3, 4), maleimide (5) and squaramide (6) derivatives were designed, respectively, through the strategy of scaffold morphing and hydrogen-bond introduction, using the selective Mtb ATP synthase inhibitor compound 2 as the lead compound. The result demonstrated that diamino substituted cyclobut-3-ene-1,2-dione compounds 6ab and 6ah displayed good to excellent in vitro anti-TB activities (MIC 0.452-0.963 μg/mL) with low cytotoxicity (IC50 > 64 μg/mL). In addition, not only did compound 6ab show effective activity against clinically isolated resistant strains, it also revealed good druggability profiles including improved metabolic stability, no hERG channel inhibition potential, and acceptable oral bioavailability. The preliminary result of docking study and in vitro anti-bedaquiline-resistant strain test compared to compound 2 suggested that Mtb ATP synthase is most likely the target of compound 6ab. The structure-activity relationship laid a good foundation for the identification of novel squaramides as a potential treatment of drug-resistant tuberculosis.


Application and prospect of metabolomics-related technologies in food inspection.
Food inspection covers a broad range of topics, including nutrient analysis, food pollutants, food auxiliary materials, additives, and food sensory identification. The foundation of diverse subjects like food science, nutrition, health research, and the food industry, as well as the desired reference for drafting trade and food legislation, makes food inspection highly significant. Because of their high efficiency, sensitivity, and accuracy, instrumental analysis methods have gradually replaced conventional analytical methods as the primary means of food hygiene inspection. Metabolomics-based analysis technology, such as nuclear magnetic resonance (NMR), gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), and capillary electrophoresis-mass spectrometry (CE-MS), has become a widely used analytics platform. This research provides a bird's eye view of the application and future of metabolomics-related technologies in food inspection. We have provided a summary of the features and the application range of various metabolomics techniques, the strengths and weaknesses of different metabolomics platforms, and their implementation in specific inspection procedures. These procedures encompass the identification of endogenous metabolites, the detection of exogenous toxins and food additives, analysis of metabolite alterations during processing and storage, as well as the recognition of food adulteration. Despite the widespread utilization and significant contributions of metabolomics-based food inspection technologies, numerous challenges persist as the food industry advances and technology continues to improve. Thus, we anticipate addressing these potential issues in the future.


Differences in doxorubicin-induced apoptotic signaling in adult and immature cardiomyocytes.
A proposed mechanism for the cardiotoxicity of doxorubicin (DOX) involves apoptosis in cardiomyocytes. In the study described here, we investigated the molecular basis for the differences in DOX-induced toxicity in adult rat cardiomyocytes (ARCM), neonatal rat cardiomyocytes (NRCM), and rat embryonic H9c2 cardiomyoblasts. Activation of caspase-9 and -3 was considerably lower in DOX-treated ARCM as compared with NRCM and H9c2 cardiomyoblasts. Addition of cytochrome c caused the activation of caspase-9 and -3 in permeabilized NRCM and H9c2 cardiomyoblasts but not in permeabilized ARCM. Expression of proapoptotic proteins, apoptotic protease activating factor-1 (Apaf1), and procaspase-9 was significantly lower, and abundance of antiapoptotic X-linked inhibitor of apoptosis protein (XIAP) was higher in ARCM, as compared with immature cardiac cells. Despite the abundance of XIAP in ARCM, its role in the inhibition of apoptosome function was dismissed, as second mitochondria-derived activator of caspases (Smac)-N7 peptide, had no effect on caspase activation in response to cytochrome c in these cells. Adenoviral expression of Apaf1 exacerbated the activation of caspase-9 and -3 in DOX-treated NRCM, but did not increase their activities in DOX-treated ARCM. This finding points to a major difference in the apoptotic signaling between immature and adult cardiomyocytes. The mitochondrial apoptotic pathway is limited in ARCM treated with DOX.


Modelling the impact of 4CMenB and MenACWY meningococcal combined vaccination strategies including potential 4CMenB cross-protection: An application to England.
Invasive meningococcal disease (IMD), an uncommon but severe disease, affects mainly infants, young children and adolescents. Meningococcal B (4CMenB) and ACWY (MenACWY) vaccines targeting IMD-causing serogroups B and A, C, W and Y, respectively are available for these mostly-affected age-groups. The objective was to assess the impact of 4CMenB and/or MenACWY vaccination strategies on IMD in England, considering MenACWY carriage protection and potential cross-protection of 4CMenB against non-B serogroups. A novel dynamic transmission model was developed, accounting for vaccine characteristics, with separate variables for meningococcal carriage and IMD for three groups: B; ACWY; and 'Other' mostly non-pathogenic serogroups. A dynamic force of infection is assumed for each group. The model analysis uses data from England before 2015 (when 4CMenB and MenACWY were introduced), and accounts for existing MenC vaccination impact. Compared with no vaccination, the smallest decrease in IMD cases is observed for MenACWY strategies (toddler and/or adolescent). 4CMenB (infant or infant/adolescent), alone or with MenACWY, always results in the most rapid and steep decline in IMD cases. Combined strategies with adolescent 4CMenB result in the largest decrease in IMD cases, whereas adding MenACWY for toddlers has a minor impact. With potential 4CMenB cross-protection, 4CMenB infant strategy has a notable impact on reduction of MenW and MenY IMD cases in strategies where MenACWY toddler and/or adolescent vaccination is absent. This novel model allows for analysis of combined 4CMenB and MenACWY strategies including potential 4CMenB cross-protection. In settings comparable to England, a comprehensive meningococcal vaccination programme should include infant 4CMenB as essential building block. Decisions to include MenACWY toddler programmes should consider herd effects of MenACWY adolescent programmes and 4CMenB potential cross-protection effects. Extending 4CMenB infant and MenACWY adolescent programmes with a 4CMenB adolescent programme allows for the largest overall reduction in IMD cases.


Executive function predict the quality of life and negative emotion in older adults with diabetes: A longitudinal study.
To investigate the influence of executive function (EF) on current and future quality of life (QoL) and negative emotion (NE) in older adults with diabetes. A total of 128 older adults with diabetes were recruited. Independent variables (demographic information, health and medical conditions, cognitive function, life function) were collected in the first year. Dependent variables (QoL and NE) were collected for 3 years. Pearson's correlation coefficient analysis and stepwise multiple linear regression analysis were performed to identify the predictors of QoL and NE. EF was the strongest predictor for overall QoL and NE in all 3 years, and accounted for 23.0-36.2% and 11.1-17.1% of the variance, respectively. The second strongest predictor for overall QoL in all 3 years was pain interference, which accounted for 3.2-5.8% of the variance. Pain interference was also the second strongest predictor for NE in the second year, accounting for 5.5% of the variance. The present study revealed that EF is more predictive than pain for current and future QoL and NE in older adults with diabetes. We recommend that EF be included as an indicator for diabetes surveillance, and that prevention of EF decline be a part of diabetes management plans.


Exome sequencing for perinatal phenotypes: The significance of deep phenotyping.
To ascertain the performance of exome sequencing (ES) technology for determining the etiological basis of abnormal perinatal phenotypes and to study the impact of comprehensive phenotyping on variant prioritization. A carefully selected cohort of 32/204 fetuses with abnormal perinatal phenotypes following postmortem/postnatal deep phenotyping underwent ES to identify a causative variant for the fetal phenotype. A retrospective comparative analysis of the prenatal versus postmortem/postnatal phenotype-based variant prioritization was performed with aid of Phenolyzer software. A review of selected literature reports was done to examine the completeness of phenotypic information for cases in those reports and how it impacted the performance of fetal ES. In 18/32 (56%) fetuses, a pathogenic/likely pathogenic variant was identified. This included novel genotype-phenotype associations, expanded prenatal phenotypes of known Mendelian disorders and dual Mendelian diagnoses. The retrospective analysis revealed that the putative diagnostic variant could not be identified on basis of prenatal findings alone in 15/22 (68%) cases, indicating the importance of comprehensive postmortem/postnatal phenotype information. Literature review was supportive of these findings but could not be conclusive due to marked heterogeneity of involved studies. Comprehensive phenotyping is essential for improving diagnostic performance and facilitating identification of novel genotype-phenotype associations in perinatal cohorts undergoing ES.


Effects of water deprivation and angiotensin II intracerebroventricular administration on brain nitric oxide synthase activity.
Intracranial administration of L-arginine causes a reduction of the water intake induced by water deprivation or by intracerebroventricular (i.c.v.) injection of angiotensin II (angiotensin II), through the release of nitric oxide (NO) in the central nervous system. We studied the effects of i.c.v. angiotensin II (120 ng/rat) in association with i.c.v. L-arginine (2.5-10 microg/rat) on blood pressure. We also studied the effects of both peripheral and central angiotensin II injection (1.5-6 mg kg(-1) i.p. and 30-120 ng rat(-1) i.c.v., respectively) on NO synthase activity in the cortex, diencephalon and brainstem, after water deprivation (24 h), conditions producing activation of the renin-angiotensin system. L-arginine dose dependently antagonized the increase in blood pressure induced by i.c.v. angiotensin II (P < 0.001). Peripheral administration of angiotensin II produced a dose-dependent reduction of NO synthase activity in the brainstem and cortex (P < 0.001), but not in the diencephalon. Water deprivation produced similar effects on brain NO synthase activity. Angiotensin II i.c.v. injection caused NO synthase activity reduction in all brain regions studied (P < 0.001). Our findings suggest that NO and angiotensin II could play opposite roles in brain regulation of blood pressure and drinking behaviour.


On the pedicle subtraction osteotomy technique and its modifications during the past two decades: a complementary classification to the Schwab's spinal osteotomy classification.
To propose a complementary classification to the Schwab's osteotomy classification that would regroup together under a common umbrella different published pedicle subtraction osteotomy (PSO) variations that are commonly used, to have a common language and complete the spine surgeon's armamentarium when dealing with rigid spinal deformities. The 2 general types corresponding to the grades 3 and 4 of the Schwab classification were separated into 6 gradual subtypes (grades 3A, 3B, 3C, 4A, 4B, 4C). The classification is based on the amount of resected pedicle, the inclusion or not of the disc above, and the location of the axis of rotation. Based on the proposed classification, a reliability study was performed using 18 cases that were classified by 8 readers with expertise in the management of adult deformities with the use of osteotomies. Clinical cases were classified according to the 6 grades proposed in the classification. The intra-rater reliability for the classification was "almost perfect agreement" with a Fleiss kappa coefficient average of 0.92 (range 0.85-1.00). The inter-rater reliability was "almost perfect agreement" with a coefficient average of 0.90 for the 2 readings that were done at an interval of 2 weeks. The developed classification proved to be reliable and intuitive. It is an original way to display a catalog of different available PSO modifications including the original technique, in a logical and gradual order to help the surgeons in their decisions and show them that between a grade 2 osteotomy and a grade 5 osteotomy, many intermediate options are available. Further work with a treatment algorithm for clinical practice based on the current classification may be developed in the future.


Host Range and Phenology of Sugarcane Aphid (Hemiptera: Aphididae) and Natural Enemy Community in Sorghum in Haiti.
To determine the factors leading to outbreaks of the sugarcane aphid, Melanaphis sacchari, (Zehntner) (Hemiptera: Aphididae) in sorghum in Haiti, a survey was carried out on farms during two cropping seasons, spring and fall of 2018. A total of 45 plots in three Haitian regions were monitored from the five-leaf stage to grain ripening. Infestation with M. sacchari was significantly higher in spring than in fall, except in one location. Melanaphis sacchari populations varied significantly according to phenological stages of sorghum, with significantly higher abundance during the heading and flowering stages than other stages. In and around sorghum fields, the sugarcane aphid was observed on plants from three families: Poaceae, Malvaceae, and Cucurbitaceae. Aphid natural enemies found in sorghum fields consisted of eight species of ladybeetles (Coleoptera: Coccinellidae), one hoverfly (Diptera: Syrphidae), one lacewing (Neuroptera: Chrysopidae), and one predatory midge (Diptera: Cecidomyiidae). In addition to these predators, two parasitoid species, Adialytus sp. (Hymenoptera: Braconidae) and Pachyneuron aphidis (Bouché) (Hymenoptera: Pteromalidae), emerged from sugarcane aphid mummies. Predator and parasitoid densities were highly affected by growing season, with most of the biological control happening in fall. This study provides insights on sugarcane aphid management in Haiti and the Caribbean Islands.


Persistent nicotinic blockade by chlorisondamine of noradrenergic neurons in rat brain and cultured PC12 cells.
Chlorisondamine (CHL) blocks behavioural responses to nicotine for several weeks or months in rats. Persistent blockade has also been demonstrated ex vivo, in assays of nicotine-evoked striatal dopamine release. Central administration of [3H]-CHL leads to long-term retention of radiolabel in nigrostriatal dopaminergic neurons and in few other cell groups. We investigated whether an analogous blockade also occurs in noradrenergic neurons in the brain and in cultured pheochromocytoma (PC12) cells, which have a similar noradrenergic phenotype. Administration of CHL (10 mg kg(-1) s.c. or 10 microg i.c.v.), 21 days prior, resulted in a near-total block of nicotine-evoked release of hippocampal [3H]-noradrenaline ([3H]-NA) from superfused rat synaptosomes; NMDA-evoked [3H]-NA release was unaffected. Three weeks after administration of [3H]-CHL (10 microg i.c.v.), preferential accumulation of radiolabel was observed in the locus coeruleus, which provides the entire noradrenergic innervation to hippocampus, as well as in previously noted structures. In rat pheochromocytoma (PC12) cells, nicotine evoked [3H]-NA release (EC50 approximately 30 microM). This effect was blocked by co-incubation with mecamylamine (10 microM) or CHL (1 microM) but was not affected by alpha-bungarotoxin. As in the hippocampus, the nicotinic agonist cytisine was at least as efficacious as nicotine. Acute exposure of PC12 cells to CHL 10 or 100 microM (but not 1 microM), followed by 90 min wash-out, almost completely blocked release evoked by 30 microM nicotine. More prolonged (24 h) exposure to CHL 100 microM (but not 1 or 10 microM), followed by 3 days of wash-out, partially inhibited release evoked by nicotine, leaving responses to high K+ unchanged. A significant (30%) reduction was also seen 5 days after exposure. We conclude that persistent nicotinic blockade by CHL is neither restricted to mesostriatal dopamine neurons, nor to the CNS, nor to neurons possessing the same nicotinic receptor pharmacology. In addition, the persistent blockade does not appear to result from an acute blocking action, but may be dependent upon intracellular accumulation of the antagonist.


Discovery and validation of serum protein changes in type 1 diabetes patients using high throughput two dimensional liquid chromatography-mass spectrometry and immunoassays.
Type 1 diabetes (T1D) is expected to cause significant changes in the serum proteome; however, few studies have systematically assessed the proteomic profile change associated with the disease. In this study, a semiquantitative spectral counting-based two dimensional liquid chromatography mass spectrometry platform was used to analyze serum samples from T1D patients and controls. In this discovery phase, significant differences were found for 21 serum proteins implicated in inflammation, oxidation, metabolic regulation, and autoimmunity. To assess the validity of these findings, six candidate proteins including adiponectin, insulin-like growth factor binding protein 2, serum amyloid protein A, C-reactive protein, myeloperoxidase, and transforming growth factor beta induced were selected for subsequent immune assays for 1139 T1D patients and 848 controls. A series of statistical analyses using cases and controls matched for age, sex, and genetic risk confirmed that T1D patients have significantly higher serum levels for four of the six proteins: adiponectin (odds ratio (OR) = 1.95, p = 10(-27)), insulin-like growth factor binding protein 2 (OR = 2.02, p < 10(-20)), C-reactive protein (OR = 1.13, p = 0.007), serum amyloid protein A (OR = 1.51, p < 10(-16)); whereas the serum levels were significantly lower in patients than controls for the two other proteins: transforming growth factor beta induced (OR = 0.74, p < 10(-5)) and myeloperoxidase (OR = 0.51, p < 10(-41)). Compared with subjects in the bottom quartile, subjects in the top quartile for adiponectin (OR = 6.29, p < 10(-37)), insulin-like growth factor binding protein 2 (OR = 7.95, p < 10(-46)), C-reactive protein (OR = 1.38, p = 0.025), serum amyloid protein A (OR = 3.36, p < 10(-16)) had the highest risk of T1D, whereas subjects in the top quartile of transforming growth factor beta induced (OR = 0.41, p < 10(-11)) and myeloperoxidase (OR = 0.10, p < 10(-43)) had the lowest risk of T1D. These findings provided valuable information on the proteomic changes in the sera of T1D patients.


Characterization of crude extract prepared from Indian curd and its potential as a biopreservative.
The adverse effects of chemical preservatives used to prevent food spoilage have led to the search for various biopreservatives. Considering this, a study was undertaken to prepare crude extract (CE) from Indian curd (a fermented dairy product) and characterized it in terms of antioxidant and antimicrobial activities against some common food-borne bacteria. The CE exhibited well pronounced antimicrobial activity against Bacillus cereus and Salmonella typhimurium. The minimum inhibitory concentration (MIC) of CE was recorded for 2-fold concentrated solution prepared from a 10-fold stock. The CE exhibited a significantly higher (p < 0.05) antioxidant and antimicrobial activities compared to its fractions. The CE was found to be heat stable (up to 100 ℃ for 30 min) and exhibited a significant (p < 0.05) increase in activity at pH 2-7 and in combination with 2% citric acid solution. Trypsin treatment suggested it to be of proteinaceous in nature. The antibacterial activity of CE remained intact at 4 ℃ for seven days, whereas non-significant (p > 0.05) changes in its activity were noted during storage at -20 ℃ for 30 days. The curd sample used for preparation of CE, when tested for bacteriocin production and subsequent antimicrobial activity, did not show inhibition against S. typhimurium. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis analysis of CE and its fractions revealed multi-banding pattern. By virtue of its bioactivities observed, CE can be explored as a promising food biopreservative.


Flexibility and enzyme activity of NADH oxidase from Thermus thermophilus in the presence of monovalent cations of Hofmeister series.
Recently, we have shown that anions of Hofmeister series affect the enzyme activity through modulation of flexibility of its active site. The enzyme activity vs. anion position in Hofmeister series showed an unusual bell-shaped dependence. In the present work, six monovalent cations (Na(+), Gdm(+), NH(4)(+), Li(+), K(+) and Cs(+)) of Hofmeister series with chloride as a counterion have been studied in relation to activity and stability of flavoprotein NADH oxidase from Thermus thermophilus (NOX). With the exception of strongly chaotropic guanidinium cation, cations are significantly less effective in promoting the Hofmeister effect than anions mainly due to repulsive interactions of positive charges around the active site. Thermal denaturations of NOX reveal unfavorable electrostatic interaction at the protein surface that may be shielded to different extent by salts. Michaelis-Menten constants for NADH, accessibility of the active site as reflected by Stern-Volmer constants and activity of NOX at high cation concentrations (1-2 M) show bell-shaped dependences on cation position in Hofmeister series. Our analysis indicates that in the presence of kosmotropic cations the enzyme is more stable and possibly more rigid than in the presence of chaotropic cations. Molecular dynamic (MD) simulations of NOX showed that active site switches between open and closed conformations [J. Hritz, G. Zoldak, E. Sedlak, Cofactor assisted gating mechanism in the active site of NADH oxidase from Thermus thermophilus, Proteins 64 (2006) 465-476]. Enzyme activity, as well as substrate binding, can be regulated by the salt mediated perturbation of the balance between open and closed forms. We propose that compensating effect of accessibility and flexibility of the enzyme active site leads to bell-shaped dependence of the investigated parameters.


Shengxian decoction protects against chronic heart failure in a rat model via energy regulation mechanisms.
Chronic heart failure (CHF) is actually a disease caused by an imbalanced energy metabolism between myocardial energy demand and supply, ultimately resulting in abnormal myocardial cell structure and function. Energy metabolism imbalance plays an important role in the pathological process of chronic heart failure (CHF). Improving myocardial energy metabolism is a new strategy for the treatment of CHF. Shengxian decoction (SXT), a well-known traditional Chinese medicine (TCM) formula, has good therapeutic effects on the cardiovascular system. However, the effects of SXT on the energy metabolism of CHF is unclear. In this study, we probed the regulating effects of SXT on energy metabolism in CHF rats using various research methods. High-performance liquid chromatography (HPLC) analysis was used to perform quality control of SXT preparations. Then, SD rats were randomly assigned into 6 groups: sham, model, positive control (trimetazidine) and high-, middle-, and low-dose SXT groups. Specific reagent kits were used to detect the expression levels of ALT and AST in rats' serum. Echocardiography was used to evaluate cardiac function. H&E, Masson and TUNEL staining were performed to examine myocardial structure and myocardial apoptosis. Colorimetry was used to determine myocardial ATP levels in experimental rats. Transmission electron microscopy was used to observe the ultrastructure of myocardial mitochondria. ELISA was used to estimate CK, cTnI, and NT-proBNP levels, and LA、FFA、MDA、SOD levels. Finally, Western blotting was used to examine the protein expression of CPT-1, GLUT4, AMPK, p-AMPK, PGC-1α, NRF1, mtTFA and ATP5D in the myocardium. HPLC showed that our SXT preparation method was feasible. The results of ALT and AST tests indicate that SXT has no side effect on the liver function of rats. Treatment with SXT improved cardiac function and ventricular remodelling and inhibited cardiomyocyte apoptosis and oxidative stress levels induced by CHF. Moreover, CHF caused decrease ATP synthesis, which was accompanied by a reduction in ATP 5D protein levels, damage to mitochondrial structure, abnormal glucose and lipid metabolism, and changes in the expression of PGC-1α related signal pathway proteins, all of which were significantly alleviated by treatment with SXT. SXT reverses CHF-induced cardiac dysfunction and maintains the integrity of myocardial structure by regulating energy metabolism. The beneficial effect of SXT on energy metabolism may be related to regulating the expression of the PGC-1α signalling pathway.


Cerebral oxygenation and hemodynamics during blood donation studied by near-infrared spectroscopy.
Blood donation is a safe human model for acute blood loss. This study investigated associated changes in regional cerebral oxygenation and cerebral blood volume (CBV) by near-infrared spectroscopy (NIRS). Fifty healthy blood donors donated 450 mL of whole blood within 4 to 9 minutes. Changes in regional cerebral oxygen saturation (rSO2) and cerebral tissue Hb concentration (HbT) were semiquantitatively measured by NIRS. Venous Hb concentration was measured before and after blood donation. The predonation and postdonation CBV was estimated from HbT and venous Hb concentration. Differences between pre- and postdonation study parameters were analyzed by paired t tests (p < 0.05). Within the study group, rSO2 decreased by 0.44 sat percent (p < 0.01) on average during blood donation, which is still within the range of individual physiologic baseline variation. The average venous Hb concentration decreased significantly by 4.6 percent, whereas HbT increased significantly by 2.5 percent and CBV increased even by 7.5 percent on average. The increase in CBV indicates cerebral vasodilation, which seems to be the major compensation mechanism during acute blood loss. The decrease in rSO2 was relatively small, indicating that cerebral oxygenation was maintained within the physiologic range.


Exploring aspects of DSM-IV interpersonal sensitivity in bipolar II.
The aim of the study was to find the prevalence of interpersonal rejection sensitivity (IRS) (a personality trait in DSM-IV) in bipolar II and unipolar depression. 557 consecutive unipolar and bipolar II outpatients, presenting for depression treatment, were interviewed with the DSM-IV Structured Clinical Interview and the Global Assessment of Functioning Scale. DSM-IV atypical features criteria (which include IRS) were followed. IRS was significantly more common in bipolar II than in unipolar patients (37.8% vs. 20.5%, odds ratio 2.3, P=0.0000). Sensitivity and specificity for bipolar II diagnosis were 37.8% and 79.4%. IRS personality trait seems to be more common in bipolar II than in unipolar depression. reliability of bipolar II diagnosis, non-blind, cross-sectional assessment, single interviewer.


Prognostic importance of radiologic extranodal extension in nasopharyngeal carcinoma treated in a Canadian cohort.
To confirm the prognostic value of radiologic extranodal extension (rENE) and its role in clinical-N classification in nasopharyngeal carcinoma (NPC) treated in a western institution. NPC treated between 2010 and 2017 were included. Pre-treatment MRI were reviewed for unequivocal rENE and its grade: grade-1: tumour invading through any nodal capsule but confined to perinodal fat; grade-2: ≥2 adjacent nodes forming a coalescent nodal mass; grade-3: tumour extending beyond perinodal fat to invade/encase adjacent structures. Overall survival (OS) and disease-free survival (DFS) were compared between rENE-positive (rENE+) and rENE-negative (rENE-) patients. Multivariable analysis (MVA) confirmed the prognostic importance of rENE and its grade. Staging schemas including rENE in N-classification were proposed and their performance evaluated. A total of 274 patients were eligible (43 cN0; 231 cN-positive). rENE was identified in 83/231 (36%) cN-positive, including grade 1/2/3 rENE in 14/58/11 cases. Compared to rENE-, rENE+ patients had a lower OS (68% vs 89%, p < 0.001) and DFS (58% vs 80%, p < 0.001). MVA confirmed the prognostic importance of grade-2 [HR: OS: 2.85 (p = 0.005); DFS: 2.89 (p < 0.001)] and grade-3 rENE [HR: OS 5.28 (p = 0.004); DFS 3.86 (p = 0.005)], with a trend for grade-1 vs rENE- [HR: OS 2.63 (p = 0.13); DFS 1.49 (p = 0.520)]. We evaluated classifying any rENE as cN3 (Proposal-I) or any grade-2/grade-3 rENE as cN3 (Proposal-II). The stage schema with Proposal-I cN-classification ranked the highest in the performance evaluation. rENE is an important prognostic factor in this western NPC cohort. We propose classifying any unequivocal rENE as cN3.


Balancing the books or balancing the scales: what should drive reforms?
John Tingle, Lecturer in Law, Birmingham Law School, University of Birmingham, considers the two opposing viewpoints on the need for change in the clinical negligence litigation system.


Development of a microemulsion-based process for synthesis of cobalt (Co) and cobalt oxide (Co3O4) nanoparticles from submicrometer rods of cobalt oxalate.
Rod-shaped nanostructures of cobalt oxalate dihydrate were synthesized at room temperature by the microemulsion (reverse micellar) route. These rods are highly uniform in length and can be modified with temperature (from approximately 6.5 microm at 50 degrees C to approximately 2.5 microm at 150 degrees C) while keeping the diameter nearly constant (200-250 nm). Thermal decomposition of these rods in a controlled atmosphere (air and H(2)) leads to nanoparticles of Co(3)O(4) and Co, respectively, while in a helium atmosphere a mixture of Co and CoO nanoparticles is obtained. Co(3)O(4) nanoparticles (approximately 35 nm) were slightly agglomerated, while Co nanoparticles were monodispersed and highly uniform (approximately 25 nm). The oxalate rods and Co(3)O(4) nanoparticles show an antiferromagnetic ordering at 54 and 35 K, respectively.


Modulation of aspartate release by ascorbic acid and endobain E, an endogenous Na+, K+ -ATPase inhibitor.
The isolation of a soluble brain fraction which behaves as an endogenous ouabain-like substance, termed endobain E, has been described. Endobain E contains two Na+, K+ -ATPase inhibitors, one of them identical to ascorbic acid. Neurotransmitter release in the presence of endobain E and ascorbic acid was studied in non-depolarizing (0 mM KCl) and depolarizing (40 mM KCl) conditions. Synaptosomes were isolated from cerebral cortex of male Wistar rats by differential centrifugation and Percoll gradient. Synaptosomes were preincubated in HEPES-saline buffer with 1 mM D-[3H]aspartate (15 min at 37 degrees C), centrifuged, washed, incubated in the presence of additions (60 s at 37 degrees C) and spun down; radioactivity in the supernatants was quantified. In the presence of 0.5-5.0 mM ascorbic acid, D-[3H]aspartate release was roughly 135-215% or 110-150%, with or without 40 mM KCI, respectively. The endogenous Na+, K+ -ATPase inhibitor endobain E dose-dependently increased neurotransmitter release, with values even higher in the presence of KCl, reaching 11-times control values. In the absence of KCl, addition of 0.5-10.0 mM commercial ouabain enhanced roughly 100% D-[3H]aspartate release; with 40 mM KCl a trend to increase was recorded with the lowest ouabain concentrations to achieve statistically significant difference vs. KCl above 4 mM ouabain. Experiments were performed in the presence of glutamate receptor antagonists. It was observed that MPEP (selective for mGluR5 subtype), failed to decrease endobain E response but reduced 50-60% ouabain effect; LY-367385 (selective for mGluR1 subtype) and dizocilpine (for ionotropic NMDA glutamate receptor) did not reduce endobain E or ouabain effects. These findings lead to suggest that endobain E effect on release is independent of metabotropic or ionotropic glutamate receptors, whereas that of ouabain involves mGluR5 but not mGluR1 receptor subtype. Assays performed at different temperatures indicated that in endobain E effect both exocytosis and transporter reversion are involved. It is concluded that endobain E and ascorbic acid, one of its components, due to their ability to inhibit Na+, K+ -ATPase, may well modulate neurotransmitter release at synapses.


Comparison of respiratory and cardiovascular effects of halothane, isoflurane, and enflurane delivered via the Jackson-Rees breathing system in rats. New anaesthesia model for small animal surgery.
We studied the respiratory (R) and cardiovascular (CV) effects of 1.25 MAC halothane (H), isoflurane (I) and enflurane (E) in oxygen, delivered by the Jackson-Rees breathing system in 5 normothermic rats. Mean arterial pressure (MAP), heart rate (HR) were depressed after 30 minutes than stabilized after 2 hours anaesthesia regardless of the inhalational agent. Respiratory rate (RR) slowed down markedly unter I and E anaesthesia. Significant R depression was developed (PCO2 53.5 +/- 2.44 Torr) under E. Stabil metabolic condition was maintained. The R and CV changes caused by H and I were far less than changes produced by E. H or I is preferable to E for small animal anaesthesia with spontaneous breathing. Maintenance of constant temperature minimizes the CV and R disturbances.


High-performance liquid chromatographic method for the determination of (-)-verbenone 10-hydroxylation catalyzed by rat liver microsomes.
A sensitive assay for the determination of (-)-verbenone 10-hydroxylation catalyzed by rat liver microsomes was developed using high-performance liquid chromatography. Verbenone was incubated in vitro with liver microsomes of untreated rats and rats treated with phenobarbital and the products thus formed were extracted with CH(2)Cl(2) and the extracts were separated by HPLC with a C(18) 5-microm analytical column. Elution was conducted with 40% methanol containing 20 mM NaClO(4) and the detection of UV absorbance was done at 251 nm. Product formation was dependent on the incubation time at least up to 30 min and the microsomal protein concentration between 0.01 and 0.1 mg protein/ml. The limit of detection of (-)-10-hydroxyverbenone with the HPLC was found to be about 40 pg, indicating that this method is about 100-fold sensitive than the GC-MS method. Optimized pH for the reaction was at 7.4 when examined with 100 mM potassium phosphate buffer in different pHs. Kinetic analysis showed that K(m) values for liver microsomes of untreated and phenobarbital-treated rats were 206 and 41 microM and V(max) values were 5.8 and 44 nmol/min/mg protein, respectively. Thus the present results provided a sensitive and useful method for the determination of verbenone 10-hydroxylation catalyzed by rat liver microsomes.


A 268 bp upstream sequence mediates the circadian clock-regulated transcription of the wheat Cab-1 gene in transgenic plants.
We previously reported that the expression of the wheat Cab-1 gene is regulated by an endogenous circadian rhythm and by the photoreceptor phytochrome both in wheat and in transgenic tobacco plants. To define regulatory elements necessary for the circadian rhythm-regulated Cab-1 gene expression, we now analysed the fluctuation of steady-state mRNA levels in a series of 5' deletion mutants in transgenic tobacco plants. We found that the expression of a deletion mutant containing 211 bp upstream sequence still exhibited circadian rhythm. Furthermore we show that an enhancer-like sequence of the Cab-1 promoter (from -357 to -90) can endow a chimaeric gene consisting of a truncated 35S promoter (from -90 to +8) and the bacterial beta-glucuronidase (GUS) gene with circadian clock-regulated gene expression. Finally we demonstrate by nuclear run-off experiments that the transcription rates of the Cab genes in wheat oscillate in a rhythmic manner, with a periodicity of approximately 24 hours. Consistent with our previous findings these results (i) indicate that the expression of the wheat Cab-1 gene is regulated mainly at the transcription level and (ii) identify a short promoter region between -211 and -90 that is responsible for the circadian clock-regulated gene expression.


Environmental SARS-CoV-2 contamination in hospital rooms of patients with acute COVID-19.
Data on the transmission of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) remain conflicting. Airborne transmission is still debated. However, hospital risk control requires better understanding of the different modes of transmission. This study aimed to evaluate the frequency of, and factors associated with, environmental air and surface contamination in the rooms of patients with coronavirus disease 2019 in the acute phase of the disease. Sixty-five consecutive patients were included in this study. For each patient, seven room surfaces, air 1 m and 3 m from the patient's head, the inner surface of the patient's mask, and the outer surface of healthcare workers' (HCW) masks were sampled. Environmental contamination was assessed by quantitative reverse transcription polymerase chain reaction (RT-qPCR) for SARS-CoV-2 RNA on surfaces, air and masks. A viral isolation test was performed on Vero cells for samples with an RT-qPCR cycle threshold (Ct) ≤37. SARS-CoV-2 RNA was detected by RT-qPCR in 34%, 12%, 50% and 10% of surface, air, patient mask and HCW mask samples, respectively. Infectious virus was isolated in culture from two samples among the 85 positive samples with Ct ≤37. On multi-variate analysis, only a positive result for SARS-CoV-2 RT-qPCR for patients' face masks was found to be significantly associated with surface contamination (odds ratio 5.79, 95% confidence interval 1.31-25.67; P=0.025). This study found that surface contamination by SARS-CoV-2 was more common than air and mask contamination. However, viable virus was rare. The inner surface of a patient's mask could be used as a marker to identify those at higher risk of contamination.


SARS-CoV-2 Omicron BA.5.2-infection and COVID-19 in persons with chronic myeloid leukaemia.
A SARS-CoV-2 Omicron (BA.5.2) epidemic began in China in December, 2022 following stopping the zero COVID policy. We studied features of the epidemic in 1,121 persons with chronic myeloid leukaemia (CML). 1103 (98%) were in chronic, 10 in accelerated and 8 in acute phases. 834 (74%) became infected almost all of whom met criteria for COVID-19. The most common symptoms were fever (91%), cough (90%) and fatigue (82%). 42 infected persons were asymptomatic. Most people quarantined at home and self-medicated. 22 were hospitalized for COVID-19. At admission 5 had mild, 14, moderate and 3, severe/critical disease according to World Health Organization (WHO) criteria. 5 received respiratory assistance, 3 were admitted to the intensive care unit (ICU) and 1 in accelerated phase died from COVID-19. Co-variates associated with a risk of COVID-19 in SARS-CoV-2-infected subjects include age ≥ 65 years, higher education level and imatinib therapy. In conclusion, most SARS-CoV-2 Omicron BA.5.2 infections in persons with CML resulted in COVID-19 most of which cases are mild with only 1 death.


The effects of cold water immersion with different dosages (duration and temperature variations) on heart rate variability post-exercise recovery: A randomized controlled trial.
The aim of the present study was to investigate the effects of cold water immersion during post-exercise recovery, with different durations and temperatures, on heart rate variability indices. Hundred participants performed a protocol of jumps and a Wingate test, and immediately afterwards were immersed in cold water, according to the characteristics of each group (CG: control; G1: 5' at 9±1°C; G2: 5' at 14±1°C; G3: 15' at 9±1°C; G4: 15' at 14±1°C). Analyses were performed at baseline, during the CWI recuperative technique (TRec) and 20, 30, 40, 50 and 60min post-exercise. The average HRV indices of all RR-intervals in each analysis period (MeanRR), standard deviation of normal RR-intervals (SDNN), square root of the mean of the sum of the squares of differences between adjacent RR-intervals (RMSSD), spectral components of very low frequency (VLF), low frequency (LF) and high frequency (HF), scatter of points perpendicular to the line of identity of the Poincaré Plot (SD1) and scatter points along the line of identity (SD2) were assessed. Mean RR, VLF and LF presented an anticipated return to baseline values at all the intervention groups, but the same was observed for SDNN and SD2 only in the immersion for 15min at 14°C group (G4). In addition, G4 presented higher values when compared to CG. These findings demonstrate that if the purpose of the recovery process is restoration of cardiac autonomic modulation, the technique is recommended, specifically for 15min at 14°C.


Residual sarcoplasmic reticulum Ca2+ concentration after Ca2+ release in skeletal myofibers from young adult and old mice.
Contrasting information suggests either almost complete depletion of sarcoplasmic reticulum (SR) Ca(2+) or significant residual Ca(2+) concentration after prolonged depolarization of the skeletal muscle fiber. The primary obstacle to resolving this controversy is the lack of genetically encoded Ca(2+) indicators targeted to the SR that exhibit low-Ca(2+) affinity, a fast biosensor: Ca(2+) off-rate reaction, and can be expressed in myofibers from adult and older adult mammalian species. This work used the recently designed low-affinity Ca(2+) sensor (Kd = 1.66 mM in the myofiber) CatchER (calcium sensor for detecting high concentrations in the ER) targeted to the SR, to investigate whether prolonged skeletal muscle fiber depolarization significantly alters residual SR Ca(2+) with aging. We found CatchER a proper tool to investigate SR Ca(2+) depletion in young adult and older adult mice, consistently tracking SR luminal Ca(2+) release in response to brief and repetitive stimulation. We evoked SR Ca(2+) release in whole-cell voltage-clamped flexor digitorum brevis muscle fibers from young and old FVB mice and tested the maximal SR Ca(2+) release by directly activating the ryanodine receptor (RyR1) with 4-chloro-m-cresol in the same myofibers. Here, we report for the first time that the Ca(2+) remaining in the SR after prolonged depolarization (2 s) in myofibers from aging (~220 μM) was larger than young (~132 μM) mice. These experiments indicate that SR Ca(2+) is far from fully depleted under physiological conditions throughout life, and support the concept of excitation-contraction uncoupling in functional senescent myofibers.


Circadian reduction of chromium in the gastric environment.
Samples of gastric juice from variously treated subjects efficiently reduced hexavalent chromium and decreased its mutagenicity. Chromium reduction was due to thermostable components of gastric secretions and was favoured by the acidity of the intragastric environment. The circadian monitoring of pH and of chromium reduction, as assessed by colorimetric analysis at hourly intervals, showed a basal activity (less than 10 micrograms/ml gastric juice) during the night and interdigestive periods, and peaks (tens of micrograms/ml) during the 3-4-h periods after each meal. Assays in the Ames reversion test confirmed that the decrease in mutagenicity of sodium dichromate produced by gastric juice was significantly enhanced after meals. This physiological mechanism is expected to provide an important protective barrier against the oral toxicity of this metal, and may explain its lack of oral carcinogenicity.


Internet-based intervention to promote mental fitness in mildly depressed adults: design of a randomized controlled trial.
Investing in mental well-being is considered a supplement to current mental health service delivery in which the treatment and prevention of mental disorders are core components. It may be possible for people to enhance their well-being by boosting their "mental fitness." Psyfit, an online, multi-component, fully automated self-help intervention, was developed with the aim of improving well-being and reducing depressive symptoms. The efficacy and cost-effectiveness of this intervention will be examined in a randomized controlled trial. In this two-armed randomized controlled trial, a total of 290 participants will be assigned to use Psyfit (experimental condition) or to a 6-month waiting list (control condition). Adults with mild to moderate depressive symptoms interested in improving their mental fitness will be recruited from the general population through advertisements on the Internet and in newspapers. Online measurements by self-assessment will be made prior to randomization (pre-test), 2 months after baseline (post-test), and 6 months after baseline (follow-up). The primary outcome is well-being. Secondary outcomes are depressive symptoms, general health, vitality, and economic costs. Analysis will be conducted in accordance with the intention-to-treat principle. This study will examine the efficacy and cost-effectiveness of an online intervention that aims to promote well-being in people with elevated levels of depressive symptoms. If shown to be effective, the intervention could prove to be an affordable and widely accessible intervention to improve well-being in the general population. The study is registered with the Netherlands Trial Register, part of the Dutch Cochrane Centre (NTR2126).


Identification and pathogenicity analysis of Fusarium spp. on peach in China.
Vascular system is affected by diseases that can seriously damage plant health by inducing browning and death of branches. This study aimed to identify and analyze the pathogenicity of Fusarium spp. isolates obtained from diseased peach branches in several peach-producing areas of China. We obtained and confirmed nine Fusarium isolates based on morphological and molecular characteristics. Phylogenetic relationships using a combination of rDNA-internal transcribed spacer (ITS), elongation factor (EF)-1α, and mitochondrial small subunit (mtSSU) gene sequences were analyzed. GJH-Z1, GJH-6, and GJH-1 were identified as F. avenaceum; HYR-Z3, and ZLZT-6 as F. concentricum, HH-2020-G2, and HYTZ-4 as F. solani, GG-2020-1 as F. asiaticum, SYGZ-1 as F. equiseti. Through acupuncture comparison, the pathogenicity of F. equiseti (SYGZ-1) was highest amongst nine strains. Meanwhile, F. concentricum (HYR-Z3 and ZLZT-6), and F. solaini (HYTZ-4) had a higher level of pathogenicity as revealed by impregnation. Our study shed light on the findings that Fusarium spp. can inflict vascular bundle browning of peach plants. Our results will extend the understanding of pathogenic diseases in China's peach industry.


Erectile function, incontinence, and other quality of life outcomes following proton therapy for prostate cancer in men 60 years old and younger.
This study sought to evaluate patient-reported health-related quality of life following proton therapy for prostate cancer in men ≤ 60 years old. Between August 2006 and January 2010, 262 hormone-naive men ≤ 60 years old were treated with definitive proton therapy for prostate cancer. Before treatment and every 6 months after treatment, patients filled out the Expanded Prostate Index Composite (EPIC) and the International Index of Erectile Function (IIEF) questionnaires. Potency was defined as successful sexual intercourse in the prior month or an EPIC sexual summary (SS) score ≥ 60. Median follow-up was 24 months; 90% of men completed follow-up EPIC forms within the last year. For EPIC urinary, bowel, and hormone subscales, the average decline from baseline to 2 years was ≤5 points, except for bowel function (5.2 points). SS scores declined 12.6 points after 2 years. Potency rates declined by 11% from baseline at 2 years, but 94% of men were potent with a baseline IIEF > 21, body mass index < 30, and no history of diabetes. At 2 years after treatment, only 1.8% of men required a pad for urge incontinence. On multivariate analysis, factors associated with a significant decline in SS score were mean penile bulb dose ≥40 cobalt Gy equivalents (P = .012) and radiation dose ≥ 80 cobalt Gy equivalents (P = .017); only diabetes was significantly associated with impotence (P = .015). Young men undergoing proton therapy for treatment of prostate cancer have excellent outcomes with respect to erectile dysfunction, urinary incontinence, and other health-related quality of life parameters during the first 2 years after treatment. Longer follow-up is needed to confirm these findings.


MiR-138-5p Suppresses Cell Growth and Migration in Melanoma by Targeting Telomerase Reverse Transcriptase.
Recent evidence suggests the existence of a miRNA regulatory network involving human telomerase reverse transcriptase gene (hTERT), with miR-138-5p playing a central role in many types of cancers. However, little is known about the regulation of hTERT expression by microRNA (miRNAs) in melanocytic tumors. Here, we investigated the effects of miR-138-5p in hTERT regulation in melanoma cells lines. In vitro studies demonstrated higher miR-138-5p and lower hTERT messenger RNA (mRNA) expression in human epidermal melanocytes, compared with melanoma cell lines (A2058, A375, SK-MEL-28) by quantitative polymerase chain reaction (qPCR) observing a negative correlation between them. A2058 melanoma cells were selected to be transfected with miR-138-5p mimic or inhibitor. Using luciferase assay, hTERT was identified as a direct target of this miRNA. Overexpression of miR-138-5p detected by Western blot revealed a decrease in hTERT protein expression (p = 0.012), and qPCR showed a reduction in telomerase activity (p < 0.001). Moreover, suppressions in cell growth (p = 0.035) and migration abilities (p = 0.015) were observed in A2058-transfected cells using thiazolyl blue tetrazolium bromide and flow cytometry, respectively. This study identifies miR-138-5p as a crucial tumor suppressor miRNA involved in telomerase regulation. Targeting it as a combination therapy with immunotherapy or targeted therapies could be used in advanced melanoma treatment; however, more preclinical studies are necessary.


[The circadian rhythm of the content of corticosteroids and of pain sensitivity in humans and rats].
The circadian relationships between blood corticosteroids and latent period of pain reaction to hot stimulation were investigated in man and rats. There were no correlation of blood corticosteroids levels and pain latent period but the latent period increased during those time of day when the corticosteroids levels were higher in total: man--morning and day, rats--evening and night.


LGR4 cooperates with PrPc to endow the stemness of colorectal cancer stem cells contributing to tumorigenesis and liver metastasis.
Cancer stem cells (CSCs) are a subpopulation of cancer cells that drive tumour progression and metastasis. Anti-CSC strategies represent new targets for cancer therapies. However, CSCs are highly plastic and heterogeneous, making validation and targeting difficult without bona fide markers that define their identity, especially in a clinical setting. Here, we report that a leucine-rich repeat containing G protein-coupled receptor 4 (LGR4) cooperates with CD44 and PrPc; the latter contributes significantly to metastatic capacity and defines the stemness characteristics of colorectal CSCs. CD44+PrPc+LGR4+ cells effectively developed into organoids and, when transplanted, generated orthotopic and metastatic tumours. Importantly, targeting LGR4 and PrPc with lentiviral shRNAs inhibited organoid development and the growth of orthotopic tumours by inhibiting Wnt/β-catenin signalling. Thus, our study offers a novel therapeutic strategy that simultaneously targets CSC stemness and metastatic properties.


Volumetric change in the shoulder capsule after open inferior capsular shift versus arthroscopic thermal capsular shrinkage: a cadaveric model.
The purpose of this study was to compare the percentage of glenohumeral intracapsular volume reduction after open inferior capsular shift and arthroscopic thermal capsulorrhaphy. Twelve matched, fresh-frozen cadaveric shoulders were used for the study. Intraarticular glenohumeral volume measurements were obtained by injecting a viscous fatty acid sulfate solution into the joint. In the 6 right shoulders, a standard anterior-inferior capsular shift was performed, and in the 6 matching left shoulders, an arthroscopic thermal capsular shrinkage was performed. After the procedures, the capsular volumes were re-measured. The open inferior shift procedure resulted in a mean decrease in glenohumeral volume of 50.2% (range, 43%-56%). Arthroscopic thermal capsulorrhaphy decreased shoulder intraarticular volume by a mean of 29.7% (range, 26%-36%). Both the open capsular shift and arthroscopic thermal shrinkage procedures produced well-documented volumetric reductions in the shoulder capsules. The open shift reduced intraarticular shoulder volume significantly more than arthroscopic thermal capsular shrinkage.


Partition number, rate priors and unreliable divergence times in Bayesian phylogenetic dating.
More loci/partitions should improve Bayesian estimation of divergence times on phylogenies but it has recently been shown that this can lead to surprisingly poor estimation due to the way it affects the prior on mean substitution rate. Here we consider the likely impact of partition number on divergence time analyses carried out using the program BEAST. Mitochondrial genome data from toad-headed lizards (genus Phrynocephalus) from the Qinghai-Tibetan Plateau were used to examine this effect. Under increased partitioning of the sequences, BEAST posterior divergence times became unreasonably narrow and downwardly biased due to misspecification of the mean substitution rate prior. This effect was detectable when relatively few partitions were used (i.e. between four and eight), but became very acute for 27-86 partitions. Fortunately, a correction that adjusts the standard deviation of the mean of locus rates led to results that were equivalent to those obtained using the latest version of the program MCMCtree, which implements a new gamma-Dirichlet prior to overcome this problem. A review of the literature shows that a substantial number of BEAST dating studies are likely to have been affected by this misspecification of the rate prior.


NIRS-aided differential diagnosis among patients with major depressive disorder, bipolar disorder, and schizophrenia.
To establish a clinically applicable neuroimaging-guided diagnostic support system that uses near-infrared spectroscopy (NIRS) for differential diagnosis at the individual level among major depressive disorder (MDD), bipolar disorder (BPD), and schizophrenia (SZ). A total of 192 participants were recruited, including 40 patients with MDD, 38 patients with BPD, 65 patients with SZ, and 49 healthy individuals. We analyzed the spatiotemporal characteristics of hemodynamic responses in the frontotemporal cortex during a verbal fluency test (VFT) measured by NIRS to assess the accuracy of single-subject classification for differential diagnosis among the three psychiatric disorders. The optimal threshold of the frontal centroid value (54 seconds) was utilized on the basis of the findings of the Japanese study. The application of the optimal threshold of the frontal centroid value (54 seconds) allowed for the accurate differentiation of patients with unipolar MDD (72.5%) from BPD (78.9%) or SZ (84.6%). These results suggest that the NIRS-aided differential diagnosis of major psychiatric disorders can be a promising biomarker in Taiwan. Future multi-site studies are needed to validate our findings.


Conspicuous histomorphological anomalies in the hippocampal formation of rats exposed prenatally to a complex sequenced magnetic field within the nanoTesla range.
The brains of adult rats, exposed prenatally to one of four intensities (between 10 nanoTesla and 1.2 microTesla) of either a frequency-modulated magnetic field or a complex sequenced field designed to affect brain development, were examined histologically. Although from each intensity some rats that had been exposed to the complex sequenced magnetic field showed minor anomalies, those exposed to intensities between 30 nT and 180 nT exhibited conspicuous anomalous organizations of cells within the hippocampal formation. In other studies, rats that had been exposed during their entire prenatal development to the complex sequenced field displayed significantly more activity in the open field and poorer spatial memory during maze learning. Photomicrographs are shown of one conspicuous morphological anomaly within the right hippocampus of an adult rat exposed prenatally to the complex sequenced magnetic field with intensities between .3 mG and .5 mG (30 nT to 50 nT). The results suggest that complex magnetic fields, whose temporal structures approach the time constants of normal biochemical processes, can permanently alter the development of the brain.


Lower socioeconomic status and co-morbid conditions are associated with reduced continuous positive airway pressure adherence among older adult medicare beneficiaries with obstructive sleep apnea.
To examine rates of adherence to continuous positive airway pressure (CPAP) therapy among a representative sample of older adult Medicare beneficiaries with obstructive sleep apnea (OSA), and to identify demographic and health-related factors associated with CPAP adherence. Using a 5% sample of Medicare claims data, we utilized Medicare policy and CPAP machine charges as a proxy for CPAP adherence. A cumulative logit model was used to identify demographic, medical, and psychiatric predictors of CPAP adherence status. Of beneficiaries who initiated CPAP (n = 3,229), 74.9% (n = 2,417) met the so-called "90-day Medicare adherence criteria," but only 58.8% of these individuals (n = 1,420) continued to use CPAP throughout the entire 13-month rent-to-own period. Anxiety, anemia, fibromyalgia, traumatic brain injury, and lower socioeconomic status (SES) were all associated with reduced CPAP adherence. These results provide the first national estimates of CPAP adherence among older adult Medicare beneficiaries in the United States. In addition, findings highlight the salience of medical and psychiatric comorbidity, as well as SES, as important markers of CPAP adherence among older adults in the United States. Future studies should seek to evaluate interventions to improve CPAP adherence among older adults of lower SES.


From tissue mechanics to transcription factors.
Changes in tissue stiffness are frequently associated with diseases such as cancer, fibrosis, and atherosclerosis. Several recent studies suggest that, in addition to resulting from pathology, mechanical changes may play a role akin to soluble factors in causing the progression of disease, and similar mechanical control might be essential for normal tissue development and homeostasis. Many cell types alter their structure and function in response to exogenous forces or as a function of the mechanical properties of the materials to which they adhere. This review summarizes recent progress in identifying intracellular signaling pathways, and especially transcriptional programs, that are differentially activated when cells adhere to materials with different mechanical properties or when they are subject to tension arising from external forces. Several cytoplasmic or cytoskeletal signaling pathways involving small GTPases, focal adhesion kinase and transforming growth factor beta as well as the transcriptional regulators MRTF-A, NFκB, and Yap/Taz have emerged as important mediators of mechanical signaling.


Identification of vulnerable populations and knowledge, attitude, and practice analysis of echinococcosis in Tibet Autonomous Region of China.
Echinococcosis is one of the 17 neglected tropical diseases recognized by the World Health Organization and causes a huge global disease burden. The Tibet Autonomous Region (Tibet) of China is the most epidemic area of echinococcosis worldwide. Echinococcosis poses an enormous threat to local public health and economic development. Identifying vulnerable populations and analyzing people's knowledge, attitudes, and practices (KAP) with respect to echinococcosis is necessary to prevent and control echinococcosis. Based on reported cases and questionnaire responses, we first used a k-prototypes clustering algorithm to identify vulnerable populations according to human demographics (including gender, age, education level, and occupation). We then used a KAP analysis to evaluate the Tibetan people's understanding of echinococcosis. The results identified three types of vulnerable population. Vulnerable population I comprised illiterate middle-aged and older women engaged in agriculture and animal husbandry. Vulnerable population II comprised illiterate middle-aged male herdsmen. Vulnerable population III comprised young male farmers with a low education level. The KAP analysis indicated that the pass rate for all participants was 72.6%, 6.4%, 95.0%, and 75.8% for KAP, K, A, and P, respectively. The pass rates were significantly different among different age and gender groups. Based on these results, it is necessary to improve public health education and professional training, and to implement effective control and management measures targeting typical hosts of echinococcosis. This study provides a direct reference for the prevention and control of echinococcosis in Tibet.


Pharmacotherapy in familial hypercholesterolemia - Current state and emerging paradigms.
Familial hypercholesterolemia is a highly prevalent but underdiagnosed disease marked by increased risk of cardiovascular morbidity and mortality. Aggressive reduction of LDL-cholesterol is a hallmark of cardiovascular risk mitigation in familial hypercholesterolemia. More recently, we have witnessed an expanded repertoire of pharmacologic agents that directly target LDL-cholesterol and/or reduce heart disease burden. In this state-of-the-art review, we explore the development, clinical efficacy and limitations of existing and potential future therapeutics in familial hypercholesterolemia.


Definition and assessment of asthma.
Bronchial obstruction, its reversibility, airway hyperreactivity and inflammation are key variables of asthma. In clinical practice they can be assessed with repeated noninvasive lung function measurements (spirometry and mucociliary clearance). The asthmatic inflammation in contrast to chronic bronchitis is characterized by increased IgE and eosinophils depending on the disease state (seasonal, perennial, chronic symptomatic or asymptomatic asthma). Based on the above-mentioned clinically applicable measurements, a classification of asthma, chronic (obstructive) bronchitis, and emphysema is proposed because the three groups of diseases have different etiology and need different prophylactic and symptomatic treatment.


Morphological and p40 immunohistochemical analysis of squamous differentiation in endoscopic ultrasound guided fine needle biopsies of pancreatic ductal adenocarcinoma.
The basal-like molecular subtype of pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis and upregulation in TP63ΔN (p40) network. Adenosquamous histology can be observed. This study assessed immunohistochemical p40 expression in fine needle biopsy (FNB) samples with PDAC and association with cytomorphological features of squamous differentiation and clinical data. 106 EUS FNBs with PDAC were assessed for eight cytomorphological features of squamous differentiation. P40 H-score (intensity 0-3 × percentage positive nuclei) was analysed for association with morphological features, patient age, gender, operability, chemotherapy and survival. P40 H-score in 14 paired FNBs and resections was compared. P40 h-score was 1-3 in 31%, 4-30 in 16% and > 30 in 13% of FNBs. It was significantly associated with intercellular bridges, elongated cell shape, sharp cell borders, angular nuclei with homogenous chromatin (p < 0.001) and dense cytoplasm (p = 0.002). Keratinisation was not seen. Inoperable patients (n = 81) had a shorter median survival for h-score > 30 (n = 9, 1.8 months) than for h-score ≤ 30 (n = 66, 6.7 months) not quite reaching statistical significance (p = 0.08). P40 was significantly associated with squamous morphology in FNBs with PDAC. P40 H-score > 30 showed a trend towards shorter survival in inoperable patients. Squamous differentiation may be a treatment target in PDAC.


GSH-Depleted Nanozymes with Hyperthermia-Enhanced Dual Enzyme-Mimic Activities for Tumor Nanocatalytic Therapy.
Nanocatalytic therapy, using artificial nanoscale enzyme mimics (nanozymes), is an emerging technology for therapeutic treatment of various malignant tumors. However, the relatively deficient catalytic activity of nanozymes in the tumor microenvironment (TME) restrains their biomedical applications. Here, a versatile and bacteria-like PEG/Ce-Bi@DMSN nanozyme is developed by coating uniform Bi2 S3 nanorods (NRs) with dendritic mesoporous silica (Bi2 S3 @DMSN) and then decorating ultrasmall ceria nanozymes into the large mesopores of Bi2 S3 @DMSN. The nanozymes exhibit dual enzyme-mimic catalytic activities (peroxidase-mimic and catalase-mimic) under acidic conditions that can regulate the TME, that is, simultaneously elevate oxidative stress and relieve hypoxia. In addition, the nanozymes can effectively consume the overexpressed glutathione (GSH) through redox reaction. Photothermal therapy (PTT) is introduced to synergistically improve the dual enzyme-mimicking catalytic activities and depletion of the overexpressed GSH in the tumors by photonic hyperthermia. This is achieved by taking advantage of the desirable light absorbance in the second near-infrared (NIR-II) window of the PEG/Ce-Bi@DMSN nanozymes. Subsequently the reactive oxygen species (ROS)-mediated therapeutic efficiency is significantly improved. Therefore, this study provides a proof of concept of hyperthermia-augmented multi-enzymatic activities of nanozymes for tumor ablation.


Diagnostic value of ST-segment deviations during cardiac exercise stress testing: Systematic comparison of different ECG leads and time-points.
Exercise ECG stress testing is the most widely available method for evaluation of patients with suspected myocardial ischemia. Its major limitation is the relatively poor accuracy of ST-segment changes regarding ischemia detection. Little is known about the optimal method to assess ST-deviations. A total of 1558 consecutive patients undergoing bicycle exercise stress myocardial perfusion imaging (MPI) were enrolled. Presence of inducible myocardial ischemia was adjudicated using MPI results. The diagnostic value of ST-deviations for detection of exercise-induced myocardial ischemia was systematically analyzed 1) for each individual lead, 2) at three different intervals after the J-point (J+40ms, J+60ms, J+80ms), and 3) at different time points during the test (baseline, maximal workload, 2min into recovery). Exercise-induced ischemia was detected in 481 (31%) patients. The diagnostic accuracy of ST-deviations was highest at +80ms after the J-point, and at 2min into recovery. At this point, ST-amplitude showed an AUC of 0.63 (95% CI 0.59-0.66) for the best-performing lead I. The combination of ST-amplitude and ST-slope in lead I did not increase the AUC. Lead I reached a sensitivity of 37% and a specificity of 83%, with similar sensitivity to manual ECG analysis (34%, p=0.31) but lower specificity (90%, p<0.001). When using ECG stress testing for evaluation of patients with suspected myocardial ischemia, the diagnostic accuracy of ST-deviations is highest when evaluated at +80ms after the J-point, and at 2min into recovery.


Non-surgical Treatments for Lung Metastases in Patients with Soft Tissue Sarcoma: Stereotactic Body Radiation Therapy (SBRT) and Radiofrequency Ablation (RFA).
Radio-frequency ablation (RFA) and Stereotactic Body Radiation Therapy (SBRT) are two emerging therapies for lung metastases. Aliterature review was performed to evaluate the outcomes and complications of these procedures in patients with lung metastases from soft tissue sarcoma (STS). After selection, seven studies were included for each treatment encompassing a total of 424 patients: 218 in the SBRT group and 206 in the RFA group. The mean age ranged from 47.9 to 64 years in the SBRT group and from 48 to 62.7 years in the RFA group. The most common histologic subtype was, in both groups, leiomyosarcoma. In the SBRT group, median overall survival ranged from 25.2 to 69 months and median disease- free interval was from 8.4 to 45 months. Two out of seven studies reported G3 and one G3 toxicity, respectively. In RFA patients, overall survival ranged from 15 to 50 months. The most frequent complication was pneumothorax. Local control showed a high percentage for both procedures. SBRT is recommended in patients unsuitable to surgery, in synchronous bilateral pulmonary metastases, in case of deep lesions and patients receiving high-risk systemic therapies. RFA is indicated in case of a long disease-free interval, in oligometastatic disease, when only the lung is involved, in small size lesions far from large vessels. Further large randomized studies are necessary to establish whether these treatments may also represent a reliable alternative to surgery.