Hybrid nanoparticle-microcavity-based plasmonic nanosensors with improved detection resolution and extended remote-sensing ability.
Optical nanosensors based on plasmonic nanoparticles have great potential for chemical and biological sensing applications, but their spectral detection resolution is severely constrained by their broad resonance linewidth, and their spatial sensing depth is limited to several tens of nanometres. Here we demonstrate that coupling a strong dipolar plasmonic resonance of a single metallic nanoparticle to the narrow bandwidth resonances of an optical microcavity creates a hybrid mode and discretizes the broad localized resonance, boosting the sensing figure-of-merit by up to 36 times. This cavity-nanoparticle system effectively combines the advantages of Fabry-Perot microresonators with those of plasmonic nanoparticles, providing interesting features such as remote-sensing ability, incident-angle independent resonances, strong polarization dependence, lateral ultra small sensing volume and strongly improved detection resolution. Such a hybrid system can be used not only to locally monitor specific dynamic processes in biosensing, but also to remotely sense important film parameters in thin-film nanometrology.


Differential alterations in intestinal permeability after trauma-hemorrhage.
Recent studies have shown that the intestinal barrier function is altered and macromolecules can translocate after trauma and hemorrhagic shock. The translocated molecules are absorbed from the lymphatic tissue or directly enter the circulation in the gut. However, it remains unknown to what degree these compartments contribute to the clearance of the macromolecules. Male Sprague-Dawley rats (350-400 g) underwent a 5-cm midline laparotomy (i.e., soft tissue injury), were bled to a mean arterial pressure of 35 mmHg and maintained for approximately 90 min, and then resuscitated with Ringer's lactate (4x the shed blood volume) over 60 min. At 2 h after resuscitation, a solution containing 51Cr-EDTA, FITC-dextran-4 kDa, and rhodamine B-dextran-40 kDa was instilled into a jejunal blind loop and their concentrations were determined in mesenteric lymph and blood samples harvested between 2 h and 4 h after resuscitation. Trauma-hemorrhage and crystalloid resuscitation significantly increased mesenteric lymph flow and the mucosal permeability for the three marker molecules. There was no difference in the concentrations of 51Cr-EDTA between the blood and lymph compartment after trauma-hemorrhage. However, the high molecular weight marker (rhodamine-B-dextran-40 kDa) accumulated in significantly higher concentrations in the mesenteric lymph than in the plasma under such conditions. The accumulation of macromolecules in the mesenteric lymph suggests that this compartment plays an important role in the altered gut barrier function after trauma-hemorrhage.


The effect of quantum size confinement on the optical properties of PbSe nanocrystals under exposure to heat and hydrostatic pressure.
A study based on photoluminescence and absorption measurements as a function of temperature and pressure for PbSe nanocrystals with sizes in the range 3-13 nm reveals the influence of size quantum confinement on the observed variation. In the case of the temperature variation, the effective bandgap changes from showing a positive rate of change to showing a negative one (for a quantum dot 3 nm in diameter), which can be accounted for by incorporating a linear variation of the carrier effective masses into a simple calculation of the exciton ground state in the quantum dot. In the case of the pressure variation, we observe a clear inverse correlation between the absolute value of the pressure coefficient and the nanocrystal size, a signature of quantum size confinement, with values changing from -76 to -41 meV GPa⁻¹ for quantum dots ranging from 13 to 3 nm in diameter, respectively, clearly smaller in absolute value than the rate for bulk PbSe (-84 meV GPa⁻¹). We used again the hypothesis of a linear variation of the carrier effective masses with pressure in order to fit this experimental variation quantitatively.


A double surrogate approach for the quantitation of 2-Hydroxyglutarate - An oncometabolite in human brain tumors via LC-MS/MS.
We are reporting a validated LC-MS/MS assay for the quantitation of 2-Hydroxyglutarate (2-HG), an endogenous oncometabolite, in human brain tumors. To address the challenges of endogenous levels of 2-HG in biological matrix and the limited availability of human brain tumors, a surrogate analyte in conjunction with a surrogate matrix approach was used (stable isotope labeled 2-HG in monkey brain homogenate). Human brain tumor homogenate samples were spiked with stable isotope labeled internal standard, processed by protein precipitation, and analyzed using LC-MS/MS. The mass spectrometer was optimized to ensure equal molar response between 2-HG - the authentic analyte and 13C5 2-HG - the surrogate analyte. Parallelism was successfully demonstrated between human brain tumor homogenate (the authentic matrix) and monkey brain homogenate (the surrogate matrix). The linear analytical range of the assay was set at 0.15-150 μM. This validated LC-MS/MS method demonstrated excellent accuracy and precision. For 13C5 2-HG in monkey brain homogenate and human brain tumor homogenate, the overall accuracy was between 98.4 % and 102 %, and the intra- and inter-assay precision (%CV) were less than 5.7 %. 2-HG was found to be stable in human brain tumor homogenate for at least 26 h at room temperature, 454 days when stored at 70 °C and after five freeze/thaw cycles. The assay has been successfully applied to human brain tumor samples to support clinical studies. Novel Aspect: A surrogate matrix and surrogate analyte approach to quantify endogenous 2-HG concentrations in human brain tumors.


Lipoprotein changes in women taking low-dose combined oral contraceptive pills: a cross-sectional study in Basra, Iraq.
We assessed lipid and lipoprotein levels in 100 women taking low-dose COCs and a control group of 100 non-users attending the family planning centre Basra Maternity and Child Hospital, Iraq. Venous blood was collected after 12-14 hours fasting, and serum triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and very low-density lipoprotein (VLDL) levels were measured. Serum TG, HDL-C and VLDL levels were significantly higher and LDL-C levels lower in users than non-users but TC levels did not differ between the 2 groups. TG, HDL-C and VLDL levels rose with age and duration of use while LDL-C levels decreased; TC levels did not change.


Proteasome inhibition enhances resistance to DNA damage via upregulation of Rpn4-dependent DNA repair genes.
The 26S proteasome is an ATP-dependent multi-subunit protease complex and the major regulator of intracellular protein turnover and quality control. However, its role in the DNA damage response is controversial. We addressed this question in yeast by disrupting the transcriptional regulation of the PRE1 proteasomal gene. The mutant strain has decreased proteasome activity and is hyper-resistant to various DNA-damaging agents. We found that Rpn4-target genes MAG1, RAD23, and RAD52 are overexpressed in this strain due to Rpn4 stabilisation. These genes represent three different pathways of base excision, nucleotide excision and double strand break repair by homologous recombination (DSB-HR). Consistently, the proteasome mutant displays increased DSB-HR activity. Our data imply that the proteasome may have a negative role in DNA damage response.


Subspecialist abdominal wall reconstruction services in Canada.
Recent years have seen considerable increases in both the demand for, and complexity of, ventral hernia repairs. This has led to calls for abdominal wall surgery to become a recognized subspecialty in the United States and Europe, with some centres responding by forming specialized, multidisciplinary teams for abdominal wall reconstruction. At present, however, no Canadian city has followed suit. In this article, we outline the major arguments underlying the drive toward the centralization of complex abdominal wall services.


Hyperprolactinemia reduces vasoactive intestinal peptide in the anterior pituitary glands of rats.
The concentration of vasoactive intestinal polypeptide (VIP) in the anterior pituitary gland of female rats was significantly reduced by pituitary implants, prolactin-secreting tumours or dopamine blockade-induced hyperprolactinemia. Oestradiol implants increased plasma prolactin (PRL) to 12 times and increased pituitary VIP to 3.5 times that of controls after one week. The dopamine agonist bromocriptine significantly reduced pituitary VIP at doses within the clinically used range. These results provide evidence for a suppressive effect of plasma PRL on pituitary VIP, which may be effected by a dopaminergic mechanism, but is over-ridden by oestrogen.


Phenotype-informed polygenic risk scores are associated with worse outcome in individuals at risk of Alzheimer's disease.
Patients with predementia Alzheimer's disease (AD) and at-risk subjects are targets for promising disease-modifying treatments, and improved polygenic risk scores (PRSs) could improve early-stage case selection. Phenotype-informed PRSs were developed by selecting AD-associated variants conditional on relevant inflammatory or cardiovascular traits. The primary outcome was longitudinal changes in measures of AD pathology, namely development of pathological amyloid deposition, medial temporal lobe atrophy, and cognitive decline in a prospective cohort study including 394 adults without AD dementia. High-risk groups defined by phenotype-informed AD PRSs had significantly steeper volume decline in medial temporal cortices, and the high-risk group defined by the cardiovascular-informed AD PRS had significantly increased hazard ratio of pathological amyloid deposition, compared to low-risk groups. AD PRSs informed by inflammatory disorders or cardiovascular risk factors and diseases are associated with development of AD pathology markers and may improve identification of subjects at risk for progression of AD.


A mathematical framework for the analysis and comparison of contact detection methods for ellipses and ellipsoids.
The purpose of this research is to provide a framework for the analysis and comparison of contact detection algorithms for pairs of ellipses and ellipsoids. This work focuses primarily on the category of algorithms that are the most computationally efficient and can produce estimates of the separation and the penetration distance between ellipses and ellipsoids. Specifically, only analytic representations of the ellipses and ellipsoids are considered and contact detection for moving pairs of ellipsoids is not treated. The first contribution is a mathematical framework for the study of these algorithms, most notably with existence and uniqueness proofs for classes of contact detection algorithms, formal descriptions of the asymptotics of pairs of ellipses in close contact (or overlap), and a global analysis of constraints on the normals. The framework highlights the key role played by the different definitions of contact found in the literature, independent of the numerical strategies deployed to estimate the separation/penetration distance. Specifically, it is shown that all the studied algorithms can be expressed as minimization problems, with or without non-binding constraints on the normal(s) at the contact point(s), and that the constraints can be used to identify the global minima among the critical points in the minimization problem. Another contribution of this research, based on the mathematical framework introduced, is a better classification of the known algorithms. These algorithms are compared on established test problems, and their strengths and weaknesses are highlighted and explained in terms of their classification. Furthermore, this research provides comparisons in speed and stability between the most efficient algorithms in each category over a large sample size of test problems. Among the other contributions, this research describes inexpensive but effective initial estimates of the contact to be used in iterative algorithms. Finally, the usefulness of the new framework is illustrated with the introduction of a fast algorithm combining some new and old ideas.


Effects of reclaimed wastewater irrigation on soil-crop systems in China: A review.
Reclaimed wastewater (RW) use represents a substantial opportunity to alleviate the growing scarcity of water for irrigation of agricultural crops in China. However, insufficient understanding of the effects and fates of possible contaminants in RW promotes concerns over crop safety and prevents the extensive incorporation of RW in agriculture. We reviewed the characteristics of contaminants in RW, the fate of contaminants in soil-crop systems, and the effects of RW irrigation on soil quality and crop growth in China. We found that concentrations of heavy metals in RW were higher than the permissible limits in some areas. The total concentrations and main categories of emerging contaminants and pathogens in RW varied markedly among municipal wastewater treatment plants, and the greatest risks of contamination were posed by ofloxacin, sulfamethoxazole, and erythromycin, the most frequently observed compounds with risk quotients >1. The negative effects of salts and nutrients in RW on soil quality and crop growth were minor and manageable. The accumulation of heavy metals and emerging contaminants in soils irrigated with RW did not pose an immediate risk to soils and crops. Changes in soil microbial populations, diversity, and activity caused by RW irrigation increased crop yields and protected crops against contaminants. However, attention is necessary to the risks of bioaccumulation in soils and crops of heavy metals, emerging contaminants, intermediate metabolites, and pathogens, and their effects on human health with long-term RW irrigation. We recommend irrigation practices, crop screening, soil treatments, prioritizing the risks of contaminants, and comprehensive management to increase safety in RW used for agricultural irrigation.


Aging and mitochondria.
Aging is a complex physiological phenomenon and several different theories have been elaborated about its origin. Among such theories, the 'mitochondrial theory of aging', which has gained a large support, indicates the accumulation of somatic mutations of mitochondrial DNA leading to the decline of mitochondrial functionality as one of the driving forces for the process itself. In this review data on rat and man from our laboratory and from recent literature have been thoroughly examined and compared in order to provide the 'state-of-the-art' on the role of mitochondria in aging. Alterations of structure and expression of mitochondrial genome with aging, to find out the eventual relevant changes of mitochondrial biogenesis, have been studied in rat whereas the relationship between cytochrome c oxidase activity and 'common deletion' has been studied in man. Results on the effect of acetyl-L-carnitine on the mitochondrial functionality are also reported.


Sensitive detection using microfluidics technology of single cell PCR products from high and low abundance IgH VDJ templates in multiple myeloma.
Human cancer is inherently heterogeneous, so the ability to monitor individual cancer cells at every clinic visit would be a valuable tool. This work describes the first step towards developing handheld and automated devices for molecular and phenotypic analysis of cancer cells. Here, we show that use of capillary electrophoresis to detect PCR product amplified from either transcripts (high abundance template) or genomic DNA (low abundance template) encoding clonotypic immunoglobulin heavy chain VDJ of plasma cells from patients with multiple myeloma. High abundance IgH VDJ transcripts amplified in conventional systems or by capillary electrophoresis through channels on microfluidic chips or, alternatively, PCR product amplified from individual myeloma plasma cells in a single stage RT-PCR reaction was readily detectable on microfluidic chips. For low abundance templates, a nested PCR strategy was needed to detect PCR product by any method. Using microfluidic chips, PCR products amplified from genomic IgH VDJ DNA were detected in six out of eight plasma cells. Comparison of the ABI3100 and the microfluidic chip indicates that approximately 20 times more sample is injected into the ABI 3100 capillary than for the microfluidics chip. Overall, for high and low abundance template in individual cells, the microfluidic separation/detection system is at least as sensitive as the ABI 3100. In the future, integrated microfluidic platforms that incorporate both PCR cycling and product detection on the same chip are likely to exceed conventional systems in sensitivity and speed of genetic analysis by RT-PCR or PCR.


Familial bladder cancer in an oncology clinic.
We have evaluated family history and cigarette smoking history on 49 consecutively ascertained patients with urinary bladder carcinoma and compared them with 956 consecutively ascertained patients with histologically verified cancer (all sites), all of whom were being treated in the same oncology clinics. Data was collected through interviews, questionnaires, and primary medical and pathology documents. Cancer risks were compared on the basis of anatomic sites involved and with cumulative risk estimated from data in the Third National Cancer Survey. A permutation test was also employed. Significant heterogeneity of risk (z = 4.85, p less than or equal to 0.02) for bladder cancer was found in relatives of probands with bladder cancer. Significant heterogeneity or increase in risk of bladder cancer was not observed when families with lung, other smoking related cancer, and nonsmoking related cancer were analyzed. Though based on a limited number of verified bladder cancer patients, we have provided statistical evidence in support of our hypothesis that bladder cancer may have a stronger familial etiologic component than heretofore recognized.


Medicaid expansion and postpartum depressive symptoms: evidence from the 2009-2018 Pregnancy Risk Assessment Monitoring System survey.
This population-representative study examined the association of Medicaid expansion under the Patient Protection and Affordable Care Act (ACA) with postpartum depressive symptoms among low-income women. We used data from the 2009 - 2018 Pregnancy Risk Assessment Monitoring System (PRAMS) surveys for 13 Medicaid expansion and 7 non-expansion states. We used a generalized difference-in-differences approach and log-binomial regression models to calculate prevalence ratios (PRs) and 95% confidence intervals (CIs) comparing the likelihood of postpartum depressive symptoms among low-income women (≤138% of the federal poverty level) who delivered in expansion and non-expansion states. Adjusting for state and year fixed-effects and individual- and state-level confounders, low-income women who delivered in Medicaid expansion states had a decreased likelihood of postpartum depressive symptoms compared to low-income women who delivered in non-expansion states (PR = 0.93, 95% CI 0.80, 1.07). Results were largely consistent across multiple sensitivity analysis specifications. Results were robust to falsification tests among women with incomes >138% of the federal poverty level. Our results indicate that Medicaid expansion may be associated with a small reduction in the likelihood of postpartum depressive symptoms. Future research should examine the potential for implementation of multiple supportive policies to achieve larger gains in treatment and prevention.


West Indian adolescents' perceptions of family functioning.
A total of 424 Barbadians aged 13-15 years completed the Family Functioning in Adolescence Questionnaire, developed in Australia by Roelofse and Middleton (1985). Findings revealed most adolescents, like their Australian peers, reported fairly favourable perceptions of their families. However, neither total nor sub-scale scores served to discriminate between sub-groups based on sex, age or household structure to any great extent. A re-grouping of items based on results of Varimax analysis also failed to yield many significant group differences, although some directions for future research were indicated. Adolescents not living with their fathers seemed to have a somewhat lower sense of personal security, but in other respects did not report their family life any less favourably than did those living with both natural parents.


Dietary protein and the intestinal microbiota: An understudied relationship.
Diet has a profound impact on the microbial community in the gastrointestinal tract, the intestinal microbiota, to the benefit or detriment of human health. To understand the influence of diet on the intestinal microbiota, research has focused on individual macronutrients. Some macronutrients (e.g. fiber) have been studied in great detail and have been found to strongly influence the intestinal microbiota. The relationship between dietary protein, a vital macronutrient, and the intestinal microbiota has gone largely unexplored. Emerging evidence suggests that dietary protein strongly impacts intestinal microbiota composition and function and that protein-microbiota interactions can have critical impacts on host health. In this review, we focus on recent studies investigating the impact of dietary protein quantity and source on the intestinal microbiota and resulting host health consequences. We highlight major open questions critical to understanding health outcomes mediated by interactions between dietary protein and the microbiota.


A Meta-analysis of Randomized Controlled Trials Comparing the Efficacy and Safety of Pregabalin and Gabapentin in the Treatment of Postherpetic Neuralgia.
To systematically evaluate the clinical efficacy of pregabalin and gabapentin in the treatment of postherpetic neuralgia (PHN), including the difference in pain control and occurrence of adverse reactions. PubMed, MEDLINE, EMBASE, Cochrane Library, and Web of Science databases were searched for randomized controlled trials (RCTs) comparing the efficacy of pregabalin and gabapentin in patients with PHN. Data from studies meeting the inclusion criteria were extracted and the Cochrane Risk of Bias risk assessment tool was used to evaluate the quality of the included studies. Revman 5.3 and Stata17 were used to perform the meta-analysis and to detect publication bias. A total of 14 RCTs with 3545 patients were included in this study, including 926 in the pregabalin treatment group, 1256 in the gabapentin treatment group, and 1363 in the placebo control group. Pregabalin was better than gabapentin in alleviating pain and improving the global perception of change in pain and sleep (P < 0.05). Gabapentin was associated with a lower incidence of adverse events than pregabalin (P < 0.05). Funnel plot and Begg's and Egger's tests showed no significant publication bias. Pregabalin appears to have a better overall therapeutic effect than gabapentin for patients with PHN, but gabapentin has a lower incidence of adverse reactions and a better safety profile. Clinicians should comprehensively consider patient factors and fully evaluate the advantages and disadvantages of each treatment option to select the most suitable drugs for patient use. Considering the limited quantity and quality of the existing literature, high-quality RCTs are needed to confirm the advantages of pregabalin over gabapentin in the treatment of PHN and guide clinical decision-making.


Anxiolytic-like effects of olanzapine, risperidone and fluoxetine in the elevated plus-maze test in rats.
In the present study was examined the effect of treatment with olanzapine or risperidone, given separately or in combination with fluoxetine, in the elevated plus-maze test (an animal model of anxiety) in male Wistar rats. The obtained results showed that treatment with olanzapine (1 mg/kg), risperidone (0.1 and 0.3 mg/kg) or fluoxetine (5 and 10 mg/kg) induced an anxiolytic-like effect in the elevated plus-maze test. Olanzapine, risperidone and fluoxetine, tested in doses effective in the model of anxiolytic-like actions, did not affect motor coordination, while olanzapine (3 mg/kg) and risperidone (0.3 mg/kg) produced a significant reduction of exploratory activity in the open field test. In a combination study, the anxiolytic-like effect of olanzapine or risperidone was significantly antagonized by co-treatment with fluoxetine. Additionally, co-treatment with olanzapine or risperidone and fluoxetine disturbed the motor coordination of rats in a rota-rod test. These findings indicate that olanzapine, risperidone and fluoxetine per se may be clinically effective in treating anxiety disorders, but their effects may be attenuated when they are used in combination with other medications.


Metal binding to myosin and to myosin DTNB-light chain.
The effects of various divalent cations, Ca2+, Mg2+ and Mn2+ on the intrinsic fluorescence of heavy meromyosin (HMM) and myosin 5,5'-dithio-bis-(2-nitrobenzoate) DTNB-light chain of rabbit striated muscle, are compared. At pH 6.4, th fluorescence change induced by the metal ions is present only in the isolated light chain and disappears in HMM, thus indicating an interaction between the heavy and light chains with respect to the binding of the metal ions. Whereas Mg2+ binds more strongly than Ca2+ to myosin, this order is reversed in the case of the DTNB-light chain.


Safety and Effectiveness of the Hyaluronic Acid Filler, HYC-24L, for Lip and Perioral Augmentation.
Hyaluronic acid gels are increasingly used for augmentation of the lips. To assess the safety and effectiveness of Juvéderm Ultra XC, a 24 mg/mL hyaluronic acid gel containing 0.3% (wt/wt) lidocaine (HYC-24L), for augmentation of the lips. This ongoing, multicenter, single-blind study randomized 213 subjects to the treatment group (n = 157) or concurrent no-treatment control group that received delayed treatment (n = 56). The primary effectiveness endpoint was the responder rate (≥1 point improvement from baseline) based on the blinded evaluating investigator's assessment of the subject's overall lip fullness (or fullness of the eligible lip) using the validated Allergan 5-point Lip Fullness Scale. To meet this endpoint, the treatment group had to have a responder rate ≥60% and significantly greater than the treatment control group at Month 3. The primary endpoint was met, with a 79.1% responder rate for the treatment group and 26.1% for the treatment control group (p < 0.0001). More than half of subjects (56.4%) maintained treatment response for 12 months. Common injection site responses were swelling, bruising, and firmness; most were of mild or moderate severity. HYC-24L is safe and effective for aesthetic lip augmentation, with results lasting up to 1 year.


Caregiver perceptions of snacks for young children: A thematic synthesis of qualitative research.
Snacks are inconsistently defined in nutrition research and dietary guidelines for young children, challenging efforts to improve diet quality. Although some guidelines suggest that snacks include at least two food groups and fit into an overall health promoting dietary pattern, snacks high in added sugars and sodium are highly marketed and frequently consumed. Understanding how caregivers perceive "snacks" for young children may aid in development of effective nutrition communications and behaviourally-informed dietary interventions for obesity prevention. We aimed to synthesize caregivers' perceptions of snacks for young children across qualitative studies. Four databases were searched for peer-reviewed qualitative articles including caregiver perceptions of "snacks" for children ≤5 years. We conducted thematic synthesis of study findings, concluding with the development of analytical themes. Data synthesis of fifteen articles from ten studies, conducted in the U.S., Europe, and Australia, revealed six analytical themes that captured food type, hedonic value, purpose, location, portion size, and time. Caregivers perceived snacks as both "healthy" and "unhealthy" foods. Less healthy snacks were described as highly liked foods, which required restriction and were consumed outside the home. Caregivers used snacks to manage behavior and curb hunger. Snack portions were described as "small", although caregivers reported various methods to estimate child portion size. Caregivers' perceptions of snacks revealed opportunities for targeted nutrition messaging, especially supporting responsive feeding and nutrient-dense food choices. In high-income countries, expert recommendations should consider caregivers' perceptions of snacks, more clearly defining nutrient-dense snacks that are enjoyable, achieve dietary requirements, reduce hunger, and promote healthy weight.


CAR and PXR: xenosensors of endocrine disrupters?
The pregnane X-receptor (PXR) and the constitutive androstane receptor (CAR) are orphan nuclear receptors activated by a variety of ligands. Currently it remains uncertain whether these receptors have a high-affinity ligand or instead function as more generalized steroid/xenobiotic sensors. Both receptors are important regulators of several steroid and xenobiotic detoxification enzymes and transporters (phases I-III) in the liver and intestine and thus are important regulators of adaptation to chemical stress. The detoxification proteins induced are responsible for the metabolism, deactivation and transport of bile acids, thyroid and steroid hormones, numerous environmental chemicals, and several drugs. PXR and CAR received their names because of steroid ligands that activate and inhibit their transcriptional activity, respectively. Interestingly, some steroids and steroid mimics activate one or both receptors, including several endocrine disrupting chemicals. Environmental estrogens, such as the pesticides methoxychlor, endosulfan, dieldrin, DDT, and the plasticizer nonylphenol activate either PXR or both PXR and CAR. Because PXR and CAR are activated by numerous steroids and endocrine disrupters, it appears that these receptors protect the integrity of the endocrine system. They recognize an increase in steroid-like chemicals and, in turn, induce detoxification. Furthermore, PXR and CAR induce enzymes, such as the CYP2B and CYP3A family members, responsible for the metabolism of steroid and thyroid hormones and this may alter their normal physiological function. This review summarizes the available data on the activity of endocrine disrupters and endocrine active chemicals on PXR and CAR, examines the role of PXR and CAR in protection from these chemicals, and evaluates potential adverse physiological consequences of PXR and CAR activation.


A new approach to sample size calculation for reference interval studies.
A new criterion is proposed for determining the sample size required for a study performed for the purpose of establishing reference intervals. The basic idea behind the criterion is to compare the empirical coverage (i.e. the probability content) of the reference region obtained from the sample with its target value (e.g. 95 per cent) and to set suitable limits delta1, delta2 to the difference between both quantities which must not be exceeded with sufficiently large probability beta (e.g. beta=90 per cent). For the most frequently used parametric and distribution-free methods of estimating univariate reference limits, implicit formulae are derived relating the sample size to the design parameters delta1, delta2 and beta. For symmetric specification of (delta1, delta2), explicit approximation formulae for the computation of n are given. Exact values obtained by means of suitable numerical techniques are presented in a set of tables covering specifications of delta1, delta2 and beta which can be recommended for real applications. The tables can be used both for one- and two-sided reference intervals.


Peripheral vascular reactions to smoking--profound vasoconstriction by atherosclerosis.
Analyses of direct effects of smoking on peripheral arteries were done using thermography, blood fluorometry and echography on 97 habitual smoker-diabetics without triopathy. There were found to be four types of thermographic changes following smoking, which varied according to the degree of atherosclerosis of the artery. The smoking-stimulated thermographic pattern in the control group of healthy volunteers was a small wavy pattern, fluctuating along the base line every few minutes within a temperature range of 1.0-1.5 degrees C (N type). In diabetics, four types of thermographic patterns were produced: normal (N) type as control, increasing (I) type (increasing in skin temperature), decreasing (D) type (decreasing in temperature), and F type (no changes in temperature). The most significant finding was the decreasing pattern which closely connected to clinical and echographic aspects of macroangiopathic changes. The increasing type was characterized by a paradoxical increase in temperature after smoking in order diabetics with good blood glucose control and who were less atherosclerotic. Blood flow was correlated to the skin temperature at the base state and changes after smoking. Moreover, blood flow changes measured by fluorometry suggest that vasoconstriction or vasodilatation following smoking took place. These results suggest that this smoking test might be a good tool for diagnosing for the degree of atherosclerosis and for its following up.


Inhibition of enzyme activities and the antiwrinkle effect of polyphenol isolated from the persimmon leaf (Diospyros kaki folium) on human skin.
Many studies have been conducted to find a natural material that has high biologic functions for human skin without any side effects. Persimmon leaf has a substantial amount of tannins in different forms; therefore, it was selected as a target material. The biosynthesis rate of the collagen was also investigated to clarify the beneficial functions for the human skin. Persimmon leaves were obtained, extracted with 80% ethanol, and isolated into PFs I, II, and III after column chromatography using a Sephadex LH-20 column followed by thin-layer chromatography. The xanthine oxidase inhibition effect of both PFs II and III was over 40% at a 100 ppm concentration. PF II, containing higher flavonoids levels, had a significantly higher tyrosinase inhibition than that of PF III. Collagenase inhibition was 16.3 and 8.1% for PF III and PF II, respectively, at 100 ppm. On the other hand, elastase inhibition activity was significantly higher in PF II than PF III. Collagen biosynthesis rates of PF III were over 25% from a 1 to 10 ppm concentration. Consequently, PFs isolated from the persimmon leaf can be used as natural materials or additives for human skin owing to their beneficial biologic functions, including the antiwrinkle effect and the inhibition of skin problems, for food or cosmetic compositions.


The pathology of lymphoreticular and genital tissues of silvered leaf monkeys (Presbytis cristata) experimentally infected with Wuchereria bancrofti.
The discovery of the silvered leaf monkey, Presbytis cristata, as a suitable experimental host for the human filarial parasite, Wuchereria bancrofti, opened the door for major advances in our understanding of the disease caused by this parasite. To study the pathogenesis of bancroftian filariasis in this model, 15 adult P. cristata which had been experimentally infected with 250 infective third-stage larvae of the parasite were examined. After inoculation with larvae, the monkeys were maintained under study for periods of 2 to 3 years, at which time all had achieved patent infections. At necropsy, Wuchereria-induced macroscopic lesions were not detected in experimentally infected monkeys. Microscopic findings included nematodiasis, microfilariasis, lymphadenitis, lymphangiectasis, perilymphangitis, splenitis, orchitis, periorchitis, epididymitis and funiculitis. Sections of normal adult worms were most often found in lymphatic vessels near lymph nodes, or in the lymphatics of the male genital system. These worms caused microfiliariasis in some regional lymph nodes. Inflammatory responses to filariae were most prominent in proximity to degenerated and dead worms, whereas intact, normal appearing adult worms elicited only minimal cellular response.


Chronic high-fat diet induces galectin-3 and TLR4 to activate NLRP3 inflammasome in NASH.
NOD-like receptor protein 3 (NLRP3) inflammasome activation triggers inflammation progression in some metabolism disorders, frequently accompanying the up-regulation of galectin-3 (Gal-3). However, the precise mechanisms of Gal-3 activating NLRP3 inflammasome remain unclear in nonalcoholic steatohepatitis (NASH). Here, male C57BL/6J mice were fed by high-fat diet (HFD) for 32 weeks to induce NASH and then the hepatic damage, cytokines, Gal-3 and TLR4 expression, and NLRP3 inflammasome activation were examined. Such indicators were similarly determined when HepG2 cells were co-incubated with palmitic acid (PA, 200 μM), β-lactose, and TAK-242, or pre-transfected with TLR4. Immunofluorescence, immunohistochemistry, and co-immunoprecipitation were conducted to confirm the potential interaction between Gal-3 and TLR4. To further identify the inflammatory regulation roles of Gal-3 and its terminals in TLR4/NLRP3, HepG2 cells were transfected with Gal-3 and its variants. Chronic HFD induced sustained hepatic steatosis and inflammatory injury, with increased inflammatory cytokines, Gal-3 and TLR4 expression, and NLRP3 inflammasome activation. Similar changes were found in PA-dosed HepG2 cells, which were rescued by β-lactose but deteriorated with TLR4 overexpression. However, TAK-242 treatment decreased AST, ALT, cytokines, and normalized NLRP3, caspase-1, and ASC expression. Furthermore, TLR4 was pulled down when Gal-3 was enriched. Only full-length Gal-3 and its carbohydrate recognition domain (CRD) promoted cytokines, TLR4 expression, and NLRP3 inflammasome activation. Thus, gal-3 may induce chronic HFD-derived NASH progression by activating TLR4-mediating NLRP3 inflammasome via its CRD, which sheds new light on candidate target for the treatment and prevention of NASH inflammation despite further research for its precise roles in the future.


Physicochemical characterization and cancer cell antiproliferative effect of silver-doped magnesia nanoparticles.
Silver-doped magnesia nanoparticles (Ag/MgO) were synthesized using the precipitation method and characterized by various techniques such as X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), thermal gravimetric analysis (TGA), Brunner-Emmett-Teller (BET) surface area measurements, and dispersive X-ray spectroscopy (EDX). The morphology of Ag/MgO nanoparticles was determined by transmission and scanning electron microscopy, which revealed cuboidal shaped nanoparticles with sizes ranging from 31 to 68 nm and an average size of 43.5 ± 10.6 nm. The anticancer effects of Ag/MgO nanoparticles were evaluated on human colorectal (HT29) and lung adenocarcinoma (A549) cell lines, and their caspase-3, -8, and -9 activities, as well as Bcl-2, Bax, p53, cytochrome C protein expressions were estimated. Ag/MgO nanoparticles showed selective toxicity towards HT29 and A549 cells while remaining relatively innocuous towards the normal human colorectal, CCD-18Co, and lung, MRC-5 cells. The IC50 values of Ag/MgO nanoparticles on the HT29 and A549 cells were found to be 90.2 ± 2.6 and 85.0 ± 3.5 μg/mL, respectively. The Ag/MgO nanoparticles upregulated caspase-3 and -9 activities, downregulated Bcl-2, upregulated Bax and p53 protein expressions in the cancer cells. The morphology of the Ag/MgO nanoparticle treated HT29 and A549 cells was typical of apoptosis, with cell detachment, shrinkage, and membrane blebbing. The results suggest that Ag/MgO nanoparticles induce apoptosis in cancer cells and exhibit potential as a promising anticancer agent.


Application of a simple methylation procedure for the analyses of glycosphingolipids.
Acid and neutral glycosphingolipids (0.01-1 mumol) were completely methylated in high yields and with little formation of by-products in 10 min at room temperature, using methyl sulphoxide, methyl iodide, and powdered NaOH. Re-methylation of methylated and LiAlH4-reduced gangliosides gave a new derivative that was useful for the analysis of gangliosides by mass spectrometry.


Affixment arrangements of peribronchiolar alveoli in normal and emphysematous lungs.
Our investigation of the radially affixed alveoli of nonrespiratory bronchioles showed that the interalveolar interval was basically constant for normal bronchioles of all sizes, with a mean value of 0.146 mm. The mean interalveolar interval increased significantly to 0.173 and 0.209 mm, respectively, in the two most severe grades of emphysema. The pattern of alveolar affixment to the walls of bronchioles was also altered in emphysema, with irregular interruptions, variations in size and shape of abutting luminal spaces, and loss of alveolar attachment surface. These changes reflected the disruptive phase of emphysema and corroborated previous studies. A dominant extrinsic force normally responsible for bronchiolar patency is thus compromised. Any bronchiole so affected would logically be prone to collapse or contracture of its wall, luminal deformities, diminution of luminal caliber, and retarded airflow.


Chrysovirus structure: repeated helical core as evidence of gene duplication.
Chrysoviruses are double-stranded RNA viruses with a multipartite genome. Structure of two fungal chrysoviruses, Penicillium chrysogenum virus and Cryphonectria nitschkei chrysovirus 1, has been determined by three-dimensional cryo-electron microscopy analysis and in hydrodynamic studies. The capsids of both viruses are based on a T=1 lattice containing 60 subunits, remain structurally undisturbed throughout the viral cycle, and participate in genome metabolism. The capsid protein is formed by a repeated α-helical core, indicative of gene duplication. Whereas the chrysovirus capsid protein has two motifs with the same fold, most dsRNA virus capsid subunits consist of dimers of a single protein with similar folds. The arrangement of the chrysovirus α-helical core is conserved in the totivirus L-A capsid protein, suggesting a shared basic fold. The encapsidated genome is organized in concentric shells; whereas inner dsRNA shells are diffuse, the outermost layer is organized into a dodecahedral cage beneath the protein capsid. This genome ordering could constitute a framework for dsRNA transcription in the capsid interior and/or have a structural role for capsid stability.


Sperm Motility Requires Wnt/GSK3 Stabilization of Proteins.
Inhibition of GSK3 by Wnt signaling stabilizes many cellular proteins, but proof that this effect is independent of β-catenin-mediated transcription is lacking. Koch, Acebron, and colleagues (2015) now demonstrate that transcriptionally silent mammalian sperm require Wnt signaling via exosomes to prevent protein degradation during their lengthy travels through the epididymis.


Plasma fatty acid responses to a calorie-restricted, DASH-style diet with lean beef.
Plasma fatty acid (FA) levels are used as biomarkers of health outcomes and nutritional intake. This was an exploratory analysis of the plasma FA profile from a parallel-designed, controlled-feeding study in older, obese adults (females, n = 17; males, n = 11) consuming a DASH-based diet with two levels of lean beef (3oz and 6oz per day). Plasma FA levels (as percent composition) were measured by gas chromatography from five timepoints over the 12-week intervention. The primary plasma FA change patterns modeled were sustained (initial change to 'new normal') or homeostatic (initial change, then return toward original baseline). The study diet was low in fat (< 60 g/d), especially polyunsaturated FAs (PUFAs; < 5 g/d), compared to the average American diet of obese individuals as described by a nationally representative sample. Participants lost ∼6% of body mass and lowered plasma fasting triglyceride levels by ∼9% over the course of the study. With strong to very strong strength of evidence, the individual FAs displaying a sustained response were C16:1n7t, C18:1n9, C20:1n9, and C18:2n6, and homeostatic response, C18:0, 24:0, C24:1n9, C18:3n6, C20:4n6, and C22:6n3 (Ps < 0.0021, Bonferroni-adjusted). The data suggested that systematic changes in both the PUFA and de novo lipogenesis pathways occurred. Diet can affect plasma FA changes both due to nutritional composition and by affecting metabolic processes.


Most international guidelines on prevention of healthcare-associated infection lack comprehensive recommendations for neonates and children.
International infection prevention and control (IPC) guidelines provide standardized recommendations for healthcare-associated infection (HCAI) prevention in adults, but often lack specific information about neonates and children. We reviewed ten international IPC/HCAI guidelines to identify paediatric-specific recommendations for HCAI prevention. Hand hygiene, bloodstream infection, ventilator-associated pneumonia, environmental control and outbreak management were frequently reported with recommendations applicable to children and newborns, but documents on catheter-associated urinary tract infection and surgical site infection were lacking.


Chloroperoxidase-catalyzed oxidation of N-methyl-4-chloroaniline.
Chloroperoxidase catalyzed the H2O2 oxidative conversion of N-methyl-4-chloroaniline to 4-chloronitrosobenzene, 4-chloroaniline and a mixture of complex products.


Identification of large ancient duplications associated with human gene deserts.
We identified 15 regions of >1 Mb in the human genome composed of large ancient local duplications corresponding to gene deserts. We detected these intrachromosomal duplications in mouse and dog but not in chicken; they present as patches of similarity as low as 60%. These findings suggest that some human gene deserts originated from duplications of segments lacking genes in a mammalian common ancestor.


[Main Cellular Redox Couples].
Most of the living cells maintain the continuous flow of electrons, which provides them by energy. Many of the compounds are presented in a cell at the same time in the oxidized and reduced states, forming the active redox couples. Some of the redox couples, such as NAD+/NADH, NADP+/NADPH, oxidized/reduced glutathione (GSSG/GSH), are universal, as they participate in adjusting of many cellular reactions. Ratios of the oxidized and reduced forms of these compounds are important cellular redox parameters. Modern research approaches allow setting the new functions of the main redox couples in the complex organization of cellular processes. The following information is about the main cellular redox couples and their participation in various biological processes.


Molecular cloning and functional characterization of a novel apple MdCIPK6L gene reveals its involvement in multiple abiotic stress tolerance in transgenic plants.
CBL-interacting protein kinases (CIPKs) are involved in many aspects of plant responses to abiotic stresses. However, their functions are poorly understood in fruit trees. In this study, a salt-induced MdCIPK6L gene was isolated from apple. Its expression was positively induced by abiotic stresses, stress-related hormones and exogenous Ca(2+). MdCIPK6L was not homologous to AtSOS2, however, its ectopic expression functionally complemented Arabidopsis sos2 mutant. Furthermore, yeast two-hybrid assay showed that MdCIPK6L protein interacted with AtSOS3, indicating that it functions in salt tolerance partially like AtSOS2 through SOS pathway. As a result, the overexpression of both MdCIPK6L and MdCIPK6LT175D remarkably enhanced the tolerance to salt, osmotic/drought and chilling stresses, but did not affect root growth, in transgenic Arabidopsis and apple. Also, T-to-D mutation to MdCIPK6L at Thr175 did not affect its function. These differences between MdCIPK6L and other CIPKs, especially CIPK6s, indicate that MdCIPK6L encodes a novel CIPK in apple. Finally, MdCIPK6L overexpression also conferred tolerance to salt, drought and chilling stresses in transgenic tomatoes. Therefore, MdCIPK6L functions in stress tolerance crossing the species barriers, and is supposed to be a potential candidate gene to improve stress tolerance by genetic manipulation in apple and other crops.


The role of cellular and molecular neuroimmune crosstalk in gut immunity.
The gastrointestinal tract is densely innervated by the peripheral nervous system and populated by the immune system. These two systems critically coordinate the sensations of and adaptations to dietary, microbial, and damaging stimuli from the external and internal microenvironment during tissue homeostasis and inflammation. The brain receives and integrates ascending sensory signals from the gut and transduces descending signals back to the gut via autonomic neurons. Neurons regulate intestinal immune responses through the action of local axon reflexes or through neuronal circuits via the gut-brain axis. This neuroimmune crosstalk is critical for gut homeostatic maintenance and disease resolution. In this review, we discuss the roles of distinct types of gut-innervating neurons in the modulation of intestinal mucosal immunity. We will focus on the molecular mechanisms governing how different immune cells respond to neural signals in host defense and inflammation. We also discuss the therapeutic potential of strategies targeting neuroimmune crosstalk for intestinal diseases.


Activities and Compensation of Advanced Heart Failure Specialists: Results of the Heart Failure Society of America (HFSA) Survey.
In the current era, where advanced heart failure (AHF) has become an American Board of Internal Medicine-certified subspecialty, new data are needed to benchmark and value levels of clinical effort performed by AHF specialists (AHFMDs). A 36-question survey was sent to 728 AHFMDs, members of the Heart Failure Society of America, and 224 (31%) responded. Overall, 56% worked in academic medical centers (AMCs) and were younger (48 ± 9 y vs 52 ± 10 y; P < .01) and were represented by a higher proportion of women (34% vs 21%, P < .01) compared with non-AMCs. The percentage of time in clinical care was lower in AMCs (64 ± 19% vs 78 ± 18%; P = .002), with similar concentration on evaluation and management services (79 ± 18% in AMCs vs 72 ± 18 % in non-AMCs; P = NS). The majority of nonclinical time was spent in program administration (10% in both AMCs and non-AMCs) and education/research (15% in AMC vs 5% in non-AMCs). Although 69% of respondents were compensated by work-relative value units (wRVUs), only a small percentage knew their target or the amount of RVUs generated. The mean annual wRVUs generated were lower in AMCs compared to non-AMCs (5,452 ± 1,961 vs 9,071 ± 3,484; P < .001). The annual compensation in AMCs was lower than in non-AMCs (45% vs 10% <$250,000 and 17% vs 61% >$350,000; P < .001) and the satisfaction with compensation was higher in non-AMCs. AHFMDs' compensation is largely dependent by practice type (AMC vs non-AMC) and clinical productivity as measured by wRVUs. These data provide an opportunity for benchmarking work effort and compensation for AHFMDs, allowing distinction from segments of cardiologists with greater opportunity to accrue procedural wRVUs. They also show several differences between AMCs and non-AMCs that should be considered when formulating work assignment and compensation for AHFMDs.


Efficacy of gamma interferon and specific antibody for treatment of microsporidiosis caused by Encephalitozoon cuniculi in SCID mice.
Microsporidia are eukaryotic, obligate, intracellular protists that are emerging pathogens in immunocompromised hosts, including AIDS patients and organ transplant recipients. The efficacy of gamma interferon (IFN-gamma) for the treatment of microsporidiosis caused by Encephalitozoon cuniculi was studied by means of adoptive transfer and IFN-gamma administration in SCID mice. While the adoptive transfer of CD4(+) T cells from immunocompetent mice prolonged survival of SCID mice infected perorally with E. cuniculi, survival was not improved by adoptive transfer of CD4(+) T lymphocytes from IFN-gamma-deficient mice. The protective effect of IFN-gamma was confirmed in cytokine therapy experiments in which SCID mice receiving IFN-gamma survived significantly longer than mice receiving mock injections. The administration of serum containing specific antibodies against E. cuniculi was found to prolong the survival of concurrently IFN-gamma-treated SCID mice. The data presented in this study suggest that IFN-gamma is potentially useful as a cytokine therapy for microsporidiosis, especially in CD4(+) T-cell-deficient patients.


Assessment of mutagenicity induced by MMS and DES in Capsicum annuum L.
Seeds of Capsicum annuum L. var. G4 were subjected to different concentrations of methyl methane sulphonate (MMS) and diethyl sulphate (DES). The effects of different mutagenic treatments on meiosis, chiasma frequency, and pollen fertility have been studied in M1 generation. Various types of meiotic aberrations such as univalent, multivalent, stickiness, bridge, laggards, cytomixis etc. were observed in all the treatments. However, the MMS treatments proved to be more effective in inducing meiotic aberrations as compared to DES. Moreover, the frequency of meiotic aberrations was at its maximum at metaphase followed by anaphase and telophase stages. As the concentrations increase, reduction in chiasma frequency and pollen fertility was observed in all the treatments and, MMS again was found to be more effective than DES treatments.


Gender, temperament, and the clinical picture in dysphoric mixed mania: findings from a French national study (EPIMAN).
This research derives from the French national multisite collaborative study on the clinical epidemiology of mania (EPIMAN). Our aim is to establish the validity of dysphoric mania along a "spectrum of mixity" extending into mixed mania with subthreshold depressive manifestations; to demonstrate the feasibility of obtaining clinically meaningful data on this entity on a national level; and to characterize the contribution of temperamental attributes and gender in its origin. EPIMAN involves training 23 French psychiatrists in four different sites, representing four regions of France; to rigorously apply a common protocol deriving from the criteria of DSM-IV and McElroy et al.; the use of such instruments as the Beigel-Murphy, Ahearn-Carroll, modified HAM-D; and measures of affective temperaments based on the Akiskal-Mallya criteria; obtaining data on comorbidity, and family history (according to Winokur's approach as incorporated into the FH-RDC); and prospective follow-up for at least 12 months. The present report concerns the clinical and temperamental features of 104 manic patients during the acute hospital phase. Dysphoric mania (DM defined conservatively with fullblown depressive admixtures of five or more symptoms) occurred in 6.7%; the rate of dysphoric mania defined broadly (DM, presence of > or = 2 depressive symptoms) was 37%. Depressed mood and suicidal thoughts had the best positive predictive values for mixed mania. In comparison to pure mania (0-1 depressive symptoms), DM was characterized by female over-representation; lower frequency of such typical manic symptomatology as elation, grandiosity, and excessive involvement; higher prevalence of associated psychotic features; higher rate of mixed states in first episodes; and complex temperamental dysregulation along primarily depressive, but also cyclothymic, and irritable dimensions; such irritability was particularly apparent in mixed mania at the lowest threshold of depressive admixtures of two symptoms only. In a study involving hospitalized affectively unstable psychotic patients, it was difficult to assure that psychiatrists making the clinical diagnoses would be blind to the temperamental measures. However, bias was minimized by the systematic and/or semi-structured nature of all evaluations. Mixed mania, defined cross-sectionally by the simultaneous presence of at least two depressive symptoms, represents a prevalent and clinically distinct form of mania. Subthreshold depressive admixtures with mania actually appear to represent the more common expression of dysphoric mania. Moreover, an irritable dimension appears to be relevant to the definition of the expression of mixed mania with the lowest threshold of depressive symptoms. Neither an extreme, nor an endstage of mania, "mixity" is best conceptualized as intrusion of mania into its "opposite" temperament - especially that defined by lifelong depressive traits - and favored by female gender. These data suggest that reversal from a temperament to an episode of "opposite" polarity represents a fundamental aspect of the dysregulation that characterizes bipolar disorder. In both men and women with hyperthymic temperament, there appears "protection" against depressive symptom formation during a manic episode which, accordingly, remains relatively "pure". Because men have higher rates of this temperament, pure mania is overrepresented in men; on the other hand, the depressive temperament in manic women seems to be a clinical marker for the well-known female tendency for depression, hence the higher prevalence of mixed mania in women.


Fluorescence and biological evaluation of the La(III) and Eu(III) complexes with 7-methoxychromone-3-carbaldehyde benzoyl hydrazone Schiff base.
A novel Schiff base ligand (L = 7-methoxychromone-3-carbaldehyde benzoyl hydrazone) and its La(III) and Eu(III) complexes have been successfully prepared. The crystal structure of [LaL(2)(NO(3))(3)].H(2)O was characterized by X-ray crystallography. It crystallizes in monoclinic, space group C2/c with crystallographic data: a = 27.7173(17) A, b = 10.0002(6) A, c = 14.7884(9) A, beta = 102.6870(10) degrees and Z = 4. In the structure, the La(III) ion satisfies 12 coordination and three nitrate coordinate as bidentate ligand. The biological experiments show that the ligand and its two complexes can strongly bind to DNA through intercalation mode, and the three compounds also exhibit good antioxidant activities against OH(*) and O(2) (-*). Moreover, it is found that the Eu(III) complex exhibits characteristic fluorescence of europium ion in different organic solvent.


Pyrrolidine analogs of GZ-793A: synthesis and evaluation as inhibitors of the vesicular monoamine transporter-2 (VMAT2).
Central heterocyclic ring size reduction from piperidinyl to pyrrolidinyl in the vesicular monoamine transporter-2 (VMAT2) inhibitor GZ-793A and its analogs resulted in novel N-propane-1,2(R)-diol analogs 11a-i. These compounds were evaluated for their affinity for the dihydrotetrabenazine (DTBZ) binding site on VMAT2 and for their ability to inhibit vesicular dopamine (DA) uptake. The 4-difluoromethoxyphenethyl analog 11f was the most potent inhibitor of [(3)H]-DTBZ binding (Ki=560 nM), with 15-fold greater affinity for this site than GZ-793A (Ki=8.29 μM). Analog 11f also showed similar potency of inhibition of [(3)H]-DA uptake into vesicles (Ki=45 nM) compared to that for GZ-793A (Ki=29 nM). Thus, 11f represents a new water-soluble inhibitor of VMAT function.


Methylation of ribonucleic acid in a cell-free system from mouse myeloma cells.
Isolated nuclei incorporate few methyl groups into RNA when they are incubated with S-adenosyl[methyl-3H3]methionine and four ribotriphosphates. When the nuclei were supplemented with a soluble total cell protein extract, the incorporation of methyl groups into RNA was stimulated 3-6-fold. All classes of RNA were methylated. Methylation of the 2'-OH of ribose and the bases of ribosomal RNA occurred predominantly on endogenous ribosomal RNA precursors, with a minority (20%) occurring on the newly synthesized rRNA precursor. Methylation of the tRNA precursor occurred on both endogenous (40%) and newly synthesized (60%) molecules. The methylation of adenosine in hnRNA occurred predominantly on molecules transcribed in vitro and was sensitive to 1 microgram/mL alpha-amanitin. A final site of methylation was the 7 position of guanosine of the cap structure. About 10% of the RNA polymerase II transcripts were capped in vitro. Capping was blocked 90% by 1 microgram/mL alpha-amanitin and was independent of the presence of the cell protein extract.


Quantum Mechanics/Molecular Mechanics Studies of the Mechanism of Cysteine Proteases Inhibition by Dipeptidyl Nitroalkenes.
In this work a computational study of the mechanism of inhibition of cruzain, rhodesain, and cathepsin L cysteine proteases by the dipeptidyl nitroalkene Cbz-Phe-Ala-CH=CH-NO2 has been carried out by means of molecular dynamics simulations with hybrid QM/MM potentials. The free-energy surfaces confirmed that the inhibition takes place by the formation of a covalent bond between the protein and the β-carbon atom of the inhibitor. According to the results, the tested inhibitor should be a much more efficient inhibitor of cruzain than of rhodesain, and little activity would be expected against cathepsin L, in total correspondence with the available experimental data. The origin of these differences may lie in the different stabilizing electrostatic interactions established between the inhibitor and the residues of the active site and S2 pocket of these enzymes. These results may be useful for the rational design of new dipeptidyl nitroalkenes with higher and more selective inhibitory activity against cysteine proteases.


Characterization of a community-acquired methicillin-resistant sequence type 338 Staphylococcus aureus strain containing a staphylococcal cassette chromosome mec type VT.
To determine the molecular characteristics of a sequence type 338 community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) strain and the relationship among MRSA strains from various lineages and areas. Whole-genome sequencing, genomic comparison, antimicrobial susceptibility testing, and hemolysis analysis were performed to identify the resistance determinants and virulence factors of strain ZY05 and the relationships among CC59 clones. MRSA strain ZY05 was resistant to tetracycline, erythromycin, and clindamycin, and the resistance genes erm(B) and tet(K) were detected in the genome. ZY05 harbors the genomic islands νSaα, νSaβ, νSaγ, and ΦSa2, the pathogenicity island νSa1, and virulence factors such as Panton-Valentine leukocidin, phenol-soluble modulins, alpha-hemolysin, enterotoxin B, enterotoxin K, and enterotoxin Q, which are the same as those present in ST59 strains. In addition, the virulence potential of ST338 did not differ from that of ST59. This strain contains the staphylococcal cassette chromosome mec (SCCmec) type VT, a distinct SCCmec type previously reported from Taiwan. The results of core genome multilocus sequence typing (cgMLST) analysis showed that the gene distances between ST59 and ST338 were close among CC59 isolates, while strains from Taiwan were identical to isolates from the Chinese mainland with respect to these two sequence types. The ST338 strain ZY05, which has a close genetic relationship to ST59 strains, is multidrug-resistant and highly virulent. Strains of two identical lineages, ST59 and ST338, from Taiwan and the Chinese mainland may have the same genetic background.


MELD or MELD-Na as a Predictive Model for Mortality Following Transjugular Intrahepatic Portosystemic Shunt Placement.
The model for end-stage liver disease (MELD) was originally developed to predict survival after transjugular intrahepatic portosystemic shunt (TIPS). The MELD-sodium (MELD-Na) score has replaced MELD for organ allocation for liver transplantation. However, there are limited studies to compare the MELD with MELD-Na to predict mortality after TIPS. We performed a retrospective chart review of patients who underwent TIPS placement between 2006 and 2016 at our institution. The primary outcome was mortality, and the secondary outcomes sought to assess which variables could provide prognostic information for mortality after TIPS placement. We performed receiver operating characteristic (ROC) curve analysis to assess the performance of MELD and MELD-Na. There were 186 eligible patients in the analysis. The mean pre-TIPS MELD and MELD-Na were 13 and 15, respectively. Overall, mortality after TIPS was 15% at 30 days and 16.7% at 90 days. In a comparison of the areas under the ROCs for MELD and MELD-Na, MELD was superior to MELD-Na for 30-day (0.762 vs. 0.709) and 90-day (0.780 vs. 0.730) mortality after TIPS. The optimal cutoff score for 30-day mortality was 15 (0.676-0.848) for MELD and 17 (0.610-0.808) for MELD-Na, whereas the optimal cutoff score for 90-day mortality was 16 (95% CI: 0.705-0.855) for MELD and 17 (95% CI: 0.643-0.817) for MELD-Na. There were 24 patients with high MELD-Na ≥17, but with low MELD <15, and 90-day mortality in this group was 8.3%. Although MELD-Na is a superior prognostic tool to MELD for predicting overall mortality in cirrhotic patients, MELD tended to outperform MELD-Na to predict mortality after TIPS.


Effect of transient expression of fluorescent protein probes in synovial and myoblast cell lines.
Here, we investigate the appropriate fluorescent proteins for use in the culture of synovial MH7A and myoblast C2C12 cells. Fluorescent signal intensities of 3 different fluorescent proteins were examined in these cell lines. The fluorescent intensity of transiently expressed AcGFP, DsRed, and mStrawberry were examined in these cell lines, and the influence of the amount of plasmid used on transfection efficiency and cell viability were investigated.


Teaching of dentistry to medical students in English at the Jagiellonian University, Krakow, Poland.
The significance of teaching dental subjects to medical students as well as medicine to dental students is considered. The authors' experience in teaching dentistry to medical students in English at the University of Krakow is described.


Activity of HMR 3647 compared to those of six compounds against 235 strains of Enterococcus faecalis.
Agar dilution was used to test the activities of HMR 3647, erythromycin A, azithromycin, clarithromycin, roxithromycin, clindamycin, and quinupristin-dalfopristin against 235 strains of Enterococcus faecalis. HMR 3647 was the most active compound (MICs at which 50 and 90% of the isolates are inhibited [MIC50 and MIC90, respectively] of 0.06 and 4.0 microg/ml, respectively). The MIC50 and MIC90 (with the MIC50 given first and the MIC90 given second; both in micrograms per milliliter) for other compounds were as follows: 4.0 and >32.0 for erythromycin A, 16.0 and >32.0 for azithromycin, 2.0 and >32 for clarithromycin, 32.0 and >32.0 for roxithromycin, 32.0 and >32.0 for clindamycin, and 8.0 and 16.0 for quinupristin-dalfopristin. All compounds were only bacteriostatic.


On the positivity of the test for anti-HCV considerations in dialized patients.
We have tested dialized patients with the ELISA test of 1st generation for anti-HCV. All patients who resulted positive were subjected to the RIBA test of 1st and 2nd generation. Since the positivity rate with this test is considerably more reliable, we suggest to confirm by RIBA test all anti-HCV-positive patients with ELISA in time.


Conjugation in the spirotrich ciliate Halteria grandinella (Müller, 1773) Dujardin, 1841 (Protozoa, Ciliophora) and its phylogenetic implications.
The conjugation of Halteria grandinella was studied in protargol preparations. The isogamontic conjugants fuse partially with their ventral sides to a homopolar pair. The first maturation division generates dramatic transformations: (i) the partners obtain an interlocking arrangement; (ii) the number of bristle kineties decreases from seven to four in each partner; and (iii) the right conjugant loses its buccal membranelles, the left the whole adoral zone. The remaining collar membranelles arrange around the pair's anterior end and are shared by both partners; finally, the couple resembles a vegetative specimen in size and outline. The vegetative macronucleus fragments before pycnosis. The micronucleus performs three maturation divisions, but only one derivative each performs the second and third division. The synkaryon divides twice, producing a micronucleus, a macronucleus anlage, and two disintegrating derivatives. Scattered somatic kinetids occur during conjugation, but disappear without reorganization. An incomplete oral primordium originates in both partners. The conjugation of Halteria grandinella resembles in several respects that of hypotrich spirotrichs; however, the majority of morphological, ontogenetical, and ultrastructural features still indicates an affiliation with the oligotrich and choreotrich spirotrichs. Accordingly, the cladistic analysis still contradicts the genealogy based on the sequences of the small subunit rRNA gene.


Ethanol ingestion: differences in blood acetaldehyde concentrations in relatives of alcoholics and controls.
Blood acetaldehyde concentrations were significantly elevated after a moderate ethanol dose in 20 healthy young men with alcoholic parents or siblings compared to matched controls with no familial alcoholism.


Substrate specificity for pancreatic amylase.
Substrates commonly used for the determination of amylase activity include potato starch, corn starch and dye-labeled starch. Determination of the amylase activity of serum using these different starches has shown that the measured value varies depending upon the ratio of isoamylases present, namely between pancreatic amylase (P-type) and salivary amylase (S-type), contained in the serum. With corn starch as substrate, the P-type dominant serum exhibited an apparently higher value than the S-type dominant serum. In the use of blue-starch which is employed as a chromogenic method, the P-type dominant serum gave a higher value than the S-type dominant serum. Red-starch which is also used as a chromogenic method, however, did not cause the P-type dominant serum to show such a high level of amylase activity as blue-starch. These differences in amylase activity can be also shown by determining the Km values of pancreatic amylase and salivary amylase using these substrates. Thus, corn starch and blue-starch showed smaller Km values to pancreatic amylase than to salivary amylase. They were thus proved to have a strong affinity for pancreatic amylase. In contrast, potato starch, red-starch and glycogen had good affinity for salivary amylase. In pancreatic disease in which pancreatic amylase is increased without much elevation in the total amylase level in the serum, it might be possible to detect the abnormality of pancreatic amylase activity if either corn starch or blue-starch is used as a substrate for measurement of the serum amylase activity.


Equilibrium DNA-binding of AraC protein. Compensation for displaced ions.
Experiments on the AraC regulatory protein of Escherichia coli suggest a mechanism that DNA-binding proteins can use to reduce potentially drastic alterations in their affinity for DNA resulting from changes in salt concentration. Measurement of the net number of ions apparently displaced as AraC protein binds DNA and of fluorescence changes in the protein lead to the following picture. About 14 ions are displaced from the DNA as the protein binds the araI site. As the protein binds the DNA, however, it undergoes a conformational change and binds about ten ions. Consequently, the net order of the reaction is reduced from 15th to about fourth order in salt concentration.


Medication adherence and its correlates among patients affected by schizophrenia with an episodic course: A large-scale multi-center cross-sectional study in China.
The Medication Adherence Rating Scale (MARS) is a fast, non-intrusive way of measuring adherence to medication in order to improve the management of patients with schizophrenia. The current cross-sectional study evaluated the reliability of the Chinese (Mandarin) version of the MARS and explored clinical and demographic correlates to medication adherence in a large sample of patients affected by schizophrenia with an episodic course in China. 1198 patients were recruited from 37 different hospitals in 17 provinces/municipalities of China and evaluated with the Medication Adherence Rating Scale (MARS), Clinical Global Impression-Severity of Illness (CGI-SI) and Sheehan Disability Scale-Chinese version (SDS-C). The MARS showed good internal consistency; Cronbach's alpha of total MARS was 0.83. Among the cohort of patients affected by schizophrenia with an episodic course, 28.5 % met the criteria of good adherence to antipsychotic medication; age, steady income, and severity of illness had significant effects on medication adherence. Medication adherence of patients affected by schizophrenia in mainland China was found to be relatively low, calling for urgent attention and intervention. Risk factors for non-adherence to medication among patients affected by schizophrenia with an episodic course include older age, unsteady income, being in the acute period of the disease, and severity of illness.


Penicillin activity in brain tissue: a method for continuous measurement.
A double-barrelled microelectrode is described which permits the continuous and simultaneous measurement of penicillin concentration and of the local bioelectric activity in nervous tissue. The electrode, which is based on a chloride ligand (Corning no. 477315), has a short response time and enables reproducible measurements of penicillin concentration even below 500 IU/ml.


Comparison of occlusal contact errors of 6 chairside CAD/CAM crowns: a self-controlled clinical study.
The purpose of this self-controlled clinical study was to evaluate the trueness of occlusal contacts of chairside CAD/CAM crowns fabricated using different ceramic materials. Ten volunteers (8 females, 2 males, average aged 20-30) were recruited in this study registered in the Clinical Trials Registry (#NCT05346744). After tooth preparation on tooth 36 or 46, an optical scan unit (CEREC Omnicam, Sirona Dental Systems, Germany) was utilized to perform the intraoral scanning. For each volunteer, 6 crowns were fabricated via the chairside CAD/CAM process (CEREC, Sirona Dental Systems, Germany) using the following materials: InCoris TZI (ZIR), Celtra Duo (CD), e.max CAD (EMA), UP.CAD (UP), Enamic (ENA) and Hyramic (HY). The microhardness of the milled surfaces was measured through a Vickers hardness Tester (HVS-50Z, Trojan, China). Together with the amount of occlusal adjustment, the occlusal contact trueness at both milling and postprocessing stages were quantitatively analyzed by using a high-precision scanner (ATOS, GOM Technologies, USA) and a reverse engineering software (Geomagic Control, 3D Systems, Rock Hill, SC). The times of chairside occlusal adjustment were also recorded. Data were analyzed by one-way analysis of variance (ANOVA) and ANOVA with randomized block design followed by Bonferroni test (p = 0.05). Significant differences were found in surface microhardness of the materials tested (CD > EMA ~ UP > ENA > HY > ZIR, p < 0.05). Regarding the occlusal contact trueness at milling stage, ZIR showed the lowest (p < 0.05), while no significant difference was found among others (p > 0.05). At postprocessing stage, except for ENA, the occlusal contact trueness of ZIR was significantly lower than that of others (p < 0.05). As for occlusal adjustment amount, ZIR was lower than CD and ENA (p < 0.05). In addition, ENA, HY and ZIR required fewer times of occlusal adjustment than EMA, UP and CD. The type of chairside CAD/CAM ceramic materials affected the occlusal contact trueness throughout the process of manufacturing and the amount of clinical occlusal adjustment as well. Zirconia exhibited the worst occlusal contact trueness at both milling and postprocessing stages, while the amount of occlusal adjustment was the least, which recommended the least occlusal compensation. For better trueness, different negative occlusal offsets are suggested to be applied in the design process, so as to suit the material of the restoration.


Thalamic stimulation for parkinsonian tremor: correlation between regional cerebral blood flow and physiological tremor characteristics.
We used (15)O-labeled water (H(2)(15)O) positron emission tomography (PET) to study eight Parkinson's disease (PD) patients with unilateral ventral intermediate (Vim) thalamic nucleus deep brain stimulation (DBS) for severe tremor. Triaxial accelerometry (TRIAX) was used during imaging to obtain on-line measures of tremor characteristics. Regional cerebral blood flow (rCBF) scans together with TRIAX recordings were collected in three stimulation conditions (OFF, MID, and ON, corresponding, respectively, to 0%, 50%, and 100% reductions in mean accelerometry signal). Statistical Parametric Mapping (SPM99) revealed significant rCBF reductions during stimulation in the ipsilateral sensorimotor cortex (SMC) and the contralateral cerebellum, as well as concurrent increases in the ipsilateral ventral thalamus (P < 0.05, corrected). Covariate analysis of rCBF with physiological tremor characteristics revealed that tremor acceleration correlated positively with changes in the SMC and supplementary motor cortex ipsilaterally (P < 0.05, uncorrected), and negatively with changes in the ipsilateral cuneus (P < 0.05, corrected). After removing tremor acceleration effects, changes in tremor frequency correlated negatively with changes in the contralateral dentate nucleus and pons (P < 0.05, uncorrected). Our results suggest that Vim DBS for PD tremor modulates the activity of cerebello-thalamo-cortical pathways. Specific tremor characteristics relate to activity in different nodes of this system.


Synthesis and spectroscopic properties of elongated ruthenium dihydrogen complexes: temperature and isotope dependence of H-H distances.
Several dihydrogen complexes of ruthenium of the form [Cp/Cp*Ru(P-P)H(2)](+) (P-P = chelating diphosphine ligand) have been prepared by reaction of the corresponding neutral chloride complexes with H(2) in the presence of NaB(ArF)(4). Treatment with D(2) or T(2) gas leads to incorporation of deuterium or tritium in the dihydrogen ligand. Measurement of the resulting H-D and H-T couplings as a function of the temperature and magnetic field gives results consistent with computational studies which predict that the H-H bond distance will increase with temperature and will be significantly shortened by isotopic substitution. The degree of the observed temperature dependence is found to be a critical function of the ancillary ligand set.


An LC-MS/MS assay to determine plasma pharmacokinetics of cyclic thymic hexapeptide (cTP6) in rhesus monkeys.
A robust and simple method for absolute quantification of a novel bidirectional immunomodulatory drug candidate, cyclic thymic hexapeptide (cTP6), in rhesus monkey plasma was developed and validated by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Plasma proteins were precipitated by adding four volumes of acetonitrile. Peptides in the supernatant were separated by liquid chromatography on an Agilent Zorbax Eclipse Plus-C18 chromatographic column with gradient elution using 0.1% formic acid in water (mobile phase A) and 0.1% formic acid in methanol (mobile phase B) at 0.2 mL/min. The analytes were identified by triple quadrupole mass spectrometry in positive ion-mode. The assay was linear over a concentration range of 10-5000 ng/mL for cTP6, with a lower limit of quantification (LLOQ) of 10 ng/mL. Intra- and inter-day precision of the assay at three concentrations were 1.51-7.70% with accuracy of 95.1-104.2%. The average recovery of cTP6 for three concentration levels was 59.6-64.0%. No significant matrix effect was observed. Peptide cTP6 was detected in plasma of live rhesus monkeys up to 6-8h after intra-muscular injection. The half-life was 2.24-2.95 h. The result revealed a nonlinear pharmacokinetic response to increasing doses of cTP6 (100, 200, 500 μg/kg). For the multiple dose study of cTP6, the drug did not accumulate during daily administration at 100 μg/kg for 7 consecutive days in rhesus monkeys.


Intracranial complications before and after endoscopic skull base reconstruction.
Endoscopic skull base reconstruction (ESBR) has been widely accepted in the management of cerebrospinal fluid (CSF) leaks. However, it is not the CSF leak itself but the potential for life-threatening intracranial complications (ICCs) that is of primary clinical concern. The risk of developing complications, such as meningitis, in a skull base defect is unknown. Many ESBR are multilayered soft tissue repairs, and long-term prevention of ICCs is not well described. Retrospective chart review and telephone consultation was used to assess patients who had an ESBR from 2002 to 2008. The incidence of an ICCs (meningitis, cerebral abscess, and pneumocephalus) and associated risk factors were assessed before and after surgery. One hundred six patients underwent ESBR (mean age (+/-SD), 47.7 +/- 18.5 years; range, 2-78 years) with 95.3% long-term follow-up (mean, 19.9 +/- 16.3 months). ICCs occurred in 21.7% of patients at presentation, in 2.8% of patients during the perioperative period (<2 weeks), and in one patient (0.9%) during the postoperative period. Risk factors for presenting with an ICC and meningitis were revision cases performed elsewhere (chi(2) = 9.10; p = 0.007) and leaking encephaloceles (chi(2) = 5.98; p = 0.014). Factors not associated with increased ICC were an active CSF leak at presentation (chi(2) = 3.03; p = 0.082) and previous radiotherapy. ESBR offers an excellent long-term option in preventing subsequent ICC with low perioperative complications. ESBR is robust with delayed (>2weeks) CSF leakage occurring in only 1.9% regardless of etiology. The presence of identifiable risk factors for ICC may guide the surgeon in determining the urgency of ESBR.


Amplitude-modulation detection by gerbils in reverberant sound fields.
Reverberation can dramatically reduce the depth of amplitude modulations which are critical for speech intelligibility. Psychophysical experiments indicate that humans' sensitivity to amplitude modulation in reverberation is better than predicted from the acoustic modulation depth at the receiver position. Electrophysiological studies on reverberation in rabbits highlight the contribution of neurons sensitive to interaural correlation. Here, we use a prepulse-inhibition paradigm to quantify the gerbils' amplitude modulation threshold in both anechoic and reverberant virtual environments. Data show that prepulse inhibition provides a reliable method for determining the gerbils' AM sensitivity. However, we find no evidence for perceptual restoration of amplitude modulation in reverberation. Instead, the deterioration of AM sensitivity in reverberant conditions can be quantitatively explained by the reduced modulation depth at the receiver position. We suggest that the lack of perceptual restoration is related to physical properties of the gerbil's ear input signals and inner-ear processing as opposed to shortcomings of their binaural neural processing.


Feasibility and suitability of the routine use of bilateral internal thoracic arteries.
It has been demonstrated that bilateral use of internal thoracic arteries (ITAs) confers better long-term results in patients than does unilateral use. However, routine use of bilateral ITAs has usually been avoided. Since 1997, we have used bilateral ITAs extensively for patients who required multivessel bypasses. Recently, 243 consecutive patients, including 127 diabetic patients, were reviewed. Every patient received at least one ITA graft, and 200 patients (82%) received bilateral ITAs. The majority (93%) of ITA grafts were used as in situ grafts. The hospital mortality rate was 0.41%, and deep sternal infections were observed in 5 patients (2.0%). There was no difference in the incidence of chest wound infection between the group treated with bilateral ITA grafting and that treated by unilateral ITA grafting. These observations suggest that ITAs can be used bilaterally for treatment in the majority of patients who require multivessel bypass, with low mortality and morbidity.


Incidental finding of meconium-stained amniotic fluid in elective cesarean deliveries: Features and perils.
To characterize pregnancies in which meconium-stained amniotic fluid (MSAF) was incidentally discovered during elective caesarean delivery (CD), and to evaluate the association with adverse neonatal outcomes. A retrospective study was performed on all patients who underwent elective CD with singleton pregnancies between March 2011 and June 2020. Data analyzed included maternal, pregnancy, and neonatal characteristics. A comparison was made between pregnancies with clear amniotic fluid, MSAF, and thick MSAF. During the study period, 10 445 patients with singleton pregnancies underwent elective CD. Of them, 368 (3.5%) had MSAF and 31 (0.3%) had thick MSAF. Patients with MSAF gained more weight during pregnancy and suffered more from diabetes compared with patients with clear fluid. Significantly more pregnancies with MSAF had either oligohydramnios or polyhydramnios. Pregnancies in the thick-MSAF group had more intrahepatic cholestasis of pregnancy. No differences were found between the groups in the composite adverse neonatal outcome, including 5-min Apgar score, need for mechanical ventilation, and admission to the neonatal intensive care unit. The incidental finding of MSAF during elective CD is not associated with increased risks of adverse neonatal outcomes.


The pathology of the lower leg muscles in pure forefoot pes cavus.
Enlargement of the peroneus longus muscle is a common occurrence in patients with forefoot pes cavus, and may contribute to the cavus deformity. The present study compares the morphology of up to five lower leg muscles from 17 patients with forefoot pes cavus with those of normal muscles. Eight cases had an identifiable neurogenic cause for the cavus. In four cases of hereditary motor-sensory neuropathy, the tibialis anterior showed more severe damage than the peroneus longus. In two cases of cerebral palsy, fibre atrophy and increased oxidative enzyme activity were observed. In nine clinically idiopathic cases, the histological appearances ranged from normal to generalised fibre atrophy or hypertrophy in individual muscles. There was a trend for the mean fibre area to be greater in peroneus longus than in tibialis anterior in six of the idiopathic group of patients. The muscle cross-sectional area on magnetic resonance imaging was correlated closely with the mean fibre area measured on tissue sections. In idiopathic forefoot pes cavus, fibre hypertrophy in peroneus longus (relative to tibialis anterior) may contribute to the cavus deformity. Muscle fibre hyperplasia may contribute to the peroneal muscle enlargement in Friedreich's ataxia. In none of the cases was peroneus longus enlargement due to fat or fibrous tissue replacement.


p38 MAPK inhibition reduces myocardial reperfusion injury via inhibition of endothelial adhesion molecule expression and blockade of PMN accumulation.
In vitro evidence suggests that the p38 mitogen-activated protein kinase (p38 MAPK) plays a crucial role in PMN activation and inflammatory cytokine production. However, the effect of p38 MAPK on myocardial reperfusion injury, a pathologic condition involving a typical inflammatory response, has not been fully examined. In the present study, we investigated the effect of SB 239063, a specific p38 MAPK inhibitor, on myocardial injury in a murine ischemia/reperfusion (I/R) model and elucidated the mechanism by which p38 MAPK inhibitor may exert its protective effect against I/R injury. I/R resulted in a significant myocardial injury (myocardial infarct 45 +/- 2.9%) and marked PMN accumulation (myeloperoxidase activity 1.03 +/- 0.16 U/100 g tissue). Administration of SB 239063 significantly inhibited the myocardial inflammatory response as evidenced by reduced PMN accumulation in I/R myocardial tissue (0.62 +/- 0.008 U/100 g tissue, P<0.01 vs. vehicle), and markedly attenuated myocardial reperfusion injury (myocardial infarct size: 28 +/- 2.4%, P<0.01 vs. vehicle). Moreover, treatment with SB 239063 significantly attenuated I/R-induced P-selectin and ICAM-1 upregulation (13.8 +/- 2.7 vs. 23.9 +/- 3.1%, and 29.4 +/- 1.6 vs. 56.3 +/- 4.8%, respectively P<0.01). In addition, pre-treatment with R15.7, a monoclonal antibody against CD 18 adhesion molecule on PMN surface that virtually abolished PMN accumulation in ischemic-reperfused myocardial tissue, significantly, but not completely, blocked the cardioprotection exerted by SB 239063. These results demonstrated for the first time that p38 MAPK activation plays a significant role in adhesion molecule upregulation on ischemia-reperfused endothelial cells and is an important signaling step in the pathogenesis of PMN-mediated tissue injury.


Total Knee Arthroplasty in Obesity: In-Hospital Outcomes and National Trends.
Both the prevalence of obesity and the utilization rate of total knee arthroplasty are increasing. The rate and proportion of total knee arthroplasty (TKA) performed in the setting of obesity/morbid obesity is increasing significantly over time. Using International Classification of Diseases-Ninth Revision codes, we searched the National Hospitals Discharge Survey national database for patients admitted for primary TKA between 2001 and 2010. We then used International Classification of Diseases-Ninth Revision codes for obesity (body mass index = 30-40 kg/m2) and morbid obesity (body mass index, ≥ 40 kg/m2) to select the obese cohorts. We found 29,694 nonobese, 2645 obese, and 1150 morbidly obese patients. There was an increase in each group over time. The rate of obesity/morbid obesity was strongly correlated with time. Obese and morbidly obese patients were more likely to be younger, female, diabetic, and have Medicaid than nonobese patients. Obese and morbidly obese patients had shorter hospital stays and higher home discharge rates than nonobese patients. Obese and morbidly obese patients had lower transfusion rates, shorter hospital stays, and no increase in inpatient wound infection or venous thromboembolic complications than nonobese patients. The Midwest region saw a greater burden of obese TKA patients. With the right measures and precautions, satisfactory inhospital outcomes are possible in the obese patient after primary TKA. A limitation of this study is short inhospital stay of the index procedure as complications may present later after discharge.


Distance Education in Nutrition and Dietetics Education over the Past 30 Years: A Narrative Review.
The coronavirus disease 2019 pandemic necessitated the use of distance education, which sparked a technological transformation that was long overdue in higher education. The purpose of this narrative review is two-fold: to summarize the state of knowledge regarding distance education in nutrition and dietetics education over the past 30 years to inform recommendations for future education/research and implications for practice and to determine the influence that distance education has had on the knowledge, skills, and attitudes of both nutrition and dietetics educators and their students. A narrative review of 822 publications yielded 25 that met the search criteria. In the scope of 30 years, the literature shows that attitudes and perceptions of distance education have changed as barriers to online access have diminished and the availability of online nutrition and dietetics courses and Accreditation Council for Education in Nutrition and Dietetics-accredited distance education programs has expanded. However, whereas the limited results are promising, the paucity of large-sample research about the use of distance education in nutrition and dietetics education restricts educators' knowledge of and ability to evaluate the learning outcomes of distance programs and courses. Moreover, differences in how accreditors, government agencies, and institutions define distance education could have significant influence on funding and financial aid benefits for students and research. Recommendations for future research and implications for practice are provided given the relevance and importance of distance education to nutrition and dietetics education.


Quantifying neurological function in patients undergoing transcatheter aortic valve implantation.
Transcatheter aortic valve implantation (TAVI) is a routine procedure that is often performed on older adults that are high-risk patients with severe aortic stenosis. Patients after TAVI may experience neurological complications. However, there is a lack of objective neurological testing available for patients undergoing cardiac surgery. This brief communication seeks to explore the use of robotic technology to quantify distinctive patterns of visuospatial, sensorimotor, and cognitive functioning in patients undergoing TAVI. Patients undergoing TAVI were recruited for this prospective observational study. Prior to their procedure, study participants performed four robotic reaching tasks using the Kinarm robotic system. Patients repeated the assessment three months after their TAVI procedure. Significant changes in overall task score and parameters were determined. Ten patients were recruited and included in this brief report. In a simple reaching task, patients show significant improvement in performance post-TAVI. However, patients do not improve nor worsen in a complex reaching task after TAVI. Similarly, patients demonstrate impairments in both trail making tasks before and after their TAVI procedure. This study captures the variability in neurological functioning in older patients undergoing TAVI. Robotic technology and quantified assessment procedures can be extremely valuable for detecting perioperative neurological impairments in this patient population.


Antitumor Effect of 5-Aminolevulinic Acid Through Ferroptosis in Esophageal Squamous Cell Carcinoma.
Due to its tumor-specific metabolic pathway characteristics, 5-aminolevulinic acid (5-ALA) is a natural amino acid widely used in cancer treatment. The current study, demonstrated that 5-ALA induced ferroptosis via glutathione peroxidase 4 (GPX4) and heme oxygenase 1 (HMOX1) and had an antitumor effect in esophageal squamous cell carcinoma (ESCC). Expression of GPX4 and HMOX1 in pathologic specimens of 97 ESCC patients was examined, and prognostic analyses were performed. Real-time polymerase chain reaction (RT-PCR), RNA microarray, and Western blotting analyses were used to evaluate the role of 5-ALA in ferroptosis in vitro. In addition, this study used ferrostatin-1, a ferroptosis inhibitor, and a lipid peroxidation reagent against cell lines treated with 5-ALA. Finally, the role of 5-ALA was confirmed by its effect on an ESCC subcutaneous xenograft mouse model. The study showed that upregulation of GPX4 and downregulation of HMOX1 were poor prognostic factors in ESCC. In an RNA microarray analysis of KYSE30, ferroptosis was one of the most frequently induced pathways, with GPX4 suppressed and HMOX1 overexpressed by 5-ALA treatment. These findings were verified by RT-PCR and Western blotting. Furthermore, 5-ALA led to an increase in lipid peroxidation and exerted an antitumor effect in various cancer cell lines, which was inhibited by ferrostatin-1. In vivo, 5-ALA suppressed GPX4 and overexpressed HMOX1 in tumor tissues and led to a reduction in tumor size. Modulation of GPX4 and HMOX1 by 5-ALA induced ferroptosis in ESCC. Thus, 5-ALA could be a promising new therapeutic agent for ESCC.


Multiple approaches to the reduction of dental fear.
Participant modeling, symbolic modeling, and graduated exposure were compared with each other and with two control treatments for effectiveness in reducing fear of dentistry in 33 adults who had avoided dental treatment for from 1 to 10 yr. Assessment of in-chair psychological responsiveness and overt behavior showed no significant pre-post change for any group although all of them reported significant reduction in state anxiety and expected pain. During the 24 months following treatment, from 50 to 87.5% of the subjects were able to return to regular dental care with the highest "return" rate appearing in the participant modeling condition.


Kinetic studies of protein-protein interactions.
The structure of a protein-protein interaction, its affinity and thermodynamic characteristics depict a 'frozen' state of a complex. This picture ignores the kinetic nature of complex formation and dissociation, which are of major biological and biophysical interest. This review highlights recent advances in deciphering the kinetic pathway of protein-protein complexation, the nature of the encounter complex, transition state and intermediate along the reaction, and the effects of mutation, viscosity, pH and salt on association.


Genome-wide identification and expression profile analysis of metal tolerance protein gene family in Eucalyptus grandis under metal stresses.
Metal tolerance proteins (MTPs) as Me2+/H+(K+) antiporters participate in the transport of divalent cations, leading to heavy metal stress resistance and mineral utilization in plants. In the present study, to obtain better knowledge of the biological functions of the MTPs family, 20 potential EgMTPs genes were identified in Eucalyptus grandis and classified into seven groups belonging to three cation diffusion facilitator groups (Mn-CDFs, Zn/Fe-CDFs, and Zn-CDFs) and seven groups. EgMTP-encoded amino acids ranged from 315 to 884, and most of them contained 4-6 recognized transmembrane domains and were clearly prognosticated to localize into the cell vacuole. Almost all EgMTP genes experienced gene duplication events, in which some might be uniformly distributed in the genome. The numbers of cation efflux and the zinc transporter dimerization domain were highest in EgMTP proteins. The promoter regions of EgMTP genes have different cis-regulatory elements, indicating that the transcription rate of EgMTP genes can be a controlled response to different stimuli in multiple pathways. Our findings provide accurate perception on the role of the predicted miRNAs and the presence of SSR marker in the Eucalyptus genome and clarify their functions in metal tolerance regulation and marker-assisted selection, respectively. Gene expression profiling based on previous RNA-seq data indicates a probable function for EgMTP genes during development and responses to biotic stress. Additionally, the upregulation of EgMTP6, EgMTP5, and EgMTP11.1 to excess Cd2+ and Cu2+ exposure might be responsible for metal translocation from roots to leaves.