Effects of Continuous Glucose Monitoring on Metrics of Glycemic Control in Diabetes: A Systematic Review With Meta-analysis of Randomized Controlled Trials.
Continuous glucose monitoring (CGM) provides important information to aid in achieving glycemic targets in people with diabetes. We performed a meta-analysis of randomized controlled trials (RCTs) comparing CGM with usual care for parameters of glycemic control in both type 1 and type 2 diabetes. Many electronic databases were searched for articles published from inception until 30 June 2019. We selected RCTs that assessed both changes in HbA1c and time in target range (TIR), together with time below range (TBR), time above range (TAR), and glucose variability expressed as coefficient of variation (CV). Data were extracted from each trial by two investigators. All results were analyzed by a random effects model to calculate the weighted mean difference (WMD) with the 95% CI. We identified 15 RCTs, lasting 12-36 weeks and involving 2,461 patients. Compared with the usual care (overall data), CGM was associated with modest reduction in HbA1c (WMD -0.17%, 95% CI -0.29 to -0.06, I 2 = 96.2%), increase in TIR (WMD 70.74 min, 95% CI 46.73-94.76, I 2 = 66.3%), and lower TAR, TBR, and CV, with heterogeneity between studies. The increase in TIR was significant and robust independently of diabetes type, method of insulin delivery, and reason for CGM use. In preplanned subgroup analyses, real-time CGM led to the higher improvement in mean HbA1c (WMD -0.23%, 95% CI -0.36 to -0.10, P < 0.001), TIR (WMD 83.49 min, 95% CI 52.68-114.30, P < 0.001), and TAR, whereas both intermittently scanned CGM and sensor-augmented pump were associated with the greater decline in TBR. Heterogeneity was high for most of the study outcomes; all studies were sponsored by industry, had short duration, and used an open-label design. CGM improves glycemic control by expanding TIR and decreasing TBR, TAR, and glucose variability in both type 1 and type 2 diabetes.


Effect of 2,5-dimethylpyrazine on uterine contraction in late stage of pregnant female rats.
Effect of 2,5-dimethylpyrazine (2,5-DMP) on oxytocic agent-induced late pregnant uterine contraction in female rats was studied. Oxytocic agents induced-hypercontraction in the late phase of pregnant uterine movements were inhibited by administration of 2,5-DMP. The inhibition of uterine contraction was obtained more strengthening by presence of a low dose of ritodrine hydrochloride than 2,5-DMP alone. These results suggests that 2,5-DMP has an inhibitory action on uterine hypercontraction induced by oxytocic agent through the beta2-adrenoceptor in the pregnant uterus and supports the applicability of relaxing drugs for oxytocic agent-induced accidents.


A role of disordered domains in regulating protein oligomerization and stability.
Intrinsically disordered proteins (IDPs) or regions (IDRs) in proteins hold many functions but their biological roles are still not fully understood. Here we describe a new role of such regions. Using the HIV-1 Rev protein, we show that disordered domains have a role in maintaining the correct oligomeric state and the thermodynamic stability of proteins.


From genes to proteins to behavior: a laboratory project that enhances student understanding in cell and molecular biology.
In the laboratory, students can actively explore concepts and experience the nature of scientific research. We have devised a 5-wk laboratory project in our introductory college biology course whose aim was to improve understanding in five major concepts that are central to basic cellular, molecular biology, and genetics while teaching molecular biology techniques. The project was focused on the production of adenine in Saccharomyces cerevisiae and investigated the nature of mutant red colonies of this yeast. Students created red mutants from a wild-type strain, amplified the two genes capable of giving rise to the red phenotype, and then analyzed the nucleotide sequences. A quiz assessing student understanding in the five areas was given at the start and the end of the course. Analysis of the quiz showed significant improvement in each of the areas. These areas were taught in the laboratory and the classroom; therefore, students were surveyed to determine whether the laboratory played a role in their improved understanding of the five areas. Student survey data demonstrated that the laboratory did have an important role in their learning of the concepts. This project simulated steps in a research project and could be adapted for an advanced course in genetics.


Effects of exogenous and endogenous opiates on the hypothalamic--pituitary--gonadal axis in the male.
Narcotics acutely depress serum testosterone levels in the male. Three mechanisms could be involved: an enhancement of the degradation of testosterone; a direct inhibition of testicular steroidogenesis; or, finally, an inhibition of the hypothalamic-pituitary-luteinizing hormone (LH) axis resulting in a reduction in LH-dependent testicular steroidogenesis. The currently available evidence indicates that narcotics do not affect the catabolism of testosterone by the liver or testicular steroidogenesis. Rather, the data favor a direct action on the hypothalamic--pituitary--LH axis, probably by inhibiting the secretion of LH-releasing hormone (LH-RH) from the hypothalamus. The effects of narcotics on serum LH appear to be mediated via specific opioid receptors, suggesting that a naturally occurring opioid-like substance exists that normally inhibits LH. In support of this conclusion, opiate receptor blockers markedly increase serum LH levels shortly after their subcutaneous administration. In addition, endogenous opioids also seem to participate in testosterone's negative feedback control of the hypothalamic--pituitary--LH axis. Thus, it appears that opiate drugs inhibit the function of the hypothalamic-pituitary-gonadal axis by occupying opiate receptors in the hypothalamus and, moreover, that endogenous opioids exist that normally bind to these receptors and regulate activity in this axis.


Tobacco and cancer: approaches using carcinogen biomarkers and chemoprevention.
Tobacco products are the leading cause of avoidable cancer death in the U.S., accounting for approximately 30% of all cancer deaths. While avoidance of tobacco and smoking cessation are clearly the best way to decrease tobacco-related cancer, these approaches have not been uniformly successful. Approximately 25% of the U.S. population over 18 years of age smokes cigarettes, while 6% use smokeless tobacco products; these figures have not changed markedly in recent years. Our approach toward the tobacco and cancer problem is based on an understanding of the carcinogens in tobacco smoke. These carcinogens form the link between nicotine addiction and cancer. In this paper, two strategies for cancer prevention--the development of carcinogen-derived biomarkers and chemopreventive agents--are discussed. Carcinogen-derived biomarkers can provide specific information on individual metabolic activation and detoxification of tobacco carcinogens. This information can be used to assess individual risk for cancer development upon exposure to tobacco products. Chemopreventive agents can be targeted against the important carcinogens in tobacco smoke. Isothiocyanates, strong inhibitors of lung cancer development by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, are discussed as an example of this approach.


Go with the flow-biology and genetics of the lactation cycle.
Lactation is a dynamic process, which evolved to meet dietary demands of growing offspring. At the same time, the mother's metabolism changes to meet the high requirements of nutrient supply to the offspring. Through strong artificial selection, the strain of milk production on dairy cows is often associated with impaired health and fertility. This led to the incorporation of functional traits into breeding aims to counteract this negative association. Potentially, distributing the total quantity of milk per lactation cycle more equally over time could reduce the peak of physiological strain and improve health and fertility. During lactation many factors affect the production of milk: food intake; digestion, absorption, and transportation of nutrients; blood glucose levels; activity of cells in the mammary gland, liver, and adipose tissue; synthesis of proteins and fat in the secretory cells; and the metabolic and regulatory pathways that provide fatty acids, amino acids, and carbohydrates. Whilst the endocrine regulation and physiology of the dynamic process of milk production seems to be understood, the genetics that underlie these dynamics are still to be uncovered. Modeling of longitudinal traits and estimating the change in additive genetic variation over time has shown that the genetic contribution to the expression of a trait depends on the considered time-point. Such time-dependent studies could contribute to the discovery of missing heritability. Only very few studies have estimated exact gene and marker effects at different time-points during lactation. The most prominent gene affecting milk yield and milk fat, DGAT1, exhibits its main effects after peak production, whilst the casein genes have larger effects in early lactation. Understanding the physiological dynamics and elucidating the time-dependent genetic effects behind dynamically expressed traits will contribute to selection decisions to further improve productive and healthy breeding populations.


A CRM1-dependent nuclear export pathway is involved in the regulation of IRF-5 subcellular localization.
Interferon regulatory factors (IRFs) are involved in gene regulation in many biological processes including the antiviral, growth regulatory, and immune modulatory functions of the interferon system. Several studies have demonstrated that IRF-3, IRF-5, and IRF-7 specifically contribute to the innate antiviral response to virus infection. It has been reported that virus-specific phosphorylation leads to IRF-5 nuclear localization and up-regulation of interferon, cytokine, and chemokine gene expression. Two nuclear localization signals have been identified in IRF-5, both of which are sufficient for nuclear translocation and retention in virus-infected cells. In the present study, we demonstrate that a CRM1-dependent nuclear export pathway is involved in the regulation of IRF-5 subcellular localization. IRF-5 possesses a functional nuclear export signal (NES) that controls dynamic shuttling between the cytoplasm and the nucleus. The NES element is dominant in unstimulated cells and results in the predominant cytoplasmic localization of IRF-5. Mutation of two leucine residues in the NES motif to alanine, or three adjacent Ser/Thr residues to the phosphomimetic Asp, results in constitutively nuclear IRF-5 and suggests that phosphorylation of adjacent Ser/Thr residues may contribute to IRF-5 nuclear accumulation in virus-induced cells. IKK-related kinases TBK1 and IKKepsilon have been shown to phosphorylate and activate IRF-3 and IRF-7, leading to the production of type 1 interferons and the development of a cellular antiviral state. We examined the phosphorylation and activation of IRF-5 by TBK1 and IKKepsilon kinases. Although IRF-5 is phosphorylated by IKKepsilon and TBK1 in co-transfected cells, the phosphorylation of IRF-5 did not lead to IRF-5 nuclear localization or activation.


Mesenchymal, non-meningothelial tumors of the central nervous system.
The spectrum of non-meningothelial mesenchymal tumors that may arise within the central nervous system is presented, based on the current classification of soft tissue tumors. Among malignant types, hemangiopericytoma, rhabdomyosarcoma, mesenchymal chondrosarcoma, and malignant fibrous histiocytoma are the most frequent ones. Rare tumor entities are mentioned. As in soft tissue sarcomas, diagnosis is mainly based on light and electron microscopy, while immunohistochemistry can improve accuracy of diagnosis.


Endovascular Treatment of Chronic Mesenteric Ischemia in the Setting of Occlusive Superior Mesenteric Artery Lesions.
Endovascular intervention is considered the first-line treatment for chronic mesenteric ischemia (CMI) when feasible. Two-vessel revascularization is most definitive when celiac (CA) and superior mesenteric arteries (SMA) are diseased, but single-vessel intervention may be performed in patients with 2-vessel disease due to anatomic/technical factors. We evaluated anatomic predictors of clinical outcomes associated with endovascular treatment of CMI among patients with occlusive SMA lesions. Patients with CMI treated with endovascular revascularization over 10 years were identified. Patients with SMA occlusions were selected for analysis. Between-group comparisons based on inclusion of an SMA revascularization were evaluated using t-test and chi-squared test. Freedom from symptomatic recurrence or repeat intervention was analyzed using proportional hazards regression. Fifty-four patients with CMI were analyzed. Sixteen (29.6%) patients had CA-only intervention, and 38 (70.4%) patients had SMA revascularization with or without CA intervention. No significant differences in demographics or comorbidity were identified between groups. In the CA-only intervention group, 8 of the 16 (50%) patients developed symptomatic recurrence compared with 8 of the 31 (21.1%) patients whose intervention included the SMA. Patients treated without SMA intervention also had decreased freedom from both symptomatic recurrence (hazard ratio [HR] 3.2, 95% confidence interval [CI] 1.2-8.6, P = 0.016) and repeat intervention (HR 5.5, 95% CI 1.8-16.3, P = 0.001). Among patients with CMI and occlusive SMA lesions, SMA revascularization appears to be the key determinant for symptomatic outcomes and repeat intervention. Patient counseling should include potential future need for surgical revascularization if endovascular SMA treatment cannot be accomplished.


Autoimmune Epilepsy and/or Limbic Encephalitis Can Lead to Changes in Sleep Spindles.
Sleep disorders have been described in patients with autoimmune limbic encephalitis (LE). The changes in sleep structure were also reported. Recently sleep spindle abnormalities such as asynchronous or prolonged spindles were observed children with LE. We studied the sleep and number of sleep spindles in the continuous electroencephalography-polysomnography (EEG-PSG) recordings of 6 patients with autoimmune epilepsy and/or LE. The longest NREM 2 period was selected. We evaluated the spindle density (spindles per minute), and compared that to the spindle densities of epilepsy patients with bilateral hippocampal sclerosis and healthy controls. We have demonstrated that patients with autoimmune epilepsy and/or LE had reduced slow wave sleep with decreased number of sleep spindles. The mean number of spindles in 60 seconds was 5.86±5.03 in patients with autoimmune epilepsy and/or LE. But spindle density was higher in two control groups (10.6±1.65 and 9.95±0.79). The sleep abnormalities in LE can result from the disruption of thalamo-limbic circuits, and lead to changes in spindle wave activity. Although density of spindles decreased with acute lesions in thalamo-limbic circuits, the relations with structural lesions or chronicity of disease are not clear. That may be related to functional disruption of neural circuitry.


Evidence for the involvement of 3-oxo-delta 4 intermediates in ecdysteroid biosynthesis.
Although the involvement of 3-oxo-delta 4 compounds as intermediates in arthropod ecdysteroid biosynthesis has been postulated for a long time, it has not yet been directly demonstrated. In the present study, 3-oxo-delta 4-steroids have been synthesized and incubated in vitro with dissociated moulting gland cells from the crab Carcinus maenas. The tritiated compounds were converted into 3-dehydroecdysone, ecdysone and/or 25-deoxyecdysone, i.e. final ecdysteroids. This means that the 3-oxo-delta 4 compounds had undergone a 5 beta-reduction, to give the 5 beta-conformation of ecdysteroids. Our results suggest that the 3-oxo-delta 4-steroid 4,7-cholestadien-14 alpha-ol-3,6-dione may be an intermediate in the biosynthetic pathway. The 5 beta-reduction reaction involves a cytosolic enzyme which requires NADPH as electron donor and seems specific for 3-oxo-delta 4 substrates. This reaction was the most active in crab Y-organs, as compared with other tissues. The characteristics of the 5 beta-reductase (subcellular localization, substrate and cofactor requirements) appear similar to those of the vertebrate 3-oxo-delta 4-steroid 5 beta-reductase involved in steroid hormone catabolism and bile acid biosynthesis.


Shaken baby syndrome and a triple-dose strategy for its prevention.
Inflicted traumatic brain injury associated with Shaken Baby Syndrome (SBS) is a leading cause of injury mortality and morbidity in infants. A triple-dose SBS prevention program was implemented with the aim to reduce the incidence of SBS. The objectives of this study were to describe the epidemiology of SBS, the triple-dose prevention program, and its evaluation. Descriptive and spatial epidemiologic profiles of SBS cases treated at Children's Hospital, London Health Sciences Centre, from 1991 to 2010 were created. Dose 1 (in-hospital education): pre-post impact evaluation of registered nurse training, with a questionnaire developed to assess parents' satisfaction with the program. Dose 2 (public health home visits): process evaluation of additional education given to new parents. Dose 3 (media campaign): a questionnaire developed to rate the importance of factors on a 7-point Likert scale. These factors were used to create weights for statistical modeling and mapping within a geographic information system to target prevention ads. Forty-three percent of severe infant injuries were intentional. A total of 54 SBS cases were identified. The mean age was 6.7 months (standard deviation, 10.9 months), with 61% of infant males. The mean Injury Severity Score was 26.3 (standard deviation, 5.5) with a 19% mortality rate. Registered nurses learned new information on crying patterns and SBS, with a 47% increase in knowledge posttraining (p < 0.001). Over 10,000 parents were educated in-hospital, a 93% education compliance rate. Nearly all parents (93%) rated the program as useful, citing "what to do when the crying becomes frustrating" as the most important message. Only 6% of families needed to be educated during home visits. Locations of families with a new baby, high population density, and percentage of lone parents were found to be the most important factors for selecting media sites. The spatial analysis revealed six areas needed to be targeted for ad locations. SBS is a devastating intentional injury that often results in poor outcomes for the child. Implementing a triple-dose prevention program that provides education on crying patterns, coping strategies, and the dangers of shaking is key to SBS prevention. The program increased knowledge. Parents rated the program as useful. The media campaign allowed us to extend the primary prevention beyond new parents to help create a cultural change in the way crying, the primary trigger for SBS, is viewed. Targeting our intervention increased the likelihood that our message was reaching the population in greatest need.


The role of innate immune cells in obese adipose tissue inflammation and development of insulin resistance.
Obesity is characterised by a chronic state of low-grade inflammation in different tissues including the vasculature. There is a causal link between adipose tissue (AT) inflammation and obesity-related metabolic complications, such as the development of insulin resistance and subsequently of type 2 diabetes. Intense efforts in the recent years have aimed at dissecting the pathophysiology of AT inflammation. The role of both innate and adaptive immune cells, such as macrophages or cytotoxic T cells in AT inflammation has been demonstrated. Besides these cells, more leukocyte subpopulations have been recently implicated in obesity, including neutrophils and eosinophils, mast cells, natural killer cells or dendritic cells. The involvement of multiple leukocyte subpopulations underlines the complexity of obesity-associated AT inflammation. In this review, we discuss the role of innate immune cells in AT inflammation, obesity and related metabolic disorders.


The role of laminin-5 in TGF alpha/EGF-mediated corneal epithelial cell motility.
Transforming growth factor alpha (TGF alpha) and epidermal growth factor (EGF) stimulate corneal epithelial cell wound closure. However, the role of these growth factors in regulating corneal epithelial cell motility on basement membrane proteins such as laminin has not been elucidated. In the present study we demonstrate that in an in vitro model of corneal wound healing, TGF alpha has no deleterious effects on the deposition of the laminin-5 isoform into the extracellular matrix structure underlying epithelial cells resurfacing bare collagenous stroma. In primary culture, a population of corneal epithelial cells are stimulated by TGF alpha or EGF to become highly motile. These cells are associated with an endogenously secreted, and extracellularly deposited, 'trail' of laminin-5. The laminin-5 trail is specifically associated with motile cells, as non-motile corneal epithelium exhibiting numerous cell-cell contacts does not display a similar laminin-5 localization pattern. In contrast to these observations, a preparation of laminin-5 known to promote cell spreading, adhesion, and formation of hemidesmosomes, when presented exogenously to cultured corneal epithelial cells, does not stimulate motility. However, a commercially available preparation of laminin derived from human placenta which does not contain laminin-5 does significantly promote the migration of TGF alpha- or EGF-stimulated corneal epithelial cells. From these results, it is hypothesized that endogenously secreted laminin-5 functions to promote migration in corneal epithelial cells which have been treated with TGF alpha or EGF. Exogenously presented laminin-5 does not function similarly, but functions to promote corneal epithelial cell adhesion.


Mesh infections after laparoscopic inguinal hernia repair.
Several complications like hematoma and seroma have been reported after laparoscopic inguinal hernia repair (LH). Sepsis due to infection of the patch is an uncommon complication. In this retrospective trial, we evaluated three male patients who developed postoperative mesh infection after LH by transabdominal preperitoneal patch (TAPP) technique in two institutions. Diagnosis was confirmed by clinical symptoms, signs, ultrasonography, and computerized tomography (CT), and definitive treatment was provided by removing the mesh. In the first case, mesh infection occurred 10 months after laparoscopic left inguinal hernia repair with TAPP for recurrence. The infection manifested itself as an external fistula at the drain site. The mesh was removed laparoscopically due to persistent suppuration. In the second case, mesh infection occurred 3 months after transabdominal preperitoneal hernia repair on the left. The patch was removed because of the persistent suppuration despite repetitive drainage and lavage. In the third case, mesh infection occurred in 15 days after transabdominal preperitoneal hernia repair on the right. External drainage was performed under CT guidance, but suppuration could not be stopped. Thus the mesh was removed. In three cases, infection could not be stopped after diagnosis despite drainage and antibiotic coverage, and then it was decided to remove the mesh. The meshes were removed under general anesthesia for the first two cases and under local anesthesia for the third one. During the follow-up period, no recurrences were noted. The mesh infections of these three cases, resistant to conservative treatment methods, completely disappeared after mesh removal.


The Potential of Vitamin K as a Regulatory Factor of Bone Metabolism-A Review.
Vitamin K (VK), a fat-soluble vitamin, is essential for the clotting of blood because of its role in the production of clotting factors in the liver. Moreover, researchers continue to explore the role of VK as an emerging novel bioactive molecule with the potential function of improving bone health. This review focuses on the effects of VK on bone health and related mechanisms, covering VK research history, homologous analogs, dietary sources, bioavailability, recommended intake, and deficiency. The information summarized here could contribute to the basic and clinical research on VK as a natural dietary additive and drug candidate for bone health. Future research is needed to extend the dietary VK database and explore the pharmacological safety of VK and factors affecting VK bioavailability to provide more support for the bone health benefits of VK through more clinical trials.


Filling of lactose-based formulations in a tamping-pin capsule filler.
We studied three lactose-based formulations in terms of bulk powder properties and capsule-filling behavior in a tamping-pin capsule filling system, to which several mechanical adaptions were made for process optimization in light of future continuous production. The model formulations were thoroughly characterized and filled into size 1 capsules according a well-defined design of experiments (DoE). Overall, the three entirely different formulations were successfully filled within the selected design space. The fill weight and fill weight variability can be adjusted by fine-tuning the process settings, like the pin immersion depth and the maximum compaction pressure (pneumatic or spring-controlled), and by using the appropriate powder bed height and mechanical adaptions. This study demonstrated that selection of process parameters and mechanical adaptions could enhance the filling performance, especially in continuous production, since they reduce the powder volume in the process. Moreover, we showed that a tamping-pin system is capable of successfully filling a broad range of powders with various material characteristics and can potentially be used in a continuous production mode.


Imputation of missing single nucleotide polymorphism genotypes using a multivariate mixed model framework.
The objective of this paper was to investigate, for various scenarios at low and high marker density, the accuracy of imputing genotypes when using a multivariate mixed model framework using information from 2, 4, or 10 surrounding markers. This model predicts genotypes at a locus, using genotypes at nearby loci as correlated traits, and the additive genetic relationship matrix to use information from genotyped relatives. For 2 scenarios this method was compared with the population-based imputation algorithms FastPHASE and Beagle. Accuracies of imputation were obtained with Monte Carlo simulation and predicted with selection index theory, using input from the simulated data. Five different scenarios of missing genotypes were considered: 1) genotypes of some loci are missing due to genotyping errors, 2) juvenile selection candidates are genotyped using a smaller SNP panel, 3) some animals in the pedigree of a breeding population are not genotyped, 4) juvenile selection candidates are not genotyped, and 5) 1 generation of animals in the top of the pedigree are not genotyped. Surrounding marker information did not improve accuracy of imputation when animals whose genotypes were imputed were not genotyped for those surrounding markers. When those animals were genotyped for surrounding markers, results indicated a limited gain when linkage disequilibrium (LD) between SNP was low, but a substantial increase in accuracy when LD between SNP was high. For scenario 1, using 1 vs. 11 SNP, accuracy was respectively 0.75 and 0.81 at low, and 0.75 and 0.93 at high density. For scenario 2, using 1 vs. 11 SNP, accuracy was, respectively, 0.70 and 0.73 at low, and 0.71 and 0.84 at high density. Beagle outperformed the other methods at high SNP density, whereas the multivariate mixed model was clearly superior when SNP density was low and animals where genotyped with a reduced SNP panel. The results showed that extending the univariate gene content method to a multivariate BLUP model with inclusion of surrounding marker information only yields greater imputation accuracy when the animals with imputed loci are at least genotyped for some SNP that are in LD with the SNP to be imputed. The equation derived from selection index theory accurately predicted the accuracy of imputation using the multivariate mixed model framework.


Developmental Relations Between ADHD Symptoms and Reactive Versus Proactive Aggression Across Childhood and Adolescence.
Objective: Past research has provided some preliminary evidence that ADHD and reactive aggression have overlapping neurocognitive bases. Based on this, we tested the hypothesis that ADHD symptoms are closely coupled in developmental terms with reactive aggression, more so than with proactive aggression with which it has been postulated to be only indirectly linked. Method: We used latent growth curve analysis to estimate the developmental relations between ADHD symptoms and subtypes of aggressive behavior in a normative sample of 1,571 youth (761 female, 810 male) measured from ages 7 to 15. Results: Individual ADHD trajectories were significantly and substantially correlated with individual trajectories in both aggressive subtypes; however, consistent with our hypothesis, the relation with reactive aggression was significantly stronger. Conclusion: Our study provides some of the first evidence for a differential relation between ADHD symptoms and aggression subtypes not only cross-sectionally but also in terms of their longitudinal developmental trajectories.


Skeletal effects of androgen withdrawal.
Hypogonadism is considered to be one of the major risk factors for osteoporosis in men. Therefore, it is an important goal for skeletal research to improve our understanding of the skeletal effects of androgens. Androgen deficiency during growth is associated with a failure to acquire normal peak bone mass, and there is good evidence that the effects of androgens on skeletal growth and the development of a male skeletal phenotype are mediated through the androgen receptor. In adult men, acute withdrawal of androgens by surgical or chemical castration induces high turnover bone loss. Similarly, orchidectomy of aged, non-growing male rats is associated with a pronounced and sustained increase in bone turnover and with true loss of cancellous and cortical bone. Interestingly, the changes in bone turnover induced by orchidectomy are paralleled by a concomitant increase in B lymphopoiesis in bone marrow of rats and mice. Although there is firm evidence that male bone metabolism can be influenced by androgens and estrogen, a variety of clinical and animal experimental data have strongly suggested that, under physiological circumstances, the maintenance of cancellous bone mass in males involves the skeletal action of estrogen derived from aromatization of androgens. Aged male rats appear to closely mimic the conditions induced by androgen withdrawal in adult humans, and this animal model may be used 1) to elucidate further the role of muscle as a mediator of the actions of androgens on bone, 2) to explore the regulatory functions of androgens and estrogens in the male skeleton and the immune system, and 3) to find new treatment strategies for the prevention and treatment of osteoporosis in men.


Cognitive Evaluation in Liver Transplant Patients Under Calcineurin Inhibitor Maintenance Therapy.
Neurological disorders due to calcineurin inhibitor (CNI) treatment pose a well-known problem after liver transplantation (LTx). In this study, the impact of CNIs on cognitive functioning during maintenance therapy was analyzed. A possible improvement of cognitive functioning, compliance and health-related quality of life (HRQoL) after conversion to a once-daily tacrolimus formulation was prospectively assessed. In a cross-section analysis cognitive functioning of living donors (LD), waiting list patients and LTx patients was tested using a 4 times trail making test (4-TTMT). In a further investigator-initiated trial a possible improvement of cognitive functioning, HRQoL and compliance after conversion to the once-daily tacrolimus formulation was prospectively assessed over 1 year. HRQoL was assessed using an EORTC-QLQ C30 questionnaire and patient's compliance was assessed by the Basel Assessment of Compliance with Immunosuppressive Medication Scales questionnaire. Correlated data were sex, age, time after surgery, liver disease, model of end-stage liver disease score, creatinine, CNI type, and CNI trough levels. Two hundred eleven patients were included in this cross-section analysis. Twenty-seven patients agreed to participate in the investigator-initiated trial. LTx patients completed the 4-TTMT slower than living donor patients and faster than waiting list patients. Patients with twice daily cyclosporine A (CSA) formulation needed longer to finish the 4-TTMT than patients with the once-daily tacrolimus formulation. After drug conversion of a twice-daily CNI formulation to a once-daily tacrolimus formulation, CSA-treated patients needed longer to improve their cognitive functioning. HRQoL and compliance did not improve after drug conversion. Patients with once-daily tacrolimus formulation had a better psychomotor speed than CSA-treated patients. The conversion to once-daily tacrolimus formulation significantly improved cognitive functioning, but had no impact on HRQoL or compliance.


Universal hepatitis B vaccination coverage in children and adolescents with intellectual disabilities.
There is little information of hepatitis B vaccination coverage for people with intellectual disabilities (ID). The present paper aims to examine the completed hepatitis B vaccination coverage rate and its determinants of children and adolescents with ID in Taiwan. A cross-sectional questionnaire survey, with the entire response participants was composed of 495 primary caregivers of children and adolescents with ID (age 3-24 years) who studying in 3 special education schools in Taiwan. The results showed that coverage rate of completed hepatitis B vaccination was 74.34% in children and adolescents with ID. Although hepatitis B vaccination is a universal health policy in Taiwan, the uncompleted coverage rate of our study subjects was 2 times of the Taiwan general population at the same age. In the logistic regression analysis of hepatitis B vaccination coverage, we found that the factors of household income and ID individual's age were variables that can significantly predict they did not accept a completed vaccination. The present study suggests that parents and providers should routinely review immunizations of children and adolescents with ID.


[Endoscopic management of biliary fistula].
To assess safety and efficacy of endoscopic therapy for patients with a postoperative biliary fistula. Biliary fistula that occur after operations on the biliary tract may be due to bile duct injury or distal bile duct obstruction. These fistulas has been managed with surgical correction. At present, endoscopic methods of improving biliary drainage has been found to be highly successful in the management of postsurgical biliary leaks. PATIENTS-METHODS-RESULTS: By endoscopic cholangiopancreatography (ERCP) we diagnosed 35 patients (23 females and 12 males) with postoperative biliary fistula. Four patients had history of laparoscopic cholecystectomy. We used endoscopic sphincterotomy (18 cases) or endoprosthesis placement (17 cases) in the treatment. Seventeen patients with fistula plus common bile duct (CBD) stones and one patient with benign papillary stenosis were treated with endoscopic sphincterotomy alone. Seventeen patients without CBD stones were treated with only endoprosthesis placement. A second ERCP confirmed healing of the leakage after 4-16 weeks. Postoperative bile leakage could be diagnosed safely and effectively by ERCP, subsequent endoscopic management in most cases is successful. Sphincterotomy alone is the preferred treatment for biliary fistula-complicating surgery for gallstone disease. Alternatively, when a fistula is large, endoscopic placement of an endoprosthesis can be proposed as the first treatment.


ULTRA: A Unique Instrument for Time-Resolved Spectroscopy.
We report the development of a high-sensitivity time-resolved infrared and Raman spectrometer with exceptional experimental flexibility based on a 10-kHz synchronized dual-arm femtosecond and picosecond laser system. Ultrafast high-average-power titanium sapphire lasers and optical parametric amplifiers provide wavelength tuning from the ultraviolet (UV) to the mid-infrared region. Customized silicon, indium gallium arsenide, and mercury cadmium telluride linear array detectors are provided to monitor the probe laser intensity in the UV to mid-infrared wavelength range capable of measuring changes in sample absorbance of ΔOD ~ 10(-5) in 1 second. The system performance is demonstrated for the time-resolved infrared, two-dimensional (2D) infrared, and femtosecond stimulated Raman spectroscopy techniques with organometallic intermediates, organic excited states, and the dynamics of the tertiary structure of DNA.


Emotional reactivity following surgery to the prefrontal cortex.
We aimed to elicit emotion in patients with surgically circumscribed lesions of the prefrontal cortex (PFC) in order to elucidate the precise functional roles in emotion processing of the discrete subregions comprising the ventromedial PFC, including the medial PFC and orbitofrontal cortex (OFC). Three components of emotional reactivity were measured: subjective experience, behaviour, and physiological response. These included measures of self-reported emotion, observer-rated facial expression of emotion and measurements of heart rate and heart rate variability (HRV) during film viewing, and a measure of subjective emotional change since surgery. Patients with lesions to the ventromedial PFC demonstrated significant differences compared with controls in HRV during the film clips, suggesting a shift to greater dominance of sympathetic input. In contrast, patients with lesions restricted to the OFC showed significant differences in HRV suggesting reduced sympathetic input. They also showed less facial expression of emotion during positive film clips, and reported more subjective emotional change since surgery compared with controls. This human lesion study is important for refining theoretical models of emotion processing by the ventromedial PFC, which until now have primarily been based on anatomical connectivity, animal lesion, and human functional neuroimaging research. Such theories have implications for the treatment of a wide variety of emotional disorders.


Economic analysis of a tailored behavioral intervention to improve blood pressure control for primary care patients.
Few telemedicine programs have undergone cost analyses, impeding their implementation into practice. We report on the economic analysis of a nurse-administered intervention designed to improve blood pressure control among hypertensive veterans. We randomized hypertensive patients at the Durham Veterans Affairs Medical Center primary care clinic to behavioral (n = 294) or nonbehavioral (n = 294) interventions. Behavioral intervention patients received tailored information bimonthly for 2 years via telephone. To calculate intervention cost, we microcosted the nurse's labor cost and computer hardware and software costs, applied a direct-to-indirect cost ratio, and distributed the costs over an estimated cohort of patients. We analyzed data from the Veterans Affairs Decision Support System to assess whether the intervention impacted overall health care utilization and costs. We used life expectancy estimates from the literature to develop decision models to calculate cost per life-year saved. The mean annual intervention cost was $112 (range $61-$259). During 2 years of follow-up, patients in the intervention group incurred $7,800 in inpatient costs and $9,741 in outpatient costs; the nonintervention group incurred $6,866 in inpatient costs and $9,599 in outpatient costs. The total cost difference was not statistically significant (P = .56). Cost-effectiveness of the behavioral intervention ranged from $42,457 per life-year saved for normal-weight women to $87,300 per life-year saved for normal-weight men. The study results suggest that a nurse-administered, tailored behavioral intervention can be implemented at nominal cost and be cost-effective; however, there was no apparent lowering of health care utilization and costs during the 2 years of follow-up.


mCherry Fusion Proteins Facilitate Production of Recombinant, Cysteine-Rich Leptospira interrogans Proteins in Escherichia coli.
Recombinant fluorescent fusion proteins are fundamental to advancing many aspects of protein science. Such proteins are typically used to enable the visualization of functional proteins in experimental systems, particularly cell biology. An important problem in biotechnology is the production of functional, soluble proteins. Here we report the use of mCherry-fusions of soluble, cysteine-rich, Leptospira-secreted exotoxins in the PF07598 gene family, the so-called virulence modifying (VM) proteins. The mCherry fusion proteins facilitated the production of the VM proteins (LA3490 and LA1402) by enabling the visual detection of pink colonies and following them through lysis and sequential chromatography steps. CD-spectroscopy analysis confirmed the stability and robustness of the mCherry-fusion protein, with a structure comparable to AlphaFold structural predictions. LA0591, a unique member of the PF07598 gene family that lacks N-terminal ricin B-like domains, was produced as a tagless protein that strengthens the recombinant protein production protocol. The current study provides the approaches for the synthesis of 50-125 kDa soluble, cysteine-rich, high-quality mCherry tagged or tagless fast protein liquid chromatography (FPLC)-purified protein. The use of mCherry-fusion proteins enables a streamlined, efficient process of protein production and qualitative and quantitative downstream analytical and functional studies. Approaches for troubleshooting and optimization were systemically evaluated to overcome difficulties in recombinant protein expression and purification, demonstrating biotechnology utility in accelerating recombinant protein production.


Characterization of sphere-forming HCT116 clones by whole RNA sequencing.
To determine CD133(+) cells defined as cancer stem cells (CSCs) in colon cancer, we examined whether CD133(+) clones in HCT116 demonstrate known features of CSCs like sphere-forming ability, chemodrug-resistance, and metastatic potential. Magnetic cell isolation and cell separation demonstrated that <1% of HCT116 cells expressed CD133, with the remaining cells being CD133(-) clones. In colon cancer cells, radioresistance is also considered a CSC characteristic. We performed clonogenic assay using 0.4 Gy γ-irradiation. Interestingly, there were no differences between HCT116 parental and HCT116 CD133(+) clones when the cells comprised 0.5% of the total cells, and CD133(-) clone demonstrated radiosensitive changes compared with parental and CD133(+) clones. Comparing gene expression profiles between sphere-forming and nonforming culture conditions of HCT116 subclones by whole RNA sequencing failed to obtain specific genes expressed in CD133(+) clones. Despite no differences of gene expression profiles in monolayer attached culture conditions of each clone, sphere-forming conditions of whole HCT116 subclones, parental, CD133(+), and CD133(-) increased 1,761 coding genes and downregulated 1,384 genes related to CSCs self-renewal and survival. Thus, spheroid cultures of HCT116 cells could be useful to expand colorectal CSCs rather than clonal expansion depending on CD133 expressions.


Pharmacokinetics and Abuse Potential of Benzhydrocodone, a Novel Prodrug of Hydrocodone, After Intranasal Administration in Recreational Drug Users.
Developing an acetaminophen-free, immediate-release hydrocodone product remains an unmet medical need; however, new opioid analgesics should not introduce new abuse risks. Benzhydrocodone is a prodrug of hydrocodone that must be metabolized into hydrocodone by enzymes in the intestinal tract to optimally deliver its pharmacologic effects. This study evaluated the intranasal pharmacokinetics and abuse potential of benzhydrocodone active pharmaceutical ingredient (API) compared with hydrocodone bitartrate (HB) API. Single-center, randomized, double-blind, crossover study. Clinical research site. Healthy adult, nondependent, recreational opioid users. Subjects (N = 51 Completers) were randomized to receive 13.34 mg of intranasal benzhydrocodone API and 15.0 mg of intranasal HB API (molar-equivalent doses of hydrocodone). Blood samples were taken, and Drug Liking scores (assessed on a bipolar visual analog scale) were obtained throughout each dosing interval. Nasal irritation and safety were assessed. Peak hydrocodone plasma concentration (Cmax) was 36.0% lower, and total hydrocodone exposures (AUClast and AUCinf) were 20.3% and 19.5% lower, respectively, for benzhydrocodone API compared with HB API (P < 0.0001). All partial AUC values were lower for benzhydrocodone API, with a ≥ 75% reduction in hydrocodone exposure at all time intervals up to one hour postdose (P < 0.0001). Median Tmax of hydrocodone following benzhydrocodone API was delayed by more than one hour compared with HB. Drug Liking score, as assessed by maximal liking (Emax), was significantly lower for benzhydrocodone API vs HB API (P = 0.004), with 45% of subjects showing a ≥ 30% reduction in Drug Liking Emax. Reductions in hydrocodone exposure and associated decreases in Drug Liking relative to HB suggest that the prodrug benzhydrocodone may deter intranasal abuse.


Analysis of flagellar size control using a mutant of Chlamydomonas reinhardtii with a variable number of flagella.
A mutant of Chlamydomonas reinhardtii with a variable number of flagella per cell has been used to investigate flagellar size control. The mutant and wild-type do not differ in cell size nor in flagellar length, yet the size of the intracellular pool of flagellar precursor protein can differ dramatically among individual mutant cells, with, for example, triflagellate cells having three times the pool of monoflagellate cells. Because cells of the same size, but with very different pool sizes, have flagella of identical length, it appears that the concentration of the unassembled flagellar precursor protein pool does not regulate flagellar length. The relation between cell size, pool size, and flagellar length has also been investigated for wild-type cells of different sizes and ploidies. Again, flagellar length appears to be maintained independent of pool size or concentration.


[Nuclear structures in the late oogenesis of Rana temporaria. III. Electron microscopic studies].
The ultrastructural organization of the vitellogenic oocyte nucleus (stage VI, according to Duryee, 1950) was studied in normal and in vitro hormone-stimulated maturing oocytes of Rana temporaria. At this stage, numerous nucleoli are gathered around the knot of highly contracted chromosomes (the karyosphere) thus making the karyosphere capsule. Light microscope observations reveal three zones in the capsule: a central fibrous zone separating the chromosomes from the nucleoli, a middle zone, consisting of numerous nucleoli and a distinct fibrous componen; in addition a fibrous zone on the capsule periphery is seen. The nucleoli are fibrillar, bear no proribosomal granules and do not synthesize RNA. This period is characterized by an intensive fragmentation and segregation of the nucleolar material. Numerous micronucleoli and nuclear bodies occur in the nucleus. The nucleoli are normally compound and irregular in shape to become spherical in hormone-stimulated maturing oocytes. In the central fibrous zone of the capsule, separating the chromosomes from the nucleoli, some peculiar abundant accumulations of annuli were detected lacking the membranes component. Annuli are linked with the fibrous material and are regularily packed making peculiar pseudomembranes (PMM). The chromatin is connected with PMM directly. In the middle zone of the capsule, accumulations of PMM are also seen, though less abundant and less regularly packed; along with annuli, membranous areas of various size and form are met in PMM. PMM are connected with the micronucleoli with filaments 20 nm thick. In the peripheral zone of the capsule, a variety of membranous structures is detected: intranuclear annuli lamellae, component of the capsule consists of different membranous and pseudomembranous (with annuli) structures. A question of the contribution of the chromatin material in the formation of the fibrous capsular component (PMM and membranous structures) is discussed.


Activated α2-macroglobulin binding to human prostate cancer cells triggers insulin-like responses.
Ligation of cell surface GRP78 by activated α2-macroglobulin (α2M*) promotes cell proliferation and suppresses apoptosis. α2M*-treated human prostate cancer cells exhibit a 2-3-fold increase in glucose uptake and lactate secretion, an effect similar to insulin treatment. In both α2M* and insulin-treated cells, the mRNA levels of SREBP1-c, SREBP2, fatty-acid synthase, acetyl-CoA carboxylase, ATP citrate lyase, and Glut-1 were significantly increased together with their protein levels, except for SREBP2. Pretreatment of cells with α2M* antagonist antibody directed against the carboxyl-terminal domain of GRP78 blocks these α2M*-mediated effects, and silencing GRP78 expression by RNAi inhibits up-regulation of ATP citrate lyase and fatty-acid synthase. α2M* induces a 2-3-fold increase in lipogenesis as determined by 6-[(14)C]glucose or 1-[(14)C]acetate incorporation into free cholesterol, cholesterol esters, triglycerides, free fatty acids, and phosphatidylcholine, which is blocked by inhibitors of fatty-acid synthase, PI 3-kinase, mTORC, or an antibody against the carboxyl-terminal domain of GRP78. We also assessed the incorporation of [(14)CH3]choline into phosphatidylcholine and observed similar effects. Lipogenesis is significantly affected by pretreatment of prostate cancer cells with fatostatin A, which blocks sterol regulatory element-binding protein proteolytic cleavage and activation. This study demonstrates that α2M* functions as a growth factor, leading to proliferation of prostate cancer cells by promoting insulin-like responses. An antibody against the carboxyl-terminal domain of GRP78 may have important applications in prostate cancer therapy.


Intraparenchymal meningioma originating from underlying meningioangiomatosis. Case report and review of the literature.
The authors present the case of a 20-year-old woman with right-sided temporal intraparenchymal meningioma originating from underlying meningioangiomatosis. The patient manifested temporal-type seizures as the initial symptom. She had no stigmata of neurofibromatosis Type 2. Neuroradiological studies revealed an intraaxial, contrast-enhancing lesion in the right temporal lobe. After gross-total removal of the tumor, histological examination revealed a transitional meningioma with surrounding neural parenchyma and features of meningioangiomatosis. Although there were no signs of anaplasia, necrosis, or increased mitosis, tumor islands were observed in the adjacent neuropil. The rare association of meningioangiomatosis and meningioma is discussed, along with radiological and surgical findings.


Flexible nanomechanical bit based on few-layer graphene.
Mechanical computers have gained intense research interest at size scales ranging from nano to macro as they may complement electronic computers operating in extreme environments. While nanoscale mechanical computers may be easier to integrate with traditional electronic components, most current nanomechanical computers are based on volatile resonator systems that require continuous energy input. In this study, we propose a non-volatile nanomechanical bit based on the quasi-stable configurations of few-layer graphene with void defects, and demonstrate its multiple quasi-stable states by deriving an analytic relationship for the void configuration based on a competition between the bending energy and the cohesive energy. Using this nanomechanical bit, typical logic gates are constructed to perform Boolean calculations, including NOT, AND, OR, NAND and NOR gates, and demonstrate reprogrammability between these logic gates. We also study the accuracy and the stability of the nanomechanical bits based on the few-layer graphene. These findings provide a novel approach to realize the nanomechanical computing process.


Gene expression profiles in pancreatic intraepithelial neoplasia reflect the effects of Hedgehog signaling on pancreatic ductal epithelial cells.
Invasive pancreatic cancer is thought to develop through a series of noninvasive duct lesions known as pancreatic intraepithelial neoplasia (PanIN). We used cDNA microarrays interrogating 15,000 transcripts to identify 49 genes that were differentially expressed in microdissected early PanIN lesions (PanIN-1B/2) compared with microdissected normal duct epithelium. In this analysis, a cluster of extrapancreatic foregut markers, including pepsinogen C, MUC6, KLF4, and TFF1, was found to be up-regulated in PanIN. Up-regulation of these genes was further validated using combinations of real-time reverse transcription-PCR, in situ hybridization, and immunohistochemistry in a total of 150 early PanIN lesions from 81 patients. Identification of these gastrointestinal transcripts in human PanIN prompted assessment of other foregut markers by both semiquantitative and real-time reverse transcription-PCR, revealing similar up-regulation of Sox-2, Gastrin, HoxA5, GATA4/5/6, Villin and Forkhead 6 (Foxl1). In contrast to frequent expression of multiple gastric epithelial markers, the intestinal markers intestinal fatty acid binding protein, CDX1 and CDX2 were rarely expressed either in PanIN lesions or in invasive pancreatic cancer. Hedgehog pathway activation induced by transfection of immortalized human pancreatic ductal epithelial cells with Gli1 resulted in up-regulation of the majority of foregut markers seen in early PanIN lesions. These data show frequent up-regulation of foregut markers in early PanIN lesions and suggest that PanIN development may involve Hedgehog-mediated conversion to a gastric epithelial differentiation program.


[Dependence of the anticodon stem conformation of tRNA Trp on the anticodon loop structure].
After conversion of the exposed cytosine bases of the anticodon loop into uridines with bisulfite the pattern of hydrolysis of the tRNATrp anticodon stem under the action of cobra venom endonuclease is altered. A removal of the 3'-CCA end has no influence on the hydrolytic pattern of the anticodon stem in tRNATrp. Thus, the nucleotide sequence of the anticodon loop influences the conformation of the neighbouring stem.


Band 3 is the basolateral anion exchanger of dark epithelial cells of turtle urinary bladder.
The turtle urinary bladder serves as a model for collecting duct functions in the mammalian kidney. The epithelium of both the turtle bladder and the mammalian collecting duct can generate a steep gradient for H+ ions between blood and urine. Secretion of H+ into the urine is coupled to a basolateral efflux of HCO-3 that appears to be exchanged mainly against Cl-. Here we show that approximately 80% of the dark cells of the bladder contain a 110,000 relative molecular weight (Mr) analogue of the turtle erythrocyte anion exchanger, band 3. The band 3 analogue is confined to the basolateral cell surface and is absent from the apical membrane. A minor population of the dark cells (approximately 20%), which have been previously suggested to represent reverse cells that are involved in HCO-3 secretion rather than absorption, appears not to express a band 3-like anion exchanger, at either the apical or the basolateral membrane. The bladder band 3 protein is colocalized with actin and isoforms of ankyrin (200,000 Mr) and spectrin (230,000 Mr) along the basolateral membrane. Linkage of band 3 via ankyrin to the spectrin-actin lattice may restrict this anion exchanger to the basolateral membrane surface. In view of our previous observation of a band 3-like anion exchanger in the collecting duct epithelium of the rat kidney, these findings point to a common molecular basis for acid-base transport in the mammalian collecting duct and the reptilian urinary bladder.


Six-month Follow-up of the Effect of Nonvital Bleaching on IL-1β and RANK-L: A Randomized Clinical Trial.
It has been reported that bleaching generates an increase in the activity of osteoclasts in vitro. We quantified the RANK-L and IL-1β biomarkers in a double-blind, randomized clinical trial evaluating the in vivo effect of hydrogen peroxide (35%) and peroxide carbamide (37%) six months after whitening. Fifty volunteers participated, each with color change in a nonvital tooth. Fifty teeth were randomly divided into two groups (n=25), and the teeth were bleached using either 35% hydrogen peroxide (G1) or 37% carbamide peroxide (G2). Intracoronal bleaching was carried out by a technical "walking bleach" over four sessions. Gingival crevicular fluid samples were collected and used to quantify the IL-1β and RANK-L secreted levels. Samples of six periodontal sites (three vestibular and three palatal) were collected for up to six months (at the beginning of the study [baseline] and at one week, one month, and six months posttreatment). The color change was visually monitored using the Vita Bleached Guide (ΔSGU). Comparing each time to baseline assessment, a significant increase in the levels of IL-1β and RANK-L across time points was detected (p<0.05). The color change was 4 in G1 and G2, and a statistically significant difference (p<0.05) was found at the month time point between the groups. Using the Spearman test, a strong correlation (>0.8) between the IL-1β and RANK-L levels in both groups at all time points was detected. Nonvital bleaching using a technical walking bleach induces an increase in the IL-1β and RANKL production in periodontal tissues, which persists for six months after treatment. Both biomarkers were highly correlated in both groups and at all time points.


Antispasmodics for Chronic Abdominal Pain: Analysis of North American Treatment Options.
Chronic abdominal pain is a common gastrointestinal (GI) symptom that characterizes many functional GI disorders/disorders of gut-brain interaction, including irritable bowel syndrome, functional dyspepsia, and centrally mediated abdominal pain syndrome. The symptoms of abdominal pain in these highly prevalent disorders are often treated with antispasmodic agents. Antispasmodic treatment includes a broad range of therapeutic classes with different mechanisms of action, including anticholinergic/antimuscarinic agents (inhibition of GI smooth muscle contraction), calcium channel inhibitors (inhibition of calcium transport into GI smooth muscle), and direct smooth muscle relaxants (inhibition of sodium and calcium transport). The aim of this review article was to examine the efficacy and safety of antispasmodics available in North America (e.g., alverine, dicyclomine, hyoscine, hyoscyamine, mebeverine, otilonium, pinaverium, and trimebutine) for the treatment of chronic abdominal pain in patients with common disorders of gut-brain interaction. For the agents examined, comparisons of studies are limited by inconsistencies in treatment dosing and duration, patient profiles, and diagnostic criteria employed. Furthermore, variability in study end points limits comparisons. Risk of selection, performance, detection, attrition, and reporting bias also differed among studies, and in many cases, risks were considered "unclear." The antispasmodics evaluated in this review, which differ in geographic availability, were found to vary dramatically in efficacy and safety. Given these caveats, each agent should be considered on an individual basis, rather than prescribed based on information across the broad class of agents.


Shared Medical Appointments May Be Effective for Improving Clinical and Behavioral Outcomes in Type 2 Diabetes: A Narrative Review.
Type 2 diabetes mellitus (T2DM) is a complex chronic disease affecting over 400 million people worldwide. Managing T2DM and its associated complications in individual patient consultations poses substantial challenges to physicians due to limited time and resources and lack of access to multidisciplinary teams. Shared medical appointments (SMAs) are consecutive medical consultations provided by a physician in a group setting, where integrated medical care and patient education are delivered in a single session. SMAs allow physicians to deliver the same level of care to multiple patients at the same time, thereby maximizing available resources. However, the effectiveness and practicality of SMAs in the management of T2DM remains unknown. This narrative review summarizes current and emerging evidence regarding the effectiveness of SMAs in improving clinical outcomes in patients with T2DM, as well as whether SMAs are associated with reduced costs and improved diabetes-related behavioral and lifestyle changes. An extensive literature search was conducted on major electronic databases including PubMed and Google Scholar using keywords, including SMAs, group visits, and T2DM to identify all studies of SMAs in patients with T2DM. Studies in type 1 diabetes or mixed or unspecified populations were excluded, as well as studies where SMAs did not involve a physician since these do not meet the classical definition of a SMA. Nineteen studies were identified and are included in this review. Overall, current evidence suggests that SMAs delivered regularly over time may be effective in improving glycemic outcomes, diabetes knowledge, and some diabetes-related behaviors. However, the main limitation of existing studies was the paucity of comparisons with standard care which limits the ability to draw conclusions regarding whether SMAs are superior to standard care in T2DM management. Moreover, the small number of studies and substantial heterogeneity in study designs, populations, and interventions creates difficulties in establishing the practicality and efficiency of SMAs in the clinical care setting. We conclude that there remains a need for larger studies to identify populations who may or may not benefit from the SMA model of care and to clarify the potential benefits and barriers to implementing SMAs into routine diabetes care.


Interanimal "memory" transfer: results from brain and liver homogenates.
Sixty mice received either shock or no shock in a shuttle box, or nonspecific stress in another apparatus. Brain and liver homogenates from these animals were then injected into 120 naive recipients, who were all tested in the shuttle box. Subjects receiving brain or liver from shocked or stressed donors had significantly higher latencies than control counterparts. These results are interpreted in terms of stress, rather than a memory transfer hypothesis.


Applying the right statistics: analyses of measurement studies.
The study of measurement error, observer variation and agreement between different methods of measurement are frequent topics in the imaging literature. We describe the problems of some applications of correlation and regression methods to these studies, using recent examples from this literature. We use a simulated example to show how these problems and misinterpretations arise. We describe the 95% limits of agreement approach and a similar, appropriate, regression technique. We discuss the difference vs. mean plot, and the pitfalls of plotting difference against one variable only. We stress that these are questions of estimation, not significance tests, and show how confidence intervals can be found for these estimates.


Hydrolytic polyketide shortening by ayg1p, a novel enzyme involved in fungal melanin biosynthesis.
The pentaketide 1,3,6,8-tetrahydroxynaphthalene (T4HN) is a key precursor of 1,8-dihydroxynaphthalene-melanin, an important virulence factor in pathogenic fungi, where T4HN is believed to be the direct product of pentaketide synthases. We showed recently the involvement of a novel protein, Ayg1p, in the formation of T4HN from the heptaketide precursor YWA1 in Aspergillus fumigatus. To investigate the mechanism of its enzymatic function, Ayg1p was purified from an Aspergillus oryzae strain that overexpressed the ayg1 gene. The Ayg1p converted the naphthopyrone YWA1 to T4HN with a release of the acetoacetic acid. Although Ayg1p does not show significant homology with known enzymes, a serine protease-type hydrolytic motif is present in its sequence, and serine-specific inhibitors strongly inhibited the activity. To identify its catalytic residues, site-directed Ayg1p mutants were expressed in Escherichia coli, and their enzyme activities were examined. The single substitution mutations S257A, D352A, and H380A resulted in a complete loss of enzyme activity in Ayg1p. These results indicated that the catalytic triad Asp352-His380-Ser257 constituted the active-site of Ayg1p. From a Dixon plot analysis, 2-acetyl-1,3,6,8-tetrahydroxynaphthalene was found to be a strong mixed-type inhibitor, suggesting the involvement of an acyl-enzyme intermediate. These studies support the mechanism in which the Ser257 at the active site functions as a nucleophile to attack the YWA1 side-chain 1'-carbonyl and cleave the carbon-carbon bond between the naphthalene ring and the side chain. Acetoacetic acid is subsequently released from the Ser257-O-acetoacetylated Ayg1p by hydrolysis. An enzyme with activity similar to Ayg1p in melanin biosynthesis has not been reported in any other organism.


Cure With Interferon-Free Direct-Acting Antiviral Is Associated With Increased Survival in Patients With Hepatitis C Virus-Related Hepatocellular Carcinoma From Both East and West.
Survival data among patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) after achieving sustained virologic response (SVR) with interferon-free direct-acting antivirals (DAAs) in both Asian and western countries are limited. Survival rates were compared between patients with HCV-related HCC who were untreated for HCV and those who achieved SVR. Using data from two U.S. and six Asian centers from 2005 to 2017, we categorized 1,676 patients who were mono-infected with HCV-related HCC into patients untreated for HCV (untreated group) and DAA-treated patients with SVR (SVR group) and matched by propensity score matching (PSM); multivariable Cox regression with HCV treatment status as a time-varying covariate was used to determine mortality risk and landmark analysis to avoid immortal time bias. There were 1,239 untreated patients and 437 patients with SVR. After PSM, background risks of the 321 pairs of matched patients were balanced (all P > 0.05). After time-varying adjustment for HCV treatment initiation compared with untreated patients, patients with SVR had significantly higher 5-year overall survival (87.78% vs. 66.05%, P < 0.001). Multivariable Cox regression showed that SVR was independently associated with a 63% lower risk of 5-year all-cause mortality (hazard ratio [HR], 0.37; 95% confidence interval [CI], 0.16-0.83; P = 0.016) and 66% lower risk of 5-year liver-related mortality (HR, 0.34; 95% CI, 0.13-0.88; P = 0.026) with similar trends after removing patients with liver transplants. Landmark analysis at 90, 180, and 360 days showed consistent results (HRs ranged 0.22 to 0.44, all P < 0.05). In this multinational consortium, patients with HCV-related HCC who obtained SVR achieved a 60%-70% improvement in 5-year survival (both all-cause and liver related) compared with patients untreated for HCV. Patients eligible for HCC therapy should also be considered for DAA therapy.


Wood ants produce a potent antimicrobial agent by applying formic acid on tree-collected resin.
Wood ants fight pathogens by incorporating tree resin with antimicrobial properties into their nests. They also produce large quantities of formic acid in their venom gland, which they readily spray to defend or disinfect their nest. Mixing chemicals to produce powerful antibiotics is common practice in human medicine, yet evidence for the use of such "defensive cocktails" by animals remains scant. Here, we test the hypothesis that wood ants enhance the antifungal activity of tree resin by treating it with formic acid. In a series of experiments, we document that (i) tree resin had much higher inhibitory activity against the common entomopathogenic fungus Metarhizium brunneum after having been in contact with ants, while no such effect was detected for other nest materials; (ii) wood ants applied significant amounts of endogenous formic and succinic acid on resin and other nest materials; and (iii) the application of synthetic formic acid greatly increased the antifungal activity of resin, but had no such effect when applied to inert glass material. Together, these results demonstrate that wood ants obtain an effective protection against a detrimental microorganism by mixing endogenous and plant-acquired chemical defenses. In conclusion, the ability to synergistically combine antimicrobial substances of diverse origins is not restricted to humans and may play an important role in insect societies.


Mycoplasma enhydrae sp. nov. isolated from southern sea otters (Enhydra lutris nereis).
Five Mycoplasma strains have been isolated from the oropharynx of southern sea otters (Enhydra lutris nereis) from the Central California Coast, USA. These strains were phenotypically and genetically characterized and compared to other established Mycoplasma species. All five strains hydrolysed arginine but not urea, but did not produce acid from glucose, and all were isolated and propagated under anaerobic and aerobic atmospheric conditions at +35-37 ˚C using either SP4 or PPLO medium supplemented with arginine. Colonies on solid medium showed a typical fried-egg appearance and transmission electron microscopy revealed a typical mycoplasma cellular morphology. Molecular characterization included assessment of the following genetic loci: 16S rRNA, 16S-23S rRNA ITS, rpoB, rpoC, polC, topIIA, tufB, arcA and smc. Complete 16S rRNA gene sequence analysis indicated that these strains were most closely related to M.ycoplasma phocicerebrale, and to M.ycoplasma arginini, M.ycoplasma gateae and M.ycoplasma canadense with nucleotide similarities of 99 and 98 %, respectively. Nucleotide analysis of other genetic loci revealed 73-91 % nucleotide similarity to the corresponding genes of the above closely related species. All five strains clustered into a distinct group on the 16S rRNA and rpoB phylogenetic trees. Serological testing via growth inhibition and metabolic inhibition tests employing antiserum to type strains of M. phocicerebrale, M. arginini, M. gateae and M. canadense failed to recognize these novel strains. Our results suggest that the strains isolated from southern sea otters represent a novel species of the genus Mycoplasma, for which the name Mycoplasma enhydrae sp. nov. is proposed; the type strain is 6243-11T (=DSM 106704T=ATCC TSD-140T).


Genome structure of avian sarcoma virus Y73 and unique sequence coding for polyprotein p90.
The genome structure of a newly isolated sarcoma virus, Y73, was studied. Y73 is a defective, potent sarcomagenic virus and contains 4.8-kilobase (kb) RNA as its genome; in contrast, helper virus associated with Y73 had 8.5-kb RNA, similar to other avian leukemia viruses. Fingerprinting analysis these RNAs demonstrated that the 4.8-kb RNA contains a specific RNA sequence of 2.5 kb, which represents the transforming gene (yas) of Y73. This specific sequence was mapped in the middle of the genome and had at both ends 1- to 1.5-kb sequences in common with Y73-associated virus RNA. This structure is very similar to those of avian and mammalian leukemia viruses. In vitro translation of the 4.8-kb RNA and the immunospecificity of the products directly demonstrated that polyprotein p90, containing p19, is a product translated from capped 4.8-kb RNA and that the specific peptide portion is coded by the yas sequence. Protein 90, which was also found in cells transformed with Y73, was suggested to be a transforming protein.


Gender of the immediate manager and women's wages: The importance of managerial position.
One argument for increasing female representation in management is the expectation that female managers will be particularly beneficial for female employees through, e.g., role modeling, mentoring or providing other incentives to enhance female productivity. We explore this issue by analyzing the association between women's wages and the gender of their immediate managers using Swedish matched employee-employer data from 2010. Contrary to the expected positive association, we find that wages are overall 3% lower for female employees with a female instead of male manager. However, dividing the sample by managerial position and controlling for the sorting of employees with respect to, e.g., non-cognitive traits, work tasks, family commitment and establishment gender composition, the negative association is found only for female employees working for lower-level managers, not for women with a manager at the highest rank. One possible explanation could be a difference in decision-making power if lower-level female managers have more limited resources for their subordinates compared to lower-level male managers.


A population-level investigation of cancer clinical trials participation in a UK region.
The aim of this study was to document cancer trial participation since establishment of the Northern Ireland Cancer Trials Network and investigate population and disease factors associated with trial participation. An independent cohort of over 51 000 cancer patients from the Northern Ireland Cancer Registry covering the same population (2007-2012) was linked to a database of 1316 interventional cancer trial participants in a UK region. The primary outcome measure was participation in an intervention clinical trial. Patients were followed up until 31 March 2013. Kaplan-Meier tests and Cox proportional hazard models using person days at risk to allow for death were used to investigate factors associated with trial participation. Multivariate analysis assessed the impact of age, cancer type and stage, distance from the cancer centre (radiotherapy), marital status, deprivation quintile and rurality. Participation was analysed separately for children (<15 years) and young individuals (15-24 years). Trial recruitment increased three-fold with establishment of a network. Participation was the highest for children at 21%, but relatively low at 2.05% for adults, although higher for haematological malignancies (4.5%). Lower likelihood of trial participation in adults was associated with female sex, older age, distance from regional Cancer Centre and stage 1 disease. The introduction of a regional Cancer Trials Network was associated with increased participation; however, trial participation remains relatively low at the population level especially among elderly patients. Linkage of clinical trials and cancer registry database provide an easy mechanism to monitor trial representativeness at the population level.


Biophysical constraints on the evolution of tissue structure and function.
Phylogenetic analyses based on models of molecular sequence evolution have driven to industrial scale the generation, cataloguing and modelling of nucleic acid and polypeptide structure. The recent application of these techniques to study the evolution of protein interaction networks extends this analytical rigour to the study of nucleic acid and protein function. Can we further extend phylogenetic analysis of protein networks to the study of tissue structure and function? If the study of tissue phylogeny is to join up with mainstream efforts in the molecular evolution domain, the continuum field description of tissue biophysics must be linked to discrete descriptions of molecular biochemistry. In support of this goal we discuss tissue units, and biophysical constraints to molecular function associated with these units, to present a rationale with which to model tissue evolution. Our rationale combines a multiscale hierarchy of functional tissue units (FTUs) with the corresponding application of physical laws to describe molecular interaction networks and flow processes over continuum fields within these units. Non-dimensional numbers, derived from the equations governing biophysical processes in FTUs, are proposed as metrics for comparative studies across individuals, species or evolutionary time. We also outline the challenges inherent to the systematic cataloguing and phylogenetic analysis of tissue features relevant to the maintenance and regulation of molecular interaction networks. These features are key to understanding the core biophysical constraints on tissue evolution.


Effect of dissolution fluid and presence of hog intestinal barrier on the dissolution of theophylline from bioadhesive granules.
The effect of dissolution fluid and the presence of a natural barrier (hog intestine) on the release of theophylline from some bioadhesive granules is presented. A higher quantity of the drug was released in simulated intestinal fluid (SIF) than O. IN HCl. When a hog intestine was used as the diffusion barrier, the availability of the drug through the barrier into the sink solution was low, ranging from 20-35%.


From panic to pedagogy: Using online active learning to promote inclusive instruction in ecology and evolutionary biology courses and beyond.
The rapid shift to online teaching in spring 2020 meant most of us were teaching in panic mode. As we move forward with course planning for fall and beyond, we can invest more time and energy into improving the online experience for our students. We advocate that instructors use inclusive teaching practices, specifically through active learning, in their online classes. Incorporating pedagogical practices that work to maximize active and inclusive teaching concepts will be beneficial for all students, and especially those from minoritized or underserved groups. Like many STEM fields, Ecology and Evolution shows achievement gaps and faces a leaky pipeline issue for students from groups traditionally underserved in science. Making online classes both active and inclusive will aid student learning and will also help students feel more connected to their learning, their peers, and their campus. This approach will likely help with performance, retention, and persistence of students. In this paper, we offer broadly applicable strategies and techniques that weave together active and inclusive teaching practices. We challenge instructors to commit to making small changes as a first step to more inclusive teaching in ecology and evolutionary biology courses.


Hypoxia enhances CXCR4 expression by activating HIF-1 in oral squamous cell carcinoma.
Hypoxia promotes the invasive and metastatic potential of tumour cells. A recent study has shown that the activation of the chemokine receptor CXCR4 by lack of oxygen in breast cancer is HIF-1-dependent. We have previously demonstrated that CXCR4 signalling is involved in the establishment of lymph node metastasis in oral squamous cell carcinoma (OSCC). In this study, we investigated a correlation between CXCR4 and HIF-1alpha expression in OSCC. Immunohistochemistry showed that CXCR4 was expressed in 20 of 85 OSCC tissues, while HIF-1alpha was expressed in 51 of 85 samples. There was a significant correlation between the expression of CXCR4 and HIF-1alpha. In human OSCC cells, hypoxia markedly enhanced the expression of both HIF-1alpha and CXCR4. Furthermore, synthetic small interfering RNA specific for HIF-1alpha significantly suppressed the expression of this protein, and also attenuated the induction of CXCR4 expression under hypoxic conditions. These results indicated that HIF-1alpha regulated hypoxia-induced CXCR4 expression in OSCC.


Enhanced Understanding of the Levels of Palliative Care in Pharmacy Students Through Participating in Clinical Training in Hospitals.
A palliative care knowledge survey was conducted involving pharmacy students to examine their perceived usefulness and the educational effect of clinical training in hospitals. A questionnaire sheet was distributed to fifth-year pharmacy students before and after clinical training. The questionnaire consisted of questions to clarify the details of palliative care-related training in hospitals and students' knowledge of such care. The respondents were divided into 2 groups: those who participated in palliative care team (PCT) rounds (group A: 57) and those who did not (group B: 57). The mean total correct answer rate markedly increased after training in group A, from 37.9 to 47.1% (P < .01). Such an increase was also observed in the domains of philosophy and pain in this group ( P < .01). In contrast, group B did not show differences in the mean correct answer rate between before and after training; there was no significant increase in the rate in any domain. Pharmacy students' knowledge was enhanced by participating in the PCT, confirming the usefulness of such participation during training as part of palliative care education.


The effect of isoflurane on survival and myocardial infarction: a meta-analysis of randomized controlled studies.
The aim of this meta-analysis was to investigate the cardioprotective properties of isoflurane versus any comparator in terms of the rate of myocardial infarction and all-cause mortality. Pertinent studies were searched independently in Biomed, Central, PubMed, Embase, and the Cochrane Central Register of clinical trials. The primary endpoint was mortality at the longest follow-up available. A hospital. Randomized controlled trials. A meta-analysis of 37 trials. The 37 included trials randomized 3,539 patients in cardiac (16 studies) and in noncardiac surgery (21 studies) with noninhalation comparators in 55% of trials. The overall analysis showed no difference in mortality between the isoflurane and control groups (16/1,602 [1.0%] v 23/1,937 [1.2%], odds ratios (OR) = 0.76 [0.39-1.47], p = 0.4 with 37 studies included) and no difference in the rate of myocardial infarction (3/1,312 [0.2%] v 1/1,532 [0.07%], OR = 2.03 [0.27-15.49], p = 0.5 with 30 studies included). Mortality was reduced in the isoflurane group when only studies with a low risk of bias were included in the analyses (0/540 [0%] v 5/703 [0.7%] in the control arm, OR = 0.13 [0.02-0.76], p = 0.02) with 4 cardiac and 6 noncardiac trials included and 5 noninhalation and 5 inhalation agents as the comparator. A trend was noted when a subanalysis was performed with propofol as a comparator (1/544 [0.2%] v 6/546 [1.1%], p = 0.05, with 16 studies included). Isoflurane reduced mortality in high-quality studies and showed a trend toward a reduction in mortality when it was compared with propofol. No differences in the rates of overall mortality and myocardial infarction were noted.


[Hormonal modifications induced by food intake contribute to the regulation of the body weight and to metabolic variations].
In the rat the energy content of the body is subject to homeostatic control. The level of energy content depends on internal and external conditions. In the adult individual food intake is matched exactly to energy expenditure. Food intake leads to profound alterations in several hormonal plasma levels affecting metabolism e.g. insulin, glucagon and catecholamines. These hormones play an important feedback role in the storage and depletion of reserve tissues such as liver and fat cells. In this paper it is discussed that messages reporting energy content of the body may influence feeding motivation and that the CNS and especially the hypothalamus plays a directing role in this respect. Among these motivation setting messages the pancreatic hormones insulin and glucagon may be prominent factors in respectively long- and short-term regulation of food intake.


Heart murmurs auscultation as professional learning problems.
To compare the effectiveness of traditional and innovative methods of training for heart auscultation in medical students, physicians, and medical teachers, to find out the major reasons of the deficient auscultative skills, and to determine a place and significance of alternative methods of auscultation training. By principle of other equal conditions, the comparison of traditional and algorithmic diagnostics by the same auscultative signs in textual tasks, magnetic sound records and heart auscultation of patients. The independent diagnostics has been reflected the results of usual medical education. The same data have been used by the same examinees for diagnostics by original innovative diagnostic algorithm of heart auscultation, and programmed training. Murmurs diagnostics on magnetic recording was erroneous frequently. For reliable diagnostics of acoustic phenomena is needed the constant feedback, and much more time, than is scheduled in standard curriculum. Conventional training for heart auscultation is ineffective. Auscultation skills acquired by medical students do not grow up during their program of study. Even graduated cardiologists and instructors clinicians themselves make frequent errors in diagnostics of heart murmurs. The proposed diagnostic algorithm decreases the number of errors many times. The programmed teaching with constant feedback is the optimal method for flawless recognition of acoustic signs.


[Autoimmune encephalitis. Anti-NMDA receptor and new immunophenotypes].
Autoimmune encephalitis (AE) is defined as neurological syndromes of subacute installation of compromise of consciousness, alteration of working memory and psychiatric disorders associated with abnormal movements and epileptic seizures and that are produced by the action of anti-neuronal antibodies. They bind to neurotransmitter receptors or membrane proteins. Antibody to NMDAR is the origin of the majority of cases of AD in children and young adults, followed by anti-LGI1 antibody for presentation in adults. The AE has increased in the last decade, with a large number of new agents described that produce mostly neurological syndromes that involve the central nervous system, with predominance of psychiatric signaling, except in children and the predominant abnormal movements, epileptic seizures and compromise of conscience. They are frequently associated with tumors in adults but in children this association is more infrecuent. All AEs respond to immunomodulatory therapy although in different measures depending on the type of antibody involved. In general, the evolution to improvement is slow and can be completed in months or even in one year or more. In this review, the main EA clinical pictures related to specific antibodies are highlighted, also mentioning recently discovered immunophenotypes.


Effects of resource constraint on health care services.
Starting with the duty of Governments to provide adequate resources for the establishment and development of health services, this paper draws on experiences in four developed countries to illustrate the problems and their outcomes. The examples chosen demonstrate the contrast in philosophies and approach to resource allocation for health care.


Synthesis and biological evaluation of memantine nitrates as a potential treatment for neurodegenerative diseases.
A series of memantine nitrate derivatives, as dual functional compounds with neuroprotective and vasodilatory activity for neurodegenerative diseases, was designed and synthesized. These compounds combined the memantine skeleton and a nitrate moiety, and thus inhibited the N-methyl-d-aspartic acid receptor and released NO in the central nervous system. The biological evaluation results revealed that the new memantine nitrates were effective in protecting neurons against glutamate-induced injury in vitro. Moreover, memantine nitrates dilated aortic rings against phenylephrine-induced contraction. The structure-activity relationships of neuroprotection and vasodilation were both analyzed. In further studies, compound MN-05 significantly protected cortical neurons by inhibiting Ca2+ influx, reducing free radical production and maintaining the mitochondrial membrane potential. Further research on MN-05 is warranted.


Preparative isolation and purification of alkannin/shikonin derivatives from natural products by high-speed counter-current chromatography.
Alkannin and shikonin (A/S) and their derivatives have been found in the roots of several Boraginaceous species and are also produced through plant tissue cultures. The chiral compounds A/S are potent pharmaceutical substances with a wide spectrum of biological and pharmacological activities like wound healing, antimicrobial, anti-inflammatory, anticancer and antioxidant activity. High-speed counter-current chromatography (HSCCC) was applied for the first time to the separation, preparative isolation and purification of A/S and their esters from extracts of Alkanna tinctoria roots, as well as commercial samples. The constituents of HSCCC fractions and their purity were determined by high-performance liquid chromatography-diode array detection-mass spectrometry (HPLC-DAD-MS), since DAD cannot detect oligomeric A/S derivatives that are present in most of the samples containing the respective monomeric derivatives. The purity of HSCCC fractions was compared with the one of fractions isolated by column chromatography (CC) using as stationary phases silica gel and Sephadex LH-20. As shown, the purity of monomeric alkannin/shikonin was greater by HSCCC than CC separation of commercial A/S samples.


Epidemiology of Weaning Outcome according to a New Definition. The WIND Study.
The weaning process concerns all patients receiving mechanical ventilation. A previous classification into simple, prolonged, and difficult weaning ignored weaning failure and presupposed the use of spontaneous breathing trials. To describe the weaning process, defined as starting with any attempt at separation from mechanical ventilation and its prognosis, according to a new operational classification working for all patients under ventilation. This was a multinational prospective multicenter observational study over 3 months of all patients receiving mechanical ventilation in 36 intensive care units, with daily collection of ventilation and weaning modalities. Pragmatic definitions of separation attempt and weaning success allowed us to allocate patients in four groups. A total of 2,729 patients were enrolled. Although half of them could not be classified using the previous definition, 99% entered the groups on the basis of our new definition as follows: 24% never started a weaning process, 57% had a weaning process of less than 24 hours (group 1), 10% had a difficult weaning of more than 1 day and less than 1 week (group 2), and 9% had a prolonged weaning duration of 1 week or more (group 3). Duration of ventilation, intensive care unit stay, and mortality (6, 17, and 29% for the three groups, respectively) all significantly increased from one group to the next. The unadjusted risk of dying was 19% after the first separation attempt and increased to 37% after 10 days. A new classification allows us to categorize all weaning situations. Every additional day without a weaning success after the first separation attempt increases the risk of dying.


[Preventive screening in Child Health Services].
Early detection in the framework of secondary prevention is an important task, although not the only one, of youth health care, 'the preventive and socio-medical complement of curative medicine'. The primary aim of youth health care is 'promoting and protecting health, growth and development of children and youths'. Periodic health examinations (PHE'S) are an effective and efficient mean to this end. Like all medical consultations PHE is characterised by the integration of its two components: the analysis which focuses on the individual child and its environment (history and physical examination) and the synthesis (general health education and specific counseling). Moreover PHE provides the basis for epidemiological research, collective health education and policy-planning. Complementary examination of a child, usually less extensive than PHE, is executed on the basis of an individual indication. For practical reasons groups of children may be examined in screening-programs. It is preferable to incorporate screening results in the total medical assessment, which is the result of a series of individual PHE'S. Fractionated and isolated screening-programs are not in accordance with the intrinsic value of youth health care. Therefore an integral approach of the child and its environment demands the maximum incorporation into the PHE of systematic and standardized methods of examination. The concept of the 'group at risk' threatens to supplant the search for the 'child at risk'. Collective health education programs are supplementary to individual counseling and health education, but cannot replace the latter.(ABSTRACT TRUNCATED AT 250 WORDS)


[Esthetic repair of crown margins with composite. A case report].
Gingival recessions can cause severe aesthetical problems, especially when associated with the exposure of the margin of crown or bridge restorations. When complete root coverage can not be achieved by periodontal surgery techniques, prosthetic restorations are usually replaced to improve the aesthetic situation. This clinical report describes the application of a composite repair filling as an alternative technique to correct the restoration margin and cover the exposed root surface. From the published literature it is known that metallic and ceramic surfaces can be repaired adhesively using composite materials. This procedure is less costly and invasive, but provides satisfactorily aesthetic results.


Pharmacotherapy of cluster headache.
Cluster headache belongs to the trigemino-autonomic cephalgias and is one of the most devastating idiopathic pain syndromes. Despite its extreme severity and its prevalence of about 0.1%, little attention has been paid to this painful syndrome by either basic or clinical research. All clinical trials on the acute and prophylactic drug treatment of cluster headache are reviewed, including review articles and book chapters. The treatment of cluster headache is based on acute and prophylactic drug treatment. Oxygen inhalation, subcutaneous or intranasal sumatriptan, and intranasal zolmitriptan are recommended to stop an attach. For prophylaxis, verapamil is drug of first choice. Other drugs efficacious in cluster headache are steroids, lithium, some anticonvulsants and methysergide. Recently, interventional procedures have been studied for the treatment of refractory cluster headache. In the future, new anticonvulsants and unconventional ways of immunotherapy should be evaluated. In most cases, cluster headache can be treated sufficiently (i.e., with sufficient quality of life) by an individual concept of acute and prophylactic drug treatment.


MINERALS IN THE HUMAN BODY: Erionite and offretite from the Killdeer Mountains, Dunn County, North Dakota, U.S.A.
The carcinogenic potential of erionite has sparked concern about human exposure in areas where it is present in regional bedrock. The Arikaree Formation in western North Dakota contains altered tuffaceous units with authigenic zeolites. We sampled stratigraphic profiles in the Killdeer Mountains, Dunn County, North Dakota, to determine the distribution and chemical composition of zeolites. Powder X-ray diffraction, SEM/EDS and electron microprobe analyses were carried out on sample concentrates. Only samples stratigraphically in or below the distinctive burrowed marker unit were found to contain zeolites. Erionite and offretite were the most common zeolites identified, with offretite being more abundant based on frequency of measured Mg/(Ca+Na) ratios. Intermediate chemical compositions could be natural or due to intimate intergrowths of the two minerals. A better understanding is needed of the potential toxicity across the range of erionite and offretite compositions.


Effectiveness of an education programme by a general practice assistant for asthma and COPD patients: results from a randomised controlled trial.
In this study a randomised controlled trial was carried out to investigate the effectiveness of an education programme for patients with asthma or chronic obstructive pulmonary disease (COPD). All asthma and COPD patients using medication and experiencing pulmonary symptoms were randomly assigned to the intervention (n=139) or usual-care group (n=137). The intervention consisted of taylor-made education conducted by a general practice assistant and focussing on a patients' technical skills and coping with the disease. Measurements took place at baseline, and after 1 and 2 years of follow-up. After 1 and 2 years the inhalation technique was significantly better in the intervention group compared to the usual-care group. No significant differences were observed regarding disease symptoms, health related quality of life, compliance, smoking cessation, self-efficacy, and coping. The results only support the implementation of the intervention regarding the technical skills (inhalation technique). However, given the importance of improvement of patients' coping and the need for more efficient care, we recommend further exploration of the possibilities of a more structured and intensive education programme.


Piperlongumine as a potential activator of AMP-activated protein kinase in HepG2 cells.
AMP-activated protein kinase (AMPK) is a key regulator of fatty acid biosynthesis and fatty acid oxidation throughout the body. Piperlongumine (PL) isolated from Piper longum (L.) was shown to potently upregulate activation of AMPK via phosphorylation and inactivation of acetyl-CoA carboxylases in cultured HepG2 cells, presumably enhancing the transfer of fatty acids into mitochondrial cells by inhibiting malonyl-CoA production. PL showed cytotoxicity on HepG2 cell growth at the concentration of 5 μM of PL, while more than 80% of HepG2 cells were survived at the concentration of 2 μM of PL. Overall, the results of this study indicate that PL activates AMPK phosphorylation and possesses cytotoxicity in HepG2 cells.