Monogenic Diabetes: From Genetic Insights to Population-Based Precision in Care. Reflections From a Diabetes Care Editors' Expert Forum.
Individualization of therapy based on a person's specific type of diabetes is one key element of a "precision medicine" approach to diabetes care. However, applying such an approach remains difficult because of barriers such as disease heterogeneity, difficulties in accurately diagnosing different types of diabetes, multiple genetic influences, incomplete understanding of pathophysiology, limitations of current therapies, and environmental, social, and psychological factors. Monogenic diabetes, for which single gene mutations are causal, is the category most suited to a precision approach. The pathophysiological mechanisms of monogenic diabetes are understood better than those of any other form of diabetes. Thus, this category offers the advantage of accurate diagnosis of nonoverlapping etiological subgroups for which specific interventions can be applied. Although representing a small proportion of all diabetes cases, monogenic forms present an opportunity to demonstrate the feasibility of precision medicine strategies. In June 2019, the editors of Diabetes Care convened a panel of experts to discuss this opportunity. This article summarizes the major themes that arose at that forum. It presents an overview of the common causes of monogenic diabetes, describes some challenges in identifying and treating these disorders, and reports experience with various approaches to screening, diagnosis, and management. This article complements a larger American Diabetes Association effort supporting implementation of precision medicine for monogenic diabetes, which could serve as a platform for a broader initiative to apply more precise tactics to treating the more common forms of diabetes.


Time series-based hybrid ensemble learning model with multivariate multidimensional feature coding for DNA methylation prediction.
DNA methylation is a form of epigenetic modification that impacts gene expression without modifying the DNA sequence, thereby exerting control over gene function and cellular development. The prediction of DNA methylation is vital for understanding and exploring gene regulatory mechanisms. Currently, machine learning algorithms are primarily used for model construction. However, several challenges remain to be addressed, including limited prediction accuracy, constrained generalization capability, and insufficient learning capacity. In response to the aforementioned challenges, this paper leverages the similarities between DNA sequences and time series to introduce a time series-based hybrid ensemble learning model, called Multi2-Con-CAPSO-LSTM. The model utilizes multivariate and multidimensional encoding approach, combining three types of time series encodings with three kinds of genetic feature encodings, resulting in a total of nine types of feature encoding matrices. Convolutional Neural Networks are utilized to extract features from DNA sequences, including temporal, positional, physicochemical, and genetic information, thereby creating a comprehensive feature matrix. The Long Short-Term Memory model is then optimized using the Chaotic Accelerated Particle Swarm Optimization algorithm for predicting DNA methylation. Through cross-validation experiments conducted on 17 species involving three types of DNA methylation (6 mA, 5hmC, and 4mC), the results demonstrate the robust predictive capabilities of the Multi2-Con-CAPSO-LSTM model in DNA methylation prediction across various types and species. Compared with other benchmark models, the Multi2-Con-CAPSO-LSTM model demonstrates significant advantages in sensitivity, specificity, accuracy, and correlation. The model proposed in this paper provides valuable insights and inspiration across various disciplines, including sequence alignment, genetic evolution, time series analysis, and structure-activity relationships.


The impact of self-reported oligo-amenorrhea and hirsutism on fertility and lifetime reproductive success: results from the Northern Finland Birth Cohort 1966.
To what extent do self-reported oligo-amenorrhea and hirsutism affect reproductive performance (childlessness, age at first delivery, family size and miscarriage rates)? At the age of 44, among women with both self-reported oligo-amenorrhea and hirsutism the prevalence of childlessness was not significantly different from non-symptomatic women but they had a smaller family size than non-symptomatic women. Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by oligo-amenorrhea or amenorrhea, hyperandrogenism and hirsutism and it is the most frequent cause of anovulatory infertility, but there are few studies on the reproductive capacity of women with PCOS. In our previous population-based cohort study the women with self-reported oligo-amenorrhea and hirsutism were found to have more infertility problems and smaller family size than non-symptomatic women at the age of 31. A prospective population-based cohort study. The population of the study is derived from the prospective Northern Finland Birth Cohort 1966 (NFBC1966), comprising all expected births from the year 1966 in the two northernmost provinces of Finland (n = 12 058). Of them, 5889 were females. Enrollment in this database begun at the 24th gestational week and so far data have been collected from the subjects at the ages of 1, 14 and 31 years. A postal questionnaire including questions about oligo-amenorrhea and hirsutism was sent to all women at the age of 31 (n = 5608, response rate 81%, n = 4535) and a clinical examination was performed (attendance rate 76.5%). Those who reported both hirsutism and oligo-amenorrhea were defined as women with both symptoms (n = 153). Data on pregnancies/deliveries were obtained from the Finnish Medical Birth Register (FMBR) in 2010 when the women were 44 years old. Women with both symptoms had delivered at least one child as often as non-symptomatic women [75.2 versus 79.0%, adjusted odds ratio (OR) 0.86, 95% confidence intervals (CI) 0.57-1.30], were of similar age [mean (SD)] at first delivery [27.7 (4.81) versus 27.3 (4.71)] and had similar incidence of miscarriages. However, non-symptomatic women had more often ≥2 deliveries (61.6 versus 52.9%, adjusted OR 0.70, 95% CI 0.49-1.00, P = 0.048) and had larger family size [mean (SD)] [2.4 (1.4) versus 1.9 (0.8), P < 0.001]. Women with both symptoms had been treated more often for infertility than non-symptomatic women (6.1 versus 2.4%, adjusted OR 2.74, 95% CI 1.14-6.60, P = 0.024). The diagnosis of oligo-amenorrhea and hirsutism was based on a questionnaire, suggesting a risk of information bias in reporting the symptoms. However, we have previously shown that self-reported oligo-amenorrhea and hirsutism can distinguish most women with the typical profile of PCOS. Only the women who had delivered at least once were recorded in the FMBR, thus excluding from the study those who had experienced miscarriages and/or infertility treatments but did not have a live birth. This feature could potentially decrease the differences in incidence of miscarriages and/or infertility treatment between symptomatic and non-symptomatic subjects. This is one of the few studies, in which the impact of self-reported oligo-amenorrhea and hirsutism on lifetime reproductive success can be measured. Our results suggest that even at more advanced age, women with both symptoms do not quite match the parity of healthy non-symptomatic women, and that infertility treatment does not always restore normal reproductive capacity in these women. Obese women with both symptoms had the worst prognostic as regards reproduction, which emphasizes the importance of life intervention and preventive politics against obesity in this group of women. This work was supported by grants from the Finnish Medical Society Duodecim, the North Ostrobothnia Regional Fund, the Academy of Finland, University Hospital Oulu, Biocenter, University of Oulu, Finland, the European Commission and the Medical Research Council, UK, the National Institute for Health Research (NIHR). None of the authors has any conflict of interest to declare.


Opacification of lenses cultured in the presence of Pb.
Occupational and environmental Pb-exposure is associated with protein aggregation diseases which typically present in elderly populations (Parkinsons and cataract). Post-translational processing of crystallins, the major structural proteins of the lens, is altered with short-term Pb-exposure in Fisher 344 rats. In addition, lenses from aged rats become opaque upon long-term exposure to Pb in organ culture. To explore the route to lens opacification in the presence of Pb, cultured lenses from young rats which exhibit higher metabolic activity in lens culture and are more susceptible to experimental cataract in vivo and in vitro were exposed to Pb and evaluated for morphological and biochemical alterations. Following culture in Pb (as lead nitrate) for four days (in the presence/absence of oxidative challenge), lenses were examined for clarity, integrity of epithelial layer, and molecular stability including crystallin post-translational modification and choline transport. Clarity of lenses cultured with/without Pb for up to 8 days was assessed to determine if Pb exposure would accelerate opacification. Lenses cultured in Pb for four days exhibited epithelial abnormalities including epithelial cell multilayering and nuclei abnormalities with extension of the nucleated epithelial cells past the bow region. Alterations in crystallin post-translational modifications and decreased membrane transport of choline were noted without corresponding lens opacification or altered α-crystallin chaperone activity. Lenses treated with Pb according to the same exposure protocol with subsequent challenge by hydrogen peroxide became opaque while the contralateral control lenses did not. Lenses which were cultured in the presence of Pb for longer periods with no subsequent oxidative insult exhibited lens failure at earlier time points than did the controls. These data indicate that Pb-exposure can accelerate the degradation of the cultured lens through induction of epithelial cell abnormalities, induce structural protein modifications before opacity, and predispose the lens to opacification with subsequent oxidant challenge.


Genome-scan for loci involved in cleft lip with or without cleft palate in consanguineous families from Turkey.
Cleft lip with or without cleft palate (CL/P) is a common congenital anomaly, with birth prevalence ranging from 1/500 to 1/1,000. A number of genetic loci have shown positive linkage or association results in European Caucasian populations. The purpose of the current study was to assess whether any of those loci have positive results in Turkish Caucasian CL/P families, and to perform a 10 cM genome scan to identify other regions potentially containing cleft susceptibility loci. Eighteen affected individuals with consanguineous parents were identified as part of our on-going studies of orofacial clefts in Ankara, Turkey. Genotyped were 383 genome-scan markers, and 70 additional markers, including markers in six candidate loci or regions on chromosomes 2, 4, 6, 14, 17, and 19 (TGFA, D4S175, F13A1, TGFB3, D17S250, and APOC2) that have been implicated in other studies of families with orofacial clefting. LOD scores (two point and multiple point) and family-based association statistics (TDT) were calculated between each of the markers and CL/P. For the LOD score calculations, an autosomal recessive model was assumed for the inheritance of CL/P. Of the six candidate markers, significant TDT results were obtained with TGFA (P = 0.05). The most statistically significant multipoint results from the linkage genome scan were between putative genes controlling risk of CL/P and regions on chromosomes 4, 10, 12, and 15 (maximum multipoint HLOD's of 1.25, 1.30, 2.73, and 1.28 respectively). These results demonstrate the power of small numbers of families with inbred probands to detect linkage and association.


Design of a modular and low-latency virtual-environment platform for applications in motor adaptation research, neurological disorders, and neurorehabilitation.
We have developed a modular virtual environment platform for movement research and rehabilitation. The system uses several networked computers running Linux to share computation. An electromagnetic tracker is the primary position tracker and both a head-mounted display and stereo goggles are used for visual display. System software is written in a combination of C++, JAVA, and Python and makes considerable use of the open-source toolkits VR Juggler and OpenSceneGraph. These are integrated with additional toolkits and custom modules written specifically for the study of motor control and rehabilitation. The system performs well with low latency, accurate calibration, and a consistently high graphics update rate. Preliminary applications have confirmed that the system is a powerful tool for sensory-motor investigation and has considerable potential as a tool for neurorehabilitation. Its primary advantage over other systems is its ability to utilize different display and input devices, and run a range of experiments simply by changing XML configuration files. Additionally, the use of powerful open-source libraries provides a feature-rich foundation for advanced features and low-cost duplication. Further work and experiments are needed to extend, further validate, and fully utilize this platform.


Quality of reporting of multivariable logistic regression models in Chinese clinical medical journals.
Multivariable logistic regression (MLR) has been increasingly used in Chinese clinical medical research during the past few years. However, few evaluations of the quality of the reporting strategies in these studies are available.To evaluate the reporting quality and model accuracy of MLR used in published work, and related advice for authors, readers, reviewers, and editors.A total of 316 articles published in 5 leading Chinese clinical medical journals with high impact factor from January 2010 to July 2015 were selected for evaluation. Articles were evaluated according 12 established criteria for proper use and reporting of MLR models.Among the articles, the highest quality score was 9, the lowest 1, and the median 5 (4-5). A total of 85.1% of the articles scored below 6. No significant differences were found among these journals with respect to quality score (χ = 6.706, P = .15). More than 50% of the articles met the following 5 criteria: complete identification of the statistical software application that was used (97.2%), calculation of the odds ratio and its confidence interval (86.4%), description of sufficient events (>10) per variable, selection of variables, and fitting procedure (78.2%, 69.3%, and 58.5%, respectively). Less than 35% of the articles reported the coding of variables (18.7%). The remaining 5 criteria were not satisfied by a sufficient number of articles: goodness-of-fit (10.1%), interactions (3.8%), checking for outliers (3.2%), collinearity (1.9%), and participation of statisticians and epidemiologists (0.3%). The criterion of conformity with linear gradients was applicable to 186 articles; however, only 7 (3.8%) mentioned or tested it.The reporting quality and model accuracy of MLR in selected articles were not satisfactory. In fact, severe deficiencies were noted. Only 1 article scored 9. We recommend authors, readers, reviewers, and editors to consider MLR models more carefully and cooperate more closely with statisticians and epidemiologists. Journals should develop statistical reporting guidelines concerning MLR.


Molecular and functional characterization of a novel low-affinity cation transporter (LCT1) in higher plants.
The transport of cations across membranes in higher plants plays an essential role in many physiological processes including mineral nutrition, cell expansion, and the transduction of environmental signals. In higher plants the coordinated expression of transport mechanisms is essential for specialized cellular processes and for adaptation to variable environmental conditions. To understand the molecular basis of cation transport in plant roots, a Triticum aestivum cDNA library was used to complement a yeast mutant deficient in potassium (K+) uptake. Two genes were cloned that complemented the mutant: HKT1 and a novel cDNA described in this report encoding a cation transporter, LCT1 (low-affinity cation transporter). Analysis of the secondary structure of LCT1 suggests that the protein contains 8-10 transmembrane helices and a hydrophilic amino terminus containing sequences enriched in Pro, Ser, Thr, and Glu (PEST). The transporter activity was assayed using radioactive isotopes in yeast cells expressing the cDNA. LCT1 mediated low-affinity uptake of the cations Rb+ and Na+, and possibly allowed Ca2+ but not Zn2+ uptake. LCT1 is expressed in low abundance in wheat roots and leaves. The precise functional role of this cation transporter is not known, although the competitive inhibition of cation uptake by Ca2+ has parallels to whole plant and molecular studies that have shown the important role of Ca2+ in reducing Na+ uptake and ameliorating Na+ toxicity. The structure of this higher plant ion transport protein is unique and contains PEST sequences.


[History of sciatica].
The long history of sciatica is recalled from the 18th century observations through the contributions of Lasègue (a philosopher who worked with Claude Bernard), Valleix, Brissaud, Dejerine, Sicard, Forestier, Alajouanine and Petit-Dutaillis. Two papers by professor de Sèze on the significance of herniations of lumbar disks were published in December 1939 and June 1940, a most unfavourable period in France. Since then many advances are to be recorded among which the use of metrizamide instead of the old lipiodol and, most of all, the advent of CT Scan.


Observers for Phenomenological Models of Epileptic Seizures.
Progress towards effective treatment of epileptic seizures has seen much improvement in the past decade. In particular, the emergence of phenomenological models of epileptic seizures specifically designed to capture the electrical seizure dynamics in the Epileptor model is inspiring new approaches to predicting and controlling seizures. These new models present in various forms and contain important but unmeasurable variables that control the occurrence of seizures. These models have been used mostly as nodes in large networks to study the complex brain behaviour of seizures. In order to use this model for the purposes of seizure forecasting or to control seizures through deep brain stimulation, the states of the model will need to be estimated. Although devices such as EEG electrodes can be related to some of the states of the model, most remain unmeasured and would require an observer (as defined in control theory) for their estimation. Additionally, we would like to consider the case for large nodes of systems where the number of electrodes is far smaller than the number of nodes being estimated. In this paper, we provide methods towards obtaining the full states of these phenomenological models using nonlinear observers. In particular, we explore the effectiveness of the Extended Kalman Filter for small networks of nodes of a smoothed sixth order Epileptor model. We show that observer design is possible for this family of systems and identify the difficulties in doing so.Clinical relevance-The methods presented here can be applied with an individual epileptic patient's EEG to reveal previously hidden biomarkers of epilepsy for seizure forecasting.


[Simultaneous occurrence of hereditary angioneurotic edema and Crohn disease].
Hereditary C1 esterase inhibitor deficiency is often associated with immunpathologic disorders. The authors present a case of the rare coincidence of hereditary angioedema (HAE) and Crohn's disease. The history of the patient is analysed along with the familial occurrence of the disease. Characteristic abdominal manifestations of C1 esterase inhibitor deficiency are compared to the clinical signs of Crohn's disease. Differential diagnostic pitfalls are described along with efficatious therapeutic options.


Study protocol for a randomised controlled trial of internet-based cognitive-behavioural therapy for obsessive-compulsive disorder.
Obsessive-Compulsive Disorder (OCD) is a common chronic psychiatric disorder that constitutes a leading cause of disability. Although Cognitive-Behaviour Therapy (CBT) has been shown to be an effective treatment for OCD, this specialised treatment is unavailable to many due to access issues and the social stigma associated with seeing a mental health specialist. Internet-based psychological treatments have shown to provide effective, accessible and affordable treatment for a range of anxiety disorders, and two Randomised Controlled Trials (RCTs) have demonstrated the efficacy and acceptability of internet-based CBT (iCBT) for OCD, as compared to waitlist or supportive therapy. Although these initial findings are promising, they do not isolate the specific effect of iCBT. This paper details the study protocol for the first randomised control trial evaluating the efficacy of therapist-assisted iCBT for OCD, as compared to a matched control intervention; internet-based therapist-assisted progressive relaxation training (iPRT). It will aim to examine whether therapist-assisted iCBT is an acceptable and efficacious treatment, and to examine how effectiveness is influenced by patient characteristics. A randomised controlled trial using repeated measures with two arms (intervention and matched control) will be used to evaluate the efficacy and acceptability of iCBT for OCD. The RCT will randomise 212 Australian adults with a primary diagnosis of OCD into either the active intervention or control condition, for 12 weeks duration. Outcomes for participants in both study arms will be assessed at baseline and post-intervention. Participants in iCBT will be further assessed at six month follow-up, while participants in the control condition will be crossed over to receive the iCBT intervention and reassessed at post-intervention and six month follow-up. The primary outcome will be clinically significant change in obsessive-compulsive symptom scores. This will be the first known therapist assisted internet-based trial of a comprehensive CBT treatment for OCD as compared to a matched control intervention. Demonstrating the efficacy of an internet-based treatment for OCD will allow the development of models of care for broad-based access to an evidence-based but complex treatment.


Delayed Hospital Presentation and Neuroimaging in Non-surgical Spinal Cord Infarction.
Lack of timely recognition and neuroimaging may be a barrier to reperfusion efforts in acute spinal cord infarction. We performed a retrospective study of patients diagnosed with acute non-surgical spinal cord infarction at our tertiary academic center from 2001 to 2015. We studied parameters associated with time from symptom onset to initial hospital presentation and magnetic resonance imaging (MRI) of the spinal cord. We identified 39 patients among whom anterior spinal artery syndrome was the most frequent presentation (87.2%) and atherosclerosis the most common etiology (56.4%). Nearly, half of the patients presented to the emergency department on the same day of symptom onset (48.7%) but only nine (23.1%) within the first 6 h. Average time from symptom onset to spinal cord MRI was 3.2 days. We could not identify clinical, radiological, or outcome patterns associated with early vs. delayed presentation and imaging. Our study found a time lag from symptom onset to hospital presentation and spinal cord MRI in patients with acute spinal cord infarction. These findings point at low clinical suspicion of spinal cord syndromes and limited recognition as a potentially treatable medical emergency.


Inoculum effect of beta-lactam antibiotics on Enterobacteriaceae.
Seven beta-lactam antibiotics were studied for both their antimicrobial activity and the degree to which they produced inoculum effect on Escherichia coli, Klebsiella pneumoniae, and Salmonella typhimurium. Aztreonam, cefoperazone, and ceftazidime were poorly bactericidal, caused marked bacterial filamentation, and exhibited a large inoculum effect on E. coli, K. pneumoniae, and S. typhimurium. Cefotaxime and ceftriaxone were more rapidly bactericidal, caused only a moderate amount of filamentous forms, and exhibited a modest inoculum effect, while cefoxitin and imipenem both were rapidly bactericidal and exhibited only a minimal-to-no-inoculum effect. The inoculum effect did not correlate with drug stability during incubation with the bacteria. Inoculum effect on these species of the family Enterobacteriaceae appears to be a manifestation of increase in optical density secondary to the development of filamentous bacterial forms with an increase in bacterial mass during exposure to antibiotics which are not rapidly bactericidal. These observations have a clear significance for the susceptibility testing of beta-lactam antibiotics when turbidity is used as a parameter to determine presence of bacterial growth.


The effect of defects and disorder on the electronic properties of ZnIr2O4.
We analyze by means of ab initio calculations the role of imperfections on the electronic structure of ZnIr2O4, ranging from point defects in the spinel phase to the fully amorphous phase. We find that interstitial defects and anion vacancies in the spinel have large formation energies, in agreement with the trends observed in other spinels. In contrast, cation vacancies and antisites have lower formation energies. Among them, the zinc antisite and the zinc vacancy are the defects with the lowest formation energy. They are found to act as acceptors, and may be responsible for the spontaneous hole doping in the material. They may also induce optical transitions that would reduce the transparency of the material. Amorphization of ZnIr2O4 leads a large decrease of the band gap and appearance of localized states at the edges of the band gap region, which may act as charge traps and prevent amorphous ZnIr2O4 from being a good hole conductor.


Sodium ion diffusion in Al2O3: a distinct perspective compared with lithium ion diffusion.
Surface coating of active materials has been one of the most effective strategies to mitigate undesirable side reactions and thereby improve the overall battery performance. In this direction, aluminum oxide (Al2O3) is one of the most widely adopted coating materials due to its easy synthesis and low material cost. Nevertheless, the effect of Al2O3 coating on carrier ion diffusion has been investigated mainly for Li ion batteries, and the corresponding understanding for emerging Na ion batteries is currently missing. Using ab initio molecular dynamics calculations, herein, we first find that, unlike lithiation, sodiation of Al2O3 is thermodynamically unfavorable. Nonetheless, there can still exist a threshold in the Na ion content in Al2O3 before further diffusion into the adjacent active material, delivering a new insight that both thermodynamics and kinetics should be taken into account to describe ionic diffusion in any material media. Furthermore, Na ion diffusivity in NaxAl2O3 turns out to be much higher than Li ion diffusivity in LixAl2O3, a result opposite to the conventional stereotype based on the atomic radius consideration. While hopping between the O-rich trapping sites via an Na-O bond breaking/making process is identified as the main Na ion diffusion mechanism, the weaker Na-O bond strength than the Li-O counterpart turns out to be the origin of the superior diffusivity of Na ions.


Medical and obstetric complications among pregnant women aged 45 and older.
The number of women aged 45 and older who become pregnant is increasing. The objective of this study was to estimate the risk of medical and obstetric complications among women aged 45 and older. The Nationwide Inpatient Sample was used to identify pregnant woman during admission for delivery. Deliveries were identified using International Classification of Diseases, Ninth Revision (ICD-9-CM) codes. Using ICD-9-CM codes, pre-existing medical conditions and medical and obstetric complications were identified in women at the time of delivery and were compared for women aged 45 years and older to women under age 35. Outcomes among women aged 35-44 were also compared to women under age 35 to determine if women in this group demonstrated intermediate risk between the older and younger groups. Logistic regression analyses were used to calculate odds ratios with 95% confidence intervals for pre-existing medical conditions and medical and obstetric complications for both older groups relative to women under 35. Multivariable logistic regression analyses were also developed for outcomes at delivery among older women, while controlling for pre-existing medical conditions, multiple gestation, and insurance status, to determine the effect of age on the studied outcomes. Women aged 45 and older had higher adjusted odds for death, transfusion, myocardial infarction/ischemia, cardiac arrest, acute heart failure, pulmonary embolism, deep vein thrombosis, acute renal failure, cesarean delivery, gestational diabetes, fetal demise, fetal chromosomal anomaly, and placenta previa compared to women under 35. Pregnant women aged 45 and older experience significantly more medical and obstetric complications and are more likely to die at the time of a delivery than women under age 35, though the absolute risks are low and these events are rare. Further research is needed to determine what associated factors among pregnant women aged 45 and older may contribute to these findings.


Autoantibodies that stabilize U1snRNP are a significant component of human autoantibodies to snRNP and delay proteolysis of sm antigens in vitro.
Autoantibodies to U1-C have been considered a minor component of anti-snRNP (nRNP, Sm) response based on Western blotting. However, we have previously shown that virtually all human anti-nRNP sera contain antibodies to native U1-C, as well as novel autoantibodies that stabilize the molecular interaction of the U1-C-Sm core particle. The biological significance of stabilizing antibodies was investigated by titering anti-U1-C/U1-A compared to stabilizing antibodies, and by examining the effects of stabilizing antibodies on antigen processing. Autoantibodies to individual native components of U1snRNP (immunoprecipitation of RNase-treated cell extract) and stabilizing antibodies (dissociation of snRNP on anti-Sm monoclonal antibodies by 1 M MgCl2) in human autoimmune sera were titered. Effects of stabilizing antibodies on proteolysis were assessed by incubating UsnRNP with anti-snRNP/Sm autoimmune sera prior to protease digestion. Autoantibodies to native U1-C and U1-C-Sm core particle stabilizing antibodies were universally present in human anti-nRNP or anti-nRNP + anti-Sm sera, but not in anti-Sm sera. Antibodies to U1-A were less common. The titers of stabilizing antibodies were higher than those of antibodies to U1-C (p < 0.01), indicating that the stabilizing antibodies were a significant component of the anti-snRNP response. The stabilizing anti-nRNP, but not anti-Sm antibodies, protects the Sm core particle from dissociation and proteolysis. Autoantibodies stabilizing the U1-C-Sm core particle were universally present in anti-nRNP sera and delay proteolysis of the Sm core particle. They may suppress spreading of the autoimmune response to Sm by delaying or altering processing of the Sm core proteins by antigen-presenting cells.


Susceptibility of Toxoplasma gondii to autophagy in human cells relies on multiple interacting parasite loci.
Autophagy is a process used by cells to recycle organelles and macromolecules and to eliminate intracellular pathogens. Previous studies have shown that some stains of Toxoplasma gondii are resistant to autophagy-dependent growth restriction, while others are highly susceptible. Although it is known that autophagy-mediated control requires activation by interferon gamma, the basis for why parasite strains differ in their susceptibility is unknown. Our findings indicate that susceptibility involves at least five unlinked parasite genes on different chromosomes, including several secretory proteins targeted to the parasite-containing vacuole and exposed to the host cell cytosol. Our findings reveal that susceptibility to autophagy-mediated growth restriction relies on differential recognition of parasite proteins exposed at the host-pathogen interface, thus identifying a new mechanism for cell-autonomous control of intracellular pathogens.


Association of parathyroid adenoma and pregnancy with preeclampsia.
Case reports have described associations between calcium metabolism disturbances and primary hyperparathyroidism with preeclampsia, suggesting parathyroid involvement in preeclampsia etiology. This study examines whether parathyroid adenoma, the main cause of hyperparathyroidism, diagnosed and treated before pregnancy is associated with preeclampsia. We conducted a register-based study to assess the association between parathyroid adenoma and subsequent preeclampsia. Births among Sweden's general population were studied. The study population included 52 women with a diagnosis of parathyroid adenoma and 519 without, all of whom had a subsequent singleton pregnancy between 1973 and 1997. We performed a conditional logistic regression investigating the association of parathyroid adenoma with subsequent preeclampsia in the first singleton pregnancy with adjustment for potential confounding factors. The main outcome was a diagnosis of preeclampsia that does not include women with prior chronic hypertension. To ensure that treatment of parathyroid adenoma was completed before pregnancy, those with a diagnosis of parathyroid adenoma made less than 2 yr before delivery (and the matched comparison women) were excluded. Statistically, parathyroid adenoma prior to delivery is significantly (P < 0.001) associated with preeclampsia, producing an adjusted odds ratio of 6.89 (95% confidence interval, 2.30, 20.58). A history of parathyroid adenoma should be viewed as a risk for preeclampsia.


Simplified bioassay method for measurement of flucytosine or ketoconazole.
A simple agar-well diffusion bioassay suitable for measurement of flucytosine or ketoconazole was developed by using Candida pseudotropicalis ATCC 46764 as the assay organism. A test medium composed of (per liter) 7 g of Trypticase peptone, 7 g of YNB (yeast-nitrogen base), 15 g of glucose, and 15 g of agar was seeded with an inoculum which had been grown to no. 2 McFarland turbidity after 4 to 6 h in YNB-glucose broth. Determinations of flucytosine or ketoconazole were performed without necessity of heating or diluting of serum samples to alleviate amphotericin B interference. A linear relationship between zone diameters and log10 concentration of the drugs was observed over the pharmacologically relevant ranges of 25 to 160 micrograms/ml for flucytosine and 0.5 to 20 micrograms/ml for ketoconazole. The mean coefficient of variability for samples measured on 5 separate days was 2.4% for flucytosin and 4.0% for ketoconazole. This assay represents a significant improvement over previous bioassay methods in that a single test system may be used for measurement of either flucytosine or ketoconazole, no serum dilution or pretreatment is required, inoculum preparation is accomplished entirely on the day of the assay, and sharp, clearly defined zones of inhibition are obtained with both drugs.


The making and transnationalization of an ethnic niche: Vietnamese manicurists.
The article addresses how Vietnamese immigrant women developed an urban employment niche in the beauty industry, in manicuring. They are shown to have done so by creating a market for professional nail care, through the transformation of nailwork into what might be called McNails, entailing inexpensive, walk-in, impersonal service, in stand-alone salons, nationwide, and by making manicures and pedicures de riguer across class and racial strata. Vietnamese are shown to have simultaneously gained access to institutional means to surmount professional manicure credentializing barriers, and to have developed formal and informal ethnic networks that fueled their growing monopolization of jobs in the sector, to the exclusion of non-Vietnamese. The article also elucidates conditions contributing to the Vietnamese build-up and transformation of the niche, to the nation-wide formation of the niche and, most recently, to the transnationalization of the niche. It also extrapolates from the Vietnamese manicure experience propositions concerning the development, expansion, maintenance, and transnationalization of immigrant-formed labor market niches.


Unusual breast cancers: useful clues to expanding the differential diagnosis.
Invasive ductal carcinoma and ductal carcinoma in situ account for about 85% of breast cancers. Unusual breast neoplasms may be broadly divided into invasive lobular carcinoma, well-differentiated subtypes of invasive ductal carcinoma, cancers of stromal origin, and metastatic neoplasms. Clues are often present in imaging characteristics, patient demographics, and/or clinical features that may suggest that the finding is not the usual type of breast cancer. Some rare malignancies also provide specific clues to their diagnosis. This review provides an overview of unusual and a few rare malignant breast neoplasms, highlighting particular or specific clinical or imaging findings that will enable residents to expand their differential diagnosis of breast lesions beyond invasive ductal carcinoma.


[Conjugative transfer and expression of R plasmids of the genus Pseudomonas in the cells of Pseudomonas mallei C-5].
Conjugative transfer of the incompatibility group plasmids Inc P-2, Inc P-3, Inc P-4 and Inc P-5 as well as the plasmids of Pseudomonas sp. of an unknown incompatibility group to the cells of Pseudomonas mallei C-5 was shown possible for the first time. The inheritance of the transferred plasmids and the expression of the markers of resistance to antibacterial drugs were stable. Clones with reserved virulence, lowered virulence and no virulence were detected among the transconjugants. The results of the immunization by the avirulent cells of P. mallei C-5 (RP4) were evident of low immunogenic capacity of the microbe.


Mitral valve billowing and prolapse: perspective at 25 years.
The syndrome of primary mitral leaflet billow, with or without prolapse, is associated with myxomatous degeneration of the mitral valve apparatus, mainly the posterior leaflet, and the syndrome may be familial. It manifests clinically with an isolated nonejection systolic click (billow), a murmur of mitral regurgitation that is usually late systolic (prolapse), or a combination of murmur and click. Echocardiography identifies and assesses the extent of the billowing of mitral leaflet bodies but there are no specific echocardiographic criteria that can differentiate normal from pathological billowing. Similarly, a prolapsed leaflet is not detected echocardiographically when there is localized and mild failure of leaflet edge apposition but a more severely prolapsed, or flail, leaflet can be demonstrated and confirmed by that technique. Symptoms of the syndrome include anxiety, chest pain and palpitations. The resting electrocardiogram may show ST segment and T wave abnormalities. The majority of patients have a benign course and require reassurance only. Complications include systemic emboli, infective endocarditis, progression to severe mitral regurgitation, arrhythmias and, rarely, sudden death. Patients with prolapse of a leaflet edge are more likely to develop complications than those with only billowing of the leaflet bodies. Surgery, preferably valvuloplasty, is required for severe regurgitation and may also be indicated for potentially lethal tachyarrhythmias unresponsive to medical therapy. Mitral leaflet billow and prolapse may be secondary to, or associated with, many conditions. The prognosis is then principally that of the underlying disease of which ischemic heart disease and hypertrophic cardiomyopathy are the most important.


Sarcoids in captive zebras (Equus burchellii): association with bovine papillomavirus type 1 infection.
Sarcoids were diagnosed in two captive zebras from different facilities. Zebra 1 (Equus burchellii boehmi) was a 4.5-yr-old, captive-born male that presented with a 9- by 7-cm inguinal mass. Seven months after surgical excision of the inguinal mass, the zebra presented with a similar lesion in the right upper eyelid that has relapsed repeatedly and has not responded to treatment including local cisplatin injections and cryosurgery. Zebra 2 (of undetermined taxon) was housed at a private wild animal farm. The zebra presented with a single, raised, 2.5- by 2.0- by 2.0-cm, ulcerated mass on the nose, and surgical excision was curative. Histologically, the three masses consisted of a dermal, compact, nonencapsulated, poorly demarcated neoplasm composed of well-differentiated spindle cells arranged in streams and whorls and accompanied by moderate epidermal hyperplasia with long rete pegs. On the basis of the morphologic resemblance to the unique equine cutaneous neoplasm, "sarcoid" was diagnosed. This is the first description of sarcoids in captive zebras. Association with bovine papillomavirus (BPV) type 1, as it occurs in horses, was demonstrated by polymerase chain reaction, nucleic acid sequencing, and in situ hybridization (ISH) on paraffin-embedded tissues from the inguinal mass of zebra 1. Sequencing revealed 98% identity of the 244-bp fragment with BPV type 1. The ISH for BPV type 1 DNA intensely stained the nuclei of neoplastic mesenchymal spindle cells. The sites and the clinical behavior of the sarcoids in these zebras are similar to those described in horses.


Net expansion of dried demineralized dentin matrix produced by monomer/alcohol saturation and solvent evaporation.
The purpose of this work was to determine if nonaqueous methacrylate monomer/alcohol mixtures could expand dried collapsed demineralized dentin matrix. Thin disks (ca. 200 microm) of human dentin were demineralized and placed in wells beneath contact probes of linear variable differential transformers. The probes were placed on water-saturated expanded matrices to record the shrinkage associated with drying. Monomer mixtures containing hydroxyethyl methacrylate, 2,2-bis[4-(2-hydroxy-3 methacryloyloxy)propoxyphenyl] propane, or triethyleneglycol dimethacrylate were mixed with methanol or ethanol at alcohol/monomer mass fraction % of 90/10, 70/30, 50/50, or 30/70. They were randomly applied to the dried matrices to determine the rate and magnitude of expansion; then shrinkage was recorded during evaporation of the alcohols. The results indicated that matrix expansion was positively correlated with the Hoy's solubility parameters for hydrogen bonding forces (delta(h)) of the monomer/solvent mixtures (p < 0.001). Expansions were more rapid with methanol-containing than with ethanol-containing monomer mixtures. For the test solutions, triethyleneglycol dimethacrylate-containing mixtures produced the slowest rate of matrix expansion and hydroxyethyl methacrylate-containing mixtures the most rapid expansion. When the solvents were evaporated, the matrix shrank in proportion to the solvent content and the delta(h) of the monomer-solvent mixtures. The results indicate that expansion of dried, collapsed dentin matrices requires that the delta(h) of the mixtures be larger than 17 (J/cm(3))(1/2). The greater the delta(h) of the monomer solutions, the greater the rate and extent of expansion.


Estimating blood flow velocity using time-resolved 3D angiography and a derived physical law of contrast media.
Four-dimensional (4D) digital subtraction angiography (DSA) offers a method for evaluating hemodynamics. It is, however, unclear how the delivered contrast medium interacts with the physiological blood flow, and how hemodynamic information may be inferred from the mixture of the contrast medium and blood. In this study, we present a theoretical explanation of contrast dynamics, and an accompanying algorithm for estimating blood flow velocity. We retrospectively recruited 23 patients who underwent both 4D DSA and magnetic resonance (MR) phase-contrast imaging. The 4D DSA-reconstructed contrast dynamics were first studied for the internal carotid arteries. Using physical laws governing fluid motion within a curved tube, we showed that the reconstructed contrast dynamics obeyed a simple advection equation. We then proposed an algorithm for estimating the contrast dynamics using angiographic data, and subsequently estimated the axial blood flow velocity using an advection equation. The estimated velocities were compared using three techniques: the Fourier technique, Lin's method, and MR phase contrast. Testing with noise-corrupted artificial data showed that the proposed algorithm was noise resistant. The velocities of 23 patients computed by 4D DSA using the proposed algorithm showed a moderate correlation with the MR phase contrast (r = 0.61), and good correlations with the other two techniques (r = 0.75 and r = 0.72). The proposed algorithm and has been applied to blood vessel segments with poor signal-to-noise ratios and axial lengths of less than 3 cm, and has a physical basis for computing axial flow velocities using an advection equation. The results of the proposed algorithm are consistent with existing methods.


Diploid strains of the pathogenic basidiomycete Cryptococcus neoformans are thermally dimorphic.
Cryptococcus neoformans is an opportunistic human pathogenic fungus with a defined sexual cycle. Clinical and environmental isolates of C. neoformans are haploid, and the diploid stage of the lifecycle is thought to be transient and unstable. In contrast, we find that diploid strains are readily obtained following genetic crosses of congenic MATalpha and MATa strains. At 37 degrees C, the diploid strains grow as yeast cells with a single nucleus that is larger than a haploid nucleus, contains a 2n content of DNA by FACS analysis, and is heterozygous for the MATalpha and MATa loci. At 24 degrees C, these diploid self-fertile strains filament and sporulate, producing recombinant haploid progeny in which meiotic segregation has occurred. In contrast to dikaryotic filament cells that are typically linked by fused clamp connections during mating, self-fertile diploid strains produce monokaryotic filament cells with unfused clamp connections. We also show that these diploid strains can be transformed and sporulated and that an integrated selectable marker segregates in a mendelian fashion. The diploid state could play novel roles in the lifecycle and virulence of the organism and can be exploited for the analysis of essential genes. Finally, the observation that dimorphism is thermally regulated suggests similarities between the lifecycle of C. neoformans and other thermally dimorphic human pathogenic fungi, including Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis, Paracoccidioides brasiliensis, and Sporothrix schenkii.


TLR4 mediates LPS-induced HO-1 expression in mouse liver: role of TNF-alpha and IL-1beta.
Heme oxygenase (HO)-1 catalyzes the conversion of heme to biliverdin, iron and carbon monoxide. HO-1 is induced by many stimuli including heme, Hb, heat stress,lipopolysaccharide (LPS) and cytokines. Previous studies demonstrated that LPS induced HO-1 gene activation and HO-1 expression in liver. However, the mechanisms of LPS-induced HO-1 expression in liver remain unknown. The effect of toll-like receptor-4 (TLR4) on LPS-induced liver HO-1 expression and the role of TNF-alpha and IL-1beta in this condition were determined. HO-1 expression was determined by immunofluorescent staining and immunoblotting. Double immunofluorescent staining was performed to determine the cell type of HO-1 expression in liver. A low dose of LPS significantly increased HO-1 expression in the liver which was localized in Kupffer cells only. Furthermore, HO-1 expression was enhanced by three doses of LPS. HO-1 expression was significantly inhibited in the liver of TLR4 mutant mice. While the liver HO-1 expression in TNF KO mice was much lower than that in C57 mice following the same LPS treatment, IL-1beta KO had a slight influence on liver HO-1 expression following LPS treatment. The present results confirm that macrophages are the major source of HO-1 in the liver induced by LPS. This study demonstrates that TLR4 plays a dominant role in mediating HO-1 expression following LPS. LPS-induced HO-1 expression is mainly mediated by endogenous TNF-alpha, but only partially by endogenous IL-1beta.


Histone demethylase Lsd1 is required for the differentiation of neural cells in Nematostella vectensis.
Chromatin regulation is a key process in development but its contribution to the evolution of animals is largely unexplored. Chromatin is regulated by a diverse set of proteins, which themselves are tightly regulated in a cell/tissue-specific manner. Using the cnidarian Nematostella vectensis as a basal metazoan model, we explore the function of one such chromatin regulator, Lysine specific demethylase 1 (Lsd1). We generated an endogenously tagged allele and show that NvLsd1 expression is developmentally regulated and higher in differentiated neural cells than their progenitors. We further show, using a CRISPR/Cas9 generated mutant that loss of NvLsd1 leads to developmental abnormalities. This includes the almost complete loss of differentiated cnidocytes, cnidarian-specific neural cells, as a result of a cell-autonomous requirement for NvLsd1. Together this suggests that the integration of chromatin modifying proteins into developmental regulation predates the split of the cnidarian and bilaterian lineages and constitutes an ancient feature of animal development.


Increased use of hypnotics in individuals with celiac disease: a nationwide case-control study.
Although poor sleep is common in numerous gastrointestinal diseases, data are scarce on the risk of poor sleep in celiac disease. The objective of this study was to estimate the risk of repeated use of hypnotics among individuals with celiac disease as a proxy measure for poor sleep. This is a nationwide case-control study including 2933 individuals with celiac disease and 14,571 matched controls from the general Swedish population. Poor sleep was defined as ≥2 prescriptions of hypnotics using prospective data from the National Prescribed Drug Register (data capture: July 2005-January 2008). We estimated odds ratios and hazard ratios for poor sleep before and after celiac disease diagnosis respectively. In this study, poor sleep was seen in 129/2933 individuals (4.4%) with celiac disease, as compared with 487/14,571 controls (3.3%) (odds ratio = 1.33; 95% CI = 1.08-1.62). Data restricted to sleep complaints starting ≥1 year before celiac disease diagnosis revealed largely unchanged risk estimates (odds ratio = 1.23; 95% CI = 0.88-1.71) as compared with the overall risk (odds ratio 1.33). The risk of poor sleep in celiac disease was essentially not influenced by adjustment for concomitant psychiatric comorbidity (n = 1744, adjusted odds ratio =1.26; 95% CI = 1.02-1.54) or restless legs syndrome (n = 108, adjusted odds ratio = 1.33; 95% CI = 1.08-1.63). Poor sleep was also more common after celiac disease diagnosis as compared with matched controls (hazard ratio = 1.36; 95% CI = 1.30-1.41). In conclusion, individuals with celiac disease suffer an increased risk of poor sleep, both before and after diagnosis. Although we cannot rule out that surveillance bias has contributed to our findings, our results are consistent with previous data suggesting that sleep complaints may be a manifestation of celiac disease.


Modular derivation of diverse, regionally discrete human posterior CNS neurons enables discovery of transcriptomic patterns.
Our inability to derive the neuronal diversity that comprises the posterior central nervous system (pCNS) using human pluripotent stem cells (hPSCs) poses an impediment to understanding human neurodevelopment and disease in the hindbrain and spinal cord. Here, we establish a modular, monolayer differentiation paradigm that recapitulates both rostrocaudal (R/C) and dorsoventral (D/V) patterning, enabling derivation of diverse pCNS neurons with discrete regional specificity. First, neuromesodermal progenitors (NMPs) with discrete HOX profiles are converted to pCNS progenitors (pCNSPs). Then, by tuning D/V signaling, pCNSPs are directed to locomotor or somatosensory neurons. Expansive single-cell RNA-sequencing (scRNA-seq) analysis coupled with a novel computational pipeline allowed us to detect hundreds of transcriptional markers within region-specific phenotypes, enabling discovery of gene expression patterns across R/C and D/V developmental axes. These findings highlight the potential of these resources to advance a mechanistic understanding of pCNS development, enhance in vitro models, and inform therapeutic strategies.


Serum levels of copeptin, C-reactive protein and cortisol in different severity groups of sickle cell anaemia.
It is well known that individuals with SCA undergo constant physiological stress even, in steady state. However, there is little information on the relationship between the severity of sickle cell anaemia (SCA) and serum levels of biomarkers of stress. This study therefore determined the serum levels of copeptin, cortisol and CRP in adults with SCA in different severity groups. Sixty adults with sickle cell anaemia in steady state (27.1±6.3 years) and in vaso-occlusive crisis (24.9±4.9 years) were recruited into this cross-sectional study. Degree of severity (mild, moderate or severe) was determined using a scoring system incorporating annual number of blood transfusions, crisis and presence of anaemia, vaso-occlusive pain and organ complications. Standard methods were used for the determination of packed cell volume (PCV), total white blood cell count (WBC), blood pressure measurements and anthropometric indices. Serum levels of copeptin, cortisol and CRP were determined using ELISA with the ratios calculated accordingly. Data obtained were statistically analyzed using the Student's t-test, Mann Whitney U and Chi-square test as appropriate. P<0.05 was considered significant. The mean systolic blood pressure (SBP) and copeptin level were significantly higher in subjects with moderate SCA compared with those with mild SCA. Similarly SBP, pulse, WBC, copeptin and cortisol were significantly higher while body weight was significantly lower in subjects with severe SCA compared with subjects with mild SCA. However, WBC and cortisol-to-copeptin ratio were significantly higher in subjects with severe SCA compared with subjects with moderate SCA. There was progressive rise in serum levels of CRP from mild SCA through severe SCA but the differences were not statistically significant. Also, proportions of subjects with elevated SBP and WBC were higher than the proportion of subjects with lower SBP and WBC in the severe SCA group. Serum levels of cortisol, copeptin, and their ratio could differentiate severe SCA from mild or moderate SCA. Also, elevated systolic blood pressure and total white blood cell count are associated with severe sickle cell anaemia.


A strategic approach to the unfinished fortification agenda: feasibility, costs, and cost-effectiveness analysis of fortification programs in 48 countries.
Food fortification is a promising strategy for combating micronutrient deficiencies, which plague one-third of the world's population. Which foods to fortify, with which micronutrients, and in which countries remain essential questions that to date have not been addressed at the global level. To provide a tool for international agencies to identify and organize the next phase of the unfinished global fortification agenda by prioritizing roughly 250 potential interventions in 48 priority countries. By explicitly defining the structure and operations of the fortification interventions in a detailed and transparent manner, and incorporating a substantial amount of country-specific data, the study also provides a potentially useful starting point for policy discussions in each of the 48 countries, which--it is hoped--will help to catalyze the development of public-private partnerships and accelerate the introduction of fortification and reduction of micronutrient deficiencies. Forty-eight high-priority countries were identified, and the feasibility of fortifying vegetable oil and sugar with vitamin A and fortifying wheat flour and maize flour with two alternative multiple micronutrient formulations was assessed. One hundred twenty-two country-, food-, and fortification formulation-specific interventions were assessed to be feasible, and the costs of each intervention were estimated. Assuming a 30% reduction in the micronutrient deficiencies of the persons consuming the food, the number of disability-adjusted life years (DALYs) saved by each of the programs was estimated. The cost per DALY saved was calculated for each of the 122 interventions, and the interventions were rank-ordered by cost-effectiveness. It is estimated that the 60 most cost-effective interventions would carry a 10-year price tag of US$1 billion and have costs per DALY saved ranging from US$1 to US$134. The single "best bet" intervention--i.e., the most cost-effective intervention--in each of the 48 countries was identified. This study provides a detailed, transparent, evidence-based approach to defining and estimating the costs and cost-effectiveness of the unfinished global fortification agenda in the 48 priority countries. Other considerations in designing a strategic approach to the unfinished global fortification agenda are also discussed.


Cystatin C, renal function, and atherosclerosis in rheumatoid arthritis.
We examined the hypothesis that cystatin C, a novel marker of renal function, is elevated in rheumatoid arthritis (RA) and is associated with inflammation and coronary atherosclerosis. We measured serum cystatin C, creatinine, tumor necrosis factor-α and interleukin 6 concentrations, coronary artery calcium score (CACS), and Modified Diet in Renal Disease estimated glomerular filtration rate in 167 patients with RA and 91 controls. Cystatin C was higher in RA patients [median (IQR) 1.16 (0.99-1.35) mg/l] than controls [1.01 (0.90-1.19) mg/l; p < 0.001] and correlated positively with erythrocyte sedimentation rate (p < 0.001), C-reactive protein (p = 0.01), 28-joint Disease Activity Score (p = 0.006), and Framingham risk score (FRS; p = 0.02). Cystatin C was correlated with CACS (p < 0.001) in RA, but this was not significant after adjustment for age, race, sex, and FRS (p = 0.44). Cystatin C concentrations are higher in RA than controls and may reflect inflammation and undetected subclinical renal dysfunction. Cystatin C provides information regarding the risk of atherosclerosis in RA, but this is not independent of the information provided by conventional cardiovascular risk factors.


Reinforcement learning to adaptive control of nonlinear systems.
Based on the feedback linearization theory, this paper presents how a reinforcement learning scheme that is adopted to construct artificial neural networks (ANNs) can linearize a nonlinear system effectively. The proposed reinforcement linearization learning system (RLLS) consists of two sub-systems: The evaluation predictor (EP) is a long-term policy selector, and the other is a short-term action selector composed of linearizing control (LC) and reinforce predictor (RP) elements. In addition, a reference model plays the role of the environment, which provides the reinforcement signal to the linearizing process. The RLLS thus receives reinforcement signals to accomplish the linearizing behavior to control a nonlinear system such that it can behave similarly to the reference model. Eventually, the RLLS performs identification and linearization concurrently. Simulation results demonstrate that the proposed learning scheme, which is applied to linearizing a pendulum system, provides better control reliability and robustness than conventional ANN schemes. Furthermore, a PI controller is used to control the linearized plant where the affine system behaves like a linear system.


Insect muscarinic acetylcholine receptor: pharmacological and toxicological profiles of antagonists and agonists.
The insect muscarinic acetylcholine receptor (mAChR) is evaluated as a potential target for insecticide action. The mammalian M2/M4-selective antagonist radioligand [3H]AF-DX 384 (a pirenzepine analogue) binds to Drosophila mAChR at a single high-affinity site identical to that for the nonselective antagonist [3H]quinuclidinyl benzilate (QNB) and with a pharmacological profile distinct from that of all mammalian mAChR subtypes. Three nonselective antagonists (QNB, scopolamine, and atropine) show the highest affinity (Ki=0.5-2.4 nM) at the Drosophila target, and AF-DX 384 and M3-selective 4-DAMP (dimethyl-4-(diphenylacetoxy)piperidinium iodide) rank next in potency (Ki=5-18 nM). Eleven muscarinic antagonists generally exhibit higher affinity than eight agonists. On injection into houseflies, the antagonists 4-DAMP and (S)-(+)-dimethindene produce suppressed movement, the agonist (methyloxadiazolyl)quinuclidine causes knockdown and tremors, and all of them inhibit [3H]QNB binding ex vivo, indicating possible mAChR-mediated intoxication. The insect mAChR warrants continuing study in lead generation to discover novel insecticides.


Specific ubiquitin-conjugating enzymes promote degradation of specific nuclear receptor coactivators.
Nuclear receptor coactivators (NRCoAs) are nuclear hormone receptor-associated regulatory proteins that interact with members of the nuclear receptor superfamily in the presence of their cognate ligand, enhancing their transcriptional activity. The identification of ubiquitin-proteasome pathway proteins as coactivators provides evidence that ubiquitin-proteasome-mediated protein degradation plays an integral role in eukaryotic gene transcription. It has also been observed that nuclear receptors themselves are ubiquitinated and degraded in a hormone-dependent manner and that ubiquitin-proteasome function is essential for most nuclear receptors to function as transactivators. Here, we show that specific ubiquitin-proteasome pathway enzymes target specific NRCoA proteins in vivo and in vitro. First, using a temperature-sensitive cell line that contains a thermolabile ubiquitin-activating E1 enzyme, we confirmed that NRCoA proteins are targets of the ubiquitin-proteasome pathway. Then using coimmunoprecipitation studies, we also demonstrate that in vivo, NRCoA proteins are ubiquitinated. Finally, we illustrate that in vitro, NRCoA ubiquitination and degradation depend on the ubiquitin-activating enzyme (E1) and on specific ubiquitin-conjugating enzymes (E2) for each of the coactivators.


Iopamidol and metrizamide in cervical myelography: side effects, EEG, and CSF changes.
Two nonionic contrast media, iopamidol and metrizamide (Amipaque), were used for cervical myelography (C1-C2 puncture) in 95 consecutive patients. Both contrast media gave excellent radiographic results. Headache and vagal symptoms were similar in both groups, whereas metrizamide produced more electroencephalographic changes and epileptic seizures. Meningeal irritation occurred in both groups and was severe in three cases. Cerebrospinal fluid showed protein and cellular changes of inflammatory type in both groups. Iopamidol is considered to be the more suitable contrast medium for cervical myelography despite its slight neurotoxicity.


Preschoolers' parent-rated health disparities are strongly associated with measures of adiposity in the Lifeways cohort study children.
To examine the relationship between lifecourse factors from preschoolers' microecosystem and their parent-reported (mother-reported) health (PRH), following them prospectively from preconception to age 5 years. To investigate if preschoolers' body mass index (BMI) and waist circumference were associated with preschoolers' PRH when controlled for lifecourse predictors. Lifeways cross-generation cohort study. Ireland. Of 1082 families, 62% mothers responded on a health and lifestyle questionnaire at follow-up. Food frequency, BMI and waist circumference were measured. There were 547 family data sets available for analysis of children's PRH. Mother-reported children's PRH at age 5. Associations with child's individual and familial exposures from preconception to age 5 years examined using logistic regression. In univariate analysis, relatively positive rating of children's PRH were associated with children's lower intake of fats (OR (95% CI) 2.2 (1.1 to 4.3)), higher intake of fruits/vegetables (OR (95% CI) 2.2 (1.1 to 4.3)); as well as familial socioeconomic characteristics {higher household income (OR (95% CI) 3.0 (1.6 to 5.9)), non-entitlement to means-tested healthcare (OR (95% CI) 2.1 (1.0 to 4.3)), mothers' higher education (OR (95% CI) 1.9 (1.0 to 3.6))}, psychosocial characteristics {father's participation in study (OR (95% CI) 2.1 (1.0 to 4.3)), mothers' perceiving better support from partner (OR (95% CI) 2.3 (1.2 to 4.3)), children (OR (95% CI) 1.9 (1.0 to 3.7)) or relatives (OR (95% CI) 2.2 (1.1 to 4.1))}, parents' lifestyle {mothers' lower intake of energy (OR (95% CI) 2.2 (1.1 to 4.3)), fathers' non-smoking status (OR (95% CI) 2.2 (1.1 to 4.4))} and parents' health {mothers' self-rated health relatively positive (OR (95% CI) 5.1 (2.6 to 9.9)), fathers' self-rated health relatively positive (OR (95% CI) 3.0 (1.5 to 6.0))}. In multivariable analysis (χ(2)=34.2, df=21, N=303, R(2 )= 0.26, p<0.05), one of the two strong predictors of children's relatively positive PRH was child not being obese by International Obesity Task Force classification (OR (95% CI) 5.5 (1.4 to 21.0)), observed also using BMI (kg/m(2); OR (95% CI) 0.73 (0.58 to 0.93)) or waist circumference (cm; OR (95% CI) 0.89 (0.81 to 0.98)) as continuous variables. The other significant predictor was mothers' self-rated health relatively positive (OR (95% CI) 4.2 (1.5 to 12.2)). Preschoolers' health is adversely associated with obesity and this is independent of lifecourse and social and environmental inequalities. The findings suggest that reducing childhood obesity and improving maternal health may be useful ways to improve child's global health.


Pragmatic perspective on conservation genetics and demographic history of the last surviving population of Kashmir red deer (Cervus elaphus hanglu) in India.
The hangul (Cervus elaphus hanglu) is of great conservation concern because it represents the easternmost and only hope for an Asiatic survivor of the red deer species in the Indian subcontinent. Despite the rigorous conservation efforts of the Department of Wildlife Protection in Jammu & Kashmir, the hangul population has experienced a severe decline in numbers and range contraction in the past few decades. The hangul population once abundant in the past has largely become confined to the Dachigam landscape, with a recent population estimate of 218 individuals. We investigated the genetic variability and demographic history of the hangul population and found that it has shown a relatively low diversity estimates when compared to other red deer populations of the world. Neutrality tests, which are used to evaluate demographic effects, did not support population expansion, and the multimodal pattern of mismatch distribution indicated that the hangul population is under demographic equilibrium. Furthermore, the hangul population did not exhibit any signature of bottleneck footprints in the past, and Coalescent Bayesian Skyline plot analysis revealed that the population had not experienced any dramatic changes in the effective population size over the last several thousand years. We observed a strong evidence of sub-structuring in the population, wherein the majority of individuals were assigned to different clusters in Bayesian cluster analysis. Population viability analysis demonstrated insignificant changes in the mean population size, with a positive growth rate projected for the next hundred years. We discuss the phylogenetic status of hangul for the first time among the other red deer subspecies of the world and strongly recommend to upgrade hangul conservation status under IUCN that should be discrete from the other red deer subspecies of the world to draw more conservation attention from national and international bodies.


Development of Recyclable Polystyrene-Supported Phosphonic Acid Resins for Carbohydrate Immobilization and Glycosylation.
This article describes the development of a recyclable polystyrene-based phosphonic acid resin and its use for the synthesis of immobilized glycosyl phosphonate donors and subsequent glycosylation reaction. This solid support was generated on a decagram scale from the commercially available Merrifield resin and subsequently functionalized via two different methods into eight different glycosylphosphonates. The resultant glycosylphosphonate-containing resins were obtained in 59-96% yields and were found to be bench-stable at room temperature. These donors could be activated using trifluoroborane etherate at 80 °C to react with various alcohol- and thiol-based acceptors to provide 17 different glycosides in good-to-excellent yields (53-98%). In addition, it was demonstrated that glycosylated resin could be recovered and recycled multiple times to regenerate immobilized glycosylphosphonate donors and could be subjected to on-resin glycan elongation.


TRAF6-dependent NF-kB transcriptional activity during mouse development.
Nuclear factor-kappa B (NF-kB) transcriptional activity is induced by numerous stimuli. To identify tissues exhibiting NF-kB transcriptional activity during development, we analyzed transgenic reporter mice that express beta-galactosidase from an NF-kB-responsive element. We report that NF-kB activation is widespread and present in numerous epithelial structures and within vasculature. Several regions of the developing central nervous system, including the roof plate and floor plate of the midbrain, show prominent NF-kB activation. To assess the role of the TRAF6 adaptor protein in developmental NF-kB activity, we analyzed NF-kB activation in reporter mice rendered null for TRAF6. Deletion of TRAF6 resulted in the loss of NF-kB activity in epithelia, in vasculature, and in roof and floor plate but had no effect on NF-kB activity developing telencephalon, choroid plexus, cochlear canal, and thymus. These data indicate that NF-kB transcriptional activity is present in a broad range of structures during development and that TRAF6 plays a critical role mediating developmental NF-kB activation in many but not all tissues.


Effect of unclipping on pressor responses in rats with renovascular hypertension.
Pressor responses to angiotensin II and noradrenaline have been examined in two models of renovascular hypertension (two-kidney one-clip and one-kidney one-clip) before and 24 h after removal of the renal artery clip to examine the possible role of pressor hyper-responsiveness in the maintenance of hypertension. Early and chronic hypertension was studied to assess the part played by progressive structural hypertrophy. Plasma renin concentration was elevated in early two-kidney hypertensive rats, whereas it was similar to that in age-matched normal rats in early one-kidney and chronic two-kidney hypertensive rats. Twenty-four hours after unclipping plasma renin concentration was the same in all groups. Unclipping restored blood pressure to normal levels by 24 h, whereas sham-operated animals remained hypertensive. Angiotensin II responses in both early and chronic two-kidney one-clip hypertensive rats were lower than in age-matched normal rats. In unclipped rats responses were similar to those in normals. One-kidney hypertensive rats had similar angiotensin II responses to normal rats and there was no change with unclipping. Blockade of endogenous angiotensin II production by converting enzyme inhibition resulted in similar angiotensin II responses in hypertensive and unclipped groups. In normal rats, angiotensin II responses were inversely related to plasma renin concentration (r = -0.47, P less than 0.001). Angiotensin II responses in hypertensive and unclipped rats were found to show a similar relationship to plasma renin concentration as normal rats. Noradrenaline responses in hypertensive rats were similar to those in age-matched normals and there was no significant change with unclipping.(ABSTRACT TRUNCATED AT 250 WORDS)


Multistructural biomimetic substrates for controlled cellular differentiation.
Multidimensional scaffolds are considered to be ideal candidates for regenerative medicine and tissue engineering based on their potential to provide an excellent microenvironment and direct the fate of the cultured cells. More recently, the use of stem cells in medicine has opened a new technological opportunity for controlled tissue formation. However, the mechanism through which the substrate directs the differentiation of stem cells is still rather unclear. Data concerning its specific surface chemistry, topology, and its signaling ability need to be further understood and analyzed. In our study, atomic force microscopy was used to study the stiffness, roughness, and topology of the collagen (Coll) and metallized collagen (MC) substrates, proposed as an excellent substrate for regenerative medicine. The importance of signaling molecules was studied by constructing a new hybrid signaling substrate that contains both collagen and laminin extracellular matrix (ECM) proteins. The cellular response-such as attachment capability, proliferation and cardiac and neuronal phenotype expression on the metallized and non-metallized hybrid substrates (collagen + laminin)-was studied using MTT viability assay and immunohistochemistry studies. Our findings indicate that such hybrid materials could play an important role in the regeneration of complex tissues.


[Food sensitization in children with Opisthorchis felineus invasion].
To determine the mechanism of food sensitization in children with chronic Opisthorchis felineus invasion. During the epidemiological study the groups of patients (7-10 years) with chronic opisthorchiasis (n = 237) and children without chronic opisthorchiasis (n = 496) were formed. The investigation included interviewing of parents/guardians, measurement of total IgE, specific IgE to food allergens and component-resolved diagnostic, real-time PCR in stool samples. The chronic opisthorchiasis invasion in children is associated with reduced risk of food sensitization, compared with non-infected group (9.7 vs 16.94%, OR = 0.53; 95% CI 0.31-0.88; p = 0.01). Opisthorchiasis of high intensity negatively correlated with increased level of specific IgE to food allergens in serum (OR = 0.46; 95% CI 0.24-0.91; p = 0.023). The association between level of total IgE and intensity of opisthorchiasis combinated with food sensitization was found. The sensitization to allergens class I (cyp c1, cor a11, gal d2, pru p3) is more prevalent in patients with opisthorchiasis, in uninfected children the sensitization to bet v1-homologues (mal d1, pru p1, cor a1, ara h8) is most common. The epidemiological data on the effect of the Opisthorchis felineus invasion on mechanisms of food sensitization in children were obtained.


Increased colonic motility in a rat model of irritable bowel syndrome is associated with up-regulation of L-type calcium channels in colonic smooth muscle cells.
This paper aimed to investigate the relationship between up-regulation of L-type calcium channels and altered motility disorder in a rat model of irritable bowel syndrome (IBS). Male Sprague-Dawley rats were subjected to neonatal maternal separation (NMS) from postnatal day 2-14 or normal handling (NH), and used when weighted 250-300 g. Colonic smooth muscle contractions was studied in an organ bath system. L-type Ca(2+) channel alpha(1c) subunit expression in smooth muscles from rat colon were studied by immunofluorescence and Western blotting analysis. The intracellular calcium concentration ([Ca(2+)](i)) of enzymatically isolated single colonic smooth muscle cell was studied with laser confocal fluorescent microscopy. The fecal pellets during 1 h water avoidance stress (WAS) were significantly increased; the amplitude of spontaneous contractions and contractions induced by Bay K 8644 (10 nM-1 microM), KCl (10-60 mM) and ACh (100 nM-10 microM) were significantly increased in NMS rats, when comparing with that of NH rats. [Ca(2+)]i induced by Bay K 8644 (1 microM), KCl (40 mM), and ACh (10 microM) significantly increased in muscle cells of NMS rats than NH rats. Further, alpha(1c) protein expression was significantly up-regulated in colonic smooth muscle of NMS rats than NH rats. These results suggest that NMS lead to up-regulation of L-type Ca(2+) channels expression in the colon, which contributes to the colonic motility disorder. Our findings provide direct evidence to help understanding the underlying mechanism of chronic stress-induced colonic motility disorder in IBS.


[Surgical treatment of benign tumors of the lungs].
The results of treatment analysis of 314 patients with benign bronchogenic tumor was conducted. All the lung was preserved in 84% of patients due to the application of the bronchial resection and plasty methods, its partial resection was conducted in 15.4%, pulmonectomy-in 0.6%. All the patients have survived.


Modeling cellular co-infection and reassortment of bluetongue virus in Culicoides midges.
When related segmented RNA viruses co-infect a single cell, viral reassortment can occur, potentially leading to new strains with pandemic potential. One virus capable of reassortment is bluetongue virus (BTV), which causes substantial health impacts in ruminants and is transmitted via Culicoides midges. Because midges can become co-infected by feeding on multiple different host species and remain infected for their entire life span, there is a high potential for reassortment to occur. Once a midge is co-infected, additional barriers must be crossed for a reassortant virus to emerge, such as cellular co-infection and dissemination of reassortant viruses to the salivary glands. We developed three mathematical models of within-midge BTV dynamics of increasing complexity, allowing us to explore the conditions leading to the emergence of reassortant viruses. In confronting the simplest model with published data, we estimate that the average life span of a bluetongue virion in the midge midgut is about 6 h, a key determinant of establishing a successful infection. Examination of the full model, which permits cellular co-infection and reassortment, shows that small differences in fitness of the two infecting strains can have a large impact on the frequency with which reassortant virions are observed. This is consistent with experimental co-infection studies with BTV strains with different relative fitnesses that did not produce reassortant progeny. Our models also highlight several gaps in existing data that would allow us to elucidate these dynamics in more detail, in particular the times it takes the virus to disseminate to different tissues, and measurements of viral load and reassortant frequency at different temperatures.


Thyroid Autoimmunity: Role of Anti-thyroid Antibodies in Thyroid and Extra-Thyroidal Diseases.
Autoimmune diseases have a high prevalence in the population, and autoimmune thyroid disease (AITD) is one of the most common representatives. Thyroid autoantibodies are not only frequently detected in patients with AITD but also in subjects without manifest thyroid dysfunction. The high prevalence raises questions regarding a potential role in extra-thyroidal diseases. This review summarizes the etiology and mechanism of AITD and addresses prevalence of antibodies against thyroid peroxidase, thyroid-stimulating hormone receptor (TSHR), and anti-thyroglobulin and their action outside the thyroid. The main issues limiting the reliability of the conclusions drawn here include problems with different specificities and sensitivities of the antibody detection assays employed, as well as potential confounding effects of altered thyroid hormone levels, and lack of prospective studies. In addition to the well-known effects of TSHR antibodies on fibroblasts in Graves' disease (GD), studies speculate on a role of anti-thyroid antibodies in cancer. All antibodies may have a tumor-promoting role in breast cancer carcinogenesis despite anti-thyroid peroxidase antibodies having a positive prognostic effect in patients with overt disease. Cross-reactivity with lactoperoxidase leading to induction of chronic inflammation might promote breast cancer, while anti-thyroid antibodies in manifest breast cancer might be an indication for a more active immune system. A better general health condition in older women with anti-thyroid peroxidase antibodies might support this hypothesis. The different actions of the anti-thyroid antibodies correspond to differences in cellular location of the antigens, titers of the circulating antibodies, duration of antibody exposure, and immunological mechanisms in GD and Hashimoto's thyroiditis.


Efficacy of levodopa therapy on motor function after posteroventral pallidotomy for Parkinson's disease.
We evaluated motor function in 41 consecutive PD patients undergoing unilateral MRI/microelectrode-guided posteroventral pallidotomy to determine whether the motor effects of levodopa therapy change after surgery. Total Unified Parkinson's Disease Rating Scale motor "off" and motor "on" subscores all improved and the rapidity of action, magnitude, and duration of motor response to levodopa therapy were all maintained after pallidotomy.


Resonant exciton transfer in mixed-dimensional heterostructures for overcoming dimensional restrictions in optical processes.
Nanomaterials exhibit unique optical phenomena, in particular excitonic quantum processes occurring at room temperature. The low dimensionality, however, imposes strict requirements for conventional optical excitation, and an approach for bypassing such restrictions is desirable. Here we report on exciton transfer in carbon-nanotube/tungsten-diselenide heterostructures, where band alignment can be systematically varied. The mixed-dimensional heterostructures display a pronounced exciton reservoir effect where the longer-lifetime excitons within the two-dimensional semiconductor are funneled into carbon nanotubes through diffusion. This new excitation pathway presents several advantages, including larger absorption areas, broadband spectral response, and polarization-independent efficiency. When band alignment is resonant, we observe substantially more efficient excitation via tungsten diselenide compared to direct excitation of the nanotube. We further demonstrate simultaneous bright emission from an array of carbon nanotubes with varied chiralities and orientations. Our findings show the potential of mixed-dimensional heterostructures and band alignment engineering for energy harvesting and quantum applications through exciton manipulation.


Dose titration and patient selection increases the efficacy of GH replacement in severely GH deficient adults.
Previous studies of GH replacement in adults have used unselected cohorts of GH deficient (GHD) adults and weight-based dosing regimens resulting in supraphysiological serum IGF-I levels and a high frequency of side-effects and withdrawal from these studies. By choosing patients with a high level of morbidity at baseline and using a low dose GH titration regimen we aimed to avoid over-replacement and increase the efficacy of treatment. An open study of GH replacement, initiating treatment with a dose of 0. 8 U/day and titrating the dose by 0.4 U increments to normalize the IGF-I SDS between - 2.0 and + 2.0 SD of the age-related normal range. 65 severely GHD patients (peak GH < 9 mU/l to provocative testing), 25 males, of mixed adult and childhood-onset and mean age 38.7 (range 17-72) years. Inclusion criterion was that of subjectively poor quality of life on clinical interview. Height, weight, waist and hip circumference were measured to allow calculation of body mass index (BMI) and waist-hip ratio (WHR). Bone mineral density (BMD) was measured by dual X-ray absorptiometry (DEXA). Serum haemoglobin A1C (HbA1C), lipid profile and insulin like growth factor 1 (IGF-I) were measured. The Psychological General Well-Being Schedule (PGWB) and Adult Growth Hormone Deficiency Assessment (AGHDA) self-rating questionnaires (SRQ) were used to assess quality of life. Baseline characteristics were consistent with those previously described in severely GHD adults; mean IGF-I SDS - 2.4 (+/- 2.7), BMI 28.8 (+/- 5. 4) kg/m2, total cholesterol 6.17 (+/- 1.2) mmol/l, reduced BMD z-scores at the lumbar spine (- 0.8 +/- 1.2) and femoral neck (- 0. 44 +/- 1.4), and SRQ scores considerably lower than reported in previous studies of GH deficient adults and normal controls. Following initiation of GH serum IGF-I SDS was increased significantly from baseline to a mean level of 0.15 +/- 2.7 (P < 0. 001) and 0.31 +/- 2.0 (P < 0.001) at three and eight months, respectively. The mean PGWB score increased from 59.7 +/- 19.9 to 75. 8 +/- 15.0 (P < 0.001) and 73.7 +/- 19.5 (P = 0.001) at three and eight months, respectively. An increase of 14 points represents the largest improvement in quality of life, using this index, that has been reported in GHD adults. The mean AGHDA score also demonstrated considerable improvement, falling from 15.3 +/- 6.0 to 10.4 +/- 6.2 (P < 0.001) and 9.8 +/- 6.5 (P < 0.001) at three and eight months, respectively. The changes observed in both the PGWB and AGHDA scores between baseline and at both three and eight months were shown to correlate significantly with the respective baseline score. A significantly greater improvement was observed in the PGWB following GH replacement in those with a baseline PGWB score of < 60 than in those with a score > 60. This observation was significant at both three (27.1 vs 6.7, P = 0.0001) and eight (25.6 vs 3.3, P = 0.0003) months. All PGWB subscales showed significant improvement though that of vitality was of greatest magnitude. A strong correlation was observed between the generic and disease-specific SRQ (r = - 0.73, P < 0.001). The observed improvement in quality of life in GH deficient adults is proportional to the degree of impairment before commencing therapy. The use of low-dose titration and selection of a population with greater morbidity reduces the occurrence of over-replacement and increases the efficacy of treatment. This allows direction of resources to those in greatest need.


Toward the improvement of 3D-printed vessels' anatomical models for robotic surgery training.
Multi-Detector Computed Tomography is nowadays the gold standard for the pre-operative imaging for several surgical interventions, thanks to its excellent morphological definition. As for vascular structures, only the blood flowing inside vessels can be highlighted, while vessels' wall remains mostly invisible. Image segmentation and three-dimensional-printing technology can be used to create physical replica of patient-specific anatomy, to be used for the training of novice surgeons in robotic surgery. To this aim, it is fundamental that the model correctly resembles the morphological properties of the structure of interest, especially concerning vessels on which crucial operations are performed during the intervention. To reach the goal, vessels' actual size must be restored, including information on their wall. Starting from the correlation between vessels' lumen diameter and their wall thickness, we developed a semi-automatic approach to compute the local vessels' wall, bringing the vascular structures as close as possible to their actual size. The optimized virtual models are suitable for manufacturing by means of three-dimensional-printing technology to build patient-specific phantoms for the surgical simulation of robotic abdominal interventions. The proposed approach can effectively lead to the generation of vascular models of optimized thickness wall. The feasibility of the approach is also tested on a selection of clinical cases in abdominal surgery, on which the robotic surgery is performed on the three-dimensional-printed replica before the actual intervention.


Topical corticosteroid therapy for children: alclometasone dipropionate cream 0.05%.
The safety and efficacy of twice-daily applications of alclometasone dipropionate cream 0.05% were evaluated in 39 children with eczema during a three-week open study. Early-morning plasma cortisol levels were monitored at weekly intervals (visits 1, 2, and 3) for six children. For the remaining 33 children, levels were measured at visits 1 and 2 and two weeks later, at visit 4. Improvement in signs and symptoms of erythema, induration, and pruritus and a global response to therapy were determined weekly. Plasma cortisol levels remained within the acceptable normal range of 7 to 25 micrograms/100 ml throughout the study in all 39 children. At the conclusion of treatment, a favorable global response--complete clearing of monitored signs and symptoms--was observed in 28 (72%) children, and marked or moderate improvement was recorded for seven (18%) children.


A unifying family of group sequential test designs.
Currently, the design of group sequential clinical trials requires choosing among several distinct design categories, design scales, and strategies for determining stopping rules. This approach can limit the design selection process so that clinical issues are not fully addressed. This paper describes a family of designs that unifies previous approaches and allows continuous movement among the previous categories. This unified approach facilitates the process of tailoring the design to address important clinical issues. The unified family of designs is constructed from a generalization of a four-boundary group sequential design in which the shape and location of each boundary can be independently specified. Methods for implementing the design using error-spending functions are described. Examples illustrating the use of the design family are also presented.


Appraising the causal relationship between thyroid function and rheumatoid arthritis: a two-sample bidirectional Mendelian randomization study.
Hypothyroidism and hyperthyroidism are observationally associated with rheumatoid arthritis (RA), but causality is unclear. To evaluate the causal relationship between thyroid function and RA, we conducted a two-Sample bidirectional Mendelian Randomization (MR) study. Single nucleotide polymorphisms associated with six phenotypes were selected from the FinnGen biobank database, The ThyroidOmics Consortium database, and the IEU Open GWAS database. For the forward MR analysis, we selected hypothyroidism (N=213,390), Graves' disease (GD) (N=199,034), other types of hyperthyroidism (N=190,799), free thyroxine (FT4, N=49,269), and thyroid-stimulating hormone (TSH, N=54,288) as the five related thyroid function phenotypes for exposure, with RA (N=58,284) as the outcome. Reverse MR analysis selected RA as the exposure and five phenotypes of thyroid function as the outcome. The Inverse variance weighting (IVW) method was used as the primary analysis method, supplemented by weighted median (WM) and MR-Egger methods. Cochran's Q test, MR-PRESSO, MR-Egger regression methods, and leave-one-out analysis were employed to assess sensitivity and pleiotropy. Forward MR evidence indicates that genetic susceptibility to hypothyroidism is associated with an increased risk of RA (ORIvw=1.758, P=7.61×10-5). Reverse MR evidence suggests that genetic susceptibility to RA is associated with an increased risk of hypothyroidism (ORIvw=1.274, P=3.88×10-20), GD (ORIvw=1.269, P=8.15×10-05), and other types of hyperthyroidism (ORIvw=1.141, P=1.80×10-03). There is no evidence to support a forward or reverse causal relationship between genetic susceptibility to RA and FT4, TSH. Our results provide genetic evidence supporting bidirectional causal relationships between thyroid function and RA. These findings inform preventive strategies and interventions targeting RA and thyroid dysfunction.


Cervical mediastinoscopy for paratracheal masses in pediatric patients.
A cytological diagnosis is essential for a definitive diagnosis in children who have paratracheal lesions. Thirteen pediatric patients were biopsied using cervical mediastinoscopy. Age, gender, preoperative diagnosis, and postoperative biopsy results and complications were reviewed. Five patients had mediastinal lesions residuing or recurring after chemotherapy for either Hodgkin disease or non-Hodgkin lymphoma. In 2 of these patients, the diagnosis was recurrent disease. Among the 8 patients presenting with a paratracheal mass or enlarged lymph nodes, histopathologic diagnosis showed tuberculosis in 3 children, Hodgkin disease in 2 children, and histiocytosis X and non-Hodgkin lymphoma 1 patient in each. This study shows that cervical mediastinoscopy gave 100% correct diagnosis for mediastinal residual malignancies or uncommon forms of mycobacterium tuberculosis with paratracheal masses.


Office-based potassium titanyl phosphate laser-assisted endoscopic vocal polypectomy.
Vocal polyps are common exophytic laryngeal lesions that usually necessitate microscopic laryngeal surgery under general anesthesia. Office-based indirect laryngoscopic procedures provide an alternative management option and can be performed comfortably under flexible endoscopic guidance. Combining angiolytic potassium titanyl phosphate (KTP) laser treatment and flexible endoscopic polypectomy should alleviate the risks of surgery under general anesthesia and expedite lesion regression. To combine angiolytic KTP laser treatment and endoscopic polyp removal and to evaluate the clinical applicability, treatment outcomes, and adverse effects of office-based KTP laser-assisted vocal polypectomy. Case series of KTP laser treatment (n = 16) and KTP laser-assisted polypectomy (n = 20). Patients underwent pretreatment and 2- and 6-week posttreatment evaluation with videolaryngostroboscopy (VLS), maximal phonation time, and a 10-item voice handicap index. Perceptual (GRB [grade, roughness, breathiness] scale) and acoustic analyses were performed before and 6 weeks after treatment. Tertiary teaching hospital. Thirty-six outpatients with unilateral hemorrhagic vocal polyps. Under local anesthesia, the KTP laser fiber was passed through the working channel of the flexible laryngoscope to photocoagulate the microvasculature of the polyp in all patients. Removal of coagulated vocal polyp using a flexible, endoscopic, blunt-ended grasping forceps immediately after KTP laser application was performed in the polypectomy group. Results of VLS, maximal phonation time, 10-item voice handicap index, and perceptual and acoustic analyses. Six weeks after KTP laser treatment with and without polypectomy, 19 and 12 patients, respectively, experienced complete recovery and much improvement of mucosal wave. Maximal phonation time and the voice handicap index improved significantly 2 weeks after KTP laser with polypectomy (P < .01), whereas significant improvements were noted 6 weeks postoperatively in both treatment groups (P < .05). Acoustic and perceptual analyses also revealed significant improvements in both study groups (P < .05). During follow-up, we did not notice significant adverse effects. Potassium titanyl phosphate laser-assisted vocal polypectomy is a safe, practical, and effective alternative option to treat hemorrhagic vocal polyps in the outpatient department, offering comparable but earlier therapeutic effects than KTP laser alone.


[Adverse reactions to herbal remedies: analysis of reported adverse reactions in the Netherlands].
To analyse reports of suspected adverse reactions in the use of herbal remedies in the Netherlands. Descriptive, retrospective. All reports of suspected adverse reactions to herbal remedies in the database of the Netherlands Pharmacovigilance Centre Lareb during the period 1991 - March 2013 were assessed on causal link between use of the medication and the reported adverse reaction. Adverse reactions were classified by severity according to international standards. An overview was made of all reports of severe adverse reactions. The Lareb database contained 336 reports of suspected adverse reactions to herbal remedies. Of the 336 herbal remedies in the reports, 247 cases contained a single herbal ingredient. In total, the herbal remedies contained 221 different herbs, some ingredients being used in multiple products. 518 adverse reactions to the use of various herbal remedies were reported. Fifty-five reports were classified as serious. Herbs can cause adverse reactions or interactions with medicinal products, but herbal remedies can also be adulterated with regular medicines or illegal - even toxic - ingredients. Reporting adverse reactions significantly contributes to our knowledge about this subject. Physicians and pharmacists should ask patients about the use of alternative medications, particularly those based on herbs.


A heterozygous, intragenic deletion of CNOT2 recapitulates the phenotype of 12q15 deletion syndrome.
Only a few individuals with 12q15 deletion have been described, presenting with a disorder characterized by learning disability, developmental delay, nasal speech, and hypothyroidism. The smallest region of overlap for this syndrome was included in a genomic segment spanning CNOT2, KCNMB4, and PTPRB genes. We report on an additional patient harboring a 12q15 microdeletion encompassing only part of CNOT2 gene, presenting with a spectrum of clinical features overlapping the 12q15 deletion syndrome phenotype. We propose CNOT2 as the phenocritical gene for 12q15 deletion syndrome and its haploinsufficiency being associated with an autosomal dominant disorder, presenting with developmental delay, hypotonia, feeding problems, learning difficulties, nasal speech, skeletal anomalies, and facial dysmorphisms.