Mesenchymal stem cell-based therapy for type 1 diabetes.
Diabetes has increasingly become a worldwide health problem, causing huge burden on healthcare system and economy. Type 1 diabetes (T1D), traditionally termed "juvenile diabetes" because of an early onset age, is affecting 5-10% of total diabetic population. Insulin injection, the predominant treatment for T1D, is effective to ameliorate the hyperglycemia but incompetent to relieve the autoimmunity and to regenerate lost islets. Islet transplantation, an experimental treatment for T1D, also suffers from limited supply of human islets and poor immunosuppression. The recent progress in regenerative medicine, especially stem cell therapy, has suggested several novel and potential cures for T1D. Mesenchymal stem cell (MSC) based cell therapy is among one of them. MSCs are a type of adult stem cells residing in bone marrow, adipose tissue, umbilical cord blood, and many other tissues. MSCs, with self-renewal potential and transdifferentiation capability, can be expanded in vitro and directed to various cell lineages with relatively less efforts. MSCs have well-characterized hypoimmunogenicity and immunomodulatory effect. All these features make MSCs attractive for treating T1D. Here, we review the properties of MSCs and some of the recent progress using MSCs as a new therapeutic in the treatment of T1D. We also discuss the strength and limitations of using MSC therapy in human trials.


Translating the Research Diagnostic Criteria for Temporomandibular Disorders into Malay: evaluation of content and process.
To develop a Malay-language version of the Axis II Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) through a formal translation/back-translation process and to summarize available data about the psychometric properties of the translated scales. To cross-culturally adapt the instrument, the RDC/TMD underwent translation using a forward-backward method. Subjects were recruited to test the congruency between translated and original versions of the RDC/TMD. The psychometric properties of 3 domains (Graded Chronic Pain Scale, Nonspecific Physical Symptoms, and Depression) of the RDC/TMD were examined, and the literature on this topic was reviewed. All the items scored 93% to 100% congruency. Cronbach's alphas for Graded Chronic Pain Scale, Nonspecific Physical Symptoms, and Depression were 0.77, 0.71, and 0.88, respectively (n = 40). The test-retest reliability of scores (intraclass correlation coefficient [ICC]) and levels (Spearman's rho) for these domains showed ICCs of 0.97, 0.94, and 0.95, respectively, with a lowest ICC value of 0.84 (n = 40); the Spearman's rho values were 0.93, 0.74, and 0.74, respectively. The discriminant validity between patients with pain symptoms (n = 40) and normal pain-free controls (n = 40) were statistically significant (P < .001). These correlations provide support for the internal consistency and validity of the Graded Chronic Pain Scale, Nonspecific Physical Symptoms, and Depression domains of the translated version of the RDC/TMD, which were found to be comparable to the psychometric properties of the original and other international translated versions. The cross-cultural adaptation of the RDC/TMD into the Malay language is suitable for use in Malaysia.


Hepatitis B vaccination during pregnancy for preventing infant infection.
Infant hepatitis B infection increases the risk of chronic infection, cirrhosis or liver cancer (hepatocellular carcinoma) in the adult. Perinatal transmission is a common route of infection. To assess the effectiveness and adverse effects of hepatitis B vaccine administered to pregnant women for preventing hepatitis B virus infection in infants. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2014). Randomized controlled trials (RCTs) assessing hepatitis B vaccination compared with placebo or no treatment during pregnancy for preventing infant infection. Quasi-RCTs and cross-over studies were not eligible for inclusion. Two review authors independently assessed trials for inclusion. If any studies had been included, we planned to assess the risk of bias, extract data and check the data for accuracy of all included studies. We did not identify any studies for inclusion. We found no RCTs that assessed the effects of hepatitis B vaccine during pregnancy for preventing infant infection. Consequently, this review cannot provide guidance for clinical practice in this area. However, it does identify the need for well-designed randomized clinical trials to assess the effect of hepatitis B vaccine during pregnancy on the incidence of infant infection and to determine any adverse effects.


A virtual valve for smooth contamination-free flow switching.
We present a channel geometry that allows for clean switching between different inlets of a microchip without any contamination of the inlets or the downstream flow. We drive this virtual valve with a pneumatic pressure setup that minimizes disturbance of the downstream flow during the switching procedure by simultaneous variation of the pressures applied to the different inlets. We assess the efficiency of the setup by spectroscopic measurement of downstream dye concentrations, and demonstrate its practical utility by sequentially constructing multiple layers of alginate hydrogel. The method is potentially useful for a whole series of further applications, such as changing perfusion liquids for cell culture and cell analysis, metering, chemical-reaction initiation and multi-sample chromatography, to name a few.


Kalman Smoothing for Objective and Automatic Preprocessing of Glucose Data.
A method for preprocessing a time series of glucose measurements based on Kalman smoothing is presented. Given a glucose data time series that may be irregularly sampled, the method outputs an interpolated time series of glucose estimates with mean and variance. The method can provide homogenization of glucose data collected from different devices by using separate measurement noise parameters for differing glucose measurement equipment. We establish a link between the ISO 15197 standard and the measurement noise variance used by the Kalman smoother for self-monitoring of blood glucose (SMBG) measurements. The method provides phaseless smoothing, and it can automatically correct errors in the original datasets like small fallouts and erroneous readings when surrounding data allow. The estimated variance can be used for deciding at which times the data are trustworthy. The method can be used as a preprocessing step in many kinds of glucose data processing and analysis tasks, such as computing the mean absolute relative deviation between measurement systems or estimating the plasma-to-interstitial fluid glucose dynamics of continuous glucose monitor or flash glucose monitor (FGM) signals. The method is demonstrated on SMBG and FGM glucose data from a clinical study. A MATLAB implementation of the method is publicly available.


Structure of a glycomimetic ligand in the carbohydrate recognition domain of C-type lectin DC-SIGN. Structural requirements for selectivity and ligand design.
In genital mucosa, different fates are described for HIV according to the subtype of dendritic cells (DCs) involved in its recognition. This notably depends on the C-type lectin receptor, langerin or DC-SIGN, involved in gp120 interaction. Langerin blocks HIV transmission by its internalization in specific organelles of Langerhans cells. On the contrary, DC-SIGN enhances HIV trans-infection of T lymphocytes. Thus, approaches aiming to inhibit DC-SIGN, without blocking langerin, represent attractive anti-HIV strategies. We previously demonstrated that dendrons bearing multiple copies of glycomimetic compounds were able to block DC-SIGN-dependent HIV infection in cervical explant models. Optimization of such ligand requires detailed characterization of its binding mode. In the present work, we determined the first high-resolution structure of a glycomimetic/DC-SIGN complex by X-ray crystallography. This glycomimetic, pseudo-1,2-mannobioside, shares shape and conformational properties with Manα1-2Man, its natural counterpart. However, it uses the binding epitope previously described for Lewis X, a ligand specific for DC-SIGN among the C-type lectin family. Thus, selectivity gain for DC-SIGN versus langerin is observed with pseudo-1,2-mannobioside as shown by surface plasmon resonance analysis. In parallel, ligand binding was also analyzed by TR-NOESY and STD NMR experiments, combined with the CORCEMA-ST protocol. These studies demonstrate that the complex, defined by X-ray crystallography, represents the unique binding mode of this ligand as opposed to the several binding orientations described for the natural ligand. This exclusive binding mode and its selective interaction properties position this glycomimetic as a good lead compound for rational improvement based on a structurally driven approach.


Hydrogel Functionalized Polyester Fabrics by UV-Induced Photopolymerization.
We address a strategy to graft hydrogels onto polyethylene terephthalate (PET) fabrics using different acrylate-based monomers. The hydrogel-modified fabrics were prepared by a two-step modification. To this end, double functional groups were firstly introduced onto the PET surface via an aminolysis reaction involving allylamine. The final grafted polymer networks were then obtained after UV-induced radical photopolymerization by varying acrylate monomer types in the presence of a cross-linker. After characterization, the resulting hydrogels showed different morphologies and abrasion resistance performances depending on their chemical nature. UV-photopolymerization is a fast and low-cost method to achieve technical fabrics with specific desired properties.


Provision of family planning services in Lesotho.
One of Lesotho's population goals is to achieve replacement-level fertility by 2011, but the contraceptive prevalence rate of 41% is considerably below the target of 70-75%. A situation analysis framework was used to assess family planning providers' readiness to provide services and women's perceptions of service delivery. Data were collected in 1997-1998 through surveys of 38 service delivery points and 52 providers, and focus group discussions with 50 women. Most facilities were open five days a week, during working hours; closure during lunchtime and on weekends restricted access by employed people. There were no clear guidelines on the provision of family planning methods, and providers created their own rules and restrictions. Some women were discouraged by provider bias, lack of visual privacy and recurrent shortages of their preferred brand of pills. Although the government had a uniform pricing policy for contraceptive methods, costs varied and generally were higher in rural than in urban areas. In rural areas, transportation costs increased the overall cost of using family planning methods. Expanding women's access to service sites, developing guidelines for family planning providers and ensuring that standard prices are adopted should be government priorities if contraceptive prevalence is to increase.


Preserved neutrophil response to Candida albicans stimulation in AIDS patients with candida esophagitis.
Polymorphonuclear neutrophils (PMNs) and their interaction with immunoglobulins constitute a major line of defence against invading Candida albicans. The function of neutrophils, assessed by superoxide production, and the opsonizing efficacy of sera from 15 AIDS patients with esophageal candidiasis and 15 healthy control subjects were studied. When stimulated with opsonized C. albicans the superoxide generation of PMNs from AIDS patients did not differ from the response observed in healthy subjects. However, a significant depression was demonstrated when PMNs were maximally stimulated by phorbol-12-myristate-13-acetate (PMA). A reduction in opsonizing capability of serum from AIDS patients was detected when tested with zymosan particles. However, the opsonizing capacities of serum from AIDS patients and control subjects were comparable in anticandidal activity, a result that may be explained by a compensatory stimulation of the specific humoral anticandidal response due to perpetual mucous candidiasis in the AIDS patients. These results suggest that anticandidal activity of PMNs and sera from AIDS patients with esophageal candidiasis is preserved, matching the clinical evidence that systemic candidiasis is seldom seen in non-neutropenic AIDS patients.


WEARABLE SENSOR-BASED GAIT CLASSIFICATION IN IDIOPATHIC TOE WALKING ADOLESCENTS.
Idiopathic toe walking on the balls of the feet is commonly found in children. Many toddlers who are just beginning to walk show signs of toe walking, but when toe walking persists after two years of age, the child's risk of falling increases as well as the risk of other developmental delays. Idiopathic toe-walking is estimated to occur in 7 to 24% of children. In order to address the problem of toe walking and assess improvements due to intervention, one needs to identify heel-toe gait versus toe-toe gait in natural environments of idiopathic toe walkers. The aim of this study was to investigate if learning algorithms utilizing triaxial accelerometers and gyroscopes from wearable sensors could detect and differentiate heel-toe gait versus toe-toe gait. In this study, 5 adolescents (13± 5 years) patients with idiopathic toe walking characteristics wore inertial sensor at L5 - S1 joint. New interventions can be designed for idiopathic toe walking population, but currently, it is a challenge to quantify the efficiency of toe-walking intervention. In recent times, with the advancement of machine learning classification methods and powerful computing, longitudinal data from wearable sensors can be used to accurately classify gait abnormalities. The aim of this study was to investigate machine learning methods to classify toe-toe walking versus heel-toe walking using data from a single inertial sensor. We found that k-means clustering was successful in differentiating toe walking with that of typical walking signals. We found that some of the linear variability based features such as standard deviation, Root Mean Square (RMS), and kurtosis contained most of the variability among the data and could therefore distinguish toe-toe gait versus heeltoe gait through clustering. The k-means cluster provided an 82% accuracy score with a specificity of 83% and sensitivity of 86%. We further utilized Recurrent Convolution Neural Network (RNN) such as Long Short-Term Memory (LSTM). The LSTM model was another classification method that was used to distinguish between toe-toe gait and heel-toe gait. Wearable sensors integrated with machine and deep learning algorithms have the capability to transform current on-going therapy methods and monitor patients longitudinally for their improvement in gait. These novel learning-based techniques could successfully classify toe walking gait and help in estimating the efficacy of the treatment in idiopathic toe walking adolescents.


Multisensory interactions in the depth plane in front and rear space: a review.
In this review, we evaluate the neurophysiological, neuropsychological, and psychophysical evidence relevant to the claim that multisensory information is processed differently depending on the region of space in which it happens to be presented. We discuss how the majority of studies of multisensory interactions in the depth plane that have been conducted to date have focused on visuotactile and audiotactile interactions in frontal peripersonal space and underline the importance of such multisensory interactions in defining peripersonal space. Based on our review of studies of multisensory interactions in depth, we question the extent to which peri- and extra-personal space (both frontal and rear) are characterized by differences in multisensory interactions (as evidenced by multisensory stimuli producing a different behavioral outcome as compared to unisensory stimulation). In addition to providing an overview of studies of multisensory interactions in different regions of space, our goal in writing this review has been to demonstrate that the various kinds of multisensory interactions that have been documented may follow very similar organizing principles. Multisensory interactions in depth that involve tactile stimuli are constrained by the fact that such stimuli typically need to contact the skin surface. Therefore, depth-related preferences of multisensory interactions involving touch can largely be explained in terms of their spatial alignment in depth and their alignment with the body. As yet, no such depth-related asymmetry has been observed in the case of audiovisual interactions. We therefore suggest that the spatial boundary of peripersonal space and the enhanced audiotactile and visuotactile interactions that occur in peripersonal space can be explained in terms of the particular spatial alignment of stimuli from different modalities with the body and that they likely reflect the result of prior multisensory experience.


[Scintigraphic assessment of alterations in cardiopulmonary haemodynamics and renal functional activity in patients with endured coronary artery bypass grafting].
By means of scintigraphic methods to assess alterations in cardiopulmonary haemodynamics and renal functional activity in patients with coronary artery disease (CAD) after endured coronary artery bypass grafting (CABG) performed in conditions of extracorporeal circulation (EC) and on the functioning heart. We examined a total of 40 patients presenting with CAD (mean age 54.90±1.12 years) after endured CABG. All patients were subdivided into 2 groups: Group One consisting of 20 patients subjected to CABG performed on the beating heart with the use of myocardial "stabilizer" "Acrobat" (Study Group) and Group Two also comprising 20 patients but undergoing surgery with the use of extracorporeal circulation (Comparison Group). All patients included into the study were subjected to radiocardiopulmonography with (99m)Tc-pertechnetate and dynamic radionuclide renoscintigraphy with (99m)Tc-DTPA before and 6-7 days after operative treatment. In the early postoperative period after CABG, the patients of the both groups were found to have a significant increase in the minute volume, cardiac index, and circulation efficiency coefficient, accompanied by a significant decrease in the period of half-emptying of the left ventricle, thus suggesting improvement of LV contractility. Improved pulmonary microcirculation resulting from operative treatment in the compared groups of patients was confirmed by significantly shortened time of the indicator's passing through pulmonary vessels at the expense of both arterial (TAM) and venous (TVM) components. At the same time, a decrease in these parameters in the Study Group patients was more pronounced as compared with the Comparison Group patients. Thus, the means of the difference between the pre- and postoperative values of TAM and TVM in the Study Group amounted to 1.78 ± .40 s and 1.78 ± 0.32 s, and in the Comparison Group to 0.95 ± 0.22 s and 0.98 ± 0.16 s, respectively (p=0.029 and p=0.031 for TAM and TVM, respectively). The Comparison Group patients after CABG were found to have a significant decrease in the mean values of the total glomerular filtration rate (GFR) in combination with decelerated clearance of the indicator from blood. 30% of patients under the effect of nonpulsating blood flow developed relatively pronounced renal dysfunction (a decrease in the total GFR and/or GRF of one of the kidneys by 15% and more as compared with the initial level). Besides, these patients also demonstrated significant changes in the half-clearance of the radiopharmaceutical from the renal parenchyma and the index of cortical retention of the indicator on the both sides. Unlike the Comparison Group, in patients without EC the average values of the majority of parameters of renal filtration activity underwent no statistically significant alterations as compared with the baseline (prior to CABG) values. Coronary artery bypass grafting without cardiac arrest exerts less pronounced negative influence upon the state of the renal function as compared with the open-heart surgery with extracorporeal circulation, which may partially be conditioned by statistically more significant positive dynamics of microcirculation in the system of pulmonary circulation under the effect of myocardial revascularization with the use of the myocardial stabilizer "off-pump".


A Pharmacist-Led Practice to Improve Perioperative Glycemic Control in Elective Surgery.
Quality Improvement Success Stories are published by the American Diabetes Association in collaboration with the American College of Physicians and the National Diabetes Education Program. This series is intended to highlight best practices and strategies from programs and clinics that have successfully improved the quality of care for people with diabetes or related conditions. Each article in the series is reviewed and follows a standard format developed by the editors of Clinical Diabetes. The following article describes an effort to facilitate the timely identification and treatment of pre- and postoperative hyperglycemia in people with diabetes having elective surgery at a tertiary care hospital in Calgary, Alberta, Canada.


Model-based restoration of underwater spectral images captured with narrowband filters.
Underwater spectral imaging is a promising method for mapping, classification and health monitoring of coral reefs and seafloor inhabitants. However, the spectrum of light is distorted during the underwater imaging process due to wavelength-dependent attenuation by the water. This paper presents a model-based method that accurately restores brightness of underwater spectral images captured with narrowband filters. A model is built for narrowband underwater spectral imaging. The model structure is derived from physical principles, representing the absorption, scattering and refraction by water and the optical properties of narrowband filters, lenses and image sensors. The model coefficients are calibrated based on spectral images captured underwater and in air. With the imaging model available, energy loss due to water attenuation is restored for images captured at different underwater distances. An experimental setup is built and experiments are carried out to verify the proposed method. Underwater images captured within an underwater distance of 260 cm are restored and compared with those in air. Results show that the relative restoration error is 3.58% on average for the test images, thus proving the accuracy of the proposed method.


Dialysis reduces portal pressure in patients with chronic hepatitis C.
The purpose of this study was to characterize changes in hepatic venous pressures in patients with chronic hepatitis C. The histology and laboratory data from patients with chronic hepatitis C who underwent a transjugular liver biopsy (TJLB) and hepatic venous pressure gradient measurement were analyzed. Portal hypertension was defined as hepatic venous pressure gradient > or =6 mm Hg. A single pathologist masked to hepatic venous pressure gradient scored liver sections for inflammation and fibrosis. The patients with high-grade inflammation (relative risk [RR] 2.82, P = 0.027, multivariate analysis) and late-stage fibrosis (RR 2.81, P = 0.022) were more likely to have a hepatic venous pressure gradient > or =6 mm Hg, while the patients on dialysis (RR 0.32, P = 0.01) were less likely to have a hepatic venous pressure gradient > or =6 mm Hg. The patients on dialysis (n = 58) had an elevated serum blood urea nitrogen and creatinine when compared with those who were not (n = 75) (47.6 +/- 3.3 and 7.98 +/- 0.4 vs. 25.9 +/- 2.0 and 1.66 +/- 0.22 mg/dL, respectively; P < 0.001). While the hepatic venous pressure gradient increased with the rising levels of liver fibrosis in the latter group (P < 0.01), it did not change in the patients on dialysis (P = 0.41). The median hepatic venous pressure gradient was especially low in late-stage fibrosis patients on dialysis when compared with the latter group (5 vs. 10 mm Hg, P = 0.017). In patients on dialysis, serum transaminases were low across all levels of fibrosis. Twenty-three of the 92 patients with early fibrosis had a hepatic venous pressure gradient > or =6 mm Hg. In patients with chronic hepatitis C, concomitant TJLB and hepatic venous pressure gradient measurement identify those who have early fibrosis and portal hypertension. Long-term hemodialysis may reduce portal pressure in these patients.


Pandemic influenza preparedness in Latin America: analysis of national strategic plans.
The threat of a human pandemic of influenza has prompted the development of national influenza pandemic preparedness plans over the last 4 years. Analyses have been carried out to assess preparedness in Europe, Asia and Africa. We assessed plans to evaluate the national strategic pandemic influenza preparedness in the countries of Latin America. Published national pandemic influenza preparedness plans from Latin American countries were evaluated against criteria drawn from the World Health Organization checklist. Plans were eligible for inclusion if formally published before 16 November 2007. Fifteen national plans were identified and retrieved from the 17 Latin American countries surveyed. Latin American countries demonstrated different degrees of preparedness, and that a high level of completeness of plans was correlated to a country's wealth to a certain extent. Plans were judged strong in addressing surveillance requirements, and provided appropriate communication strategies directed to the general public and health care personnel. However, gaps remained, including the organization of health care services' response; planning and maintenance of essential services; and the provision of containment measures such as the stockpiling of necessary medical supplies including vaccines and antiviral medications. In addition, some inconsistencies and variations which may be important, such as in border control measures and the capacity to contain outbreaks, exist between country plans-issues that could result in confusion in the event of a pandemic. A number of plans remain developmental in nature and, as elsewhere, more emphasis should be placed on strengthening the operability of plans, and in testing them. Whilst taking account of resources constraints, plans should be further developed in a coherent manner with both regional and international imperatives.


The Quilty lesion enigma: focal apoptosis/necrosis and lymphocyte subsets in human cardiac allografts.
Quilty lesions, as first described by Billingham in 1981, or 'Quilty Effect' (QE) are distinct endomyocardial mononuclear cell infiltrates that have been observed in human heart transplant recipients, as well as in experimental models of heart transplantation. In the present investigations, the pattern and extent of apoptosis (programmed cell death) and myocyte necrosis, as well as specific lymphocyte subsets in Quilty lesions was assessed. Endomyocardial biopsies obtained from 13 patients at 10-3362 days post-transplant were examined. Apoptosis, as identified by DNA nick end-labeling, was found in myocytes at the periphery of Quilty lesions in 11 of 13 cases (85%), and 'early' stages of myocyte necrosis, as demonstrated by specific staining with alpha light chain myosin monoclonal antibodies (mAb), was observed at the same sites in 10 of 13 cases (77%) of both Quilty type A and type B lesions. Apoptosis was not identified in the lymphocyte infiltrates of any of the lesions examined. Lymphocyte subsets were characterized using mAb for T cell receptor (CD3), for helper/inducer T cells (CD4), for cytotoxic/suppressor T cells (CD8) and for mature B cells (CD20). Immunostaining revealed separate clusters of T lymphocytes with less prevalent B cells within the Quilty lesions. CD4+ cells were found in larger numbers than CD8+ cells in all cases. Non-B, non-T large lymphocytes were occasionally present. Except for the extent of the cellular infiltrate, no major cytochemical lymphocyte distribution differences were found between Quilty type A and B lesions. Myocyte apoptosis and early necrosis at the periphery of Quilty lesions suggest that early myocyte injury occurring in B lesions may represent initial or 'abortive stages' of cardiac allograft rejection. Why these lesions do not progress to overt rejection indeed warrant further detailed studies.


Overcoming insomnia: protocol for a large-scale randomised controlled trial of online cognitive behaviour therapy for insomnia compared with online patient education about sleep.
Insomnia is a major public health concern. While cognitive behaviour therapy for insomnia (CBT-I) is acknowledged as the best available intervention, there are unanswered questions about its wider dissemination, socioeconomic benefits and its impact on health resource utilisation. The aim of this randomised controlled trial (RCT) is to investigate the effectiveness of a fully automated online version of CBT-I compared with online patient education about sleep (PE). Outcome measures comprise changes in symptoms of insomnia, time off work due to sick leave as well as medication and health resource utilisation. Also, we will examine (i) putative mediators of the effects of CBT-I on insomnia severity and (ii) selected potential psycho-bio-social moderators of the effects of the interventions. A parallel-group RCT will be conducted in a target sample of about 1500 adults recruited across Norway. Participants will complete an online screening and consent process. Those who meet eligibility criteria will be randomised to receive direct access to fully automated online CBT-I or to an online PE programme. The primary outcome is change in insomnia severity immediately postintervention; secondary outcomes are change in daytime functioning and other sleep measures postintervention and at 6-month and 24-month follow-up. Objective data from national registries will be obtained at two time points (1 year and 2 years post-treatment), allowing a mirror image study of preintervention and postintervention rates of sick leave, and of medication and healthcare utilisation by condition. The study protocol was approved by the Regional Committee for Medical and Health Research Ethics in South East Norway (2015/134). Findings from the RCT will be disseminated in peer-reviewed publications and conference presentations. Exploratory analyses of potential mediators and moderators will be reported separately. User-friendly outputs will be disseminated to patient advocacy and other relevant organisations. NCT02558647; Pre-results.


Molecular biology and clinical management of arrhythmogenic right ventricular cardiomyopathy/dysplasia.
In the last two decades the extraordinary advances in molecular biology of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) have provided significant insights into our understanding of the disease aetiology by showing that it is a genetic disorder of the cardiac desmosomes and that interactions between mechanical disruption of cell-cell adhesion and defects of desmosomal-mediated intracellular signalling are likely to be involved in the pathogenesis of the ARVC/D phenotype. The discovery of the causative genes for ARVC/D offers the possibility of identifying genetically-affected individuals before potentially malignant clinical phenotype occurs. Moreover, the evaluation of abnormal localisation of desmosomal proteins by immunohistochemical analysis on endomyocardial biopsy samples represents a promising test for ARVC/D diagnosis. Early detection of ARVC/D and preventive therapy of young individuals at highest risk of experiencing sudden cardiac death may be improved by molecular genetic screening within affected families and may alter the clinical management of patients. At present, however, the clinical use of genotyping is limited by the incomplete knowledge of causative mutations and the complex genetic background of the disease, which accounts for the incomplete penetrance and the marked variability of the phenotype expression. This review addresses the advances in the molecular biology of ARVC/D, with particular reference to the genetic basis of the disease, and how these advances have impacted on understanding the disease pathogenesis, on diagnosis and in establishing management strategies.


Modeling the downward transport of (210)Pb in Peatlands: Initial Penetration-Constant Rate of Supply (IP-CRS) model.
The vertical distribution of (210)Pb is commonly used to date peat deposits accumulated over the last 100-150 years. However, several studies have questioned this method because of an apparent post-depositional mobility of (210)Pb within some peat profiles. In this study, we introduce the Initial Penetration–Constant Rate of Supply (IP-CRS) model for calculating ages derived from 210Pb profiles that are altered by an initial migration of the radionuclide. This new, two-phased, model describes the distribution of atmospheric-derived (210)Pb ((210)Pbxs) in peat taking into account both incorporation of (210)Pb into the accumulating peat matrix as well as an initial flushing of (210)Pb through the uppermost peat layers. The validity of the IP-CRS model is tested in four anomalous (210)Pb peat records that showed some deviations from the typical exponential decay profile not explained by variations in peat accumulation rates. Unlike the most commonly used (210)Pb-dating model (Constant Rate of Supply (CRS)), the IP-CRS model estimates peat accumulation rates consistent with typical growth rates for peatlands from the same areas. Confidence in the IP-CRS chronology is also provided by the good agreement with independent chronological markers (i.e. (241)Am and (137)Cs). Our results showed that the IP-CRS can provide chronologies from peat records where (210)Pb mobility is evident, being a valuable tool for studies reconstructing past environmental changes using peat archives during the Anthropocene.


Expression analysis in response to drought stress in soybean: Shedding light on the regulation of metabolic pathway genes.
Metabolomics analysis of wild type Arabidopsis thaliana plants, under control and drought stress conditions revealed several metabolic pathways that are induced under water deficit. The metabolic response to drought stress is also associated with ABA dependent and independent pathways, allowing a better understanding of the molecular mechanisms in this model plant. Through combining an in silico approach and gene expression analysis by quantitative real-time PCR, the present work aims at identifying genes of soybean metabolic pathways potentially associated with water deficit. Digital expression patterns of Arabidopsis genes, which were selected based on the basis of literature reports, were evaluated under drought stress condition by Genevestigator. Genes that showed strong induction under drought stress were selected and used as bait to identify orthologs in the soybean genome. This allowed us to select 354 genes of putative soybean orthologs of 79 Arabidopsis genes belonging to 38 distinct metabolic pathways. The expression pattern of the selected genes was verified in the subtractive libraries available in the GENOSOJA project. Subsequently, 13 genes from different metabolic pathways were selected for validation by qPCR experiments. The expression of six genes was validated in plants undergoing drought stress in both pot-based and hydroponic cultivation systems. The results suggest that the metabolic response to drought stress is conserved in Arabidopsis and soybean plants.


Different patterns of pelvic ureteral endometriosis. What is the best treatment? Results of a retrospective analysis.
Endometriosis is an estrogendependent disease. The incidence of urinary tract endometriosis (UE) increased during the last few years and, nowadays, it ranges from 0.3 to 12% of all women affected by the disease. The ureter is the second most common site affected. The ureteral endometriosis is classified in extrinsic and intrinsic. The aim of this study is to individuate the best treatments for each subset of ureteral endometriosis. 32 patients diagnosed with surgically treated UE were retrospectively reviewed. The patients were divided into 3 subsets (intrinsic UE, extrinsic UE with and without obstruction). The patients with intrinsic UE (n = 10) were treated with laser endoureterotomy. The patients with extrinsic UE (n = 22) were divided in two subsets with (n = 16) and without (n = 6) hydronephrosis. All the patients underwent ureteral stenting, and resection and reimplantation was performed in the first group, and when the mass was > 2.5 cm (n = 3) Boari flap was performed. Laparoscopic ureterolysis (shaving) was performed in the second group. In the extrinsic subset of UE, we obtained an high therapeutic success (84%). Conversely, in the intrinsic subset there was a recurrence rate of the disease in 6/10 of the patients (60%). Ureterolysis seems to be a good treatment in extrinsic UE without obstruction. Resection and reimplantation allows excellent results in the extrinsic UE with obstruction. In the intrinsic subset, the endoureterotomy approach is inadequate.


Alternatively spliced variants of the insulin receptor protein. Expression in normal and diabetic human tissues.
Two insulin receptor mRNA transcripts resulting from alternative splicing of exon 11 in the receptor gene are expressed in a highly regulated tissue-specific fashion. To date, there is no information about the relative abundance of the protein isoforms encoded by these mRNAs in tissues of normal or diabetic subjects. We employed an antibody raised against the peptide sequence encoded by exon 11 to develop a specific immunoprecipitation assay that is capable of determining the fraction of receptors that include this amino acid sequence. The assay is based on the relative ability of the exon 11 specific monoclonal antibody (alpha IR alpha) compared to a nonspecific anti-receptor antiserum (B-2) to immunoprecipitate solubilized receptors that are first labeled with 125I-insulin. The assay was validated using standard curves generated with samples composed of known ratios of the two receptor isoforms. Our results in general confirm observations regarding the relative abundance of the two mRNA species in human tissues, with marked predominance of the exon 11+ isoform in liver, and the exon 11- isoform in leukocytes. Similar amounts of both variants are present in placenta, skeletal muscle, and adipose tissue. In studies with this assay using skeletal muscle extracts from control and noninsulin-dependent diabetes mellitus (NIDDM) subjects, as well as in studies of the two mRNAs in control versus NIDDM muscle using a quantitative polymerase chain reaction assay, we could find no significant difference between control and diabetic subjects. This data contradicts a recent report claiming that normal individuals have only the exon 11- mRNA transcript in their skeletal muscle, whereas NIDDM subjects have similar expression of both mRNAs. Given the emerging evidence that functional differences exist between the two receptor isoforms, these studies are relevant to our understanding of insulin receptor function in health and disease.


Characterization of drug efficacy regions based on dosage and frequency schedules.
This paper proposes a framework to study the drug effect at the molecular level in order to address the following question of current interest in the drug community: Given a fixed total delivered drug, which is better, frequent small or infrequent large drug dosages? A hybrid system model is proposed to link the drug's pharmacokinetic and pharmacodynamic information, and allows the drug effects for different dosages and treatment schedules to be compared. A hybrid model facilitates the modeling of continuous quantitative changes that leads to discrete transitions. An optimal dosage-frequency regimen and the necessary and sufficient conditions for the drug to be effective are obtained analytically when the drug is designed to control a target gene. Then, we extend the analysis to the case where the target gene is part of a genetic regulatory network. A crucial observation is that there exists a "sweet spot," defined as the "drug efficacy region (DER)" in this paper, for certain dosage and frequency arrangements given the total delivered drug. This paper quantifies the therapeutic benefits of dosage regimen lying within the DER. Simulations are performed using MATLAB/SIMULINK to validate the analytical results.


First Report of Leaf Blight of Cyperus iria Caused by Fusarium equiseti in India.
In India, rice (Oryza sativa L.) plays a major role in national food security, with total production of 102.75 million t, harvested from 44 million ha during 2011 (1). Weeds are one of the major causes of losses in rice. Cyperus iria, locally known as chatriwala dela (rice flat sedge), is an annual weed in the Cyperaceae that can reach 50 to 60 cm tall. A leaf blight of C. iria was observed during August 2010 in a 20-ha rice field (cv. Basmati 370) at the University Research Farm, Chatha, Jammu (32° 43' N, 74° 54' E). Symptomatic plants were scattered randomly in the field and had water-soaked spots on the upper leaf surfaces initially, which turned brown after 4 days and developed a yellow halo, resulting in a blighted appearance. The diseased leaves shriveled and infected plants died. Infected C. iria leaf pieces with adjacent healthy tissue were collected, surface-sterilized in 0.1% mercuric chloride for 20 s, then rinsed three times in sterilized distilled water. The pieces were plated onto potato dextrose agar (PDA) and incubated at 27 ± 1°C for 4 days. A pure fungal culture was obtained by single-spore technique on 2% water agar and maintained on PDA at 10°C. The fungus initially produced white mycelium that became brown with age. Dark brown spots or flecks of pigment formed in the agar. Macroconidia were long and slender, with tapered apical cells that were elongated or even whip-like. Basal cells of macroconidia were prominent, foot shaped, and elongated. Macroconidia were 39.55 to 56.74 × 3.75 to 4.5 μm with 3 to 5 septa. Conidiophores were compact, penicillately branched, and arose from lateral branches which initially were one-celled and bore 2 to 4 phialides at the apex. Chlamydospores were intercalary, solitary, in chains or in knots, globose, and 7 to 9 μm in diameter. On the basis of morphological characteristics (2), the fungus was identified as Fusarium equiseti (Corda) Sacc. and deposited in the Indian Type Culture Collection, New Delhi (8424.11). The ITS (internal transcribed spacer) region of rDNA was amplified by PCR with primers ITS1/ITS2 and sequenced. BLASTn analysis of the sequence showed 100% homology with the ITS sequence of F. equiseti in the NCBI database (JN596252.1), and the sequence was deposited in GenBank (KC434458). To confirm pathogenicity of the F. equiseti isolate, 10 seeds of C. iria were planted in five clay pots (each 38 cm in diameter) filled with sterilized soil. Three seedlings were used for the experiment and the remaining seedlings removed from each pot. A total of 15 seedlings (5 pots × 3 seedlings per pot) at the two-leaf stage were spray-inoculated with a 50-ml conidial suspension of the isolate (105 cfu/ml) using a hand atomizer. The control treatment included three seedlings treated similarly with sterile distilled water. The spore suspension was prepared in potato dextrose broth using a culture of the fungus incubated for 10 days and then homogenized at 140 rpm. Tween 20 (1%) was added to the spore suspension. Small spots developed 4 days after inoculation, and the lesions then coalesced into large necrotic areas, resulting in leaf blight 10 days after inoculation. F. equiseti was reisolated from inoculated leaves using the method described above, whereas no fungus was reisolated from control plants, fulfilling Koch's postulates. The isolated fungus displayed the same morphological and cultural features as the original isolate. F. equiseti has been reported to infect Echinochloa spp. in Iran (3), but to our knowledge, this is the first report of F. equiseti infecting C. iria in India. Thus, F. equiseti represents a potential biocontrol agent for managing C. iria in rice fields. References: (1) Anonymous. Direct. Rice Res. Newslett. 10:2, 2012. (2) C. Booth. The Genus Fusarium. Commonwealth Mycological Institute, Kew, Surrey, England, p. 157, 1971. (3) M. R. S. Motlagh. Austral. J. Crop Sci. 4:457, 2010.


Endothelial expression of thrombomodulin is reversibly regulated by fluid shear stress.
The vascular endothelium, by virtue of its position at the interface between blood and the vessel wall, is known to play a critical role in the control of thrombosis and fibrinolysis. Thrombomodulin (TM) is a surface receptor that binds thrombin and is a potent activator of the protein C anticoagulant pathway. Although TM expression is known to be regulated by various cytokines, little is known about its response to ever-present biomechanical stimuli. We have explored the role of fluid shear stress, imparted on the luminal surface of the endothelial cell as a result of blood flow, on the expression of TM mRNA and protein in both bovine aortic endothelial (BAE) and bovine smooth muscle (BSM) cells in an in vitro system. We report in the present study that TM expression is regulated by flow. Subjecting BAE cells to fluid shear stress in the physiological range of magnitude of 15 (moderate shear stress) and 36 (elevated shear stress) dynes/cm2 resulted in a mild transient increase followed by a significant decrease in TM mRNA to 37% and 16% of its resting level, respectively, by 9 hours after the onset of flow. In contrast, shear stress at the low magnitude of 4 dynes/cm2 did not affect TM mRNA levels. The sensitivity of TM mRNA expression by flow was found to be specific to endothelium, since it was not observed in BSM cells exposed to steady laminar shear stress of 15 dynes/cm2. Furthermore, unlike BAE cells, BSM cells did not exhibit altered cell shape nor align in the direction of flow after 24 hours of shear stress at 15 dynes/cm2.(ABSTRACT TRUNCATED AT 250 WORDS)


Prospective study of skin surgery in patients with and without known diabetes.
To study the association between known diabetes and complications after skin surgery. In a 5-year prospective observational study, 7,224 lesions were excised on 4,197 patients in a referral center involving one surgeon in a southern Australian locale. One hundred ninety-six patients with known diabetes (4.7%) underwent 551 excision procedures (7.6%) 4,001 people without diabetes underwent 6,673 procedures. Patients with diabetes were older (72 +/- 13) than those without (64 +/- 17) (p<.001.) Infection incidence was significantly higher in patients with diabetes (4.2%, 23/551) than in those without (2.0%, 135/6,673) (p<.001). There were five bleeds in patients with diabetes (0.9%) versus 47 in those without (0.7%) (p=.58). The incidence of wound dehiscence in patients with diabetes (2) was not different from that in those without (22), (p=.90). Noninfective complications were 1.8% for patients both with diabetes (10/551) and those without (118/6,673). Two thousand three hundred seventy-one flaps resulted in 14 (0.6%) cases of end-flap necrosis, but no case occurred in patients with diabetes. Multivariate analysis using binary logistic regression demonstrated that known diabetes was predictive of infection (odds ratio=1.66, 95% confidence interval=1.05-2.65). Diabetes was not predictive of other complications. Patients with known diabetes suffer more postoperative skin infections than those without. Noninfective complications are similar. Clinicians may consider antibiotic prophylaxis in their patients with diabetes facing high-risk skin surgery.


Improvements in Cycling but Not Handcycling 10 km Time Trial Performance in Habitual Caffeine Users.
Caffeine supplementation during whole-/lower-body exercise is well-researched, yet evidence of its effect during upper-body exercise is equivocal. The current study explored the effects of caffeine on cycling/handcycling 10 km time trial (TT) performance in habitual caffeine users. Eleven recreationally trained males (mean (SD) age 24 (4) years, body mass 85.1 (14.6) kg, cycling/handcycling peak oxygen uptake ( V · peak) 42.9 (7.3)/27.6 (5.1) mL∙kg∙min(-1), 160 (168) mg/day caffeine consumption) completed two maximal incremental tests and two familiarization sessions. During four subsequent visits, participants cycled/handcycled for 30 min at 65% mode-specific V · peak (preload) followed by a 10 km TT following the ingestion of 4 mg∙kg(-1) caffeine (CAF) or placebo (PLA). Caffeine significantly improved cycling (2.0 (2.0)%; 16:35 vs. 16:56 min; p = 0.033) but not handcycling (1.8 (3.0)%; 24:10 vs. 24:36 min; p = 0.153) TT performance compared to PLA. The improvement during cycling can be attributed to the increased power output during the first and last 2 km during CAF. Higher blood lactate concentration (Bla) was reported during CAF compared to PLA (p < 0.007) and was evident 5 min post-TT during cycling (11.2 ± 2.6 and 8.8 ± 3.2 mmol/L; p = 0.001) and handcycling (10.6 ± 2.5 and 9.2 ± 2.9 mmol/L; p = 0.006). Lower overall ratings of perceived exertion (RPE) were seen following CAF during the preload (p < 0.05) but not post-TT. Lower peripheral RPE were reported at 20 min during cycling and at 30 min during handcycling, and lower central RPE was seen at 30 min during cycling (p < 0.05). Caffeine improved cycling but not handcycling TT performance. The lack of improvement during handcycling may be due to the smaller active muscle mass, elevated (Bla) and/or participants' training status.


Critical role of gut microbiota in the production of biologically active, free catecholamines in the gut lumen of mice.
There is increasing interest in the bidirectional communication between the mammalian host and prokaryotic cells. Catecholamines (CA), candidate molecules for such communication, are presumed to play an important role in the gut lumen; however, available evidence is limited because of the lack of actual data about luminal CA. This study evaluated luminal CA levels in the gastrointestinal tract and elucidated the involvement of gut microbiota in the generation of luminal CA by comparing the findings among specific pathogen-free mice (SPF-M), germ-free mice (GF-M), and gnotobiotic mice. Substantial levels of free dopamine and norepinephrine were identified in the gut lumen of SPF-M. The free CA levels in the gut lumen were lower in GF-M than in SPF-M. The majority of CA was a biologically active, free form in SPF-M, whereas it was a biologically inactive, conjugated form in GF-M. The association of GF-M with either Clostridium species or SPF fecal flora, both of which have abundant β-glucuronidase activity, resulted in the drastic elevation of free CA. The inoculation of E. coli strain into GF-M induced a substantial amount of free CA, but the inoculation of its mutant strain deficient in the β-glucuronidase gene did not. The intraluminal administration of DA increased colonic water absorption in an in vivo ligated loop model of SPF-M, thus suggesting that luminal DA plays a role as a proabsorptive modulator of water transport in the colon. These results indicate that gut microbiota play a critical role in the generation of free CA in the gut lumen.


Processed Gingers: Current and Prospective Use in Food, Cosmetic, and Pharmaceutical Industry.
Ginger (Zingiber officinale) has been widely used in traditional medicine, and as raw material for cosmetics, beverages, and health functional foods. However, some adverse effects of ginger have been reported. In addition, the hot and pungent taste of ginger leads to reduced consumption. To overcome these problems, methods for the production of fermented, steamed (or steamed-dried), aged, roasted and beopje ginger have been developed. This review provides an overview and summary of new ginger processing procedures, including methods to reduce the pungent flavor of ginger, extend shelf-life, increase the health-functional compound content, and improve safety. These attempts might improve the consumption of ginger as well as prospective applications of processed ginger for food, cosmetics, and the pharmaceutical industry, also as discussed in various patents.


Totally endoscopic atrial septal defect repair with robotic assistance.
The development of minimally invasive cardiac surgery has been characterized by the performance of increasingly complex operations through progressively smaller incisions. Computer (robotic) enhancement has emerged as a potential facilitator of these procedures, initially by providing enhanced endoscopic camera control and, more recently, by allowing the manipulation of surgical instruments through limited thoracic incisions. This report describes the next step in this progression, namely the performance of an atrial septal defect (ASD) repair entirely through thoracoscopic port incisions. This represents the first U.S. application of robotic technology for totally endoscopic open-heart surgery. A 33-year-old woman with a secundum atrial septal defect underwent totally endoscopic repair through four port incisions by means of the Da Vinci (Intuitive Surgical, Mountain View, CA) robotic surgical system. Cardiopulmonary bypass was achieved peripherally (femoral Estech endoaortic balloon cannula; femoral and right internal jugular venous Bio-medicus cannulae). The myocardium was protected with antegrade cold blood cardioplegia delivered through the distal port of the arterial cannula. After port insertion, the entire operation, including pericardiotomy, bicaval occlusion, atriotomy, atrial septopexy, and atrial closure, was performed by computer-aided control of a camera and two instrument arms manipulated by a surgeon seated 15 feet away. The fourth port was used for suction and suture passage by the patient-side assistant. The aortic cross-clamp time was 43 minutes, and the postoperative transesophageal echocardiogram demonstrated normal ventricular function and the absence of interatrial shunting. The patient was extubated on the night of surgery, was ambulatory within 15 hours, and was discharged on the morning of postoperative day 3, 63 hours after the procedure. At 30-day follow-up, the patient was well and without complaints, and transthoracic echocardiogram confirmed the continued absence of interatrial shunting. Computer-aided robotic surgical technology can be used to perform open-heart procedures with a totally endoscopic approach. The benefits of this approach may include decreased perioperative pain, decreased recovery times, and improved cosmesis and patient acceptance. Clinical trials currently in progress will demonstrate whether this technology will be of reproducible value in the management of patients with intracardiac disease on a larger scale.


Electrophile-modified lipoic derivatives of PDC-E2 elicits anti-mitochondrial antibody reactivity.
Our laboratory has hypothesized that xenobiotic modification of the native lipoyl moiety of the major mitochondrial autoantigen, the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), may lead to loss of self-tolerance in primary biliary cirrhosis (PBC). This thesis is based on the finding of readily detectable levels of immunoreactivity of PBC sera against extensive panels of protein microarrays containing mimics of the inner lipoyl domain of PDC-E2 and subsequent quantitative structure-activity relationships (QSARs). Importantly, we have demonstrated that murine immunization with one such mimic, 2-octynoic acid coupled to bovine serum albumin (BSA), induces anti-mitochondrial antibodies (AMAs) and cholangitis. Based upon these data, we have focused on covalent modifications of the lipoic acid disulfide ring and subsequent analysis of such xenobiotics coupled to a 15mer of PDC-E2 for immunoreactivity against a broad panel of sera from patients with PBC and controls. Our results demonstrate that AMA-positive PBC sera demonstrate marked reactivity against 6,8-bis(acetylthio)octanoic acid, implying that chemical modification of the lipoyl ring, i.e. disruption of the S-S disulfide, renders lipoic acid to its reduced form that will promote xenobiotic modification. This observation is particularly significant in light of the function of the lipoyl moiety in electron transport of which the catalytic disulfide constantly opens and closes and, thus, raises the intriguing thesis that common electrophilic agents, i.e. acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs), may lead to xenobiotic modification in genetically susceptible individuals that results in the generation of AMAs and ultimately clinical PBC.


Rituximab is associated with improved survival for aggressive B cell CNS lymphoma.
The optimal treatment strategy in patients with aggressive B cell central nervous system lymphoma suitable to receive intensive therapy is unknown. The benefit of incorporating rituximab in systemic therapy remains unclear. We performed a retrospective study examining the impact of rituximab in the context of concomitant therapies, including methotrexate, cytarabine, and radiotherapy, in patients treated with curative intent at 4 university teaching hospitals during 1996-2011. A retrospective study of CNS lymphoma cases treated at the participating institutions was performed in accordance with institutional ethical guidelines. Patients were included if they received a diagnosis of primary diffuse large B cell lymphoma of the CNS, were HIV negative, and were treated with curative intent. One hundred twenty patients aged 21-81 years were identified. Rituximab recipients and nonrecipients were similar, except for rituximab recipients being more likely to have received a diagnosis after 2004. The median follow-up of surviving patients was 30 months. The 5-year overall survival was 46%. Univariate analysis revealed age ≤60 years, ECOG performance status ≤1, normal lactate dehydrogenase, diagnosis after 2004, and treatment with cytarabine and rituximab as predictive of favorable overall survival. Multivariate analysis identified age to be an independent predictor of overall survival, with a trend toward improved survival from the other variables that were significant in univariate analyses. In this retrospective analysis, the addition of rituximab to high-dose methotrexate-based chemotherapy in patients with aggressive B cell CNS lymphoma was associated with improved overall survival. Further studies are underway to prospectively validate these findings.


Laryngotracheal rhinosporidiosis.
Rhinosporidiosis is a chronic granulomatous disease caused by Rhinosporidium seeberi. It usually affects mucous membranes of the nose, nasopharynx, and ocular conjunctiva. Cutaneous, laryngeal, tracheal, genital, and bony dissemination is rare. Laryngotracheal involvement poses many diagnostic and therapeutic challenges. A 45-year-old South Indian man presented with complaints of a mass in both nostrils for 2 years, associated with progressive hoarseness of voice and difficulty in breathing for 6 months. Rhinosporidial lesions were seen bilaterally in the nasal cavity. Telescopic and fiberoptic laryngoscopic examinations showed reddish, strawberry-like masses with whitish spots on their surface involving the larynx and trachea. Computed tomography of the head and neck revealed soft-tissue mass lesions involving the bilateral nasal cavities and nasopharynx, extending to the oropharynx and involving the larynx and trachea. A preliminary tracheostomy was performed, followed by direct laryngoscopic excision of the laryngeal lesions and rigid-bronchoscopy-guided excision of the tracheal lesions. The patient was prescribed dapsone and advised to take it for 2 years. At 2 years of follow-up, there was no recurrence.


Comparing the effectiveness of twine- and binder-seeding in the Laminariales species Alaria esculenta and Saccharina latissima.
The continuing expansion of seaweed cultivation could assist in ensuring future global food security. The Laminariales species Alaria esculenta and Saccharina latissima are each cultivated for food across their European ranges. The predominant method for cultivating European kelps involves growing juveniles on twine within a hatchery which is then deployed at a farm site. The associated hatchery and deployment cost of this approach are relatively high. A new and innovative methodology-called binder-seeding-can reduce these costs, but, has yet to be validated. We compare the biomass yield and morphology of A. esculenta and S. latissima cultured using either the traditional twine-longline method or binder-seeding onto AlgaeRope and AlgaeRibbon, specially designed textiles. In a controlled growth experiment, A. esculenta had a similar biomass yield on all materials, but fronds were shorter (23 ± 7%) and thinner on the AlgaeRibbon (42 ± 4%) due to a 3-4-fold higher density of developing sporophytes compared to the twine-longline. In contrast, S. latissima gave a 4-fold higher biomass yield on the AlgaeRibbon in June (4.0 kg m-1), but frond morphology was not different between materials, despite a 4-fold higher sporophyte density on the AlgaeRibbon. The stipe length of both species also increased at the higher sporophyte density on the AlgaeRibbon. The AlgaeRope gave an intermediate response or was similar to the twine-longline. These results show that binder-seeding onto the AlgaeRibbon significantly increases the achieved biomass yield in S. latissima. These results can assist cultivators to select the most appropriate method of kelp cultivation depending on morphological/yield requirements of the end use. Further study is needed on the optimisation of the binder-seeding density and its impact on thallus morphology.


The Birmingham parallel genetic algorithm and its application to the direct DFT global optimisation of Ir(N) (N = 10-20) clusters.
A new open-source parallel genetic algorithm, the Birmingham parallel genetic algorithm, is introduced for the direct density functional theory global optimisation of metallic nanoparticles. The program utilises a pool genetic algorithm methodology for the efficient use of massively parallel computational resources. The scaling capability of the Birmingham parallel genetic algorithm is demonstrated through its application to the global optimisation of iridium clusters with 10 to 20 atoms, a catalytically important system with interesting size-specific effects. This is the first study of its type on Iridium clusters of this size and the parallel algorithm is shown to be capable of scaling beyond previous size restrictions and accurately characterising the structures of these larger system sizes. By globally optimising the system directly at the density functional level of theory, the code captures the cubic structures commonly found in sub-nanometre sized Ir clusters.


Modified pair technique for treatment of hydatid cysts in the spleen.
The aim of this study was to evaluate the results of single-session sclerotherapy with mixture of alcohol and polidocanol and a subsequent injection of albendazole for devisceration of hydatid cysts in the spleen. Eight patients (four women and four men, average age 22.9+/-11.4 with hydatid cyst in the spleen were treated with 10 minutes time of exposure to mixture of ethanol 95% and polidocanol 1%. After that, 2 to 5 ml of albendazole was injected into the cyst cavity. Two patients had 2 cysts. At follow-up the patients were examined with clinical and biochemical examinations, ultrasonography, and serologic test for echinococcal antibody titres. The mean hospital stay was 2.5+/-0.93 days. During the follow-up period, mean cyst diameter decreased from 46+/-16.4 mm to 13.6+/-16.26 mm. In all ten cysts, a reduction of post procedural recolection of fluid over 40% was observed. Five cysts (50%) disappeared during the follow-up period. All cysts (5) smaller then 50 mm in diameter disappeared during follow-up period. After an initial rise, the echinococcal-antibody titres fell progressively and at the last follow-up were negative (< 1: 160) in 7 (88%) patients. No complications were observed, except for pain, fever and urticaria during the first 24-hours after the procedure. Sclerotherapy using only one session and 10 min time of exposure to the mixture of ethanol and polidocanol, and a subsequent injection of albendasole solution represents an effective treatment of hydatid cysts in the spleen. This procedure is even more efficacious for hydatid cyst with diametar smaller then 50 mm.


Efficient translation of the RpoS sigma factor in Salmonella typhimurium requires host factor I, an RNA-binding protein encoded by the hfq gene.
The RpoS transcription factor (also called sigma Sor sigma 38) is required for the expression of a number of stationary-phase and osmotically inducible genes in Escherichia coli. RpoS is also a virulence factor for several pathogenic bacteria, including Salmonella typhimurium. The activity of RpoS is regulated in response to several different signals, at the transcriptional and translational levels as well as by proteolysis. Here we report that host factor I (HF-I), the product of the hfq gene, is required for efficient expression of rpoS in S. typhimurium. HF-I is a small, heat-stable, site-specific RNA-binding protein originally characterized for its role in replication of the RNA bacteriophage Q beta of E. coli. Its role in the uninfected bacterial cell has previously been unknown. Assays of Beta-galactosidase in strains with rpoS-lac fusions, Western blot (immunoblot) analysis, and pulse-labeling and immunoprecipitation of both fusion proteins and native RpoS show that an S. typhimurium hfq mutant has a four- to sevenfold reduction in expression of rpoS that is attributable primarily to a defect in translation. These results add a new level of complexity to the regulation of RpoS activity.


Extracting multiple features in the CID color space for face recognition.
This correspondence presents a novel face recognition method that extracts multiple features in the color image discriminant (CID) color space, where three new color component images, D1, D2, and D3, are derived using an iterative algorithm. As different color component images in the CID color space display different characteristics, three different image encoding methods are presented to effectively extract features from the component images for enhancing pattern recognition performance. To further improve classification performance, the similarity scores due to the three color component images are fused for the final decision making. Experimental results using two large-scale face databases, namely, the face recognition grand challenge (FRGC) version 2 database and the FERET database, show the effectiveness of the proposed method.


Serum levels and genotype distribution of α1-antitrypsin in the general population.
α1-Antitrypsin (AAT) deficiency is one of the commonest rare respiratory disorders worldwide. Diagnosis, assessment of risk for developing chronic obstructive pulmonary disease (COPD), and management of replacement therapy require the availability of precise and updated ranges for protein serum levels. This paper aims to provide ranges of serum AAT according to the main genotype classes in the general population. The authors correlated mean AAT serum levels with the main SERPINA1 variants (M1Ala/M1Val (rs6647), M3 (rs1303), M2/M4 (rs709932), S (rs17580) and Z (rs28929474)) in 6057 individuals enrolled in the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) cohort. The following ranges (5th-95th percentile) of AAT were found in the serum (g/litre): 1.050-1.640 for PI*MM, 0.880-1.369 for PI*MS, 0.730-1.060 for PI*SS, 0.660-0.997 for PI*MZ and 0.490-0.660 for PI*SZ. There was very little overlap in AAT serum levels between genotype classes generally not believed to confer an enhanced health risk (MM and MS) and those associated with an intermediate AAT deficiency and a potentially mildly enhanced health risk (SS, MZ). This work resulted in three important findings: technically updated and narrower serum ranges for AAT according to PI genotype; a suggestion for a population-based 'protective threshold' of AAT serum level, used in decision-making for replacement therapy; and more precise ranges framing the intermediate AAT deficiency area, a potential target for future primary prevention.


Effects of intravenous and intracoronary adenosine 5'-triphosphate as compared with adenosine on coronary flow and pressure dynamics.
Measurements of Doppler derived coronary flow reserve (CFR) and pressure derived fractional flow reserve (FFR) for coronary stenosis assessment depend on the induction of maximal hyperemia. Adenosine is the most widely used pharmacological agent but is expensive and poorly tolerated by some patients. The objective of this study was to test the equivalency of adenosine 5'-triphosphate (ATP) to adenosine in their ability to cause maximal hyperemia as compared with the hyperemic response of complete coronary occlusion in 6 canines. Intracoronary administration of either ATP or adenosine resulted in a significant increase in CFR (2.79+/-0.64 and 2.22+/-0.7 for 10 microgram versus 4. 65+/-1.22 and 4.25+/-0.78 for 100 microgram for ATP and adenosine, respectively, P for trend <0.001) but not reaching the level of coronary occlusion (6.35+/-2.26). Additionally, FFR and CFR were measured in 35 different stenoses using ATP, adenosine, and coronary occlusion. There was an excellent linear correlation between ATP and adenosine for both CFR (R=0.934, P<0.001) and FFR (R=0.985, P<0.001). However, hyperemia with either ATP or adenosine was less than postocclusion hyperemia, resulting in significantly different reserve measurements (CFR: 1.93+/-0.66 and 2.08+/-0.81 versus 2.35+/-0.97, P<0.001; FFR: 0.62+/-0.24 and 0.63+/-0.23 versus 0.58+/-0.2, P<0.001). 1) Step up in dosage of ATP and adenosine beyond currently recommended clinical doses resulted in a significant increase in coronary hyperemia; 2) ATP was equivalent to adenosine for both CFR and FFR; and 3) complete coronary occlusion yielded a better hyperemic response than either drug, indicating that maximal hyperemia was not achieved by either pharmacological stimulus.


A molecular map of G protein alpha chains in microdissected rat nephron segments.
Membrane-associated guanine nucleotide binding proteins regulate many receptor-mediated signals. Heterogeneity of biochemical and functional properties in nephron segments could be due to differences in G protein expression. To ascertain whether such heterogeneity of G proteins is present in various nephron segments, this study examines the distribution and relative abundance of G protein alpha chains in microdissected medullary thick ascending limb, cortical collecting tubules, outer medullary collecting tubules, proximal inner medullary tubules, and distal inner medullary tubules. Reverse transcription and polymerase chain reactions were employed using oligonucleotides encoding highly conserved regions of all known alpha chains. The cDNA was sequenced for alpha chain identification. The alpha i2 versus alpha s distribution was different in the outer medullary collecting tubules, when compared with the medullary thick ascending limb (P < 0.001) or the cortical collecting tubule, the proximal inner medullary tubules, and the distal inner medullary tubules (P < 0.05). These latter four segments did not significantly differ from each other. A similar analysis was applied to the frequently used line of kidney cells, LLC-PK1, whose exact cellular origin remains unclear. Interestingly, we detected both alpha i2 and alpha i3, while only alpha i2 was detected in the rat distal nephron. No alpha o or alpha z reverse transcription PCR products were detected. In contrast alpha 11 and alpha 14 members of the more recently described alpha q family were detected in the outer medullary collecting tubules and the proximal inner medullary tubules, respectively. We conclude that the majority of nephron segments have a relatively constant distribution of G protein alpha chains.


No effect of sex steroids on compensatory muscle hypertrophy.
We studied the effects of sex steroids on muscle weight and oxidative capacity of rat plantaris muscles subjected to functional overload by removal of synergistic muscles. Eight weeks after bilateral synergist removal, plantaris muscles were strikingly hypertrophic compared with unoperated controls. After this period, there were selective alterations in the ability of the muscles to oxidize three substrates of oxidative metabolism. Thus 14CO2 production from [6-14C]glucose and [2-14C]pyruvate was significantly reduced, whereas there was no alteration in 14CO2 production from beta-[3-14C]hydroxybutyrate. Succinate dehydrogenase specific activity was decreased in overloaded muscle. There was no effect of sex hormone status on any of these parameters. Finally, 30 days of functional overload did not influence cytosolic androgen receptor binding. These results are not consistent with the idea that sex steroids and functional overload act synergistically.


The development and evolution of bristle patterns in Diptera.
The spatial distribution of sensory bristles on the notum of different species of Diptera is compared. Species displaying ancestral features have a simple organization of randomly distributed, but uniformly spaced, bristles, whereas species thought to be more derived bear patterns in which the bristles are aligned into longitudinal rows. The number of rows of large bristles on the scutum was probably restricted to four early on in the evolution of cyclorraphous Brachyceran flies. Most species have stereotyped patterns based on modifications of these four rows. The possible constraints placed upon the patterning mechanisms due to growth and moulting within the Diptera are discussed, as well as within hemimetabolous insects. The holometabolic life cycle and the setting aside of groups of imaginal cells whose function is not required during the growth period, may have provided the freedom necessary for the evolution of elaborate bristle patterns. We briefly review the current state of knowledge concerning the complex genetic pathways regulating achaete-scute gene expression and bristle pattern in Drosophila melanogaster, and consider mechanisms for the genetic regulation of the bristle patterns of other species of Diptera.


High-Resolution Structures of the Amyloid-β 1-42 Dimers from the Comparison of Four Atomistic Force Fields.
The dimer of the amyloid-β peptide Aβ of 42 residues is the smallest toxic species in Alzheimer's disease, but its equilibrium structures are unknown. Here we determined the equilibrium ensembles generated by the four atomistic OPLS-AA, CHARMM22*, AMBER99sb-ildn, and AMBERsb14 force fields with the TIP3P water model. On the basis of 144 μs replica exchange molecular dynamics simulations (with 750 ns per replica), we find that the four force fields lead to random coil ensembles with calculated cross-collision sections, hydrodynamics properties, and small-angle X-ray scattering profiles independent of the force field. There are, however, marked differences in secondary structure, with the AMBERsb14 and CHARMM22* ensembles overestimating the CD-derived helix content, and the OPLS-AA and AMBER99sb-ildn secondary structure contents in agreement with CD data. Also the intramolecular beta-hairpin content spanning residues 17-21 and 30-36 varies between 1.5% and 13%. Overall, there are significant differences in tertiary and quaternary conformations among all force fields, and the key finding, irrespective of the force field, is that the dimer is stabilized by nonspecific interactions, explaining therefore its possible transient binding to multiple cellular partners and, in part, its toxicity.


Bacterial pathogens associated with bloody diarrhea in Uruguayan children.
Diarrheal disease continues to be a serious health problem, especially in developing countries. Bloody diarrhea represents approximately 20-30% of all cases and has higher morbidity and mortality. Treatment with antibiotics is beneficial in cases of Shigella, Campylobacter, Yersinia and Salmonella infection, principally in those children with a higher risk of invasive disease. The aims of this study were to detect the bacterial agents associated with bloody diarrhea in children and to determine their antimicrobial susceptibility patterns. Between June 2001 and January 2008, 249 children with bloody diarrhea were studied. Shigella and Shiga toxin-producing Escherichia coli (STEC) were recovered from 48 (19.3%) and 3 (1.2%) of the total of cases, respectively. In 49 out of 249 children, in whom other enteropathogens were investigated, we recovered Campylobacter jejuni from 7 children (14.3%), Salmonella spp. from 2 (4.1%) and Aeromonas spp. from 1 (2%) in addition to Shigella from 7 children (14.3%). Thirty-four (70%) Shigella isolates showed resistance to ampicillin and 13 (27%) to trimethoprim-sulfamethoxazole. All Shigella isolates were susceptible to nalidixic acid, ciprofloxacin and ceftriaxone. Salmonella and STEC isolates were susceptible to all antibiotics assayed. Thus, the use of trimethoprim-sulfamethoxazole or ampicillin would not be appropriate for the empirical treatment of Shigella - associated diarrhea.


The status of neuroendocrine tumor imaging: from darkness to light?
Diagnostic imaging plays a pivotal role in the diagnosis, staging, treatment selection and follow-up for neuroendocrine tumors. The available diagnostic strategies are morphologic imaging, including computed tomography, magnetic resonance imaging (MRI) and ultrasound techniques, and molecular imaging, including scintigraphy with (111)In-pentetreotide and positron emission tomography with (68)Ga-DOTA-peptides, (18)F-DOPA and (11)C-5-HTP. A combination of anatomic and functional techniques is routinely performed to optimize sensitivity and specificity. The introduction of diffusion-weighted MRI and dynamic contrast-enhanced techniques represents a promising advance in radiologic imaging, whereas new receptor-binding peptides, including somatostatin agonists and antagonists, represent the recent most favorable innovation in molecular imaging. Future development includes the short-term validation of these techniques, but in extension also a more comprehensive multilevel integration of biologic information pertaining to a specific tumor and patient, possibly encompassing genomic considerations, currently evolving as a new entity denoted 'precision medicine'. The ideal is a diagnostic sequence that captures the global status of an individual's tumor and encompasses a multidimensional characterization of tumor location, metabolic performance and target identification. To date, advances in imagery have focused on increasing resolution, discrimination and functional characterization. In the future, the fusion of imagery with the parallel analysis of biological and genomic information has the potential to considerably amplify diagnosis.


Device-specific weighted T-score for two quantitative ultrasounds: operational propositions for the management of osteoporosis for 65 years and older women in Switzerland.
The World Health Organization (WHO) criteria for the diagnosis of osteoporosis are mainly applicable for dual X-ray absorptiometry (DXA) measurements at the spine and hip levels. There is a growing demand for cheaper devices, free of ionizing radiation such as promising quantitative ultrasound (QUS). In common with many other countries, QUS measurements are increasingly used in Switzerland without adequate clinical guidelines. The T-score approach developed for DXA cannot be applied to QUS, although well-conducted prospective studies have shown that ultrasound could be a valuable predictor of fracture risk. As a consequence, an expert committee named the Swiss Quality Assurance Project (SQAP, for which the main mission is the establishment of quality assurance procedures for DXA and QUS in Switzerland) was mandated by the Swiss Association Against Osteoporosis (ASCO) in 2000 to propose operational clinical recommendations for the use of QUS in the management of osteoporosis for two QUS devices sold in Switzerland. Device-specific weighted "T-score" based on the risk of osteoporotic hip fractures as well as on the prediction of DXA osteoporosis at the hip, according to the WHO definition of osteoporosis, were calculated for the Achilles (Lunar, General Electric, Madison, Wis.) and Sahara (Hologic, Waltham, Mass.) ultrasound devices. Several studies (totaling a few thousand subjects) were used to calculate age-adjusted odd ratios (OR) and area under the receiver operating curve (AUC) for the prediction of osteoporotic fracture (taking into account a weighting score depending on the design of the study involved in the calculation). The ORs were 2.4 (1.9-3.2) and AUC 0.72 (0.66-0.77), respectively, for the Achilles, and 2.3 (1.7-3.1) and 0.75 (0.68-0.82), respectively, for the Sahara device. To translate risk estimates into thresholds for clinical application, 90% sensitivity was used to define low fracture and low osteoporosis risk, and a specificity of 80% was used to define subjects as being at high risk of fracture or having osteoporosis at the hip. From the combination of the fracture model with the hip DXA osteoporotic model, we found a T-score threshold of -1.2 and -2.5 for the stiffness (Achilles) determining, respectively, the low- and high-risk subjects. Similarly, we found a T-score at -1.0 and -2.2 for the QUI index (Sahara). Then a screening strategy combining QUS, DXA, and clinical factors for the identification of women needing treatment was proposed. The application of this approach will help to minimize the inappropriate use of QUS from which the whole field currently suffers.


Lack of insurance negatively affects trauma mortality in US children.
Uninsured children face health-related disparities in screening, treatment, and outcomes. To ensure payer status would not influence the decision to provide emergency care, the Emergency Medical Treatment and Active Labor Act (EMTALA) was passed in 1986, which states patients cannot be refused treatment or transferred from one hospital to another when medically unstable. Given findings indicating the widespread nature of disparities based on insurance, we hypothesized that a disparity in patient outcome (death) after trauma among the uninsured may exist, despite the EMTALA. Data on patients age 17 years or younger (n = 174,921) were collected from the National Trauma Data Bank (2002-2006), containing data from more than 900 trauma centers in the United States. We controlled for race, injury severity score, sex, and injury type to detect differences in mortality among the uninsured and insured. Logistic regression with adjustment for clustering on hospital was used. Crude analysis revealed higher mortality for uninsured children and adolescents compared with the commercially or publicly insured (odds ratio [OR] 2.97; 95% confidence interval [CI], 2.64-3.34; P < .001). Controlling for sex, race, age, injury severity, and injury type, and clustering within hospital facility, uninsured children had the highest mortality compared with the commercially insured (OR, 3.32; 95% CI, 2.95-3.74; P < .001], whereas children and adolescents with Medicaid also had higher mortality (OR, 1.19; 95% CI, 1.07-1.33; P = .001). These results demonstrate that uninsured and publicly insured American children and adolescents have higher mortality after sustaining trauma while accounting for a priori confounders. Possible mechanisms for this disparity include treatment delay, receipt of fewer diagnostic tests, and decreased health literacy, among others.


An enantioselective artificial Suzukiase based on the biotin-streptavidin technology.
Introduction of a biotinylated monophosphine palladium complex within streptavidin affords an enantioselective artificial Suzukiase. Site-directed mutagenesis allowed the optimization of the activity and the enantioselectivity of this artificial metalloenzyme. A variety of atropisomeric biaryls were produced in good yields and up to 90% ee. The hybrid catalyst described herein shows comparable TOF to the previous aqueous-asymmetric Suzuki catalysts, and excellent stability under the reaction conditions to realize higher TON through longer reaction time.


Mutations in the VPS45 gene, a SEC1 homologue, result in vacuolar protein sorting defects and accumulation of membrane vesicles.
Genetic analyses of vacuolar protein sorting in Saccharomyces cerevisiae have uncovered a large number of mutants (vps) that missort and secrete vacuolar hydrolases. A small subset of vps mutants exhibit a temperature-conditional growth phenotype and show a severe defect in the localization of soluble vacuolar proteins, yet maintain a near-normal vacuole structure. Here, we report on the cloning and characterization of the gene affected in one of these mutants, VPS45, which has been found to encode a member of a protein family that includes the yeast proteins Sec1p, Sly1p and Vps33p, as well as n-Sec1, UNC18 and Rop from other eukaryotic organisms. These proteins are thought to participate in vesicle-mediated protein transport events. Polyclonal antiserum raised against a TrpE-Vps45 fusion protein specifically detects a stable 67 kDa protein in labeled yeast cell extracts. Subcellular fractionation studies demonstrate that the majority of Vps45p is associated with a high-speed membrane pellet fraction that includes Golgi, transport vesicles and, potentially, endosomal membranes. Significantly, this fraction lacks ER, vacuole and plasma membranes. Overexpression of Vps45p saturates the sites with which Vps45p associates. A vps45 null mutant accumulates vesicles, many of which were found to be present in large clusters. This accumulation of potential transport vesicles indicates that Vps45p may facilitate the targeting and/or fusion of these vesicles in the vacuolar protein sorting pathway.


Benzimidazole derivatives as new serotonin 5-HT6 receptor antagonists. Molecular mechanisms of receptor inactivation.
On the basis of our previously described pharmacophore model for serotonin 5-HT(6) receptor (5-HT(6)R) antagonists, we have designed, synthesized, and pharmacologically characterized a series of benzimidazole derivatives 1-20 that represent a new family of potent antagonists at the human 5-HT(6)R. Site-directed mutagenesis and a beta(2)-adrenoceptor-based homology model of the 5-HT(6)R were used to predict the mode of binding of antagonist SB-258585 and the new synthesized ligands. Substitution of W6.48, F6.52, or N6.55 by Ala fully impedes compound 4 to block 5-HT-induced activation. Thus, we propose that D3.32 in TM 3 anchors the protonated piperazine ring, the benzimidazole ring expands parallel to EL 2 to hydrogen bond N6.55 in TM 6, and the aromatic ring is placed between TMs 3 and 5 in CH(2)-containing compounds and between TMs 3 and 6 in CO-containing compounds. This combined experimental and computational study has permitted to propose the molecular mechanisms by which the new benzimidazole derivatives act as 5-HT(6)R antagonists.


Pharmacist initiation of postexposure doxycycline for Lyme disease prophylaxis.
OBJECTIVES To enhance public access to prophylaxis for Lyme disease following an identified Ixodes scapularis tick bite through pharmacist-initiated antibiotic therapy and to assess patient satisfaction with the pharmacy-based service provided. SETTING Independent community pharmacy in Charlestown, RI, from May to October 2012. PRACTICE DESCRIPTION Under a collaborative practice agreement, trained pharmacists at an independent pharmacy identified patients eligible for postexposure antibiotic prophylaxis following attachment and removal of an I. scapularis tick (commonly known as a deer tick) and dispensed two 100 mg tablets of doxycycline. Patients were included if they were 18 years or older, provided informed consent, had an estimated time of tick attachment of 36 hours or more, had the tick removed within 72 hours of visit, denied contraindications to doxycycline therapy, and reported telephone access for follow-up. Patients enrolled in the study protocol were given counseling related to doxycycline, signs and symptoms of Lyme disease, and future tick prevention strategies. PRACTICE INNOVATION Pharmacist initiation of doxycycline prophylaxis has not been described in the literature previously. Successful pharmacist initiation of antibiotic prophylaxis may have broader implications for states with endemic Lyme disease or other infectious disease public health concerns. MAIN OUTCOME MEASURES Patient self-reported adverse outcomes and satisfaction with the pharmacy-based service. RESULTS Eight patients enrolled in the study and completed the follow-up survey. The results indicated a high level of satisfaction with the pharmacy services provided, with no reports of the subsequent development of Lyme disease symptoms or major adverse events. CONCLUSION The project has expanded to three community pharmacy sites in southern Rhode Island based on this experience. Similar pharmacy-based collaborative practice models should be considered in highly endemic Lyme disease areas.


Infection-associated FUT2 (Fucosyltransferase 2) genetic variation and impact on functionality assessed by in vivo studies.
The secretor (Se)/nonsecretor (se) histo-blood group variation depends on the action of the FUT2 enzyme and has major implications for human susceptibility to infections. To characterize the functionality of FUT2 variants, we assessed the correlation between saliva phenotypes and sequence variation at the FUT2 gene in sixty seven individuals from northern Portugal. While most non-secretor haplotypes were found to carry the 428G > A nonsense mutation in association with a 739G > A missense substitution, we have also identified a recombinant haplotype carrying the 739*A allele together with the efficient 428*G variant in individuals with the Se phenotype. This finding suggested, in contrast to previous results, that the 739*A allele encodes an efficient Se allele. To test this hypothesis we evaluated the in vivo enzyme activity of full coding expression constructs in transient transfection of CHO-K1 cells using FACS (fluorescence-activated cell sorting) analysis and expression of type 2 and type 3 chain H structures as read out. We detected FUT2 activity for the 739*A expression construct, demonstrating that the 739G > A substitution is indeed not inactivating. In accordance with the hypothesis that FUT2 is under long standing balancing selection, we estimated that the time depth of FUT2 global genetic variation is as old as 3 million years. Age estimates of specific variants suggest that the 428G > A mutation occurred at least 1.87 million years ago while the 739G > A substitution is about 816,000 years old. The 385A > T missense mutation underlying the non-secretor phenotype in East Asians appears to be more recent and is likely to have occurred about 256,000 years ago.


Segmentation, Inference and Classification of Partially Overlapping Nanoparticles.
This paper presents a method that enables automated morphology analysis of partially overlapping nanoparticles in electron micrographs. In the undertaking of morphology analysis, three tasks appear necessary: separate individual particles from an agglomerate of overlapping nano-objects; infer the particle's missing contours; and ultimately, classify the particles by shape based on their complete contours. Our specific method adopts a two-stage approach: the first stage executes the task of particle separation, and the second stage conducts simultaneously the tasks of contour inference and shape classification. For the first stage, a modified ultimate erosion process is developed for decomposing a mixture of particles into markers, and then, an edge-to-marker association method is proposed to identify the set of evidences that eventually delineate individual objects. We also provided theoretical justification regarding the separation capability of the first stage. In the second stage, the set of evidences become inputs to a Gaussian mixture model on B-splines, the solution of which leads to the joint learning of the missing contour and the particle shape. Using twelve real electron micrographs of overlapping nanoparticles, we compare the proposed method with seven state-of-the-art methods. The results show the superiority of the proposed method in terms of particle recognition rate.


Detecting and adjusting for artifacts in fMRI time series data.
We present a new method to detect and adjust for noise and artifacts in functional MRI time series data. We note that the assumption of stationary variance, which is central to the theoretical treatment of fMRI time series data, is often violated in practice. Sporadic events such as eye, mouth, or arm movements can increase noise in a spatially global pattern throughout an image, leading to a non-stationary noise process. We derive a restricted maximum likelihood (ReML) algorithm that estimates the variance of the noise for each image in the time series. These variance parameters are then used to obtain a weighted least squares estimate of the regression parameters of a linear model. We apply this approach to a typical fMRI experiment with a block design and show that the noise estimates strongly vary across different images and that our method detects and appropriately weights images that are affected by artifacts. Furthermore, we show that the noise process has a global spatial distribution and that the variance increase is multiplicative rather than additive. The new algorithm results in significantly increased sensitivity in the ability to detect regions of activation. The new method may be particularly useful for studies that involve special populations (e.g., children or elderly) where sporadic, artifact-generating events are more likely.


Validation of an imaging based cardiovascular risk score in a Scottish population.
A radiological risk score that determines 5-year cardiovascular disease (CVD) risk using routine care CT and patient information readily available to radiologists was previously developed. External validation in a Scottish population was performed to assess the applicability and validity of the risk score in other populations. 2915 subjects aged ≥40 years who underwent routine clinical chest CT scanning for non-cardiovascular diagnostic indications were followed up until first diagnosis of, or death from, CVD. Using a case-cohort approach, all cases and a random sample of 20% of the participant's CT examinations were visually graded for cardiovascular calcifications and cardiac diameter was measured. The radiological risk score was determined using imaging findings, age, gender, and CT indication. Performance on 5-year CVD risk prediction was assessed. 384 events occurred in 2124 subjects during a mean follow-up of 4.25 years (0-6.4 years). The risk score demonstrated reasonable performance in the studied population. Calibration showed good agreement between actual and 5-year predicted risk of CVD. The c-statistic was 0.71 (95%CI:0.67-0.75). The radiological CVD risk score performed adequately in the Scottish population offering a potential novel strategy for identifying patients at high risk for developing cardiovascular disease using routine care CT data.


Multicenter study of unicompartmental knee revision. PCA, Marmor, and St Georg compared in 3,777 cases of arthrosis.
The prospective Swedish Knee Arthroplasty Project contained 772 PCA, 1564 Marmor and 1441 St Georg unicompartment prostheses, implanted for gonarthrosis during the period December 1983-July 1990. Follow-up was performed in September 1991. There was a significant difference in the cumulative revision rate after only 2 years, increasing to 15 percent for the PCA, compared with 5-7 percent for the two other types. The difference between PCA and Marmor/St Georg was loosening of the femoral component. Major polyethylene wear was noted in a quarter of the revised PCA tibial components. The wear pattern of Marmor/St Georg was not analyzed in this study.


Phantoms in the snow: Canadians' use of health care services in the United States.
To examine the extent to which Canadian residents seek medical care across the border, we collected data about Canadians' use of services from ambulatory care facilities and hospitals located in Michigan, New York State, and Washington State during 1994-1998. We also collected information from several Canadian sources, including the 1996 National Population Health Survey, the provincial Ministries of Health, and the Canadian Life and Health Insurance Association. Results from these sources do not support the widespread perception that Canadian residents seek care extensively in the United States. Indeed, the numbers found are so small as to be barely detectible relative to the use of care by Canadians at home.


[Ethical considerations regarding the use of transcranial magnetic stimulation in the treatment of depression].
Transcranial magnetic stimulation (TMS) has proved effective in the treatment of depression. However, the step that was needed to progress from positive research results to the actual use of TMS to treat patients has raised a number of ethical concerns. The concerns extend beyond matters such as the safety of the technique, the patient's right of access to therapy and the patient's informed consent; ethics are involved because the new treatment can be mind-bending and can interfere with the patient's autonomy and decision-making capacity. To discuss ethical issues raised by the use of TMS in the treatment of depression. We reviewed the relevant scientific literature. The effects of the treatment on the patient's genuine wishes and on his or her views on the efficacy of the treatment are technique-related ethical issues that have not yet been adequately addressed. Furthermore, the effects of TMS on the patient's autonomy and mental capacity and the 'last resort' argument in relation to the effectiveness of the therapy are context-related considerations that warrant further discussion. There will have to be more research and discussion among researchers and clinicians about specific ethical questions before TMS can take its rightful place in clinical practice.