Tempo-Spectral EEG Biomarkers for Odour Identification.
Different odours evoke different activity in the brain. Among the non-invasive methods, electroencephalogram (EEG) is the most widely used mode to measure brain activity. While there has been significant work around EEG signal analysis, studies in the area of EEG with odour as stimuli is nascent. In this paper, we experiment and study different EEG biomarkers with an aim to understand which biomarker shows promise for odour identification. We show, on a widely used and publicly available data-set, through a series of experiments that it is possible to get a Subject Dependent (SD) odour classification accuracy of over 90%, using a set of tempo-spectral EEG biomarkers. We further experiment with Subject Independent (SI) odour classification, which has not been addressed and show that the performance drops to under 50% for SI odour classification.Clinical Relevance - The study shows that the same odour evoke different brain responses from the subject.


Does adherence therapy improve medication adherence among patients with schizophrenia? A systematic review.
Non-adherence to medication is highly prevalent in patients with schizophrenia. Adherence therapy aims to improve medication adherence of these patients by applying techniques of cognitive behavioural therapy, psycho-education, and motivational interviewing. Even though adherence therapy is frequently discussed and researched, its effectiveness is still uncertain. This paper aims to review the effectiveness of adherence therapy on the medication adherence of patients with schizophrenia. To this end, six electronic databases were systematically searched for randomized, controlled trials on adherence therapy from January 2002 to March 2013. Four trials met the inclusion criteria and were incorporated into the review. The findings suggest that adherence therapy does not improve patients' medication adherence in comparison to treatment as usual or a control intervention. However, all the studies reviewed showed high-adherence ratings at baseline. Thus, further well-designed studies that target adherence therapy to patients who are non-adherent to their medication are needed for a more profound understanding of its effectiveness. In addition, if adherence therapy is aimed not only at improving medication adherence, but also to reach an agreement whereby the patient's decision not to take his medication is accepted, the shared decision-making process needs to be assessed as well.


Characterization of UDP-glucuronosyltransferases (UGTS) involved in the metabolism of troglitazone in rats and humans.
UDP-glucuronosyltransferases (UGTs) involved in troglitazone glucuronidation in rats and humans have been characterized to support the previous toxicity study on troglitazone in Gunn rats and to examine whether the UGT polymorphism or inhibition of bilirubin metabolism is related to the clinically reported rare cases of liver failure. The experiments using Gunn rats revealed that UGT1 enzymes are not involved in troglitazone glucuronidation and that the responsible enzyme in rats was suggested to be UGT2B2, an androsterone UGT, by inhibition studies. In humans, contribution of UGT1A1 was estimated to be about 30% of the total troglitazone glucuronidation by UGTs, using human liver microsomes and recombinant UGTs. Other UGT1 and UGT2 enzymes seem to be responsible for the rest of the troglitazone glucuronidation in humans. The multiplicity of UGTs involved in troglitazone glucuronidation in humans may allow even patients lacking bilirubin UGT (UGT1A1) activity to produce troglitazone glucuronide. These observations suggest that the polymorphism of UGT is not the reason behind the liver failure induced by the troglitazone treatment, and troglitazone does not inhibit bilirubin glucuronidation in clinical treatment. In addition, the increased bilirubin level in the blood of patients who have troglitazone-induced liver failure is a consequence of liver injury and not due to inhibition of bilirubin glucuronidation by troglitazone.


[A case of red blood cell(RBC) agglutination on peripheral blood smear and effect of cefpirom sulfate].
We observed red blood cell (RBC) agglutination on peripheral blood smear and an abnormal RBC distribution histogram that suggested the influence of cefpirom sulfate. The patient was receiving cefpirom sulfate when RBC agglutination and the abnormal pattern were recognized, but these abnormalities disappeared as soon as the drug was withdrawn. When the peripheral blood sample was re-examined after warming for an hour at 37 degrees C, the abnormal pattern almost disappeared and RBC agglutination became minimal. We also observed cold agglutination reaction by using O type washed RBCs from a healthy individual that were reacted with cefpirom sulfate, but found only minimal agglutination at RT. As the drug concentration and plasma concentration were increased, we observed more agglutination at 4 degrees C, but this agglutination disappeared after incubation for an hour at 37 degrees C. The cold agglutinin titer was normal. We thus believe that the cause of RBC agglutination in this case was caused by cefpirom sulfate.


MSX2 represses tumor stem cell phenotypes within oral squamous cell carcinomas via SOX2 degradation.
Oral squamous cell carcinoma (OSCC) is the sixth malignancy in the world with high incidence. The MSX2 (muscle segment homeobox 2)-Sry-related high-mobility box 2 (SOX2) signaling pathway plays a significant role in maintaining cancer stem cells, which are the origin of malignancy, leading to unfavorable outcomes in several carcinomas. This study aims to elucidate the mechanisms through which the MSX2-SOX2 pathway controls the cancer stem cell-like characterization in OSCC. The results showed that MSX2 was remarkably downregulated in OSCC and that the MSX2 expression level was related to unfavorable outcomes in patients with OSCC. Meanwhile, the MSX2 expression level was lower in the CD44+/CD24- population than in the other populations of OSCC cells. The OSCC2 cells exhibited decreased percentage of CD44+/CD24- cells, owing to MSX2 overexpression but increased owing to MSX2 knockdown. Moreover, a negative correlation was observed between MSX2 expression and is SOX2 transcriptional levels in different populations within the OSCC cell lines. Regarding the loss and gain of function, cancer stem cell phenotypes such as tumor globular formation, CD44+ subpopulation cells, and stem cell-associated gene expression were enhanced by MSX2 knockdown in OSCC CD44+/CD24- cells but decreased by MSX2 overexpression in other OSCC populations. However, these events were counteracted by the co-knockdown or SOX2 overexpression. Cells with MSX2 overexpression or knockdown formed smaller or bigger cancers in vivo, thereby showing a lower or a higher tumor incidence, respectively. Thus, our results confirm that MSX2 has a tumor suppression effect on the cancer stem cell phenotypes of OSCC and indicate that the MSX2-SOX2 signaling pathway could be a useful target for OSCC treatment.


Catching errors with in vivo EPID dosimetry.
The potential for detrimental incidents and the ever increasing complexity of patient treatments emphasize the need for accurate dosimetric verification in radiotherapy. For this reason, all curative treatments are verified, either pretreatment or in vivo, by electronic portal imaging device (EPID) dosimetry in the Radiation Oncology Department of The Netherlands Cancer Institute-Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands. Since the clinical introduction of the method in January 2005 until August 2009, treatment plans of 4337 patients have been verified. Among these plans, 17 serious errors were detected that led to intervention. Due to their origin, nine of these errors would not have been detected with pretreatment verification. The method is illustrated in detail by the case of a plan transfer error detected in a 5 x 5 Gy intensity-modulated radiotherapy (IMRT) rectum treatment. The EPID reconstructed dose at the isocenter was 6.3% below the planned value. Investigation of the plan transfer chain revealed that due to a network transfer error, the plan was corrupted. 3D analysis of the acquired EPID data revealed serious underdosage of the planning target volume: On average 11.6%, locally up to 20%. This report shows the importance of in vivo (EPID) dosimetry for all treatment plans as well as the ability of the method to assess the dosimetric impact of deviations found.


Physical measurements with a high-energy proton beam using liquid and solid tissue substitutes.
The measurement of the physical parameters of a high-energy proton beam, using a range of liquid and solid tissue substitutes, is described. The system, the detectors used and the experimental verification of the tissue equivalence of the new tissue substitutes is presented. The measurements with the scattered but uncollimated proton beam in muscle- and brain-equivalent liquids and in water are compared to similar data obtained from the scattered but collimated beam. The effect of lung, fat and bone on the dose distributions in composite phantoms is also investigated and the necessary corrections established. A simulated patient treatment indicated that the Bragg peak can be positioned with an error not exceeding +/- 0.5 mm.


[Analgesic efficacy of magnetoledotherapy in patients with low back pain syndromes].
Low back pain syndromes most often occur due to overloading of the musculoskeletal system. The cause is a frequent, improper lifting of heavy objects, most commonly by those working physically, with repetitive movements of bending and straightening of the trunk (turning and bending with load). This problem affects not only adults but also children and adolescents. There is a growing interest in new forms of analgesic therapy nowadays, especially in those that exhibit synergistic therapeutic effects. The aim of this work is to evaluate the analgesic efficacy of magnetoledotherapy in patients with lumbar--sacrum spinal pain syndromes caused by joints degenerative changes. The examination was carried out in 66 patients of both sexes aged 30 to 76 (average 54.7 +/- 13.8) with low back pain syndrome caused by spinal degenerative changes. The patients were divided into three groups according to the applied analgesic therapy (magnetoledotherapy, magnetostimulation, TENS currents). Level of pain has been evaluated four times in all patients--before the start of therapy and after 5, 10 and 15 applications with the use of the modified Laitinen Questionnaire and Visual-Analoque Scale (VAS). Post therapy levels of pain in the studied patients decreased significantly. According to Laitinen questionnaire, the greatest improvement was observed in the group treated with magnetoledotherapy and TENS currents and the smallest improvement was observed in the group treated with magnetostimulation. 1. Magnetoledotherapy shows significant analgesic efficacy in patients with low back pain syndrome and shows no side effects. 2. Concurrent application of both the infrared radiation generated by LED's and magnetostimulation synergistically reinforces analgesic effect in patients with low back pain syndrome, especially in level of pain and frequency of its occurrence, which results in the increase of movement activity and decrease in administration of analgesics.


Quantifying the thermodynamics of protein unfolding using 2D NMR spectroscopy.
A topic that has attracted considerable interest in recent years is the possibility to perform thermodynamic studies of proteins directly in-cell or in complex environments which mimic the cellular interior. Nuclear magnetic resonance (NMR) could be an attractive technique for these studies but its applicability has so far been limited by technical issues. Here, we demonstrate that 2D NMR methods can be successfully applied to measure thermodynamic parameters provided that a suitable choice of the residues used for the calculation is made. We propose a new parameter, named RAD, which reflects the level of protection of a specific amide proton in the protein core and can guide through the selection of the resonances. We also suggest a way to calibrate the volumes to become independent of technical limitations. The methodology we propose leads to stability curves comparable to that calculated from CD data and provides a new tool for thermodynamic measurements in complex environments.


Increased frequency of germline BRCA2 mutations associates with prostate cancer metastasis in a racially diverse patient population.
Germline mutations in BRCA2 have been linked to a higher risk of prostate cancer (PCa), and high frequency of BRCA1 and BRCA2 (BRCA1/2) gene alterations was recently reported in metastatic castration-resistant PCa specimens. Mutations in BRCA2 vary in racial and ethnic groups including African-American (AA) and Caucasian-American (CA) populations. BRCA1 and BRCA2 genes were sequenced (Ion AmpliSeq targeted sequencing) in archived blood DNA specimens in 1240 PCa patients, including 30% AA patients, in three different cohorts: localized early stage (T2) PCa (N = 935); advanced PCa (50% T3-4) (N = 189); and metastatic PCa (N = 116). The sequences were analyzed for known and novel mutations in BRCA1/2. Statistical analyses were performed to determine associations of the mutations with clinico-pathological parameters. BRCA2 mutations with known pathogenic annotation were significantly more prevalent in men with advanced and metastatic PCa (3.1%) compared to patients with an organ-confined disease (0.7%). AA patients carried more frequently BRCA1/2 variants of unknown significance (VUS) when compared to Caucasian Americans (4.6 vs. 1.6%, respectively). Significantly, pathogenic BRCA2 mutations in men with localized early stage PCa increased the risk of distant metastasis. Germline variants of unknown significance in BRCA1/2 are more frequent in AA than CA PCa patients; however, the prevalence of pathogenic mutations were similar across the races. Patients carrying BRCA2 pathogenic mutations are more likely to progress to metastasis.


Primary Care Appointment Availability and the ACA Insurance Expansions.
In the current debate in Congress over the Affordable Care Act (ACA), the issue of provider access is a major concern. Fortunately, our 10-state audit study published in JAMA Internal Medicine finds that primary care appointment availability for new patients with Medicaid increased 5.4 percentage points between 2012 and 2016 and remained stable for patients with private coverage. Over the same period, both Medicaid patients and the privately insured experienced a one-day increase in median wait times. Higher appointment availability for Medicaid patients is a surprising result given the increase in demand for care from millions of new Medicaid enrollees. In this Issue Brief, we summarize our study's findings, expand on possible explanations, and extend the analysis by examining the relationship between appointment availability and state-level Medicaid expansions. We find that access to primary care increased for Medicaid patients only in states that extended Medicaid eligibility to low-income, nonelderly adults. Combined, these results suggest coverage provisions in the ACA have not overwhelmed primary care capacity.


Prevalence of adult overweight and obesity in 20 European countries, 2014.
Monitoring obesity and overweight prevalence is important for assessing interventions aimed at preventing or reducing the burden of obesity. This study aimed to provide current data regarding the prevalence of overweight and obesity of adults, from 20 European countries. Participants were 34 814 (16 482 men) adults with mean age 50.8 ± 17.7. Data from European Social Survey round 7, 2014, were analysed. Body mass index (BMI) was calculated from self-reported height and weight. The proportion of underweight was only 2%, and 44.9% for normal weight. Overweight and obese accounted for 53.1%. More men than women were overweight (44.7% vs. 30.5%). Older adults were significantly more overweight (42.4%) and obese (20.9%) than middle age and younger adults. Retired people account for a greater proportion of overweight (42.0%) and obese (21.5%), when compared with employed, unemployed and students. People from rural areas were significantly more overweight (39.1 vs. 36.1%) and obese (17.0 vs. 15.3%) than those who lived in urban areas. The estimates indicate that the highest prevalence of overweight was in Czech Republic (45.2%), Hungary (43.7%) and Lithuania (41.7%). For obesity, Slovenia (20.8%), Estonia (19.7%) and the United Kingdom (19.2%) were the countries with the highest prevalence. Even though data was self-reported, and individuals tend to overestimate their height and underestimate their weight, the prevalence of overweight and obesity is considered high. More than half of the European population is overweight and obese. This study strengthens and updates the claims of an excessive weight epidemic in Europe.


Fast Dynamical Coupling Enhances Frequency Adaptation of Oscillators for Robotic Locomotion Control.
Rhythmic neural signals serve as basis of many brain processes, in particular of locomotion control and generation of rhythmic movements. It has been found that specific neural circuits, named central pattern generators (CPGs), are able to autonomously produce such rhythmic activities. In order to tune, shape and coordinate the produced rhythmic activity, CPGs require sensory feedback, i.e., external signals. Nonlinear oscillators are a standard model of CPGs and are used in various robotic applications. A special class of nonlinear oscillators are adaptive frequency oscillators (AFOs). AFOs are able to adapt their frequency toward the frequency of an external periodic signal and to keep this learned frequency once the external signal vanishes. AFOs have been successfully used, for instance, for resonant tuning of robotic locomotion control. However, the choice of parameters for a standard AFO is characterized by a trade-off between the speed of the adaptation and its precision and, additionally, is strongly dependent on the range of frequencies the AFO is confronted with. As a result, AFOs are typically tuned such that they require a comparably long time for their adaptation. To overcome the problem, here, we improve the standard AFO by introducing a novel adaptation mechanism based on dynamical coupling strengths. The dynamical adaptation mechanism enhances both the speed and precision of the frequency adaptation. In contrast to standard AFOs, in this system, the interplay of dynamics on short and long time scales enables fast as well as precise adaptation of the oscillator for a wide range of frequencies. Amongst others, a very natural implementation of this mechanism is in terms of neural networks. The proposed system enables robotic applications which require fast retuning of locomotion control in order to react to environmental changes or conditions.


Active surveillance management of head and neck paragangliomas: case series and review of the literature.
Head and neck paragangliomas are rare. They are usually slow-growing, benign, non-catecholamine secreting tumours, traditionally treated with surgical excision. Complications of surgical excision include lower cranial nerve palsies, stroke and death. A retrospective case note analysis was conducted of patients with head and neck paragangliomas treated with a watch-and-scan policy from March 2003 to September 2015, and the relevant literature was reviewed. Fifteen head and neck paragangliomas were identified. None of the patients developed a new lower cranial nerve palsy or progression of their presenting hearing loss during the follow-up period. Five patients displayed an increase in maximum linear dimension of 4 mm over an average of 57.4 months. A review of the literature showed that a watch-and-surveillance scan policy is evolving as a treatment option for head and neck paragangliomas without malignant risk factors. Readily available surveillance scanning in head and neck paragangliomas enables the monitoring of head and neck paragangliomas, which may allow for avoidance of major surgery.


New treatment options in the management of glioblastoma multiforme: a focus on bevacizumab.
Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults and carries the poorest prognosis. Despite recent progress in molecular biology, neuro-imaging and neuro-surgical care, the management of patients with GBM continues to harbor significant challenges. Survival after diagnosis is poor even with the most aggressive approach using multimodality therapy. Although the etiology of malignant gliomas is not known, the dependency of tumor growth on angiogenesis has identified this pathway as a promising therapeutic target. Bevacizumab was the first antiangiogenic therapy approved for use in cancer and received accelerated Food and Drug Administration approval for the treatment of recurrent GBM in 2009, the first new drug for this disease in over a decade. This review describes the rationale behind the treatment of GBM with bevacizumab. The pharmacology, efficacy, safety and tolerability of bevacizumab will also be reviewed.


Which imaging modality is superior for prediction of response to neoadjuvant chemotherapy in patients with triple negative breast cancer?
Background and Objectives. Triple negative breast cancer (TNBC) has been shown to be generally chemosensitive. We sought to investigate the utility of mammography (MMG), ultrasonography (US), and breast magnetic resonance imaging (MRI) in predicting residual disease following neoadjuvant chemotherapy for TNBC. Methods. We identified 148 patients with 151 Stage I-III TNBC treated with neoadjuvant chemotherapy. Residual tumor size was estimated by MMG, US, and/or MRI prior to surgical intervention and compared to the subsequent pathologic residual tumor size. Data were compared using chi-squared test. Results. Of 151 tumors, 44 (29%) did not have imaging performed prior to surgical treatment. Thirty-eight (25%) tumors underwent a pathologic complete response (pCR), while 113 (75%) had residual invasive disease. The imaging modality was accurate to within 1 cm of the final pathologic residual disease in 74 (69%) cases and within 2 cm in 94 (88%) cases. Groups were similar with regards to patient age, race, tumor size and grade, and clinical stage (P > 0.05). Accuracy to within 1 cm was the highest for US (83%) and the lowest for MMG (56%) (P < 0.05). Conclusions. Breast US and MRI were more accurate than MMG in predicting residual tumor size following neoadjuvant chemotherapy in patients with TNBC. None of the imaging modalities were predictive of a pCR.


Sarcomas of the head and neck at Kenyatta National Hospital.
To determine the pattern of occurrence of sarcomas afflicting the neck and craniofacial region. A retrospective study (1982-1991). Cancer Registry, Kenyatta National Hospital, Nairobi, Kenya. Examination was performed of the cancer records in the registry over the period 1982 to 1991 inclusive. Histopathological types of the sarcomas were then analysed to indicate the numbers that occurred per year; and also the pattern of occurrence according to age groups, gender and site. Of the 10,897 whole body neoplasms, 985 were sarcomas. Among these sarcomas, 160 (16%) were located in the neck and craniofacial region. The histopathological types of the neoplasms included Kaposi's sarcoma (39%), osteosarcoma (23%), rhabdomyosarcoma (21%), fibrosarcoma (13%), chondrosarcoma (two per cent), malignant fibrous histiocytoma (one per cent) and dermatofibrosarcoma protuberans (one per cent). The results of this investigation, in concordance with those of other series worldwide, indicate that the various sarcomas afflicting the neck and craniofacial area are generally rare.


[Recommendations from CDC for the prevention of catheter-related infections (2013 update)].
Nosocomial infections or infections related to health-care system have a great impact in the healthcare due to its high frequency and high morbidity and mortality they caused. Inside of them, there are the catheter-related bacteraemia. The paper of the nursing in the care and maintenance of the intravenous therapy is basic to avoid this type of infections. There has been demonstrated the efficacy of the implementation of catheter-related infections prevention programmes through a bundle of measures about the insertion, maintenance, surveillance and prevention of adverse events in the vascular access. The aim of this work is to show and emphasize the last updated recommendations collected in the 2011 Guidelines for the Prevention of Intravascular Catheter-Related Infections to nursing staff.


Options for long-term care financing reform: a view from the inside out.
The goals for any proposal for long-term care financing reform must include the development of a deliberative, organized and coordinated structure of consistent benefits and service capacity that is accessible to individuals with administrative simplicity and operating certainty for providers. The best way to achieve these program goals is to foster a radical new system that relies on the maximum use of private long-term care insurance. Elimination of the Medicaid program as the primary funding vehicle for long-term care and federalization of all nursing home and home care services will serve as an interim measure until private options are developed and in place. A continued federal role will be needed for maximum risk pooling, standard setting and acting as the stop-loss reinsurer and ultimate safety net for those outside the reach of the private market. Certain interest groups, including the state governors and the advocacy groups on women's issues have unique roles to play in shaping the coming debate. The shifts in thinking and in behavior change needed to commit to such a vision will not be easily achieved. Long-term care is as much about roles, relationships and responsibilities as it is about health, illness, rules or regulations. These inherent and intimate characteristics of long-term care mandate a clear vision of what the system should look like and very deliberate steps to devise and to enact the progressive reforms necessary to meet the coming demand. Reasonable people will differ about the appropriate mix of public and private responsibilities in any system to provide long-term care.(ABSTRACT TRUNCATED AT 250 WORDS)


New configuration of a lens for a 35-mm cinema projector.
A new lens system configuration having seven uncemented elements made of Indian optical glasses has been developed. It has focal length of 75 mm, relative aperture of f/1.4 and is to be used in a 35-mm cinema projector objective. To compare the performance of this lens system, a commonly used design of seven uncemented elements based on double-Gauss configuration was also developed. The performance of the designs was evaluated by plotting aberration curves, energy distribution curves, and the geometrical MTF curves. The proposed new configuration gives better performance compared with the double-Gauss configuration being used currently.


The two [4Fe-4S] clusters in Chromatium vinosum ferredoxin have largely different reduction potentials. Structural origin and functional consequences.
The 2[4Fe-4S] ferredoxin from Chromatium vinosum arises as one prominent member of a recently defined family of proteins found in very diverse bacteria. The potentiometric circular dichroism titrations of the protein and of several molecular variants generated by site-directed mutagenesis have established that the reduction potentials of the two clusters differ widely by almost 200 mV. This large difference has been confirmed by electrochemical methods, and each redox transition has been assigned to one of the clusters. The unusually low potential center is surprisingly the one that displays a conventional CX1X2CX3X4C (Xn, variable amino acid) binding motif and a structural environment similar to that of clusters having less negative potentials. A comparison with other ferredoxins has highlighted factors contributing to the reduction potential of [4Fe-4S] clusters in proteins. (i) The loop between the coordinating cysteines 40 and 49 and the C terminus alpha-helix of C. vinosum ferredoxin cause a negative, but relatively moderate, shift of approximately 60 mV for the nearby cluster. (ii) Very negative potentials, below -600 mV, correlate with the presence of a bulky side chain in position X4 of the coordinating triad of cysteines. These findings set the framework in which previous observations on ferredoxins can be better understood. They also shed light onto the possible occurrence and properties of very low potential [4Fe-4S] clusters in less well characterized proteins.


Effect of brain stimulation on aldosterone secretion in the rhesus monkey (Macaca Mulatta).
The lateral hypothalamus, and various sites within the limbic system and frontal lobe of the rhesus monkey brain were electrically stimulated using chronically implanted electrodes. A considerble increase in plasma aldosterone levels was observed after stimulation of the lateral hypothalamic area, certain localized sites in the cingulate area, and lower medial parts of the frontal lobe. Inactive sites included most of the amygdala, hippocampus, and basal ganglia, together with other areas within the frontal lobe and cingulate gyrus. Stimulation of all active areas was followed by an increase in plasma renin activity. Plasma cortisol also increased considerably after hypothalamic stimulation but in the case of extra-hypothalamic sites the cortisol response was much less.


IMGT, the international ImMunoGeneTics database.
IMGT, the international ImMunoGeneTics database (http://imgt.cnusc. fr:8104), is a high-quality integrated database specialising in Immunoglobulins (Ig), T cell Receptors (TcR) and Major Histocompatibility Complex (MHC) molecules of all vertebrate species, created in 1989 by Marie-Paule Lefranc, Université Montpellier II, CNRS, Montpellier, France (email@example.com). IMGT comprises three databases: LIGM-DB, a comprehensive database of Ig and TcR, MHC/HLA-DB, and PRIMER-DB (the last two in development); a tool, IMGT/DNAPLOT, developed for sequence analysis and alignments; and expertised data based on the IMGT scientific chart, the IMGT repertoire. By its high quality and its easy data distribution, IMGT has important implications in medical research (repertoire in autoimmune diseases, AIDS, leukemias, lymphomas), therapeutic approaches (antibody engineering), genome diversity and genome evolution studies. IMGT is freely available at http://imgt.cnusc. fr:8104


Serotyping and strain identification of maize streak virus isolates.
Four strains of maize streak virus, namely the Panicum maximum, Digitaria setigera and sugarcane strains, have been identified from 19 isolates by ELISA using polyclonal antisera cross-absorbed with particles of the maize strain. The results suggest there is an epitope of the maize strain which is not dependent on the capsid being intact and which is common to all the members of the group; other strain-specific epitopes are probably conformation-dependent. A specific epitope (probably internal) occurs on the coat protein of a maize strain isolate, D(R)D, grown in D. velutina, that is also present on the coat protein of the D. setigera (previously reported as D. sanguinalis) strain. Specific internal epitopes also occur in the coat proteins of sugarcane and P. maximum strains. The use of indirect ELISA was necessary for accurate serotyping. The serological reactivities of particles of all the members of each type were identical irrespective of the host from which they were extracted. Sap extracts proved to be more reliable sources of antigen than virus preparations, which could vary in their serological reactivity. Nevertheless, serological differentiation index values determined in tests using either type of antigen proved reliable and consistent.


Molecular characterization of antigen-processing function in nasopharyngeal carcinoma (NPC): evidence for efficient presentation of Epstein-Barr virus cytotoxic T-cell epitopes by NPC cells.
Potentiation of the EBV-specific CTL response by immunization with CTL epitopes has been proposed as a logical approach for immune-targeting nasopharyngeal carcinoma (NPC) cells in vivo. This approach will undoubtedly be influenced by the ability of these malignant cells to endogenously process and present target epitopes on their cell surface for immune recognition by CTLs. Analysis of NPC cells in fresh tumor biopsies and long-term, established NPC tumors in nude mice revealed normal expression of the MHC-encoded putative peptide transporters TAP1 and TAP2, as well as the proteasome components LMP2 and LMP7, which have been shown previously to be essential components of the class I processing pathway. Moreover, these tumor cells also showed high levels of HLA class I alleles on the cell surface, suggesting that peptides are available for binding to nascent MHC molecules in the endoplasmic reticulum. Using a recombinant vaccinia virus to transiently express the EBV nuclear antigens, we studied the antigen-processing efficiency of NPC cells. Our findings demonstrate that, in contrast to cells from another EBV-associated malignancy, Burkitt's lymphoma, NPC cells display normal antigen-processing function and are efficiently recognized by HLA class I-restricted, virus-specific CTLs. These studies also provide a rationale for focusing on strategies designed to activate CTLs specific for EBV antigens that are expressed in NPC cells in vivo.


Evaluation of Anti-Inflammatory Activities of Qingre-Qushi Recipe (QRQS) against Atopic Dermatitis: Potential Mechanism of Inhibition of IL-33/ST2 Signal Transduction.
To evaluate the anti-inflammatory activities of QRQS against AD and the inhibitory molecular mechanisms of IL-33/ST2 signal transduction, BALB/c mice were divided into six groups (normal control, OVA control, low-dose of QRQS, middle-dose of QRQS, high-dose of QRQS, and cetirizine) and epicutaneously exposed to ovalbumin or PBS for 3 weeks and treated with QRQS for 2 weeks. Skin biopsies and blood samples were obtained for histological study, antibody analysis, and RNA isolation. HaCaT cells, stimulated by TNF-α and IFN-γ, were treated with QRQS to evaluate mRNA and protein expression by RT-PCR and ELISA. QRQS decreased both epidermal and dermal thickness, alleviated dermatitis, and reduced IL-33 and ST2 positive cell numbers. The concentration of specific IgE, IgG, IgG1, and IgG2a antibodies in serum and the expression of IL-33, ST2, IL-1RAcP, IL-4, and IL-13 mRNA in the skin were suppressed. No significant difference exists in TNF-α or IFN-γ. QRQS decreased IL-33 mRNA and protein secretion in HaCaT cells exposed to TNF-α and IFN-γ in a time- and concentration-dependent manner. QRQS regulates related molecule expression of ovalbumin-induced dermatitis involved in the IL-33/ST2 signaling axis in the treatment of acute AD.


Both a holistic and external focus of attention enhance the learning of a badminton short serve.
Attentional focus research consistently demonstrates a benefit of an external focus relative to an internal focus. However, this dichotomous comparison may oversimplify the variety of attentional focus strategies a learner uses when acquiring a motor skill. Recent research suggests a holistic focus of attention provides a similar benefit over an internal focus in performing a standing long jump, but the generalizability of this effect is unknown. The purpose of this study was to determine how an internal (IF), external (EF), and holistic focus (HF) and control condition impact the learning of a badminton short serve. Novice participants (N = 60) were randomly assigned to IF, EF, HF, or control groups. They practiced the badminton short serve for 150 trials over 5 days and completed retention and transfer tests 48-h post-acquisition. Serve accuracy was analyzed in separate repeated-measures ANOVAs for acquisition and pretest/retention/transfer. All groups improved accuracy through acquisition with the HF group serving more accurately than the IF and control groups. In retention, the HF and EF group served more accurately than the control group, and in transfer, the HF group was more accurate than the IF and control groups. The present findings suggest a benefit of both a holistic and external focus in the learning of an accuracy-based task.


Hypoxia in human trophoblasts stimulates the expression and secretion of connective tissue growth factor.
The mechanisms underlying cellular injury when human placental trophoblasts are exposed to hypoxia are unclear. Connective tissue growth factor (CTGF) mediates cell injury and fibrosis in diverse tissues. We hypothesized that hypoxia enhances the production of CTGF in primary term human trophoblasts. Using cultured term primary human trophoblasts as well as villous biopsies from term human placentas, we showed that CTGF protein is expressed in trophoblasts. When compared with cells cultured in standard conditions (FiO2 = 20%), exposure of primary human trophoblasts to low oxygen concentration (FiO2 = 8% or <or= 1%) enhanced the expression of CTGF mRNA in a time-dependent manner, with a significant increase in CTGF levels after 16 h (2.7 +/- 0.7-fold; P < 0.01), reaching a maximum of 10.9 +/- 3.2-fold at 72 h. Whereas exposure to hypoxia had no effect on cellular CTGF protein levels, secretion of CTGF to the medium was increased after 16 h in hypoxia and remained elevated through 72 h. The increase in cellular CTGF transcript levels and CTGF protein secretion was recapitulated by exposure of trophoblasts to agents that enhance the activity of hypoxia-inducible factor (HIF)1alpha, including cobalt chloride or the proline hydroxylase inhibitor dimethyloxaloylglycine, and attenuated using the HIF1alpha inhibitor 2-methoxyestradiol. Although all TGFbeta isoforms stimulated the expression of CTGF in trophoblasts, only the expression of TGFbeta1 mRNA was enhanced by hypoxia. We conclude that hypoxia increases cellular CTGF mRNA levels and CTGF protein secretion from cultured trophoblasts, likely in a HIF1alpha-dependent manner.


Characterization and expression pattern analysis of the facilitative glucose transporter 10 gene (slc2a10) in Danio rerio.
The SLC2A10 gene located on chromosome 20q13.1 encodes the facilitative glucose transporter 10 (GLUT10), a class III member of the SLC2A facilitative glucose transporter family. Mutations in the human SLC2A10 gene cause arterial tortuosity syndrome (ATS), a rare autosomal recessive connective tissue disorder. In this work, we report the characterization of the slc2a10 ortholog gene in zebrafish (Danio rerio) and its expression pattern during embryonic development and in adult tissues. The slc2a10 gene consists of 5 exons, spanning 8 kb and mapping to a region on chromosome 11 that exhibits conserved synteny with human chromosome 20. The gene encodes Glut10, a 513 amino acid protein that maintains the 12 transmembrane domain structure typical of the GLUTs family, and shares the specific functional motifs involved in sugar transport with the vertebrate GLUT10. RT-PCR analysis showed that two specific splice variants, both including the 5'-UTR region, were expressed during embryogenesis and in different adult zebrafish tissues and organs. In situ hybridization analyses demonstrated a maternal origin of the total slc2a10 mRNA and its ubiquitous distribution until the early somitogenesis stage. In later embryonic stages, slc2a10 mRNA was detected in the otic vesicles, hatching gland cells, pectoral fin, posterior tectum and swim bladder. Overall, these results suggest a wide role of slc2a10 during zebrafish development.


Retinal cell transplantation in retinitis pigmentosa.
Retinitis pigmentosa is the most common hereditary retinal disease. Dietary supplements, neuroprotective agents, cytokines, and lately, prosthetic devices, gene therapy, and optogenetics have been employed to slow down the retinal degeneration or improve light perception. Completing retinal circuitry by transplanting photoreceptors has always been an appealing idea in retinitis pigmentosa. Recent developments in stem cell technology, retinal imaging techniques, tissue engineering, and transplantation techniques have brought us closer to accomplish this goal. The eye is an ideal organ for cell transplantation due to a low number of cells required to restore vision, availability of safe surgical and imaging techniques to transplant and track the cells in vivo, and partial immune privilege provided by the subretinal space. Human embryonic stem cells, induced pluripotential stem cells, and especially retinal organoids provide an adequate number of cells at a desired developmental stage which may maximize integration of the graft to host retina. However, stem cells must be manufactured under strict good manufacturing practice protocols due to known tumorigenicity as well as possible genetic and epigenetic stabilities that may pose a danger to the recipient. Immune compatibility of stem cells still stands as a problem for their widespread use for retinitis pigmentosa. Transplantation of stem cells from different sources revealed that some of the transplanted cells may not integrate the host retina but slow down the retinal degeneration through paracrine mechanisms. Discovery of a similar paracrine mechanism has recently opened a new therapeutic path for reversing the cone dormancy and restoring the sight in retinitis pigmentosa.


Association of systemic risk factors with the severity of retinal hard exudates in a north Indian population with type 2 diabetes.
The various risk factors for diabetic retinopathy and its spectrum are still poorly understood in the Indian population. To study the association of various systemic risk factors with retinal hard exudates in type 2 diabetic north Indian patients and to measure the incidence of dyslipidemia in them. A tertiary-hospital-based cross-sectional study. An observational case-study which included 180 type 2 diabetic patients (180 eyes) of nonproliferative diabetic retinopathy (NPDR) with clinically significant macular edema (CSME). In these patients the retinal hard exudates were graded on a central 500 fundus picture using modified Airlie House classification and divided into three groups of absent or minimal hard exudates (Group 1), hard exudates present (Group 2) and prominent hard exudates (Group 3). Their association with various risk factors, namely the age of onset of diabetes and its duration, gender, insulin therapy, and various systemic parameters like hypertension, blood hemoglobin, glycosylated hemoglobin, serum (s.) creatinine levels, 24-h proteinuria and complete lipid profile including total s. cholesterol, low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), very low-density lipoprotein cholesterol (VLDL) and s. triglyceride (TG) was studied. The incidence of dyslipidemia was also calculated among these groups of patients. ANOVA test, linear regression analysis and Spearman's correlation test. On univariate analysis, the retinal hard exudates were significantly associated with s. creatinine (P=0.016), systolic blood pressure (P=0.014), s. cholesterol (P < 0.001), s. LDL (P=0.008) and s. TG (P=0.013) levels. While on linear regression analysis, s. cholesterol (P < 0.001) and s. LDL cholesterol (P=0.028) were found to be independent risk factors affecting the density of retinal hard exudates. On Spearman's correlation test, the retinal hard exudates showed a significant positive correlation with systolic blood pressure (P=0.019), s. cholesterol (P < 0.001), LDL (P=0.002) and TG (P=0.014) levels. The incidence of dyslipidemia varied from as high as nearly 70% among patients of Group 3 compared to as low as 18% among Group 1 patients. Serum cholesterol and LDL are independent risk factors for retinal hard exudates in type 2 diabetic north Indian patients who suffer from a remarkably high incidence of dyslipidemia.


Postoperative Time Course of Avulsion-Type Herniation Focused on the Development of New Modic Changes and Their Effect on Short-Term Residual Low Back Pain.
Retrospective study. To investigate the characteristics of newly developing Modic changes following discectomy and their impact on residual low back pain (LBP) in the early postoperative stage of lumbar disc herniation. We included 96 patients who underwent microscopic discectomy. Through MRI, we assessed new developments of Modic changes and the progression of disc degeneration at the surgical level. The presence of cartilaginous endplates was evaluated using resected specimens, and the main outcome was assessed using the visual analog scale (VAS). Further, the prevalence and time course of Modic changes, and their effects on clinical outcomes in the early postoperative period were examined. A new development of Modic changes was detected in 28% of cartilaginous herniations at 6 months. Modic changes were observed more frequently in patients with cartilaginous herniation than in those without cartilaginous herniation postoperatively (P < .001). The VAS scores for LBP up to 6 months were greater in patients with Modic changes (P < .001) than those without; however, no significant differences were identified in the presence or absence of Modic changes over the year follow-up. The development of Modic changes was closely associated with residual LBP at 6 months (β:0.511, P < .001). Modic changes develop predominantly in patients with avulsion-type herniation than in those with annular rupture at an earlier phase after discectomy. Furthermore, disc herniation with cartilaginous endplates may be associated with a slower decrease in LBP for up to 6 months, supporting the notion that newly developing endplate changes may cause residual LBP.


Trends in health care expenditure among US adults with heart failure: The Medical Expenditure Panel Survey 2002-2011.
Population-based national data on the trends in expenditures related to heart failure (HF) are scarce. Assessing the time trends in health care expenditures for HF in the United States can help to better define the burden of this condition. Using 10-year data (2002-2011) from the national Medical Expenditure Panel Survey (weighted sample of 188,708,194US adults aged ≥18years) and a 2-part model (adjusting for demographics, comorbidities, and time); we estimated adjusted mean and incremental medical expenditures by HF status. The costs were direct total health care expenditures (out-of-pocket payments and payments by private insurance, Medicaid, Medicare, and other sources) from various sources (office-based visits, hospital outpatient, emergency department, inpatient hospital, pharmacy, home health care, and other medical expenditures). Compared with expenditures for individuals without HF ($5511 [95% CI 5405-5617]), individuals with HF had a 4-fold higher mean expenditures of ($23,854 [95% CI 21,733-25,975]). Individuals with HF had $3446 (95% CI 2592-4299) higher direct incremental expenditures compared with those without HF, after adjusting for demographics and comorbidities. Among those with HF, costs continuously increased by $5836 (28% relative increase), from $21,316 (95% CI 18,359-24,272) in 2002/2003 to $27,152 (95% CI 20,066-34,237) in 2010/2011, and inpatient costs ($11,318 over the whole period) were the single largest component of total medical expenditure. The estimated unadjusted total direct medical expenditures for US adults with HF were $30 billion/y and the adjusted total incremental expenditure was $5.8 billion/y. Heart failure is costly and over a recent 10-year period, and direct expenditure related to HF increased markedly, mainly driven by inpatient costs.


Artificial neural networks for material parameter extraction in terahertz time-domain spectroscopy.
Terahertz time-domain spectroscopy (THz-TDS) is a proven technique whereby the complex refractive indices of materials can be obtained without requiring the use of the Kramers-Kronig relations, as phase and amplitude information can be extracted from the measurement. However, manual pre-processing of the data is still required and the material parameters require iterative fitting, resulting in complexity, loss of accuracy and inconsistencies between measurements. Alternatively approximations can be used to enable analytical extraction but with a considerable sacrifice of accuracy. We investigate the use of machine learning techniques for interpreting spectroscopic THz-TDS data by training with large data sets of simulated light-matter interactions, resulting in a computationally efficient artificial neural network for material parameter extraction. The trained model improves on the accuracy of analytical methods that need approximations while being easier to implement and faster to run than iterative root-finding methods. We envisage neural networks can alleviate many of the common hurdles involved in analyzing THz-TDS data such as phase unwrapping, time domain windowing, slow computation times, and extraction accuracy at the low frequency range.


Phthalate monoesters act through peroxisome proliferator-activated receptors in the mouse ovary.
Widespread use of phthalates as solvents and plasticizers leads to everyday human exposure. The mechanisms by which phthalate metabolites act as ovarian toxicants are not fully understood. Thus, this study tested the hypothesis that the phthalate metabolites monononyl phthalate (MNP), monoisononyl phthalate (MiNP), mono(2-ethylhexyl) phthalate (MEHP), monobenzyl phthalate (MBzP), monobutyl phthalate (MBP), monoisobutyl phthalate (MiBP), and monoethyl phthalate (MEP) act through peroxisome proliferator-activated receptors (PPARs) in mouse granulosa cells. Primary granulosa cells were isolated from CD-1 mice and cultured with vehicle control (dimethyl sulfoxide) or MNP, MiNP, MEHP, MBzP, MBP, MiBP, or MEP (0.4-400 μM) for 24 h. Following culture, qPCR was performed for known PPAR targets, Fabp4 and Cd36. Treatment with the phthalate metabolites led to significant changes in Fabp4 and Cd36 expression relative to control in dose-dependent or nonmonotonic fashion. Primary granulosa cell cultures were also transfected with a DNA plasmid containing luciferase expressed under the control of a consensus PPAR response element. MNP, MiNP, MEHP, and MBzP caused dose-dependent changes in expression of luciferase, indicating the presence of functional endogenous PPAR receptors in the granulosa cells that respond to phthalate metabolites. The effects of phthalate metabolites on PPAR target genes were inhibited in most of the cultures by co-treatment with the PPAR-γ inhibitor, T0070907, or with the PPAR-α inhibitor, GW6471. Collectively, these data suggest that some phthalate metabolites may act through endogenous PPAR nuclear receptors in the ovary and that the differing structures of the phthalates result in different levels of activity.


Effects and cost-effectiveness of pharmacogenetic screening for CYP2D6 among older adults starting therapy with nortriptyline or venlafaxine: study protocol for a pragmatic randomized controlled trial (CYSCEtrial).
Nortriptyline and venlafaxine are commonly used antidepressants for treatment of depression in older patients. Both drugs are metabolized by the polymorphic cytochrome P450-2D6 (CYP2D6) enzyme and guidelines for dose adaptations based on the CYP2D6 genotype have been developed. The CYP2D6 Screening Among Elderly (CYSCE) trial is designed to address the potential health and economic value of genotyping for CYP2D6 in optimizing dose-finding of nortriptyline and venlafaxine. In a pragmatic randomized controlled trial, patients diagnosed with a major depressive disorder according to the DSM-IV and aged 60 years or older will be recruited from psychiatric centers across the Netherlands. After CYP2D6 genotyping determined in peripheral blood obtained by finger-prick, patients will be grouped into poor, intermediate, extensive, or ultrarapid metabolizers. Patients with deviant genotype (that is poor, intermediate or ultrarapid genotype) will be randomly allocated to an intervention group in which the genotype and dosing advice is communicated to the treating physician, or to a control group in which patients receive care as usual. Additionally, an external reference group of patients with the extensive metabolizer genotype is included. Primary outcome in all groups is time needed to obtain an adequate blood level of the antidepressant drug. Secondary outcomes include adverse drug reactions measured by a shortened Antidepressant Side-Effects Checklist (ASEC), and cost-effectiveness of the screening. Results of this trial will guide policy-making with regard to pharmacogenetic screening prior to treatment with nortriptyline or venlafaxine among older patients with depression. ClinicalTrials.gov: NCT01778907 ; registration date: 22 January 2013.


Restriction of major surface protein 2 (MSP2) variants during tick transmission of the ehrlichia Anaplasma marginale.
Anaplasma marginale is an ehrlichial pathogen of cattle that establishes lifelong persistent infection. Persistence is characterized by rickettsemic cycles in which new A. marginale variant types, defined by the sequence of the expressed msp2 transcripts, emerge. The polymorphic msp2 transcripts encode structurally distinct MSP2 proteins and result in an antigenically diverse and continually changing A. marginale population within the blood. In this manuscript, we used sequence analysis of msp2 transcripts to show that a restricted repertoire of variant types, designated SGV1 and SGV2, is expressed within the tick salivary gland. The same SGV1 and SGV2 variant types were expressed in ticks regardless of the variant types expressed in the blood of infected cattle at the time of acquisition feeding by the ticks. Importantly, subsequent tick transmission to susceptible cattle resulted in acute rickettsemia composed of organisms expressing only the same SGV1 and SGV2 variant types. This indicates that the msp2 expressed by organisms within the tick salivary gland predicts the variant type responsible for acute rickettsemia and disease. This restriction of transmitted A. marginale variant types, in contrast to the marked diversity within persistently infected cattle, supports development of MSP2 vaccines to prevent acute rickettsemia in tick-transmitted infections.


Draft genome sequence of the chemolithoheterotrophic, halophilic methylotroph Methylophaga thiooxydans DMS010.
Methylophaga thiooxydans is a mesophilic, obligately halophilic bacterium that is capable of methylotrophic growth on a range of one-carbon compounds as well as chemolithoheterotrophic growth at the expense of thiosulfate. Here we present the draft genome sequence of Methylophaga thiooxydans DMS010 (DSM 22068(T), VKM B2586(T)), the type strain of the species, which has allowed prediction of the genes involved in one-carbon metabolism, nitrogen metabolism, and other aspects of central metabolism.


Simultaneous recording of mandibular condylar movement and single motor-unit activity at verified sites in the human lateral pterygoid muscle.
In recent years, understanding of normal jaw-muscle function has been enhanced by detailed descriptions of their complex internal architecture and of the functional activity of single motor units (SMUs). The lateral pterygoid muscle, however, has been poorly studied, although it is thought to play an important part in the control of jaw and jaw-joint movement. The present study is the first of a series of SMU studies to clarify the normal function of this muscle. The aims were to demonstrate (a) the unequivocal isolation of SMU activity from one or two verified recording sites within the lateral pterygoid, and (b) that these SMUs can be recorded reliably together with condylar movement during simple command jaw movements. Recordings of SMU activity were made with fine-wire electrodes from sites within the superior and inferior heads of the right lateral pterygoid during biting or command lateral jaw movements and combined with recordings of condylar and mid-incisor point movement. Recording sites were verified by computed tomography. In four young adults, the activities of 17 SMUs were reliably discriminated at seven recording sites within the lateral pterygoid. The units could be recorded during repeated trials of the same movement throughout a recording session with no appreciable change in amplitude or waveform. Units could also be discriminated simultaneously at separate recording sites--one in the superior head and the other in the inferior head. These data demonstrate that SMU activity can be recorded from verified sites within the lateral pterygoid simultaneously with condylar movement during command jaw movements.


Proneurotrophins Induce Apoptotic Neuronal Death After Controlled Cortical Impact Injury in Adult Mice.
The p75 neurotrophin receptor (p75NTR) can regulate multiple cellular functions including proliferation, survival, and apoptotic cell death. The p75NTR is widely expressed in the developing brain and is downregulated as the nervous system matures, with only a few neuronal subpopulations retaining expression into adulthood. However, p75NTR expression is induced following damage to the adult brain, including after traumatic brain injury, which is a leading cause of mortality and disability worldwide. A major consequence of traumatic brain injury is the progressive neuronal loss that continues secondary to the initial trauma, which ultimately contributes to cognitive decline. Understanding mechanisms governing this progressive neuronal death is key to developing targeted therapeutic strategies to provide neuroprotection and salvage cognitive function. In this study, we demonstrate that a cortical impact injury to the sensorimotor cortex elicits p75NTR expression in apoptotic neurons in the injury penumbra, confirming previous studies. To establish whether preventing p75NTR induction or blocking the ligands would reduce the extent of secondary neuronal cell death, we used a noninvasive intranasal strategy to deliver either siRNA to block the induction of p75NTR, or function-blocking antibodies to the ligands pro-nerve growth factor and pro-brain-derived neurotrophic factor. We demonstrate that either preventing the induction of p75NTR or blocking the proneurotrophin ligands provides neuroprotection and preserves sensorimotor function.


EpCAM-Mediated Cellular Plasticity Promotes Radiation Resistance and Metastasis in Breast Cancer.
Substantial number of breast cancer (BC) patients undergoing radiation therapy (RT) develop local recurrence over time. During RT therapy, cells can gradually acquire resistance implying adaptive radioresistance. Here we probe the mechanisms underlying this acquired resistance by first establishing radioresistant lines using ZR-75-1 and MCF-7 BC cells through repeated exposure to sub-lethal fractionated dose of 2Gy up to 15 fractions. Radioresistance was found to be associated with increased cancer stem cells (CSCs), and elevated EpCAM expression in the cell population. A retrospective analysis of TCGA dataset indicated positive correlation of high EpCAM expression with poor response to RT. Intriguingly, elevated EpCAM expression in the radioresistant CSCs raise the bigger question of how this biomarker expression contributes during radiation treatment in BC. Thereafter, we establish EpCAM overexpressing ZR-75-1 cells (ZR-75-1EpCAM), which conferred radioresistance, increased stemness through enhanced AKT activation and induced a hybrid epithelial/mesenchymal phenotype with enhanced contractility and invasiveness. In line with these observations, orthotopic implantation of ZR-75-1EpCAM cells exhibited faster growth, lesser sensitivity to radiation therapy and increased lung metastasis than baseline ZR-75-1 cells in mice. In summary, this study shows that similar to radioresistant BC cells, EpCAM overexpressing cells show high degree of plasticity and heterogeneity which ultimately induces radioresistant and metastatic behavior of cancer cells, thus aggravating the disease condition.


beta-Particle-emitting radioactive stent implantation. A safety and feasibility study.
This study represents the Heart Center Rotterdam's contribution to the Isostents for Restenosis Intervention Study, a nonrandomized multicenter trial evaluating the safety and feasibility of the radioactive Isostent in patients with single coronary artery disease. Restenosis after stent implantation is primarily caused by neointimal hyperplasia. In animal studies, beta-particle-emitting radioactive stents decrease neointimal hyperplasia by inhibiting smooth muscle cell proliferation. The radioisotope (32)P, a beta-particle emitter with a half-life of 14.3 days, was directly embedded into the Isostent. The calculated range of radioactivity was 0.75 to 1.5 microCi. Quantitative coronary angiography measurements were performed before and after the procedure and at 6-month follow-up. A total of 31 radioactive stents were used in 26 patients; 30 (97%) were successfully implanted, and 1 was embolized. Treated lesions were in the left anterior descending coronary artery (n=12), the right coronary artery (n=8), or the left circumflex coronary artery (n=6). Five patients received additional, nonradioactive stents. Treated lesion lengths were 13+/-4 mm, with a reference diameter of 2.93+/-0. 47 mm. Minimum lumen diameter increased from 0.87+/-0.28 mm preprocedure to 2.84+/-0.35 mm postprocedure. No in-hospital adverse cardiac events occurred. All patients received aspirin indefinitely and ticlopidine for 4 weeks. Twenty-three patients (88%) returned for 6-month angiographic follow-up; 17% of them had in-stent restenosis, and 13% had repeat revascularization. No restenosis was observed at the stent edges. Minimum lumen diameter at follow-up averaged 1.85+/-0.69 mm, which resulted in a late loss of 0.99+/-0. 59 mm and a late loss index of 0.53+/-0.35. No other major cardiac events occurred during the 6-month follow-up. The use of radioactive stents with an activity of 0.75 to 1.5 microCi is safe and feasible.


Covered TIPS versus endoscopic band ligation plus propranolol for the prevention of variceal rebleeding in cirrhotic patients with portal vein thrombosis: a randomised controlled trial.
Limited data are available on the prevention of variceal rebleeding in cirrhotic patients with portal vein thrombosis (PVT). This study aimed to compare transjugular intrahepatic portosystemic shunt (TIPS) with covered stents versus endoscopic band ligation (EBL) plus propranolol for the prevention of variceal rebleeding among patients with cirrhosis and PVT. Consecutive cirrhotic patients (94% Child-Pugh class A or B) with PVT who had variceal bleeding in the past 6 weeks were randomly assigned to TIPS group (n=24) or EBL plus propranolol group (EBL+drug, n=25), respectively. Primary endpoint was variceal rebleeding. Secondary endpoints included survival, overt hepatic encephalopathy (OHE), portal vein recanalisation and rethrombosis, other complications of portal hypertension and adverse events. During a median follow-up of 30 months in both groups, variceal rebleeding was significantly less frequent in the TIPS group (15% vs 45% at 1 year and 25% vs 50% at 2 years, respectively; HR=0.28, 95% CI 0.10 to 0.76, p=0.008), with a significantly higher portal vein recanalisation rate (95% vs 70%; p=0.03) and a relatively lower rethrombosis rate (5% vs 33%; p=0.06) compared with the EBL+drug group. There were no statistically significant differences in survival (67% vs 84%; p=0.152), OHE (25% vs 16%; p=0.440), other complications of portal hypertension and adverse events between groups. Covered TIPS placement in patients with PVT and moderately decompensated cirrhosis was more effective than EBL combined with propranolol for the prevention of rebleeding, with a higher probability of PVT resolution without increasing the risk of OHE and adverse effects, but this benefit did not translate into improved survival. ClinicalTrials.gov: NCT01326949.


Consciousness and the structure of neuronal representations.
The hypothesis is defended that brains expressing phenomenal awareness are capable of generating metarepresentations of their cognitive processes, these metarepresentations resulting from an iteration of self-similar cortical operations. Search for the neuronal substrate of awareness therefore converges with the search for the nature of neuronal representations. It is proposed that evolved brains use two complementary representational strategies. One consists of the generation of neurons responding selectively to a particular constellation of features and is based on selective recombination of inputs in hierarchically structured feedforward architectures. The other relies on the dynamic association of feature-specific cells into functionally coherent cell assemblies that, as a whole, represent the constellation of features defining a particular perceptual object. Arguments are presented that favour the notion that the metarepresentations supporting awareness are established in accordance with the second strategy. Experimental data are reviewed that are compatible with the hypothesis that evolved brains use assembly codes for the representation of contents and that these assemblies become organized through transient synchronization of the discharges of associated neurons. It is argued that central states favouring the formation of assembly-based representations are similar to those favouring awareness.


Compensation versus halo: the unique relations between the fundamental dimensions of social judgment.
Recent work on the relations between the two dimensions of social judgment, that is, warmth and competence, evidenced compensation such that a group seen more positively than another group on one dimension is seen less positively on the second. The authors examine the status of this compensatory relation by introducing a third dimension in the judgment context. Experiment 1 extends earlier work in a different population, comparing compensation as a function of whether warmth or competence is manipulated and competence or warmth is the unmanipulated dimension. Experiments 2 and 3 use healthiness as the unmanipulated dimension and reveal the presence of halo rather than compensation between warmth or competence on one hand and healthiness on the other. These findings suggest that compensation may not only stem from a concern for distributive justice but may also derive from the unique structural and functional relations between the two fundamental dimensions of social judgment.


Long-term health-related quality of life in eating disorders.
There is limited evidence on the long-term development of health-related quality of life (HRQoL) in eating disorders and its relation to eating disorder symptoms. Our objective was to measure long-term change in the HRQoL of eating disorder patients and compare it to normal population. Fifty-four bulimia nervosa (BN) and forty-seven anorexia nervosa (AN) patients (ICD-10 diagnosis) entering treatment completed the 15D HRQoL questionnaire and the Eating Disorder Inventory (EDI) before and approximately 8 years after the start of treatment. Baseline HRQoL was severely impaired in the patients. During follow-up, mean HRQoL, body mass index (BMI) and EDI improved statistically significantly in both groups. BMI of AN patients reached normal values, but HRQoL was still severely impaired in both AN and BN compared to general population. The long-term HRQoL after treatment continues to improve, but is still after 8 years poor. Eating disorders are very serious conditions with long-lasting impact on quality of life even after symptom remission.


Conflict resolution at the University of Ottawa Faculty of Medicine: The Pelican and the sign of the triangle.
In 1997 the University of Ottawa Medical School adopted a conflict-resolution policy for informally dealing with complaints of abuse, harassment and intimidation, sexual harassment, and scientific misconduct or misappropriation of intellectual property. In collaboration with the university's Faculty of Law, general conflict-resolution workshops were given for faculty and administration and mediation training was provided to medical faculty designated "complaint officers" under the policy. In this article, the authors describe the policy and training and then analyze the first major incident arising after the policy's implementation: the publication of disrespectful misogynist material in The Pelican, a medical student society newsletter. The Pelican incident is used as a "lessons learned" case study both in terms of its multiple outcomes and as an opportunity to pinpoint some important policy and practical considerations that emerged in implementing a conflict-resolution policy. The article also describes the results of a learning environment survey conducted after the Pelican incident.


Fluoride release and uptake from glass ionomer cements and composite resins.
The aim of this investigation was to evaluate fluoride release and uptake from 4 glass ionomer cements (GICs)--Vitremer (VIT), Fuji II LC (FII LC), Fuji IX (FIX), Chelon Fill (CHE)--and 2 composite resins (CRs)--Heliomolar (H) and Zeta-100 (Z-100). Eight discs (8 mm x 2 mm) were made of each material and were stored in plastic vials containing artificial saliva at 37 degrees C. In group 1 (N = 3), the specimens were immersed in artificial saliva which was changed daily for 25 days. In group 2 (N = 5), besides receiving the same treatment as group 1, the specimens were immersed, after 24 hours, in a fluoride solution (1% NaF) for 1 min before daily saliva change. An ion-specific electrode (9609 BN-Orion) connected to an ion analyzer (SA-720 Procyon) was used to determine the amount of fluoride released at days 1, 2, 5, 10, 15, 20 and 25. Data were analyzed using two way ANOVA and Friedman's test. GICs released more fluoride during the first day and after this period the mean fluoride released decreased. Composite resin H released fluoride during the first day only and Z-100 did not release fluoride. In terms of NaF treatment, CRs did not show fluoride uptake, whereas the GICs showed fluoride uptake (VIT = FII LC = CHE > FIX).


Gait pattern in 9-11-year-old children with generalized joint hypermobility compared with controls; a cross-sectional study.
To study differences in gait patterns in 10-year-old children with Generalized Joint Hypermobility (GJH) and with no GJH (NGJH). A total of 37 children participated (19 GJH, 18 NGJH, mean age 10.2 (SD 0.5) years). Inclusion criteria for GJH were a Beighton score of ≥5, with at least one hypermobile knee joint; for NGJH a Beighton score of ≤4, and no hypermobile knees and for both groups no knee pain during the previous week. All children were recorded by five video cameras, while they walked across three force platforms. Net joint moments were calculated in 3D by inverse dynamics and peak values provided input to statistical analyses. In the frontal plane, children with GJH had a significantly lower peak knee abductor moment and peak hip abductor moment. In the sagittal plane, the peak knee flexor moment and the peak hip extensor moment were significantly lower in the GJH group although the absolute difference was small. The walking pattern was the same for children with GJH and for healthy children, as there were no differences in kinematics, but it was, however, performed with different kinetics. Children with GJH walked with lower ankle, knee and hip joint moments compared to children with NGJH. However, the clinical importance of these differences during normal gait is unknown. To obtain this knowledge, children with GJH must be followed longitudinally. The study was approved by the Committee on Biomedical Research Ethics for Copenhagen and Frederiksberg, Denmark (jnr. KF01-2006-178).


[The effect of phenobarbital and cimetidine on the elimination kinetics and distribution in the heart and liver of propranolol in rats with acute and chronic inflammations].
Intravenous administration of propranolol (10 mg/kg) to rats with turpentine-induced inflammation and adjuvant-induced arthritis results in the reduction of the systemic clearance (Cltot.p), volume distribution (Vd,ss) and free fraction (fu). At the same time the area under the pharmacokinetic curve (AUC) increases and the half-life period (t1/2 beta) remains the same. In the phenobarbital-treated rats with acute inflammation Cltot.p increases, AUC and t1/2 beta decreased. Administration of cimetidine resulted in the opposite effect. In rats with adjuvant arthritis phenobarbital and cimetidine administration did not affect the propranolol elimination kinetics. In the phenobarbital-treated rats with inflammation Vd,ss significantly decreased and virtually did not change in cimetidine treated rats. The fu of propranolol increased markedly after the cimetidine treatment in all rats with inflammation, whereas phenobarbital treatment appeared effective only in rats with acute inflammation. The tissue-to plasma concentration ratio (Kp) of propranolol decreased in the liver of rats both with acute and chronic inflammation, whereas in the heart the effect was observed only in rats with chronic inflammation. The tissue to plasma concentration ratio of unbound propranolol (Kpu) decreased only in the liver of rats with acute inflammation. In the phenobarbital-treated rats with adjuvant arthritis Kp of propranolol in the liver increased and in the heart decreased, whereas cimetidine-treatment did not change Kp of propranolol in heart and decreased it in the liver. The Kpu of propranolol decreased only in the heart of rats with acute inflammation after phenobarbital treatment, whereas after cimetidine administration this parameter decreased in the heart and in the liver of rats regardless of the character of inflammation.


Recommendations of the Polish Speaking Working Group of the International Society for Forensic Genetics for forensic mitochondrial DNA testing.
Although mitochondrial DNA (mtDNA) testing has been used in forensic genetics only since the mid-1990s, forensic DNA laboratories have been recently increasing the range of mtDNA sequencing, employing new analytical approaches and methods of data analysis. Therefore, it seems fitting to gather and systematize existing recommendations in the field of mtDNA analysis for forensic purposes, and formulate a set of interpretative guidelines which are especially relevant in view of recent developments in the forensic casework. The starting point is the recommendations of the International Society for Forensic Genetics (ISFG) which, in the opinion of the Polish Speaking Working Group of the ISFG (ISFG- PL), should be followed by all Polish laboratories conducting forensic testing.


Sepsis-Induced Coagulopathy and Disseminated Intravascular Coagulation: What We Need to Know and How to Manage for Prolonged Casualty Care.
Coagulopathy can occur in trauma, and it can affect septic patients as a host tries to respond to infection. Sometimes, it can lead to disseminated intravascular coagulopathy (DIC) with a high potential for mortality. New research has delineated risk factors that include neutrophil extracellular traps and endothelial glycocalyx shedding. Managing DIC in septic patients focuses on first treating the underlying cause of sepsis. Further, the International Society on Thrombolysis and Haemostasis (ISTH) has DIC diagnostic criteria. "Sepsis-induced coagulopathy" (SIC) is a new category. Therapy of SIC focuses on treating the underlying infection and the ensuing coagulopathy. Most therapeutic approaches to SIC have focused on anticoagulant therapy. This review will discuss SIC and DIC and how they are relevant to prolonged casualty care (PCC).


Attitudes of Family Medicine Program Directors Toward Osteopathic Residents Under the Single Accreditation System.
Between 2015 and 2020, residency programs accredited through the American Osteopathic Association (AOA) are preparing the single graduate medical education (GME) system through the Accreditation Council for Graduate Medical Education (ACGME). (1) To assess the attitudes of family medicine program directors in programs accredited dually by the AOA and ACGME (AOA/ACGME) or ACGME only toward the clinical and academic preparedness of osteopathic residency candidates and (2) to determine program director attitudes toward the perceived value of osteopathic-focused education, including osteopathic manipulative treatment (OMT) curricula. A survey was sent to program directors of AOA/ACGME and ACGME-only accredited family medicine residency programs. Items concerned program directors' perception of the academic and clinical strength of osteopathic residents at the onset of residency, the presence of osteopathic faculty and residents currently in the program, and the presence of formal curricula for teaching OMT. The perceived value of osteopathic focus was obtained through a composite score of 5 items. A total of 38 AOA/ACGME family medicine residency program directors (17%) and 211 ACGME family medicine residency program directors (45.6%) completed the survey (N=249). No difference was found in the ranking of the perceived clinical preparation of osteopathic residents vs allopathic residents in programs with and without OMT curricula (P=.054). Directors of programs with OMT curricula perceived the academic preparation of their osteopathic residents vs allopathic residents more highly than those without OMT curricula (P=.039). Directors of AOA/ACGME programs perceived both the academic preparation and clinical preparation of their osteopathic residents more highly than those at ACGME-only programs (P=.004 and P=.002, respectively). Directors of AOA/ACGME programs, as well as those whose programs have an osteopathic focus in curricular offerings, were more likely to rank the academic preparation of osteopathic residents higher than directors of ACGME-only programs and those without OMT curricula. Further research is needed to determine the value of osteopathic recognition in attracting strong family medicine residency candidates.


A multi-cohort consortium for GEnder-Sensitive Analyses of mental health trajectories and implications for prevention (GESA) in the general population in Germany.
Mental health is marked by gender differences. We formed a multi-cohort consortium to perform GEnder-Sensitive Analyses of mental health trajectories and study their implications for prevention (GESA). GESA aims at (1) identifying gender differences regarding symptoms and trajectories of mental health over the lifespan; (2) determining gender differences regarding the prevalence, impact of risk and protective factors; and (3) determining effects of mental health on primary and secondary outcomes (eg, quality of life, healthcare behaviour and utilisation). We plan to perform secondary analyses on three major, ongoing, population-based, longitudinal cohorts (Gutenberg Health-Study (GHS), Study of Health in Pomerania (SHIP), Cooperative Health Research in the Augsburg Region (KORA)) with data on mental and somatic symptoms, medical assessments and diagnoses in north-east, middle and southern Germany (n>40 000). Meta-analytic techniques (using DataSHIELD framework) will be used to combine aggregated data from these cohorts. This process will inform about heterogeneity of effects. Longitudinal regression models will estimate sex-specific trajectories and effects of risk and protective factors and secondary outcomes. The cohorts were approved by the ethics committees of the Statutory Physician Board of Rhineland-Palatinate (837.020.07; GHS), the University of Greifswald (BB 39/08; SHIP) and the Bavarian Chamber of Physicians (06068; KORA). Together with stakeholders in medical care and medical training, findings will be translated and disseminated into gender-sensitive health promotion and prevention.


Molecular detection of Aphanomyces astaci - An improved species specific qPCR assay.
The parasitic oomycete Aphanomyces astaci is the causative agent of crayfish plague, a devastating disease for European freshwater crayfish. Species specific quantitative real-time PCR (qPCR) can offer rapid detection of the pathogen. However, the well established A. astaci qPCR assay recommended by the World Organization for Animal Health (WOAH) amplifies the recently described Aphanomyces fennicus. Consequently, false-positive results may occur. This calls for the improvement of the established species specific A. astaci qPCR assay in order to avoid amplifying A. fennicus while screening for A. astaci. We developed an improved species specific A. astaci qPCR assay and validated the assay across three laboratories, using established procedures including different qPCR master mixes for each respective laboratory. Genomic DNA from A. astaci, A. fennicus and closely related Aphanomyces spp. was analysed and compared with both the improved and established assay. Additionally, DNA from crayfish tissue and environmental samples were analysed with both assays. The improved assay showed similar sensitivity with the established assay for all sample types, while proving highly specific for A. astaci avoiding amplification of A. fennicus and the other tested Aphanomyces spp. Environmental DNA (eDNA) samples collected at River Lierelva in Norway amplified with the established assay, but not with the improved assay indicating false positive. We were able to sequence a 530 bp fragment of the ITS region from these eDNA samples and the consensus sequence showed 99.9-100 % pairwise identity with A. fennicus and 97.2-98 % pairwise identity with A. astaci, suggesting that the occurrence of A. fennicus is not limited to Finland, where it was first discovered.


Arthrogryposis multiplex congenita: analysis of twelve cases.
The term arthrogryposis multiplex congenita (AMC) refers to multiple joint contractures present at birth. AMC is not a specific disorder but is the consequence of neurological, muscular, connective tissue, and skeletal abnormalities or intrauterine crowding, which may lead to limitation of fetal joint mobility and the development of contractures. Cases referred to our perinatology department for detailed examination were retrospectively analyzed. Twelve cases with AMC were detected during the antenatal period. The ultrasound features related to the "lack of movement" included limb abnormalities (multiple contractures, clenched hands, and clubbed feet), short umbilical cord, polyhydramnios, pulmonary hypoplasia, camptodactyly, and micrognathia. Five of the early detected cases (71%) were found to have increased nuchal translucency or nuchal fold. All of the cases at the third trimester resulted in neonatal death. First trimester screening may be useful for early diagnosis of AMC. Sonographic findings in late pregnancy might be helpful in predicting the prognosis. Due to the high recurrence risk, a specific screening program should be performed for the following pregnancies by examination of the fetus several times for movement and position of the limbs.


Droplet-based methodology for investigating bacterial population dynamics in response to phage exposure.
An alarming rise in antimicrobial resistance worldwide has spurred efforts into the search for alternatives to antibiotic treatments. The use of bacteriophages, bacterial viruses harmless to humans, represents a promising approach with potential to treat bacterial infections (phage therapy). Recent advances in microscopy-based single-cell techniques have allowed researchers to develop new quantitative methodologies for assessing the interactions between bacteria and phages, especially the ability of phages to eradicate bacterial pathogen populations and to modulate growth of both commensal and pathogen populations. Here we combine droplet microfluidics with fluorescence time-lapse microscopy to characterize the growth and lysis dynamics of the bacterium Escherichia coli confined in droplets when challenged with phage. We investigated phages that promote lysis of infected E. coli cells, specifically, a phage species with DNA genome, T7 (Escherichia virus T7) and two phage species with RNA genomes, MS2 (Emesvirus zinderi) and Qβ (Qubevirus durum). Our microfluidic trapping device generated and immobilized picoliter-sized droplets, enabling stable imaging of bacterial growth and lysis in a temperature-controlled setup. Temporal information on bacterial population size was recorded for up to 25 h, allowing us to determine growth rates of bacterial populations and helping us uncover the extent and speed of phage infection. In the long-term, the development of novel microfluidic single-cell and population-level approaches will expedite research towards fundamental understanding of the genetic and molecular basis of rapid phage-induced lysis and eco-evolutionary aspects of bacteria-phage dynamics, and ultimately help identify key factors influencing the success of phage therapy.


Evaluating the cognition, behavior, and social profile of an adolescent with learning disabilities and assessing the effectiveness of an individualized educational program.
The present study seeks to outline a holistic assessment method that was used in understanding problems experienced by an adolescent boy and in designing and implementing an individualized educational program. An adolescent child referred for concerns in learning was screened for learning disability using standardized inventories and test batteries. The Connors Parent and Teacher Rating Scales (short forms), Wechsler's Intelligence Scale for Children (WISC), the Vineland Social Maturity Scale (VSMS), and the Kinetic Family Drawing (KFD) test were used to assess the behavior, cognition, and social profile of the child. An individualized educational program was designed and this intervention was provided for 6 months by using parents as co-therapists. Participant and parent interview schedules were used in identifying underlying issues of concern. The child was reassessed 6 months after the intervention was provided. Findings on the Connors Parent Rating Scale revealed scores that were greater than the 50(th) percentile on the domains of inattention and cognitive problems. On the Connors Teacher Rating Scale, we observed scores greater than the 50(th) percentile on the hyperactivity, cognitive problems, and the inattention domains. The WISC revealed that the child had a "Dull Normal" Intellectual functioning and there was also a deficit of 2 years on the social skills as tested by the Vineland Social Maturity Scale (VSMS). The Kinetic Family Drawing Test revealed negative emotions within the child. Post intervention, we noticed a remarkable improvement in the scores across all domains of behavior, social, and cognitive functioning. Designing an individualized education program that is tailored to the specific needs of the child and using parents as co-therapists proved to be an effective intervention.


A new general method for the assessment of the molecular-weight distribution of polydisperse preparations. Its application to an intestinal epithelial glycoprotein and two dextran samples, and comparison with a monodisperse glycoprotein.
A specimen of intestinal glycoprotein isolated from the pig and two samples of dextran, all of which are polydisperse (that is, the preparations may be regarded as consisting of a continuous distribution of molecular weights), have been examined in the ultracentrifuge under meniscus-depletion conditions at equilibrium. They are compared with each other and with a glycoprotein from Cysticercus tenuicollis cyst fluid which is almost monodisperse. The quantity c(-(1/3)) (c=concentration) is plotted against xi (the reduced radius); this plot is linear when the molecular-weight distribution approximates to the ;most probable', i.e. when M(n):M(w):M(z): M((z+1))....... is as 1:2:3:4: etc. The use of this plot, and related procedures, to evaluate qualitatively and semi-quantitatively molecular-weight distribution functions where they can be realistically approximated to Schulz distributions is discussed. The theoretical basis is given in an Appendix.


Pathogen manipulation of B cells: the best defence is a good offence.
B cells have long been regarded as simple antibody production units, but are now becoming known as key players in both adaptive and innate immune responses. However, several bacteria, viruses and parasites have evolved the ability to manipulate B cell functions to modulate immune responses. Pathogens can affect B cells indirectly, by attacking innate immune cells and altering the cytokine environment, and can also target B cells directly, impairing B cell-mediated immune responses. In this Review, we provide a summary of recent advances in elucidating direct B cell-pathogen interactions and highlight how targeting this specific cell population benefits different pathogens.


Dietary thiamin level influences levels of its diphosphate form and thiamin-dependent enzymic activities of rat liver.
This study was prompted by our incomplete understanding of the mechanism responsible for the clinical benefits of pharmacological doses of thiamin in some patients with maple syrup urine disease (MSUD) and the question of whether thiamin diphosphate (TDP), a potent inhibitor of the activity of the protein kinase that phosphorylates and inactivates the isolated branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex, affects the activity state of the complex. Rats were fed a chemically-defined diet containing graded levels of thiamin (0, 0.275, 0.55, 5.5, and 55 mg thiamin/kg diet). Maximal weight gain was attained over a 3-wk period only in rats fed diets with 5.5 and 55 mg thiamin/kg. Feeding rats the thiamin-free diet for just 2 d caused loss of nearly half of the TDP from liver mitochondria. Three more days caused over 70% loss, an additional 3 wk, over 90%. Starvation for 2 d had no effect, suggesting a mechanism for conservation of TDP in this nutritional state. Mitochondrial TDP was higher in rats fed pharmacological amounts of thiamin (55 mg thiamin/kg diet) than in rats fed adequate thiamin for maximal growth. Varying dietary thiamin had marked but opposite effects on the activities of alpha-ketoglutarate dehydrogenase (alpha-KGDH) and BCKDH. Thiamin deficiency decreased alpha-KGDH activity, increased BCKDH activity, and increased the proportion of BCKDH in the active, dephosphorylated, state. Excess dietary thiamin had the opposite effects. TDP appears to be more tightly associated with alpha-KGDH than BCKDH in thiamin-deficient rats, perhaps denoting retention of alpha-KGDH activity at the expense of BCKDH activity. Thus, thiamin deficiency and excess cause large changes in mitochondrial TDP levels that have a major influence on the activities of the keto acid dehydrogenase complexes.


Exploration of Fluid Dynamics in Perioperative Patients Using Bioimpedance Analysis.
Perioperative fluid restriction is advocated to reduce complications after major surgeries. Current methods of monitoring body fluids rely on indirect volume markers that may at times be inadequate. In our study, bioimpedance analysis (BIA) was used to explore fluid dynamics, in terms of intercompartmental shift, of perioperative patients undergoing operation for hepato-pancreato-biliary (HPB) diseases. A retrospective review was conducted, examining 36 patients surgically treated for HPB diseases between March 2010 and August 2012. Body fluid compartments were estimated via BIA at baseline (1 day prior to surgery), immediately after surgery, and on postoperative day 1, recording fluid balance during and after procedures. Patients were stratified by net fluid status as balanced (≤500 mL) or imbalanced (>550 mL) and outcomes of BIA compared. Mean net fluid balance volumes in balanced (n = 16) and imbalanced (n = 20) patient subsets were 231.41 ± 155.44 and 1050.18 ± 548.77 mL, respectively. Total body water (TBW) (p = 0.091), extracellular water (ECW) (p = 0.125), ECW/TBW (p = 0.740), and intracellular water (ICW) (p = 0.173) did not fluctuate significantly in fluid-balanced patients. Although TBW (p = 0.069) in fluid-imbalanced patients did not change significantly (relative to baseline), ECW (p = 0.001), ECW/TBW (p = 0.019), and ICW (p = 0.012) showed significant postoperative increases. The exploration of fluid dynamics using BIA has shown importance of balanced fluid management during perioperative period. Increased ECW/TBW in fluid-imbalanced patients suggests possible causality for the development of ascites or fluid collections during postoperative period in patients undergoing HPB operations.


Impairment of cardiovascular autonomic pattern in obese adolescents with Type 2 diabetes mellitus.
The aim of this study was to assess the behaviour of insulin sensitivity and insulin resistance (IR) indexes in a group of obese adolescents with Type 2 diabetes mellitus (T2DM) in comparison to obese adolescents without diabetes and normal controls, moreover to compare these parameters with the cardiac autonomic pattern. Seven T2DM obese (12.7 ± 0.5 yr), 18 obese without T2DM, and 10 nonobese control adolescents age matched were studied. In all subjects we performed oral glucose tolerance test (OGTT) with insulin and glucose determination, 24-h electrocardiogram Holter, blood pressure monitoring, ecohocardiogram. serum lipids were significantly higher in obese and T2DM. Insulin sensitivity was significantly reduced in T2DM and obese vs controls; T2DM showed a more pronounced oral glucose insulin sensitivity (OGIS) reduction vs obese. Both obese and T2DM presented an higher IR. T2DM showed an impaired β-cell function, with insulin areas under the curve and disposition index significantly reduced in comparison to controls and obese who showed similar values. A progressive reduction of vagal indexes and an increase of sympathetic indexes were found in obese adolescents and were more pronounced in T2DM. These parameters were correlated with OGIS and β-cell function parameters in both obese and T2DM adolescents. T2DM showed a significant relative wall thickness increase suggesting a trend toward concentric remodeling. In conclusion, T2DM adolescents are characterized by a more marked IR reduced β-cell function in comparison to non-diabetic obese. These modifications may lead to an early impairment of the autonomic pattern.


Motivating factors and barriers to help-seeking for casino gamblers: results from a survey in Swiss casinos.
Gambling can have serious consequences for many aspects of a person's life. Yet relatively few people with gambling problems seek help. This study examines the extent to which exclusion from casino venues among other factors may act as a motivator for further help-seeking among casino gamblers (both landbased and remote) with at-risk or disordered gambling behavior. In addition, the barriers that prevent gamblers from accepting help are examined. Gamblers from Swiss casinos completed a written questionnaire twice, at 6-month intervals. The questions included whether they had sought help in the past 6 months. For those with a SOGS-R rating of 1 or over (n = 173) at the second survey point, a difference in help-seeking was found between the excluded and non-excluded gamblers (p < .001), suggesting that exclusion may be a motivator for help-seeking. Reported differences in levels of debt (p = .006), recognition of gambling problems (p = .010) and severity of gambling-related problems (p = .004) can be taken to suggest that other motivating factors may also influence help-seeking behavior. With regard to the support sought, the most frequently used forms of support were specialized addiction counseling centers (39.5%), followed by self-help groups (21.1%) and remote counseling centers (10.5%). In terms of barriers, reasons relating to attitude, such as denial, appear to pose greater barriers than treatment-related concerns. From a public health perspective, an overarching strategy is required to increase the share of help-seekers among casino gamblers through targeted measures.


Managed ventricular pacing compared with conventional dual-chamber pacing for elective replacement in chronically paced patients: results of the Prefer for Elective Replacement Managed Ventricular Pacing randomized study.
Several studies have shown that unnecessary right ventricular pacing has detrimental effects. To evaluate whether minimization of ventricular pacing as compared with standard dual-chamber pacing (DDD) improves clinical outcomes in patients referred for pacemaker or implantable cardioverter-defibrillator (ICD) replacement. In an international single-blind, multicenter, randomized controlled trial, we compared DDD with managed ventricular pacing (MVP), a pacing mode developed to minimize ventricular pacing by promoting intrinsic atrioventricular conduction. We included patients referred for device replacement with >40% ventricular pacing, no cardiac resynchronization therapy upgrade indication, no permanent atrial fibrillation (AF), and no permanent complete atrioventricular block. Follow-up was for 2 years. The primary end point was cardiovascular hospitalization. The intention-to-treat analysis was performed by using Kaplan-Meier method and the log-rank test. We randomized 605 patients (556 referred for pacemaker and 49 referred for ICD replacement; mean age 75 ± 11 years; 365 [60%] men, at 7.7 ± 3.3 years from first device implantation) to MVP (n = 299) or DDD (n = 306). We found no significant differences in the primary end point cardiovascular hospitalization (MVP: 16.3% vs DDD: 14.5%; P = .72) and the secondary end point persistent AF (MVP: 15.4% vs DDD: 11.2%; P = .08), permanent AF (MVP: 4.1% vs DDD: 3.1%; P = .44), and composite of death and cardiovascular hospitalization (MVP: 23.9% vs DDD: 20.2%; P = .48). MVP reduced right ventricular pacing (median 5% vs 86%; Wilcoxon, P < .0001) as compared with DDD. In patients referred for pacemaker and ICD replacement with clinically well-tolerated long-term exposure to >40% ventricular pacing in the ventricle, a strategy to minimize ventricular pacing is not superior to standard DDD in reducing incidence of cardiovascular hospitalizations.