An evaluation of health care expenditures in Crohn's disease using the United States Medical Expenditure Panel Survey from 2003 to 2013.
Previous estimates of the economic burden of Crohn's disease (CD) varied widely from $2.0 to $18.2 billion per year (adjusted to 2015 $US). However, these estimates do not reflect recent changes in pharmaceutical treatment options and guidelines. The goal of this study was to update cost estimates of Crohn's disease based on a representative sample of the US population from the most recent 11 years (2003-2013) of the Medical Expenditure Panel Survey (MEPS). A secondary aim described expenditure trends in respondents with and without Crohn's disease pre-post FDA approvals of new biologics and the American College of Gastroenterology Crohn's disease treatment guidelines. Average annual expenditures (total, prescription, inpatient, and outpatient) were evaluated using a pooled cross-sectional design. Respondent data from the most recent 11 years (2003-2013) of MEPS were analyzed. Two-part generalized linear models with power-link were used to estimate the average annual expenditures per patient adjusted to multiple covariates. Confidence intervals (CI) were estimated using bootstrap methods. Difference-in-differences estimations were performed to compare the changes in health care expenditures pre-post FDA approvals of new biologics and the American College of Gastroenterology Crohn's disease treatment guidelines. The annual aggregate economic burden of CD was $6.3 billion in the US. Respondents with CD had higher total (+$6442; 95% CI: $4864 to $8297), prescription (+$3283; 95% CI: $2289 to $4445), inpatient (+$1764; 95% CI: $748 to $3551), and outpatient (+$1191; 95% CI: $592 to $2160) expenditures compared to respondents without CD. In the difference-in-differences estimation, respondents with CD had significantly higher total (P = 0.001) and prescription (P < 0.001) expenditures compared with respondents without CD. Although inpatient and outpatient expenditures were higher in respondents with CD, they were not statistically significant. Respondents with CD diagnosis had higher expenditures compared to respondents without CD diagnosis from 2003 to 2013. This study captured the most recent availability of new treatment options and changes to treatment guidelines, while providing updated estimates of the economic burden of CD in the US. However, this research was unable to study the causes of these increased health care expenditures in respondents with CD. Future investigations will need to determine the causal factors for increased expenditures in CD.


A Survey of Data Semantization in Internet of Things.
With the development of Internet of Things (IoT), more and more sensors, actuators and mobile devices have been deployed into our daily lives. The result is that tremendous data are produced and it is urgent to dig out hidden information behind these volumous data. However, IoT data generated by multi-modal sensors or devices show great differences in formats, domains and types, which poses challenges for machines to process and understand. Therefore, adding semantics to Internet of Things becomes an overwhelming tendency. This paper provides a systematic review of data semantization in IoT, including its backgrounds, processing flows, prevalent techniques, applications, existing challenges and open issues. It surveys development status of adding semantics to IoT data, mainly referring to sensor data and points out current issues and challenges that are worth further study.


Computer-aided detection for the automated evaluation of pulmonary embolism.
There are few quantitative studies that directly evaluate methods of determining pulmonary embolism (PE). New computer-aided detection (CAD) methods for measuring PE may help in defining the relationship of PE to right heart failure (RHF). We used CAD to investigate the severity of PE and explored whether the severity of PE was associated with RHF. A fully automatic calculation conducted by CAD was made of the embolism area/lumen area, which was used to evaluate the severity of the PE. The vascular obstruction index (VOI) was also used to evaluate PE, using the Mastora and Qanadli scores. Paired t tests were used to compare the severity of PE evaluated by Mastora or Qanadli score, to the severity determined by CAD. Correlation between the severity of the PE and RHF was also evaluated by Spearman's rank correlation analysis. There was no significant difference between the PE evaluated by Mastora compared with the measurement by CAD (P= 0.720), and also no difference between evaluation by Qanadli and automatic measurement by CAD (P= 0.617). The severity of PE evaluated by Mastora, Qanadli, and CAD had significant positive correlation with RHF (R= 0.75 P= 0.01, R= 0.69 P= 0.02, R= 0.80 P= 0.00). We found strong correlation between RHF and the severity of PE evaluated by CAD, and the method was found to be simple and reliable.


Upregulation of Cyclooxygenase-2/Prostaglandin E2 (COX-2/PGE2) Pathway Member Multiple Drug Resistance-Associated Protein 4 (MRP4) and Downregulation of Prostaglandin Transporter (PGT) and 15-Prostaglandin Dehydrogenase (15-PGDH) in Triple-Negative Breast Cancer.
Elevated levels of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) are indicators of a poor prognosis in breast cancer. Using several independent publicly available breast cancer gene expression databases, we investigated other members of the PGE2 pathway. PGE2 is produced by COX-2 and actively exported by multiple drug resistance-associated protein 4 (MRP4) into the extracellular microenvironment, where PGE2 can bind four cognate EP receptors (EP1-EP4) and initiate diverse biological signaling pathways. Alternatively, PGE2 is imported via the prostaglandin transporter (PGT) and metabolized by 15-prostaglandin dehydrogenase (15-PGDH/HPGD). We made the novel observation that MRP4, PGT, and 15-PGDH are differentially expressed among distinct breast cancer molecular subtypes; this finding was confirmed in independent datasets. In triple-negative breast cancer, the observed gene expression pattern (high COX-2, high MRP4, low PGT, and low 15-PGDH) would favor high levels of tumor-promoting PGE2 in the tumor microenvironment that may contribute to the overall poor prognosis of triple-negative breast cancer.


Aortic Pressure Estimation Using Blind Identification Approach on Single Input Multiple Output Nonlinear Wiener Systems.
Aortic pressure () is important for diagnosis of cardiovascular diseases, but it cannot be directly measured by noninvasive means. We present a method for its estimation by modeling arterial system as multichannel Weiner system with linear finite impulse response filter accounting for larger arteries transmission channel and nonlinear memoryless function block accounting for all nonlinearities due to narrowing of arteries, branching and visco-elastic forces. With this structure when pressure waveforms are measured from two distinct peripheral locations, multichannel blind system identification (MBSI) technique can be used to estimate common input pressure signal or . Nonlinear MBSI method was employed on previously acquired human hemodynamic measurements (seven datasets); results show can be accurately derived. This method by nature is self-calibrating to account for any interpersonal, along with intrapersonal, vascular dynamics inconstancy. Besides Pa estimation, the proposed MBSI method also allows extraction of system dynamics for vascular channels.


Discriminatory Value of the Ascending Aorta Diameter in Suspected Acute Type A Aortic Dissection.
The objective was to determine if ascending aorta (AscAo) diameters measured by noncontrast computed tomography (CT) allow for meaningful discrimination between patients with and without type A aortic dissection (TAAD), ideally with 100% sensitivity. This study was a retrospective analysis of cases of TAAD, as well as controls, undergoing evaluation for TAAD with CT aortography, presenting to 21 emergency departments within an integrated health system between 2007 and 2015. AscAo diameters were determined using axial noncontrast CT images at the level of the right main pulmonary artery by two readers. AscAo diameters were additionally normalized for age, sex, and body surface area (assessed by a Z-score, which is the number of standard deviations between the observed and expected AscAo diameters). Overall model discrimination was assessed using the area under the receiver operating characteristic curve (AUC). Comparative discrimination was assessed using both the change in AUC (∆AUC) and the continuous net reclassification index (NRI). A total of 230 cases of TAAD and 325 controls were included in the study. The median ages for cases and controls were 65 and 62 years, and the median AscAo diameters were 50 and 35 mm, respectively. The raw and normalized AscAo diameters demonstrated similarly excellent discrimination (AUCs of 0.96 vs. 0.97, respectively; ∆AUC = 0.01, p = 0.09) and an NRI of 0.30 (95% confidence interval [CI] = 0.13-0.47), both indicating small incremental improvements in classification with the use of the normalized AscAo measures. A raw AscAo diameter of 34 mm and a normalized Z-score of 1.84 both yielded 100% sensitivity for TAAD, with respective specificities of 35% (95% CI = 29.6%-40.2%) and 67% (95% CI = 61.7%-72.2%). Nearly all patients with TAAD appear to have enlarged AscAo diameters as measured by noncontrast CT, whereas most patients with suspected but absent TAAD have relatively normal AscAo diameters. Both raw and normalized AscAo measures provided relatively comparable discriminatory value. If validated, these data may be useful in adjudicating risk among patients with suspected TAAD in whom a criterion standard test is unavailable, nondiagnostic, or contraindicated.


Potassium-stimulated respiration and intra-cellular calcium releae in from skeletal muscle.
1. In 1931 Fenn showed that the respiration of frog twitch muscles increases when [K(+)](o) is raised. The present paper is a further study of potassium-stimulated respiration. Stimulation depends on membrane potential, since respiration is also stimulated by elevated [Rb(+)](o) or [Cs(+)](o) in direct relation to their ability to depolarize.2. When [K(+)](o) is elevated to 25 mM there is an increase in respiration which is sustained for hours. If [K(+)](o) is 30 mM or above, there is a transitory burst of stimulated respiration, followed by a decline back to the basal level.3. If [K(+)](o) is raised in steps from 20 to 30 mM, there may never be a burst of increased oxygen consumption. Often a rise in [K(+)](o) from 20 to 24 mM decreases respiration.4. The response to elevated [K(+)](o) can be blocked by divalent cations or by local anaesthetics; the blocking agents do not interfere with the depolarization of the membrane. The blocking agents act rapidly; they probably take effect soon after they contact the cell membrane.5. Either extracellular Ca(2+) or Sr(2+) is important for the stimulation of respiration. The burst produced by 50 mM [K(+)](o) is transformed into a sustained rise in respiration when [Ca(2+)](o) or [Sr(2+)](o) are also raised. If a muscle is stimulated with 25 mM [K(+)](o) in the absence of extracellular calcium, respiration is elevated as usual, but now the rise is transitory unless Ca(2+) or Sr(2+) are added back to the extracellular solution.6. Depolarization seems to stimulate respiration by causing the release of Ca(2+) into the sarcoplasm. Since respiration is increased by a depolarization below the threshold for producing a contracture, respiration is more sensitive than contraction as an indicator of sarcoplasmic calcium concentration.7. A model for the relation between sarcoplasmic calcium and membrane potential is proposed. The model accounts for the time course of the stimulation of respiration and also for much of the available data on potassium contracture. In the model, Ca(2+) is released into the sarcoplasm from a store in the cell. With depolarization, the release of Ca(2+) from the store is increased, but the rate at which extracellular Ca(2+) can replenish the store is decreased. The ability of the longitudinal reticulum to pump Ca(2+) from the sarcoplasm does not vary with membrane potential.


Human cytomegalovirus activates glucose transporter 4 expression to increase glucose uptake during infection.
Glucose transport into mammalian cells is mediated by a group of glucose transporters (GLUTs) on the plasma membrane. Human cytomegalovirus (HCMV)-infected human fibroblasts (HFs) demonstrate significantly increased glucose consumption compared to mock-infected cells, suggesting a possible alteration in glucose transport during infection. Inhibition of GLUTs by using cytochalasin B indicated that infected cells utilize GLUT4, whereas normal HFs use GLUT1. Quantitative reverse transcription-PCR and Western analysis confirmed that GLUT4 levels are greatly increased in infected cells. In contrast, GLUT1 was eliminated by a mechanism involving the HCMV major immediate-early protein IE72. The HCMV-mediated induction of GLUT4 circumvents characterized controls of GLUT4 expression that involve serum stimulation, glucose concentration, and nuclear functions of ATP-citrate lyase (ACL). In infected cells the well-characterized Akt-mediated translocation of GLUT4 to the cell surface is also circumvented; GLUT4 localized on the surface of infected cells that were serum starved and had Akt activity inhibited. The significance of GLUT4 induction for the success of HCMV infection was indicated using indinavir, a drug that specifically inhibits glucose uptake by GLUT4. The addition of the drug inhibited glucose uptake in infected cells as well as viral production. Our data show that HCMV-specific mechanisms are used to replace GLUT1, the normal HF GLUT, with GLUT4, the major glucose transporter in adipose tissue, which has a 3-fold-higher glucose transport capacity.


[The pathology and genetic background of lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia].
Lymphoplasmacytic lymphoma is a rare low-grade B-cell lymphoma, which is composed of a mixture of small lymphocytes, plasmacytoid cells and plasma cells that typically infiltrate the bone marrow, but lymph nodes and rarely other organs can be involved as well. Waldenström macroglobulinaemia is a lymphoplasmacytic lymphoma with typical bone marrow involvement and is associated with detectable IgM paraproteins. The diagnosis of lymphoplasmacytic lymphoma/Waldenström macroglobulinaemia (LPL/WM) can be challenging, due to similarities to other small B-cell lymphomas with plasmacytic differentiation and/or with IgM paraproteins. The recently discovered MYD88 mutation may help in the diagnosis, as it is present in over 90% of LPL/WMs. This short review covers the pathology of LPL/WM and offers some insight into the new molecular findings that may help in the diagnostic procedure and in the new therapeutic choices.


Pulmonary function studies in healthy non-smoking adults in Sri Aurobindo Ashram, Pondicherry.
Pulmonary functions are used for diagnosis, assessment and clinical management of breathlessness, and, as epidemiological and research tools. In India the wide range of geographical and climatic conditions is associated with regional differences in lung functions. Most of the studies have restricted themselves to specific regions/ethnicities and a relatively short age span of 15-40 yr. The purpose of the present study is to fill these two lacunae by studying the pulmonary functions of the inmates (17-70 yr and of different ethnicities) of Sri Aurobindo Ashram, Pondicherry. A total of 397 non-smoking, healthy individuals aged 17 to 70 yr (195 men, 202 women) were investigated. The parameters measured included forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV1, FEV1%), peak expiratory flow rate (PEF) and mean expiratory flow rate (MEF). The standing height and weight were also recorded. In both men and women, age showed significant negative correlations with all spirometric functions, the height showed significant positive correlations with all pulmonary function test (PFT) parameters except FEV1 per cent while the weight did not show any significant correlation with any of the parameters except PEF. Men had significantly (P < 0.001) higher values than those of women for all parameters except FEV1 per cent. Prediction equations for all PFT parameters based on the age and height were derived for men and women. The ventilatory norms of both men and women based on age and height appear reliable for the FVC and FEV1. They can therefore be used to derive the normal values for healthy, non-smoking Indian adults between 17 and 70 yr. The coefficient for age obtained from the regression equations for FVC were found to be consistently smaller than those of others indicating that in the Ashram environment, age seems to have a lesser negative influence on pulmonary functions.


Ozone and other air quality-related variables affecting visibility in the southeast United States.
An analysis of ozone (O3) concentrations and several other air quality-related variables was performed to elucidate their relationship with visibility at five urban and semi-urban locations in the southeast United States during the summer seasons of 1980-1996. The role and impact of O3 on aerosols was investigated to ascertain a relationship with visibility. Regional trend analysis over the 1980s reveals an increase in maximum O3 concentration coupled with a decrease in visibility. However, a similar analysis for the 1990s shows a leveling-off of both O3 and visibility; in both cases, the results were not statistically significant at the 5% level. A case study of site-specific trends at Nashville, TN, followed similar trends. To better understand the relationships between O3 concentration and visibility, the analysis was varied from yearly through daily to hourly averaged values. This increased temporal resolution showed a statistically significant inverse relationship between visibility and O3. Site-specific hourly r2 values ranged from 0.02 to 0.43. Additionally, by performing back-trajectory analysis, it was found that the visibility degraded by air mass migration over polluted areas.


Exploring Nurses' Perception of Antibiotic Use and Resistance: A Qualitative Inquiry.
Quality use of antibiotics and the development of antibiotic resistance is a global catastrophe. In the conceptual context, the phenomenon is correlated with the healthcare practitioners' understanding of antibiotic use and resistance. Therefore, the study aimed to highlight nurses' perception of antibiotic use and resistance at a public healthcare institute in Quetta City, Pakistan. By using a semi-structured interview guide through the phenomenology-based approach, in-depth, face-to-face interviews were conducted. Nurses practicing at the surgical and medical units of Sandeman Provincial Hospital (SPH), Quetta, were approached for the study. All interviews were audio-taped, transcribed verbatim, and were then analyzed for thematic contents by the standard content analysis framework. Although the saturation was reached after the 13th interview, an additional two were interviewed for absolute validation. Content analysis revealed five major themes: (1) defining antibiotics and antibiotic resistance, (2) antibiotic use: awareness and concern, (3) antimicrobial resistance: awareness and concern, (4) responding to antibiotic use and resistance, and (5) barriers to quality use of antibiotics and prevention of antibiotic resistance. Even though the understanding of nurses regarding antibiotic use and resistance was promising, certain apprehensions were also observed. The respondents were aware of the critical situation and provided valuable insights that can offer significant input while promoting the quality use of antibiotics in a developing country. While the perception towards antibiotics appeared positive, potential areas of concern and contributing factors regarding antibiotic resistance were also identified. Importantly, nurses too highlighted possible solutions to address the issue of irrational antibiotic use and the development of antibiotic resistance.


What happens to patients after upper and lower gastrointestinal tract barium studies?
We investigated the occurrence of new constipation, diarrhea, nausea, vomiting, visible blood in stool, abdominal pain, black stools, belching, and flatus in 324 outpatients following upper or lower gastrointestinal tract barium procedures. We also evaluated the roles of age, sex, patient mobility, and types of barium enema (single- or double-contrast). At least one new symptom was reported after 51% of all examinations. Constipation was the most frequently reported single symptom after barium meal or small bowel examinations. Fifty percent of all constipation occurred following upper gastrointestinal examinations. Abdominal pain was common in patients of the seventh decade, especially following barium enema. Nausea typically followed barium swallow or upper gastrointestinal series. Belching and passage of flatus were the most frequently reported symptoms after barium enema, both single- and double-contrast. No significant relationship between the frequency of symptoms and patient age, sex, or the type of barium enema was established.


Basal ganglia infarction associated with HHV-6 infection.
A 6 year old boy presented with meningoencephalitis and was found to have serological evidence of acute human herpes virus-6 (HHV-6) infection. He did not develop symptomatic seizures or the rash of exanthum subitum (roseola). His course was marked by severe spastic quadriparesis associated with radiological evidence of basal ganglia infarction. HHV-6 infection should be considered in any child with acute meningoencephalitis.


Endogenous glucose production, insulin sensitivity, and insulin secretion in normal glucose-tolerant Pima Indians with low birth weight.
Individuals with low birth weight (LBW) are at increased risk of developing type 2 diabetes in later life. Whether impairments in endogenous glucose production (EGP), insulin action, insulin secretion, or a combination thereof account for this association is unclear. We, therefore, examined these parameters in Pima Indians with normal glucose tolerance. Body composition, glucose and insulin responses during a 75-g oral glucose tolerance test (OGTT), EGP, insulin-stimulated glucose disposal during low- and high-dose insulin infusion (M-low and M-high, hyperinsulinemic glucose clamp), and acute insulin response (AIR) to a 25-g intravenous glucose challenge were measured in 230 Pima Indians (147 men and 83 women, aged 25 +/- 0.4 years [mean +/- SE; range, 18 to 44]) with normal glucose tolerance. A subgroup of 63 subjects additionally underwent biopsies of subcutaneous adipose tissue for determination of adipocyte cell size and lipolysis. Subjects in the lowest quartile of birth weight (birth weight: 2,891 +/- 33 g, LBW, n = 58) were compared to those whose birth weight was in the upper 3 quartiles (birth weight: 3,657 +/- 28 g, NBW, n = 172). Age- and sex-adjusted body mass index (BMI), percent body fat, and waist-to-thigh ratio (WTR) were similar in LBW and NBW subjects. Suppression of EGP during the clamp was less in LBW than in NBW subjects before (P = .002) and after adjustment for age, sex, percent body fat, and M-low (P = .02). M-low and M-high were less in LBW than in NBW subjects before (P = .05 and P = .01) and after adjustment for age, sex, percent body fat, and WTR (P = .04 and P = .05). AIR was not different in LBW compared to NBW subjects before adjustments (P = .06), but it was lower in LBW than in NBW subjects after adjustment for age, sex, percent body fat, and M-low (P = .02), suggesting that AIR did not increase appropriately for the decrease in insulin-stimulated glucose disposal (M). In addition, average adipocyte cell size (P = .08) and basal lipolysis (P = .02) were higher in the LBW than in the NBW group. These results show that Pima Indians with LBW manifest a variety of impairments in metabolism in adulthood. Among these, a lesser insulin-stimulated suppression of EGP and a lesser insulin secretory capacity are the predominant ones. We conclude that interaction of multiple defects may contribute to increased susceptibility to type 2 diabetes among individuals with LBW.


Failure at the effector phase: immune barriers at the level of the melanoma tumor microenvironment.
The clinical investigation of numerous therapeutic cancer vaccine strategies has resulted in relative disappointment. Whereas a minority of patients have indeed experienced clinical benefit, the majority of patients show disease progression even in cases in which induction of functional tumor antigen-specific T-cell responses as measured in the blood is easily detected. This observation has led to interrogation of the tumor microenvironment for potential mechanisms of tumor resistance to the effector phase of the antitumor T-cell response. Poor chemokine-mediated trafficking of effector cells and the action of negative regulatory pathways that inhibit T-cell function have been identified as key limiting factors. Important negative regulatory pathways include T-cell anergy from insufficient B7 costimulation, extrinsic suppression by regulatory T-cell populations, direct inhibition through inhibitory ligands such as PD-L1, and metabolic dysregulation such as through the activity of indoleamine 2,3-dioxygenase. Recognition of these evasion mechanisms has pointed toward new therapeutic approaches for cancer immunotherapy.


Use of indoor tanning sunlamps by US youth, ages 11-18 years, and by their parent or guardian caregivers: prevalence and correlates.
Tanning parlors have become common in the United States. Artificial ultraviolet radiation exposure from this source may be harmful and may increase the risk of melanoma, particularly when done for recreational purposes during childhood and early adult years. Population-based data on the prevalence and correlates of this activity is important in the evaluation of potential public health interventions for skin cancer prevention. In 1998, we conducted a population-based telephone survey of youth and their primary caregiver. The sample (N = 1192) was weighted to represent the population of US youth living in households with a primary caregiver. Interviewers used a standardized questionnaire to document the characteristics of the participant and their practices, attitudes, and experiences regarding ultraviolet exposures. METHOD OF ANALYSIS: Weighted prevalence and adjusted prevalence odds ratios (aPOR) and 95% confidence interval (95% CI) were estimated. Independent factors were evaluated with multivariate logistic regression. Ten percent of youth and 8% of their primary caregivers used indoor tanning sunlamps in the previous year. Thirty percent of the youth whose caregivers used indoor tanning sunlamps did so themselves as well. Independent predictors associated with indoor tanning sunlamp use were as follows: age 17 to 18 years (aPOR = 11.1; 95% CI: 5.0, 25.0); female (aPOR = 8.3; 95% CI: 3.6, 19.2); having a parent who used indoor tanning sunlamps in the previous year (aPOR = 8.7; 95% CI: 4.0, 18.9); nonuser of Sun Protection Factor 15 sunscreen at the beach or pool (aPOR = 1.9; 95% CI: 1.0, 3.4); and low sun sensitivity (aPOR = 2.3; 95% CI: 1.0, 5.3). A substantial minority of American youth engages in indoor tanning. However, it is particularly prevalent among older youth, girls, and youth whose parents themselves use indoor tanning sunlamps. The knowledge of these trends may help focus public health initiatives.


Synaptopathies in Developmental and Epileptic Encephalopathies: A Focus on Pre-synaptic Dysfunction.
The proper connection between the pre- and post-synaptic nervous cells depends on any element constituting the synapse: the pre- and post-synaptic membranes, the synaptic cleft, and the surrounding glial cells and extracellular matrix. An alteration of the mechanisms regulating the physiological synergy among these synaptic components is defined as "synaptopathy." Mutations in the genes encoding for proteins involved in neuronal transmission are associated with several neuropsychiatric disorders, but only some of them are associated with Developmental and Epileptic Encephalopathies (DEEs). These conditions include a heterogeneous group of epilepsy syndromes associated with cognitive disturbances/intellectual disability, autistic features, and movement disorders. This review aims to elucidate the pathogenesis of these conditions, focusing on mechanisms affecting the neuronal pre-synaptic terminal and its role in the onset of DEEs, including potential therapeutic approaches.


[Is there a noticeable temporary protective function of homologous skin grafts of variable thickness in deep burns against the effect of atmospheric oxygen?].
The injurious influence of atmospheric oxygen upon healing of large wound areas for instance of burn wounds is well known, in differently thick skin grafts different protective functions can be demonstrated. Experiments show the isolation functions of the full-thickness on the one and split skin grafts on the other hand in burn wounds by measuring the subcutaneous pO2: under temporary full-thickness grafts there are with regard to the atmospheric oxygen clearly lower oxygen partial pressures than under split skin grafts.


Definition of minimum procedures required to certify competence in gastrointestinal endoscopy using the Delphi method.
As part of the training framework for medical specialities, it is vital to provide an agreed list of the type and number of practices involved in the professional work of a given specialty. Thus, the purpose of this study is to define a list of minimum procedures to ensure competence in Gastrointestinal Endoscopy based on a structured and agreed upon process, as well as to explore the opinions of experts in gastrointestinal endoscopy on the training of endoscopy physicians in Argentina and the need to certify competencies. a mixed-method prospective study was carried out using the Delphi method as a qualitative group research technique, followed by the implementation of a structured survey. The final consolidated list included 17 procedures considered essential for certification of competence in gastrointestinal endoscopy. Median was used given the range in the minimum number of procedures required to achieve competence. In the case of upper gastrointestinal endoscopy, the minimum number of procedures agreed was 200, while in the case of colonoscopy it was 150. This list is a fundamental element to develop a national training framework in gastrointestinal endoscopy, as well as a competence certification program.


Effects of Cumulative Head Impact Exposure in Adolescent Male Contact and Collision Sport Student Athletes.
This prospective cohort study aimed to investigate the association between head impact exposure (HIE) and neuropsychological sequelae in high school football and ice hockey players over 1 year. Community sample. A cohort of 52 adolescent American football and ice hockey players were enrolled in the study, with a final study sample of 35 included in analyses. The study followed a prospective cohort design, with participants undergoing neuropsychological screening and accelerometer-based measurement of HIE over 1 season. Changes in cognition, emotions, behavior, and reported symptoms were assessed using standardized neuropsychological tests and self-reported questionnaires. Cumulative HIE was not consistently associated with changes in cognition, emotions, behavior, or reported symptoms. However, it was linked to an isolated measure of processing speed, showing inconsistent results based on the type of HIE. History of previous concussion was associated with worsened verbal memory recognition (ImPACT Verbal Memory) but not on a more robust measure of verbal memory (California Verbal Learning Test [CVLT]). Reported attention-deficit/hyperactivity disorder history predicted improved neurocognitive change scores. No associations were found between reported history of anxiety/depression or headaches/migraines and neuropsychological change scores. Overall, our findings do not support the hypothesis that greater HIE is associated with an increase in neuropsychological sequelae over time in adolescent football and ice hockey players. The results align with the existing literature, indicating that HIE over 1 season of youth sports is not consistently associated with significant neuropsychological changes. However, the study is limited by a small sample size, attrition over time, and the absence of performance validity testing for neurocognitive measures. Future studies with larger and more diverse samples, longer follow-up, and integration of advanced imaging and biomarkers are needed to comprehensively understand the relationship between HIE and neurobehavioral outcomes. Findings can inform guidelines for safe youth participation in contact sports while promoting the associated health and psychosocial benefits.


Partial Nephrectomy in Adults - A Single-Centre Experience.
Partial nephrectomy is the preferred procedure in benign renal lesions requiring surgical removal. It has also been accepted procedure for malignant renal conditions of smaller size. The aim of this observational study was to determine the outcome of partial nephrectomy in terms of complications and recurrence rates. Twenty patients with renal mass underwent this procedure from January 2010 till June 2014 at our Department, with mean age of 46.51 ±1.53 years. There were 14 males and 6 females. Renal mass on CT scan had the mean size of 3.80 ±1.15cm. The mean hospital stay in this series was 5.11 ±1.42 days, while mean operative time was 247 ±79.71 minutes. Twelve patients had malignant histology. They were followed using CT scan abdomen and pelvis with contrast at six and 12 months. Out of these, 10 (83.3%) patients were found to have no recurrence after six months.


[Of calabash gourds and other patient histories].
In the culture of primal peoples, the dumbbell-shaped bottle gourd or calabash is a symbol for the universe, two equal halves inextricably linked. They represent heaven and earth, Yin and Yang--balance and harmony. This essay reflects personal memories, where case histories, patient stories and a doctor's story are intertwined.


Sound-Intensity Feedback During Running Reduces Loading Rates and Impact Peak.
Study Design Controlled laboratory study, within-session design. Background Gait retraining has been proposed as an effective intervention to reduce impact loading in runners at risk of stress fractures. Interventions that can be easily implemented in the clinic are needed. Objective To assess the immediate effects of sound-intensity feedback related to impact during running on vertical impact peak, peak vertical instantaneous loading rate, and vertical average loading rate. Methods Fourteen healthy, college-aged runners who ran at least 9.7 km/wk participated (4 male, 10 female; mean ± SD age, 23.7 ± 2.0 years; height, 1.67 ± 0.08 m; mass, 60.9 ± 8.7 kg). A decibel meter provided real-time sound-intensity feedback of treadmill running via an iPad application. Participants were asked to reduce the sound intensity of running while receiving continuous feedback for 15 minutes, while running at their self-selected preferred speed. Baseline and follow-up ground reaction force data were collected during overground running at participants' self-selected preferred running speed. Results Dependent t tests indicated a statistically significant reduction in vertical impact peak (1.56 BW to 1.13 BW, P≤.001), vertical instantaneous loading rate (95.48 BW/s to 62.79 BW/s, P = .001), and vertical average loading rate (69.09 BW/s to 43.91 BW/s, P≤.001) after gait retraining, compared to baseline. Conclusion The results of the current study support the use of sound-intensity feedback during treadmill running to immediately reduce loading rate and impact force. The transfer of within-session reductions in impact peak and loading rates to overground running was demonstrated. Decreases in loading were of comparable magnitude to those observed in other gait retraining methods. J Orthop Sports Phys Ther 2017;47(8):565-569. Epub 6 Jul 2017. doi:10.2519/jospt.2017.7275.


The enhancer sequence of human hepatitis B virus can enhance the activity of its surface gene promoter.
The transcriptional enhancer sequence has recently been demonstrated in the hepatitis B viral genome. This enhancer sequence has also been shown to increase the activity of HBcAg gene promoter. Using the chloramphenicol acetyltransferase gene expression system, we demonstrated that the intrinsic promoter activity of HBsAg gene promoter was stronger than that of HBcAg gene promoter in both human hepatoma cell lines, Hep3B and HuH-7. Furthermore, we showed that the HBV enhancer sequence not only stimulated the HBcAg gene promoter activity, but also stimulated the HBsAg gene promoter activity in both Hep3B and HuH-7 cells. The enhancer sequence increased the HBsAg gene promoter activity 20-fold in both Hep3B and HuH-7 cell lines, while the increase of the HBcAg gene promoter was 2- and 8-fold in Hep3B and HuH-7 cells, respectively.


Sensory gating and alpha-7 nicotinic receptor gene allelic variants in schizoaffective disorder, bipolar type.
Single nucleotide allelic variants in the promoter region of the chromosome 15 alpha-7 acetylcholine nicotinic receptor gene (CHRNA7) are associated with both schizophrenia and the P50 auditory evoked potential sensory gating deficit. The purpose of this study was to determine if CHRNA7 promoter allelic variants are also associated with abnormal P50 ratios in persons with schizoaffective disorder, bipolar type. P50 auditory evoked potentials were recorded in a paired stimulus paradigm in 17 subjects with schizoaffective disorder, bipolar type. The P50 test to conditioning ratio was used as the measure of sensory gating. Mutation screening of the CHRNA7 promoter region was performed on the subjects' DNA samples. Comparisons to previously obtained data from persons with schizophrenia and controls were made. Subjects with schizophrenia, regardless of allele status, had an abnormal mean P50 ratio. Subjects with schizoaffective disorder, bipolar type and a variant allele had an abnormal mean P50 ratio, whereas those schizoaffective subjects with the common alleles had a normal mean P50 ratio. Normal control subjects had a normal mean ratio, but controls with variant alleles had higher P50 ratios. In persons with bipolar type schizoaffective disorder, CHRNA7 promoter region allelic variants are linked to the capacity to inhibit the P50 auditory evoked potential and thus are associated with a type of illness genetically and biologically more similar to schizophrenia.


In-silico, evolutionary, and functional analysis of CHUP1 and its related proteins in Bienertia sinuspersici-a comparative study across C3, C4, CAM, and SCC4 model plants.
Single-cell C4 (SCC4) plants with bienertioid anatomy carry out photosynthesis in a single cell. Chloroplast movement is the underlying phenomenon, where chloroplast unusual positioning 1 (CHUP1) plays a key role. This study aimed to characterize CHUP1 and CHUP1-like proteins in an SCC4 photosynthetic plant, Bienertia sinuspersici. Also, a comparative analysis of SCC4 CHUP1 was made with C3, C4, and CAM model plants including an extant basal angiosperm, Amborella. The CHUP1 gene exists as a single copy from the basal angiosperms to SCC4 plants. Our analysis identified that Chenopodium quinoa, a recently duplicated allotetraploid, has two copies of CHUP1. In addition, the numbers of CHUP1-like and its associated proteins such as CHUP1-like_a, CHUP1-like_b, HPR, TPR, and ABP varied between the species. Hidden Markov Model analysis showed that the gene size of CHUP1-like_a and CHUP1-like_b of SCC4 species, Bienertia, and Suaeda were enlarged than other plants. Also, we identified that CHUP1-like_a and CHUP1-like_b are absent in Arabidopsis and Amborella, respectively. Motif analysis identified several conserved and variable motifs based on the orders (monocot and dicot) as well as photosynthetic pathways. For instance, CAM plants such as pineapple and cactus shared certain motifs of CHUP1-like_a irrespective of their distant phylogenetic relationship. The free ratio model showed that CHUP1 maintained purifying selection, whereas CHUP1-like_a and CHUP1-like_b have adaptive functions between SCC4 plants and quinoa. Similarly, rice and maize branches displayed functional diversification on CHUP1-like_b. Relative gene expression data showed that during the subcellular compartmentalization process of Bienertia, CHUP1 and actin-binding proteins (ABP) genes showed a similar pattern of expression. Altogether, the results of this study provide insight into the evolutionary and functional details of CHUP1 and its associated proteins in the development of the SCC4 system in comparison with other C3, C4, and CAM model plants.


Alitretinoin as a treatment modality for ichthyosis in women of childbearing age - a case series and review of the literature.
Acitretin, a synthetic vitamin A derivative, is the most studied and widely used oral retinoid for ichthyoses. Its major disadvantage is the need for contraceptive measures during three years after discontinuation. An alternative is needed for women of childbearing age. With alitretinoin, another retinoid, pregnancy is considered safe one month after discontinuation. To provide evidence for alitretinoin as an alternative for acitretin for ichthyosis in women of childbearing age. Our experience is shared in a case series combined with an overview of the current literature. Nine women of childbearing age (19-31 years, median 21) with different subtypes of ichthyosis (autosomal recessive congenital ichthyosis, (superficial) epidermolytic ichthyosis, erythrokeratoderma variabilis, and epidermolytic epidermal nevi, a mosaic form of epidermolytic ichthyosis) were included and treated with 30mg alitretinoin during 2-28 months. Severity was measured by Ichthyosis Area Severity Index (IASI) and Investigator Global Assessment (IGA). A literature search in Pubmed using the Mesh terms "alitretinoin", "skin diseases, genetic" and "ichthyosis" was performed. Significant reduction in the mean scores of IGA, IASI-erythema, IASI-scaling and IASI-total was seen. Seven patients are still being treated, one patient stopped to become pregnant, one patient discontinued due to financial reasons. Observed side effects were reversible headache (n=6), asteatotic eczema (n=1), 'not feeling well' temporarily (n=1) and easier blistering of the feet (n=1). The literature search resulted in six case reports and case series about alitretinoin in ichthyosis and ichthyosis syndromes with in total 29 patients. The vast majority (21/29) reported significant improvement or even complete remission of skin symptoms. However, validated outcome measures to support these results were lacking. Side effects (n=16) were relatively mild, except for benign intracranial hypertension (n=1) and autoimmune hypothyroidism (n=1). Our study shows, with validated outcome measures, that alitretinoin is effective to mitigate the symptoms of ichthyosis in women of childbearing age and a suitable alternative to acitretin.


Photocatalytic oxidation of pesticide rinsate.
Pesticide rinsate has been considered as one of the major threats for the environment. In this study, photocatalysts such as TiO2 and O3 were used to promote the efficiency of direct UV photolysis to prevent such wastewater pollution. Carbofuran (a carbamate pesticide) and mevinphos (an organophosphate pesticide) with a concentration of 100 mg/L were selected as the test pesticide rinsates. Parent pesticide compound, COD, and microtoxicity analysis were employed to investigate the effect of photocatalyst on the degradation efficiency of pesticide in rinsate. It was found that the photocatalytic oxidation process (UV/O3, UV/TiO2) showed much higher COD removal and microtoxicity reduction efficiency for pesticide rinsate than did direct UV photolysis under the imposed conditions, suggesting that photocatalytic oxidation processes such as UV/O3 and UV/TiO2 could be a better alternative to treat pesticide rinsate. In addition, it was noted that increasing the initial pH of mevinphos rinsate to a basic level was required to reach higher COD removal efficiency and positive microtoxicity reduction efficiency while it was not necessary for the treatment of carbofuran rinsate.


Novel Antitumor Invasive Actions of p-Cymene by Decreasing MMP-9/TIMP-1 Expression Ratio in Human Fibrosarcoma HT-1080 Cells.
p-Cymene (4-isopropyltoluene) has been reported to have beneficial actions such as anti-inflammatory and antinociceptive activities. To evaluate whether p-cymene exhibits antitumor invasive actions, we examined the effects of p-cymene on the production of matrix metalloproteinase 9 (MMP-9)/gelatinase B and tissue inhibitor of metalloproteinases-1 (TIMP-1) in human fibrosarcoma HT-1080 cells. p-Cymene was found to dose-dependently inhibit the 12-O-tetradecanoylphorbol 13-acetate (TPA)-augmented production and gene expression of MMP-9 in HT-1080 cells. In contrast, p-cymene enhanced the TPA-augmented production and gene expression of TIMP-1 in HT-1080 cells. However, there was no change in the constitutive level of MMP-9 and TIMP-1 mRNAs and TIMP-1 protein in p-cymene-treated cells. In addition, we found that the in-vitro TPA-augmented invasiveness of HT-1080 cells was inhibited by p-cymene in a dose-dependent manner. Furthermore, p-cymene was found to suppress the constitutive and/or TPA-augmented phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) in HT-1080 cells. Thus, these results provide novel evidence that p-cymene is an effective candidate for the prevention of tumor invasion and metastasis through mechanisms that include the inhibition of MMP-9 expression and the augmentation of TIMP-1 production along with the suppression of ERK1/2 and p38 MAPK signal pathways in tumor cells.


Socioeconomic influence on orofacial cleft patient care.
Cleft lip and palate is the most common craniofacial birth defect in the UK. Orofacial clefts have functional and aesthetic implications requiring intensive multi-disciplinary follow-up to optimise development. Failure to attend follow-up is likely to have a negative impact on patient outcomes. The aim of this retrospective audit is to establish if socioeconomic status influences attendance, DNA and cancellation rates in cleft patients. A retrospective audit of 74 orofacial cleft patients born and operated on at the Royal Hospital for Sick Children Glasgow between 2006 and 2007. There was higher rate of DNA in more deprived social groups-21% (SIMD 1) against 10% (SIMD 5). A higher rate of DNA in cleft lip and palate patients was noted. This group of patients showed a marked difference in attendance between SIMD 1 (38%) and SIMD 5 (78%). More deprived areas have a higher outpatient DNA rate for cleft patients resulting in suboptimal follow-up. Ultimately, causation of poorer outcomes in this group is likely to be multi-factorial but the financial implication of travelling to multiple clinics should be considered and it may be that resource reallocation is the answer to address the current inequality of health care provision.


A SMN2 Splicing Modifier Rescues the Disease Phenotypes in an In Vitro Human Spinal Muscular Atrophy Model.
Spinal muscular atrophy (SMA) is caused by the mutation or deletion of the survival motor neuron 1 (SMN1) gene. Only ∼10% of the products of SMN2, a paralogue of SMN1, are functional full-length SMN (SMN-FL) proteins, whereas SMN2 primarily produces alternatively spliced transcripts lacking exon 7. Reduced SMN protein levels in SMA patients lead to progressive degeneration of spinal motor neurons (MNs). In this study, we report an advanced platform based on an SMN2 splicing-targeting approach for SMA drug screening and validation using an SMN2 splicing reporter cell line and an in vitro human SMA model through induced pluripotent stem cell (iPSC) technology. Through drug screening using a robust cell-based luciferase assay to quantitatively measure SMN2 splicing, the small-molecule candidate compound rigosertib was identified as an SMN2 splicing modulator that led to enhanced SMN protein expression. The therapeutic potential of the candidate compound was validated in MN progenitors differentiated from SMA patient-derived iPSCs (SMA iPSC-pMNs) as an in vitro human SMA model, which recapitulated the biochemical and molecular phenotypes of SMA, including lower levels of SMN-FL transcripts and protein, enhanced cell death, and reduced neurite length. The candidate compound exerted strong splicing correction activity for SMN2 and potently alleviated the disease-related phenotypes of SMA iPSC-pMNs by modulating various cellular and molecular abnormalities. Our combined screening platform representing a pMN model of human SMA provides an efficient and reliable drug screening system and is a promising resource for drug evaluation and the exploration of drug modes of action.


The PPARα activator fenofibrate inhibits voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells.
We examined the effects of the PPARα activator fenofibrate on voltage-dependent K+ (Kv) channels using a patch clamp technique in native rabbit coronary arterial smooth muscle cells. Kv current was inhibited by application of fenofibrate in a concentration-dependent manner, with an apparent IC50 value of 6.39 ± 0.53μM and a slope value (Hill coefficient) of 1.63 ± 0.10. Fenofibrate accelerated the decay rate of Kv channel inactivation. The rate constants of association and dissociation for fenofibrate were 0.81± 0.05μM-1s-1 and 4.70 ± 0.47s-1, respectively. Although fenofibrate did not affect the steady-state activation curves, fenofibrate shifted the inactivation curves toward a more negative potential. Application of train pulses (1 or 2Hz) progressively increased the fenofibrate-induced inhibition of the Kv channel, and the recovery time constant from inactivation was increased in the presence of fenofibrate, which suggested that the inhibitory effect of fenofibrate is use-dependent. Another PPARα activator, bezafibrate and PPARα inhibitor, GW 6471, did not affect the Kv current and also did not change the inhibitory effect of fenofibrate on the Kv current. From these results, we suggest that fenofibrate inhibited Kv current in a state-, time-, and use-dependent manner, completely independent of PPARα activation.


[Availability of Local Therapy to Castration-Resistant Prostate Cancer for M0 Patients with Initial Prostate Specific Antigen 100 ng/ml or Higher].
Prostate cancer patients with initial PSA 100 ng/ml or greater who received transrectal ultrasoundguided prostate biopsy and were staged as M0 by imaging studies from 2011 to 2014 in seven hospitals, were enrolled in the study. Castration-resistant prostate cancer (CRPC)-free survival was compared between the two treatment groups : androgen deprivation therapy (ADT) alone and ADT plus local therapy. Of 142 prostate cancer patients with initial PSA 100 ng/ml or greater, 49 (34.5%) had no metastases and final analysis was performed on 46 patients. Thirty one M0 patients received ADT alone, and 15 received ADT plus local therapy. During follow-up (median 31 months, range 1-56 months) 13 patients (42%) in the ADT alone group progressed to CRPC. One- and two-year CRPC-free survival rates were 72.5 and 53%, respectively. No patients with ADT plus local therapy developed CRPC, and time to CRPC was prolonged significantly (p=0.002). On multivariate analysis for the group with ADT alone, PSA nadir of more than 0. 2 ng/ml and cN1 were independent predictors for progression to CRPC (p=0.009, 0.031). About one third of prostate cancer patients with initial PSA 100 ng/ml or greater had clinically no metastases. Local therapy to prostate combined with ADT may prolong time to CRPC compared with ADT alone. A subset of men with a PSA nadir of more than 0.2 ng/ml after ADT and cN1 could benefit from local therapy.


Evolution of bacteriophage in continuous culture: a model system to test antiviral gene therapies for the emergence of phage escape mutants.
The emergence of viral escape mutants is usually a highly undesirable phenomenon. This phenomenon is frequently observed in antiviral drug applications for the treatment of viral infections and can undermine long-term therapeutic success. Here, we propose a strategy for evaluating a given antiviral approach in terms of its potential to provoke the appearance of resistant virus mutants. By use of Q beta RNA phage as a model system, the effect of an antiviral gene therapy, i.e., a virus-specific repressor protein expressed by a recombinant Escherichia coli host, was studied over the course of more than 100 generations. In 13 experiments carried out in parallel, 12 phage populations became resistant and 1 became extinct. Sequence analysis revealed that only two distinct phage mutants emerged in the 12 surviving phage populations. For both escape mutants, sequence variations located in the repressor binding site of the viral genomic RNA, which decrease affinity for the repressor protein, conferred resistance to translational repression. The results clearly suggest the feasibility of the proposed strategy for the evaluation of antiviral approaches in terms of their potential to allow resistant mutants to appear. In addition, the strategy proved to be a valuable tool for observing virus-specific molecular targets under the impact of antiviral drugs.


Aortopexy - an effective strategy for relief of left main bronchus compression.
Congenital anomalies of aortic arch and pulmonary arteries can cause airway compression in children. We present a rare case of left main bronchus compression between the right pulmonary artery and descending thoracic aorta, which was successfully treated by aortopexy.


Tosylhydrazones: new uses for classic reagents in palladium-catalyzed cross-coupling and metal-free reactions.
Tosylhydrazones are useful synthetic intermediates that have been used in organic chemistry for almost 60 years. The recent discovery of a palladium-catalyzed cross-coupling reaction involving a tosylhydrazone coupling partner has triggered renewed interest in these reagents. This reaction shows nearly universal generality with regard to the hydrazone and can be employed for the preparation of polysubstituted alkenes. In the course of this research, novel metal-free C-C and C-O bond-forming reactions have been discovered. Since tosylhydrazones are readily prepared from carbonyl compounds, these transformations offer new synthetic opportunities for the unconventional modification of carbonyl compounds. This Minireview discusses all of these new reactions of a classic reagent.


Antibacterial Activity of Amidodithiophosphonato Nickel(II) Complexes: An Experimental and Theoretical Approach.
The reactions of 2,4-bis(4-methoxyphenyl)-1,3-dithio-2,4-diphosphetane-2,4-disulfide (Lawesson's Reagent, LR) with benzylamine (BzNH2) and 4-phenylbutylamine (PhBuNH2) yield benzylammonium P-(4-methoxyphenyl)-N-benzyl-amidodithiophosphonate (BzNH3)(BzNH-adtp) and 4-phenylbutylammonium P-(4-methoxyphenyl)-N-(4-phenylbutyl)-amidodithiophosphonate (PhBuNH3)(PhBuNH-adtp). The relevant nickel complexes [Ni(BzNH-adtp)2] and [Ni(PhBuNH-adtp)2] and the corresponding hydrolysed derivatives (BzNH3)2[Ni(dtp)2] and (PhBuNH3)2[Ni(dtp)2] were prepared and fully characterized. The antimicrobial activity of the aforementioned amidodithiophosphonates against a set of Gram-positive and Gram-negative pathogen bacteria was evaluated, and [Ni(BzNH-adtp)2] and [Ni(PhBuNH-adtp)2] showed antiproliferative activity towards Staphylococcus aureus and Staphylococcus haemolyticus strains. density functional theory (DFT) calculations were performed to shed some light on the activity of reported compounds related to their tendency towards P-N bond cleavage.


Improved statistics for contrasting means of two samples under non-normality.
This paper presents the asymptotic expansions of the distributions of the two-sample t-statistic and the Welch statistic, for testing the equality of the means of two independent populations under non-normality. Unlike other approaches, we obtain the null distributions in terms of the distribution and density functions of the standard normal variable up to n(-1), where n is the pooled sample size. Based on these expansions, monotone transformations are employed to remove the higher-order cumulant effect. We show that the new statistics can improve the precision of statistical inference to the level of o (n(-1)). Numerical studies are carried out to demonstrate the performance of the improved statistics. Some general rules for practitioners are also recommended.


Direct measurement of the negative Goos-Hänchen shift of single reflection in a two-dimensional photonic crystal with negative refractive index.
The negative Goos-Hänchen shift (GHS) on a two-dimensional photonic crystal with an effective negative refractive index is investigated by simulation and experiment. The measured refractive index of the fabricated photonic crystal is nearly -0.44. The difference between the Goos-Hänchen shift of the transverse electric wave GTE and that of the transverse magnetic wave GTM (DGHS) in the height direction of a silicon rod is measured at three incident angles. The result shows that DGHS is always smaller than -GTM, thus GTE<0; therefore, the negative GHS does occur on the surface of the photonic crystal with a negative refractive index.


Evaluating the effectiveness of undergraduate clinical education programs.
Medical schools should use a variety of measures to evaluate the effectiveness of their clinical curricula. Both outcome measures and process measures should be included, and these can be organized according to the four-level training evaluation model developed by Donald Kirkpatrick. Managing evaluation data requires the institution to employ deliberate strategies to monitor signals in real-time and aggregate data so that informed decisions can be made. Future steps in program evaluation includes increased emphasis on patient outcomes and multi-source feedback, as well as better integration of existing data sources.


O-GlcNAcylation homeostasis controlled by calcium influx channels regulates multiple myeloma dissemination.
Multiple myeloma (MM) cell motility is a critical step during MM dissemination throughout the body, but how it is regulated remains largely unknown. As hypercalcemia is an important clinical feature of MM, high calcium (Ca2+) and altered Ca2+ signaling could be a key contributing factor to the pathological process. Bioinformatics analyses were employed to assess the clinical significance of Ca2+ influx channels in clinical specimens of smoldering and symptomatic MM. Functional and regulatory roles of influx channels and downstream signaling in MM cell migration and invasion were conducted and experimental MM dissemination was examined in a xenograft mouse model using in vivo live imaging and engraftment analysis. Inhibition of TRPM7, ORAI1, and STIM1 influx channels, which are highly expressed in MM patients, and subsequent blockage of Ca2+ influx by CRISPR/Cas9 and small molecule inhibitors, effectively inhibit MM cell migration and invasion, and attenuate the experimental MM dissemination. Mechanistic studies reveal a nutrient sensor O-GlcNAcylation as a downstream regulator of Ca2+ influx that specifically targets cell adhesion molecules. Hyper-O-GlcNAcylation following the inhibition of Ca2+ influx channels induces integrin α4 and integrin β7 downregulation via ubiquitin-proteasomal degradation and represses the aggressive MM phenotype. Our findings unveil a novel regulatory mechanism of MM cell motility via Ca2+ influx/O-GlcNAcylation axis that directly targets integrin α4 and integrin β7, providing mechanistic insights into the pathogenesis and progression of MM and demonstrating potential predictive biomarkers and therapeutic targets for advanced MM.


Biocompatibility of different nanostructured TiO2 scaffolds and their potential for urologic applications.
Despite great efforts in tissue engineering of the ureter, urinary bladder, and urethra, further research is needed in order to improve the patient's quality of life and minimize the economic burden of different lower urinary tract disorders. The nanostructured titanium dioxide (TiO2) scaffolds have a wide range of clinical applications and are already widely used in orthopedic or dental medicine. The current study was conducted to synthesize TiO2 nanotubes by the anodization method and TiO2 nanowires and nanospheres by the chemical vapor deposition method. These scaffolds were characterized with scanning electron microscopy (SEM) and X-ray diffraction (XRD) methods. In order to test the urologic applicability of generated TiO2 scaffolds, we seeded the normal porcine urothelial (NPU) cells on TiO2 nanotubes, TiO2 nanowires, TiO2 nanospheres, and on the standard porous membrane. The viability and growth of the cells were monitored everyday, and after 3 weeks of culturing, the analysis with scanning electron microscope (SEM) was performed. Our results showed that the NPU cells were attached on all scaffolds; they were viable and formed a multilayered epithelium, i.e., urothelium. The apical plasma membrane of the majority of superficial NPU cells, grown on all three different TiO2 scaffolds and on the porous membrane, exhibited microvilli; thus, indicating that they were at a similar differentiation stage. The maximal caliper diameter measurements of superficial NPU cells revealed significant alterations, with the largest cells being observed on nanowires and the smallest ones on the porous membrane. Our findings indicate that different nanostructured TiO2 scaffolds, especially nanowires, have a great potential for tissue engineering and should be further investigated for various urologic applications.


A reassessment of the prognosis of diabetic patients treated by chronic hemodialysis (CHD).
Our early results in 25 diabetics treated by CHD prior to 1972, compared to results in a further 66 diabetics starting CHD since 1972, show an improvement in survival related to a reduction in deaths from myocardial infarction and sepsis. There has been a reduction in complications requiring hospital admission, related to a lower incidence of sepsis. Access survival has been markedly improved since the introduction of the bovine fistula.


Extending ATOFMS measurements to include refractive index and density.
An absolute calibration of the light scattering region in an aerosol time-of-flight mass spectrometer (ATOFMS) has been performed enabling a direct comparison of the average experimentally measured light scattering intensity to theory. A fitting procedure allows for the determination of both refractive index and density for spherical homogeneous particles. The scattering information has been correlated with the other single-particle information measured by the ATOFMS. Size, chemical composition, and scattering intensity can all be linked to establish a better understanding of the relationships between the chemical and physical properties of aerosol particles. Currently, inputs into climate models are derived from data acquired from bulk aerosol composition measurements, and therefore, assumptions must be made regarding the chemical associations within individual particles (mixing state) to enable modelers to calculate the relevant aerosol optical properties. These new measurements aim for the goal of directly testing the model assumptions by utilizing single-particle chemical information to derive the optical properties of the different particle classes.


Detection and molecular characteristics of bovine rotavirus A in dairy calves in China.
Bovine group A rotavirus (BoRVA) is a major cause of severe gastroenteritis in newborn dairy calves. Only one study has investigated the G and P genotypes among dairy calves in a few regions of China, which were G6 and P[5]. Therefore, data on the prevalence and molecular characteristics of BoRVA in dairy calves in China remains limited. The purpose of this study was to investigate the prevalence and molecular characteristics of BoRVA in dairy calves in China. 269 dairy calves diarrheic samples from 23 farms in six provinces in China were collected to detect BoRVA using reverse transcription polymerase chain reaction. 71% of samples were determined to be BoRVA-positive. Two G genotypes (G6, G10) and two P genotypes (P[1], P[5]) were identified, and G6P[1] BoRVA was the predominant strain. Moreover, the VP7 and VP4 gene sequences of these dairy calf BoRVA strains revealed abundant genetic diversity. Interestingly, eight out of 17 complete G6 VP7 sequences were clustered into G6 lineage VI and analysis showed the strains were closely related to Chinese yak BoRVA strains. The results of this study show that BoRVA circulates widely among dairy calves in China, and the dominant genotype in circulation is G6P[1], first report on molecular characteristics of complete P[5] VP4 genes in chinese dairy calves. These results will help us to further understand the prevalence and genetic evolution of BoRVA among dairy calves in China and, thus, prevent the disease more effectively.


Task-selective memory effects for successfully implemented encoding strategies.
Previous behavioral evidence suggests that instructed strategy use benefits associative memory formation in paired associate tasks. Two such effective encoding strategies--visual imagery and sentence generation--facilitate memory through the production of different types of mediators (e.g., mental images and sentences). Neuroimaging evidence suggests that regions of the brain support memory reflecting the mental operations engaged at the time of study. That work, however, has not taken into account self-reported encoding task success (i.e., whether participants successfully generated a mediator). It is unknown, therefore, whether task-selective memory effects specific to each strategy might be found when encoding strategies are successfully implemented. In this experiment, participants studied pairs of abstract nouns under either visual imagery or sentence generation encoding instructions. At the time of study, participants reported their success at generating a mediator. Outside of the scanner, participants further reported the quality of the generated mediator (e.g., images, sentences) for each word pair. We observed task-selective memory effects for visual imagery in the left middle occipital gyrus, the left precuneus, and the lingual gyrus. No such task-selective effects were observed for sentence generation. Intriguingly, activity at the time of study in the left precuneus was modulated by the self-reported quality (vividness) of the generated mental images with greater activity for trials given higher ratings of quality. These data suggest that regions of the brain support memory in accord with the encoding operations engaged at the time of study.


Effects of refractive index on glories.
Atmospheric glories are caused by backscattering of sunlight from spherical droplets of water (e.g., from fog or clouds). But what would glories look like if they were caused by scattering from more exotic substances, such as clouds of ethane as found on Titan? Examining backscattering as a function of the refractive index n of spherical droplets leads to the surprising conclusion that a glory's appearance is almost independent of n (at least for 1.03<n<1.7)--unlike the colors of rainbows, which are critically dependent on the variation of n across the visible spectrum.


Detection of urea cycle enzymopathies in childhood.
Inborn errors of ureagenesis must be considered in the differential diagnosis of recurrent vomiting and lethargy in childhood. Elevations of liver enzyme levels are often present during these episodes and may lead to an erroneous diagnosis of hepatic encephalopathy. We studied two cases of urea cycle defects.


ZnO-Nanorods as an Efficient Heterogeneous Catalyst for the Synthesis of Thiazole Derivatives in Water.
Aims & Scope: Thiazole derivatives are produced using one-pot multicomponent reactions of acid chlorides, potassium thiocyanate, amino acids, alkyl bromides and ZnO nanorods (NR-ZnO) as the catalyst in water at ambient temperature. These reactions were no't performed without using NR-ZnO as the catalyst. Nanorods of ZnO have been prepared by reflux procedure using sodium dodecylsulfate (SDS). Nanorods of ZnO showed a considerable improvement in the yield of the product and displayed significant reusable activity. In these reactions, all chemicals were prepared from Fluka (Buchs, Switzerland). Nanorods of ZnO were synthesized in the laboratory according to literature report. By using an electrothermal 9100 apparatus, melting points of synthesized compounds were determined. Heraeus CHN-O-Rapid analyzer was employed for elemental analyses for C, H, and N. FINNIGANMAT 8430 spectrometer operating at an ionization potential of 70 eV was used for mass spectra. Shimadzu IR-460 spectrometer was employed for IR spectra. BRUKER DRX-500 AVANCE spectrometer at 500.1 and 125.8 MHz was used for 1H, and 13C NMR spectra for solutions in CDCl3 with TMS as internal standard or 85% H3PO4 as external standard, respectively. We describe a facile and green synthetic method for the synthesis of thiazole derivatives 5 from acid chlorides, potassium thiocyanate, alkyl bromides and amino acids using NR-ZnO- as the catalyst in water at room temperature. In conclusion, we describe an efficient, green procedure and high yielding synthesis of thiazole derivatives using acid chlorides, potassium thiocyanate, alkyl bromides and amino acids in the presence of NR-ZnO as the catalyst in water at room temperature.


Pharmacokinetics of thiopentone enantiomers following intravenous injection or prolonged infusion of rac-thiopentone.
Thiopentone is administered as a racemate (rac-thiopentone) for induction of anaesthesia as well as for neurological and neurosurgical emergencies. The pharmacokinetics and pharmacodynamics of rac-thiopentone have been extensively studied but the component R-(+)- and S-(-)- enantiomers, until very recently, have been largely ignored. The present study analyses the pharmacokinetics of R-(+)- and S-(-)-thiopentone in 12 patients given rac-thiopentone intravenously for induction of anaesthesia and five patients given a prolonged infusion of rac-thiopentone used for treatment of intracranial hypertension. The mean total body clearance (CLT) and apparent volume of distribution at steady-state (Vss) showed trends towards higher values for R-(+)- than for S-(-)-thiopentone in both patient groups; CLT and Vss of unbound fractions of R-(+)- and S-(-)-thiopentone, however, did not show these trends. The time courses of R-(+)- and S-(-)- thiopentone serum concentrations were so similar that EEG effect could not be attributed to one or other enantiomer. Serum protein binding for S-(-)-thiopentone was greater than for R-(+)-thiopentone (P = 0.02) and 24 h urinary excretion of R-(+)-thiopentone was greater than for S-(-)-thiopentone (P = 0.03). In one patient, concomitant measurement of CSF and serum thiopentone concentrations found that serum: CSF equilibration of unbound fractions of both enantiomers was essentially complete. The study was unable to determine any pharmacokinetic difference of clinical significance between the R-(+)- and S-(-)-thiopentone enantiomers and concludes that minor differences in CLT and Vss could be explained by enantioselective difference found in serum protein binding.


Understanding the effects of neutron scattering for neutron-yield-isotropy measurements at the NIF.
Neutron-yield diagnostics at the NIF have been upgraded to include 48 detectors placed around the NIF target chamber to assess the DT-neutron-yield isotropy for inertial confinement fusion experiments. Real-time neutron-activation detectors are used to understand yield asymmetries due to Doppler shifts in the neutron energy attributed to hotspot motion, variations in the fuel and ablator areal densities, and other physics effects. In order to isolate target physics effects, we must understand the contribution due to neutron scattering associated with the different hardware configurations used for each experiment. We present results from several calibration experiments that demonstrate the ability to achieve our goal of 1% or better precision in determining the yield isotropy.


Secretion of alpha-amylase and multiple forms of glucoamylase by the yeast Trichosporon pullulans.
Trichosporon pullulans IGC 3488 produced extracellular alpha-amylase and glucoamylase activities when grown in batches in a medium containing corn steep liquor and soluble starch or corn starch. alpha-Amylase, unlike glucoamylase activity, was secreted biphasically. For both amylases the maximum concentration was found in stationary phase cultures. The amylolytic enzymes, previously concentrated by ammonium sulfate precipitation, were separated into a glucoamylase fraction and an alpha-amylase fraction by Ultrogel AcA 54 gel filtration. Pullulanase activity was located in the glucoamylase fraction, whereas cyclodextrinase activity was restricted to the alpha-amylase fraction. Isoamylase and alpha-glucosidase were not detected. Electrophoretic analysis showed that alpha-amylase activity was due to a single protein. Glucoamylase, however, occurred in multiple forms. The four glucoamylases and the alpha-amylase were glycoproteins.


Epidemiology, treatment, and outcomes of nosocomial bacteremic Staphylococcus aureus pneumonia.
To describe outcomes associated with nosocomial bacteremic Staphylococcus aureus pneumonia (NBSAP) and to determine whether delay in adequate antimicrobial treatment is a risk factor for negative clinical and microbiological outcomes. Retrospective cohort analysis. This study was conducted at Detroit Receiving Hospital and University Health Center, which is a 279-bed, level 1 trauma center in Detroit, MI. All episodes of NBSAP identified from January 1, 1999, to April 30, 2004. Of 206 patients identified over a 5-year period with positive blood and respiratory cultures for S aureus, 60 patients met strict clinical, radiographic, and microbiological criteria for NBSAP. The overall mean (+/- SD) characteristics include the following: age, 55.5 +/- 15.0 years; acute physiology and chronic health evaluation II score, 20 (range, 3 to 41); ICU at onset, 93.3%; mechanical ventilation, 83.3%; length of stay (LOS) prior to NBSAP, 9 days (range, 2 to 81 days); methicillin-resistant S aureus (MRSA) rate, 70%; and all-cause hospital and infection-related mortality (IRM), 55.5% and 40.0%, respectively. Overall, S aureus pneumonia developed late in the patient's hospital stay in ICU patients previously receiving mechanical ventilation and was associated with high crude mortality and IRM rates. No significant difference existed with respect to mortality or infection-related LOS between patients who had received early appropriate antibiotic therapy vs those who had received delayed appropriate antibiotic therapy at the onset of pneumonia or in patients with methicillin-sensitive S aureus pneumonia vs those with MRSA pneumonia. IRM from NBSAP is high, and standard therapies evaluated at the time of this study resulted in poor clinical outcomes. Delayed therapy was not found to be a predictor of adverse outcomes; however, this lack of ability to detect a difference may be a product of small sample size. These findings suggest that newer agents with enhanced clinical activity in NBSAP are needed and that these should be evaluated in a real-world setting, where outcomes of the most ill patients can be assessed.


Differential activation of protein kinase C delta and epsilon gene expression by gonadotropin-releasing hormone in alphaT3-1 cells. Autoregulation by protein kinase C.
The effect of gonadotropin-releasing hormone (GnRH) upon protein kinase C (PKC) delta and PKCepsilon gene expression was investigated in the gonadotroph-derived alphaT3-1 cell line. Stimulation of the cells with a stable analog [D-Trp6]GnRH (GnRH-A) resulted in a rapid elevation of PKCepsilon mRNA levels (1 h), while PKCdelta mRNA levels were elevated only after 24 h of incubation. The rapid elevation of PKCepsilon mRNA by GnRH-A was blocked by pretreatment with a GnRH antagonist or actinomycin D. The PKC activator 12-O-tetradecanoylphorbol-13-acetate (TPA), but not the Ca2+ ionophore ionomycin, mimicked the rapid effect of GnRH-A upon PKCepsilon mRNA elevation. Additionally, the rapid stimulatory effect of GnRH-A was blocked by the selective PKC inhibitor GF109203X, by TPA-mediated down-regulation of endogenous PKC, or by Ca2+ removal. Interestingly, serum-starvation (24 h) advanced the stimulation of PKCdelta mRNA levels by GnRH-A and the effect could be detected at 1 h of incubation. The rapid effect of GnRH-A upon PKCdelta mRNA levels in serum-starved cells was mimicked by TPA, but not by ionomycin, and was abolished by down-regulation of PKC or by Ca2+ removal. Preactivation of alphaT3-1 cells with GnRH-A for 1 h followed by removal of ligand and serum resulted in elevation of PKCdelta mRNA levels after 24 h of incubation. Western blot analysis revealed that GnRH-A and TPA stimulated (within 5 min) the activation and some degradation of PKCdelta and PKCepsilon. We conclude that Ca2+ and PKC are involved in GnRH-A elevation of PKCdelta and PKCepsilon mRNA levels, with Ca2+ being necessary but not sufficient, while PKC is both necessary and sufficient to mediate the GnRH-A response. A serum factor masks PKCdelta but not PKCepsilon mRNA elevation by GnRH-A, and its removal exposes preactivation of PKCdelta mRNA by GnRH-A which can be memorized for 24 h. PKCdelta and PKCepsilon gene expression evoked by GnRH-A is autoregulated by PKC, and both isotypes might participate in the neurohormone action.


Second trimester marginal cord insertion is associated with adverse perinatal outcomes.
Objectives: To determine the feasibility in visualizing placental cord insertion (PCI) during second-trimester fetal anatomical survey and the association between marginal cord insertion (MCI) and preterm delivery (PTD) and low birth weight (LBW). Our secondary objectives were to evaluate the association of MCI with adverse composite obstetrical and neonatal outcomes. Methods: A prospective cohort study was performed over a 28-month period. Women with singleton pregnancies presenting for routine anatomical survey between 18 and 22 weeks' gestation were included. PCI site was visualized on 2D grayscale and color Doppler and the shortest distance from the sagittal and transverse planes to the placental edge were recorded. MCI was diagnosed when any of measured distances was ≤2 cm. Correlations were assessed via bivariate chi-squared, independent t-test analyses and Fisher's exact tests. Regression models evaluated associations between MCI and adverse composite outcomes. Results: Three hundred one women were included and PCI was feasible in all cases. The incidence of MCI was 11.3% (n = 34). Baseline characteristics between those with and without MCI were similar, except for story of prior PTD, which was greater among those with MCI (17.65 versus 7.17%, p = .04). MCI was associated with increased likelihood of LBW (RR four; 95%CI, 1.46-10.99) and PTD (RR 3.2; 95%CI, 1.53-6.68); in multivariate analysis, we found associations between MCI and composite adverse obstetrical (RR 2.33; 95%CI, 1.30-4.19) and neonatal (RR 2.46; 95%CI, 1.26-4.81) outcomes. Conclusions: Evaluation of PCI is feasible in all cases. Second-trimester MCI is associated with increased likelihood for LBW, PTD, and composite adverse obstetrical and neonatal outcomes.


Real-time PCR quantification of human cytomegalovirus DNA in amniotic fluid samples from mothers with primary infection.
A real-time PCR assay was developed to quantify human cytomegalovirus (HCMV) DNA in amniotic fluid (AF) samples collected from 30 pregnant women with primary HCMV infection as detected either from HCMV-immunoglobulin G (IgG) seroconversion or by the presence of HCMV-specific IgG and IgM associated with a low IgG avidity. Clinical information available for each case included ultrasonographic examination and fetal or newborn outcome. HCMV infection of fetuses or newborns was confirmed for the 30 studied cases. AF samples were subdivided into three groups. In group A (n = 13), fetuses presented major ultrasound abnormalities, and pregnancy was terminated. In group B (n = 13), fetuses had normal ultrasound findings, the pregnancy went to term, and the newborns were asymptomatic at birth. In group C (n = 4), fetuses had no or minor ultrasonographic signs, and pregnancy was terminated. The HCMV DNA load values in AF samples were significantly higher in group A (median, 2.8 x 10(5) genome equivalents [GE]/ml) than in group B (median, 8 x 10(3) GE/ml) (P = 0.014). Our findings suggest that HCMV load level in AF samples correlates with fetal clinical outcome but might also be dependent on other factors, such as the gestational age at the time of AF sampling and the time elapsed since maternal infection.


Same critical features are used for identification of familiarized and unfamiliar faces.
Many studies have shown better recognition for faces we have greater experience with, relative to unfamiliar faces. However, it is still not clear if and how the representation of faces changes during the process of familiarization. In a previous study, we discovered a subset of facial features, for which we have high perceptual sensitivity (PS), that were critical for determining the identity of unfamiliar faces. This was done by assigning values to 20 different facial features based on perceptual rating, converting faces into feature-vectors, and measuring the correlations between face similarity ratings and distances between feature-vectors. In the current study, we examined the contribution of high and low-PS features to face identity after familiarization. To familiarize participants with unfamiliar faces, we used an individuation training protocol that was found to be effective in previous studies, in which different names are assigned to different faces and participants are asked to learn the face-name association. Our findings show that even after repeated exposure to the same image of each identity, which allows close examination of all facial features, only high-PS features contributed to face identity, while low-PS features did not. This subset of high-PS features includes both internal and external features and part and configuration features. We therefore conclude that identification of familiarized and unfamiliar faces may rely on the same subset of critical features. These findings further support a new categorization of facial features according to their perceptual sensitivity.


Paraxial ray-tracing equations for optical systems containing triangular prisms.
Conventional paraxial ray-tracing procedures are widely used for optical systems design and analysis. However, they are not applicable to multiple-dispersion-prism systems. Accordingly, the present study simplifies the equations given by the present group in a previous paper [Optik117, 329 (2006)OTIKAJ0030-402610.1016/j.ijleo.2005.10.004] to the form of 3×3 matrix equations for tracing paraxial rays in optical systems containing triangular prisms. The accuracy and validity of the proposed approach are demonstrated by means of four numerical examples. The results confirm that the proposed equations provide a convenient and practical tool for analyzing paraxial rays traveling through non-axially symmetrical optical systems containing triangular and rectangular prisms.


Signal acquisition via polarization modulation in single photon sources.
A simple model system is introduced for demonstrating how a single photon source might be used to transduce classical analog information. The theoretical scheme results in measurements of analog source samples that are (i) quantized in the sense of analog-to-digital conversion and (ii) corrupted by random noise that is solely due to the quantum uncertainty in detecting the polarization state of each photon. This noise is unavoidable if more than 1 bit per sample is to be transmitted and we show how it may be exploited in a manner inspired by suprathreshold stochastic resonance. The system is analyzed information theoretically, as it can be modeled as a noisy optical communication channel, although unlike classical Poisson channels, the detector's photon statistics are binomial. Previous results on binomial channels are adapted to demonstrate numerically that the classical information capacity, and thus the accuracy of the transduction, increases logarithmically with the square root of the number of photons, N. Although the capacity is shown to be reduced when an additional detector nonideality is present, the logarithmic increase with N remains.


The size, morphology, site, and access score predicts critical outcomes of endoscopic mucosal resection in the colon.
The SMSA (size, morphology, site, access) polyp scoring system is a method of stratifying the difficulty of polypectomy through assessment of four domains. The aim of this study was to evaluate the ability of SMSA to predict critical outcomes of endoscopic mucosal resection (EMR). We retrospectively applied SMSA to a prospectively collected multicenter database of large colonic laterally spreading lesions (LSLs) ≥ 20 mm referred for EMR. Standard inject-and-resect EMR procedures were performed. The primary end points were correlation of SMSA level with technical success, adverse events, and endoscopic recurrence. 2675 lesions in 2675 patients (52.6 % male) underwent EMR. Failed single-session EMR occurred in 124 LSLs (4.6 %) and was predicted by the SMSA score (P < 0.001). Intraprocedural and clinically significant postendoscopic bleeding was significantly less common for SMSA 2 LSLs (odds ratio [OR] 0.36, P < 0.001 and OR 0.23, P < 0.01) and SMSA 3 LSLs (OR 0.41, P < 0.001 and OR 0.60, P = 0.05) compared with SMSA 4 lesions. Similarly, endoscopic recurrence at first surveillance was less likely among SMSA 2 (OR 0.19, P < 0.001) and SMSA 3 (OR 0.33, P < 0.001) lesions compared with SMSA 4 lesions. This also extended to second surveillance among SMSA 4 LSLs. SMSA is a simple, readily applicable, clinical score that identifies a subgroup of patients who are at increased risk of failed EMR, adverse events, and adenoma recurrence at surveillance colonoscopy. This information may be useful for improving informed consent, planning endoscopy lists, and developing quality control measures for practitioners of EMR, with potential implications for EMR benchmarking and training.


Association of the SEL1L protein transmembrane domain with HRD1 ubiquitin ligase regulates ERAD-L.
Misfolded proteins in the endoplasmic reticulum (ER) are transported to the cytoplasm for degradation by the ubiquitin-proteasome system, a process otherwise known as ER-associated degradation (ERAD). Mammalian HRD1, an integral membrane ubiquitin ligase that ubiquitinates ERAD substrates, forms a large assembly in the ER membrane including SEL1L, a single-pass membrane protein, and additional components. The mechanism by which these molecules export misfolded proteins through the ER membrane remains unclear. Unlike Hrd3p, the homologue in Saccharomyces cerevisiae, human SEL1L is an unstable protein, which is restored by the association with HRD1. Here we report that the inherently unstable nature of the human SEL1L protein lies in its transmembrane domain, and that association of HRD1 with the SEL1L transmembrane domain restored its stability. On the other hand, we found that the SEL1L luminal domain escaped degradation, and inhibited the degradation of misfolded α1 -antitrypsin variant null Hong Kong by retaining the misfolded cargo in the ER. Overexpression of HRD1 inhibited the degradation of unfolded secretory cargo, which was restored by the interaction of HRD1 with the SEL1L transmembrane domain. Hence, we propose that SEL1L critically regulates HRD1-mediated disposal of misfolded cargo through its short membrane spanning stretch.


iTRAQ-based Proteomic Analysis of APPSw,Ind Mice Provides Insights into the Early Changes in Alzheimer's Disease.
Several proteins have been identified as potential diagnostic biomarkers in imaging, genetic, or proteomic studies in Alzheimer disease (AD) patients and mouse models. However, biomarkers for presymptom diagnosis of AD are still under investigation, as are the presymptom molecular changes in AD pathogenesis. In this study, we aim to analyzed the early proteomic changes in APPSw,Ind mice and to conduct further functional studies on interesting proteins. We used the isobaric tags for relative and absolute quantitation (iTRAQ) approach combined with mass spectrometry to examine the early proteomic changes in hippocampi of APPSw,Ind mice. Quantitative reverse transcription polymerase chain reaction (RT-PCR) and immuno-blotting were performed for further validation. Finally, the functions of interesting proteins β-spectrin and Rab3a in APP trafficking and processing were tested by shRNA knockdown, in N2A cells stably expressing β-amyloid precursor protein (APP). The iTRAQ and RT-PCR results revealed the detailed molecular changes in oxidative stress, myelination, astrocyte activation, mTOR signaling and Rab3-dependent APP trafficking in the early stage of AD progression. Knock down of β -spectrin and Rab3a finally led to increased APP fragment production, indicating key roles of β-spectrin and Rab3a in regulating APP processing. Our study provides the first insights into the proteomic changes that occur in the hippocampus in the early stages of the AD mouse model. In addition to improving the understanding of molecular alterations and functional cascades involved in early AD pathogenesis, our findings raise the possibility of developing potential biomarkers and therapeutic targets for early AD.


[New approaches to prenatal diagnosis of rhesus incompatibility].
Despite generalisation of anti-D immunoprophylaxis, RhD allo-immunisation still remains the major cause of severe haemolytic disease of the fetus and of the newborn (HDFN). The routine follow up of pregnant women comprises: the ABO/D, Rh/Kell red cells typing and the search for irregular antibodies. In case of anti-D immunisation, the paternal Rh phenotype, when known, provides useful information regarding the probability for the fetus to have inherited the D antigen and thereby to be exposed to the risk of HDFN. The antibody titre, which is predictive of possible in vivo haemolysis, must be interpreted in the light of the previous obstetric history, and can lead to the decision of invasive amniocentesis. Then the measurement of the optical density (deltaOD450 nm) and the fetal RhD typing can be realised on amniotic fluid. New molecular techniques make it possible now to demonstrate the presence of fetal DNA in maternal plasma. These methods lying on non invasive procedures could advantageously be applied to the genotyping of fetal RHD during pregnancy. The present paper aims to discuss the predictive values of RHD fetal genotype in maternal plasma of RhD negative mothers. The ante-partum management of immunised pregnant women is reviewed in the light of this new molecular approach combined to Doppler ultrasonography of the fetal middle cerebral artery. This non invasive method for determining fetal RHD genotype could be systematically proposed to all RhD negative pregnant women for a better targeted prenatal follow-up and an increased efficacy of RhD prophylaxis.


Lupus erythematosus in children: a report of six cases.
The clinical features of childhood discoid lupus erythematosus (DLE) are similar to those of adult DLE in presentation and chronic course. However, children have a particularly high levels of transition to systemic disease. Systemic lupus erythematosus (SLE) is the most common rheumatic disease associated with significant morbidity and mortality in children. This is a retrospective study reporting all cases of childhood lupus erythematosus observed in the dermatology department of Habib Thameur Hospital over a 14-year period. From 1989 to 2003, six cases of childhood lupus erythematosus are included, three patients with discoid lupus erythematosus (2 girls, 1 boy), and three patients with systemic lupus erythematosus (2 boys, 1 girl). The mean age of onset was 12 years (range 10-16 years). Skin manifestations were localized in sun exposed areas in both discoid and systemic lupus erythematosus. Photosensitivity was noted in all cases. The diagnosis was confirmed by histopathologic examination, direct immunofluorescence, and immunologic findings. Treatment included sun avoidance, oral hydroxychloroquine, and topical and systemic steroids. An average follow-up time was 18.1 months (1-96 months). The severity of onset of SLE is usually greater in children than adults. We note that lupus erythematosus is not a static disease and progression from DLE to SLE is possible.


Clinical pharmacokinetics of anxiolytics and hypnotics in the elderly. Therapeutic considerations (Part I).
Anxiolytic and hypnotic drugs are extensively prescribed for elderly individuals throughout Western society. Old age may be associated with an altered clinical response to this class of compounds, and there is a considerable ethical and economic stake in understanding these changes so that therapy may be approached with a maximum likelihood of therapeutic benefit and a minimum risk of side effects. Old age may lead to altered pharmacokinetics of sedative-anxiolytic drugs, causing higher plasma concentrations (relative to young individuals) after single or multiple doses. By far the majority of the available scientific data refer to the benzodiazepines, which have become the most widely prescribed class of sedative-anxiolytic drugs. Although there is not complete consistency in the available data, the weight of evidence indicates that old age is associated with impaired clearance of the benzodiazepines which are biotransformed by microsomal oxidation (such as diazepam, desmethyldiazepam, desalkylflurazepam, bromazepam, alprazolam, triazolam and others). For those benzodiazepines metabolised mainly by glucuronide conjugation (oxazepam, lorazepam, temazepam) or nitroreduction (nitrazepam), there are minimal, if any, age-related decrements in clearance. Only in the case of triazolam is there direct evidence linking impaired clearance to enhanced clinical effects in the elderly. The logical suggestion that benzodiazepines biotransformed by conjugation or by nitroreduction may be safer for the elderly than those biotransformed by oxidation has not yet been directly validated. Reasonable epidemiological evidence has linked the use of long (versus short) half-life benzodiazepines (regardless of the specific metabolic pathway) with an increased incidence of adverse reactions such as confusion, falls and hip fractures in elderly persons. However, the decreased clearance and increased accumulation of the benzodiazepines in question are not clearly validated as the cause of the increased frequency of adverse reactions. Old age may also be associated with an increased intrinsic sensitivity to benzodiazepines; that is, enhanced pharmacodynamic response, relative to young individuals, at any given plasma or target organ concentration. This change in sensitivity may coexist with, or be independent of, alterations in pharmacokinetics. Altered benzodiazepine sensitivity has been documented both in the course of clinical use of benzodiazepines prior to endoscopy or cardioversion, and in placebo-controlled laboratory trials. Animal models of aging have validated an enhanced response to benzodiazepines as a consequence of impaired clearance, increased intrinsic sensitivity or both. However, many studies directly assessing benzodiazepine receptor affinity, density and function in aging animals have failed to identify significant age-related changes.(ABSTRACT TRUNCATED AT 400 WORDS)


Mapping effector genes at lupus GWAS loci using promoter Capture-C in follicular helper T cells.
Systemic lupus erythematosus (SLE) is mediated by autoreactive antibodies that damage multiple tissues. Genome-wide association studies (GWAS) link >60 loci with SLE risk, but the causal variants and effector genes are largely unknown. We generated high-resolution spatial maps of SLE variant accessibility and gene connectivity in human follicular helper T cells (TFH), a cell type required for anti-nuclear antibodies characteristic of SLE. Of the ~400 potential regulatory variants identified, 90% exhibit spatial proximity to genes distant in the 1D genome sequence, including variants that loop to regulate the canonical TFH genes BCL6 and CXCR5 as confirmed by genome editing. SLE 'variant-to-gene' maps also implicate genes with no known role in TFH/SLE disease biology, including the kinases HIPK1 and MINK1. Targeting these kinases in TFH inhibits production of IL-21, a cytokine crucial for class-switched B cell antibodies. These studies offer mechanistic insight into the SLE-associated regulatory architecture of the human genome.