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Monovision, the use of a monocular addition for near viewing, is a clinical technique sometimes used to correct presbyopia. This technique attempts to maintain binocular function while requiring a degree of central suppression. We examined suppression behavior in spectacle monovision as a function of addition power. Suppression behavior was determined by measuring the length and frequency of periods of suppression for a range of monocular addition powers. Testing was conducted at viewing distances of 6 m and 40 cm. The most striking result is the existence of a near/distance differential: the monocular addition power required to stabilize suppression at near is greater than at distance. It was also found that suppression behavior may be stable even in the presence of a relatively high level of stereoscopic acuity. The relation between the contradictory needs for suppression and binocular functioning under monovision conditions is discussed.

Obestatin, derived from the same gene as the hunger hormone ghrelin, may reduce food intake in animals. The role of obestatin in human physiology is unclear. We evaluated cross-sectional associations between participant characteristics and fasting levels of obestatin as well two other hormones associated with energy balance, ghrelin and leptin. Data are from the baseline visit of the Optimal Macronutrient Intake Trial to Prevent Heart Disease (OMNI-Heart) Trial that enrolled adults with elevated blood pressure (systolic 120-159 mm Hg or a diastolic of 80-99 mm Hg) but who were otherwise healthy. Partial Spearman's correlations and linear regression models estimated the association between age, gender, BMI, physical activity, and smoking with fasting hormones. Obestatin was directly associated with ghrelin (r = 0.45, P < 0.05). On average, overweight (BMI 25-30) and obese (BMI > 30) individuals had obestatin concentrations that were 12.6 (s.d. 8.8) and 25.4 (s.d. 8.4) pg/ml lower compared to normal weight (BMI < 25) individuals, respectively (P for trend = 0.002). Overweight (BMI 25-30) and obese (BMI > 30) individuals had ghrelin concentrations that were 161.7 (s.d. 69.6) and 284.7 (s.d. 66.5) pg/ml lower compared to normal weight (BMI < 25) individuals, respectively (P for trend <0.0001). A 5 unit increase in BMI was associated with 41.3% (s.d. 4.3%) (P < 0.0001) higher leptin. Obestatin and ghrelin are directly correlated and share the same patterns of association with participant characteristics. Modifiable risk factors for chronic diseases, such as BMI, are associated with fasting levels of leptin, obestatin, and ghrelin.

This report presents a retrospective study of 26 Japanese children with recurrent anaplastic large cell lymphoma. The first relapses were documented at a median of 10.5 months after the initial diagnosis. Twenty-four patients achieved a second remission. After a median follow-up period of 47 months, 18 patients are still alive: 15 patients are in second complete remission (CR), three patients are in third CR or later. The 5 year overall and relapse-free survival rates were 61 +/- 12% and 51 +/- 12% respectively. The patients who received allogeneic haematopoietic stem cell transplantation during second CR showed a superior outcome to other patients.

BACKGROUND: Fetal tachycardia is an uncommon condition that if sustained may lead to fetal death. There is no consensus regarding the optimum treatment. The aim of this study was to evaluate the safety and efficacy of sotalol in the treatment of fetal tachycardia.METHODS: This was a retrospective study of patients treated for fetal tachycardia with sotalol in a pediatric cardiology department over a ten-year period.RESULTS: There were eight fetuses treated for supraventricular tachycardia and sotalol was used in six of them. Mean gestational age was 30 weeks. None of them had congenital heart disease; two fetuses had hydrops and one had hydrocephalus. All had supraventricular tachycardia and two had atrial flutter. Drug treatment was successful in establishing sinus rhythm in five of the six fetuses treated with sotalol and no adverse effects were recorded in the mothers. There were no deaths. Supraventricular tachycardia was present in three infants at birth.CONCLUSIONS: In this study sotalol was successful and safe in the treatment of fetal tachycardia, but given the small sample size, more studies are needed to validate this conclusion.

BACKGROUND: No agreement has been made about the optimal extent of thyroidectomy or lymph node dissection in papillary thyroid microcarcinoma (PTMC). Our aim was to find out the factors associated with the presence of lymph node metastases in the patients with PTMC and to discuss the extent of thyroidectomy and lymphadenectomy.METHODS: A total of 254 patients with PTMC (212 women, 42 men; age 14 to 85 years, median 47 years) were treated at our institute between 1975 and 2007. Lymph node metastases were confirmed in 59 patients (23%) by histopathology. The median observation time was 56 (range, 1-397) months, and the recurrence was diagnosed in seven patients. Modified radical neck dissection and central neck dissection were performed in 55 and 30 patients, respectively. The data on the clinicopathological characteristics of patients and treatment were collected.RESULTS: An incidental PTMC was diagnosed in 107 patients postoperatively. In none of them was a lymph node metastasis or tumor recurrence detected. Preoperatively, an overt PTMC was diagnosed in 147 patients. Clinically manifest metastases were diagnosed in 59 (40%) of them: in 51 preoperatively, and in 8 during the surgical procedure. In 147 patients who had preoperative diagnosis of PTMC, the factors that correlated (P < 0.05) with the presence of lymph node metastases were sex, age, and tumor type.CONCLUSIONS: The patients with high-risk PTMC with preoperatively confirmed lymph node metastases had a higher recurrence rate than those with low-risk PTMC without preoperatively detectable lymph node metastases; therefore, careful therapeutic node dissection is necessary in high-risk patients.

PURPOSE: To assess the feasibility and to optimize imaging parameters of diffusion kurtosis imaging (DKI) in human kidneys.METHODS: The kidneys of ten healthy volunteers were examined on a clinical 3T MR scanner. For DKI, respiratory triggered EPI sequences were acquired in the coronal plane (3 b-values: 0, 300, 600s/mm(2), 30 diffusion directions). A goodness of fit analysis was performed and the influence of the signal-to-noise ratio (SNR) on the DKI results was evaluated. Region-of-interest (ROI) measurements were performed to determine apparent diffusion coefficient (ADC), fractional anisotropy (FA) and mean kurtosis (MK) of the cortex and the medulla of the kidneys. Intra-observer and inter-observer reproducibility using Bland-Altman plots as well as subjective image quality of DKI were examined and ADC, FA, and MK parameters were compared.RESULTS: The DKI model fitted better to the experimental data (r=0.99) with p<0.05 than the common mono-exponential ADC model (r=0.96). Calculation of reliable kurtosis parameters in human kidneys requires a minimum SNR of 8.31 on b=0s/mm(2) images. Corticomedullary differentiation was possible on FA and MK maps. ADC, FA and MK revealed significant differences in medulla (ADC=2.82 ? 10(-3)mm(2)/s±0.25, FA=0.42±0. 05, MK=0.78±0.07) and cortex (ADC=3.60 ? 10(-3)mm(2)/s±0.28, FA=0.18±0.04, MK=0.94±0.07) with p<0.001.CONCLUSION: Our initial results indicate the feasibility of DKI in the human kidney presuming an adequate SNR. Future studies in patients with kidney diseases are required to determine the value of DKI for functional kidney imaging.

Two open-label, randomized, two-period, crossover studies were performed to determine the safety, delivery rates, and pharmacokinetic properties of a combination estradiol (E2)/levonorgestrel (LNG) transdermal delivery system (TDS). Study 1 enrolled 24 postmenopausal women who received a single TDS containing 4.4 mg E2 and 1.39 mg of LNG (E2/LNG Low) or E2 0.050 mg/24 hours TDS and 0.090 mg LNG oral tablet. Study 2 enrolled 44 postmenopausal women who received either E2/LNG Low or TDS containing 4.4 mg E2 and 2.75 mg LNG (E2/LNG High) weekly for a period of 4 weeks. E2, estrone (E1), LNG, and sex hormone-binding globulin (SHBG) serum concentrations were determined. Overall, both E2/LNG TDS were well tolerated and had excellent adhesion properties. The average daily delivery for E2/LNG Low was 0.045 mg for E2 and 0.0132 mg for LNG. Following weekly delivery of E2/LNG Low or High for 4 weeks, the combination of E2 with two different strengths of LNG did not alter the pharmacokinetic profile of E2. SHBG, total cholesterol, and triglycerides concentrations significantly decreased compared to baseline. Both E2/LNG Low and High TDSs were well tolerated and provided continuous drug delivery over 7 days supporting the benefits of the transdermal route of administration in optimally delivering hormonal therapy.

On the basis of monthly runoff series obtained in 1950-2013 and annual sediment load measured in 1956--2013 at five key hydrological stations in the middle and lower reaches of the Yangtze River basin, this study used the Mann-Kendall methods to identify trend and abrupt changes of runoff and sediment load in relation to human activities. The results were as follows: (1) The annual and flood season runoffs showed significant decreasing trends at Yichang station, and showed slight downward trends at Hankou and Datong stations, while the abrupt changes of dry season runoff at Yichang, Hankou and Datong stations occurred in about 2007 and the change points were followed by significant increasing trends. The construction of the Three Gorges Dam, which began to operate in 2003, influenced the variations of runoff in the mainstream of Yangtze River, but the effect weakened with the distance along the downstream direction from TGD. (2) Since the 1990s, annual sediment loads at Yichang, Hankou, and Datong stations have been decreasing significantly, and after 2002, the annual sediment load at Yichang dropped below that of Hankou and Datong. The dams and deforestation/forestation contributed to the significant decreasing trend of the sediment load. In addition, the Three Gorges Dam aggravated the downward trend and caused the erosion of the riverbed and riverbanks in the middle and lower reaches. (3) The runoff and sediment load flowing from Dongting Lake into the mainstream of the Yangtze River showed significant decreasing trends at Chenglingji station after 1970s, and in contrast, slight increase in the sediment flow from Poyang Lake to the mainstream of the Yangtze River at Hukou station were detected over the post-TGD period (2003-2013). The result of the study will be an important foundation for watershed sustainable development of the Yangtze River under the human activities.

The effect of prothrombin fragment 2 on the inhibition of thrombin by antithrombin III has been studied. Fragment 2 was found to slow the rate of inhibition of thrombin by antithrombin III about 3-fold. The effect of prothrombin fragment 2 on antithrombin III inhibition was examined by comparing its action in the presence of either thrombin or meizothrombin (des fragment 1). The second order rate constants for antithrombin III inhibition of thrombin with saturating fragment 2 and antithrombin III inhibition of meizothrombin (des fragment 1) were the same. Prothrombin fragment 2 had no effect on either antithrombin III inhibition of meizothrombin (des fragment 1) or Factor Xa. The effect of the fragment on the reaction mechanism of thrombin inhibition was evaluated to see if the fragment altered binding of antithrombin III to thrombin or inhibited the formation of the covalent complex. The fragment was found to have no inhibitory effect on the rate of covalent complex formation, indicating that the protective effect of the fragment is by inhibiting binding of antithrombin III to thrombin. These data suggest that prothrombin fragment 2 may be an important factor in controlling the localization of clot formation by regulating the interaction between thrombin and antithrombin III.

PURPOSE: A C-arm CT system has been shown to be capable of scanning a single cadaver leg under loaded conditions by virtue of its highly flexible acquisition trajectories. In Part I of this study, using the 4D XCAT-based numerical simulation, the authors predicted that the involuntary motion in the lower body of subjects in weight-bearing positions would seriously degrade image quality and the authors suggested three motion compensation methods by which the reconstructions could be corrected to provide diagnostic image quality. Here, the authors demonstrate that a flat-panel angiography system is appropriate for scanning both legs of subjects in vivo under weight-bearing conditions and further evaluate the three motion-correction algorithms using in vivo data.METHODS: The geometry of a C-arm CT system for a horizontal scan trajectory was calibrated using the PDS-2 phantom. The authors acquired images of two healthy volunteers while lying supine on a table, standing, and squatting at several knee flexion angles. In order to identify the involuntary motion of the lower body, nine 1-mm-diameter tantalum fiducial markers were attached around the knee. The static mean marker position in 3D, a reference for motion compensation, was estimated by back-projecting detected markers in multiple projections using calibrated projection matrices and identifying the intersection points in 3D of the back-projected rays. Motion was corrected using three different methods (described in detail previously): (1) 2D projection shifting, (2) 2D deformable projection warping, and (3) 3D rigid body warping. For quantitative image quality analysis, SSIM indices for the three methods were compared using the supine data as a ground truth.RESULTS: A 2D Euclidean distance-based metric of subjects' motion ranged from 0.85 mm (±0.49 mm) to 3.82 mm (±2.91 mm) (corresponding to 2.76 to 12.41 pixels) resulting in severe motion artifacts in 3D reconstructions. Shifting in 2D, 2D warping, and 3D warping improved the SSIM in the central slice by 20.22%, 16.83%, and 25.77% in the data with the largest motion among the five datasets (SCAN5); improvement in off-center slices was 18.94%, 29.14%, and 36.08%, respectively.CONCLUSIONS: The authors showed that C-arm CT control can be implemented for nonstandard horizontal trajectories which enabled us to scan and successfully reconstruct both legs of volunteers in weight-bearing positions. As predicted using theoretical models, the proposed motion correction methods improved image quality by reducing motion artifacts in reconstructions; 3D warping performed better than the 2D methods, especially in off-center slices.

OBJECTIVES: The aim of the study was to examine the possible influence of minor deterioration of the renal function after stent implantation not fulfilling the criteria for acute kidney injury on long-term outcomes after stent thrombosis (ST).BACKGROUND: Decreased renal function (DRF) is associated with an increased risk for worse outcome after percutaneous coronary intervention. There is no data if the deterioration of renal function after stent implantation influences the prognosis after ST. If so patients with a higher risk for worse outcome after ST could be identified already at the time of stent implantation.METHODS: Data from 4824 consecutive patients treated with percutaneous coronary intervention in our center was recorded from March 2004 to April 2010. We excluded patients with acute kidney injury at stent implantation and 86 of them with ST without acute kidney injury at stent implantation were involved in the study. They were prospectively followed until December 2012 for 50.2 ± 28.1 months. Only patients with definite ST were included in the study. The Academic Research Consortium definition of ST was used. Data on death, myocardial infarction, and repeated percutaneous or operative revascularization after ST were ascertained from the hospital database, by phone or with clinical examinations. The outcomes after definite ST were compared in patients with and without deterioration of renal function after stent implantation (DRFafterSI).RESULTS: During the observational period patients with DRFafterSI had a higher mortality rate after ST than patients without DRFafterSI (35.1 vs. 10.3 %; p <0.019). The incidence of major adverse cardiac events (major adverse coronary event (MACE)-death, myocardial infarction, repeated revascularization) rate after ST was similar in both groups (66.1 % with DRFafterSI vs. 55.2 % without DRFafterSI). The prevalence of myocardial infarction was also similar in both groups (31.6 vs. 34.5 %) as was the revascularizations rate (43.9 vs. 48.3 %). Death was predicted by DRFafterSI (adjusted hazard ratio (HR) 3.96; 95 % confidence interval (CI) 1.11 to 14.10; p <0.034) and age > 75 years (adjusted HR 2.85: 95 % CI 1.12-7.30; p = 0.029). We could not find any predictor for MACE.CONCLUSIONS: Even more subtle DRFafterSI (not fulfilling the criteria for acute kidney injury) at stent implantation were associated with higher long-term mortality after ST. Especially at risk were patients older than 75 years at stent implantation. DRFafterSI and age more than 75 years pointed out the group of patients with a high risk for death after ST already at the time of stent implantation. The best treatment option for preventing ST in these patients is still to be determined. Until then, we must pay a special attention to proper patients' preparation and hydration to avoid DRFafterSI.

Five patients with idiopathic orthostatic hypotension who had physiologic and biochemical evidence of severe autonomic dysfunction were included in the study. They all exhibited markedly reduced plasma catecholamines and plasma renin activity in both recumbent and upright positions and had marked hypersensitivity to the pressor effects of infused norepinephrine. Treatment with propanolol administered intravenously (1-5 mg) produced increases in supine and upright blood pressure in 4 of the 5 individuals with rises ranging from 11/6 to 22/11 mmHg. Chronic oral administration of propranolol (40-160 mg/day) also elevated the blood pressures of these individuals with increases in the order of 20-35/15-25 mmg being observed. In 1 patient, marked hypertension was induced by propranolol and the drug had to be withdrawn. It otherwise was well tolerated and no important side effects were observed. Treatment has been continued in 3 individuals for 6-13 months with persistence of the pressor effect, although there appears to have been some decrease in the degree of response with time. Hemodynamic measurements in 1 of the patients demonstrated an increase in total peripheral resistance and essentially no change in cardiac output following propranolol therapy. The studies suggest that propranolol is a useful drug in selected patients with severe idiopathic orthostatic hypotension.

The oceans play an important role in the biogeochemical cycle of methyl bromide (CH3Br), as not only the sinks but also the sources. However, many uncertainties exist regarding the way of CH3Br generation in the marine environment. To illustrate the possibility of photochemical formation of CH3Br in saline water, its generation in bromide aqueous solution containing humic acid (HA) and ferric ions (Fe(iii)) was investigated. CH3Br was obviously generated after irradiation, and its amounts increased with increasing HA concentration from 0.82 to 12.2 mgC L-1. Fe(iii) significantly promoted CH3Br production, and the described production process in the presence of Fe(iii) was pH-dependent, decreasing with the increase of pH. Finally, the concentrations of CH3Br in natural coastal seawater and seawater with HA were measured, and the results showed that CH3Br was significantly generated under irradiation. Our results suggest that the photochemical process of dissolved organic matter may be one source of CH3Br in the marine environment.

BACKGROUND: Due to demographic projections, and lack of an algorithm in the case of a prostate specific antigen (PSA)-positive donor, the loss of organ recovery may occur more frequently in the near future without approved procedures. In Poland in recent years it has been recommended to determine tumor markers in potential donors. In the first year of the recommendation 10% of potential deceased donors were disqualified in our transplantation center on the basis of the elevated PSA levels (high PSA >10 ng/mL). Histopathologic evaluation of prostate was implemented in a donor qualification procedure to prevent reduction of the actual organ donor pool.MATERIAL AND METHODS: In the period of January 2010-January 2014 each donor reported to a coordination center (n = 52; median age, 54 years) and underwent the routine histological evaluation of the whole prostate, regardless of the PSA level.RESULTS: Pathologist revealed in the study group of 52 male donors, 6 cases of carcinoma of the prostate (CaP; 12%). There was no correlation between PSA level and CaP (-)/CaP(+) (median 7.0 vs 3.9 ng/mL, respectively; P = .51) nor high-grade prostate intraepithelial neoplasia (HGPIN) (+)/HGPIN (-) (median 5.9 vs 4.3 ng/mL; P = .14). All of the recovered organs (12 kidneys and 3 livers) from donors with CaP were transplanted, resulting in a 15% increase in the organ donor pool.CONCLUSIONS: There is no association between PSA values and CaP occurrence in deceased organ donors. Histological verification allowed for an increase in the organ pool with maintenance of safety standards.

PURPOSE: To evaluate the response rate (RR) and time to local recurrence (TTLR) among patients who received salvage radiation therapy for relapsed or refractory aggressive non-Hodgkin lymphoma (NHL) and investigate whether RR and TTLR differed according to disease characteristics.METHODS AND MATERIALS: A retrospective review was performed for all patients who completed a course of salvage radiation therapy between January 2001 and May 2011 at Brigham and Women's Hospital/Dana-Farber Cancer Institute. Separate analyses were conducted for patients treated with palliative and curative intent. Predictors of RR for each subgroup were assessed using a generalized estimating equation model. For patients treated with curative intent, local control (LC) and progression-free survival were estimated with the Kaplan-Meier method; predictors for TTLR were evaluated using a Cox proportional hazards regression model.RESULTS: Salvage radiation therapy was used to treat 110 patients to 121 sites (76 curative, 45 palliative). Salvage radiation therapy was given as part of consolidation in 18% of patients treated with curative intent. Median dose was 37.8 Gy, with 58% and 36% of curative and palliative patients, respectively, receiving 39.6 Gy or higher. The RR was high (86% curative, 84% palliative). With a median follow-up of 4.8 years among living patients, 5-year LC and progression-free survival for curative patients were 66% and 34%, respectively. Refractory disease (hazard ratio 3.3; P=.024) and lack of response to initial chemotherapy (hazard ratio 4.3; P=.007) but not dose (P=.93) were associated with shorter TTLR. Despite doses of 39.6 Gy or higher, 2-year LC was only 61% for definitive patients with refractory disease or disease that did not respond to initial chemotherapy.CONCLUSIONS: Relapsed or refractory aggressive NHL is responsive to salvage radiation therapy, and durable LC can be achieved in some cases. However, refractory disease is associated with a shorter TTLR, suggesting that radiation dose escalation, addition of radiosensitizers, or a combination of both may be indicated in these patients.

Based on the historical records, 18 of the 26 ethnic groups in Yunnan Province are the descendant populations of three ancient tribes, Bai-Yue, Bai-Pu and Di-Qiang, linguistically belonging to the Daic, Austro-Asiatic and Tibeto-Burman, respectively. In order to trace the origins of these native ethnic groups, a total of 13 East Asian specific Y-chromosome biallelic markers were used to study the genetic structure of 20 local populations covering all the 18 ethnic groups in Yunnan Province. Haplotypes were analysis by PCR-RFLP method. Our results showed that H11 and H12 were the predominant haplotypes in the descendant populations of Bai-Yue tribe. H5, H6 and H8 were the dominant haplotypes in Di-Qiang descendants, and the frequencies of H6, H8 and H11 were very high in the descendant populations of Bai-Pu. To investigate relationships among 20 populations, a three dimensional PC analysis were performed based on the distribution of the 13 haplotypes. All populations were divided into two clusters in the PC plot. The first cluster was mainly composed by the descendant populations of Bai-Yue, and the second one was mainly composed by the descendants of Di-Qiang tribe. This result indicated that Bai-Yue and Di-Qiang's paternal lineage had different origins, which was in agreement with the historical documents and linguistic classification.

OBJECTIVE: Electronic medical records (EMRs) facilitate abnormal test result communication through "alert" notifications. The aim was to evaluate how primary care providers (PCPs) manage alerts related to critical diagnostic test results on their EMR screens, and compare alert-management strategies of providers with high versus low rates of timely follow-up of results.DESIGN: 28 PCPs from a large, tertiary care Veterans Affairs Medical Center (VAMC) were purposively sampled according to their rates of timely follow-up of alerts, determined in a previous study. Using techniques from cognitive task analysis, participants were interviewed about how and when they manage alerts, focusing on four alert-management features to filter, sort and reduce unnecessary alerts on their EMR screens.RESULTS: Provider knowledge of alert-management features ranged between 4% and 75%. Almost half (46%) of providers did not use any of these features, and none used more than two. Providers with higher versus lower rates of timely follow-up used the four features similarly, except one (customizing alert notifications). Providers with low rates of timely follow-up tended to manually scan the alert list and process alerts heuristically using their clinical judgment. Additionally, 46% of providers used at least one workaround strategy to manage alerts.CONCLUSION: Considerable heterogeneity exists in provider use of alert-management strategies; specific strategies may be associated with lower rates of timely follow-up. Standardization of alert-management strategies including improving provider knowledge of appropriate tools in the EMR to manage alerts could reduce the lack of timely follow-up of abnormal diagnostic test results.

In this study, the comparative serum proteome profile of Day 5, 12 and 16 of gestation, representing three early embryonic events, namely formation, elongation and implantation of blastocysts, and non-pregnant control were explored by a label-free quantitation-based mass spectrometric approach to identify early pregnancy biomarkers in pigs. A total of 131 proteins were identified with respect to different groups, out of which 105 were found to be differentially expressed proteins (DEPs). Among the DEPs, 54 and 66 proteins were found to be up and downregulated respectively in early pregnancy groups (fold change >2) and the maximum number of upregulated proteins was observed in the Day 12 pregnancy stage. Functional classification and pathway analysis of the DEPs revealed involvement of most of the proteins in complement and coagulation cascades, metabolic processes and immune and inflammatory responses. Proteins such as glutathione peroxidise (GPX), pregnancy zone protein (PZP), thrombospondin-1 (THBS1), á-1-antitrypsin (AAT) and mannose-binding lectin C (MBLC) were differentially expressed during early pregnancy and actively involved in different pregnancy-related activities. To the best of our knowledge, this is the first report on comparative serum protein profiling of different early pregnancy stages in pigs and our results provide a set of proteins that can be used as potential biomarkers for early pregnancy diagnosis in pigs.

The effects of connexin (Cx) and its derived homotypic gap junctional intercellular communication (GJIC) between tumor cells on the invasion of metastatic cancers and the underlying mechanisms remain unclear. In this study, we investigated the influence of Cx32 and the homotypic GJIC mediated by this Cx on the migration, invasion and intercellular adhesion of transfected HeLa cells. The expression of Cx32 significantly increased cell adhesion and inhibited migration and invasion. The inhibition of GJIC by oleamide, a widely used GJIC inhibitor, reduced the enhanced adhesion and partly reversed the decreased migration and invasion that had been induced by Cx32 expression. Blockage of the p38 and extracellular signal-regulated kinase 1 and 2 mitogen-activated protein kinase (ERK1/2 MAPKs) pathways using their specific inhibitors attenuated the effects of Cx32, but not those of GJIC, on cell adhesion, migration and invasion. These results indicate that the homotypic GJIC mediated by Cx32, as well as the Cx itself, inhibit cell migration and invasion, most likely through the elevation of intercellular adhesion. The suppressive effect of Cx32 on the migration and invasion of cancer cells, but not that of its derived homotypic GJIC, partly depends on the activation of the p38 and the ERK1/2 MAPKs pathways.

BACKGROUND AND AIM: Our previous work showed that the performance of MDRD equations could be improved by modifying the original MDRD equation. However, during the modification we recognized that reference GFR (rGFR) distribution was not similar between the MDRD study and the Chinese Estimating GFR (eGFR) Investigation Study. This present study was designed to illustrate that the GFR estimating equation might be influenced by the difference of rGFR distribution in the development population. Racial factors might not be as important as once thought.PATIENTS AND METHODS: The Chinese eGFR Investigation Study dataset containing 684 CKD patients was defined as Dataset I, the modified MDRD equation for Chinese was defined as Equation 1. Datasets II and III were generated respectively by deleting 125 cases of CKD Stage 1 from Dataset I and by adding 297 cases of apparently healthy Chinese adults into Dataset I. eGFR was estimated using Equation 1. Using rGFR as dependent and eGFR as independent, linear regression models were constructed using Dataset II and Dataset III, respectively, and generated Equation 2 and Equation 3. The prevalence of eGFR less than 60 ml/min/1.73 m2 in the adult Beijing population was calculated using Equation 1, 2 and 3.RESULTS: The previous reported prevalence of decreased GFR using Equation 1 in the Beijing adult population was 1.3% (0.8 - 1.8). By using Equation 2 and Equation 3, the prevalence increased to 3.2% (2.49 - 4.13) and decreased to 0.8% (0.57 - 1.28), respectively.CONCLUSIONS: GFR estimating equation was influenced by rGFR distribution of the development dataset.

AIMS: To assess the efficacy and safety of rituximab in refractory pemphigus and the possible benefit of an additional prophylactic infusion at 6 months.METHODS: Seventeen patients with pemphigus vulgaris, 1 with pemphigus foliaceus and 1 with pemphigus vegetans were treated with 4 weekly infusions of rituximab (375 mg/m(2)). Nine patients received an additional prophylactic infusion after 6 months while the rest received no maintenance therapy. In case of recurrence, an additional single infusion was administered.RESULTS: Control of the disease was obtained after 3-8 weeks. End of the consolidation phase for all patients was observed after 16 weeks. Patients remained in full remission for 7-42 months. All immunosuppressive agents, including prednisone, were discontinued after 2-12 months. The disease relapsed in 5 out of 9 patients who received the additional prophylactic infusion, and in 3 out of 10 patients among those skipping the prophylactic additional infusion.CONCLUSION: One course of rituximab and treatment of relapses is highly effective and well tolerated in the treatment of refractory pemphigus. In this pilot study of 19 patients, the prophylactic infusion does not appear to have provided any additional benefit to the patients receiving it.

The computational platform ENVIRONMENT, developed to simulate stochastically reaction systems in varying compartmentalized conditions [Mavelli and Ruiz-Mirazo: Philos Trans R Soc Lond B Biol Sci 362:1789-1802, 2007; Physical Biology 7(3): 036002, 2010], is here applied to study the dynamic properties and stability of model protocells that start producing their own lipid molecules (e.g., phospholipids), which get inserted in previously self-assembled vesicles, made of precursor amphiphiles (e.g., fatty acids). Attention is mainly focused on the changes that this may provoke in the permeability of the compartment, as well as in its eventual osmotic robustness.

BACKGROUND: There is little information on the clinical characteristics and outcomes of patients with surgically resected, incidentally detected lung cancers. Our hypothesis was that among patients with surgically resected non-small cell lung cancer (NSCLC), incidentally detected cancers were common, were less likely to require pneumonectomy, and were associated with better stage-adjusted survival.METHODS: Two hundred seventy-four patients with NSCLC who underwent surgical resection between 1999 and 2004 were studied. The clinical characteristics of patients with incidentally detected and symptomatic NSCLC were compared. A proportional hazards model was used to compare the stage-adjusted mortality rate of patients with incidentally detected and symptomatic NSCLC.RESULTS: One hundred patients (36%) had incidentally detected NSCLC. Patients with incidentally detected NSCLC had smaller and earlier-stage cancers, were less likely to undergo pneumonectomy (3% versus 13%, p = 0.005), and were more likely to have bronchioloalveolar carcinoma (15% versus 5%, p = 0.003). Patients with incidentally detected cancers had a stage-adjusted hazards ratio (HR) of mortality of 0.9 compared with symptomatic patients (0.6-1.4, p = 0.64). Patients with cancers detected incidentally on computed tomography (CT) had a stage-adjusted HR of 0.5 (0.2-1.5, p = 0.15).CONCLUSIONS: Early-stage NSCLC is commonly detected incidentally. Patients with incidentally detected lung cancers are more likely to have bronchioloalveolar carcinoma histology, less likely to undergo pneumonectomy, and overall have similar stage-adjusted survival compared with symptomatic patients. Patients with cancers detected incidentally by CT scan may have better stage-adjusted survival, but our study was not sufficiently powered to detect this effect.

Intraluminal pressures were recorded in 14 patients who had undergone oesophagogastrectomy. Seven of these had a mid-thoracic and seven a high cervical oesophagogastrostomy. The incidence of postoperative reflux complications in each group was noted. No pressure gradient across the anastomosis was detected in any patient but the upper oesophageal sphincter was shown to be retained as a functioning unit in all cases. It is considered that the thoracic anastomosis provides no demonstrable barrier to reflux. In addition, a high cervical oesophagogastrostomy does not adversely affect the upper oesophageal sphincter. The wider application of this latter procedure may be associated with a decreased incidence of postoperative reflux complications.

The response of two types of linear filters to sinusoidal bursts was calculated to demonstrate how filters can distort EEG waveforms. Results show that the wider the filter bandwidth the less is the distortion, and for a given bandwidth, the higher the filter order the greater the distortion. The response of a linear phase filter was also calculated to demonstrate that this type of filter can also cause waveform distortion, although it is normally less than that caused by Butterworth, Tchebychev and elliptic filters.

BACKGROUND: Vascular endothelial growth factor (VEGF) is overexpressed in hyperproliferative diseases such as psoriasis and cancer, which are characterized by an increased angiogenesis. It was reported that insulin-like growth factor (IGF)-II is highly expressed during hepatocarcinogenesis and is increased in psoriatic lesions. The increase in IGF-II is believed to be associated with the pathogenesis of these diseases by increasing angiogenesis.OBJECTIVES: In order to investigate the relationship between IGF-II and angiogenesis-related VEGF, VEGF expression in the IGF-II-treated human keratinocytes was monitored and the IGF-II signalling pathways were examined with respect to VEGF expression.METHODS: Northern blot analysis for the VEGF mRNA levels and an enzyme-linked immunosorbent assay for the VEGF protein were performed to determine if IGF-II (100 ng mL(-1)) can increase the VEGF expression levels with or without a pretreatment with protein inhibitors in primary normal human keratinocytes and HaCaT cells.RESULTS: The mRNA and protein levels of VEGF by IGF-II were increased in a time-dependent manner and reached the maximum level 2 h and 8 h after the IGF-II treatment, respectively. However, this increase was abrogated by pretreatment with an extracellular signal-regulated kinase (ERK) inhibitor but not by a p38 inhibitor. The IGF-II-mediated VEGF induction was also effectively inhibited by a pretreatment with the tyrosine kinase inhibitor and Src inhibitor. The PI3-kinase inhibitor also inhibited the expression of VEGF by IGF-II. However, the phospholipase C (PLC) and protein kinase C (PKC) inhibitors did not block the increases of VEGF mRNA level and its protein level by IGF-II, and the PKC inhibitor instead increased VEGF expression by IGF-II.CONCLUSIONS: These results suggest that the tyrosine kinase-Src-ERK1/2 pathway and the PI3-kinase pathway are involved in IGF-II-mediated VEGF expression, but PKC is negatively associated in the IGF-II-mediated VEGF expression.

Sixty patients treated with whole abdominal radiotherapy who had remained disease-free since completion of treatment participated in a study to assess the late clinical and biochemical effects of bilateral renal irradiation. Minimum follow-up was 5 years with a maximum of 20 years and a median of 9 years. Fifty-two patients in the study group were treated for primary ovarian cancer. Seven had non-Hodgkins lymphoma arising in the gastrointestinal tract and one patient had a carcinoid tumour arising in small bowel. None of the patients received chemotherapy. Abdominal radiation was given using an open beam technique to a mean dose of 22.92 Gy (range 6.68-27.54 Gy) in 1.02 to 1.25 Gy fractions treated once daily. Posterior kidney shields were used in order to limit the renal dose to < 20 Gy. Mean radiation dose to both kidneys (retrospectively calculated) was 19.28 Gy (range 6.68-22.99 Gy). Patients ranged in age from 32-81 years with a median of 61 years. No patient had clinical evidence of renal impairment. Nine patients were hypertensive prior to radiotherapy and a further five patients became hypertensive after treatment. Serum creatinine values ranged from 44-123 mumol/l, with a mean of 87 mumol/l. Creatinine clearance ranged from 0.61-2.38 ml/s (mean 1.28 ml/s). Tubular function tests revealed one borderline high 24-h protein excretion and normal 24-h phosphorous and uric acid. Using a multiple linear regression analysis with creatinine clearance as the endpoint, age was the only significant variable (P < 0.00001) and renal dose and interval from treatment were not independently significant. There was no evidence of late renal toxicity more than 5 years after whole abdominal radiotherapy delivered with this technique and dose/fractionation schedule, and using the clinical and biochemical endpoints assessed in this study.

The idea of maternity--and paternity as well--reaches far beyond the field of biological reproduction inasmuch as it implies a subject's desire, besides being regulated by the symbolic order: Language, myths, patterns and values of a given culture. From this point of view, infertility cannot be considered as a mere somatic illness, but as a human problem implying psychological and social aspects that require a search for solutions unlikely to be reduced to a sole medical operation. The development of the new reproductive technology is in keeping with the increasing medicalization of human lives, human sexuality, and human bodies.

Alcohol use and risky single occasion drinking are common among adolescents and are associated with a higher risk of various negative social, physical, academic, or sexual consequences. Studies have shown that among college students, willingness to experience negative consequences is associated with a higher likelihood of experiencing these consequences in the future. However, it remains unclear how experiencing negative consequences influences adolescents' willingness to experience them again. Based on a representative sample of 1,333 alcohol-using 14- to 15-year-olds (47.9% female), a path model was used to examine the associations between risky drinking, negative social and physical consequences, and willingness to experience the specific consequence in the future. As hypothesized, more frequent risky drinking was positively associated with experiencing negative consequences (i.e., saying or doing embarrassing things, regretted sexual experiences, impairment of schoolwork, problems with parents/friends, accident or injury, hangover, vomiting, memory lapses). Contrary to our second hypothesis, adolescents who experienced a negative consequence were also consistently willing to experience it in the future. Findings suggest that adolescents may see the experience of negative consequences as a necessary evil to attain the positive consequences. Prevention efforts may benefit from focusing on ways of attaining positive consequences by promoting alternatives to engaging in risky drinking practices, as well as reducing negative consequences (e.g., by promoting protective behavioral strategies). (PsycINFO Database Record

OBJECTIVE: To evaluate the clinical accuracy and clinical impact of positron emission tomography (PET) or positron emission tomography/computed tomography (PET/CT) in detecting and treating tumor recurrence in patients with treated uterine sarcoma.METHODS: Results of 36 patients who underwent PET or PET/CT in post-therapy surveillance of uterine sarcoma were retrospectively assessed. Histopathologic confirmation or clinical/radiological outcome at least 6 months after PET or PET/CT was standard of reference.RESULTS: The 36 patients underwent 48 PET or PET/CT scans as part of post-therapy surveillance. Thirty scans (8 PET and 22 PET/CT) were performed due to suspicion of disease recurrence on CT, whereas 18 scans (4 PET and 14 PET/CT) were performed as part of routine post-therapy surveillance in asymptomatic patients. The sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of PET or PET/CT were 92.9%, 100%, 94.4%, 100% and 80%, respectively, in patients with suspected recurrence and 87.5%, 95.5%, 93.3%, 87.5% and 95.5%, respectively, in asymptomatic patients. PET or PET/CT influenced the management of 12 patients (33.3%), by initiation of previously unplanned treatment in 8 patients and by avoidance of previously planned treatment in 4 patients.CONCLUSION: PET or PET/CT was highly effective in discriminating true recurrence in patients with suspected recurrence and was highly sensitive in detecting recurrence in asymptomatic patients. It had impacts on clinical decision making in a high proportion of patients.

Background: We have previously reported that in utero and early life exposure to diesel exhaust particulates predisposes mice to adult heart failure, and that in utero exposure alone is sufficient to confer this predisposition. This follow up study addresses whether neonatal exposure alone can also confer this predisposition. Methods: Newborn male C57BL/6 mice were exposed to diesel exhaust (DE) particulates immediately after birth until weaning at 21 days of age, whereupon they were transferred to filtered air (FA) conditions. At the age of 12 weeks, transverse aortic constriction (TAC) was performed followed by weekly echocardiography for three weeks. After the last echocardiogram, mice were euthanized for organ harvest, gravimetry and histology. Results: Neonatal exposure to DE particulates did not increase susceptibility to cardiac hypertrophy or heart failure after TAC when compared to FA exposed controls (ventricular weight/body weight ratio 7.505 vs. 7.517 mg/g, p = Not Significant (NS)). The left ventricular ejection fraction after TAC was similar between groups at one week, two weeks, and three weeks after procedure. Histological analysis showed no difference in the degree of cardiac hypertrophy or fibrosis. Conclusions: Neonatal exposure to DE particulates does not predispose mice to TAC-induced cardiac hypertrophy and heart failure in adulthood, in contrast to previously published results showing susceptibility due to in utero exposure.

We present the case of a 58-year-old woman with multiple brain infarcts and livedo racemosa, a distinctive branched and irregular skin discoloration, on the trunk and limbs. Skin biopsy showed intimal proliferation with occlusion of a subcutaneous arteriole. We diagnosed Sneddon's syndrome, a rare neurocutaneous disorder likely caused by a noninflammatoryvasculopathy.

In 16 dog experiments we were able to demonstrate that the conventional selective angiography of the superior mesenteric artery (sma) is performed in a status of underperfusion. By the injection of 50% glucose in a well defined time interval preceding the application of the contrast medium an increase of blood flow can be achieved, which allows the contrast medium to pass through the mesenteric circulation as a bolus. This shows a significantly better opacity of parenchyma and of the venous phase. This technique is easily applicable, carries no side effects on the general circulation and can be recommended for clinical use.

INTRODUCTION AND OBJECTIVE: The aim of this job is to evaluate brain maturation by means of Electroencephalogram (EEG) and Visual Evoked Potentials stimulated with flash (VEP-flash) quantitative analysis techniques.MATERIAL AND METHODS: The transversal study is made on a sample of 96 subjects in which EEG and VEP-flash, first isolated and then joining both, are analyzed. The selection of spectral parameters was done taking care of all the subjects were selected in the sense of maximizing brain maturation discrimination. Multivariate analysis techniques for classifying subjects were used. EEG and VEP-flash variables were selected with the linear discriminant analysis. In the EEG case the variables take into account, as a reference, either the median of the power spectrum or either the time instant in which the spectral power in every band reaches its maximum value. In the joined EEG-VEP-flash the VEP variables which give more information were related with the slopes and distances between the basic peaks of the evoked response (N1, P1 and N2) and age. For brain maturation evaluation the variables in the occipital channels are sufficient, being those of the right hemisphere the most diagnostic significative ones.CONCLUSION: The joined use of EEG and VEP-flash means an improvement in the maturative level discrimination regarding to the isolated consideration of any of them. Variables obtained from the EEG-VEP-flash are enough for brain maturation evaluation.

Previous work from our laboratory (Biochem. J. 219:689-697 (1984] had shown that hydrocortisone stimulated the net accumulation of the myelin-specific sulfolipid in cultures of cells dissociated from embryonic mouse cerebra. This accumulation caused by hydrocortisone was shown to be due to a decrease of sulfolipid degradation by arylsulfatase A (ASA) and not due to a stimulation of its synthesis by a sulfotransferase. Both ASA activity and the turnover of sulfolipid were decreased by hydrocortisone to 60-62% of untreated cells. In current work the same decrease in enzyme activity was obtained and enzyme linked immunosorbent assays demonstrate that hydrocortisone decreased the number of ASA protein molecules to 61% of untreated cells [(-)hydrocortisone: 0.31 +/- 0.06 ng ASA/microgram protein; (+)hydrocortisone: 0.18 +/- 0.04 ng ASA/microgram protein]. This decrease in the number of ASA molecules correlates well with the decrease in both the enzyme activity and the sulfolipid turnover, which suggests that the major mode of inhibition of ASA activity by hydrocortisone involves a decrease in the concentration of ASA in the cells rather than some other mechanism of inhibition.

We randomised 250 patients undergoing unilateral, elective hip arthroplasty for osteoarthritis to receive either a cemented or a non-cemented Mallory Head prosthesis. Aspirin was used as prophylaxis against thromboembolism during the first half of the study and adjusted-dose warfarin during the second half. Postoperatively, all patients were asked to have bilateral venography and 80% agreed. All were evaluated clinically for pulmonary embolism. There was no difference in the frequency of deep-venous thrombosis between the two groups (50% cemented nu 47% non-cemented, p = 0.73; 95% CI of the difference -13.6% to 19.3%). Three of the 64 patients (5%) in whom venography had demonstrated isolated distal thrombi developed pulmonary emboli.

OBJECTIVE: This study aims to provide the first description of the computed tomographic (CT) appearances of intracardiac embolized brachytherapy seeds in patients undergoing electrocardiogram (ECG)-gated cardiac CT.METHODS: The institutional Picture Archive and Communication System was searched for male patients who underwent enhanced ECG-gated cardiac CT, and reports were searched for the key words "metallic," "prostate," "brachytherapy," "radiation," "embolized," and "radioactive." Each study was identified and examined for an intracardiac metallic object conforming to the size of a prostate seed.RESULTS: Between January 01, 2005, and June 30, 2014, a total of 3206 male patients underwent ECG-gated cardiac CT. Five patients (0.15%) had a history of prostate cancer and an intracardiac metallic object with CT imaging characteristics consistent with an embolized prostate seed. In all 5 patients, the seeds were embedded in the trabeculations of the inferior aspect of the basal right ventricular free wall.CONCLUSIONS: Intracardiac embolized brachytherapy seeds appear as small objects with surrounding metallic artifact characteristically embedded in the inferior aspect of the basal right ventricular free wall.

Purpose: Previous human epidermal growth factor receptor-2 (HER2)-derived resistance studies were based on ex vivo models, which could not mirror evolutionary expression of HER2 during therapy. To investigate dynamic expression of HER2 and its contribution to developing therapeutic resistance conferred by chromosome aneuploidy, both the HER2 phenotype and chromosome 8 (Chr 8) aneuploidy on circulating tumor cells (CTC) were coexamined in advanced gastric cancer (AGC) patients.Experimental Design: A total of 115 AGC patients, including 56 of histopathologic HER2+ (hHER2+) subjects who received first-line HER2-targeted therapy plus chemotherapy, and 59 of hHER2- patients who received chemotherapy alone, were prospectively enrolled. Both HER2 phenotype and Chr8 aneuploidy of CTCs in patients were coexamined by HER2-iFISH during therapy.Results: A fluctuated positive HER2 phenotype on CTCs (cHER2+) was revealed, showing cHER2+ at different time intervals during treatment. Acquisition of the cHER2+ phenotype in 91.0% of hHER2+ and 76.2% hHER2- patients was demonstrated to correlate with development of resistance to trastuzumab-targeted therapy for hHER2+ patients and chemotherapy alone for hHER2- patients. Aneuploid Chr8 was demonstrated to participate in the acquisition of the cHER2+ phenotype, which provides a growth advantage to HER2+ CTCs against therapeutic pressure, leading to the development of therapeutic resistance.Conclusions: Compared with low positivity of conventional histopathologic hHER2 examination routinely performed once, significant higher positivity of cHER2+ on CTCs was observed. Continuously examining cHER2 shows unique advantages with respect to monitoring therapeutic resistance in real time in carcinoma patients. Moreover, contribution of chromosome aneuploidy to the phenotypic evolution of HER2 expression on CTCs may help elucidate underlying mechanisms of developing therapeutic resistance. Clin Cancer Res; 24(21); 5261-71. ©2018 AACR.

AIM: To determine the predictive value of the hypo-osmotic swelling (HOS) test to identify viable, non-motile sperm.METHODS: Semen samples from 20 men with severe asthenozoospermia underwent traditional seminal analysis, eosin-nigrosin (EN) staining and the HOS test. A further EN stain was then performed on a HOS pre-treated aliquot and a total of 2000 further sperm examined.RESULTS: The median sperm density was 5.1 million/mL (IQR 4.3 approximately 13.1) and the median motility was 3.0% (IQR 0 approximately 7). Seven samples showed complete asthenozoospermia. Initial EN staining showed 59% viability (range 48 approximately 69) despite the poor standard parameters and 47% (range 33 approximately 61) in the complete asthenozoospermia subgroup. The HOS test showed 49.9% reacted overall (range 40 approximately 59) and 41.7% (range 22 approximately 61) in the complete asthenozoospermia subgroup. The combined HOS/EN stain showed the positive predictive value of the HOS test to identify viable sperm was 84.2 % overall and 79.7% in the complete asthenozoospermia subgroup.CONCLUSION: The HOS test can effectively predict sperm viability in patients with severe and complete asthenozoospermia.

Patients with metastatic prostatic cancer were treated by means of an LHRH agonist, Buserelin, by nasal administration. The serum testosterone levels were permanently decreased to castration levels in all patients. The objective response rate (CR + PR) was 50%.

In 4 women with anencephalic fetuses, the oxytocin level was measured in the maternal plasma in the second stage of labor and in the umbilical artery (UA) and umbilical vein (UV) by radioimmunoassay (RIA). In these cases, the mean maternal OT level was 13.4 +/- 8.0 microU/ml (mean +/- S.E.), which was not significantly different from the OT levels in cases of normal spontaneous birth and elective cesarean section. The UA and UV plasma OT levels in these cases were below the detectable level (less than 2 microU/ml), whereas in normal spontaneous births, they were 18.2 +/- 4.9 microU/ml and 12.2 +/- 2.3 microU/ml, respectively. The OT level in the UA was higher than that in the UV. There was no difference between the mean OT levels in patients with, versus those without contractions, but the plasma OT levels in the second stage of labor were higher than those in the first stage. In normal pregnancies the plasma OT concentration increased during parturition. These results suggest that placental transfer of maternal plasma OT to the fetal circulation is limited, and that in cases of anencephalic fetuses, maternal labor does not necessarily require fetal OT as a trigger or for its maintenance.

A Gram-positive bacterium (strain CC-YMP-6(T)) was isolated from soil samples collected from Yang-Ming Mountain, Taiwan. On the basis of 16S rRNA gene sequence analysis, strain CC-YMP-6(T) clearly belonged to the genus Virgibacillus and was most closely related to the type strains of Virgibacillus halophilus (96.2 % similarity) and Virgibacillus kekensis (96.3 %). The predominant isoprenoid quinone was menaquinone MK-7 and the polar lipid profile was composed of the major components diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and one unidentified phospholipid plus moderate amounts of two unidentified aminophospholipids and a phospholipid. The polyamine pattern comprised spermidine as the single major component with spermine and putrescine present in minor amounts. The major fatty acids of strain CC-YMP-6(T) were iso-C(15 : 0) and anteiso-C(15 : 0). The results of physiological and biochemical tests allowed the clear phenotypic differentiation of strain CC-YMP-6(T) from all recognized species of the genus Virgibacillus. Strain CC-YMP-6(T) is therefore considered to represent a novel species of the genus Virgibacillus, for which the name Virgibacillus soli sp. nov. is proposed. The type strain is CC-YMP-6(T) (=DSM 22952(T)=CCM 7714(T)).

The aims of the study were to evaluate the contribution of visceral adipose tissue (AT) accumulation and insulin sensitivity to the determination of circulating free fatty acid (FFA) concentrations measured during a 2-hour euglycemic-hyperinsulinemic clamp and to verify whether elevated FFAs are associated with other components of the metabolic syndrome in postmenopausal women. This cross-sectional study included 115 postmenopausal women (46-68 years old). Visceral AT was estimated by computed tomography. Insulin sensitivity was assessed by a 2-hour euglycemic-hyperinsulinemic clamp. Free fatty acid concentration was measured in the fasting state and every 30 minutes during the clamp. Fasting plasma glucose and 2-hour plasma glucose were measured by an oral glucose tolerance test. Visceral AT was associated positively and insulin sensitivity negatively with FFA area under the curve (AUC) measured during the clamp. Women with high visceral AT accumulation and low insulin sensitivity had higher FFA AUC than women with high visceral AT accumulation and high insulin sensitivity or women with low visceral AT combined with either low or high insulin sensitivity. Free fatty acid AUC was positively associated with triglyceride (r = 0.25, P < .05), fasting plasma glucose (r = 0.26, P < .01), 2-hour plasma glucose (r = 0.27, P < .01), and diastolic blood pressure (r = 0.21, P < .05) independently of visceral AT and insulin sensitivity. In postmenopausal women, the presence of both high visceral AT and low insulin sensitivity is needed to observe an elevated FFA AUC. Moreover, FFA AUC is associated with some components of the metabolic syndrome, independently of visceral AT and insulin sensitivity.

Protoplasts of Saccharomyces cerevisiae swelled, lysed and disintegrated when exposed to hypotonic solutions at neutral pH. At pH 4.5 or lower the hypotonically treated protoplasts did not disintegrate and they retained their intracellular proteins, nucleic acids and nucleotides. However, they became leaky for K+ and Ca2+, indicating that pores had been created in the surface membrane, relaxing the osmotic stress. Upon readjustment of pH to neutral, the hypotonically treated protoplasts released the intracellular content and disintegrated. Also, at low pH, protoplasts did not swell in isotonic ammonium acetate and were refractory to the permeabilizing effect of nystatin and to lysis with low concentrations of detergents. Protoplasts were similarly protected against lysis and disintegration by hypotonic treatment or by detergents, even at neutral pH, if the incubation media contained polyvalent cations, especially Zn2+, La3+, spermine, and Ca2+ chelated with EDTA. The protoplasts exposed to hypotonic stress at low pH did not respire and could not regenerate into viable cells. Effects of H+ and polyvalent cations on intramembrane forces acting between molecules of membrane phospholipids are considered along with possible changes in interactions between membrane proteins.

AIMS: To examine the antinociceptive effects of N-Methyl-D-aspartate (NMDA) receptor NR2 subunit antagonists in a rat model of the facial formalin test.METHODS: Experiments were carried out on adult male Sprague-Dawley rats weighing 220 to 280 g. Anesthetized rats were individually mounted on a stereotaxic frame and a polyethylene tube was implanted for intracisternal injection and, 72 hours later, formalin tests were performed. NMDA receptor antagonists were administered intracisternally 10 minutes prior to subcutaneous injection of 5% formalin (50 MicroL) into the vibrissal pad.RESULTS: The intracisternal administration of 25, 50, or 100 Microg of memantine, an antagonist that acts at the NMDA ion channel site, significantly suppressed the number of scratches in the second phase of the behavioral responses to formalin. Intracisternal administration of a range of doses of 5,7-dichlorokynurenic acid, a glycine site antagonist, or DL-2-amino-5-phosphonopentanoate (AP-5), a nonselective NMDA site antagonist, produced significant antinociceptive effects in the second phase. Intracisternal administration of 1, 2.5, or 5 Microg of (2R,4S)-4-(3 Phosphonopropyl)-2-piperidine_carboxylic acid (PPPA), a competitive NR2A antagonist, significantly suppressed the number of scratches in the second phase, while only the highest dose of PPPA (5 Microg) significantly suppressed the number of scratches in the first phase. The antinociceptive effects of intracisternal injection of (alphaR, betaS)-alpha-(4Hydroxyphenyl)-_ methyl-4-(phenylmethyl)-1-Piperidinepropanol maleate(Ro 25-6981), a selective NR2B antagonist, were similar to those of PPPA. Injection of memantine, AP-5, Ro 25-6981, or vehicle did not result in any motor dysfunction. A low dose of PPPA (1 microg) or 5,7-dichlorokynurenic acid (2.5 microg) did not affect motor function. However, higher doses of PPPA and 5,7-dichlorokynurenic acid produced motor dysfunction.CONCLUSION: The present results suggest that central NR2 subunits play an important role in orofacial nociceptive transmission. Moreover, this data also indicate that targeted inhibition of the NMDA receptor NR2 subunit is a potentially important new treatment approach for inflammatory pain originating in the orofacial area.

The mechanism and electrophysiologic manifestations of concealed re-entry were studied in human electrocardiograms and intracardiac recordings. Previously described patterns of concealed re-entry were documented in 49 patients. In seven cases concealed re-entry was involved in the genesis of Wenckebach periodicity and alternating Wenckebach periodicity in the AV node, and "reversed" Wenckebach periods in the His-Purkinje system. These manifestations of concealed re-entry were not described so far. In five cases re-entry was apparently concealed. Complete (but hidden) circus movement of the supraventricular impulses in these patients were detected by intracardiac recordings and by analysing the effects of echo beats on timing of the subsequent sinus beats. Concealed re-entry of the cardiac impulse is a well-documented electrophysiologic event which explains many common and peculiar manifestations of impulse formation and impulse conduction in the human heart.

[18F]6-fluoro-L-DOPA ([18F]FDOPA) is a diagnostic radiopharmaceutical for positron emission tomography (PET) imaging that is used to image Parkinson's disease, brain tumors, and focal hyperinsulinism of infancy. Despite these important applications, [18F]FDOPA PET remains underutilized because of synthetic challenges associated with accessing the radiotracer for clinical use; these stem from the need to radiofluorinate a highly electron-rich catechol ring in the presence of an amino acid. To address this longstanding challenge in the PET radiochemistry community, we have developed a one-pot, two-step synthesis of high-molar-activity [18F]FDOPA by Cu-mediated fluorination of a pinacol boronate (BPin) precursor. The method is fully automated, has been validated to work well at two separate sites (an academic facility with a cyclotron on site and an industry lab purchasing [18F]fluoride from an outside vendor), and provides [18F]FDOPA in reasonable radiochemical yield (2.44 ± 0.70 GBq, 66 ± 19 mCi, 5 ± 1%), excellent radiochemical purity (>98%) and high molar activity (76 ± 30 TBq/mmol, 2,050 ± 804 Ci/mmol), n = 26. Herein we report a detailed protocol for the synthesis of [18F]FDOPA that has been successfully implemented at two sites and validated for production of the radiotracer for human use.

BACKGROUND: Drug-related overdoses were declared a public health emergency in British Columbia, Canada in April, 2016 facilitating the scale-up of responses including rapid sanctioning and implementation of overdose prevention sites (OPSs). OPSs are a health service providing supervised injection and immediate overdose response. In BC, OPSs were operational within weeks of sanctioning. In the first year of operation over 20 OPSs were established with approximately 550,000 visits and no overdose deaths at any site. In this paper, we examine the implementation of OPSs as a novel and nimble response to prevent overdose deaths as a result of injection drug use.METHODS: A multiple case study design was used with the Consolidated Framework for Implementation (CFIR) informing the analysis. Three sites in a single city were included with each site constituting a case. In this paper, we focus on qualitative interviews with 15 staff and their perceptions of the implementation of the OPSs as well as provincial and local documents.RESULTS: The legislative process to implement OPSs was unprecedented as it sanctioned supervised injection services as an extraordinary measure under a declared public health emergency. Innovative and inclusionary practices were possible within state-sanctioned OPSs, as the sites were government-directed yet community-developed, with PWUD centred in service design, implementation and delivery. OPSs lack permanency and may be limited to the duration of the public health emergency.CONCLUSION: The rapid implementation of OPSs provides an international example of an alternative to lengthy and often onerous sanctioning processes for supervised consumption services (SCSs). Overdose prevention sites provide an example of a novel service design and nimble implementation process that combines the benefits of state-sanctioned injection services with community-driven implementation. Such evidence questions the continued acceptability of governments' restrictive sanctioning processes, which have limited expansion of SCSs internationally and the implementation of services that are not necessarily aligned with the needs of PWUD.

Rehabilitative treatment with the beta-blocker anaprilin was performed in 58 patients with coronary heart disease within early periods (on days 7 to 21) after aortocoronary bypass surgery. Group 1 patients were given oral anaprilin. Group 2 patients took the drug by sinusoidal modulated current electrophoresis. With the latter drug administration, its negative chronotropic effect and abolished adverse decrease in myocardial contractivity were detected in the patients from that group. Bearing in mind the results of pharmacokinetic studies, it was suggested that the therapeutic effect of small blood anaprilin concentrations was due to the electrophoresis-induced passage of only its therapeutically beneficial left isomer and L-propranolol glucuronide, a metabolite.

OBJECTIVE: To study the modulation of somatosensory evoked potentials (SEP) using transcranial magnetic intermittent theta burst stimulation (iTBS) over human primary motor (M1) and sensory (S1) cortices.METHODS: Eleven healthy subjects participated in the study. Median nerve SEP were elicited by electrical stimulation at the right wrist before and after 600-pulse iTBS over M1 or S1 of the left hemispheres at the intensity of 80% active motor threshold.RESULTS: iTBS over S1 facilitated the N20o-N20p, N20p-P25 and P25-N33 amplitudes significantly and the maximal effect appeared 15 min after the stimulation. The facilitating effect was observed when the initial phase of the current in the brain was directed antero-medially, whereas the facilitation did not appear when the inverted coil direction was applied. On the other hand, no changes were observed after iTBS over M1. The latencies of the measured onsets and peaks were not affected through the experiments.CONCLUSIONS: iTBS over S1 has the facilitating effect on the central somatosensory pathway, and the position and direction of the coil are the determinant factors of the effects.SIGNIFICANCE: iTBS can be useful technique to induce synaptic plasticity in human central somatosensory pathway.

The purpose of this study is to demonstrate the developmental changes of the experimental hydronephrotic kidney using immunohistochemical, histoplanimetrical, and Northern blot techniques. At 1 month after ligation of the ureter, a large number of renin-positive cells were detected immunohistochemically even at a dilution of 1:10,000 in this hydronephrotic kidney; however, there were few renin-positive cells in the non-ligated side. At 6 months after ligation, no difference in reactivity for renin between ligated and non-ligated kidneys was demonstrated. In the morphometrical analysis of the renin-positive region, the numerical value of the ligated side was already increased at 2 weeks, reached the highest value at 1 month, and then decreased gradually to almost the same value as the control kidney by the end of the experiment. On the other hand, the value of the non-ligated side decreased immediately after the unilateral ligation, increased later, and finally reached almost the same value as the control kidney. In the Northern blot analysis, the activity of renin mRNA in the ligated side at 1 month after ligation was markedly higher than that in the non-ligated side. However, the difference between the ligated and the non-ligated sides was not demonstrated at 6 months and the value came to be almost the same as in the non-operated kidney.

BACKGROUND AND PURPOSE: Patients with renal impairment (RI) have an increased risk of both thrombotic and hemorrhagic events. We aimed to clarify whether RI increases the risk of intracerebral hemorrhage (ICH) after intravenous thrombolysis with recombinant tissue plasminogen activator.METHODS: Patients who received intravenous thrombolysis with recombinant tissue plasminogen activator within 4.5 hours of symptom onset were retrospectively analyzed. Creatinine levels on admission served to calculate glomerular filtration rate (GFR) to estimate RI according to International Classification of Diseases criteria. Effect of RI on symptomatic ICH (sICH) was assessed using dichotomized (GFR <90 and <30 mL/min) and continuous GFR (centered data to test for linear and centered and squared data to test for curvilinear association).RESULTS: Of the 740 patients included, 83% had any RI (GFR <90 mL/min) and 5% had severe RI (GFR <30 mL/mL); 4.6% experienced sICH. Univariate comparisons revealed higher prevalence of sICH in patients with severe RI (P<0.01) but not with any RI. GFR as a continuous variable (centered and squared) was also associated with sICH (P=0.02), but GFR on its own was not. Severe RI and GFR (centered and squared) remained independently associated with sICH in multiple regression analyses.CONCLUSIONS: Severe RI (GFR <30 mL/min) is associated with sICH after intravenous thrombolysis with recombinant tissue plasminogen activator. The association is curvilinear. Severe RI must be taken into account when balancing the risk-benefit ratio of intravenous thrombolysis with recombinant tissue plasminogen activator.

For series determining of small dimensions at high accuracy a pistollike measuring instrument has been devised which is well suitable for planning mandible prostheses, for instance for obtaining the with dimensions of the mandibula corpus basalis or for example for determining the mesio distal diameter of the teeth.

Ureteral obstruction causes impaired salt wastage and K+ secretion in the distal nephron segments, including the cortical collecting duct (CCD). Recently, we demonstrated that conductances of Na+ and K+ in the apical membrane, as well as the electrogenic Na(+)-K+ pump activity and the relative K+ conductance in the basolateral membrane of the collecting duct cell, were inhibited in the obstructed kidney after unilateral ureteral obstruction (UUO). To examine whether the increased intrarenal pressure might be causally related to these abnormalities in the CCD, the effects of unilateral renal decapsulation, a maneuver that partially blocks the increase in renal pressure, were evaluated with microelectrode techniques in isolated CCDs from UUO and sham-operated (control) rabbits 24 h after operation. Renal decapsulation had no effects on barrier voltages and conductances in the CCD from control animals. The lumen-negative transepithelial (VT) and basolateral membrane (VB) voltages as well as the transepithelial (GT) and the apical membrane (GA) conductances were decreased in the CCD from UUO animals compared with control animals. Pretreatment of renal decapsulation partially corrected the decreases in VT, VB, GT, and GA seen in the CCD from UUO animals. The changes in apical membrane voltage and GT upon addition of luminal amiloride and Ba2+, and the changes in VB upon addition of bath ouabain, were also decreased in the CCD from UUO animals compared with control animals. Pretreatment of renal decapsulation also partially corrected the above abnormalities seen in UUO animals, whereas it had no effect in control animals. The transference numbers for Cl- (tCl) and K+ (tK) in the basolateral membrane were, respectively, increased and decreased in the CCD from UUO animals compared with control animals. Pretreatment of renal decapsulation also partially corrected the changes in tCl and tK seen in UUO animals, whereas it had no effect in control animals. We conclude that, in UUO animals, renal decapsulation partially corrects the inhibition of apical Na+ and K+ conductances as well as basolateral Na(+)-K+ pump activity and relative K+ conductance seen after UUO, whereas in control animals it has no effect. The increased renal pressure may partly contribute to the defects in Na+ and K+ transport in the CCD from obstructed kidneys. Renal decapsulation has protective effects on impaired Na+ and K+ transports in the CCD after ureteral obstruction.

Photodynamic therapy (PDT) using photosensitizer drug has become an important therapeutic modality. However, the stability and targeted delivery of photosensitizer remain a critical challenge for efficient PDT treatment. In the present study, we developed chlorin e6 (Ce6)-conjugated and folic acid (FA)-decorated silica nanoparticles (silica-Ce6-FA) for targeted delivery of photosensitizer to the cancer cells. The synthesized NPs exhibited excellent stability and biocompatibility with MDA-MB-231 cells. The formulated particles were efficiently taken up by folate receptor-positive MDA-MB-231 cells, which were confirmed by comparative analysis with folate receptor-negative HepG2 cells. The folate receptor-targeted silica-Ce6-FA was highly accumulated inside the MDA-MB-231 cells than free Ce6. The obtained NPs produced singlet oxygen efficiently under 670-nm laser exposure. The cell-killing effect of silica-Ce6-FA was higher when compared with free Ce6 under PDT treatment. The PDT-induced mitochondrial damage and apoptotic cell death were detected in silica-Ce6-FA-treated cells.

Pancreatic metastasis from colorectal cancer is rare, and accounts for less than 2% of all pancreatic metastases. There have been no studies that have reported the differences in the sensitivity to chemotherapy between the primary lesion and the pancreatic metastasis in colorectal cancer. We experienced a rare example of pancreatic metastasis from colorectal cancer, and report here the difference in the sensitivity to the antitumor drug. A 68-year-old female underwent colectomy for rectal carcinoma with a mass in the pancreatic tail and the liver. The patient also underwent a distal pancreatectomy and a segmental liver resection at the same time. v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and tumor protein 53 (TP53) gene mutation analyses, in addition to the histopathological examinations, revealed tumors of the liver and the pancreatic tail as being metastases from the primary carcinoma. We employed a collagen gel droplet-embedded culture drug sensitivity test for both the primary lesion and the pancreatic metastasis. The sensitivity to oxaliplatin and FOLFOX (5-flurouracil, folinic acid and oxaliplatin) were lower in the pancreatic metastasis compared to the primary lesion. In conclusion, pancreatic metastasis from colorectal malignancy is rare, and the present results suggest that there are potential differences in the sensitivity to chemotherapy between the primary colorectal tumor and its pancreatic metastasis.

Early markers of neurological outcome in the absence of overt brain damage are scarce in extreme prematurity. The aim of this study was to compare spectral EEG values of infants born near term with those of infants born at extremely low gestational age (ELGA) but having attained near term age. We aimed also to evaluate whether spectral EEG features were related with neurological outcome. The ELGA group consisted of 12 neonates born between 23+2 and 27+6 weeks; the control group consisted of nine infants born 34-35+2 weeks, tested within the first week of life. All neonates underwent multichannel EEG recordings at 35 weeks post-conception. None of the subjects had apparent neurological abnormalities or risk factors at the time of recording. EEG data were transformed into the frequency domain and divided into delta (0.5-4Hz), theta (5-7Hz), alpha (8-13Hz), beta (14-20Hz) frequency bands; relative EEG power values were calculated. ELGA group was compared with the control group using a mixed analysis of variance. Outcome was evaluated at one year of age by Griffiths' scales. A principal effect of frequency and an interaction effect of frequency * group was found. The total relative power of the delta band was significantly higher in ELGA than in control group, whereas in the remaining frequency bands total relative power was lower in ELGA than in control group. Higher values of delta and lower values of alpha and beta spectral power correlated with poor outcome. We provide preliminary results suggesting that, as early as 35 weeks post conception, infants born extremely preterm fail to develop the age specific pattern of EEG spectral activity, in the absence of neurological neonatal risk.

The mechanism whereby the human neutrophil membrane heterodimer, CD11b/CD18 (Mac-1, Mo1), mediates neutrophil adherence is not known. We studied the role of CD11b/CD18 surface expression in the promotion of neutrophil adhesiveness. We found that phorbol myristate acetate (PMA), calcium ionophore (A23187), and FMLP caused a three- to sevenfold increase in surface expression of both CD11b (alpha M) and CD18 (beta) as assayed by binding of MAbs 60.1 (anti-CD11b) and 60.3 (anti-CD18). Increased binding of MAbs was temporally associated with the promotion of neutrophil aggregation and adherence to cultured endothelial monolayers. Pretreatment of neutrophils with the anion channel-blocking agent, DIDS (4,4'-diisothiocyanostilbene-2,2'-disulfonic acid), inhibited the increased surface expression of CD11b and CD18 after stimulation by PMA, A23187, or FMLP and resulted in nearly complete inhibition of neutrophil aggregation. However, pretreatment with DIDS did not diminish either PMA-, A23187-, or FMLP-stimulated neutrophil adherence to endothelial monolayers. We also observed that stimulation of granule-depleted neutrophil cytoplasts by PMA, A23187, or FMLP induced aggregation and adherence to endothelial monolayers without increasing surface expression of CD11b or CD18. We conclude that the increased surface expression of CD11b/CD18 that occurs after stimulation is neither sufficient nor necessary for enhanced adherence to endothelium. Moreover, though both are CD11b/CD18-dependent, the mechanisms involved in neutrophil aggregation are different from those involved in neutrophil adherence to endothelium.

An histophysiological evaluation was performed of adult rat testes 30 days after vasectomy. A higher frequency of stage VII-VIII of the tubular cycle was observed, indicating sperm accumulation. Seminiferous tubules and tubular lumen having increased diameters were also observed, but these results cannot be explained only in terms of increase in retrograde intratubular pressure. The rise in basal gonadotrophin levels as well as in testosterone levels observed under basal conditions and 30 and 60 min after stimulation with human chorionic gonadotrophin (hCG) suggested hyperactivity of the Leydig cells. The observed increased frequency of Leydig cells with smaller nuclear volumes may be correlated with higher luteinizing hormone levels. The results are discussed in terms of the possible role of neuromotor components resected during vasectomy, which may alter the spermatogenic and the secretory functions of the testis.

This article examines the British child guidance movement's claim to scientific status and what it sought to gain by the wider acceptance of such a claim. The period covered is from the movement's origins in the 1920s to the end of the Second World War, by which point it had been incorporated into the welfare state. This was also an era when science commanded high intellectual and cultural status. Child guidance was a form of psychiatric medicine that addressed the emotional and psychological difficulties that any child might experience. It thus saw itself as a form of preventive medicine and as a component of the international movement for mental hygiene. Child guidance was organized around the clinic and employed the knowledge and skills of three distinct professions: psychiatrists, psychologists and psychiatric social workers. Its claim to scientific status was underpinned by the movement's clinical and organizational approach and in turn derived from developments in the laboratory sciences and in academic medicine. There were, however, those even within the movement itself who challenged child guidance's purported scientific status. Such objections notwithstanding, it is suggested here that at least in its own terms the claim was justified, particularly because of the type of psychiatric approach which child guidance employed, based as it was on a form of medical holism.

The qualitative study reported in this article is part of a larger multimethod investigation of child-rearing practices and child-behavior problems in indigenous Sami and majority Norwegian populations in the Sami core area in Northern Norway. In the primary quantitative study we found significant ethnic differences between Sami and Norwegian parents in various areas of child rearing and family structure. Seeking the deeper cultural meaning underlying the parental practices and attitudes that had emerged in the indigenous Sami group, we performed additional indepth interviews. Four parents, selected from the sample of 134 Sami parents, served as subjects. Giorgi's descriptive phenomenological method was used. Data analysis of the interviews identified seven key consitituents of Sami child rearing, which in their interrelationships formed a common structure that constitutes the results of this study. These constituents were: (1) Independence, (2) Hardiness, (3) Autonomy, (4) Closeness/Love, (5) Sami Language, (6) Sami Traditions, and (7) Extended Family. The first four constituents are constituents pertaining to child-rearing values, while the latter three are contextual constituents, related to the promotion of ethnic identity. The study discusses the contemporary dilemmas and challenges that face Sami families in raising their children. It highlights the phenomenon of cultural transition in minority families as an important topic in family research.

The Gamma Knife is currently the only radiosurgical device which has been used in functional neurosurgery. This mode of utilization is possible because the instrument can make lesions in normal brains with a volume as small as 50 mm3. The experience of functional radiosurgery accumulated at the Karolinska Institute over 21 years is reviewed, and the possible implications of the new developments in imaging techniques for the future of functional radiosurgery are considered. The review covers gamma thalamotomy for pain and tremor, radiosurgery for trigeminal neuralgia, gamma capsulotomy for severe anxiety and obsessive-compulsive neurosis, and Gamma Knife surgery for focal epilepsy. The important role of stereotactic MRI localization in functional radiosurgery is pointed out, and a preliminary report of the recent experience with stereotactic magnetoencephalography combined with stereotactic MRI for physiological and anatomic target localization is given. It is concluded that functional radiosurgery should only be performed with radiation of very small volumes of brain, as the very high doses required would be devastating if delivered to even small volumes.

We propose a reinforcement learning approach for real-time exposure control of a mobile camera that is personalizable. Our approach is based on Markov Decision Process (MDP). In the camera viewfinder or live preview mode, given the current frame, our system predicts the change in exposure so as to optimize the trade-off among image quality, fast convergence, and minimal temporal oscillation. We model the exposure prediction function as a fully convolutional neural network that can be trained through Gaussian policy gradient in an end-to-end fashion. As a result, our system can associate scene semantics with exposure values; it can also be extended to personalize the exposure adjustments for a user and device. We improve the learning performance by incorporating an adaptive metering module that links semantics with exposure. This adaptive metering module generalizes the conventional spot or matrix metering techniques. We validate our system using the MIT FiveK [1] and our own datasets captured using iPhone 7 and Google Pixel. Experimental results show that our system exhibits stable real-time behavior while improving visual quality compared to what is achieved through native camera control.

Heterosis refers to the phenomenon that progeny of diverse varieties of a species or crosses between species exhibit greater biomass, speed of development, and fertility than both parents. Various models have been posited to explain heterosis, including dominance, overdominance, and pseudo-overdominance. In this Perspective, we consider that it might be useful to the field to abandon these terms that by their nature constrain data interpretation and instead attempt a progression to a quantitative genetic framework involving interactions in hierarchical networks. While we do not provide a comprehensive model to explain the phenomenology of heterosis, we provide the details of what needs to be explained and a direction of pursuit that we feel should be fruitful.

BACKGROUND: In trauma patients, pancreatic injury is rare; however, if undiagnosed, it is associated with high morbidity and mortality rates. Few predictive models are available for the identification of pancreatic injury in trauma patients with elevated serum pancreatic enzymes. In this study, we aimed to construct a model for predicting pancreatic injury using a decision tree (DT) algorithm, along with data obtained from a population-based trauma registry in a Level I trauma center.METHODS: A total of 991 patients with elevated serum levels of amylase (>137 U/L) or lipase (>51 U/L), including 46 patients with pancreatic injury and 865 without pancreatic injury between January 2009 and December 2016, were allocated in a ratio of 7:3 to training (n = 642) or test (n = 269) sets. Using the data on patient and injury characteristics as well as laboratory data, the DT algorithm with Classification and Regression Tree (CART) analysis was performed based on the Gini impurity index, using the rpart function in the rpart package in R.RESULTS: Among the trauma patients with elevated amylase or lipase levels, three groups of patients were identified as having a high risk of pancreatic injury, using the DT model. These included (1) 69% of the patients with lipase level ?306 U/L; (2) 79% of the patients with lipase level between 154 U/L and 305 U/L and shock index (SI) ? 0.72; and (3) 80% of the patients with lipase level <154 U/L with abdomen injury, glucose level <158 mg/dL, amylase level <90 U/L, and neutrophil percentage ?76%; they had all sustained pancreatic injury. With all variables in the model, the DT achieved an accuracy of 97.9% (sensitivity of 91.4% and specificity of 98.3%) for the training set. In the test set, the DT achieved an accuracy of 93.3%, sensitivity of 72.7%, and specificity of 94.2%.CONCLUSIONS: We established a DT model using lipase, SI, and additional conditions (injury to the abdomen, glucose level <158 mg/dL, amylase level <90 U/L, and neutrophils ?76%) as important nodes to predict three groups of patients with a high risk of pancreatic injury. The proposed decision-making algorithm may help in identifying pancreatic injury among trauma patients with elevated serum amylase or lipase levels.

The ability to recognize faces accurately and rapidly is an evolutionarily adaptive process. Most studies examining the neural correlates of face perception in adult humans have focused on a distributed cortical network of face-selective regions. There is, however, robust evidence from phylogenetic and ontogenetic studies that implicates subcortical structures, and recently, some investigations in adult humans indicate subcortical correlates of face perception as well. The questions addressed here are whether low-level subcortical mechanisms for face perception (in the absence of changes in expression) are conserved in human adults, and if so, what is the nature of these subcortical representations. In a series of four experiments, we presented pairs of images to the same or different eyes. Participants' performance demonstrated that subcortical mechanisms, indexed by monocular portions of the visual system, play a functional role in face perception. These mechanisms are sensitive to face-like configurations and afford a coarse representation of a face, comprised of primarily low spatial frequency information, which suffices for matching faces but not for more complex aspects of face perception such as sex differentiation. Importantly, these subcortical mechanisms are not implicated in the perception of other visual stimuli, such as cars or letter strings. These findings suggest a conservation of phylogenetically and ontogenetically lower-order systems in adult human face perception. The involvement of subcortical structures in face recognition provokes a reconsideration of current theories of face perception, which are reliant on cortical level processing, inasmuch as it bolsters the cross-species continuity of the biological system for face recognition.

Objective. - Mice with targeted deletion of caspase-1 (interleukin-1beta (IL-1beta)-converting enzyme) lack the active forms of IL-1beta and IL-18, two cytokines implicated in maladaptive ventricular remodeling following cardiac injury. We, therefore, investigated the extent of ventricular dilation in caspase-1-knockout (KO) mice. Methods and results. - Transthoracic echocardiography was performed at days 1, 4, and 9 following left anterior descending artery ligation in caspase-1-KO and wild-type (WT) control animals, including M-mode and short-axis imaging at both mid-papillary and apical levels. Although initial post-operative mortality was lower in KO than in WT animals (21.4% WT, 12.0% KO, P < 0.001), there was no difference in mortality between 24 h and 9 d (P = n.s.). Caspase-1 KOs exhibited significantly less mid-papillary ventricular dilatation at days 4 and 9 compared to day 1 post-myocardial infarction (MI) (P < 0.05). Caspase-1 KOs also had a marked (50%) reduction in the level of matrix metalloproteinase 3 (MMP-3), although no significant changes occurred in other MMPs or in tissue inhibitors of metalloproteinase 1 levels by immunoblot analysis. Although IL-beta plasma levels were not detectable, both IL-18 levels and the rate of apoptosis in remodeling, non-infarcted muscle were significantly higher in WT compared to caspase-1-KO animals.Conclusion. - Mice lacking caspase-1 exhibited both improved peri-infarct survival and a decreased rate of ventricular dilatation, possibly due in part to a decrease in MMP-3 activity, IL-18 production, and a reduction in the rate of apoptosis after experimental MI.

The red nucleus (RN) has been widely used to study the formation and remodeling of synaptic connections during development and in post-lesion plasticity. Since glial cells are thought to contribute to synaptic plasticity, and information on functional properties of brain stem glia is missing, we analyzed voltage-gated ion channels as well as glutamate receptors expressed by glial cells of the RN. The patch-clamp technique was applied to identified cells in acute brain stem slices of 5- to 12-days-old rats. Based on their pattern of membrane currents, two types of glial cells could be distinguished. A first type was characterized by passive, symmetrical currents. The second population of cells, which was the focus of the present study, expressed a complex pattern of voltage-gated channels. These cells could be labeled with antibodies against glutamine synthetase and S100 beta, suggesting an astroglial origin. Depolarizing voltage steps activated transient and delayed rectifier K+ currents as well as Na+ currents. In addition, a subset of cells expressed Ba2+ sensitive inward rectifier K+ currents activated by hyperpolarization. All "complex" glial cells analyzed possessed ionotropic glutamate receptors of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype, while functional kainate and N-methyl-D-aspartate (NMDA) receptors could not be detected. Receptor activation blocked outward rectifying K+ currents, similar to previous observations in glial cells of the hippocampus and the corpus callosum.

Sequence-specific interference with the nuclear pre-mRNA splicing machinery has received increased attention as an analytical tool and for development of therapeutics. It requires sequence-specific and high affinity binding of RNaseH-incompetent DNA mimics to pre-mRNA. Peptide nucleic acids (PNA) or phosphoramidate morpholino oligonucleotides (PMO) are particularly suited as steric block oligonucleotides in this respect. However, splicing correction by PNA or PMO conjugated to cell penetrating peptides (CPP), such as Tat or Penetratin, has required high concentrations (5-10 microM) of such conjugates, unless an endosomolytic agent was added to increase escape from endocytic vesicles. We have focused on the modification of existing CPPs to search for peptides able to deliver more efficiently splice correcting PNA or PMO to the nucleus in the absence of endosomolytic agents. We describe here R6-Penetratin (in which arginine-residues were added to the N-terminus of Penetratin) as the most active of all CPPs tested so far in a splicing correction assay in which masking of a cryptic splice site allows expression of a luciferase reporter gene. Efficient and sequence-specific correction occurs at 1 muM concentration of the R6Pen-PNA705 conjugate as monitored by luciferase luminescence and by RT-PCR. Some aspects of the R6Pen-PNA705 structure-function relationship have also been evaluated.

We examined the effect of propofol and thiopental, intravenous anesthetics, on the hyperpolarization-activated inward current (I(H)), whose functional role on the neuronal activity has been evaluated. Whole-cell recordings of I(H) evoked by hyperpolarizing step pulses were taken from hippocampal CA1 neurons in rat brain slices. Propofol reduced I(H) current in a dose-dependent manner. However, thiopental had no significant effect on the activation of I(H). According to the functional role of I(H), the suppression of I(H) should result in a reduction of neuronal activity. We suggest that the effectiveness of propofol as an anticonvulsant or an antiemetic is associated with the blockade of the I(H) channel.

The chemical modifications induced by trifluoperazine (TFP) in erythrocyte ghosts have been investigated by fluorescence quenching. The apparent distance separating the membrane protein tryptophans and bound 1-aniline-8-naphthalene sulfonate (ANS) molecules decreased after treating erythrocyte membranes with TFP. This effect was accompanied by a significant decrease in the maximum efficiency of energy transfer. We conclude that TFP-induced alterations in the structure of membrane proteins lead to a rearrangement of the surrounding lipids, and consequently to local conformational changes in membrane organization.

CONTEXT: The Centers for Disease Control and Prevention (CDC) evaluated the economics of the National Program of Cancer Registries to provide the CDC, the registries, and policy makers with the economics evidence-base to make optimal decisions about resource allocation. Cancer registry budgets are under increasing threat, and, therefore, systematic assessment of the cost will identify approaches to improve the efficiencies of this vital data collection operation and also justify the funding required to sustain registry operations.OBJECTIVES: To estimate the cost of cancer registry operations and to assess the factors affecting the cost per case reported by National Program of Cancer Registries-funded central cancer registries.METHODS: We developed a Web-based cost assessment tool to collect 3 years of data (2009-2011) from each National Program of Cancer Registries-funded registry for all actual expenditures for registry activities (including those funded by other sources) and factors affecting registry operations. We used a random-effects regression model to estimate the impact of various factors on cost per cancer case reported.RESULTS: The cost of reporting a cancer case varied across the registries. Central cancer registries that receive high-quality data from reporting sources (as measured by the percentage of records passing automatic edits) and electronic data submissions, and those that collect and report on a large volume of cases had significantly lower cost per case. The volume of cases reported had a large effect, with low-volume registries experiencing much higher cost per case than medium- or high-volume registries.CONCLUSIONS: Our results suggest that registries operate with substantial fixed or semivariable costs. Therefore, sharing fixed costs among low-volume contiguous state registries, whenever possible, and centralization of certain processes can result in economies of scale. Approaches to improve quality of data submitted and increasing electronic reporting can also reduce cost.

The keratins, members of the intermediate filament family, are characteristically expressed in epithelial cells. In the various types of epithelia, the keratin expression pattern is characterized by cell-type specific combinations of the keratin isotypes with a plain pattern in monolayered (simple) epithelia and more complex patterns in stratified and pseudostratified epithelia. Here we demonstrate that the transitional epithelium of the human urinary tract holds an exceptional position between the pseudostratified and stratified epithelia. We show that the simple epithelia keratins 7, 8, 18 and 19 are expressed throughout the whole epithelium as known from pseudostratified epithelia. In addition, we demonstrate expression of keratins 5, 14 and 17, otherwise present in basal cells of multilayered epithelia, and keratins 4 and 13, present in suprabasal areas of non cornified multilayered epithelia. Moreover, we report differences in expression in the various morphological parts of the urinary tract which might be related to their specific functions. Keratin 20, a typical component of the simple epithelia of the digestive tract, is present in bladder and ureter but not in the renal pelvis. Keratin 6, typical for stratified epithelia, is found only in parts of the renal pelvis. We further show that changes in keratin pattern occur during the development from embryonic to adult bladder urothelium. In contrast to adult tissue, the simple type keratins 7, 8 and 18 are not synthesized in basal embryonic cells. Further, keratin 20, present in cells facing the bladder lumen in adult urothelium, is expressed in all but the basal cells in embryonic bladder.

A study of the metabolism of in vivo cocaine (COC) and the stability of in vitro COC suggests that the presence of benzoylecgonine (BE) in unpreserved blood arises from in vivo COC metabolism and that ecgonine methyl ester (EME) in unpreserved blood arises from in vitro COC hydrolysis. Postmortem cases positive for COC were studied to determine if molar concentrations of EME in unpreserved blood could be used to estimate the blood COC concentration at the time of death when added to the molar COC concentrations. COC was analyzed in 10 postmortem blood specimens between 1 and 8 days following death and again 10 to 70 days after further storage. The COC lost was accounted for by its hydrolysis to EME. Good correlation (r = 0.9677, p < 0.001) was observed when the blood COC concentrations in postmortem cases were compared to blood COC concentrations predicted by the addition of blood COC and EME concentrations; hence, analysis for EME and estimation of perimortem COC concentrations can assist in defining deaths associated with COC use.

BACKGROUND: Replacement of peanut extracts by recombinant peanut components is an important step in allergy serologic testing. Criteria are needed for the unbiased inclusion of patients into a study to validate such a replacement.METHODS: Plasma samples from 64 peanut-positive children (42 reactors, 22 nonreactors in a double-blind, placebo-controlled food challenge) were used to compare IgE reactivity to six recombinant peanut allergens with reactivity to natural peanut proteins extracted at neutral or low pH. We tested the hypothesis that poor extractability of Ara h 9 and other basic allergens at neutral pH leads to under-representation of patients with such sensitization.RESULTS: IgE reactivity to the components did not fully explain IgE reactivity to peanut extract in 5 of 32 reactors with IgE to peanut extract ?100 kUA /l. IgE reactivity to components was stronger than to the extract in 11 plasma samples, which was largely due to a low Ara h 8 reactivity of the extract. IgE reactivity to Ara h 9 was much lower than reactivity to other basic proteins, some of which bound IgE well in the RAST, but lost IgE reactivity upon immunoblotting.CONCLUSIONS: Conventional peanut extracts are deficient in significant IgE-binding components. The inclusion of patients for a validation study should be based on serology performed with improved peanut reagents to avoid a bias against these under-represented, potentially important allergens. To judge clinical relevance of an allergen, the reagent used for inclusion of patients needs to be efficient in detecting IgE to this component.

Dr J?rg Zimmermann is the inventor of the drug imatinib (Gleevec(®), Glivec(®)), which entered the market in 2001 and revolutionized the treatment of chronic myelogenous leukemia. He talks to Future Medicinal Chemistry about his career as a medicinal chemist, current issues in pharmaceutical R&D and his experiences of developing Gleevec, the first protein kinase to get onto market.

A new allele (he) of hooded white spotting is described. The typical homozygous phenotype is an almost or completely white rat. The almost white animals have variable coloured spots on the sides of the head, usually around or above the eyes or covering the ears. Superficially, the eyes are dark but careful examination shows that pupil glows a dull red in bright illumination in all or the majority of individuals.

This study demonstrates that the deltaproteobacterium Desulfurivibrio alkaliphilus can grow chemolithotrophically by coupling sulfide oxidation to the dissimilatory reduction of nitrate and nitrite to ammonium. Key genes of known sulfide oxidation pathways are absent from the genome of D. alkaliphilus Instead, the genome contains all of the genes necessary for sulfate reduction, including a gene for a reductive-type dissimilatory bisulfite reductase (DSR). Despite this, growth by sulfate reduction was not observed. Transcriptomic analysis revealed a very high expression level of sulfate-reduction genes during growth by sulfide oxidation, while inhibition experiments with molybdate pointed to elemental sulfur/polysulfides as intermediates. Consequently, we propose that D. alkaliphilus initially oxidizes sulfide to elemental sulfur, which is then either disproportionated, or oxidized by a reversal of the sulfate reduction pathway. This is the first study providing evidence that a reductive-type DSR is involved in a sulfide oxidation pathway. Transcriptome sequencing further suggests that nitrate reduction to ammonium is performed by a novel type of periplasmic nitrate reductase and an unusual membrane-anchored nitrite reductase.IMPORTANCE Sulfide oxidation and sulfate reduction, the two major branches of the sulfur cycle, are usually ascribed to distinct sets of microbes with distinct diagnostic genes. Here we show a more complex picture, as D. alkaliphilus, with the genomic setup of a sulfate reducer, grows by sulfide oxidation. The high expression of genes typically involved in the sulfate reduction pathway suggests that these genes, including the reductive-type dissimilatory bisulfite reductases, are also involved in as-yet-unresolved sulfide oxidation pathways. Finally, D. alkaliphilus is closely related to cable bacteria, which grow by electrogenic sulfide oxidation. Since there are no pure cultures of cable bacteria, D. alkaliphilus may represent an exciting model organism in which to study the physiology of this process.

Type VII collagen, the major component of anchoring fibrils, consists of a central collagenous triple-helical domain flanked by two noncollagenous domains, NC1 and NC2. The NC2 domain has been implicated in catalyzing the antiparallel dimer formation of type VII procollagen. In this study, we produced the entire 161 amino acids of the NC2 domain plus 186 amino acids of adjacent collagenous domain (NC2/COL) and purified large quantities of the recombinant NC2/COL protein. Recombinant NC2/COL readily formed disulfide-bonded hexamers, each representing one antiparallel dimer of collagen VII. Removal of the collagenous helical domain from NC2/COL by collagenase digestion abolished the antiparallel dimer formation. Using site-directed mutagenesis, we found that mutation of either cysteine 2802 or cysteine 2804 alone within the NC2 domain blocked antiparallel dimer formation. In contrast, a single cysteine mutation, 2634, within the collagenous helical domain had no effect. A generated methionine to lysine substitution, M2798K, that is associated with recessive dystrophic epidermolysis bullosa, was unable to form antiparallel dimers. Furthermore, autoantibodies from epidermolysis bullosa acquisita patients also reacted with NC2/COL. We conclude that NC2 and its adjacent collagenous segment mediate antiparallel dimer formation of collagen VII. Epidermolysis bullosa acquisita autoantibodies bound to this domain may destabilize anchoring fibrils by interfering with antiparallel dimer assembly leading to epidermal-dermal disadherence.

Background: Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis with nasal polyps in Japanese. ECRS highly associated with asthma is a refractory eosinophilic airway inflammation and requires comprehensive care as part of the united airway concept. We recently reported a series of ECRS patients with asthma treated with fine-particle inhaled corticosteroid (ICS) exhalation through the nose (ETN). Objective: To evaluate fine-particle ICS ETN treatment as a potential therapeutic option in ECRS with asthma. Methods: Twenty-three patients with severe ECRS under refractory to intranasal corticosteroid treatment were randomized in a double-blind fashion to receive either HFA-134a-beclomethasone dipropionate (HFA-BDP) metered-dose inhaler (MDI) ETN (n = 11) or placebo MDI ETN (n = 12) for 4 weeks. Changes in nasal polyp score, computed tomographic (CT) score, smell test, and quality of life (QOL) score from baseline were assessed. Fractionated exhaled nitric oxide (FENO) was measured as a marker of eosinophilic airway inflammation. Response to corticosteroids was evaluated before and after treatment. Additionally, deposition of fine-particles was visualized using a particle deposition model. To examine the role of eosinophils on airway inflammation, BEAS-2B human bronchial epithelial cells were co-incubated with purified eosinophils to determine corticosteroid sensitivity. Results: HFA-BDP MDI ETN treatment improved all assessed clinical endpoints and corticosteroid sensitivity without any deterioration in pulmonary function. FENO and blood eosinophil number were reduced by HFA-BDP MDI ETN treatment. The visualization study suggested that ETN at expiratory flow rates of 10-30 L/min led to fine particle deposition in the middle meatus, including the sinus ostia. Co-incubation of eosinophils with BEAS-2B cells induced corticosteroid resistance. Conclusions: Additional HFA-BDP MDI ETN treatment was beneficial in patients with ECRS and should be considered as a potential therapeutic option for eosinophilic airway inflammation such as ECRS with asthma. (UMIN-CTR: R000019325) (http://www.umin.ac.jp/ctr/index.htm).

A highly sensitive flow analysis manifold for rapid determination of dissolved reactive phosphate was developed which uses ethanol and UV light to reduce phosphomolybdic acid, instead of the reactive and short-lived chemical reductants typically employed in molybdenum blue chemistry. This reaction is impractical to perform reproducibly in batch mode, yet is very simple to handle in a flow analysis system and uses a single, very long-lived reagent solution. Interference from common inorganic anions and organic phosphorus species was minimal, and good spike recoveries for a range of sample matrices were obtained. The proposed flow analysis system is characterised by a limit of detection of 1.3 ìg L(-1) P, linear range of 5-1000 ìg L(-1) P, dynamic range of 5-5000 ìg L(-1) P, repeatability of 0.8% (1000 ìg L(-1) P, n=10) and 5.6% (10 ìg L(-1) P, n=10), and sample throughput of 57 h(-1). It is expected that this method will improve the feasibility of autonomous long-term environmental monitoring of dissolved reactive phosphate using inexpensive apparatus.

PURPOSE: Retraction pocket and extrusion of the ossicular prosthesis remain significant problems after tympanoplasty in cholesteatoma surgery. This study presents an alternative surgical technique with a total compact ossicular prosthesis including cartilage, wire, and temporalis fascia.MATERIALS AND METHODS: A total of 42 patients (27 adults, 15 children) underwent an ear operation for cholesteatoma requiring total ossicular chain replacement during a 10-year period. Surgery included canal wall down mastoidectomy and reconstruction of the middle ear in one stage. The total ossicular replacement prosthesis was made by a stainless steel wire passed and secured through a piece of conchal cartilage and temporalis fascia positioned on the free end of the wire. The analysis of our data included hearing results pre-surgery and post-surgery, complications recorded in the case notes, and postoperative otoscopic findings.RESULTS: The mean air-bone gap decreased from 39.2 to 22.4 dB in the early postoperative period (mean follow-up, 12.8 months). Eight patients with a long-term follow-up (mean, 7.1 years) presented a small deterioration of their postoperative hearing improvement. The bone conduction did not present significant changes. Three patients developed postoperative infection and treated successfully with medical therapy. No significant complications as displacement or extrusion of the prosthesis and retraction pocket were detected postoperatively.CONCLUSION: This is an alternative tympanoplasty technique with a stable cartilage-wire-fascia total ossicular prosthesis. This technique has a low complication rate; good hearing results and offers another surgical option to the surgeon especially for cases where the cost is a concern.

A one step electrophoretic procedure for the isolation of protein uH2A has been devised which may improve the overall yield. The improvement involves elimination of intermediate steps which might result in the decrease of the yield. The method may serve as an alternate to the conventional methods and can also be used successfully for the isolation of several different proteins.

Cacodylate buffer, frequently used in the assay of galactosyltransferase, causes inhibition of enzyme purified from human pleural effusion. The inhibition is reflected by an increase in the Km (UDP-galactose) and a decrease in Vmax and cannot be reversed by the addition of 2-mercaptoethanol. It is suggested that alternative buffers be used for the study of the enzyme.

The anatomy of the medial suprapatellar plica and medial synovial shelf was studied arthroscopically in 500 knees. The medical suprapatellar plica extended up to one third of the way across the suprapatellar pouch in 64.2% of knees, between one and two thirds in 4%, and two thirds or more in 31.6%. The medial synovial shelf was absent or vestigial in 36% of knees and broader than 1 cm in 13.2%. When both knees were examined arthroscopically, the similarity between the appearances of the plica and the shelf in the two knees was statistically significant. No relationship between age and the pattern of plica or shelf could be found. There was no association between large plicae and large shelves, but the shelf was absent significantly more often in knees with a narrow plica.

BACKGROUND: This study evaluated the effectiveness of elastosonography (ES) scoring and strain index (SI) in diagnosing patients with thyroid nodules composed primarily of Hurthle cells.METHODS: This study retrospectively analyzed 57 patients with thyroid nodules composed predominantly of Hurthle cells on fine needle aspiration cytology (FNAC). Patients were evaluated by thyroid ultrasonography (US), ES scoring, SI, US guided FNAC, and histopathology.RESULTS: Histopathologically, 12 (21.1%) nodules were malignant and 45 (78.9%) were benign. Mean age, sex distribution, thyroid function tests, and morphologic features on US were similar in the malignant and benign groups. Mean SI (40.98±31.28 vs 21.24±25.47, p=0.027) and thyroid peroxidase antibody (anti-TPOab) positivity (p=0.004) were significantly higher in malignant than in benign nodules. Receiver operating curve (ROC) analysis showed that an SI cutoff of 10.326 had a sensitivity of 91.7% and a specificity of 49%, and an SI cut-off of 64.807 had a specificity of 91.1% and a sensitivity of 25%. The optimal SI cut-off value, 17.877, had a sensitivity of 66.7%, a specificity of 66.7%, a positive predictive value (PPV) of 34.8%, a negative predictive value (NPV) of 88.2%, and an area under the ROC curve of 73.1±0.074% (95% CI: 58.7-87.6.5%). The sensitivity, specificity, PPV, NPV and diagnostic accuracy of ES scoring were 41.6%, 91.1%, 55.5%, 85.4% and 80.7%, respectively.CONCLUSIONS: This is the first study to investigate ES scoring and SI in nodules composed predominantly of Hurthle cells on FNAC. ES scoring and SI may add some contribution to ultrasonography in the characterization of thyroid nodules with Hurthle cells.

G-protein-coupled receptors (GPCRs) respond to external stimuli by activating heterotrimeric G proteins inside the cell. There is increasing evidence that many GPCRs exist as dimers or higher oligomers, but the biochemical nature of such dimers and what roles they have, if any, in signal transduction remains unclear. We conducted a comprehensive study of dimerization of the 5HT2c serotonin receptor using disulphide-trapping experiments. We found a dimer interface between transmembrane (TM) helices IV and V that is markedly sensitive to the state of receptor activation. This dimer seems to be quasisymmetrical in interfacial geometry and asymmetrical in its association with its cognate G alpha protein. We also found a second interface at TM I helices, which is insensitive to the state of activation.

Insulin is a major therapy for diabetes, and therefore, its role and mechanisms in the regulation of drug-metabolizing enzymes (DMEs), is of clinical importance to facilitate the rational drug use. Carboxylesterases are regarded as one of the major determinants of the metabolism and disposition of various substrates through their actions in the liver and intestine, alterations in the activity of CESs enzymes are often important causes of drug interactions. Therefore, investigation on the mechanism of CESs regulation is significantly important. In this study, we demonstrated that insulin markedly down-regulated CESs expression and suppressed the hydrolytic activity of CESs in an Akt-dependent manner. Moreover, overexpression of PXR abrogated the decrease of CES1 and CES2 expression induced by insulin in HepG2 cells, suggesting PXR was involved in insulin-induced reduction of CESs. Mechanistically, luciferase reporter assay showed that PXR increased the transcriptional activity of CES1 and CES2 gene promoter, and chromatin immunoprecipitation assay verified that PXR bound to the site (-244 to -234) in CES1 gene promoter region and bound to the site (-814 to -804 and -794 to -784) in CES2 gene promoter region for the first time. In summary, our data indicate that down-regulation of PXR mediates insulin-induced suppression of CESs. Accordingly, insulin may impact the therapeutic effects of carboxylesterases substrate drugs and also inhibit expression of other genes targeted by PXR, thus inducing a wide range of potential drug-drug interactions (DDIs) during the treatment of diabetes.

Quinocetone (QCT, 3-methyl-2-quinoxalin benzenevinylketo-1, 4-dioxide) is widely used as a veterinary drug and animal feed additive in China. Although it promotes growth and improves feed efficiency, QCT's in vitro and in vivo toxicities remain uncertain. This study was conducted to explore the mechanism of QCT-induced autophagy in HepG2 cells. By the results obtained from monodansylcadaverine (MDC) staining, ultrastructural observation by transmission electron microscopy (TEM), as well as Western blotting analysis for LC3, p62, and Beclin-1, it was demonstrated that QCT induced autophagy in HepG2 cells. Furthermore, PI3K/AKT inhibitor significantly enhanced QCT-induced autophagy, while TSC2 knockdown attenuated this process. In addition, inhibition of autophagy by pharmacological approach remarkably increased the viability of QCT-treated cells detected by MTT assay, suggesting that QCT-triggered autophagy may play as a promotion mechanism for cell death. Meanwhile, apoptosis was markedly downregulated after autophagy blockage, and evaluated by flow cytometry and Western blotting analysis for caspase-3 cleavage. Consequently, these results suggested that QCT-induced autophagy was mediated by AKT/TSC2/p70S6K signaling pathway, and inhibition of autophagy promoted QCT-treated cell survival by attenuating apoptosis.

OBJECTIVE: Cardiac electrophysiology (EP) procedures can be performed under moderate sedation without the direct involvement of an anaesthetist. However, concerns have been raised over the safety of this approach. This study examines the use of a standardised nurse-led physician-directed sedation protocol for EP procedures to determine the safety of moderate sedation administered by non-anaesthesia personnel who have been trained in sedation techniques.METHODS AND RESULTS: Consecutive EP procedures done under moderate sedation over 12 years at our institution were evaluated. Serious adverse events were defined as (i) procedural death related to sedation; (ii) intubation and ventilation; and (iii) hypotension requiring inotropic support. Reversal of sedation constituted a minor adverse event. Up to 7117 procedures were included. These comprised ablations (55%), devices (43%) and other procedures (2%). A majority of patients were men with a mean age of 61±10 years. 99.98% of procedures were completed successfully without sedation-related serious adverse events. Two patients (0.02%) required anaesthetic support for intubation. Sedation was reversed in 1.2% of procedures with less than 1% requiring reversal because of persistent drop in oxygen saturation, hypoventilation or markedly reduced level of consciousness. There was no significant difference in the patient characteristics, mean doses of sedative agents and procedure types in the group requiring reversal of sedation when compared with the whole cohort.CONCLUSIONS: Our study demonstrates that nurse-led, physician-directed moderate sedation is safe. Anaesthesia services are not required routinely for invasive cardiac EP procedures and should be available on a need basis.

BACKGROUND: The present study reports the antibacterial capacity of alkaloid compounds in combination with Methicillin and Ampicillin-resistants bacteria isolated from clinical samples. The resistance of different bacteria strains to the current antibacterial agents, their toxicity and the cost of the treatment have led to the development of natural products against the bacteria resistant infections when applied in combination with conventional antimicrobial drugs.METHOD: The antibacterial assays in this study were performed by using inhibition zone diameters, MIC, MBC methods, the time-kill assay and the Fractional Inhibitory Concentration Index (FICI) determination. On the whole, fifteen Gram-positive bacterial strains (MRSA/ARSA) were used. Negative control was prepared using discs impregnated with 10 % DMSO in water and commercially available Methicillin and Ampicillin from Alkom Laboratories LTD were used as positive reference standards for all bacterial strains.RESULTS: We noticed that the highest activities were founded with the combination of alkaloid compounds and conventional antibiotics against all bacteria strains. Then, results showed that after 7 h exposition there was no viable microorganism in the initial inoculums.CONCLUSION: The results of this study showed that alkaloid compounds in combination with conventional antibiotics (Methicillin, Ampicillin) exhibited antimicrobial effects against microorganisms tested. These results validate the ethno-botanical use of Cienfuegosia digitata Cav. (Malvaceae) in Burkina Faso. Moreover, this study demonstrates the potential of this herbaceous as a source of antibacterial agent that could be effectively used for future health care purposes.

The Coxian phase-type distribution is a special type of Markov model which can be utilised both to uncover underlying stages of a survival process and to make inferences regarding the rates of flow of individuals through these latent stages before an event of interest occurs. Such models can be utilised, for example, to identify individuals who are likely to deteriorate faster through a series of disease states and thus require more aggressive medical intervention. Within this paper, a two-stage approach to the analysis of longitudinal and survival data is presented. In Stage 1, a linear mixed effects model is first used to represent how some longitudinal response of interest changes through time. Within this linear mixed effects model, the individuals' random effects can be considered as a proxy measure for the effect of the individuals' genetic profiles on the response of interest. In Stage 2, the Coxian phase-type distribution is employed to represent the survival process. The individuals' random effects, estimated in Stage 1, are incorporated as covariates within the Coxian phase-type distribution so as to evaluate their effect on the individuals' rates of flow through the system represented by the Coxian. The approach is illustrated using data collected on individuals suffering from chronic kidney disease, where focus is given to an emerging longitudinal biomarker of interest - an individual's haemoglobin level.

The effects of ruminal concentrations of CO2 and oxygen on the end products of endogenous metabolism and fermentation of D-glucose by the ruminal entodiniomorphid ciliate Polyplastron multivesiculatum were investigated. The principal metabolic products were butyric, acetic, and lactic acids, H2, and CO2. 13C nuclear magnetic resonance spectroscopy identified glycerol as a previously unknown major product of D-[1-13C]glucose fermentation by this protozoan. Metabolite formation rates were clearly influenced by the headspace gas composition. In the presence of 1 to 3 microM O2, acetate, H2, and CO2 formation was partially depressed. A gas headspace with a high CO2 content (66 kPa) was found to suppress hydrogenosomal pathways and to favor butyrate accumulation. Cytochromes were not detected (less than 2 pmol/mg of protein) in P. multivesiculatum; protozoal suspensions, however, consumed O2 for up to 3 h at 1 kPa of O2. Under gas phases of greater than 2.6 kPa of O2, the organisms rapidly became vacuolate and the cilia became inactive. The results suggest that fermentative pathways in P. multivesiculatum are influenced by the O2 and CO2 concentrations that prevail in situ in the rumen.

We present two cases of subclavian steal syndrome from the ipsilateral vertebral artery (VA) to the subclavian artery (SCA), one with the left VA originating from the aortic arch and the other with the left VA originating very close to the origin of the SCA, proximal to the occluded segment. In both cases, angiographic demonstration of these anatomic variations and successful endovascular treatment are presented.

This study measured the differences in motor output between groups of 8- and 10-yr.-old learning disabled and normal boys. Variability of motor output was investigated by having children learn an alternating tapping task to a criterion of a specified number of taps per minute and then having them transfer to more difficult tapping tasks with the same rhythmic beat but requiring more distance to move or more accuracy. Results suggest variability of motor output distinguishes normal and learning disabled boys.

The formation of urinary stones is presumed to be associated with polymorphism of the osteocalcin gene. The most frequently seen polymorphism is the Hind III type located at the promoter region. This polymorphism has been used as a genetic marker in the search for a correlation between urolithiasis and normal subjects. In our study, a normal control group of 105 healthy people and 102 patients with calcium oxalate stones were examined. The polymorphism was seen following polymerase chain reaction-based restriction analysis. The results revealed no significant differences between normal individuals and stone patients (P = 0.978), and distribution of the TT homozygote in the control group (42.9%) was similar to that in the patient group (42.2%). Further categorization of the stone patients into normocalciuric and hypercalciuric groups also revealed no statistical differences from controls. We conclude that Hind III polymorphism of the osteocalcin gene is not a suitable genetic marker of urinary stone disease. Further searches for other polymorphisms on this gene correlated with stone disease are suggested.

Significant upper gastrointestinal bleeding following operation was noted in 14 of 218 patients undergoing external biliary drainage. None of these patients sustained hepatic injury or needed hepatic resection. Three patients died from causes related to the upper gastrointestinal hemorrhage, and in 12 of the 14 patients the episode of hemorrhage occurred within three days of the biliary tract operation. The majority of the patients were febrile or septic at the time of the biliary operation. Biliary tract infection, when combined with external biliary drainage, may predipose to major upper gastrointestinal hemorrhage.

The results presented in this paper refer to a host survey, lasting approximately three and a half years (February 2003-July 2006), undertaken in the Vale do Rio Doce Natural Reserve, a remnant area of the highly endangered Atlantic Rain Forest located in Linhares County, State of Esp?rito Santo, Brazil. A total of 330 fruit samples were collected from native plants, representing 248 species and 51 plant families. Myrtaceae was the most diverse family with 54 sampled species. Twenty-eight plant species, from ten families, are hosts of ten Anastrepha species and of Ceratitis capitata (Wiedemann). Among 33 associations between host plants and fruit flies, 20 constitute new records, including the records of host plants for A. fumipennis Lima and A. nascimentoi Zucchi. The findings were discussed in the light of their implications for rain forest conservation efforts and the study of evolutionary relationships between fruit flies and their hosts.

A global conformational space of 6253 dinucleoside monophosphate (DMP) units consisting of RNA and DNA (free and protein/drug-bound) was 'mapped' using high resolution crystal structures cataloged in the Nucleic Acid Database (NDB). The torsion angles of each DMP were clustered in a reduced three-dimensional space using a classical multi-dimensional scaling method. The mapping of the conformational space reveals nine primary clusters which distinguish among the common A-, B- and Z-forms and their various substates, plus five secondary clusters for kinked or bent structures. Conformational relationships and possible transitional pathways among the substates are also examined using the conformational states of DNA and RNA bound with proteins or drugs as potential pathway intermediates.

Cell surface hydrophobicity of group A, B, C, D and G streptococcal strains has been studied and compared in a new test based on the fact that the degree of bacterial aggregation in ammonium sulphate depends on amphiphilic surface antigens. M-positive group A strains showing good growth in normal human blood aggregated in the standard salt aggregation test at very low concentrations of ammonium sulphate, while M-negative strains, which were killed in normal human blood, usually aggregated at high salt concentrations. Agents such as 2 M-KSCN, 2 M-guanidine. HC1 or 2 M-urea decreased the aggregation of the M-positive strains in the salt aggregation test while non ionic detergents such as Tween 20 (1%, w/v) and ethylene glycol (2 M) did not affect cell aggregation. Binding of fibrinogen and albumin resulted in a decrease of surface hydrophobicity of the group A M-positive strains. Group B strains possess a hydrophilic surface character and did not aggregate, while group C and G strains behaved in the salt aggregation test like M-negative strains of group A streptococci. Group D strains did not aggregate even at high ammonium salt concentrations. The results are discussed in relation to the influence of lipoteichoic acid and other surface antigens on strains of the various groups, and it is suggested that M protein and possibly also other surface proteins contribute to the high surface hydrophobicity of group A strains.