[Comparative analysis of Light's criteria and other biochemical parameters to distinguish exudates from transudates].
Light's criteria have classically been used to differentiate exudates from transudates. Nevertheless, a number of studies have attempted to identify more efficient parameters. The objective of our study was to determine the usefulness of biochemical parameters to differentiate transudates from exudates, and to compare them with the so far best studied criteria: the Light's criteria. We prospectively analysed 850 non selected cases of pleural effusion, with closed final diagnosis after its confirmation, therapeutic response and follow-up, collected consecutively at the Pleura Unit of our hospital. The parameters evaluated as potentially discriminatory between transudates and exudates included: glucose, proteins, albumin, lactate-dehydrogenase (LDH), cholesterol, triglycerides, bilirubin, alkaline phosphatase and adenosin-deaminase (ADA), both separately and in combination to obtain the highest yield. The highest diagnostic yield was observed with the combination of pleural cholesterol, pleural LDH, and the pleural fluid/serum protein ratio, but without significant differences between combinations of pleural cholesterol and LDH, pleaural LDH and pleural proteins, Light's criteria or modified Light's criteria. We recommend the use of pleural cholesterol higher than 47 mg/dl and pleural LDH higher than 222 IU/l to offer the same yield as the combination of three parameters, due to its lower cost and because the necessity of serum determinations is avoided.


Chloroplast DNA variation in the Quercus affinis-Q. laurina complex in Mexico: geographical structure and associations with nuclear and morphological variation.
The geographical distribution of chloroplast DNA (cpDNA) variation in 39 populations of two hybridizing Mexican red oaks, Quercus affinis and Q. laurina, was investigated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Six haplotypes were identified. Of these, two (H1 and H4), separated by four mutations, had high frequencies (58 and 23% of the individuals, respectively) and were present across the whole geographical range of both species, often co occurring in the same populations. The other four haplotypes were rare, geographically restricted, and are probably derived from the two frequent haplotypes. Latitudinal or other clinal patterns in diversity levels or haplotype composition of populations were not apparent. The pattern of haplotype distribution was characterized by some mosaicism, with contrasting populations often situated in proximity. Average within-population diversity (hS=0.299) and population differentiation (GST=0.499) were, respectively, higher and lower than values reported in previous studies of oak species. There was evidence for phylogeographical structure, as indicated by NST (0.566) being significantly higher than GST. Haplotypic variation was largely species-independent, although some very weak associations were detected between haplotypes H1 and H4 and morphological and nuclear molecular variation correspondingly characterizing Q. affinis and Q. laurina. These oaks probably did not experience a marked restriction to one or a few particular subregions of their present range during the last glacial cycle. It is more likely that substantial populations persisted throughout several episodes of climatic change, but experienced recurrent latitudinal and altitudinal migrations which may have caused the widespread distribution of haplotypes H1 and H4 and frequent intermixing of populations.


A deep learning approach for automation in neurite tracing and cell size estimation from differential contrast images under healthy and hypoxic condition.
Chronic hypoxia is known to be a major cause of neurite length retraction followed be degeneration. Specifically, laser scanning confocal microscopy (LSCM) based-contrast imaging is used for monitoring neuronal morphology under hypoxic condition. Although imaging of neurons using LSCM via differential contrast imaging (DIC) is a powerful tool to identify the neuronal states under degenerative condition, fully automated quantification of neurite length and cell shape remains challenging. In this context, we propose an integrated framework that combines panorama imaging of neuronal morphology using LSCM, and deep learning model that allows automated tracing of neurites and cell shape. First, we establish an in vitro hypoxic model using cobalt chloride treatment of N2A cells and perform the large-scale imaging using DIC optics. Next, we tested the performance of U-Net, U-Net++ and FCN architecture using DIC images, where U-Net and U-Net++ demonstrates robustness and accuracy in tracing neurite length and segmentation of cell shape. The result shows that the U-Net++ is able to depict the difference in cell size and neurite length for control and chronic hypoxic condition. The proposed method was also validated and compared with other CNN models including FCN and U-Net. Moreover, the analysis indicates a significant alteration of cell shape and neurite length under hypoxic condition via deep-learning based automated cell segmentation.Clinical Relevance-The proposed framework assumes importance where quantification of neurite length and cell shape from a large dataset remains challenging due to time-consuming manual segmentation by experts. Specially, the framework based on labeling of a small dataset (15-20 images) can be used to identify the neuronal state under neurodegeneration and image-based assessment of neuroprotective drugs.


Trajectories of fathers' childcare involvement and child behavioral outcomes.
Father's closeness and playful behavior influence a child's emotional and cognitive development. In this study, we aimed to assess the long-term association of paternal involvement in childcare at 1-3 years of life on subsequent behavioral outcomes at 8 years of age. Data were obtained from the 2010 cohort of the Longitudinal Survey of Newborns in the 21st century in Japan. We used group-based trajectory modeling to predict the trajectory of total childcare scores in surveys 1, 2 and 3 to determine the overall involvement of fathers in childcare during early childhood. The level of fathers' involvement in childcare was categorized as "low", "medium" and "high". Responses from the eighth survey were used to assess child behavioral outcomes using five indicators when the child was 8 years old. Crude and adjusted logistic regression analysis was conducted to estimate the odds ratio (OR) separately for each of the behavioral outcomes of the child. Among the 17,027 father-child dyads included in this study, two-thirds of the fathers were of the age group 30-39 years. Compared to low involvement, children of fathers with high involvement in childcare during the early childhood years were less likely to not want to go to school even after adjusting for covariates (adjusted OR, 0.46; 95% CI: 0.32-0.66). Children benefit from their fathers' involvement in early childcare activities. To improve a child's well-being, fathers should be encouraged by providing them with a suitable working environment with flexible arrangements and the opportunity to involve in childcare.


Point absorbers in Advanced LIGO.
Small, highly absorbing points are randomly present on the surfaces of the main interferometer optics in Advanced LIGO. The resulting nanometer scale thermo-elastic deformations and substrate lenses from these micron-scale absorbers significantly reduce the sensitivity of the interferometer directly though a reduction in the power-recycling gain and indirect interactions with the feedback control system. We review the expected surface deformation from point absorbers and provide a pedagogical description of the impact on power buildup in second generation gravitational wave detectors (dual-recycled Fabry-Perot Michelson interferometers). This analysis predicts that the power-dependent reduction in interferometer performance will significantly degrade maximum stored power by up to 50% and, hence, limit GW sensitivity, but it suggests system wide corrections that can be implemented in current and future GW detectors. This is particularly pressing given that future GW detectors call for an order of magnitude more stored power than currently used in Advanced LIGO in Observing Run 3. We briefly review strategies to mitigate the effects of point absorbers in current and future GW wave detectors to maximize the success of these enterprises.


Alexis St. Martin Gastropexy: A Novel Technique for Gastropexy During Percutaneous Endoscopic Gastrostomy Tube Placement.
Percutaneous endoscopic gastrostomy (PEG) is a preferred method of long-term enteral nutritional support. Despite its ease of placement, it has a 4% major complication rate, requiring surgical intervention or hospitalization. Early PEG tube dislodgment can cause peritonitis, requiring emergent laparotomy at significant morbidity and cost. T-fasteners have been used as an adjunct gastropexy, but nearly one third migrate into the abdominal wall within the first 2 weeks. We describe a low-cost, minimally invasive technique using widely available surgical instruments to appose the gastric and abdominal walls. All PEG procedures were performed in our 60-bed surgical intensive care unit. Institutional IRB approval was obtained along with procedure specific consent for all patients. The adjunctive gastropexy procedure was performed on four patients at high risk for early PEG tube dislodgment. Following routine PEG tube placement, both ends of four 2-0 polyglactin ties were brought through the gastric and abdominal walls through separate stab incisions adjacent to the PEG tube exit site in the 3, 6, 9, and 12 o'clock positions. These were tied in the subcutaneous tissue, securing the gastric wall to the abdominal wall. No PEG tube complications occurred. All patients were discharged to long-term care facilities with PEG tubes intact or electively removed. We describe the results of a pilot study for a cost-effective, easily implementable, adjunct technique, named after the namesake of our institution, to decrease the incidence and severity of complications associated with PEG tube dislodgment. It was used in 4 patients at high risk for PEG tube dislodgment with satisfactory early results in all 4. Further recruitment of larger numbers of patients using this technique is ongoing to determine if this technique is truly effective at reducing PEG tube complications.


Obesity and effects of dapagliflozin on cardiovascular and renal outcomes in patients with type 2 diabetes mellitus in the DECLARE-TIMI 58 trial.
We investigated the associations between obesity, cardiorenal events, and benefits of dapagliflozin in patients with type 2 diabetes mellitus (T2DM). DECLARE-TIMI 58 randomized patients with T2DM and either atherosclerotic cardiovascular (CV) disease or multiple risk factors to dapagliflozin vs. placebo. Patients were stratified by body mass index (BMI, kg/m2): normal (18.5 to <25), overweight (25 to <30), moderately obese (30 to <35), severely obese (35 to <40), and very-severely obese (≥40). Outcomes analysed were CV death, hospitalization for heart failure (HHF), renal-specific composite outcome, and atrial fibrillation or flutter (AF/AFL). Of 17 134 patients, 9.0% had a normal BMI, 31.5% were overweight, 32.4% were moderately, 17.2% severely, and 9.8% were very-severely obese. Higher BMI was associated with a higher adjusted risk of HHF and AF/AFL (hazard ratio 1.30 and 1.28, respectively, per 5 kg/m2; P < 0.001 for all). Dapagliflozin reduced body weight by similar relative amounts consistently across BMI categories (percent difference: -1.9 to -2.4%). Although relative risk reductions in CV and renal-specific composite outcomes with dapagliflozin did not significantly differ across the range of BMI (P for interaction ≥0.20 for all outcomes), obese patients (BMI ≥ 30 kg/m2) tended to derive greater absolute risk reduction in HHF and AF/AFL (P for interaction 0.02 and 0.09, respectively) than non-obese patients. In DECLARE-TIMI 58, patients with T2DM and higher BMI were more likely to have HHF and AF/AFL. Whereas relative risk reductions in CV and renal outcomes with dapagliflozin were generally consistent across the range of BMI, absolute risk reduction in obesity-related outcomes including HHF and AF/AFL tended to be larger in obese patients with T2DM. URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01730534.


Oxytocin Attenuates the Stress-Induced Reinstatement of Alcohol-Seeking in Male Rats: Role of the Central Amygdala.
Factors such as stress and anxiety often contribute to alcohol-dependent behavior and can trigger a relapse of alcohol addiction and use. Therefore, it is important to investigate potential pharmacological interventions that may alleviate the influence of stress on addiction-related behaviors. Previous studies have demonstrated that the neuropeptide oxytocin has promising anxiolytic potential in mammals and may offer a pharmacological target to diminish the emotional impact on reinstatement of alcohol-seeking. The purpose of the present study was to investigate the effect of oxytocin on stress-induced alcohol relapse and identify a neural structure mediating this effect through the use of an ethanol self-administration and yohimbine-induced reinstatement paradigm. While yohimbine administration resulted in the reinstatement of ethanol-seeking behavior, the concurrent administration of yohimbine and oxytocin attenuated this effect, suggesting that oxytocin may disrupt stress-induced ethanol-seeking behavior. The central amygdala (CeA) is a structure that drives emotional responses and robustly expresses oxytocin receptors. Intra-CeA oxytocin similarly attenuated the yohimbine-induced reinstatement of ethanol-seeking behavior. These results demonstrate that oxytocin has the potential to attenuate stress-induced relapse into ethanol-seeking behavior, and that this mechanism occurs specifically within the central amygdala.


The prevalence of tuberculosis infection among foreign-born Canadians: a modelling study.
The prevalence of tuberculosis infection is critical to the design of tuberculosis prevention strategies, yet is unknown in Canada. We estimated the prevalence of tuberculosis infection among Canadian residents born abroad. We estimated the prevalence of tuberculosis infection by age and year of migration to Canada for people from each of 168 countries by constructing country-specific and calendar year-specific trends for annual risk of infection using a previously developed model. We combined country-specific prevalence estimates with Canadian Census data from 2001, 2006, 2011, 2016 and 2021 to estimate the overall prevalence of tuberculosis infection among foreign-born Canadian residents. The estimated overall prevalence of tuberculosis infection among foreign-born people in Canada was 25% (95% uncertainty interval [UI] 20%-35%) for census year 2001, 24% (95% UI 20%-33%) for 2006, 23% (95% UI 19%-30%) for 2011, 22% (95% UI 19%-28%) for 2016 and 22% (95% UI 19%-27%) for 2021. The prevalence increased with age at migration and incidence of tuberculosis in the country of origin. In 2021, the estimated prevalence of infection among foreign-born residents was lowest in Quebec (19%, 95% UI 16%-24%) and highest in Alberta (24%, 95% UI 21%-28%) and British Columbia (24%, 95% UI 20%-30%). Among all foreign-born Canadian residents with tuberculosis infection in 2021, we estimated that only 1 in 488 (95% UI 185-1039) had become infected within the 2 preceding years. About 1 in 4 foreign-born Canadian residents has tuberculosis infection, but very few were infected within the 2 preceding years (the highest risk period for progression to tuberculosis disease). These data may inform future tuberculosis infection screening policies.


Validity of a physical activity questionnaire among African-American Seventh-day Adventists.
Physical activity has been identified as an important predictor of chronic disease risk in numerous studies in which activity levels were measured by questionnaire. Although the validity of physical activity questionnaires has been documented in a number of studies of U.S. adults, few have included a validation analysis among blacks. We have examined the validity and reliability of a physical activity questionnaire that was administered to 165 black Seventh-day Adventists from Southern California. Subjects completed a self-administered physical activity questionnaire and then "reference" measures of activity (7-d activity recalls, pedometer readings) and fitness (treadmill test) were completed in subsets of this population. The authors found that 7-d recall activity levels correlated well with the corresponding questionnaire indices among women (total activity, r = 0.65; vigorous, r = 0.85; moderate, r = 0.44; inactivity, r = 0.59; sleep duration, r = 0.52) and men (total activity, r = 0.51; vigorous, r = 0.65; moderate, r = 0.53; inactivity, r = 0.69; sleep duration, r = 0.39). Vigorous activity from 7-d recalls was best measured by gender-specific indices that included only recreational activities among men and emphasized nonrecreational activities among women. Correlations between questionnaire data and the other "reference" measures were lower. Test-retest correlations of questionnaire items over a 6-wk interval were high (r = 0.4-0.9). Simple questions can measure activities of different intensity with good validity and reliability among black Adventist men and women.


A monoclonal antibody (TA-1) reactive with human T lymphocytes and monocytes.
Several monoclonal antibodies were produced against the human T lymphocyte leukemia cell line HSB-2 by fusing spleen cells from hyperimmune mice with NS-1 myeloma cells. One clone, designated TA-1, was initially characterized for reactivity with normal and leukemic human hematopoietic cells. Using indirect immunofluorescence, TA-1 was shown to bind to approximately 75% of peripheral blood lymphocytes. Enrichment for T and B lymphocytes followed by double fluorochrome labeling studies revealed that most if not all E+ T lymphocytes and approximately 10% of B lymphocytes were TA-1+. TA-1 also reacted with approximately 67% of thymocytes, mixed lymphocyte culture-activated T lymphocytes, the entire peripheral blood monocyte population, and approximately 13% of nucleated bone marrow cells. TA-1+ cells in bone marrow included both phagocytic and nonphagocytic cells. TA-1 did not bind to peripheral blood granulocytes, red blood cells, or platelets. Studies of acute lymphoblastic leukemia (ALL) revealed that 6 of 11 T-ALL and 1 of 21 E-, SIg--ALL were TA-1+, whereas cells from 10 patients with chronic lymphocytic leukemia were TA-1-. Interestingly, TA-1 was able to distinguish acute myelomonocytic leukemic cells (TA-1+) from acute myelocytic leukemic cells (TA-1-). In summary, these studies demonstrate the existence of determinant recognized by TA-1 that is primarily expressed on cells of T lymphocyte and monocyte/macrophage lineage.


Fatigue, symptom burden, and health-related quality of life in patients with myelodysplastic syndrome, aplastic anemia, and paroxysmal nocturnal hemoglobinuria.
Fatigue is distressing and affects quality of life (QoL) among patients with myelodysplastic syndrome (MDS), aplastic anemia (AA), and paroxysmal nocturnal hemoglobinuria (PNH). Limited data exist on the impact of fatigue, QoL, and related symptoms in these patients. Prospectively assess fatigue (functional assessment of cancer therapy-anemia [FACT-An]); QoL (FACT-An subscales); pain (brief pain inventory); and depression, anxiety, and stress (depression anxiety stress scale-21) and strategies used to manage these symptoms in patients with MDS, AA, and PNH. Surveys were administered via the AA and MDS International Foundation website and database from October 2014 through April 2015 in a cross-sectional study. Results were summarized using descriptive statistics. Of 303 patients, 145 (48%) had MDS, 84 (28%) had AA, and 74 (24%) had PNH; 31 (10%) had >1 diagnosis. The mean age was 57 years, 200 (66%) were female, and 195 (92%) were white. The mean fatigue scores were 25 (range 1-52) for the whole cohort, 28 for AA, 25 for MDS, and 24 for PNH (P = 0.117); these are all considered severe level. The mean QoL score was 68 (range 10-104) for the whole cohort, 67 for AA, 69 for MDS, and 67 for PNH (P = 0.821). The ranges for stress were normal; pain and depression, mild; and anxiety, moderate. The most common management strategies perceived as helpful for fatigue in the past month were preserving energy, physical activity, and naps. Many patients with MDS, AA, and PNH report severe fatigue. The helpfulness of fatigue management strategies may impact patients' continued use; whether these strategies are beneficial and decrease fatigue levels needs more study.


[The comparision of clinical effects between Dyract complex and glass ionomer cement(GIC) treatment of wedge-shaped defect]
OBJECTIVE:To evaluate the curative effects of Dyract and Glass ionomer cement treating wedge-shaped defects.METHODS:92 patients with 312 teeth wedge shaped defects were filled with Dyract and 145 patients with 346 teeth were filled with glass ionomer cement(GIC).The curative effect as to the shape,adaptation,edge coloring,tint,secondary caries,pulp electrical test and gingivitis were observed regularly for 2 years. RESULTS:There was no difference between two groups in half a year (P>0.05),but it showed significant difference after one year (P<0.05)and highly dramatic difference after two years ( P<0.005). The curative effect of Dyract was obviously better than that of GIC in shape,tint,adaptation,secondary caries and gingivitis.CONCLUSION:The long-term curative effect of Dyract was better than that of GIC.


Selective interaction of peripheral and central nervous system cells with two distinct cell-binding domains of fibronectin.
Mechanisms of cell interaction with fibronectin have been studied with proteolytic fibronectin fragments that have well-defined ligand binding properties. Results of a previous study (Rogers, S. L., J. B. McCarthy, S. L. Palm, L. T. Furcht, and P. C. Letourneau, 1985, J. Neurosci., 5:369-378) demonstrated that (a) central (CNS) and peripheral (PNS) nervous system neurons adhere to, and extend neurites on a 33-kD carboxyl terminal fibronectin fragment that also binds heparin, and (b) neurons from the PNS, but not the CNS, have stable interactions with a 75-kD cell-binding fragment and with intact fibronectin. In the present study domain-specific reagents were used in inhibition assays to further differentiate cell surface interactions with the two fibronectin domains, and to define the significance of these domains to cell interactions with the intact fibronectin molecule. These reagents are (a) a soluble synthetic tetrapeptide Arg-Gly-Asp-Ser (RGDS; Pierschbacher, M. D., and E. Ruoslahti, 1984, Nature (Lond.), 309:30-33) representing a cell-binding determinant in the 75-kD fragment, and (b) an antibody raised against the 33-kD fragment that binds specifically to that fragment. Initial cell attachment to, and neurite extension upon, fibronectin and the two different fragments was evaluated in the presence and absence of the two reagents. Attachment of both PNS and CNS cells to intact fibronectin was reduced in the presence of RGDS, the former more so than the latter. In contrast, the antibody to the 33-kD fragment did not affect attachment of PNS cells to fibronectin, but significantly decreased attachment of CNS cells to the molecule. RGDS inhibited attachment of CNS cells to the molecule. RGDS inhibited attachment of both cell types to the 75-kD fragment to a greater degree than it did attachment to the intact molecule. Cell interaction with the 33-kD fragment was not affected by RGDS. Reduction of neurite lengths (determined after 24 h of culture) by the domain-specific reagents paralleled the reduction in initial adhesion to each substratum. Therefore, it appears that (a) both PNS and CNS cells have receptors for each cell-binding domain of fibronectin, (b) the receptor(s) for the two domains are distinct, with attachment to the 33-kD fragment being independent of RGDS, and (c) the relative importance of each domain to cell interaction with intact fibronectin is different for CNS and PNS cells.


Neighborhood poverty during childhood prospectively predicts adolescent functional brain network architecture.
Family poverty has been associated with altered brain structure, function, and connectivity in youth. However, few studies have examined how disadvantage within the broader neighborhood may influence functional brain network organization. The present study leveraged a longitudinal community sample of 538 twins living in low-income neighborhoods to evaluate the prospective association between exposure to neighborhood poverty during childhood (6-10 y) with functional network architecture during adolescence (8-19 y). Using resting-state and task-based fMRI, we generated two latent measures that captured intrinsic brain organization across the whole-brain and network levels - network segregation and network segregation-integration balance. While age was positively associated with network segregation and network balance overall across the sample, these associations were moderated by exposure to neighborhood poverty. Specifically, these positive associations were observed only in youth from more, but not less, disadvantaged neighborhoods. Moreover, greater exposure to neighborhood poverty predicted reduced network segregation and network balance in early, but not middle or late, adolescence. These effects were detected both across the whole-brain system as well as specific functional networks, including fronto-parietal, default mode, salience, and subcortical systems. These findings indicate that where children live may exert long-reaching effects on the organization and development of the adolescent brain.


Outcomes for endocarditis surgery in North America: a simplified risk scoring system.
Operation for infective endocarditis is associated with the highest mortality of any valve disease, with overall rates of in-hospital mortality exceeding 20%. The Society of Thoracic Surgeons Adult Cardiac Surgery Database was examined to develop a simple risk scoring system and identify areas for quality improvement. From 2002 through 2008, 19,543 operations were performed for infective endocarditis. Logistic regression analysis related baseline characteristics to both operative mortality and a composite of mortality and major morbidity within 30 days. Points were assigned to each risk factor, and estimated risk was obtained by averaging events for all patients having the same number of points. Overall unadjusted mortality was 8.2%, and complications occurred in 53%. Significant preoperative risk factors for mortality (associated points) were as follows: emergency, salvage status, or cardiogenic shock (17), preoperative hemodialysis, renal failure, or creatinine level less than 2.0 (12), preoperative inotropic or balloon pump support (10), active (vs treated) endocarditis (10), multiple valve involvement (9), insulin-dependent diabetes (8), arrhythmia (8), previous cardiac surgery (7), urgent status without cardiogenic shock (6), non-insulin-dependent diabetes (6), hypertension (5), and chronic lung disease (5), with a C statistic of 0.7578 (all P < .001). Risk-adjusted mortality and major morbidity were unchanged over the course of the study. In the entire data set, mortality was better if "any valve" was repaired (odds ratio = 0.76; P = .0023). Operative mortality for surgically treated infective endocarditis is substantially lower than reported in-hospital mortality rates for infective endocarditis. The described risk scoring system will inform clinical decision-making in these complex patients.


Effect of collagen endometrial patch loaded with adipose-derived mesenchymal stem cells on endometrial regeneration in rats with a thin endometrium.
This study aimed to investigate the effects of a collagen endometrial patch (EM patch) loaded with adipose-derived mesenchymal stem cells (ADSCs) on endometrial regeneration in a rat model with thin endometrium. Thin endometrium was induced in female rats and divided into treatment groups as outlined: control, group 1(G1), local injection of ADSCs into the uterus, group 2 (G2), an EM patch without ADSCs, group 3 (G3), and an EM patch loaded with ADSCs, group 4 (G4). The rats were euthanized at either two weeks or four weeks after modeling and treatment followed by histological and biochemical analyses to examine the regenerative effects on the injured endometrium. Transplantation of the ADSC-loaded EM patch significantly promoted endometrial proliferation and increased the luminal epithelial area. Two weeks after treatment, the mean number of von Villebrand factor (vWF)+ or cluster of differentiation (CD) 31+-stained blood vessels was significantly higher in G4 than in G1 and G2. The mRNA and protein expression levels of TGF-β and FGF2 were significantly upregulated in G4 compared to those in the control. G4 exhibited significantly increased LIF mRNA levels and immunoreactivity compared with the other groups at both two weeks and four weeks after treatment. Cell tracking after ADSCs treatment revealed the presence of a substantial number of ADSCs grafted in the uterine tissues of G4, whereas a low number of ADSCs that were focally clustered were present in G2. Transplantation of EM patches loaded with ADSCs resulted in the histological and biochemical restoration of an injured endometrium. The strategic integration of EM patches and ADSCs holds significant promise as an innovative therapeutic approach for effectively treating impaired endometrial conditions.


Perinatal exposure to aged and diluted sidestream cigarette smoke produces airway hyperresponsiveness in older rats.
Exposing rats to aged and diluted sidestream cigarette smoke (ADSS) throughout in utero and postnatal life results in airway hyperresponsiveness and an increase in pulmonary neuroendocrine cells (PNECs) and neuroepithelial bodies (NEBs) in 7- to 10-week-old rats. Since human epidemiologic studies suggest that perinatal exposure to environmental tobacco smoke (ETS) may be detrimental to the lung function of older children, this study was designed to determine if perinatal exposure alone results in airway hyperresponsiveness and increased PNECs/NEBs later in life in rats. Pregnant Sprague-Dawley rats were exposed to filtered air (FA, n = 7) or ADSS (1 mg/m3 total suspended particulates, n = 7) for 4 to 6 h/day starting on Day 3 of gestation. Their pups continued to receive the same exposure regimen postnatally until 21 days of age. Thereafter all pups were exposed to FA until about 8 weeks of age. The airway responsiveness of one female pup from each litter was then assessed using an isolated perfused lung system whereby increasing doses of methacholine (-9.25 to -7.50 log mol) were administered into the pulmonary artery and lung resistance (Rl), dynamic compliance (Cdyn), and pulmonary pressure (Ppa) were measured. The number of PNECs/NEBs and mast cells per millimeter basal lamina were determined using immunocytochemical and histological staining and morphometric analysis. Statistics were performed using an unpaired Student's t test and repeated measures analysis of variance. Perinatal ADSS exposure enhanced methacholine-induced changes in Rl (p = 0.02), Cdyn (p = 0.004), and Ppa (p = 0.007). At the highest dose of methacholine, Rl in the ADSS-exposed lungs was threefold that in FA-exposed lungs. Although total PNEC number increased approximately twofold in the ADSS-exposed animals, this change was not found to be statistically significant. Mast cell number also was not different between groups. These data suggest that exposure to ADSS during the perinatal period followed by 5 weeks exposure to FA induces airway hyperresponsiveness in the absence of a significant change in PNECs, NEBs, or mast cells.


Severe aortic stenosis with low transvalvular gradient and severe left ventricular dysfunction:result of aortic valve replacement in 52 patients.
The outcome of aortic valve replacement in patients with severe aortic stenosis, low transvalvular gradient, and severe left ventricular dysfunction is not well known. Between 1985 and 1995, 52 patients with left ventricular ejection fraction (EF) < or =35% and aortic stenosis with transvalvular mean gradient <30 mm Hg underwent aortic valve replacement. The mean (+/-SD) preoperative characteristics included EF, 26+/-8%; aortic valve mean gradient, 23+/-4 mm Hg; aortic valve area, 0.7+/-0.2 cm(2); and cardiac output, 3.7+/-1.2 L/min. Simultaneous coronary artery bypass graft surgery was performed in 32 patients (62%). Perioperative (30-day) mortality was 21% (11 of 52 patients). Ten additional patients died during follow-up. Advanced age (P=0.048) and small aortic prosthesis size (P=0.03) were significant predictors of hospital mortality by univariate analysis. By multivariate analysis, the only predictor of surgical mortality was smaller prosthesis size. The only predictor of postoperative survival was improvement in postoperative functional class (P=0.04). Postoperative functional improvement occurred in most patients. Postoperative EF was assessed in 93% of survivors; 74% demonstrated improvement. Positive change in EF was related to smaller preoperative aortic valve area and female sex. Despite severe left ventricular dysfunction, low transvalvular mean gradient, and increased operative mortality, aortic valve replacement was associated with improved functional status. Postoperative survival was related to younger patient age and larger aortic prosthesis size, and medium-term survival was related to improved postoperative functional class.


Immunomodulatory and protective roles of quorum-sensing signaling molecules N-acyl homoserine lactones during infection of mice with Aeromonas hydrophila.
Aeromonas hydrophila leads to both intestinal and extraintestinal infections in animals and humans, and the underlying mechanisms leading to mortality are largely unknown. By using a septicemic mouse model of infection, we showed that animals challenged with A. hydrophila die because of kidney and liver damage, hypoglycemia, and thrombocytopenia. Pretreatment of animals with quorum-sensing-associated signaling molecules N-acyl homoserine lactones (AHLs), such as butanoyl and hexanoyl homoserine lactones (C(4)- and C(6)-HSLs), as well as N-3-oxododecanoyl (3-oxo-C(12))-HSL, prevented clinical sequelae, resulting in increased survivability of mice. Since little is known as to how different AHLs modulate the immune response during infection, we treated mice with the above AHLs prior to lethal A. hydrophila infection. When we compared results in such animals to those in controls, the treated animals exhibited a significantly reduced bacterial load in the blood and other mouse organs, as well as various levels of cytokines/chemokines. Importantly, neutrophil numbers were significantly elevated in the blood of C(6)-HSL-treated mice compared to those in animals given phosphate-buffered saline and then infected with the bacteria. These findings coincided with the fact that neutropenic animals were more susceptible to A. hydrophila infection than normal mice. Our data suggested that neutrophils quickly cleared bacteria by either phagocytosis or possibly another mechanism(s) during infection. In a parallel study, we indeed showed that other predominant immune cells inflicted during A. hydrophila infections, such as murine macrophages, when they were pretreated with AHLs, rapidly phagocytosed bacteria, whereas untreated cells phagocytosed fewer bacteria. This study is the first to report that AHL pretreatment modulates the innate immune response in mice and enhances their survivability during A. hydrophila infection.


Reduced Neurog3 Gene Dosage Shifts Enteroendocrine Progenitor Towards Goblet Cell Lineage in the Mouse Intestine.
Transient expression of Neurog3 commits intestinal secretory progenitors to become enteroendocrine-biased progenitors and hence drive enteroendocrine differentiation. Loss of Neurog3 in mouse resulted in the depletion of intestinal enteroendocrine cells (EECs) and an increase in goblet cells. Earlier studies in developing mouse pancreas identified a role of Neurog3 gene dosage in endocrine and exocrine cell fate allocation. We aimed to determine whether Neurog3 gene dosage controls fate choice of enteroendocrine progenitors. We acquired mutant Neurog3 reporter mice carrying 2, 1, or null Neurog3 alleles to study Neurog3 gene dosage effect by lineage tracing. Cell types arising from Neurog3+ progenitors were determined by immunohistochemistry using antibodies against intestinal lineage-specific markers. RNA sequencing of sorted Neurog3+/+, Neurog3+/-, or bulk intestinal cells were performed and differentially expressed genes were analyzed. We identified 2731 genes enriched in sorted Neurog3+/+-derived cells in the Neurog3+/+EYFP mouse intestine when compared with bulk duodenum epithelial cells. In the intestine of Neurog3+/-EGFP heterozygous mouse, we observed a 63% decrease in EEC numbers. Many Neurog3-derived cells stained for goblet marker Mucin 2. RNA sequencing of sorted Neurog3+/- cells uncovered enriched expression of genes characteristic for both goblet and enteroendocrine cells, indicating the mixed lineages arose from Neurog3+ progenitors. Consistent with this hypothesis, deletion of both Neurog3 alleles resulted in the total absence of EECs. All Neurog3+-derived cells stained for Mucin 2. We identified that the fate of Neurog3+ enteroendocrine progenitors is dependent on Neurog3 gene dosage. High Neurog3 gene dosage enforces the commitment of secretory progenitors to an EE lineage, while constraining their goblet cell lineage potential. Transcriptome profiling data was deposited to Gene Ontology omnibus, accession number: GSE149203.


Magnetic anchor for more effective endoscopic mucosal resection.
Technical difficulties are involved in endoscopic mucosal resection (EMR) of gastric cancer since it is a "one handed surgery". These difficulties prevent this technique from being indicated for larger lesions, even when it can possibly be performed for patients with such lesions. If microforceps could assist EMR, this procedure would become easier and safer. Since magnetic force can control objects without direct contact, it can be applied to control microforceps internally in assistance with EMR. We developed a magnetic anchor consisting of three parts: a magnetic weight with dimensions of 1.0 x 1.0 x 1.5 cm, microforceps and a connecting thread. Endoscopic clips used in hemostasis were used as the microforceps of the magnetic anchor in this study. The magnetic control system consisted of a 0.68 kOe/10 cm/100 A electromagnet, 350 mm in diameter and a circumventing positional frame. The microforceps were inserted into a sheath within the endoscope, and the magnetic weight was secured to the tip of the sheath protruding from the endoscope. The magnetic anchor, along with the endoscope, was inserted through an overtube into the gastric cavity of a swine under general anesthesia. The magnetic anchor was used in a manner similar to that in standard surgery, and EMR was thereby performed. The mucosa to be resected was satisfactorily dragged and stabilized. The magnetic anchor facilitated EMR, regardless of the technical skills of the endoscopist and region of the stomach at which the technique was performed. The magnetic anchor is considered to have alleviated some technical problems involved in EMR. It has the potential for making EMR a safer and quicker procedure for the treatment of early gastric cancer, when appropriately indicated.


Evidence that phorbol ester interferes with stimulated Ca2+ redistribution by activating Ca2+ efflux in neutrophil leucocytes.
The free calcium ion concentration, [Ca2+]i, in the cytoplasmic matrix of quin2-loaded neutrophil leucocytes increases rapidly after addition of concanavalin A. This increase is effectively abolished by a short (3 min) preincubation with 10 nM-TPA (12-O-tetradecanoylphorbol 13-acetate). TPA also inhibits a [Ca2+]i rise of similar magnitude induced by low concentrations (10 nM) of calcium ionophore A23187, suggesting that phorbol ester does not interfere with a physiological influx mechanism. To investigate the effects of TPA further, cells were depleted of Ca2+ during quin2 loading and then re-equilibrated with normal extracellular [Ca2+]. The return to a stable [Ca2+]i value was preceded by a transient overshoot in [Ca2+]i, implying delayed activation of an efflux mechanism by rising [Ca2+]i. TPA abolished the transient, suggesting preactivation by TPA of the efflux mechanism before Ca2+ influx. TPA also stimulates net Ca2+ efflux from neutrophils and neutrophil cytoplasts. These observations are consistent with the thesis that TPA stimulates a Ca2+-efflux mechanism in these cells.


Trichobezoar in a 11-year old girl: a case report.
Bezoars are masses of solidified organic or nonbiological material commonly found in the stomach and small bowel. Identification, therapy, and long-term management of patients with bezoars depends on accurate classification and knowledge on the pathophysiology of formation. Four types of bezoars have been described based on their composition: phytobezoars, trichobezoars, lactobezoars, and miscellaneous. Pediatric trichobezoars are associated to emotional disturbed children with aberrant appetite (trichophagia). Hair strands become retained and attached in the folds of the gastric mucosa because the friction surface is insufficient for propulsion by peristalsis. They generally are asymptomatic until enlargement produce pain, compression or intestinal obstruction. Bezoars are diagnosed with conventional radiology and gastroscopy permits identification of its nature. Currently, management of bezoars consists of: dissolution, suction, lavage, mechanical endoscopic fragmentation using pulsating jet of water, fragmentation with extracorporeal shock wave lithotripsy and surgical removal. Treatment should also focus on prevention of recurrence, since elimination of the mass will not alter the conditions contributing to their formation.


Parathyroid hormone and vitamin D receptors.
Parathyroid hormone (PTH), an 84-amino-acid polypeptide hormone, interacts with plasma membrane-bound receptors on bone and kidney cells, thereby increasing intracellular cAMP. Although the synthetic amino terminal 1-34 fragment of PTH possesses full biological activity, there is no firm evidence that hormone cleavage is a requisite step in the biological action of PTH. In contrast, vitamin D must undergo hydroxylations in the 1 and 25 positions in order to become fully active on target organs. 1,25(OH)2D, a steroid-like hormone, interacts with cytoplasmic receptors in small intestinal and bone cells. The 1,25(OH)2D-receptor complex (in the same manner as other steroid hormones) directs the synthesis of specific proteins. The integrated actions of PTH and vitamin D maintain serum calcium within narrow limits, thereby permitting normal neuromuscular and secretory function, as well as normal bone mineralization. Abnormalities in hormone secretion (PTH) or metabolic activation (vitamin D) lead to clinical disturbances in hormone action. Abnormalities at the level of the receptor-effector system for PTH and vitamin D also lead to clinical disturbances characterized by resistance to hormone action. Specific examples of the latter include pseudohypoparathyroidism, in which deficient activity of a component (the G unit) of the adenylate cyclase complex may lead to resistance to PTH, and hereditary vitamin D-dependent rickets type II, in which abnormalities in the nuclear uptake of 1,25(OH)2D may lead to impaired response to 1,25(OH)2D.


Intensity-specific leisure-time physical activity and the built environment among Brazilian adults: a best-fit model.
There is little understanding about which sets of environmental features could simultaneously predict intensity-specific leisure-time physical activity (LTPA) among Brazilians. The objectives were to identify the environmental correlates for intensity-specific LTPA, and to build the best-fit linear models to predict intensity-specific LTPA among adults of Curitiba, Brazil. Cross sectional study in Curitiba, Brazil (2009, n = 1461). The International Physical Activity Questionnaire and Abbreviated Neighborhood Environment Assessment Scale were used. Ninety-two perceived environment variables were categorized in 10 domains. LTPA was classified as walking for leisure (LWLK), moderate-intensity leisure-time PA (MLPA), vigorous-intensity leisure-time PA (VLPA), and moderate-to-vigorous intensity leisure-time PA (MVLPA). Best fitting linear predictive models were built. Forty environmental variables were correlated to at least 1 LTPA outcome. The variability explained by the 4 best-fit models ranged from 17% (MLPA) to 46% (MVLPA). All models contained recreation areas and aesthetics variables; none included residential density predictors. At least 1 neighborhood satisfaction variable was present in each of the intensity-specific models, but not for overall MVLPA. This study demonstrates the simultaneous effect of sets of perceived environmental features on intensity-specific LTPA among Brazilian adults. The differences found compared with high-income countries suggest caution in generalizing results across settings.


Priapism in sickle cell anemia: emerging mechanistic understanding and better preventative strategies.
Sickle cell anemia is a common and disabling disorder profoundly affecting mortality as well as quality of life. Up to 35% of men with sickle cell disease are affected by painful, prolonged erections termed ischemic priapism. A priapic episode may result in fibrosis and permanent erectile dysfunction. The severity of sickle cell disease manifestations is variable dependent on a number of contributing genetic factors; however, priapism tends to cluster with other severe vascular complications including pulmonary hypertension, leg ulceration, and overall risk of death. The mechanisms underlying priapism in sickle cell disease have begun to be elucidated including hemolysis-mediated dysregulation of the nitric oxide signaling pathway and dysregulation of adenosine-mediated vasodilation. A better understanding of these mechanisms is leading toward novel preventative strategies. This paper will focus on the mechanisms underlying development of ischemic priapism in sickle cell disease, current acute and preventative treatment strategies, and future directions for improved management of this disorder.


An observational single-center study of nivolumab in Indian patients with recurrent advanced non-small cell lung cancer.
Limited treatment options are available for patients with advanced non-small cell lung cancer (NSCLC) after failure of first-line platinum-based chemotherapy. The treatment of recurrent advanced NSCLC progressed with the arrival of nivolumab and other immunotherapeutic agents. Our single-center prospective study aimed to present the effectiveness and safety of nivolumab in second-line setting after first-line platinum doublet in Indian patients with advanced NSCLC. Twenty-nine adult patients with stage IV NSCLC treated with nivolumab after failure of first-line platinum-based chemotherapy at Bhagwan Mahaveer Cancer Hospital and Research Centre, Jaipur, India, between October 2016 and January 2018, were included in the study. Overall survival (OS), hematological, and nonhematological toxicities were evaluated. A total of 29 patients (mean age of 59.6 years at enrollment) were evaluated. Histological evaluation revealed adenocarcinoma (44.8%) and squamous (55.2%) type of cancer. The Eastern Cooperative Oncology Group performance score was II in 7 patients (24.1%) and I in 22 (75.9%) patients. Patients received an average of four cycles of nivolumab. The median survival duration was 101 days, and OS rate in the study was 51.7%. Six patients (20.7%) had stable disease response, five patients (17.2%) had partial response, and three patients (10.3%) were lost to follow-up. Asthenia and cough were the most common nonhematological toxicities. Only three patients developed hematological toxicities (anemia and thrombocytopenia). Data from our study suggest nivolumab is well-tolerated and effective in Indian patients with recurrent advanced NSCLC after failure of the multiple first lines of platinum-based combination chemotherapy.


The concentration of progesterone, 20 alpha-dihydroprogesterone, testosterone, oestrone and oestradiol-17 beta in serum, amniotic fluid and placental tissue of pregnant rabbits.
The concentrations of progesterone (delta 4P), 20 alpha-dihydroprogesterone (20 alpha-DHP), testosterone (T), oestrone (E1) and oestradiol-17 beta (E2 beta) in peripheral blood serum (PBS), amniotic fluid (AF) and placental tissue of rabbits during gestation were determined by radioimmunoassay. The placenta of the 10-day pregnant rabbit was fragile and composed mainly of maternal tissue. By the 12th day of pregnancy it was separable into maternal and foetal placentae. The mean concentration of delta 4P in PBS rose from 200 pg/ml (day 1 pregnancy) to 17--21 ng/ml (days 10--15) and decreased gradually to 1 ng/ml a few hours before parturition. The 20 alpha-DHP in PBS also showed an increase from 1.5 ng/mg (day 1) to 12 ng/ml (day 6) but fluctuated thereafter. The concentration of 20 alpha-DHP in the PBS tended to be lower than that of delta 4 P during pregnancy until the regression of the corpus luteum. An interesting observation was an increase of T on days 6--8 of pregnancy, the time when implantation occurs. The concentrations of E1 and E2 beta in PBS remained very low throughout pregnancy. delta 4P and 20 alpha-DHP in AF ranged between 25 pg to 1 ng/ml and in no case during the course of pregnancy were the levels of T, E1 and E2 beta in AF higher than in PBS. Where the maternal placental delta 4P content remained between 1--2 ng/placenta, the foetal placenta delta 4P rose to a level of 15 ng/placenta by day 31 of pregnancy. A similar trend was recorded for 20 alpha-DHP content. It is concluded that although a parallelism between PBS and myometrial steroid concentration was observed, no relationship could be drawn between the concentrations of steroid in PBS and those of the placental tissue and AF.


Convolutional neural network-based encoding and decoding of visual object recognition in space and time.
Representations learned by deep convolutional neural networks (CNNs) for object recognition are a widely investigated model of the processing hierarchy in the human visual system. Using functional magnetic resonance imaging, CNN representations of visual stimuli have previously been shown to correspond to processing stages in the ventral and dorsal streams of the visual system. Whether this correspondence between models and brain signals also holds for activity acquired at high temporal resolution has been explored less exhaustively. Here, we addressed this question by combining CNN-based encoding models with magnetoencephalography (MEG). Human participants passively viewed 1,000 images of objects while MEG signals were acquired. We modelled their high temporal resolution source-reconstructed cortical activity with CNNs, and observed a feed-forward sweep across the visual hierarchy between 75 and 200 ms after stimulus onset. This spatiotemporal cascade was captured by the network layer representations, where the increasingly abstract stimulus representation in the hierarchical network model was reflected in different parts of the visual cortex, following the visual ventral stream. We further validated the accuracy of our encoding model by decoding stimulus identity in a left-out validation set of viewed objects, achieving state-of-the-art decoding accuracy.


Phylogenetic analysis of pestiviruses from domestic and wild ruminants.
Infections with pestiviruses occur in cattle, sheep, pigs and also in numerous other ungulate species. In the present study, pestiviruses from goat, buffalo, deer and giraffe were analysed at the molecular level; unusual strains from cattle and pigs were also included. A phylogenetic analysis of the respective pestiviruses was undertaken on the basis of a fragment from the 5' noncoding region as well as the gene encoding autoprotease Npro. Statistical analyses of the respective phylogenetic trees-based on the 5' NCR revealed low confidence levels for most of the branches, while the structure of the tree based on the Npro gene was supported by high bootstrap values. Accordingly, the isolates from goat, buffalo and deer can be grouped together with bovine viral diarrhoea virus (pestivirus type 1); within this genotype three subgroups and one disparate virus have been identified. One isolate from pig and one from cattle belong to the group of 'true' border disease virus (pestivirus type 3), which can be further subdivided into two major subgroups. Interestingly, the giraffe isolate does not belong to one of the four established pestivirus genotypes. The phylogenetic analysis strongly suggests that genotype 1 pestiviruses occur world-wide in many ruminant species. Furthermore, phylogenetic trees based on the Npro gene nucleotide sequences show that the respective sequences do not segregate into discrete lineages based on host-species origin.


Epidemiology and impact of urinary incontinence, overactive bladder, and other lower urinary tract symptoms: results of the EPIC survey in Russia, Czech Republic, and Turkey.
To estimate the prevalence of urinary incontinence (UI), overactive bladder (OAB), and other lower urinary tract symptoms (LUTS) in the Czech Republic, Russia, and Turkey. Stage one of this population-based survey consisted of computer-assisted telephone interviews to obtain prevalence estimates of storage, voiding, and post-micturition LUTS. Stage two face-to-face interviews evaluated subjects with mixed urinary incontinence (MUI), stress urinary incontinence (SUI) or OAB (case group) and a control group (subjects with other incontinence or LUTS complaints, or no symptoms). Prevalence of LUTS categories were determined for each country based on International Continence Society (ICS) criteria. A total of 3130 individuals agreed to participate in the survey, which found high rates of LUTS (men 80%; women 84%) and OAB (men 18%; women 28%). Duration of urinary symptoms was relatively brief (approximately 60% ≤ 3 years) and was associated with relatively modest effects on quality of life and work performance in the majority of individuals. Forty percent had consulted with a healthcare provider about their urinary symptoms, of whom 37% had consulted with a physician and 34% with an urologist, and 12% had been treated with a prescription medication. Drug therapy, while uncommon, was associated with a high degree of self-reported improvement (96%). Because of between-country population differences, aggregate results may not always be representative of results for each of the three countries individually. Study limitations include reliance on patient self-report, and potential bias introduced by patients who declined to participate in the survey. The results of this epidemiologic survey found high rates of LUTS and OAB, but low levels of medical consultation and very low use of medication treatment, despite high levels of improvement when medications were used.


Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial.
Preferred neoadjuvant regimens for early-stage triple-negative breast cancer (TNBC) include anthracycline-cyclophosphamide and taxane-based chemotherapy. IMpassion031 compared efficacy and safety of atezolizumab versus placebo combined with nab-paclitaxel followed by doxorubicin plus cyclophosphamide as neoadjuvant treatment for early-stage TNBC. This double-blind, randomised, phase 3 study enrolled patients in 75 academic and community sites in 13 countries. Patients aged 18 years or older with previously untreated stage II-III histologically documented TNBC were randomly assigned (1:1) to receive chemotherapy plus intravenous atezolizumab at 840 mg or placebo every 2 weeks. Chemotherapy comprised of nab-paclitaxel at 125 mg/m2 every week for 12 weeks followed by doxorubicin at 60 mg/m2 and cyclophosphamide at 600 mg/m2 every 2 weeks for 8 weeks, which was then followed by surgery. Stratification was by clinical breast cancer stage and programmed cell death ligand 1 (PD-L1) status. Co-primary endpoints were pathological complete response in all-randomised (ie, all randomly assigned patients in the intention-to-treat population) and PD-L1-positive (ie, patients with PD-L1-expressing tumour infiltrating immune cells covering ≥1% of tumour area) populations. This study is registered with ClinicalTrials.gov (NCT03197935), Eudra (CT2016-004734-22), and the Japan Pharmaceutical Information Center (JapicCTI-173630), and is ongoing. Between July 7, 2017, and Sept 24, 2019, 455 patients were recruited and assessed for eligibility. Of the 333 eligible patients, 165 were randomly assigned to receive atezolizumab plus chemotherapy and 168 to placebo plus chemotherapy. At data cutoff (April 3, 2020), median follow-up was 20·6 months (IQR 8·7-24·9) in the atezolizumab plus chemotherapy group and 19·8 months (8·1-24·5) in the placebo plus chemotherapy group. Pathological complete response was documented in 95 (58%, 95% CI 50-65) patients in the atezolizumab plus chemotherapy group and 69 (41%, 34-49) patients in the placebo plus chemotherapy group (rate difference 17%, 95% CI 6-27; one-sided p=0·0044 [significance boundary 0·0184]). In the PD-L1-positive population, pathological complete response was documented in 53 (69%, 95% CI 57-79) of 77 patients in the atezolizumab plus chemotherapy group versus 37 (49%, 38-61) of 75 patients in the placebo plus chemotherapy group (rate difference 20%, 95% CI 4-35; one-sided p=0·021 [significance boundary 0·0184]). In the neoadjuvant phase, grade 3-4 adverse events were balanced and treatment-related serious adverse events occurred in 37 (23%) and 26 (16%) patients, with one patient per group experiencing an unrelated grade 5 adverse event (traffic accident in the atezolizumab plus chemotherapy group and pneumonia in the placebo plus chemotherapy group). In patients with early-stage TNBC, neoadjuvant treatment with atezolizumab in combination with nab-paclitaxel and anthracycline-based chemotherapy significantly improved pathological complete response rates with an acceptable safety profile. F Hoffmann-La Roche/Genentech.


Unicellular life balances asymmetric allocation and repair of somatic damage representing the origin of r/K selection.
Over the course of multiple divisions, cells accumulate diverse non-genetic, somatic damage including misfolded and aggregated proteins and cell wall defects. If the rate of damage accumulation exceeds the rate of dilution through cell growth, a dedicated mitigation strategy is required to prevent eventual population collapse. Strategies for somatic damage control can be divided into two categories, asymmetric allocation and repair, which are not, in principle, mutually exclusive. Through mathematical modelling, we identify the optimal strategy, maximizing the total cell number, over a wide range of environmental and physiological conditions. The optimal strategy is primarily determined by extrinsic (damage-independent) mortality and the physiological model for damage accumulation that can be either independent (linear) or increasing (exponential) with respect to the prior accumulated damage. Under the linear regime, the optimal strategy is either exclusively repair or asymmetric allocation whereas under the exponential regime, the optimal strategy is mixed. Repair is preferred when extrinsic mortality is low, whereas at high extrinsic mortality, asymmetric damage allocation becomes the strategy of choice. We hypothesize that optimization over somatic damage repair and asymmetric allocation in early cellular life forms gave rise to the r and K selection strategies.


Effect of topical nitroglycerine on the survival of ischemic flow-through venous flaps in rabbits.
The purpose of this study was to investigate the effect of transdermal nitroglycerin on the survival of an ischemic one-vein flow-through venous flap (FTVF) model in the rabbit ear. Fifteen New Zealand white male rabbits were randomly divided into three groups: Group 1 (n = 5, 10 flaps)- no dressing on the operative wound; Group 2 (n = 5, 10 flaps)-occlusive film dressing group [polyurethane semipermeable membrane (Op-Site)]; and Group 3 (n = 5, 10 flaps)- transdermal nitroglycerine pad (Novartis-Nitroderm TTS 5 mg) on the wound. Nitroderm TTS and the occlusive film dressing were changed daily postoperatively for 3 days. The percentage of the surviving area and the mean extent of the surviving area to the axial vein were calculated on the postoperative 14 (th) day. Necrotic and surviving areas of flaps were consistent with histopathologic findings. Group 3 (83 percent +/-10.46, 17.4 +/- 3.0 mm) had larger flap surviving areas and longer distances to the axial vein than Group 1 (60 percent +/-15.29, 11.8 +/- 4.3 mm) and Group 2 (58 percent +/-10.25, 12.8 +/- 2.8 mm). The difference was statistically significant ( p < 0.05). This study demonstrated that postoperatively applied transdermal nitroglycerine significantly increased the ischemic FTVF survival area and the survival width to the axial vein.


Potential Tear Biomarkers for the Diagnosis of Parkinson's Disease-A Pilot Study.
Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. In this study, the tear proteome profile of patients with idiopathic PD (iPD, n = 24), carriers of the E46K-SNCA mutation (n = 3) and healthy control (CT, n = 27) subjects was analyzed to identify candidate biomarkers for the diagnosis of PD. An observational, prospective and case-control pilot study was carried out, analyzing the participants tear samples by nano-liquid chromatography-mass spectrometry (nLC-MS/MS) and assessing their neurological impairment. The proteomic data obtained are available at ProteomeXchange with identifier 10.6019/PXD028811. These analyses led to the identification of 560 tear proteins, some of which were deregulated in PD patients and that have been implicated in immune responses, inflammation, apoptosis, collagen degradation, protein synthesis, defense, lipid transport and altered lysosomal function. Of these proteins, six were related to neurodegenerative processes and showed a good capacity to classify patients and controls. These findings revealed that certain proteins were upregulated in the tears of PD patients, mainly proteins involved in lysosomal function. Thus, in this study, tear proteins were identified that are implicated in neurodegeneration and that may be related to an aggressive disease phenotype in PD patients.


Influence of sensory and proprioceptive impairment on the development of phantom limb syndrome during regional anesthesia.
The relation between impairment of sensorimotor function and occurrence of phantom limb syndrome (PLS) during regional anesthesia has not been described. This study assessed the temporal relation between PLS and the progression of sensorimotor impairment during placement of a brachial plexus nerve block. Fifty-two patients had their arm randomly placed either alongside their body (group A) or in 90 degrees abduction (group B) immediately after brachial plexus nerve block placement. Responses to pin prick, cold, heat, touch, proprioception, and voluntary movement were assessed every 5 min for 60 min. Meanwhile, patients described their perceptions of the size, shape, and position of their anesthetized limb. Phantom limb syndrome occurred 19 +/- 9 min after nerve block placement. Proprioception was impaired and abolished after 22 +/- 9 and 43 +/- 17 min, respectively (P < 0.05 vs. PLS onset). When PLS occurred, responses to pin prick, cold, heat, and proprioception were abolished in 96, 94, 87, and 4% of patients, respectively. Patients were more likely to feel their anesthetized limb in adduction and in abduction in groups A and B (P < 0.05 vs. group A), respectively. After PLS had become motionless, two stereotyped positions were identified: arm adduction, elbow flexion, hand over the abdomen (68% of group A patients) and arm abduction, elbow flexion, hand held close to the homolateral ear (48% of group B patients). This study provides a better understanding of the determinants of PLS by showing that the final position of PLS is related both to the abolition of proprioception and the initial position of the anesthetized limb.


Macromolecular prodrug of dexamethasone prevents particle-induced peri-implant osteolysis with reduced systemic side effects.
Aseptic implant loosening related to implant wear particle-induced inflammation is the most common cause of failure after joint replacement. Modulation of the inflammatory reaction to the wear products represents a rational approach for preventing aseptic implant failure. Long-term treatment using anti-inflammatory agents, however, can be associated with significant systemic side effects due to the drugs' lack of tissue specificity. To address this issue, N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-dexamethasone conjugate (P-Dex) was developed and evaluated for prevention of wear particle-induced osteolysis and the loss of fixation in a murine prosthesis failure model. Daily administration of free dexamethasone (Dex) was able to prevent wear particle-induced osteolysis, as assessed by micro-CT and histological analysis. Remarkably, monthly P-Dex administration (dose equivalent to free Dex treatment) was equally effective as free dexamethasone, but was not associated with systemic bone loss (a major adverse side effect of glucocorticoids). The reduced systemic toxicity of P-Dex is related to preferential targeting of the sites of wear particle-induced inflammation and its subcellular sequestration and retention by local inflammatory cell populations, resulting in sustained therapeutic action. These results demonstrate the feasibility of utilizing a macromolecular prodrug with reduced systemic toxicity to prevent wear particle-induced osteolysis.


Intrasellar rupture of a paraclinoid aneurysm with subarachnoid hemorrhage: usefulness of MR imaging in diagnosis.
Characterization of paraclinoid aneurysms may be difficult because of the complexity of anatomic structures involved, and differentiation between intradural and extradural lesions is crucial. We report a case of a patient with a unique presentation of a paraclinoid aneurysm with intrasellar hemorrhage in which the presence of intrasellar blood and the relationship of the paraclinoid aneurysmal neck and sac to the dural rings were elegantly demonstrated on MR imaging and were critical in choosing the target lesion for treatment.


The adipokinetic hormones and their cognate receptor from the desert locust, Schistocerca gregaria: solution structure of endogenous peptides and models of their binding to the receptor.
Neuropeptides exert their activity through binding to G protein-coupled receptors (GPCRs). GPCRs are well-known drug targets in the pharmaceutical industry and are currently discussed as targets to control pest insects. Here, we investigate the neuropeptide adipokinetic hormone (AKH) system of the desert locust Schistocerca gregaria. The desert locust is known for its high reproduction, and for forming devastating swarms consisting of billions of individual insects. It is also known that S. gregaria produces three different AKHs as ligands but has only one AKH receptor (AKHR). The AKH system is known to be essential for metabolic regulation, which is necessary for reproduction and flight activity. Nuclear magnetic resonance techniques (NMR) in a dodecylphosphocholin (DPC) micelle solution were used to determine the structure of the three AKHs. The primary sequence of the S. gregaria AKHR was used to construct a 3D molecular model. Next, the three AKHs were individually docked to the receptor, and dynamic simulation of the whole ligand-receptor complex in a model membrane was performed. Although the three endogenous AKHs of S. gregaria have quite different amino acids sequences and chain length (two octa- and one decapeptide), NMR experiments assigned a turn structure in DPC micelle solution for all. The GPCR-ModSim program identified human kappa opioid receptor to be the best template after which the S. gregaria AKHR was modeled. All three AKHs were found to have the same binding site on this receptor, interact with similar residues of the receptor and have comparable binding constants. Molecular switches were also identified; the movement of the receptor could be visually shown when ligands (AKHs) were docked and the receptor was activated. The study proposes a model of binding of the three endogenous ligands to the one existing AKHR in the desert locust and paves the way to use such a model for the design of peptide analogs and finally, peptide mimetics, in the search for novel species-specific insecticides based on receptor-ligand interaction.


Inhibition of the progesterone nuclear receptor during the bone linear growth phase increases peak bone mass in female mice.
Augmentation of the peak bone mass (PBM) may be one of the most effective interventions to reduce the risk of developing osteoporosis later in life; however treatments to augment PBM are currently limited. Our study evaluated whether a greater PBM could be achieved either in the progesterone nuclear receptor knockout mice (PRKO) or by using a nuclear progesterone receptor (nPR) antagonist, RU486 in mice. Compared to their wild type (WT) littermates the female PRKO mice developed significantly higher cancellous and cortical mass in the distal femurs, and this was associated with increased bone formation. The high bone mass phenotype was partially reproduced by administering RU486 in female WT mice from 1-3 months of age. Our results suggest that the inhibition of the nPR during the rapid bone growth period (1-3 months) increases osteogenesis, which results in acquisition of higher bone mass. Our findings suggest a crucial role for progesterone signaling in bone acquisition and inhibition of the nPR as a novel approach to augment bone mass, which may have the potential to reduce the burden of osteoporosis.


Syntheses of pseudoceramines A-D and a new synthesis of spermatinamine, bromotyrosine natural products from marine sponges.
Herein we report the total syntheses of pseudoceramine A-D (2-5) and spermatinamine (1) isolated from the marine sponge Pseudoceratina sp. Direct acyl substitution of α-hydroxyiminoesters with amine nucleophiles was developed as a key transformation. The synthetic compounds confirm the reported structures and importantly gives access to non-symmetrical spermine based natural products carrying two different bromotyrosine building blocks. Our new synthesis of spermatinamine is two steps shorter and more efficient than the previously reported sequence.


Idiopathic Restrictive Cardiomyopathy in Children and Young Adults.
Idiopathic restrictive cardiomyopathy (IRC) is a rare condition characterized by reduced ventricular compliance. Children with IRC have poor outcomes with most patients proceeding to cardiac transplantation. We sought to analyze our institutional experience and assess contemporary outcomes for children with IRC. We reviewed the medical record for patients (<21 years old) evaluated for a primary diagnosis of IRC between 1975 and 2013 at our institution. Demographic, clinical, echocardiographic, and catheterization data were abstracted. The patients were divided into 2 groups comprising a historical cohort (HC) (diagnosis: 1975 to 1993, n = 8) and a contemporary cohort (CC) (diagnosis: 1994 to 2013, n = 12). Twenty children were identified with IRC (mean age at presentation 9.7 ± 6.5 years, 55% female). Mean length of follow-up was 6.5 ± 8.4 years (range 0.1 to 35.6 years). In the CC, 7 of 12 patients (58%) progressed to cardiac transplantation (mean age of 9 ± 4 years at transplant, mean interval from diagnosis of IRC: 1.5 ± 0.9 years). Overall survival was improved significantly in the CC compared with the HC (80% vs. 38%, p = 0.02), but transplantation free survival was no different between the CC and HC over 5 years (38% vs 38%, p = 0.65). In the CC, elevation of mitral valve Doppler E/e' ratio on echocardiography was associated with increased mortality (p = 0.01). In conclusion, IRC continues has a poor prognosis. Early referral for transplantation was associated with improved overall survival in the modern era. Patients with markedly elevated E/e' ratio may have increased risk of death.


The neonatal microenvironment programs innate γδ T cells through the transcription factor STAT5.
IL-17-producing RORγt+ γδ T cells (γδT17 cells) are innate lymphocytes that participate in type 3 immune responses during infection and inflammation. Herein, we show that γδT17 cells rapidly proliferate within neonatal lymph nodes and gut, where, upon entry, they upregulate T-bet and coexpress IL-17, IL-22, and IFN-γ in a STAT3- and retinoic acid-dependent manner. Neonatal expansion was halted in mice conditionally deficient in STAT5, and its loss resulted in γδT17 cell depletion from all adult organs. Hyperactive STAT5 mutant mice showed that the STAT5A homolog had a dominant role over STAT5B in promoting γδT17 cell expansion and downregulating gut-associated T-bet. In contrast, STAT5B preferentially expanded IFN-γ-producing γδ populations, implying a previously unknown differential role of STAT5 gene products in lymphocyte lineage regulation. Importantly, mice lacking γδT17 cells as a result of STAT5 deficiency displayed a profound resistance to experimental autoimmune encephalomyelitis. Our data identify that the neonatal microenvironment in combination with STAT5 is critical for post-thymic γδT17 development and tissue-specific imprinting, which is essential for infection and autoimmunity.


Time-lapse observation of branching morphogenesis of the lung bud epithelium in mesenchyme-free culture and its relationship with the localization of actin filaments.
It has been shown that branching morphogenesis of the lung bud is mediated by epithelial-mesenchymal interaction via such molecules as FGF10, BMP4 and Shh. However, a recent study showed that the isolated lung epithelium still undergoes branching morphogenesis in vitro even in the absence of mesenchyme (Nogawa and Ito, 1995). In the present study, we observed in vitro the dynamic movement of the isolated lung epithelium of the fetal mouse using time-lapse recording, and investigatedthe roles of actinfilaments in branching of the lung bud. First, time-lapse observation of the initial phase of lung branching morphogenesis revealed that at the sites of cleft formation, the epithelial surface was retracted inward from its original position. From this observation we assumed that there should be some structures which exert a physical force on the epithelium, and the localization and arrangement of actin fibers in the cultured lung epithelium were examined at various stages of branching morphogenesis. At the prebudding (6 h) and onset-budding (24 h) stages, no specific localization of actin filaments was observed in the lung bud epithelium, but at the postbudding stage (48 h) they were localized densely in the cells at the tip of the branched lung epithelium. The cell density was not different between the tip and cleft regions of the lung bud epithelium. When cultured with FGF-soaked beads, an actin-rich region was induced at the tip of the lung bud which was growing toward an FGF-soaked bead. These results indicate that actin fibers do not play a significant part in cleft formation but can be secondarily induced by FGF in the surrounding matrix and play some roles at later shaping of the branch in lung morphogenesis.


Optimization of mean-shift scale parameters on the EGEE grid.
This paper studies the optimization of Mean-Shift (MS) image filtering scale parameters. A parameter sweep experiment representing 164 days of CPU is performed on the EGEE grid. The mathematical foundations of Mean-Shift and the grid environment used for the deployment are described in details. The experiments and results are then discussed highlighting the efficiency of gradient ascent algorithm for MS parameters optimization and a number of grid observations related to data transfers, reliability, task scheduling, CPU time and usability.


Gout is associated with an increased risk for incident heart failure among older adults: the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort study.
Gout has been associated with a higher risk for coronary heart disease (CHD) and stroke in some prior studies. Few studies have assessed the association of gout with incident heart failure (HF). We analyzed data from 5713 black and white men and women ≥ 65.5 years of age in the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort study who had Medicare coverage without a history of HF, CHD, or stroke at baseline between 2003 and 2007. Gout was defined by ≥ 1 hospitalization or ≥ 2 outpatient visits with a diagnosis code for gout in Medicare claims prior to each participant's baseline study examination. REGARDS study participants were followed for HF hospitalization, CHD, stroke, and all-cause mortality as separate outcomes through December 31, 2016. Analyses were replicated in a random sample of 839,059 patients ≥ 65.5 years of age with Medicare coverage between January 1, 2008, and June 30, 2015, who were followed through December 31, 2017. Among REGARDS study participants included in the current analysis, the mean age at baseline was 72.6 years, 44.9% were men, 31.4% were black, and 3.3% had gout. Over a median follow-up of 10.0 years, incidence rates per 1000 person-years among participants with and without gout were 13.1 and 4.4 for HF hospitalization, 16.0 and 9.3 for CHD, 9.3 and 8.2 for stroke, and 55.0 and 37.1 for all-cause mortality, respectively. After multivariable adjustment for sociodemographic variables and cardiovascular risk factors, hazard ratios (95% CI) comparing participants with versus without gout were 1.97 (1.22, 3.19) for HF hospitalization, 1.21 (0.79, 1.84) for CHD, 0.83 (0.48, 1.43) for stroke, and 1.08 (0.86, 1.35) for all-cause mortality. The multivariable-adjusted hazard ratio for HF hospitalization with reduced and preserved left ventricular ejection fraction among participants with versus without gout was 1.77 (95% CI 0.83, 3.79) and 2.32 (95% CI 1.12, 4.79), respectively. The multivariable-adjusted hazard ratio for heart failure hospitalization associated with gout among the 839,059 Medicare beneficiaries was 1.32 (95% CI 1.25, 1.39). Among older adults, gout was associated with an increased risk for incident HF but not for incident CHD, incident stroke, or all-cause mortality.


Malignant melanoma of the choroid with balloon cells a clinicopathologic study of three cases.
We report the findings on clinicopathologic examination of three patients with balloon cell melanoma of the choroid. Ophthalmoscopically, all three had small, slowly progressive tumors at the posterior pole, with an encircling yellow halo. With fluorescein angiography, the yellow halo showed fluorescence similar to the remainder of the tumor, thus differentiating this substance from lipofuscin pigment, drusen and exudates. Light microscopy demonstrated prominent balloon cells which were most numerous at the tumor margins. These cells showed variable melanin pigmentation and were negative for lipid, acid mucopolysaccharide, and glycogen. Special enzyme studies (lactic dehydrogenase, succinic dehydrogenase, acid phosphatase, beta glucoronidase and aminopeptidase) demonstrated some similarity to melanocytic cells. Electron microscopy revealed premelanosomes and complex melanosomes in the cytoplasm of balloon cells without evidence of significant lipid.


Hyperglycemia Acutely Increases Cytosolic Reactive Oxygen Species via O-linked GlcNAcylation and CaMKII Activation in Mouse Ventricular Myocytes.
Diabetes mellitus is a complex, multisystem disease, affecting large populations worldwide. Chronic CaMKII (Ca2+/calmodulin-dependent kinase II) activation may occur in diabetes mellitus and be arrhythmogenic. Diabetic hyperglycemia was shown to activate CaMKII by (1) O-linked attachment of N-acetylglucosamine (O-GlcNAc) at S280 leading to arrhythmia and (2) a reactive oxygen species (ROS)-mediated oxidation of CaMKII that can increase postinfarction mortality. To test whether high extracellular glucose (Hi-Glu) promotes ventricular myocyte ROS generation and the role played by CaMKII. We tested how extracellular Hi-Glu influences ROS production in adult ventricular myocytes, using DCF (2',7'-dichlorodihydrofluorescein diacetate) and genetically targeted Grx-roGFP2 redox sensors. Hi-Glu (30 mmol/L) significantly increased the rate of ROS generation-an effect prevented in myocytes pretreated with CaMKII inhibitor KN-93 or from either global or cardiac-specific CaMKIIδ KO (knockout) mice. CaMKII KO or inhibition also prevented Hi-Glu-induced sarcoplasmic reticulum Ca2+ release events (Ca2+ sparks). Thus, CaMKII activation is required for Hi-Glu-induced ROS generation and sarcoplasmic reticulum Ca2+ leak in cardiomyocytes. To test the involvement of O-GlcNAc-CaMKII pathway, we inhibited GlcNAcylation removal by Thiamet G (ThmG), which mimicked the Hi-Glu-induced ROS production. Conversely, inhibition of GlcNAcylation (OSMI-1 [(αR)-α-[[(1,2-dihydro-2-oxo-6-quinolinyl)sulfonyl]amino]-N-(2-furanylmethyl)-2-methoxy-N-(2-thienylmethyl)-benzeneacetamide]) prevented ROS induction in response to either Hi-Glu or ThmG. Moreover, in a CRSPR-based knock-in mouse in which the functional GlcNAcylation site on CaMKIIδ was ablated (S280A), neither Hi-Glu nor ThmG induced myocyte ROS generation. So CaMKIIδ-S280 is required for the Hi-Glu-induced (and GlcNAc dependent) ROS production. To identify the ROS source(s), we used different inhibitors of NOX (NADPH oxidase) 2 (Gp91ds-tat peptide), NOX4 (GKT137831), mitochondrial ROS (MitoTempo), and NOS (NO synthase) pathway inhibitors (L-NAME, L-NIO, and L-NPA). Only NOX2 inhibition or KO prevented Hi-Glu/ThmG-induced ROS generation. Diabetic hyperglycemia induces acute cardiac myocyte ROS production by NOX2 that requires O-GlcNAcylation of CaMKIIδ at S280. This novel ROS induction may exacerbate pathological consequences of diabetic hyperglycemia.


Linear chain aldehydes evoke calcium responses in B16 melanoma cells.
Oxidative stress is involved in various physiological impairing stages, such as aging, diabetes, atherosclerosis, cirrhosis, and neurological disorders. Recent research indicates that aldehyde compounds derived from oxidized lipids increase in cancer patients compared to healthy individuals. Among of them, hexanal, a six-carbon liner chain aldehyde, is commonly found in cancer patients. Lipid oxidation products including aldehydes are in general chemically unstable and react with biological molecules such as proteins. The purpose of this study is to investigate effects of lipid-derived aldehydes and the related compounds on intracellular Ca2+ responses in B16 melanoma cells. Hexanal-induced [Ca2+]i elevation is observed in B16 cells in a dose dependent manner, but [Ca2+]i changes were observed neither in 3T3-L1 cells nor Caco-2 cells. Propanal, a chain length analogue of hexanal, elicited no change in [Ca2+]i, but nonanal initiated [Ca2+]i increases. Analogue compounds of hexanal failed to induce [Ca2+]i elevation. Furthermore, unsaturated aldehydes known as TRPA1 channel agonists also failed to alter [Ca2+]i levels in B16 melanoma cells. Pharmacological spectra using inhibitors against intracellular Ca2+ signaling suggest that hexanal-induced [Ca2+]i responses in B16 cells might be involved in TRP channels other than TRPA1. Our results suggest that saturated aliphatic chain aldehydes would be novel compounds for initiating [Ca2+]i increases through very strict recognitions of chain saturation, aldehydic base structures, and chain lengths in B16 melanoma cells. B16 cells would have sensing mechanisms for oxidative status and/or metabolic activities in their growth environment.


The effect of short-term sleep fragmentation produced by intense auditory stimuli on the arousal response to upper airway obstruction in lambs.
Upper airway obstruction is recognized to cause apnoea in newborns as well as in adults. However, very little is known about factors that influence the arousal response from sleep during upper airway obstruction in newborns. Experiments were therefore done to investigate the effect of short-term sleep fragmentation on the arousal response to upper airway obstruction in six lambs aged 8 to 14 days. Each lamb was anaesthetized and instrumented for recordings of electrocorticogram, electro-oculogram, nuchal and diaphragm electromyograms and measurements of systemic arterial blood pressure and oxygen saturation (fiberoptic catheter oximeter). A tracheostomy was done and a fenestrated tracheostomy tube placed in the trachea. Experiments were not done before the third postoperative day. During a study, a 5F balloon tipped catheter was inserted into the tube so that airflow could be obstructed by inflating the balloon. Measurements were made during 30 s control periods and during experimental periods of upper airway obstruction in at least three epochs of quiet sleep and active sleep in each animal. These measurements were made following a period of uninterrupted sleep and repeated following a 36-42 h period of sleep fragmentation. Sleep fragmentation was produced by 30 s of noise separated by 2 min of quiet. Sleep fragmentation produced small but statistically significant increases in the time to arousal and decreases in the haemoglobin oxygen saturation at arousal during upper airway obstruction in quiet sleep but not active sleep. However, these changes, although consistent, were small and are of questionable biological significance. Therefore, I believe it is unlikely that short-term sleep fragmentation per se significantly impairs the arousal response to respiratory stimuli in newborns.


Stability of ex vivo coagulation factor activity in never-frozen and thawed refrigerated canine plasma stored for 42 days.
The primary objective of this study was to document coagulation factor activity in canine "NEVER-FROZEN" and "THAWED" refrigerated plasma for the purposes of defining recommended expiration dates. We hypothesized that NEVER-FROZEN and THAWED refrigerated plasma would maintain >50% activity of coagulation factors V (FV), VII (FVII), VIII (FVIII), IX (FIX), X (FX), and von Willebrand factor antigen (vWF) and a concentration of fibrinogen above the lower bound of the reference interval (>0.982 g/L) for greater than 14 days but less than 42 days. Prospective laboratory-based study. University teaching hospital blood bank. Ten canine plasma units derived from healthy client-owned blood donors. Serial sampling (days 0, 1, 3, 5, 7, 10, 14, 17, 21, 24, 28, 32, 35, 39, 42) from NEVER-FROZEN and THAWED refrigerated canine plasma units was conducted for measurement of activities of FV, FVII, FVIII, FIX, FX, vWF, and fibrinogen concentrations using the ACL TOP 300. Plasma was defined as "suitable for transfusion" at a given time point if the entire 95% confidence interval for each factor was above 50% activity and above a fibrinogen concentration of 0.982 g/L. The lower bounds of the FVIII and vWF confidence intervals were above 50% up to and including day 32 for NEVER-FROZEN refrigerated plasma and day 28 for THAWED refrigerated plasma. Confidence intervals for FV, FVII, FIX, and FX remained above 50% activity at all time points. The lower bound of the fibrinogen concentration was <0.982 g/L on day 39 for NEVER-FROZEN refrigerated plasma and on day 35 for THAWED refrigerated plasma. Refrigerated canine plasma from these 10 dogs retained coagulation factor activity above the limit that we defined as suitable for transfusion for up to 32 days when NEVER-FROZEN and 28 days when THAWED. Further studies should evaluate the clinical outcomes and effects on coagulation factor activity of dogs receiving refrigerated plasma transfusions.


[Pelvimetry by digitalized radiography].
We studied the ability of digital radiographs generated on a computed tomography scanner to replace conventional pelvimetry. Two digital radiograph's and one CT section permit us to measure the maternal pelvis. The anteroposterior digital radiograph allows measurement of the maximum transverse and median transverse diameters of the pelvic inlet. These two distances are corrected for magnification after reference to the lateral digital radiograph and to a graph determined owing to a phantom. The anteroposterior digital radiograph also permits to perform a CT section passing through the ischial spines with direct measurement of the inter spinous diameter. The lateral digital radiograph gives us the true values for the anteroposterior diameter of the pelvic inlet, the low sagittal diameter, the cord and the rise of the sacrum. The dosimetry studies demonstrated that maternal skin doses and fetal gonad doses were very low. Pelvimetry using digital radiography is a simple and rapid to perform procedure which offers the advantage of low radiation exposure to both fetus and mother and a high accuracy of measurement.


Crustacean (malacostracan) Hox genes and the evolution of the arthropod trunk.
Representatives of the Insecta and the Malacostraca (higher crustaceans) have highly derived body plans subdivided into several tagma, groups of segments united by a common function and/or morphology. The tagmatization of segments in the trunk, the part of the body between head and telson, in both lineages is thought to have evolved independently from ancestors with a distinct head but a homonomous, undifferentiated trunk. In the branchiopod crustacean, Artemia franciscana, the trunk Hox genes are expressed in broad overlapping domains suggesting a conserved ancestral state (Averof, M. and Akam, M. (1995) Nature 376, 420-423). In comparison, in insects, the Antennapedia-class genes of the homeotic clusters are more regionally deployed into distinct domains where they serve to control the morphology of the different trunk segments. Thus an originally Artemia-like pattern of homeotic gene expression has apparently been modified in the insect lineage associated with and perhaps facilitating the observed pattern of tagmatization. Since insects are the only arthropods with a derived trunk tagmosis tested to date, we examined the expression patterns of the Hox genes Antp, Ubx and abd-A in the malacostracan crustacean Porcellio scaber (Oniscidae, Isopoda). We found that, unlike the pattern seen in Artemia, these genes are expressed in well-defined discrete domains coinciding with tagmatic boundaries which are distinct from those of the insects. Our observations suggest that, during the independent tagmatization in insects and malacostracan crustaceans, the homologous 'trunk' genes evolved to perform different developmental functions. We also propose that, in each lineage, the changes in Hox gene expression pattern may have been important in trunk tagmatization.


Can participatory approaches strengthen the monitoring of cyanobacterial blooms in developing countries? Results from a pilot study conducted in the Lagoon Aghien (Ivory Coast).
Monitoring of cyanobacteria in freshwater ecosystems is a complex task, which is time consuming and expensive due to the chaotic population dynamics and highly heterogeneous distribution of cyanobacteria populations in water bodies. The financial cost constitutes a strong limitation for the implementation of long-term monitoring programs in developing countries, particularly in Africa. The work presented here was performed in the framework of an international project addressing the sustainable monitoring and management of surface water resources used for the production of drinking water in three African countries. We tested the potential of a citizen approach for monitoring cyanobacterial blooms, which are a growing threat to the drinking water supply. This pilot study was designed, implemented and evaluated in close interaction with the Pasteur Institute of the Ivory Coast and with the populations of three villages located on the shoreline of a freshwater lagoon located near Abidjan city. Based on the use of a smartphone application, the citizens of the three villages were invited to report water color changes, as these changes could reflect cyanobacteria proliferations. A two-year experimentation period has shown that it is possible to mobilize the local populations to monitor cyanobacterial blooms. The data collected by citizens were consistent with the data obtained by a classical monitoring of cyanobacteria performed over seven months, but it appeared that new approaches were needed to validate the citizen data. This participatory approach also provided great improvements to the understanding and awareness of local populations regarding water quality and cyanobacterial bloom issues. Finally, we discuss some of the difficulties and limitations of our participatory monitoring approach that should be considered by further implementations. Despite these difficulties, our work suggests that citizen monitoring is a promising approach that may complement the classical approach to sustainable monitoring of cyanobacteria in developing countries.


A rapid method for the determination of perfluoroalkyl substances including structural isomers of perfluorooctane sulfonic acid in human serum using 96-well plates and column-switching ultra-high performance liquid chromatography tandem mass spectrometry.
To facilitate high-throughput analysis suitable for large epidemiological studies we developed an automated column-switching ultra-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for determination of perfluorocarboxylic acids (PFCAs; C5, C6, C7, C8, C9, C10, C11, C12, and C13), perfluoroalkyl sulfonic acids (PFSAs; C4, C6, C8, and C10), perfluorooctane sulfonamide (PFOSA), and five groups of structural perfluorooctane sulfonic acid (PFOS) isomers in human serum or plasma. The analytical procedure involves rapid protein precipitation using 96-well plates followed by an automated sample clean-up using an on-line trap column removing many potentially interfering sample components while through the mobile phase gradient the target analytes are eluted onto the analytical column for further separation and subsequent mass detection. The method was linear (R(2)<0.995) at concentrations ranging from 0.01 to 60ngmL(-1) with method detection limits ranging between 0.01 and 0.17ngmL(-1) depending on the analyte. The developed method was precise, with repeatability (n=7) and reproducibility (n=103) coefficients of variation between 2% and 20% for most compounds including PFOS (2% and 8%) and its structural isomers (2-6% and 4-8%). The method was in conformity with a standard reference material. The column-switching HPLC-MS/MS method has been successfully applied for the determination of perfluoroalkyl substances including structural PFOS isomers in human plasma from an epidemiological study.


Synthesis of novel indole-isoxazole hybrids and evaluation of their cytotoxic activities on hepatocellular carcinoma cell lines.
Liver cancer is predicted to be the sixth most diagnosed cancer globally and fourth leading cause of cancer deaths. In this study, a series of indole-3-isoxazole-5-carboxamide derivatives were designed, synthesized, and evaluated for their anticancer activities. The chemical structures of these of final compounds and intermediates were characterized by using IR, HRMS, 1H-NMR and 13C-NMR spectroscopy and element analysis. The cytotoxic activity was performed against Huh7, MCF7 and HCT116 cancer cell lines using sulforhodamine B assay. Some compounds showed potent anticancer activities and three of them were chosen for further evaluation on liver cancer cell lines based on SRB assay and real-time cell growth tracking analysis. Compounds were shown to cause arrest in the G0/G1 phase in Huh7 cells and caused a significant decrease in CDK4 levels. A good correlation was obtained between the theoretical predictions of bioavailability using Molinspiration calculation, Lipinski's rule of five, and experimental verification. These investigations reveal that indole-isoxazole hybrid system have the potential for the development of novel anticancer agents. This study has provided data that will form the basis of further studies that aim to optimize both the design and synthesis of novel compounds that have higher anticancer activities.


Brief review: Airway rescue with insertion of laryngeal mask airway devices with patients in the prone position.
Unintentional extubation of the trachea while the anesthetized patient is in the prone position is a potentially life-threatening situation that is usually managed by turning the patient supine for emergent re-intubation. However, this approach may delay definitive airway management and lead to irreversible complications. This review evaluates the efficacy of insertion of a laryngeal mask airway device (LMAD) with the patient in the prone position as a rescue method in airway management for unintentional tracheal extubation. We searched MEDLINE and EMBASE databases in the English language for the period 1980 to October 2009 in order to identify observational studies and case reports describing insertion of the LMAD with the patient in the prone position. We found 12 such articles (n = 526 patients) consisting of four retrospective studies, one prospective cohort with a control group, one non-controlled prospective study, and six case reports. On the first attempt, the LMAD was inserted successfully in 87.5-100% of the patients involved in the included reports. On the second attempt, the LMAD was inserted successfully in all patients, with or without laryngoscopy. Ventilation was maintained successfully in the lungs of 83.3-100% of the patients involved in the reported articles. Following insertion of the LMAD with patients in the prone position, the most common complications reported were sore throat, bleeding, bradycardia, and laryngospasm. Cumulative experience from published reports suggests the feasibility of placing the LMAD with the patient in the prone position in the elective setting; however, the evidence is lacking regarding the use of this method for emergency management of unintended tracheal extubation with the patient in the prone position.