Surgical repair of complete proximal hamstring tendon ruptures in water skiers and bull riders: a report of four cases and review of the literature.
Hamstring strains are one of the most common muscle strains in athletes; however, complete rupture of the proximal hamstring origin is rare and results from significant trauma. The objective of this paper is to present our experience of management of complete ruptures where surgical repair resulted in good results in both acute and delayed cases. Two water skiers and two bull riders sustained complete rupture of the proximal origin of the hamstring muscles. All underwent repair of the hamstring origin and sciatic nerve neurolysis. A post operative hamstring rehabilitation programme was instituted. Regular follow up was performed at 2, 3, 6, 9, and 12 months. At a minimum final follow up of 12 months all patients had regained functional knee flexion strength with no pain and a near normal range of knee flexion. All four individuals were able to return to their previous line of work and three were able to return to their pre-injury level of sport. Complete rupture of the hamstring origin is a potentially devastating sports injury that has implications affecting the individual's activities of daily living as well as potential as a sportsperson. Surgical repair restores the distorted anatomy, allows early functional rehabilitation, and avoids the potential debilitating neurological problem of gluteal sciatica.


Many different teaching strategies are used to promote learning in an academic or professional environment. Among these can be noted the emergence of simulation, based on the concept of escape games. To identify methodologies relating to the use, design, and implementation of escape games in health care. The Pubmed, Embase, and CINAHL databases were searched up to December 3, 2018. All studies focusing on the design or development of escape games in the health care field (published in English or French) were included. For each study, the country, target population, design, development, method of evaluation, and results were extracted for analysis. Seven poster abstracts and 9 published articles were included. Twelve escape games were developed in the United States. They were used in medicine (n = 5), pharmacy (n = 4), nursing (n = 4) and other fields (n = 3), mainly within academic teaching contexts (n = 12) but also in professional settings (n = 4). Their goals were to improve knowledge (n = 8), to increase participants' interest and motivation regarding a specific topic (n = 2), and to improve cohesion and communication within a team (n = 2). Ten of the escape games described in the articles were based on a clinical scenario. Ten of the research teams held debriefings with participants, and one did not; 5 articles did not report information about debriefing. Few data exist concerning the use of escape games in the health care setting, and it is too early to judge the efficiency of this approach to learning. However, growing interest justifies systematic monitoring of the literature to follow the evolution of such strategies and to better understand their place in health care education.


Abnormal FHIT protein expression may be correlated with poor prognosis in gastric cancer: a meta-analysis.
Our current meta-analysis is aimed to investigate the relationships between fragile histidine triad (FHIT) protein expression and prognosis in gastric cancer patients. We searched MEDLINE (1966 ~ 2013), the Cochrane Library Database (Issue 12, 2013), EMBASE (1980 ~ 2013), CINAHL (1982 ~ 2013), Web of Science (1945 ~ 2013), and the Chinese Biomedical Database (CBM) (1982 ~ 2013) without any language restrictions. The meta-analysis was conducted using the STATA 12.0 software. Crude hazard ratios (HR) with its 95 % confidence interval (95 % CI) were calculated. Eight clinical cohort studies with a total of 1,361 gastric cancer patients were involved in our meta-analysis. Our results revealed that FHIT-negative patients exhibited a shorter overall survival (OS) time than FHIT-positive patients (HR = 1.23, 95 % CI = 1.01 ~ 1.44, P < 0.001). Ethnicity-stratified analysis demonstrated that FHIT-negative patients have significantly poorer prognosis than FHIT-positive patients among both Caucasians and Asians (all P < 0.05). In conclusion, our meta-analysis provides evidences that negative expression of FHIT protein may be correlated with poor prognosis in patients with gastric cancer. Thus, FHIT expression level may be utilized as an independent prognostic marker for gastric cancer.


Split abdominal wall muscle flap repair vs patch repair of large congenital diaphragmatic hernias.
Large congenital diaphragmatic hernias are commonly repaired with a prosthetic patch. We hypothesized that a split abdominal wall muscle flap would reduce the risk of recurrence. A retrospective review of neonates with congenital diaphragmatic hernia in whom primary repair was not possible was performed. Kaplan-Meier analyses and Cox proportional hazards modeling were performed. Of 153 patients, 46 could not have repair with primary closure of the diaphragm. Thirty-three survived to discharge and were subjected to analysis for recurrence. Ten underwent repair with a patch, whereas 23 had a muscle flap (internal oblique and transversalis) patch. The groups were similar with regard to demographics, need for extracorporeal membrane oxygenation, repair on extracorporeal membrane oxygenation, and size of the defect. Fifty percent of patch repairs recurred with a median time of 0.5 years. Only one (4.3%) of the patients who had muscle flap patch developed a recurrence. This was significant on Kaplan-Meier analysis (P = .0009) and had a hazard ratio of 14.3 on Cox regression (P = .018). Median follow-up exceeded 4 years. No children required surgery for an abdominal wall hernia. The split abdominal wall muscle flap allows for closure of large congenital diaphragmatic hernia defects with autologous tissue. This approach is associated with significantly fewer recurrences than patch repairs.


Effects of indigo carmine intravenous injection on oxygen reserve index (ORi™) measurement.
To retrospectively investigate the effects of indigo carmine intravenous injection on oxygen reserve index (ORi™) in 20 patients who underwent elective gynecologic surgery under general anesthesia. The study subjects were patients who underwent elective gynecologic surgery under general anesthesia between April 2016 and January 2017, and were administered a 5-ml intravenous injection of 0.4% indigo carmine for clinical purposes during surgery with ORi monitoring. Changes in ORi within 20 min after indigo carmine injection were observed. A relevant decrease in ORi was defined as ≥ 10% reduction in ORi from pre-injection level. ORi rapidly decreased after indigo carmine intravenous injection in all patients. In 10 of 19 patients, ORi decreased to 0 after indigo carmine injection. The median lowest value of ORi was 0 (range 0-0.16) and the median time to reach the lowest value of ORi was 2 min (range 1-4 min) after injection. ORi values returned to pre-injection levels within 20 min in 13 of 19 patients, and the median time to return to pre-injection levels was 10 min (range 6-16 min) after injection. During ORi monitoring it is necessary to consider the rapid reduction in ORi after intravenous injection of indigo carmine.


The impact of environmental and climatic variables on genetic diversity and plant functional traits of the endangered tuberous orchid (Orchis mascula L.).
Understanding how environmental factors shape patterns of genetic and phenotypic variations in a species is necessary for conservation and plant breeding. However, these factors have not yet been completely understood in tuberous orchid species used to make 'Salep', an important ingredient in traditional medicine and beverages in middle eastern countries and India. In many areas, increasing demand has pushed species to the brink of extinction. In this study, 198 genotypes from 18 populations of the endangered species Orchis mascula L. spanning a large-scale climatic gradient in northern Iran were used to investigate patterns of genetic diversity and plant functional traits. Populations were sampled from three land cover types (woodland, shrubland, and pastureland/grassland). Plant height, stem length, number of flowers, bulb fresh and dry weight, glucomannan, and starch concentrations showed high variation among populations and were significantly related to land cover type. In general, genetic diversity was high, particularly in those from eastern Hyrcanian; additionally, populations showed a high level of genetic differentiation (G'st = 0.35) with low gene flow (Nm = 0.46). The majority of genetic differentiation occurred within populations (49%) and land cover types (20%). The population structural analysis using the AFLP marker data in K = 4 showed a high geographical affinity for 198 O. mascula genotypes, with some genotypes having mixed ancestry. Temperature and precipitation were found to shape genetic and phenotypic variation profoundly. Significant isolation by the environment was observed, confirming the strong effect of environmental variables on phenotypic and genetic variation. Marker-trait association studies based on MLM1 and MLM2 models revealed significant associations of P-TGG + M-CTT-33 and E-AGG + M-CGT-22 markers with plant height and glucomannan content. Overall, a combination of large-scale climatic variables and land cover types significantly shaped genetic diversity and functional trait variation in O. mascula populations.


A mathematical model reveals the influence of NPIs and vaccination on SARS-CoV-2 Omicron Variant.
An SVEIR SARS-CoV-2 Omicron variant model is proposed to provide some insights to coordinate non-pharmaceutical interventions (NPIs) and vaccination. Mathematically, we define the basic reproduction number R 0 and the effective reproduction number R e to measure the infection potential of Omicron variant and formulate an optimal disease control strategy. Our inversion results imply that the sick period of Omicron variant in the United States is longer than that of Delta variant in India. The decrease in the infectious period of the infection with infectiousness implies that the risk of hospitalization is reduced; but the increasing period of the infection with non-infectiousness signifies that Omicron variant lengthens the period of nucleic acid test being negative. Optimistically, Omicron's death rate is only a quarter of Delta's. Moreover, we forecast that the cumulative cases will exceed 100 million in the United States on February 28, 2022, and the daily confirmed cases will reach a peak on February 2, 2022. The results of parameters sensitivity analysis imply that NPIs are helpful to reduce the number of confirmed cases. In particular, NPIs are indispensable even if all the people were vaccinated when the efficiency of vaccine is relatively low. By simulating the relationships of the effective reproduction number R e , the vaccination rate and the efficacy of vaccine, we find that it is impossible to achieve the herd immunity without NPIs while the efficiency of vaccine is lower than 88.7 % . Therefore, the herd immunity area is defined by the evolution of relationships between the vaccination rate and the efficacy of vaccine. Finally, we present that the disease-induced mortality rate demonstrates the periodic oscillation and an almost periodic function is deduced to match the curve. A discussion completes the paper.


Expression of an extracellular calcium-sensing receptor in rat stomach.
Circulating levels of Ca2+ can influence secretory functions and myoelectrical properties of the stomach. A Ca2+-sensing receptor (CaR) has recently been identified in tissues that regulate systemic Ca2+ homeostasis. The aim of this study was to evaluate expression of CaR in the stomach of the rat. In forestomach and glandular stomach, reverse-transcription polymerase chain reaction was used to amplify a 380-base pair product, which is 99% homologous with transcripts obtained in parathyroid and kidney. Northern analysis of gastric mucosal polyA+ RNA revealed 7. 5- and 4.1-kilobase transcripts, similar to those obtained in rat parathyroid and kidney. Immunohistochemistry revealed CaR expression in regions of the submucosal plexus and myenteric neurons. In sections of intact tissue, preparations of primary culture surface cells and surgically dissected gastric glands, staining was observed consistently in epithelial cells of the gastric glands and in gastric surface cells. In parietal cells in isolated gastric glands, intracellular levels of Ca2+ responded to conditions that are known to activate CaR. These are the first reported observations that CaR is expressed in different epithelial cells of mammalian gastric mucosa and its enteric nerve regions. The effects of extracellular Ca2+ on gastric function may be attributable to activation of CaR.


Equalization enhanced phase noise in Nyquist-spaced superchannel transmission systems using multi-channel digital back-propagation.
Superchannel transmission spaced at the symbol rate, known as Nyquist spacing, has been demonstrated for effectively maximizing the optical communication channel capacity and spectral efficiency. However, the achievable capacity and reach of transmission systems using advanced modulation formats are affected by fibre nonlinearities and equalization enhanced phase noise (EEPN). Fibre nonlinearities can be effectively compensated using digital back-propagation (DBP). However EEPN which arises from the interaction between laser phase noise and dispersion cannot be efficiently mitigated, and can significantly degrade the performance of transmission systems. Here we report the first investigation of the origin and the impact of EEPN in Nyquist-spaced superchannel system, employing electronic dispersion compensation (EDC) and multi-channel DBP (MC-DBP). Analysis was carried out in a Nyquist-spaced 9-channel 32-Gbaud DP-64QAM transmission system. Results confirm that EEPN significantly degrades the performance of all sub-channels of the superchannel system and that the distortions are more severe for the outer sub-channels, both using EDC and MC-DBP. It is also found that the origin of EEPN depends on the relative position between the carrier phase recovery module and the EDC (or MC-DBP) module. Considering EEPN, diverse coding techniques and modulation formats have to be applied for optimizing different sub-channels in superchannel systems.


Spinal deformities in a wild line of Poecilia wingei bred in captivity: report of cases and review of the literature.
To describe the occurrence of various spinal deformations in a captive-bred wild line of Poecilia wingei (P. wingei). Fish belonging to a wild line of P. wingei caught from Laguna de Los Patos, Venezuela, were bred in an aquarium home-breeding system during a period of three years (2006-2009). The spinal curvature was observed to study spinal deformities in P. wingei. Out of a total of 600 fish, 22 showed different types of deformities (scoliosis, lordosis, kyphosis), with a higher incidence in females. Growth, swimming and breeding of deformed fish were generally normal. Possible causes for spinal curvature in fish are discussed on the basis of the current literature. While it is not possible to determine the exact cause(s) of spinal deformities observed in the present study, traumatic injuries, nutritional imbalances, genetic defects or a combination of these factors can be supposed to be involved in the pathogenesis of such lesions.


Giant serpentine intracranial aneurysm after carotid ligation. Case report.
A case is reported of a giant aneursym of the intracavernous portion of the left internal carotid artery that was treated initially with a left common carotid artery ligation. Six months later the aneurysm was partially removed. During this time the development and evolution of thrombus formation, a serpentine channel, and a hypervascular capsule was easily followed with recreated computerized tomography and angiography of the aneurysm.


Treatment patterns and outcomes among women with brain metastases from gynecologic malignancies.
Brain metastasis secondary to gynecologic malignancy is rare and has no definitive management guidelines. In this descriptive study, we aimed to identify prognostic factors and treatments that may be associated with longer overall survival. Patients with brain metastases from gynecologic malignancies were identified between 2004 and 2019 at two institutions. Descriptive statistics were performed using N (%) and median (interquartile range). Univariate cox proportional hazards regression was performed to evaluate the effect of different factors on overall survival. 32 patients presented with brain metastasis from gynecologic primaries (ovarian/fallopian tube/primary peritoneal n = 14, uterine n = 11, cervical n = 7). Median age of initial cancer diagnosis was 61 (34-79). At initial cancer diagnosis 83% of patients were Stage III/IV and underwent surgery (66%), chemotherapy (100%), and/or pelvic radiation (33%). Median time from initial cancer diagnosis to brain metastasis was 18 months. Treatment of brain metastasis with surgery and radiation compared to stereotactic radiosurgery or whole brain radiation therapy alone revealed a trend toward longer overall survival (p = 0.07). Time from initial cancer diagnosis to brain metastasis was associated with longer overall survival with each one-month increase from initial cancer diagnosis associated with a 7% reduction in risk of death (HR 0.93, 95% CI = 0.89-0.97, p = 0.01). Initial cancer treatment, stage, histology, and number of brain lesions did not affect overall survival. Patients with brain metastasis secondary to gynecologic malignancies with the longest overall survival had the greatest lag time between initial cancer diagnosis and brain metastasis. Brain metastasis treated with surgery and radiation was associated with longer overall survival.


Efficient synthesis and cell-based silencing activity of siRNAS that contain triazole backbone linkages.
An efficient synthesis of siRNAs modified at the backbone with a triazole functionality is reported. Through the use of 4,4'-dimethoxytrityl (DMT) phosphoramidite chemistry, triazole backbone dimers were site-specifically incorporated throughout various siRNAs targeting both firefly luciferase and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene transcripts as representatives of an exogenous and endogenous gene, respectively. Following the successful silencing of the firefly luciferase reporter gene, triazole-modified siRNAs were also found to be capable of silencing GAPDH in a dose-dependent manner. Backbone modifications approaching the 3'-end on the sense strand were tolerated without compromising siRNA potency. This study highlights the compatibility of triazole-modified siRNAs within the RNAi pathway, and the modification's potential to impart favorable properties to siRNAs designed to target other endogenous genes.


A prospective cohort study investigating contributors to mild cognitive impairment in adults with spinal cord injury: study protocol.
Studies report rates of mild cognitive impairment (MCI) in spinal cord injury (SCI) range between 10 and 60%. This broad estimate of MCI in SCI is most likely a result of: (i) inconsistent operationalization of MCI; (ii) heterogeneity among individuals with SCI; (iii) failure to account for MCI subtypes, thereby adding to the heterogeneity of samples; and, (iv) poor control for traumatic brain injury (TBI) that obscures differentiation of MCI attributable to TBI versus other factors. There is a paucity of longitudinal studies following the course of MCI in SCI, and none that account for multiple predictors of MCI, including interactions among predictors. An inception cohort longitudinal study will assess approximately 100 individuals aged 17-80 years with acute SCI, with measures taken at three timepoints (baseline, 3 months post-baseline, and 12 months post-injury). Data relevant to medical care received within the first 24-48 h of presentation to the emergency department will be analysed, as will measures of cognition, injury characteristics, medical history, personal factors, psychological status, psychosocial functioning, and quality of life. Latent class mixture modelling will determine trajectories for the primary outcome of interest, cognitive functioning and its subtypes, and secondary outcomes of interest such as depression. Multiple regression analyses will identify predictors of MCI and its subtypes. The prospective design will reveal change in cognitive functioning across time and unveil different outcome trajectories; thus addressing the lack of knowledge on trajectories of MCI and MCI subtypes in SCI. Through subtyping MCI, we hope to yield groups of cognitively impaired individuals with SCI that are potentially more homogenous and thereby stable and predictable. This is the first study to capture emergency department and acute care diagnostic evidence of mild TBI, which has been poorly controlled in previous studies. Our study will also be the first to distinguish the contribution of TBI from other factors to the development of MCI in individuals with SCI. The study was prospectively registered with the Australian and New Zealand Clinical Trial Registry ( ACTRN12619001702101 ) on 3rd December 2019.


ATF3 plays a role in adipocyte hypoxia-mediated mitochondria dysfunction in obesity.
Obesity-associated adipose tissue hypoxia plays a pivotal role in insulin resistance via impaired adipocyte dysfunction including mitochondria dysfunction. In this study, we investigated the involvement of hypoxia-inducible ATF3 in adipocyte hypoxia-mediated mitochondrial dysfunction. While HIF-1α and ATF3 were increased in white adipose tissue of high fat diet (HFD) obese mice compared with control lean mice, mitochondria-related genes were significantly reduced. Treatment with hypoxia mimetics CoCl(2) or incubation with 2% O(2) impaired mitochondria function as demonstrated by decreases in ATP production, NADH dehydrogenase activity, mitochondrial membrane potential, and reduced expression of mitochondria-related genes including NRF-1, PGC-1α, COX1 and SOD in 3T3-L1 adipocyte cells. Furthermore, overexpression of ATF3 in 3T3-L1 cells also decreased mitochondria function as well as expression of mitochondria-related genes. ATF3 knockdown in 3T3-L1 cells partly prevented the hypoxia-mediated decrease in mitochondria function and expression of mitochondria-related genes. The mitochondria-related genes were decreased in white adipose tissue of ATF3-overexpressing mice compared with wild-type mice. These results suggest that ATF3 may play a role in adipocyte hypoxia-mediated mitochondrial dysfunction in obesity.


Recurrent inhibition in human spinal spasticity.
The study was performed on a group of 17 patients with spastic paraparesis: 12 with hereditary spastic paraparesis, 3 with cord compression and 2 with complete spinal transection. 10 healthy volunteers acted as controls. Recurrent inhibition of the soleus alpha-motoneurones was estimated at rest and during voluntary contraction of triceps surae. At rest, there was evidence for a substantial decrease in the excitability of Renshaw cells in 9 out of the 12 patients with hereditary spastic paraparesis; this was also observed in the 2 patients with complete spinal transection, while the 3 patients with cord compression exhibited a normal Renshaw cell activity. In 3 out of 4 patients with hereditary spastic paraparesis, the changes in Renshaw cell excitability expected to occur during voluntary contraction were not found, whereas in one patient with hereditary spastic paraparesis and one with spastic paraparesis due to cord compression recurrent inhibition was normally influenced by the motor command. Our results indicate that recurrent inhibition is likely to be differently affected according to the type and/or localization of the lesion. It is also suggested that the central nervous system might control the excitability of Renshaw cells at rest and during voluntary contraction via partly separate pathways. The role of recurrent inhibition in spasticity is discussed.


Atomoxetine Decreases Mitochondrial Biogenesis, Fission and Fusion In Human Neuron-like Cells But Does Not Alter Antioxidant Defences.
Atomoxetine (ATX) is a presynaptic norepinephrine transporter (NET) inhibitor widely prescribed for attention-deficit/hyperactivity disorder (ADHD) due to its low abuse potential and absence of psychostimulant effects. While NET inhibition is implicated in the clinical response, several additional pharmacoactivities may contribute to clinical efficacy or unwanted side effects. We recently reported that ATX can dose-dependently alter mitochondrial function and cellular redox status. Here, we assessed potential alterations in mitochondrial biogenesis, mitochondrial dynamics and cellular antioxidant capacity following high- and low-dose ATX treatment of differentiated human neuroblastoma cells. Human SH-SY5Y neuroblastoma cells were treated with ATX (1, 5, 10, 20 and 50 μM) for 7 days under differentiation culture conditions. Changes in the expression levels of protein markers for mitochondrial biogenesis, fusion and fission as well as of antioxidant proteins were analysed by Western blot. High-dose ATX (50 μM) reduced while low-dose ATX (10 μM) increased mitochondrial biogenesis as evidenced by parallel changes in SDHA, COX-I, PGC1α and TFAM expression. High-dose ATX also reduced mitochondrial fusion as evidenced by OPA1 and MFN2 downregulation, and mitochondrial fission as indicated by DRP1 and Fis1 downregulation. In contrast, ATX did not alter expression of the antioxidant enzymes SOD1 and catalase, the phase II transcription factor Nfr2, or the Nfr2-regulated antioxidant enzyme NQO1. Clinical responses and side effects of ATX may be mediated by dose-dependent modulation of mitochondrial biogenesis and dynamics as well as NET inhibition.


Practice patterns and career satisfaction of Canadian female general surgeons.
We wanted to study how female general surgeons in Canada manage lifestyle and career demands. All female Canadian general surgeons registered with the Royal College of Physicians and Surgeons of Canada were asked to complete a survey evaluating their practice patterns, personal lives, and levels of satisfaction related to these factors. Eighty-five surveys (66%) were returned. Most respondents work in full-time clinical practices. While it was rare to find women in part-time or shared practices, 35% of women reported interest in these alternative models. Respondents described the necessary factors for a transition into alternative models. Job satisfaction was high (3.8 out of 5), with personal and parenting satisfaction being less highly rated (3.3 and 3.2, respectively). Canadian female general surgeons have active and satisfying careers, although many would like to work in alternative practice models that better conform to their lifestyle demands. This pressure will have a significant impact on the future surgical workforce.


Epitranscriptome marks detection and localization of RNA modifying proteins in mammalian ovarian follicles.
Most of the resources that support the early development of the embryo are stored in the oocyte. Clearing of maternal resources and activation of the embryonic genome to produce its own mRNA transcripts marks the maternal-to-embryo transition. Dependence on stored mRNA can last from a few hours to several days, depending on animal species. The mechanisms regulating stabilization and recruitment of stored maternal transcripts have not yet been described in full detail but are known to involve reversible polyadenylation and modulation of 3'UTR-mediated elements. RNA epigenetic modifications, new players in this field, have an important role in RNA regulation and stabilization. The objectives of this study were first to determine if some of post-transcriptional methylation of stored mRNA is greater in oocytes than in somatic cells. We found that m6A, known to be the most prevalent and involved in various aspects of RNA metabolism and physiological functions, is particularly abundant in porcine oocyte mRNA compared to liver used as a somatic tissue reference. The second objective was to compare the epitranscriptome machinery, such as methyltransferases ("writers"), binding proteins ("readers") and demethylases ("erasers") catalyzing the different process, in follicles and oocytes of different mammalian species by immunofluorescence and confocal microscopy. The expression and localization patterns of these proteins differ between mice, pigs and cows ovaries and oocytes. m5C-associated proteins were generally less abundant. In contrast, m6A-associated proteins were expressed strongly during the early and late stages of folliculogenesis. Transzonal projections were found to contain more granules bearing the m5C mark in mice but both m5C and m6A methylation marks in association with mature oocytes of pigs and cows. Eraser proteins showed the greatest interspecies diversity in terms of distribution in the germinal tissues. So far, few studies have looked at the oocyte and ovarian epitranscriptomic profile. Our findings indicate that a hitherto unrecognized species-specific layer of transcript regulation occurs at the RNA level and might be consequential during the oocyte transcriptional silencing period.


A simple method to estimate functional residual capacity in mechanically ventilated patients.
The aim of the present study was to evaluate a simplified method for FRC measurement. Accuracy and precision of the method were assessed in a physical lung model; reproducibility was tested in 10 mechanically ventilated patients. In each patient FRC was measured at three PEEP levels. Post-operative intensive care unit in a university hospital. Gas flow, CO2 concentration, and O2 concentration were measured during in- and expiration by pneumotachography, a mainstream capnometer and a sidestream O2-analyser. For FRC-measurement inspiratory O2 concentration was changed by 30%. FRC was determined as mean value of a N2 washout and N2 washin procedure. Evaluation of this method in a lung model shows a good correlation between FRC set in the lung model and FRC measured (FRC measured = 1.028*FRG model + 22.92 ml; r2 = 0.957; n = 30). The mean difference was 4.4% of FRC-reference (range -8.4% to +21.7%). Duplicate determinations in 10 mechanically ventilated patients differed by an average of -2.7% (range -30.1% to +27.3%). Our results suggest that the proposed method can be used in daily clinical work.


Seizure outcome with responsive neurostimulation (RNS) comparing strip versus depth leads.
This study aimed to compare seizure outcomes and complication rates in patients treated with only responsive neurostimulation (RNS) strip leads with those treated with only RNS depth leads. A retrospective cohort study was performed using the institutional epilepsy surgery database. Included was any patient implanted with the RNS system between August 2015 and May 2018 with either two depth (2D) or two strip (2S) leads connected to the device and at least 6 months follow-up. Excluded were those with a combination of active depth and strip leads. Data extracted from the charts comprised demographic information, duration of epilepsy, presence of a magnetic resonance imaging (MRI) lesion, prior resective surgery, clinically disabling seizures at baseline and follow-up, prior invasive monitoring, location (mesial temporal or neocortical) and number of seizure foci, unilateral or bilateral RNS lead placement, and postoperative complications. Of 48 screened patients, 34 met study inclusion criteria. Of these, 15 were treated with 2D leads and 19 with 2S leads. Groups 2D and 2S were comparable with respect to age at onset, duration of epilepsy, baseline seizure frequency, and exposure time to RNS. After adjustment for patient age and duration of epilepsy, seizure frequency in 2S patients was noted to be decreased by 83% (p = 0.046), while it was reduced by 51% (p = 0.080) in 2D patients. The complication rate was not significantly different between the two groups. In our small retrospective population, patients with RNS strip leads experienced a significantly greater seizure reduction than patients with RNS depth leads, without a difference in complication rate.


Revisiting depressive-prone bipolar disorder: polarity of initial mood episode and disease course among bipolar I systematic treatment enhancement program for bipolar disorder participants.
We examined the hypothesis that a first depressive rather than manic episode in bipolar disorder might herald a subsequent course notable for greater burden of depressive symptoms. We analyzed retrospective data on the polarity of first mood episode obtained from 704 bipolar I subjects entering the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study. Subjects with an initial manic or depressive episode and those in whom both poles occurred within the same year were compared. Depressive-onset bipolar disorder was more common in women and those with earlier onset of illness. Adjusting for these differences, it was significantly associated with more lifetime depressive episodes and a greater proportion of time with depression and anxiety in the year prior to study entry. Polarity of first mood episode may be useful in distinguishing subsets of bipolar patients at risk for a more chronic course.


Guinea pig lung eosinophil: purification and prostaglandin production.
Guinea pig lung eosinophils have been purified from bronchoalveolar lavage (BAL) fluid, and the production of prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and 6-keto-PGF1 alpha was measured after stimulation with phorbol myristate acetate (PMA), platelet-activating factor (PAF), and formyl-methionyl-leucyl-phenylalanine (fMLP). A combination of plating and discontinuous Percoll gradient centrifugation was used to purify eosinophils. The purity of eosinophils in fraction E (interface between Percoll density 1.057-1.068) was around 96%, and the viability was 99%, with a mean yield of 2.7 x 10(6) cells per guinea pig. Similarly, in fraction D (interface between Percoll density 1.047-1.057), the mean purity of eosinophils was 76% and the viability of cells was 99%, with a mean yield of 1.1 x 10(6) cells per guinea pig. Purified eosinophils produced TXB2 predominantly after stimulation with PMA, fMLP, and PAF. The 6-keto-PGF1 alpha was slightly increased in cell supernatants after stimulation with PMA and fMLP, but PGE2 was not elevated with any stimulus. The highly purified eosinophils of fraction E generated amounts of TXB2 and 6-keto-PGF1 alpha similar to the amount generated by eosinophils contaminated with some macrophages (fraction D). These results suggest a role for eosinophils in the production of TXA2 by guinea pig lung.


Imaging technique and clinical utility for electrophysiologic procedures of lower frequency (9 MHz) intracardiac echocardiography.
Intracardiac echocardiography using a new 9-MHz ultrasound catheter was performed in 30 patients undergoing percutaneous catheter mapping and radiofrequency ablation of a tachyarrhythmia, because the imaging capabilities with this intracardiac echocardiographic catheter permit detailed identification of normal and abnormal cardiac anatomy with improved imaging depth. Intracardiac echocardiography is of significant clinical utility during ablation for guiding interatrial septal puncture, assessing placement and contact of mapping/ablation catheters, monitoring ablation lesion morphologic changes, and diagnosing procedure-related complications.


Discovery of novel nonpeptide small-molecule NRP1 antagonists: Virtual screening, molecular simulation and structural modification.
Multifaceted roles of vascular endothelial growth factor (VEGF)-neuropilin-1 (NRP1) interaction have been implicated in cancer, but reports on small-molecule inhibitors of VEGF-NRP1 interaction are scarce. Herein, we describe the identification of 1, a novel nonpeptide small-molecule NRP1 antagonist with moderate activity via structure-based virtual screening. Ensemble docking and molecular dynamics (MD) simulations of 1 were carried out and an interesting binding model was obtained. We found that the "aromatic box" enclosed by Tyr297, Trp301 and Tyr353 of NRP1 is critical for NRP1-1 binding. Further structure modification of 1 based on the binding model derived from MD simulations resulted in the identification of 12a with significantly improved activity.


The impact of volume substitution on post-operative atrial fibrillation.
Post-operative atrial fibrillation (POAF) represents a common complication after cardiac valve or coronary artery bypass surgery. While strain of atrial tissue is known to induce atrial fibrillating impulses, less attention has been paid to potentially strain-promoting values during the peri- and post-operative period. This study aimed to determine the association of peri- and post-operative volume substitution with markers of cardiac strain and subsequently the impact on POAF development and promotion. A total of 123 (45.4%) individuals were found to develop POAF. Fluid balance within the first 24 hours after surgery was significantly higher in patients developing POAF as compared to non-POAF individuals (+1129.6 mL [POAF] vs +544.9 mL [non-POAF], P = .044). Post-operative fluid balance showed a direct and significant correlation with post-operative N-terminal pro-brain natriuretic peptide (NT-ProBNP) values (r = .287; P = .002). Of note, the amount of substituted volume significantly proved to be a strong and independent predictor for POAF with an adjusted odds ratio per one litre of 1.44 (95% CI: 1.09-1.31; P = .009). In addition, we observed that low pre-operative haemoglobin levels at admission were associated with a higher need of intraoperative transfusions and volume-demand. Substitution of larger transfusion volumes presents a strong and independent predictor for the development of POAF. Via the observed distinct association with NT-proBNP values, it can reasonably be assumed that post-operative atrial fibrillating impulses are triggered via increased global cardiac strain. Optimized pre-operative management of pre-existing anaemia should be considered prior surgical intervention in terms of a personalized patient care.


Merlin links to the cAMP neuronal signaling pathway by anchoring the RIbeta subunit of protein kinase A.
The cAMP-protein kinase A (PKA) pathway, important in neuronal signaling, is regulated by molecules that bind and target PKA regulatory subunits. Of four regulatory subunits, RIbeta is most abundantly expressed in brain. The RIbeta knockout mouse has defects in hippocampal synaptic plasticity, suggesting a role for RIbeta in learning and memory-related functions. Molecules that interact with or regulate RIbeta are still unknown. We identified the neurofibromatosis 2 tumor suppressor protein merlin (schwannomin), a molecule related to the ezrin-radixin-moesin family of membrane-cytoskeleton linker proteins, as a binding partner for RIbeta. Merlin and RIbeta demonstrated a similar expression pattern in central nervous system neurons and an overlapping subcellular localization in cultured hippocampal neurons and transfected cells. The proteins were coprecipitated from brain lysates by cAMP-agarose and coimmunoprecipited from cellular lysates with specific antibodies. In vitro binding studies verified that the interaction is direct. The interaction appeared to be under conformational regulation and was mediated via the alpha-helical region of merlin. Sequence comparison between merlin and known PKA anchoring proteins identified a conserved alpha-helical PKA anchoring protein motif in merlin. These results identify merlin as the first neuronal binding partner for PKA-RIbeta and suggest a novel function for merlin in connecting neuronal cytoskeleton to PKA signaling.


Light- and pH-dependent structural changes in cyanobacteriochrome AnPixJg2.
Cyanobacteriochromes (CBCRs) are phytochrome-related photosensory proteins that play an essential role in regulating phototaxis, chromatic acclimation, and cell aggregation in cyanobacteria. Here, we apply solid-state NMR spectroscopy to the red/green GAF2 domain of the CBCR AnPixJ assembled in vitro with a uniformly 13C- and 15N-labeled bilin chromophore, tracking changes in electronic structure, geometry, and structural heterogeneity of the chromophore as well as intimate contacts between the chromophore and protein residues in the photocycle. Our data confirm that the bilin ring D is strongly twisted with respect to the B-C plane in both dark and photoproduct states. We also identify a greater structural heterogeneity of the bilin chromophore in the photoproduct than in the dark state. In addition, the binding pocket is more hydrated in the photoproduct. Observation of interfacial 1H contacts of the photoproduct chromophore, together with quantum mechanics/molecular mechanics (QM/MM)-based structural models for this photoproduct, clearly suggests the presence of a biprotonated (cationic) imidazolium side-chain for a conserved histidine residue (322) at a distance of ~2.7 Å, generalizing the recent theoretical findings that explicitly link the structural heterogeneity of the dark-state chromophore to the protonation of this specific residue. Moreover, we examine pH effects on this in vitro assembled holoprotein, showing a substantially altered electronic structure and protonation of the photoproduct chromophore even with a small pH drop from 7.8 to 7.2. Our studies provide further information regarding the light- and pH-induced changes of the chromophore and the rearrangements of the hydrogen-bonding and electrostatic interaction network around it. Possible correlations between structural heterogeneity of the chromophore, protonation of the histidine residue nearby, and hydration of the pocket in both photostates are discussed.


Identifying drivers affecting air quality in metropolitan areas of developing countries: evidence from Tehran metropolitan area.
Environmental issues and the significant reduction of air quality in the metropolitan areas of developing countries have become chronic challenges. While the impacts of many reasons such as the rapid trend of urbanization, lacking sustainable thinking in urban planning approaches, and urban sprawl have been explored in previous literature, the role of political economy, especially the structure based on the rentier economy, in the change of air quality as an environmental challenge in the metropolitan areas of developing countries has received little attention. To fill this gap, this study focuses on the role of the rentier economy and identifies the drivers based on it that have a tremendous impact on the air quality in Tehran metropolitan area, Iran. To this end, using the Grounded Theory (GT) foundation database and two-round Delphi survey, the opinions of 19 experts were used to identify and explain major drivers that impact air quality in Tehran. Our findings revealed that nine major drivers have an increasing impact on the air quality in the metropolitan area of Tehran. These drivers considering the dominance of the rentier economy are interpreted as the lack of powerful local governance, the rental economy, centralized structure of government, unsustainable economic development, institutional conflicts, a faulty planning system, financial unsustainability of municipalities, unfair distribution of power, and inefficient urban development policies. Among the drivers, the impacts of institutional conflicts and lack of powerful local governance on air quality are more considerable. This study highlights the role of the rentier economy as a major obstacle to resilient responses and constructive actions against chronic environmental challenges such as drastic changes in air quality in metropolitan areas of developing countries.


Establishment and characterization of a new human renal cell carcinoma cell line (KRC/Y).
A new renal cell carcinoma (RCC) cell line (KRC/Y) has been established from a surgical specimen of a 41-yr-old Japanese female patient with RCC composed of both clear cells and granular cells. This cell line has been maintained for more than 15 mo. through 45 passages with a stable growth. KRC/Y cells have clear or eosinophilic polygonal cytoplasm and round to oval nuclei with one or two nucleoli, and proliferate in a pavementlike cell arrangement with a lack of contact inhibition. By electron microscopy, these cells contain abundant fat droplets and glycogen granules or well-developed organelles or both, which were also observed in the original tumor. The doubling time of these cells at the 15th passage was 73 h. The chromosome number was from 37 to 45 with a hypodiploid modal number of 42. Tumorigenicity was identified by tumor formation after subcutaneous injections of KRC/Y cells in nude mice, which showed close resemblance to the original tumor by light and electron microscope observations.


Magnetically engineered smart thin films: toward lab-on-chip ultra-sensitive molecular imaging.
Magnetically responsive engineered smart thin films of nanoferrites as contrast agent are employed to develop surface based magnetic resonance imaging to acquire simple yet fast molecular imaging. The work presented here can be of significant potential for future lab-on-chip point-of-care diagnostics from the whole blood pool on almost any substrates to reduce or even prevent clinical studies involve a living organism to enhance the non-invasive imaging to advance the '3Rs' of work in animals-replacement, refinement and reduction.


Aptameric GT oligomers need to be complexed to ethoxylated polyethylenimine as pre-paired duplexes to efficiently exert their cytotoxic activity in human lymphoblastic cancer cells.
The aptameric oligonucleotides GT were found to exert a selective, specific and dose-dependent cell growth inhibition effect on a variety of human cancer cells by recognising specific nuclear proteins and among these in particular an isoform of the eukaryotic elongation factor 1A1 (EEF1A1). The potential development of these aptameric oligomers needs that they retain serum and intracellular stabilities. Polycations are safe non-viral carriers of the nucleic acids. We demonstrated that a weakly basic polycation, the ethoxylated polyethylenimine (EPEI), can efficiently deliver cytotoxic GT oligomers when they were complexed as partial pre-paired duplex. In this way, nuclease-resistance of the oligomer was markedly improved and the administration of the duplex complexed with EPEI to lymphoblastic cancer cells caused a specific cytotoxic effect at concentrations lower than that of naked GT. However, the cytotoxic activity of the oligomer-EPEI complex resulted strictly related to the GC content and Tm of the duplex region. The single-stranded GT and the duplex with high GC content and Tm, although complexed with EPEI failed to exert cytotoxicity. Overall results indicated that aptameric oligomers complexed with polycations can be efficiently delivered into the cells and display the desired biological effect designing a balanced partial duplex whose stability can allow oligomer release from the polycation under the physiological cellular conditions.


Improved usability of a new handle design for laparoscopic dissection forceps.
Recent studies have shown that the shape of most instrument handles causes user discomfort and that none of the handles currently available on the market satisfies all ergonomic criteria. Therefore, we designed a handle with improved usability; i.e., it is easier to manipulate and its use entails less risk of injury for the operator. The aim of this study was to demonstrate that the intended improvements of the new design were successful. Six handles representative of the types that are currently available were compared with the new version. Eight surgeons used the seven handles during a precision task and a rough task in a pelvi-trainer. A questionnaire and video analyses were used to assess the usability of the handles. Based on the responses to the questionnaire, we determined that there were significant differences between the new handle and the Aesculap handle (means of rotation and angle between handle and shaft). No significant differences were found between the new handle and the five other handles. The video analyses (documenting extreme vs neutral wrist excursions) showed significant differences between the new handle and the six other handles. Compared to the six existing handles, the new handle has significantly improved usability; in particular, its hinged design obviates the need to make extreme wrist excursions.


An effective technique for open reduction of mandibular angle fractures using new reduction forceps: technical innovations.
We demonstrate a new technique that is useful for precompressing and holding mandibular angle fractures by means of new reduction forceps. The forceps were designed for application in the mandibular angle area via a transoral approach.


Interactions between essential and toxic elements in lead exposed children in Katowice, Poland.
To determine the influence of the essential element status on blood concentrations of lead and other toxic metals. A group of 157 children from Katowice, an industrial area in Poland, was investigated for concentrations of lead and cadmium in whole blood, and mercury, selenium, zinc, copper, and magnesium in whole blood and serum. Relations between these elements, serum ferritin, hematological parameters, as well as serum selenoprotein P and glutathione peroxidase (GSH-px) were examined. Conversion factors for element concentrations (mumol to microgram): lead 207.19, cadmium 112.41, mercury 200.59, selenium 78.96, magnesium 24.31, copper 63.55, and zinc 65. Blood lead was negatively associated with concentrations of selenium in whole blood and serum as well as selenoprotein P and glutathione peroxidase in serum. The association was mainly apparent at low blood lead concentrations, which may indicate an influence of selenium on the kinetics of lead, rather than an effect of lead on the selenium status. Children with low serum ferritin levels had statistically higher blood cadmium levels and a tendency for higher blood lead levels, indicating increased gastrointestinal absorption of these metals at reduced iron stores. Blood lead was negatively correlated with mean corpuscular hemoglobin concentration, which may reflect the effect of lead on hemoglobin synthesis. There was an association between blood mercury and selenium, indicating a common source of intake through fish consumption. The results indicate that selenium and iron status may influence the kinetics of lead.


Noninvasive transvesical pressure monitoring using controlled continuous flow resectoscope.
This is a review of 400 cases performed with a controlled continuous flow (CCF) resectoscope which incorporates the use of a noninvasive transvesical pressure monitor. Two series of 200 cases each are compared. The results indicate that the second group of cases performed more recently, had a lower incidence of CVP elevation and serum sodium change. An alteration in surgical technique using the CCF may be responsible for the improved outcome in the second set of cases.


Effects of habitat drying on size at and time to metamorphosis in the tree hole mosquito Aedes triseriatus.
Models of complex life cycles predict that greater mortality of immature stages should induce earlier metamorphosis at smaller sizes. We tested for effects of one source of mortality, habitat drying, on size at and time to metamorphosis of the tree hole mosquito Aedes triseriatus. In a laboratory experiment, we manipulated two variables associated with drying, volume of water and solute concentration, and recorded mean mass at and median days to eclosion for males and females in replicate cohorts. We also tested for treatment effects on the correlation of mass at and time to eclosion. For females, decreasing volume consistently induced metamorphosis at smaller sizes than did constant volume. Decreasing volume also led to earlier metamorphosis of females than did constant volume, but only in one of two experimental runs. For both sexes, increasing concentration led to greater size at metamorphosis and, for males, earlier metamorphosis than did constant volume, but again only in one of two experimental runs. Correlations of size at and time to metamorphosis tended to be positive for females and negative for males, and this difference was significant. For both sexes, decreasing volume led to larger (more positive) correlations than did constant volume, but only in one of two experimental runs. The effects of decreasing volume on females are consistent with the predictions of models of complex life cycles, and suggest that A. triseriatus can perceive volume changes and modify metamorphosis to escape a deteriorating habitat. The effects of increasing concentration are opposite to those predicted, and are consistent with enhanced growth rates, possibly due to enhanced microbial growth, as solutes become concentrated due to drying. The responses of these mosquitoes to habitat drying are complex, and we suggest that habitat drying increases both mortality and growth rates, yielding no simple predictions of how habitat drying will affect these mosquitoes in natural tree holes.


Helix 1 tryptophan variants in Galleria mellonella apolipophorin III.
Apolipophorin III (apoLp-III) from Galleria mellonella is a critical apolipoprotein aiding in lipid transport and has gained considerable interest for a role in innate immunity. Both functions are likely related and form the rationale to gain a more detailed understanding of the lipid binding properties of this insect apolipoprotein. Tryptophan residues were introduced at positions 16, 20 or 24, all in helix 1 as it may play a critical role in the initial steps of lipid binding. Steady-state fluorescence analysis showed that each tryptophan displayed unique properties, indicating different environments both in lipid-free as in lipid-bound states, and demonstrating potential for use in lipid binding analysis. While α-helical contents of wild-type and the tryptophan variant proteins were similar, W20- and W24-apoLp-III displayed increased protein stability. These variants were significantly slower in their ability to convert phosphatidylcholine vesicles into discoidal lipoproteins, which was employed as a measure for lipid binding. In contrast, W16-apoLp-III displayed decreased protein stability but an order of magnitude higher rate of discoidal lipoprotein formation. This demonstrates an inverse correlation between protein stability and the ability to convert vesicles in discoidal lipoproteins. The most stable W20-apoLp-III variant displayed comprised LDL binding capabilities, indicating a partial loss of function. Thus, there is a delicate balance between helix bundle stability and the ability to bind lipids, and helix 1 may play a critical role in this process.


Tumor-overexpressed enzyme responsive amphiphiles small molecular self-assembly nano-prodrug for the chemo-phototherapy against non-small-cell lung cancer.
Rational design of self-assembly drug amphiphiles can provide a promising strategy for constructing nano-prodrug with high drug loading, smart stimuli-responsive drug release and high tumor selectivity. Herein, we report a small molecular amphiphile prodrug that can self-assemble into multifunctional nano-prodrug for enhanced anticancer effect by the combination of chemotherapy and phototherapy (PDT/PTT). In this prodrug, the simple insertion of quinone propionate into hydrophilic drug Irinotecan (Ir) generates suitable amphiphiles that endow a good self-assembly behavior of the prodrug and transform it into a stable and uniform nanoparticle. Interestingly, this excellent self-assembly behavior can load phototherapy agent ICG to form a multifunctional nano-prodrug, thereby enhancing the chemotherapeutic effect with PDT/PTT. Importantly, the quinone propionic acid moiety in the prodrug showed a high sensitivity to the overexpressed NAD(P)H:quinone oxidoreductase-1 (NQO1) in non-small cell lung cancer (NSCLC) cells, and this sensitivity enables the disassembly of nano-prodrug and efficient NQO1-responsive drug release. To further enhance the drug accumulation on tumor tissue and migrate the blood clearance, a biomimetic nano-prodrug has been successfully explored by coating hybrid membrane on the above nano-prodrug, which displays high selective inhibition of tumor growth and metastasis on NSCLC mice model. Our findings provide new insights into the rational design of tumor-overexpressed enzyme responsive nano-prodrug for cancer combinational therapy.


Ions Everywhere? Mg2+ in the μ-Opioid GPCR and Atomic Details of Their Impact on Function.
Filizola and co-workers have applied a combination of long-time molecular dynamics and oscillating chemical potential grand canonical Monte Carlo/molecular dynamics to investigate the distribution of Mg2+ and Na+ in the μ-opioid receptor and their impact on its function. Results indicate atomic details of potential mechanisms by which Mg2+ leads to increased efficacy of opioid analgesics. The presence of information flow between the extracellular loops and the intracellular region of the G-protein-coupled receptors that interacts with G-proteins in the presence of Mg2+ may be a phenomenon occurring in other G-protein-coupled receptors and, therefore, potentially of broad impact.


Does energy consumption, financial development, and investment contribute to ecological footprints in BRI regions?
This study applies augmented mean group (AMG) along with common correlated effect mean group (CCEMG) estimator and panel heterogeneous causality to examine the interrelationship between GDP, energy consumption, financial development, foreign investment, and ecological footprints for five Belt and Road initiative (BRI) regions and in aggregated panel of BRI over the time 1990-2016. Using a multivariate framework, this study examines four alternative and conceivable hypotheses, including Pollution haven hypothesis, environmental Kuznets curve hypothesis, energy push emission hypothesis, and finance push emission hypothesis. The empirical results supported all four hypotheses for the panel of BRI and partially supported the existence of these hypotheses across the regions. Moreover, a variety of causal nexuses has been discussed in the study. Based on these results, the current research has proposed policy implications to combat the ecological footprints of BRI countries and across the regions.


Dicavitary uteri with twin gestation: a case following clomiphene citrate therapy and review of obstetric outcomes.
We report the first case of dicavitary twin pregnancy, following clomiphene citrate therapy, in a patient with uterus bicornis bicollis and anovulation. A review of the literature is presented, and obstetric outcomes and management of these rare pregnancies are discussed.


Association of single nucleotide polymorphism miRNA-146a (rs2910164) with increased predisposition to oral squamous cell carcinoma in central India population.
miRNAs play a crucial role in the genesis of cancer, either as tumor suppressor genes or as oncogenes. Single Nucleotide Polymorphisms (SNPs) in the seed region of microRNAs (miRNAs) can dysregulate their levels in the tissues and thereby affect carcinogenesis. The association of SNP in miR-146a (rs2910164) with the risk of oral squamous cell carcinoma (OSCC) has not been understood. In the present study, we have determined the association and functional significance of miR-146a (rs2910164) SNP with susceptibility to OSCC predisposition. In the present case-control study, we enrolled 430 subjects from central India (215 OSCC cases and 215 healthy controls). We performed genotyping by Kompetitive Allele Specific PCR (KASP), and their correlation with OSCC susceptibility was analyzed. miRNA expression profiling in tumor tissues and adjacent normal tissues from six OSCC patients was done by a NanoString n-Counter-based assay. Subsequently, gene ontology and pathway analysis were performed with FunRich version 3.13. The CC genotype of rs2910164 miR-146a was significantly associated with the increased risk for OSCC (CC vs GC, OR = 2.62; 95% CI: 1.48-4.66; p value = 0.001). However, the GC genotype was protective with GC vs CC (OR = 0.38, 95%CI =0.21-0.67, p-value = 0.001), and GC vs GG (OR = 0.58, 95%CI = 0.37-0.89, p-value = 0.01). Our finding suggests that SNP rs2910164 of miR-146a may be a genetic risk factor for OSCC susceptibility in the Central India population. However, more extensive multicenter studies are required to validate these findings.


Effects of calcium and vitamin D supplementation on blood pressure and serum lipids and carotenoids: a randomized, double-blind, placebo-controlled, clinical trial.
To estimate the effects of calcium or vitamin D supplementation or a combination of both on blood pressure and serum lipid and carotenoid levels. Ninety-two colorectal adenoma patients were randomized in a pilot, double-blind, placebo-controlled clinical trial of supplemental vitamin D3 800 IU and elemental calcium 2.0 g (as calcium carbonate) alone or in combination in divided doses twice daily with meals over 6 months. Relative to placebo, mean serum triglycerides decreased 30% (P = .10) and 32% (P = .10) in the calcium and calcium plus vitamin D3 treatment groups, respectively. When the two calcium intervention groups were pooled and compared with the pooled noncalcium groups, the estimated supplemental calcium treatment effects were statistically significant for triglycerides (P = .04). Similar but nonstatistically significant decreases (5%-7%) were observed for serum total cholesterol levels. Mean systolic blood pressure increased 6% (P = .08) in the calcium group; otherwise, there were no appreciable changes in systolic or diastolic blood pressures in any active treatment group. Mean serum total carotenoid levels decreased 14% (P = .07) in the calcium and 9% (P = .10) in the calcium plus vitamin D3 groups. Our results suggest that supplemental calcium alone or combined with vitamin D3 but not vitamin D3 alone may reduce serum lipids and lipophilic micronutrients.


Night-time blood pressure: a role in the prediction and prevention of diabetes?
This commentary discusses and reviews the implications of two studies published in this issue of Diabetologia by Hermida et al (DOIs: 10.1007/s00125-015-3748-8 and 10.1007/s00125-015-3749-7 ) suggesting that high nocturnal blood pressure could have a role in the prediction of diabetes and act as a therapeutic target to prevent diabetes. This overview addresses the clinical implications of this work and new research that is likely to advance this field. It also provides a framework for interpreting claims of causality from observational studies and clinical trials.


Testing for circadian differences in lethality for intravenous ouabain in male mice.
Using a randomized, balanced design and double-blind methodology, ouabain octahydrate was administered intravenously to male mice at six clock times. Eight runs were conducted using six constant dosage levels. All the dose-response curves at the clock times of 02:30, 06:30, 10:30, 14:30, 18:30 and 22:30 were parallel and no significant differences were noted between the respective LD50 determinations using nomograph methods. Independent chi-square analysis of all lethality data indicated no significant variation in response between clock times and between runs but a very highly significant difference between doses. Using regression methods, onset time for death was shown to vary inversely with log-dosage, but those periods of possible increased susceptibility could not be correlated with a shortened time to death. These findings are consistent with a random variation in lethality in regard to clock time rather than a true circadian pattern. The pooled (N = 576) intravenous LD50 for ouabain octahydrate was 3.75 mg/kg with 95% confidence limits of 3.60-3.90 mg/kg or, when calculated as anhydrous ouabain, 3.01 (2.89-3.13) mg/kg.


Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of nine randomized trials.
Considerable uncertainty exists regarding relative effects of allogeneic peripheral blood stem cells transplantation (PBSCT) versus bone marrow transplantation (BMT) on outcomes of patients with hematologic malignancies. To provide the totality of research evidence related to the effects of PBSCT versus BMT, we conducted an individual-patient data meta-analysis using data from nine randomized trials enrolling 1,111 adult patients. Compared with BMT, PBSCT led to faster neutrophil (odds ratio [OR] = 0.31; 95% CI, 0.25 to 0.38; P < .00001) and platelet engraftment (OR = 0.52; 95% CI, 0.44 to 0.61; P < .00001). PBSCT was associated with a significant increase in the development of grade 3-4 acute graft-versus-host disease (GVHD; OR = 1.39; 95% CI, 1.03 to 1.88) and extensive (47% v 31% at 3 years; OR = 1.89; 95% CI, 1.47 to 2.42; P < .000001) and overall chronic GVHD (68% v 52% at 3 years; OR = 1.92; 95% CI, 1.47 to 2.49; P < .000001), but not grade 2-4 acute GVHD (54% v 53%; P = .49). PBSCT was associated with a decrease in relapse (21% v 27% at 3 years; OR = 0.71; 95% CI, 0.54 to 0.93; P = .01) in both late-stage-(33% v 51% at 3 years; OR = 0.59; 95% CI, 0.38 to 0.93; P = .02) and early-stage-disease patients (16% v 20% at 3 years; OR = 0.69; 95% CI, 0.49 to 0.98; P = .04). Nonrelapse mortality was not different between groups. Overall and disease-free survival were only statistically significantly improved in patients with late-stage disease (overall survival: 46% v 31% at 3 years; OR = 0.64; 95% CI, 0.46 to 0.90; P = .01; disease-free survival: 41% v 27% at 3 years; OR = 0.63 95% CI, 0.45 to 0.87; P = .01). PBSCT is associated with a decreased relapse rate in hematologic malignancies and improvement in overall and disease-free survival in patients with late-stage disease. PBSCT is also associated with a significant risk of extensive chronic GVHD.


Correction to: Examining Race/Ethnicity Differences in the Association between the Experience of Workplace Racial Discrimination and Depression or Negative Emotions.
Please note that the name of coauthor Shauna Carlisle was presented incorrectly in this article as published: The correct rendering of her name is Carlisle, S.K. (instead of the incorrect rendering of Carlisle, S.E., which incorrectly notes E. [surname] as her middle initial).


Massive Pediatric Burn Injury: A 10-Year Review.
Advances in the care of burn-injured pediatric patients have improved mortality over the last 20 years. However, massive burn injuries (50% TBSA or greater) in pediatric patients, while overall rare, have a significant morbidity and mortality. The primary aim for this study is to analyze treatment and outcomes in massive pediatric burn injuries. A retrospective study of children with burn injuries 50% TBSA or greater who were admitted to Shriners Hospital for Children Northern California, from May 1, 2009 to May 22, 2020, was conducted. Data were collected from the electronic health records through a comprehensive chart review that included: patient demographics, past medical history, treatment interventions, and outcomes. This study included 69 patients (59.4% male) with a mean age of 8.7 ± 6 years. The median time from injury to admission was 2 (1-4) days. In this study, 63.8% of patients were from Mexico, 34.8% were from the United States, and 1% patient was from American Samoa. The median time from injury to admission was 2 (1-4) days. Mean TBSA was 66% ± 12%. The median TBSA of second-degree burns was 0 (0-6) %, and the mean TBSA of third-degree burns was 60% ± 16%. Forty percent of patients suffered an inhalation injury and 83% of patients received a tracheostomy. The median number of days requiring ventilator assistance was 26 (12-58) days. Mean length of hospitalization was 90 ± 60 days, with 61 ± 41 days spent in the intensive care unit. The mean number of surgical procedures was 6 ± 4. The time between surgical procedures was 12 ± 6 days. The median time from admission to the first surgical procedure was 1 (0-2) day. At the first procedure, a mean of 42% ± 15% TBSA of the burn injury was excised. Sixty-two percent of patients received autografting (22% ± 11% TBSA) and 52% of patients received allografting (27% ± 17% TBSA) during the first procedure. For survivors, the median number of inpatient occupational therapy encounters was 143.5 (83-215) and inpatient physical therapy encounters was 139.5 (81-215). Twenty-five percent of the patients included in this study died as a result of their burn injury. Multivariate regression revealed that sustaining an inhalation injury was a significant and independent predictor of death (odds ratio: 3.4, 95% confidence interval: 1.05 to 11, P = .04). Massive burn injuries in children required a very high number of surgical procedures and hospital resources. Most children who died as a result of their massive burn injury died within the first month of admission. Inhalation independently increases the risk of dying in pediatric patients with a massive burn injury.


BATL: Bayesian annotations for targeted lipidomics.
Bioinformatic tools capable of annotating, rapidly and reproducibly, large, targeted lipidomic datasets are limited. Specifically, few programs enable high-throughput peak assessment of liquid chromatography-electrospray ionization tandem mass spectrometry data acquired in either selected or multiple reaction monitoring modes. We present here Bayesian Annotations for Targeted Lipidomics, a Gaussian naïve Bayes classifier for targeted lipidomics that annotates peak identities according to eight features related to retention time, intensity, and peak shape. Lipid identification is achieved by modeling distributions of these eight input features across biological conditions and maximizing the joint posterior probabilities of all peak identities at a given transition. When applied to sphingolipid and glycerophosphocholine selected reaction monitoring datasets, we demonstrate over 95% of all peaks are rapidly and correctly identified. BATL software is freely accessible online at https://complimet.ca/batl/ and is compatible with Safari, Firefox, Chrome and Edge. Supplementary data are available at Bioinformatics online.


Manually calculated oesophageal bolus clearance time increases in parallel with reflux severity at impedance-pH monitoring.
Oesophageal clearance has been scarcely studied. Oesophageal clearance in endoscopy-negative heartburn was assessed to detect differences in bolus clearance time among patients sub-grouped according to impedance-pH findings. In 118 consecutive endoscopy-negative heartburn patients impedance-pH monitoring was performed off-therapy. Acid exposure time, number of refluxes, baseline impedance, post-reflux swallow-induced peristaltic wave index and both automated and manual bolus clearance time were calculated. Patients were sub-grouped into pH/impedance positive (abnormal acid exposure and/or number of refluxes) and pH/impedance negative (normal acid exposure and number of refluxes), the former further subdivided on the basis of abnormal/normal acid exposure time (pH+/-) and abnormal/normal number of refluxes (impedance+/-). Poor correlation (r=0.35) between automated and manual bolus clearance time was found. Manual bolus clearance time progressively decreased from pH+/impedance+ (42.6s), pH+/impedance- (27.1s), pH-/impedance+ (17.8s) to pH-/impedance- (10.8s). There was an inverse correlation between manual bolus clearance time and both baseline impedance and post-reflux swallow-induced peristaltic wave index, and a direct correlation between manual bolus clearance and acid exposure time. A manual bolus clearance time value of 14.8s had an accuracy of 93% to differentiate pH/impedance positive from pH/impedance negative patients. When manually measured, bolus clearance time reflects reflux severity, confirming the pathophysiological relevance of oesophageal clearance in reflux disease.


MicroRNA-326 attenuates hepatic stellate cell activation and liver fibrosis by inhibiting TLR4 signaling.
Hepatic fibrosis is a chronic inflammatory and reversible repair reaction of the liver under the continuous action of virus or various injuries. In this study, we aimed at identifying the role of miR-326 in the hepatic stellate cell (HSC) activation and liver fibrosis and its potential mechanism. In this study, the liver fibrosis mouse model was developed by injecting CCl4 . Liver tissue morphology was observed and the expression level of α-smooth muscle actin, collagen1α1 and miR-326 was measured. Target gene identification was performed by loss-of-function and gain-of-function. The effect of miR-326 on the expression level of the cytokines associated with the TLR4/MyD88/nuclear factor-κB (NF-κB) pathway was assessed in vitro and in vivo. We show that miR-326 was downregulated in CCl4 -induced fibrotic mice and activated HSCs. The target gene of miR-326 is TLR4. Moreover, miR-326 inhibited the activation of HSCs in vitro through TLR4/MyD88/NF-κB signaling. miR-326 attenuated hepatic fibrosis and inflammation of CCl4 -induced mice in vivo. Our results demonstrate for the first time that miR-326 inhibits HSC activation through TLR4/MyD88/NF-κB signaling. Furthermore, miR-326 plays critical roles in attenuating liver fibrosis and inflammation, suggesting the therapeutic potential of miRNAs.


A possible regulatory role for conserved promoter motifs in an adult-specific muscle myosin gene from mouse.
The mouse gene encoding a myosin heavy chain (MHC) protein expressed in type IIB fibers of adult skeletal muscle has been cloned and its promoter isolated. A number of DNA sequence motifs are found within the first 2.5 kilobases of the promoter which are similar to motifs present in the promoters of other muscle-specific genes. One sequence located at approximately -940 base pairs corresponds to the motif called MEF1 which has been shown in other muscle genes to bind the myogenic regulatory factors of which MyoD is one example. The MEF1 site of this adult IIB MHC promoter does indeed bind MyoD although this factor is normally thought to be involved in early muscle cell differentiation. The IIB MHC promoter also has several motifs located in the first 200 base pairs which are strikingly conserved between this mouse gene and several chicken skeletal MHC genes. Of these evolutionarily conserved sequences, two motifs rich in A and T residues appear to be major contributors to the muscle-specific transcriptional activity of the mouse IIB MHC promoter when transfected into quail myogenic and non-myogenic cells. These observations suggest an important functional role for these AT-rich sequence motifs in the regulation of genes of the MHC family.


Effects of verapamil on ventricular rhythm during acute coronary occlusion.
The effects of verapamil on electrophysiologic parameters of the ventricle were studied during acute coronary occlusion in anesthetized open-chest dogs. Those parameters measured in the study were idioventricular automaticity, ventricular conduction, and fibrillation threshold. The incidence of rapidly repetitive beats and fibrillation induced by two successive premature beats was also studied. Verapamil significantly decreased idioventricular automaticity (in five dogs), improved conduction through the ischemic area (in six dogs), and increased fibrillation threshold of the ischemic ventricular (in eight dogs). The drug was effective in abolishing rapidly repetitive beats and fibrillation induced by closely coupled premature beats during acute coronary occlusion. Rapidly repetitive beats occurred in nine out of 15 dogs and these repetitive beats were degenerated into fibrillation in seven dogs before verapamil. Following pretreatment with the drug, rapidly repetitive beats and fibrillation occurred in none of the 15 dogs. The results indicate that verapamil can be very effective against ventricular arrhythmias occurring in association with myocardial infarction.


Polyethylene glycol-induced heteroassociation of malate dehydrogenase and citrate synthase.
Studies by dynamic and total intensity light scattering, ultracentrifugation, electron microscopy, and chemical crosslinking on solutions of the pig heart mitochondrial enzymes, malate dehydrogenase and citrate synthase (separately and together) demonstrate that polyethylene glycol induces very large homoassociations of each enzyme, and still larger heteroenzyme complexes between these two enzymes in the solution phase. Specificity of this heteroassociation is indicated by the facts that heteroassociations with bovine serum albumin were not observed for either the mitochondrial dehydrogenase or the synthase or between cytosolic malate dehydrogenase and citrate synthase. The weight fraction of the enzymes in the mitochondrial dehydrogenase-synthase associated particles in the solution phase was less than 0.03% with the dilute conditions used in the dynamic light scattering measurements. Neither palmitoyl-CoA nor other solution conditions tested significantly increased this weight fraction of associated enzymes in the solution phase. Because of the extremely low solubility of the associated species, however, the majority of the enzymes can be precipitated as the heteroenzyme complex. This precipitation is a classical first-order transition in spite of the large particle sizes and broad size distribution. Ionic effects on the solubility of the heteroenzyme complex appear to be of general electrostatic nature. Polyethylene glycol was found to be more potent in precipitating this complex than dextrans, polyvinylpyrrolidones, ficoll, and beta-lactoglobulin.


[Effect of arginine vasopressin on vascular reactivity and calcium sensitivity of vascular smooth muscle and its relationship to protein kinase C following hemorrhagic shock in rats].
To investigate the effect of arginine vasopressin (AVP) on vascular reactivity and calcium sensitivity following hemorrhagic shock and their relationship to protein kinase C (PKC) isoforms. With endothelium denuded superior mesenteric artery (SMA) rings procured from rats in hemorrhagic shock, the effects of AVP (5x10(-11), 5x10(-10) and 5x10(-9) mol/L) on contractile responses to norepinephrine (NE) and calcium sensitivity of SMA from hemorrhagic shock in rats and their relationship to alpha and Delta isoforms of PKC with isolated organ perfusion system were observed. AVP (5x10(-11), 5x10(-10) and 5x10(-9) mol/L) markedly restored the vascular reactivity and calcium sensitivity following hemorrhagic shock, converting the cumulative concentration-response curve of NE and Ca2+ shift to the left, and its maximum concentration force (Emax) was significantly increased (all P<0.01) in a concentration dependent manner. Significant statistical differences were observed between the AVP groups (all P<0.05). Go6976 (5x10(-6) mol/L) and Rottlerin (10(-5) mol/L),respectively as the specific PKC alpha and PKC Delta isoforms inhibitor, antagonized AVP (5x10(-10) mol/L)-induced increase in vascular reactivity and calcium sensitivity of SMA following hemorrhagic shock and inhibited AVP-induced shift to the left of cumulative concentration-response curve of NE and Ca2+, and the Emax was significantly decreased (P<0.05 or P<0.01). AVP significantly restored the decreased vascular reactivity and calcium sensitivity of vascular smooth muscle following hemorrhagic shock, and its underlying mechanisms may be related to both alpha and Delta isoforms of PKC activation.


Rerefinement of the crystal structure of SnTe0.73(2)Se0.27(2) from single-crystal X-ray diffraction data.
Compounds of the solid solution series SnTe1-x Se x , derived from pristine SnSe and SnTe, are considered as thermoelectric lead-free materials. The crystal structure re-refinement of NaCl-type SnTe0.73 (2)Se0.27 (2) is based on single-crystal X-ray diffraction data and results in higher precision of the bond length [Sn-(Te,Se) = 3.0798 (3) Å] compared to a previous report on basis of powder X-ray data [Krebs & Langner (1964 ▸). Z. Anorg. Allg. Chem. 334, 37-49].


Specificity of amyloid precursor-like protein 2 interactions with MHC class I molecules.
The ubiquitously expressed amyloid precursor-like protein 2 (APLP2) has been previously found to regulate cell surface expression of the major histocompatibility complex (MHC) class I molecule K(d) and bind strongly to K(d). In the study reported here, we demonstrated that APLP2 binds, in varied degrees, to several other mouse MHC class I allotypes and that the ability of APLP2 to affect cell surface expression of an MHC class I molecule is not limited to K(d). L(d), like K(d), was found associated with APLP2 in the Golgi, but K(d) was also associated with APLP2 within intracellular vesicular structures. We also investigated the effect of beta(2)m on APLP2/MHC interaction and found that human beta(2)m transfection increased the association of APLP2 with mouse MHC class I molecules, likely by affecting H2 class I heavy chain conformation. APLP2 was demonstrated to bind specifically to the conformation of L(d) having folded outer domains, consistent with our previous results with K(d) and indicating APLP2 interacts with the alpha1alpha2 region on each of these H2 class I molecules. Furthermore, we observed that binding to APLP2 involved the MHC alpha3/transmembrane/cytoplasmic region, suggesting that conserved as well as polymorphic regions of the H2 class I molecule may participate in interaction with APLP2. In summary, we demonstrated that APLP2's binding, co-localization pattern, and functional impact vary among H2 class I molecules and that APLP2/MHC association is influenced by multiple domains of the MHC class I heavy chain and by beta(2)m's effects on the conformation of the heavy chain.


A scoping review of mentorship of health personnel to improve the quality of health care in low and middle-income countries.
Most Low and Middle-Income Countries are facing a crisis in human resources for health which compromises their ability to meet health related targets outlined by the Sustainable Development Goals. The crisis is not limited to the availability of health personnel but also the quality of care and the training and development of the workforce. To address these challenges, evidence based education strategies are urgently required. Mentorship has been found to improve health personnel performance in High-Income Countries however, little is known about its role in Low and Middle-Income Countries. To address this gap in understanding, we conducted a scoping review of the current literature. CINAHL, EMBASE and OVID Medline were systematically searched along with grey literature for peer-reviewed research papers specific to the research question. A six-step scoping review framework was utilised to identify the relevant literature and summarise the pertinent findings. The initial search identified 592 records, and five papers, reporting on four studies, were retained for data charting and extraction. All four studies described a positive effect of mentorship on the quality of care outcomes. The results are collated according to features of the intervention including mentor training, mentor-mentee ratios, mentorship model, intervention intensity and key findings in terms of outcome measures. This review identifies a paucity of evidence of mentorship in this context however, current evidence supports the assertion that effective mentorship contributes to the improvement of certain quality of care outcomes. The features of successful mentorship interventions are outlined and the implications are discussed in the context of existing evidence.


Effect of intrauterine injection of chlorpromazin on implantation in the rat.
In rats, injection of chlorpromazin hydrochloride (CPZ), a calmodulin antagonist, to each uterine horn had a significant (87%) anti-implantation effect and 100% antifertility effect. Both of these rates were zero in the saline control group. Polyacrylamide gel electrophoresis analysis of the uterine fluid showed a decrease in the protein content and certain changes in its chemical composition, in particular, a marked reduction in the number of bands of estradiol-induced 70 kD proteins in the experimental group. No significant difference was found in the ovarian weight and the serum estradiol (E2) and progesterone (P) levels between the two groups. These results suggest that calmodulin influences the process of implantation and this effect is not directly related to the serum concentrations of E2 and P. It is believed that CPZ probably exerted its anti-implantation effect by a direct action on the uterus.


Successful pregnancy after Intralipid addition to sildenafil and enoxaparin in woman with history of recurrent pregnancy loss (RPL).
Does addition of Intralipid to sildenafil and enoxaparin immunotherapy improve pregnancy outcome? Report of a striking case of a patient with history of 4 recurrent pregnancy losses (RPL) and IVF failures. Adding of Intralipid resulted in giving birth to a healthy male baby in the 3th IVF cycle. Combination therapy that includes Intralipid may generate successful IVF outcome, although this problem merits further study, especially regarding safety issues.


The use of cuffed versus uncuffed endotracheal tubes in pediatric intensive care.
To report our experience with cuffed endotracheal tubes (ETT) in a large cohort of critically ill children. Study design We prospectively collected data over a 1-year period concerning long-term intubation on 860 critically ill children admitted to our intensive care unit. Tube sizes were dictated by the modified Cole formula for uncuffed ETT (age [y]/4+4 mm ID) and chosen one-half size less for cuffed ETT. Cuff pressure was regularly monitored to maintain a small leak at peak inspiratory pressure. The choice of ETT was made by the physician responsible for the initial airway management. There were 597 patients in the first 5 years of life, with 210 having cuffed ETT. There were no significant differences in the use of racemic epinephrine for postextubation subglottic edema, the rate of successful extubation or the need for tracheotomy between those with cuffed and uncuffed ETT in any age group. Our data suggest that the traditional teaching in pediatric anesthesia and intensive care, including current pediatric life support recommendations, need to be reviewed for children to benefit from the advantages of modern low-pressure cuffed ETT during critical illnesses.


Comparison among the effects of nifedipine, nimodipine and nisoldipine on the brain biogenic amines of normal or haloperidol treated rats.
1. Previous studies have shown that dihydropyridine calcium antagonists affected the metabolism of the brain biogenic amines more extensively than the non-dihydropyridine ones. The effects of three dihydropyridines (nifedipine, nimodipine or nisoldipine, 0.05-0.10 mmol/kg i.p.) on brain monoamines and metabolites have been evaluated on both normal and haloperidol treated rats. 2. The small changes induced by the drugs on normal rats were markedly increased in the haloperidol treated rats, clearly showing an inhibition of dopaminergic systems. 3. These effects were selective for the striatum and cerebral cortex, with nisoldipine being more effective than nimodipine or nifedipine. 4. The effects of the three drugs on serotonergic systems were similar or more marked on haloperidol treated rats than on normal rats. These effects, showing activation of serotonergic systems, displayed some regional specificity and different potency of the three compounds. Nisoldipine also appeared to be the most effective drug on serotonergic systems. 5. In conclusion nisoldipine, as well as other calcium antagonists, may have a place in the treatment of some mood disorders.


Appraising growth differentiation factor 15 as a promising biomarker in digestive system tumors: a meta-analysis.
Previous studies have highlighted cytokine growth differentiation factor 15 (GDF-15) as a potential biomarker for digestive system tumors (DST). This study sought to assess the feasibility of using GDF-15 as a diagnostic and prognostic biomarker in DST. Eligible studies from multiple online databases were reviewed. Meta-analyses of diagnostic parameters were carried out using standard statistical methods. Study-specific hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to estimate the strength of the relationship between GDF-15 levels and clinical prognosis. We identified 17 eligible studies comprising 3966 patients with DST. The sensitivity, specificity, and area under the curve (AUC) for the discriminative performance of GDF-15 as a diagnostic biomarker were 0.74 (95% CI: 0.68-0.80), 0.83 (95% CI: 0.75-0.89), and 0.84, respectively. Moreover, increased GDF-15 expression levels were markedly associated with unfavorable overall survival (OS) in patients with DST (HR = 2.34, 95% CI: 2.03-2.70, P < 0.001; I2 = 0.0%) and colorectal cancer (CRC) (HR = 2.27, 95% CI: 1.96-2.63, P < 0.001; I2 = 0.0%). Stratification by cancer type, test matrix, ethnicity, and cut-off setting also illustrated the robustness of the diagnostic value of GDF-15 in DST. Collectively, our data suggest that GDF-15 expression level may have value as a diagnostic and prognostic biomarker, independent of other, traditional biomarkers.


Mast cell activation is differentially affected by heat shock.
Mast cells play pivotal roles in immediate-type and inflammatory allergic and nonallergic reactions. Cross-linking of the high-affinity receptor for IgE (FcepsilonRI) on mast cells activates a signaling pathway leading to Ca2+ mobilization and is followed by degranulation and the release of histamine and other preformed mediators, as well as de novo synthesis of arachidonic acid metabolites. In a previous study, we have demonstrated that heat shock activates heat shock transcription factor-1 (HSF-1), induces heat shock protein 70 (HSP70), and suppresses cytokine production in bone marrow-derived mast cells (BMMC). In this study, we further investigated the effects of heat shock on the activation of mast cells and the release of mast cell mediators. In mouse mast cells, derived from a culture of bone marrow cells of male BALB/cBy and null HSF-1(-/-)mice, responsiveness to heat shock was monitored by measuring beta-hexosaminidase and leukotriene C4 (LTC4) release. Using BMMC, we found that heat shock inhibits degranulation of BMMC without affecting leukotriene production. To further elucidate the mechanism of suppression of degranulation, we studied the effects of heat shock on the regulation of signal transduction in more detail. We found that heat shock inhibits calcium mobilization and tyrosine phosphorylation of Syk and SHIP upon IgE receptor activation, but increases the phosphorylation of SHP-1 and -2. Moreover, our results revealed that suppression of tyrosine phosphorylation of Syk and SHIP coincided with an increased tyrosine phosphatase activity. The inhibitory action of heat shock toward mast cell degranulation is likely due to shifting the balance between kinase and phosphatase activity.


RNA polymerase-cNMP-ligated cAMP receptor protein (CRP) mutant interactions in the enhancement of transcription by CRP mutants.
The enhancement of the transcription of three synthetic promoters by cNMP-ligated cAMP receptor protein (CRP)/mutant complexes was determined from the transcription yields of a short AAUU transcript in an abortive initiation in vitro transcription assay. The cNMP-ligated CRP and mutants were cAMP, cGMP, and cIMP ligated with CRP, T127L CRP, S128A CRP, and T127L/S128A CRP. The transcriptional activation of a 152-base pair lacUV5 promoter (synlac promoter) with a CRP consensus binding site sequence (syncon promoter) was enhanced by an average factor of 12.3 +/- 0.5 with the cAMP-ligated complexes of CRP/mutants and cGMP-ligated T127L, although their promoter binding site affinities varied by a factor of 5. However, in the presence of bound RNA polymerase, the binding affinities only ranged from 0.8 +/- 0.2 x 10(7) m(-)(1) for cAMP-ligated CRP* to 1.8 +/- 0. 3 x 10(7) m(-)(1) for cAMP-ligated CRP, indicating that the CRP/mutant interacts with the bound RNA polymerase, which would account for the near constancy of the enhancement factors. The corresponding enhancement factors for the synlac promoter and a promoter with a different CRP binding site sequence (syngal promoter) were also nearly the same, 7.2 +/- 0.7 and 6 +/- 1, respectively. The binding reaction of the syncon promoter to the RNA polymerase is exothermic, with a binding constant (K(b)) = 2.1 +/- 0. 2 x 10(7) m(-1).


Positive surgical margins after radical prostatectomy: What should we care about?
Positive surgical margins (PSMs) after radical prostatectomy (RP) are a known factor associated with biochemical recurrence (BCR) and raise the issue of adjuvant treatment by radiotherapy versus salvage treatment at recurrence. To help this choice, our study aimed to analyze BCR-free survival and factors associated with BCR in patients with PSM and undetectable postoperative prostate-specific antigen (PSA). Between 2005 and 2008, 630 patients had RP for localized prostate cancer in our center. We included patients with PSM, uninvaded nods, undetectable postoperative PSA and no adjuvant treatment. The 5-year BCR-free survival was calculated using Kaplan-Meier method. Logistic regression models were used to determine the factors associated with BCR in univariate and multivariate analyses (Cox model). The PSM rate was 32.7 % (n = 206 patients), and 110 patients corresponded to the inclusion criteria. The median follow-up was 72 months. The BCR rate was 30 % with a 5-year BCR-free survival of 83.9 %. The factors significantly associated with BCR were preoperative PSA, predominance and percentage of Gleason 4, tumor volume, PSM length and predominance of Gleason 4 at the margin. In the multivariate analysis, the remaining two significant factors were PSM length [OR 4.35, 95 % CI (1.011-1.421), p = 0.037] and tumor volume [OR 4.29, 95 % CI (1.011-1.483), p = 0.038]. Over a 5-year follow-up, only one-third of patients experienced BCR. It might be reasonable to postpone adjuvant radiotherapy for patients with PSM and undetectable PSA after RP. Tumor volume and PSM length were associated with BCR and should be taken into account in the postoperative treatment management.


Evaluative threat and ambulatory blood pressure: cardiovascular effects of social stress in daily experience.
Physiological effects of social evaluation are central in models of psychosocial influences on physical health. Experimental manipulations of evaluative threat evoke substantial cardiovascular and neuroendocrine responses in laboratory studies, but only preliminary evidence is available regarding naturally occurring evaluative threats in daily life. In such nonexperimental ambulatory studies, it is essential to distinguish effects of evaluative threat from related constructs known to alter stress, such as ability perceptions and concerns about appearance. 94 married, working couples (mean age 29.2 years) completed a 1-day (8 a.m. to 10 p.m.) ambulatory blood pressure protocol with random interval-contingent measurements using a Suntech monitor and Palm Pilot-based measures of control variables and momentary experiences of social-evaluative threat, concerns about appearance, and perceived ability. In hierarchical analyses for couples and multiple measurement occasions (Proc Mixed; SAS) and controlling individual differences (BMI, age, income) and potential confounds (e.g., posture, activity), higher reports of social-evaluative threat were associated with higher concurrent systolic (estimate = .87, SE = .34) and diastolic blood pressure (estimate = 1.06; SE = .26), both p < .02. Effects of social-evaluative threat remained significant when perceived ability and appearance concerns were controlled. Naturally occurring social-evaluative threat during daily activity is associated with increased systolic and diastolic blood pressure. Given associations between ambulatory blood pressure and risk of cardiovascular disease, the findings support conceptual models of threats to the social self as a potentially important influence on physical health.


Minimal inhibitory concentrations and time-kill determination of moxifloxacin against aerobic and anaerobic isolates.
Moxifloxacin is a new oral 8-methoxy-quinolone with a wide spectrum of activity against Gram-negative and anaerobic bacteria, atypical micro-organisms and multi-resistant Gram-positive bacteria. This study was designed to assess the in vitro activity of moxifloxacin against Gram-positive bacteria with different resistance patterns, anaerobes and atypical micro-organisms such as Chlamydia and Mycoplasma. Moxifloxacin had good activity against Streptococcus pneumoniae with all strains inhibited by < or =0.12 mg/l. The minimal inhibitory concentrations (MICs) of moxifloxacin for Streptococcus pyogenes and Streptococcus agalactiae ranged from 0.03 to 0.5 mg/l while those of ciprofloxacin were about two- to four-fold higher (MICs=0.12-1 mg/l). Moxifloxacin was poorly active against enterococci but its activity against Clostridium and Bacteroides spp. was in the same range as that of metronidazole and superior to that of clindamycin. Moxifloxacin was substantially more active than both ciprofloxacin and sparfloxacin against Chlamydia.