Synergistic protective effect of astragaloside IV-tetramethylpyrazine against cerebral ischemic-reperfusion injury induced by transient focal ischemia.
Astragaloside IV and tetramethylpyrazine have been extensively used in the cardio-cerbrovascular diseases of medicine as a chief ingredient of glycoside or alkaloid formulations for the treatment of stroke and myocardial ischemia diseases. To investigate the effects of astragaloside IV (ASG IV) and tetramethylpyrazine (TMPZ) on cerebral ischemia-reperfusion (IR) injury model in rat model. Rats were randomly divided into the following five groups: sham group, IR group and treatment group including ASG IV, ASG IV-TMPZ and nimodipine treatment. The therapeutic effect was evaluated by micro-positron emission tomography (Micro-PET) using (18)F-fluoro-2-deoxy-d-glucose. The neurological examination, infarct volume and the levels of oxidative stress- and cell apoptosis-related molecules were assessed. Micro-PET imaging showed that glucose metabolism in the right hippocampus was significantly decreased in the IR group compared to the sham group (P<0.01). ASG IV and ASG IV-TMPZ treatments reversed the decreased glucose metabolism in the model group (P<0.05 and P<0.01, respectively). IR induced the increase of Caspase-3 mRNA levels, MDA content and iNOS activity, but it caused the decrease of SOD activity and Bcl-2 expression compared the sham group (P<0.01). ASG IV-TMPZ and ASG IV reversed the IR-induced changes of these parameters, i.e. the down regulation of Caspase-3 mRNA, MDA content and iNOS activity, and the up regulation of SOD activity and Bcl-2 expression (P<0.05). This study showed that ASG IV-TMPZ played a pivotal synergistic protective role against focal cerebral ischemic reperfusion damage in a rat experimental model.


Human iPSC-Derived Cerebellar Neurons from a Patient with Ataxia-Telangiectasia Reveal Disrupted Gene Regulatory Networks.
Ataxia-telangiectasia (A-T) is a rare genetic disorder caused by loss of function of the ataxia-telangiectasia-mutated kinase and is characterized by a predisposition to cancer, pulmonary disease, immune deficiency and progressive degeneration of the cerebellum. As animal models do not faithfully recapitulate the neurological aspects, it remains unclear whether cerebellar degeneration is a neurodevelopmental or neurodegenerative phenotype. To address the necessity for a human model, we first assessed a previously published protocol for the ability to generate cerebellar neuronal cells, finding it gave rise to a population of precursors highly enriched for markers of the early hindbrain such as EN1 and GBX2, and later more mature cerebellar markers including PTF1α, MATH1, HOXB4, ZIC3, PAX6, and TUJ1. RNA sequencing was used to classify differentiated cerebellar neurons generated from integration-free A-T and control induced pluripotent stem cells. Comparison of RNA sequencing data with datasets from the Allen Brain Atlas reveals in vitro-derived cerebellar neurons are transcriptionally similar to discrete regions of the human cerebellum, and most closely resemble the cerebellum at 22 weeks post-conception. We show that patient-derived cerebellar neurons exhibit disrupted gene regulatory networks associated with synaptic vesicle dynamics and oxidative stress, offering the first molecular insights into early cerebellar pathogenesis of ataxia-telangiectasia.


Ntrk1 Promotes Resistance to PD-1 Checkpoint Blockade in Mesenchymal Kras/p53 Mutant Lung Cancer.
The implementation of cancer immunotherapeutics for solid tumors including lung cancers has improved clinical outcomes in a small percentage of patients. However, the majority of patients show little to no response or acquire resistance during treatment with checkpoint inhibitors delivered as a monotherapy. Therefore, identifying resistance mechanisms and novel combination therapy approaches is imperative to improve responses to immune checkpoint inhibitors. To address this, we performed an in vivo shRNA dropout screen that focused on genes encoding for FDA-approved drug targets (FDAome). We implanted epithelial and mesenchymal Kras/p53 (KP) mutant murine lung cancer cells expressing the FDAome shRNA library into syngeneic mice treated with an anti-PD-1 antibody. Sequencing for the barcoded shRNAs revealed Ntrk1 was significantly depleted from mesenchymal tumors challenged with PD-1 blockade, suggesting it provides a survival advantage to tumor cells when under immune system pressure. Our data confirmed Ntrk1 transcript levels are upregulated in tumors treated with PD-1 inhibitors. Additionally, analysis of tumor-infiltrating T cell populations revealed that Ntrk1 can promote CD8+ T cell exhaustion. Lastly, we found that Ntrk1 regulates Jak/Stat signaling to promote expression of PD-L1 on tumor cells. Together, these data suggest that Ntrk1 activates Jak/Stat signaling to regulate expression of immunosuppressive molecules including PD-L1, promoting exhaustion within the tumor microenvironment.


1,6-methano[10]annulene-stabilized radicals.
The rate of the methylenecyclopropane rearrangement is remarkably enhanced by the 1,6-methano[10]annulene group, which greatly stabilizes the biradical intermediate. The diastereomeric products argue against a concerted rearrangement mechanism and support a stabilized biradical intermediate that lives long enough to undergo rotation before ring closure. [structure: see text]


Chemical Composition, Insecticidal, Persistence and Detoxification Enzyme Inhibition Activities of Essential Oil of Artemisia maritima against the Pulse Beetle.
Pulse beetle is the major pests of pulses that cause significant loss to grains leads to unfit for consumption and marketing. Indiscriminate use of synthetic pesticides for the control of pulse beetle (Callosobruchus chinensis and Callosobruchus maculatus) led to insect resistance, pesticide residues on grains which affect consumer's health and environment. Essential oils (EOs) are good alternatives to synthetics due to their safety to the environment and consumers' health. The main objective of the present study was to explore the chemical composition, fumigant, repellency, ovipositional deterrence, persistence, and detoxification enzyme inhibition of Artemisia maritima essential oil against pulse beetle. Results showed that primary components of the EO were 1,8-Cineole and bornyl acetate. EO showed promising fumigant toxicity to C. chinensis and C. maculatus (LC50 = 1.17 and 0.56 mg/L, respectively) after 48 h. In the repellent assay, EO at 8 mg/L showed 92-96% repellence after 1 h. In ovipositional deterrence assay, EO showed more ovipositional deterrence against C. chinensis (OD50 = 3.30 mg/L) than C. maculatus (OD50 = 4.01 mg/L). Higher concentrations of oil (8 and 6 mg/L) in C. maculatus showed significant inhibition of the glutathione-S-transferase enzyme (7.14 and 5.61 n mol/min/mL, respectively).


Entry-level degrees for midwifery practice.
The Governing Board of the ACNM Division of Accreditation (DOA) has been charged by the ACNM Board of Directors to consider requiring an entry-level degree for nurse-midwifery practice. This decision has far-reaching implications and must be considered with utmost care. The decision will not be based on the issue of clinical competence but rather, the political statement to be made through the imposition of a degree requirement. The author urges the DOA's Governing Board to consider the implications of its action on a variety of audiences, including potential students, potential consumers, other health professionals, current and future employers, our international colleagues, health insurers and managed care organizations, and policymakers and lawmakers.


Chronic pigmented purpura associated with odontogenic infection.
Five patients with chronic pigmented purpura associated with odontogenic infection are described. Four patients had Schamberg's disease, and one had itching purpura. These patients were resistant to topical corticosteroid treatment, but appearance of purpuric spots ceased after treatment for periodontitis, pulpitis, or both. No circulating immune complexes were detected, and neither immunoglobulin nor complement was deposited in the papillary vessels of the skin. Odontogenic infection might be one of the precipitating factors for chronic pigmented purpura.


Burnout and collegial support in state psychiatric hospital staff.
To determine the correlates of burnout, 47 employees of a state psychiatric hospital completed measures of burnout, collegial support, prolonged anxiety, physical health, and job attitude. Results showed that burnout was associated positively with anxiety, frequency of illness, and contrary job attitudes, and correlated negatively with level of satisfaction with the collegial support network. Partial correlations showed that satisfaction with support systems diminished the effects of burnout on frequency of illness and job attitudes. Tests for divergent validity showed that these findings were specific to burnout and not other measures of job satisfaction or fulfillment. The results suggest that facilitating staff satisfaction with colleagues may reduce burnout and some of its deleterious effects.


A multicenter randomized controlled trial of injections of sterile water and saline for chronic myofascial pain syndromes.
A randomised controlled trial was used to test the hypothesis that cutaneous injections of sterile water (SWI) have no benefit over saline (PSI) as a method of pain reduction among patients with myofascial pain syndromes. Six general practitioners located at 6 different clinics of general practice treated 117 patients (91 female, 26 male, aged > or = 25 years) with myofascial pain syndrome for at least 3 months in one or both of the upper quadrants of the body. Patients were randomised to receive either SWI or PSI which was administered sub- and intracutaneously on 1 occasion. The patients received a mean number of 10 injections of 0.5 ml of either substance. The main outcome measure was pain intensity which was measured with visual analogue scales before intervention, 10 min after intervention and 14 days after intervention. We found no statistically or clinically significant difference in pain level reduction between the 2 groups. However, patients who received SWI reported a much more painful treatment experience than those who received PSI. Our study shows that injections of sterile water are substantially more painful but demonstrate no better clinical outcome than similar injections of saline as a method to treat patients with chronic myofascial pain syndrome.


Dendritic cells: a double-edge sword in atherosclerotic inflammation.
Functional heterogeneity of dendritic cells (DCs) observed in atherosclerosis suggest for their complex and multifaced role in the pathogenesis of atherosclerotic disease. A delicate balance between anti-inflammatory and pro-inflammatory mechanisms drives atherogenesis, and local microenvironment triggers the actual involvement of DCs in atherosclerosis-associated inflammation. Responding to microenvironment stimuli, DCs contribute to atherogenesis in both ways being involved in supporting proatherogenic vascular inflammation and by suppressing inflammatory responses via induction of self-tolerogenic properties and regulatory T cells (Tregs). The local microenvironment and extrinsic stimuli influence DC phenotype and hence could control the phenotypic switch toward inflammation or tolerance.


Hyperglycemia Induces Toll-Like Receptor Activity Through Increased Oxidative Stress.
Hyperglycemia-induced oxidative stress and inflammation are central in the genesis of diabetic vascular complications. Toll-like receptors (TLRs) play a crucial role in promoting inflammatory responses and are known to be activated in diabetic patients. Also in animal models, they have been shown to have a role in the pathogenesis of diabetic vasculopathies. However, the mechanisms underlying this increase in TLR activity in diabetes are not well documented. Since increased reactive oxygen species (ROS) are also produced in various tissues under diabetic conditions, we postulated that ROS act as a potential activator of TLR. Several studies support our hypothesis that hyperglycemia-induced oxidative stress appears to be an important factor in promoting TLR activity in monocytes, both microvascular and macrovascular endothelial cells and cardiomyocytes and in animal models. Most importantly, the increase in ROS and TLR activity is ameliorated with antioxidant strategies. Thus, targeting ROS/NADPH oxidase with small molecular inhibitors could be a promising strategy to reduce both oxidative stress and TLR-mediated inflammation in diabetic vascular diseases.


A Phase I, Randomized, Single-Dose Study to Evaluate the Biosimilarity of QL1206 to Denosumab Among Chinese Healthy Subjects.
This study was conducted to explore the tolerance, variability, pharmacokinetics (PK), and pharmacodynamics (PD) of denosumab biosimilar (QL1206) in healthy Chinese subjects. This is a randomized, double-blind, two-arm, parallel study performed to examine the bioequivalence of denosumab biosimilar, QL1206, with that of Xgeva® (Denosumab) as a reference drug. A single dose of 120 mg/kg of the denosumab biosimilar or Xgeva® was administered to the subjects, who were followed up for 134 days. Similar PK properties as those of Xgeva® were exhibited by QL1206. When compared to QL1206 with Xgeva®, the 90% confidence intervals of the ratios for Cmax, AUC0-t, and AUC0-∞ were observed to be within 80-125%. The inter-subject variability (inter-CV) ranged from 29% to 39.5%. Six and three subjects in the QL1206 and Xgeva® groups were found to be positive for the ADA and negative for the NAb, respectively. The CTX1 concentration-time profiles appeared similar (about 80% decrease from 48 hours to134 days) between the QL1206 and Xgeva® groups. Adverse events (AEs) were observed in 92.6% and 93.4% of subjects in the QL1206 and Xgeva® groups, respectively. Reduction in blood calcium level was found to be the most common AE recorded, with an incidence of 72.8% versus 72.4% in the QL1206 and Xgeva® groups, respectively. Similar PK and PD characteristics were exhibited by QL1206 as compared to those of Xgeva®. The inter-CV was slightly large. The safety profiles of denosumab biosimilars and Xgeva® were found to be similar.


Significance of circulating tumor cells in soft tissue sarcoma.
Circulating tumor cells can be detected from the peripheral blood of cancer patients. Their prognostic value has been established in the last 10 years for metastatic colorectal, breast, and prostate cancer. On the contrary their presence in patients affected by sarcomas has been poorly investigated. The discovery of EpCAM mRNA expression in different sarcoma cell lines and in a small cohort of metastatic sarcoma patients supports further investigations on these rare tumors to deepen the importance of CTC isolation. Although it is not clear whether EpCAM expression might be originally present on tumor sarcoma cells or acquired during the mesenchymal-epithelial transition, the discovery of EpCAM on circulating sarcoma cells opens a new scenario in CTC detection in patients affected by a rare mesenchymal tumor.


Hypertension in the haemodialysis population: any relationship to 2-years survival?
Few studies have quantified the effect of hypertension on survival in the haemodialysis (HD) population. We have previously reported lack of adverse effect of hypertension on 1-year mortality in a cohort of 649 haemodialysis patients (Am J Kidney Dis 1996; 28: 737-744). We report here the effect of hypertension on 2-year survival in the same cohort of patients. We reviewed the complete computerized files on 649 HD patients enrolled in 10 haemodialysis centres in the state of Mississippi, USA. One-month dialysis records for each patient from mid-October 1994 to mid-November 1994 were reviewed. Predialysis mean arterial pressure was calculated as immediate predialysis diastolic pressure plus one-third the difference between systolic and diastolic pressure. Patients were classified as hypertensive if their average pre-MAP was more than 114 mmHg or they were receiving antihypertensive drugs during the study period. Normotensives had a pre-MAP < 114 and were not receiving any antihypertensives. We followed these patients for 2 years to determine their survival and the effect of their BP status, as determined in October 1994, on 2-year mortality. In univariate analysis, hypertension was associated with improved 2-years survival (relative risk 0.64, P=0.08 compared to normotensives). Furthermore, among the hypertensives, good blood pressure control (less than 140/90) was associated with increased relative risk of death at 2 years (RR 1.86, P=0.004). In multivariate analysis, taking age, race, serum albumin, and diabetic status into consideration, there was a 27% reduction in mortality among hypertensives compared to normtensives (RR 0.73, P=0.06). Other factors of significance in multivariate analysis were age (RR 1.03/year, P=0.02), serum albumin (RR 0.36/g, P<0.0001), diabetes mellitus (RR 1.35, P=0.07), and race (RR 0.64, P=0.05). Our study suggests that hypertension has no adverse effect on survival at 2 years in the haemodialysis population.


Evidence for 5 alpha-androstane-3 beta, 17 beta-diol binding to the estrogen receptor in the cytosol from male rat pituitary.
The binding of [3H]5 alpha-androstane-3 beta, 17 beta-diol (3 beta-Adiol) in the pituitary cytosol of prepubertal male rats was studied. The following criteria indicated that 3 beta-Adiol was bound to specific proteins and, in all probability, to the estrogen receptor. 1) The binding was of relatively high affinity and low capacity. 2) The complex was destroyed by proteolytic enzymes and by heating. 3) It was precipitable with protamine sulfate and 35% ammonium sulfate. 4) In sucrose linear gradients (5-20%), 3 beta-Adiol was bound in the 7S region. The 3-4S 3 beta-Adiol complex, previously found, was due to the dissociation of 3 beta-Adiol from the 7S complex and further association with nonspecific proteins. 5) Bound hormone was only displaced by 3 beta-Adiol itself and estrogens. 6) Translocation of the estrogen receptor from cytosol to nuclei resulted in a parallel decrease in the number of cytosol 3 beta-Adiol-binding sites. It was also shown that 3 beta-Adiol was not bound to contaminating serum proteins, particularly to alpha-fetoprotein. We interpret these results to indicate that in the male rat pituitary, 3 beta-Adiol is bound to the estrogen receptor.


Blood Transfusion Therapy.
Transfusion of red blood cells (RBCs) is a balance between providing benefit for patients while avoiding risks of transfusion. Randomized, controlled trials of restrictive RBC transfusion practices have shown equivalent patient outcomes compared with liberal transfusion practices, and meta-analyses have shown improved in-hospital mortality, reduced cardiac events, and reduced bacterial infections. This body of level 1 evidence has led to substantial, improved blood utilization and reduction of inappropriate blood transfusions with implementation of clinical decision support via electronic medical records, along with accompanying educational initiatives.


Case report: hepatic hydrothorax without ascites.
Pleural effusion due to hepatic cirrhosis and ascites is well known. We describe three patients with right-sided hepatic hydrothorax in the absence of ascites. The formation of pleural fluid in these patients is probably a result of fluid movement from peritoneal to pleural space across diaphragmatic defects before ascites can form. The differential diagnosis of a right-sided transudative pleural effusion in a patient with chronic liver disease with or without ascites includes congestive left ventricular failure and nephrotic syndrome. These diseases are usually ruled out with standard clinical tests. Patients with hepatic hydrothorax should be treated with fluid restriction and diuretics. Patients with severe symptoms due to refractory hepatic hydrothorax might benefit from pleural sclerosis and surgical closure of diaphragmatic defects.


In vitro metabolic zonation through oxygen gradient on a chip.
Among the multiple metabolic signals involved in the establishment of the hepatic zonation, oxygen could play a key role. Indeed, depending on hepatocyte position in the hepatic lobule, gene expression and metabolism are differently affected by the oxygen gradient present across the lobule. The aim of this study is to understand whether an oxygen gradient, generated in vitro in our developed device, is sufficient to instruct a functional metabolic zonation during the differentiation of human embryonic stem cells (hESCs) from endoderm toward terminally differentiated hepatocytes, thus mimicking the in vivo situation. For this purpose, a microfluidic device was designed for the generation of a stable oxygen gradient. The oxygen gradient was applied to differentiating hESCs at the pre-hepatoblast stage. The definitive endoderm and hepatic endoderm cells were characterized by the expression of the transcription factor SOX-17 and alpha-fetoprotein (AFP). Immature and mature hepatocytes were characterized by hepatocyte nuclear factor 4-alpha (HNF-4α) and albumin (ALB) expression and also analyzed for cytochrome P450 (CYP3A4) zonation and glycogen accumulation through PAS staining. Metabolic zonated genes expression was assessed through quantitative real time PCR. Application of the oxygen gradient during differentiation induced zonated glycogen storage, which was higher in the hepatocytes grown in high pO2 compared to those grown in low pO2. The mRNA levels of glutamine synthetase (GLUL), beta-catenin (CTNNB) and its direct target cyclin D1 (CCND1) showed significantly higher expression in the cells grown in low pO2 compared to those grown in high pO2. On the contrary, carbamoyl-phosphate synthetase 1 (CPS1), ALB, the proliferative marker ki67 (MKI67) and cyclin A (CCNA) resulted to be significantly higher expressed in cells cultured in high pO2 compared to those cultured in low pO2. These results indicate that the oxygen gradient generated in our device can instruct the establishment of a functional metabolic zonation in differentiating hESCs. The possibility to obtain differentiated hepatocytes in vitro may allow in the future to deepen our knowledge about the physiology/pathology of hepatocytes in relation to the oxygen content.


Eosinophilic peritonitis with colon cancer: a case report.
Eosinophilic gastrointestinal disorders (EGIDs) are a rare group of inflammatory disorders that can occur anywhere along the gastrointestinal tract, from the esophagus to the rectum. In particular, those with malignant or benign tumors are extremely rare. A 62-year-old man was referred to our hospital with a chief complaint of abdominal fullness. The peripheral white blood cell count was 19,400/µL, and the eosinophil count was 13,300/µL. Abdominal computed tomography showed massive ascites. Cytology of the ascitic fluid showed a large amount of eosinophils and no malignancy. Upper and lower gastrointestinal endoscopies were performed on the suspicion of EGIDs, and colon cancer with no other abnormalities was found. The biopsies of the cancer lesions and non-cancer lesions also showed significant differences in eosinophil counts per high-power field (HPF) between the cancer and non-cancer lesions (median 77.5 [IQR 52-115] vs. 40.5 [35-56]/HPF, P < 0.05). Exploratory laparoscopy showed cloudy massive ascites and thickening of the mesentery. Pathological examination of the mesentery showed a large amount of eosinophils (median 177.5 [IQR 91-227]/HPF) and no malignancy. Based on these findings, it was suspected that the massive ascites due to eosinophilic peritonitis could be associated with colon cancer. Steroid administration resulted in immediate disappearance of the ascites, and laparoscopic left hemicolectomy was safely performed 6 weeks after steroid administration. This report presented a case of eosinophilic peritonitis that could be related to colon cancer. Exploratory laparoscopy was useful to detect the cause of ascites. The possibility that eosinophilic peritonitis was associated with colon cancer is discussed based on the histopathological findings.


Radioactivity levels in major French rivers: summary of monitoring chronicles acquired over the past thirty years and current status.
Since the beginning of the 1990 s, liquid releases of gamma-emitting radionuclides from French nuclear facilities have generally fallen by almost 85%. Almost 65% of gamma-emitting liquid effluents released into freshwater rivers concerned the River Rhône (Southeast France), with around 85% of this originating from the Marcoule spent fuel reprocessing plant. Upstream of French nuclear plants, artificial radionuclides still detected by gamma spectrometry in 2006, include (137)Cs, (131)I as well as (60)Co, (58)Co and (54)Mn in the case of the Rhine (Switzerland nuclear industries). In the wake of the fallout from the Chernobyl accident, (103)Ru, (106)Rh-Ru, (110 m)Ag, (141)Ce and (129)Te were detected in rivers in the east of France. Some of these radionuclides were found in aquatic plants until 1989. In eastern France, (137)Cs activity in river sediments and mosses is still today two to three times greater than that observed in similar environments in western France. No (134)Cs has been detected upstream of nuclear plants in French rivers since 2001. Downstream of nuclear plants, the gamma emitters still detected regularly in rivers in 2006 are (137)Cs, (134)Cs, (60)Co, (58)Co, (110 m)Ag, (54)Mn, (131)I, together with (241)Am downstream of the Marcoule spent fuel reprocessing plant. Alpha and beta emitters such as plutonium isotopes and (90)Sr first entered freshwaters at the early 1950s due to the leaching of soils contaminated by atmospheric fallout from nuclear testing. These elements were also introduced, in the case of the Rhône River, via effluent from the Marcoule reprocessing plant. Until the mid 1990 s, plutonium isotope levels observed in the lower reaches of the Rhône were 10 to 1000 times higher than those observed in other French freshwaters. Data gathered over a period of almost thirty years of radioecological studies reveal that the only radionuclides detected in fish muscles are (137)Cs, (90)Sr, plutonium isotopes and (241)Am. At the scale of the French territory, there is no significant difference since the mid 1990 s between (137)Cs activity observed downstream of nuclear facilities and that observed upstream, whether in sediments, mosses and fish. Finally, this study highlights that the natural radioactivity of surface freshwaters are around 25 times greater than artificial radioactivity from gamma emitters. However, non gamma emitters released by nuclear industries, such as (3)H, may lead to artificial activity levels 2 to 20 times higher than natural levels.


Docking studies of phthalimide pharmacophore as a sodium channel blocker.
Recently, phthalimide derivatives were designed based on ameltolide and thalidomide as they possess a similar degree of anticonvulsant potency due to their phenytoin-like profile. The ability of phthalimide pharmacophore to interact with neuronal voltage-dependent sodium channels was studied in the batrachotoxin affinity assay. Therefore, in the present study, a series of 19 compounds of phthalimide pharmacophore possessing a variety of substituents (NO2, NH2, Me, Cl, COOH, MeO) at 2-, 3-, and 4- position of the N-phenyl ring and N-(3-amino-2-methylphenyl) succinimide, were subjected to docking studies in order to inhibit voltage-gated sodium channels. Materials and Methods : Chemical structures of all compounds were designed using HYPERCHEM program and Conformational studies were performed through semi-empirical molecular orbital calculations method followed by PM3 force field. Total energy gradient calculated as a root mean square (RMS) value, until the RMS gradient was 0.01 kcal mol(-1). Among all energy minima conformers, the global minimum of compounds was used in docking calculations. Using a model of the open pore of Na channels, docking study was performed by AUTODOCK4.2 program. Results : Docking studies have revealed that these types of ligands interacted mainly with II-S6 residues of NaV1.2 through making hydrogen bonds and have additional hydrophobic interactions with domain I, II, III and IV in the channel's inner pore. These computational studies have displayed that these compounds are capable of inhibiting Na channel, efficiently.


[What are the advantages of UTN (unreamed tibial nail) in open tibial fractures?].
The AO-unreamed tibial nail (UTN) is an alternative to external fixation in the treatment of open tibial fractures. In order to compare the two implants we did a retrospective study. 70 unselected cases of open tibial fractures were treated by either method. 35 patients with primary UTN were compared to another 35 patients with primary external fixator. Demographic data, localisation and classification of fractures and soft tissue trauma showed no differences between the two groups. The main complications in UTN-group were hardware problems, in external fixator-group infections. Following UTN-treatment duration of first hospital stay and whole fracture treatment were shortened with earlier full weight bearing and fracture healing. Our study shows advantages in the treatment of open tibial fractures using the UTN compared to the external fixation.


Speaking up in groups: a cross-level study of group voice climate and voice.
Despite a growing body of research on employee voice—defined as the discretionary communication of ideas, suggestions, or opinions intended to improve organizational or unit functioning—the effects of shared or collective-level cognitions have received scant attention. There has also been relatively little research on voice within work groups. Our goal in this study was to address these important gaps by focusing on the effects of group-level beliefs about voice (i.e., group voice climate) on individual voice behavior within work groups. We conducted a cross-level investigation of voice behavior within 42 groups of engineers from a large chemical company. Consistent with our hypotheses, group voice climate was highly predictive of voice and explained variance beyond the effects of individual-level identification and satisfaction, and procedural justice climate. Also consistent with predictions, the effect of identification on voice was stronger in groups with favorable voice climates. These findings provide evidence that voice is shaped not just by individual attitudes and perceptions of the work context, as past research has shown, but also by group-level beliefs. The results also highlight the importance of broadening our conceptual models of voice to include shared cognitions and of conducting additional cross-level research on voice.


Lessons learned about human stem cell responses to ionizing radiation exposures: a long road still ahead of us.
Human stem cells (hSC) possess several distinct characteristics that set them apart from other cell types. First, hSC are self-renewing, capable of undergoing both asymmetric and symmetric cell divisions. Second, these cells can be coaxed to differentiate into various specialized cell types and, as such, hold great promise for regenerative medicine. Recent progresses in hSC biology fostered the characterization of the responses of hSC to genotoxic stresses, including ionizing radiation (IR). Here, we examine how different types of hSC respond to IR, with a special emphasis on their radiosensitivity, cell cycle, signaling networks, DNA damage response (DDR) and DNA repair. We show that human embryonic stem cells (hESCs) possess unique characteristics in how they react to IR that clearly distinguish these cells from all adult hSC studied thus far. On the other hand, a manifestation of radiation injuries/toxicity in human bodies may depend to a large extent on hSC populating corresponding tissues, such as human mesenchymal stem cells (hMSC), human hematopoietic stem cells (hHSC), neural hSC, intestine hSC, etc. We discuss here that hSC responses to IR differ notably across many types of hSC which may represent the distinct roles these cells play in development, regeneration and/or maintenance of homeostasis.


Controlling surface morphology and sensitivity of granular and porous silver films for surface-enhanced Raman scattering, SERS.
The design of efficient substrates for surface-enhanced Raman spectroscopy (SERS) for large-scale fabrication at low cost is an important issue in further enhancing the use of SERS for routine chemical analysis. Here, we systematically investigate the effect of different radio frequency (rf) plasmas (argon, hydrogen, nitrogen, air and oxygen plasma) as well as combinations of these plasmas on the surface morphology of thin silver films. It was found that different surface structures and different degrees of surface roughness could be obtained by a systematic variation of the plasma type and condition as well as plasma power and treatment time. The differently roughened silver surfaces act as efficient SERS substrates showing greater enhancement factors compared to as prepared, sputtered, but untreated silver films when using rhodamine B as Raman probe molecule. The obtained roughened silver films were fully characterized by scanning electron microscopy (SEM), atomic force microscopy (AFM), X-ray diffraction (XRD), transmission electron microscopy (TEM), X-ray photoelectron (XPS and Auger) and ultraviolet-visible spectroscopy (UV-vis) as well as contact angle measurements. It was found that different morphologies of the roughened Ag films could be obtained under controlled conditions. These silver films show a broad range of tunable SERS enhancement factors ranging from 1.93 × 102 to 2.35 × 105 using rhodamine B as probe molecule. The main factors that control the enhancement are the plasma gas used and the plasma conditions, i.e., pressure, power and treatment time. Altogether this work shows for the first time the effectiveness of a plasma treatment for surface roughening of silver thin films and its profound influence on the interface-controlled SERS enhancement effect. The method can be used for low-cost, large-scale production of SERS substrates.


Risk of malignancy associated with use of tocilizumab versus other biologics in patients with rheumatoid arthritis: A multi-database cohort study.
To examine the rate of incident malignancies excluding non-melanoma skin cancer (NMSC) in patients with rheumatoid arthritis (RA) newly treated with tocilizumab versus other biologic drugs. We conducted a cohort study using data from 3 U.S. insurance claims databases - Medicare (2010-2015), 'IMS' PharMetrics Plus (2011-2015) and Truven 'MarketScan' (2011-2015). Adults with RA who newly started tocilizumab or a TNF inhibitor (TNFi) after failing a different TNFi, abatacept or tofacitinib were included. The primary outcome was development of any malignancies excluding NMSC. For confounding control, tocilizumab starters were propensity score (PS)-matched to TNFi starters with a variable ratio of 1:3 within each database. Hazard ratios (HR) from the 3 PS-matched cohorts were combined by an inverse variance-weighted, fixed-effects model. We conducted a secondary analysis where we compared tocilizumab initiators with abatacept initiators. We included 13,102 tocilizumab initiators PS-matched to 26,727 TNFi initiators in all three databases. The incidence rate of malignancies per 1,000 person-years ranged from 8.27 (IMS) to 23.18 (Medicare) in the tocilizumab group and from 9.64 (MarketScan) to 21.46 (Medicare) in the TNFi group. The risk of incident malignancies was similar between tocilizumab and TNFi initiators across all three databases, with a combined HR of 0.98 (95%CI 0.80-1.19) in tocilizumab versus TNFi. The secondary analysis comparing tocilizumab versus abatacept showed similar results (combined HR 0.97, 95%CI 0.74-1.27). This large multi-database cohort study found no difference in the risk of malignancies excluding NMSC in RA patients who newly started tocilizumab compared with TNFi or abatacept.


Water buffaloes (Bubalus bubalis) only have A2A2 genotype for beta-casein.
Beta-casein is a milk protein that has two variants: A1 and A2. Some individuals have difficulties digesting beta-casein A1, which can cause gastrointestinal disorders. A2 milk has emerged as an alternative. This milk only contains beta-casein A2 and is obtained from females carrying the A2A2 genotype of the gene. In cattle, allele and genotype frequencies vary according to breed and marker-assisted selection is performed to obtain A2A2 animals and the consequent production of A2 milk that is easier to digest. This study aimed to evaluate the alleles of beta-casein in buffaloes. A total of 657 buffaloes of four different breeds were genotyped and all animals carried the A2A2 genotype, i.e., allele A1 does not exist in the buffalo species. Thus, all milk products of buffaloes are naturally A2. This result adds value to products derived from buffalo milk.


Adrenal Insufficiency, Sex Reversal, and Angelman Syndrome due to Uniparental Disomy Unmasking a Mutation in CYP11A1.
Cholesterol side-chain cleavage enzyme (P450scc) deficiency is a rare genetic disorder causing primary adrenal insufficiency with or without a 46,XY disorder of sexual development (DSD). Herein, we report a case of the combination of primary adrenal insufficiency, a DSD (testes with female external genitalia in a setting of a 47,XXY karyotype), and Angelman syndrome. Comprehensive genetic analyses were performed, including a single nucleotide polymorphism microarray and whole-exome sequencing. In vitro studies were performed to evaluate the pathogenicity of the novel mutation that was identified by whole-exome sequencing. The patient was found to have segmental uniparental disomy (UPD) of chromosome 15 explaining her diagnosis of Angelman syndrome. Whole-exome sequencing further revealed a novel homozygous intronic variant in CYP11A1, the gene encoding P450scc, found within the region of UPD. In vitro studies confirmed that this variant led to decreased efficiency of CYP11A1 splicing. We report the first case of the combination of 2 rare genetic disorders, Angelman syndrome, and P450scc deficiency. After 20 years of diagnostic efforts, significant advances in genetic diagnostic technology allowed us to determine that these 2 disorders originate from a unified genetic etiology, segmental UPD unmasking a novel recessive mutation in CYP11A1.


Dose-response relationship between cigarette smoking and risk of ischemic stroke in young women.
Although cigarette smoking is known to be a risk factor for ischemic stroke, there are few data on the dose-response relationship between smoking and stroke risk in a young ethnically diverse population. We used data from the Stroke Prevention in Young Women Study, a population-based case-control study of risk factors for ischemic stroke in women aged 15 to 49 years to examine the relationship between cigarette smoking and ischemic stroke. Historical data, including smoking history, was obtained through standardized interviews. Odds ratios (OR) were estimated using logistic regression. Cases (n=466) were women with stroke in the greater Baltimore-Washington area, and controls (n=604) were women free of a stroke history identified by random digit dialing. After multivariable adjustment, the OR comparing current smokers to never smokers was 2.6 (P<0.0001); no difference in stroke risk was observed between former smokers and never smokers. Adjusted OR increased with increasing number of cigarettes smoked per day (OR=2.2 for 1 to 10 cigs/d; 2.5 for 11 to 20 cigs/d; 4.3 for 21 to 39 cigs/d; 9.1 for 40 or more cigs/d). These results suggest a strong dose-response relationship between cigarette smoking and ischemic stroke risk in young women and reinforce the need for aggressive smoking cessation efforts in young adults.


Transcriptomics and proteomics show that selenium affects inflammation, cytoskeleton, and cancer pathways in human rectal biopsies.
Epidemiologic studies highlight the potential role of dietary selenium (Se) in colorectal cancer prevention. Our goal was to elucidate whether expression of factors crucial for colorectal homoeostasis is affected by physiologic differences in Se status. Using transcriptomics and proteomics followed by pathway analysis, we identified pathways affected by Se status in rectal biopsies from 22 healthy adults, including 11 controls with optimal status (mean plasma Se = 1.43 μM) and 11 subjects with suboptimal status (mean plasma Se = 0.86 μM). We observed that 254 genes and 26 proteins implicated in cancer (80%), immune function and inflammatory response (40%), cell growth and proliferation (70%), cellular movement, and cell death (50%) were differentially expressed between the 2 groups. Expression of 69 genes, including selenoproteins W1 and K, which are genes involved in cytoskeleton remodelling and transcription factor NFκB signaling, correlated significantly with Se status. Integrating proteomics and transcriptomics datasets revealed reduced inflammatory and immune responses and cytoskeleton remodelling in the suboptimal Se status group. This is the first study combining omics technologies to describe the impact of differences in Se status on colorectal expression patterns, revealing that suboptimal Se status could alter inflammatory signaling and cytoskeleton in human rectal mucosa and so influence cancer risk.-Méplan, C., Johnson, I. T., Polley, A. C. J., Cockell, S., Bradburn, D. M., Commane, D. M., Arasaradnam, R. P., Mulholland, F., Zupanic, A., Mathers, J. C., Hesketh, J. Transcriptomics and proteomics show that selenium affects inflammation, cytoskeleton, and cancer pathways in human rectal biopsies.


Efficacy of Oral Versus Injectable Iron in Patients With Chronic Kidney Disease: A Two-Year Cross-Sectional Study Conducted at a Rural Teaching Hospital.
Aim Anaemia (particularly iron deficiency) is of important concern in patients with chronic kidney disease (CKD) as it reflects the outcome of the disease. Current recommendations for the use of intravenous iron (IV) therapy in the management of anaemia in such patients are limited. This study highlights the comparison of oral to intravenous iron in patients with chronic kidney disease. Materials and methods This is a prospective case-control study comparing intravenous iron to oral iron in chronic kidney disease patients admitted to the Medicine Department of Acharya Vinoba Bhave Rural Hospital, in central India from October 2018 to October 2020. A total of 150 patients were divided into two groups of 75 each, one receiving oral iron (ferrous sulfate 325 mg tablets) and the other intravenous iron (IV iron sucrose). Results Serum iron, serum ferritin, and transferrin saturation (TS) showed increased levels in the IV iron group than in the oral iron group. In the IV group, a statistically significant increase was found in haemoglobin levels after therapy among all stages of kidney disease (p<0.05) while the same was not reported in the oral iron group. Conclusion IV iron sucrose therapy had been found to be effective, well-tolerated, and more successful than oral iron treatment in chronic kidney disease patients as far as the parameter of iron deficiency anaemia is concerned.


Spermathecal cytology of Ambystoma opacum (Amphibia: Ambystomatidae) and the phylogeny of sperm storage organs in female salamanders.
Sperm storage glands, spermathecae, were examined from mated female Ambystoma opacum during the breeding season. No differences occur in the spermathecal ultrastructure of individuals sacrificed prior to oviposition and those sacrificed within 3 days of removal from tended clutches of recently oviposited eggs. The simple tubuloalveolar glands produce two types of secretory vacuoles. Apical secretory vacuoles contain glycosaminoglycans for export into the lumen to bathe stored sperm, perhaps providing the chemical/osmotic environment necessary for sperm quiescence. The other type of secretory vacuole contains an unsaturated lipid that is produced for export into the connective tissue surrounding the spermathecae. The role of this secretion may involve the contraction of myoepithelial cells, resulting in sperm expulsion. Some sperm undergo degradation in the spermathecal epithelium, and an interepithelial leukocyte was observed in one specimen. Apical secretory vacuoles and sperm are absent from the spermathecae of a specimen sacrificed 62 days after removal from a tended egg clutch. This is the first report on the spermathecal cytology of a salamander from the Ambystomatidase, and comparisons with salamanders from other families provide a morphological basis for considering spermathecae polyphyletic within the Caudata.


Sexual Dysfunction in Patients with Hidradenitis Suppurativa: A Systematic Review and Meta-Analysis.
Hidradenitis suppurativa (HS) can be a severe condition that impacts patients' health and quality of life. One aspect that can be impaired is sexual health, with many patients suffering from sexual dysfunction (SD). There are numerous articles describing this association. We sought to synthesize and analyze the recent available evidence on HS and SD. A systematic review was conducted. Three medical databases were used: Medline, Embase, and Cochrane. All types of epidemiological articles were included, while reviews, guidelines, protocols, conference abstracts, and case report articles were excluded. This review covers the past eight years. Twelve studies were included for review, with the most common study design being cross-sectional. Most studies involved surveys and questionnaires, with some using control groups to compare results. SD affected roughly half of patients with HS, and was found more frequently in women. Comorbidities included psychological conditions, such as depression and low self-esteem, as well as metabolic and cardiovascular diseases. HS is significantly associated with sexual health issues, including SD in women and erectile dysfunction in men.


Defining Caenorhabditis elegans as a model system to investigate lipoic acid metabolism.
Lipoic acid (LA) is a sulfur-containing cofactor that covalently binds to a variety of cognate enzymes that are essential for redox reactions in all three domains of life. Inherited mutations in the enzymes that make LA, namely lipoyl synthase, octanoyltransferase, and amidotransferase, result in devastating human metabolic disorders. Unfortunately, because many aspects of this essential pathway are still obscure, available treatments only serve to alleviate symptoms. We envisioned that the development of an organismal model system might provide new opportunities to interrogate LA biochemistry, biology, and physiology. Here we report our investigations on three Caenorhabditis elegans orthologous proteins involved in this post-translational modification. We established that M01F1.3 is a lipoyl synthase, ZC410.7 an octanoyltransferase, and C45G3.3 an amidotransferase. Worms subjected to RNAi against M01F1.3 and ZC410.7 manifest larval arrest in the second generation. The arrest was not rescued by LA supplementation, indicating that endogenous synthesis of LA is essential for C. elegans development. Expression of the enzymes M01F1.3, ZC410.7, and C45G3.3 completely rescue bacterial or yeast mutants affected in different steps of the lipoylation pathway, indicating functional overlap. Thus, we demonstrate that, similarly to humans, C. elegans is able to synthesize LA de novo via a lipoyl-relay pathway, and suggest that this nematode could be a valuable model to dissect the role of protein mislipoylation and to develop new therapies.


Characterization of a positive regulatory element in the mts1 gene.
The first intron of the mts1 gene, a gene that is selectively expressed in metastatic cells and in normal cells that are motile, was found to be highly homologous to the CD3 delta enhancer element. Because of the homology between the CD3 delta enhancer and the first intron of mts1, we analysed the first intron of the mts1 gene to determine whether it functions as a transcriptional regulatory element. Highly metastatic CSML-100 cells transfected with chloramphenicol acetyl transferase-containing plasmids demonstrated the ability of the mts1 first intron to function as a positive regulatory element. In vitro footprinting analysis using extracts from CSML-0 cells (which express mts1 at low levels) or CSML-100 cells (which express mts1 at high levels) identified a protected 16-nucleotide element in the first intron of mts1, regardless of the extract used. However, in vivo footprinting analysis of the same region identified the protected 16-nucleotide fragment only in the mts1 intron from CSML-100 cells, not from CSML-0 cells. Differences in the methylation pattern of the mts1 gene in CSML-100 cells and CSML-0 cells are known to exist, and may in part be responsible for the mts1 footprinting differences observed in vivo from the different cell lines.


Effect of modified brain histamine contents on prolactin and thyrotropin secretion in male rats.
Effects of modified brain histamine contents on thyrotropin and prolactin secretion were studied in male rats. Under basal conditions the histamine content in the hypothalamus was approximately 8-10-fold higher than that in the striatum and the rest of the brain. L-histidine (1000 mg/kg, ip), a histamine precursor, and metoprine (20 mg/kg, ip), an inhibitor of histamine methyltransferase, elevated histamine content in the brain by 65% and 167%, respectively. When the treatments were given together an additive effect (119-250% increase) on brain histamine was observed. Metoprine significantly decreased serum prolactin levels, while L-histidine had no effect. This effect of metoprine was not modified by treatment with L-histidine. Thus, metoprine has an inhibitory effect on prolactin secretion that is not related to elevated brain histamine contents. The increased brain histamine content after L-histidine treatment had no effect on prolactin secretion. Basal levels of serum thyrotropin were decreased by both L-histidine and metoprine, L-histidine being more potent. In rats treated with alpha-fluoromethylhistidine, an inhibitor of L-histidine decarboxylase, the cold-induced (rats kept for 60 min at +4 degrees C) thyrotropin secretion was increased while the stress-induced prolactin secretion was decreased. In these rats, metoprine did not affect thyrotropin release but blunted the prolactin response. In conclusion, endogenous histamine inhibits thyrotropin secretion but does not affect prolactin release. Owing to its other effects, metoprine is not suitable as a tool to elevate endogenous histamine contents in the brain, at least when the regulation of anterior pituitary hormone release is being studied.


On the involvement of single-bond rotation in the primary photochemistry of photoactive yellow protein.
Prior experimental observations, as well as theoretical considerations, have led to the proposal that C(4)-C(7) single-bond rotation may play an important role in the primary photochemistry of photoactive yellow protein (PYP). We therefore synthesized an analog of this protein's 4-hydroxy-cinnamic acid chromophore, (5-hydroxy indan-(1E)-ylidene)acetic acid, in which rotation across the C(4)-C(7) single bond has been locked with an ethane bridge, and we reconstituted the apo form of the wild-type protein and its R52A derivative with this chromophore analog. In PYP reconstituted with the rotation-locked chromophore, 1), absorption spectra of ground and intermediate states are slightly blue-shifted; 2), the quantum yield of photochemistry is ∼60% reduced; 3), the excited-state dynamics of the chromophore are accelerated; and 4), dynamics of the thermal recovery reaction of the protein are accelerated. A significant finding was that the yield of the transient ground-state intermediate in the early phase of the photocycle was considerably higher in the rotation-locked samples than in the corresponding samples reconstituted with p-coumaric acid. In contrast to theoretical predictions, the initial photocycle dynamics of PYP were observed to be not affected by the charge of the amino acid residue at position 52, which was varied by 1), varying the pH of the sample between 5 and 10; and 2), site-directed mutagenesis to construct R52A. These results imply that C(4)-C(7) single-bond rotation in PYP is not an alternative to C(7)=C(8) double-bond rotation, in case the nearby positive charge of R52 is absent, but rather facilitates, presumably with a compensatory movement, the physiological Z/E isomerization of the blue-light-absorbing chromophore.


Late-onset non-islet cell tumor hypoglycemia: A case report.
Hypoglycemia due to non-insulin-producing tumors is referred to as non-islet cell tumor hypoglycemia (NICTH). As NICTH is a rare lesion, the natural course of NICTH is not well understood. We report a case of NICTH that was observed 30 years before the onset of hypoglycemia. A 50-year-old man was diagnosed with an abnormal right chest shadow during a routine X-ray examination, but no further examination was undertaken because the lesion appeared benign. Thirty years after the tumor discovery, the patient was admitted to the hospital with symptoms of severe hypoglycemia, which was diagnosed as NICTH based on a complete examination. The tumor was resected and found to be a solitary fibrous mass (15.6 cm × 13.7 cm × 10.4 cm); thereafter, the patient's blood glucose levels normalized and he completely recovered. NICTH can have an acute onset, even if the tumor has been present and asymptomatic over a long time period.


Investigation of the role of SDHB inactivation in sporadic phaeochromocytoma and neuroblastoma.
Germline mutations in the succinate dehydrogenase (SDH) (mitochondrial respiratory chain complex II) subunit B gene, SDHB, cause susceptibility to head and neck paraganglioma and phaeochromocytoma. Previously, we did not identify somatic SDHB mutations in sporadic phaeochromocytoma, but SDHB maps to 1p36, a region of frequent loss of heterozygosity (LOH) in neuroblastoma as well. Hence, to evaluate SDHB as a candidate neuroblastoma tumour suppressor gene (TSG) we performed mutation analysis in 46 primary neuroblastomas by direct sequencing, but did not identify germline or somatic SDHB mutations. As TSGs such as RASSF1A are frequently inactivated by promoter region hypermethylation, we designed a methylation-sensitive PCR-based assay to detect SDHB promoter region methylation. In 21% of primary neuroblastomas and 32% of phaeochromocytomas (32%) methylated (and unmethylated) alleles were detected. Although promoter region methylation was also detected in two neuroblastoma cell lines, this was not associated with silencing of SDHB expression, and treatment with a demethylating agent (5-azacytidine) did not increase SDH activity. These findings suggest that although germline SDHB mutations are an important cause of phaeochromocytoma susceptibility, somatic inactivation of SDHB does not have a major role in sporadic neural crest tumours and SDHB is not the target of 1p36 allele loss in neuroblastoma and phaeochromocytoma.


Comparison of the uptake of untargeted and targeted immunostimulatory nanoparticles by immune cells in the microenvironment of metastatic breast cancer.
To alter the immunosuppressive tumor microenvironment (TME), we developed an immunostimulatory nanoparticle (NP) to reprogram a tumor's dysfunctional and inhibitory antigen-presenting cells (APCs) into properly activated APCs that stimulate tumor-reactive cytotoxic T cells. Importantly, systemic delivery allowed NPs to efficiently utilize the entire microvasculature and gain access into the majority of the perivascular TME, which coincided with the APC-rich tumor areas leading to uptake of the NPs predominantly by APCs. In this work, a 60 nm NP was loaded with a STING agonist, which triggered robust production of interferon β, resulting in activation of APCs. In addition to untargeted NPs, we employed 'mainstream' ligands targeting fibronectin, αvβ3 integrin and P-selectin that are commonly used to direct nanoparticles to tumors. Using the 4T1 mouse model, we assessed the microdistribution of the four NP variants in the tumor immune microenvironment in three different breast cancer landscapes, including primary tumor, early metastasis, and late metastasis. The different NP variants resulted in variable uptake by immune cell subsets depending on the organ and tumor stage. Among the NP variants, therapeutic studies indicated that the untargeted NPs and the integrin-targeting NPs exhibited a remarkable short- and long-term immune response and long-lasting antitumor effect.


Syncope as etiology of road crashes involving elderly drivers.
A significant number of elderly drivers present without discernible external cause for their road crash. We hypothesize that syncope may contribute to their crash etiology and prospectively evaluated drivers older than 60 years with unexplained crash, presenting to our trauma center during a 1-year period. Prehospital data and prior medical history were obtained on all, followed by a standard syncope work-up. Of 79 drivers ages 60-98, 58 (73%) were at fault in the crash. In 33 (57%), the crash etiology could not be determined. Thirteen had prior syncope history. Workup was negative in two patients, and six died or were transferred before evaluation. Twenty-five of 33 (76%) had positive workups for syncope: cardiac causes in 10; neurologic in seven; psychiatric in five, endocrine in two; one indeterminant. Ten of 18 who survived had license revocation for medical reasons. Syncopal episodes are a frequent contributor to unexplained crashes among elderly drivers and should be suspected whenever external causes are not apparent.


Epigenetic and risk factors of testicular germ cell tumors: a brief review.
Testicular germ cell cancer (TGCT) is the most common malignancy among young adult males, which has become important due to its increased incidence and mortality in the population worldwide. The etiology is multifactorial. Recent studies have shown some associations between the development of isolated TGCT and certain risk factors, such as exposure to endocrine disruptors, cryptorchidism, and family history of cancer, in order to identify the key pieces in carcinogenesis. Some of the most important findings in recent years is the association of different genes, such as c-KIT/KITLG, expression of the miR-371-373 cluster and protein expression as c-KIT and POU5F1 in the development of this neoplasia, and the identification of new molecular markers as TGFBR3 gene, identifying aberrant methylation patterns in promoter regions of several genes, expression of miR-1297 which regulates PTEN and protein expression as DMTR1. In the future, a multidisciplinary research strategy could provide valuable new insights into the etiology of TGCTs, which support clinical diagnosis of TGCT in the next years to increase survival in this kind of patients.


Idiotypic characterisation of monoclonal antibodies with restricted epitope specificity for retinal S-antigen.
This paper describes the idiotypic specificities of eight murine monoclonal antibodies directed to three independent epitopes on retinal S-antigen. The antigenic sites recognised by these monoclonal antibodies have previously been localised to a small region near the C-terminal of bovine S-antigen. Xenogeneic, site-related anti-idiotypes prepared against each of the monoclonal antibodies recognised common idiotypes only amongst those monoclonal antibodies which reacted with the same epitope on S-antigen. Two of the three idiotypes were detected in the sera of BALB/c mice but not in two strains of rat immunised with xenogeneic S-antigen and none could be detected in the sera of patients with anti-photoreceptor autoantibodies. Our results demonstrate that the idiotypes of murine monoclonal antibodies to retinal S-antigen exhibit restricted epitope specificity but are species-restricted and imply that the S-antigen lacks a dominant antigenic epitope.


Heparin-Free Lung Transplantation on Venovenous Extracorporeal Membrane Oxygenation Bridge.
Extracorporeal membrane oxygenation (ECMO) bridge to lung transplantation (LuTX) exposes the patients to a high risk of perioperative bleeding secondary to systemic anticoagulation and coagulation factors deficiency. With this case series, we propose innovative "no-heparin" management of ECMO-bridge support during LuTX, based upon 1) control heparin resistance with antithrombin III in the preoperative period; 2) relying upon a fully functional, brand new heparinized ECMO circuit; 3) completely avoiding perioperative heparin; 4) hampering fibrinolysis with tranexamic acid; and 5) limiting venoarterial (VA) ECMO escalation, and the following need for full anticoagulation. Following the application of this new approach, we carried out three challenging clinical cases of bilateral ECMO-bridged LuTX effectively, with limited intraoperative blood requirement and no major postoperative bleeding or thromboembolic events. Of note, two of them had an extremely high risk for hemorrhage due to complete right lung anatomic derangement in case number 2 and surgical adhesion following first LuTX in case number 3, while for the case number 1, no blood products were administered during surgery. Despite the limited patient population, such an approach relies on a strong rationale and may be beneficial for managing ECMO bridging to LuTX. Prospective studies are necessary to confirm the validity of our strategy.


Neural pathways of olfactory kin imprinting and kin recognition in zebrafish.
Teleost fish exhibit extraordinary cognitive skills that are comparable to those of mammals and birds. Kin recognition based on olfactory and visual imprinting requires neuronal circuits that were assumed to be necessarily dependent on the interaction of mammalian amygdala, hippocampus, and isocortex, the latter being a structure that teleost fish are lacking. We show that teleosts-beyond having a hippocampus and pallial amygdala homolog-also have subpallial amygdalar structures. In particular, we identify the medial amygdala and neural olfactory central circuits related to kin imprinting and kin recognition corresponding to an accessory olfactory system despite the absence of a separate vomeronasal organ.


Pancreatic duct abnormalities in gall stone disease: an endoscopic retrograde cholangiopancreatographic study.
This study was carried out to assess pancreatic duct abnormalities in gall stone disease. Endoscopic retrograde cholangiopancreatograms of 50 patients with gall stone disease were analysed and the results compared with those obtained in 33 patients investigated for cholestatic jaundice who were found to have a normal biliary tree (control group). Abnormal pancreatograms were obtained in 24 (48%) patients with gall stone disease and in only two (6%) in the control group; the differences were statistically significant (chi 2 = 14.3; p less than 0.001). The patients in the control group showed mild abnormalities as did those in the gall stone group. The frequency of various abnormalities were: mild 16 (32%), moderate five (10%), and severe three (6%). Pancreatic duct abnormalities were more severe and occurred more frequently in patients with gall stones who had stones in the biliary tree than in patients with a normal biliary tree (postcholecystectomy patients, 55% v 25%) but the difference between the two groups just failed to be significant (chi 2 = 3.34). In conclusion, nearly half of all patients with gall stone disease have pancreatic duct abnormalities and in 16% these were severe enough to be labelled as chronic pancreatitis.


Protective effect of isoprinosine in genetically susceptible BALB/c mice infected with Leishmania major.
The effects of an immunopotentiating drug Inosine Pranobex (isoprinosine) were investigated in an experimental cutaneous leishmaniasis model. The highly susceptible BALB/c mice treated orally with isoprinosine developed significantly delayed onset of disease when infected with Leishmania major compared to untreated mice. The drug itself is not toxic to the parasite up to millimolar levels in vitro. The increase in resistance to L. major infection is accompanied by a marked decrease in the CD4+/CD8+ ratio and the leishmanial antigen-specific proliferative response of the spleen cells of isoprinosine-treated mice compared to untreated mice. There was a significant increase in the production of IFN-gamma but a decrease in the secretion of IL-3 and IL-4 by the spleen cells of isoprinosine-treated mice in response to concanavalin A with or without L. major infection compared to untreated controls. There was, however, no significant difference in the level of IL-2 production by the spleen cells between mice with or without isoprinosine treatment. These data are consistent with the interpretation that isoprinosine potentiates the resistance to leishmanial infection by up-regulating the host-protective Th1 cells and down-regulating the disease-promoting Th2 cells or, alternatively, by increasing CD8+ T-cell function.


Acute Changes in Arterial Function Post High-Intensity Lower Extremity Cycling.
The purpose of this study was to assess the acute arterial blood flow velocity of the lower extremity (LE) immediately after a bout of high-intensity LE cycling exercise. Twenty-eight healthy males (n = 14) and females (n = 14) aged 20.9 ± 1.7 years participated in this study. All subjects performed a single bout of high-intensity cycling (70% of HRR) for 45 min. The subjects' LE blood flow velocity, heart rate (HR), systolic blood pressure (SBP), and oxygen saturation (SpO2) were measured at rest, immediately post-, post-15 min., and post- 30 min. intervention. A repeated-measures ANOVA with a Bonferroni adjustment was used for each measure to compare the responses at each time point. Resting blood flow velocity (37.5 ± 11.3 cm/s) and HR (64.9 ± 11.8 bpm) measures were significantly different (p < 0.05) compared to measures of immediately post cycling (44.8 ± 13.7 cm/s; 118.3 ± 17.2 bpm), post-15 min. (50.1 ± 15.0 cm/s; 80.1 ± 12.0 bpm) and post-30 min. (52.7 ± 18.1 cm/s; 73.9 ± 11.9 bpm). SBP measures were significantly different (p < 0.05) at immediately post (118.2 ±17.0 mmHg) compared to post-15 min. (108.1 ± 13.6 mmHg). Resting SpO2 (98.2 ± 1.3 %) measures were significantly different (p < 0.05) compared to measures immediately post (96.5 ± 1.1 %) and post-15 min. (96.9 ± 1.2 %). This study indicates that LE blood flow velocity was increased, and HR was elevated following a single bout of high-intensity LE cycling up to 30 min.-post. Additionally, SBP was elevated, while SpO2 dropped following a bout of exercise to 15 min.-post activity.


Phylogenetic position of Chitinophaga pinensis in the Flexibacter-Bacteroides-Cytophaga phylum.
Comparison of the 16S rRNA gene sequence determined for Chitinophaga pinensis showed that this species is most closely related to Flexibacter filiformis in the Flexibacter-Bacteroides-Cytophaga phylum. These two chitinolytic bacteria, which are characterized by transformation into spherical bodies on ageing, belong to a strongly supported lineage that also includes Cytophaga arvensicola, Flavobacterium ferrugineum and Flexibacter sancti. The lineage is distinct from the microcyst-forming species Sporocytophaga myxococcoides.


Hemodynamic responses to sarafotoxin 6 peptides.
Hemodynamic responses to sarafotoxin (SFTX6) peptides and endothelin-1 (ET-1) were compared in the anesthetized cat. SFTX6a and ET-1 at a dose of 0.3 nmol/kg i.v. produced a biphasic change in arterial pressure characterized by an initial decrease followed by a secondary increase in pressure. In contrast, similar doses of SFTX6b and SFTX6c produced mainly decreases in arterial pressure. Each peptide produced increases in central venous pressure, pulmonary arterial pressure, left atrial pressure, and cardiac output. Secondary decreases in cardiac output could be observed in response to SFTX6a and ET-1. SFTX6a and ET-1 produced biphasic changes, whereas SFTX6b and SFTX6c produced only decreases in systemic vascular resistance. In contrast, each peptide produced biphasic changes in pulmonary vascular resistance. The initial fall in pulmonary vascular resistance may be passively related to an increase in pulmonary blood flow because it occurs at a time when cardiac output is increased and no initial fall in pulmonary arterial pressure is observed. The present data show that the SFTX6 peptides can produce different patterns of responses in the systemic vascular bed of the cat, whereas responses in the pulmonary vascular bed are similar.


Expression of vitamin D and vitamin D receptor in chorionic villous in missed abortion.
The contemporary world despite its enough developed medicine and generally highly enlightened population faces a great problem of vitamin, micro-element and nutrient deficiency turning to become the XXI century pandemic. Along with that significant growth of interest can be seen towards vitamin D importance for reproductive physiology. The fact is that vitamin D receptors (VDR) have been detected in women's ovarium tissue, fallopian tubes, decidua and placenta. Some recent years studies have proven that vitamin D may act as immune regulator during implantation. During early pregnancy the trophoblast release vitamin D, which produces anti-inflammatory reaction and also induce decidual tissue growth for successive pregnancy. It was a comparison between the expression of Vitamin D and VDR in chorionic villous in cases of normal pregnancy and missed abortion groups. 64 samples of chorionic villous were taken: 32 from missed abortion and 32 from the induced abortion group. Abortive material was taken from two groups of women residing in North-West region of Russia: missed abortion and pregnancy terminated at woman's wish (induced abortion); 6-12 weeks of gestation, singleton pregnancy. Immune histochemical examination showed homogenous distribution of vitamin D and VDR expression in syncytiotrophoblasts, cytotrophoblasts and chorion villus stroma.Vitamin D expression relative area was 10,3% which is statistically different from the induced abortion group - 15,4% (p<0,01). VDR expression analysis showed its homogenous distribution in chorionic villus structures in both groups. High VDR expression was detected in chorion villus stromal components. In missed abortion group, the morphometry results showed distinctly lower relative area of vitamin D expression against the comparison group (35,9 ± 1,8; 56,1 ± 2,4 p < 0,01). Also in missed abortion group, positively significant correlation has been determined between the level of vitamin D in blood and VDR relative area expression (r = 0,412). In missed abortion group, definite vitamin D and VDR expression decrease was detected compared to the induced abortion group. The results witness vitamin D importance for pregnancy progress.


Opto-magnetic capture of individual cells based on visual phenotypes.
The ability to isolate rare live cells within a heterogeneous population based solely on visual criteria remains technically challenging, due largely to limitations imposed by existing sorting technologies. Here, we present a new method that permits labeling cells of interest by attaching streptavidin-coated magnetic beads to their membranes using the lasers of a confocal microscope. A simple magnet allows highly specific isolation of the labeled cells, which then remain viable and proliferate normally. As proof of principle, we tagged, isolated, and expanded individual cells based on three biologically relevant visual characteristics: i) presence of multiple nuclei, ii) accumulation of lipid vesicles, and iii) ability to resolve ionizing radiation-induced DNA damage foci. Our method constitutes a rapid, efficient, and cost-effective approach for isolation and subsequent characterization of rare cells based on observable traits such as movement, shape, or location, which in turn can generate novel mechanistic insights into important biological processes.


High levels of BCL-2 messenger RNA detected by in situ hybridization in human hepatocellular and cholangiocellular carcinomas.
Immunocytochemistry has indicated that, in the liver, the bcl-2 gene is generally expressed in bile duct cells and tumors of biliary origin. Both in situ hybridization and immunocytochemistry were used to analyze the expression of bcl-2 messenger RNA (mRNA) and its protein product (Bcl-2) in the tissue of 50 pure primary liver tumor (PLT) specimens including 40 hepatocellular carcinoma (HCC) specimens and 10 cholangiocellular carcinoma (CC) specimens. The phenotype of the tumors expressing bcl-2 was confirmed by immunocytochemical assessment of the cytokeratin (CK) profile (CK8, CK18, CK7, and CK19). Whereas positive immunoreaction with the anti-Bcl-2 MoAb was revealed in only 8 (20%) of 40 HCC specimens and 1 (10%) of 10 CC specimens, high contents of bcl-2 mRNA were found in 26 (65%) of 40 HCC specimens and 9 (90%) of 10 CC specimens. Regarding the CK profile, only 25 (62%) of 40 HCC specimens showed pure hepatocytic lineage (CKs 8-18), whereas among the remaining 15 HCC specimens, positivity for either CK7 (12 specimens) or CK19 (5 specimens) was observed. All 10 CC specimens stained with CKs 8-18-19, and 8 of 10 stained with CK 7 as well. These results indicate that PLTs display a greater expression of bcl-2 mRNA than of the Bcl-2 protein. Furthermore, CK profile assessment confirmed that bcl-2 expression is not confined to liver tumors of biliary origin. In the absence of a well-demonstrated post-transcriptional control of the gene, the authors propose the detection of bcl-2 mRNA by in situ hybridization as a possible alternative method for assessing the expression of bcl-2 mRNA in PLT.


High Pregnane X Receptor (PXR) Expression Is Correlated with Poor Prognosis in Invasive Breast Carcinoma.
Pregnane X Receptor (PXR) is involved in human cancer, either by directly affecting carcinogenesis or by inducing drug-drug interactions and chemotherapy resistance. The clinical significance of PXR expression in invasive breast carcinoma was evaluated in the present study. PXR protein expression was assessed immunohistochemically on formalin fixed paraffin-embedded breast invasive carcinoma tissue sections, obtained from 148 patients, and was correlated with clinicopathological parameters, molecular phenotypes, tumor cells' proliferative capacity, and overall disease-free patients' survival. Additionally, the expression of PXR was examined on human breast carcinoma cell lines of different histological grade, hormonal status, and metastatic potential. PXR positivity was noted in 79 (53.4%) and high PXR expression in 48 (32.4%), out of 148 breast carcinoma cases. High PXR expression was positively associated with nuclear grade (p = 0.0112) and histological grade of differentiation (p = 0.0305), as well as with tumor cells' proliferative capacity (p = 0.0051), and negatively with luminal A subtype (p = 0.0295). Associations between high PXR expression, estrogen, and progesterone receptor negative status were also recorded (p = 0.0314 and p = 0.0208, respectively). High PXR expression was associated with shorter overall patients' survival times (log-rank test, p = 0.0009). In multivariate analysis, high PXR expression was identified as an independent prognostic factor of overall patients' survival (Cox-regression analysis, p = 0.0082). PXR expression alterations were also noted in breast cancer cell lines of different hormonal status. The present data supported evidence that PXR was related to a more aggressive invasive breast carcinoma phenotype, being a strong and independent poor prognosticator.


Dimerization of tyrosine phosphatase PTPRO decreases its activity and ability to inactivate TrkC.
Receptor-protein tyrosine phosphatases (RPTPs), like receptor tyrosine kinases, regulate neuronal differentiation. While receptor tyrosine kinases are dimerized and activated by extracellular ligands, the extent to which RPTPs dimerize, and the effects of dimerization on phosphatase activity, are poorly understood. We have examined a neuronal type III RPTP, PTPRO; we find that PTPRO can form dimers in living cells, and that disulfide linkages in PTPROs intracellular domain likely regulate dimerization. Dimerization of PTPROs transmembrane and intracellular domains, achieved by ligand binding to a chimeric fusion protein, decreases activity toward artificial peptides and toward a putative substrate, tropomyosin-related kinase C (TrkC). Dephosphorylation of TrkC by PTPRO may be physiologically relevant, as it is efficient, and TrkC and PTPRO can be co-precipitated from transfected cells. Inhibition of PTPROs phosphatase activity by dimerization is interesting, as dimerization of a related RPTP, CD148/PTPRJ, increases activity. Thus, our results suggest a complex relationship between dimerization and activity in type III RPTPs.


The effect of situation-evoked anxiety and gender on pain report using the cold pressor test.
The aims of the present study were to investigate the influence of anxiety on pain perception and to test whether gender differences in pain perception are anxiety dependent. Sixty male and female university students exposed to situation-evoked anxiety or a control procedure were measured for their pain threshold, tolerance, and perceived intensity during a cold pressor test. Both subjective and autonomic responses indicated that anxiety was successfully induced in participants exposed to the anxiety condition. Increased situational anxiety had no significant effect on pain threshold or pain tolerance. Significant increases in pain intensity were found for the anxiety group. Levels of anxiety, however, did not correlate with this increased intensity, raising doubt as to the role of anxiety in producing this effect. No gender differences were found for pain tolerance or pain intensity. Gender differences were found for pain threshold in the anxiety group with, contrary to past findings, females showing significantly higher pain thresholds than males. The results are discussed in the light of related studies.


Change in diagnosis from the emergency department to hospital discharge in dyspnoeic patients.
To improve the outcomes of dyspnoeic patients, it is potentially important to determine the influence of uncertain diagnostic aetiology and to characterise this patient group. A change in diagnosis from emergency department (ED) contact to hospital discharge (i.e., a discordant diagnosis) served as a surrogate measure for an uncertain diagnostic aetiology. This study investigated the association between a change in diagnosis from ED contact to hospital discharge and length of stay (LOS), readmission and mortality in patients whose chief complaint was dyspnoea. The study also characterises the group of patients found to have a discordant diagnosis. This cohort study was based on data from all ED contacts at Aarhus University Hospital from 1 July 2016 to 30 June 2017. Patients triaged with dyspnoea and subsequently admitted to an inpatient unit were included. Concordant contacts had an average LOS of 3.63 days, whereas discordant contacts had an average LOS of 4.65 days; the adjusted relative difference was 1.28 (95% CI: 1.10-1.48). Readmission, whether at seven or 30 days, was not significantly different between the groups. The 30-day mortality was 5% in the concordant and 10% in the discordant group, with an adjusted OR of 2.32 (95% CI: 1.08-4.96). We found an association between a change in diagnosis and longer LOS, and between a change in diagnosis and 30-day mortality. The effort made to achieve diagnostic certainty in the ED may have an impact lasting throughout the entire hospital stay. none. not relevant.


[The properties of the extracellular alkaline phosphatase of the causative agent of melioidosis].
After growing P. pseudomallei VPA on solid medium extracellular alkaline phosphatase with a molecular weight of 93,000 AMU was isolated, and practically purified from the extract of this medium by precipitation with ammonium sulfate, subsequent gel chromatography and concentration on membrane filters. The optimum conditions for enzymatic reaction were found to be pH 9.0 and a temperature of 50 degrees C. The enzyme was resistant to freezing and to heating at a temperature of up 60 degrees C for 30 minutes, as well as to the action of pH 3.0-10.5, but became completely inactivated after heating at 90 degrees C for 10 minutes and incubation at pH 2.0 for 20 hours.


Nitric oxide neurotoxicity.
Derangements in glutamate neurotransmission have been implicated in several neurodegenerative disorders including, stroke, epilepsy, Huntington's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS). Activation of the N-methyl-D-aspartate (NMDA) receptor subtype of glutamate receptors results in the influx of calcium which binds calmodulin and activates neuronal nitric oxide synthase (nNOS), to convent L-arginine to citrulline and nitric oxide (NO). NO has many roles in the central nervous system as a messenger molecule, however, when generated in excess NO can be neurotoxic. Excess NO is in part responsible for glutamate neurotoxicity in primary neuronal cell culture and in animal models of stroke. It is likely that most of the neurotoxic actions of NO are mediated by peroxynitrite (ONOO-), the reaction product from NO and superoxide anion. In pathologic conditions, peroxynitrite and oxygen free radicals can be generated in excess of a cell antioxidant capacity resulting in severe damage to cellular constituents including proteins, DNA and lipids. The inherent biochemical and physiological characteristics of the brain, including high lipid concentrations and energy requirements, make it particularly susceptible to free radical and oxidant mediated insult. Increasing evidence indicates that many neurologic disorders may have components of free radical and oxidative stress induced injury.


Effects of Erythropoietin on Gliogenesis during Cerebral Ischemic/Reperfusion Recovery in Adult Mice.
Erythropoietin (EPO) promotes oligodendrogenesis and attenuates white matter injury in neonatal rats. However, it is unknown whether this effect extends to adult mice and whether EPO regulate microglia polarization after ischemic stroke. Male adult C57BL/6 mice (25-30g) were subjected to 45 min of middle cerebral artery occlusion (MCAO). EPO (5000 IU/kg) or saline was injected intraperitoneally every other day after reperfusion. Neurological function was evaluated using the rotarod test at 1, 3, 7 and 14 days after MCAO. Brain tissue loss volume was determined by hematoxylin-eosin staining. Immunofluorescence staining and Western blot were also used to assess the severity of white matter injury and phenotypic changes in microglia/macrophages. Bromodeoxyuridine (BrdU) was injected intraperitoneally daily for 1 week to analyze the number of newly proliferating glia cells (oligodendrocytes, microglia, and astrocytes). We found that EPO significantly reduced Brain tissue loss volume, ameliorated white matter injury, and improved neurobehavioral outcomes at 14 days after MCAO (P<0.05). In addition, EPO also increased the number of newly generated oligodendrocytes and attenuated the rapid hypertrophy and hyperplasia of microglia and astrocytes after ischemic stroke (P<0.05). Furthermore, EPO reduced M1 microglia and increased M2 microglia (P<0.05). Taken together, our results suggest that EPO treatment improves white matter integrity after cerebral ischemia, which could be attributed to EPO attenuating gliosis and facilitating the microglial polarization toward the beneficial M2 phenotype to promote oligodendrogenesis.


Evolutionary history of larval skeletal morphology in sea urchin Echinometridae (Echinoidea: Echinodermata) as deduced from mitochondrial DNA molecular phylogeny.
The larval skeletons of sea urchins show considerable morphological diversity, even between closely related species, although the evolutionary history and functional significance of this diversity are poorly understood. To infer the evolutionary history of the skeletal morphology, we focused on echinometrid species for which the morphological variation in larval skeletons had been investigated qualitatively and quantitatively. We reconstructed the phylogenetic relationships among 14 echinometrid species based on mitochondrial ND1 and ND2 genes and mapped the morphological characters onto the resultant trees. The monophyly of each genus in the Echinometridae was well supported by our results, as was the close affinity between Colobocentrotus, Heterocentrotus, and Echinometra. The mapping of the morphological characters of the larval skeletons indicated that the length, direction, and density of spines on the postoral rods was well conserved in each group of Echinometridae and that the abundance of spines and the size and shape of the body skeleton changed relatively frequently and hence were less conserved. In Echinometrid species, morphological variation in relatively unconserved features tends to be associated with latitudinal distributions, rather than phylogenetic relationships, indicating that the morphological diversity of larval skeletons could have been caused by adaptation to the habitat environment. Some morphological differences, however, seem to be nonfunctional and generated by the constraints on larval skeletogenesis. Thus, echinometrid species can be a good model with which to study the evolutionary history from both ecological and developmental standpoints.


Interleukin-2 induces corneal neovascularization in A/J mice.
Mitogen-stimulated lymphocytes induce a highly reproducible form of corneal neovascularization (CNV) in inbred mice. To determine if supernatants derived from stimulated lymphocytes and their constituent mediators were also angiogenic, we injected conditioned medium (CM) from mitogen-stimulated lymphocytes, control non-conditioned medium, recombinant interleukin-2 (rIL-2), or control bovine serum albumin (BSA), a component of rIL-2, into the corneas of syngeneic A/J mice. Control, nonconditioned medium was not angiogenic. While the other injections all induced some CNV, the CM and rIL-2 both induced a significantly greater area of CNV than BSA (p less than 0.05). The area of CNV induced by the CM was greater than that induced by IL-2 (p = 0.03). These data show that IL-2, which stimulates vascular endothelial cells in vitro and is elaborated during corneal immune reactions in vivo, is one of the potential mediators of immunologically mediated CNV.


H-ATPase Activity from Storage Tissue of Beta vulgaris: II. H/ATP Stoichiometry of an Anion-Sensitive H-ATPase.
The H(+)/ATP stoichiometry was determined for an anion-sensitive H(+)-ATPase in membrane vesicles believed to be derived from tonoplast. Initial rates of proton influx were measured by monitoring the alkalinization of a weakly buffered medium (pH 6.13) following the addition of ATP to a suspension of membrane vesicles of Beta vulgaris L. Initial rates of ATP hydrolysis were measured in an assay where ATP hydrolysis is coupled to NADH oxidation and monitored spectrophotometrically (A(340)) or by monitoring the release of (32)P from [gamma-(32)P]ATP. Inasmuch as this anion-sensitive H(+)-ATPase is strongly inhibited by NO(3) (-), initial rates of H(+) influx and ATP hydrolysis were measured in the absence and presence of NO(3) (-) to account for ATPase activity not involved in H(+) transport. The NO(3) (-)-sensitive activities were calculated and used to estimate the ratio of H(+) transported to ATP hydrolyzed. These measurements resulted in an estimate of the H(+)/ATP stoichiometry of 1.96 +/- 0.14 suggesting that the actual stoichiometry is 2 H(+) transported per ATP hydrolyzed. When compared with the reported values of the electrochemical potential gradient for H(+) across the tonoplast measured in vivo, our result suggests that the H(+)-ATPase does not operate near equilibrium but is regulated by cellular factors other than energy supply.


General acteoside of Rehmanniae leaves in the treatment of primary chronic glomerulonephritis: a randomized controlled trial.
The objective of the study was to investigate the effectiveness and efficacy of the randomized, parallel, and controlled trial of Traditional Chinese Medicine, general acteoside of Rehmanniae leaves, compared with piperazine ferulate in the treatment of primary chronic glomerulonephritis. Rehmanniae leaves and piperazine ferulate can reduce proteinuria and erythrocyturia effectively in the treatment of primary chronic glomerulonephritis. A total of 400 patients diagnosed with primary chronic glomerulonephritis were recruited from outpatient clinics and were randomly assigned to the treatment group (general acteoside of Rehmanniae leaves, two 200mg tablets, bid) or the control group (piperazine ferulate, four 50-mg tablets, bid ). The primary outcome was 24-h urinary protein. Secondary outcome measures included estimated glomerular filtration rate (eGFR), erythrocyturia, and electrolytes. After 8 weeks of treatment, the treatment group and the control group showed a mean reduction in 24-h proteinuria of 34.81% and 37.66%. The 95% CI of difference of the mean reduction in 24-h proteinuria between the two groups was [-11.50%, 5.80%]. No significant differences were found between the two groups in the erythrocyturia reduction. Neither group showed obvious changes between baseline and 8 weeks in eGFR or electrolytes. Adverse events occurred at a similarly low rate in the treatment group (1.5%) and control group (2.5%, P = 0.7238). Both general acteoside of Rehmanniae leaves and piperazine ferulate can reduce proteinuria and erythrocyturia effectively in the treatment of primary chronic glomerulonephritis.


Proposed pathway for therapeutic drug monitoring and dose escalation of vedolizumab.
Vedolizumab is a gut-selective monoclonal antibody approved for the management of Crohn's disease and ulcerative colitis. The available data demonstrate a favourable response to dose escalation in patients with primary non-response or secondary loss of response to vedolizumab. While therapeutic drug monitoring has a proven clinical utility for tumour necrosis factor antagonists, the available guidance for therapeutic drug monitoring and dose escalation of vedolizumab is rather limited. The present review proposes a practical algorithm to use vedolizumab trough levels in the management of treatment failure. Therapeutic drug monitoring can differentiate underexposed patients from those with mechanistic failure. Underdosed patients can respond to dose escalation instead of unnecessarily switching to other treatment modalities. We also review the safety and potential cost-effectiveness of vedolizumab dose escalation, the role of antidrug antibodies and the possible applicability of this strategy to subcutaneous vedolizumab.


Application of the missing-indicator method in matched case-control studies with incomplete data.
A common practice in matched case-control studies with incomplete data is to perform two analyses in parallel: a matched analysis of the complete pairs and an unmatched analysis of all subjects carried out after breaking the matching in the complete pairs. The missing-indicator method, which has the advantage of making use of the data in the incomplete pairs while still preserving the matching in the complete pairs, is recommended as an alternative method of analysis. It is shown here that its estimate of the odds ratio is a compromise between the odds ratios estimated by a matched analysis of the complete pairs and an unmatched analysis of the incomplete pairs. The method is illustrated using data from a matched case-control study of the risk of childhood leukemia from exposure to residential electric and magnetic fields.


Upper GI tract lesions in familial adenomatous polyposis (FAP): enrichment of pyloric gland adenomas and other gastric and duodenal neoplasms.
Patients with familial adenomatous polyposis (FAP), an autosomal dominant cancer predisposition syndrome caused by mutations in the APC gene, develop neoplasms in both the upper and lower gastrointestinal (GI) tract. To clarify the upper GI tract lesions in FAP patients in a tertiary care setting, we reviewed specimens from 321 endoscopies in 66 patients with FAP. Tubular adenomas in the small bowel were the most common neoplasms (present in 89% of patients), although only 1 patient developed invasive carcinoma of the small bowel. Several types of gastric neoplasms were identified--65% of patients had at least 1 fundic gland polyp, and 23% of patients had at least 1 gastric foveolar-type gastric adenoma. Pyloric gland adenomas were also enriched, occurring in 6% of patients--this is a novel finding in FAP patients. Despite the high frequency of gastric neoplasms, only 1 patient developed carcinoma in the stomach. The very low frequency of carcinoma in these patients suggests that current screening procedures prevent the vast majority of upper GI tract carcinomas in patients with FAP, at least in the tertiary care setting.


Magnetic-Field Effect in High-Order Above-Threshold Ionization.
We experimentally and theoretically investigate the influence of the magnetic component of an electromagnetic field on high-order above-threshold ionization of xenon atoms driven by ultrashort femtosecond laser pulses. The nondipole shift of the electron momentum distribution along the light-propagation direction for high energy electrons beyond the 2U_{p} classical cutoff is found to be vastly different from that below this cutoff, where U_{p} is the ponderomotive potential of the driving laser field. A local minimum structure in the momentum dependence of the nondipole shift above the cutoff is identified for the first time. With the help of classical and quantum-orbit analysis, we show that large-angle rescattering of the electrons strongly alters the partitioning of the photon momentum between electron and ion. The sensitivity of the observed nondipole shift to the electronic structure of the target atom is confirmed by three-dimensional time-dependent Schrödinger equation simulations for different model potentials. Our work paves the way toward understanding the physics of extreme light-matter interactions at long wavelengths and high electron kinetic energies.


Note: A high Mach number arc-driven shock tube for turbulence studies.
A high Mach arc-driven shock tube has been built at the Center for Plasma Science and Technology of Florida A&M University to study shock waves. A larger apparatus with higher voltage was built to study more stable shock waves and subsequent plasmas. Initial measurements of the apparatus conclude that the desired Mach numbers can be reached using only two-thirds the maximum possible energy that the circuit can provide.


Individual and collective impact of Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae in patients admitted to the ICU.
KPC-producing Klebsiella pneumoniae (KPC-Kp) raises major concerns in the context of intensive care, owing to limited treatment options and the ability to cause outbreaks in this specific setting. The objectives of this review are to give an overview of the burden of KPC-Kp in ICU patients and to discuss methodological issues and limitations regarding the quality of data available. Robust and reliable assessment of the KPC-Kp impact in the ICU should take into consideration not only characteristics of the individuals, but also of the health systems including length of stay, costs and hospital organization issues. Estimates of mortality reported in the current literature are weakened by the poor quality of adjustment for age-specific risks, co-morbidities, and appropriateness of therapy. All these confounding factors should be taken into account in models, with consideration of control groups and competing risks that is currently lacking in the published literature. Since development of antibiotic resistance is an unstoppable phenomenon and economic and human resources are facing progressive limitations due to budget constraints, cost-saving strategies targeted to avoid ICU closure, temporary limitation of admissions or delayed hospital discharge are necessary. The early identification of KPC-Kp-colonized patients through active screening strategies is likely to be the cornerstone of such a cost-saving strategy. However, there are still many open issues concerning which of these strategies are the most effective. Owing to extreme heterogeneity and several methodological flaws in current publications, future studies investigating the long-term sequelae and economic impact of KPC-Kp in the ICU are urgently needed.


A functional genome-wide RNAi screen identifies TAF1 as a regulator for apoptosis in response to genotoxic stress.
Evasion from apoptotic cell death is a characteristic of cancer; genes that modulate this process may be optimal for therapeutic attack. Identifying key regulators of apoptosis is thus a central goal in cancer therapy. Here, we describe a loss-of-function screen that uses RNA interference libraries to identify genes required for induction of apoptosis. We used a short-hairpin RNA expressing vector with high gene-expression silencing activity that contained fetal brain cDNAs. Survived cells from genotoxic stress were isolated to determine knock-down of molecules that are crucial for induction of apoptosis. We identified TBP-associated factor 1 (TAF1), a gene previously implicated as an essential component of transcription machinery. Depletion of TAF1 was associated with substantial attenuation of apoptosis induced by oxidative as well as genotoxic stress. Microarray analysis further demonstrated that a number of genes were transcriptionally declined in cells silenced for TAF1. Surprisingly, knocking down TAF1 exhibited a marked decrease in p27(Kip1) expression, allowing cells resistant from oxidative stress-induced apoptosis. These results suggest that TAF1 regulates apoptosis by controlling p27(Kip1) expression. Our system provides a novel approach to identifying candidate genes that modulate apoptosis.