Effect of hydroxylic solvent on the fluorescence behavior of some bioactive 9-oxo-imidazo[1,2-a]purine derivatives.
The spectral and photophysical behavior of four fluorescent 9-oxo-imidazo[1,2-a]purine derivatives containing pyridyl, pyridylphenyl, phenyl, and biphenylyl substituents at the C(6) position of the tricyclic skeleton is described. The studies were performed in several aprotic and protic organic solvents using absorption spectroscopy as well as steady-state and time-resolved fluorescence spectroscopy. The results are also presented of TDDFT calculations on singlet-singlet excitation energies and oscillator strengths for two models of 9-oxo-imidazo[1,2-a]purine, with phenyl or pyridyl substituents, both in the gas phase and in methanol solution. While the derivatives with aryl substituents did not show any significant dependence of their static and dynamic fluorescence properties on the nature of the solvent, the compounds containing a pyridine residue exhibited a remarkable reduction of their fluorescence quantum yields and lifetimes in the alcoholic solutions. The solute-solvent hydrogen-bonding interaction in the first excited singlet state is responsible for the fast radiationless decay rates determined for pyridyl- and pyridylphenyl-substituted compounds in protic solvents. The results of experimental and theoretical studies show that the hydrogen of the alcohols' hydroxyl group and the nitrogen atom of the pyridine moiety are involved in the interaction. The fluorescence-quenching experiments performed for the pyridyl-substituted 9-oxo-imidazo[1,2-a]purine derivative using trifluoroethanol, methanol, and butanol as quenchers revealed that the quenching efficiencies, expressed by the Stern-Volmer quenching constants, correlate with the H-bond donating abilities of the alcohols. The quenching is a dynamic process, and the H-bonded complex formed is nonfluorescent. The experimentally determined and the calculated values of the dipole moment change associated with the electronic excitation indicate that the excited S(1) states of all of the molecules studied in this work have an intramolecular charge-transfer character and that electronic charge is transferred to the C(6) substituent upon excitation. Thus, the ability of the pyridyl substituent nitrogen atom to act as an H-bond acceptor in the excited S(1) state is enhanced. The 6-pyridyl-9-oxo-imidazo[1,2-a]purine presents a novel fluorophore, which, besides its medical applications, may be useful as a sensor of hydroxyl groups in microorganized systems.


Atrial fibrillation and its complications in arterial hypertension: The potential preventive role of ω-3 polyunsaturated fatty acids.
Atrial fibrillation (AF) is the most common type of arrhythmia in the general population with a prevalence that reaches one third of patients with arterial hypertension. Several risk factors frequently associated with hypertension predispose the myocardium to AF by inducing atrial inflammation and fibrosis and altering atrial electrical and mechanical characteristics. AF influences the quality of life of hypertensive patients since it increases incidence of stroke and other thromboembolic events, and mortality. Polyunsaturated fatty acids of the ω-3 family (ω-3 PUFA) have been demonstrated to be beneficial in cardiovascular disease prevention by reducing plasma lipids and blood pressure levels and decreasing the risk of sudden death. These fatty acids can act as potent anti-inflammatory and anti-arrhythmic agents. Many studies have investigated a possible preventive effect of ω-3 PUFA on incident AF reporting contradictory results. This article overviews the evidence currently available on this important topic and provides some conclusive remarks on the possibility that these fatty acids could be beneficial in hypertensive patients.


Analysis of the correlation between non-alcoholic fatty liver disease and bone metabolism indicators in healthy middle-aged men.
To investigate the relationship between bone metabolic indicators and non-alcoholic fatty liver disease (NAFLD) in healthy middle-aged men. The bone metabolic indicators of 232 healthy middle-age men with NAFLD (NAFLD group) and 308 healthy controls without fatty liver (Control group) were measured, including non-collagenous osteocalcin, the procollagen type 1 N-terminal propeptide (P1NP), beta-C-terminal telopeptide of type I collagen (β-CTX). The Student's t-test was used to analyze the differences in the bone metabolic indicators, age, clinical data, biochemical indicators, and the indicators of glucose and lipid metabolism between the two groups. The correlation of fatty liver-related indicators was detected using the logistic regression analysis. The body mass index (BMI), diastolic blood pressure, and heart rate in NAFLD group were significantly higher than those in Control group. Among the indicators of glucose and lipid metabolism in NAFLD group, the levels of blood glucose [fasting plasma glucose, postprandial blood glucose and hemoglobin A1c (HbA1c)] were significantly higher than those in Control group. In addition, the insulin resistance and secretion indexes were also significantly higher than those in Control group. The levels of lipid metabolic indicators such as triglyceride were higher, but high-density lipoprotein cholesterol was lower than that in Control group. From logistic regression analysis, the BMI, Homeostasis model assessment (HOMA)-β, HOMA-IR, HbA1c and P1NP were positively associated with the occurrence of NAFLD. The bone metabolic indicator P1NP might be a potential predicator for the diagnosis of NAFLD in clinical application.


Evaluation of anxiety and depression in mothers of children with asthma.
Asthma is the most common chronic disease in childhood. Parents have an important role in managing asthma in children. Studies have shown a higher degree of depression and anxiety and lower family performance in mothers of asthmatic children in comparison with the control group. The aim of this study was to evaluate the parenting styles and also depression, anxiety and stress parameters in mothers of children with asthma. This case-control study was performed on 45 mothers of 3 to 15 years old asthmatic children in the allergy clinic of Mashhad University of Medical Sciences, Mashhad, Iran, during the years of 2014 to 2016. The control group was 45 mothers of non-asthmatic children who were matched for the age of their children with the case group in the same population. The parenting styles, as well as depression and anxiety of mothers were evaluated using parenting scales, and the depression-anxiety-stress scales (DASS). The mothers were also asked to fill a strengths and difficulties questionnaire (SDQ) for their children. Furthermore, parenting styles in the case group were compared to mothers of children without asthma as the control group. The data were then analyzed by SPSS 11.5, using Chi-square, ANOVA, and independent-samples t-test. The results of this study showed that 21 mothers (74.6%) were normal, but 12 mothers (26.7%) had a mild -, 9 (20%) a moderate - and 3 (6.7%) a severe degree of abnormality according to DASS. Independent-samples t-test showed a significant difference between the case and control groups regarding depression in mothers and laxness (p<0.001), over reactivity (p<0.013) and verbosity (p<0.031) in children with asthma. The results of this study demonstrated that anxiety and depression are partially frequent in mothers of children with asthma, and parenting styles are less affective in these families.


Surgeon-associated variation in breast cancer staging with sentinel node biopsy.
Sentinel lymph node biopsy is the gold standard for axillary staging in early-stage, clinically node-negative breast cancer, so it is paramount that this operation be both precise and accurate, because excessive sentinel lymph node removal increases morbidity, whereas understaging risks inadequate treatment. The goal of this study was to assess surgeon variation in the number of sentinel lymph nodes removed and the oncologic yield of sentinel lymph node biopsy for breast cancer. All patients in the Surveillance, Epidemiology, and End Results-Medicare database who underwent operative treatment for breast cancer from 2007-2011 were eligible for inclusion. Deidentified provider codes were used to track operations performed by individual surgeons. Only records in which an individual surgeon could be linked to a specific breast cancer operation were analyzed. The total number of sentinel lymph nodes removed and the number that were pathologically positive (oncologic yield) were recorded. Surgeon variation by T stage was analyzed using linear mixed-effects regression and logistic mixed-effects regression models. Query of the database identified 15,571 patients who met inclusion criteria, representing 2,478 providers. The mean number of sentinel lymph node procedures performed per provider per year was 1.3 (range 1-103). The lowest quartile of providers performed 1 or fewer sentinel lymph node procedures per year. The highest quartile of providers performed >8 sentinel lymph node procedures per year. The average number of sentinel lymph node removed per operation increased with increasing T stage for all providers (P < .001), including when N0 (P < .001) and node-positive (P = .003) patients were evaluated separately. There was surgeon-associated variation in the number of sentinel lymph node removed for each T stage (P < .001). In addition, there was surgeon-associated variation in the oncologic yield (sentinel lymph node positivity rate) by T stage (P < .001). This study found surgeon-associated variation in axillary sentinel lymph node staging of breast cancer patients, which suggests the need to improve standardization of surgical practices to optimize the oncologic yield of these procedures and ensure accurate staging.


Flow-cytometric DNA analysis as a means for early detection of malignancy in patients with chronic ulcerative colitis.
A new approach to the problem of monitoring patients with chronic ulcerative colitis is presented and discussed in connection with a case report. When annual colonoscopies are performed, biopsies are taken for histopathological examination and DNA measurements are made using flow-cytometric techniques (FCM). Using the latter approach, gross chromosomal aberrations indicating malignant transformation in a cell population may be detected. In a 46 year old man with a long history of ulcerative colitis, an area with slight mucosal dysplasia at light microscopy was accompanied by two aneuploid cells lines - that is, colonic mucosa cells with an abnormal amount of DNA in the nuclei. An operation one year later revealed a 5 X 2 mm large adenocarcinoma in the corresponding area of the colon. We suggest that flow-cytometric techniques can be used as a complement to already practised methods for monitoring the colorectal mucosa in colitic patients for the early detection of malignancy.


Microglia as mediators of inflammatory and degenerative diseases.
Microglia are the principal immune cells in the central nervous system (CNS) and have a critical role in host defense against invading microorganisms and neoplastic cells. However, as with immune cells in other organs, microglia may play a dual role, amplifying the effects of inflammation and mediating cellular degeneration as well as protecting the CNS. In entities like human immunodeficiency virus (HIV) infection of the nervous system, microglia are also critical to viral persistence. In this review we discuss the role of microglia in three diseases in which their activity is at least partially deleterious: HIV, multiple sclerosis, and Alzheimer's disease.


A case of Rictularia infection of man in New York.
A gravid female nematode was found in histopathologic sections of an appendix in a postmortem examination. This parasite was identified as Rictularia, a genus of small intestinal parasites in numerous mammals. The parasites of this genus have not previously been identified in man.


Identification of phosphotyrosine binding domain-containing proteins as novel downstream targets of the EphA8 signaling function.
Eph receptors and ephrins have been implicated in a variety of cellular processes, including morphology and motility, because of their ability to modulate intricate signaling networks. Here we show that the phosphotyrosine binding (PTB) domain-containing proteins AIDA-1b and Odin are tightly associated with the EphA8 receptor in response to ligand stimulation. Both AIDA-1b and Odin belong to the ankyrin repeat and sterile alpha motif domain-containing (Anks) protein family. The PTB domain of Anks family proteins is crucial for their association with the juxtamembrane domain of EphA8, whereas EphA8 tyrosine kinase activity is not required for this protein-protein interaction. In addition, we found that Odin is a more physiologically relevant partner of EphA8 in mammalian cells. Interestingly, overexpression of the Odin PTB domain alone attenuated EphA8-mediated inhibition of cell migration in HEK293 cells, suggesting that it acts as a dominant-negative mutant of the endogenous Odin protein. More importantly, small interfering RNA-mediated Odin silencing significantly diminished ephrinA5-induced EphA8 signaling effects, which inhibit cell migration in HEK293 cells and retract growing neurites of Neuro2a cells. Taken together, our findings support a possible function for Anks family proteins as scaffolding proteins of the EphA8 signaling pathway.


Characteristics and Outcomes of Black and White Patients Hospitalized With Nonalcoholic Steatohepatitis: A Nationwide Analysis.
Nonalcoholic steatohepatitis (NASH) is an increasingly common etiology for liver-related hospitalizations in the United States. The aim of this study was to examine the differences of disease characteristics and outcomes between hospitalized Black and White patients with NASH. We used the National Inpatient Sample (NIS) to identify all adult hospitalizations with NASH (ICD-10 code: K75.81) from 2016 to 2018. We compared demographic and clinical characteristics between Black and White patients. Multivariable models were computed to compare all-cause mortality, length of stay (LOS), and total hospital costs between the groups. There were 43,409 hospitalizations with NASH (41,143 White, 2266 Black). Black patients were less likely to have cirrhosis (33.6%) compared with Whites (56.4%), P <0.0001. Black patients were less likely to have esophageal variceal bleeding (1.2% vs. 3.5%), ascites (17.1% vs. 28.8%), and acute liver failure (16.2% vs. 28.9%) compared with Whites (all P <0.0001). These findings were consistent among patients with cirrhosis. Mortality was higher among Blacks compared with Whites (3.9% vs. 3.7%, adjusted odds ratio=1.34; 95% confidence interval: 1.05-1.71, P =0.018). Compared with Whites, Blacks had a longer LOS (6.3 vs. 5.6, P <0.001), and higher hospital costs ($18,602 vs. $17,467; P =0.03). In this large population of inpatients with NASH, Black patients were less likely to have cirrhosis and liver disease-related complications, but had overall worse hospital mortality, longer LOS, and higher hospital costs. Further research is warranted to elaborate on factors that generate the health inequities in NASH outcomes between Black and White patients.


CXCR4 gene transfer prevents pressure overload induced heart failure.
Stem cell and gene therapies are being pursued as strategies for repairing damaged cardiac tissue following myocardial infarction in an attempt to prevent heart failure. The chemokine receptor-4 (CXCR4) and its ligand, CXCL12, play a critical role in stem cell recruitment post-acute myocardial infarction. Whereas progenitor cell migration via the CXCL12/CXCR4 axis is well characterized, little is known about the molecular mechanisms of CXCR4 mediated modulation of cardiac hypertrophy and failure. We used gene therapy to test the effects of CXCR4 gene delivery on adverse ventricular remodeling due to pressure overload. We assessed the effect of cardiac overexpression of CXCR4 during trans-aortic constriction (TAC) using a cardiotropic adeno-associated viral vector (AAV9) carrying the CXCR4 gene. Cardiac overexpression of CXCR4 in mice with pressure overload prevented ventricular remodeling, preserved capillary density and maintained function as determined by echocardiography and in vivo hemodynamics. In isolated adult rat cardiac myocytes, CXCL12 treatment prevented isoproterenol induced hypertrophy and interrupted the calcineurin/NFAT pathway. Finally, a complex involving the L-type calcium channel, β2-adrenoceptor, and CXCR4 (Cav1.2/β2AR/CXCR4) was identified in healthy cardiac myocytes and was shown to dissociate as a consequence of heart failure. CXCR4 administered to the heart via gene transfer prevents pressure overload induced heart failure. The identification of CXCR4 participation in a Cav1.2-β2AR regulatory complex provides further insight into the mechanism by which CXCR4 modulates calcium homeostasis and chronic pressure overload responses in the cardiac myocyte. Together these results suggest that AAV9.CXCR4 gene therapy is a potential therapeutic approach for congestive heart failure.


Validation of the Prognostic Kidney Donor Risk Index Scoring System of Deceased Donors for Renal Transplantation in the Netherlands.
The prognostic Kidney Donor Risk Index (KDRI)-developed and internally validated in the United States-is a widely used tool to predict transplant outcome of a deceased donor kidney. The KDRI is currently used for longevity matching between donors and recipients in the United States. We aimed to externally validate the KDRIdonor-only and KDRIfull as proposed by Rao et al (2009). KDRIdonor-only consist of 10 donor factors, and KDRIfull with an additional 4 transplant factors. We used the Dutch Organ Transplantation Registry to include 3201 adult recipients transplanted from 2002 to 2012. The median Dutch KDRI was 1.21 and comparable with the year 2012 in the United States (median of 1.24). The calibration-slope was 0.98 and 0.96 for the KDRIfull and KDRIdonor-only, respectively, indicating that predictions of graft failure were on average similar. The discriminative ability (Harrell C) of the KDRIfull and the KDRIdonor-only at 5 years was 0.63 (95% confidence interval [CI], 0.62-0.64), and 0.62 (95% CI, 0.61-0.63), respectively. We found misspecification of 3 KDRI factors: age (P = 0.002), weight (P = 0.017), and cold ischemia time (P < 0.001). Adding the use of inotropic drugs before donation (P = 0.040) and the interaction between circulatory-death donor kidneys and prolonged cold ischemic time (>24 hours vs 12 hours; P = 0.059) could improve predictive ability. The KDRI performs equal in the Dutch population. Discriminative ability of the KDRI indicates limited clinical use for adequate individualized decisions. An updated KDRI may contribute to a standardized policy meeting the growing demand of donor kidneys in the Eurotransplant region.


Rivalries and controversies during early ether anaesthesia.
National and international rivalries can intrude into the arena of medical and scientific advances. Editorials and reports published in North American, British, and French medical journals in early 1847 regarding the discovery and initial use of ether anaesthesia illustrate these rivalries. The effects of these opinions and attitudes on the spread of ether anaesthesia are analyzed.


Insight Into the Distribution of Staphylococci and Their Enterotoxins in Cheeses Under Natural Conditions.
Staphylococcal food poisoning outbreaks are a major cause of food-borne illness in the European Union and their notification has been mandatory since 2005. Criteria for the enumeration of coagulase-positive Staphylococci (CPS) and the detection of staphylococcal enterotoxins (SEs) in cheese have been set down in Commission Regulation EC 2073/2005. Currently, few information are available about the distribution of SEs in naturally contaminated cheeses, including raw-milk and artisanal dairy products. The aim of this study was therefore to investigate at both the CPS enumeration and the succession of the enterotoxigenic Staphylococcus aureus and produced enterotoxins levels on the rind and the core of a raw-milk semi-hard cheese, produced on farm. The study has been conducted in three steps: (I) seven wheels at different time of ripening where tested for the presence of SEs. (II) from each wheel, four portions were subsequently sampled from four different areas (peripheral rind, central rind, peripheral core and central core). (III) two cheese wheels, characterized by the highest and lowest CPS numbers and SEs quantification, based on the second step of the study, were further analyzed. A significant difference has been observed in the distribution of CPS and SEs in the four areas sampled, irrespectively of the batch and the time of ripening. The results of this study provided a set of previously unknown information on the influence of natural conditions on the distribution of CPS and SEs thereof in the cheese matrix, filling a gap in the understanding of SEs biosynthesis process.


[Diagnosis of Wegener's granulomatosis in patients with ocular inflamatory disease].
Report the ophthalmologic manifestations among patients with Wegener 's Granulomatosis (WG). We reviewed the database of the Instituto de Oftalmologia Fundación Conde de Valenciana in order to collect information regarding complete ophthalmic examination, laboratory and cabinet tests, treatment, and disease progression. We included 11 patients with WG (18 eyes). Seven men and four women, mean age 43.7 years (range = 28-55). Three patients had a prior diagnosis of WG and the remaining eight patients were diagnosed by our study team. Seven subjects developed a bilateral affection and four had unilateral involvement. The clinical presentation was necrotizing scleritis with peripheral ulcerative keratitis (PUK) (7/18), diffuse scleritis (3/18), nodular scleritis (1/18), non-granulomatous uveitis (1/18), optic ischemic neuropathy (1/18), retrobulbar neuritis (1/18), serous retinal detachment (2/18), and dacryocystitis (2/18). Final visual acuity was better or equal to 20/40 (13/18), 20/400 (3/18), finger-counting or no-perception of light in 1/18. Currently, seven patients are symptom free. The most frequent ophthalmic manifestations among our patients with WG were: necrotizing scleritis and PUK. In most cases, WG was diagnosed after ophthalmic manifestations; however, all patients displayed prior systemic or ocular symptoms.


Evidence for complex contagion models of social contagion from observational data.
Social influence can lead to behavioural 'fads' that are briefly popular and quickly die out. Various models have been proposed for these phenomena, but empirical evidence of their accuracy as real-world predictive tools has so far been absent. Here we find that a 'complex contagion' model accurately describes the spread of behaviours driven by online sharing. We found that standard, 'simple', contagion often fails to capture both the rapid spread and the long tails of popularity seen in real fads, where our complex contagion model succeeds. Complex contagion also has predictive power: it successfully predicted the peak time and duration of the ALS Icebucket Challenge. The fast spread and longer duration of fads driven by complex contagion has important implications for activities such as publicity campaigns and charity drives.


An mRNA decapping mutant deficient in P body assembly limits mRNA stabilization in response to osmotic stress.
Yeast is exposed to changing environmental conditions and must adapt its genetic program to provide a homeostatic intracellular environment. An important stress for yeast in the wild is high osmolarity. A key response to this stress is increased mRNA stability primarily by the inhibition of deadenylation. We previously demonstrated that mutations in decapping activators (edc3∆ lsm4∆C), which result in defects in P body assembly, can destabilize mRNA under unstressed conditions. We wished to examine whether mRNA would be destabilized in the edc3∆ lsm4∆C mutant as compared to the wild-type in response to osmotic stress, when P bodies are intense and numerous. Our results show that the edc3∆ lsm4∆C mutant limits the mRNA stability in response to osmotic stress, while the magnitude of stabilization was similar as compared to the wild-type. The reduced mRNA stability in the edc3∆ lsm4∆C mutant was correlated with a shorter PGK1 poly(A) tail. Similarly, the MFA2 mRNA was more rapidly deadenylated as well as significantly stabilized in the ccr4∆ deadenylation mutant in the edc3∆ lsm4∆C background. These results suggest a role for these decapping factors in stabilizing mRNA and may implicate P bodies as sites of reduced mRNA degradation.


High-dimensional generalized propensity score with application to omics data.
Propensity score (PS) methods are popular when estimating causal effects in non-randomized studies. Drawing causal conclusion relies on the unconfoundedness assumption. This assumption is untestable and is considered more plausible if a large number of pre-treatment covariates are included in the analysis. However, previous studies have shown that including unnecessary covariates into PS models can lead to bias and efficiency loss. With the ever-increasing amounts of available data, such as the omics data, there is often little prior knowledge of the exact set of important covariates. Therefore, variable selection for causal inference in high-dimensional settings has received considerable attention in recent years. However, recent studies have focused mainly on binary treatments. In this study, we considered continuous treatments and proposed the generalized outcome-adaptive LASSO (GOAL) to select covariates that can provide an unbiased and statistically efficient estimation. Simulation studies showed that when the outcome model was linear, the GOAL selected almost all true confounders and predictors of outcome and excluded other covariates. The accuracy and precision of the estimates were close to ideal. Furthermore, the GOAL is robust to model misspecification. We applied the GOAL to seven DNA methylation datasets from the Gene Expression Omnibus database, which covered four brain regions, to estimate the causal effects of epigenetic aging acceleration on the incidence of Alzheimer's disease.


Hippocampal Apoptosis and Cognitive Function in Dysbindin-1B+/+ Mice.
Objective To explore the apoptosis in the hippocampus of dysbindin-1B+/+ mice and the behaviors of 4-month-old dysbindin-1B+/+ mice and wild-type mice. Methods The hippocampus of dysbindin-1B+/+ mice and corresponding wild-type mice were assessed by TUNEL assay and transmission electron microscopy. Then twelve 4-month-old male dysbindin-1B+/+ mice and twelve wild-type mice were enrolled. The open field and T maze test were conducted to observe locomotor activity,exploratory behaviors,and spatial memory. Result TUNEL+ neurons were found in hippocampus of dysbindin-1B+/+ mice,especially in dentate gyrus region,but not in that of wild-type mice(t=12.98,P<0.0001). Transmission electron microscopy showed the presence of middle-and late-stage apoptosis in the hippocampus of dysbindin-1B+/+ mice,while there was no apoptosis in wild-type mice. Open field test showed that,compared with the moving distance of wild-type mice [(3632±606)cm],dysbindin-1B+/+ mice presented significantly lower moving distances [(2887±376)cm] (t=2.993,P=0.0122). Meanwhile,compared with the moving time of wild-type mice in the central area [(114.00±34.09)s],dysbindin-1B+/+ mice presented lower moving time [(64.22±14.67)s] (t=4.649,P=0.0023). T maze test showed that when the interval between forced run and test run were 60 s and 180 s,respectively,the accuracy of dysbindin-1B+/+ was (70.40±15.17)% and (59.28±9.10)%,which was significantly lower than those of wild type mice (91.67±13.94)% (t=3.261,P=0.0258) and (83.33±14.89)% (t=3.687,P=0.0291);when the interval was 15 s,there was no significant difference between these two groups [100% vs.(94.45±6.08)%; t=0.851,P=0.0756]. Conclusion Dysbindin-1B+/+ expression can cause the apoptosis of neurons,which may cause anxious behavior and impair the locomotor activity and spatial memory.


Orthostatic hypotension.
A common problem among elderly people, orthostatic hypotension is associated with significant morbidity and mortality, which may be caused by medications, the cumulative effects of age- and hypertension-related alterations in blood pressure regulation, or age-associated diseases that impair autonomic function. Evaluation requires multiple blood pressure measurements taken at different times of the day and after meals or medications. Central and peripheral nervous system disorders should be sought, and the laboratory evaluation should concentrate on ruling out diabetes mellitus, amyloidosis, occult malignancy, and vitamin deficiencies. If orthostatic hypotension is detected, it should be considered a risk factor for adverse outcomes and treated first with nonpharmacologic interventions, including the withdrawal of potentially hypotensive medications. In patients with hypertension and orthostatic hypotension, the judicious treatment of hypertension may be helpful. For persistent, symptomatic orthostatic hypotension caused by autonomic failure, pharmacologic interventions include fludrocortisone, midodrine, and a variety of other agents. The careful evaluation and management of orthostatic hypotension will hopefully result in a significant reduction in falls, syncope, and fractures, and an attenuation of functional decline in elderly patients.


An Education Programme on Sickle Cell Anemia and ß-Thalassemia for the 8th Grade Students.
ß-thalassemia and sickle cell anemia (SCA) are major health problems in Çukurova. Screening studies have been carried on in this region for many years. The government started premarital screening programme and prenatal diagnosis has been done in Çukurova University Medical Faculty since 1992. In spite of all these, the prevention programme has not been successful. The purpose of this study was to start an education programme to increase the awareness of the people for these severe hereditary diseases. The target population was the 8th grade students. A visual presentation was given to students on Thalassemia and SCA after examining the curriculum in the Biology and/or the Science books. A total of 1221 students in seven Elementary Schools were informed. A questionnaire was given to five schools before the presentation and to two after the presentation. The comparison of the two group's result showed that the information given was well received. Thus, an extensive education programme encompassing doctors, health personel, civil and religious leaders and the support of the government will result in nil SCA and Thalassemia births.


Immunopotentiating activity of septilin.
Oral administration of septilin (100mg/animal/dose; five doses) was found to enhance natural killer cell mediated cytotoxicity and antibody-dependent cellular cytotoxicity in normal mice as well as tumour-bearing mice. Septilin treatment also activated the peritoneal macrophages which produced cytotoxicity to L929 cells. Septilin increased proliferation of bone-marrow cells and there was an increase in the number of alpha-naphthyl acetate esterase staining cells in the bone-marrow. In addition to the activation of cellular immunity, septilin was found to increase the number of antibody producing cells in the spleen and activation of antibody-dependent complement-mediated cell lysis. These studies justifies the use of this herbal preparation in improving immunocompetence in disease states.


Phase I and phase II metabolism of lithocholic acid in hepatic acinar zone 3 necrosis. Evaluation in rats by combined radiochromatography and gas-liquid chromatography-mass spectrometry.
In the present study, lithocholic acid (LCA) metabolism was assessed by radiochromatography and gas-liquid chromatography-mass spectrometry, and its relationship to cholestasis was investigated. In addition, the role of the perivenous zone in LCA-induced cholestasis and LCA biotransformation was examined by using bromobenzene (BZ), a chemical that causes selective necrosis of hepatocytes in this zone. LCA injection induced cholestasis of comparable amplitude in both control and BZ-treated rats. The biliary recovery of bile salts (BS) was 65-70% 2 hr after LCA injection. Excretion of LCA and its cholestatic metabolite, LCA glucuronide, was similar in both groups, although LCA excretion was delayed in BZ-treated animals. The appearance of LCA and LCA glucuronide in bile occurred early, and their proportion decreased with time. Concentrations of choleretic hydroxylated metabolites were low immediately after LCA injection but increased with time. 3 alpha,6 beta-Dihydroxy-5 beta-cholanoic and 3 alpha,6 beta,7 beta-trihydroxy-5 beta-cholanoic acids were the major species arising from LCA, indicating the importance of 6 beta hydroxylation in LCA detoxification in rats. Other metabolites were found, but their contribution was either minor or negligible. Overall amounts of hydroxylated metabolites were comparable in both groups, but trihydroxylated metabolites predominated over their dihydroxylated counterparts in control rats, whereas the production of dihydroxylated forms was more pronounced in BZ-treated animals. These results suggest that the destruction of perivenous hepatocytes does not exacerbate LCA-induced cholestasis, and that there may be an acinar zonation of LCA biotransformation to trihydroxylated metabolites in the rat liver.


Transient rise in His-lead threshold due to acute myocardial infarction.
An 85-year-old male was admitted to our center with a non-ST elevation myocardial infarction. The patient had a dual-chamber pacemaker in situ with an atrial and His lead. A transient increase in His threshold and loss of nonselective capture occurred at the presentation of right coronary artery infarction, peaking during rotational atherectomy therapy causing loss of capture and complete atrioventricular block. A follow-up interrogation, 2 weeks postrevascularization, showed a return to a normal nonselective capture morphology and threshold measurements. Physicians should be aware of this complication in patients with His leads, particularly those with a history of coronary artery disease.


Macrophage migration inhibitory factor promotes innate immune responses by suppressing glucocorticoid-induced expression of mitogen-activated protein kinase phosphatase-1.
The pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) acts as a physiological counter-regulator of the immuno-suppressive effects of glucocorticoids. However, the mechanisms whereby MIF exerts its counter-balancing effect remain largely unknown. Here we report that MAPK phosphatase 1 (MKP-1), an archetypal member of dual specificity phosphatase that inactivates MAPK activity in response to pro-inflammatory stimuli, is a critical target of MIF-glucocorticoid crosstalk. Recombinant MIF counter-regulated in a dose-dependent fashion dexamethasone inhibition of TNF and IL-8 production by RAW 264.7 macrophages and U-937 promonocytes stimulated with lipopolysaccharides (LPS) or with LPS plus phorbol 12-myristate 13-acetate. Stimulation of RAW 264.7 macrophages with dexamethasone or dexamethasone plus LPS led to a robust up-regulation of MKP-1 mRNA and protein expressions that were counter-regulated by addition of recombinant MIF. Antisense MIF macrophages expressing reduced levels of endogenous MIF produced higher amount of MKP-1 and lower amount of TNF after exposure to dexamethasone and dexamethasone plus LPS, indicating that endogenous MIF acts in an autocrine fashion to override glucocorticoid-induced MKP-1 expression and inhibition of cytokine production. Taken together, these data identify MKP-1 as a molecular target of MIF-glucocorticoid crosstalk and provide a molecular basis for the control of macrophage responses by a pair of physiological regulators of innate immunity.


A new highly troglomorphic Loxosceles (Araneae: Sicariidae) from Brazil.
The spiders of the genus Loxosceles have been reported from caves in several regions of the world. Despite their commonness in subterranean habitats, the occurrence of troglomorphic species is quite rare. A new cave-dwelling species found in the Brazilian Caatinga can be included in the restricted list of troglomorphic Loxosceles by presenting the following troglomorphic traits: eyes with reduced diameter, absence of pigment around the eyes, appendage elongation and pale coloration. Thus, the aim of this study is to describe a new highly troglomorphic species of Loxosceles from Brazil, corresponding to the first troglomorphic species from South America. Loxosceles troglobia sp. nov. belongs to the gaucho group and can be distinguished from the other species of this group mainly by the presence of the troglomorphic characteristics mentioned above and by the shape of the female spermathecae and the male palp. The morphological traits, together with the fact that the new species was found only in inner and very humid portions of two nearby caves, indicate that it is troglobitic.


Relationship Power Among Same-Sex Male Couples in New York and San Francisco: Laying the Groundwork for Sexual Risk Reduction Interventions Focused on Interpersonal Power.
Research is clear that power differentials between women and men shape women's human immunodeficiency virus (HIV) risks; however, little research has attempted to examine power differentials within same-sex male (SSM) couples and whether these influence sexual risk outcomes. To produce the first quantitative scale that measures power in SSM relationships, the current work was a Phase 1 qualitative study that sought to understand domains of relationship power and how power operated in the relationship among 48 Black, White, and interracial (Black-White) SSM couples recruited from San Francisco and New York. Interview domains were focused on definitions of power and perceptions of how power operated in the relationship. Findings revealed that couples described power in three key ways: as power exerted over a partner through decision-making dominance and relationship control; as power to accomplish goals through personal agency; and as couple-level power. In addition, men described ways that decision-making dominance and relationship control could be enacted in the relationship-through structural resources, emotional and sexual influence, and gender norm expectations. We discuss the implications of these findings for sexual risks and HIV care and treatment with SSM couples that are focused on closing gaps in power.


What compatibility in 2017 for the haematopoietic stem cell transplantation?
The diversification of potential donors to perform stem cell allografts now enables to propose a compatible graft cell source adapted to the different clinical situations. Transplants with a geno-identical sibling donor, otherwise with the most HLA-compatible unrelated donor, remain the first-line solutions. Alternative transplants allow to graft patients having no donors in international registries, owing to the rarity of their HLA typing. They are carried out with fairly incompatible grafts and are therefore limited by the existence in the recipient of preformed anti-HLA antibodies which predispose to their rejection. The simple prevention of acute Graft-versus-host disease in haplo-identical transplants, as well as the availability of donors, explain why they have very often replaced placental stem cell transplants. These latter remain useful for pediatric patients or in the absence of family donors.


The development and validation of the Workplace Ostracism Scale.
This article outlines the development of a 10-item measure of workplace ostracism. Using 6 samples (including multisource and multiwave data), the authors developed a reliable scale with a unidimensional factor structure that replicated across 4 separate samples. The scale possessed both convergent and discriminant validity, and criterion-related validity was demonstrated through the scale's relation with basic needs, well-being, job attitudes, job performance, and withdrawal. Overall, the present study suggests that the Workplace Ostracism Scale is a reliable and valid measure and that the workplace ostracism construct has important implications for both individuals and organizations.


Supporting optimal dietary behaviors in women with perinatal depression: A qualitative exploration of experiences, practices, and challenges.
Women with perinatal depression (PD) are at high risk for unhealthy dietary behaviors and suboptimal child feeding practices. Despite evidence supporting the importance of healthful nutrition-related behaviors during and after pregnancy, few behavioral nutrition interventions for women with PD have been developed. The objectives of this study were to identify nutrition-related challenges and needs among women with PD and to elucidate the role that feeding plays in mother-infant interaction, to inform the development of nutrition interventions. Using a qualitative study design, in-depth interviews were conducted with 18 mothers with a history of PD and 10 interdisciplinary healthcare providers with expertise in PD. Data were thematically analyzed using a hybrid inductive and deductive coding approach. Mean age of mothers was 31 ± 6 years, 56% identified as non-Hispanic White, and 33% identified as Black/African American. Eighty percent of healthcare providers practiced for more than five years. Six themes were identified: (a) Time scarcity mindset; (b) Importance of social support; (c) Unrealistic expectations of motherhood; (d) Mom as the last priority; (e) Postpartum body changes and shape ideals; and (f) Contentment associated with infant and young child feeding. Women with PD have several needs pertaining to their nutrition and that of their children. The findings from this study illustrate key considerations and recommendations for addressing these needs.


The second-language vocabulary trajectories of Turkish immigrant children in Norway from ages five to ten: the role of preschool talk exposure, maternal education, and co-ethnic concentration in the neighborhood.
Little research has explored how preschools can support children's second-language (L2) vocabulary development. This study keenly followed the progress of twemty-six Turkish immigrant children growing up in Norway from preschool (age five) to fifth grade (age ten). Four different measures of preschool talk exposure (amount and diversity of teacher-led group talk and amount and diversity of peer talk), as well as the demographic variables of maternal education and co-ethnic concentration in the neighborhood, were employed to predict the children's L2 vocabulary trajectories. The results of growth analyses revealed that maternal education was the only variable predicting children's vocabulary growth during the elementary years. However, teacher-led talk, peer talk, and neighborhood predicted children's L2 vocabulary skills at age five, and these differences were maintained up to age ten. This study underscores the importance of both preschool talk exposure (teacher-led talk and peer talk) and demographic factors on L2 learners' vocabulary development.


Contributions of intrinsic renal cells to crescentic glomerulonephritis.
The pro-inflammatory contributions of leukocytes, particularly macrophages and T cells, to the immunopathogenesis of proliferative forms of glomerulonephritis (GN) have been clearly established by various techniques, including in vivo depletion studies in experimental models. The evidence for an active pro-inflammatory role for intrinsic renal cells in GN has relied on studies demonstrating their production of pro-inflammatory mediators in vitro and during the development of GN. Until recently,the specific in vivo contributions of mediators from intrinsic renal cells to inflammatory injury in GN have proven difficult to define. Utilising 'chimeric' mice as a tool, several studies have explored the involvement of intrinsic renal cells via their production of cytokines and other key pro-inflammatory molecules. These studies provide evidence of important functional contributions of intrinsic renal cells to inflammatory injury in GN via their expression of cytokines, cytokine receptors, MHC-II and co-stimulatory molecules. They suggest a sequence of interactions between cytokines from leukocytes and intrinsic renal cells and important contributions of glomerular epithelial cell proliferation to crescent formation.


An Assessment of Curve of Spee in Healthy Human Permanent Dentitions: A Cross Sectional Analytical Study in a Group of Young Indian Population.
An awareness of the standard value of the maxillary and the mandibular curves of Spee may aid the clinician in developing occlusion in the sagittal plane and would be useful when providing prosthetic rehabilitation for patients with occlusal derangement. To assess and compare the radius and depth of curve of Spee in maxillary and mandibular arches in men and women, in a group of young Indian population. The study cohort consisted of 25 men and 25 women between 19 to 24 years. Impression of maxillary and mandibular arches were made with alginate. Casts were poured in die stone. Standardized digital pictures of the right side of maxillary and mandibular dental casts were made with a digital camera and transferred to a computer. Tips of the distal cusps of molars, premolars and canines of the maxilla and mandible were located. The radius and the depth of the curve of Spee were measured from the digital photographs of dental casts, with the help of 'dimension tool' in the computer software (Corel DRAW X5). Mann-Whitney test was used to analyze the difference in the curve of Spee between men and women and the difference between maxillary and mandibular arches. The mean values were as follows: a) Men: Radii of curve of Spee in the maxillary and mandibular arch were 140.22±65.98 and 109.67±46.80 respectively; depths of curve of Spee in maxillary and mandibular arch were 1.65±0.67 and 1.49±0.74 respectively; b) Women: Radii of curve of Spee in the maxillary and mandibular arch were 120.58±63.91 and 98.31±63.59 respectively; depths of curve of Spee in maxillary and mandibular arch were 1.45±0.54 and 1.40±0.61 respectively. In the mandibular arch, the difference in the radii (p=0.0467) was statistically significant between men and women. In women, the difference in radii (p=0.0467) between maxillary and mandibular arches was statistically significant. The radii and depths of curve of Spee were larger in maxillary than mandibular arches in both men and women. Also, the difference in the radii of mandibular arch was statistically significant between men and women.


Development of hyaluronic acid-silica composites via in situ precipitation for improved penetration efficiency in fast-dissolving microneedle systems.
Fast-dissolving microneedles (DMNs) hold significant promise for transdermal drug delivery, offering improved patient compliance, biocompatibility, and functional adaptability for various therapeutic purposes. However, the mechanical strength of the biodegradable polymers used in DMNs often proves insufficient for effective penetration into human skin, especially under high humidity conditions. While many composite strategies have been developed to reinforce polymer-based DMNs, simple mixing of the reinforcements with polymers often results in ineffective penetration due to inhomogeneous dispersion of the reinforcements and the formation of undesired micropores. In response to this challenge, this study aimed to enhance the mechanical performance of hyaluronic acid (HA)-based microneedles (MNs), one of the most commonly used DMN systems. We introduced in situ precipitation of silica nanoparticles (Si) into the HA matrix in conjunction with conventional micromolding. The precipitated silica nanoparticles were uniformly distributed, forming an interconnected network within the HA matrix. Experimental results demonstrated that the mechanical properties of the HA-Si composite MNs with up to 20 vol% Si significantly improved, leading to higher penetration efficiency compared to pure HA MNs, while maintaining structural integrity without any critical defects. The composite MNs also showed reduced degradation rates and preserved their drug delivery capabilities and biocompatibility. Thus, the developed HA-Si composite MNs present a promising solution for efficient transdermal drug delivery and address the mechanical limitations inherent in DMN systems. STATEMENT OF SIGNIFICANCE: HA-Si composite dissolving microneedle (DMN) systems were successfully fabricated through in situ precipitation and conventional micromolding processes. The precipitated silica nanoparticles formed an interconnected network within the HA matrix, ranging in size from 25 to 230 nm. The optimal silica content for HA-Si composite MN systems should be up to 20 % by volume to maintain structural integrity and mechanical properties. HA-Si composite MNs with up to 20 % Si showed improved penetration efficiency and reduced degradation rates compared to pure HA MNs, thereby expanding the operational window. The HA-Si composite MNs retained good drug delivery capabilities and biocompatibility.


Developmental differences in the influence of phonological similarity on spoken word processing in Mandarin Chinese.
The developmental trajectory of spoken word recognition has been well established in Indo-European languages, but to date remains poorly characterized in Mandarin Chinese. In this study, typically developing children (N=17; mean age 10; 5) and adults (N=17; mean age 24) performed a picture-word matching task in Mandarin while we recorded ERPs. Mismatches diverged from expectations in different components of the Mandarin syllable; namely, word-initial phonemes, word-final phonemes, and tone. By comparing responses to different mismatch types, we uncovered evidence suggesting that both children and adults process words incrementally. However, we also observed key developmental differences in how subjects treated onset and rime mismatches. This was taken as evidence for a stronger influence of top-down processing on spoken word recognition in adults compared to children. This work therefore offers an important developmental component to theories of Mandarin spoken word recognition.


Treatment of chronic type B hepatitis in Southeast Asia.
In Southeast Asia, 15 to 20 percent of the population are hepatitis B surface antigen carriers. The majority of these carriers have chronic hepatitis and would progress to cirrhosis or hepatocellular carcinoma at an annual incidence of 2 percent and 1 percent, respectively. Previous studies from Southeast Asia suggested that immunosuppressive therapy could be harmful, or at best of no value, and antiviral treatment with vidarabine, picibanil, or even interferon was also unsatisfactory. Currently, a randomized controlled trial of human lymphoblastoid interferon, with or without prednisolone pretreatment, versus placebo in patients with hepatitis B core antigen in the liver and hepatitis B e antigen in the serum is being conducted. Forty-five patients (29 receiving interferon, 16 receiving placebo) have been entered in the trial for at least two months. Actuarial analysis shows that the response to interferon therapy was better than that to placebo. Although flu-like symptoms, hair loss, and body weight loss were seen, no side effect requiring specific treatment has been encountered. These preliminary results suggest that human lymphoblastoid interferon is effective and safe in Oriental patients.


Self-assembled mononuclear complexes: open metal sites and inverse dimension-dependent catalytic activity for the Knoevenagel condensation and CO2 cycloaddition.
To lessen the greenhouse effect, measures such as improving the recovery of crude oil and converting carbon dioxide (CO2) into valuable chemicals are necessary to create a sustainable low-carbon future. To this end, the development of efficient new oil-displacing agents and CO2 conversion has aroused great interest in both academia and industry. The Knoevenagel condensation and CO2 cycloaddition are the key reactions to solve the above problems. Four Cu- or Zn-based molecular complexes built from different ligands possessing hydrophilic-hydrophobic layers and different dimensionalities were chosen as solid catalysts for this study. Structural analysis revealed the presence of hydrophilic-hydrophobic layers and open metal sites in the low-dimensional complexes. To obtain deep insight into the reaction mechanism, first-principles density functional theory (DFT) calculations were carried out. These calculations confirmed that in the Knoevenagel condensation reaction, the final formation of benzylidenemalononitrile is the rate-determining step (an energy barrier (ΔE) value of 73.2 kJ mol-1). The zero-dimensional (0D) Cu molecular complex with unsaturated metal centers, hydrophilic and hydrophobic layers, exhibited higher catalytic activity (yield: 100%, temperature: room temperature, and time: 2 h) compared with one- and two-dimensional Cu complexes. In the presence of a 0D Zn complex co-catalyzed with Br- in the CO2 cycloaddition reaction, the ΔE value reduces to 35.5 kJ mol-1 for the ring opening of styrene oxide (SO), which is significantly lower than Br- catalyzed (80.9 kJ mol-1) reactions. The roles of unsaturated metal centers, hydrophilic-hydrophobic layers and dimensionality in the Knoevenagel condensation and CO2 cycloaddition were explained in the results of structure-activity relationships.


Effectiveness of conjugated estrogen in orthotopic liver transplantation.
A retrospective study was conducted at a university hospital to determine the efficacy of conjugated estrogen in reducing blood product transfusion during orthotopic liver transplantation. The charts of patients who had orthotopic liver transplantation were retrospectively reviewed. Only those having a reaction time > 30 mm or 15 minutes (normal = 19 mm to 28 mm) on computerized thromboelastogram (CTEG) at the beginning of surgery were included. One group of patients received a first dose of conjugated estrogen (100 mg i.v.) at the beginning of the case and a second dose (100 mg i.v.) just after reperfusion of the new graft. The control group did not receive estrogen. The two groups were similar in age, weight, first TEG measurements, final intraoperative hemoglobin concentration and platelet count. Blood products were given in response to hematocrit and CTEG measurements, which were determined every hour during surgery. The two groups did not differ in units of cryoprecipitate and platelets administered, but the intraoperative requirements for red blood cells and fresh frozen plasma were significantly lower in the estrogen group than in the control group. Administration of conjugated estrogen is associated with a statistically significant decrease in use of red blood cells and fresh frozen plasma during orthotopic liver transplantation.


Photonic technologies for liquid biopsies: recent advances and open research challenges.
The recent development of sophisticated techniques capable of detecting extremely low concentrations of circulating tumor biomarkers in accessible body fluids, such as blood or urine, could contribute to a paradigm shift in cancer diagnosis and treatment. By applying such techniques, clinicians can carry out liquid biopsies, providing information on tumor presence, evolution, and response to therapy. The implementation of biosensing platforms for liquid biopsies is particularly complex because this application domain demands high selectivity/specificity and challenging limit-of-detection (LoD) values. The interest in photonics as an enabling technology for liquid biopsies is growing owing to the well-known advantages of photonic biosensors over competing technologies in terms of compactness, immunity to external disturbance, and ultra-high spatial resolution. Some encouraging experimental results in the field of photonic devices and systems for liquid biopsy have already been achieved by using fluorescent labels and label-free techniques and by exploiting super-resolution microscopy, surface plasmon resonance, surface-enhanced Raman scattering, and whispering gallery mode resonators. This paper critically reviews the current state-of-the-art, starting from the requirements imposed by the detection of the most common circulating biomarkers. Open research challenges are considered together with competing technologies, and the most promising paths of improvement are discussed for future applications.


The role of exogenous electron carriers in NAD(P)-dependent dehydrogenase cytochemistry studied in vitro and with a model system of polyacrylamide films.
The applicability of phenazine methosulfate, 1-methoxyphenazine methosulfate, menadione, and meldola blue as exogenous electron carriers for the cytochemical staining of nicotinamide adenine dinucleotide (phosphate) (NAD(P))-dependent dehydrogenases has been studied quantitatively with tetranitro BT in vitro and with a model system of polyacrylamide films incorporating either purified glucose-6-phosphate dehydrogenase or intact rat liver parenchymal cells. It was found that every assay in which a tetrazolium salt is used, whether or not an electron carrier is present, has to be carried out in darkness. Menadione did not appear to be useful, because electrons were not found to be transferred directly from reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) to this compound. Phenazine methosulfate at higher concentrations and meldola blue at concentrations optimal for carrying electrons to tetrazolium salts yielded a high level of "nothing dehydrogenase" activity in cell-containing films, but no inhibition of enzymatic activity was found. Factors involved in the interference of oxygen with tetrazolium salt reduction are discussed. 1-Methoxyphenazine methosulfate did not stain cellular compounds and caused only a very low nothing dehydrogenase activity. The cytochemical demonstration of dehydrogenase activity was shown to be independent on the concentration of 1-methoxyphenazine methosulfate used (50-1000 microM). It is concluded that 1-methoxyphenazine methosulfate is the exogenous electron carrier of choice.


A dietary polyphenol resveratrol acts to provide neuroprotection in recurrent stroke models by regulating AMPK and SIRT1 signaling, thereby reducing energy requirements during ischemia.
Polyphenol resveratrol (RSV) has been associated with Silent Information Regulator T1 (SIRT1) and AMP-activated protein kinase (AMPK) metabolic stress sensors and probably responds to the intracellular energy status. Our aim here was to investigate the neuroprotective effects of RSV and its association with SIRT1 and AMPK signaling in recurrent ischemia models. In this study, elderly male Wistar rats received a combination of two mild transient middle cerebral artery occlusions (tMCAOs) as an in vivo recurrent ischemic model. Primary cultured cortical neuronal cells subjected to combined oxygen-glucose deprivation (OGD) were used as an in vitro recurrent ischemic model. RSV administration significantly reduced infarct volumes, improved behavioral deficits and protected neuronal cells from cell death in recurrent ischemic stroke models in vivo and in vitro. RSV treatments significantly increased the intracellular NAD(+) /NADH ratio, AMPK and SIRT1 activities, decreased energy assumption and restored cell energy ATP level. SIRT1 and AMPK inhibitors and specific small interfering RNA (siRNA) for SIRT1 and AMPK significantly abrogated the neuroprotection induced by RSV. AMPK-siRNA and inhibitor decreased SIRT1 activities; however, SIRT1-siRNA and inhibitor had no impact on phospho-AMPK (p-AMPK) levels. These results indicated that the neuroprotective effects of RSV increased the intracellular NAD(+) /NADH ratio as well as AMPK and SIRT1 activities, thereby reducing energy ATP requirements during ischemia. SIRT1 is a downstream target of p-AMPK signaling induced by RSV in the recurrent ischemic stroke model.


Increased miR-6875-5p inhibits plasmacytoid dendritic cell differentiation via the STAT3/E2-2 pathway in recurrent spontaneous abortion.
Recurrent spontaneous abortion (RSA) is a common complication of early pregnancy. Dendritic cells (DCs) are thought to confer fetal-maternal immunotolerance and play a crucial role in ensuring a successful pregnancy. A decrease of plasmacytoid dendritic cells (pDCs) was found to be involved in RSA, but the underlying mechanisms of decreased pDC in RSA remain unclear. MicroRNAs (miRNAs) play critical roles in RSA as well as the development, differentiation and functional regulation of pDCs; however, the regulatory effect of miRNAs on pDC in RSA has not been fully investigated. Here we demonstrated that both the proportion of pDC and signal transducer and activator of transcription (STAT3)/transcription factor 4 (Tcf4/E2-2) expression decreased in the peripheral blood mononuclear cells and decidua of patients with RSA compared to those with normal pregnancy (NP), and there was a significantly positive correlation between pDC and STAT3 mRNA. MiRNA microarray assay and quantitative reverse transcription PCR results showed that miR-6875-5p expression was markedly increased in women with RSA and negatively correlated with mRNA expression level of STAT3. Up-regulated miR-6875-5p could sensitively discriminate patients with RSA from NP subjects. Overexpression of miR-6875-5p significantly down-regulated the mRNA expression of STAT3 and E2-2 as well as the protein and phosphorylation level of STAT3, while miR-6875-5p knockdown showed opposite results. Dual luciferase reporter verified that miR-6875-5p regulated STAT3 expression by directly binding to its 3'untranslated region. Overall, our results suggested that increased miR-6875-5p is involved in RSA by decreasing the differentiation of pDCs via inhibition of the STAT3/E2-2 signaling pathway. miR-6875-5p may be explored as a promising diagnostic marker and therapeutic target for RSA.


c-di-GMP inhibits LonA-dependent proteolysis of TfoY in Vibrio cholerae.
The LonA (or Lon) protease is a central post-translational regulator in diverse bacterial species. In Vibrio cholerae, LonA regulates a broad range of behaviors including cell division, biofilm formation, flagellar motility, c-di-GMP levels, the type VI secretion system (T6SS), virulence gene expression, and host colonization. Despite LonA's role in cellular processes critical for V. cholerae's aquatic and infectious life cycles, relatively few LonA substrates have been identified. LonA protease substrates were therefore identified through comparison of the proteomes of wild-type and ΔlonA strains following translational inhibition. The most significantly enriched LonA-dependent protein was TfoY, a known regulator of motility and the T6SS in V. cholerae. Experiments showed that TfoY was required for LonA-mediated repression of motility and T6SS-dependent killing. In addition, TfoY was stabilized under high c-di-GMP conditions and biochemical analysis determined direct binding of c-di-GMP to LonA results in inhibition of its protease activity. The work presented here adds to the list of LonA substrates, identifies LonA as a c-di-GMP receptor, demonstrates that c-di-GMP regulates LonA activity and TfoY protein stability, and helps elucidate the mechanisms by which LonA controls important V. cholerae behaviors.


Massive open online courses in health sciences from Latin American institutions: A need for improvement?
Background: Massive open online courses (MOOCs) have undergone exponential growth over the past few years, offering free and worldwide access to high-quality education. We identified the characteristics of MOOCs in the health sciences offered by Latin American institutions (LAIs). Methods: We screened the eight leading MOOCs platforms to gather their list of offerings. The MOOCs were classified by region and subject. Then, we obtained the following information: Scopus H-index for each institution and course instructor, QS World University Ranking® 2015/16 of LAI, and official language of the course. Results: Our search identified 4170 MOOCs worldwide. From them, 205 MOOCs were offered by LAIs, and six MOOCs were health sciences related. Most of these courses (n = 115) were offered through Coursera. One health science MOOC was taught by three instructors, of which only one was registered in Scopus (H-index = 0). The remaining five health science MOOCs had solely one instructor (H-index = 4 [0-17]). The Latin American country with the highest participation was Brazil (n = 11). Conclusion: The contribution of LAI to MOOCs in the health sciences is low.


Tests of Concrete Strength across the Thickness of Industrial Floor Using the Ultrasonic Method with Exponential Spot Heads.
The accepted methods for testing concrete are not favorable for determining its heterogeneity. The interpretation of the compressive strength result as a product of destructive force and cross-section area is burdened with significant understatements. It is assumed erroneously that this is the lowest value of strength at the height of the tested sample. The top layer of concrete floors often crumble, and the strength tested using sclerometric methods does not confirm the concrete class determined using control samples. That is why it is important to test the distribution of compressive strength in a cross-section of concrete industrial floors with special attention to surface top layers. In this study, we present strength tests of borehole material taken from industrial floors using the ultrasonic method with exponential spot heads with a contact surface area of 0.8 mm2 and a frequency of 40 kHz. The presented research project anticipated the determination of strength for samples in various cross-sections at the height of elements and destructive strength in the strength testing machine. It was confirmed that for standard and big borehole samples, it is not possible to test the strength of concrete in the top layer of the floor by destructive methods. This can be done using the ultrasonic method. After the analysis, certain types of distributions of strength across concrete floor thickness were chosen from the completed research program. The gradient and anti-gradient of strength were proposed as the new parameters for the evaluation of floor concrete quality.


Texture Enhancement of Medical Images for Efficient Disease Diagnosis with Optimized Fractional Derivative Masks.
For the past two decades, fractional-order derivatives have been used to model many systems in science and engineering with more accuracy than existing integer-order derivatives. Many of these applications have been employed in the image processing field. It is undeniable that an image enhancement algorithm is very much desirable for medical image analysis to diagnose various kinds of diseases more efficiently. These requirements demand that the image should be of high quality. Hence, accurate edge-detection and denoising models are required in medical image processing, improving, and enhancing the contrast of an image to attain a better texture and avoid noise. In this study, we employ and compare the conventional methods and recent and most popular fractional-order-based methods for medical image analysis texture enhancement. To make a fair comparison, the fractional-order operators are optimized for all images with gray wolf optimizer while considering the performance metric mean squared error. The results showed that fractional differential-based operators perform better than conventional integer-order operators for texture enhancement of medical images.


Guidelines for privileging and credentialing physicians for sacrocolpopexy for pelvic organ prolapse.
Surgically complex procedures require a balance of knowledge, surgical skill, and experience with appropriate ongoing surgical volume and monitoring of outcomes and adverse events. Sacrocolpopexy has the potential to improve patient outcomes. These guidelines are meant to provide guidance for privileging and credentialing of physicians planning to implement or continue to use this procedure in their clinical practice.


Genetic Variants and Phenotypic Characteristics of Salmonella Typhimurium-Resistant Mutants after Exposure to Carvacrol.
The emergence of antimicrobial resistance has raised questions about the safety of essential oils and their individual constituents as food preservatives and as disinfection agents. Further research is required to understand how and under what conditions stable genotypic resistance might occur in food pathogens. Evolution experiments on Salmonella Typhimurium cyclically exposed to sublethal and lethal doses of carvacrol permitted the isolation of SeSCar and SeLCar strains, respectively. Both evolved strains showed a significant increase in carvacrol resistance, assessed by minimum inhibitory and bactericidal concentrations, the study of growth kinetics in the presence of carvacrol, and the evaluation of survival under lethal conditions. Moreover, antibiotic susceptibility tests revealed a development of SeLCar resistance to a wide range of antibiotics. Whole genome sequencing allowed the identification of single nucleotide variations in transcriptional regulators of oxidative stress-response: yfhP in SeSCar and soxR in SeLCar, which could be responsible for the increased resistance by improving the response to carvacrol and preventing its accumulation inside the cell. This study demonstrates the emergence of S. Typhimurium-resistant mutants against carvacrol, which might pose a risk to food safety and should therefore be considered in the design of food preservation strategies, or of cleaning and disinfection treatments.


Preliminary Clinical Application of Removable Partial Denture Frameworks Fabricated Using Computer-Aided Design and Rapid Prototyping Techniques.
The aim of this study was to explore the application of computer-aided design and rapid prototyping (CAD/RP) for removable partial denture (RPD) frameworks and evaluate the fitness of the technique for clinical application. Three-dimensional (3D) images of dentition defects were obtained using a lab scanner. The RPD frameworks were designed using commercial dental software and manufactured using selective laser melting (SLM). A total of 15 cases of RPD prostheses were selected, wherein each patient received two types of RPD frameworks, prepared by CAD/RP and investment casting. Primary evaluation of the CAD/RP framework was performed by visual inspection. The gap between the occlusal rest and the relevant rest seat was then replaced using silicone, and the specimens were observed and measured. Paired t test was used to compare the average thickness and distributed thickness between the CAD/RP and investment casting frameworks. Analysis of variance test was used to compare the difference in thickness among different zones. The RPD framework was designed and directly manufactured using the SLM technique. CAD/RP frameworks may meet the clinical requirements with satisfactory retention and stability and no undesired rotation. Although the average gap between the occlusal rest and the corresponding rest seat of the CAD/RP frameworks was slightly larger than that of the investment casting frameworks (P < .05), it was acceptable for clinical application. RPD frameworks can be designed and fabricated directly using digital techniques with acceptable results in clinical application.


Transition from spiral waves to defect-mediated turbulence induced by gradient effects in a reaction-diffusion system.
The transition from spiral waves to defect-mediated turbulence was studied in a spatial open reactor using Belousov-Zhabotinsky reaction. The experimental results show a new mechanism of the transition from spirals to spatiotemporal chaos, in which the gradient effects in the three-dimensional system are essential. The transition scenario consists of two stages: first, the effects of gradients in the third dimension cause a splitting of the spiral tip and a deletion of certain wave segments, generating new wave sources; second, the waves sent by the new wave sources undergo a backfire instability, and the back waves are laterally unstable. As a result, defects are automatically generated and fill all over the system. The result of numerical simulation using the FitzHugh-Nagumo model essentially agrees with the experimental observation.


[Evaluation of prophylactic intra-hepatic-arterial infusion chemotherapy after resection of hepatic metastases from colorectal primaries].
To prevent recurrence in the residual liver after surgical treatment for colorectal metastases, the efficacy of intermittent or continuous intra-hepatic-arterial chemotherapy was analyzed. The three- and five-year survival rate of patients with intermittent infusion of ADM or MMC (n = 11) was 36.4% and 36.4%, respectively, while the survival rate of the patients without the regional chemotherapy (n = 32) was 41.9% and 23.3%, respectively, indicating no statistical significance. On the other hand, one patient out of 8 with continuous infusion of 5-FU and 2 patients out of 6 without local chemotherapy developed recurrent disease during the median follow-up time of 12 months. No serious complication such as sclerotic cholangitis or hepatic necrosis was observed. Although the follow-up was not long enough to accurately evaluate the efficacy, local chemotherapy with continuous infusion of 5-FU could be a promising method as an adjuvant chemotherapy after hepatic resection for colorectal metastases.


A humanised tissue-engineered bone model allows species-specific breast cancer-related bone metastasis in vivo.
Bone metastases frequently occur in the advanced stages of breast cancer. At this stage, the disease is deemed incurable. To date, the mechanisms of breast cancer-related metastasis to bone are poorly understood. This may be attributed to the lack of appropriate animal models to investigate the complex cancer cell-bone interactions. In this study, two established tissue-engineered bone constructs (TEBCs) were applied to a breast cancer-related metastasis model. A cylindrical medical-grade polycaprolactone-tricalcium phosphate scaffold produced by fused deposition modelling (scaffold 1) was compared with a tubular calcium phosphate-coated polycaprolactone scaffold fabricated by solution electrospinning (scaffold 2) for their potential to generate ectopic humanised bone in NOD/SCID mice. While scaffold 1 was found not suitable to generate a sufficient amount of ectopic bone tissue due to poor ectopic integration, scaffold 2 showed excellent integration into the host tissue, leading to bone formation. To mimic breast cancer cell colonisation to the bone, MDA-MB-231, SUM1315, and MDA-MB-231BO breast cancer cells were cultured in polyethylene glycol-based hydrogels and implanted adjacent to the TEBCs. Histological analysis indicated that the breast cancer cells induced an osteoclastic reaction in the TEBCs, demonstrating analogies to breast cancer-related bone metastasis seen in patients.


Mnemonic networks in the hippocampal formation: from spatial maps to temporal and conceptual codes.
The hippocampal formation has been associated with a wide variety of functions including spatial navigation and planning, memory encoding and retrieval, relational processing, novelty detection, and imagination. These functions are dissimilar in terms of their behavioral consequences and modality of representation. Consequently, theoretical standpoints have focused on explaining the role of the hippocampal formation in terms of either its spatial or nonspatial functions. Contrary to this dichotomy, we propose that it is essential to look beyond these traditional boundaries between mnemonic and spatial functions and focus instead on the processes that these functions have in common. In this framework, we use electrophysiology data from the spatial domain to predict effects on the systems level, both in spatial and nonspatial domains. We initially outline the results of studies that have used findings from spatial navigation in rodents to predict the patterns of brain activity observable in people who are exploring virtual environments. We discuss how certain properties of space-defining neurons enable space to be represented as a mental map of interconnected locations, which are expressed at multiple spatial scales in separate modules in the hippocampal formation. We then suggest that memories are also organized in networks, characterized by mnemonic and temporal hierarchies. We finish by discussing how virtual-reality techniques can be used to create novel lifelike episodes allowing us to look at episodic memory processes while multivariate analysis tools can be used to explore the organizational structure of mnemonic networks.


Properties of Pseudomonas enalia, a marine bacterium pathogenic for the invertebrate Crassostrea gigas (Thunberg).
Bacteriological investigations of dead and dying oysters in populations of Crassostrea gigas grown in Hood Canal, Oyster Bay, and Willapa Bay, Washington, were undertaken. Living, and presumably normal, oysters within the same sample set were also examined. Results indicated that the natural flora of Crassostrea gigas (Thunberg) is composed of organisms representing the genera Pseudomonas, Achromobacter, Flavobacterium, and Vibrio. Pollution indicator organisms such as Escherichia coli were not found. The flora of dead or dying oysters included a somewhat greater incidence of Pseudomonas sp.; a seawater-requiring organism isolated on several occasions from oyster gapers which had been collected from different geographical areas was identified as P. enalia. A description of the organism has been provided, and the characteristics are listed to facilitate identification by other workers encountering the organism in future studies of a similar kind. The seawater requirement exhibited by P. enalia was deduced to be a requirement for sodium chloride for growth of the organism. Experiments to determine the pathogenicity of Pseudomonas enalia were performed by use of experimentally infected animals maintained in aerated seawater tanks. Death of C. gigas occurred when the animal body tissue was injected with viable bacterial cell suspension. Results of histological studies of the normal and infected oyster tissue suggest that bacterial invasion of the tissue occurred.


[Prototype analysis on beliefs about people with depression: Examining Japanese university students].
The present studies examined what kinds of beliefs are typically held about people with depression based on data from samples of Japanese university students. Study 1a utilized text describing people with depression that was divided into categories, and examined which categories were most frequently described. In Study 1b, participants rated how much they agreed with the beliefs categorized in Study 1a. A similar approach was taken in Study 2a (qualitative) and 2b (quantitative), in order to examine prototypic negative beliefs. Results from Study 1a and 1b indicated that prototypic beliefs were the "serious and working too hard" belief in regard to characteristics of people with depression, and the "taking too much things on oneself" belief related to personal responsibility. Results from 2a and 2b indicated that prototypic negative beliefs were the "gloomy" belief in regard to characteristics of people with depression, and the "mental weakness" belief related to personal responsibility. Implications for research on stigma toward people with depression are discussed.


Physiological profile of an elite freestyle wrestler preparing for competition: a case study.
The purpose of the present investigation was to describe the physiological changes of a nationally ranked older elite freestyle wrestler during a 7-month observation period as he prepared for the 2000 Olympic freestyle wrestling trials. A 33-year-old male wrestler was evaluated 3 times during the study for measurements of body composition, resting energy expenditure, maximal oxygen consumption, isometric strength, anaerobic power and capacity, nutritional intake, and various serum plasma constituents. Body weight decreased by 1 kg, which consisted of fat-free mass (FFM), whereas body fat remained stable at 5.8%. Muscular strength and aerobic power were maintained throughout the study. Measures of anaerobic work capacity tended to be higher and blood lactate lower as the subject progressed throughout the investigation. All serum plasma constituents were within clinically normal ranges and remained relatively stable. Despite a small loss of FFM, the subject was able to maintain muscular strength and aerobic fitness while concomitantly enhancing anaerobic capacity and power capabilities throughout the study period as he prepared for the 2000 Olympic freestyle wrestling trials.


H-Transfer reactions of internal alkenes with tertiary amines as H-donors on carbon supported noble metals.
A hydride transfer reaction with tertiary amines was observed in the presence of noble metals on a carbon support. Hydride transfer had been documented previously in terms of activated allyl-type carbon-carbon double bonds containing carbonyl derivatives in the presence of triethyl amine (conjugate reduction). The proposed mechanism is a hydride transfer reaction in which the metal serves as the reaction partner of the hydrido-metal iminium adduct formation. The saturation of a non-activated internal double bond containing compound, such as methyl oleate and trans-5-decene as substrates, was observed for the first time in this work. The pre-reduced catalyst samples showed high activity; in the presence of Pd/C, Pt/C and Rh/C partial to complete conversion was detected at 140 °C in a p-xylene solvent without molecular hydrogen. Higher molecular weight byproducts of the amines were formed, while in the case of the substrates negligible amounts of unreacted but double bond migrated species were present. There is a possibility of usage of alkyl amines other than triethylamine; thus use of tributyl-, tripentyl-, trihexylamine and N,N-diisopropylethylamine, as well as cyclic 1-ethylpyrrolidine and 1-ethylpiperidine, was investigated. Cyclic amines and diisopropyl derivatives as H sources produced the highest conversion, while amines with longer alkyl chains showed minor activity. As a clear indication of H-donation, the formation of unsaturated amine species such as 1-ethyl-pyrrole and pyridine was observed.


The Relevance of Family History Taking in the Detection and Management of Birt-Hogg-Dubé Syndrome.
Birt-Hogg-Dubé syndrome (BHDS) is a rare autosomal-dominant inherited disorder characterized by inactivation of the gene Folliculin (FLCN), pulmonary cysts with recurrent spontaneous pneumothorax, dermatological lesions, and an increased risk of developing renal malignancies. We aimed to investigate the real prevalence of BHDS and its prevalence among patients with a familial history of pneumothorax. From July 2014 to December 2016, we consecutively studied all patients with spontaneous pneumothorax and a positive family history for the same condition referring to our Institution. The suspicious cases underwent genetic analysis of the BHDS-causative gene FLCN. FLCN-positive cases were further evaluated with routine blood tests, chest radiography, chest CT, abdominal MRI, and dermatological evaluation. Among 114 patients admitted with spontaneous pneumothorax, 7 patients had a family history of pneumothorax, and 6/7 (85.7%) patients had positive genetic test for FLCN as well as 7/13 family members. Pulmonary cysts were found in all patients with a FLCN-positive genetic test. Most patients (10/13, 76.9%) had tiny pulmonary cysts less than 1 cm in diameter. The vast majority of cysts were intraparenchymal (12/13, 92.3%) and located in lower lobes. Dermatological lesions were found in 7/13 (54%) patients, renal cysts in 4/13 (31%) patients, and renal cancer in 1 (1/13, 7.7%) patient. Although BHDS is considered a rare disease, BHDS underlies spontaneous pneumothorax more often than usually believed, especially whenever a family history of pneumothorax is present. Diagnosis of BHDS is essential to start monitoring patients for the risk of developing renal malignancies.


Employee drug use, demographic characteristics, work reactions, and absenteeism.
Employees in a large work organization participated in an investigation of relationships between drug use and absenteeism and tardiness. Specifically, the study investigated the extent to which both self-reported and urine-screened drug use accounted for variance in several types of absenteeism, as well as tardiness, above and beyond that accounted for by demographic and work reaction variables. The results showed that employee drug use accounted for additional statistically significant variance in overall absenteeism and in absenteeism due to injuries and suspensions, as well as days tardy. Implications of these findings for organizational drug testing are discussed.


A novel dielectrophoresis potential spectroscopy for colloidal nanoparticles.
Dielectrophoresis (DEP) has been widely used to manipulate nanoparticles in microfluidic applications. However, determination of the DEP force of nanoparticles by theoretical models is not easy due to complications caused by the polarization of electrical double layer. Additionally, there is a lack of suitable experimental techniques to quantify the DEP force of nanoparticles. This article reports a statistical mechanics-based experimental method to determine the DEP potential energy of a single particle by measuring the equilibrium number density of particles in a DEP force field. Results show that at high frequencies, the measured potentials agree with the Maxwell-Wagner-O'Konski (MWO) theory. At frequencies lower than the crossover frequency (ωco ), the measured potential values are larger than MWO theory's predictions. When an effective particle radius (particle radius plus Debye length) is used to replace the particle radius, MWO theory fits better with the measured potentials on both sides of ωco . Also, the measured ωco was found inversely proportional to the effective particle radius, which agrees with MWO theory. The new DEP potential spectroscopy is not limited to the size or shape of particles, opening doors to investigate the DEP response functions of quantum dots and proteins in an alternating current electric field.


Comments on the nature of the bonding in oxygenated dinuclear copper enzyme models.
The nature of the bonding in model complexes of di-copper metalloenzymes has been analyzed by means of the electronic localization function (ELF) and by the quantum theory of atoms in molecules (QTAIM). The constrained space orbital variations (CSOV) approach has also been used. Density functional theory (DFT) and CASSCF calculations have been carried out on several models of tyrosinase such as the sole Cu2O22+ central core, the Cu2O2(NH3)62+ complex and the Cu2O2(Imidazol)62+ complex. The influence on the central Cu(2)O(2) moiety of both levels of calculation and ligand environment have been discussed. The distinct bonding modes have been characterized for the two major known structures: [Cu(2)(mu-eta(2): eta(2)-O(2))](2+) and [Cu(2)(mu-O(2))](2+). Particular attention has been given to the analysis of the O-O and Cu-O bonds and the nature of the bonding modes has also been analyzed in terms of mesomeric structures. The ELF topological approach shows a significant conservation of the topology between the DFT and CASSCF approaches. Particularly, three-center Cu-O-Cu bonds are observed when the ligands are attached to the central core. At the DFT level, the importance of self interaction effects are emphasized. Although, the DFT approach does not appear to be suitable for the computation of the electronic structure of the isolated Cu(2)O(2) central core, competitive self interaction mechanisms lead to an imperfect but acceptable model when using imidazol ligands. Our results confirm to a certain extent the observations of [M.F. Rode, H.J. Werner, Theoretical Chemistry Accounts 4-5 (2005) 247.] who found a qualitative agreement between B3LYP and localized MRCI calculations when dealing with the Cu(2)O(2) central core with six ammonia ligands.


Semi-synthesis of a HGF/SF kringle one (K1) domain scaffold generates a potent in vivo MET receptor agonist.
The development of MET receptor agonists is an important goal in regenerative medicine, but is limited by the complexity and incomplete understanding of its interaction with HGF/SF (Hepatocyte Growth Factor/Scatter Factor). NK1 is a natural occurring agonist comprising the N-terminal (N) and the first kringle (K1) domains of HGF/SF. In the presence of heparin, NK1 can self-associate into a "head to tail" dimer which is considered as the minimal structural module able to trigger MET dimerization and activation whereas isolated K1 and N domains showed a weak or a complete lack of agonistic activity respectively. Starting from these structural and biological observations, we investigated whether it was possible to recapitulate the biological properties of NK1 using a new molecular architecture of isolated N or K1 domains. Therefore, we engineered multivalent N or K1 scaffolds by combining synthetic and homogeneous site-specifically biotinylated N and K1 domains (NB and K1B) and streptavidin (S). NB alone or in complex failed to activate MET signaling and to trigger cellular phenotypes. Importantly and to the contrary of K1B alone, the semi-synthetic K1B/S complex mimicked NK1 MET agonist activity in cell scattering, morphogenesis and survival phenotypic assays. Impressively, K1B/S complex stimulated in vivo angiogenesis and, when injected in mice, protected the liver against fulminant hepatitis in a MET dependent manner whereas NK1 and HGF were substantially less potent. These data reveal that without N domain, proper multimerization of K1 domain is a promising strategy for the rational design of powerful MET agonists.


DNA double-strand break repair and radiation response in human tumour primary cultures.
The accumulation and repair of radiation-induced DNA double-strand breaks (dsbs) were determined by neutral filter elution on 20 primary cultures obtained from ovarian cancer and malignant melanoma clinical specimens. The initial frequency of DNA dsbs after exposure to 50 Gy gamma-irradiation varied greatly for the individual cultures. However, melanomas were generally more efficient than ovarian cancers in repairing these DNA lesions (mean percentage of DNA dsb rejoined after 2 h: 83 versus 62%). In 13 of 20 cultures radiosensitivity was also assessed by the Courtenay clonogenic assay. The mean +/- SD of the surviving fraction at 2 Gy (SF2) was slightly higher for melanomas (0.56 +/- 0.25) than for ovarian carcinomas (0.43 +/- 0.23). No correlation was observed between SF2 and in vitro plating efficiencies or any biological characteristics of the tumour cell population, such as proliferative activity and DNA ploidy. Similarly, we failed to find any relation between the initial frequencies of DNA dsbs and SF2 in individual tumours. In contrast, a significant and direct relationship (r = 0.86, p < 0.01) was observed between SF2 and the percentages of DNA dsbs rejoined 2 h after irradiation. In agreement with reported data on human tumour established cell lines, our results indicate that the ability to repair DNA dsbs is an important determinant for radiation response even in primary cultures of clinical tumours.


Comparison of Efficacy of Endogenous and Exogenous IGF-I in Stimulating Matrix Production in Neonatal and Mature Chondrocytes.
The goal of this study was to compare the efficacy of endogenous upregulation of IGF-I by gene therapy and exogenous addition of insulin-like growth factor I (IGF-I) in enhancing proteoglycan synthesis by skeletally mature and neonatal chondrocytes. Chondrocyte transplantation therapy is a common treatment for focal cartilage lesions, with both mature and neonatal chondrocytes used as a cell source. Additionally, gene therapy strategies to upregulate growth factors such as IGF-I have been proposed to augment chondrocyte transplantation therapies. Both skeletally mature and neonatal chondrocytes were exposed to either an adeno-associated virus-based plasmid containing the IGF-I gene or exogenous IGF-I. Analysis of IGF-I and glycosaminoglycan production using a 4-parameter dose-response model established a clear connection between the amount of IGF-I produced by cells and their biosynthetic response. Both neonatal and mature chondrocytes showed this relationship, but the sensitivities were quite different, with EC50 of 0.57 ng/mL for neonatal chondrocytes and EC50 of 8.70 ng/mL IGF-I for skeletally mature chondrocytes. These data suggest that IGF-I gene therapy may be more effective with younger cell sources. Both cell types were less sensitive to exogenous IGF-I than endogenous IGF-I.


Reversible inactivation of the sarcoplasmic reticulum Ca(2+)-ATPase coupled to rearrangement of cytoplasmic protein domains as revealed by changes in trypsinization pattern.
Repetitive homogenization of skeletal muscle sarcoplasmic reticulum (SR) membranes in the presence of chelating agents at low ionic strength leads to the loss of the Ca-ATPase activity. This inactive state of the enzyme is coupled to an extensive rearrangement of the cytosolic domains as visualized by a completely different trypsinization pattern of the enzyme. In addition to the primary cleavage site (Arg 505), a novel trypsinization site (Arg 334), just N-terminal of the phosphorylation domain and localized on the primary tryptic fragment A, becomes exposed. Cleavage at the latter site yields a soluble fragment of M(r) 20,117 and the membrane-bound N-terminal one-third of the ATPase of M(r) 35,279. Two additional trypsinization sites C-terminal of the nucleotide binding domain become exposed in the inactive Ca(2+)-ATPase conformation. Rapid cleavage at these sites yields two soluble fragments of about 15 and 10 kDa. All together, the three soluble fragments comprise most of the large cytosolic loop of the Ca(2+)-ATPase. The inactivation and the change in trypsinization pattern can be reversed by rehomogenization of the extracted membranes in the presence of divalent cations. The results suggest the presence of an occluded site for divalent cations which can be depleted or refilled during application of sheer forces. Occupation of this site is essential to confer to the enzyme an active conformation.


Glucagonomas of transgenic mice express a wide range of general neuroendocrine markers and bioactive peptides.
Pancreatic tumours of transgenic mice carrying a glucagon-promoted simian virus 40 (SV40) T antigen oncogene have been analysed by histological, histochemical, ultrastructural and radioimmunological means. Seven transgenic mice were examined revealing dysplastic and neoplastic lesions in the endocrine pancreas. Four tumours were identified, one of which metastasized to periadrenal spaces and paravertebral lymph nodes. Benign tumours were composed of argyrophilic, endocrine cells reactive to a range of antibodies against neuroendocrine markers (neuron-specific enolase, protein gene product 9.5, chromogranin A, synaptophysin and protein 7B2) and different fragments of the proglucagon molecule (glucagon, glicentin, glucagon-like polypeptides 1 and 2). A few tumour cells expressed pancreatic polypeptide, somatostatin or insulin. Conventional ultrastructural analysis and immunogold labelling revealed typical glucagon-immunoreactive alpha granules which co-stored glicentin and glucagon-like polypeptides 1 and 2. The malignant primary tumour and its metastases were composed mainly of cells which did not show immunoreactivity for neuroendocrine markers or peptides. Atypical, glucagon-immunogold labelled granules were detected at electron microscopy in differentiated tumour cells and C-type retroviral particles in the largest tumour population of degranulated cells. The transgene-encoded oncoprotein SV40 large T-antigen was detected in the nuclei of well-differentiated tumour cells and in alpha cells of some dysplastic islets. All tumour-bearing mice showed high levels of circulating glucagon-like immunoreactivity. Transgenic mice harbouring the glucagon-promoted SV40 T antigen oncogene may provide a model for human glucagonoma.


Pathogenesis, treatment, and therapeutic trials in hemolytic uremic syndrome.
Diarrhea-associated hemolytic uremic syndrome is one of the most common causes of acute renal failure in childhood. Nearly all cases are the result of an antecedent infection by Shiga toxin--producing strains of Escherichia coli, especially the O157:H7 serotype. Most cases occur after ingestion of contaminated meat; however, new food sources such as leaf lettuce, alfalfa sprouts, and goat's milk have been identified, and diarrhea-associated hemolytic uremic syndrome can occur after exposure to contaminated water in recreational swimming sites. Diarrhea-associated hemolytic uremic syndrome is a systemic disease with activation of a variety of inflammatory cytokines. Kidney injury may result from direct effects of the Shiga toxin on renal tubular epithelial cells as well as endothelial cells. Early diagnosis of diarrhea-associated hemolytic uremic syndrome may be expedited by the introduction of new techniques to rapidly detect toxin and microorganism in stool samples. Optimal therapy of diarrhea-associated hemolytic uremic syndrome includes intensive management of the renal failure and serious extrarenal complications that may occur during the course of disease. The role of antibiotics in prevention and amelioration of diarrhea-associated hemolytic uremic syndrome remains controversial. Experimental therapies that are undergoing evaluation in clinical trials include SYNSORB Pk (SYNSORB Biotech, Inc., Calgary, Alberta, Canada), a drug designed to bind Shiga toxin in the lumen of gastrointestinal tract. Immunization strategies are also being developed and tested. It is hoped that with continued progress in this field the incidence of diarrhea-associated hemolytic uremic syndrome in children will be substantially reduced in the coming years.


Human papillomavirus type 16 DNA detected in pulmonary metastases from a penile squamous cell carcinoma: a case study.
This report describe the case of a patient presenting with pulmonary metastases from a penile cancer, where the presence of the human papillomavirus (HPV) type 16 DNA both in the primary tumor and in the distant metastases confirmed the spreading of the disease, ruling out a possible primary lung squamous cell carcinoma. Indeed, according to the findings, the HPV genotyping test might help in the identification of metastatic disease from anogenital malignancies or other HPV-related cancers.