Effect of tinnitus on distortion product otoacoustic emissions varies with hearing loss.
The aim of this study was to measure the effect of tinnitus, while accounting for the effect of hearing loss and aging, on distortion product otoacoustic emissions (DPOAEs). DPOAEs were measured twice in both ears in 5 groups of participants: young adults with normal hearing, middle-age adults with normal hearing, adults with high-frequency sensorineural hearing loss, age-matched adults with similar hearing loss and tinnitus, and adults with normal hearing and chronic tinnitus. Multivariate analysis revealed a main effect of hearing loss and age, but no effect of tinnitus, across all 5 groups. Separate tests revealed significant effects of age and tinnitus in the normal-hearing groups and hearing loss in adults with or without tinnitus, but no effect of tinnitus in those with hearing loss. DPOAE levels in the group of adults with hearing loss and tinnitus were diminished, but those in the group with normal hearing and tinnitus were enhanced, relative to DPOAE levels in the controls. Outer hair cell function, as indexed by DPOAEs, exhibits a complex association with tinnitus, and this has implications in the use of DPOAEs as a tool both for testing for tinnitus presence and for creating a model of neural mechanisms underlying tinnitus.


Characteristics of informal caregivers who provide transportation assistance to older adults.
The study aim was to gain a better understanding of the characteristics of informal caregivers who provide transportation assistance and to explore the types and frequency of this assistance. A telephone survey was administered to a representative sample of 268 informal caregivers (age 45-80) who provide transportation assistance to older adults (age 70 and older) in Michigan. Responses were analyzed overall and by the caregiver sex and care recipient age. Informal transportation caregivers were: most often women; on average 61 years old; generally college educated; employed full- or part-time jobs; relatively healthy; providing care to a parent/family member 1-4 times per week, living close to the care recipient; and providing assistance by giving rides. Less than one-half of caregivers sought information to help them provide assistance. No significant burden was reported and there were few differences by sex of the caregiver of the age group of the care recipient.


Isolation of epithelial cells from toad bladder.
The epithelial cells of the toad bladder have been isolated by brief exposure to ethylenediaminetetraacetic acid followed by treatment with collagenase, DNAse, and the application of shearing forces. This approach eliminates the need for scraping of the mucosal surface and reduces mechanical damage during harvesting of the epithelium. The method yields intact, isolated epithelial cells and few clumps. The three major types of epithelial cells described in the intact toad bladder were present in the final preparation. The cellular contents of nucleic acids and proteins (in pg/cell) were: DNA 22.5 +/- 1.1; RNA, 12.9 +/- 0.6; and protein, 192 +/- 9. The isolated cells possess rates of oxygen consumption and amino acid incorporation higher than those of epithelial sheets obtained by collagenase treatment and scraping of the intact bladder. However, the production of cyclic nucleotides in response to stimulation by vasopressin and carbachol is comparable in both preparations.


Pseudosarcomatous fibromyxoid tumor of the prostate.
We present the case of a 61-year-old patient who was evaluated for benign infravesical obstruction due to a pseudosarcomatous fibromyxoid tumor of the prostate. This entity is rare and difficult to distinguish from a malignant lesion. A discussion of the pathological features and a review of the literature are given.


Identification of Enzymes Oxidizing the Tyrosine Kinase Inhibitor Cabozantinib: Cabozantinib Is Predominantly Oxidized by CYP3A4 and Its Oxidation Is Stimulated by cyt b5 Activity.
Herein, the in vitro metabolism of tyrosine kinase inhibitor cabozantinib, the drug used for the treatment of metastatic medullary thyroid cancer and advanced renal cell carcinoma, was studied using hepatic microsomal samples of different human donors, human recombinant cytochromes P450 (CYPs), flavin-containing mono-oxygenases (FMOs) and aldehyde oxidase. After incubation with human microsomes, three metabolites, namely cabozantinib N-oxide, desmethyl cabozantinib and monohydroxy cabozantinib, were detected. Significant correlations were found between CYP3A4 activity and generation of all metabolites. The privileged role of CYP3A4 was further confirmed by examining the effect of CYP inhibitors and by human recombinant enzymes. Only four of all tested human recombinant cytochrome P450 were able to oxidize cabozantinib, and CYP3A4 exhibited the most efficient activity. Importantly, cytochrome b5 (cyt b5) stimulates the CYP3A4-catalyzed formation of cabozantinib metabolites. In addition, cyt b5 also stimulates the activity of CYP3A5, whereas two other enzymes, CYP1A1 and 1B1, were not affected by cyt b5. Since CYP3A4 exhibits high expression in the human liver and was found to be the most efficient enzyme in cabozantinib oxidation, we examined the kinetics of this oxidation. The present study provides substantial insights into the metabolism of cabozantinib and brings novel findings related to cabozantinib pharmacokinetics towards possible utilization in personalized medicine.


Luteal activity and effect of dietary energy restriction on follicular development in lactating cows.
The aim of this research has been to evaluate the presence of anomalies in the ovarian cycle activity during postpartum and to verify whether 72-hr dietary fasting during the dominance phase, the phase before ovulation, might modify the ovarian follicle population. The presence of anomalies in ovarian cycle activity has been evaluated in 30 Italian Friesian cows starting from 20 days postpartum until 211 days of lactation. Long oestrus and brief dioestrus or scarce luteal activity have been the main anomalies found through measuring progesterone concentrations in the whey. Until 100 days of lactation, the BCS values of the problematic animals have been significantly lower than those in animals with normal ovarian activity. After 100 days of lactation, the ovarian anomalies continued to appear despite the fact that all the animals have reached comparable BCS values. Starting from the results of this trial, the effect of 72-hr dietary fasting on dominant follicles has been studied in six cows. Ultrasonography revealed that the diameter of the follicles at 71 days postpartum has been significantly lower than at 181 days. A 72-hr dietary restriction at 101 and 211 days postpartum did not affect the size of the dominant follicle. However, at 101 days postpartum, half of the animals presented follicular cysts. The effect of fasting differed if the animal has been in early postpartum or 211 days of lactation. Further researches are necessary to understand how different metabolic conditions can modify the follicular population but on the other hand the study shows the utility for farmers and field veterinarians of monitoring the resumption of the ovarian cycle postpartum through the whey progesterone concentrations.


Hepatic trauma.
Two hundred thirty-three patients were operated on for hepatic trauma during a two-year period. There were 101 patients with stab wounds, 90 with gunshot wounds, and 42 with blunt trauma. There were 56 isolated liver injuries. Three hundred seventy-five associated injuries occurred among the remaining 177 patients. The majority of patients required only drainage. "Liver sutures" were employed in 66 patients. Only 18 patients required débridement, resection, or packing. Twenty-eight patients (12%) died. Perioperatively, 13 patients died of hemorrhage from the hepatic wound and from the associated major vascular injuries that were present in eight of the 13 cases. The remaining deaths were not primarily a consequence of the hepatic wound. Control of hemorrhage remains the dominant consideration in the treatment of major hepatic wounds.


Pregnancy weight gain a balancing act: The experience and perspectives of women participating in a pilot randomised controlled trial.
Supporting women to achieve healthy gestational weight gain is a global health challenge. Inadequate and excessive gestational weight gains are associated with short and long-term adverse maternal and infant health outcomes. Qualitative studies suggest that symptoms of pregnancy, health professional attitudes, lack of guidance, personal knowledge and beliefs, lack of support, weight stigma, and lack of time and money, are barriers to achieving healthy weight gain. Less is known about women's perceptions and experience of gestational weight gain within normal body mass index categories with even less known about the experience of women motivated to participate in pregnancy weight management intervention trials. To describe the experience and perspectives of women participating in an Australian weight management pilot randomised controlled trial. Five women from regional New South Wales enrolled in the Eating 4 Two trial, participated in semi - structured interviews during the post-natal period. A qualitative descriptive methodology and inductive thematic analysis was applied. Two main themes emerged: 1) Addressing weight gain in pregnancy; and 2) Pregnancy weight the balancing act. Women identified weight gain as an important topic, the need for improvements within maternity services, responsive feedback and realistic support strategies. Women identified pregnancy symptoms, occurring during early and late pregnancy as barriers to achieving healthy weight gain. Further investigation into the effects of pregnancy symptoms on eating and physical activity patterns across pregnancy is warranted. Both qualitative and quantitative research is needed to monitor the translation of guideline recommendations into clinical practice.


Optimal cutoff scores for dementia and mild cognitive impairment of the Montreal Cognitive Assessment among elderly and oldest-old Chinese population.
All versions of the Montreal Cognitive Assessment (MoCA) lack population-based data of 80-plus individuals. The norms and cut-off scores for mild cognitive impairment (MCI) and dementia of the MoCA are different among five Chinese versions. To provide the cut-off scores in detecting MCI and dementia of the Peking Medical Union College Hospital version of the MoCA (MoCA-P). In a cross-sectional survey, Chinese veterans aged ≥60 years completed the MoCA-P and the Mini-Mental State Examination (MMSE). Among 7,445 elderly veterans, 5,085 (68.30%) were aged ≥80 years old, 2,621 (35.20%) had 6 years of education or less, 6,847 (91.97%) were male, and 2,311 (31.04%) and 984 (13.22%) veterans were diagnosed as having MCI and dementia, respectively. Adding two points and one point to the MoCA scores for the primary and middle school groups, respectively, can fully adjust for the notable impact of education but cannot compensate for the effect of age. In the three age groups (60-79, 80-89, and ≥90 years old), the optimal MoCA-P cut-off scores for detecting MCI were ≤25, ≤24, and ≤23, respectively, and for detecting dementia were ≤24, ≤21, and ≤19, respectively, which demonstrated relatively high sensitivities and specificities. The areas under the curves for the MoCA-P for detecting MCI and dementia (0.937 and 0.908, respectively) were greater than those for the MMSE (0.848 and 0.892, respectively). Compared with the MMSE, the MoCA-P is significantly better for detecting MCI in the elderly, particularly in the oldest old population, and it also displays more effectiveness in detecting dementia.


Development, implementation, and impact of an automated early warning and response system for sepsis.
Early recognition and timely intervention significantly reduce sepsis-related mortality. Describe the development, implementation, and impact of an early warning and response system (EWRS) for sepsis. After tool derivation and validation, a preimplementation/postimplementation study with multivariable adjustment measured impact. Urban academic healthcare system. Adult non-ICU patients admitted to acute inpatient units from October 1, 2011 to October 31, 2011 for tool derivation, June 6, 2012 to July 5, 2012 for tool validation, and June 6, 2012 to September 4, 2012 and June 6, 2013 to September 4, 2013 for the preimplementation/postimplementation analysis. An EWRS in our electronic health record monitored laboratory values and vital signs in real time. If a patient had ≥4 predefined abnormalities at any single time, the provider, nurse, and rapid response coordinator were notified and performed an immediate bedside patient evaluation. Screen positive rates, test characteristics, predictive values, and likelihood ratios; system utilization; and resulting changes in processes and outcomes. The tool's screen positive, sensitivity, specificity, and positive and negative predictive values and likelihood ratios for our composite of intensive care unit (ICU) transfer, rapid response team call, or death in the derivation cohort was 6%, 16%, 97%, 26%, 94%, 5.3, and 0.9, respectively. Validation values were similar. The EWRS resulted in a statistically significant increase in early sepsis care, ICU transfer, and sepsis documentation, and decreased sepsis mortality and increased discharge to home, although neither of these latter 2 findings reached statistical significance. An automated prediction tool identified at-risk patients and prompted a bedside evaluation resulting in more timely sepsis care, improved documentation, and a suggestion of reduced mortality.


Acupuncture Therapy and Incidence of Depression After Stroke.
We investigated whether use of acupuncture within a 3-month poststroke period after hospital discharge is associated with reduced risk of depression. This cohort study included 16 046 patients aged ≥18 years with an initial hospitalization for stroke during 2000 and 2012 in the claims database of a universal health insurance program. Patients who had received acupuncture therapies within 3 months of discharge were defined as acupuncture users (n=1714). All patients were followed up for incidence of depression until the end of 2013. We assessed the association between use of acupuncture and incidence of depression using Cox proportional hazards models in all subjects and in propensity score-matched samples consisting of 1714 pairs of users and nonusers. During the follow-up period, the incidence of depression per 1000 person-years was 11.1 and 9.7 in users and nonusers, respectively. Neither multivariable-adjusted Cox models (hazard ratio, 1.04; 95% confidence interval, 0.84-1.29) nor the propensity score-matching model (hazard ratio, 1.06; 95% confidence interval, 0.79-1.42) revealed an association between use of acupuncture and incidence of depression. In patients admitted to hospital for stroke, acupuncture therapy within 3 months after discharge was not associated with subsequent incidence of depression.


Preventing dyslipidemia by Chlorella pyrenoidosa in rats and hamsters after chronic high fat diet treatment.
The effects of Chlorella pyrenoidosa on serum lipid profiles, after concomitant long-term treatment of high-fat diet (HFD) in rats and hamsters was studied. Wistar rats and Syrian hamsters were fed with or without various concentrations of Chlorella pyrenoidosa contained high-fat diet (CHFD) for 2, 4 and 8 weeks prior to assay of serum lipids. Fasting triglycerides, total cholesterol, and LDL cholesterol as well as HDL cholesterol levels in high-fat diet treated rats and hamster were determined. Results showed that triglycerides, total cholesterol and LDL cholesterol levels in HFD treated rats and hamsters were increased from the normal rodent diet (NRD) treated controls after 2, 4, and 8-week treatments. However, the presence of Chlorella pyrenoidosa in high-fat diets significantly decreased the levels of triglycerides, total cholesterol and LDL cholesterol with comparison to HFD group in rats and hamsters. The total cholesterol/HDL ratios, an indication of occurrence of coronary heart disease, were decreased in all CHFD treated grouped rats and hamsters which suggests administration of Chlorella pyrenoidosa could lower the occurring risk of heart diseases. In conclusion, Chlorella pyrenoidosa has the ability to prevent dyslipidemia in chronic high-fat fed animals and could be potential in use to prevent intestinal absorption of redundant lipid from our daily intake and subsequently to prevent hyperlipidemia as well as atherosclerosis.


Activation of the Mating Pheromone Response Pathway of Lentinula edodes by Synthetic Pheromones.
Pheromone (PHB)-receptor (RCB) interaction in the mating pheromone response pathway of Lentinula edodes was investigated using synthetic PHBs. Functionality of the C-terminally carboxymethylated synthetic PHBs was demonstrated by concentration-dependent induction of a mating-related gene (znf2) expression and by pseudoclamp formation in a monokaryotic strain S1-11 of L. edodes. Treatment with synthetic PHBs activated the expression of homeodomain genes (HDs) residing in the A mating type locus, and of A-regulated genes, including znf2, clp1, and priA, as well as genes in the B mating type locus, including pheromone (phb) and receptor (rcb) genes. The synthetic PHBs failed to discriminate self from non-self RCBs. PHBs of the B4 mating type (B4 PHBs) were able to activate the mating pheromone response pathway in both monokaryotic S1-11 and S1-13 strains, whose B mating types were B4 (self) and B12 (non-self), respectively. The same was true for B12 PHBs in the B4 (non-self) and B12 (self) mating types. The synthetic PHBs also promoted the mating of two monokaryotic strains carrying B4-common incompatible mating types (A5B4 × A1B4). However, the dikaryon generated by this process exhibited abnormally high content of hyphal branching and frequent clamp connections and, more importantly, was found to be genetically unstable due to overexpression of mating-related genes such as clp1. Although synthetic PHBs were unable to discriminate self from non-self RCBs, they showed a higher affinity for non-self RCBs, through which the mating pheromone response pathway in non-self cells may be preferentially activated.


DMP1-derived peptides promote remineralization of human dentin.
Remineralization of dentin during dental caries is of considerable clinical interest. Dentin matrix protein 1 (DMP1) is a non-collagenous calcium-binding protein that plays a critical role in biomineralization. In the present study, we tested if peptides derived from DMP1 can be used for dentin remineralization. Peptide pA (pA, MW = 1.726 kDa) and peptide pB (pB, MW = 2.185), containing common collagen-binding domains and unique calcium-binding domains, were synthesized by solid-phase chemistry. An extreme caries lesion scenario was created by collagenase digestion, and the biomineral-nucleating potential of these peptides was ascertained when coated on collagenase-treated dentin matrix and control, native human dentin matrix under physiological levels of calcium and phosphate. Scanning electron microscopy analysis suggests that peptide pB was an effective nucleator when compared with pA. However, a 1:4 ratio of pA to pB was determined to be ideal for dentin remineralization, based on hydroxyapatite (HA) morphology and calcium/phosphorus ratios. Interestingly, HA was nucleated on collagenase-challenged dentin with as little as 20 min of 1:4 peptide incubation. Electron diffraction confirmed the presence of large HA crystals that produced a diffraction pattern indicative of a rod-like crystal structure. These findings suggest that DMP1-derived peptides may be useful to modulate mineral deposition and subsequent formation of HA when exposed to physiological concentrations of calcium and phosphate.


Comparing the Effectiveness of Sexual Counseling Based on PLISSITand BETTER Models on Sexual Selfdisclosure in Women with Sexual Problems after Childbirth: A Randomized Trial.
Sexual self-disclosure is one of the factors that affect sexual satisfaction. The aim of this study was to assess the efficacy of individual therapy using the Bring up, Explain, Tell, Timing, Educate, and Record (BETTER model) in comparison to individual therapy using the Permission, Limited Information, Specific Suggestions, and Intensive Therapy (PLISSIT model) in terms of increasing sexual self-disclosure in women with sexual problems after childbirth. This randomized trial was conducted in 2017 in Mashhad, Iran. 80 women with sexual problems within 4 weeks to 6 months after childbirth were randomized into two equal groups and received the interventions in 2 sessions of 60-90 minutes. The research instruments included a demographic questionnaire, the Female Sexual Function Index (FSFI) and Hulbert sexual self-disclosure index. Changes in mean (SD) scores of sexual self-disclosures between groups were assessed before and 4 weeks after the intervention and the results (mean changes) were compared between groups. The data analysis was conducted using independent t-test, paired t-test, Chi-square, analysis of covariance (ANOVA), and Mann-Whitney U test in SPSS (p < 0.05). In the PLISSIT group, the mean (SD) sexual self-disclosure score at baseline was 43.80 (9.50) and after 4 weeks was 51.60 (8.30). In the BETTER group, at baseline and after 4 weeks the mean (SD) sexual self-disclosure score was, respectively, 44.10 (10.30) and 55.60 (8.20) (Z = -2.5, p = 0.013). The findings confirm the effectiveness of the BETTER counseling model in increasing sexual self-disclosure after childbirth.


A novel measure of non-coding genome conservation identifies genomic regulatory blocks within primates.
Clusters of extremely conserved non-coding elements (CNEs) mark genomic regions devoted to cis-regulation of key developmental genes in Metazoa. We have recently shown that their span coincides with that of topologically associating domains (TADs), making them useful for estimating conserved TAD boundaries in the absence of Hi-C data. The standard approach-detecting CNEs in genome alignments and then establishing the boundaries of their clusters-requires tuning of several parameters and breaks down when comparing closely related genomes. We present a novel, kurtosis-based measure of pairwise non-coding conservation that requires no pre-set thresholds for conservation level and length of CNEs. We show that it performs robustly across a large span of evolutionary distances, including across the closely related genomes of primates for which standard approaches fail. The method is straightforward to implement and enables detection and comparison of clusters of CNEs and estimation of underlying TADs across a vastly increased range of Metazoan genomes. The data generated for this study, and the scripts used to generate the data, can be found at https://github.com/alexander-nash/kurtosis_conservation. Supplementary data are available at Bioinformatics online.


Establishing a clinic-based pancreatic cancer and periampullary tumour research registry in Quebec.
Enrolling patients in studies of pancreatic ductal adenocarcinoma (pdac) is challenging because of the high fatality of the disease. We hypothesized that a prospective clinic-based study with rapid ascertainment would result in high participation rates. Using that strategy, we established the Quebec Pancreas Cancer Study (qpcs) to investigate the genetics and causes of pdac and other periampullary tumours (pats) that are also rare and underrepresented in research studies. Patients diagnosed with pdac or pat were introduced to the study at their initial clinical encounter, with a strategy to enrol participants within 2 weeks of diagnosis. Patient self-referrals and referrals of unaffected individuals with an increased risk of pdac were also accepted. Family histories, epidemiologic and clinical data, and biospecimens were collected. Additional relatives were enrolled in families at increased genetic risk. The first 346 completed referrals led to 306 probands being enrolled, including 190 probands affected with pdac, who represent the population focus of the qpcs. Participation rates were 88.4% for all referrals and 89.2% for pdac referrals. Family history, epidemiologic and clinical data, and biospecimens were ascertained from 91.9%, 54.6%, and 97.5% respectively of patients with pdac. Although demographics and trends in risk factors in our patients were consistent with published statistics for patients with pdac, the qpcs is enriched for families with French-Canadian ancestry (37.4%), a population with recurrent germ-line mutations in hereditary diseases. Using rapid ascertainment, a pdac and pat research registry with high participation rates can be established. The qpcs is a valuable research resource and its enrichment with patients of French-Canadian ancestry provides a unique opportunity for studies of heredity in these diseases.


Intracellular phospholipase A(2) group IVA and group VIA play important roles in Wallerian degeneration and axon regeneration after peripheral nerve injury.
We provide evidence that two members of the intracellular phospholipase A(2) family, namely calcium-dependent group IVA (cPLA(2) GIVA) and calcium-independent group VIA (iPLA(2) GVIA) may play important roles in Wallerian degeneration in the mouse sciatic nerve. We assessed the roles of these PLA(2)s in cPLA(2) GIVA(-/-) mice, and mice treated with a selective inhibitor of iPLA(2) GVIA (FKGK11). Additionally, the effects of both these PLA(2)s were assessed by treating cPLA(2) GIVA(-/-) mice with the iPLA(2) inhibitor. Our data suggest that iPLA(2) GVIA may play more of a role in the early stages of myelin breakdown, while cPLA(2) GIVA may play a greater role in myelin clearance by macrophages. Our results also show that the delayed myelin clearance and Wallerian degeneration after sciatic nerve crush injury in mice lacking cPLA(2) and iPLA(2) activities is accompanied by a delay in axon regeneration, target re-innervation and functional recovery. These results indicate that the intracellular PLA(2)s (cPLA(2) GIVA and iPLA(2) GVIA) contribute significantly to various aspects of Wallerian degeneration in injured peripheral nerves, which is then essential for successful axon regeneration. This work has implications for injury responses and recovery after peripheral nerve injuries in humans, as well as for understanding the slow clearance of myelin after CNS injury and its potential consequences for axon regeneration.


Hospital Volume and Mortality in Acute Ischemic Stroke Patients: Effect of Adjustment for Stroke Severity.
Stroke severity of 1 hospital is a crucial information when assessing hospital performance. We aimed to determine the effect of stroke severity in the association between hospital patient volume and outcome after acute ischemic stroke. Data from National Acute Stroke Quality Assessment in 2013 and 2014 were analyzed. Hospital patient volume was defined as the annual number of acute ischemic stroke patients who admitted to each hospital. Comparisons among hospital patient volume quartiles before and after adjusting age, sex, onset to arrival and stroke severity were made to determine the associations between hospital patient volume and mortality at 30 days, 90 days and 1 year. Assessments for the nonlinear associations, with treating hospital patient volume as a continuous variable, and the associations between hospital patient volume and quality of care were also made. A total of 14,666 acute ischemic stroke patients admitted to 202 hospitals were analyzed. In the crude analysis, patients admitted to hospitals with lower patient volume showed higher mortality with a non-linear inverse association with a cut-off value of 227 patients/year. While the associations remained significant after adjusting age, sex and onset to arrival time (P's < .05), they disappeared when stroke severity was further adjusted (P's > .05). In contrary, hospital patient volume showed a nonlinear positive association with a plateau for summary measures of quality indicators even after adjustments for covariates including stroke severity (P < .001). Our study implicates that stroke severity should be considered when assessing hospital performance regarding outcomes of acute stroke care.


[Effects of orthostatism on heart rate and arterial pressure in sedentary subjects and in those in good physical condition].
Heart rate (HR), Systolic (SBP), Diastolic (DBP), and Mean Blood Pressures (MBP), were evaluated during a resting sitting and during upright moveless positions, in fifty seven highly trained runners with a maximal oxygen consumption equal or superior to 55 ml/kg. min. (VO2 max greater than or equal to 55 ml/kg . min., group I), and in fifty seven sedentary untrained men (group II). During sitting position the members of group I, had a significantly lower DBP and MBP than the members of group II. In the members of group II the assumption of upright posture did not produce significant changes in blood pressure, whereas subjects of group I showed a significantly drop in SBP, DBP and MBP. The results of this investigation indicated that in human, vigorous physical activity produce lower values of arterial blood pressure, and might be of value in the prevention of high blood pressure. On the other hand, the observed responses in group I during orthostatism, reveal a different regulation of the cardiovascular system. Changes in sympathetic and parasympathetic nervous system, venous compliance and plasma volume are designated as responsible of observed differences. This finding might also support the tendency to faintness reported by some authors in athletes.


miRNA in pluripotent stem cells.
Embryonic stem cells and induced pluripotent stem cells are characterized by their ability to self-renew and differentiate into any cell type. The molecular mechanism behind this process is a complex interplay between the transcriptional factors with epigenetic regulators and signaling pathways. miRNAs are an integral part of this regulatory network, with essential roles in pluripotent maintenance, proliferation and differentiation. miRNAs are a class of small noncoding RNAs that target protein-encoding mRNA to inhibit translation and protein synthesis. Discovered close to 20 years ago, miRNAs have rapidly emerged as key regulatory molecules in several critical cellular processes across species. Recent studies have begun to clarify the specific role of miRNA in regulatory circuitries that control self-renewal and pluripotency of both embryonic stem cells and induced pluripotent stem cells. These advances suggest a critical role for miRNAs in the process of reprogramming somatic cells to pluripotent cells.


Serologic and hematologic values of wild coyotes in Wisconsin.
Blood samples were obtained from 30 coyotes (Canis latrans) captured in northern Wisconsin in conjunction with radio-telemetry studies. Samples were assayed for seven hematologic values, seven serum chemistries, serum albumin, globulin and total protein. Results are given with respect to sex and age and are compared with available data for captive wild and pen-raised coyotes. Leukocyte counts were greater for males than females and packed cell volumes were greater for adults than young, possibly due to differential response to capture and handling stress. Hemoglobin concentrations and calcium levels suggest differences in nutrition between pen-raised and wild coyotes. Sex and age differences in serum calcium for wild coyotes probably reflect nutritional differences between groups examined. Juvenile coyote serum alkaline phosphatase levels declined curvilinearly with age for coyotes less than one year old, suggesting a possible technique for separating juveniles and yearlings captured in autumn that are released for research purposes. Elevated glucose levels and leukocyte counts in wild coyotes may reflect greater handling stress than for pen-raised and captive coyotes. No significant sex or age effects were found for levels of serum urea nitrogen, total protein, cholesterol, and total bilirubin.


[Complex febrile Seizures or Dravet syndrome?: Description of 3 case reports].
Dravet syndrome (DS) is one of the most intractable forms of epilepsy that begins in infancy. This syndrome is characterized by beginning with complex febrile seizures (FS) in a healthy infant and progresses to refractory epilepsy with psychomotor regression. The detection of a SCN1A mutation encoding the sodium channel can confirm the diagnosis. To report 3 confirmed cases of genetically DS. We describe 3 girls diagnosed with complex FS that started when they were between 2 and 7 months old. FS were frequent, hemi generalized and myoclonic associated with recurrent febrile status epilepticus (SE). Despite FS and SE recurrence, the psychomotor development, electrophysiological studies and magnetic resonance imaging (MRI) of the brain were normal. After a year, they developed afebrile seizures progressing to refractory epilepsy with developmental regression. A molecular study detected SCN1A mutation confirming DS. The specific antiepileptic treatment and prevention of febrile episodes allowed partial control of epilepsy with some recovery of psychomotor skills. The high frequency complex FS associated with recurrent SE in a previously healthy infant should alert about the possibility of DS. Molecular diagnostics helps us to establish a drugs and non-drug therapies treatment, as well as long-term prognosis and genetic counseling.


Compounds from silicones alter enzyme activity in curing barnacle glue and model enzymes.
Attachment strength of fouling organisms on silicone coatings is low. We hypothesized that low attachment strength on silicones is, in part, due to the interaction of surface available components with natural glues. Components could alter curing of glues through bulk changes or specifically through altered enzyme activity. GC-MS analysis of silicone coatings showed surface-available siloxanes when the coatings were gently rubbed with a cotton swab for 15 seconds or given a 30 second rinse with methanol. Mixtures of compounds were found on 2 commercial and 8 model silicone coatings. The hypothesis that silicone components alter glue curing enzymes was tested with curing barnacle glue and with commercial enzymes. In our model, barnacle glue curing involves trypsin-like serine protease(s), which activate enzymes and structural proteins, and a transglutaminase which cross-links glue proteins. Transglutaminase activity was significantly altered upon exposure of curing glue from individual barnacles to silicone eluates. Activity of purified trypsin and, to a greater extent, transglutaminase was significantly altered by relevant concentrations of silicone polymer constituents. Surface-associated silicone compounds can disrupt glue curing and alter enzyme properties. Altered curing of natural glues has potential in fouling management.


[Molecular Aspects of Translational Cardiology in Vascular Wall Research].
Clinical-biochemical research of vascular wall hydrated state, water-electrolyte balance has broadened substantially our notions concerning initiation mechanism of vessel damages, methods of their prevention and treatment. Consecutive study of endothelial glycocalyx functioning, computational research of its interaction with oxidative stress, regulation of its state has been aimed at development of novel means of the vascular system protection. Mutual efforts of clinicians and scientists should contribute to the productivity of results of translational cardiology.


The current scope and future direction of perioperative nursing practice in Victoria, Australia.
The current scope and future direction of perioperative nursing practice in Victoria, Australia Unlike some overseas countries, perioperative nursing roles in Australia are largely undeveloped, and very little research has explored the opinions of perioperative nurses regarding the development of their specialty. This study was undertaken to identify the current scope, possible future directions, and the barriers to developing perioperative nursing practice in the state of Victoria (Australia). The study design was descriptive and utilized survey methodology. An instrument was constructed by the researcher for the specific purposes of the study, and comprised three stages of development: questionnaire development; validation by a panel of experts; and a pilot study. The questionnaire was sent randomly to selected perioperative nurses (n=224) and a response rate of 79% (n=176) was obtained. Data were analysed using the Statistical Package for the Social Sciences (SPSS). Descriptive statistics were used to summarize data, and independent sample t-tests, one-way ANOVA and Wilcoxon signed rank tests were used to test differences between groups. For the purpose of data reduction factor analysis was undertaken. The findings of the study indicated that the perioperative nursing model in its espoused form is not being practised, but a large majority of participants believe that perioperative nursing practice should not be restricted to the intraoperative phase of the perioperative model. Expanded rather than extended activities and functions were perceived as more important for development of the specialty, and perceived barriers to advanced perioperative nursing practice centred predominantly on the current application of the perioperative model. Recommendations include refinement of the perioperative nursing model to reflect changes in the delivery of healthcare, addressing issues of cost associated with further education, and undertaking interpretive research to provide more detailed information on the possible future direction for perioperative nursing.


A Pharmacokinetic Natural Product-Disease-Drug Interaction: A Double Hit of Silymarin and Nonalcoholic Steatohepatitis on Hepatic Transporters in a Rat Model.
Patients with nonalcoholic steatohepatitis (NASH) exhibit altered hepatic protein expression of metabolizing enzymes and transporters and altered xenobiotic pharmacokinetics. The botanical natural product silymarin, which has been investigated as a treatment of NASH, contains flavonolignans that inhibit organic anion-transporting polypeptide (OATP) transporter function. The purpose of this study was to assess the individual and combined effects of NASH and silymarin on the disposition of the model OATP substrate pitavastatin. Male Sprague Dawley rats were fed a control or a methionine- and choline-deficient diet (NASH model) for 8 weeks. Silymarin (10 mg/kg) or vehicle followed by pitavastatin (0.5 mg/kg) were administered intravenously, and the pharmacokinetics were determined. NASH increased mean total flavonolignan area under the plasma concentration-time curve (AUC0-120 min) 1.7-fold. Silymarin increased pitavastatin AUC0-120 min in both control and NASH animals approx. 2-fold. NASH increased pitavastatin plasma concentrations from 2 to 40 minutes, but AUC0-120 min was unchanged. The combination of silymarin and NASH had the greatest effect on pitavastatin AUC0-120 min, which increased 2.9-fold compared with control vehicle-treated animals. NASH increased the total amount of pitavastatin excreted into the bile 2.7-fold compared with control animals, whereas silymarin decreased pitavastatin biliary clearance approx. 3-fold in both control and NASH animals. This double hit of NASH and silymarin on hepatic uptake transporters is another example of a multifactorial pharmacokinetic interaction that may have a greater impact on drug disposition than each hit alone. SIGNIFICANCE STATEMENT: Multifactorial effects on xenobiotic pharmacokinetics are within the next frontier for precision medicine research and clinical application. The combination of silymarin and NASH is a probable clinical scenario that can affect drug uptake, liver concentrations, biliary elimination, and ultimately, efficacy and toxicity.


Al(III) -catalysed formation of poly(limonene)carbonate: DFT analysis of the origin of stereoregularity.
Amino-triphenolate derived Al(III) complexes combined with suitable nucleophiles have been investigated as binary catalysts for the coupling of limonene oxide and carbon dioxide to afford alternating polycarbonates. These catalysts are able to produce stereoregular, perfectly alternating trans-polymers from cis-limonene oxide, whereas the pure trans isomer and cis/trans mixture give rise to lower degrees of stereoregularity. The best Al(III) catalyst shows the potential to mediate the conversion of both stereoisomers of limonene oxide with high conversion levels of up to 71 % under neat conditions, indicating the high degree of robustness and atom-efficiency of this catalytic process. Computational studies have revealed unique features of the binary catalyst system, among which is the preferred nucleophilic attack on the quaternary carbon centre in the limonene oxide substrate.


One-year outcomes of patients undergoing percutaneous coronary intervention with the revived directional coronary atherectomy catheter: Insights from the J-PCI OUTCOME registry.
We sought to investigate the 1-year outcomes, including all-cause and cardiovascular mortality, major adverse cardiovascular events (MACEs), and major bleeding, of patients undergoing percutaneous coronary intervention (PCI) with or without the revived directional coronary atherectomy (DCA) catheter in a Japanese nationwide registry. Clinical data regarding the midterm outcomes of patients undergoing PCI with DCA are scarce in contemporary real-world practice. We analyzed the data of 74,764 patients who underwent PCI at 179 hospitals from January 2017 to December 2018. The baseline characteristics and 1-year outcomes of patients with stable coronary artery disease or unstable angina who underwent PCI with or without DCA were assessed. Overall, 431 patients (0.6%) underwent PCI with DCA. Patients in the DCA group were younger and predominantly male, with fewer comorbidities than patients in the non-DCA group. Stentless PCI with DCA following additional drug-coated balloon (DCB) angioplasty was the dominant strategy in the DCA group (43.6%). One-year outcomes, including all-cause mortality (1.2% in the DCA group vs. 2.5% in the non-DCA group, respectively, p = 0.075), cardiovascular death (0.9% vs. 1.0%, p = 0.69), MACEs (1.9% vs. 1.8%, p = 0.96), and nonfatal major bleeding requiring readmission (1.2% vs. 1.4%, p = 0.62), were comparable between the two groups. In the DCA group, 1-year outcomes were comparable, regardless of whether the stent or DCB was used. One-year clinical outcomes after PCI with DCA in patients with stable coronary artery disease or unstable angina are acceptable, regardless of stent use.


Response to a change in transport noise exposure: competing explanations of change effects.
Annoyance response to a change in noise exposure appears to demonstrate an excess response relative to those predicted from exposure-response curves obtained under steady-state conditions. This change effect also appears to persist well after the change. Numerous explanations have been postulated for this phenomenon. This paper catalogs the different explanations and reviews the evidence for each. The evidence is of limited and variable quality but, while inadequate to endorse any one explanation, is sufficient to reject some notions and to identify a residual set of plausible explanations. These include two explanations based on modifiers of exposure-response relationships that potentially change between before and after conditions, an explanation based on differential response criteria of respondents chronically exposed to different steady-state levels of noise, and an explanation based on retention of coping strategies. All have ramifications for the assessment of human response (annoyance) where noise exposure changes, and some have wider implications for the interpretation of generalized exposure-response curves obtained in the steady state.


Detection of G-Quadruplex DNA Structures in Macrophages.
In addition to the canonical B-DNA conformation, DNA can fold into different secondary structures. Among them are G-quadruplex structures (G4s). G4 structures are very stable and can fold in specific guanine-rich regions in DNA and RNA. Different in silico, in vitro, and in cellulo experiments have shown that G4 structures form so far in all tested organisms. There are over 700,000 predicted G4s in higher eukaryotes, but it is so far assumed that not all will form at the same time. Their formation is dynamically regulated by proteins and is cell type-specific and even changes during the cell cycle or during different exogenous or endogenous stimuli (e.g., infection or developmental stages) can alter the G4 level. G4s have been shown to accumulate in cancer cells where they contribute to gene expression changes and the mutagenic burden of the tumor. Specific targeting of G4 structures to impact the expression of oncogenes is currently discussed as an anti-cancer treatment. In a tumor microenvironment, not only the tumor cells will be targeted by G4 stabilization but also immune cells such as macrophages. Although G4s were detected in multiple organisms and different cell types, only little is known about their role in immune cells. Here, we provide a detailed protocol to detect G4 formation in the nucleus of macrophages of vertebrates and invertebrates by microscopic imaging.


Future Perspectives and Review on Organic Carbon Dots in Electronic Applications.
Over the span of the past decade, carbon dots (CDs) synthesized from renewable organic resources (organic CDs) have gathered a considerable amount of attention for their photoluminescent properties. This review will focus on organic CDs synthesized using clean chemistry and conventional synthetic chemistry from organic sources and their fluorescence mechanisms, such as quantum confinement effect and surface/edge defects, before outlining their performance in electronic applications, including organic photovoltaic devices, organic light-emitting devices, biosensors, supercapacitors, and batteries. The various organic resources and methods of organic CDs synthesis are briefly covered. Many challenges remain before the adoption of CDs can become widespread; their characterization, structure, functionality, and exact photoluminescent mechanism all require additional research. This review aims to summarize the current research outcomes and highlight the area where further research is needed to fully use these materials.


Proteomic analysis of blood level of proteins before and after operation in patients with esophageal squamous cell carcinoma at high-incidence area in Henan Province.
To characterize the protein files in blood from same patients with esophageal squamous cell carcinoma (ESCC) before and after operation at the high-incidence area for ESCC in Henan Province, China. Two-dimensional electrophoresis, silver staining and ImageMaster 2-DE analysis software were applied to the determination of protein files in the blood obtained from normal controls and ESCC patients before and after operation. A total of 655, 662 and 677 protein spots were identified, respectively, from the normal controls and ESCC patients before and after operation. No significant difference in the number of protein spots was observed between the normal group and ESCC patients. A total of seven protein spots were identified with a dramatic difference among the samples before and after operation. Six protein spots were up-regulated and one protein spot was down-regulated in the group after operation compared with those in normal and before operation. Three protein spots were further characterized by matrix-assisted laser desorption/ionization time of flying mass spectrometry (MALDI-TOF-MS). The proteins from these three spots were identified as serum amyloid A (SAA), amyloid related serum protein and haptoglobin. Serum amyloid A, amyloid related serum protein and haptoglobin may be related with ESCC and/or surgery. The significance of these proteins needs to be further characterized. The present study provides informative data for the establishment of serum protein profiles related with ESCC.


Strio-pallido-dentate calcinosis: a diagnostic approach in adult patients.
Familial idiopathic bilateral strio-pallido-dentate calcinosis is a rare autosomal dominant disorder characterized by massive symmetric calcification, detectable by CT, into the globus pallidus and striatum, with or without the involvement of the dentate nucleus, thalamus and white matter in the absence of alterations of calcium metabolism. Clinically, it has been associated with movement and/or neuropsychiatric disorders with age at onset typically in the fourth or fifth decade. Other sporadic or familial diseases can be responsible for brain calcifications with a similar anatomic strio-pallidal or strio-pallido-dentate pattern and, a restricted number of them, for neurological symptoms with onset in adulthood. Moreover, physiological age-related basal ganglia calcifications are often incidentally found, although with a far different CT aspect, in elderly patients with movement disorders. Indentifying familial and idiopathic cases may offer the opportunity to study the molecular mechanisms underlying this minerals deposition.


Management of C2 fractures using Iso-C(3D) guidance: a single institution's experience.
About 20 % of cervical fractures involve the C2 vertebra. Many surgical techniques have been proposed according to the type of fracture. However, morbidity and mortality of these procedures is often high, which can be attributed to the old age and significant co-morbidities of the affected population and the complex anatomy of C2. To target the latter, several authors have applied iso-C(3D) guidance for most of the common techniques. We here present our experience using a fixed protocol and iso-C(3D) guidance in all cases of traumatic C2 fractures. Sixteen patients were operated upon between April 2011 and April 2012 using Iso-C(3D) guidance, following a fixed routine protocol. The screw position was verified by CT-scanning. Intraoperative and clinical parameters were evaluated. Six patients received anterior lag-screw fixation of odontoid fractures. Two underwent isolated posterior lag-screw fixation of hangman's fracture. C1 and/or C3 lateral mass, and/or C2 isthmic screws were placed in eight patients. No screw had to be revised, 3 minor breachings of the cortical bone of <2 mm were observed.The same standard protocol for draping, registration of the navigation and Iso-C(3D) guided drilling could be applied for anterior and posterior procedures, leaving only two variables. This led to rapid acceptance of the technique among OR-staff and surgeons, who felt comfortable with iso-C(3D) guidance after only five cases. Iso-C(3D) guidance is a safe and straightforward technique for anterior and posterior screw placement in the upper cervical spine.


Usefulness of human epididymis protein 4 in predicting optimal cytoreductive therapy in patients with advanced ovarian cancer.
Human Epididymis Protein 4 (HE4) is a novel promising serum biomarker of high sensitivity and specificity for ovarian cancer (OC). We investigated the usefulness of HE4 in predicting the outcome of surgery of advanced OC. Fifty patients with OC (FIGO stage III and IV) entered the study. Serum concentrations of HE4 and CA125 were evaluated preoperatively. All patients had been operated between January 2014 - January 2016. Preoperatively, the mean concentration of HE4 was 628pmol/L. Optimal cytoreduction was achieved in 44% of the patients, accompanied with decline of the mean values to HE4 478pmol/L, while in patients with suboptimal cytoreduction these values were 756pmol/L (p<0.001). Optimal cytoreduction was achieved in 52.9% of the patients with ascites ≤1,000 ml and in 48% of those with ascites >1,000 ml (p=0.023). These patients had preoperative values of HE4 405 and 713pmol/L, respectively (p=0.001). Optimal debulking was achieved in those patients with positive lymph nodes and ascites >1000ml, whose preoperative values of HE4 and CA125 were <413pmol/L and <500U/ mL, respectively. Our results indicated that the significant predictor of optimal cytoreduction was the value of HE4≤413pmol/L. In patients whose preoperative values HE4 were ≥413pmol/L the optimal cytoreduction was less probable (odds ratio 4.921, p=0.021). Preoperative concentrations of HE4 can be of predictive value for the achievement of optimal debulking of OC. Additional research in larger populations is necessary to prove the ability of preoperative values of HE4 in helping answer the question of whether or not optimal cytoreduction would be achieved.


Immune response to Chlamydophila abortus POMP91B protein in the context of different Pathogen Associated Molecular Patterns (PAMP); role of antigen in the orientation of immune response.
In a previous study, we used bacterial flagellin to deliver antigens such as p27 of Mycobacterium tuberculosis to a host immune system and obtained a potent Th1 response compared to those obtained with Freund's adjuvant and DNA immunization. In the current study, using a POMP91B antigen of Chlamydophila abortus, a human and animal pathogen, as a model, we found that this antigen is unable to promote Th1 response. However, this antigen, unlike others, was able to induce a good Th2 response and IL-4 production after immunization by recombinant protein in Freund's adjuvant or in phosphate buffered saline. Our results suggest that immune response is not only dependent on the immunization adjuvant, but also dependent on the nature of antigen used.


Systematic, early rhythm control strategy for atrial fibrillation in patients with or without symptoms: the EAST-AFNET 4 trial.
Clinical practice guidelines restrict rhythm control therapy to patients with symptomatic atrial fibrillation (AF). The EAST-AFNET 4 trial demonstrated that early, systematic rhythm control improves clinical outcomes compared to symptom-directed rhythm control. This prespecified EAST-AFNET 4 analysis compared the effect of early rhythm control therapy in asymptomatic patients (EHRA score I) to symptomatic patients. Primary outcome was a composite of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome, analyzed in a time-to-event analysis. At baseline, 801/2633 (30.4%) patients were asymptomatic [mean age 71.3 years, 37.5% women, mean CHA2DS2-VASc score 3.4, 169/801 (21.1%) heart failure]. Asymptomatic patients randomized to early rhythm control (395/801) received similar rhythm control therapies compared to symptomatic patients [e.g. AF ablation at 24 months: 75/395 (19.0%) in asymptomatic; 176/910 (19.3%) symptomatic patients, P = 0.672]. Anticoagulation and treatment of concomitant cardiovascular conditions was not different between symptomatic and asymptomatic patients. The primary outcome occurred in 79/395 asymptomatic patients randomized to early rhythm control and in 97/406 patients randomized to usual care (hazard ratio 0.76, 95% confidence interval [0.6; 1.03]), almost identical to symptomatic patients. At 24 months follow-up, change in symptom status was not different between randomized groups (P = 0.19). The clinical benefit of early, systematic rhythm control was not different between asymptomatic and symptomatic patients in EAST-AFNET 4. These results call for a shared decision discussing the benefits of rhythm control therapy in all patients with recently diagnosed AF and concomitant cardiovascular conditions (EAST-AFNET 4; ISRCTN04708680; NCT01288352; EudraCT2010-021258-20).


Molecular Markers of Regulatory T Cells in Cancer Immunotherapy with Special Focus on Acute Myeloid Leukemia (AML) - A Systematic Review.
The next-generation immunotherapy can only be effective if researchers have an in-depth understanding of the function and regulation of Treg cells in antitumor immunity combined with the discovery of new immunity targets. This can enhance clinical efficacy of future and novel therapies and reduces any adverse reactions arising from the latter. This review discusses tumor treatment strategies using regulatory T (Treg) cell therapy in a Tumor Microenvironment (TME). It also discusses factors affecting TME instability as well as relevant treatments to prevent future immune disorders. It is prognosticated that PD-1 inhibitors are risky and their adverse effects should be taken into account when they are administered to treat Acute Myeloid Leukemia (AML), lung adenocarcinoma, and prostate adenocarcinoma. In contrast, Treg molecular markers FoxP3 and CD25 analyzed here have stronger expression in almost all kinds of cancers compared with normal people. However, CD25 inhibitors are more effective compared to FoxP3 inhibitors, especially in combination with TGF-β blockade, in predicting patient survival. According to the data obtained from the Cancer Genome Atlas, we then concentrate on AML immunotherapy and discuss different therapeutic strategies including anti-CD25/IL-2, anti-CTLA-4, anti-IDO, antityrosine kinase receptor, and anti-PI3K therapies and highlight the recent advances and clinical achievements in AML immunotherapy. In order to prognosticate the risk and adverse effects of key target inhibitors (namely against CTLA-4, FoxP3, CD25, and PD-1), we finally analyzed and compared the Cancer Genome Atlas derived from ten common cancers. This review shows that Treg cells are strongly increased in AML and the comparative review of key markers shows that Tregbased immunotherapy is not effective for all kinds of cancer. Therefore, blocking CD25(+)FoxP3(+) Treg cells is suggested in AML more than other kinds of cancer; meanwhile, Treg markers studied in other cancers have also great lessons for AML immunotherapy.


Maternal and neonatal outcome of controlled gestational diabetes mellitus versus high risk group without gestational diabetes mellitus: a comparative study.
To analyze maternal and neonatal short term outcomes in pregnancies with controlled gestational diabetes mellitus (GDM) versus high risk group without GDM. The data about all singleton pregnancies with diagnosis of GDM was retrospectively retrieved from patients' files from 1st June 2008 to 30th November 2008 by the Department of Endocrinology, Alnoor Specialist Hospital, Makkah, Saudi Arabia. The diagnosis of GDM was made according to O'Sullivan and National Diabetes Data Group (NDDG) criteria. Subjects were divided into Controlled GDM group (A) and high risk group without GDM (B). Odd ratio (OR) and 95% confidence interval (CI) was measured for GDM. group. Incidence of GDM was found 5.9%. The risk of cesarean section (CS), pregnancy induced hypertension (PIH) and pre-term delivery was significantly high in the group A than B, i.e., OR 2.5, 95% CI 1.1-5.8, p=0.04; OR 2.6, 95% CI 1.1-6.2, p=0.03; OR 3.2, 95% CI 1.1-9.5, p=0.04; respectively. On the other hand, risks for gestational age (LGA) newborns, neonatal hypoglycemia, respiratory distress and neonatal intensive care unit (NICU) admissions were also significantly higher in the group A than B neonates, i.e., OR 3.6, 95% CI 1.1-11.9, p=0.04; OR 4.7, 95% CI 1.7-12.6, p=0.002; OR 4.2, 95% CI 1.4-12.2, p=0.009; OR 3.2, 95% CI 1.1- 9.4, p=0.04, respectively. Pregnancy outcome was found unfavorable even with controlled GDM in comparison with high risk subjects.


Effect of udenafil administration on postmicturition dribbling in men: a prospective, multicenter, double-blind, placebo-controlled, randomized clinical study.
Postmicturition dribbling (PMD) is a stressful symptom in middle-aged men characterized by urinary leakage after the completion of normal voiding. Appropriate treatments have not yet been introduced. This study assessed the efficacy of treatment of PMD with 75 mg udenafil daily. The study included 138 men with regular sexual lifestyles. The Hallym PMD questionnaire (HPMDQ) was used to assess PMD symptoms. After all basic examinations, patients were randomly assigned to either udenafil or placebo. Patients completed the surveys, uroflowmetry (UFM), a bladder scan, and the paper test during the follow-up visit. The mean age of the patients was 57.6 years. PMD with one of every three urinations was experienced by 59 patients (42.8%), whereas 45 patients (32.6%) experienced PMD with two of every three urinations. PMD with every urination was experienced by 34 patients (24.6%). More than half of the patients (89 patients, 65.4%) indicated that persistent PMD symptoms would likely result in moderate to severe discomfort in their daily activities. As time passed, the udenafil group showed significant improvement in PMD symptoms (p = 0.001). Udenafil 75 mg once daily can be an effective treatment for patients with PMD symptoms.


Rapid and Sensitive Detection of H1N1/2009 Virus from Aerosol Samples with a Microfluidic Immunosensor.
Influenza A H1N1/2009 is a highly infectious, rapidly spreading airborne disease that needs to be monitored in near real time, preferably in a microfluidic format. However, such demonstration is difficult to find as H1N1 concentration in aerosol samples is extremely low, with interference from dust particles. In this work, we measured Mie scatter intensities from a microfluidic device with optical waveguide channels, where the antibody-conjugated latex beads immunoagglutinated with the target H1N1 antigens. Through careful optimizations of optical parameters, we were able to maximize the Mie scatter increase from the latex immunoagglutinations while minimizing the background scatter from the dust particles. The aerosol samples were collected from a 1:10 mock classroom using a button air sampler, where a nebulizer generated aerosols, simulating human coughing. The detection limits with real aerosol samples were 1 and 10 pg/mL, using a spectrometer or a cell phone camera as an optical detector, respectively. These are several orders of magnitudes more sensitive than the other methods. The microfluidic immunosensor readings are in concordance with the results of reverse transcription polymerase chain reaction. The assay time was 30 s for sampling and 5 min for the microfluidic assay.


OPTN/SRTR 2011 Annual Data Report: deceased organ donation.
In 2011, the number of eligible deaths (death of a patient aged 70 years or younger who is legally declared brain dead and does not exhibit any excluding factors) was 9023, a slight decrease from 2010; 72.9 eligible donors per 100 eligible deaths were converted to organ donors. The unadjusted donation rate varied by donation service area (DSA), as did the number of transplant programs. The observed/expected organ yield ratio for all organs varied by DSA from 0.89 to 1.13. The total number of organs recovered divided by the number of donors was 3.54, slightly lower than in 2010; this value varied by DSA from 2.91 to 4.19. The number of organs transplanted per donor was 3.07, varying by DSA from 2.28 to 3.37. The discard rate for all organs combined was 0.13 per recovered organ, a value that varied substantially by DSA and by organ type. Reasons for not procuring or for discarding organs varied by organ type. Numbers of intestines, hearts, and lungs procured for transplant but not used are smaller than numbers of kidneys, pancreata, and livers because intestines, hearts, and lungs are recovered only after a transplant center has accepted the organ for transplant.


In vitro utilization of amylopectin and high-amylose maize (Amylomaize) starch granules by human colonic bacteria.
It has been well established that a certain amount of ingested starch can escape digestion in the human small intestine and consequently enters the large intestine, where it may serve as a carbon source for bacterial fermentation. Thirty-eight types of human colonic bacteria were screened for their capacity to utilize soluble starch, gelatinized amylopectin maize starch, and high-amylose maize starch granules by measuring the clear zones on starch agar plates. The six cultures which produced clear zones on amylopectin maize starch- containing plates were selected for further studies for utilization of amylopectin maize starch and high-amylose maize starch granules A (amylose; Sigma) and B (Culture Pro 958N). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was used to detect bacterial starch-degrading enzymes. It was demonstrated that Bifidobacterium spp., Bacteroides spp., Fusobacterium spp., and strains of Eubacterium, Clostridium, Streptococcus, and Propionibacterium could hydrolyze the gelatinized amylopectin maize starch, while only Bifidobacterium spp. and Clostridium butyricum could efficiently utilize high-amylose maize starch granules. In fact, C. butyricum and Bifidobacterium spp. had higher specific growth rates in the autoclaved medium containing high-amylose maize starch granules and hydrolyzed 80 and 40% of the amylose, respectively. Starch-degrading enzymes were cell bound on Bifidobacterium and Bacteroides cells and were extracellular for C. butyricum. Active staining for starch-degrading enzymes on SDS-PAGE gels showed that the Bifidobacterium cells produced several starch-degrading enzymes with high relative molecular (M(r)) weights (>160,000), medium-sized relative molecular weights (>66,000), and low relative molecular weights (<66,000). It was concluded that Bifidobacterium spp. and C. butyricum degraded and utilized granules of amylomaize starch.


Nosocomial infections by Staphylococcus epidermidis: how a commensal bacterium turns into a pathogen.
Staphylococcus epidermidis is a commensal bacterium of the human skin. However, S. epidermidis and other coagulase-negative staphylococci (CNS) emerge also as common nosocomial pathogens infecting immunocompromized patients carrying medical devices. Antibiotic resistance and the ability of many nosocomial S. epidermidis isolates to form biofilms on inert surfaces make these infections hard to treat. Epidemiological analyses using multilocus sequence typing (MLST) and genetic studies suggest that S. epidermidis isolates in the hospital environment differ from those obtained outside of medical facilities with respect to biofilm formation, antibiotic resistance, and the presence of mobile DNA elements. Since S. epidermidis isolates exhibit high genome flexibility, they are now regarded as reservoirs for the evolution and spread of resistance traits within nosocomial bacterial communities.


Implementation of an electronic medical record system in previously computer-naïve primary care centres: a pilot study from Cyprus.
The computer-based electronic medical record (EMR) is an essential new technology in health care, contributing to high-quality patient care and efficient patient management. The majority of southern European countries, however, have not yet implemented universal EMR systems and many efforts are still ongoing. We describe the development of an EMR system and its pilot implementation and evaluation in two previously computer-naïve public primary care centres in Cyprus. One urban and one rural primary care centre along with their personnel (physicians and nurses) were selected to participate. Both qualitative and quantitative evaluation tools were used during the implementation phase. Qualitative data analysis was based on the framework approach, whereas quantitative assessment was based on a nine-item questionnaire and EMR usage parameters. Two public primary care centres participated, and a total often health professionals served as EMR system evaluators. Physicians and nurses rated EMR relatively highly, while patients were the most enthusiastic supporters for the new information system. Major implementation impediments were the physicians' perceptions that EMR usage negatively affected their workflow, physicians' legal concerns, lack of incentives, system breakdowns, software design problems, transition difficulties and lack of familiarity with electronic equipment. The importance of combining qualitative and quantitative evaluation tools is highlighted. More efforts are needed for the universal adoption and routine use of EMR in the primary care system of Cyprus as several barriers to adoption exist; however, none is insurmountable. Computerised systems could improve efficiency and quality of care in Cyprus, benefiting the entire population.


Transcriptional regulation via TF-modifying enzymes: an integrative model-based analysis.
Transcription factor activity is largely regulated through post-translational modification. Here, we report the first integrative model of transcription that includes both interactions between transcription factors and promoters, and between transcription factors and modifying enzymes. Simulations indicate that our method is robust against noise. We validated our tool on a well-studied stress response network in yeast and on a STAT1-mediated regulatory network in human B cells. Our work represents a significant step toward a comprehensive model of gene transcription.


Assessment of magnesium levels in children with attention deficit hyperactivity disorder (ADHD).
A positive influence of magnesium in the prevention and treatment of hyperactivity in children is more and more frequently raised in the literature. The aim of our work was to estimate magnesium contents in children with attention deficit hyperactivity disorder, (ADHD). The investigations comprised 116 children (94 boys and 20 girls), aged 9-12 years, with recognized ADHD. In 68 out of 116 patients examined ADHD occurred with other coexisting disorders specific to the developmental age and in the remaining 48 patients it occurred together with disruptive behaviour. Magnesium levels have been determined in blood serum, red blood cells and in hair with the aid of atomic absorption spectroscopy. Magnesium deficiency was found in 95 per cent of those examined, most frequently in hair (77.6 per cent), in red blood cells (58.6 per cent) and in blood serum (33.6 per cent) of children with ADHD. The conclusion from the investigations is that magnesium deficiency in children with ADHD occurs more frequently than in healthy children. Analysis of the material indicated the correlation between levels of magnesium and the quotient of development to freedom from distractibility.


The immunohistopathology of glomerular antigens. II. The glomerular basement membrane, actomyosin, and fibroblast surface antigens in normal, diseased, and transplanted human kidneys.
Immunofluorescent studies have demonstrated that actomyosin (AMY) is present in the mesangium in a restrictive pattern, whereas fibroblast surface antigen (FSA) has a more extensive mesangial distribution. Antibody to glomerular basement membrane (GBM) is localized to the GBM. One hundred ninety-six tissue samples, including 17 from normal subjects, 94 from patients with primary renal diseases, and 85 from transplanted kidneys, were examined for changes in distribution of AMY, FSA, and GBM antigens. The distribution of AMY and FSA in the mesangium is markedly increased in width in patients with diabetic nephropathy, and the GBM is thickened. AMY and FSA are mildly increased in patients with glomerulonephritis and GBM is normal. Patients with membranoproliferative glomerulonephritis (MPGN) show a loss of all glomerular antigens. Increased mesangial AMY was found in 12 of 37 transplanted kidneys in diabetic patients vs 4 of 33 nondiabetics 0 to 4 years after transplantation (P < 0.025). This difference is more notable at 2 to 4 years, with 5 of 9 diabetics showing increased AMY vs 0 of 6 nondiabetic patients (P < 0.0005). In MPGN, 5 of 8 tissues showed decreased mesangial AMY vs 3 of 36 diabetic patients (P < 0.0005) and 1 of 32 patients with other glomerulopathies (P < 0.0005). GBM thickening is not associated with specific pretransplant diseases. In transplanted kidneys, the pattern of FSA is dissociated from that of AMY: over half of all patients have increased FSA, even when AMY is normal. Whether this unique finding in transplanted kidneys reflects an increase in the synthesis of FSA by mesangial cells or the failure to clear this (circulating) antigen from the mesangial matrix is unknown.


Nanoscale graphene Hall sensors for high-resolution ambient magnetic imaging.
A major challenge to routine non-invasive, nanoscale magnetic imaging is the development of Hall sensors that are stable under ambient conditions and retain low minimum detectable fields down to nanoscale dimensions. To address these issues we have fabricated and characterised chemical vapour deposition (CVD) graphene Hall sensors with wire widths between 50 nm and 1500 nm, in order to exploit the high carrier mobility and tuneability of this material. The measured Hall voltage noise is in good agreement with theoretical models and we demonstrate that minimum detectable fields at fixed drive current are lowest in the vicinity of the charge neutrality point. Our best performing deep sub-micron sensors, based on a wire width of 85 nm, display the excellent room temperature resolution of 59 µT/√Hz at a dc drive current of 12 µA and measurement frequency of 531 Hz. We observe a weak increase in minimum detectable field as the active sensor area is reduced while the Hall offset field is largely independent of size. These figures-of-merit significantly surpass prior results on larger probes in competing materials systems, with considerable scope for further optimisation. Our results clearly demonstrate the feasibility of using CVD graphene to realise very high spatial resolution nanosensors for quantitative room temperature magnetic imaging.


Depletion of O6-methylguanine-DNA-methyltransferase in human fibroblasts increases the mutagenic response to N-methyl-N'-nitro-N-nitrosoguanidine.
We showed previously that resistance of a series of human fibroblast cell lines to the cytotoxic and mutagenic effects of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) is highly correlated with their level of O6-methylguanine-DNA-methyltransferase (MT) activity. In the present study, MT activity in normal fibroblasts was decreased to between 40 and 20% of the constitutive level by 15 or 24 h exposure of the cells to exogenous O6-methylguanine (O6-MeG). MT-depleted and non-depleted populations were then challenged with various doses of MNNG and assayed for cytotoxicity and mutagenicity. At every dose the frequency of 6-thioguanine resistant cells induced by MNNG was higher in the MT-depleted populations than in the controls. Since the MT activity in these cells does not remove methyl from the O4 position of thymine, these results strongly support the hypothesis that O6-methylguanine is the principal mutagenic lesion induced by MNNG. Cells with decreased levels of MT were not significantly more sensitive to the cytotoxic effect of MNNG. If O6-methylguanine is a potentially cytotoxic lesion, this lack of increased sensitivity may reflect the fact that regeneration of MT protein occurred rapidly enough to remove these lesions before they resulted in cell death (i.e., inability to form a clone). Consistent with this explanation is the fact that 7 h after removal of the exogenous O6-MeG, the level of MT activity had regenerated to 51% of normal; by 18 h, it was 65% of normal.


Treatment of superficial vascular lesions with the KTP 532-nm laser: experience with 647 patients.
Superficial vascular lesions are a common dermatological diagnosis but are often difficult to treat. Numerous lasers (especially the dye laser) and intense pulsed light sources have been used, but there have been very few reports on the effectiveness of the potassium-titanyl phosphate (KTP) laser. We have extensive experience of this modality at our institution, and the purpose of this survey is to report on the safety and efficacy of the KTP laser. Using an in-house database, we retrospectively collected data from patients who had undergone treatment with the KTP laser for superficial vascular lesions. Patients of Fitzpatrick skin type I-IV were included. Exclusion criteria were Fitzpatrick skin type V, patients with obvious suntan and those on potentially phototoxic medications or minocycline therapy. Diagnoses included discrete or matted telangiectasia, strawberry naevus, spider angioma, rosaceal erythema, rosaceal telangiectasia, telangiectatic naevus, angioma, combined rosaceal erythema/telangiectasia, port-wine stain, venous lake haemangioma and hereditary haemorrhagic telangiectasia. Patients underwent an initial test treatment and further treatment at 6-week intervals as required. Clinical photographs were taken pre- and post-treatment, and outcome was graded by patient and physician. Adverse effects were recorded including scarring, hypo- or hyperpigmentation, marked swelling, blistering, scabbing and bruising. Six hundred forty-seven patients with 13 diagnoses on 9 different body sites were recorded. Four hundred eighty-six were female, and the median age was 39.5 years. Of the lesions treated, 33.7 % (n = 218) were discrete telangiectases and 31.8 % (n = 206) were spider angiomas. A 92.7 % of lesions were on the face. Four hundred thirteen (77.6 %) patients who had outcomes recorded at 6 weeks were graded as "clearance" or "marked improvement". Only 38 (5.8 %) patients experienced adverse effects, all of which were minor; the main adverse effect was swelling. Unlike the dye laser, there was only one case of bruising out of 647 patients. This is the largest survey of patients to have undergone KTP laser treatment reported in the literature. Our results show that the KTP laser is a safe and effective modality for the treatment of superficial vascular lesions.


Aquatic prey capture in ray-finned fishes: a century of progress and new directions.
The head of ray-finned fishes is structurally complex and is composed of numerous bony, muscular, and ligamentous elements capable of intricate movement. Nearly two centuries of research have been devoted to understanding the function of this cranial musculoskeletal system during prey capture in the dense and viscous aquatic medium. Most fishes generate some amount of inertial suction to capture prey in water. In this overview we trace the history of functional morphological analyses of suction feeding in ray-finned fishes, with a particular focus on the mechanisms by which suction is generated, and present new data using a novel flow imaging technique that enables quantification of the water flow field into the mouth. We begin with a brief overview of studies of cranial anatomy and then summarize progress on understanding function as new information was brought to light by the application of various forms of technology, including high-speed cinematography and video, pressure, impedance, and bone strain measurement. We also provide data from a new technique, digital particle image velocimetry (DPIV) that allows us to quantify patterns of flow into the mouth. We believe that there are three general areas in which future progress needs to occur. First, quantitative three-dimensional studies of buccal and opercular cavity dimensions during prey capture are needed; sonomicrometry and endoscopy are techniques likely to yield these data. Second, a thorough quantitative analysis of the flow field into the mouth during prey capture is necessary to understand the effect of head movement on water in the vicinity of the prey; three-dimensional DPIV analyses will help to provide these data. Third, a more precise understanding of the fitness effects of structural and functional variables in the head coupled with rigorous statistical analyses will allow us to better understand the evolutionary consequences of intra- and interspecific variation in cranial morphology and function.


[Overview of researches on the underlying mechanism of that "Hegu (LI 4) is indicated for orofacial disorders"].
It has been well documented in Chinese acupuncture medicine that "Hegu (LI 4) is indicated for orofacial problems". In the present paper, the authors analyze their correlation from the learning of modern medicine and results of recent experimental studies instead of traditional meridian theory of acupuncturology. The afferent nerve fibers from the LI 4 region and the orofacial part ascend to the spinal cord, nucleus of solitary tract, reticular formation, thalamus and the cerebral cortex, respectively, and overlap in the thalamus, cerebral cortex, etc. Under the circumstances, the interaction and functional integration of the afferent signals from LI 4 acupoint and the orofacial region may occur in the central nervous system. In addition, many relevant neuroactive substances (for example, serotonin, substance P, enkephalin, y-aminobutyric acid, glycine, calcitonin gene-related peptide, etc.) released from the sensory and motor neurons in the corresponding cerebral regions may constitute part of the substantial basis of that "Hegu (LI 4) is indicated for many orofacial disorders".


Polymerase chain reaction of secA1 on sputum or oral wash samples for the diagnosis of pulmonary tuberculosis.
Nucleic acid amplification tests are sensitive and specific for identifying Mycobacterium tuberculosis in sputum smear-positive populations, but they are less sensitive in sputum smear-negative populations. Few studies have assessed their performance among patients infected with HIV, and no studies have assessed their performance with oral wash specimens, which may be easier to obtain than sputum samples. We performed a prospective study involving 127 adults from 2 populations who were undergoing evaluation for respiratory complaints at Mulago Hospital in Kampala, Uganda. We obtained and tested sputum samples for Mycobacterium tuberculosis, and we simultaneously obtained oral wash specimens to test for M. tuberculosis DNA by polymerase chain reaction (PCR) amplification of a novel locus, the secA1 gene. A positive mycobacterial culture of sputum was used to define cases of tuberculosis; we calculated the sensitivity and specificity of the PCR assay with sputum or oral wash specimens in reference to the standard of sputum culture results. Tuberculosis (75 [59%] of 127 patients) and HIV infection (58 [46%] of 126 patients) were both common in the study population. PCR of sputum samples was highly sensitive (sensitivity, 99%; 95% confidence interval, 93%-100%) and specific (specificity, 88%; 95% confidence interval, 77%-96%) for detection of pulmonary tuberculosis and performed well among HIV-infected patients and among patients with negative sputum smear results. PCR of oral wash specimens was less sensitive (sensitivity, 73%; 95% confidence interval, 62%-83%) but also detected a substantial proportion of tuberculosis cases. PCR targeting the secA1 gene was highly sensitive and specific for identifying M. tuberculosis in sputum samples, independent of smear or HIV infection status. Oral washes showed promise as an easily obtained respiratory specimen for tuberculosis diagnosis. PCR of sputum for detection of the secA1 gene could be a rapid, effective diagnostic tool for tuberculosis referral centers.


Interreality for the management and training of psychological stress: study protocol for a randomized controlled trial.
Psychological stress occurs when an individual perceives that environmental demands tax or exceed his or her adaptive capacity. Its association with severe health and emotional diseases, points out the necessity to find new efficient strategies to treat it. Moreover, psychological stress is a very personal problem and requires training focused on the specific needs of individuals. To overcome the above limitations, the INTERSTRESS project suggests the adoption of a new paradigm for e-health--Interreality--that integrates contextualized assessment and treatment within a hybrid environment, bridging the physical and the virtual worlds. According to this premise, the aim of this study is to investigate the advantages of using advanced technologies, in combination with cognitive behavioral therapy (CBT), based on a protocol for reducing psychological stress. The study is designed as a randomized controlled trial. It includes three groups of approximately 50 subjects each who suffer from psychological stress: (1) the experimental group, (2) the control group, (3) the waiting list group. Participants included in the experimental group will receive a treatment based on cognitive behavioral techniques combined with virtual reality, biofeedback and mobile phone, while the control group will receive traditional stress management CBT-based training, without the use of new technologies. The wait-list group will be reassessed and compared with the two other groups five weeks after the initial evaluation. After the reassessment, the wait-list patients will randomly receive one of the two other treatments. Psychometric and physiological outcomes will serve as quantitative dependent variables, while subjective reports of participants will be used as the qualitative dependent variable. What we would like to show with the present trial is that bridging virtual experiences, used to learn coping skills and emotional regulation, with real experiences using advanced technologies (virtual reality, advanced sensors and smartphones) is a feasible way to address actual limitations of existing protocols for psychological stress. http://clinicaltrials.gov/ct2/show/NCT01683617.


DDX58 Is Associated With Susceptibility to Severe Influenza Virus Infection in Children and Adolescents.
Seasonal influenza virus infection causes a range of disease severity, including lower respiratory tract infection with respiratory failure. We evaluated the association of common variants in interferon (IFN) regulatory genes with susceptibility to critical influenza infection in children. We performed targeted sequencing of 69 influenza-associated candidate genes in 348 children from 24 US centers admitted to the intensive care unit with influenza infection and lacking risk factors for severe influenza infection (PICFlu cohort, 59.4% male). As controls, whole genome sequencing from 675 children with asthma (CAMP cohort, 62.5% male) was compared. We assessed functional relevance using PICFlu whole blood gene expression levels for the gene and calculated IFN gene signature score. Common variants in DDX58, encoding the retinoic acid-inducible gene I (RIG-I) receptor, demonstrated association above or around the Bonferroni-corrected threshold (synonymous variant rs3205166; intronic variant rs4487862). The intronic single-nucleotide polymorphism rs4487862 minor allele was associated with decreased DDX58 expression and IFN signature (P < .05 and P = .0009, respectively) which provided evidence supporting the genetic variants' impact on RIG-I and IFN immunity. We provide evidence associating common gene variants in DDX58 with susceptibility to severe influenza infection in children. RIG-I may be essential for preventing life-threatening influenza-associated disease.


Fibrin has larger pores when formed in the presence of erythrocytes.
Due to difficulties caused by the presence of hemoglobin-containing erythrocytes, the structures of whole blood clots have not been reported. A perfusion technique described herein allowed the study of plasma and blood clots. Gel fiber diameter, fiber mass-to-length ratio, and average pore diameter were calculated from measurements of solvent flow through gels. When perfused with saline, intact erythrocytes washed from clots of whole blood. Subsequent perfusion with water resulted in rapid hemolyzing of remaining erythrocytes and flushing of hemoglobin from the network. The minimal impact of erythrocytes on fibrin fiber structure was indicated by similar fiber mass-to-length ratios, 7.4 vs. 9.3 X 10(13) Da/cm, for plasma and blood clots, respectively. Pore sizes were larger in gels formed in the presence of erythrocytes, increasing from 3.3 X 10(-4) cm for plasma gels to 5.1 X 10(-4) for gels containing 20% erythrocytes. The washing of red cells from clots confirmed calculated clot pore sizes (approximately 5 microns) and was testimony to the size of the spaces within the gel. Egress of cells and macromolecules to the site of injury during wound healing may be a function of the size of these spaces. The demonstrated applicability of this technique should allow study of this question.


In vivo release of inflammatory mediators by hyperosmolar solutions.
Hyperosmolar environments induce histamine release from mast cells and basophils in vitro. To assess whether the same stimulus induces mediator release in vivo, 15 healthy human volunteers underwent nasal challenges with instilled solutions of differing osmolalities: lactated Ringer's solution (257 +/- 3 mOsm/kg), isosmolar mannitol (277 +/- 6 mOsm/kg), and hyperosmolar mannitol (869 +/- 8 mOsm/kg). The effect of these challenges on the volume, osmolality, and inflammatory mediator content of subsequent 5-ml isosmolar lavages was determined. The volumes of lavages returned after hyperosmolar challenges were significantly greater than those after isosmolar challenges (5.5 +/- 0.2 ml versus 4.2 +/- 0.1 ml; p less than 0.01) and these lavage solutions had higher osmolalities. Even when corrected for increased volumes, the lavages after hyperosmolar challenges contained significantly higher quantities of inflammatory mediators such as histamine (29.0 versus 10.1 ng; p less than 0.01), TAME-esterase activity (32.7 versus 11.1 cpm x 10(-3); p less than 0.01), and immunoreactive leukotrienes (9.9 versus 3.4 ng; p less than 0.01). The changes in mediators were dose dependent in that incremental increase in challenge osmolality were associated with incremental increases in histamine release. Therefore, when exposed to hyperosmolar stimuli in vivo, the nasal respiratory airway releases inflammatory mediators and fluid rapidly shifts into the airway lumen. It has been suggested that the mediator release observed on breathing cold and dry air is due to increased osmolality of airway secretions; the present data confirm that osmotic variations at the airway surface can provide an adequate stimulus for cell activation.


Biochemical characterization and crystal structure of a Dim1 family associated protein: Dim2.
The U4/U6*U5 tri-snRNP complex is the catalytic core of the pre-mRNA splicing machinery. The thioredoxin-like protein hDim1 (U5-15 kDa) constitutes an essential component of the U5 particle, and its functions have been reported to be highly conserved throughout evolution. Recently, the Dim1-like protein (DLP) family has been extended to other proteins harboring similar sequence motifs. Here we report the biochemical characterization and crystallographic structure of a 149 amino acid protein, hDim2, which shares 38% sequence identity with hDim1. The crystallographic structure of hDim2 solved at 2.5 A reveals a classical thioredoxin-fold structure. However, despite the similarity in the thioredoxin fold, hDim2 differs from hDim1 in many significant features. The structure of hDim2 contains an extra alpha helix (alpha3) and a beta strand (beta5), which stabilize the protein, suggesting that they may be involved in interactions with hDim2-specific partners. The stability and thermodynamic parameters of hDim2 were evaluated by combining circular dichroism and fluorescence spectroscopy together with chromatographic and cross-linking approaches. We have demonstrated that, in contrast to hDim1, hDim2 forms stable homodimers. The dimer interface is essentially stabilized by electrostatic interactions and involves tyrosine residues located in the alpha3 helix. Structural analysis reveals that hDim2 lacks some of the essential structural motifs and residues that are required for the biological activity and interactive properties of hDim1. Therefore, on the basis of structural investigations we suggest that, in higher eukaryotes, although both hDim1 and hDim2 are involved in pre-mRNA splicing, the two proteins are likely to participate in different multisubunit complexes and biological processes.


Human cytotoxicity and octanol/water partition coefficients of fluorinated ionic liquids.
The use of fluorinated ionic liquids (FILs) as novel materials in biological and pharmaceutical applications is an emerging research field. The knowledge of their cytotoxicity and that of 1-octanol/water partition coefficients are essential to assess their environmental risks, to estimate their toxicity and activity, or the hydrophilic/lipophilic balance, as well as to explore their properties as solvents in extraction processes or for successful drug design. The study of the cytotoxicity in four different human cell lines and the experimental measurement of the partition coefficient between 1-octanol and water (Po/w), using the slow-stirring method, were carried out for several FILs. In both studies, the effect of the cation ([C2C1Im]+, [C2C1py]+, [C4C1pyr]+, [N1112(OH)]+, or [N4444]+), the cationic alkyl side-chain length ([CnC1Im]+, with n = 2, 6, 8 or 12), and the anionic fluorinated chain length/anionic fluorinated domain size ([C4F9SO3]¯, [C8F17SO3]¯, or [N(C4F9SO3)2]¯) were analysed. The results reveal that both toxicity and partition properties are mainly influenced by the size of the cationic hydrogenated alkyl side-chain and that of the anionic fluorinated domain. The intrinsic tuneability of the FILs allows for their selection according to the lipophilic or hydrophilic character of the target biological system under consideration. The toxicity studies corroborate the biocompatible nature of some FILs tested in this work. Along, for all the FILs under study Po/w < 1.00. Accordingly, a decadic logarithm of the bioconcentration factor in fish of 0.5 would be estimated, which is below the regulatory endpoint used by regulatory agencies.


Critical appraisal of STAT3 pattern in adult cardiomyocytes.
The signal transducer and activator of transcription 3, STAT3, transfers cellular signals from the plasma membrane to the nucleus, acting as a signaling molecule and a transcription factor. Reports proposed an additional non-canonical role of STAT3 that could regulate the activity of complexes I and II of the electron transport chain and the opening of the mitochondrial permeability transition pore (PTP) after ischemia-reperfusion in various cell types. The native expression of STAT3 in heart mitochondria, together with a direct versus an indirect transcriptional role in mitochondrial functions, have been recently questioned. The objective of the present study was to investigate the cellular distribution of STAT3 in mouse adult cardiomyocytes under basal and stress conditions, along with assessing its presence and activity in cardiac mitochondria using structural and functional approaches. The analysis of the spatial distribution of STAT3 signal in the cardiomyocytes interestingly showed that it is transversely distributed along the T-tubules and in the nucleus. This distribution was neither affected by hypoxia nor by hypoxia/re‑oxygenation conditions. Focusing on the mitochondrial STAT3 localization, our results suggest that serine-phosphorylated STAT3 (PS727-STAT3) and total STAT3 are detected in crude but not in pure mitochondria of mouse adult cardiomyocytes, under basal and ischemia-reperfusion conditions. The inhibition of STAT3, with a pre-validated non-toxic Stattic dose, had no significant effects on mitochondrial respiration, but a weak effect on the calcium retention capacity. Overall, our results exclusively reveal a unique cellular distribution of STAT3 in mouse adult cardiomyocytes, along the T-tubules and in nucleus, under different conditions. They also challenge the expression and activity of STAT3 in mitochondria of these cells under basal conditions and following ischemia-reperfusion. In addition, our results underline technical methods, complemental to cell fractionation, to evaluate STAT3 roles during hypoxia-reoxygenation and at the interface between nucleus and endoplasmic reticulum.


Current role of resurfacing lasers.
Resurfacing lasers have been the treatment of choice for diminishing rhytids and tightening skin. The carbon dioxide and erbium lasers have been the gold and silver standards. Despite their effectiveness, these resurfacing lasers have a very high risk profile including scarring, hyperpigmentation and hypopigmentation. Because of these side effects, various practitioners have tried alternative settings for these lasers as well as alternative wavelengths, particularly in the infrared spectrum. These devices have had less downtime, but their effectiveness has been limited to fine wrinkles. As with selective photothemolysis, a major advance in the field has been fractionated resurfacing which incorporates grids of microthermal zones that spares islands of skin. This concept permits less tissue damage and quicker tissue regeneration. Initially, fractionated resurfacing was limited to the nonablative mid-infrared spectrum. These resurfacing lasers is appropriate for those patients with acne scars, uneven skin tone, mild to moderate photodamage, and is somewhat effective for melasma. Importantly, because there is less overall tissue damage and stimulation of melanocytes, these lasers can be used in darker skin types. Downtime is 2-4 days of erythema and scaling. Yet, these nonablative fractionated devices required 5-6 treatments to achieve a moderate effect. Logically, the fractionated resurfacing has now been applied to the CO2 and the Erbium:Yag lasers. These devices can treat deeper wrinkles and tighten skin. Downtime appears to be 5-7 days. The long term effectiveness and the question of whether these fractionated devices will approach the efficacy of the standard resurfacing lasers is still in question. Ultimately either integrated devices which may use fractionated resurfacing, radiofrequency and a sensitizer, or combining different lasers in a single treatment may prove to be the most effective in reducing rhtyides, smoothing the skin topography and tightening the skin envelope.