Adrenal incidentaloma: an overview of hormonal data from the National Italian Study Group.
Adrenal masses are more and more frequently detected by adrenal ultrasound, computed tomography or nuclear magnetic resonance carried out for a reason other than the suspicion of adrenal disease (incidentalomas). The findings of an incidentaloma still leaves many diagnostic and therapeutic questions open. We report the results of a multicentric retrospective evaluation of patients with adrenal incidentalomas, performed by a Study Group of the Italian Society of Endocrinology. According to the definition of incidentaloma, exclusion criteria a priori were: severe or paroxysmal hypertension, frank hypokalemia and clinical signs of hypercortisolism or hyperandrogenism. 29 centers participated in the study and the data obtained by questionnaire were collected in 2 centers for final elaboration. Center 1 carried out the epidemiological and clinical evaluation. Basal and dynamic hormonal evaluation of 786 among the 1013 cases recruited were performed in our center (center 2). Functional studies included: diurnal rhythm of cortisol, urinary free cortisol (UFC), ACTH, DHEAS, 17-OH progesterone, testosterone, androstenedione, supine and upright plasma renin activity (PRA) and aldosterone, urinary aldosterone, urinary catecholamines and VMA. The hormonal dynamic evaluation included the overnight dexamethasone suppression test (1 mg), CRH test and ACTH test. In our study, 89% (702 patients) of adrenal incidentalomas were non-hypersecretory masses; 6.2% (49 patients) showed a preclinical Cushing's syndrome (PCS) (at least two altered parameters of pituitary-adrenal axis); 3.4% (27 patients) were pheochromocytomas; 0.89% (7 patients) were aldosteronomas. One tumor was a masculinizing adrenocortical carcinoma. Two hundred sixty patients underwent surgical exploration and the histological diagnosis showed: 138 adenomas (53%), 32 carcinomas (12%), 26 pheochromocytomas (10%). 16 myelolipomas (8%), 13 cystic lesions (5.5%), 7 tumors of neuronal lineage (3%). 12 metastases (4%), 13 others (5%). The 138 patients with adenomas had the following hormonal diagnosis: 103 nonfunctional adenomas (74%), 31 PCS (23%) and 4 cases of hyperaldosteronism (3%). In the patients with PCS an abnormal dexamethasone suppression test was found in 86% of cases (37/41 patients). Values for ACTH were low in 78% (32/41 patients). UFC was elevated in 64% of patients, the diurnal rhythm of cortisol evaluated in 14 patients was absent in 7. Only in 50% of cases DHEAS values (12/24 patients) were decreased, whereas they were normal in the other 50%. Interestingly, 8 patients with normal DHEAS and normal UFC showed nonsuppressible cortisol by dexamethasone test (1 mg). Blunted ACTH response to CRH was detected in 9 of 14 patients (64%). Thus our data suggest that the best parameter for evaluating subclinical hypercortisolism seems to be the overnight dexamethasone suppression test. In 27 patients with pheochromocytoma 24-hour urinary catecholamine and VMA levels were elevated in 86 and 46% of cases respectively. In 7 patients with hyperaldosteronism upright PRA was suppressed in 100% of cases and aldosterone plasma levels were elevated in 6 patients (86%); serum potassium level was slightly decreased in 60% of cases. In 86 of 138 histologically proven adenomas, DHEAS levels were: normal in 59% of patients, decreased in 36% and elevated in 4.6%, whereas in 22 of 32 cortical carcinomas evaluated. DHEAS levels were normal in 63% of cases, decreased in 18% and elevated 18%. Post-ACTH 17-OH progesterone levels were elevated in 52% (62/118 patients) of non-functioning adenomas and in 2 of 4 carcinomas. Not enough data are yet available postoperatively. In summary, endocrine evaluation can lead to the identification of a nonnegligible number of cases of clinically unsuspected pheochromocytomas and subtle hypercortisolism (about 3.4 and 6.2%, respectively of all adrenal incidentalomas), while cases of primary subclinical aldosteronism are rarely found. (ABSTRACT TRUNCATED)


Mouse models of lupus: what they tell us and what they don't.
Lupus is a complex heterogeneous disease characterised by autoantibody production and immune complex deposition followed by damage to target tissues. Animal models of human diseases are an invaluable tool for defining pathogenic mechanisms and testing of novel therapeutic agents. There are perhaps more applicable murine models of lupus than any other human disease. There are spontaneous models of lupus, inducible models of lupus, transgenic-induced lupus, gene knockout induced lupus and humanised mouse models of lupus. These mouse models of lupus have contributed significantly to our knowledge of the pathogenesis of lupus and served as valuable preclinical models for proof of concept for new therapies. Despite their utility, mouse models of lupus have their distinct limitations. Although similar, mouse and human immune systems are different and thus one cannot assume a mechanism for disease in one is translatable to the other. Efficacy and toxicity of compounds can vary significantly between humans and mice, also limiting direct translation. Finally, the heterogeneous aspects of human lupus, both in clinical presentation, underlying pathogenesis and genetics, are not completely represented in current mouse models. Thus, proving a therapy or mechanism of disease in one mouse model is similar to proving a mechanism/therapy in a limited subset of human lupus. These limitations, however, do not marginalise the importance of animal models nor the significant contributions they have made to our understanding of lupus.


Vascularized Fibular Epiphyseal Transfer for Pediatric Limb Salvage: Review of Applications and Outcomes.
Vascularized fibular epiphyseal transfer (VFET) offers a functional advantage in pediatric limb salvage due to the preservation of growth potential and an articular surface for remodeling. This review summarizes the available evidence on the clinical characteristics and outcomes of pediatric reconstruction applying VFET at different recipient sites and with varying techniques. VFET was used to reconstruct the proximal humerus, distal radius or ulna, proximal femur, distal fibula, calcaneus, and mandible. Although most often harvested on the anterior tibial artery, VFET has also been performed using the peroneal artery, the inferior lateral genicular artery, and a dual pedicle. Recipient site flap inset most often involved fixation with plates and/or screws as well as soft tissue reconstruction using a retained slip of biceps femoris tendon. Outcomes included limb growth, range of motion, and strength. The most common reported complications were bone flap fracture and peroneal nerve palsy. The anterior tibial artery was the most applied pedicle with reliable limb growth, but with the added risk of postoperative peroneal palsy. Bone flap fracture most often occurred at the proximal humerus and femur recipient sites. Plate fixation and the combined use of allograft had lower instances of bone flap fracture. This review highlights how the anticipated dynamic growth and remodeling this free flap offers in the long term must be weighed against its complexity and potential complications.


Production of transgenic rats using pregnant and pseudopregnant rats prepared at a breeding farm.
We used pregnant and pseudopregnant Wistar-Imamichi rats, prepared at a breeding farm, for production of transgenic rats. The donor and recipient rats were transported to our facility for ova manipulation and embryo implantation, respectively. As a foreign gene, 1.9 kb of a hybrid gene was constructed with the rat renin promoter and chloramphenicol acetyltransferase-coding gene. Fertilized oocytes were collected from the donor and the foreign DNA was microinjected into the pronuclei of 539 oocytes by the method of Hochi. The manipulated oocytes were cultured to the 2-cell stage. One hundred seventeen 2-cell embryos were implanted in the recipient rats. Of 67 newborns, 55 rats grew up to be 3-week-old weanlings. Genomic DNA was extracted from the tail of these weanlings and examined by polymerase chain reaction analysis. Six transgenic rats were found to have been generated by the present method. In this way, transgenic rats were produced by an efficient combination of breeding farm utilization and laboratory research.


Selective dye-labeling of newly synthesized proteins in bacterial cells.
We describe fluorescence labeling of newly synthesized proteins in Escherichia coli cells by means of Cu(I)-catalyzed cycloaddition between alkynyl amino acid side chains and the fluorogenic dye 3-azido-7-hydroxycoumarin. The method involves co-translational labeling of proteins by the non-natural amino acids homopropargylglycine (Hpg) or ethynylphenylalanine (Eth) followed by treatment with the dye. As a demonstration, the model protein barstar was expressed and treated overnight with Cu(I) and 3-azido-7-hydroxycoumarin. Examination of treated cells by confocal microscopy revealed that strong fluorescence enhancement was observed only for alkynyl-barstar treated with Cu(I) and the reactive dye. The cellular fluorescence was punctate, and gel electrophoresis confirmed that labeled barstar was localized in inclusion bodies. Other proteins showed little fluorescence. Examination of treated cells by fluorimetry demonstrated that cultures supplemented with Eth or Hpg showed an 8- to 14-fold enhancement in fluorescence intensity after labeling. Addition of a protein synthesis inhibitor reduced the emission intensity to levels slightly above background, confirming selective labeling of newly synthesized proteins in the bacterial cell.


Phage Interactions with the Nervous System in Health and Disease.
The central nervous system manages all of our activities (e.g., direct thinking and decision-making processes). It receives information from the environment and responds to environmental stimuli. Bacterial viruses (bacteriophages, phages) are the most numerous structures occurring in the biosphere and are also found in the human organism. Therefore, understanding how phages may influence this system is of great importance and is the purpose of this review. We have focused on the effect of natural bacteriophages in the central nervous system, linking them to those present in the gut microbiota, creating the gut-brain axis network, as well as their interdependence. Importantly, based on the current knowledge in the field of phage application (e.g., intranasal) in the treatment of bacterial diseases associated with the brain and nervous system, bacteriophages may have significant therapeutic potential. Moreover, it was indicated that bacteriophages may influence cognitive processing. In addition, phages (via phage display technology) appear promising as a targeted therapeutic tool in the treatment of, among other things, brain cancers. The information collected and reviewed in this work indicates that phages and their impact on the nervous system is a fascinating and, so far, underexplored field. Therefore, the aim of this review is not only to summarize currently available information on the association of phages with the nervous system, but also to stimulate future studies that could pave the way for novel therapeutic approaches potentially useful in treating bacterial and non-bacterial neural diseases.


Incidence of extreme hyperglycemia and hypoglycemia in hospitalized patients during the month of July in teaching hospitals.
Blood glucose control has been found to be an important component in the care of hospitalized patients. Maintaining blood glucose within a target range using insulin intensively is a challenging task for physicians and requires skill and experience. We hypothesized that there may be more hyper- and hypoglycemia in July in teaching hospitals when new resident physicians begin their training. We reviewed point-of-care blood glucose data from hospitalized patients at four community teaching hospitals for 2010. We defined severe hypoglycemia as blood glucose < 41 mg/dL and severe hyperglycemia as blood glucose > 399 mg/dL. Occurrence of hyper- and hypoglycemic events was assessed overall at the particular hospital globally and based on individual nursing units. Monthly occurrence rates were compared against the annual mean for that unit. The occurrence of hyper- and hypoglycemic events in July 2010 did not differ from the mean annual percentage of events at the applicable hospital. However, when the data were analyzed by the nursing unit, these extreme glucose events were significantly more common in 4 of the 11 units studied. Three of those four units were resident teaching units. These data suggest that there is some potential for increased risk of extreme hyper- and hypoglycemia at teaching hospitals in July, when new residents begin training.


Compartment Syndrome Due to Reperfusion Injury from an Axillary Artery Occlusion: A Case Report and Review of the Literature.
While commonly caused by traumatic injury and fracture, compartment syndrome can also result from reperfusion injury. Very few cases of prophylactic fasciotomy are mentioned when considering time to revascularization after prolonged vascular ischemia. We present a case of a patient who underwent multiple compartment prophylactic fasciotomies following reperfusion injury in the upper extremity. We report a 72-year-old male that suffered from an anterior shoulder dislocation after a ground-level fall. After reduction, pulses were not measurable, and angiography indicated an axillary artery occlusion. Immediately after operative reperfusion, compartments became tense. Orthopedic surgeons subsequently performed arm anterior, posterior, and forearm volar and mobile wad compartment fasciotomies, after 13 h of ischemia. The patient tolerated the procedure, and at the latest follow-up, was working to improve strength in the extremity. Even when the circumstances of injury seem to be less traumatic as in this case of a ground-level fall, we document the importance of prompt recognition and intervention of suspected compartment syndrome following prolonged ischemia and revascularization of the upper extremity.


3-D visualization and identification of biological microorganisms using partially temporal incoherent light in-line computational holographic imaging.
We present a new method for three-dimensional (3-D) visualization and identification of biological microorganisms using partially temporal incoherent light in-line (PTILI) computational holographic imaging and multivariate statistical methods. For 3-D data acquisition of biological microorganisms, the band-pass filtered white light is used to illuminate a biological sample. The transversely and longitudinally diffracted pattern of the biological sample is magnified by microscope objective (MO) and is optically recorded with an image sensor array interfaced with a computer. Three-dimensional reconstruction of the biological sample from the diffraction pattern is accomplished by using computational Fresnel propagation method. Principal components analysis and nonparametric inference algorithms are applied to the 3-D complex amplitude biological sample for identification purposes. Experiments indicate that the proposed system can be useful for identifying biological microorganisms. To the best of our knowledge, this is the first report on using PTILI computational holographic microscopy for identification of biological microorganisms.


Colchicine-antimicrobial drug interactions: what pharmacists need to know in treating gout.
Review the magnitude and clinical relevance of drug-drug interactions between a new formulation of colchicine, used to treat gout, and antibiotics. SETTING AND PRACTICE DESCRIPTION: Relevant to community and institutional pharmacists servicing patients with gout. Pharmacists have clear roles for the identification of drug-drug interactions, providing recommendations for alternative therapy or dose adjustments/modifications, and monitoring for interactionrelated adverse events. Colchicine is metabolized via cytochrome P450 3A4 (CYP3A4); therefore, coadministration with agents that inhibit this isoenzyme can produce elevated colchicine plasma concentrations, resulting in severe and sometimes fatal adverse events. Knowledge of the potential for drug-drug interactions involving antibiotics (e.g., macrolide antibiotics, azole antifungals) allows pharmacists to help patients avoid serious adverse events. Pharmacokinetic studies have demonstrated that the maximum plasma concentration (C(max)) and drug exposure (as assessed by area under the plasma concentration time curve [AUC]) of colchicine are increased by 277% and 282%, respectively, after coadministration with clarithromycin. Similarly, coadministration with ketoconazole increases colchicine C(max) and AUC by 102% and 212%, respectively. Other antibiotics that are strong CYP3A4 inhibitors include itraconazole and telithromycin, whereas erythromycin and fluconazole are moderate inhibitors of the isoenzyme CYP3A4. Coadministration of CYP3A4 inhibitors (particularly clarithromycin) and colchicine has resulted in acute colchicine toxicity manifested by severe gastrointestional toxicity, bone marrow suppression, multiorgan failure, and death. Pharmacist awareness of potentially clinically significant interactions between colchicine and antibiotics that inhibit CYP3A4 can help to ensure the efficacy of colchicine is realized while mitigating serious toxicities and minimizing the risk of adverse events.


Undergraduate Biology Education Research Gordon Research Conference: A Meeting Report.
The 2019 Undergraduate Biology Education Research Gordon Research Conference (UBER GRC), titled "Achieving Widespread Improvement in Undergraduate Education," brought together a diverse group of researchers and practitioners working to identify, promote, and understand widespread adoption of evidence-based teaching, learning, and success strategies in undergraduate biology. Graduate students and postdocs had the additional opportunity to present and discuss research during a Gordon Research Seminar (GRS) that preceded the GRC. This report provides a broad overview of the UBER GRC and GRS and highlights major themes that cut across invited talks, poster presentations, and informal discussions. Such themes include the importance of working in teams at multiple levels to achieve instructional improvement, the potential to use big data and analytics to inform instructional change, the need to customize change initiatives, and the importance of psychosocial supports in improving undergraduate student well-being and academic success. The report also discusses the future of the UBER GRC as an established meeting and describes aspects of the conference that make it unique, both in terms of facilitating dissemination of research and providing a welcoming environment for conferees.


Methods of coping with labor pain used by Jordanian women.
The purpose of this study is to explore labor pain coping methods among Jordanian parturients. Descriptive statistics and content analysis were used to analyze data on demographics and coping methods from 100 low-risk parturients who were recruited from the postpartum unit in a major hospital in Jordan: Four labor pain-coping methods that included physiological, psychological, spiritual, and cognitive coping were reported. This study confirms previous findings regarding coping methods and adds new knowledge on coping with labor pain among Jordanian parturients: The significance of childbirth education as a means to inform Jordanian women about coping with labor pain is emphasized. This study also highlighted the important roles that nurses and midwives can play as educators and supporters during pregnancy and labor.


Ontogeny of peroxidase activity in epithelium and eosinophils of the mouse uterus.
Outbred CD-1 mice treated for 1 or 4 days with 1 mg/kg of diethylstilbestrol (DES) at various ages after birth were examined for histochemical localization of peroxidase in the uterine epithelium. Peroxidase activity in uterine extracts was also measured by a radiometric assay and the conversion of [3H]DES to [3H]Z,Z-diensestrol (Z,Z-DIES). While no peroxidase activity was detected by a histochemical method in uterine epithelium from untreated 5-day old mice, the enzyme was apparent in mice treated for 4 days with DES; uterine eosinophils were absent at this age. By day 9, DES-induced staining for peroxidase in uterine epithelial cells and the number of uterine eosinophils had increased significantly. In addition, at this age, the biochemical assays for uterine peroxidase were sensitive enough to show that DES is converted to Z,Z-DIES and that [3H]estradiol gives rise to 3H2O and water-soluble radioactive metabolites. The peroxidase response to DES, determined by both histochemical and biochemical methods, increased with the age of the immature mice. These data indicate that the neonatal uterus, although deficient in eosinophils, demonstrates a peroxidase response to estrogen and that this response is localized primarily in the luminal epithelium. The role of this DES-induced peroxidase activity in converting DES to activated metabolites that may cause cell damage is discussed.


Coronary artery bypass grafting in patients with low ejection fraction.
Patients with low ejection fraction (EF) are at a higher risk for postoperative complications and mortality. Our objective was to assess the effect of low EF on clinical outcomes after coronary artery bypass grafting (CABG). We analyzed 55,515 patients from New York State database who underwent CABG between 1997 and 1999. Patients were stratified into 1 of the 4 EF groups: Group I (EF< or =20%), Group II (EF 21% to 30%), Group III (EF 31% to 40%), and Group IV (EF>40%). History of previous myocardial infarction, renal failure, and congestive heart failure were higher in patients with low EF (all P<0.001). Group I experienced a higher incidence of postoperative respiratory failure (10.1% versus 2.9%), renal failure (2.5% versus 0.6%), and sepsis (2.5% versus 0.6%) compared with Group IV. In-hospital mortality was significantly higher in Group I (6.5% versus 1.4%; P<0.001). Multivariate analysis showed hepatic failure [odds ratio (OR), 11.2], renal failure (OR, 4.1), previous myocardial infarction (OR, 3.4), reoperation (OR, 3.4), emergent procedures (OR, 3.2), female gender (OR, 1.7), congestive heart failure (OR, 1.6), and age (OR, 1.04) as independent predictors of in-hospital mortality in the low EF group. The discharges to home rate were significantly lower in Group I versus Group IV (73.1% and 87.7%, respectively; P<0.001). Patients with low EF are sicker at baseline and have >4 times higher mortality than patients with high EF. However, outcomes are improving over time and are superior to historical data. Therefore, CABG remains a viable option in selected patients with low EF.


Mapping services at two Nairobi County primary health facilities: identifying challenges and opportunities in integrated mental health care as a Universal Health Coverage (UHC) priority.
There is a need to scale-up mental health service provision in primary health care. The current extent of integration of mental health in primary care is pertinent to promoting and augmenting mental health at this level. We describe a facility mapping exercise conducted in two low-income/primary health facilities in Kenya to identify existing barriers and facilitators in the delivery of mental health services in general and specifically for peripartum adolescents in primary health care as well as available service resources, cadres, and developmental partners on the ground. This study utilized a qualitative evidence synthesis through mapping facility-level services and key-stakeholder interviews. Services-related data were collected from two facility in-charges using the Nairobi City County Human Resource Health Strategy record forms. Additionally, we conducted 10 key informant interviews (KIIs) with clinical officers (Clinicians at diploma level), Nurses, Community Health Assistants (CHAs), Prevention of Mother-to-child Transmission of HIV Mentor Mothers (PMTCTMs), around both general and adolescent mental health as well as psychosocial services they offered. Using the World Health Organization Assessments Instrument for Mental Health Systems (WHO-AIMS) as a guideline for the interview, all KII questions were structured to identify the extent of mental health integration in primary health care services. Interview transcripts were then systematically analyzed for common themes and discussed by the first three authors to eliminate discrepancies. Our findings show that health care services centered around physical health were offered daily while the mental health services were still vertical, offered weekly through specialist services by the Ministry of Health directly or non-governmental partners. Despite health care workers being aware of the urgent need to integrate mental health services into routine care, they expressed limited knowledge about mental disorders and reported paucity of trained mental health personnel in these sites. Significantly, more funding and resources are needed to provide mental health services, as well as the need for training of general health care providers in the identification and treatment of mental disorders. Our stakeholders underscored the urgency of integrating mental health treatment, prevention, and well-being promotive activities targeting adolescents especially peripartum adolescent girls. There is a need for further refining of the integrated care model in mental health services and targeted capacity-building for health care providers to deliver quality services.


Evaluation of botulinum toxin type A effectiveness in preventing postoperative intraperitoneal adhesions.
Postoperative intraperitoneal adhesions (PIAs) are one of the most important problems surgeons have to face after laparotomies. In this study, we aimed to evaluate the effectiveness of local application of botulinum toxin type A (BoNT-A) in various dosages on the prevention of intra-abdominal adhesions in rats with experimental intra-abdominal adhesions. Forty Wistar Albino female rats were randomly separated into 4 groups. The 4 groups were determined as follows: Control (group 1, n = 10); Sham (group 2, n = 10); 10-µg/kg low-dose BoNT-A (group 3, n = 10) and 30-µg/kg high-dose BoNT-A (group 4, n = 10). Subserosal injuries were created on the caecum of all rats. Laparotomy was performed on the fifth day. Adhesion scores, histopathological examination, and E-cadherin expression levels were evaluated. General adhesion scores for groups 1 and 2 were determined to be significantly high when compared to group 4 (P < 0.001). A significant difference was also determined between groups 3 and 4 in terms of general adhesion scores (P < 0.05). In pair comparisons, a significant decrease in high-dose BoNT-A group (group 4) when compared to groups 1 and 2 in terms of neovascularization, fibroblast density, collagen deposition and inflammatory cell count was determined (P < 0.05). A significant decrease was observed only in postoperative PIAs in the high-dose BoNT-A group between all 4 rat-groups with experimentally created postoperative PIAs. In this study, high-dose BoNT-A is determined to be an effective agent in preventing postoperative PIAs.


Work related asthma - diagnosis and management.
Work related asthma (WRA) is a common condition and is under recognised in Australia. Work related asthma refers to the development of new asthma due to occupational factors (occupational asthma) and the worsening of asthma control due to occupational factors (work exacerbated asthma). This article discusses the diagnosis and management of work related asthma in Australia. All clinicians who treat adult patients with asthma should enquire about the patient's occupation. Key features of WRA include: a temporal association between asthma symptoms and work activities (especially an improvement in symptoms when away from the workplace), identification of relevant workplace exposures (eg. use of a known cause of occupational asthma) and the development of respiratory symptoms in coworkers. Optimal management of WRA requires early recognition and accurate diagnosis. Increased awareness of WRA and the introduction of effective workplace control should reduce the prevalence of WRA and the overall burden of asthma in our community.


The cost of incentive compatibility in auction-based mechanisms for carrier collaboration.
Collaboration has been one of the important trends in vehicle routing. A typical mechanism to enable carrier collaboration is to use combinatorial auctions, where requests are not traded individually but are combined into bundles. Previous literature on carrier collaboration has focused on issues such as bundle formation or winner determination, typically assuming truthfulness of all agents and absence of any strategic behavior. This article considers the interdependencies and problems that arise from bidders acting as buyers and sellers of requests at the same time. From standard auction theory, desirable properties of exchange mechanisms are identified as efficiency, incentive compatibility, individual rationality, and budget balance. It is shown that these desirable properties cannot be fulfilled at the same time. In particular, the properties efficiency and incentive compatibility induce that budget balance is violated, that is, an outside subsidy is required. We propose two incentive compatible exchange mechanisms. One is more closely related to the classical VCG approach, while the other one uses a more complicated concept for computing payments to participants. A numerical study investigates how frequently desired properties are violated. We show that both mechanisms can be acceptable in practical situations, but none of them can satisfy all desired properties.


Interaction of caffeine with acetaminophen. 1. Correlation of the effect of caffeine on acetaminophen hepatotoxicity and acetaminophen bioactivation following treatment of mice with various cytochrome P450 inducing agents.
The combination of caffeine with acetaminophen (APAP) is used widely in the treatment of headache. The effects of caffeine on APAP-induced hepatotoxicity and APAP bioactivation by liver microsomes from uninduced mice and from mice pretreated with various agents that induce cytochrome P450 were studied. When 1 mM caffeine was included, the rate of glutathione-APAP conjugate (GS-APAP) formation was increased significantly by 33 and 39% in microsomes from phenobarbital (PB)- and dexamethasone (DEX)-treated mice, respectively, whereas this parameter was decreased 39 and 12% by caffeine in microsomes from beta-naphthoflavone (beta NF)- and acetone-treated mice, respectively. A 5 mM concentration of caffeine increased GS-APAP formation by 47, 107 and 117% in microsomes from control, PB-, and DEX-treated mice, respectively, and decreased it 39 and 25% in microsomes from beta NF- and acetone-treated mice, respectively. Caffeine was a competitive inhibitor of APAP bioactivation in microsomes from beta NF- and acetone-treated mice. While caffeine increased APAP bioactivation in microsomes from uninduced, PB-, and DEX-treated mice, the apparent Km values for APAP were increased by caffeine, indicating that this enhancement was not due to a direct effect of caffeine on APAP binding to cytochrome P450 but may be due to an effect of caffeine on the substrate-enzyme complex. The variable effect of caffeine on APAP hepatotoxicity correlated with the effect of caffeine on APAP bioactivation by liver microsomes, regardless of pretreatment. Lack of correlation of aminopyrine N-demethylase, but good correlation of erythromycin N-demethylase activity with the extent of caffeine enhancement of APAP bioactivation following PB or DEX treatment suggests that a murine P450 subfamily similar to the rat P450 3A subfamily may be the candidate in mediating the stimulatory effect of caffeine on APAP bioactivation and APAP-induced hepatotoxicity.


Parasitism of antigen presenting cells in hyperbacillary leprosy.
Full thickness skin biopsies from four patients with borderline lepromatous leprosy (BL leprosy) have been examined. Immunohistological techniques have been employed to analyse the non-lymphoid mononuclear cells present in the dermal infiltrates associated with the BL lesions. This analysis was performed using three monoclonal antibodies, RFD2 (recognizing macrophages), RFD1 (recognizing interdigitating cells) and NA1/34 (recognizing Langerhans cells). It was found that the vast majority of non-lymphoid mononuclear cells in the lesions were RFD2+ macrophages. However, a significant number (15-30%) of macrophage like cells were RFD1+ interdigitating cells. A very small number of NA1/34+ Langerhans cells were also identified within the dermal infiltrates. Combination immunohistology and Ziehl Neelsen staining revealed that all these cell types could be found containing the Mycobacterium leprae organisms. The proportions of parasitized cells within each subpopulation was equivalent to the overall proportion of each cell type within the infiltrate. The significance of parasitism of cell types thought to be involved in antigen presentation and induction of immune responses is discussed.


Synthesis and RNA polymerase incorporation of the degenerate ribonucleotide analogue rPTP.
The synthesis and enzymatic incorporation into RNA of the hydrogen bond degenerate nucleoside analogue 6-(beta-d-ribofuranosyl)-3, 4-dihydro-8H-pyrimido[4,5-c]-[1,2]oxazin-7-one (P) is described. The 5'-triphosphate of this analogue is readily incorporated by T3, T7 and SP6 RNA polymerases into RNA transcripts, being best incorporated in place of UTP, but also in place of CTP. When all the uridine residues in an HIV-1 TAR RNA transcript are replaced by P the transcript has similar characteristics to the wild-type TAR RNA, as demonstrated by similar melting temperatures and CD spectra. The P-substituted TAR transcript binds to the Tat peptide ADP-1 with only 4-fold lowered efficiency compared with wild-type TAR.


Self-esteem in adolescents with Angle Class I, II and III malocclusion in a Peruvian sample.
To compare self-esteem scores in 12 to 16-year-old adolescents with different Angle malocclusion types in a Peruvian sample. A cross-sectional study was conducted in a sample of 276 adolescents (159, 52 and 65 with Angle Class I, II and III malocclusions, respectively) from Trujillo, Peru. Participants were asked to complete the Rosenberg Self-Esteem Scale (RSES) and were also clinically examined, so as to have Angle malocclusion classification determined. Analysis of covariance (ANCOVA) was used to compare RSES scores among adolescents with Class I, II and III malocclusions, with participants' demographic factors being controlled. Mean RSES scores for adolescents with Class I, II and III malocclusions were 20.47 ± 3.96, 21.96 ± 3.27 and 21.26 ± 4.81, respectively. The ANCOVA test showed that adolescents with Class II malocclusion had a significantly higher RSES score than those with Class I malocclusion, but there were no differences between other malocclusion groups. Supplemental analysis suggested that only those with Class II, Division 2 malocclusion might have greater self-esteem when compared to adolescents with Class I malocclusion. This study shows that, in general, self-esteem did not vary according to adolescents' malocclusion in the sample studied. Surprisingly, only adolescents with Class II malocclusion, particularly Class II, Division 2, reported better self-esteem than those with Class I malocclusion. A more detailed analysis assessing the impact of anterior occlusal features should be conducted.


Investigation of naphthofuran moiety as potential dual inhibitor against BACE-1 and GSK-3β: molecular dynamics simulations, binding energy, and network analysis to identify first-in-class dual inhibitors against Alzheimer's disease.
BACE-1 and GSK-3β are potential therapeutic drug targets for Alzheimer's disease. Recently, both the targets received attention for designing dual inhibitors for Alzheimer's disease. Until now, only two-scaffold triazinone and curcumin have been reported as BACE-1 and GSK-3β dual inhibitors. Docking, molecular dynamics, clustering, binding energy, and network analysis of triazinone derivatives with BACE-1 and GSK-3β was performed to get molecular insight into the first reported dual inhibitor. Further, we designed and evaluated a naphthofuran series for its ability to inhibit BACE-1 and GSK-3β with the computational approaches. Docking study of naphthofuran series showed a good binding affinity towards both the targets. Molecular dynamics, binding energy, and network analysis were performed to compare their binding with the targets and amino acids responsible for binding. Naphthofuran series derivatives showed good interaction within the active site residues of both of the targets. Hydrogen bond occupancy and binding energy suggested strong binding with the targets. Dual-inhibitor binding was mostly governed by the hydrophobic interactions for both of the targets. Per residue energy decomposition and network analysis identified the key residues involved in the binding and inhibiting BACE-1 and GSK-3β. The results indicated that naphthofuran series derivative 11 may be a promising first-in-class dual inhibitor against BACE-1 and GSK-3β. This naphthofuran series may be further explored to design better dual inhibitors. Graphical abstract Naphthofuran derivative as a dual inhibitor for BACE-1 and GSK-3β.


MiR-101: a potential therapeutic target of cancers.
MicroRNAs (miRNAs) are small noncoding RNAs that could regulate gene expressions transcriptionally or post-transcriptionally through binding to 3' untranslated region (3'UTR) of target messenger RNAs (mRNAs), which were identified to be associated with tumorigenesis in various neoplasms. Among them, miR-101, encoded by two precursor transcripts (miR-101-1 and miR-101-2), was recognized to serve as a tumor suppressor via targeting critical oncogenes or anti-oncogenes. Additionally, studies have shown that miR-101 was participated in multiple cancer-related biological processes, including proliferation, apoptosis, angiogenesis, drug resistance, invasion and metastasis. In this review, we aim to summarize the function of miR-101 in different biological processes by figuring out the underlying target gene networks and explore its potential role as a biomarker in diverse neoplasms, which will provide a brand-new insight in molecular targeting cancer treatment.


Spatiotemporal phase unwrapping for real-time phase-contrast flow MRI.
To develop and evaluate a practical phase unwrapping method for real-time phase-contrast flow MRI using temporal and spatial continuity. Real-time phase-contrast MRI of through-plane flow was performed using highly undersampled radial FLASH with phase-sensitive reconstructions by regularized nonlinear inversion. Experiments involved flow in a phantom and the human aorta (10 healthy subjects) with and without phase wrapping for velocity encodings of 100 cm·s(-1) and 200 cm·s(-1) . Phase unwrapping was performed for each individual cardiac cycle and restricted to a region of interest automatically propagated to all time frames. The algorithm exploited temporal continuity in forward and backward direction for all pixels with a "continuous" representation of blood throughout the entire cardiac cycle (inner vessel lumen). Phase inconsistencies were corrected by a comparison with values from direct spatial neighbors. The latter approach was also applied to pixels exhibiting a discontinuous signal intensity time course due to movement-induced spatial displacements (peripheral vessel zone). Phantom and human flow MRI data were successfully unwrapped. When halving the velocity encoding, the velocity-to-noise ratio (VNR) increased by a factor of two. The proposed phase unwrapping method for real-time flow MRI allows for measurements with reduced velocity encoding and increased VNR.


PRELIMINARY RESULTS OF TOPICAL HEPATIC HYPOTHERMIA IN A MODEL OF LIVER ISCHEMIA/REPERFUSION INJURY IN RATS.
Ischemia/reperfusion causes organ damage but it is mandatory in hepatic transplantation, trauma and other complex liver surgeries, when Pringle maneuver is applied to minimize bleeding during these procedures. It is well known that liver ischemia/reperfusion leads to microcirculatory disturbance and cellular injury. In this setting hypothermia is known to reduce oxygen demand, lowering intracellular metabolism. To evaluate the effects of hypothermia in liver ischemia/reperfusion injury, using a new model of topic isolated liver hypothermia. We used male Wistar rats weighting about 250 grams, kept in ad libitum feeding regime and randomly divided into two groups of nine animals: 1) Normothermic group, rats were submitted to normothermic ischemia of the median and left hepatic lobes, with subsequent resection of right and caudate lobes during liver reperfusion; and 2) Hypothermic group, rats were submitted to liver ischemia under hypothermia at 10°C. Liver ischemia was performed for 45 minutes. The animals were euthanized 48 hours after liver reperfusion for blood and liver tissue sampling. The transaminases analyses showed a significant decrease of AST and ALT in Hypothermic group (P<0.01) compared to Normothermic group (1403±1234 x 454±213 and 730±680 x 271±211 U/L, respectively). Histology showed severe necrosis in 50% and mild necrosis in 50% of cases in Normothermic group, but severe necrosis in 10% and mild or absent necrosis 90% of the cases in hypothermic group. A simplified model of liver ischemia/reperfusion that simulates orthotopic liver autotransplantion was demonstrated. Topical hypothermia of isolated hepatic lobules showed liver protection, being a viable and practical method for any kind of in vivo liver preservation study.


The first case of domino-split-liver transplantation in maple syrup urine disease.
The enzymatic defect in MSUD results in accumulation of neurotoxic metabolites of BCAAs. LTX has shown to be a feasible strategy in patients non-responsive to diet. Because of sufficient enzyme activity in extrahepatic tissues in healthy people, the MSUD liver graft is a suitable domino organ. We present the first case of a technical challenging ex situ split of a MSUD domino organ transplanted into two pediatric recipients. The domino graft donor was a 21-year-old female (58 kg) suffering from MSUD with recurrent metabolic decompensation despite strict diet. The organ was allocated to a 14-year-old girl (55 kg) with primary sclerosing cholangitis. Due to excellent organ quality and suitable anatomy, a backward split for a girl of 3 months (5 kg) with decompensated liver cirrhosis due to biliary atresia was performed. The postoperative course was without relevant complications, and the three recipients were discharged on postoperative days 28, 29, and 45, respectively, with good organ function. BCAAs in plasma were normal in the two domino graft recipients, and the MSUD patient showed mildly elevated but stable BCAA concentrations despite an unrestricted diet. Split-domino LTX enabled successful transplantation of three patients of the waiting list with only one deceased donor graft.


Discrimination, perceived control, and psychological health among African Americans with hypertension.
Hypertensive individuals represent a "vulnerable" population regarding psychological health. While African Americans are disproportionally burdened with hypertension, pathways predicting their psychological health remain understudied. We examine if discrimination is associated with psychological health, through an indirect effect of perceived control within a sample of African American individuals with prevalent hypertension (n = 990). Discrimination was significantly associated with an increase psychological distress and a decrease in psychological well-being through a reduction in perceived control, supporting Minority Stress Theory. Cardiovascular disease risk factor management implications are discussed.


An empirical test of the generic model of psychotherapy.
This study examined the propositions of Orlinsky and Howard's generic model of psychotherapy with regard to self-relatedness, therapeutic bond, therapeutic realizations, session outcome, and termination outcome. Measures representing these constructs were derived from therapy session reports obtained from patients after sessions three and seven. A multiple-regression data analytic strategy was used that focused on the proportion of variance accounted for by single variables as well as combinations of process and outcome variables. Self-relatedness and therapeutic bond accounted for significant proportions of variance in therapeutic realizations. In addition, therapeutic realizations, therapeutic bond, and self-relatedness accounted for significant proportions of variance in session outcome. Finally, session outcome accounted for a significant proportion of variance in termination outcome.


A functional compartmental model of the Synechocystis PCC 6803 phycobilisome.
In the light-harvesting antenna of the Synechocystis PCC 6803 phycobilisome (PB), the core consists of three cylinders, each composed of four disks, whereas each of the six rods consists of up to three hexamers (Arteni et al., Biochim Biophys Acta 1787(4):272-279, 2009). The rods and core contain phycocyanin and allophycocyanin pigments, respectively. Together these pigments absorb light between 400 and 650 nm. Time-resolved difference absorption spectra from wild-type PB and rod mutants have been measured in different quenching and annihilation conditions. Based upon a global analysis of these data and of published time-resolved emission spectra, a functional compartmental model of the phycobilisome is proposed. The model describes all experiments with a common set of parameters. Three annihilation time constants are estimated, 3, 25, and 147 ps, which represent, respectively, intradisk, interdisk/intracylinder, and intercylinder annihilation. The species-associated difference absorption and emission spectra of two phycocyanin and two allophycocyanin pigments are consistently estimated, as well as all the excitation energy transfer rates. Thus, the wild-type PB containing 396 pigments can be described by a functional compartmental model of 22 compartments. When the interhexamer equilibration within a rod is not taken into account, this can be further simplified to ten compartments, which is the minimal model. In this model, the slowest excitation energy transfer rates are between the core cylinders (time constants 115-145 ps), and between the rods and the core (time constants 68-115 ps).


New enigmatic species of the genus Pediobius (Hymenoptera, Eulophidae) from Afrotropics, with notes on related genera.
Three new species groups and seven species of the genus Pediobius Walker are described from the Afrotropical realm: the marjoriae group, with P. marjoriae Kerrich (described from Uganda), P. rohombaya Gumovsky sp. n. (from the Central African Republic (CAR), the Democratic Republic of the Congo (DRC), Gabon, Uganda) and P. orungu Gumovsky sp. n. (from Gabon); the afroteres group with P. afroteres Gumovsky sp. n. (from South Africa, Zimbabwe, Malawi, Kenya, Uganda, DRC, Cameroon) and P. kafroteres Gumovsky sp. n. (from Cameroon); the askari group with P. askari Gumovsky sp. n. (from South Africa, Zimbabwe, Kenya, Tanzania, DRC, Ivory Coast) and P. maleficus Gumovsky sp. n. (from Kenya, DRC, CAR, Cameroon, Gabon); and P. nganga Gumovsky sp. n. (from DRC) (not assigned to any group). All these species are characterized by the relatively wide and robust head with elongate and/or narrowed lower face and the antennae attached near or below the lower eye margins. Morphological features of the species, as well as their habitat distribution, are discussed. The comparison of the new species with similar taxa of Entedoninae suggested the following synonymies: Rhynchentedon Girault and Pediobomyia Girault under Pediobius (syn. n.); Bomyiabius frontus Narendran, Pediobomyia budaicus Narendran and Pediobomyia lankicus Narendran under Pediobomyia darwini Girault (syn. n.). The following new combinations are proposed: Pediobius maximus (Girault), P. achterbergi (Gumovsky), P. narendrani (Gumovsky), P. brevicaulis (Hansson), P. canaliculatus (Hansson) and P. darwini (Girault) (comb. n.). Ant parasitoids P. marjoriae and Myrmokata diparoides Bouček are recorded from DRC for the first time.


Atomic-scale regulation of anionic and cationic migration in alkali metal batteries.
The regulation of anions and cations at the atomic scale is of great significance in membrane-based separation technologies. Ionic transport regulation techniques could also play a crucial role in developing high-performance alkali metal batteries such as alkali metal-sulfur and alkali metal-selenium batteries, which suffer from the non-uniform transport of alkali metal ions (e.g., Li+ or Na+) and detrimental shuttling effect of polysulfide/polyselenide anions. These drawbacks could cause unfavourable growth of alkali metal depositions at the metal electrode and irreversible consumption of cathode active materials, leading to capacity decay and short cycling life. Herein, we propose the use of a polypropylene separator coated with negatively charged Ti0.87O2 nanosheets with Ti atomic vacancies to tackle these issues. In particular, we demonstrate that the electrostatic interactions between the negatively charged Ti0.87O2 nanosheets and polysulfide/polyselenide anions reduce the shuttling effect. Moreover, the Ti0.87O2-coated separator regulates the migration of alkali ions ensuring a homogeneous ion flux and the Ti vacancies, acting as sub-nanometric pores, promote fast alkali-ion diffusion.


An innovative strategy to increase a professional workforce: the fast track initiative for health visitors in England.
Fast tracking is one strategy that organizations use to ameliorate workforce shortfalls by attracting new recruits, and accelerating their skills development and experience. In response to the Government's target of rapidly expanding the number of health visitors in England's National Health Service, the fast track initiative was launched to recruit newly qualified (fast track) as well as experienced (standard entry) nurses and midwives onto health visiting programmes. This paper evaluates the fast track initiative, from the perspective of fast track and standard entry students, practice teachers and health visitor managers. A mixed methods design was used comprising a questionnaire survey (n = 71 students), semi-structured interviews (n = 37 students), telephone interviews (n = 13 managers) and six focus groups (n = 24 practice teachers). Data were collected between April 2012 and July 2013. Descriptive statistics, t-tests and the Pearson Chi-square test were used to analyse the quantitative data. The qualitative data were analysed thematically. Motivations for health visiting as a career choice were similar for fast track and standard entry students, with career progression and interest in health promotion being key motivators. There was consensus that personal qualities and characteristics were more important than experience or qualifications. However, fast track students were significantly less confident about their public health competencies in leadership and management (p < 0.05) and communication (p < 0.02). Practice teachers and managers also reported that fast track students required more intensive supervision particularly at the beginning of the programme. Programme completion including pass rates and academic achievement showed no significant difference by route of entry (p > 0.5). Fast tracking offers a useful recruitment strategy in order to expand the health visitor workforce, but longitudinal research is needed to confirm benefits such as retention and career trajectories.


Cortical calculation localization using electrostimulation.
A naming task has been used to spare cortical areas involved in language. In the present study, a calculation task was combined with electrostimulation mapping (awake surgery) to spare cortical areas involved in calculation in patients undergoing surgery for brain lesions. The organization of language and calculation areas was analyzed in relation to these surgical data. Twenty patients with brain lesions close to areas possibly involved in calculation (dominant parietal lobe and F2) were prospectively studied over a 4-year period. Four patients had preoperative symptoms of acalculia and therefore were not included in the brain mapping procedure. In 16 patients, direct electrostimulation caused calculation interferences in localized small cortical areas (< 2 cm(2)). Of the 53 calculation interferences found, 23 were independent of language areas, especially those in the inferior left parietal lobule. Various patterns of interference were observed (11 complete acalculia, 5 acalculia with wrong answers, 2 hesitations, and 5 mixed responses), although error patterns were fairly similar across angular, parietal, and frontal stimulation sites. Calculation areas in 4 patients could not be spared for oncological reasons; postoperatively, 3 of these patients showed significant acalculia symptoms. In contrast, none of the patients whose calculation areas were spared had arithmetic difficulties 1 month after surgery. Improvements in acalculia symptoms after surgery were also found in 3 of the 4 patients with preoperative calculation difficulties. To limit the risk of personal and professional disturbances caused by acquired anarithmetia in patients undergoing surgery for brain tumors or epilepsy, the authors think it is necessary to use a calculation task during brain mapping, especially when operating in the dominant parietal lobe.


The effects of Tim-3 activation on T-cells in gastric cancer progression.
The incidence of gastric cancer is high, especially in China. The present study aims to provide a novel therapeutic target for gastric cancer. Peripheral blood, cancerous and paracancerous tissues were collected from patients with gastric cancer. T-cell immunoglobulin mucin domain-3 (Tim-3) expression in T-cells was measured and the correlation between Tim-3 expression and the T staging of gastric cancer was analyzed. The levels of T-cell secreted interferon (IFN)-γ and tumor necrosis factor (TNF)-α were assessed following Tim-3 signaling pathway activation. A nude mouse model of gastric cancer was established and Tim-3-stimulated T-cells were injected into the mice to evaluate tumor growth. The results of the present study demonstrated that Tim-3 expression levels from the paracancerous and cancerous gastric tissues were significantly increased compared with the peripheral blood, while its expression was significantly increased in cancerous compared with paracancerous gastric tissues. With the T staging of gastric cancer increasing, the expression of Tim-3 gradually increased. The activation of the Tim-3 signaling pathway in T-cells may inhibit IFN-γ and TNF-α secretion, and the results from the nude mice tumor model demonstrated that the inhibitory effect on tumor growth by T-cells was reduced by Tim-3 signaling pathway activation. The expression level of Tim-3 on the surface of tumor infiltrating T-cells in gastric cancer tissue increases significantly and the increased Tim-3 signaling may inhibit the function of T-cells. The results suggest that the increased expression of Tim-3 on T-cells may be involved the development of gastric cancer.


Elderly people's accounts of home care rationing: missing voices in long-term care policy debates.
Fundamental shifts in state intervention in recent years have resulted in steady curtailment in public provision of community and social care. A longitudinal study of elderly women receiving home care in Ontario explored the reverberations of these shifts in the texture of frail elderly people's lives. Three distinct accounts of negotiating unstable and rationed home care were discernible. "Taking charge" was an active account of women successfully impressing their particular needs and identities on home care provision. "Pushed over the edge" was a vulnerable account of insufficient and depersonalized care in which participants felt themselves practically and emotionally out of control. In "Restraining expectations", women adjusted silently to the shortcomings of home care, stoically making themselves smaller as they found their previous orbits and identities unsupported. Home care's front line emerged as a complex site of struggle for identity and agency--a struggle in which elderly people engage with inventiveness and determination but also with dwindling support, few witnesses and in mounting isolation.


Review of atomic data needs for active charge-exchange spectroscopy on ITER.
The quantitative exploitation of active beam spectra is largely based on an advanced atomic modeling. Under the ITER operating conditions the penetration depth of a diagnostic beam into the plasma core crucially affects the intensities of spectral lines and hence the uncertainties of derived plasma parameters. A critical review of atomic data and an assessment of its error margins are, therefore, urgently needed. The aim of the present work is to verify the existing beam-stopping and beam-emission data for hydrogen beam in fusion plasmas. The agreement between the ADAS database and the present calculations is found to be within 5% for the beam-stopping data in a H-plasma. The calculation of beam attenuation in the presence of He-ash (4%) and Be ions (2%) demonstrates the agreement between the present data and the ADAS database within 10%. Finally, the maximum deviation of 15% is found only for beam-emission data at the electron density of 1x10(12)-2x10(12) cm(-3), which is significantly below the ITER density of 10(14) cm(-3).


[SERS and electrochemistry studies on the structure of thiourea adsorption layer on silver electrode].
The structure of thiourea adsorption layer on silver electrode was studied by SERS and electrochemistry. It was found that the thiourea can be adsorbed on the electrode surface and can inhibit the reaction of hydrogen separation. And a change in structure of the thiourea adsorption layer on electrode surface took place at the voltage of about -0.6V. The further SERS experiment showed that the thiourea adsorption layer has a loose structure at about -0.9V and a compact structure at about -0.3V - -0.5V. The transition region is at about -0.6V - -0.8V.


Polyunsaturated fatty acids and endocannabinoids in health and disease.
Polyunsaturated fatty acids (PUFAs) are lipid derivatives of omega-3 (docosahexaenoic acid, DHA, and eicosapentaenoic acid, EPA) or of omega-6 (arachidonic acid, ARA) synthesized from membrane phospholipids and used as a precursor for endocannabinoids (ECs). They mediate significant effects in the fine-tune adjustment of body homeostasis. Phyto- and synthetic cannabinoids also rule the daily life of billions worldwide, as they are involved in obesity, depression and drug addiction. Consequently, there is growing interest to reveal novel active compounds in this field. Cloning of cannabinoid receptors in the 90s and the identification of the endogenous mediators arachidonylethanolamide (anandamide, AEA) and 2-arachidonyglycerol (2-AG), led to the characterization of the endocannabinoid system (ECS), together with their metabolizing enzymes and membrane transporters. Today, the ECS is known to be involved in diverse functions such as appetite control, food intake, energy balance, neuroprotection, neurodegenerative diseases, stroke, mood disorders, emesis, modulation of pain, inflammatory responses, as well as in cancer therapy. Western diet as well as restriction of micronutrients and fatty acids, such as DHA, could be related to altered production of pro-inflammatory mediators (e.g. eicosanoids) and ECs, contributing to the progression of cardiovascular diseases, diabetes, obesity, depression or impairing conditions, such as Alzheimer' s disease. Here we review how diets based in PUFAs might be linked to ECS and to the maintenance of central and peripheral metabolism, brain plasticity, memory and learning, blood flow, and genesis of neural cells.


Biodegradable resistive switching memory based on magnesium difluoride.
This study presents a new type of resistive switching memory device that can be used in biodegradable electronic applications. The biodegradable device features magnesium difluoride as the active layer and iron and magnesium as the corresponding electrodes. This is the first report on magnesium difluoride as a resistive switching layer. With on-off ratios larger than one hundred, the device on silicon switches at voltages less than one volt and requires only sub-mA programming current. AC endurance of 10(3) cycles is demonstrated with ±1 V voltage pulses. The switching mechanism is attributed to the formation and rupture of conductive filaments comprising fluoride vacancies in magnesium difluoride. Devices fabricated on a flexible polyethylene terephthalate substrate are tested for functionality, and degradation is subsequently demonstrated in de-ionized water. An additional layer of magnesium difluoride is used to hinder the degradation and extend the lifetime of the device.


Is treatment with N-acetylcysteine to prevent contrast-induced nephropathy when using bicarbonate hydration out of date?
Chronic renal failure (CRF) is a major risk factor for contrast-induced nephropathy (CIN) and could be prevented by bicarbonate hydration. The effect of N-acetylcysteine (NAC) in preventing CIN in patients treated by bicarbonate hydration has never been investigated. Patients admitted for cardiac angiography from January 2002 to November 2004, with stable CRF (glomerular filtration rate (GFR) < 56 ml/min, Cockcroft-Gault formula) were included in a prospective, randomized, double-blind study comparing the efficacy of oral NAC + bicarbonate hydration vs oral placebo + bicarbonate hydration to prevent CIN. NAC 1,200 mg twice daily or placebo was given on Day -1 and Day 0 (Day 0 = cardiac angiography). A 1.4% bicarbonate solution (1 ml/ kg/h) was administered 12 hours before and after cardiac angiography. The overall CIN incidence on Day 2 was defined by one or more of the following criteria: increase in serum creatinine > 44.2 micromol/l, increase in serum creatinine > 25% or decrease in GFR > 5 ml/ min. Between NAC group (n = 28) and placebo group (n = 32) there was no difference in baseline demographics (age, sex ratio, weight, arterial hypertension, diabetes), in Day 0 characteristics (serum creatinine, GFR, hematocrit, protidemia) and in Day 0 cardiac angiography procedure (diagnostic or interventional, number of stents, type and volume of contrast media infused). The overall incidence of CIN in the NAC and placebo groups was 7.1 vs 9.3% (p = 1), respectively, and the rates of the observed criteria a, b, and c were 0 vs 6.3% (p = 0.49), 3.5 vs 6.3% (p = 1), and 7.1 vs 9.3% (p = 1). In CRF patients undergoing cardiac angiography, the use of bicarbonate hydration is associated with a very low incidence of CIN. In these conditions, on the basis of our results, we cannot draw any meaningful conclusion on the effect of NAC on the prevention of CIN.


Microglia activation precedes the anti-opioid BDNF and NMDA receptor mechanisms underlying morphine analgesic tolerance.
Herein, we investigated the role of periaqueductal gray (PAG)-resident microglia in the development of morphine tolerance and its underlying mechanisms. We showed that clodronate and minocycline known as microglia inhibitors reversed morphine tolerance, providing proof that microglia activation has key role in the development of morphine tolerance. The microglia-mediated anti-opioid mechanism occurs via sequential BDNF release and NMDA expression. Experimental evidence is provided here as conditional bdnf knockout mice (bdnf⁻/⁻) failed to develop tolerance following Cre-recombinase adenovirus treatment. Increased BDNF expression followed microglia activation in acute minocycline treatment reversible manner. Following BDNF release, NR2A subunit of NMDA receptor was upregulated in anti-BDNF reversible manner showing the contribution of BDNF signaling in the control of NMDA receptor expression following chronic morphine treatment. Our data provide compelling evidence that microglia activation and BDNF release are key regulators in opioid tolerance mechanism via glutaminergic synapse plasticity.


Sex, ADHD symptoms, and CHRNA5 genotype influence reaction time but not response inhibition.
People showing symptoms of attention deficit hyperactivity disorder (ADHD) often present an impairment of reaction time and response inhibition. These executive functions are influenced by nicotinergic acetylcholine receptors (nAchr) as mediators of cholinergic signaling, and show differences between both sexes. We examined the effects of two functional polymorphisms rs3841324 (S/L) and rs16969968 (G/A) of the cholinergic gene CHRNA5, ADHD symptoms and sex on response inhibition/reaction time in the Stop Signal Task. In the analyses, 183 participants (52.4% females) were included. In participants carrying the diplotype (SS_GG), men with ADHD symptoms responded faster, while men without ADHD symptoms were slower than women (F = 5.313; p = 0.023; ηp ² = 0.034). Although explorative, this threefold interaction on reaction time but not response inhibition extend previous findings, suggesting a moderating effect of ADHD symptoms in men carrying the CHRNA5 diplotype SS_GG and might inspire research on genotype- and gender-specific ADHD medication.


Long-term Follow-up of Autologous Fat Transfer vs Conventional Breast Reconstruction and Association With Cancer Relapse in Patients With Breast Cancer.
Autologous fat transfer (AFT or fat grafting) has become an invaluable tool for the correction of disfiguring deformities after breast cancer surgery. However, clinical and animal studies have shown conflicting results regarding its oncologic safety. To determine whether exposure to AFT vs conventional breast reconstruction is associated with increased rates of cancer relapse in patients with breast cancer. This matched cohort study involved retrospective medical record review to identify all patients in a local patient database receiving AFT between 2006 and 2014. Each AFT case was matched with a nonexposed control patient with similar baseline characteristics. The mean (SD) follow-up of patients receiving AFT was 9.3 (4.9) years including 5.0 (1.7) years following AFT. Control patients were followed up for a mean (SD) of 8.6 (1.8) years from the primary surgery. Patients were identified through the local patient database of the Tergooi Hospital in Hilversum, the Netherlands. A total of 287 patients with breast cancer (300 affected breasts) who received AFT for breast reconstruction after cancer were included in the intervention group. Each AFT case was matched with a respective control patient based on age, type of oncologic surgery, tumor invasiveness, and disease stage. In addition, individual AFT-control pairs were selected to have the same locoregional recurrence-free interval at baseline. Data were analyzed between 2016 and 2017. Reconstruction with AFT vs conventional breast reconstruction or none. Primary end points were the cumulative incidences of oncologic events in AFT and control patients and their respective hazard ratios. Of the 587 total patients, all were women and the mean age was 48.1 years for the patients undergoing AFT and 49.4 years for the control patients. Eight locoregional recurrences were observed in the treatment group (287 patients) and 11 among the control group (300 patients), leading to an unadjusted hazard ratio of 0.63 (95% CI, 0.25-1.60; P = .33). No increased locoregional recurrence rates were seen in relevant subgroups based on the type of oncological surgery, tumor invasiveness, or pathological stage. In addition, no increased risks with AFT were detected with respect to distant recurrences or breast cancer-specific mortality. No significant differences in the locoregional recurrence rates between the AFT and control groups were observed after 5 years of follow-up. These findings confirm the results of previous studies; therefore, clinical evidence suggesting that AFT is associated with increased risk for cancer relapse is still lacking.


Establish the habit: influenza vaccination for health care personnel.
Influenza vaccination of health care personnel (HCP) is a patient safety issue, but the national rate is only 42%. Following an intervention in 2006-2007, HCP in a large health system were surveyed. Self-reported influenza vaccination rate was 61.6% overall, did not differ by race, education level, or employment status but was higher for older HCP (> or =50 years; p=.002). In logistic regression, the strongest predictor of vaccination was receiving influenza vaccine the previous year, although other factors were significantly associated for younger and older HCP groups. Establishing the influenza vaccination habit using age-based targeted messages may be the most effective way to increase rates for HCP without mandates.


[A case of combined resection of multiple adjacent organs in a patient with locally advanced residual gastric cancer].
A 69-year-old man with a history of distal gastrectomy for early gastric cancer consulted our department concerning a possible diagnosis of sigmoid colon cancer. After detailed examination, he was diagnosed with type 3 advanced sigmoid colon cancer with colonic stenosis and large type 3 gastric cancer in the residual stomach with gross infiltration of the adjacent organs. The patient first underwent sigmoidectomy and then received a regimen of neoadjuvant combination chemotherapy with S-1, cisplatin( CDDP), and Lentinan( LNT)( S-1 80 mg/m2, CDDP 60 mg/m2, and LNT 2 mg/body twice weekly for 2 weeks) for gastric cancer( cT4b[ SI, liver, pancreas], N2M0H0, Stage IIIC). After 2 courses of treatment, the gastric tumor had reduced in size but had penetrated the transverse colon. We performed total resection of the gastric remnant, D2 lymph node dissection, and en bloc resection of the transverse colon, partial liver, pancreas body and tail, partial diaphragm, and pericardium. S-1/CDDP (a total of 11 courses) followed by single-agent S-1 therapy was continued as adjuvant chemotherapy. With a follow-up time of 3 years and 10 months, no recurrence was noted following total resection of the gastric remnant.


Responsiveness, affinity constants and beta-adrenoceptor reserves for isoprenaline on aortae from normo-, pre- and hypertensive rats.
The objective of this study was to determine the responsiveness, affinity constants and beta-adrenoceptor reserves for isoprenaline on the isolated aorta in the maturation of normotensive and hypertensive rats. The effects of a very slowly reversible antagonist, bromoacetylal-prenololmenthane (BAAM), on the relaxant responses of the aortae of 5- and 14-week-old Wistar Kyoto normotensive rats (WKY) and spontaneously hypertensive rats (SHRs) to isoprenaline were determined. Five-week-old SHRs are pre-hypertensive and the aortic rings are less responsive to isoprenalinethan age-matched WKY (pD2 values: WKY, 8.40; SHRs, 8.03). Similar relaxant responses to forskol in were obtained on the aortae of 5- and 14-week-old WKY and SHRs. The K(A) value for isoprenaline at the aortic beta2-adrenoceptors of the 5-week-old WKY was 2.1 x 10(-7) M, and similar values were obtained on the aortae of 5-week-old SHR and 14-week-old WKY and SHRs. In the maturation of the WKY aortae from 5 to 14 weeks, there was a reduction in the maximum response, a major loss of sensitivity and a loss of beta2-adrenoceptor reserve for isoprenaline. On 5-week-old SHR aorta, the sensitivity to isoprenaline was 2.5-fold lower, and the beta2-adrenoceptor reserve was less than on age-matched WKY. In the development of hypertension on the SHR aorta from 5 to 14 weeks, there was a reduction in the maximum response to isoprenaline. At 14 weeks, the sensitivity and the beta-adrenoceptor reserve to isoprenaline were similar, but the maximum responses were lower on the SHR than WKY. As there are differences in pre-hypertensive SHR and age-matched WKY aortic responses to isoprenaline, it is no longer valid to consider that the loss of responsiveness to isoprenaline in hypertension is solely owing to the hypertension. There are no changes in affinity, but major changes in the sensitivity, maximum responses and aortic beta2-adrenoceptor reserves to isoprenaline in the maturation of normotensive and pre-hypertensive aortae.


Inferring the dynamics of mutated hematopoietic stem and progenitor cells induced by IFNα in myeloproliferative neoplasms.
Classical BCR-ABL-negative myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells (HSCs) caused mainly by recurrent mutations in genes encoding JAK2 (JAK2), calreticulin (CALR), or the thrombopoietin receptor (MPL). Interferon α (IFNα) has demonstrated some efficacy in inducing molecular remission in MPNs. To determine factors that influence molecular response rate, we evaluated the long-term molecular efficacy of IFNα in patients with MPN by monitoring the fate of cells carrying driver mutations in a prospective observational and longitudinal study of 48 patients over more than 5 years. We measured the clonal architecture of early and late hematopoietic progenitors (84 845 measurements) and the global variant allele frequency in mature cells (409 measurements) several times per year. Using mathematical modeling and hierarchical Bayesian inference, we further inferred the dynamics of IFNα-targeted mutated HSCs. Our data support the hypothesis that IFNα targets JAK2V617F HSCs by inducing their exit from quiescence and differentiation into progenitors. Our observations indicate that treatment efficacy is higher in homozygous than heterozygous JAK2V617F HSCs and increases with high IFNα dose in heterozygous JAK2V617F HSCs. We also found that the molecular responses of CALRm HSCs to IFNα were heterogeneous, varying between type 1 and type 2 CALRm, and a high dose of IFNα correlates with worse outcomes. Our work indicates that the long-term molecular efficacy of IFNα implies an HSC exhaustion mechanism and depends on both the driver mutation type and IFNα dose.


Factors associated with health-related quality of life in patients and significant others one month after coronary artery bypass grafting.
To describe and compare the health-related quality of life of patients and their significant others and to identify factors associated with health-related quality of life one month after coronary artery bypass surgery. Heart disease and coronary artery bypass surgery affect the life of patients and their significant others. Following surgery, some patients might feel their quality of life is poor. Significant others are a major source of support for patients; therefore, it is important to know how their health-related quality of life is affected. This study is part of a major longitudinal research project. The questionnaire data for the study were collected one month after the surgical procedure from 270 patients and 240 significant others at one Finnish university hospital. Data analysis was by descriptive and inferential statistics. Stepwise linear regression analysis was used as a multivariate method. Coronary artery bypass grafting patients had a poorer health-related quality of life than both the age and gender-standardised general population and their significant others. Significant others, on the other hand, had the same health-related quality of life as the general population. In patients, health-related quality of life was associated with the occurrence of cardiac symptoms and New York Heart Association class; in significant others, it was explained by chronic illnesses, employment, gender and emotional support received from members of the support network. In the early stages of recovery, the health-related quality of life of coronary artery bypass grafting patients is inferior to that of the general population. There are also differences in the health-related quality of life of patients and their significant others. Postcoronary artery bypass grafting rehabilitation programmes should provide support for both patients and significant others through networks that involve both professionals and peer supporters.


Influence of renal function on anticoagulation control in patients with non-valvular atrial fibrillation taking vitamin K antagonists.
Chronic kidney disease (CKD) has been related to poor anticoagulation control and an increased risk of bleeding. This study aims to evaluate the association between impaired renal function (eGFR <60 mL/min/1.73 m2 ) and anticoagulation control in patients with non-valvular atrial fibrillation (AF) on vitamin K antagonists (VKA) therapy. We also assessed whether the predictive value of the SAMe-TT2 R2 score prevailed for subgroups both with and without CKD. This is an ancillary analysis of 1381 patients from the PAULA study, which was a cross-sectional, retrospective and nationwide multicenter study. A total of 370 patients had eGFR <60 mL/min/1.73 m2 . Anticoagulation control levels progressively worsened across each stage of CKD. Multiple linear regression analysis showed CKD as an independent predictor of time in therapeutic range (TTR). In the subgroup of patients with preserved renal function, female sex, diet affecting INR, polypharmacy and amiodarone were associated with poorer TTR. The SAMe-TT2 R2 score had a significant but modest predictive value for TTR<65% (AUC, area under the curve 0.558, P = .002). In the subgroup of patients with CKD, the SAMe-TT2 R2 (>2 points) showed no significant predictive capacity for TTR (AUC 0.528, P = .354). The average TTR was similar for both sexes (P = .255), but with a higher percentage of males subjects with TTR ≥65% (P = .013). Chronic kidney disease is associated with poor anticoagulation control in patients with non-valvular AF taking VKA. The SAMe-TT2 R2 score was not predictive of poor TTR in the subgroup with CKD, although a modest predictive value for poor TTR was found in those without CKD.


Voice problems of group fitness instructors: diagnosis, treatment, perceived and experienced attitudes and expectations of the industry.
To determine the anatomical and physiological nature of voice problems and their treatment in those group fitness instructors (GFIs) who have sought a medical diagnosis; the impact of voice disorders on quality of life and their contribution to activity limitations and participation restrictions; and the perceived attitudes and level of support from the industry at large in response to instructor's voice disorders and need for treatment. Prospective self-completion questionnaire design. Thirty-eight individuals (3 males and 35 females) currently active in the Australian fitness industry who had been diagnosed with a voice disorder completed an online self-completion questionnaire administered via SurveyMonkey. Laryngeal pathology included vocal fold nodules (N = 24), vocal fold cysts (N = 2), vocal fold hemorrhage (N = 1), and recurrent chronic laryngitis (N = 3). Eight individuals reported vocal strain and muscle tension dysphonia without concurrent vocal fold pathology. Treatment methods were variable, with 73.68% (N = 28) receiving voice therapy alone, 7.89% (N = 3) having voice therapy in combination with surgery, and 10.53% (N = 4) having voice therapy in conjunction with medication. Three individuals (7.89%) received no treatment for their voice disorder. During treatment, 82% of the cohort altered their teaching practices. Half of the cohort reported that their voice problems led to social withdrawal, decreased job satisfaction, and emotional distress. Greater than 65% also reported being dissatisfied with the level of industry and coworker support during the period of voice recovery. This study identifies that GFIs are susceptible to a number of voice disorders that impact their social and professional lives, and there is a need for more proactive training and advice on voice care for instructors, as well as those in management positions within the industry to address mixed approaches and opinions regarding the importance of voice care.


Improving a fish intestinal barrier model by combining two rainbow trout cell lines: epithelial RTgutGC and fibroblastic RTgutF.
An in vitro model of the fish intestine is of interest for research and application in diverse fields such as fish physiology, aquaculture and chemical risk assessment. The recently developed epithelial barrier model of the fish intestine relies on the RTgutGC cell line from rainbow trout (Oncorhynchus mykiss), cultured in inserts on permeable membranes. Our aim was to extend the current system by introducing intestinal fibroblasts as supportive layer in order to reconstruct the epithelial-mesenchymal interface as found in vivo. We therefore initiated and characterized the first fibroblast cell line from the intestine of rainbow trout, which has been termed RTgutF. Co-culture studies of RTgutGC and RTgutF were performed on commercially available electric cell substrate for impedance sensing (ECIS) and on newly developed ultrathin, highly porous alumina membranes to imitate the cellular interaction with the basement membrane. Cellular events were examined with non-invasive impedance spectroscopy to distinguish between barrier tightness and cell density in the ECIS system and to determine transepithelial electrical resistance for cells cultured on the alumina membranes. We highlight the relevance of the piscine intestinal fibroblasts for an advanced intestinal barrier model, particularly on ultrathin alumina membranes. These membranes enable rapid crosstalk of cells cultured on opposite sides, which led to increased barrier tightening in the fish cell line-based epithelial-mesenchymal model.


Management of musculoskeletal dysfunction in infants.
Excessive crying (or infant colic) is a common pain syndrome of infancy without any specific known aetiology or effective management. Many cases result in long-term poor sleep, behavioral problems and parental stress. The biomechanical aspects of this condition lack adequate investigation despite its strong link with assisted and/or difficult births. The present review focused on the current trends in the management of this mal-musculoskeletal health of infants associated with the condition of excessive crying. In addition, the risk factors associated with therapeutic procedures used to manage the above conditions were also discussed.


A tomato bZIP transcription factor, SlAREB, is involved in water deficit and salt stress response.
Abiotic stresses such as cold, water deficit, and salt stresses severely reduce crop productivity. Tomato (Solanum lycopersicum) is an important economic crop; however, not much is known about its stress responses. To gain insight into stress-responsive gene regulation in tomato plants, we identified transcription factors from a tomato cDNA microarray. An ABA-responsive element binding protein (AREB) was identified and named SlAREB. In tomato protoplasts, SlAREB transiently transactivated luciferase reporter gene expression driven by AtRD29A (responsive to dehydration) and SlLAP (leucine aminopeptidase) promoters with exogenous ABA application, which was suppressed by the kinase inhibitor staurosporine, indicating that an ABA-dependent post-translational modification is required for the transactivation ability of SlAREB protein. Electrophoretic mobility shift assays showed that the recombinant DNA-binding domain of SlAREB protein is able to bind AtRD29A and SlLAP promoter regions. Constitutively expressed SlAREB increased tolerance to water deficit and high salinity stresses in both Arabidopsis and tomato plants, which maintained PSII and membrane integrities as well as water content in plant bodies. Overproduction of SlAREB in Arabidopsis thaliana and tomato plants regulated stress-related genes AtRD29A, AtCOR47, and SlCI7-like dehydrin under ABA and abiotic stress treatments. Taken together, these results show that SlAREB functions to regulate some stress-responsive genes and that its overproduction improves plant tolerance to water deficit and salt stress.


Single-tooth osteotomy for intention replantation.
The conventional replantation technique has many drawbacks. The tooth may break during extraction; thus, teeth with diverged or curved roots are not good candidates for such a procedure. The occurrence of root ankylosis after replantation, with subsequent resorption, does not permit the replanted tooth to support any additional load, such as an orthodontic appliance or to be used as a bridge abutment. The procedure described here is designed to eliminate these drawbacks. The technique is based on leaving the delicate periodontal ligament fibers intact and transferring the wound created to the bone tissue. Extraction is achieved by a single-tooth osteotomy with the hope of improving the success rate of replantation.


[Seniors and cardiovascular medications].
Authors analyze the situation in the therapy of cardiovascular diseases--unsatisfactory situation especially from the dyslipidaemia point of view. Different groups of medications are discussed and their risks for elderly patients. Angiotensin converting enzyme blockers and their influence on the endothelial dysfunction, but the risk of hyperpotassemia are showed. The risk of gastrointestinal bleeding during the treatment with antiagregants and anticoagulants, the risk of bradycardia in beta-blockade, possible interactions with other medications lowering the heart rate are discussed. Attention is paid to calcium channel blockers, diuretics and digoxin. The table containing possible clinical symptoms of unwanted side effect of most frequently used cardiovascular medications in elderly is added as the conclusion of the article.


Comparative study of the 48-hour response to soluble antigens obtained from human and armadillo leprosy material in lepromatous leprosy patients and normal persons, contacts of leprosy patients.
We prepared antigens by precipitating with 80% ammonium sulfate supernatants of human and armadillo antigen at a concentration of 160 X 10(6) bacteria per ml. The precipitate was resuspended, dialyzed and filtered. The antigen obtained was inactivated with trypsin during 30 minutes. The tests made with these antigens were negative for the 48-hour test in lepromatous patients and highly positive in normal persons who were contacts of leprosy patients.


Thoracoscopic findings and pharmacokinetics of inhaled fluorescein in a pig model.
Fluorescein-enhanced autofluorescence thoracoscopy (FEAT) reveals regions of abnormal fluorescence in patients with primary spontaneous pneumothorax and in normal subjects. Some of these lesions are undetectable by white light thoracoscopy and it has been hypothesized that they represent underlying pleural and/or parenchymal abnormalities. In order to standardize and evaluate this novel technique, we developed an animal model. Six pigs underwent thoracoscopy after the inhalation of nebulized sodium fluorescein by either volume-controlled mechanical ventilation or spontaneous ventilation. Pleural cavity and lung surface were inspected by white light thoracoscopy and FEAT during a period of 90 min. Fluorescence intensities were quantified in pleura and in blood. Regions of interest were examined postmortem for a histological assessment of the lesions. FEAT lesions were observed in all animals, with a maximum intensity of the lesions 20-30 min after the onset of fluorescein administration. The plasma concentrations of sodium fluorescein reached a maximum after approximately 20 min. The microscopic findings suggest that fluorescein accumulates in the subpleural space of better ventilated lung areas. This is the first animal model using FEAT. Valuable information has been gathered but further investigations are required to explain the phenomena observed in humans and pigs.


On the designs of thorough QT/QTc clinical trials.
A thorough QT trial is typically designed to test for two set of hypotheses. The primary set of hypotheses is for demonstrating that the test treatment will not prolong QT interval. The second set of hypotheses is to demonstrate the assay sensitivity of the positive control treatment in the study population. The conventional designs of thorough QT studies are parallel arms and crossover trials. Although the sample size requirements, the time points of analysis, and the durations of drug administration to reach a steady stage are all different between the test and positive control treatments, the trials are often designed with equal study duration and sample size for the different treatment arms or periods. In order to reduce the number of subjects needed for the parallel-arm thorough QT clinical trial, unconventional designs were proposed and used in the recent years. In this article, we review and discuss a few of the designs and propose some additional designs in the form of unbalanced, group sequential, and adaptive designs with the objective to improve trial efficiency or to reduce the risk of unnecessarily exposure of subjects to the potentially harmful positive control treatment.


Close to the Edge: Growth Restrained by the NAD(P)H/ATP Formation Flux Ratio.
Most fermentative microorganisms grow well-under anaerobic conditions managing a balanced redox and appropriate energy metabolism, but a few species do exist in which cells have to cope with inadequate energy recovery or capture and/or redox balancing. Two cases of these species, i.e., the metabolically engineered Saccharomyces cerevisiae enabling it to ferment xylose and Lactobacillus reuteri fermenting glucose via the phosphoketolase pathway, are here used to introduce a quantification parameter to capture what limits the growth rate of these microorganisms under anaerobic conditions. This dimensionless parameter, the cofactor formation flux ratio (RJ ), is the ratio between the redox formation flux (JNADH+NADPH), and the energy carrier formation flux (JATP), which are mainly connected to the central carbon pathways. Data from metabolic flux analyses performed in previous and present studies were used to estimate the RJ -values. Even though both microorganisms possess different central pathways, a similar relationship between RJ and the specific growth rate (μ) was found. Furthermore, for both microorganisms external electron acceptors moderately reduced the RJ -value, thereby raising the μ accordingly. Based on the emerging profile of this relationship an interpretation is presented suggesting that this quantitative analysis can be applied beyond the two microbial species experimentally investigated in the current study to provide data for future targeted strain development strategies.


Antipsychotic medication side effect assessment tools: A systematic review.
The aim of this systematic review was to critically appraise the psychometric properties of antipsychotic medication side effect assessment tools. Systematic searches were undertaken in PubMed, CINAHL and CENTRAL from inception to October 2014. Studies were included if they detailed the evaluation of psychometric properties of antipsychotic medication side effect assessment tools in mental health populations. Studies were excluded if they examined the use of antipsychotic medication side effect assessment tools in non-mental health populations, including people suffering from dementia, Parkinsonism and Alzheimer's. Narrative reviews and studies published in any language other than English were also excluded. Content validity was appropriately established for only one of the tools, reliability was inappropriately evaluated for all but one tool, and the assessment of responsiveness was not acceptable for any tool. Further psychometric studies are warranted to consolidate the psychometric properties of the included antipsychotic medication side effect assessment tools before any of these tools can be confidently recommended for either research or clinical purposes.


An analysis of topics and vocabulary in Chinese oral narratives by normal speakers and speakers with fluent aphasia.
This study analysed the topic and vocabulary of Chinese speakers based on language samples of personal recounts in a large spoken Chinese database recently made available in the public domain, i.e. Cantonese AphasiaBank ( http://www.speech.hku.hk/caphbank/search/ ). The goal of the analysis is to offer clinicians a rich source for selecting ecologically valid training materials for rehabilitating Chinese-speaking people with aphasia (PWA) in the design and planning of culturally and linguistically appropriate treatments. Discourse production of 65 Chinese-speaking PWA of fluent types (henceforth, PWFA) and their non-aphasic controls narrating an important event in their life were extracted from Cantonese AphasiaBank. Analyses of topics and vocabularies in terms of part-of-speech, word frequency, lexical semantics, and diversity were conducted. There was significant overlap in topics between the two groups. While the vocabulary was larger for controls than that of PWFA as expected, they were similar in distribution across parts-of-speech, frequency of occurrence, and the ratio of concrete to abstract items in major open word classes. Moreover, proportionately more different verbs than nouns were employed at the individual level for both speaker groups. The findings provide important implications for guiding directions of aphasia rehabilitation not only of fluent but also non-fluent Chinese aphasic speakers.


Osteopontin promoter polymorphisms at locus -443 are associated with metastasis and poor prognosis of human intrahepatic cholangiocarcinoma in Chinese population.
Osteopontin (OPN) is known to be a secreted adhesive glycoprotein. Role of OPN in human intrahepatic cholangiocarcinoma (ICC) has not been well understood. This study explored whether genetic variations in the osteopontin gene are associated with ICC risk, progression and metastasis. 260 patients with stages I to IV between 2008 and 2013 were recruited in this study and same number healthy persons were used as control. OPN-66 T/G, -156 G/GG and -443 C/T variants were genotyped using DNA from blood lymphocytes. Chi-square test and a Fisher's exact test were used to analyze the genotype distribution between healthy subjects and patients, and further its distribution among TNM stages and incidence metastasis in patients. For the variant at nt- 443 (CC), there was a significant difference between the number of patients with stage IV and those with all other stages of ICC (P < 0.01). Patients with -443 (CC) variant had significant higher incidence of lymph and distant metastasis development compared to other genotypes. For the variant at nt- 443 (CT), there was a significant difference between the number of ICC patients with stage III + IV and those with stage I + II (P < 0.01). The survival rates for ICC patients with the C/C genotype were significantly lower than for patients with the other two genotypes (C/T, T/T). OPN -443 C/T polymorphism is a potential predictive marker of metastasis and poor prognosis in ICC patients.


A longitudinal study of pulmonary involvement in primary Sjögren's syndrome: relationship between alveolitis and subsequent lung changes on high-resolution computed tomography.
Eighteen non-smoking women suffering from primary Sjögren's syndrome (pSS) with previously documented alveolitis were re-examined, clinically and by pulmonary function tests (PFT), bronchoalveolar lavage (BAL), chest X-ray and high-resolution computed tomography (HRCT) after a 2 yr follow-up period. Longitudinal evaluation revealed unchanged PFT. The final BAL study showed a normal differential count in six of 14 patients with initial lymphocyte alveolitis, and a persistent alveolar lymphocytosis in the remaining eight patients, associated with an increased percentage of neutrophils in one of them. In four patients with initial mixed alveolitis, the BAL cell profile was unchanged 2 yr later. Five of 18 patients (28%) had abnormal HRCT, represented by isolated septal/subpleural lines in three patients, ground-glass opacities with irregular pleural margins in one patient, and ground-glass opacities associated with septal/subpleural lines in another. All these patients had abnormal BAL results with an increased proportion of both neutrophils and lymphocytes. The presence of alveolar neutrophils was associated with a significantly (P=0.005) greater mean rate of reduction of carbon monoxide diffusing capacity (DLCO) -- more than four times the normal rate of loss of DLCO. Chest X-ray, repeated at the end of the 2 yr follow-up period, showed parenchymal abnormalities in only one patient who had evidence of fibrosis on HRCT. This study provides evidence that lung involvement is not an uncommon extraglandular manifestation of pSS and that a BAL neutrophilia may play an important role in the pathogenesis of pulmonary disease in this autoimmune disorder.


Bronchial responsiveness after inhalation of cotton bract extract.
This study examined nonspecific airway responsiveness to methacholine (MC) after inhalation of cotton bract extract (CBE). In a randomized double-blind, crossover trial, 13 healthy volunteers underwent an MC inhalation challenge test prior to inhalation of CBE and normal saline solution (NSS) aerosol sham as well as 2, 8, 24, and 168 h (7 days) later. The response parameter was the concentration of MC required to induce a 25% decrement in the maximal expiratory flow at 40% of the vital capacity below total lung capacity on the partial expiratory flow-volume curve (PC25MEF40%(P]. Five of 13 subjects demonstrated a ventilatory response to CBE with a 20% or larger decrement in the MEF40%(P); no subject demonstrated such change with NSS. For the group, the maximal decrement in MEF40%(P) was to 76.5 +/- 20.3% of baseline (mean +/- SD), occurring approximately 60 to 90 min after provocation, whereas the largest decrement after normal saline was to 88 +/- 10.6% of baseline, occurring immediately after inhalation. Changes in airway responsiveness to MC were transient. For example, the PC25MEF40%(P) for the group (mean +/- SD) was 51.3 +/- 41.1 mg/ml at baseline and 25.8 +/- 30.3 and 52.2 +/- 57.3 mg/ml at 2 and 8 h. After a pre-sham baseline of 50.4 +/- 43.2 mg/ml, PC25MEF40%(P) was 57.6 +/- 83.8 and 153.8 +/- 148 mg/ml at 2 and 8 h. Repeated measures ANOVA on these acute, same-day changes (i.e., 2 and 8 h after provocation) demonstrated a statistically significant effect of CBE on airway responsiveness (p = 0.048). These data demonstrate that inhalation of CBE, in addition to bronchospasm, causes a transient increase in airway responsiveness.