Efficacy of a new implant-abutment connection to minimize microbial contamination: an in vitro study.
The aim of the present study is to evaluate the effectiveness of Ditron implants abutment connection (IAC) to sealing the gap between two pieces. To identify the efficacy of a new IAC, the passage of genetically modified bacteria across IAC was evaluated. A total of five Ditron Implants were used. All implants were immerged in a bacterial culture for forty-eight hours and then bacteria amount was measured inside and outside IAC with Real-time PCR. Bacterial quantification was performed by Real-Time Polymerase Chain Reaction using the absolute quantification with the standard curve method. In all the tested implants, bacteria were found in the inner side, with a median percentage of 1.35%. The analysis revealed that, in untreated implants, bacteria grew (internally and externally). Moreover, the difference between outer and inner bacteria concentration was statistically significant at each time point. Ditron Implant IAC (MPI, Ditron Dental, Israel) is efficacy in reducing bacterial leakage.


Actuarial analysis of private payer administrative claims data for women with endometriosis.
Endometriosis is a painful, chronic disease affecting 5.5 million women and girls in the United States and Canada and millions more worldwide. The usual age range of women diagnosed with endometriosis is 20 to 45 years. Endometriosis has an estimated prevalence of 10% among women of reproductive age, although estimates of prevalence vary greatly. Endometriosis is the most common gynecological cause of chronic pelvic pain, but published information on its associated medical care costs is scarce. The aim of this study was to determine (1) the prevalence of endometriosis in the United States, (2) the amount of health care services used by women coded with endometriosis in a commercial medical claims database during 1999 to 2003, and (3) the endometriosis-related costs for 2003, the most recent data available at the time the study was performed. This study was a retrospective review of administrative data for commercial payers, which included enrollment, eligibility, and claims payment data contained in the Medstat Marketscan database for approximately 4 million commercial insurance members. All claims and membership data were extracted for each woman aged 18 to 55 years who had at least 1 medical or hospital claim with a diagnosis code for endometriosis (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 617.00-617.99) for 1999 through 2003. Claims data from 1999 through 2003 were used to determine prevalence and health care resource utilization (i.e., annual admission rate, annual surgical rate, distribution of endometriosis-related surgeries, and prevalence of comorbid conditions). The cost analysis was based on claims from 2003 only. Cost was defined as the payer-allowed charge, which equals the net payer cost plus member cost share. The prevalence of women with medical claims (inpatient and/or outpatient) containing ICD-9-CM codes for endometriosis was 1.1% for the age band of 30 to 39 years and 0.7% over the entire age span of 18 to 55 years. The medical costs per patient per month (PPPM) for women with endometriosis were 63% greater ($706 PPPM) than those of the average woman per member per month ($433) in 2003; inpatient hospital costs accounted for 32% of total direct medical costs. Between 1999 and 2003, these women with endometriosis who were identified by either inpatient and/or outpatient claims had high rates of hospital admission (53% for any reason; 38% for an endometriosis-related reason) and a high annual surgical procedure rate (64%). Additionally, women with endometriosis frequently suffered from comorbid conditions, and these conditions were associated with greater PPPM costs of 15% to 50% for women with an endometriosis diagnosis code, depending on the condition. Interstitial cystitis was associated with 50% greater cost ($1,061 PPPM); depression, 41% ($997 PPPM); migraine, 40% ($988 PPPM); irritable bowel syndrome, 34% ($943 PPPM); chronic fatigue syndrome, 29% ($913 PPPM); abdominal pain, 20% ($846 PPPM); and infertility, 15% ($813 PPPM). Women with endometriosis have a high hospital admission rate and surgical procedure rate and a high incidence of comorbid conditions. Consequently, these women incur total medical costs that are, on average, 63% higher than medical costs for the average woman in a commercially insured group.


Peacocks, Porsches, and Thorstein Veblen: conspicuous consumption as a sexual signaling system.
Conspicuous consumption is a form of economic behavior in which self-presentational concerns override desires to obtain goods at bargain prices. Showy spending may be a social signal directed at potential mates. We investigated such signals by examining (a) which individuals send them, (b) which contexts trigger them, and (c) how observers interpret them. Three experiments demonstrated that conspicuous consumption is driven by men who are following a lower investment (vs. higher investment) mating strategy and is triggered specifically by short-term (vs. long-term) mating motives. A fourth experiment showed that observers interpret such signals accurately, with women perceiving men who conspicuously consume as being interested in short-term mating. Furthermore, conspicuous purchasing enhanced men's desirability as a short-term (but not as a long-term) mate. Overall, these findings suggest that flaunting status-linked goods to potential mates is not simply about displaying economic resources. Instead, conspicuous consumption appears to be part of a more precise signaling system focused on short-term mating. These findings contribute to an emerging literature on human life-history strategies.


Ethylene-responsive element-binding factor 5, ERF5, is involved in chitin-induced innate immunity response.
Our recent work demonstrated that chitin treatment modulated the expression of 118 transcription factor (TF) genes in Arabidopsis. To investigate the potential roles of these TF in chitin signaling and plant defense, we initiated an interaction study among these TF proteins, as well as two chitin-activated mitogen-activated protein kinases (MPK3 and MPK6), using a yeast two-hybrid system. This study revealed interactions among the following proteins: three ethylene-responsive element-binding factors (ERF), five WRKY transcription factors, one scarecrow-like (SCL), and the two MPK, in addition to many other interactions, reflecting a complex TF interaction network. Most of these interactions were subsequently validated by other methods, such as pull-down and in planta bimolecular fluorescence complementation assays. The key node ERF5 was shown to interact with multiple proteins in the network, such as ERF6, ERF8, and SCL13, as well as MPK3 and MPK6. Interestingly, ERF5 appeared to negatively regulate chitin signaling and plant defense against the fungal pathogen Alternaria brassicicola and positively regulate salicylic acid signaling and plant defense against the bacterial pathogen Pseudomonas syringae pv. tomato DC3000. Therefore, ERF5 may play an important role in plant innate immunity, likely through coordinating chitin and other defense pathways in plants in response to different pathogens.


Unravelling the link between neurodevelopmental disorders and short tandem CGG-repeat expansions.
Neurodevelopmental disorders (NDDs) encompass a diverse group of disorders characterised by impaired cognitive abilities and developmental challenges. Short tandem repeats (STRs), repetitive DNA sequences found throughout the human genome, have emerged as potential contributors to NDDs. Specifically, the CGG trinucleotide repeat has been implicated in a wide range of NDDs, including Fragile X Syndrome (FXS), the most common inherited form of intellectual disability and autism. This review focuses on CGG STR expansions associated with NDDs and their impact on gene expression through repeat expansion-mediated epigenetic silencing. We explore the molecular mechanisms underlying CGG-repeat expansion and the resulting epigenetic modifications, such as DNA hypermethylation and gene silencing. Additionally, we discuss the involvement of other CGG STRs in neurodevelopmental diseases. Several examples, including FMR1, AFF2, AFF3, XYLT1, FRA10AC1, CBL, and DIP2B, highlight the complex relationship between CGG STR expansions and NDDs. Furthermore, recent advancements in this field are highlighted, shedding light on potential future research directions. Understanding the role of STRs, particularly CGG-repeats, in NDDs has the potential to uncover novel diagnostic and therapeutic strategies for these challenging disorders.


Regulated binding of PTP1B-like phosphatase to N-cadherin: control of cadherin-mediated adhesion by dephosphorylation of beta-catenin.
Cadherins are a family of cell-cell adhesion molecules which play a central role in controlling morphogenetic movements during development. Cadherin function is regulated by its association with the actin containing cytoskeleton, an association mediated by a complex of cytoplasmic proteins, the catenins: alpha, beta, and gamma. Phosphorylated tyrosine residues on beta-catenin are correlated with loss of cadherin function. Consistent with this, we find that only nontyrosine phosphorylated beta-catenin is associated with N-cadherin in E10 chick retina tissue. Moreover, we demonstrate that a PTP1B-like tyrosine phosphatase associates with N-cadherin and may function as a regulatory switch controlling cadherin function by dephosphorylating beta-catenin, thereby maintaining cells in an adhesion-competent state. The PTP1B-like phosphatase is itself tyrosine phosphorylated. Moreover, both direct binding experiments performed with phosphorylated and dephosphorylated molecules, and treatment of cells with tyrosine kinase inhibitors indicate that the interaction of the PTP1B-like phosphatase with N-cadherin depends on its tyrosine phosphorylation. Concomitant with the tyrosine kinase inhibitor-induced loss of the PTP1B-like phosphatase from its association with N-cadherin, phosphorylated tyrosine residues are retained on beta-catenin, the association of N-cadherin with the actin containing cytoskeleton is lost and N-cadherin-mediated cell adhesion is prevented. Tyrosine phosphatase inhibitors also result in the accumulation of phosphorylated tyrosine residues on beta-catenin, loss of the association of N-cadherin with the actin-containing cytoskeleton, and prevent N-cadherin mediated adhesion, presumably by directly blocking the function of the PTP1B-like phosphatase. We previously showed that the binding of two ligands to the cell surface N-acetylgalactosaminylphosphotransferase (GalNAcPTase), the monoclonal antibody 1B11 and a proteoglycan with a 250-kD core protein, results in the accumulation of phosphorylated tyrosine residues on beta-catenin, uncoupling of N-cadherin from its association with the actin containing cytoskeleton, and loss of N-cadherin function. We now report that binding of these ligands to the GalNAcPTase results in the absence of the PTP1B-like phosphatase from its association with N-cadherin as well as the loss of the tyrosine kinase and tyrosine phosphatase activities that otherwise co-precipitate with N-cadherin. Control antibodies and proteoglycans have no such effect. This effect is similar to that observed with tyrosine kinase inhibitors, suggesting that the GalNAcPTase/proteoglycan interaction inhibits a tyrosine kinase, thereby preventing the phosphorylation of the PTP1B-like phosphatase, and its association with N-cadherin. Taken together these data indicate that a PTP1B-like tyrosine phosphatase can regulate N-cadherin function through its ability to dephosphorylate beta-catenin and that the association of the phosphatase with N-cadherin is regulated via the interaction of the GalNAcPTase with its proteoglycan ligand. In this manner the GalNAcPTase-proteoglycan interaction may play a major role in morphogenetic cell and tissue interactions during development.


Path Integral Simulations of Proton Transfer Reactions in Aqueous Solution Using Combined QM/MM Potentials.
A bisection sampling method was implemented in path integral simulations of chemical reactions in solution in the framework of the quantized classical path approach. In the present study, we employ a combined quantum mechanical and molecular mechanical (QM/MM) potential to describe the potential energy surface and the path integral method to incorporate nuclear quantum effects. We examine the convergence of the bisection method for two proton-transfer reactions in aqueous solution at room temperature. The first reaction involves the symmetrical proton transfer between an ammonium ion and an ammonia molecule. The second reaction is the ionization of nitroethane by an acetate ion. To account for nuclear quantum mechanical corrections, it is sufficient to quantize the transferring light atom in the ammonium ion-ammonia reaction, while it is necessary to also quantize the donor and acceptor atoms in the nitroethane-acetate ion reaction. Kinetic isotope effects have been computed for isotopic substitution of the transferring proton by a deuteron in the nitroethane-acetate reaction. In all computations, it is important to employ a sufficient number of polymer beads along with a large number of configurations to achieve convergence in these simulations.


The promise of N-acetylcysteine in neuropsychiatry.
N-Acetylcysteine (NAC) targets a diverse array of factors germane to the pathophysiology of multiple neuropsychiatric disorders including glutamatergic transmission, the antioxidant glutathione, neurotrophins, apoptosis, mitochondrial function, and inflammatory pathways. This review summarises the areas where the mechanisms of action of NAC overlap with known pathophysiological elements, and offers a précis of current literature regarding the use of NAC in disorders including cocaine, cannabis, and smoking addictions, Alzheimer's and Parkinson's diseases, autism, compulsive and grooming disorders, schizophrenia, depression, and bipolar disorder. There are positive trials of NAC in all these disorders, and although many of these require replication and are methodologically preliminary, this makes it one of the most promising drug candidates in neuropsychiatric disorders. The efficacy pattern of NAC interestingly shows little respect for the current diagnostic systems. Its benign tolerability profile, its action on multiple operative pathways, and the emergence of positive trial data make it an important target to investigate.


When Does the Rate-Determining Step in the Hepatic Clearance of a Drug Switch from Sinusoidal Uptake to All Hepatobiliary Clearances? Implications for Predicting Drug-Drug Interactions.
For dual transporter-enzyme substrate drugs, the extended clearance model can be used to predict the rate-determining step(s) (RDS) of a drug and hence predict its drug-drug interaction (DDI) liabilities (i.e., transport, metabolism, or both). If the RDS of the hepatic clearance of the drug is sinusoidal uptake clearance (CLs in), even if the drug is eliminated mainly by hepatic metabolism, its DDI liability (as viewed from changes to systemic drug concentrations) is expected to be inhibition or induction of uptake transporters but not hepatic enzymes; however, this is true only if the condition required to maintain CLs in as the RDS is maintained. Here, we illustrate through theoretical simulations that the RDS condition may be violated in the presence of a DDI. That is, the RDS of a drug can switch from CLs in to all hepatobiliary clearances [i.e., metabolic/biliary clearance (CLmet + bile) and CLs in], leading to unexpected systemic DDIs, such as metabolic DDIs, when only transporter DDIs were anticipated. As expected, these analyses revealed that the RDS switch depends on the ratio of CLmet + bile to sinusoidal efflux clearance (CLs ef). Additional analyses revealed that for intravenously administered drugs, the RDS switch also depends on the magnitude of CLs in We analyzed published in vitro quantified hepatobiliary clearances and observed that most drugs have a CLmet + bile/CLs ef ratio < 4; hence, in practice, the magnitude of CLs in must be considered when establishing the RDS. These analyses provide insights previously not appreciated and a theoretical framework to predict DDI liabilities for drugs that are dual transporter-enzyme substrates.


The human cytotoxic T cell response to influenza A vaccination.
The human cytotoxic T lymphocyte (CTL) response to challenge with influenza A vaccine was studied. Six of eight volunteers given killed whole influenza virus A/USSR (H1N1) vaccine showed substantial increases on the level of CTL memory 1 month after immunization. The CTL measured at this time showed complete cross-reactivity in their specificity for influenza A/USSR (H1N1) and A/X31 (H3N2) infected cells and also showed HLA restriction. The level of CTL memory increased in only three out of nine donors given subunit vaccine and showed no change in those not given vaccine. If cytotoxic T cells are important in influenza prophylaxis, killed whole virus vaccine should offer better protection than subunit vaccine.


Evaluating prophylactic heparin in ambulatory patients with solid tumours: a systematic review and individual participant data meta-analysis.
Study-level meta-analyses provide high-certainty evidence that heparin reduces the risk of symptomatic venous thromboembolism for patients with cancer; however, whether the benefits and harms associated with heparin differ by cancer type is unclear. This individual participant data meta-analysis of randomised controlled trials examines the effect of heparin on survival, venous thromboembolism, and bleeding in patients with cancer in general and by type. In this systematic review and meta-analysis we searched MEDLINE, Embase, and The Cochrane Library for randomised controlled trials comparing parenteral anticoagulants with placebo or standard care in ambulatory patients with solid tumours and no indication for anticoagulation published from the inception of each database to January 14, 2017, and updated it on May 14, 2020, without language restrictions. We calculated the effect of parenteral anticoagulant administration on all-cause mortality, venous thromboembolism occurrence, and bleeding related outcomes through multivariable hierarchical models with patient-level variables as fixed effects and a categorical trial variable as a random effect, adjusting for age, cancer type, and metastatic status. Interaction terms were tested to investigate effects in predefined subgroups. This study is registered with PROSPERO, CRD42013003526. We obtained individual participant data from 14 of 20 eligible randomised controlled trials (8278 [79%] of 10 431 participants; 4139 included in the low-molecular-weight heparin group and 4139 in the control group). Meta-analysis showed an adjusted relative risk (RR) of mortality at 1 year of 0·99 (95% CI 0·93-1·06) and a hazard ratio of 1·01 (95% CI 0·96-1·07). The number of patients with venous thromboembolic events was 158 (4·0%) of 3958 with available data in the low-molecular-weight heparin group compared with 279 (7·1%) of 3957 in the control group. Major bleeding events occurred in 71 (1·7%) of 4139 patients in the control population and 88 (2·1%) in the low-molecular-weight heparin group, and minor bleeding events in 478 (12·1%) of 3945 patients with available data in the control group and 652 (16·6%) of 3937 patients in the low-molecular-weight heparin group. The adjusted RR was 0·58 (95% CI 0·47-0·71) for venous thromboembolism, 1·27 (0·92-1·74) for major bleeding, and 1·34 (1·19-1·51) for minor bleeding. Prespecified subgroup analysis of venous thromboembolism occurrence by cancer type identified the most certain benefit from heparin treatment in patients with lung cancer (RR 0·59 [95% CI 0·42-0·81]), which dominated the overall reduction in venous thromboembolism. Certainty of the evidence for the outcomes ranged from moderate to high. Low-molecular-weight heparin reduces risk of venous thromboembolism without increasing risk of major bleeding compared with placebo or standard care in patients with solid tumours, but it does not improve survival. Canadian Institutes of Health Research.


Failure of oral atorvastatin to modulate a murine model of systemic lupus erythematosus.
Inhibitors of the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase enzyme (statins) are cholesterol-lowering drugs that have shown promise as therapeutic agents in various animal models of autoimmune disease. The results of initial clinical trials with statins in multiple sclerosis and rheumatoid arthritis have also been encouraging. In this study, we attempted to treat a widely studied murine model of spontaneous systemic lupus erythematosus (SLE) with atorvastatin. (NZB x NZW)F1 (NZB/NZW) mice received daily oral doses of atorvastatin for 20 weeks. The mice were monitored weekly for survival and proteinuria. Anti-double-stranded DNA (anti-dsDNA) antibody levels in sera were determined by enzyme-linked immunosorbent assay (ELISA). T lymphocyte cytokine production in vitro, as well as cytokine levels in vivo, were measured by ELISA. T cell proliferation was assessed by thymidine incorporation assay. Serum cholesterol levels were determined using a standard fluorometric assay. Kidney tissue was harvested and evaluated for pathologic changes. In NZB/NZW mice, oral atorvastatin had significant effects on T cell proliferation and cytokine production in vitro. Atorvastatin also induced significant increases in serum levels of interleukin-4. However, atorvastatin treatment in NZB/NZW mice had no significant impact on proteinuria, survival, serum anti-dsDNA antibody and cholesterol levels, or extent of renal disease. Monotherapy with oral atorvastatin has no protective effects in a murine model of spontaneous SLE. The efficacy of atorvastatin in human SLE remains to be determined.


Manifestations and drivers of mistreatment of women during childbirth in Kenya: implications for measurement and developing interventions.
Disrespect and abuse or mistreatment of women by health care providers in maternity settings has been identified as a key deterrent to women seeking delivery care. Mistreatment includes physical and verbal abuse, stigma and discrimination, a poor relationship between women and providers and policy and health systems challenges. This paper uses qualitative data to describe mistreatment of women in Kenya. Data are drawn from implementation research conducted in 13 facilities and communities. Researchers conducted a range of in-depth interviews with women (n-50) who had given birth in a facility policy makers health managers and providers (n-63); and focus group discussions (19) with women and men living around study facilities. Data were captured on paper and audio tapes, transcribed and translated and exported into Nvivo for analysis. Subsequently we applied a typology of mistreatment which includes first order descriptive themes, second and third-order analytical themes. Final analysis was organized around description of the nature, manifestations and experiences, and factors contributing to mistreatment. Women describe: their negative experiences of childbirth; frustration with lack of confidentiality and autonomy; abandonment by the providers, and dirty maternity units. Providers admit to challenges but describe reasons for apparent abuse (slapped on thighs to encourage women to focus on birthing process) and 'detention' is because relatives have abandoned them. Men try to overcome challenges by paying providers to ensure they look after their wives. Drivers of mistreatment are perpetuated by social and gender norms at family and community levels. At facility level, poor managerial oversight, provider demotivation, and lack of equipment and supplies, contribute to a poor experience of care. Weak or non-existent legal redress perpetuate the problem. This paper builds on the expanding literature on mistreatment during labour and childbirth -outlining drivers from an individual, family, community, facility and policy level. New frameworks to group the manifestations into themes or components makes it increasingly more focused on specific interventions to promote respectful maternity care. The Kenya findings resonate with budding literature - demonstrating that this is indeed a global issue that needs a global solution.


Restoration of knee volume using selected arthroscopic releases.
Inflammation and subsequent fibrosis, adhesions, or plicae may limit normal capsular compliance and decrease volume capacity of the knee. Patients with fibrosis, anterior interval scarring, adhesions, or palpable painful plicae will have decreased knee volumes when compared to controls, and selective arthroscopic releases will restore volume to normal levels. Descriptive laboratory study and cohort study; Level of evidence, 2. In part I, knee volume and pressure were recorded in 14 fresh-frozen human cadaveric knees, and the maximum volume capacity was identified before capsular disruption. In part II, 49 patients undergoing arthroscopy were divided into 2 groups based on intraoperative volume assessment at 50 mm H(2)O pressure: group 1 (n = 20) with normal volume (<1 standard deviation below the mean established in part I) and group 2 (n = 29) knees with deficient volume (>1 standard deviation below mean). Group 2 underwent volume-changing procedures such as lysis of adhesions, anterior interval release, and plica resections, while group 1 underwent volume-neutral procedures including meniscal or chondral surgery. The knee volume was then reassessed after arthroscopy. The average volume capacity of the knees in the cadaveric study was 87.5 ± 21.7 mL (range, 50-120 mL). There was no statistical difference between the presurgical (98.9 ± 29.8 mL) and postsurgical volumes (99.4 ± 29.1 mL) in group 1; P = .65. The presurgical volume in group 2 (46.1 ± 13.0 mL) was significantly lower than group 1 (P = .001). The group 2 volume increased to 78.5 ± 24.2 mL after surgery (P = .001), with an average change in volume of 75.5%. The mean change in volume after surgery was significantly greater in group 2 (32.3 mL) versus group 1 (0.45 mL) (P = .001). At 1-year follow-up, the mean Tegner score in the volume-compromised group 2 increased from 2.0 ± 1.4 preoperatively to 4.0 ± 2.0 postoperatively (P = .01), the Lysholm score increased from 45.0 ± 24.0 preoperatively to 76.8 ± 25.4 postoperatively (P = .003), and the average Short Form-12 quality of life score increased from 32.4 ± 8.7 preoperatively to 45.0 ± 11.0 postoperatively (P = .005). The average volume of the human knee in this study was between 65 and 110 mL (±1 standard deviation of mean of 87.5 mL). Although patients with chronic knee pain may have pain from multiple sources, some may have diminished knee volume, and selected arthroscopic releases can restore knee volume to near-normal levels.


Transumbilical laparoscopically assisted appendectomy: an alternative minimally invasive technique in pediatric patients.
Transumbilical laparoscopically assisted appendectomy (TULAA) has been reported in the literature as an alternative to traditional three-port laparoscopic appendectomy (LA). Our study compares outcomes between LA and the one-trocar transumbilical technique in a single institution over a concurrent time frame for all cases of pediatric appendicitis. An Institutional Review Board-approved retrospective chart review of all appendectomies from July 2007 through June 2009 was performed. All appendectomies were performed either laparoscopically or transumbilically. One surgeon predominantly used the TULAA method, whereas the other 2 surgeons used strictly the LA method. No cases were converted to open. Categorization of specimens as normal, acute, or ruptured was based on pathology reports. Outcomes analyzed for each group included surgical duration, cost, length of stay, fever (>101.5F), wound infection, ileus, and postoperative abdominal-pelvic abscess. A total of 131 appendectomies were performed by 3 surgeons, 83 were LA and 48 were TULAA. For all stages of appendicitis, outcomes differed significantly only for operating room cost, with the TULAA being significantly less expensive. All other outcomes were similar between the two techniques. Our study suggests that TULAA is a reasonable alternative to the standard minimally invasive technique for appendicitis in both acute and ruptured situations. All analyzed complications were similar between the groups, suggesting that TULAA is an acceptable surgical method in pediatric patients for all stages of appendicitis.


Open notes: doctors and patients signing on.
Few patients read their doctors' notes, despite having the legal right to do so. As information technology makes medical records more accessible and society calls for greater transparency, patients' interest in reading their doctors' notes may increase. Inviting patients to review these notes could improve understanding of their health, foster productive communication, stimulate shared decision making, and ultimately lead to better outcomes. Yet, easy access to doctors' notes could have negative consequences, such as confusing or worrying patients and complicating rather than improving patient-doctor communication. To gain evidence about the feasibility, benefits, and harms of providing patients ready access to electronic doctors' notes, a team of physicians and nurses have embarked on a demonstration and evaluation of a project called OpenNotes. The authors describe the intervention and share what they learned from conversations with doctors and patients during the planning stages. The team anticipates that "open notes" will spread and suggests that over time, if drafted collaboratively and signed by both doctors and patients, they might evolve to become contracts for care.


Inflammation and protein metabolism studies of carbon-14-labeled proteins in dogs with sterile abscesses.
Carbon-14-labeled plasma proteins given by mouth to dogs with sterile abscesses undergo decreased absorption, presumably owing to impaired digestion of protein. The turnover of plasma albumin is greatly accelerated but the globulins, excluding fibrinogen, show little change during the acute stage of the sterile inflammation. Fibrinogen shows very rapid production and utilization during acute inflammation. Large amounts of C(14) are incorporated in fibrinogen within a few hours after ingestion of the labeled material. The labeled fibrinogen largely disappears within 2 to 4 days after its production. The appearance of C(14) in new red cells from labeled protein or amino acid sources is reduced by inflammation-evidence of impaired synthesis. The pus of the sterile abscess contains a good deal of C(14) activity which at times is as much as that found in the liver. Pus cell C(14) activity per milliliter is similar after injection of labeled plasma and ingestion of labeled plasma or lysine. However, the pus cell fraction contains 3 to 4 times more C(14) activity per milliliter than does the supernatant fluid when the isotope is fed. In the supernatant fluid the activity is all within precipitable protein, much of which is probably derived from the blood plasma. In spite of increased loss of C(14) as CO(2) in the expired air and in the pus, there is evidence of conservation of protein-building materials for maintenance of new plasma proteins and tissue proteins in the more active organs (e.g. liver)-a shift of protein C(14) from the less active tissues (muscle and skin).


MUC1 oncogene amplification correlates with protein overexpression in invasive breast carcinoma cells.
The MUC1 gene is aberrantly overexpressed in approximately 90% of human breast cancers. Several studies have shown that MUC1 overexpression is due to transcriptional regulatory events. However, the importance of gene amplification as a mechanism leading to the increase of MUC1 expression in breast cancer has been poorly characterized. The aim of this study was to evaluate the role of MUC1 gene amplification and protein expression in human breast cancer development. By means of real-time quantitative polymerase chain reaction and immunohistochemical methods, 83 breast tissue samples were analyzed for MUC1 gene amplification and protein expression. This analysis showed MUC1 genomic amplification and a positive association with the histopathological group in 12% (1 out of 8) of benign lesions and 38% (23 out of 60) of primary invasive breast carcinoma samples (P = 0.004). Array-comparative genomic hybridization meta-analysis of 886 primary invasive breast carcinomas obtained from 22 studies showed MUC1 genomic gain in 43.7% (387 out of 886) of the samples. Moreover, we identified a highly statistical significant association between MUC1 gene amplification and MUC1 protein expression assessed by immunohistochemistry and Western blot test (P < 0.0001). In conclusion, this study demonstrated that MUC1 copy number increases from normal breast tissue to primary invasive breast carcinomas in correlation with MUC1 protein expression.


Ethical challenges in rheumatology: a survey of the American College of Rheumatology membership.
Despite the frequency of ethical issues arising in patient care, ethical discourse in the rheumatology literature is negligible. To better understand the scope of ethical problems occurring in our specialty, the American College of Rheumatology (ACR) Committee on Ethics and Conflict of Interest surveyed ACR members. Specific objectives of the survey were 1) to learn the perceived frequency of ethical issues in rheumatology, 2) to identify activities that pose ethical problems in rheumatologic practice, 3) to determine the extent of education on, and self-perceived knowledge about, ethics among ACR members, and 4) to determine member interest in, and suggest content for, future ACR-sponsored educational activities related to bioethics. The survey included 12 non-open-ended questions addressing 5 core areas: 1) ethical dilemmas in daily practice, 2) ethical concerns in basic and clinical research, 3) influence of industry, 4) ethics of regulatory policies, potential conflicts, and disclosure, and 5) personal education on and interest in ethics. Two open-ended questions were also included, asking respondents to list the ethical issues most relevant to rheumatology and to provide any comments. Data analysis was descriptive. Seven hundred seventy-one responses were received. Respondents believed that ethical issues arise most frequently in practice and in clinical research. The most common ethical issues cited were the high cost of treatment for patients (51% of respondents) and for society (48%), and the practice of defensive medicine (45%). The survey results suggest that ethical problems in rheumatology are of concern to the ACR membership. Further, there is a perceived need for educational programs targeted at helping members address such professional challenges.


Occupational exposure to metals and risk of meningioma: a multinational case-control study.
The aim of the study was to examine associations between occupational exposure to metals and meningioma risk in the international INTEROCC study. INTEROCC is a seven-country population-based case-control study including 1906 adult meningioma cases and 5565 population controls. Incident cases were recruited between 2000 and 2004. A detailed occupational history was completed and job titles were coded into standard international occupational classifications. Estimates of mean workday exposure to individual metals and to welding fumes were assigned based on a job-exposure-matrix. Adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) were estimated using conditional logistic regression. Although more controls than cases were ever exposed to metals (14 vs. 11 %, respectively), cases had higher median cumulative exposure levels. The ORs for ever vs. never exposure to any metal and to individual metals were mostly greater than 1.0, with the strongest association for exposure to iron (OR 1.26, 95 % CI 1.0-1.58). In women, an increased OR of 1.70 (95 % CI 1.0-2.89) was seen for ever vs never exposure to iron (OR in men 1.19, 95 % CI 0.91-1.54), with positive trends in relation with both cumulative and duration of exposure. These results remained after consideration of other occupational metal or chemical co-exposures. In conclusion, an apparent positive association between occupational exposure to iron and meningioma risk was observed, particularly among women. Considering the fact that meningioma is a hormone dependent tumor, the hypothesis that an interaction between iron and estrogen metabolism may be a potential mechanism for a carcinogenic effect of iron should be further investigated.


Neural induction, neural fate stabilization, and neural stem cells.
The promise of stem cell therapy is expected to greatly benefit the treatment of neurodegenerative diseases. An underlying biological reason for the progressive functional losses associated with these diseases is the extremely low natural rate of self-repair in the nervous system. Although the mature CNS harbors a limited number of self-renewing stem cells, these make a significant contribution to only a few areas of brain. Therefore, it is particularly important to understand how to manipulate embryonic stem cells and adult neural stem cells so their descendants can repopulate and functionally repair damaged brain regions. A large knowledge base has been gathered about the normal processes of neural development. The time has come for this information to be applied to the problems of obtaining sufficient, neurally committed stem cells for clinical use. In this article we review the process of neural induction, by which the embryonic ectodermal cells are directed to form the neural plate, and the process of neural-fate stabilization, by which neural plate cells expand in number and consolidate their neural fate. We will present the current knowledge of the transcription factors and signaling molecules that are known to be involved in these processes. We will discuss how these factors may be relevant to manipulating embryonic stem cells to express a neural fate and to produce large numbers of neurally committed, yet undifferentiated, stem cells for transplantation therapies.


The virtual dental home: implications for policy and strategy.
Widely recognized problems with the U.S. health care system, including rapidly increasing costs and disparities in access and outcomes also exist in oral health. If oral health systems are to meet the "Triple Aim" of improving the experience of care, improving the health of populations, and reducing per capita costs of health care, new and innovative strategies will be needed including new regulatory, delivery, and financing systems. The virtual dental home is one such system.


Microbial invasion of the amniotic cavity in preeclampsia as assessed by cultivation and sequence-based methods.
Infection has been implicated in the pathogenesis of preeclampsia, yet the association between microbial invasion of the amniotic cavity (MIAC) and preeclampsia has not been determined. The aim of this study was to determine the prevalence, and microbial diversity associated with MIAC, as well as the nature of the host response to MIAC in patients with preeclampsia. Amniotic fluid (AF) from 62 subjects with preeclampsia, not in labor, was analyzed with both cultivation and molecular methods. Broad-range and group-specific PCR assays targeting small subunit ribosomal DNA, or other gene sequences, from bacteria, fungi and archaea were used. Results were correlated with measurements of host inflammatory response, including AF white blood cell count and AF concentrations of glucose, interleukin-6 (IL-6) and MMP-8. 1) The rate of MIAC in preeclampsia was 1.6% (1/62) based on cultivation techniques, 8% (5/62) based on PCR, and 9.6% (6/62) based on the combined results of both methods; 2) among the six patients diagnosed with MIAC, three had a positive PCR for Sneathia/Leptotrichia spp.; and 3) patients with MIAC were more likely to have evidence of an inflammatory response in the amniotic cavity than those without MIAC, as determined by a higher median AF IL-6 [1.65 ng/mL interquartile range (IQR): 0.35-4.62 vs. 0.22 ng/mL IQR: 0.12-0.51; P=0.002). The prevalence of MIAC in preeclampsia is low, suggesting that intra-amniotic infection plays only a limited role in preeclampsia. However, the unexpectedly high number of positive AF specimens for Sneathia/Leptotrichia warrants further investigation.


Low DPP4 expression and activity in multiple sclerosis.
Multiple sclerosis (MS) is a prototypic Th1/Th17 chronic autoimmune disease of the central nervous system. Dipeptidyl peptidase 4 (DPP4 or CD26) is a multifunctional molecule involved in autoimmune diseases' pathophysiology. We sought to integrate disparate pieces of data and analyze the plasma levels of sDPP4, DPP activity and DPP4 surface expression on T-cells in 129 MS patients with different clinical forms and 53 healthy controls, across two independent cohorts. Herein, we provide new evidence that sDPP4 concentration and DPP activity are significantly lower in MS patients than controls (p < 0.0001 and p < 0.01, respectively). In contrast, the frequency of circulating CD8(+)DPP4(hi) T-cells (p = 0.02) was increased in MS patients. This is the first study that simultaneously analyzes DPP4 expression and function in a large cohort of MS patients. Our data indicate a putative role for DPP4 in MS pathophysiology and suggest that a deeper understanding of surface versus shed DPP4 biology is warranted.


Disparities in Patterns of Health Care Travel Among Inpatients Diagnosed With Congestive Heart Failure, Florida, 2011.
Congestive heart failure (CHF) is a major public health problem in the United States and is a leading cause of hospitalization in the elderly population. Understanding the health care travel patterns of CHF patients and their underlying cause is important to balance the supply and demand for local hospital resources. This article explores the nonclinical factors that prompt CHF patients to seek distant instead of local hospitalization. Local hospitalization was defined as inpatients staying within hospital service areas, and distant hospitalization was defined as inpatients traveling outside hospital service areas, based on individual hospital discharge data in 2011 generated by a Dartmouth-Swiss hybrid approach. Multiple logistic and linear regression models were used to compare the travel patterns of different groups of inpatients in Florida. Black patients, no-charge patients, patients living in large metropolitan areas, and patients with a low socioeconomic status were more likely to seek local hospitalization than were white patients, those who were privately insured, those who lived in rural areas, and those with a high socioeconomic status, respectively. Findings indicate that different populations diagnosed with CHF had different travel patterns for hospitalization. Changes or disruptions in local hospital supply could differentially affect different groups in a population. Policy makers could target efforts to CHF patients who are less likely to travel to seek treatment.


The Healing Effect of Amniotic Membrane in Burn Patients.
Different methods for dressing of donor site of skin graft in burn patients have similarly pain, limitation of mobility of donor site and local complications such as infection and scar. Amniotic membrane has used for improvement of healing in some wounds. Accordingly in this study amnion was used as biologic dressing for donor site of skin graft to evaluate it's efficacy in improvement of pain, move score and the risk of local infection. Study was done as clinical trial over 32 admitted patients in burn department of Beasat hospital. Amnion was prepared in elective caesarean section after rule out any placental site for risk of torch and viral infection. Skin graft was taken from two sites in every patient. One site dressed with amnion and another with routine dressing. Then two sites were compared about severity of pain, move score, infection and time of dressing sloughing. Fourteen patients were women and 18 men. Mean score of pain and movement up to fourth and fifth post operative day respectively was less than control site. No difference is seen about infection and dressing slough in two sites. It seems use of amnion for dressing of donor site probably cause rapid epithelialisation and wound healing and can improve pain and move score in early post operative days. Accordingly it is expected to need less analgesia and low rate of immobilization and following complications and earlier discharge of patients.


Creatinine- versus cystatin C-based renal function assessment in the Northern Manhattan Study.
Accurate glomerular filtration rate estimation informs drug dosing and risk stratification. Body composition heterogeneity influences creatinine production and the precision of creatinine-based estimated glomerular filtration rate (eGFRcr) in the elderly. We compared chronic kidney disease (CKD) categorization using eGFRcr and cystatin C-based estimated GFR (eGFRcys) in an elderly, racially/ethnically diverse cohort to determine their concordance. The Northern Manhattan Study (NOMAS) is a predominantly elderly, multi-ethnic cohort with a primary aim to study cardiovascular disease epidemiology. We included participants with concurrently measured creatinine and cystatin C. eGFRcr was calculated using the CKD-EPI 2009 equation. eGFRcys was calculated using the CKD-EPI 2012 equation. Logistic regression was used to estimate odds ratios and 95% confidence intervals of factors associated with reclassification from eGFRcr≥60ml/min/1.73m2 to eGFRcys<60ml/min/1.73m2. Participants (n = 2988, mean age 69±10yrs) were predominantly Hispanic, female, and overweight/obese. eGFRcys was lower than eGFRcr by mean 23mL/min/1.73m2. 51% of participants' CKD status was discordant, and only 28% maintained the same CKD stage by both measures. Most participants (78%) had eGFRcr≥60mL/min/1.73m2; among these, 64% had eGFRcys<60mL/min/1.73m2. Among participants with eGFRcr≥60mL/min/1.73m2, eGFRcys-based reclassification was more likely in those with age >65 years, obesity, current smoking, white race, and female sex. In a large, multiethnic, elderly cohort, we found a highly discrepant prevalence of CKD with eGFRcys versus eGFRcr. Determining the optimal method to estimate GFR in elderly populations needs urgent further study to improve risk stratification and drug dosing.


General practitioners and carers: a questionnaire survey of attitudes, awareness of issues, barriers and enablers to provision of services.
Approximately one in ten of the UK population are unpaid carers supporting a family member or friend who could not manage without their help, saving the UK economy an estimated £87 billion. This role is known to sometimes have a negative impact on carers and to require support both informally and from statutory services. General practice is a first point of contact for carers but research investigating general practitioners' (GPs') attitudes towards carers and awareness of issues facing carers is rare. This study therefore aimed to identify GPs' attitudes, awareness of issues, and perceptions of the barriers and enablers to provision of services. Using a self-completion questionnaire distributed at a series of workshops, this study investigates GPs' attitudes to carers; awareness and knowledge of carers' issues; services offered in general practice and barriers to supporting carers. Seventy eight out of a total of 95 GPs (82% response rate) from a variety of areas in England completed the questionnaires. The GPs identified time, resources and lack of knowledge as barriers, but only 9% agreed with the statement that there is little support they can offer carers. However, nine in ten GPs (89%) feel they have insufficient training here and approximately half of them (47%) lack confidence that they are meeting carers' needs. Confidence in identifying carers is also low (45%). Issues that GPs would look out for amongst carers include emotional and physical health problems and financial and isolation difficulties. GPs specifically highlighted educational and isolation issues for young carers. Few services were described that targeted carers. GPs recognise that they have an important role to play in supporting carers but would like training and support. Further investigation is needed both to determine how best to train and facilitate GPs and general practice teams in their role in supporting carers and to identify what carers need and want from general practice. Identifying carers' leads or carers' champions amongst practice staff is possibly one way forward. Given the proposed greater commissioning role for primary care, greater understanding here is particularly important.


Characterization of meiotic recombination intermediates through gene knockouts in founder hybrid mice.
Mammalian meiotic recombination proceeds via repair of hundreds of programmed DNA double-strand breaks, which requires choreographed binding of RPA, DMC1, and RAD51 to single-stranded DNA substrates. High-resolution in vivo binding maps of these proteins provide insights into the underlying molecular mechanisms. When assayed in F1-hybrid mice, these maps can distinguish the broken chromosome from the chromosome used as template for repair, revealing more mechanistic detail and enabling the structure of the recombination intermediates to be inferred. By applying CRISPR-Cas9 mutagenesis directly on F1-hybrid embryos, we have extended this approach to explore the molecular detail of recombination when a key component is knocked out. As a proof of concept, we have generated hybrid biallelic knockouts of Dmc1 and built maps of meiotic binding of RAD51 and RPA in them. DMC1 is essential for meiotic recombination, and comparison of these maps with those from wild-type mice is informative about the structure and timing of critical recombination intermediates. We observe redistribution of RAD51 binding and complete abrogation of D-loop recombination intermediates at a molecular level in Dmc1 mutants. These data provide insight on the configuration of RPA in D-loop intermediates and suggest that stable strand exchange proceeds via multiple rounds of strand invasion with template switching in mouse. Our methodology provides a high-throughput approach for characterization of gene function in meiotic recombination at low animal cost.


Current concentrations and spatial and temporal trends in mercury in Great Lakes Herring Gull eggs, 1974-2009.
Current concentrations and spatial and temporal trends of total mercury (Hg) were assessed in eggs of the Herring Gull (Larus argentatus) over the period 1974-2009 at 15 sites in the Great Lakes: 2-3 sites per lake and one site in each of 3 connecting channels. Current (2009) concentrations ranged from 0.064 μg/g (wet weight) at Chantry Island (Lake Huron) to 0.246 μg/g at Middle Island (Lake Erie). There were significant inter-colony differences in mean Hg concentrations (2005-2009). Mercury concentrations at 14 of 15 sites declined from 23 to 86% between when it was first measured (usually 1974) and 2009. Declining temporal trends over the entire period (1974-2009) were significant at 10 of the 15 sites. On the other hand, there were no significant trends in mercury over the last 15 years. In the early years, declines of Hg in Herring Gull eggs tracked those in Rainbow Smelt (Osmerus mordax) in most Great Lakes. More recently, declines in gull eggs were more evident than in smelt and may be partially explained by temporal changes in the gull diet. When gull Hg data were adjusted for temporal changes in the gull diet, as inferred from stable nitrogen isotope values in eggs, significant declines in egg mercury levels were found only at 4 of 15 sites. Overall, Hg concentrations have declined in Great Lakes Herring Gull eggs over the period 1974-2009 but changes in the gull diet may be contributing, in part, to those declines. Examination of contaminant temporal trends in multiple indicator species will ensure accurate inferences regarding contaminant availability in the environment.


Comprehensive Molecular Screening in Chinese Usher Syndrome Patients.
Usher syndrome (USH) refers to a group of autosomal recessive disorders causing deafness and blindness. The objectives of this study were to determine the mutation spectrum in a cohort of Chinese patients with USH and to describe the clinical features of the patients with mutations. A total of 119 probands who were clinically diagnosed with USH were recruited for genetic analysis. All probands underwent ophthalmic examinations. A combination of molecular screening methods, including targeted next-generation sequencing, Sanger-DNA sequencing, and multiplex ligation probe amplification assay, was used to detect mutations. We found biallelic mutations in 92 probands (77.3%), monoallelic mutations in 5 patients (4.2%), and 1 hemizygous mutation in 1 patient (0.8%), resulting in an overall mutation detection rate of 78.2%. Overall, 132 distinct disease-causing mutations involving seven USH (ABHD12, CDH23, GPR98, MYO7A, PCDH15, USH1C, and USH2A) genes; 5 other retinal degeneration genes (CHM, CNGA1, EYS, PDE6B, and TULP1); and 1 nonsyndromic hearing loss gene (MYO15A) were identified, and 78 were novel. Mutations of MYOA7 were responsible for 60% of USH1 families, followed by PCDH15 (20%) and USH1C (10%). Mutations of USH2A accounted for 67.7% of USH2 families, and mutation c.8559-2A>G was the most frequent one, accounting for 19.1% of the identified USH2A alleles. Our results confirm that the mutation spectrum for each USH gene in Chinese patients differs from those of other populations. The formation of the mutation profile for the Chinese population will enable a precise genetic diagnosis for USH patients in the future.


Inhibition of fungal appressorium formation by pepper (Capsicum annuum) esterase.
A pepper esterase gene (PepEST) that is highly expressed during an incompatible interaction between pepper (Capsicum annuum) and the anthracnose fungus Colletotrichum gloeosporioides has been previously cloned. Glutathione-S-transferase-tagged recombinant PepEST protein expressed in Escherichia coli showed substrate specificity for p-nitrophenyl esters. Inoculation of compatible unripe pepper fruits with C. gloeosporioides spores amended with the recombinant protein did not cause anthracnose symptoms on the fruit. The recombinant protein has no fungicidal activity, but it significantly inhibits appressorium formation of the anthracnose fungus in a dose-dependent manner. An esterase from porcine liver also inhibited appressorium formation, and the recombinant protein inhibited appressorium formation in the rice blast fungus, Magnaporthe grisea. Inhibition of appressorium formation in M. grisea by the recombinant protein was reversible by treatment with cyclic AMP (cAMP) or 1,16-hexadecanediol. The results suggest that the recombinant protein regulates appressorium formation by modulating the cAMP-dependent signaling pathway in this fungus. Taken together, the PepEST esterase activity can inhibit appressorium formation of C. gloeosporioides, which may result in protection of the unripe fruit against the fungus.


Physical activity and survival after colorectal cancer diagnosis.
Physically active individuals have a lower risk of developing colorectal cancer but the influence of exercise on cancer survival is unknown. By a prospective, observational study of 573 women with stage I to III colorectal cancer, we studied colorectal cancer-specific and overall mortality according to predefined physical activity categories before and after diagnosis and by change in activity after diagnosis. To minimize bias by occult recurrences, we excluded women who died within 6 months of their postdiagnosis physical activity assessment. Increasing levels of exercise after diagnosis of nonmetastatic colorectal cancer reduced cancer-specific mortality (P for trend = .008) and overall mortality (P for trend = .003). Compared with women who engaged in less than 3 metabolic equivalent task [MET] -hours per week of physical activity, those engaging in at least 18 MET-hours per week had an adjusted hazard ratio for colorectal cancer-specific mortality of 0.39 (95% CI, 0.18 to 0.82) and an adjusted hazard ratio for overall mortality of 0.43 (95% CI, 0.25 to 0.74). These results remained unchanged even after excluding women who died within 12 and 24 months of activity assessment. Prediagnosis physical activity was not predictive of mortality. Women who increased their activity (when comparing prediagnosis to postdiagnosis values) had a hazard ratio of 0.48 (95% CI, 0.24 to 0.97) for colorectal cancer deaths and a hazard ratio of 0.51 (95% CI, 0.30 to 0.85) for any-cause death, compared with those with no change in activity. Recreational physical activity after the diagnosis of stages I to III colorectal cancer may reduce the risk of colorectal cancer-specific and overall mortality.


Greenhouse gas emission potential of the municipal solid waste disposal sites in Thailand.
Open dumping and landfilling are the prevalent solid waste disposal practices in Thailand. Surveys on the disposal sites revealed the presence of 95 landfills and 330 open dumps. Methane emission potential at these sites was estimated by three methods. Results of the Intergovernmental Panel on Climate Change (IPCC) method, Landfill Gas Emission model (LandGEM), and closed flux chamber technique were compared. The methane emission potential of 366 Gg/yr using the IPCC method was higher than the estimations of the LandGEM and closed flux chamber method of 115 Gg/yr and 103 Gg/yr, respectively. An understanding of the methane emission potential initiated the analysis of upgrading the open dumps into landfills, adding landfills to meet the future needs and utilization of landfill gases. Upgrading the open dumps to landfills increased the methane emission rates and their utilization potential. Approximately 20 additional landfills may be required to meet future demands. Landfill gas (LFG) utilization appears to be feasible in the large-scale landfills.


Evaluation of a Miniaturized Biologically Vascularized Scaffold in vitro and in vivo.
In tissue engineering, the generation and functional maintenance of dense voluminous tissues is mainly restricted due to insufficient nutrient supply. Larger three-dimensional constructs, which exceed the nutrient diffusion limit become necrotic and/or apoptotic in long-term culture if not provided with an appropriate vascularization. Here, we established protocols for the generation of a pre-vascularized biological scaffold with intact arterio-venous capillary loops from rat intestine, which is decellularized under preservation of the feeding and draining vascular tree. Vessel integrity was proven by marker expression, media/blood reflow and endothelial LDL uptake. In vitro maintenance persisted up to 7 weeks in a bioreactor system allowing a stepwise reconstruction of fully vascularized human tissues and successful in vivo implantation for up to 4 weeks, although with time-dependent decrease of cell viability. The vascularization of the construct lead to a 1.5× increase in cellular drug release compared to a conventional static culture in vitro. For the first time, we performed proof-of-concept studies demonstrating that 3D tissues can be maintained within a miniaturized vascularized scaffold in vitro and successfully implanted after re-anastomosis to the intrinsic blood circulation in vivo. We hypothesize that this technology could serve as a powerful platform technology in tissue engineering and regenerative medicine.


Repair of bile duct defect with degradable stent and autologous tissue in a porcine model.
To introduce and evaluate a new method to repair bile duct defect with a degradable stent and autologous tissues. Eight Ba-Ma mini-pigs were used in this study. Experimental models with common bile duct (CBD) defect (0.5-1.0 cm segment of CBD resected) were established and then CBD was reconstructed by duct to duct anastomosis with a novel degradable stent made of poly [sebacic acid-co-(1,3-propanediol)-co-(1,2-propanediol)]. In addition, a vascularized greater omentum was placed around the stent and both ends of CBD. Cholangiography via gall bladder was performed for each pig at postoperative months 1 and 3 to rule out stent translocation and bile duct stricture. Complete blood count was examined pre- and post-operatively to estimate the inflammatory reaction. Liver enzymes and serum bilirubin were examined pre- and post-operatively to evaluate the liver function. Five pigs were sacrificed at month 3 to evaluate the healing of anastomosis. The other three pigs were raised for one year for long-term observation. All the animals underwent surgery successfully. There was no intraoperative mortality and no bile leakage during the observation period. The white blood cell counts were only slightly increased on day 14 and month 3 postoperatively compared with that before operation, the difference was not statistically significant (P = 0.652). The plasma level of alanine aminotransferase on day 14 and month 3 postoperatively was also not significantly elevated compared with that before operation (P = 0.810). Nevertheless, the plasma level of γ-glutamyl transferase was increased after operation in both groups (P = 0.004), especially 2 wk after operation. The level of serum total bilirubin after operation was not significantly elevated compared with that before operation (P = 0.227), so did the serum direct bilirubin (P = 0.759). By cholangiography via gall bladder, we found that the stent maintained its integrity of shape and was still in situ at month 1, and it disappeared completely at month 3. No severe CBD dilation and stricture were observed at both months 1 and 3. No pig died during the 3-mo postoperative observation period. No sign of necrosis, bile duct stricture, bile leakage or abdominal abscess was found at reoperation at month 3 postoperatively. Pigs had neither fragments of stent nor stones formed in the CBD. Collagen deposit was observed in the anastomosis by hematoxylin and eosin (HE) and Masson's trichrome stains. No severe cholestasis was observed in liver parenchyma by HE staining. Intestinal obstruction was found in a pig 4 mo after operation, and no bile leakage, bile duct stricture or biliary obstruction were observed in laparotomy. No sign of bile duct stricture or bile leakage was observed in the other two pigs. The novel method for repairing bile duct defect yielded a good short-term effect without postoperative bile duct stricture. However, the long-term effect should be further studied.


Rates, Characteristics, and Outcomes of Patients Transferred to Specialized Stroke Centers for Advanced Care.
Background While many patients are transferred to specialized stroke centers for advanced acute ischemic stroke (AIS) care, few studies have characterized these patients. We sought to determine variation in the rates and differences in the baseline characteristics and clinical outcomes between AIS cases presenting directly to stroke centers' front door versus Transfer-Ins from another hospital. Methods and Results We analyzed 970 390 AIS cases in the Get With The Guidelines-Stroke registry from January 2010 to March 2014 to compare hospitals with high Transfer-In rates (≥15%) versus those with low Transfer-In rates (<5%) and to compare the front-door versus Transfer-In patients admitted to those hospitals with high Transfer-In rates (high Transfer-In hospitals). Of 970 390 patients discharged from 1646 hospitals, 87% initially presented via the emergency department versus 13% were a Transfer-In from another hospital. High Transfer-In hospitals had a median 31% Transfer-In rate among all stroke discharges, were larger, had higher annual AIS volume and intravenous tPA (tissue-type plasminogen activator) rates, and were more often Midwest teaching hospitals and stroke centers. Compared with front-door, Transfer-In patients were younger, more often white, had higher median National Institutes of Health Stroke Scale scores, less often hypertension and previous stroke/transient ischemic attack, and higher in-hospital mortality (7.9% versus 4.9%; standardized difference, 12.4%). After multivariable adjustment, Transfer-In patients had higher in-hospital mortality and discharge modified Rankin scale. Conclusions There is significant regional variability in the transfer of patients with AIS. Because Transfer-In patients seem to have worse short-term outcomes, these patients have the potential to negatively influence institutional mortality rates and should be accounted for explicitly in hospital risk-profiling measures.


The International Alcohol Control (IAC) study-evaluating the impact of alcohol policies.
This paper describes a new multicountry collaborative project to assess the impact of alcohol control policy. Longitudinal surveys of drinkers in a number of participating countries and analysis of the policy context allow for the assessment of change over time within countries and comparison between countries. The design of the study is modeled on the International Tobacco Control study and aims to assess the impact of alcohol policies in different cultural contexts on policy-related behaviors and alcohol consumption. A survey instrument and protocol for policy analysis have been developed by the initial participating countries: England, Scotland, Thailand, South Korea, and New Zealand. The first round of data collection is scheduled for 2011-2012. The survey instrument (International Alcohol Control [IAC] survey) measures key policy relevant behaviors: place and time of purchase, amounts purchased and price paid; ease of access to alcohol purchase; alcohol marketing measures; social supply; perceptions of alcohol affordability and availability and salience of price; perceptions of enforcement; people's experiences with specific alcohol restrictions; support for policy and consumption (typical quantity, frequency using beverage and location-specific measures). The Policy Analysis Protocol (PoLAP) assesses relevant aspects of the policy environment including regulation and implementation. It has proved feasible to design instruments to collect detailed data on behaviors relevant to alcohol policy change and to assess the policy environment in different cultural settings. In a policy arena in which the interest groups and stakeholders have different perceptions of appropriate policy responses to alcohol-related harm, a robust methodology to assess the impact of policy will contribute to the debate.


The RNA-binding protein QKI5 regulates primary miR-124-1 processing via a distal RNA motif during erythropoiesis.
MicroRNA (miRNA) biogenesis is finely controlled by complex layers of post-transcriptional regulators, including RNA-binding proteins (RBPs). Here, we show that an RBP, QKI5, activates the processing of primary miR-124-1 (pri-124-1) during erythropoiesis. QKI5 recognizes a distal QKI response element and recruits Microprocessor through interaction with DGCR8. Furthermore, the recruited Microprocessor is brought to pri-124-1 stem loops by a spatial RNA-RNA interaction between two complementary sequences. Thus, mutations disrupting their base-pairing affect the strength of QKI5 activation. When erythropoiesis proceeds, the concomitant decrease of QKI5 releases Microprocessor from pri-124-1 and reduces mature miR-124 levels to facilitate erythrocyte maturation. Mechanistically, miR-124 targets TAL1 and c-MYB, two transcription factors involved in normal erythropoiesis. Importantly, this QKI5-mediated regulation also gives rise to a unique miRNA signature, which is required for erythroid differentiation. Taken together, these results demonstrate the pivotal role of QKI5 in primary miRNA processing during erythropoiesis and provide new insights into how a distal element on primary transcripts affects miRNA biogenesis.


Molecular insights into DNA polymerase deterrents for ribonucleotide insertion.
DNA polymerases can misinsert ribonucleotides that lead to genomic instability. DNA polymerase β discourages ribonucleotide insertion with the backbone carbonyl of Tyr-271; alanine substitution of Tyr-271, but not Phe-272, resulted in a >10-fold loss in discrimination. The Y271A mutant also inserted ribonucleotides more efficiently than wild type on a variety of ribonucleoside (rNMP)-containing DNA substrates. Substituting Mn(2+) for Mg(2+) decreased sugar discrimination for both wild-type and mutant enzymes primarily by increasing the affinity for rCTP. This facilitated crystallization of ternary substrate complexes of both the wild-type and Y271A mutant enzymes. Crystallographic structures of Y271A- and wild type-substrate complexes indicated that rCTP is well accommodated in the active site but that O2' of rCTP and the carbonyl oxygen of Tyr-271 or Ala-271 are unusually close (∼2.5 and 2.6 Å, respectively). Structure-based modeling indicates that the local energetic cost of positioning these closely spaced oxygens is ∼2.2 kcal/mol for the wild-type enzyme. Because the side chain of Tyr-271 also hydrogen bonds with the primer terminus, loss of this interaction affects its catalytic positioning. Our results support a model where DNA polymerase β utilizes two strategies, steric and geometric, with a single protein residue to deter ribonucleotide insertion.


Alcohol use disorders and panic disorder: a review of the evidence of a direct relationship.
It is generally agreed that alcohol use disorders and panic disorder with (PD[A]) or without agoraphobia (PD) tend to occur within the same individual. However, the cause of this comorbidity remains controversial. Three main explanations are that (1) PD(A) promotes pathologic alcohol use as self-medication, (2) chronic alcohol use and alcohol withdrawal induce changes in the neurochemical system that promote panic, and (3) a third factor, such as familial transmission, promotes both conditions. The aim of this review was to survey the literature in order to determine the validity of these explanatory models. A review of epidemiologic, family, and laboratory studies was performed. Studies were identified using PubMed (English-language articles published from 1960 to 2006, using the search term alcohol and panic). Twenty studies were reviewed and selected according to the following criteria: PD(A) and alcohol abuse/dependence diagnosed according to the DSM, no additional comorbidity, use of adult samples, comparison with a nonclinical control group, or application of a crossover design. Nonsignificant results or trends only were reported as "no difference." Data on "anxiety disorders" or "substance abuse" in general were not included. In PD(A), alcohol lessens anxious apprehension, thereby decreasing the likelihood of panic. In alcohol use disorders, alcohol increases CO2 sensitivity and may thereby promote panic. In both cases, a significant familial transmission contributes to the co-occurrence. Findings would seem to indicate that PD(A) and alcohol use disorders can both serve to initiate the other via independent mechanisms. Further studies are warranted.


Monetary cost for time spent in everyday physical activities.
We measured utility curves for the hypothetical monetary costs as a function of time engaged in three everyday physical activities: walking, standing, and sitting. We found that activities requiring more physical exertion resulted in steeper discount curves, i.e., perceived cost as a function of time. We also examined the effects of gain vs. loss framing (whether the activity brought additional rewards or prevented losses) as well as the effects of the individual factors of gender, income, and BMI. Steeper discount curves were associated with higher income (annual household ≥ median of $45,000) and gain framing (which indicates loss aversion). There were interactions between gender and frame, and also income and frame: Females and higher income participants showed loss aversion whereas males and lower income participants were not affected by framing. Males showed less discounting in gain frames relative to females, whereas females showed less discounting in loss frames relative to males. In gain frames, higher income participants discounted more but in loss frames there was no effect of income. We also found individual tendencies for discounting across activities: if an individual exhibited steeper discounting for one activity, they were also more likely to exhibit steeper discounting for the other activities. These results have implications for designers of interventions to encourage non-exercise physical activities, suggesting that loss-framed incentives are more effective for women and those with middle class (or greater) incomes. Furthermore loss framed incentives have more uniform impact across income brackets because people discount loss frames similarly regardless of income whereas those with middle-class incomes are not as motivated by gain frames. Our results also demonstrate a general method for examining the costs of effort associated with everyday activities.


High-quality permanent draft genome sequence of Ensifer sp. PC2, isolated from a nitrogen-fixing root nodule of the legume tree (Khejri) native to the Thar Desert of India.
Ensifer sp. PC2 is an aerobic, motile, Gram-negative, non-spore-forming rod that was isolated from a nitrogen-fixing nodule of the tree legume P. cineraria (L.) Druce (Khejri), which is a keystone species that grows in arid and semi-arid regions of the Indian Thar desert. Strain PC2 exists as a dominant saprophyte in alkaline soils of Western Rajasthan. It is fast growing, well-adapted to arid conditions and is able to form an effective symbiosis with several annual crop legumes as well as species of mimosoid trees and shrubs. Here we describe the features of Ensifer sp. PC2, together with genome sequence information and its annotation. The 8,458,965 bp high-quality permanent draft genome is arranged into 171 scaffolds of 171 contigs containing 8,344 protein-coding genes and 139 RNA-only encoding genes, and is one of the rhizobial genomes sequenced as part of the DOE Joint Genome Institute 2010 Genomic Encyclopedia for Bacteria and Archaea-Root Nodule Bacteria (GEBA-RNB) project proposal.


Implementing community-based education in basic nursing education programs in South Africa.
Education of health professionals using principles of community-based education is the recommended national policy in South Africa. A paradigm shift to community-based education is reported in a number of nursing education institutions in South Africa. Reviewed literature however revealed that in some educational institutions planning, implementation and evaluation of Community-based Educational (CBE) programmes tended to be haphazard, uncoordinated and ineffective, resulting in poor student motivation. Therefore the purpose of this study was to analyse the implementation of community-based education in basic nursing education programmes in South Africa. Strauss and Corbin's (1990) grounded theory approach guided the research process. Data were collected by means of observation, interviews and document analysis. The findings revealed that collaborative decision-making involving all stakeholders was crucial especially during the curriculum planning phase. Furthermore, special criteria should be used when selecting community learning sites to ensure that the selected sites are able to facilitate the development of required graduate competencies. Collaborative effort, true partnership between academic institutions and communities, as well as government support and involvement emerged as necessary conditions for the successful implementation of community-based education programmes.


Control of the Na-Ca exchanger in isolated heart cells. II. Beat-dependent activation in normal cells by intracellular calcium.
Electrical stimulation of isolated adult rat heart cells in suspension at 4 Hz resulted in a fourfold increase in the rate of sodium influx and efflux across the sarcolemma, with no change in total cell sodium, as measured with 22Na. The magnitude of stimulation-dependent sodium fluxes under these conditions averaged 17 nmol/min/mg protein. The increased rate of efflux was inhibited by tetrodotoxin, verapamil, or dichlorobenzamil and required extracellular calcium. The inhibition by tetrodotoxin was overcome by Bay K 8644. The basal rate of 22Na efflux in cells at rest was inhibited only slightly by dichlorobenzamil. The stimulation-induced efflux was not inhibited by ouabain, but in the presence of ouabain, stimulation increased the rate of accumulation of total sodium by 4 nmol/min/mg. This increase was inhibited by tetrodotoxin or verapamil. A calcium-dependent increase in rate of 22Na influx and efflux could also be induced by KCl addition. This was inhibited by verapamil and dichlorobenzamil but not by tetrodotoxin and was reversed by EGTA, but only after a delay. We conclude the following. 1) The Na-Ca exchanger in cells at rest is no more than 10% activated. 2) The exchanger becomes activated directly or indirectly by calcium that enters the cell through calcium channels during excitation. 3) In this preparation the major part of excitation-induced sodium fluxes are mediated by the Na-Ca exchanger, with only a relatively small direct participation of sodium channels. These channels participate indirectly by promoting calcium channel activation. 4) If all the calcium-dependent sodium fluxes were Na-Ca exchange, then calcium flux through the exchanger per beat would be about sevenfold larger than that through the calcium channels. An undetermined part of the calcium-dependent sodium fluxes, however, could be a direct Na-Na exchange through the activated Na-Ca exchanger.


New insights into central roles of cerebral oxygen metabolism in the resting and stimulus-evoked brain.
The possible role of oxygen metabolism in supporting brain activation remains elusive. We have used a newly developed neuroimaging approach based on high-field in vivo (17)O magnetic resonance spectroscopic (MRS) imaging to noninvasively image cerebral metabolic rate of oxygen (CMRO(2)) consumption in cats at rest and during visual stimulation. It was found that CMRO(2) increases significantly (32.3%+/-10.8%, n=6) in the activated visual cortical region as depicted in blood oxygenation level dependence functional maps; this increase is also accompanied by a CMRO(2) decrease in surrounding cortical regions, resulting a smaller increase (9.7%+/-1.9%) of total CMRO(2) change over a larger cortical region displaying either a positive or negative CMRO(2) alteration. Moreover, a negative correlation between stimulus-evoked percent CMRO(2) increase and resting CMRO(2) was observed, indicating an essential impact of resting brain metabolic activity level on stimulus-evoked percent CMRO(2) change and neuroimaging signals. These findings provide new insights into the critical roles of oxidative metabolism in supporting brain activation and function. They also suggest that in vivo (17)O MRS imaging should provide a sensitive neuroimaging modality for mapping CMRO(2) and its change induced by brain physiology and/or pathologic alteration.


Evaluation of haemodynamic changes in hypertensive patients during tooth extraction under local anaesthesia.
This study was conducted to determine the changes in blood pressure and the pulse rate of patients with controlled hypertension having dental extraction under local anaesthesia utilizing 2% lignocaine with adrenaline, and to evaluate whether these changes in blood pressure were are attributable to addition of adrenaline. This prospective study was carried out in 33 consecutive hypertensive patients who presented at the exodontia clinic of the Department of Oral and Maxillofacial Surgery, Lagos University Teaching Hospital (LUTH), Idi-Araba, Lagos, from December 2004 to August 2005 for intra-alveolar tooth extraction. Patients were randomly allocated to two groups according to the type of anaesthetic solution employed. Group A had tooth extraction done under 2% lignocaine with 1:80 000 adrenaline while group B had tooth extraction done under 2% lignocaine without vasoconstrictor (plain lignocaine). One tooth was extracted from each patient. Blood pressure and pulse rate measurements were recorded in the waiting room before surgery, in the surgery after local anaesthetic injection, during tooth extraction and 15 minutes after tooth extraction. The sample consisted of 20 females and 13 males age range 24 to 75 years (mean +/- SD = 50.1 +/- 11.7 years). There was no statistically significant difference between the systolic and diastolic blood pressure and pulse rate in the two groups after administration of local anaesthesia. However the highest alteration in parameters was observed during tooth extraction in the two groups. The haemodynamic changes induced by injecting 2% lignocaine with adrenaline in patients with controlled hypertension during tooth extraction is within normal range and is not different from that induced by 2% lignocaine without adrenaline. We consider it essential that all precautions to prevent inadvertent intravascular injection be undertaken by the care provider.


Are clinical trial eligibility criteria an accurate reflection of a real-world population of advanced non-small-cell lung cancer patients?
Advanced non-small-cell lung cancer (nsclc) represents a major health issue globally. Systemic treatment decisions are informed by clinical trials, which, over years, have improved the survival of patients with advanced nsclc. The applicability of clinical trial results to the broad lung cancer population is unclear because strict eligibility criteria in trials generally select for optimal patients. We performed a retrospective chart review of all consecutive patients with advanced nsclc seen in outpatient consultation at our academic institution between September 2009 and September 2012, collecting data about patient demographics and cancer characteristics, treatment, and survival from hospital and pharmacy records. Two sets of arbitrary trial eligibility criteria were applied to the cohort. Scenario A stipulated Eastern Cooperative Oncology Group performance status (ecog ps) 0-1, no brain metastasis, creatinine less than 120 μmol/L, and no second malignancy. Less-strict scenario B stipulated ecog ps 0-2 and creatinine less than 120 μmol/L. We then used the two scenarios to analyze treatment and survival of patients by trial eligibility status. The 528 included patients had a median age of 67 years, with 55% being men and 58% having adenocarcinoma. Of those 528 patients, 291 received at least 1 line of palliative systemic therapy. Using the scenario A eligibility criteria, 73% were trial-ineligible. However, 46% of "ineligible" patients actually received therapy and experienced survival similar to that of the "eligible" treated patients (10.2 months vs. 11.6 months, p = 0.10). Using the scenario B criteria, only 35% were ineligible, but again, the survival of treated patients was similar in the ineligible and eligible groups (10.1 months vs. 10.9 months, p = 0.57). Current trial eligibility criteria are often strict and limit the enrolment of patients in clinical trials. Our results suggest that, depending on the chosen drug, its toxicities and tolerability, eligibility criteria could be carefully reviewed and relaxed.


Neuro-oxidative-nitrosative stress in sepsis.
Neuro-oxidative-nitrosative stress may prove the molecular basis underlying brain dysfunction in sepsis. In the current review, we describe how sepsis-induced reactive oxygen and nitrogen species (ROS/RNS) trigger lipid peroxidation chain reactions throughout the cerebrovasculature and surrounding brain parenchyma, due to failure of the local antioxidant systems. ROS/RNS cause structural membrane damage, induce inflammation, and scavenge nitric oxide (NO) to yield peroxynitrite (ONOO(-)). This activates the inducible NO synthase, which further compounds ONOO(-) formation. ROS/RNS cause mitochondrial dysfunction by inhibiting the mitochondrial electron transport chain and uncoupling oxidative phosphorylation, which ultimately leads to neuronal bioenergetic failure. Furthermore, in certain 'at risk' areas of the brain, free radicals may induce neuronal apoptosis. In the present review, we define a role for ROS/RNS-mediated neuronal bioenergetic failure and apoptosis as a primary mechanism underlying sepsis-associated encephalopathy and, in sepsis survivors, permanent cognitive deficits.


Mechanism and regulation of folate uptake by pancreatic acinar cells: effect of chronic alcohol consumption.
Folate plays an essential role in one-carbon metabolism, and a relationship exists between methyl group metabolism and pancreatic exocrine function. Little, however, is known about the mechanism(s) and regulation of folate uptake by pancreatic acinar cells and the effect of chronic alcohol use on the process. We addressed these issues using the rat-derived pancreatic acinar cell line AR42J and freshly isolated primary rat pancreatic acinar cells as models. We found [(3)H]folic acid uptake to be 1) temperature and pH dependent with a higher uptake at acidic than at neutral/alkaline pH; 2) saturable as a function of substrate concentration at both buffer pH 7.4 and 6.0; 3) inhibited by folate structural analogs and by anion transport inhibitors at both buffer pH 7.4 and 6.0; 4) trans-stimulated by unlabeled folate; 5) adaptively regulated by the prevailing extracellular folate level, and 6) inhibited by modulators of the cAMP/PKA-mediated pathway. Both the reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT) were found to be expressed in AR42J and in primary pancreatic acinar cells, as well as in native human pancreas with expression of RFC being higher than PCFT. Chronic alcohol feeding of rats (4 wk; 36% of calories from ethanol) led to a significant decrease in folate uptake by freshly isolated primary pancreatic acinar cells compared with cells from pair-fed controls; this effect was associated with a parallel decrease in the level of expression of RFC and PCFT. These studies reveal that folate uptake by pancreatic acinar cells is via a regulated carrier-mediated process which may involve RFC and PCFT. In addition, chronic alcohol feeding leads to a marked inhibition in folate uptake by pancreatic acinar cells, an effect that is associated with reduction in level of expression of RFC and PCFT.


Metal Oxide Photoelectrodes for Solar Fuel Production, Surface Traps, and Catalysis.
The photoelectrochemical reduction of water or CO2 is a promising route to sustainable solar fuels but hinges on the identification of a stable photoanode for water oxidation. Semiconductor oxides like Fe2O3 and BiVO4 have been gaining significant attention as promising materials. However, they exhibit a major drawback of a large required overpotential for solar water oxidation. In this Perspective, recent efforts to characterize and reduce the overpotential are critically examined. The accumulation of photogenerated holes at the semiconductor-liquid interface, recently observed with multiple techniques, is rationalized with surface state models. Transient absorption spectroscopy and electrochemical impedance spectroscopy suggest that surface treatments designed to either passivate surface traps or increase reaction rates (as catalysts) actually perform identically. This calls into question the definition of a catalyst when coupled to a semiconductor photoelectrode. In contrast, results from transient photocurrent spectroscopy suggest that two separate loss mechanisms are indeed occurring and can be addressed separately.


[Surgical treatment of stress urinary incontinence in our setting: analysis of results].
Surgical repair is the most effective option for the treatment of stress urinary incontinence (SUI) between the different therapeutical options available at present. The main objective of our study is to compare the outcome of the different techniques employed in the treatment of SUI in our setting. We have performed a retrospective analysis of the patients who underwent surgical intervention for SUI between 1991 to 1999 (213 surgical interventions in 194 patients) clustering the surgical procedures into three groups: abdominal, abdomino-vaginal, and sling procedures. The results of the treatment were defined as follows: total continence, significant improvement and insufficient improvement. Comparison of continence rates was performed with chi 2 test and Fisher's exact test. Association between qualitative variables was also evaluated by means of chi 2 test. Multivariate analysis of predictive factors was performed with a Cox model. The outcome was also evaluated by Kaplan-Meier's curves, and comparisons made with log-rank test. Statistical significance level was established for p < 0.05. Global cure rate at 24 months was 54.5% (116 patients). Significant improvement was observed in 33 patients (15.5%), and insufficient improvement was seen in 64 patients (30%). The most frequent postoperative complications were suprapubic pain (33%), acute urinary retention (26%), significant postvoiding residual urine (24%) and wound seroma or infection (20%). None of the analyzed factors (age, weight, number of births, preoperative pads, postoperative acute urinary retention, and need for postoperative bladder clean intermittent catheterization were independent predictive factors for postoperative continence. The actuarial analysis with Kaplan-Meier curves shows no statistical differences between the studied techniques (log rank p = 0.41). Sling techniques presented with a superior rate of most postoperative complications. The cure rate of our serie was 54.5% at 24 months, with a 70% of clinically satisfactory responses. With regard to continence status, it seems that there is not a better surgical technique in our hands, presenting sling techniques with a higher rate of postoperative complications. We could not find no pre o postoperative independent factors as predictors of postoperative continence.


[Primary hyperaldosteronism in cats].
Primary hyperaldosteronism is a clinical syndrome characterized by an elevated aldosterone secretion by the adrenals. The present case series describes 7 cats with primary hyperaldosteronism, which were presented between 2002 and 2011. Common clinical symptoms were weakness, anorexia, cervical ventroflexion and blindness. All cats showed hypokalemia. In 6 cats, blood pressure was determined: 5 cats showed hypertension, of which 4 animals exhibited retinal detachment and blindness. In the ultrasonographic examination, unilateral adrenomegaly was present in 6 cats whereas one animal showed normal adrenals. In 4 cats, the serum aldosterone concentration was above the reference range. Five cats underwent unilateral adrenalectomy, which was accomplished uneventfully and returned the electrolytes back to normal. Histopathological examination of the adrenals revealed 2 carcinomas and 4 adenomas; one cat with ultrasonographic normal adrenals exhibited bilateral nodular hyperplasia.


Association between hypoxic volume and underlying hypoxia-induced gene expression in oropharyngeal squamous cell carcinoma.
Hypoxia imaging is a promising tool for targeted therapy but the links between imaging features and underlying molecular characteristics of the tumour have not been investigated. The aim of this study was to compare hypoxia biomarkers and gene expression in oropharyngeal squamous cell carcinoma (OPSCC) diagnostic biopsies with hypoxia imaged with 64Cu-ATSM PET/CT. 64Cu-ATSM imaging, molecular and clinical data were obtained for 15 patients. Primary tumour SUVmax, tumour to muscle ratio (TMR) and hypoxic volume were tested for association with reported hypoxia gene signatures in diagnostic biopsies. A putative gene signature for hypoxia in OPSCCs (hypoxic volume-associated gene signature (HVS)) was derived. Hypoxic volume was significantly associated with a reported hypoxia gene signature (rho=0.57, P=0.045), but SUVmax and TMR were not. Immunohistochemical staining with the hypoxia marker carbonic anhydrase 9 (CA9) was associated with a gene expression hypoxia response (rho=0.63, P=0.01). Sixteen genes were positively and five genes negatively associated with hypoxic volume (adjusted P<0.1; eight genes had adjusted P<0.05; HVS). This signature was associated with inferior 3-year progression-free survival (HR=1.5 (1.0-2.2), P=0.047) in an independent patient cohort. 64Cu-ATSM-defined hypoxic volume was associated with underlying hypoxia gene expression response. A 21-gene signature derived from hypoxic volume from patients with OPSCCs in our study may be linked to progression-free survival.


Effect of death of Diana, princess of Wales on suicide and deliberate self-harm.
The death of the Princess of Wales in 1997 was followed by widespread public mourning. Such major events may influence suicidal behaviour. To assess the impact of the Princess's death on suicide and deliberate self-harm (DSH). Analysis, using Poisson regression, of the number of suicides and open verdicts ('suicides') in England and Wales following the Princess's death compared to the 3 months beforehand, and the equivalent periods in 1992-1996. Similar analysis on DSH presentations to a general hospital. Suicides increased during the month following the Princess's funeral (+17.4%). This was particularly marked in females (+33.7%), especially those aged 25-44 years (+45.1%). Suicides did not fall in the week between the death and the funeral. Presentations for DSH increased significantly during the week following the death (+44.3%), especially in females (+65.1%). Examination of case notes suggested that the influence of the death was largely through amplification of personal losses or exacerbation of existing distress. The death of a major public figure can influence rates of suicidal behaviour. For DSH, the impact may be immediate, but for suicide it may be delayed.


A neurocomputational account of taxonomic responding and fast mapping in early word learning.
We present a neurocomputational model with self-organizing maps that accounts for the emergence of taxonomic responding and fast mapping in early word learning, as well as a rapid increase in the rate of acquisition of words observed in late infancy. The quality and efficiency of generalization of word-object associations is directly related to the quality of prelexical, categorical representations in the model. We show how synaptogenesis supports coherent generalization of word-object associations and show that later synaptic pruning minimizes metabolic costs without being detrimental to word learning. The role played by joint-attentional activities is identified in the model, both at the level of selecting efficient cross-modal synapses and at the behavioral level, by accelerating and refining overall vocabulary acquisition. The model can account for the qualitative shift in the way infants use words, from an associative to a referential-like use, for the pattern of overextension errors in production and comprehension observed during early childhood and typicality effects observed in lexical development. Interesting by-products of the model include a potential explanation of the shift from prototype to exemplar-based effects reported for adult category formation, an account of mispronunciation effects in early lexical development, and extendability to include accounts of individual differences in lexical development and specific disorders such as Williams syndrome. The model demonstrates how an established constraint on lexical learning, which has often been regarded as domain-specific, can emerge from domain-general learning principles that are simultaneously biologically, psychologically, and socially plausible.