Total and high density lipoprotein cholesterol in the serum and risk of mortality: evidence of a threshold effect.
The association of serum total and high density lipoprotein cholesterol values with 15 year mortality was examined in a cohort of 10 059 Israeli male civil servants and municipal employees aged 40 and above. In 618 of 1664 deaths in the cohort (37%) coronary heart disease was documented as the cause of death. Risk of mortality was analysed by quintiles. Neither total mortality nor coronary heart disease mortality rose with serum cholesterol concentrations up to 5.6 mmol/1 (216 mg/100 ml), representing 60% of the sample. Rates rose appreciably only in the highest quintile (cholesterol concentration greater than 6.2 mmol/1; greater than 241 mg/100 ml). High density lipoprotein cholesterol was similarly, although inversely, associated with total mortality when expressed as a percentage of total cholesterol. The inverse association of high density lipoprotein cholesterol with coronary heart disease mortality was, in contrast, continuous. These data support the hypothesis that over most of the range of cholesterol values coronary mortality risk and total mortality risk are nearly independent of total cholesterol and most probably independent of low density lipoprotein cholesterol values. In multivariate analysis a low concentration of high density lipoprotein cholesterol appeared to be more predictive of mortality than a high concentration of total cholesterol. The latter was very weakly related to mortality from all causes after multivariate adjustment. It is concluded that the findings of this and other major epidemiological studies support the notion of a "threshold effect." Success in reducing mortality through the pharmacological reduction of serum cholesterol in hypercholesterolaemic patients does not warrant a similar approach in people with average or slightly above average values. These findings appear to provide support for a "high risk strategy" in reducing the risk of coronary heart disease.


Biochemical mechanisms of tumor invasion and metastases.
Cancer invasion and metastases is a complex multistep process. In order for a tumor cell to successfully traverse all the steps of this process and initiate a metastatic colony, it must express the right combination of gene products. Such gene products may include proteins which regulate cell interaction with the basement membrane and cell motility. Tumor cells attach to the basement membrane glycoprotein laminin via the cell surface laminin receptor. The human laminin receptor was purified and molecularly cloned. The level of laminin receptor mRNA is a variety of human carcinoma cells correlated with the number of laminin receptors on the cell surface of these cells. Following attachment to the basement membrane, the tumor cell next secretes proteases which may degrade type IV collagen. A genetic linkage between type IV collagenase secretion and metastases was studied using our new genetic system for inducing metastases employing the ras oncogene. Following attachment and local proteolysis, the third step of invasion is tumor cell motility. We have isolated a tumor cell autocrine motility factor (AMF). This factor is secreted by the tumor cells and binds to a cell surface receptor resulting in a profound (greater than 100x) stimulation of cell locomotion. AMF may play a major role in the autonomous invasive behavior of tumor cells.


Synthetic Transcription Amplifier System for Orthogonal Control of Gene Expression in Saccharomyces cerevisiae.
This work describes the development and characterization of a modular synthetic expression system that provides a broad range of adjustable and predictable expression levels in S. cerevisiae. The system works as a fixed-gain transcription amplifier, where the input signal is transferred via a synthetic transcription factor (sTF) onto a synthetic promoter, containing a defined core promoter, generating a transcription output signal. The system activation is based on the bacterial LexA-DNA-binding domain, a set of modified, modular LexA-binding sites and a selection of transcription activation domains. We show both experimentally and computationally that the tuning of the system is achieved through the selection of three separate modules, each of which enables an adjustable output signal: 1) the transcription-activation domain of the sTF, 2) the binding-site modules in the output promoter, and 3) the core promoter modules which define the transcription initiation site in the output promoter. The system has a novel bidirectional architecture that enables generation of compact, yet versatile expression modules for multiple genes with highly diversified expression levels ranging from negligible to very strong using one synthetic transcription factor. In contrast to most existing modular gene expression regulation systems, the present system is independent from externally added compounds. Furthermore, the established system was minimally affected by the several tested growth conditions. These features suggest that it can be highly useful in large scale biotechnology applications.


Health system factors and antihypertensive adherence in a racially and ethnically diverse cohort of new users.
The purpose of this study was to identify potential health system solutions to suboptimal use of antihypertensive therapy in a diverse cohort of patients initiating treatment. Using a hypertension registry at Kaiser Permanente Northern California, we conducted a retrospective cohort study of 44 167 adults (age, ≥18 years) with hypertension who were new users of antihypertensive therapy in 2008. We used multivariate logistic regression analysis to model the relationships between race/ethnicity, specific health system factors, and early nonpersistence (failing to refill the first prescription within 90 days) and nonadherence (<80% of days covered during the 12 months following the start of treatment), respectively, controlling for sociodemographic and clinical risk factors. More than 30% of patients were early nonpersistent and 1 in 5 were nonadherent to therapy. Nonwhites were more likely to exhibit both types of suboptimal medication-taking behavior compared with whites. In logistic regression models adjusted for sociodemographic, clinical, and health system factors, nonwhite race was associated with early nonpersistence (black: odds ratio, 1.56 [95% CI, 1.43-1.70]; Asian: 1.40 [1.29-1.51]; Hispanic: 1.46 [1.35-1.57]) and nonadherence (black: 1.55 [1.37-1.77]; Asian: 1.13 [1.00-1.28]; Hispanic: 1.46 [1.31-1.63]). The likelihood of early nonpersistence varied between Asians and Hispanics by choice of first-line therapy. In addition, racial and ethnic differences in nonadherence were appreciably attenuated when medication co-payment and mail-order pharmacy use were accounted for in the models. Racial/ethnic differences in medication-taking behavior occur early in the course of treatment. However, health system strategies designed to reduce patient co-payments, ease access to medications, and optimize the choice of initial therapy may be effective tools in narrowing persistent gaps in the use of these and other clinically effective therapies.


Epiphora drainage by DCR - Long-term results.
Dacryocystorhinostomy (DCR) refers to the surgical procedure that is used to relieve the chronic obstruction of the nasolacrimal duct obstruction (NLDO). In a maxillofacial setting, NLDO may arise subsequent to a facial trauma or orthognathic surgery. There is a dearth of literature from this part of the world. This article intends to provide a single maxillofacial center experience in DCR. This is a retrospective, noncomparative, noninterventional, record audit type of study of all consecutive patients fulfilling inclusion and exclusion criteria. All patients with epiphora and diagnosed with lacrimal apparatus damage between 1 January 2008 and 31 December 2017 requiring DCR were considered for the study. Details of demographics, phase of treatment (primary/retreatment), types of bones involved, age, complications, period suffering from epiphora, and follow-up were obtained. All data were entered and analyzed using the Statistical Package for the Social Service (version 16; IBM). Descriptive statistics of the frequency and mean ± standard deviation (SD) as appropriate were presented. Chi-square test and one-way analysis of variance were used appropriately. P ≤ 0.05 was taken to be statistically significant. In all, 83 patients fulfilled the inclusion and exclusion criteria. It is more common in males (n = 56, 67.47%) with a mean ± SD of 32.24 ± 10.80 (18-59 years) with 27 (32.53%) of them presenting primarily after fractures. Fracture was the most common pathology seen in 81.93% (n = 68) of cases, while the rest were as a result of orthognathic cases. Le Fort II and III set of bones contributed to 59% of cases, while the orbitonasal complex contributed to only three cases. NLD obstruction was seen in 68 (81.9%) of cases. On an average, the patients suffered for 9.3 ± 6.74 months (range 0.5-22 months) before seeking treatment and the average follow-up was 31.07 ± 11.69 months (range 15-54 months). Fractures and surgeries involving nasal bones carry an innate risk of damaging the NLD system. The pattern of need for DCR and occurrence of NLDO in this part of the world have been described. The extent of the anatomical variations and need for proper surgical planning are highlighted.


Differential diagnosis in a professional basketball player with foot pain: is it an avulsion fracture or an os supranaviculare?
The os supranaviculare is an accessory bone located on the dorsal aspect of the talonavicular joint close to the midpoint. This rare incidental skeletal variant has an estimated prevalence of 1%. It may rarely become symptomatic and should not be confused with cortical avulsion fractures of navicular or talar head. We present the case of a 25-year-old professional basketball player with pain on the dorsum of his right foot after twisting his ankle during a regular season match. Magnetic resonance imaging findings of the player's foot represented a flake of bone on the superior part of the talar head. The differential diagnosis and clinical outcome of this unusual case are briefly discussed.


Sexual arousal patterns of bisexual men revisited.
Men who identify themselves as bisexual report feeling sexually aroused by both men and women. However, past research has not demonstrated that such men exhibit substantial genital arousal to both male and female erotic stimuli, suggesting that they identify as bisexual for reasons other than their genital arousal pattern. The purpose of the present study was to examine arousal patterns among bisexual men who were recruited using stringent criteria involving sexual and romantic experience with both men and women in order to increase the likelihood of finding a bisexual arousal pattern. Bisexual men in the present study demonstrated bisexual patterns of both subjective and genital arousal. It remains unclear which pattern is most typical of contemporary bisexual men: the present results supporting a bisexual arousal pattern, or previous results not finding one. In either case, understanding men with bisexual arousal patterns could help illuminate the etiology and development of male sexual orientation.


Internet addiction in Greek medical students: an online survey.
The authors investigated the prevalence of Internet addiction (IA) in undergraduate medical students to identify possible associations with sociodemographics and Internet habits. All students at the Aristotle University of Thessaloniki School of Medicine, Greece, were invited to complete the online Internet Addiction Test (IAT) along with sociodemographics and preferences on Internet activities. The authors received 585 responses after three reminders (23.5 % response rate). Mild IA was found in 24.5 %, moderate in 5.4 %, and severe in 0.2 %. In multivariable analysis, the odds to develop IA were increased with visits in Internet cafes (Odds Ratio [OR] 3.49, 95 % Confidence Interval [CI]: 1.45, 8.46), the use of Facebook (OR 2.43, 95 % CI: 1.35, 4.38), Twitter (OR 2.45, 95 % CI: 1.37, 4.39), and online games (OR 1.95, 95 % CI: 1.29, 2.94). Using e-mails seemed to be protective against IA (OR 0.59, 95 % CI: 0.37, 0.94). This is the first IA prevalence study in a European medical school. Early-detection systems and other ways to help students with pathological behaviors should be developed.


Nonmyeloablative allogeneic transplantation achieves clinical and molecular remission in cutaneous T-cell lymphoma.
The majority of patients with refractory, advanced-stage mycosis fungoides (MF) or Sézary syndrome (SS) have a life expectancy of <5 years. Here, we report a phase 2 study of a novel nonmyeloablative allogeneic transplantation strategy tailored for this patient population. This study has completed the enrollment, and 35 patients (13 MF, 22 SS) have undergone transplant as planned. The majority (80%) of the patients had stage IV disease and received multiple previous systemic therapies. All patients had active disease at the time of conditioning using total skin electron beam therapy, total lymphoid irradiation, and antithymocyte globulin, and received allograft infusion as outpatients. Cyclosporine or tacrolimus and mycophenolate mofetil were used for graft-versus-host disease (GVHD) prophylaxis. Patients tolerated the transplant well, with 1- and 2-year nonrelapse mortality of 3% and 14%, respectively. The day +180 cumulative incidence of grade 2 to 4 acute GVHD was 16%, and the 2-year incidence of moderate/severe chronic GVHD was 32%. With a median posttransplant follow-up of 5.4 years, the 2-, 3-, and 5-year overall survival rates were 68%, 62%, and 56%. Using high-throughput sequencing of the T-cell receptor for minimal residual disease monitoring, we observed that 43% achieved molecular remission, which was associated with a lower incidence of disease progression or relapse (9% vs 87%; P = .02). Our study also showed that patients who were aged ≥65 years at the time of allotransplant had similar clinical outcomes compared with younger patients. Thus, we have developed an alternative and potentially curative nonmyeloablative allogeneic transplant regimen for patients with advanced stage MF/SS. This trial was registered at www.clinicaltrials.gov as #NCT00896493.


[Regional disparities in the medical care of neurological diseases in Aomori prefecture].
The population and the area of Aomori prefecture are 1,380 thousands and 9,644 km2, respectively. Aomori prefecture geographically and economically forms an independent medical district. However, only 29 neurological specialists attended work in Aomori Prefecture. The numbers of neurological specialists per 100,000 people and per 100 km(2) were 2.1 and 0.3 in Aomori, respectively, whereas those of Tokyo metropolitan area were 5.9 and 34.9, and their nationwide averages were 3.6 and 1.2, respectively. Although Aomori prefecture is divided into six medical service areas, neurologists were eccentrically-located in three cities; Aomori, Hirosaki and Hachinohe. No neurologists give full-time service in three of the six areas. The percentage of people having medical care certificate for six specified neurological disorders (multiple sclerosis, myasthenia gravis, amyotrophic lateral sclerosis, spinocerebellar degeneration, Parkinson disease and related disorders, and multisystem atrophy) in Aomori was comparable to the nationwide average. However, the number of patients with the certificate of multiple sclerosis and myasthenia gravis in areas with neurologist's service were 11.4 and 12.0 per 100,000 people, respectively, whereas those of area without full-time neurologist's service were 9.9 and 9.2, (significant lower). The patients living in the area without neurologist's service received medical care by neurologists less frequently when compared to those living in area with neurologist's service. Forty-five percent of the patients living in the area without neurologist's service went out of their living areas to see neurologists regularly. Thus, neurologists in Aomori prefecture are under strain to provide medical services. People in Aomori prefecture do not receive sufficient neurological services, especially in the area where no neurologists attend work. In addition, patients living in area without neurologist's service bear greater burden to go to hospital.


The Cosmopolitanization of Science: Experience from Chinese Stem Cell Scientists.
It is commonly perceived that the 'globalization of science' may result in a 'Westernization of science'. In this paper, however, I use the case of stem cell science in China to demonstrate that developing countries are sometimes able to effectively shape the norms of global/local scientific exchange. Based on interviews with 38 stem cell scientists in six Chinese cities in early 2008, this paper elucidates Chinese scientists' outlook towards cross-border collaborations and the effects that the internationalization of science has had on everyday laboratory operations. Findings suggest that although there still exists an asymmetry of scientific influence, and in many aspects China is still 'catching-up' to the West, there is also a changing nature of communication beyond borders. One key aspect of recent international scientific development is the growing necessity for local stakeholders to acquire a global mindset and to compare, reflect and accommodate diverse interests. This is what I define as the 'cosmopolitanization of science'. The study empirically examines the sociological and methodological implications of the cosmopolitanization process and further develops Ulrich Beck's cosmopolitan theory by delineating four main features of the 'cosmopolitanization of science': shared future benefits, passive ethicization, reflexive negotiation, and continuous performance.


Intestinal epithelial cell-derived integrin αβ6 plays an important role in the induction of regulatory T cells and inhibits an antigen-specific Th2 response.
Toleroge nic DCs and Tregs are believed to play a critical role in oral tolerance. However, the mechanisms of the generation of tolerogenic DCs and activation of Tregs in the gut remain poorly understood. This study aims to dissect the molecular mechanisms by which IECs and protein antigen induce functional tolerogenic DCs and Tregs. Expression of αvβ6 by gut epithelial cell-derived exosomes, its coupling with food antigen, and their relationship with the development of functional tolerogenic DCs and Tregs were examined by using in vitro and in vivo approaches. The results show that IECs up-regulated the integrin αvβ6 upon uptake of antigens. The epithelial cell-derived exosomes entrapped and transported αvβ6 and antigens to the extracellular environment. The uptake of antigens alone induced DCs to produce LTGFβ, whereas exosomes carrying αvβ6/antigen resulted in the production of abundant, active TGF-β in DCs that conferred to DCs the tolerogenic properties. Furthermore, αvβ6/OVA-carrying, exosome-primed DCs were found to promote the production of active TGF-β in Tregs. Thus, in vivo administration of αvβ6/OVA-laden exosomes induced the generation of Tregs and suppressed skewed Th2 responses toward food antigen in the intestine. Our study provides important molecular insights into the molecular mechanisms of Treg development by demonstrating an important role of IEC-derived exosomes carrying αvβ6 and food antigen in the induction of tolerogenic DCs and antigen-specific Tregs.


Chinese version of the positive and negative suicide ideation: instrument development.
This paper is a report of a study conducted to develop a Chinese version of the Positive and Negative Suicide Ideation Inventory and evaluate its psychometric properties. Comprehensive assessment of suicidal behaviour in youths should incorporate both protective factors and risk factors. We recruited 2341 middle- and high-school students for a longitudinal and prospective study, conducted between 2005 and 2007. To assess predictive validity, a convenience sample of 251 of the 2341 students was recruited 1 year later to follow-up on suicide attempts during the preceding 2 weeks. To evaluate construct validity, a small convenience sample of 94 adolescent inpatients and outpatients was used as a comparison group. Instruments used included the Children's Depression Inventory, the Self-Control Schedule, and the Cognitive Triad for Children. Cronbach's alpha coefficients for the Chinese version of the positive and negative suicide ideation-negative suicide ideation and the Chinese version of the positive and negative suicide ideation-positive ideation were 0.94 and 0.86 respectively. Satisfactory test-retest reliability was evident. Convergent and divergent validities were demonstrated by statistically significant correlations among subscales and the other instruments used. Construct validity was evidenced by statistically significantly different scores on the subscales among the contrasted groups. Subscale scores in the first-wave study statistically significantly predicted attempted suicide behaviour 1 year later, demonstrating evidence of predictive validity. Factor analysis showed a two-factor structure. The Chinese Version of the Positive and Negative Suicide Ideation Inventory may be a reliable and valid instrument to measure the severity of suicidal ideation in adolescents, subject to further research to test the generalizability of the present findings.


From observation to experimentation: leptin action in the mediobasal hypothalamus.
The burgeoning obesity epidemic has fueled the drive to describe, mechanistically, metabolic homeostasis. From the early theories implicating glucose as a principal modulator grew an understanding of a complex array of metabolic signals, sensed by peripheral organs along with specific locations within the central nervous system (CNS). The discovery that leptin, an adipose-derived hormone, acts within the mediobasal hypothalamus to control food intake and energy expenditure ushered in a decade of research that went on to describe not only the specific nuclei and cell type, such as proopiomelanocortin neurons of the arcuate nucleus, that respond to leptin but also the signaling cascades that mediated its effects. This review thus highlights the sites and mechanisms of action of leptin, both in the hypothalamus and in extrahypothalamic sites within the CNS, and shows our current knowledge and direction of future research aimed at understanding the multifunctional role of leptin in maintaining metabolic homeostasis.


Acute lymphoblastic leukemia in a developing country: preliminary results of a nonrandomized clinical trial in El Salvador.
To improve outcome and study biology of childhood acute lymphoblastic leukemia (ALL) in El Salvador. Between January 1994 and December 1996, 153 children of El Salvador had newly diagnosed ALL treated in a collaborative program between Hospital Benjamin Bloom and St. Jude Children's Research Hospital (SJCRH). Therapy was based on a modified SJCRH protocol, with uniform remission induction (prednisone, vincristine, L-asparaginase) followed-up by consolidation with teniposide/cytarabine and/or high-dose methotrexate. Continuation treatment was risk-stratified: 123 patients assigned to the high-risk group received weekly rotational drug pairs, and 16 assigned to the standard-risk group received daily 6-mercaptopurine, weekly methotrexate, and monthly pulses of vincristine plus dexamethasone. High risk was defined as: DNA index < 1.16, age 12 months or younger, white blood cell count > or = 50 x 10(9)/L, T-cell immunophenotype, anterior mediastinal mass, central nervous system leukemia at diagnosis, or t(4;11), t(1;19), or t(9;22). Duration of the continuation treatment was 2.5 years in both groups. The median age at diagnosis of all patients was 4.8 (range I d-17 yrs), median leukocyte count was 15 (range 1-766) x 10(9)/L, and sex distribution was equal. Immunophenotypes were early beta-progenitor in 79%, T-cell in 3.9%, and inconclusive in 17% of cases. DNA index was <1.16 in 80.5% and was > or = 1.16 in 19.5% of the 123 known cases. For the analyzes, patients who refused therapy (abandoned treatment) were considered to have treatment failure as of their last follow-up dates. Complete remission was achieved in 126 of 151 (82.4%) patients (11 abandoned therapy during induction). The overall 4-year event-free survival (EFS) rate +/- 1 standard error was 48 +/- 6%. The 4-year EFS rates in patients at high-risk and standard-risk were 46 +/- 7% (n = 121) and 69 +/- 15% (n = 16), respectively (P = 0.20). When patients who refused further treatment are censored, the corresponding 4-year estimates of EFS are 51 +/- 8% and 75 +/- 14%, respectively. These results suggest that the biology of childhood ALL in El Salvador appears to be similar to that seen in the United States. Risk-directed chemotherapy can successfully be used in developing countries, but risk factors must be carefully determined and applied.


Congenital Pulmonary Airway Malformation - 19-Year Experience from a Tertiary Care Center in India.
Background: Congenital pulmonary airway malformation (CPAM) is a collection of non-hereditary, developmental anomalies. Our aim was to analyze the histological profiles and prevalence of CPAMs diagnosed in our center. Methods: A retrospective study of all CPAMs diagnosed from January 1999 to May 2018 from a general hospital pathology service was performed. Results: There were 79 cystic lesions encountered in fetuses, neonates, and children, 15 of which were CPAMs {5/2372 (0.21%) autopsies and 10/216026 (0.0046%) surgical resections}. The male:female ratio was 1:1.14. Gestational age of antenatal cases ranged from 22 to 32 weeks, postnatal ages ranged from 7 days to 15 years (mean 2.9 years). The cases were right-sided (8/15;53.3%), left-sided (4/15;26.7%) and bilateral (3/15,20%). Seven (46.7%), 4 (26.7%),3 (20%) and 1 (6.7%) were types 1, 2, 3 and 4, respectively. None of the surgical cases had postoperative mortality or morbidity. Conclusions: Prompt recognition and surgical resectability resulted in normal growth and symptom free survival in our postnatally diagnosed patients. Mortality in antenatally diagnosed fetuses remains high (5/11;45%).


Conditional deletion of the human ortholog gene Dicer1 in Pax2-Cre expression domain impairs orofacial development.
Orofacial clefts are common worldwide and result from insufficient growth and/or fusion during the genesis of the derivatives of the first pharyngeal arch and the frontonasal prominence. Recent studies in mice carrying conditional and tissue-specific deletions of the human ortholog Dicer1, an RNAse III family member, have highlighted its importance in cell survival, differentiation, proliferation, and morphogenesis. Nevertheless, information regarding Dicer1 and its dependent microRNAs (miRNAs) in mammalian palatogenesis and orofacial development is limited. To describe the craniofacial phenotype, gain insight into potential mechanisms underlying the orofacial defects in the Pax2-Cre/Dicer1 CKO mouse, and shed light on the role of Dicer1 in mammalian palatogenesis. Histological and molecular assays of wild type (WT) and Pax2-Cre/Dicer1(loxP/loxP) (Dicer1 CKO) mice dissected tissues have been performed to characterize and analyze the orofacial dysmorphism in Pax2-Cre/Dicer1(loxP/loxP) mouse. Dicer1 CKO mice exhibit late embryonic lethality and severe craniofacial dysmorphism, including a secondary palatal cleft. Further analysis suggest that Dicer1 deletion neither impacts primary palatal development nor the initial stages of secondary palatal formation. Instead, Dicer1 is implicated in growth, differentiation, mineralization, and survival of cells in the lateral palatal shelves. Histological and molecular analysis demonstrates that secondary palatal development becomes morphologically arrested prior to mineralization around E13.5 with a significant increase in the expression levels of apoptotic markers (P < 0.01). Pax2-Cre-mediated Dicer1 deletion disrupts lateral palatal outgrowth and bone mineralization during palatal shelf development, therefore providing a mammalian model for investigating the role of miRNA-mediated signaling pathways during palatogenesis.


Loss of FTO antagonises Wnt signaling and leads to developmental defects associated with ciliopathies.
Common intronic variants in the Human fat mass and obesity-associated gene (FTO) are found to be associated with an increased risk of obesity. Overexpression of FTO correlates with increased food intake and obesity, whilst loss-of-function results in lethality and severe developmental defects. Despite intense scientific discussions around the role of FTO in energy metabolism, the function of FTO during development remains undefined. Here, we show that loss of Fto leads to developmental defects such as growth retardation, craniofacial dysmorphism and aberrant neural crest cells migration in Zebrafish. We find that the important developmental pathway, Wnt, is compromised in the absence of FTO, both in vivo (zebrafish) and in vitro (Fto(-/-) MEFs and HEK293T). Canonical Wnt signalling is down regulated by abrogated β-Catenin translocation to the nucleus whilst non-canonical Wnt/Ca(2+) pathway is activated via its key signal mediators CaMKII and PKCδ. Moreover, we demonstrate that loss of Fto results in short, absent or disorganised cilia leading to situs inversus, renal cystogenesis, neural crest cell defects and microcephaly in Zebrafish. Congruently, Fto knockout mice display aberrant tissue specific cilia. These data identify FTO as a protein-regulator of the balanced activation between canonical and non-canonical branches of the Wnt pathway. Furthermore, we present the first evidence that FTO plays a role in development and cilia formation/function.


Critical aspects of radon remediation in karst limestone areas: some experiences in schools of South Italy.
The final results of radon monitoring in 438 schools located in the province of Lecce (Puglia Region, South Italy) showed an average radon concentration of 215 ± 20 Bq m-3 and that 7% of schools exceeded 500 Bq m-3, the current Italian action level for radon in workplaces, and consequently required remedial actions. The activity described in the present paper includes the main elements of the remediation project in a subgroup of school buildings. The main radon control systems adopted were sub-slab depressurization (in 57% of schools) and the active ventilation of the crawlspace (in 21% of schools). This experience allows us to put in evidence relevant critical aspects, such as the influence of the karstic nature of the area, the optimization of remediation, the architectural constraints in the case of buildings of architectural or historical interest, which are discussion herein. Moreover, considering the new reference level for radon in workplaces introduced by the new EU Basic Safety Standards, a new analysis of data, achieved in the first survey, highlighted that 20% of schools need to be remediated.


Effects of CpG oligodeoxynucleotide 1826 on acute radiation-induced lung injury in mice.
The radiation-induced lung injury is a common complication from radiotherapy in lung cancer. CpG ODN is TLR9 activator with potential immune modulatory effects and sensitization of radiotherapy in lung cancer. This study aimed to examine the effect of CpG ODN on acute radiation-induced lung injury in mice. The mouse model of radiation-induced lung injury was established by a single dose of 20 Gy X-rays exposure to the left lung. The results showed that the pneumonia score was lower in RT+CpG group than in RT group on 15th and 30th days. Compared with RT group, CpG ODN reduced the serum concentrations of MDA (P < 0.05) and increased the serum concentrations of SOD, GSH (P < 0.05). The serum concentration of TNF-α in RT+CpG group was lower on 15th and 30th days post-irradiation (P < 0.05). The study demonstrated that CpG ODN has preventive effects of acute radiation-induced lung injury in mice. Lung inflammatory reaction and oxidative stress are promoted in the initiation of radiation-induced pneumonia. CpG ODN may reduce the injury of reactive oxygen species and adjust the serum TNF-α concentration in the mice after irradiation, which reduces the generation of the inflammatory cytokines.


[Frequency of high-fat and low-fiber diets among adolescents].
To describe the frequency and associated factors of high-fat and low-fiber diets among adolescents. A cross-sectional study was carried out in adolescents aged 10-12 years in Pelotas, southern Brazil, in 2004 and 2005. Dietary patterns in the previous 12 months were evaluated using the Block questionnaire comprising 24 food items scored according to the frequency of consumption of high-fat and low-fiber food. In the crude analysis, the prevalence of high-fat and low-fiber diets were compared according to subgroups of independent variables (sex, skin color, socioeconomic condition, maternal schooling and adolescent's nutritional status). In order to adjust for confounders, multivariable analysis using Poisson's regression was carried out for each outcome. There were 4,452 adolescents included in the study, most of them (83.9%) had low-fiber diets and more than one third (36.6%) had high-fat diets. Socioeconomic condition and maternal schooling were directly associated with consumption of high-fat diets. Adolescents from socioeconomic groups A+B and C had lower prevalence of low-fiber diet. The prevalence of low-fiber and high-fat diets was high in this population of adolescents. Public policies targeting the determinants of dietary habits are necessary and urgent.


Spine head calcium as a measure of summed postsynaptic activity for driving synaptic plasticity.
We use a computational model of a hippocampal CA1 pyramidal cell to demonstrate that spine head calcium provides an instantaneous readout at each synapse of the postsynaptic weighted sum of all presynaptic activity impinging on the cell. The form of the readout is equivalent to the functions of weighted, summed inputs used in neural network learning rules. Within a dendritic layer, peak spine head calcium levels are either a linear or sigmoidal function of the number of coactive synapses, with nonlinearity depending on the ability of voltage spread in the dendrites to reach calcium spike threshold. This is strongly controlled by the potassium A-type current, with calcium spikes and the consequent sigmoidal increase in peak spine head calcium present only when the A-channel density is low. Other membrane characteristics influence the gain of the relationship between peak calcium and the number of active synapses. In particular, increasing spine neck resistance increases the gain due to increased voltage responses to synaptic input in spine heads. Colocation of stimulated synapses on a single dendritic branch also increases the gain of the response. Input pathways cooperate: CA3 inputs to the proximal apical dendrites can strongly amplify peak calcium levels due to weak EC input to the distal dendrites, but not so strongly vice versa. CA3 inputs to the basal dendrites can boost calcium levels in the proximal apical dendrites, but the relative electrical compactness of the basal dendrites results in the reverse effect being less significant. These results give pointers as to how to better describe the contributions of pre- and postsynaptic activity in the learning "rules" that apply in these cells. The calcium signal is closer in form to the activity measures used in traditional neural network learning rules than to the spike times used in spike-timing-dependent plasticity.


CT density decrease in water intoxication rat model of brain oedema.
The aim of this study was to determine whether water intoxication affects the radiodensity of brain tissue in CT scan examination in the rat model of brain oedema. A standard CT scan of the brain was obtained in a group of rats, first at control conditions (controls - CG) and then after hyperhydration (oedema model-EG) in the region of interest (ROI) corresponding to the area of coronary sections with pixel size 0.125 mm in position A (bregma +2.43 mm), position B (bregma -2.92 mm), position C (bregma -12.73 mm). Densitometrically determined mean values (MV), expressed in Hounsfield units (HU) were processed by standard statistical methods. The average MV density was 120.49±6.79 HU for the control measurement and 88.01±4.72 HU after the hyperhydration, which represents decrease in the density by 32.48 HU (p<0.001). In the control measurement the average value of HU for the position A was 121.98, for position B 112.4 and for position C 127.08. In conditions of hyperhydration, the average MV density in position A was 89.95 HU in position B 84.67 HU and in position C 89.43 HU. The differences between the CG and EG were in all positions A, B, C statistically significant (p<0.001). In the control measurement, the differences between position A×B (p<0.05) and B×C (p<0.001) were statistically significant. After hyperhydration no significant difference between the position A, B, C was found. water intoxication caused by hyperhydration in rats can induce diffuse brain oedema, which is reflected in the CT examination by the decrease of brain tissue density, expressed in HU. The value of the measured density depends on the location and size of the measured brain area.


Genetic and epigenetic markers in the evaluation of pancreatic masses.
Methylation markers have shown promise in the early diagnosis of pancreatic carcinoma. The aim of this study was to assess the diagnostic utility of hypermethylation status of candidate genes in combination with KRAS mutation detection in the evaluation of pancreatic masses. Sixty-one fine needle aspirates of pancreatic masses (43 pancreatic adenocarcinomas and 18 chronic pancreatitis) were studied. Methylation status of HRH2, EN1, SPARC, CDH13 and APC were analysed using melting curve analysis after DNA bisulfite treatment. KRAS mutations were also analysed. The methylation panel had a sensitivity of 73% (27 of 37, CI 95% 56 to 86%) and a specificity of 100% whenever two or more promoters were found hypermethylated. KRAS mutations showed a sensitivity of 77% (33 of 43, CI 95% 62 to 88%) and a specificity of 100%. Both molecular analyses added useful information to cytology by increasing the number of informative cases. When genetic and epigenetic analyses were combined sensitivity was 84% (36 of 43 CI 95% 69 to 93%) maintaining a 100% specificity. Analysis of hypermethylation status of a panel of genes and KRAS mutation detection offer a similar diagnostic yield in the evaluation of pancreatic masses. The combined molecular analysis increases the number of informative cases without diminishing specificity.


Interaction of U2AF65 RS region with pre-mRNA branch point and promotion of base pairing with U2 snRNA [corrected].
The mammalian splicing factor U2AF65 binds to the polypyrimidine tract adjacent to the 3' splice site and promotes assembly of U2 small nuclear ribonucleoprotein on the upstream branch point, an interaction that involves base pairing with U2 small nuclear RNA (snRNA). U2AF65 contains an RNA binding domain, required for interaction with the polypyrimidine tract, and an arginine-serine-rich (RS) region, required for U2 snRNP recruitment and splicing. Here it is reported that binding of U2AF65 to the polypyrimidine tract directed the RS domain to contact the branch point and promoted U2 snRNA-branch point base pairing even in the absence of other splicing factors. Analysis of RS domain mutants indicated that the ability of U2AF65 to contact the branch point, to promote the U2 snRNA-branch point interaction, and to support splicing are related activities, requiring only a few basic amino acids. Thus, the U2AF65 RS domain plays a direct role in modulating spliceosomal RNA-RNA interactions.


Fluorescence tomographic microscopy by wavefront detection.
A new method, to our knowledge, for real-time direct access to depth information in scanning fluorescence microscopy is reported. It is based on axially exciting the sample and detecting the phase and intensity of the emitted light. Results obtained using an axicon lens to generate a Bessel beam for excitation and a microlens array as phase detector are presented.


Estrogen receptor regulation of the Na+/H+ exchange regulatory factor.
To better understand the actions of estrogens and antiestrogens in estrogen target cells, we have searched for estrogen-regulated genes in human breast cancer cells, in which the number of genes known to be directly activated by estrogen is quite small. Using differential display RNA methods, we have identified the human homolog of the Na+ -H+ exchanger regulatory factor (NHE-RF), an approximately 50-kDa protein that is also an ezrin-radixin-moesin-binding phosphoprotein, as being under rapid and direct regulation by estrogen in estrogen receptor (ER)-containing breast cancer cells. Stimulation by estrogen of NHE-RF RNA is rapid, being near maximal (approximately 6-fold) by 1 h, and is not blocked by cycloheximide, indicating that it is a primary response. Stimulation is selective for estrogen ligands, with no stimulation by other classes of steroid hormones, and stimulation by estrogen is suppressed by the antiestrogens tamoxifen and ICI 182,780. Induction is shown to require an active ER through several approaches, including the use of ER-negative breast cancer cells containing a stably integrated ER. NHE-RF protein levels, monitored using antibodies specific for this protein, increase after estrogen and reach maximal levels at 24-48 h. Interestingly, NHE-RF is a PDZ domain-containing protein that is enriched in polarized epithelia, where it is known to be localized in microvilli. Among various human tissues we have examined, we found that NHE-RF is expressed at a fairly high level in mammary tissue. NHE-RF regulates protein kinase A inhibition of the Na+ -H+ exchanger and may serve as a scaffold adaptor protein that contributes to the specificity of signal transduction events. Our findings suggest that the early, known effects of estrogen on cell cytoarchitecture (e.g. increasing microvilli on breast cancer cells) and on some cell signaling pathways (e.g. those involving cAMP) may involve rapid estrogen-mediated changes in the production of NHE-RF.


Synthesis of rotaxanes and catenanes using an imine clipping reaction.
Supramolecular chemistry and self-assembly provide a valuable chance to understand the complicated topological structures on a molecular level. Two types of classical mechanically interlocked molecules, rotaxanes and catenanes, possess non-covalent mechanical bonds and have attracted more attention not only in supramolecular chemistry but also in the fields of materials science, nanotechnology and bioscience. In the past decades, the template-directed clipping reaction based on imine chemistry has become one of the most efficient methods for the construction of functionalized rotaxanes and catenanes. In this review, we outlined the main progress of rotaxanes and catenanes using the template-directed clipping approach of imine chemistry. The review contains the novel topological structures of rotaxanes and catenanes, functions and applications.


The Tablet-Based, Engagement, Assessment, Support, and Sign-Posting (EASSi) Tool for Facilitating and Structuring Sexual Well-Being Conversations in Routine Prostate Cancer Care: Mixed-Methods Study.
Long-term side-effects associated with different prostate cancer treatment approaches are common. Sexual challenges are the most frequently occurring issues and can result in increased psychological morbidity. It is recognized that barriers to communication can make initiating discussions around sexual concerns in routine practice difficult. Health care professionals need to routinely initiate conversations, effectively engage with patients, and assess needs in order to provide essential support. One proposed method that could support health care professionals to do this involves the use of prompts or structured frameworks to guide conversations. This study aimed to assess feasibility, acceptability, and satisfaction with the tablet-based Engagement, Assessment, Support, and Sign-posting (EASSi) tool designed to facilitate and structure sexual well-being discussions in routine prostate cancer care. Health care professionals (n=8) used the EASSi tool during 89 posttreatment appointments. Quantitative data were recorded based on program usage and surveys completed by health care professionals and patients. Qualitative data exploring perceptions on use of the tool were gathered using semistructured interviews with all health care professionals (n=8) and a sample of patients (n=10). Surveys were completed by health care professionals immediately following each appointment (n=89, 100%). Postal surveys were returned by 59 patients (66%). Health care professionals and patients reported that the tool helped facilitate discussions (81/89, 91% and 50/59, 85%, respectively) and that information provided was relevant (82/89, 92% and 50/59, 85%, respectively). The mean conversation duration was 6.01 minutes (SD 2.91). Qualitative synthesis identified the tool's ability to initiate and structure discussions, improve the "depth" of conversations, and normalize sexual concerns. The EASSi tool was appropriate and acceptable for use in practice and provided a flexible approach to facilitate routine brief conversations and deliver essential sexual well-being support. Further work will be conducted to evaluate the effectiveness of using the tablet-based tool in prostate cancer care settings.


Stunting and Its Determinants among Adolescent Girls: Findings from the Nutrition Surveillance Project, Northwest Ethiopia.
Under nutrition among adolescents is a major public health problem in Ethiopia and its causes are under investigated. Therefore, this study aimed to assess the prevalence of stunting and its determinants among adolescent girls in Dabat district. A total of 1556 adolescent girls were included in the study. The WHO's Anthro-plus software was used to generate the height for age z-scores. Variables having a p-value<0.2 in the simple logistic regression were entered into multiple logistic regression and a p-value < 0.05 were considered statistically significant. About 47.4%(95%CI; 45.0, 49.6%) of adolescent girls were stunted. Being in the early (AOR = 0.027, 95%CI: 0.08, 0.09) and middle age (AOR = 0.21, 95%CI: 0.06, 0.71) were less likely to be stunted compared with the late adolescent. The odds of stunting were found to be higher among adolescent of rural area (AOR = 1.45; 95%CI: 1.01, 2.10) and from household food in-secured (AOR = 1.33; 95%CI: 1.02, 1.73)families. Higher numbers of adolescent girls are stunted in Dabat district, suggesting severe public health importance of the problem. Age, residence and food security were associated with adolescent stunting. Thus, improving food security strategies targeting rural and food insecure households is recommended. Abbreviations: AOR= Adjusted Odd Ratio,CI= Confidence Interval, COR= Crude Odd Ratio, ENSSPI=Establishing Nutrition Surveillance System and Piloting Interventions HAZ=Height for Age, HDSS=Health and Demographic Surveillance System, HFSS=Household Food Security Status, INDEPTH=International Network of Demographic Evaluation of Population and Their Health, IQR=Inter Quartile Range, NNP=National Nutrition Program, NSHFP=National School Health and Feeding Program, SPSS=Statically Package for Social Science, WHO= World Health Organization.


Rain and Sun Create Slippery Layers in Eastern Pacific Fresh Pool.
An autonomous Lagrangian float equipped with a high-resolution acoustic Doppler current profiler observed the evolution of upper-ocean stratification and velocity in the Eastern Pacific Fresh Pool for over 100 days in August-November 2016. Although convective mixing homogenized the water column to 40 m depth almost every night, the combination of diurnal warming on clear days and rainfall on cloudy days routinely produced strong stratification in the upper 10 m. Whether due to thermal or freshwater effects, the initial strong stratification was mixed downward and incorporated in the bulk of the mixed layer within a few hours. Stratification cycling was associated with pronounced variability of ocean surface boundary layer turbulence and vertical shear of wind-driven (Ekman) currents. Decoupled from the bulk of the mixed layer by strong stratification, warm and fresh near-surface waters were rapidly accelerated by wind, producing the well-known "slippery layer" effect, and leading to a strong downwind near-surface distortion of the Ekman profile. A case study illustrates the ability of the new generation of Lagrangian floats to measure rapidly evolving temperature, salinity, and velocity, including turbulent and internal wave components. Quantitative interpretation of the results remains a challenge, which can be addressed with high-resolution numerical modeling, given sufficiently accurate air-sea fluxes.


Comparative in vitro study of honey based and silver based wound preparations on cell viability.
Since the early 1980s a plethora of dressings has been developed to promote wound healing. The objective of this study was to compare the effects of silver based dressings and honey based dressings on cell viability. In this blinded study, keratinocyte cultures were exposed to prepared extracts of each of the following wound dressings for 40 h: Silver based dressings: Acticoat, Actisorb, Askina, Atrauman-Ag and Contreet. Honey based dressings: Melladerm gel, Melladerm mesh, Melladerm plus and Mellarsorb. Controls consisted of cells that were cultured in the same medium, and under the same conditions as those exposed to extracts. All dressing extracts had an effect on cell viability. Changes in cell morphology from different wound dressing extracts were noted and compared with control groups after 24 h of incubation. In the silver based extracts group, Atrauman-silver and Acticoat had the most viable cells. For the honey based group, the most viable cells were seen with Melladerm mesh and Mellasorb. There was no significant difference between the best performing silver and honey based wound preparations with regard to cell viability.


Transmural left ventricular mechanics underlying torsional recoil during relaxation.
Early relaxation in the cardiac cycle is characterized by rapid torsional recoil of the left ventricular (LV) wall. To elucidate the contribution of the transmural arrangement of the myofiber to relaxation, we determined the time course of three-dimensional fiber-sheet strains in the anterior wall of five adult mongrel dogs in vivo during early relaxation with biplane cineangiography (125 Hz) of implanted transmural markers. Fiber-sheet strains were found from transmural fiber and sheet orientations directly measured in the heart tissue. The strain time course was determined during early relaxation in the epicardial, midwall, and endocardial layers referenced to the end-diastolic configuration. During early relaxation, significant circumferential stretch, wall thinning, and in-plane and transverse shear were observed (P < 0.05). We also observed significant stretch along myofibers in the epicardial layers and sheet shortening and shear in the endocardial layers (P < 0.01). Importantly, predominant epicardial stretch along the fiber direction and endocardial sheet shortening occurred during isovolumic relaxation (P < 0.05). We conclude that the LV mechanics during early relaxation involves substantial deformation of fiber and sheet structures with significant transmural heterogeneity. Predominant epicardial stretch along myofibers during isovolumic relaxation appears to drive global torsional recoil to aid early diastolic filling.


A mouse model for slowly progressive primary tuberculosis.
The progression from primary Mycobacterium tuberculosis infection to disease is usually slow in humans. The aim of this study was to develop and characterize a mouse model for slowly progressive primary tuberculosis, using the intraperitoneal (i.p.) route of infection, and to compare it with our previously described model of latent M. tuberculosis infection. B6D2F1 hybrid mice inoculated with 1.5 x 106 colony-forming units (CFUs) of M. tuberculosis H37Rv were followed-up for 70 weeks. Lungs, livers and spleens were examined for bacillary growth, histopathological changes and mycobacterial antigens (MPT64, ManLAM and multiple antigens of M. tuberculosis), by immunohistochemical staining. The infection was found to pass through three distinctive phases. During phase 1, mice were healthy despite development of small granulomas and an increasing number of bacilli in the lungs. During phase 2, mice were unwell but mortality was low. The count of M. tuberculosis and the granuloma size stabilized. The granulomas contained an increasing population of large, vacuolated macrophages. During phase 3, mice became moribund and died rapidly, but the M. tuberculosis count remained relatively stable. The inflammatory infiltrates filled approximately 80% of the lung parenchyma and the lesions were not well demarcated. Rapidly progressing inflammation, rather than an increase in the M. tuberculosis count, seems to contribute more to mortality.


Nonreciprocal resonant transmission/reflection based on a one-dimensional photonic crystal adjacent to the magneto-optical metal film.
We study the nonreciprocal Tamm plasmon polaritons (TPPs) inside the light cone, which can be directly excited at the interface between the one-dimensional photonic crystal (1DPC) and magneto-optical (MO) metal film. Applying an external magnetic field on the MO metal, the broken time-reversal symmetry gives rise to such nonreciprocal electrons oscillation mediated plasmon mode. Separately exciting the forward and backward TPPs, light can be transmitted and reflected in one-way. An analytic dispersion relation based on admittance-matching approach is obtained. This design offers promising potential in realizing the optical diode.


Faecal stasis in proctocolitis.
Six cases of faecal stasis in active proctocolitis are reported. In each case the left colon was severely diseased but the right colon was unaffected. X-ray studies showed retention of barium in the right colon for as long as five weeks. In two patients subacute intestinal obstruction developed and in three patients constipation was a major symptom during the active phase of colitis.


SCOT: a comparison of cost-effectiveness from a large randomised phase III trial of two durations of adjuvant Oxaliplatin combination chemotherapy for colorectal cancer.
The Short Course Oncology Therapy (SCOT) study is an international, multicentre, non-inferiority randomised controlled trial assessing the efficacy, toxicity, and cost-effectiveness of 3 months (3 M) versus the usually given 6 months (6 M) of adjuvant chemotherapy in colorectal cancer. In total, 6088 patients with fully resected high-risk stage II or stage III colorectal cancer were randomised and followed up for 3-8 years. The within-trial cost-effectiveness analysis from a UK health-care perspective is presented using the resource use data, quality of life (EQ-5D-3L), time on treatment (ToT), disease-free survival after treatment (DFS) and overall survival (OS) data. Quality-adjusted partitioned survival analysis and Kaplan-Meier Sample Average Estimator estimated QALYs and costs. Probabilistic sensitivity and subgroup analysis was undertaken. The 3 M arm is less costly (-£4881; 95% CI: -£6269; -£3492) and entails (non-significant) QALY gains (0.08; 95% CI: -0.086; 0.230) due to a better significant quality of life. The net monetary benefit was significantly higher in 3 M under a wide range of monetary values of a QALY. The subgroup analysis found similar results for patients in the CAPOX regimen. However, for the FOLFOX regimen, 3 M had lower QALYs than 6 M (not statistically significant). Overall, 3 M dominates 6 M with no significant detrimental impact on QALYs. The results provide the economic case that a 3 M treatment strategy should be considered a new standard of care.


Mechanisms of endosseous integration.
Although the clinical term "osseointegration" describes the anchorage of endosseous implants to withstand functional loading, it provides no insight into the mechanisms of bony healing around such implants. Nevertheless, an understanding of the sequence of bone healing events around endosseous implants is believed to be critical in developing biologic design criteria for implant surfaces. This discussion paper shows that peri-implant bone healing, which results in contact osteogenesis (bone growth on the implant surface), can be phenomenologically subdivided into three distinct phases that can be addressed experimentally. The first, osteoconduction, relies on the migration of differentiating osteogenic cells to the implant surface, through a temporary connective tissue scaffold. Anchorage of this scaffold to the implant surface is a function of implant surface design. The second, de novo bone formation, results in a mineralized interfacial matrix, equivalent to that seen in cement lines in natural bone tissue, being laid down on the implant surface. Implant surface topography will determine if the interfacial bone formed is bonded to the implant. A third tissue response, that of bone remodeling, will also, at discrete sites, create a bone-implant interface comprising de novo bone formation. Treatment outcomes in dental implantology will be critically dependent on implant surface designs that optimize the biologic response during each of these three distinct integration mechanisms.


Children of divorce-coping with divorce: A randomized control trial of an online prevention program for youth experiencing parental divorce.
Evaluate an online coping skills program to prevent mental health problems in children and adolescents from divorced or separated families. Children ages 11-16 (N = 147) whose families had filed for divorce were recruited using public court records. Participants were blocked by risk-score and randomly assigned to either a control (Internet self-study condition, Best of the Net (BTN) or the experimental intervention, Children of Divorce-Coping With Divorce (CoD-CoD), a 5-module highly interactive online program to promote effective coping skills. Program effects were tested on measures of children's self-reported coping and parent and youth reports of children's mental health problems. Significant main effects indicated that youth in CoD-CoD improved more on self-reported emotional problems relative to BTN youth (d = .37) and had a lower rate of clinically significant self-reported mental health problems (OR = .58, p = .04). A significant Baseline × Treatment interaction indicated that the 55% of youth with highest baseline problems improved more than those in BTN on their self-report of total mental health problems. A significant interaction effect indicated that CoD-CoD improved youth coping efficacy for the 30% of those with the lowest baseline coping efficacy. For the 10% of youth with lowest parent-reported risk at baseline, those who received BTN had lower problems than CoD-CoD participants. CoD-CoD was effective in reducing youth-reported mental health problems and coping efficacy particularly for high risk youth. Parent-report indicated that, relative to BTN, CoD-CoD had a negative effect on mental health problems for a small group with the lowest risk.


Effect of release from prison and re-incarceration on the viral loads of HIV-infected individuals.
The purpose of this study was to determine the effect of release from prison and subsequent re-incarceration on the viral loads of HIV-infected individuals receiving highly active antiretroviral therapy (HAART). Fifteen re-incarcerated HIV-infected prisoners on HAART were identified from a retrospective cohort of HIV-infected prison inmates released from January 1, 1997, to August 31, 1999. The re-incarcerated prisoners were matched (1:2) to 30 HIV-infected incarcerated prisoners on HAART who remained incarcerated during the re-incarcerated participants' release time period. The outcomes measured were plasma HIV RNA levels, CD4+ lymphocyte counts, percentage of re-incarcerated and incarcerated participants with plasma HIV RNA levels <400 copies/mL, and the median change in plasma HIV RNA levels of the re-incarcerated and incarcerated participants at the end of the study. At the beginning of the study, 8/15 re-incarcerated participants had plasma HIV RNA levels <400 copies/mL, compared with 15/30 incarcerated participants. At the end of the study, only three of those eight re-incarcerated participants had plasma HIV RNA levels <400 copies/mL, compared with 14/15 incarcerated participants (p=0.0086). The median change in plasma HIV RNA levels of the re-incarcerated participants was 1.29 log10 copies/mL (interquartile range 0.04 to 1.70), compared with -0.03 log10 copies/mL (interquartile range -0.65 to 0.09) in the incarcerated participants (p=0.0183). Release from prison was associated with a deleterious effect on virological and immunological outcomes. These data suggest that comprehensive discharge planning efforts are required to make certain that HIV-infected inmates receive access to quality care following incarceration.


Satisfaction after total knee arthroplasty: a prospective matched-pair analysis of patients with customised individually made and off-the-shelf implants.
Customised individually made (CIM) total knee arthroplasty (TKA) was introduced to potentially improve patient satisfaction and other patient-reported outcome measures (PROMs). The purpose of this study was to compare PROMs, especially patient satisfaction, of patients with CIM and OTS TKA in a matched-pair analysis with a 2-year follow-up. This is a prospective cohort study with a propensity score matching of 85 CIM and 85 off-the-shelf (OTS) TKA. Follow-up was at 4 months, 1 year and 2 years. The primary outcome was patient satisfaction. Secondary outcomes were as follows: overall improvement, willingness to undergo the surgery again, Knee injury and Osteoarthritis Outcome Score (KOOS), Forgotten Joint Score (FJS-12), High-Activity Arthroplasty Score (HAAS), EQ-5D-3L, EQ-VAS, Knee Society Score (KSS) and surgeon satisfaction. Patient satisfaction ranged from 86 to 90% and did not differ between CIM and OTS TKA. The EQ-VAS after 4 months and the HAAS after 1 year and 2 years were higher for CIM TKA. KOOS, FJS-12 and EQ-5D-3L were not different at follow-up. The changes in KOOS symptoms, pain and daily living were higher for OTS TKA. The KSS was higher for patients with CIM TKA. Surgeon satisfaction was high throughout both groups. Patients who were satisfied after 2 years did not differ preoperatively from those who were not satisfied. Postoperatively, all PROMs were better for satisfied patients. Patient satisfaction was not correlated with patient characteristics, implant or preoperative PROMs, and medium to strongly correlated with postoperative PROMs. Patient satisfaction was high with no differences between patients with CIM and OTS TKA. Both implant systems improved function, pain and health-related quality of life. Patients with CIM TKA showed superior results in demanding activities as measured by the HAAS. II, prospective cohort study.


Evaluation of an algorithm for integrated management of childhood illness in an area of Vietnam with dengue transmission.
To determine whether nurses, using the WHO/UNICEF algorithm for integrated management of childhood illness (IMCI), modified to include dengue infection, satisfactorily classified children in an area endemic for dengue haemorrhagic fever (DHF). Nurses assessed and classified, using the modified IMCI algorithm, a systematic sample of 1250 children aged 2 months to 10 years (n = 1250) presenting to a paediatric hospital in Dong Nai Province, Vietnam. Their classification was compared with that of a paediatrician, blind to the result of the nurses' assessment, which could be modified in the light of simple investigations, e.g. dengue serology. In children aged 2-59 months (n = 859), the nurses were able to classify, using the modified chart, the presenting illness in >99% of children and found more than one classification in 70%. For the children with pneumonia, diarrhoea, dengue shock syndrome, severe DHF and severe disease requiring urgent admission, the nurse's classification was >60% sensitive and >85% specific compared with that of the paediatrician. For the nurse's classification of DHF the specificity was 50-55% for the children <5 years and in children with definitive dengue serology. Alterations in the DHF algorithm improved specificity at the expense of sensitivity. Using the IMCI chart, nurses classified appropriately many of the major clinical problems in sick children <5 years in southern Vietnam. However, further modifications will be required in the fever section, particularly for dengue. The impact of using the IMCI chart in peripheral health stations remains to be evaluated.


Redefining Risk and Benefit: Understanding the Decision to Undergo Contralateral Prophylactic Mastectomy.
Rates of contralateral prophylactic mastectomy (CPM) among unilateral breast cancer patients are rapidly increasing; however, there are little data documenting the decision-making process of patients with no known BRCA mutations, who elect this more aggressive treatment. We conducted semistructured interviews with nine newly diagnosed patients who elected CPM over other surgical options. Using grounded theory, we analyzed interview data to identify influential decision-making factors by prevalence and intensity across participants. Decision-making factors included subjective evaluations of risk and benefit, avoidance of future breast cancer surveillance and accompanying worry, and desire to maintain (or improve) breast appearance. Based solely on survival benefit, the decision to undergo CPM might be viewed as unnecessary or even misguided. However, our findings show the importance of psychosocial factors in patients' assessments of risk and benefit, and support the need for additional patient-provider communication regarding these factors.


Public health service options for affordable and accessible noncommunicable disease and related chronic disease prevention and management.
Globally, nations are confronted with the challenge of providing affordable health services to populations with increasing levels of noncommunicable and chronic disease. Paradoxically, many nations can both celebrate increases in life expectancy and bemoan parallel increases in chronic disease prevalence. Simply put, despite living longer, not all of that time is spent in good health. Combined with factors such as rising levels of obesity and related noncommunicable disease, the demand for health services is requiring nations to consider new models of affordable health care. Given the level of disease burden, all staff, not just doctors, need to be part of the solution and encouraged to innovate and deliver better and more affordable health care, particularly preventative primary health care services. This paper draws attention to a range of exemplars to encourage and stimulate readers to think beyond traditional models of primary health service delivery. Examples include nurse-led, allied health-led, and student-led clinics; student-assisted services; and community empowerment models. These are reported for the interest of policy makers and health service managers involved in preventative and primary health service redesign initiatives.


Structures of the Ultra-High-Affinity Protein-Protein Complexes of Pyocins S2 and AP41 and Their Cognate Immunity Proteins from Pseudomonas aeruginosa.
How ultra-high-affinity protein-protein interactions retain high specificity is still poorly understood. The interaction between colicin DNase domains and their inhibitory immunity (Im) proteins is an ultra-high-affinity interaction that is essential for the neutralisation of endogenous DNase catalytic activity and for protection against exogenous DNase bacteriocins. The colicin DNase-Im interaction is a model system for the study of high-affinity protein-protein interactions. However, despite the fact that closely related colicin-like bacteriocins are widely produced by Gram-negative bacteria, this interaction has only been studied using colicins from Escherichia coli. In this work, we present the first crystal structures of two pyocin DNase-Im complexes from Pseudomonas aeruginosa, pyocin S2 DNase-ImS2 and pyocin AP41 DNase-ImAP41. These structures represent divergent DNase-Im subfamilies and are important in extending our understanding of protein-protein interactions for this important class of high-affinity protein complex. A key finding of this work is that mutations within the immunity protein binding energy hotspot, helix III, are tolerated by complementary substitutions at the DNase-Immunity protein binding interface. Im helix III is strictly conserved in colicins where an Asp forms polar interactions with the DNase backbone. ImAP41 contains an Asp-to-Gly substitution in helix III and our structures show the role of a co-evolved substitution where Pro in DNase loop 4 occupies the volume vacated and removes the unfulfilled hydrogen bond. We observe the co-evolved mutations in other DNase-Immunity pairs that appear to underpin the split of this family into two distinct groups.


Design and Construction of a Bilateral Haptic System for the Remote Assessment of the Stiffness and Range of Motion of the Hand.
The use of haptic devices in the rehabilitation of impaired limbs has become rather popular, given the proven effectiveness in promoting recovery. In a standard framework, such devices are used in rehabilitation centers, where patients interact with virtual tasks, presented on a screen. To track their sessions, kinematic/dynamic parameters or performance scores are recorded. However, as Internet access is now available at almost every home and in order to reduce the hospitalization time of the patient, the idea of doing rehabilitation at home is gaining wide consent. Medical care programs can be synchronized with the home rehabilitation device; patient data can be sent to the central server that could redirect to the therapist laptop (tele-healthcare). The controversial issue is that the recorded data do not actually represent the clinical conditions of the patients according to the medical assessment scales, forcing them to frequently undergo clinical tests at the hospital. To respond to this demand, we propose the use of a bilateral master/slave haptic system that could allow the clinician, who interacts with the master, to assess remotely and in real time the clinical conditions of the patient that uses the home rehabilitation device as the slave. In this paper, we describe a proof of concept to highlight the main issues of such an application, limited to one degree of freedom, and to the measure of the stiffness and range of motion of the hand.


Experience with a simulator-based angiography course for neurosurgical residents: beyond a pilot program.
Simulation is an increasingly useful means of teaching in the era of duty hour restrictions. Since the completion of our diagnostic cerebral angiography simulator curriculum pilot program, we have performed this resident course at 2 Congress of Neurological Surgeons (CNS) annual meetings with larger participant numbers. To report the ongoing results of these courses. A 120-minute simulator-based training course was performed at 2 CNS annual meetings. Precourse written and simulator skills assessments were performed, followed by instructor-guided training on an endovascular simulator. Postcourse written and simulator practical assessments were then performed and compared with precourse scores. Thirty-seven neurosurgery resident participants completed the course module: 16 completed the first course provided and 21 completed the second. Posttest written scores were significantly higher than pretest scores (mean ± SEM, 8.5 ± 0.40.3 vs 4.9 ± 0.3; P < .001). Instructor assessments of practical posttest scores of participants were significantly higher than pretest practical scores for both the CNS 2011 and CNS 2012 groups (P < .001). The expansion of a curriculum-based, cerebral angiography simulator pilot program to trainees through courses at national neurosurgical meetings demonstrated excellent results with significant improvements in written test scores and instructor assessments of participant technical skills. With ever-expanding improvements in simulation technology and realism, simulator training for cerebral angiography may become an integral component of resident training in the future.


The antibiotic darobactin mimics a β-strand to inhibit outer membrane insertase.
Antibiotics that target Gram-negative bacteria in new ways are needed to resolve the antimicrobial resistance crisis1-3. Gram-negative bacteria are protected by an additional outer membrane, rendering proteins on the cell surface attractive drug targets4,5. The natural compound darobactin targets the bacterial insertase BamA6-the central unit of the essential BAM complex, which facilitates the folding and insertion of outer membrane proteins7-13. BamA lacks a typical catalytic centre, and it is not obvious how a small molecule such as darobactin might inhibit its function. Here we resolve the mode of action of darobactin at the atomic level using a combination of cryo-electron microscopy, X-ray crystallography, native mass spectrometry, in vivo experiments and molecular dynamics simulations. Two cyclizations pre-organize the darobactin peptide in a rigid β-strand conformation. This creates a mimic of the recognition signal of native substrates with a superior ability to bind to the lateral gate of BamA. Upon binding, darobactin replaces a lipid molecule from the lateral gate to use the membrane environment as an extended binding pocket. Because the interaction between darobactin and BamA is largely mediated by backbone contacts, it is particularly robust against potential resistance mutations. Our results identify the lateral gate as a functional hotspot in BamA and will allow the rational design of antibiotics that target this bacterial Achilles heel.


Global expression changes resulting from loss of telomeric DNA in fission yeast.
Schizosaccharomyces pombe cells lacking the catalytic subunit of telomerase (encoded by trt1+) lose telomeric DNA and enter crisis, but rare survivors arise with either circular or linear chromosomes. Survivors with linear chromosomes have normal growth rates and morphology, but those with circular chromosomes have growth defects and are enlarged. We report the global gene-expression response of S. pombe to loss of trt1+. Survivors with linear chromosomes had expression profiles similar to cells with native telomeres, whereas survivors with circular chromosomes showed continued upregulation of core environmental stress response (CESR) genes. In addition, survivors with circular chromosomes had altered expression of 51 genes compared to survivors with linear chromosomes, providing an expression signature. S. pombe progressing through crisis displayed two waves of altered gene expression. One coincided with crisis and consisted of around 110 genes, 44% of which overlapped with the CESR. The second was synchronized with the emergence of survivors and consisted of a single class of open reading frames (ORFs) with homology both to RecQ helicases and to dh repeats at centromeres targeted for heterochromatin formation via an RNA interference (RNAi) mechanism. Accumulation of transcript from the ORF was found not only in trt1- cells, but also in dcr1- and ago1- RNAi mutants, suggesting that RNAi may control its expression. These results demonstrate a correlation between a state of cellular stress, short telomeres and growth defects in cells with circular chromosomes. A putative new RecQ helicase was expressed as survivors emerged and appears to be transcriptionally regulated by RNAi, suggesting that this mechanism operates at telomeres.


Do allogeneic bone marrow transplant candidates match coping to controllability of pre-treatment stressors?
According to the Person x Situation theoretical framework, people adjust their coping to address the unique challenges of encountered stressors. Whether their strategies fit or appropriately address these stressor challenges influences adjustment. We examined the fit between pre-treatment stressors reported by hematological cancer patients awaiting allogeneic bone marrow transplantation (alloBMT) and their coping responses. Stressors were categorized as controllable versus uncontrollable; coping responses were categorized as problem- versus emotion-focused versus mixed (i.e., elements of both coping types). We hypothesized that patients would employ coping responses that fit the controllability of stressors (i.e., a match between stressor and coping response): problem-focused coping for controllable stressors and emotion-focused coping for uncontrollable stressors. In qualitative interviews, pre-BMT patients (10 men, 7 women) described encountered stressors and how they coped with them. Every reported stressor was linked with its associated coping response, resulting in a stressor-coping pair. We determined the proportion of total stressor-coping pairs in which the coping response matched the controllability of its linked stressor. Most stressor-coping pairs involving uncontrollable stressors showed the hypothesized match with emotion-focused or mixed coping. Contrary to hypotheses, fewer stressor-coping pairs that involved controllable stressors matched with problem-focused or mixed coping. Rather, these pairs were more likely to link controllable stressors with emotion-focused coping (i.e., mismatch between stressor controllability and type of coping). AlloBMT candidates may appraise the pre-treatment stage, globally, as permitting very little control. Coping efforts may consequently emphasize regulation of negative emotions (i.e., emotion-focused coping).


Can identification of a fourth domain of life be made from sequence data alone, and could it be done on Mars?
A central question in astrobiology is whether life exists elsewhere in the universe. If so, is it related to Earth life? Technologies exist that enable identification of DNA- or RNA-based microbial life directly from environmental samples here on Earth. Such technologies could, in principle, be applied to the search for life elsewhere; indeed, efforts are underway to initiate such a search. However, surveying for nucleic acid-based life on other planets, if attempted, must be carried out with caution, owing to the risk of contamination by Earth-based life. Here we argue that the null hypothesis must be that any DNA discovered and sequenced from samples taken elsewhere in the universe are Earth-based contaminants. Experience from studies of low-biomass ancient DNA demonstrates that some results, by their very nature, will not enable complete rejection of the null hypothesis. In terms of eliminating contamination as an explanation of the data, there may be value in identification of sequences that lie outside the known diversity of the three domains of life. We therefore have examined whether a fourth domain could be readily identified from environmental DNA sequence data alone. We concluded that, even on Earth, this would be far from trivial, and we illustrate this point by way of examples drawn from the literature. Overall, our conclusions do not bode well for planned PCR-based surveys for life on Mars, and we argue that other independent biosignatures will be essential in corroborating any claims for the presence of life based on nucleic acid sequences.


Reduced high-intensity-running rate in collegiate women's soccer when games are separated by 42 hours.
During the competitive soccer season, women's intercollegiate matches are typically played on Friday evenings and Sunday afternoons. The efficacy of a 42-h recovery period is not well understood. This investigation was conducted to determine performance differences between Friday and Sunday matches during a competitive season. Ten NCAA Division I female soccer players (20.5±1.0 y, 166.6±5.1 cm, 61.1±5.8 kg) were monitored with 10-Hz GPS devices across 8 weekends with matches played on Friday evenings and Sunday afternoons. The players were outside backs, midfielders, and forwards. All players had to participate in a minimum of 45 min/match to be included in the study. Average minutes played, total distance covered, total distance of high-intensity running (HIR) (defined as running at a velocity equal to or exceeding 3.61 m/s for longer than 1 s), the number of HIR efforts, and the number of sprints were calculated for each match. Data for Friday vs Sunday matches were averaged and then compared using dependent t tests. No differences were seen in minutes played, distance rate, or number of sprints between Friday and Sunday matches. A significant (P=.017) decrease in rate of HIR between Friday (25.37±7.22 m/min) and Sunday matches (22.90±5.70 m/min) was seen. In addition, there was a trend toward a difference (P=.073) in the number of efforts of HIR between Friday (138.41±36.43) and Sunday (126.92±31.31). NCAA Division I female soccer players cover less distance of HIR in games played less than 48 h after another game. This could be due to various factors such as dehydration, glycogen depletion, or muscle damage.


Assigning strains to bacterial species via the internet.
Methods for assigning strains to bacterial species are cumbersome and no longer fit for purpose. The concatenated sequences of multiple house-keeping genes have been shown to be able to define and circumscribe bacterial species as sequence clusters. The advantage of this approach (multilocus sequence analysis; MLSA) is that, for any group of related species, a strain database can be produced and combined with software that allows query strains to be assigned to species via the internet. As an exemplar of this approach, we have studied a group of species, the viridans streptococci, which are very difficult to assign to species using standard taxonomic procedures, and have developed a website that allows species assignment via the internet. Seven house-keeping gene sequences were obtained from 420 streptococcal strains to produce a viridans group database. The reference tree produced using the concatenated sequences identified sequence clusters which, by examining the position on the tree of the type strain of each viridans group species, could be equated with species clusters. MLSA also identified clusters that may correspond to new species, and previously described species whose status needs to be re-examined. A generic website and software for electronic taxonomy was developed. This site http://www.eMLSA.net allows the sequences of the seven gene fragments of a query strain to be entered and for the species assignment to be returned, according to its position within an assigned species cluster on the reference tree. The MLSA approach resulted in the identification of well-resolved species clusters within this taxonomically challenging group and, using the software we have developed, allows unknown strains to be assigned to viridans species via the internet. Submission of new strains will provide a growing resource for the taxonomy of viridans group streptococci, allowing the recognition of potential new species and taxonomic anomalies. More generally, as the software at the MLSA website is generic, MLSA schemes and strain databases for other groups of related species can be hosted at this website, providing a portal for microbial electronic taxonomy.


Circumstances under which practice does not make perfect: a review of the practice effect literature in schizophrenia and its relevance to clinical treatment studies.
In this article, we review the literature on practice effects in schizophrenia, an underappreciated confound in interpreting cognitive improvement in clinical trials. We first examine claims regarding first- and second-generation antipsychotic medications as cognitive enhancers, and follow it with a discussion of recent studies demonstrating how practice or placebo effects may drive 'positive' findings. Thus, this review suggests that many previous findings can be reinterpreted in this light. Critically, we also make several suggestions about test construction, study design, and statistical analyses that the field might use to overcome this potential confound. Our suggestions may also have implications for drug discovery and regulatory approval of cognitive-enhancing adjunctive agents, in terms of study design and/or test psychometric characteristics, including the development of tests that are relatively insensitive to practice-related changes. Such advances might be important for improving the methodology involved in the assessment of cognitive change in treatment studies.


Model involving gene inactivation in the generation of autosomal recessive mutants in mammalian cells in culture.
We present evidence for a two-step model for expression of the recessive phenotype at the diploid adenine phosphoribosyl transferase (aprt) locus in Chinese hamster ovary cells. This model proposes a high-frequency event leading to allelic inactivation and a low-frequency event leading to a structural alteration of the APRT protein. Either event can occur first, resulting in two types of heterozygous cells. The proposed model is based on analysis of Chinese hamster ovary presumptive aprt heterozygotes and APRT- mutants, derived by two different laboratories. The major class of heterozygotes (class 1) had approximately 50% parental APRT activity, 50% immunologically precipitable APRT protein, and only wild-type enzyme as based on two-dimensional gel electrophoresis and thermal inactivation studies. We propose that one allele at the aprt locus has been inactivated in these heterozygotes. APRT- mutants derived from any single class 1 heterozygote arose at a low frequency and contained either no immunologically detectable APRT protein or an APRT enzyme which was, in most cases, demonstrably altered. The second class of heterozygotes, consisting of two independent isolates, gave rise to APRT- cells at a high frequency (10(-3) to 10(-5). These heterozygous cell lines had 50% of parental APRT activity and only wild-type spot, or wild-type and an electrophoretic variant spot, on two-dimensional gels. These aprt heterozygotes appear to have arisen by mutation at one allele. APRT- mutants derived from either heterozygote of this class had all lost the wild-type activity, consistent with the proposed model.


Human induced pluripotent stem cell-derived models to investigate human cytomegalovirus infection in neural cells.
Human cytomegalovirus (HCMV) infection is one of the leading prenatal causes of congenital mental retardation and deformities world-wide. Access to cultured human neuronal lineages, necessary to understand the species specific pathogenic effects of HCMV, has been limited by difficulties in sustaining primary human neuronal cultures. Human induced pluripotent stem (iPS) cells now provide an opportunity for such research. We derived iPS cells from human adult fibroblasts and induced neural lineages to investigate their susceptibility to infection with HCMV strain Ad169. Analysis of iPS cells, iPS-derived neural stem cells (NSCs), neural progenitor cells (NPCs) and neurons suggests that (i) iPS cells are not permissive to HCMV infection, i.e., they do not permit a full viral replication cycle; (ii) Neural stem cells have impaired differentiation when infected by HCMV; (iii) NPCs are fully permissive for HCMV infection; altered expression of genes related to neural metabolism or neuronal differentiation is also observed; (iv) most iPS-derived neurons are not permissive to HCMV infection; and (v) infected neurons have impaired calcium influx in response to glutamate.


Protein phosphorylation is a prerequisite for intracellular Ca2+ release and ion channel control by nitric oxide and abscisic acid in guard cells.
Recent work has indicated that nitric oxide (NO) and its synthesis are important elements of signal cascades in plant-pathogen defence, and are a prerequisite for drought and abscisic acid (ABA) responses in Arabidopsis thaliana and Vicia faba guard cells. NO regulates inward-rectifying K+ channels and Cl- channels of Vicia guard cells via intracellular Ca2+ release. However, its integration with related signals, including the actions of serine-threonine protein kinases, is less well defined. We report here that the elevation of cytosolic-free [Ca2+] ([Ca2+]i) mediated by NO in guard cells is reversibly inhibited by the broad-range protein kinase antagonists staurosporine and K252A, but not by the tyrosine kinase antagonist genistein. The effects of kinase antagonism translate directly to a loss of NO-sensitivity of the inward-rectifying K+ channels and background (Cl- channel) current, and to a parallel loss in sensitivity of the K+ channels to ABA. These results demonstrate that NO-dependent signals can be modulated through protein phosphorylation upstream of intracellular Ca2+ release, and they implicate a target for protein kinase control in ABA signalling that feeds into NO-dependent Ca2+ release.


Probability of success of breeding strategies for improving pro-vitamin A content in maize.
Biofortification for pro-vitamin A content (pVAC) of modern maize inbreds and hybrids is a feasible way to deal with vitamin A deficiency in rural areas in developing countries. The objective of this study was to evaluate the probability of success of breeding strategies when transferring the high pVAC present in donors to elite modern-adapted lines. For this purpose, a genetic model was built based on previous genetic studies, and different selection schemes including phenotypic selection (PS) and marker-assisted selection (MAS) were simulated and compared. MAS for simultaneously selecting all pVAC genes and a combined scheme for selecting two major pVAC genes by MAS followed by ultra performance liquid chromatography screening for the remaining genetic variation on pVAC were identified as being most effective and cost-efficient. The two schemes have 83.7 and 84.8% probabilities of achieving a predefined breeding target on pVAC and adaptation in one breeding cycle under the current breeding scale. When the breeding scale is increased by making 50% more crosses, the probability values could reach 94.8 and 95.1% for the two schemes. Under fixed resources, larger early generation populations with fewer crosses had similar breeding efficiency to smaller early generation populations with more crosses. Breeding on a larger scale was more efficient both genetically and economically. The approach presented in this study could be used as a general way in quantifying probability of success and comparing different breeding schemes in other breeding programs.


Acetaminophen enhances pruritus in a mouse model of contact dermatitis induced by suboptimal concentration of hapten.
Acetaminophen (APAP) is one of the most commonly used drugs worldwide to reduce fever, particularly in children. It is generally considered to be a safe drug. However, a number of studies have shown that regular use of APAP increases the risk of developing allergic diseases. Nonetheless, no animal models have been used to investigate these findings. Therefore, we aimed to create an animal model of APAP-induced pruritus in mice. APAP (0.25% and 0.5%) was administered via drinking water daily from infancy, and a suboptimal concentration of 2,4,6-trinitrochlorobenzene (TNCB) was applied repeatedly to each ear three times a week for 7 weeks to evoke chronic allergic contact dermatitis. Neither 0.25% nor 0.5% APAP was overtly hepatotoxic after 73 days of daily administration. Repeated challenge with TNCB evoked increase in the number of scratching bouts compared to day 1. This increase in the number of scratching bouts was significant in 0.25% and 0.5% APAP groups but not in the group treated with TNCB alone. Daily administration of 0.5% APAP significantly increased in the number of scratching bouts compared to TNCB alone on day 29. This animal model will be useful for investigating the mechanism underlying the increased risk of development of eczema caused by regular APAP use and for examining safer and more effective therapy with APAP.


Acupuncture and assisted conception.
Acupuncture has recently been studied in assisted reproductive treatment (ART) although its role in reproductive medicine is still debated. To determine the effectiveness of acupuncture in the outcomes of ART. All reports which describe randomised controlled trials of acupuncture in assisted conception were obtained through searches of the Menstrual Disorders and Subfertility Group Specialised Register, CENTRAL, Ovid MEDLINE (1996 to August 2007), EMBASE (1980 to August 2007), CINAHL (Cumulative Index to Nursing & Allied Health Literature) (1982 to August 2007), AMED, National Research Register, Clinical Trials register (www.clinicaltrials.gov), and the Chinese database of clinical trials. Randomised controlled trials of acupuncture for couples who were undergoing ART comparing acupuncture treatment alone or acupuncture with concurrent ART versus no treatment, placebo or sham acupuncture plus ART for the treatment of primary and secondary infertility. Women with medical illness deemed contraindications for ART or acupuncture were excluded. Sixteen randomised controlled trials were identified that involved acupuncture and assisted conception. Thirteen trials were included in the review and three were excluded. Quality assessment and data extraction were performed independently by two review authors. Meta-analysis was performed using odds ratio (OR) for dichotomous outcomes. The outcome measures were live birth rate, clinical ongoing pregnancy rate, miscarriage rate, and any reported side effects of treatment. There is evidence of benefit when acupuncture is performed on the day of embryo transfer (ET) on the live birth rate (OR 1.89, 95% CI 1.29 to 2.77) but not when it is performed two to three days after ET (OR 1.79, 95% CI 0.93 to 3.44). There is no evidence of benefit on pregnancy outcomes when acupuncture is performed around the time of oocyte retrieval. Acupuncture performed on the day of ET shows a beneficial effect on the live birth rate; however, with the present evidence this could be attributed to placebo effect and the small number of women included in the trials. Acupuncture should not be offered during the luteal phase in routine clinical practice until further evidence is available from sufficiently powered RCTs.


Retaliatory RICO and the Puzzle of Fraudulent Claiming.
Over the past century, the allegation that the tort liability system incentivizes legal extortion and is chock-full of fraudulent claims has dominated public discussion and prompted lawmakers to ever-more-creatively curtail individuals' incentives and opportunities to seek redress. Unsatisfied with these conventional efforts, in recent years, at least a dozen corporate defendants have "discovered" a new fraud-fighting tool. They've started filing retaliatory RICO suits against plaintiffs and their lawyers and experts, alleging that the initiation of certain nonmeritorious litigation constitutes racketeering activity—while tort reform advocates have applauded these efforts and exhorted more "courageous" companies to follow suit. Curiously, though, all of this has taken place against a virtual empirical void. Is the tort liability system actually brimming with fraudulent claims? No one knows. There has been no serious attempt to analyze when, how often, or under what conditions fraudulent claiming proliferates. Similarly, tort reformers support RICO's use because, they say, conventional mechanisms to deter fraud fall short. But are conventional mechanisms insufficient? Hard to say, as there is no comprehensive inventory of the myriad formal and informal mechanisms already in use; nor do we have even a vague sense of how those mechanisms actually operate. Further, though courts have started to green-light retaliatory RICO actions, no one has carefully analyzed whether these suits are, on balance, beneficial. Indeed, few have so much as surfaced relevant risks. Addressing these questions, this Article attempts to bring overdue attention to a problem central to the tort system's operation and integrity.


Carbohydrates and insulin resistance in clinical nutrition: Recommendations from the ESPEN expert group.
Growing evidence underscores the important role of glycemic control in health and recovery from illness. Carbohydrate ingestion in the diet or administration in nutritional support is mandatory, but carbohydrate intake can adversely affect major body organs and tissues if resulting plasma glucose becomes too high, too low, or highly variable. Plasma glucose control is especially important for patients with conditions such as diabetes or metabolic stress resulting from critical illness or surgery. These patients are particularly in need of glycemic management to help lessen glycemic variability and its negative health consequences when nutritional support is administered. Here we report on recent findings and emerging trends in the field based on an ESPEN workshop held in Venice, Italy, 8-9 November 2015. Evidence was discussed on pathophysiology, clinical impact, and nutritional recommendations for carbohydrate utilization and management in nutritional support. The main conclusions were: a) excess glucose and fructose availability may exacerbate metabolic complications in skeletal muscle, adipose tissue, and liver and can result in negative clinical impact; b) low-glycemic index and high-fiber diets, including specialty products for nutritional support, may provide metabolic and clinical benefits in individuals with obesity, insulin resistance, and diabetes; c) in acute conditions such as surgery and critical illness, insulin resistance and elevated circulating glucose levels have a negative impact on patient outcomes and should be prevented through nutritional and/or pharmacological intervention. In such acute settings, efforts should be implemented towards defining optimal plasma glucose targets, avoiding excessive plasma glucose variability, and optimizing glucose control relative to nutritional support.