Twenty-four years after theYellowstone Fires: Are postfire lodgepole pine stands converging in structure and function?
Disturbance and succession have long been of interest in ecology, but how landscape patterns of ecosystem structure and function evolve following large disturbances is poorly understood. After nearly 25 years, lodgepole pine (Pinus contorta var. latifolia) forests that regenerated after the 1988 Yellowstone Fires (Wyoming, USA) offer a prime opportunity to track the fate of disturbance-created heterogeneity in stand structure and function in a wilderness setting. In 2012, we resampled 72 permanent plots to ask (1) How have postfire stand structure and function changed between 11 and 24 yr postfire, and what variables explain these patterns and changes? (2) How has landscape-level (among-stand) variability in postfire stand structure and function changed between 11 and 24 yr postfire? We expected to see evidence of convergence beginning to emerge, but also that initial postfire stem density would still determine trajectories of biomass accumulation. After 24 yr, postfire lodgepole pine density remained very high (mean = 21,738 stems/ha, range = 0-344,067 stems/ha). Stem density increased in most plots between 11 and 24 yr postfire, but declined sharply where 11-yr-postfire stem density was > 72,000 stems/ha. Stems were small in high-density stands, but stand-level lodgepole pine leaf area, foliage biomass, and live aboveground biomass increased over time and with increasing stem density. After 24 yr, mean annual lodgepole pine aboveground net primary production (ANPP) was high (mean = 5 Mg · ha⁻¹ · yr⁻¹, range = 0-16.5 Mg · ha⁻¹ · yr⁻¹). Among stands, lodgepole pine ANPP increased with stem density, which explained 69% of the variation; another 8% of the variation was explained by environmental covariates. Early patterns of postfire lodgepole pine regeneration, which were contingent on prefire serotiny and fire severity, remained the dominant driver of stand structure and function. We observed mechanisms that would lead to convergence in stem density (structure) over time, but it was landscape variation in functional variables that declined substantially. Stand structure and function have not converged across the burned landscape, but our evidence suggests function will converge sooner than structure.


Is repetition failure critical for the development of muscle hypertrophy and strength?
This investigation sought to determine the effect of resistance training to failure on functional, structural and neural elbow flexor muscle adaptation. Twenty-eight males completed a 4-week familiarization period and were then counterbalanced on the basis of responsiveness across; non-failure rapid shortening (RS; rapid concentric, 2 s eccentric), non-failure stretch-shortening (SSC; rapid concentric, rapid eccentric), and failure control (C, 2 s concentric, 2 s eccentric), for a 12-week unilateral elbow flexor resistance training regimen, 3 × week using 85% of one repetition maximum (1RM). 1RM, maximal voluntary contraction (MVC), muscle cross-sectional area (CSA), and muscle activation (EMG(RMS)) of the agonist, antagonist, and stabilizer muscles were assessed before and after the 12-week training period. The average number of repetitions per set was significantly lower in RS 4.2 [confidence interval (CI): 4.2, 4.3] and SSC 4.2 (CI: 4.2, 4.3) compared with C 6.1 (CI: 5.8, 6.4). A significant increase in 1RM (30.5%), MVC (13.3%), CSA (11.4%), and agonist EMG(RMS) (22.1%) was observed; however, no between-group differences were detected. In contrast, antagonist EMG(RMS) increased significantly in SSC (40.5%) and C (23.3%), but decreased in RS (13.5%). Similar adaptations across the three resistance training regimen suggest repetition failure is not critical to elicit significant neural and structural changes to skeletal muscle.


Atherosclerosis and hypertension: mechanisms and interrelationships.
Hypertension, dyslipidemia, and glucose intolerance cocluster in the population and act synergistically in increasing coronary artery disease risk. The mechanisms by which these risk factors interact in atherosclerosis are complex. First, hypertension, dyslipidemia, and altered insulin sensitivity may have a common pathophysiological basis. Activation of neurohormonal mechanisms may be implicated in many or all of these processes. In addition, underlying these processes may be common genetic and environmental influences. Second, these risk factors ultimately act on the blood vessel, thereby leading to atherosclerosis. Elevated serum lipids lead to vessel wall responses, including endothelial dysfunction, smooth muscle cell proliferation, lipid accumulation, foam cell formation, and, eventually, necrosis and plaque development. Hypertension may induce shear-related injury to the vessel. Endothelial injury (caused by hypertension) and vascular cell proliferation (induced by increased pressure and/or vasoactive substances) are effects that amplify the atherosclerotic process. In addition, diabetes and hyperinsulinemia can increase vascular tone, impair endothelial function, and stimulate vascular smooth muscle cell proliferation. Control of these risk factors should prevent or attenuate the vessel wall responses. Emphasis is now being placed on pharmacological therapeutic modalities that decrease blood pressure and improve insulin sensitivity and lipid metabolism. Identification of common links between risk factors, such as neurohormonal mechanisms (e.g., angiotensin), should lead to better therapeutic strategies.


The Role of Ki-67 and Pre-cytoreduction Parameters in Selecting Diffuse Malignant Peritoneal Mesothelioma (DMPM) Patients for Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC).
We conducted a prognostic analysis of preoperative parameters and Ki-67 determination to develop selection criteria for cytoreductive surgery (CRS) and HIPEC in patients with diffuse malignant peritoneal mesothelioma (DMPM). DMPM patients treated with CRS and HIPEC at NCI of Milan participated in this study. Multivariate analysis was conducted using Cox proportional hazard model and conditional inference tree method to select independent predictors of overall survival (OS) from the followings pre-cytoreduction parameters: age, sex, ECOG performance status, Charlson comorbidity index, previous systemic chemotherapy, CA-125, histological subtype (epithelioid vs. biphasic/sarcomatoid), Ki-67 (determined with immunohistochemistry), and peritoneal cancer index (PCI). A total of 117 patients (male/female: 67/50) with median age of 60.5 (range 22-75) years were included. Eighty-three patients had ECOG performance status = 0, median Charlson comorbidity index was 4 (range 2-9), and 102 cases had epithelioid subtype. Median Ki-67 was 5 % (range 1-60). Ninety-four (80.3 %) cases were optimally cytoreduced. The Cox analysis identified Ki-67, PCI, and histological subtype as independent prognosticators of OS. Conditional inference tree method identified three prognostic subsets: (I) Ki-67 ≤ 9 %; (II) Ki-67 > 9 % and PCI ≤ 17; and (III) Ki-67 > 9 % and PCI > 17. The median OS for subsets I, II, and III were, 86.6, 63.2, and 10.3 months, respectively. Ki-67 is a powerful prognosticator that allows, along with PCI, and histological subtype, a good prediction of OS in patients with DMPM. Patients with Ki-67 > 9 % and PCI > 17 are unlikely to benefit from the procedure and should be considered for other treatment protocols.


A model of stereocilia adaptation based on single molecule mechanical studies of myosin I.
We have used an optical tweezers-based apparatus to perform single molecule mechanical experiments using the unconventional myosins, Myo1b and Myo1c. The single-headed nature and slow ATPase kinetics of these myosins make them ideal for detailed studies of the molecular mechanism of force generation by acto-myosin. Myo1c exhibits several features that have not been seen using fast skeletal muscle myosin II. (i) The working stroke occurs in two, distinct phases, producing an initial 3 nm and then a further 1.5 nm of movement. (ii) Two types of binding interaction were observed: short-lived ATP-independent binding events that produced no movement and longer-lived, ATP-dependent events that produced a full working stroke. The stiffness of both types of interaction was similar. (iii) In a new type of experiment, using feedback to apply controlled displacements to a single acto-myosin cross-bridge, we found abrupt changes in force during attachment of the acto-Myo1b cross-bridge, a result that is consistent with the classical 'T2' behaviour of single muscle fibres. Given that these myosins might exhibit the classical T2 behaviour, we propose a new model to explain the slow phase of sensory adaptation of the hair cells of the inner ear.


Extreme tolerance and developmental buffering of UV-C induced DNA damage in embryos of the annual killifish Austrofundulus limnaeus.
Free-living aquatic embryos are often at risk of exposure to ultraviolet radiation (UV-R). Successful completion of embryonic development depends on efficient removal of DNA lesions, and thus many aquatic embryos have mechanisms to reverse DNA lesions induced by UV-R. However, little is known of how embryos that are able to enter embryonic dormancy may respond to UV-R exposure and subsequent DNA damage. Embryos of the annual killifish Austrofundulus limnaeus are unique among vertebrates because their normal embryonic development includes (1) a complete dispersion of embryonic blastomeres prior to formation of the definitive embryonic axis, and (2) entry into a state of metabolic depression and developmental arrest termed diapause. Here, we show that developing and diapausing embryos of A. limnaeus have exceptional tolerance of UV-C radiation and can successfully complete embryonic development after receiving substantial doses of UV-C, especially if allowed to recover in full-spectrum light. Recovery in full-spectrum light permits efficient removal of the most common type of DNA lesion induced by UV-R: cyclobutane pyrimidine dimers. Interestingly, whole-mount embryo TUNEL assays suggest that apoptosis may not be a major contributor to cell death in embryos UV-C irradiated during dispersion/reaggregation or diapause. We also observed embryo mortality to be significantly delayed by several weeks in diapausing embryos irradiated and allowed to recover in the dark. These atypical responses to UV-R induced DNA damage may be due to the unique annual killifish life history and provide insight into DNA damage repair and recognition mechanisms during embryonic dormancy.


Solar-powered drip irrigation enhances food security in the Sudano-Sahel.
Meeting the food needs of Africa's growing population over the next half-century will require technologies that significantly improve rural livelihoods at minimal environmental cost. These technologies will likely be distinct from those of the Green Revolution, which had relatively little impact in sub-Saharan Africa; consequently, few such interventions have been rigorously evaluated. This paper analyzes solar-powered drip irrigation as a strategy for enhancing food security in the rural Sudano-Sahel region of West Africa. Using a matched-pair comparison of villages in northern Benin (two treatment villages, two comparison villages), and household survey and field-level data through the first year of harvest in those villages, we find that solar-powered drip irrigation significantly augments both household income and nutritional intake, particularly during the dry season, and is cost effective compared to alternative technologies.


Developing a utility index for the Aberrant Behavior Checklist (ABC-C) for fragile X syndrome.
This study aimed to develop a utility index (the ABC-UI) from the Aberrant Behavior Checklist-Community (ABC-C), for use in quantifying the benefit of emerging treatments for fragile X syndrome (FXS). The ABC-C is a proxy-completed assessment of behaviour and is a widely used measure in FXS. A subset of ABC-C items across seven dimensions was identified to include in health state descriptions. This item reduction process was based on item performance, factor analysis and Rasch analysis performed on an observational study dataset, and consultation with five clinical experts and a methodological expert. Dimensions were combined into health states using an orthogonal design and valued using time trade-off (TTO), with lead-time TTO methods used where TTO indicated a state valued as worse than dead. Preference weights were estimated using mean, individual level, ordinary least squares and random-effects maximum likelihood estimation [RE (MLE)] regression models. A representative sample of the UK general public (n = 349; mean age 35.8 years, 58.2% female) each valued 12 health states. Mean observed values ranged from 0.92 to 0.16 for best to worst health states. The RE (MLE) model performed best based on number of significant coefficients and mean absolute error of 0.018. Mean utilities predicted by the model covered a similar range to that observed. The ABC-UI estimates a wide range of utilities from patient-level FXS ABC-C data, allowing estimation of FXS health-related quality of life impact for economic evaluation from an established FXS clinical trial instrument.


Incidence of Cancer in Spinal Deformity Patients Receiving High-Dose (≥40 mg) Bone Morphogenetic Protein (rhBMP-2).
Level III, Retrospective observational study. To determine if there is an increased risk of developing cancer after exposure to high-dose recombinant human bone morphogenetic protein-2 (rhBMP-2) and if risk is dose and/or exposure-dependent. Concerns have been raised regarding a relationship between rhBMP-2 and cancer. A total of 642 adult deformity patients from a single institution receiving a cumulative rhBMP-2 dose ≥40 mg from July, 2002 to July, 2009 were identified. Patients with a history of surveillance, epidemiology, and end result (SEER) cancer before rhBMP-2 exposure were excluded. To determine the occurrence of a cancer event, questionnaires were mailed and telephone follow up attempted for nonresponders. Only cancers tracked by the National Cancer Institute (NCI) SEER registry were included. Observed cancer counts were compared to expected cancer counts based on general population incidence rates within 5-year age strata. Cumulative incidence competing risk (CICR) modeling was used to evaluate the association between rhBMP-2 exposure and cancer controlling for potential confounding variables. Forty-nine patients were lost-to-follow up, leaving 593 patients (92.4%; 138 males/455 females) available for analysis. Mean age was 52.8 years at the time of first exposure. Mean cumulative rhBMP-2 dose was 113.5 mg with 85% having one exposure (range: 1-8). Mean follow-up [date of exposure to date of death (regardless of cause) or returned completed questionnaire] was 5.6 ± 1.9 years; median follow up was 5.4 years. A total of 342 patients have greater than 5-year follow up. Minimum follow up was 2.0 years or until occurrence of a SEER cancer. Our total 8-year cumulative incidence of new SEER cancer accounting for the competing risk of death was 7.4% for 30 cancers in 593 patients. Fewer cancers were observed than expected based on general population rates, though the difference was not statistically significant (expected = 34; standardized incidence ratio = 0.88, 95% confidence interval, CI = 0.60-1.26). CICR found neither cumulative rhBMP-2 dose (hazard ratio, HR = 0.995, 95% CI 0.988-1.003; P = 0.249) nor number of exposures (HR = 0.776, 95% CI 0.359-1.677; P = 0.519) increased the risk of developing a postexposure cancer after controlling for known cancer risk factors. The incidence of a SEER cancer after rhBMP-2 exposure was similar to incidence reported by the NCI. There were no significant rhBMP-2 dose or multi-exposure related risks of developing a life-threatening cancer. 3.


Primary non-hodgkin's lymphoma of bone: experience of a decade.
To study the prevalence and characterization of primary non Hodgkin's lymphoma of bone in a major referral center of Pakistan. All cases of primary non Hodgkin's lymphoma of bone, diagnosed at a referral center in Pakistan from January 1998 to July 2008 have been included. Patients with diagnosis of lymphoma at some other site prior to diagnosis in bone biopsy were excluded from the study. Sixty cases of primary non Hodgkin's lymphoma of bone were received, with a male to female ratio of 7: 3 (42 males and 18 females). Overall, 52/60 (86.6 %) patients were diagnosed with Diffuse large B-cell non-Hodgkin's lymphoma. The largest fraction of patients was found in the pediatric group i.e. 33/60(55%) followed by elderly group i.e.15/60 (15%) and adults i.e. 12/60 (20%). The commonest sites of involvement were femur (28.3 %), hip bone (16.6%) and humerus (10%). Diffuse large B-cell lymphoma is the commonest type of primary non Hodgkin's lymphoma of bone in the Pakistani population. It is common in all ages. The sites most often involved are femur followed by hip bone. Primary non Hodgkin's lymphoma of bone appears to be more common in males. Our results are comparable to international data with various studies also showing that diffuse large B cell non Hodgkin lymphoma is the commonest primary bone lymphoma. However, primary Bone Lymphoma is more common in children and young adults.


Proliferative diabetic retinopathy with lymphocyte-rich epiretinal membrane associated with poor visual prognosis.
The aim of this study was to analyze lymphocyte infiltration using immunohistochemistry in proliferative diabetic retinopathy (PDR) membranes. Sixteen patients, 13 with PDR and 3 without diabetes, underwent pars plana vitrectomy, and the epiretinal membrane was peeled. Formalin-fixed, paraffin-embedded epiretinal membrane tissues were processed for immunohistochemistry with anti-leukocyte common antigen (LCA), CD3, and CD20 antibodies. Lymphocyte density was determined by direct counting at a high magnification under a light microscope, which was compared with the patients' visual prognoses. The lymphocyte density ranged from 1 to 52 (mean, 9.5) in high-power fields. Of 13 membranes, 5 showed a lymphocyte density of >5 cells, whereas the other 8 membranes showed a cell number of <2. The former type is defined as a lymphocyte-rich epiretinal membrane (LERM). Infiltrated lymphocytes were immunohistochemically positive for CD3, a T-cell marker, but not for CD20, a B-cell marker. All patients with LERM had poor visual prognosis after vitrectomy. In contrast, the visual prognosis in 7 patients with non-LERM improved or remained unchanged. A significant association was observed between high-level lymphocyte infiltration in the epiretinal membrane and poor visual prognosis (P < 0.001). LCA(+) mononuclear cells were not observed in epiretinal membranes in the absence of diabetes. These results suggest that the high-level infiltration of T lymphocytes into the PDR membrane is well correlated with poor visual prognosis. Histopathologic observation of the epiretinal membrane in patients with PDR may provide significant prognostic information.


Emotional exhaustion among healthcare professionals: the effects of role ambiguity, work engagement and professional commitment.
The study aims at identifying the antecedents and consequences of emotional exhaustion in health professionals and, particularly, examining the process that leads from a hindrance demand, like role ambiguity, to exhaustion and job satisfaction. Emotional exhaustion is a phenomenon that affect health professionals with negative consequence on job satisfaction, and literature has underlined that job demands could be may be a cause of this chronic stress. However, the relationship among job demands, work engagement and exhaustion has produced results not always converging. A self-report questionnaire was administered to 66 health professionals. The results showed that the effect of role ambiguity on emotional exhaustion was mediated by work engagement and the emotional exhaustion impairs job satisfaction when workers are not committed to their profession. Role ambiguity represents a psychosocial risk factor that influence workers' wellbeing diminishing the level of motivation and this process leads to emotional exhaustion. However, professional commitment appears to be a resource that can protect professionals preventing a decrease in satisfaction. These findings suggest that human resource management should remove hindrance stressors and enhance the mission of Healthcare Professionals in order to increase employees' work engagement and prevent exhaustion.


Indirect two-sided relative ranking: a robust similarity measure for gene expression data.
There is a large amount of gene expression data that exists in the public domain. This data has been generated under a variety of experimental conditions. Unfortunately, these experimental variations have generally prevented researchers from accurately comparing and combining this wealth of data, which still hides many novel insights. In this paper we present a new method, which we refer to as indirect two-sided relative ranking, for comparing gene expression profiles that is robust to variations in experimental conditions. This method extends the current best approach, which is based on comparing the correlations of the up and down regulated genes, by introducing a comparison based on the correlations in rankings across the entire database. Because our method is robust to experimental variations, it allows a greater variety of gene expression data to be combined, which, as we show, leads to richer scientific discoveries. We demonstrate the benefit of our proposed indirect method on several datasets. We first evaluate the ability of the indirect method to retrieve compounds with similar therapeutic effects across known experimental barriers, namely vehicle and batch effects, on two independent datasets (one private and one public). We show that our indirect method is able to significantly improve upon the previous state-of-the-art method with a substantial improvement in recall at rank 10 of 97.03% and 49.44%, on each dataset, respectively. Next, we demonstrate that our indirect method results in improved accuracy for classification in several additional datasets. These datasets demonstrate the use of our indirect method for classifying cancer subtypes, predicting drug sensitivity/resistance, and classifying (related) cell types. Even in the absence of a known (i.e., labeled) experimental barrier, the improvement of the indirect method in each of these datasets is statistically significant.


Bioengineered bile ducts recapitulate key cholangiocyte functions.
Investigation of diseases of the bile duct system and identification of potential therapeutic targets are hampered by the lack of tractable in vitro systems to model cholangiocyte biology. Here, we show a step-wise method for the differentiation of murine Lgr5+ liver stem cells (organoids) into cholangiocyte-like cells (CLCs) using a combination of growth factors and extracellular matrix components. Organoid-derived CLCs display key properties of primary cholangiocytes, such as expressing cholangiocyte markers, forming primary cilia, transporting small molecules and responding to farnesoid X receptor agonist. Integration of organoid-derived cholangiocytes with collagen-coated polyethersulfone hollow fiber membranes yielded bioengineered bile ducts that morphologically resembled native bile ducts and possessed polarized bile acid transport activity. As such, we present a novel in vitro model for studying and therapeutically modulating cholangiocyte function.


Efficacy and safety of tobramycin inhalation powder in bronchiectasis patients with P. aeruginosa infection: Design of a dose-finding study (iBEST-1).
In patients with bronchiectasis (BE), infection with Pseudomonas aeruginosa (Pa) results in disease progression, frequent pulmonary exacerbations and lung function decline. However, at present, no inhaled antibiotics have been approved for the treatment of these patients. Tobramycin inhalation powder (TIP), approved for treatment of Pa infection in cystic fibrosis, could be a promising candidate. We aimed to assess effective and well-tolerated doses and regimens of TIP in BE patients with Pa infection. In this phase II, double-blind, placebo-controlled, randomised study, three different daily doses of TIP are administered either as continuous or cyclical regimens. The study protocol comprises 7-28 days of screening, 112 days of double-blind treatment and 56 days of follow-up. The plan was to enrol 180 patients (aged ≥18 years) with BE, documented Pa infection and a history of exacerbations. The primary outcome is change in sputum Pa density from baseline. Key secondary outcomes include number of pulmonary exacerbations, use of antipseudomonal antibiotics, serum and sputum tobramycin concentrations, quality of life and safety. Exploratory endpoints include lung clearance index, sputum inflammatory markers and microbiome analysis. As of October 2018, 107/180 patients were enrolled at 34 sites (six countries) following which recruitment was closed for administrative reasons unrelated to safety findings. Despite a reduced sample size from initially planned enrolment, the unique design may inform the benefit-risk profile of TIP in BE patients with chronic Pa infection. Moreover, several novel and exploratory endpoints (lung clearance index, inflammatory biomarkers, lung microbiome), will contribute to the advancement of research in this area.


Susceptibilities of CNS Cells towards Rabies Virus Infection Is Linked to Cellular Innate Immune Responses.
Rabies is caused by neurotropic rabies virus (RABV), contributing to 60,000 human deaths annually. Even though rabies leads to major public health concerns worldwide, we still do not fully understand factors determining RABV tropism and why glial cells are unable to clear RABV from the infected brain. Here, we compare susceptibilities and immune responses of CNS cell types to infection with two RABV strains, Tha and its attenuated variant Th2P-4M, mutated on phospho- (P-protein) and matrix protein (M-protein). We demonstrate that RABV replicates in human stem cell-derived neurons and astrocytes but fails to infect human iPSC-derived microglia. Additionally, we observed major differences in transcription profiles and quantification of intracellular protein levels between antiviral immune responses mediated by neurons, astrocytes (IFNB1, CCL5, CXCL10, IL1B, IL6, and LIF), and microglia (CCL5, CXCL10, ISG15, MX1, and IL6) upon Tha infection. We also show that P- and M-proteins of Tha mediate evasion of NF-κB- and JAK-STAT-controlled antiviral host responses in neuronal cell types in contrast to glial cells, potentially explaining the strong neuron-specific tropism of RABV. Further, Tha-infected astrocytes and microglia protect neurons from Tha infection via a filtrable and transferable agent. Overall, our study provides novel insights into RABV tropism, showing the interest in studying the interplay of CNS cell types during RABV infection.


Ethical Dilemmas of Participation of Service Users with Serious Mental Illness: A Thematic Synthesis.
Mental health professionals are expected to stimulate the participation of service users with serious mental illness. This not only changes what is expected from service users and professionals, it also changes the values underlying their relationship. The value of autonomy becomes more important as a result. This raises potential ethical dilemmas. This paper reports the findings of a thematic synthesis of 28 papers on the views of service users, professionals and family members on the care relationship in inpatient, outpatient and community services for people with serious mental illness. It puts forward various perspectives on participation of service users, foregrounding differing values, which in turn can lead to ethical dilemmas for professionals. The key implications for mental health professionals and future research are discussed.


Nursing students and the supervision of medication administration.
Up to one in five medication administrations in Australian hospitals involve an error. As registered nurses (RNs) are at the forefront of medication administration, they have been the focus of attempts to reduce errors. Given that nursing students have reported errors or experiences of near misses, their practices, as well as the supervision they receive from RNs, also deserves investigation. The aim of this study was to investigate student nurses' experiences of supervision while administering medications. Students (N= 45) completed a questionnaire on their supervision experiences while administering medications. The findings revealed that 88% of students agreed that they had been directly supervised during the entirety of administration procedures. Although 7% of students reported not receiving supervision throughout medication administration, higher percentages of students indicated that they received lower levels of supervision when wards were busy (66%), when they felt under pressure to comply with the wishes of RNs (40%), when students had been in clinical settings for extended periods of time (51%), and when the RNs trusted the student nurses (37%). Approximately one third (29%) of student nurses disagreed that RNs followed the six rights when administering medications. These findings suggest that student nurses are not always adequately supervised and are at times administering medications outside the parameters of the law. Healthcare organisations need to adapt their policies and practices to ensure that the legal requirements surrounding student nurse administration of medications are being met, as well as the educational and welfare needs of neophyte nurses.


Sbds is required for Rac2-mediated monocyte migration and signaling downstream of RANK during osteoclastogenesis.
Shwachman-Diamond syndrome (SDS) results from mutations in the SBDS gene, characterized by exocrine pancreatic insufficiency and hematologic and skeletal abnormalities. Neutropenia and neutrophil dysfunction are hallmark features of SDS; however, causes for the bone defects are unknown. Dysfunction of bone-resorbing osteoclasts, formed by the fusion of monocytic progenitors derived from the same granulocytic precursors as neutrophils, could be responsible. We report that Sbds is required for in vitro and in vivo osteoclastogenesis (OCG). Sbds-null murine monocytes formed osteoclasts of reduced number and size because of impaired migration and fusion required for OCG. Phenotypically, Sbds-null mice exhibited low-turnover osteoporosis consistent with findings in SDS patients. Western blotting of Rho GTPases that control actin dynamics and migration showed a 5-fold decrease in Rac2, whereas Rac1, Cdc42, and RhoA were unchanged or only mildly reduced. Although migration was rescued on Rac2 supplementation, OCG was not. This was attributed to impaired signaling downstream of receptor activator of nuclear factor-κB (RANK) and reduced expression of the RANK-ligand-dependent fusion receptor DC-STAMP. We conclude that Sbds is required for OCG by regulating monocyte migration via Rac2 and osteoclast differentiation signaling downstream of RANK. Impaired osteoclast formation could disrupt bone homeostasis, resulting in skeletal abnormalities seen in SDS patients.


Microbial processes driving coral reef organic carbon flow.
Coral reefs are one of the most productive ecosystems on the planet, with primary production rates compared to that of rain forests. Benthic organisms release 10-50% of their gross organic production as mucus that stimulates heterotrophic microbial metabolism in the water column. As a result, coral reef microbes grow up to 50 times faster than open ocean communities. Anthropogenic disturbances cause once coral-dominated reefs to become dominated by fleshy organisms, with several outcomes for trophic relationships. Here we review microbial processes implicated in organic carbon flux in coral reefs displaying species phase shifts. The first section presents microbial players and interactions within the coral holobiont that contribute to reef carbon flow. In the second section, we identify four ecosystem-level microbial features that directly respond to benthic species phase shifts: community composition, biomass, metabolism and viral predation. The third section discusses the significance of microbial consumption of benthic organic matter to reef trophic relationships. In the fourth section, we propose that the 'microbial phase shifts' discussed here are conducive to lower resilience, facilitating the transition to new degradation states in coral reefs.


Nonmyeloablative TLI-ATG conditioning for allogeneic transplantation: mature follow-up from a large single-center cohort.
Nonmyeloablative total lymphoid irradiation and antithymocyte globulin (TLI-ATG) conditioning is protective against graft-versus-host disease (GVHD), while retaining graft-versus-tumor activity across various hematologic malignancies. We report our comprehensive experience using TLI-ATG conditioning in 612 patients with hematologic malignancies who underwent allogeneic transplantation at Stanford University from 2001 to 2016. All patients received granulocyte colony-stimulating factor-mobilized peripheral blood grafts and cyclosporine and mycophenolate mofetil for GVHD prophylaxis. The median age was 60 years (range, 21-78), with a median follow-up of 6.0 years (range, 1.0-16.4). Common diagnoses included acute myeloid leukemia (AML; n = 193), myelodysplastic syndrome (MDS; n = 94), chronic lymphocytic leukemia (CLL; n = 80), non-Hodgkin lymphoma (NHL; n = 175), and Hodgkin lymphoma (HL; n = 35). Thirty-four percent of patients had a comorbidity index ≥3, 30% had a high to very high disease risk index, and 56% received unrelated donor grafts, including 15% with HLA-mismatched donors. Ninety-eight percent underwent transplant in the outpatient setting, and 57% were never hospitalized from days 0 through 100. The 1-year rates of nonrelapse mortality (NRM), grade II-IV acute GVHD, and extensive chronic GVHD were 9%, 14%, and 22%, respectively. The 4-year estimates for overall and progression-free survival were 42% and 32% for AML, 30% and 21% for MDS, 67% and 43% for CLL, 68% and 45% for NHL, and 78% and 49% for HL. Mixed chimerism correlated with the risk of relapse. TLI-ATG conditioning was well tolerated, with low rates of GVHD and NRM. Durable remissions were observed across hematologic malignancies, with particularly favorable outcomes for heavily pretreated lymphomas. Several efforts are underway to augment donor chimerism and reduce relapse rates while maintaining the favorable safety and tolerability profile of this regimen.


The peptidoglycan-associated protein NapA plays an important role in the envelope integrity and in the pathogenesis of the lyme disease spirochete.
The bacterial pathogen responsible for causing Lyme disease, Borrelia burgdorferi, is an atypical Gram-negative spirochete that is transmitted to humans via the bite of an infected Ixodes tick. In diderms, peptidoglycan (PG) is sandwiched between the inner and outer membrane of the cell envelope. In many other Gram-negative bacteria, PG is bound by protein(s), which provide both structural integrity and continuity between envelope layers. Here, we present evidence of a peptidoglycan-associated protein (PAP) in B. burgdorferi. Using an unbiased proteomics approach, we identified Neutrophil Attracting Protein A (NapA) as a PAP. Interestingly, NapA is a Dps homologue, which typically functions to bind and protect cellular DNA from damage during times of stress. While B. burgdorferi NapA is known to be involved in the oxidative stress response, it lacks the critical residues necessary for DNA binding. Biochemical and cellular studies demonstrate that NapA is localized to the B. burgdorferi periplasm and is indeed a PAP. Cryo-electron microscopy indicates that mutant bacteria, unable to produce NapA, have structural abnormalities. Defects in cell-wall integrity impact growth rate and cause the napA mutant to be more susceptible to osmotic and PG-specific stresses. NapA-linked PG is secreted in outer membrane vesicles and augments IL-17 production, relative to PG alone. Using microfluidics, we demonstrate that NapA acts as a molecular beacon-exacerbating the pathogenic properties of B. burgdorferi PG. These studies further our understanding of the B. burgdorferi cell envelope, provide critical information that underlies its pathogenesis, and highlight how a highly conserved bacterial protein can evolve mechanistically, while maintaining biological function.


A register-based study of long-term healthcare use before and after psychotherapy.
Psychotherapeutic treatment for non-psychotic disorders is associated with significant reduction in patients' symptoms, and therefore it is believed that treatment improves health and decreases the need for additional healthcare. However, little is known about long-term changes in utilization of healthcare services. To investigate long-term changes in utilization of public healthcare services for patients referred to psychotherapeutic treatment. A pre-post study with 761 consecutive patients and 15,220 matched individuals in a matched population reference group. Data from a comprehensive set of healthcare services were collected from central registries for 4 years prior to intake and for 4 years after completion of treatment. Of the 761 patients, 216 did not show up for treatment and 545 completed treatment. Completer patients achieved a substantial reduction in symptoms (effect size, ES = 0.99). However, completer patients increased their use of all healthcare services by 296% (ES = 0.58) in the 4th year pre-post comparison, while the reference group increased usage by 99% (ES = 0.23). Completer patients had significantly higher increase in contacts with psychiatric hospitals (P < 0.008), contacts with primary care psychologists (P < 0.001), psychotropic medication (P < 0.001) and contacts with primary care physicians (P < 0.001) than the reference group at the 4th year pre-post comparison. Over a long-term period, patients who completed psychotherapeutic treatment increased utilization of healthcare services. Studies are needed to clarify how and why psychotherapeutic treatment does not necessarily lead to a reduction in the utilization of healthcare services for the average patient and to evaluate other potential interventions for patients with mental problems and include efficiency studies in this evaluation.


The Temperature Dependence of Micro-Leakage between Restorative and Pulp Capping Materials by Cu Diffusion.
We used the Cu ions for the leakage analysis between pulp capping and restorative materials. Theoretically, Cu has more advantages than Ag ions due to their smaller radii (rCu (2+)=73 pm and rAg (2+)=94 pm), lower mass density (dCu=8.96 g/cm(3) and dAg=10.49 g/cm(3)) and higher radio opacity which can be more useful by X-ray or EDX detectors, cheaper price and more abundance in planet when compared with Ag element which is generally used in the leakage studies. The micro leakage between dental restorations and pulp capping materials has been determined by using Micro Computed Tomography, Scanning Electron Microscopy and EDX analysis. It is found that the leakage has temperature dependent mechanism which increases with the increasing temperature. As a result, using Cu solution for leakage studies in dentine is an effective and easy method which can be used in dental science.


Loosening of the porous coating of bicompartmental prostheses in patients with rheumatoid arthritis.
Thirty-four porous-coated anatomical (PCA) total knee arthroplasties in twenty-eight patients with rheumatoid arthritis were followed for an average of seventeen months. In these thirty-four knees, twenty-three tibial and fifteen femoral components were cemented. The rest were uncemented. At follow-up, more than half of the knees (nineteen of thirty-four) showed radiographic evidence of displacement of some of the beads from the porous coating. In fourteen knees the beads loosened more than three months postoperatively, and all of these knees had a radiolucent zone. Six knees had beads within the joint. Eight of nine non-cemented tibial components (excluding one tibial component) and five of the nineteen femoral components that were not cemented showed late loosening of beads (after three months). This study indicates that the metallurgical technique for porous coating with heat-sintered cobalt-chromium beads does not produce a coating that is sufficiently strong to prevent loosening in the case of the porous-coated anatomical prosthesis. The long-term clinical relevance of our findings is unclear. The mechanical strength of the porous coating on the prosthetic surface should be improved and the prosthesis should be tested in limited clinical studies before cementless fixation can be recommended.


Error-related Alpha Suppression: Scalp Topography and (Lack of) Modulation by Modafinil.
Errors in performance trigger cognitive and neural changes that are implemented to adaptively adjust to fluctuating demands. Error-related alpha suppression (ERAS)-which refers to decreased power in the alpha frequency band after an incorrect response-is thought to reflect cognitive arousal after errors. Much of this work has been correlational, however, and there are no direct investigations into its pharmacological sensitivity. In Study 1 (n = 61), we evaluated the presence and scalp distribution of ERAS in a novel flanker task specifically developed for cross-species assessments. Using this same task in Study 2 (n = 26), which had a placebo-controlled within-subject design, we evaluated the sensitivity of ERAS to placebo (0 mg), low (100 mg), and high (200 mg) doses of modafinil, a wakefulness promoting agent. Consistent with previous work, ERAS was maximal at parieto-occipital recording sites in both studies. In Study 2, modafinil did not have strong effects on ERAS (a significant Accuracy × Dose interaction emerged, but drug-placebo differences did not reach statistical significance after correction for multiple comparisons and was absent after controlling for accuracy rate). ERAS was correlated with accuracy rates in both studies. Thus, modafinil did not impact ERAS as hypothesized, and findings indicate ERAS may reflect an orienting response to infrequent events.


Cyclin A repression in quiescent cells is associated with chromatin remodeling of its promoter and requires Brahma/SNF2alpha.
Cell cycle-dependent expression of cyclin A is controlled by transcriptional repression in early phase of the cell cycle. In this study, we directly examine the chromatin structure of the mouse cyclin A promoter through in vivo micrococcal nuclease footprinting. We describe here that cyclin A repression is associated with two positioned nucleosomes and that histones progressively lose DNA contact synchronously with gene activation. This particular nucleosomal organization is disrupted by mutations of the cyclin A bipartite repressor sequence. Moreover, the same sequence recruits the chromatin remodeling factor Brahma/SNF2alpha (Brm) onto the cyclin A promoter. Accordingly, cyclin A proximal promoter is not wrapped around nucleosomes and not repressed in quiescent cells lacking Brm. These results provide molecular explanations for the transcriptional repression state of cyclin A, as well as insights into the action of Brm chromatin remodeling factor as cell cycle regulator.


Diamondlike carbon coating as a galvanic corrosion barrier between dental implant abutments and nickel-chromium superstructures.
The objectives of this study were to evaluate the galvanic corrosion behavior between titanium and nickel-chromium (Ni-Cr) alloy, to investigate the effect of diamondlike carbon (DLC) coating over titanium on galvanic corrosion behavior between titanium and Ni-Cr alloy, and to evaluate the effect of DLC coating over titanium abutments on the fit and integrity of prosthetic assemblies by scanning electron microcopy (SEM). Five Ni-Cr and 10 titanium disks with a diameter of 5 mm and thickness of 3 mm were prepared. DLC coating was applied to five titanium disks. Electrode samples were prepared, and open circuit potential measurements, galvanic current measurements over platinum electrodes, and potentiodynamic polarization tests were carried out. For the SEM evaluation, 20 Ni-Cr alloy and 10 gold alloy superstructures were cast and prepared over 30 abutments. DLC coating was applied to 10 of the abutments. Following the fixation of prosthetic assemblies, the samples were embedded in acrylic resin and cross sectioned longitudinally. Internal fit evaluations were carried out through examination of the SEM images. Titanium showed more noble and electrochemically stable properties than Ni-Cr alloy. DLC coating over the cathode electrode served as an insulating film layer over the surface and prevented galvanic coupling. Results of the SEM evaluations indicated that the DLC-coated and titanium abutments showed no statistically significant difference in fit. Hence, no adverse effects on the adaptation of prosthetic components were found with the application of DLC coating over abutment surfaces. DLC coating might serve as a galvanic corrosion barrier between titanium abutments and Ni-Cr superstructures.


Brief communication: the Australian Barrineans and their relationship to Southeast Asian negritos: an investigation using mitochondrial genomics.
The existence of a short-statured Aboriginal population in the Far North Queensland (FNQ) rainforest zone of Australia's northeast coast and Tasmania has long been an enigma in Australian anthropology. Based on their reduced stature and associated morphological traits such as tightly curled hair, Birdsell and Tindale proposed that these "Barrinean" peoples were closely related to "negrito" peoples of Southeast Asia and that their ancestors had been the original Pleistocene settlers of Sahul, eventually displaced by taller invaders. Subsequent craniometric and blood protein studies, however, have suggested an overall homogeneity of indigenous Australians, including Barrineans. To confirm this finding and determine the degree of relatedness between Barrinean people and Southeast Asian negritos, we compared indigenous Australian mitochondrial DNA (mtDNA) sequences in populations from the FNQ rainforest ecozone and Tasmania with sequences from other Australian Aboriginal populations and from Southeast Asian negrito populations (Philippines Batek and Mamanwa, and mainland Southeast Asian Jahai, Mendriq, and Batak). The results confirm that FNQ and Tasmanian mtDNA haplogroups cluster with those of other Australian Aboriginal populations and are only very distantly related to Southeast Asian negrito haplogroups.


Cellular plasticity in the neural crest and cancer.
In vertebrates, neural crest cells (NCCs) are a multipotent embryonic population generating both neural/neuronal and mesenchymal derivatives, and thus the neural crest (NC) is often referred to as the fourth germ layer. NC development is a dynamic process, where NCCs possess substantial plasticity in transcriptional and epigenomic profiles. Recent technical advances in single-cell and low-input sequencing have empowered fine-resolution characterisation of NC development. In this review, we summarise the latest models underlying NC-plasticity acquirement and cell-fate restriction, outline the connections between NC plasticity and NC-derived cancer and envision the new opportunities in studying NC plasticity and its link to cancer.


Heat Tolerance and Occupational Heat Exposure Limits in Older Men with and without Type 2 Diabetes or Hypertension.
To mitigate rises in core temperature >1°C, the American Conference of Governmental Industrial Hygienists (ACGIH) recommends upper limits for heat stress (action limit values [ALV]), defined by wet-bulb globe temperature (WBGT) and a worker's metabolic rate. However, these limits are based on data from young men and are assumed to be suitable for all workers, irrespective of age or health status. We therefore explored the effect of aging, type 2 diabetes (T2D), and hypertension (HTN) on tolerance to prolonged, moderate-intensity work above and below these limits. Core temperature and heart rate were assessed in healthy, heat unacclimatized young (18-30 yr, n = 13) and older (50-70 yr) men (n = 14) and heat unacclimatized older men with T2D (n = 10) or HTN (n = 13) during moderate-intensity (metabolic rate: 200 W·m-2) walking for 180 min (or until termination) in environments above (28°C and 32°C WBGT) and below (16°C and 24°C WBGT) the ALV for continuous work at this intensity (25°C WBGT). Work tolerance in the 32°C WBGT was shorter in men with T2D (median [IQR]; 109 [91-173] min; P = 0.041) and HTN (120 [65-170] min; P = 0.010) compared with healthy older men (180 [133-180] min). However, aging, T2D, and HTN did not significantly influence (i) core temperature or heart rate reserve, irrespective of WBGT; (ii) the probability that core temperature exceeded recommended limits (>1°C) under the ALV; and (iii) work duration before core temperature exceeded recommended limits (>1°C) above the ALV. These findings demonstrate that T2D and HTN attenuate tolerance to uncompensable heat stress (32°C WBGT); however, these chronic diseases do not significantly impact thermal and cardiovascular strain, or the validity of ACIGH recommendations during moderate-intensity work.


Dating Caral, a preceramic site in the Supe Valley on the central coast of Peru.
Radiocarbon dates from the site of Caral in the Supe Valley of Peru indicate that monumental corporate architecture, urban settlement, and irrigation agriculture began in the Americas by 4090 years before the present (2627 calibrated years B.C.) to 3640 years before the present (1977 calibrated years B.C.). Caral is located 23 kilometers inland from the Pacific coast and contains a central zone of monumental, residential, and nonresidential architecture covering an area of 65 hectares. Caral is one of 18 large preceramic sites in the Supe Valley.


Prenatal exposure to traffic-related air pollution and fetal growth in a cohort of pregnant women.
Scant evidence is available on effects of air pollution on longitudinally measured fetal biometry, and thus it remains unclear as to whether there are critical windows of exposure or specificity of effects. Our objective was to examine the association between exposure to nitrogen dioxide (NO2) during pregnancy and fetal and neonatal anthropometry in a cohort of Spanish women. Temporally adjusted land-use regression was used to estimate exposure to NO2 at home addresses. Biparietal diameter (BPD), abdominal circumference (AC), femur length (FL) and estimated fetal weight (EFW) were evaluated in each trimester by ultrasound. As neonatal outcomes, weight, length and head circumference were analysed. SD scores adjusted by gestational age, mother characteristics and fetus sex were calculated at 12, 20 and 32 weeks of gestation as well as at birth. The association between fetal growth and average exposure to NO2 in the relevant windows was investigated using regression models, adjusted for socio-demographic and lifestyle-related variables. Exposure to NO2 was inversely associated with BPD, AC and EFW at week 32 and with growth in these parameters in weeks 20-32. BPD and FL were also affected earlier, at week 20. NO2 levels above the median (38 μg/m3) reduced size at week 32 by around 9% in all parameters except for FL (6%). The critical windows of exposure were in early pregnancy, before 20 weeks. Exposure in this period was also inversely associated with neonatal length and head circumference. Maternal exposure to NO2 is associated with impaired fetal growth from mid-gestation onwards.


PAK1 is a novel cardiac protective signaling molecule.
We review here the novel cardiac protective effects of the multifunctional enzyme, p21-activated kinase 1 (PAK1), a member of a serine/threonine protein kinase family. Despite the large body of evidence from studies in noncardiac tissue indicating that PAK1 activity is key in the regulation of a number of cellular functions, the role of PAK1 in the heart has only been revealed over the past few years. In this review, we assemble an overview of the recent findings on PAK1 signaling in the heart, particularly its cardiac protective effects. We present a model for PAK1 signaling that provides a mechanism for specifically affecting cardiac cellular processes in which regulation of protein phosphorylation states by protein phosphatase 2A (PP2A) predominates.We discuss the anti-adrenergic and antihypertrophic cardiac protective effects of PAK1, as well as its role in maintaining ventricular Ca(2+) homeostasis and electrophysiological stability under physiological, β-adrenergic and hypertrophic stress conditions.


Prefrontal gray and white matter volumes in healthy aging and Alzheimer disease.
To quantify the contribution of gray and white matter volumes to total prefrontal volume in healthy aging. To determine if prefrontal tissue volumes distinguish healthy aging from Alzheimer disease (AD). Volumes of total prefrontal cortex, prefrontal gray matter, and prefrontal white matter were compared among young healthy elderly (YHE) (n = 14; mean age, 70 years), old healthy elderly (OHE) (n = 14; mean age, 90 years), and subjects with AD (n = 14; mean age, 70 years) by analysis of variance. Additionally, Pearson correlations were performed between volumes and age. Old healthy elderly and subjects with AD had significantly less total prefrontal volume (approximately 15% less in both groups) and prefrontal white matter volume (approximately 30% less and 20% less in the OHE and AD groups, respectively) than YHE, but there were no differences between the OHE and AD groups. There was a significant difference in gray-white matter volume ratio with OHE having a higher ratio than YHE. Subjects with AD did not differ from YHE or OHE in this ratio. There were significant negative correlations between age and total prefrontal volume and age and prefrontal white matter volume in the healthy subjects. In the very old, the decline of white matter volume is disproportionately greater than the decline of gray matter volume. In subjects with AD both gray and white matter loss contribute to the decline of prefrontal volume. This is demonstrated by the gray-white matter ratio that does not differ between YHE and subjects with AD. Thus, it is likely that AD is different from accelerated aging.


Derivation of the optimum dose per fraction from the linear quadratic model.
The linear quadratic equation for fractionated radiotherapy has already been adapted to include a time factor for tumour repopulation: loge cell kill (E) is given as a function of dose per fraction (d), number of fractions (n), overall treatment time (T) and the clonogen doubling time (Tp). By incorporating a normal tissue isoeffect and replacing the relationship between T and n by a function f, the equation for E can be rewritten as a more complex function of d. In this form, E and d are continuous variables so that the dose per fraction (d') required to produce maximum values of E for isoeffective late normal tissue effects can be found by differential calculus. The derived equation takes the form (beta kTp-alpha Tp)d2 + 1.386fd + 0.693fk = 0 and when solved for d provides a direct estimation of the optimum dose per fraction. Where normal tissue sparing is possible and the tumour dose z is related to the normal tissue dose d, the optimum dose per fraction z' can be found by solving the equation (beta kTp-alpha gTp)z2 + 1.386fgz + 0.693fk = 0 The results show that a critical minimum dose per fraction is required to counteract rapid tumour clonogen repopulation in both conventional and accelerated radiotherapy. The calculus method is reasonably accurate for larger fraction numbers, when clonogen doubling times are 3.5 days or longer and for conventional radiotherapy given 5 days per week. The model is even more accurate for accelerated hyperfractionated radiotherapy providing that there is complete repair between successive fractions. Where greater normal tissue sparing is possible, as with focal teletherapy methods and brachytherapy, higher tumour doses per fraction can be used to increase further the tumour cell kill without exceeding normal tissue tolerance. These predicted doses per fraction are consistent with clinical experience when the given constraints in terms of frequency of treatment are considered. The model described can be used for tumours in which repopulation occurs at a constant rate throughout treatment. For tumours in which accelerated repopulation occurs, the optimum dose per fraction can be separately calculated for the initial phase of slow repopulation (for which very small doses per fraction are optimal) and also for the second phase of rapid repopulation (for which either accelerated hyperfractionated treatments or hypofractionated focal methods of treatment would be appropriate). The limitations of the model are fully discussed including the need for accurate radiobiological predictive assays. In the future such assays of pre-treatment doubling times and tumour cell radiosensitivities could be used to determine reasonable ranges for the optimum dose per fraction in experimental tumours and subsequently in clinical trails. This approach could produce major improvements in the therapeutic potential of radiotherapy.


Hepatic encephalopathy: an updated approach from pathogenesis to treatment.
One of the most serious complications of chronic or fulminant liver failure is hepatic encephalopathy (HE), associated most commonly with cirrhosis. In the presence of chronic liver disease, HE is a sign of decompensation, while in fulminant liver failure its development represents a worrying sign and usually indicates that transplantation will be required. Despite the significance of HE in the course of liver disease, the progress in development of new therapeutic options has been unremarkable over the last 20 years. An up-to-date review regarding HE, including both research and review articles. HE is a serious and progressive, but potentially reversible, disorder with a wide spectrum of neuropsychiatric abnormalities and motor disturbances that ranges from mild alteration of cognitive and motor function to coma and death. Although a clear pathogenesis is yet to be determined, elevated ammonia in serum and the central nervous system is the mainstay for pathogenesis and treatment of HE. Management includes early diagnosis and prompt treatment of precipitating factors. Clinical trials and extensive clinical experience have established the efficacy of diverse substances in HE treatment. Novel therapies with clinical promise include: L-ornithine L-aspartate, sodium benzoate, phenylacetate, AST-120, and the molecular adsorbent recirculating system. Eventually, liver transplantation is often the most successful long-term therapy for HE.


Innovation in anterior mandibular alveolar distraction osteogenesis: introduction of a new bone-borne distraction device and first clinical results.
Segmental distraction osteogenesis of the anterior mandibular alveolar process (frontblock) is a sufficient method to avoid extractions in patients with dental crowding and to decompensate retroalveolism. Up to now dental-borne devices were used, but limitate the indications for front-block distraction. A new bone-borne distraction device for mandibular alveolar front-block movement is introduced in this study. The distractor allows sufficient segmental transport without loading on the teeth. Clinical evaluations of 7 patients have been performed including the feasibility and predictability of the distraction, postoperative pain and patients' discomfort. The results indicate that this technique is a promising strategy in the correction of dental crowding, correcting the curve of Spee and to decompensate mandibular retroalveolism even in patients with impaired periodontal health and a thin mandibular symphysis.


Type 1 fimbriation and fimE mutants of Escherichia coli K-12.
We reexamined the influence of fimE, also referred to as hyp, on type 1 fimbriation in Escherichia coli K-12. We found that one strain used previously and extensively in the analysis of type 1 fimbriation, strain CSH50, is in fact a fimE mutant; the fimE gene of CSH50 contains a copy of the insertion sequence IS1. Using a recently described allelic exchange procedure, we transferred the fimE::IS1 allele from CSH50 to our present wild-type strain, MG1655. Characterization of this IS1-containing strain (AAEC137), together with another fimE mutant of MG1655 (AAEC143), led to two conclusions about the role of fimE. First, the formation of phase variant colony types, reported widely in strains of E. coli, depends on mutation of fimE, at least in K-12 strain MG1655. Here we showed that this phenomenon reflects the ability of fimE to stimulate the rapid inversion of the fim invertible element from on to off when the bacteria are grown on agar. Second, our analysis of fimE mutants, which is limited to chromosomal constructs, provided no evidence that they are hyperfimbriate. We believe that these results, which are at odds with a previous study using fim-containing multicopy plasmids, reflect differences in gene copy number.


Individuals Maintain Similar Rates of Protein Synthesis over Time on the Same Plane of Nutrition under Controlled Environmental Conditions.
Consistent individual differences in animal performance drive individual fitness under variable environmental conditions and provide the framework through which natural selection can operate. Underlying this concept is the assumption that individuals will display consistent levels of performance in fitness-related traits and interest has focused on individual variation and broad sense repeatability in a range of behavioural and physiological traits. Despite playing a central role in maintenance and growth, and with considerable inter-individual variation documented, broad sense repeatability in rates of protein synthesis has not been assessed. In this study we show for the first time that juvenile flounder Platichthys flesus reared under controlled environmental conditions on the same plane of nutrition for 46 days maintain consistent whole-animal absolute rates of protein synthesis (As). By feeding meals containing 15N-labelled protein and using a stochastic end-point model, two non-terminal measures of protein synthesis were made 32 days apart (d14 and d46). As values (mass-corrected to a standard mass of 12 g) showed 2- to 3-fold variation between individuals on d14 and d46 but individuals showed similar As values on both days with a broad sense repeatability estimate of 0.684 indicating significant consistency in physiological performance under controlled experimental conditions. The use of non-terminal methodologies in studies of animal ecophysiology to make repeat measures of physiological performance enables known individuals to be tracked across changing conditions. Adopting this approach, repeat measures of protein synthesis under controlled conditions will allow individual ontogenetic changes in protein metabolism to be assessed to better understand the ageing process and to determine individual physiological adaptive capacity, and associated energetic costs of adaptation, to global environmental change.


Napabucasin overcomes cisplatin resistance in ovarian germ cell tumor-derived cell line by inhibiting cancer stemness.
Cisplatin resistance of ovarian yolk sac tumors (oYST) is a clinical challenge due to dismal patient prognosis, even though the disease is extremely rare. We investigated potential association between cisplatin resistance and cancer stem cell (CSC) markers in chemoresistant oYST cells and targeting strategies to overcome resistance in oYST. Chemoresistant cells were derived from chemosensitive human oYST cells by cultivation in cisplatin in vitro. Derivative cells were characterized by chemoresistance, functional assays, flow cytometry, gene expression and protein arrays focused on CSC markers. RNAseq, methylation and microRNA profiling were performed. Quail chorioallantoic membranes (CAM) with implanted oYST cells were used to analyze the micro-tumor extent and interconnection with the CAM. Tumorigenicity in vivo was determined on immunodeficient mouse model. Chemoresistant cells were treated by inhibitors intefering with the CSC properties to examine the chemosensitization to cisplatin. Long-term cisplatin exposure resulted in seven-fold higher IC50 value in resistant cells, cross-resistance to oxaliplatin and carboplatin, and increased migratory capacity, invasiveness and tumorigenicity, associated with hypomethylation of differentially methylated genes/promotors. Resistant cells exhibited increased expression of prominin-1 (CD133), ATP binding cassette subfamily G member 2 (ABCG2), aldehyde dehydrogenase 3 isoform A1 (ALDH3A1), correlating with reduced gene and promoter methylation, as well as increased expression of ALDH1A3 and higher overall ALDH enzymatic activity, rendering them cross-resistant to DEAB, disulfiram and napabucasin. Salinomycin and tunicamycin were significantly more toxic to resistant cells. Pretreatment with napabucasin resensitized the cells to cisplatin and reduced their tumorigenicity in vivo. The novel chemoresistant cells represent unique model of refractory oYST. CSC markers are associated with cisplatin resistance being possible targets in chemorefractory oYST.


Clinical Use of the Kannada and English Rate of Reading Tests.
The rate of reading test in which randomly ordered common words are read aloud has found use in optometric and educational practice as a means of assessing visual aspects of reading largely independently of comprehension. English and Kannada versions of the rate of reading test were administered to 761 children aged between 9 and 15 years. These children were recruited from four private and five state schools in Udupi Taluk that had English and Kannada, respectively, as the principal medium of instruction. The results showed that the reading rate increased with age, as expected, but depended on the language of the test and the medium of instruction. The study emphasizes the importance of using normative data based on age and the language of instruction used in school. It also suggests age-specific criteria to measure the efficacy of any visual intervention aimed at improving reading speed. The test can be used to assess (1) educational under-performance in reading and (2) the effects of optometric and educational intervention, and separate norms appropriate for each use are presented.


The role of patient beliefs in open-label placebo effects.
Recent research on open-label placebos, or placebos administered without deception or concealment, suggests that they can be effective in a variety of conditions. The current research sought to unpack the mechanisms underlying the treatment efficacy of open-label placebos. A health care provider induced an allergic reaction in 148 participants via a histamine skin prick test. Participants were then exposed to 1 of 4 conditions additively leveraging various mechanisms of open-label placebo treatments: a supportive patient-provider relationship, a medical ritual, positive expectations, and a rationale about the power of placebos. There were no main effects of condition on allergic responses. However, participant beliefs about placebos moderated the effect of open-label placebo treatment condition on physiological allergic reactions: the condition including all 4 components of open-label placebos (a supportive patient-provider relationship, a medical ritual, positive expectations, and a rationale about the power of placebos) significantly reduced physiological allergic reaction among participants with a strong belief in placebos compared with participants in the control group. Participants' beliefs about placebos interact with information from the provider to reduce physiological allergic reactions in response to an open-label placebo treatment. This study underscores the importance of measuring and understanding how participants' beliefs influence outcomes of treatment, and furthers our understanding of when and how open-label placebo treatments work. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Ataxia telangiectasia: an investigation of the repair defect in the cell line AT5BIVA by plasmid reconstitution.
The ataxia telangiectasia cell line, AT5BIVA, exhibited low repair fidelity measured by the reconstitution of transfected linear plasmid. This assay involves transfecting a linear plasmid containing two selectable marker genes: one gene (neo) is undamaged and marks transfection and the other gene (gpt) is cleaved to test functional repair. The proportion of transfected cells which have a functionally intact gpt gene gives a measure of repair fidelity. Southern analysis of individual transfected clones showed that integrated plasmids in AT5BIVA had a high frequency of sequence rearrangement. Blunt or staggered-ended termini of a linear plasmid did not determine the type of misrepair. A variety of sizes of deletions and sequence insertions were found at and around the cleavage site. Loss of intact sequence occurred similarly following transfection by linear or circular plasmid (misrepair or rearrangement error). This suggests that the action of excess exonuclease activity upon, or lack of protection of, exposed DNA termini is not the sole mechanism of misrepair. Erroneous rearrangement of circular plasmid could involve any location along the plasmid. Rearrangement of transfected circular plasmid occurred in multiple copies of the same abnormal size, suggesting that error-prone recombination rather than degradation of presumed nicked circular plasmid was the underlying mechanism. It is hypothesized that misrepair in ataxia-telangiectasia arises by error-prone recombination.


Glycogen and maltose utilization by Escherichia coli O157:H7 in the mouse intestine.
Mutant screens and transcriptome studies led us to consider whether the metabolism of glucose polymers, i.e., maltose, maltodextrin, and glycogen, is important for Escherichia coli colonization of the intestine. By using the streptomycin-treated mouse model, we found that catabolism of the disaccharide maltose provides a competitive advantage in vivo to pathogenic E. coli O157:H7 and commensal E. coli K-12, whereas degradation of exogenous forms of the more complex glucose polymer, maltodextrin, does not. The endogenous glucose polymer, glycogen, appears to play an important role in colonization, since mutants that are unable to synthesize or degrade glycogen have significant colonization defects. In support of the hypothesis that E. coli relies on internal carbon stores to maintain colonization during periods of famine, we found that by providing a constant supply of a readily metabolized sugar, i.e., gluconate, in the animal's drinking water, the competitive disadvantage of E. coli glycogen metabolism mutants is rescued. The results suggest that glycogen storage may be widespread in enteric bacteria because it is necessary for maintaining rapid growth in the intestine, where there is intense competition for resources and occasional famine. An important implication of this study is that the sugars used by E. coli are present in limited quantities in the intestine, making endogenous carbon stores valuable. Thus, there may be merit to combating enteric infections by using probiotics or prebiotics to manipulate the intestinal microbiota in such a way as to limit the availability of sugars preferred by E. coli O157:H7 and perhaps other pathogens.


Patient-reported Adherence to Adjuvant Aromatase Inhibitor Therapy Using the Morisky Medication Adherence Scale: An Evaluation of Predictors.
Endocrine therapy is part of standard adjuvant therapy for patients with hormone receptor-positive breast cancer and has been shown to improve recurrence-free and overall survival. However, adherence to endocrine therapy is suboptimal and is difficult to measure. In this study we evaluate the feasibility of using the Morisky Medication Adherence Scale (MMAS) to assess patient adherence to aromatase inhibitor (AI) therapy. Patients with stage 1 to 3, hormone receptor-positive breast cancer receiving adjuvant AI therapy were prospectively enrolled on an Institutional Review Board approved protocol. The MMAS questionnaire was administered to each patient and adherence was measured. Information on duration of AI therapy, patient and tumor characteristics, and treatment was collected. A multivariable logit model approach was utilized to evaluate potential barriers to adherence. Between 2011 and 2014, 100 patients were enrolled. The distribution of adherence levels was 13% low, 37% medium, and 50% high. High adherence was reported more frequently in white women (58%), patients with stage 2 and 3 disease (54%), and patients who did not receive chemotherapy (62%). Multivariable analysis demonstrated that higher adherence was more likely in white women compared with African American women (estimated odds ratio=2.8). Using the MMAS, only 50% of women with stage 1 to 3 breast cancer reported high adherence to AI therapy, consistent with other reports showing suboptimal adherence to adjuvant endocrine therapy. The MMAS allows for the rapid assessment of adherence to oral adjuvant endocrine therapy and is valuable in a busy clinical setting.


Role of nitric oxide in regulation of vascular resistance in postnatal intestine.
Studies were conducted to determine whether endothelial production of nitric oxide (NO) participates in the regulation of vascular resistance in postnatal swine intestine. In vivo, intra-arterial infusion of the arginine analogue NG-monomethyl-L-arginine (L-NMMA, 10(-4) M) increased intestinal vascular resistance 34% in 3-day-old animals and 9% in 35-day-old animals (P < 0.01); similar findings were noted during infusion of 10(-3) M L-NMMA. Mechanical augmentation of gut flow rate induced intestinal vasodilation in both age groups; L-NMMA eliminated this flow-induced dilation in intestine of 3- but not 35-day-old animals. In vitro, precontracted mesenteric artery rings from both age groups relaxed to a similar extent in response to the endothelium-independent nitrovasodilator sodium nitroprusside (SNP) and the calcium ionophore A-23187; the effect of A-23187, but not SNP, was eliminated by mechanical disruption of the endothelium. Acetylcholine (ACh) and substance P (SP), agents with vascular effects that are secondary to receptor-mediated activation of NO, caused greater relaxation of rings from younger than from older animals, and this effect was attenuated by L-NMMA or methylene blue. Unstimulated accumulation of guanosine 3',5'-cyclic monophosphate (cGMP) occurred to a similar extent in vessel segments from both groups. ACh and SP increased cGMP accumulation in segments from 3- but not from 35-day-old animals. We conclude that the NO-cGMP axis participates to a greater extent in regulation of intestinal vascular resistance in 3- than in 35-day-old swine.


OBJCUT: efficient segmentation using top-down and bottom-up cues.
We present a probabilistic method for segmenting instances of a particular object category within an image. Our approach overcomes the deficiencies of previous segmentation techniques based on traditional grid conditional random fields (CRF), namely that 1) they require the user to provide seed pixels for the foreground and the background and 2) they provide a poor prior for specific shapes due to the small neighborhood size of grid CRF. Specifically, we automatically obtain the pose of the object in a given image instead of relying on manual interaction. Furthermore, we employ a probabilistic model which includes shape potentials for the object to incorporate top-down information that is global across the image, in addition to the grid clique potentials which provide the bottom-up information used in previous approaches. The shape potentials are provided by the pose of the object obtained using an object category model. We represent articulated object categories using a novel layered pictorial structures model. Nonarticulated object categories are modeled using a set of exemplars. These object category models have the advantage that they can handle large intraclass shape, appearance, and spatial variation. We develop an efficient method, OBJCUT, to obtain segmentations using our probabilistic framework. Novel aspects of this method include: 1) efficient algorithms for sampling the object category models of our choice and 2) the observation that a sampling-based approximation of the expected log-likelihood of the model can be increased by a single graph cut. Results are presented on several articulated (e.g., animals) and nonarticulated (e.g., fruits) object categories. We provide a favorable comparison of our method with the state of the art in object category specific image segmentation, specifically the methods of Leibe and Schiele and Schoenemann and Cremers.


An Experimental Investigation into the Effect of State-Anxiety on State-Paranoia in People Experiencing Psychosis.
There is strong evidence to suggest that anxiety is associated with paranoia in clinical and non-clinical samples. However, no research to date has directly manipulated anxiety to investigate if state-anxiety has a causal role in state-paranoia in clinical populations. To investigate whether an anxious-mood induction leads to greater paranoia than a neutral-mood induction in people experiencing psychosis and paranoia and, if so, whether this is predicted by anxiety over and above other variables. 22 participants with a psychosis-spectrum diagnosis took part in a two condition cross-over experimental design. Participants underwent a neutral-mood and an anxious-mood induction with levels of state-anxiety, state-affect and state-paranoia being measured before and after each condition. State-paranoia was significantly higher after the anxious condition compared with the neutral condition. State-anxiety and negative-affect were significant predictors of levels of state-paranoia after the anxious condition. When both predictors were included in a regression model, only negative-affect was a significant predictor of state-paranoia after the anxious condition. There were a number of methodological limitations. State-anxiety and negative-affect may both be involved in the maintenance of paranoia in clinical populations, as predicted by cognitive models. Negative-affect may be the strongest predictor of state-paranoia in clinical populations. Reasons for this are discussed, as well as the implications. Interventions that seek to reduce negative state-affect may be beneficial in managing state-paranoia. Further research is warranted to explore the suggested clinical and theoretical implications of these findings.


ATG16L1 functions in cell homeostasis beyond autophagy.
Atg16-like (ATG16L) proteins were identified in higher eukaryotes for their resemblance to Atg16, a yeast protein previously characterized as a subunit of the Atg12-Atg5/Atg16 complex. In yeast, this complex catalyzes the lipidation of Atg8 on pre-autophagosomal structures and is therefore required for the formation of autophagosomes. In higher eukaryotes, ATG16L1 is also almost exclusively present as part of an ATG12-ATG5/ATG16L1 complex and has the same essential function in autophagy. However, ATG16L1 is three times bigger than Atg16. It displays, in particular, a carboxy-terminal extension, including a WD40 domain, which provides a platform for interaction with a variety of proteins, and allows for the recruitment of the ATG12-ATG5/ATG16L1 complex to membranes under different contexts. Furthermore, detailed analyses at the cellular level have revealed that some of the ATG16L1-driven activities are independent of the lipidation reaction catalyzed by the ATG12-ATG5/ATG16L1 complex. At the organ level, the use of mice that are hypomorphic for Atg16l1, or with cell-specific ablation of its expression, revealed a large panel of consequences of ATG16L1 dysfunctions. In this review, we recapitulate the current knowledge on ATG16L1 expression and functions. We emphasize, in particular, how it broadly acts as a brake on inflammation, thereby contributing to maintaining cell homeostasis. We also report on independent studies that converge to show that ATG16L1 is an important player in the regulation of intracellular traffic. Overall, autophagy-independent functions of ATG16L1 probably account for more of the phenotypes associated with ATG16L1 deficiencies than currently appreciated.


Dyspraxia in a patient with corticobasal degeneration: the role of visual and tactile inputs to action.
To investigate the roles of visual and tactile information in a dyspraxic patient with corticobasal degeneration (CBD) who showed dramatic facilitation in miming the use of a tool or object when he was given a tool to manipulate; and to study the nature of the praxic and neuropsychological deficits in CBD. The subject had clinically diagnosed CBD, and exhibited alien limb behaviour and striking ideomotor dyspraxia. General neuropsychological evaluation focused on constructional and visuospatial abilities, calculation, verbal fluency, episodic and semantic memory, plus spelling and writing because impairments in this domain were presenting complaints. Four experiments assessed the roles of visual and tactile information in the facilitation of motor performance by tools. Experiment 1 evaluated the patient's performance of six limb transitive actions under six conditions: (1) after he described the relevant tool from memory, (2) after he was shown a line drawing of the tool, (3) after he was shown a real exemplar of the tool, (4) after he watched the experimenter perform the action, (5) while he was holding the tool, and (6) immediately after he had performed the action with the tool but with the tool removed from his grasp. Experiment 2 evaluated the use of the same six tools when the patient had tactile but no visual information (while he was blindfolded). Experiments 3 and 4 assessed performance of actions appropriate to the same six tools when the patient had either neutral or inappropriate tactile feedback-that is, while he was holding a non-tool object or a different tool. Miming of tool use was not facilitated by visual input; moreover, lack of visual information in the blindfolded condition did not reduce performance. The principal positive finding was a dramatic facilitation of the patient's ability to demonstrate object use when he was holding either the appropriate tool or a neutral object. Tools inappropriate to the requested action produced involuntary performance of the stimulus relevant action. Tactile stimulation was paramount in the facilitation of motor performance in tool use by this patient with CBD. This outcome suggests that tactile information should be included in models which hypothesise modality specific inputs to the action production system. Significant impairments in spelling and letter production that have not previously been reported in CBD have also been documented.


Long-term clinical outcomes of biodegradable polymer biolimus-eluting stents versus durable polymer sirolimus-eluting stents in patients with coronary artery disease (LEADERS): 4 year follow-up of a randomised non-inferiority trial.
The effectiveness of durable polymer drug-eluting stents comes at the expense of delayed arterial healing and subsequent late adverse events such as stent thrombosis (ST). We report the 4 year follow-up of an assessment of biodegradable polymer-based drug-eluting stents, which aim to improve safety by avoiding the persistent inflammatory stimulus of durable polymers. We did a multicentre, assessor-masked, non-inferiority trial. Between Nov 27, 2006, and May 18, 2007, patients aged 18 years or older with coronary artery disease were randomly allocated with a computer-generated sequence to receive either biodegradable polymer biolimus-eluting stents (BES) or durable polymer sirolimus-eluting stents (SES; 1:1 ratio). The primary endpoint was a composite of cardiac death, myocardial infarction, or clinically-indicated target vessel revascularisation (TVR); patients were followed-up for 4 years. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00389220. 1707 patients with 2472 lesions were randomly allocated to receive either biodegradable polymer BES (857 patients, 1257 lesions) or durable polymer SES (850 patients, 1215 lesions). At 4 years, biodegradable polymer BES were non-inferior to durable polymer SES for the primary endpoint: 160 (18·7%) patients versus 192 (22·6%) patients (rate ratios [RR] 0·81, 95% CI 0·66-1·00, p for non-inferiority <0·0001, p for superiority=0·050). The RR of definite ST was 0·62 (0·35-1·08, p=0·09), which was largely attributable to a lower risk of very late definite ST between years 1 and 4 in the BES group than in the SES group (RR 0·20, 95% CI 0·06-0·67, p=0·004). Conversely, the RR of definite ST during the first year was 0·99 (0·51-1·95; p=0·98) and the test for interaction between RR of definite ST and time was positive (p(interaction)=0·017). We recorded an interaction with time for events associated with ST but not for other events. For primary endpoint events associated with ST, the RR was 0·86 (0·41-1·80) during the first year and 0·17 (0·04-0·78) during subsequent years (p(interaction)=0·049). Biodegradable polymer BES are non-inferior to durable polymer SES and, by reducing the risk of cardiac events associated with very late ST, might improve long-term clinical outcomes for up to 4 years compared with durable polymer SES. Biosensors Europe SA, Switzerland.


The prognostic value of hTERT expression levels in advanced-stage colorectal cancer patients: a comparison between tissue and serum expression.
Telomeres are regions of highly repetitive, non-coding DNA located at the termini of chromosomes whose principal function is to maintain the structural stability of these ends. In 90% of human tumours, telomere length is maintained by the expression and activation of telomerase reverse transcriptase. Various studies have demonstrated an increase in telomerase activity in tumour tissue, which suggests its possible prognostic value. The main objective of our study was to study the prognostic value of the expression level of telomerase catalytic component (hTERT) in patients with colorectal cancer (CRC). We analysed the prognostic value of the ratio of telomerase expression in tumour tissue to telomerase expression in the adjacent healthy mucosa and the prognostic value of the expression level of hTERT in the serum of patients diagnosed with CRC. As secondary objectives of the study, we (1) analysed the correlation between telomerase expression in the serum and that in the tumour tissue and (2) analysed the relationship between telomerase expression and different clinical parameters. Peripheral blood and tissue samples taken from 48 patients with CRC were analysed. No significant differences were observed in disease-free survival (DFS) or overall survival time (OST) between the groups of patients categorised based on the ratio of telomerase expression between tumour tissue and healthy tissue. The correlation index (Pearson's coefficient) between telomerase levels in the serum and those in tissue was 0.32. Our study of the relationship between telomerase levels in the serum and different clinical variables, such as tumour size, ganglion affectation, preoperative carcinoembryonic antigen levels and stage, revealed a higher telomerase expression level in patients with stage IV CRC. There was no significant association between telomerase expression in tumour tissue and the clinical parameters analysed. The results obtained in our study do not allow us to propose that the level of telomerase expression be used as a prognostic factor in colorectal cancer. Thus, we cannot consider telomerase expression in the serum as a surrogate marker of its expression in tumour tissue.


Less is more: A novel single-tablet regimen with two-drugs, dolutegravir/lamivudine.
Combined antiretroviral therapy (cART) has significantly reduced human immunodeficiency virus (HIV) associated morbidity and mortality and turned HIV infection into a manageable chronic condition. However, lifelong cART is still required. Two-drug regimens could reduce the number of HIV agents and lower the adverse events caused by lifelong medication. A new two-drug regimen, DEVATO, consisting of dolutegravir and lamivudine has durable efficacy, is well-tolerated, and has a high barrier to viral resistance, which is why it is recommended as a new first-line treatment option for people living with HIV infection.


Fistula treatment: The unresolved challenge.
In population-based studies, up to 50% of patients with Crohn's disease suffer from fistulas. Fistulas pose a considerable morbidity including permanent sphincter and perineal tissue destruction as well as professional and personal disabilities. Treatment options have progressed in recent years and fistula closure and fibrosis of the fistula track is achieved in some patients. Depending on severity of symptoms and fistula location, different medical and surgical therapies can be chosen. Internal fistulas such as ileoileal or ileocecal fistulas are either asymptomatic and do not require intervention or they are symptomatic and need surgery alone. They always carry a risk of abscess formation. Symptomatic perianal fistulizing disease can be treated with antibiotics (i.e. metronidazole and ciprofloxacin) for three months and/or immunosuppressant therapy (6-mercaptopurine or azathioprine). More complex cases require therapy with anti-TNF agents. Only few and preliminary data exist on cyclosporine A, tacrolimus or methotrexate in fistulizing Crohn's disease. Therefore, these therapies should mainly be used as second-line therapies. Surgery is reserved for the treatment of perianal sepsis in the presence of abscesses and refractory disease or complications of fistulas, or used in combination with pharmacological approaches. The surgical interventions in perianal disease consist of surgical drainage with or without seton placement, transient ileostomy, or in severe cases, proctectomy. The classification of fistulas in patients with Crohn's disease remains poorly defined and largely investigator dependent. The unresolved challenges in fistula treatment warrant randomized controlled trials for existing and future treatment strategies as well as a better classification system to compare available studies.


Minicircle Delivery to the Neural Retina as a Gene Therapy Approach.
Non-viral gene therapy has the potential to overcome several shortcomings in viral vector-based therapeutics. Methods of in vivo plasmid delivery have developed over recent years to increase the efficiency of non-viral gene transfer, yet further improvements still need to be made to improve their translational capacity. Gene therapy advances for inherited retinal disease have been particularly prominent over the recent decade but overcoming physical and physiological barriers present in the eye remains a key obstacle in the field of non-viral ocular drug delivery. Minicircles are circular double-stranded DNA vectors that contain expression cassettes devoid of bacterial DNA, thereby limiting the risks of innate immune responses induced by such elements. To date, they have not been extensively used in pre-clinical studies yet remain a viable vector option for the treatment of inherited retinal disease. Here, we explore the potential of minicircle DNA delivery to the neural retina as a gene therapy approach. We consider the advantages of minicircles as gene therapy vectors as well as review the challenges involved in optimising their delivery to the neural retina.


A Security Transmission and Storage Solution about Sensing Image for Blockchain in the Internet of Things.
With the rapid development of the Internet of Things (IoT), the number of IoT devices has increased exponentially. Therefore, we have put forward higher security requirements for the management, transmission, and storage of massive IoT data. However, during the transmission process of IoT data, security issues, such as data theft and forgery, are prone to occur. In addition, most existing data storage solutions are centralized, i.e., data are stored and maintained by a centralized server. Once the server is maliciously attacked, the security of IoT data will be greatly threatened. In view of the above-mentioned security issues, a security transmission and storage solution is proposed about sensing image for blockchain in the IoT. Firstly, this solution intelligently senses user image information, and divides these sensed data into intelligent blocks. Secondly, different blocks of data are encrypted and transmitted securely through intelligent encryption algorithms. Finally, signature verification and storage are performed through an intelligent verification algorithm. Compared with the traditional IoT data transmission and centralized storage solution, our solution combines the IoT with the blockchain, making use of the advantages of blockchain decentralization, high reliability, and low cost to transfer and store users image information securely. Security analysis proves that the solution can resist theft attacks and ensure the security of user image information during transmission and storage.


The basic helix-loop-helix proteins differentiated embryo chondrocyte (DEC) 1 and DEC2 function as corepressors of retinoid X receptors.
The basic helix-loop-helix proteins differentiated embryo chondrocyte 1 (DEC1) and DEC2 are involved in circadian rhythm control. Because the metabolism of dietary nutrients has been linked to circadian regulation, we examined the effect of DEC1 and DEC2 on the function of the metabolite-sensing nuclear receptors, ligand-dependent transcription factors, including retinoid X receptor (RXR) and liver X receptor (LXR). Transfection assays showed that DEC1 and DEC2 repressed ligand-dependent transactivation by RXR. Knockdown of endogenous DEC1 and DEC2 expression with small interfering RNAs augmented ligand-dependent RXRalpha transactivation. DEC1 and DEC2 interacted directly with RXRalpha, and ligand addition enhanced their association. DEC1 and DEC2 modified interaction of RXRalpha with cofactor proteins. Transfection assays using DEC1 and DEC2 mutants revealed that the C-terminal region of DEC2 is required for repression and that an LXXLL motif in DEC1 and DEC2 is necessary for RXRalpha repression. DEC1 and DEC2 repressed the induction of LXR target genes, associated with the promoter of an LXR target gene, and dissociated from the promoter with ligand treatment. Knockdown of endogenous DEC1 and DEC2 enhanced the LXR target gene expression in hepatocytes. Expression of Dec1, Dec2, and Srebp-1c showed a circadian rhythm in the liver of mice, whereas that of Lxralpha, Lxrbeta, and Rxralpha was not rhythmic. DEC1 and DEC2 also repressed the transactivation of other RXR heterodimers, such as farnesoid X receptor, vitamin D receptor, and retinoic acid receptor. Thus, the repressor function of DEC1 and DEC2 may be extended to other RXR heterodimer nuclear receptors.


Arterial distensibility and physical activity in the ARIC study.
Arterial distensibility decreases with age. This decrease may be associated with the initiation and/or progression of hypertension and atherosclerosis and may be attenuated by positive lifestyle habits, including habitual physical activity. We tested the hypothesis that self-reported sport, leisure, and work physical activity is associated with greater arterial distensibility (i.e., carotid artery pulsatile diameter changes). The Atherosclerosis Risk in Communities (ARIC) study assessed left common carotid arterial diameters and intimal-medial wall thickness (IMT) using B-mode ultrasound techniques, in 10,644 African-American and white men and women aged 45-64 yr and free of cardiovascular disease. Work activity, but not sports or leisure activity, was weakly associated with greater arterial distensibility in an ANCOVA model adjusted for blood pressure and other covariates (diastolic arterial diameter, pulse pressure, pulse pressure squared, age, race, sex, smoking, dietary fat intake, height, education, and clinical center) (P for linear trend = 0.03). Vigorous sports activity was weakly positively associated with arterial distensibility (arterial diameter change (mean +/- SE in mm) 0.42 +/- 0.004 vs 0.41 +/- 0.002 for the 12.7% of participants reporting any vs no vigorous activity, P = 0.02), and this association was not attenuated by adjustment for IMT, body mass index, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, or diabetes. Repeated analyses with traditional arterial stiffness indices showed similar findings for vigorous but not work activity. In contrast to several smaller studies, these findings do not support the hypothesis that habitual physical activity has a strong, consistent positive effect on arterial distensibility.