Multiple kisspeptin receptors in early osteichthyans provide new insights into the evolution of this receptor family.
Deorphanization of GPR54 receptor a decade ago led to the characterization of the kisspeptin receptor (Kissr) in mammals and the discovery of its major role in the brain control of reproduction. While a single gene encodes for Kissr in eutherian mammals including human, other vertebrates present a variable number of Kissr genes, from none in birds, one or two in teleosts, to three in an amphibian, xenopus. In order to get more insight into the evolution of Kissr gene family, we investigated the presence of Kissr in osteichthyans of key-phylogenetical positions: the coelacanth, a representative of early sarcopterygians, the spotted gar, a non-teleost actinopterygian, and the European eel, a member of an early group of teleosts (elopomorphs). We report the occurrence of three Kissr for the first time in a teleost, the eel. As measured by quantitative RT-PCR, the three eel Kissr were differentially expressed in the brain-pituitary-gonadal axis, and differentially regulated in experimentally matured eels, as compared to prepubertal controls. Subfunctionalisation, as shown by these differences in tissue distribution and regulation, may have represented significant evolutionary constraints for the conservation of multiple Kissr paralogs in this species. Furthermore, we identified four Kissr in both coelacanth and spotted gar genomes, providing the first evidence for the presence of four Kissr in vertebrates. Phylogenetic and syntenic analyses supported the existence of four Kissr paralogs in osteichthyans and allowed to propose a clarified nomenclature of Kissr (Kissr-1 to -4) based on these paralogs. Syntenic analysis suggested that the four Kissr paralogs arose through the two rounds of whole genome duplication (1R and 2R) in early vertebrates, followed by multiple gene loss events in the actinopterygian and sarcopterygian lineages. Due to gene loss there was no impact of the teleost-specific whole genome duplication (3R) on the number of Kissr paralogs in current teleosts.


[Basic studies on optimal intra-arterial infusion rate of cisplatin].
The relationship between platinum concentration in tissues, free CDDP concentration in plasma and infusion rate was investigated in order to determine the optimal intra-arterial infusion rate of CDDP for chemotherapy of cervical carcinoma. Platinum concentrations in uterus were in the same level in the intravenous infusion groups independent of the infusion rate. In the intra-arterial infusion groups, platinum concentrations in the uterus increased as the infusion rate decreased from 24 to 0.8 mg/hr, although Cmax and AUC were decreased. Platinum concentrations in the ovary supplied by another artery were not influenced by the intra-arterial infusion rate. It is suggested that uptake of CDDP in the targeted tissues can be increased by control of intra-arterial infusion rate.


A combined LX-NMR and molecular dynamics investigation of the bulk and local structure of ionic liquid crystals.
The unique power of NMR spectroscopy in anisotropic media (LX-NMR) as a tool to obtain local and bulk structural information, combined with the effectiveness of molecular dynamics simulations at the atomistic level, shows very attractive potentialities for the study of interesting, even though still poorly understood, materials such as Ionic Liquid Crystals (ILCs). In this work, we focused our attention, in particular, on the orientational ordering of two mesophases: 1-dodecyl-3-methylimidazolium chloride, [C12C1im]Cl, and 1-dodecyl-3-methylimidazolium tetrafluoroborate, [C12C1im][BF4]. Both ILCs were studied by a 2H NMR direct investigation of the molecules forming the phases, suitably deuterated, and by 1H NMR spectroscopy, using the small rigid probe-solutes 1,4-dichlorobenzene (DCB), dissolved in [C12C1im][BF4] and [C12C1im]Cl, and 1,4-dibromobenzene (DBB) dissolved in [C12C1im][BF4], to probe the local, internal structure and organization of the mesophases. The experimental results were then compared with the predictions, by atomistic MD simulations, of the structure of the smectic phase of the two salts, at two selected temperatures, containing a single DCB molecule as a probe. The MD simulations show that the DCB solute is distributed only within the hydrophobic layers of the ILC. Orientational order parameters of the imidazolium cations and of the DCB molecule were obtained and compared with the experiments, showing a general good agreement and allowing a deeper understanding of the microscopic structure of the systems.


Completion duplex ultrasound predicts early graft thrombosis after crural bypass in patients with critical limb ischemia.
To determine if intraoperative distal graft end-diastolic velocity (EDV) using completion duplex ultrasound (CDU) predicts patency of crural bypass in patients with critical limb ischemia (CLI). Records of 116 non-consecutive patients who underwent crural revascularization with vein conduit and CDU between 1998 and 2008 were reviewed. Bypass grafts were performed for rest pain (34%) or tissue loss (66%), while 56% of the reported cases were categorized as "disadvantaged" because of compromised vein quality or diseased arterial outflow. A 10-MHz low-profile transducer was used to image the entire bypass at case completion. Technical adequacy of the grafts was verified by absence of retained valves, arteriovenous fistulas, or localized velocity increases and presence of bypass-dependent distal pulses. Modified Rutherford scores were calculated as surrogate markers of runoff resistance and compared to distal graft EDV. The primary study end point was graft patency during a 1-year posttreatment period. Patency rates were determined using Kaplan-Meier life table methodology and compared using the log-rank test. Predictors of graft patency were determined by Cox proportional hazards. Primary, primary-assisted, and secondary patency for all crural bypasses were 62%, 66%, and 70% at 1 year, respectively. When stratified by tertiles of distal graft EDV (0 - <5 cm/s, 5-15 cm/s, >15 cm/s), 1-year primary patency rates were 32%, 64%, and 84% (P = .001). Low (0 - < 5 cm/s) distal graft EDV (hazard ratio [HR], 3.3 confidence interval [CI], 1.74-6.41; P < .001), poor-quality conduit (HR, 2.5; CI, 1.19-5.21; P = .016), age <70 (HR, 2.08; CI, 1.06-4.00; P = .031), and lack of statin use (HR, 2.04; CI, 1.04-4.00; P = .038) were independent predictors of graft failure. While the modified Rutherford score correlated with distal graft EDV (P = .05), it was not an independent predictor of patency (P = .58). Predictors of low EDV (<5 cm/s) included single-vessel runoff (odds ratio [OR], 3.33; CI, 1.14-9.71; P = .027), poor conduit (OR, 2.94; CI, 1.16-7.41; P = 0.024), and diabetes (OR, 2.86; CI, 1.14-7.21; P = .025). Distal graft EDV predicts crural vein graft patency in patients with CLI. Grafts with EDV <5 cm/s remain at high risk for early failure. The impacts on patency of statins, age, and poor-quality conduit are, again, confirmed. These results highlight the value of EDV using intraoperative CDU for anticipating and, possibly, improving results of open crural revascularization.


Ruptured anterior cerebral artery aneurysm at the origin of the accessory middle cerebral artery.
A 36-year-old female patient was admitted to our hospital with a rare case of aneurysm at the origin of the accessory middle cerebral artery (MCA) manifesting as severe headache and vomiting. Neurological examination did not detect any abnormalities or consciousness disturbance. Computed tomography demonstrated diffuse subarachnoid hemorrhage. Magnetic resonance angiography showed an aneurysm in the horizontal portion of the left anterior cerebral artery (A(1)). Digital subtraction angiography and three-dimensional digital subtraction angiography demonstrated a saccular aneurysm originating at the junction of the left A(1) and accessory MCA. Another accessory MCA originated at the proximal portion of the left A(2) without an aneurysm. Two accessory MCAs were found on the left. Neck clipping was performed via a left pterional approach. One month after admission, she was discharged without neurological deficits.


Using genetic variation and environmental risk factor data to identify individuals at high risk for age-related macular degeneration.
A major goal of personalized medicine is to pre-symptomatically identify individuals at high risk for disease using knowledge of each individual's particular genetic profile and constellation of environmental risk factors. With the identification of several well-replicated risk factors for age-related macular degeneration (AMD), the leading cause of legal blindness in older adults, this previously unreachable goal is beginning to seem less elusive. However, recently developed algorithms have either been much less accurate than expected, given the strong effects of the identified risk factors, or have not been applied to independent datasets, leaving unknown how well they would perform in the population at large. We sought to increase accuracy by using novel modeling strategies, including multifactor dimensionality reduction (MDR) and grammatical evolution of neural networks (GENN), in addition to the traditional logistic regression approach. Furthermore, we rigorously designed and tested our models in three distinct datasets: a Vanderbilt-Miami (VM) clinic-based case-control dataset, a VM family dataset, and the population-based Age-related Maculopathy Ancillary (ARMA) Study cohort. Using a consensus approach to combine the results from logistic regression and GENN models, our algorithm was successful in differentiating between high- and low-risk groups (sensitivity 77.0%, specificity 74.1%). In the ARMA cohort, the positive and negative predictive values were 63.3% and 70.7%, respectively. We expect that future efforts to refine this algorithm by increasing the sample size available for model building, including novel susceptibility factors as they are discovered, and by calibrating the model for diverse populations will improve accuracy.


When do objects become landmarks? A VR study of the effect of task relevance on spatial memory.
We investigated how objects come to serve as landmarks in spatial memory, and more specifically how they form part of an allocentric cognitive map. Participants performing a virtual driving task incidentally learned the layout of a virtual town and locations of objects in that town. They were subsequently tested on their spatial and recognition memory for the objects. To assess whether the objects were encoded allocentrically we examined pointing consistency across tested viewpoints. In three experiments, we found that spatial memory for objects at navigationally relevant locations was more consistent across tested viewpoints, particularly when participants had more limited experience of the environment. When participants' attention was focused on the appearance of objects, the navigational relevance effect was eliminated, whereas when their attention was focused on objects' locations, this effect was enhanced, supporting the hypothesis that when objects are processed in the service of navigation, rather than merely being viewed as objects, they engage qualitatively distinct attentional systems and are incorporated into an allocentric spatial representation. The results are consistent with evidence from the neuroimaging literature that when objects are relevant to navigation, they not only engage the ventral "object processing stream", but also the dorsal stream and medial temporal lobe memory system classically associated with allocentric spatial memory.


Precision care for Barrett's esophagus.
Modern recognition and management of Barrett's esophagus, a precursor to esophageal adenocarcinoma depends on diagnostic accuracy, risk assessment, technical expertise and consideration of many options to best tailor therapy for every patient. Concomitant management of acid reflux is essential, frequently with proton pump inhibitors. Ablation and resection favorably affect the evolution towards cancer. Using precision medicine tools, such as imaging, molecular diagnostics and analytics may lead to cost- and comparatively-effective therapies ultimately aiming at cancer prevention. Knowledge of the risk factors for Barrett's esophagus and progression to dysplasia and cancer can help tailor a precision medicine approach with more aggressive screening and surveillance targeted at patients that are most likely to benefit.


MicroRNA-215: From biology to theranostic applications.
MicroRNA-215 (miR-215) is one of the extensively studied microRNAs (miRNAs) in human diseases, especially in different types of cancer, where it plays various roles in the initiation and progression of tumors. There is also a high conservation of miR-215 among wide range of different species indicating that this miRNA may have vital functions that are maintained during evolution. During the last ten years, significant efforts were dedicated to uncover molecular mechanisms of miR-215 regulation and cellular functioning. In addition, miR-215 was repeatedly identified to have the causal roles in pathology of various diseases, where it may serve as a promising diagnostic, prognostic or predictive biomarker and as a therapeutic target. Here, we overview more than 150 reports focused on miR-215 to allow the synthesis of knowledge on its transcriptional and post-transcriptional regulation, and functioning in essential biological processes like cell and tissue development, cell survival, cell cycle and proliferation, cell migration and invasion, cellular microenvironment communication, and metabolism. Further, we summarized the findings on miR-215 roles in pathology of nonmalignant diseases and various types of cancer with special focus on miR-215 as a promising molecule for future development of theranostic miRNA-based approaches. Although it is difficult to evaluate the full theranostic potential of miR-215, it is probable that during the following years, an increasing number of theranostic miRNA modalities that overcome the current technological obstacles will appear, and enable the translation of miR-215 knowledge into the clinic.


Longitudinal association of neighborhood variables with Body Mass Index in Dutch school-age children: The KOALA Birth Cohort Study.
Changes in the neighborhood environment may explain part of the rapid increase in childhood overweight and obesity during the last decades. To date few theory-driven rather than data-driven studies have explored longitudinal associations between multiple neighborhood characteristics and child body weight development. We aimed to assess the relationship between physical, social and perceived safety related characteristics of the neighborhood and Body Mass Index (BMI) development in children during early school age, using a longitudinal design. We included an examination of moderating and confounding factors based on a conceptual model adapted from the EnRG framework (Environmental Research framework for weight Gain prevention) and empirical research. Analyses included 1887 children from the KOALA Birth Cohort Study followed from baseline age 4-5 years until 8-9 years. For children age 4-5 years, parents completed a questionnaire measuring characteristics of the neighborhood. Reliability and factor analyses were used to identify constructs for neighborhood characteristics. Linear regression analysis was performed to assess the relationship between neighborhood constructs and BMI z-scores cross-sectionally at age 4-5 years and longitudinally using Generalized Estimating Equations with BMI z-scores over 5 repeated measurements until age 8-9 years. Fourteen constructs were identified and grouped in three domains including perceived physical, social, or safety related characteristics of the neighborhood. Cross-sectionally, a lower BMI z-score was associated with higher perceived physical attractiveness of the neighborhood environment (standardized regression coefficient (β) -0.078, 95% CI -0.123 to -0.034) and a higher level of social capital (β -0.142, -0.264 to -0.019). Longitudinally, similar associations were observed with potentially even stronger regression coefficients. This study suggests that BMI in children is mainly related to the modifiable physical and social environment of the conceptual model and not related to safety as perceived by parents.


Diet and lung cancer mortality: a 1987 National Health Interview Survey cohort study.
To study the association between diet and lung cancer mortality in the United States. Records from 20,195 participants with usable dietary data in the 1987 National Health Interview Survey were linked to the National Death Index. Baseline diet was assessed with a 59-item food-frequency questionnaire. Food groups (fruits, vegetables, total meat/poultry/fish, red meats, processed meats, dairy products, breakfast cereals, other starches, added fats, and alcohol) were analyzed in cause-specific Cox proportional hazard regression models adjusted for age, gender and smoking. There were 158 deaths from lung cancer (median follow-up 8.5 years). Frequencies of meat/poultry/fish intake (relative risk [RR] (highest compared to lowest quartile) = 2.0; 95% confidence interval [CI] 1.2-3.5, p for trend [p] < 0.027), and red meat intake (RR = 1.6; CI 1.0-2.6, p < 0.014), were positively and significantly associated with lung cancer mortality. Specifically, the red meats, including pork (RR = 1.6; CI 1.0-2.7, p < 0.028), and ground beef (RR = 2.0; CI 1.1-3.5, p < 0.096) were associated with increased risk, although for ground beef the trend was not significant. Dairy products (RR = 0.5; CI 0.3-0.8, p < 0.009) were inversely associated with lung cancer mortality. There was no statistically significant association between intake of fruits and vegetables and lung cancer mortality. In this nationally representative study, intake of red meats was positively associated with lung cancer mortality while intake of dairy products was inversely associated. While smoking is the major risk for lung cancer mortality, diet may have a contributory role.


Overexpression of pre-pro-cholecystokinin stimulates beta-cell proliferation in mouse and human islets with retention of islet function.
Type 1 and type 2 diabetes result from a deficit in insulin production and beta-cell mass. Methods to expand beta-cell mass are under intensive investigation for the treatment of type 1 and type 2 diabetes. We tested the hypothesis that cholecystokinin (CCK) can promote beta-cell proliferation. We treated isolated mouse and human islets with an adenovirus containing the CCK cDNA (AdCMV-CCK). We measured [(3)H]thymidine and BrdU incorporation into DNA and additionally, performed flow cytometry analysis to determine whether CCK overexpression stimulates beta-cell proliferation. We studied islet function by measuring glucose-stimulated insulin secretion and investigated the cell cycle regulation of proliferating beta-cells by quantitative RT-PCR and Western blot analysis. Overexpression of CCK stimulated [(3)H]thymidine incorporation into DNA 5.0-fold and 15.8-fold in mouse and human islets, respectively. AdCMV-CCK treatment also stimulated BrdU incorporation into DNA 10-fold and 21-fold in mouse and human beta-cells, respectively. Glucose-stimulated insulin secretion was unaffected by CCK expression. Analysis of cyclin and cdk mRNA and protein abundance revealed that CCK overexpression increased cyclin A, cyclin B, cyclin E, cdk1, and cdk2 with no change in cyclin D1, cyclin D2, cyclin D3, cdk4, or cdk6 in mouse and human islets. Additionally, AdCMV-CCK treatment of CCK receptor knockout and wild-type mice resulted in equal [(3)H]thymidine incorporation. CCK is a beta-cell proliferative factor that is effective in both mouse and human islets. CCK triggers beta-cell proliferation without disrupting islet function, up-regulates a distinct set of cell cycle regulators in islets, and signals independently of the CCK receptors.


Practice location choice by new physicians: the importance of malpractice premiums, damage caps, and health professional shortage area designation.
To understand the factors affecting the choice of initial practice location by new physicians. A unique survey of exiting medical residents in New York State from 1998 to 2003. We estimate conditional logit models to examine the factors affecting the choice of initial practice location by new physicians. We identify all physicians completing their training in obstetrics/gynecology or surgery and primary care physicians (PCPs) (general internal medicine, pediatrics, and family medicine) who had accepted a job in patient care and who provided the location (zip code) of their job. This resulted in 3,758 physicians in our sample. Our results indicate that malpractice insurance premiums are a significant deterrent for surgeons, but they do not appear to deter OB/GYNs or PCPs from locating in particular areas. In addition, caps on malpractice damage awards attract surgeons to areas. Shortage area designations attract PCPs without education debt yet deter PCPs with debt, suggesting that subsidies do not outweigh the perceived costs of locating in underserved areas. In general our results highlight that new physicians are sensitive to the characteristics of the locations in which they could potentially locate when beginning their careers in patient care.


Comparative outcomes of leukotriene receptor antagonists and long-acting β-agonists as add-on therapy in asthmatic patients: a population-based study.
Recent evidence suggests that the use of leukotriene receptor antagonists (LTRAs) in addition to inhaled corticosteroids (ICSs) in asthmatic patients provides comparable benefits to the addition of long-acting β-agonists (LABAs) to ICSs. We sought to compare, in a unified framework, adherence, outcomes, and costs associated with ICS+LTRA versus ICS+LABA as step-up therapies for asthma. Using the administrative databases of British Columbia, Canada (years 1997-2007), we created a propensity score-matched sample of asthmatic patients (12-45 years old) receiving ICS+LTRA therapy versus ICS+LABA therapy after a period of monotherapy with an ICS. We compared the outcomes using 2 analyses: an intention-to-treat (ITT) analysis that followed subjects for a fixed period of 2 years and an uninterrupted treatment analysis that followed subjects for as long as they continuously dispensed their index medications. The matched cohort consisted of 1032 subjects in each group (mean age at entry, 27.4 years; 52.5% female). Adherence, which was defined as the proportion of days covered, was higher in the ICS+LABA group compared with the ICS+LTRA group. In both the ITT and uninterrupted treatment analyses, use of ICS+LTRA therapy was associated with more asthma-related outpatient visits, asthma-related medication dispensations, and dispensation of reliever medications. Dispensation of oral corticosteroids and rate of asthma exacerbations were higher in the ICS+LTRA group in the uninterrupted treatment analysis but not in the ITT analysis. In a real-world clinical setting subjects were more adherent to ICS+LABA therapy than ICS+LTRA therapy. ICS+LABA therapy seems to be more effective than ICS+LTRA therapy in the management of asthma, regardless of adherence.


Zebrafish as a model for apolipoprotein biology: comprehensive expression analysis and a role for ApoA-IV in regulating food intake.
Improved understanding of lipoproteins, particles that transport lipids throughout the circulation, is vital to developing new treatments for the dyslipidemias associated with metabolic syndrome. Apolipoproteins are a key component of lipoproteins. Apolipoproteins are proteins that structure lipoproteins and regulate lipid metabolism through control of cellular lipid exchange. Constraints of cell culture and mouse models mean that there is a need for a complementary model that can replicate the complex in vivo milieu that regulates apolipoprotein and lipoprotein biology. Here, we further establish the utility of the genetically tractable and optically clear larval zebrafish as a model of apolipoprotein biology. Gene ancestry analyses were implemented to determine the closest human orthologs of the zebrafish apolipoprotein A-I (apoA-I), apoB, apoE and apoA-IV genes and therefore ensure that they have been correctly named. Their expression patterns throughout development were also analyzed, by whole-mount mRNA in situ hybridization (ISH). The ISH results emphasized the importance of apolipoproteins in transporting yolk and dietary lipids: mRNA expression of all apolipoproteins was observed in the yolk syncytial layer, and intestinal and liver expression was observed from 4-6 days post-fertilization (dpf). Furthermore, real-time PCR confirmed that transcription of three of the four zebrafish apoA-IV genes was increased 4 hours after the onset of a 1-hour high-fat feed. Therefore, we tested the hypothesis that zebrafish ApoA-IV performs a conserved role to that in rat in the regulation of food intake by transiently overexpressing ApoA-IVb.1 in transgenic larvae and quantifying ingestion of co-fed fluorescently labeled fatty acid during a high-fat meal as an indicator of food intake. Indeed, ApoA-IVb.1 overexpression decreased food intake by approximately one-third. This study comprehensively describes the expression and function of eleven zebrafish apolipoproteins and serves as a springboard for future investigations to elucidate their roles in development and disease in the larval zebrafish model.


Fibrosing alveolitis in systemic sclerosis: increase in memory T-cells in lung interstitium.
Despite the large numbers of T-cells present in the lungs in fibrosing alveolitis, their pathogenetic role is poorly understood. If these cells are involved in pathogenesis, they are more likely to express the CD45RO+ memory phenotype. To test this hypothesis, open lung biopsies from patients with fibrosing alveolitis associated with systemic sclerosis (FASSc) were compared with grossly normal lung taken from the periphery of lobes resected for lung cancer. Biopsies from eight patients with FASSc were compared with tissue from seven cancer controls. Paraffin sections were stained with a polyclonal anti-CD3 antibody for T-lymphocytes, monoclonal anti-CD45 antibody for leucocyte common antigen, and monoclonal anti-CD45RO antibody for primed T-lymphocytes. Staining was assessed quantitatively by computerized image analysis: in each case, the number of immunopositive cells was related to alveolar wall area and alveolar wall length. Mean alveolar wall thickness was increased in patients with FASSc (60.7 +/- 24.0 microns) compared with cancer controls (15.7 +/- 5.3 microns). Patients with FASSc had greater numbers of CD45+, CD3+ and CD45RO+ cells.mm-1 alveolar wall length compared with the controls. CD45RO+ cells made up 77% (median) of the CD3+ cells in FASSc, and their numbers per unit alveolar wall length were positively associated with alveolar wall thickness (r = 0.61). In conclusion, in fibrosing alveolitis of systemic sclerosis, most interstitial T-lymphocytes express the phenotype of memory cells; these cells are likely to be involved in the persistent inflammatory process.


Disruption of Transitions in High-Risk Substance Use from Adolescence to Young Adulthood: School, Employment, and Romantic Relationship Factors.
Background: Few studies have examined social-contextual moderators of substance use transitions from adolescence to young adulthood. A better understanding of the extent to which school, employment, and romantic relationships can disrupt high-risk use patterns could inform strategies for substance use prevention and treatment.Objective: The current study examines the extent school, employment, and relationship factors can disrupt transition in high-risk substance use patterns from adolescence to young adulthood.Method: Data were collected biennially from 662 youth in six assessments across ten years (2003-2013). Using latent transition analysis (LTA) that examined transition is substance use classes, we examined school, employment, and relationship moderators of use transitions.Results: Few differences were found during adolescence with the most significant findings occurring in the transition from adolescence to young adulthood. Examining the transitions from adolescence to young adulthood (W4 to W6), we found evidence that school, employment, and relationship status disrupted problematic substance use patterns, such that, individuals that indicated entering school, working full-time, or getting married or entering a relationship were more likely to transition to a low-risk substance use class than remain in the high-risk class.Conclusions/Importance: Findings underscore the importance of school completion, obtaining stable career employment, and quality relationship to help reduce high-risk substance use patterns leading into young adulthood. Prevention and intervention efforts should consider the diverse needs of youth and be prepared to provide a wide range of services that include educational opportunities and career development if they want to reduce high-risk substance use patterns.


Multiplex assay reliability and long-term intra-individual variation of serologic inflammatory biomarkers.
Circulating cytokines, chemokines, and soluble cytokine receptors can serve as biomarkers of inflammation and immune dysregulation. Good reliability of multiplex platforms, which allow for simultaneous, comprehensive biomarker assessment, is critical for their utility in epidemiologic studies. We examined the reliability of the Meso-Scale Discovery (MSD) platform to simultaneously quantitate 15 cytokines and chemokines and the Luminex platform (R&D Systems) to quantitate 5 soluble receptors and 2 chemokines and cytokines and evaluated long-term within-person correlation of these biomarkers. The detectability and reliability of these assay systems were assessed using the same external controls across plates and archived sera from 250 HIV- men in the Multicenter AIDS Cohort Study. Using up to four visits per person from 1984 to 2009, age-adjusted intraclass correlation coefficients (ICC) of biomarkers with >80% detectability (CCL11, CXCL8, CXCL10, CCL2, CCL4, CCL13, CCL17, CXCL13, IL-10, IL-12p70, IL-6, TNF-α, BAFF, sCD14, sCD27, sgp130, sIL-2Rα, and sTNF-R2) were obtained using linear mixed models. Most biomarkers were detectable in 80% of control samples; IFN-γ, GM-CSF, and IL-2 were undetectable in >20% of samples. Among the HIV-uninfected men, most biomarkers showed fair to strong within-person correlation (ICC>0.40) up to 15years. The ICC for CXCL8 was good in the short term but decreased with increasing time between visits, becoming lower (ICC<0.40) after 8years. These multiplexed assays showed acceptable reliability for use in epidemiologic research, despite some technical variability and limitations in cytokine quantitation. Most biomarkers displayed moderate-to-excellent intra-individual variability over the long term, suggesting their utility in prospective studies investigating etiologic associations with diverse chronic conditions.


Indications and Outcomes for Temporary Mechanical Circulatory Support in Pediatric Patients with Cardiac Failure.
Temporary continuous-flow ventricular assist devices (cfVAD) and extracorporeal membrane oxygenation (ECMO) are options for temporary mechanical circulatory support in pediatric patients. Despite the increase in temporary cfVAD use, the literature describing its use in pediatrics is limited. This was a single-center retrospective review of temporary cfVAD and a cohort of similar ECMO patients between January 1, 2011, and June 30, 2016, in patients <19 years of age. Thirteen patients underwent temporary cfVAD placement and 11 patients underwent ECMO cannulation for similar indications during the study period. Precannulation data were not statistically different, except for higher lactate and lower pH in the ECMO cohort. Median length of cfVAD support was 20 days (range 6-227), compared with 9 days (range 1-15) on ECMO. Primary outcome for cfVAD patients was one decannulated with recovery, six transplanted, and six died, compared with ECMO patients with five decannulated with recovery, three transplanted after conversion to durable VAD, and three died. No patients were transplanted directly from ECMO. This review provides new evidence that temporary cfVAD use can be used to support pediatric patients more than longer periods of time compared with ECMO, with transition to durable VAD and transplant.


WONKA: objective novel complex analysis for ensembles of protein-ligand structures.
WONKA is a tool for the systematic analysis of an ensemble of protein-ligand structures. It makes the identification of conserved and unusual features within such an ensemble straightforward. WONKA uses an intuitive workflow to process structural co-ordinates. Ligand and protein features are summarised and then presented within an interactive web application. WONKA's power in consolidating and summarising large amounts of data is described through the analysis of three bromodomain datasets. Furthermore, and in contrast to many current methods, WONKA relates analysis to individual ligands, from which we find unusual and erroneous binding modes. Finally the use of WONKA as an annotation tool to share observations about structures is demonstrated. WONKA is freely available to download and install locally or can be used online at http://wonka.sgc.ox.ac.uk.


PDE5 inhibitors enhance celecoxib killing in multiple tumor types.
The present studies determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with a clinically relevant NSAID, celecoxib, to kill tumor cells. Celecoxib and PDE5 inhibitors interacted in a greater than additive fashion to kill multiple tumor cell types. Celecoxib and sildenafil killed ex vivo primary human glioma cells as well as their associated activated microglia. Knock down of PDE5 recapitulated the effects of PDE5 inhibitor treatment; the nitric oxide synthase inhibitor L-NAME suppressed drug combination toxicity. The effects of celecoxib were COX2 independent. Over-expression of c-FLIP-s or knock down of CD95/FADD significantly reduced killing by the drug combination. CD95 activation was dependent on nitric oxide and ceramide signaling. CD95 signaling activated the JNK pathway and inhibition of JNK suppressed cell killing. The drug combination inactivated mTOR and increased the levels of autophagy and knock down of Beclin1 or ATG5 strongly suppressed killing by the drug combination. The drug combination caused an ER stress response; knock down of IRE1α/XBP1 enhanced killing whereas knock down of eIF2α/ATF4/CHOP suppressed killing. Sildenafil and celecoxib treatment suppressed the growth of mammary tumors in vivo. Collectively our data demonstrate that clinically achievable concentrations of celecoxib and sildenafil have the potential to be a new therapeutic approach for cancer.


Outcome of liver transplantation in septuagenarians: a single-center experience.
We hypothesized that selected septuagenarians may do as well after transplantation as those of a younger group of older recipients. This work compares post-liver transplant survival in septuagenarians with that of patients aged 50 to 59 years. Review of a prospectively maintained database. University transplant center. First-time liver transplant recipients treated from January 1, 1988, to December 31, 2005. Group 1 consisted of liver transplant recipients aged 70 years or older at the time of transplant. Group 2 was a younger cohort of patients aged 50 to 59 years. Liver transplantation. Patient survival. Survival data were stratified, Kaplan-Meier survival was calculated, and a multivariate analysis was performed. Group 1 included 62 patients aged 70 years or older (average, 71.9 +/- 2.1 years). Group 2 included 864 patients aged 50 to 59 years (average, 54.3 +/- 2.9 years). Unadjusted patient survival of group 1 at 1, 3, 5, and 10 years was 73.3%, 65.8%, 47.1%, and 39.7%, respectively. Unadjusted patient survival of group 2 at 1, 3, 5, and 10 years was 79.4%, 71.5%, 65.3%, and 45.2%, respectively. The difference was not statistically significant (P = .14). Multivariate analysis for factors affecting survival demonstrated preoperative hospitalization, cold ischemia time, and hepatitis C/ethanol as risk factors for death. Age 70 years or more was not a strong risk factor (mortality ratio, 1.28; P = .27). When other risk factors for mortality are controlled in older recipients, risk of death due to age is reduced in well-selected recipients. Age by itself should not be used to limit liver transplantation.


Oxygen for breathlessness in patients with chronic obstructive pulmonary disease who do not qualify for home oxygen therapy.
Breathlessness is a cardinal symptom of chronic obstructive pulmonary disease (COPD). Long-term oxygen therapy (LTOT) is given to improve survival time in people with COPD and severe chronic hypoxaemia at rest. The efficacy of oxygen therapy for breathlessness and health-related quality of life (HRQOL) in people with COPD and mild or no hypoxaemia who do not meet the criteria for LTOT has not been established. To determine the efficacy of oxygen versus air in mildly hypoxaemic or non-hypoxaemic patients with COPD in terms of (1) breathlessness; (2) HRQOL; (3) patient preference whether to continue therapy; and (4) oxygen-related adverse events. We searched the Cochrane Airways Group Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase, to 12 July 2016, for randomised controlled trials (RCTs). We handsearched the reference lists of included articles. We included RCTs of the effects of non-invasive oxygen versus air on breathlessness, HRQOL or patient preference to continue therapy among people with COPD and mild or no hypoxaemia (partial pressure of oxygen (PaO2) > 7.3 kPa) who were not already receiving LTOT. Two review authors independently assessed articles for inclusion in the review. Two review authors independently collected and analysed data. We assessed risk of bias by using the Cochrane 'Risk of bias tool'. We pooled effects recorded on different scales as standardised mean differences (SMDs) with 95% confidence intervals (CIs) using random-effects models. Lower SMDs indicated decreased breathlessness and reduced HRQOL. We performed subanalyses and sensitivity analyses and assessed the quality of evidence according to the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Compared with the previous review, which was published in 2011, we included 14 additional studies (493 participants), excluded one study and included data for meta-analysis of HRQOL. In total, we included in this review 44 studies including 1195 participants, and we included 33 of these (901 participants)in the meta-analysis.We found that breathlessness during exercise or daily activities was reduced by oxygen compared with air (32 studies; 865 participants; SMD -0.34, 95% CI -0.48 to -0.21; I2 = 37%; low-quality evidence). This translates to a decrease in breathlessness of about 0.7 points on a 0 to 10 numerical rating scale. In contrast, we found no effect of short-burst oxygen given before exercise (four studies; 90 participants; SMD 0.01, 95% CI -0.26 to 0.28; I2 = 0%; low-quality evidence). Oxygen reduced breathlessness measured during exercise tests (25 studies; 442 participants; SMD -0.34, 95% CI -0.46 to -0.22; I2 = 29%; moderate-quality evidence), whereas evidence of an effect on breathlessness measured in daily life was limited (two studies; 274 participants; SMD -0.13, 95% CI, -0.37 to 0.11; I2 = 0%; low-quality evidence).Oxygen did not clearly affect HRQOL (five studies; 267 participants; SMD 0.10, 95% CI -0.06 to 0.26; I2 = 0%; low-quality evidence). Patient preference and adverse events could not be analysed owing to insufficient data. We are moderately confident that oxygen can relieve breathlessness when given during exercise to mildly hypoxaemic and non-hypoxaemic people with chronic obstructive pulmonary disease who would not otherwise qualify for home oxygen therapy. Most evidence pertains to acute effects during exercise tests, and no evidence indicates that oxygen decreases breathlessness in the daily life setting. Findings show that oxygen does not affect health-related quality of life.


One-pot production of porous assemblies by PISA of star architecture copolymers: a simulation study.
The polymerization-induced self-assembly (PISA) process of star architecture copolymers is studied by dissipative particle dynamics and a reaction model. According to the simulation results, the porous vesicles can be produced directly by PISA of these copolymers. Average pore size and distribution of pore size can be influenced by αAS (the solubility between solvophilic blocks and solvent) and αAB (the solubility between solvophilic blocks and solvophobic blocks), while different self-assembly progress can be observed at different αAS and αAB. In addition, the star architecture can promote the formation of porous vesicles compared with linear copolymers. The steric effect of two solvophobic chains is verified as the key factor in formation of the porous vesicles. Further enhancement of such an effect can widen the range of αAS for production of porous vesicles, accompanied by a shrinkage of the range of αAB and a large reduction of pore size distribution. This work provides deeper understanding of the PISA of star architecture copolymers and is instructive in the experimental production of porous nano-materials.


"Children are a blessing from God" - a qualitative study exploring the socio-cultural factors influencing contraceptive use in two Muslim communities in Kenya.
Family planning (FP) is one of the high impact public health interventions with huge potential to enhance the health and wellbeing of women and children. Yet, despite the steady progress made towards expanding access to family planning, major disparities across different regions exist in Kenya. This study explored the socio cultural factors influencing FP use among two Muslim communities in Kenya. A qualitative study involving Focus Group Discussions (FGDs) and In-depth Interviews (IDIs) was conducted (from July to October 2018) in two predominant Muslim communities of Lamu and Wajir counties. Open ended questions explore key thematic areas around knowledge, attitudes and understanding of contraception, perceived FP barriers, and decision making for contraceptives, views on Islam and contraception, and fertility preference. All interviews were conducted in the local language, recorded, transcribed verbatim and translated into English. Data was analyzed using thematic content analyses. Although Islam is the predominant religion the two communities, perceptions and belief around FP use were varied. There were differing interpretations of Islamic teaching and counter arguments on whether or not Islam allows FP use. This, in addition to desire for a large family, polygamy, high child mortality and a cultural preference for boys had a negative impact on FP use. Similarly, inability of women to make decisions on their reproductive health was a factor influencing uptake of FP. Misinterpretation of Islamic teaching on contraception likely influences uptake of family planning. Cultural beliefs and lack of women's decision power on fertility preferences were a key inhibitor to FP use. Countering the negative notions of FP use requires active engagement of religious leaders and Muslim scholars who are in position of power and influence at community level.


Alpha-glucoside formation of xenobiotics by rat liver alpha-glucosidases.
We investigated enzymes participating in alpha-glucoside formation, a novel metabolic pathway of xenobiotics in a metabolic study of indeloxazine hydrochloride in rats. When rat tissue homogenates and the indeloxazine metabolite trans-4-(2-morpholinylmethoxy)-1,2-indandiol (M-2) were incubated, M-2-alpha-glucoside formation was observed in liver. This reaction was almost completely inhibited by the alpha-glucosidase inhibitor acarbose. The liver homogenate was then separated into subcellular fractions and an acid alpha-glucosidase in lysosomes and two neutral alpha-glucosidases in microsomes and cytosol were partially purified. The chromatographic behavior and optimum pH of the glucosyltransferase activity of each of the enzyme preparations were almost identical with those of alpha-glucosidase (hydrolase) activity of the same specimen, suggesting the former activity to be also due to alpha-glucosidase. Agreeing with their hydrolytic substrate specificities, the acid enzyme transferred glucose to M-2 from a series of glucose derivatives, ranging from low molecular maltosaccharides to high molecular glycogen, whereas the neutral enzymes took only low molecular maltosaccharides as glucosyl donors. These results led to the conclusion that the formation of alpha-glucoside conjugates is catalyzed by more than one alpha-glucosidase in the liver and uses maltosaccharides or glycogen as glucosyl donors. Several other diol structure-bearing compounds were found in vitro to give rise to alpha-glucoside conjugates, and the mechanism of alpha-glucoside formation is discussed.


Physical, photophysical and structural properties of ruthenium(II) complexes containing a tetradentate bipyridine ligand.
The focus of this report is the synthesis and properties of two new analogues of ruthenium(ii) tris-bipyridine, a monomer and dimer. The complexes contain the ligand 6,6'-(ethan-1,2-diyl)bis-2,2'-bipyridine (O-bpy) which contains two bipyridine units bridged in the 6,6' positions by an ethylene bridge. Crystal structures of the two complexes formulated as [Ru(bpy)(O-bpy)](PF6)2 and [(Ru(bpy)2)2(O-bpy)](PF6)4 reveal structures of lower symmetry than D3 which affects the electronic properties of the complexes as substantiated by density functional theory (DFT) and time dependent density functional theory (TDDFT) calculations. The HOMO lies largely on the ruthenium center; the LUMO spreads its electron density over the bipyridine units, but not equally in the mixed O-bpy-bpy complexes. Calculated Vis/UV spectra using TDDFT methods agree with experimental spectra. The lowest lying triplet excited state for [Ru(bpy)(O-bpy)](PF6)2 is 3MC resulting in a low emission quantum yield and a large chloride ion photosubstitution quantum yield.


The chromokinesin, KLP3A, dives mitotic spindle pole separation during prometaphase and anaphase and facilitates chromatid motility.
Mitosis requires the concerted activities of multiple microtubule (MT)-based motor proteins. Here we examined the contribution of the chromokinesin, KLP3A, to mitotic spindle morphogenesis and chromosome movements in Drosophila embryos and cultured S2 cells. By immunofluorescence, KLP3A associates with nonfibrous punctae that concentrate in nuclei and display MT-dependent associations with spindles. These punctae concentrate in indistinct domains associated with chromosomes and central spindles and form distinct bands associated with telophase midbodies. The functional disruption of KLP3A by antibodies or dominant negative proteins in embryos, or by RNA interference (RNAi) in S2 cells, does not block mitosis but produces defects in mitotic spindles. Time-lapse confocal observations of mitosis in living embryos reveal that KLP3A inhibition disrupts the organization of interpolar (ip) MTs and produces short spindles. Kinetic analysis suggests that KLP3A contributes to spindle pole separation during the prometaphase-to-metaphase transition (when it antagonizes Ncd) and anaphase B, to normal rates of chromatid motility during anaphase A, and to the proper spacing of daughter nuclei during telophase. We propose that KLP3A acts on MTs associated with chromosome arms and the central spindle to organize ipMT bundles, to drive spindle pole separation and to facilitate chromatid motility.


Diffusive gradients in thin films technique provide robust prediction of metal bioavailability and toxicity in estuarine sediments.
Many sediment quality assessment frameworks incorporate contaminant bioavailability as a critical factor regulating toxicity in aquatic ecosystems. However, current approaches do not always adequately predict metal bioavailability to organisms living in the oxidized sediment surface layers. The deployment of the diffusive gradients in thin films (DGT) probes in sediments allows labile metals present in pore waters and weakly bound to the particulate phase to be assessed in a time-integrated manner in situ. In this study, relationships between DGT-labile metal fluxes within 5 mm of the sediment-water interface and lethal and sublethal effects to the amphipod Melita plumulosa were assessed in a range of contaminated estuarine sediments during 10-day laboratory-based bioassays. To account for differing toxicities of metals, DGT fluxes were normalized to water (WQG) or sediment quality guidelines or toxicity thresholds specific for the amphipod. The better dose-response relationship appeared to be the one based on WQG-normalized DGT fluxes, which successfully predicted toxicity despite the wide range of metals and large variations in sediment properties. The study indicated that the labile fraction of metals measured by DGT is useful for predicting metal toxicity to benthic invertebrates, supporting the applicability of this technique as a rapid monitoring tool for sediments quality assessments.


Gut microbiota and neurological effects of glyphosate.
There are currently various concerns regarding certain environmental toxins and the possible impact they can have on developmental diseases. Glyphosate (Gly) is the most utilised herbicide in agriculture, although its widespread use is generating controversy in the scientific world because of its probable carcinogenic effect on human cells. Gly performs as an inhibitor of 5-enolpyruvylshikimate-3-phospate synthase (EPSP synthase), not only in plants, but also in bacteria. An inhibiting effect on EPSP synthase from intestinal microbiota has been reported, affecting mainly beneficial bacteria. To the contrary, Clostridium spp. and Salmonella strains are shown to be resistant to Gly. Consequently, researchers have suggested that Gly can cause dysbiosis, a phenomenon which is characterised by an imbalance between beneficial and pathogenic microorganisms. The overgrowth of bacteria such as clostridia generates high levels of noxious metabolites in the brain, which can contribute to the development of neurological deviations. This work reviews the impact of Gly-induced intestinal dysbiosis on the central nervous system, focusing on emotional, neurological and neurodegenerative disorders. A wide variety of factors were investigated in relation to brain-related changes, including highlighting genetic abnormalities, pregnancy-associated problems, diet, infections, vaccines and heavy metals. However, more studies are required to determine the implication of the most internationally used herbicide, Gly, in behavioural disorders.


The Roscommon Family Study. III. Schizophrenia-related personality disorders in relatives.
We sought to clarify the familial relationship between five putative schizophrenia-related personality disorders (schizotypal [SPD], paranoid, schizoid, avoidant, and borderline) and schizophrenia, other nonaffective psychoses, and affective illness. A case-controlled epidemiologic family study using DSM-III-R criteria. Five hundred thirty-four probands selected from a psychiatric case register or electoral register, of whom 415 were personally interviewed, and 2043 living and traceable relatives, of whom 1753 were personally interviewed. Compared with relatives of unscreened controls, relatives of probands with schizophrenia had a highly significantly increased prevalence of SPD, and modest, but significant, increased prevalences of paranoid, schizoid, and avoidant personality disorders. Borderline personality disorder was rare, with a modest clustering of cases in relatives of affective disorder probands. The prevalence of SPD was also significantly elevated in relatives of probands with SPD and with other nonaffective psychoses but not in relatives of probands with psychotic or nonpsychotic affective illness. In contrast to the pattern seen for schizophrenia, the prevalence rate of SPD was substantially greater in parents than in siblings of schizophrenic probands. Schizotypal personality disorder has a strong familial relationship with schizophrenia. Paranoid, schizoid, and avoidant, but not borderline, personality disorders may have a significant familial relationship with schizophrenia. Schizotypal personality disorder also reflects the familial liability to other psychotic disorders but probably not to affective illness. Fitness effects may substantially influence the pattern of schizophrenia-related personality disorders in relatives.


The complex task of measuring intestinal permeability in basic and clinical science.
Intestinal permeability is a key feature of intestinal barrier function. Altered intestinal permeability is described in many chronic diseases and may be a risk factor for disease development and a target for emerging therapeutics. Thus, reliable and sensitive methods to measure intestinal permeability in both the clinical and preclinical setting are needed. There is currently a large array of tests to choose from, each with advantages and disadvantages. When possible, a combination of methods should be used. The choice of tests should be based on a deep understanding of intestinal barrier physiology and the recognition of their limitations. This mini-review will highlight the advantages and limitations associated with intestinal permeability tests and will identify current problems in the field and how they can be addressed in the future.


Development of a prenatal program for adults with personal histories of childhood abuse or neglect: a Delphi consensus consultation study.
Pregnancy and the birth of a child present particular challenges for adults with personal histories of childhood abuse or neglect. However, few prenatal interventions address the specific needs of this population. This research aims to determine a list of actions that should be achieved during group interventions designed for expectant parents who experienced childhood trauma. Fifteen stakeholders representing nine different Quebec health care and community organizations that work with families and/or trauma survivors participated in a Delphi process in two rounds. In round 1, three project leaders identified, from clinical and empirical literature, a set of 36 actions relevant for expectant parents who experienced childhood trauma. Using an anonymized online survey, stakeholders coded how important they considered each action and whether they were already conducting similar interventions in their clinical setting. Stakeholders subsequently participated in a one-day in-person meeting during which they discussed the pertinence of each action, proposed new ones and refined them. This was followed by a second anonymized online survey (round 2). A consensus was reached among the stakeholders regarding a final list of 22 actions. Two central clusters of actions emerged from the consultation process: actions aiming to support mentalization about self and parenthood, and actions aiming to support mentalization of trauma. The Delphi process helped to identify what should be the core of a prenatal intervention targeting adults who experienced childhood trauma, from the viewpoint of professionals who will ultimately deliver such a program.


Extraction site reconstruction for alveolar ridge preservation. Part 2: membrane-assisted surgical technique.
Alveolar ridge resorption has long been considered an unavoidable consequence of tooth extraction. Guided bone regeneration techniques and the use of bone replacement materials have both been shown to enhance socket healing and to potentially modify the resorption process. This article will describe a surgical technique using textured, high-density polytetrafluoroethylene (PTFE) membrane and particulate bone replacement materials for graft containment and prevention of soft tissue ingrowth into healing extraction sites. The technique described does not require primary closure, facilitating the preservation of keratinized mucosa and gingival architecture.


Vitamin-D in the Immune System: Genomic and Non-Genomic Actions.
More than thirty years ago functions of vitamin D other than its beneficial effects on calcium homeostasis and bone metabolism have been identified, mainly in relation to its antiproliferative effects on cancer cells. Notably, vitamin D deficiency has been associated with a number of pathological conditions, including infections, autoimmune and allergic diseases. Vitamin D, and its metabolites, are actively involved in the regulation of innate and adaptive immune responses. Vitamin D signals through the vitamin D receptor (VDR), a specific zinc-finger nuclear receptor. The functions of vitamin D are characterized as genomic, mediated through the VDR transcriptional effects inside the cell nucleus, and non-genomic, when the VDR induces rapid signaling, situated on the cell membrane and/or cytoplasm. Emerging evidence supports the notion that vitamin D enhances immunity, providing protection towards pathogens, while, concomitantly, it exerts immunosuppressive effects by preventing the detrimental effects of prolonged inflammatory responses to the host. Still, the precise molecular mechanisms involved in vitamin D's genomic and non-genomic actions remain incompletely defined. Moreover, it is unclear whether vitamin D actions require the synergistic activation of other mediators, such as nuclear membrane receptors. Understanding the biology of vitamin D and the molecular pathways utilized will pave the way for the design of more effective therapeutic strategies. In this review, we present the recent genomic and non-genomic effects of vitamin D from an immunological perspective with a focus on immune-mediated diseases.


Radiofrequency ablation of benign thyroid nodules: recommendations from the Asian Conference on Tumor Ablation Task Force.
Radiofrequency ablation (RFA) is a thermal ablation technique widely used for the management of benign thyroid nodules. To date, five academic societies in various countries have reported clinical practice guidelines, opinion statements, or recommendations regarding the use of thyroid RFA. However, despite some similarities, there are also differences among the guidelines, and a consensus is required regarding safe and effective treatment in Asian countries. Therefore, a task force was organized by the guideline committee of the Asian Conference on Tumor Ablation with the goal of devising recommendations for the clinical use of thyroid RFA. The recommendations in this article are based on a comprehensive analysis of the current literature and the consensus opinion of the task force members.


Acoustic regularities in infant-directed speech and song across cultures.
When interacting with infants, humans often alter their speech and song in ways thought to support communication. Theories of human child-rearing, informed by data on vocal signalling across species, predict that such alterations should appear globally. Here, we show acoustic differences between infant-directed and adult-directed vocalizations across cultures. We collected 1,615 recordings of infant- and adult-directed speech and song produced by 410 people in 21 urban, rural and small-scale societies. Infant-directedness was reliably classified from acoustic features only, with acoustic profiles of infant-directedness differing across language and music but in consistent fashions. We then studied listener sensitivity to these acoustic features. We played the recordings to 51,065 people from 187 countries, recruited via an English-language website, who guessed whether each vocalization was infant-directed. Their intuitions were more accurate than chance, predictable in part by common sets of acoustic features and robust to the effects of linguistic relatedness between vocalizer and listener. These findings inform hypotheses of the psychological functions and evolution of human communication.


Biologically based treatment of immature permanent teeth with pulpal necrosis: a case series.
This case series reports the outcomes of 8 patients (ages 9-14 years) who presented with 9 immature permanent teeth with pulpal necrosis and apical periodontitis. During treatment, 5 of the teeth were found to have at least some residual vital tissue remaining in the root canal systems. After NaOCl irrigation and medication with ciprofloxacin, metronidazole, and minocycline, these teeth were sealed with mineral trioxide aggregate and restored. The other group of 4 teeth had no evidence of any residual vital pulp tissue. This second group of teeth was treated with NaOCl irrigation and medicated with ciprofloxacin, metronidazole, and minocycline followed by a revascularization procedure adopted from the trauma literature (bleeding evoked to form an intracanal blood clot). In both groups of patients, there was evidence of satisfactory postoperative clinical outcomes (1-5 years); the patients were asymptomatic, no sinus tracts were evident, apical periodontitis was resolved, and there was radiographic evidence of continuing thickness of dentinal walls, apical closure, or increased root length.


The pathological upgrading after radical prostatectomy in low-risk prostate cancer patients who are eligible for active surveillance: How safe is it to depend on bioptic pathology?
Active surveillance (AS) is one of the treatment alternatives in low-risk prostate cancer (PCa). The pathological upgrading after radical prostatectomy (RP) were investigated in patients who were eligible for AS in the present study. Between August 2006 and July 2017, 627 patients underwent RP in our institution. One hundred and thirty-six patients who were eligible for AS at the time of RP were included in this study. The previously defined AS criteria Gleason 3 + 3=6 adenocarcinoma at maximum two biopsy cores, prostate-specific antigen (PSA) < 10 ng/mL and clinical T stage ≤ 2a were used in the study. The demographics, clinical, and histopathological outcomes were retrospectively compared between two groups, which were divided in accordance with the upgrading status at final pathology as Group 1 (n = 67, upgrading) and Group 2 (n = 69, nonupgrading). Gleason upgrading (GU) was found in 67 (49.3%) patients, and 17 patients (12.5%) were upstaged to pT3a. The upgrading to Gleason 3 + 4 was reported in 38.7% of patients, however, 7.4%, and 3.7% of the patients were upgraded to Gleason 4 + 3, and Gleason 4 + 4, respectively. The 10.3% of the patients had extraprostatic involvement, and the rate (19.4% vs 1.4%, P = .002) was significantly higher in Group 1. PSA density (P = .001), tumor size (P < .001), tumor percentage (P < .001), apical involvement (P = .013), and perineural invasion (P < .001) in RP specimen were higher in Group 1. Multivariate analysis showed that perineural invasion (OR = 4.26; 95%CI: 1.76-10.33; P = .001) and pathologic T stage (OR = 5.45; 95%CI: 1.08-27.4; P = .04) were independently associated with GU. Since 12.5% of the patients upstaged to pT3a disease, and there is a possible risk of Gleason 4 pattern, upgrading of the tumor should carefully be kept in mind before offering AS to low-risk patients with PCa.


Relative and contextual contribution of different sources to the composition and abundance of indoor air bacteria in residences.
The study of the microbial communities in the built environment is of critical importance as humans spend the majority of their time indoors. While the microorganisms in living spaces, especially those in the air, can impact health and well-being, little is known of their identity and the processes that determine their assembly. We investigated the source-sink relationships of airborne bacteria in 29 homes in the San Francisco Bay Area. Samples taken in the sites expected to be source habitats for indoor air microbes were analyzed by 16S rRNA-based pyrosequencing and quantitative PCR. The community composition was related to the characteristics of the household collected at the time of sampling, including the number of residents and pets, activity levels, frequency of cooking and vacuum cleaning, extent of natural ventilation, and abundance and type of vegetation surrounding the building. Indoor air harbored a diverse bacterial community dominated by Diaphorobacter sp., Propionibacterium sp., Sphingomonas sp., and Alicyclobacillus sp. Source-sink analysis suggested that outdoor air was the primary source of indoor air microbes in most homes. Bacterial phylogenetic diversity and relative abundance in indoor air did not differ statistically from that in outdoor air. Moreover, the abundance of bacteria in outdoor air was positively correlated with that in indoor air, as would be expected if outdoor air was the main contributor to the bacterial community in indoor bioaerosols. The number of residents, presence of pets, and local tap water also influenced the diversity and size of indoor air microbes. The bacterial load in air increased with the number of residents, activity, and frequency of natural ventilation, and the proportion of bacteria putatively derived from skin increased with the number of residents. Vacuum cleaning increased the signature of pet- and floor-derived bacteria in indoor air, while the frequency of natural ventilation decreased the relative abundance of tap water-derived microorganisms in air. Indoor air in residences harbors a diverse bacterial community originating from both outdoor and indoor sources and is strongly influenced by household characteristics.


The blood-brain barrier: bottleneck in brain drug development.
The blood-brain barrier (BBB) is formed by the brain capillary endothelium and excludes from the brain approximately 100% of large-molecule neurotherapeutics and more than 98% of all small-molecule drugs. Despite the importance of the BBB to the neurotherapeutics mission, the BBB receives insufficient attention in either academic neuroscience or industry programs. The combination of so little effort in developing solutions to the BBB problem, and the minimal BBB transport of the majority of all potential CNS drugs, leads predictably to the present situation in neurotherapeutics, which is that there are few effective treatments for the majority of CNS disorders. This situation can be reversed by an accelerated effort to develop a knowledge base in the fundamental transport properties of the BBB, and the molecular and cellular biology of the brain capillary endothelium. This provides the platform for CNS drug delivery programs, which should be developed in parallel with traditional CNS drug discovery efforts in the molecular neurosciences.


Molecular cloning, sequencing, and expression of the genes encoding adenosylcobalamin-dependent diol dehydrase of Klebsiella oxytoca.
The pdd genes encoding adenosylcobalamin-dependent diol dehydrase of Klebsiella oxytoca were cloned by using a synthetic oligodeoxyribonucleotide as a hybridization probe followed by measuring the enzyme activity of each clone. Five clones of Escherichia coli exhibited diol dehydrase activity. At least one of them was shown to express diol dehydrase genes under control of their own promoter. Sequence analysis of the DNA fragments found in common in the inserts of these five clones and the flanking regions revealed four open reading frames separated by 10-18 base pairs. The sequential three open reading frames from the second to the fourth (pddA, pddB, and pddC genes) encoded polypeptides of 554, 224, and 173 amino acid residues with predicted molecular weights of 60,348 (alpha), 24,113 (beta), and 19,173 (gamma), respectively. Overexpression of these three genes in E. coli produced more than 50-fold higher level of functional apodiol dehydrase than that in K. oxytoca. The recombinant enzyme was indistinguishable from the wild-type one of K. oxytoca by the criteria of polyacrylamide gel electrophoretic and immunochemical properties. It was thus concluded that these three gene products are the subunits of functional diol dehydrase. Comparisons of the deduced amino acid sequences of the three subunits with other proteins failed to reveal any apparent homology.


Accounting for health-care outcomes: implications for intensive care unit practice and performance.
The aim of this study was to understand the environment of health care, and how clinicians and managers respond in terms of performance accountability. A qualitative method was used in a tertiary metropolitan teaching intensive care unit (ICU) in Sydney, Australia, including interviews with 15 clinical managers and focus groups with 29 nurses of differing experience. The study found that a managerial focus on abstract goals, such as budgets detracted from managing the core business of clinical work. Fractures were evident within clinical units, between clinical units and between clinical and managerial domains. These fractures reinforced the status quo where seemingly unconnected patient care activities were undertaken by loosely connected individual clinicians with personalized concepts of accountability. Managers must conceptualize health services as an interconnected entity within which self-directed teams negotiate and agree objectives, collect and review performance data and define collective practice. Organically developing regimens of care within and across specialist clinical units, such as in ICUs, directly impact upon health service performance and accountability.


Controlling the efficiency of an artificial light-harvesting complex.
Adaptive femtosecond pulse shaping in an evolutionary learning loop is applied to a bioinspired dyad molecule that closely mimics the early-time photophysics of the light-harvesting complex 2 (LH2) photosynthetic antenna complex. Control over the branching ratio between the two competing pathways for energy flow, internal conversion (IC) and energy transfer (ET), is realized. We show that by pulse shaping it is possible to increase independently the relative yield of both channels, ET and IC. The optimization results are analyzed by using Fourier analysis, which gives direct insight to the mechanism featuring quantum interference of a low-frequency mode. The results from the closed-loop experiments are repeatable and robust and demonstrate the power of coherent control experiments as a spectroscopic tool (i.e., quantum-control spectroscopy) capable of revealing functionally relevant molecular properties that are hidden from conventional techniques.


Intrinsic optical signal imaging of glucose-stimulated insulin secreting β-cells.
Simultaneous monitoring of many functioning β-cells is essential for understanding β-cell dysfunction as an early event in the progression to diabetes. Intrinsic optical signal (IOS) imaging has been shown to allow high resolution detection of stimulus-evoked physiological responses in the retina and other neural tissues. In this paper, we demonstrate the feasibility of using IOS imaging for functional examination of insulin secreting INS-1 cells, a popular model for investigating diabetes associated β-cell dysfunction. Our experiments indicate that IOS imaging permits simultaneous monitoring of glucose-stimulated physiological responses in multiple cells with high spatial (sub-cellular) and temporal (sub-second) resolution. Rapid IOS image sequences revealed transient optical responses that had time courses tightly correlated with the glucose stimulation.


An Expedited Care Pathway with Ambulatory Brachial Plexus Analgesia Is a Cost-effective Alternative to Standard Inpatient Care after Complex Arthroscopic Elbow Surgery: A Randomized, Single-blinded Study.
Common standard practice after complex arthroscopic elbow surgery includes hospital admission for 72 h. The authors hypothesized that an expedited care pathway, with 24 h of hospital admission and ambulatory brachial plexus analgesia and continuous passive motion at home, results in equivalent elbow range of motion (ROM) 2 weeks after surgery compared with standard 72-h hospital admission. A randomized, single-blinded study was conducted after obtaining approval from the research ethics board. Forty patients were randomized in a 1:1 ratio using a computer-generated list of random numbers into an expedited care pathway group (24-h admission) and a control group (72-h admission). They were treated equally aside from the predetermined hospital length of stay. Patients in the control (n = 19) and expedited care pathway (n = 19) groups achieved similar elbow ROM 2 weeks (119 ± 18 degrees and 121 ± 15 degrees, P = 0.627) and 3 months (130 ± 18 vs. 130 ± 11 degrees, P = 0.897) postoperatively. The mean difference in elbow ROM at 2 weeks was 2.6 degrees (95% CI, -8.3 to 13.5). There were no differences in analgesic outcomes, physical function scores, and patient satisfaction up to 3 months postoperatively. Total hospital cost of care was 15% lower in the expedited care pathway group. The results suggest that an expedited care pathway with early hospital discharge followed by ambulatory brachial plexus analgesia and continuous passive motion at home is a cost-effective alternative to 72 h of hospital admission after complex arthroscopic elbow surgery.


Antimicrobial property, antioxidant capacity, and cytotoxicity of essential oil from cumin produced in Iran.
Cumin (Cuminum cyminum) is one of the commonly used spices in food preparations. It is also used in traditional medicine as a stimulant, a carminative, and an astringent. In this study, we characterized the antimicrobial, antioxidant, and cytotoxic activities of cumin. E. coli, S. aureus, and S. faecalis were sensitive to various oil dilutions. The total phenol content of the essential oil was estimated to be 33.43 microg GAE/mg of the oil. The oil showed higher antioxidant activity compared with that of BHT and BHA. The cumin essential oil exhibited a dose-dependent scavenging of DPPH radicals and 5.4 microg of the oil was sufficient to scavenge 50% of DPPH radicals/mL. At a concentration of 0.1 microL/mL, oil destructed Hela cells by 79%. The antioxidant activity of cumin essential oil might contribute to its cytotoxic activity. Acute and subchronic toxicity was studied in a 30-d oral toxicity study by administration to Wistar rats of the essential oil. A 17.38% decrease in WBCs count, and 25.77%, 14.24%, and 108.81% increase in hemoglobin concentration, hematocrit, and platelet count, respectively, were noted. LDL/HDL ratio was reduced to half, which adds to the nutritional effects of cumin. Thus, cumin with a high phenolic content and good antioxidant activity can be supplemented for both nutritional purposes and preservation of foods.


Effects on the ipsilateral testis during progression of experimental varicocele in rat.
We used an animal model of experimental varicocele to investigate the effects on the ipsilateral testis during the progression of experimental varicocele in rat. Experimental varicocele was induced by partial ligation of the left renal vein in rats. Rats in each control group were subjected to a sham operation. After different periods of varicocele creation (6, 12, and 18 weeks), each animal's left testis was extirpated, and Johnsen's score, ultrastructure of seminiferous tubules, intratesticular testosterone concentration, and the germ cell apoptotic index of each left testis were compared between the experimental and control groups. Johnsen's score and intratesticular testosterone concentrations in each experimental varicocele group were significantly lower than those in the corresponding control groups (P<0.05) and showed significant declines as the duration of varicocele gradually increased; the apoptotic index showed an opposite tendency. Ultrastructural injury of seminiferous tubules gradually became severe as the duration of varicocele gradually increased. Experimental varicocele caused progressive impairment of the ipsilateral testis; apoptosis mediated the pathophysiological processes of dyszoospermia.


Toxicity of PCB 105 in the rat liver: an ultrastructural and biochemical study.
PCB 105 (2,3,3',4,4'-pentachlorobiphenyl) congener was fed to weanling Sprague-Dawley rats in a diet combined with 4% corn oil. The animals were distributed randomly into 10 groups, each of which contained 10 males and 10 females, and rats in 8 groups received diets containing PCB at concentrations of 0.05, 0.5, 5, and 50 ppm. Animals in the other 2 groups served as controls. After 13 weeks, the animals were humanely killed and liver samples were obtained and prepared for transmission electron microscopy. Ultrastructural alterations revealed in the hepatocytes of animals fed the PCB included smooth endoplasmic reticulum proliferation, atypical mitochondrial cristae, and augmentation of peroxisome numbers (in animals fed high PCB concentrations). Biochemical alterations were estimated by using hepatic microsomal pentoxyresorufin-O-dealkylase (PROD) and ethoxyresorufin-O-deethylase (EROD) activities. A dose-dependent increase in EROD and PROD activities was discovered; only in the animals of highest PCB dose group, however, was EROD found to be significant (p < .05). Based on our previous work, this congener is relatively less toxic than PCB 126, 118, and 153 and is similar in toxicity to 156.


Alpha-1 Adrenergic-Antagonist Use Increases the Risk of Sleep Apnea: A Nationwide Population-Based Cohort Study.
Decreased upper-airway muscle responsiveness is one of the major phenotypes of obstructive sleep apnea. Use of α1-adrenergic antagonists is correlated with decreased muscle responsiveness in animal studies, but this association has not yet been demonstrated in humans. This study examined whether use of α1-adrenergic antagonists is an independent risk factor for sleep apnea in humans. Data for this retrospective cohort study were obtained from the National Health Insurance Research Database from Taiwan. Between 2000 and 2012, 25,466 patients with hypertension and 18,930 patients without hypertension were enrolled. These groups were divided into α1-adrenergic antagonist users and nonusers, matched by age, sex, and index year. Individuals were monitored for diagnosis of sleep apnea until 2013. After adjusting for propensity score and potential confounders, including age, geographic location, enrollee category, income, urbanization level, comorbidities, and medication, the adjusted hazard ratios (HRs) for development of sleep apnea with α1-adrenergic antagonist use were 2.38 (95% confidence interval [CI] 1.82-3.10) and 2.82 (95% CI 1.79-4.44) in the hypertension and nonhypertension groups, respectively. Similarly, the adjusted HRs for development of severe sleep apnea with α1-adrenergic antagonist use were 2.74 (95% CI 1.78-4.22) and 4.23 (95% CI 1.57-11.40) in hypertension and nonhypertension patient groups, respectively. The interaction between α1-adrenergic-antagonist user and patients with hypertension was tested using multivariable Cox regression. The results showed that there are positive additive interactions for developing sleep apnea and severe sleep apnea, respectively. Our study suggests that patients with hypertension using α1-adrenergic antagonists have a higher risk of sleep apnea. Routine sleep apnea screening would be beneficial for patients with hypertension who take α1-adrenergic antagonists.


Ablation of CCAAT/Enhancer-Binding Protein Delta (C/EBPD): Increased Plaque Burden in a Murine Alzheimer's Disease Model.
Alzheimer's disease (AD) and prion diseases carry a significant inflammatory component. The astrocytic overexpression of CCAAT/enhancer-binding protein delta (C/EBPD) in prion- and AD-affected brain tissue prompted us to study the role of this transcription factor in murine model systems of these diseases. Ablation of C/EBPD had neither in the AD model (APP/PS1double transgenic mice) nor in the prion model (scrapie-infected C57BL/6 mice) an influence on overt clinical symptoms. Moreover, the absence of C/EBPD did not affect the extent of the disease-related gliosis. However, C/EBPD-deficient APP/PS1 double transgenic mice displayed significantly increased amyloid beta (Abeta) plaque burdens while amyloid precursor protein (APP) expression and expression of genes involved in beta amyloid transport and turnover remained unchanged. Gene expression analysis in mixed glia cultures demonstrated a strong dependency of complement component C3 on the presence of C/EBPD. Accordingly, C3 mRNA levels were significantly lower in brain tissue of C/EBPD-deficient mice. Vice versa, C3 expression in U-373 MG cells increased upon transfection with a C/EBPD expression vector. Taken together, our data indicate that a C/EBPD-deficiency leads to increased Abeta plaque burden in AD model mice. Furthermore, as shown in vivo and in vitro, C/EBPD is an important driver of the expression of acute phase response genes like C3 in the amyloid-affected CNS.


Catheter-Directed Therapy in Acute Pulmonary Embolism with Right Ventricular Dysfunction: A Promising Modality to Provide Early Hemodynamic Recovery.
BACKGROUND Catheter-directed therapy (CDT) for pulmonary embolism (PE) is considered as an alternative to systemic thrombolysis (ST) in patients with hemodynamically unstable acute PE who are considered at high bleeding risk for ST. We aimed to evaluate the efficacy and safety of CDT in the management of acute PE with right ventricular dysfunction (RVD). The primary outcomes were mortality, clinical success, and complications. Secondary outcomes were change in hemodynamic parameters in the first 24 hours following the procedure. MATERIAL AND METHODS Medical records of consecutive patients diagnosed as having acute massive or submassive PE with accompanying RVD treated by immediate CDT at our institution from January 2007 to January 2014 were reviewed. Patient characteristics, mortality, achievement of clinical success, and minor and major bleeding complications were analyzed in the overall study group, as well as massive vs. submassive PE subgroups. Change in hemodynamic parameters in the second, eighth, and 24th hours after the CDT procedure were also analyzed. RESULTS The study included 15 consecutive patients (M/F=10/5) with a mean age of 54.2 ± 16.6 years who underwent immediate CDT. Nine of the patients had submassive PE, and 6 had massive PE. In-hospital mortality rate was 13.3% (95% CI, 0.04-0.38). One major, but not life-threatening, bleeding episode was evident in the whole group. Hemodynamic parameters were stabilized and clinical success was achieved in 14/15 (93.3%; 95% CI, 70.2-98.8) of the patients in the first 24 hours. Notably, the hemodynamic recovery was significantly evident in the first 8 hours after the procedure. CONCLUSIONS CDT is a promising treatment option for patients with acute PE with RVD with no fatal bleeding complication. In experienced centers, CDT should be considered as a first-line treatment for patients with acute PE and RVD and contraindications for ST, with the advantage of providing early hemodynamic recovery.


Nanoporous Polymer-Infiltrated Nanoparticle Films with Uniform or Graded Porosity via Undersaturated Capillary Rise Infiltration.
In this work, we present the fabrication of nanoporous polymer-infiltrated nanoparticle films (PINFs) with either uniform or graded porosity based on undersaturated capillary rise infiltration (UCaRI) and study the processing-structure-property relationship of these nanoporous PINFs. The UCaRI process involves first generating a bilayer film of a randomly packed nanoparticle layer atop a polymer layer, such that the volume of the polymer is less than the void volume in the nanoparticle packing. Subsequently, the bilayer film is annealed above the glass transition temperature of the polymer to induce polymer infiltration into the voids of the nanoparticle packing. Using in situ spectroscopic ellipsometry and molecular dynamics simulations, we observe that the polymer transport occurs in two stages: capillarity-induced infiltration, followed by gradual spreading, likely via surface diffusion. By varying the annealing time, UCaRI enables the generation of graded or uniform nanoporous PINFs. We also show that these nanoporous PINFs have tunable optical and mechanical properties, which can be tailored simply by changing the nanoparticle to polymer layer thickness ratio in the initial bilayer. The UCaRI approach is versatile and widely applicable to various polymers, which allows generation of nanoporous PINFs for multiple applications.


Identification of 2 DNA methylation subtypes of Waldenström macroglobulinemia with plasma and memory B-cell features.
Epigenetic changes during B-cell differentiation generate distinct DNA methylation signatures specific for B-cell subsets, including memory B cells (MBCs) and plasma cells (PCs). Waldenström macroglobulinemia (WM) is a B-cell malignancy uniquely comprising a mixture of lymphocytic and plasmacytic phenotypes. Here, we integrated genome-wide DNA methylation, transcriptome, mutation, and phenotypic features of tumor cells from 35 MYD88-mutated WM patients in relation to normal plasma and B-cell subsets. Patients naturally segregate into 2 groups according to DNA methylation patterns, related to normal MBC and PC profiles, and reminiscent of other memory and PC-derived malignancies. Concurrent analysis of DNA methylation changes in normal and WM development captured tumor-specific events, highlighting a selective reprogramming of enhancer regions in MBC-like WM and repressed and heterochromatic regions in PC-like WM. MBC-like WM hypomethylation was enriched in motifs belonging to PU.1, TCF3, and OCT2 transcription factors and involved elevated MYD88/TLR pathway activity. PC-like WM displayed marked global hypomethylation and selective overexpression of histone genes. Finally, WM subtypes exhibited differential genetic, phenotypic, and clinical features. MBC-like WM harbored significantly more clonal CXCR4 mutations (P = .015), deletion 13q (P = .006), splenomegaly (P = .02), and thrombocytopenia (P = .004), whereas PC-like WM harbored more deletion 6q (P = .012), gain 6p (P = .033), had increased frequencies of IGHV3 genes (P = .002), CD38 expression (P = 4.1e-5), and plasmacytic differentiation features (P = .008). Together, our findings illustrate a novel approach to subclassify WM patients using DNA methylation and reveal divergent molecular signatures among WM patients.


Efficacious early antiviral activity of HIV Gag- and Pol-specific HLA-B 2705-restricted CD8+ T cells.
The association between HLA-B 2705 and the immune control of human immunodeficiency virus type 1 (HIV-1) has previously been linked to the targeting of the HLA-B 2705-restricted Gag epitope KRWIILGLNK (KK10) by CD8(+) T cells. In order to better define the mechanisms of the HLA-B 2705 immune control of HIV, we first characterized the CD8(+) T-cell responses of nine highly active antiretroviral therapy (HAART)-naïve B 2705-positive subjects. Unexpectedly, we observed a strong response to an HLA-B 2705-restricted Pol epitope, KRKGGIGGY (KY9), in 8/9 subjects. The magnitude of the KY9 response was only marginally lower than that of the KK10-specific response (median, 695 versus 867 spot-forming cells [SFC]/million peripheral blood mononuclear cells [PBMCs]; not significant [NS]), and viral escape mutants were observed in both KY9 and KK10, resulting from selection pressure driven by the respective CD8(+) T-cell response. By comparing inhibitions of viral replication by CD8(+) T cells specific for the Gag KK10, Pol KY9, and Vpr VL9 HLA-B 2705-restricted epitopes, we observed a consistent hierarchy of antiviral efficacy (Gag KK10 > Pol KY9 > Vpr VL9). This hierarchy was associated with early recognition of HIV-1-infected cells, within 6 h of infection, by KK10- and KY9-specific CD8(+) T cells but not until 18 h postinfection by VL9-specific CD8(+) T cells. There was no association between antiviral efficacy and proliferative capacity, cytotoxicity, polyfunctionality, or T-cell receptor (TCR) avidity. These data are consistent with previous studies indicating an important role for the B 2705-Gag KK10 response in the control of HIV but also suggest a previously unrecognized role played by the subdominant Pol-specific KY9 response in HLA-B 2705-mediated control of HIV and that the recognition of HIV-infected cells by CD8(+) T cells early in the viral life cycle may be important for viral containment in HIV-infected individuals.


Heterometallic 3d-4f single molecule magnets containing diamagnetic metal ions.
Molecular nano magnets such as single-molecule magnets (SMMs) are a class of coordination complexes with numerous potential applications such as information storage devices, Q-bits in quantum computing and spintronics materials. One of the greatest challenges in taking these molecules to end-user applications lies in devising strategies to control and predict their magnetic properties. In this regard, lanthanide-based compounds are very attractive as they possess appealing magnetic properties such as very high barriers for magnetization reversal, very large blocking temperatures etc. Controlling the microscopic energy levels of lanthanide-based single-ion magnets (SIMs) is a challenging task and to obtain molecules having very large blocking temperatures, it is desirable to enhance the ground state-excited state gap between the mJ levels and also to quench the quantum tunnelling of magnetization that often circumvents the barrier height. One of the strategies that has been developed by us and others in this area is to employ a diamagnetic transition metal ion to achieve this goal. Over the years several diamagnetic ions such as ZnII, NiII (square planar), AlIII and CoIII have been successfully employed to obtain lanthanide-based SMMs with interesting properties. In this perspective, we discuss how incorporation of diamagnetic ion(s) in the cluster aggregation enhances the barrier height for magnetization reversal and hence improves the magnetic properties. We also discuss theoretical studies on such systems based on ab initio calculations performed using CASSCF level of theory. Such studies are helpful in affording an understanding of the role and limitation of the diamagnetic ions in enhancing the barrier height for magnetization reversal of molecular nanomagnets.


Beyond the chemical master equation: Stochastic chemical kinetics coupled with auxiliary processes.
The chemical master equation and its continuum approximations are indispensable tools in the modeling of chemical reaction networks. These are routinely used to capture complex nonlinear phenomena such as multimodality as well as transient events such as first-passage times, that accurately characterise a plethora of biological and chemical processes. However, some mechanisms, such as heterogeneous cellular growth or phenotypic selection at the population level, cannot be represented by the master equation and thus have been tackled separately. In this work, we propose a unifying framework that augments the chemical master equation to capture such auxiliary dynamics, and we develop and analyse a numerical solver that accurately simulates the system dynamics. We showcase these contributions by casting a diverse array of examples from the literature within this framework and applying the solver to both match and extend previous studies. Analytical calculations performed for each example validate our numerical results and benchmark the solver implementation.


Controlled acceleration and inhibition of bergman cyclization by metal chlorides.
The Bergman cyclization has been the subject of renewed interest with the discovery of naturally occurring enediyne-based antitumor agents that cleave DNA by means of an aromatic diradical. These natural substrates have a means to trigger this cycloaromatization process. Control of this reaction by substrate modification would allow aromatic diradicals to be generated selectively. In the studies presented here it is disclosed that the Bergman cyclization of 1,2-bis(diphenyl phosphinoethynyl) benzene was accelerated by a factor of >30,000 by the addition of palladium(II) chloride or platinum(II) chloride and was inhibited by the addition of mercury(II) chloride.


Mammalian Rap1 controls telomere function and gene expression through binding to telomeric and extratelomeric sites.
Rap1 is a component of the shelterin complex at mammalian telomeres, but its in vivo role in telomere biology has remained largely unknown to date. Here we show that Rap1 deficiency is dispensable for telomere capping but leads to increased telomere recombination and fragility. We generated cells and mice deleted for Rap1; mice with Rap1 deletion in stratified epithelia were viable but had shorter telomeres and developed skin hyperpigmentation in adulthood. By performing chromatin immunoprecipitation coupled with ultrahigh-throughput sequencing, we found that Rap1 binds to both telomeres and to extratelomeric sites through the (TTAGGG)(2) consensus motif. Extratelomeric Rap1-binding sites were enriched at subtelomeric regions, in agreement with preferential deregulation of subtelomeric genes in Rap1-deficient cells. More than 70% of extratelomeric Rap1-binding sites were in the vicinity of genes, and 31% of the genes deregulated in Rap1-null cells contained Rap1-binding sites, suggesting a role for Rap1 in transcriptional control. These findings place a telomere protein at the interface between telomere function and transcriptional regulation.


Racial differences in next-of-kin participation in an ongoing survey of satisfaction with end-of-life care: a study of a study.
Despite disparities in health care access and quality, African Americans are underrepresented in many areas of clinical investigation, including research in end-of-life care. Because of the importance of surrogate reports in assessing the quality of end-of-life care, this study examined racial differences in next-of-kin participation in an ongoing study of satisfaction with end-of-life care. The parent study includes after-death interviews with next-of-kin of elderly African Americans and Caucasians who died at Duke Hospital. This analysis included next-of-kin of elders who died at Duke Hospital from December 1, 2003 to December 31, 2004. During this period, there were 471 decedents whose next-of-kin were eligible for participation. Of these, 133 (28%) were African American and 338 (72%) were Caucasian. There were no racial differences in completion, contact, or overall response rates. Of those contacted, 39.8% of African Americans and 37.8% of Caucasians completed the study. In multivariate analysis, only the relationship of the next-of-kin to the decedent was an independent predictor of study completion. Children of decedents were significantly more likely to participate than spouses (odds ratio [OR] 2.1 [1.14, 3.86]). In this analysis, next-of-kin of African American and Caucasian decedents were equally likely to participate in an after-death interview assessing satisfaction with end-of-life care. The use of racially concordant interviewers, subject identification with the institution, and the absence of socioeconomic constraints may partly explain these findings. Given the growing diversity of the U.S. population, researchers in end-of-life care must use strategies aimed at recruiting racially and ethnically diverse samples.


Microglia facilitate repair of demyelinated lesions via post-squalene sterol synthesis.
The repair of inflamed, demyelinated lesions as in multiple sclerosis (MS) necessitates the clearance of cholesterol-rich myelin debris by microglia/macrophages and the switch from a pro-inflammatory to an anti-inflammatory lesion environment. Subsequently, oligodendrocytes increase cholesterol levels as a prerequisite for synthesizing new myelin membranes. We hypothesized that lesion resolution is regulated by the fate of cholesterol from damaged myelin and oligodendroglial sterol synthesis. By integrating gene expression profiling, genetics and comprehensive phenotyping, we found that, paradoxically, sterol synthesis in myelin-phagocytosing microglia/macrophages determines the repair of acutely demyelinated lesions. Rather than producing cholesterol, microglia/macrophages synthesized desmosterol, the immediate cholesterol precursor. Desmosterol activated liver X receptor (LXR) signaling to resolve inflammation, creating a permissive environment for oligodendrocyte differentiation. Moreover, LXR target gene products facilitated the efflux of lipid and cholesterol from lipid-laden microglia/macrophages to support remyelination by oligodendrocytes. Consequently, pharmacological stimulation of sterol synthesis boosted the repair of demyelinated lesions, suggesting novel therapeutic strategies for myelin repair in MS.


Pediatric tick-borne encephalitis in 371 cases from an endemic region in Slovenia, 1959 to 2000.
With the exception of Lyme borreliosis, tick-borne encephalitis (TBE) is the most prevalent tick-transmitted disease in Europe. Here we report clinical and epidemiologic features of the largest number of children with TBE reported to date and the longest (i.e. 42-year) retrospective survey of pediatric TBE cases from one geographic region. Case records of 371 patients, age 0 to 15 years, with serologically confirmed TBE and hospitalized between 1959 and 2000 at the Department of Infectious Diseases of the General Hospital Celje, Slovenia were reviewed and analyzed. Children represented 23.5% of 1578 confirmed TBE cases in the study period. Children were admitted to hospital throughout the year, but the majority were treated during summer months. In 178 (47.9%) children, a tick bite was noticed before admission. A biphasic course of illness occurred in 249 (67.1%) patients. The most common symptoms and signs of TBE were raised body temperature [>38 degrees C (n = 371)], headache and meningeal signs (n = 346), fatigue (n = 337) and vomiting (n = 327). Meningitis was diagnosed in 232 (62.5%) children, and meningoencephalitis was diagnosed in 139 (37.5%). There was a tendency for greater severity of TBE with increasing age. None of the children with TBE died, and none had permanent sequelae. The results of our study indicate that pediatric TBE is relatively mild disease with favorable outcome.