Efficacy of expulsive therapy using nifedipine or tamsulosin, both associated with ketoprofene, after shock wave lithotripsy of ureteral stones.
Extracorporeal shock wave lithotripsy (ESWL) is currently considered one of the main treatments for ureteral stones. Some studies have reported the effectiveness of pharmacologic therapies (calcium antagonists or alpha-blockers) in facilitating ureteral stone expulsion after ESWL. We prospectively evaluated the efficacy, after ESWL, of nifedipine on upper-middle ureteral stones, and tamsulosin on lower ureteral stones, both associated to ketoprofene as anti-edema agent. From January 2003 to March 2005 we prospectively evaluated 113 patients affected by radiopaque or radiolucent ureteral stones. Average stone size was 10.16 +/- 2.00 mm (range 6-14 mm). Thirty-seven stones were located in the upper ureter, 27 in the middle ureter, and 49 in the lower ureter. All patients received a single session of ESWL (mean number of shock waves: 3,500) by means of a Dornier Lithotripter S (mean energy power for each treatment: 84%). Both ultrasound and X-ray were used for stone scanning. After treatment, 63 of 113 patients were submitted to medical therapy to aid stone expulsion: nifedipine 30 mg/day for 14 days administered to 35 patients with upper-middle ureteral stones (group A1) and tamsulosin 0.4 mg/day for 14 days administered to 28 patients with stones located in the distal ureter (group A2). The remaining 50 patients were used as a control group (29 upper-middle ureteral stones-B1-and 21 lower ureteral stones-B2-), receiving only pain-relieving therapy. No significant difference in stone size between the groups defined was observed. Stone clearance was assessed 1 and 2 months after ESWL by means of KUB, ultrasound scan and/or excretory urography. A stone-free condition was defined as complete stone clearance or the presence of residual fragments smaller than 3 mm in diameter. The stone-free rates in the expulsive medical therapy group were 85.7 and 82.1% for the nifedipine (A1) and tamsulosin (A2) groups respectively; stone-free rates in the control groups were 51.7 and 57.1% (B1 and B2, respectively). Five patients (14.3%) in group A1, 5 (17.8%) in group A2, 14 (48.3%) in group B1 and 9 (42.8%) in group B2 were not stone-free after a single ESWL session and required ESWL re-treatment or an endoscopic treatment. Medical therapy following ESWL to facilitate ureteral stone expulsion results in increased 1- and 2-month stone-free rates and in a lower percentage of those needing re-treatment. The efficacy of nifedipine for the upper-mid ureteral tract associated with ketoprofene makes expulsive medical therapy suitable for improving overall outcomes of ESWL treatment for ureteral stones.


On the bioavailability of trace metals in surface sediments: a combined geochemical and biological approach.
The bioavailability of metals was estimated in three river sediments (Sensée, Scarpe, and Deûle Rivers) impacted by different levels of Cu, Cd, Pb, and Zn (Northern France). For that, a combination of geochemistry and biological responses (bacteria and chironomids) was used. The results obtained illustrate the complexity of the notion of "bioavailability." Indeed, geochemical indexes suggested a low toxicity, even in surface sediments with high concentrations of total metals and a predicted severe effect levels for the organisms. This was also suggested by the abundance of total bacteria as determined by DAPI counts, with high bacterial cell numbers even in contaminated areas. However, a fraction of metals may be bioavailable as it was shown for chironomid larvae which were able to accumulate an important quantity of metals in surface sediments within just a few days.We concluded that (1) the best approach to estimate bioavailability in the selected sediments is a combination of geochemical and biological approaches and that (2) the sediments in the Deûle and Scarpe Rivers are highly contaminated and may impact bacterial populations but also benthic invertebrates.


Variations in hip fracture hospitalization rates among different race/ethnicity groups in New York City.
Hip fractures are a major cause of death and disability among the elderly. Although previous studies have shown hip fracture rates to be highest among Whites, and lowest among Blacks, less is known about how these differences are affected by gender and age. We determined the hip fracture hospitalization rates for non-Hispanic Whites, Blacks, Hispanics, and Asians in New York City from 1988 to 2002 using Statewide Planning and Resource Cooperative System data from the New York state Department of Health. We found that hip fracture hospitalization rates for those aged 50 and older were higher for women than men, with a risk ratio of 1.75 (95% confidence interval [CI] 1.73-1.77). Annual age-adjusted hip fracture hospitalization rates among White, Black, Hispanic, and Asian women were 459, 137, 143, and 174 per 100,000, respectively. The corresponding rates for men were 230, 109, 87, and 104, respectively. For both genders, and all race/ethnicity groups, the rates increased sharply with age. Although overall, women had higher rates compared to men, these differences varied by race and age. For Whites and Asians, women had higher rates for all age groups older than 50 years. For Hispanics aged 50-59, men had a higher rate than did women, but this gender relationship reversed after age 60. For Blacks, however, men had higher rates than women until age 70, after which women had higher rates. These results demonstrate that race/ethnicity, as well as age and gender, influence the incidence of hip fractures. Moreover, Asians, with their low bone mass, showed no increased hip fractures, compared to non-Hispanic Blacks and Hispanics. Further study is needed to explain this paradox.


Groups or teams in health care: finding the best fit.
In the evolution of the team concept, clear distinctions between 'groups' and 'teams' were made. In this paper we argue that these distinctions were not made explicit in the translation of team structures to health care. Even though teams are appropriate for many health care settings, this paper explores the notion that when teams may not be working, it is the concept of team that may not be appropriate, not the functioning of the team itself. This paper reviews the differences between teams and groups, and identifies how these differences are expressed in health care settings using urban and rural examples from the UK and Australia. Some suggestions about matching structures to suit the unique nature of health care provision, particularly in community health settings, are made. Instead of concentrating on improving the process of teams, the focus could be better directed to ensure that whatever structure is utilized best facilitates the necessary outcomes in the most effective way. The team approach may not always be the best approach, and sometimes referring to a number of people working together as a group is sufficient.


The limits on trypanosomatid morphological diversity.
Cell shape is one, often overlooked, way in which protozoan parasites have adapted to a variety of host and vector environments and directional transmissions between these environments. Consequently, different parasite life cycle stages have characteristic morphologies. Trypanosomatid parasites are an excellent example of this in which large morphological variations between species and life cycle stage occur, despite sharing well-conserved cytoskeletal and membranous structures. Here, using previously published reports in the literature of the morphology of 248 isolates of trypanosomatid species from different hosts, we perform a meta-analysis of the occurrence and limits on morphological diversity of different classes of trypanosomatid morphology (trypomastigote, promastigote, etc.) in the vertebrate bloodstream and invertebrate gut environments. We identified several limits on cell body length, cell body width and flagellum length diversity which can be interpreted as biomechanical limits on the capacity of the cell to attain particular dimensions. These limits differed for morphologies with and without a laterally attached flagellum which we suggest represent two morphological superclasses, the 'juxtaform' and 'liberform' superclasses. Further limits were identified consistent with a selective pressure from the mechanical properties of the vertebrate bloodstream environment; trypanosomatid size showed limits relative to host erythrocyte dimensions. This is the first comprehensive analysis of the limits of morphological diversity in any protozoan parasite, revealing the morphogenetic constraints and extrinsic selection pressures associated with the full diversity of trypanosomatid morphology.


Supplemental transscleral diode laser cyclophotocoagulation after aqueous shunt placement in refractory glaucoma.
To assess the outcome of supplemental transscleral diode laser cyclophotocoagulation after aqueous tube shunt placement to obtain effective intraocular pressure (IOP) control. Retrospective non-comparative case series. Twenty-one eyes in 21 subjects with uncontrolled IOP despite the presence of an aqueous tube shunt and maximally tolerated glaucoma medications. Supplemental transscleral diode laser cyclophotocoagulation was performed. Reduction of intraocular pressure and reduction of glaucoma medications. Twelve adults and nine children underwent supplemental transscleral diode cyclophotocoagulation and were followed postoperatively for a mean of 26.9 +/- 13.4 (standard deviation [SD]) months (range, 7-58 months). Average IOP was significantly reduced from a preoperative level of 35.7 +/- 14.7 (SD) mmHg to a postoperative level of 13.6 +/- 7.1 (SD) mmHg (P < 0.001) with the mean number of medications significantly reduced to 1.5 +/- 1.3 (SD) (P < 0.001). Seven subjects (33%) had additional laser treatment to achieve IOP control. Six subjects who were therapy failures included three who developed no light perception in the setting of proliferative diabetic retinopathy, one subject with chronic angle-closure glaucoma who gradually developed no light perception after refusing further treatment or medication, and two subjects who developed retinal detachments. One child who was a qualified success underwent enucleation and debulking of an enlarging neurofibroma that caused significant proptosis and disfigurement. In cases of glaucoma that are uncontrolled despite a glaucoma aqueous tube shunt and multiple medications, adjunctive transscleral diode cyclophotocoagulation treatment(s) is a viable option to lower IOP.


[Nursing assistant care at the national Hansen's disease sanatorium in Japan: focusing on "autonomy of the life field" for physically and socially challenged residents].
Previous studies on sociology and cultural anthropology insist that it is impossible to provide sufficient autonomy to clients who enroll for group care at care facilities. The purpose of this study is to analyze the nature of nursing assistant care at the national Hansen's disease sanatorium in Japan. Semi-structured interviews were conducted with 39 nursing assistants and 6 head nurses who cared for physically and socially challenged residents at this sanatorium. The investigation revealed that as a result of facing huge conflicts in the caring process, the nursing assistants had learned to appreciate the inherent life and history of residents. Thus, the nursing assistants and residents were bound together by mutual trust with a view to maximize the "autonomy of the life field." Conflict had not stunted the self-affirmation of nursing assistants; moreover, mutual trust had reorganized the "relevant system pertaining to care" for nursing assistants, which consisted of "the unification of care" and "the equality of care." It is suggested that group care at this sanatorium promotes the "autonomy of the life field" by valuing conflicts between nursing assistants and residents.


Progressive Multifocal Leukoencephalopathy in Primary Immunodeficiencies.
Progressive multifocal leukoencephalopathy (PML) is a rare but severe demyelinating disease caused by the polyomavirus JC (JCV) in immunocompromised patients. We report a series of patients with primary immune deficiencies (PIDs) who developed PML. Retrospective observational study including PID patients with PML. Clinical, immunological, imaging features, and outcome are provided for each patient. Eleven unrelated patients with PIDs developed PML. PIDs were characterized by a wide range of syndromic or genetically defined defects, mostly with combined B and T cell impairment. Genetic diagnosis was made in 7 patients. Before the development of PML, 10 patients had recurrent infections, 7 had autoimmune and/or inflammatory manifestations, and 3 had a history of malignancies. Immunologic investigations showed CD4+ lymphopenia (median 265, range 50-344) in all cases. Six patients received immunosuppressive therapy in the year before PML onset, including prolonged steroid therapy in 3 cases, rituximab in 5 cases, anti-TNF-α therapy, and azathioprine in 1 case each. Despite various treatments, all but 1 patient died after a median of 8 months following PML diagnosis. PML is a rare but fatal complication of PIDs. Many cases are secondary to immunosuppressive therapy warranting careful evaluation before initiation subsequent immunosuppression during PIDs.


A virtual lymph node model to dissect the requirements for T-cell activation by synapses and kinapses.
The initiation of T-cell responses in lymph nodes requires T cells to integrate signals delivered by dendritic cells (DCs) during long-lasting contacts (synapses) or more transient interactions (kinapses). However, it remains extremely challenging to understand how a specific sequence of contacts established by T cells ultimately dictates T-cell fate. Here, we have coupled a computational model of T-cell migration and interactions with DCs with a real-time, flow cytometry-like representation of T-cell activation. In this model, low-affinity peptides trigger T-cell proliferation through kinapses but we show that this process is only effective under conditions of high DC densities and prolonged antigen availability. By contrast, high-affinity peptides favor synapse formation and a vigorous proliferation under a wide range of antigen presentation conditions. In line with the predictions, decreasing the DC density in vivo selectively abolished proliferation induced by the low-affinity peptide. Finally, our results suggest that T cells possess a biochemical memory of previous stimulations of at least 1-2 days. We propose that the stability of T-cell-DC interactions, apart from their signaling potency, profoundly influences the robustness of T-cell activation. By offering the ability to control parameters that are difficult to manipulate experimentally, the virtual lymph node model provides new possibilities to tackle the fundamental mechanisms that regulate T-cell responses elicited by infections or vaccines.


Gene bionetworks involved in the epigenetic transgenerational inheritance of altered mate preference: environmental epigenetics and evolutionary biology.
Mate preference behavior is an essential first step in sexual selection and is a critical determinant in evolutionary biology. Previously an environmental compound (the fungicide vinclozolin) was found to promote the epigenetic transgenerational inheritance of an altered sperm epigenome and modified mate preference characteristics for three generations after exposure of a gestating female. The current study investigated gene networks involved in various regions of the brain that correlated with the altered mate preference behavior in the male and female. Statistically significant correlations of gene clusters and modules were identified to associate with specific mate preference behaviors. This novel systems biology approach identified gene networks (bionetworks) involved in sex-specific mate preference behavior. Observations demonstrate the ability of environmental factors to promote the epigenetic transgenerational inheritance of this altered evolutionary biology determinant. Combined observations elucidate the potential molecular control of mate preference behavior and suggests environmental epigenetics can have a role in evolutionary biology.


Hurricane Sandy Evacuation Among World Trade Center Health Registry Enrollees in New York City.
Timely evacuation is vital for reducing adverse outcomes during disasters. This study examined factors associated with evacuation and evacuation timing during Hurricane Sandy among World Trade Center Health Registry (Registry) enrollees. The study sample included 1162 adults who resided in New York City's evacuation zone A during Hurricane Sandy who completed the Registry's Hurricane Sandy substudy in 2013. Factors assessed included zone awareness, prior evacuation experience, community cohesion, emergency preparedness, and poor physical health. Prevalence estimates and multiple logistic regression models of evacuation at any time and evacuation before Hurricane Sandy were created. Among respondents who evacuated for Hurricane Sandy (51%), 24% had evacuated before the storm. In adjusted analyses, those more likely to evacuate knew they resided in an evacuation zone, had evacuated during Hurricane Irene, or reported pre-Sandy community cohesion. Evacuation was less likely among those who reported being prepared for an emergency. For evacuation timing, evacuation before Hurricane Sandy was less likely among those with pets and those who reported 14 or more poor physical health days. Higher evacuation rates were observed for respondents seemingly more informed and who lived in neighborhoods with greater social capital. Improved disaster messaging that amplifies these factors may increase adherence with evacuation warnings. (Disaster Med Public Health Preparedness. 2016;10:411-419).


Selective Laser-Assisted Synthesis of Tubular van der Waals Heterostructures of Single-Layered PbI2 within Carbon Nanotubes Exhibiting Carrier Photogeneration.
The electronic and optical properties of two-dimensional layered materials allow the miniaturization of nanoelectronic and optoelectronic devices in a competitive manner. Even larger opportunities arise when two or more layers of different materials are combined. Here, we report on an ultrafast energy efficient strategy, using laser irradiation, which allows bulk synthesis of crystalline single-layered lead iodide in the cavities of carbon nanotubes by forming cylindrical van der Waals heterostructures. In contrast to the filling of van der Waals solids into carbon nanotubes by conventional thermal annealing, which favors the formation of inorganic nanowires, the present strategy is highly selective toward the growth of monolayers forming lead iodide nanotubes. The irradiated bulk material bearing the nanotubes reveals a decrease of the resistivity as well as a significant increase in the current flow upon illumination. Both effects are attributed to the presence of single-walled lead iodide nanotubes in the cavities of carbon nanotubes, which dominate the properties of the whole matrix. The present study brings in a simple, ultrafast and energy efficient strategy for the tailored synthesis of rolled-up single-layers of lead iodide (i.e., single-walled PbI2 nanotubes), which we believe could be expanded to other two-dimensional (2D) van der Waals solids. In fact, initial tests with ZnI2 already reveal the formation of single-walled ZnI2 nanotubes, thus proving the versatility of the approach.


Isolated polyethylene exchange versus acetabular revision for polyethylene wear.
Polyethylene wear and osteolysis are not uncommon in THA mid- and long-term. In asymptomatic patients the dilemma faced by the orthopaedic surgeon is whether to revise the cup and risk damage to the supporting columns and even pelvic discontinuity or to perform isolated polyethylene exchange and risk a high rate of postoperative recurrent instability and dislocation that will necessitate further surgery. We retrospectively reviewed 62 patients (67 hips) who underwent revision arthroplasty for polywear and osteolysis. Thirty-six hips had isolated polyethylene exchange, while 31 had full acetabular revision. The minimum followup was 2 years (mean, 2.8 years; range, 2-5 years). Three of 36 hips with a retained cup grafted through the cup holes failed within 5 years due to acetabular loosening. One of 31 hips with full revision underwent re-revision for aseptic cup loosening at 5 months postoperatively. Although we do not recommend prophylactic revision of all cups for polywear and osteolysis, the patient may be warned of the possibility of an approximate 10% failure rate when retaining the acetabular component. We do, however, advocate cup extraction in the following situations: damage to the locking mechanism, erosion of the femoral head through the liner and into the cup damaging the metal, and a malpositioned component that may jeopardize the stability of the revision. Level II, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.


HLA-A, B and DRB1 genetic heterogeneity in Quebec.
Recent studies have shown that under specific conditions such as high sample sizes and Hardy-Weinberg equilibrium, bone marrow donor registry data can be used to describe HLA molecular variation across a specific geographic area, thus providing excellent data sets to infer human migrations history. The province of Quebec is known to have experienced a complex history of settlement, characterized by multiple migrations and demographic changes. We thus analysed the data of more than 13 000 unrelated individuals acting as volunteer bone marrow donors who were molecularly typed for HLA-A, B and DRB1 polymorphisms in the Héma-Quebec registry. HLA allelic and haplotypic frequencies were estimated and compared among regions. The results indicate that, despite an overall low genetic diversity in Quebec, genetic variation is correlated with geography, compatible with isolation-by-distance across the province. However, some localities also harbour contrasting genetic profiles, that is a highly diversified genetic pool in the two main urban centres (Montréal and Laval) and a more pronounced genetic divergence of two specific regions characterized by a peculiar peopling history (Saguenay-Lac-St-Jean and Gaspésie-Îles-De-La-Madeleine). In agreement with other independent molecular markers, the observations based on HLA data thus account for the main demographic mechanisms that shaped the genetic structure of the present day Quebecer population. In addition, the detailed analysis of the Héma-Quebec registry provides key genetic information on which an efficient bone marrow transplantation recruitment strategy can be settled.


An effective nanosensor for organic molecules based on water-soluble mercaptopropionic acid-capped CdTe nanocrystals with potential application in high-throughput screening and high-resolution optical microscopy.
Specially-treated glass substrates coated with a thin film of water soluble mercaptopropionic acid (MPA) capped CdTe nanocrystals (NCs) were prepared and found to undergo photoluminescence changes by as much as 40% when micro-droplets of organic molecules were placed in the nanometer-range proximity of the NCs. This imaging technique involving close proximity between a nano-crystal and an organic molecule is found to provide a 2 × -3 × enhanced contrast ratio over the conventional method of fluorescence imaging. Photoluminescence of NCs is recoverable upon removal of the organic molecules, therefore validating these NCs as potential all-optical organic molecular nanosensors. Upon optimization and with proper instrumentation, these nano-crystals could eventually serve as point-detectors for purposes of super-resolution optical microscopy. No solvents are required for the proposed sensing mechanism since all solutions were dried under argon flow. Fluorophores and fluorescent proteins were investigated, including fluorescein, Rhodamine 6G, and green fluorescent protein (GFP). Furthermore, NC photoluminescence changes were systematically quantified as a function of the solution pH and of the organic molecule concentration. Long duration (> 40 minutes) continuous excitation studies were conducted in order to evaluate the reliability of the proposed sensing scheme.


Transcriptome-wide survey of pseudorabies virus using next- and third-generation sequencing platforms.
Pseudorabies virus (PRV) is an alphaherpesvirus of swine. PRV has a large double-stranded DNA genome and, as the latest investigations have revealed, a very complex transcriptome. Here, we present a large RNA-Seq dataset, derived from both short- and long-read sequencing. The dataset contains 1.3 million 100 bp paired-end reads that were obtained from the Illumina random-primed libraries, as well as 10 million 50 bp single-end reads generated by the Illumina polyA-seq. The Pacific Biosciences RSII non-amplified method yielded 57,021 reads of inserts (ROIs) aligned to the viral genome, the amplified method resulted in 158,396 PRV-specific ROIs, while we obtained 12,555 ROIs using the Sequel platform. The Oxford Nanopore's MinION device generated 44,006 reads using their regular cDNA-sequencing method, whereas 29,832 and 120,394 reads were produced by using the direct RNA-sequencing and the Cap-selection protocols, respectively. The raw reads were aligned to the PRV reference genome (KJ717942.1). Our provided dataset can be used to compare different sequencing approaches, library preparation methods, as well as for validation and testing bioinformatic pipelines.


Sperm proteomics reveals intensified selection on mouse sperm membrane and acrosome genes.
Spermatozoa are a focal point for the impact of sexual selection due to sperm competition and sperm-female interactions in a wide range of sexually reproducing organisms. In-depth molecular investigation of the ramifications of these selective regimes has been limited due to a lack of information concerning the molecular composition of sperm. In this study, we utilize three previously published proteomic data sets in conjunction with our whole mouse sperm proteomic analysis to delineate cellular regions of sperm most impacted by positive selection. Interspecific analysis reveals robust evolutionary acceleration of sperm cell membrane genes (which include genes encoding acrosomal and sperm cell surface proteins) relative to other sperm genes, and evidence for positive selection in approximately 22% of sperm cell membrane components was obtained using maximum likelihood models. The selective forces driving the accelerated evolution of these membrane proteins may occur at a number of locations during sperm development, maturation, and transit through the female reproductive tract where the sperm cell membrane and eventually the acrosome are exposed to the extracellular milieu and available for direct cell-cell interactions.


Peripheral pharmacokinetics of apomorphine in humans.
Apomorphine, a potent dopamine agonist, has been used in acute and chronic studies of parkinsonism and other neurological disorders. To define its peripheral pharmacokinetics, we administered apomorphine by subcutaneous injection, by subcutaneous infusion, and by intravenous infusion to 15 patients with parkinsonism and measured plasma apomorphine levels by high-performance liquid chromatography with electrochemical detection. The peak drug levels and area under the curve were closely correlated with the dose administered; time to peak was brief and was independent of dose. The variation in absorption was high between subjects but low within individual subjects. In 11 of 15 subjects, the disappearance of drug could be described by a two-compartment model, with a distribution half-life of 5 minutes and an elimination half-life of 33 minutes. The drug absorption, volume of distribution, plasma clearance, and half-lives were similar for subcutaneous injection, subcutaneous infusion, and intravenous infusion. We conclude that apomorphine is rapidly and completely absorbed from subcutaneous tissue, correlating with the rapid onset of clinical effects, and that the brief duration of clinical action of the drug is explained by its rapid clearance.


Distinct and common aspects of physical and psychological self-representation in the brain: A meta-analysis of self-bias in facial and self-referential judgements.
The neural representation of self is a fundamental question for brain research. Employing activation likelihood estimation (ALE) meta-analyses, we assessed the commonalities and distinctions between different components of the self by focusing on the 'physical' self and the 'psychological' self --assessed respectively through face processing and self-referential tasks. We first conducted ALE meta-analyses by computing the convergence of findings on brain activation in self-face recognition and self-referential studies respectively. Contrast and conjunction analyses of these two meta-analytic results were then applied to extract the distinctions and commonalities in self-face and self-reference tasks. Facial self processing was particularly associated with lateral brain regions with a right hemispheric dominance, while processing psychological self predominantly activated cortical midline structures, more specifically the anterior cingulate cortex/superior frontal cortex. In contrast, the conjunction analyses showed that the two aspects of self-processing recruit the dorsal anterior cingulate cortex and the left inferior frontal gyrus extending to the insula. A framework including both distinct and common neural representation of selfs is discussed.


QTL mapping in three tropical maize populations reveals a set of constitutive and adaptive genomic regions for drought tolerance.
Despite numerous published reports of quantitative trait loci (QTL) for drought-related traits, practical applications of such QTL in maize improvement are scarce. Identifying QTL of sizeable effects that express more or less uniformly in diverse genetic backgrounds across contrasting water regimes could significantly complement conventional breeding efforts to improve drought tolerance. We evaluated three tropical bi-parental populations under water-stress (WS) and well-watered (WW) regimes in Mexico, Kenya and Zimbabwe to identify genomic regions responsible for grain yield (GY) and anthesis-silking interval (ASI) across multiple environments and diverse genetic backgrounds. Across the three populations, on average, drought stress reduced GY by more than 50 % and increased ASI by 3.2 days. We identified a total of 83 and 62 QTL through individual environment analyses for GY and ASI, respectively. In each population, most QTL consistently showed up in each water regime. Across the three populations, the phenotypic variance explained by various individual QTL ranged from 2.6 to 17.8 % for GY and 1.7 to 17.8 % for ASI under WS environments and from 5 to 19.5 % for GY under WW environments. Meta-QTL (mQTL) analysis across the three populations and multiple environments identified seven genomic regions for GY and one for ASI, of which six mQTL on chr.1, 4, 5 and 10 for GY were constitutively expressed across WS and WW environments. One mQTL on chr.7 for GY and one on chr.3 for ASI were found to be 'adaptive' to WS conditions. High throughput assays were developed for SNPs that delimit the physical intervals of these mQTL. At most of the QTL, almost equal number of favorable alleles was donated by either of the parents within each cross, thereby demonstrating the potential of drought tolerant × drought tolerant crosses to identify QTL under contrasting water regimes.


Toxicology testing in fatally injured workers: a review of five years of Iowa FACE cases.
Toxicology testing of fatally injured workers is not routinely conducted. We completed a case-series study of 2005-2009 occupational fatalities captured by Iowa's Fatality Assessment and Control Evaluation (FACE) Program. The goals of our research were to: (1) measure the proportion of FACE cases that undergo toxicology testing, and describe the factors associated with being tested, and (2) measure the rate of positive toxicology tests, the substances identified and the demographics and occupations of victims who tested positive. Case documents and toxicology laboratory reports were reviewed. There were 427 occupational deaths from 2005 to 2009. Only 69% underwent toxicology testing. Younger workers had greater odds of being tested. Among occupational groups, workers in farming, fishing and forestry had half the odds of being tested compared to other occupational groups. Of the 280 cases with toxicology tests completed, 22% (n = 61) were found to have positive toxicology testing. Commonly identified drug classes included cannabinoids and alcohols. Based on the small number of positive tests, older victims (65+ years) tested positive more frequently than younger workers. Management, business, science, arts, service and sales/office workers had proportionately more positive toxicology tests (almost 30%) compared with other workers (18-22%). These results identify an area in need of further research efforts and a potential target for injury prevention strategies.


Clinical trial: protective effect of a commercial fish protein hydrolysate against indomethacin (NSAID)-induced small intestinal injury.
A partially hydrolysed and dried product of pacific whiting fish is marketed as a health food supplement supporting 'intestinal health'. To examine whether the partially hydrolysed and dried product of pacific whiting fish influenced the small intestinal damaging side effects of the nonsteroidal anti-inflammatory drug, indomethacin. Eight human volunteers completed a double-blind, placebo-controlled, crossover protocol of clinically relevant dose of indomethacin (50 mg t.d.s. p.o. for 5 days) with 7 days of fish hydrolysate or placebo starting 2 days prior to indomethacin. Changes in gut permeability were assessed using 5 h urinary lactulose:rhamnose (L/R) ratios. Fish hydrolysate given alone did not affect permeability. In the main study (n = 8), baseline values were similar for both arms (0.28 +/- 0.05 and 0.35 +/- 0.07). Administration of indomethacin (+placebo) caused a fivefold rise in L/R ratios (increasing to 1.54 +/- 0.35), whereas L/R ratios in the same subjects ingesting indomethacin + fish hydrolysate was only 0.59 +/- 0.14 (P < 0.01 vs. indomethacin alone). Dyspeptic symptoms occurred in four of eight subjects taking indomethacin alone, but zero of eight when hydrolysate was co-administered. Natural bioactive products (nutriceuticals), such as fish hydrolysates, may provide a novel approach to the prevention and treatment of NSAID-induced and other gastrointestinal injurious conditions.


Endoscopic resection of gastric gastrointestinal stromal tumors.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal tract, and about 60% of them are found in the stomach. With the widespread application of endoscopy and endoscopic ultrasonography (EUS), more and more gastric GISTs are being found in an early stage (with a relative small diameter and no metastasis), giving the chance of complete resection. Endoscopic resection such as endoscopic band ligation (EBL), endoscopic submucosal dissection (ESD), endoscopic submucosal excavation (ESE), endoscopic full-thickness resection (EFTR) and submucosal tunneling endoscopic resection (STER), is a minimally invasive method compared with the conventional surgical approaches (open or laparoscopic), and has been demonstrated to be safe and effective for treating gastric GISTs. This review summarizes the recent advances on endoscopic resection of gastric GISTs, aiming to provide a rational management strategy for gastric GISTs.


Learning face perception without vision: Rebound learning effect and hemispheric differences in congenital vs late-onset blindness.
To address the longstanding questions of whether the blind-from-birth have an innate face-schema, what plasticity mechanisms underlie non-visual face learning, and whether there are interhemispheric face processing differences in face processing in the blind, we used a unique non-visual drawing-based training in congenitally blind (CB), late-blind (LB) and blindfolded-sighted (BF) groups of adults. This Cognitive-Kinesthetic Drawing approach previously developed by Likova (e.g., 2010, 2012, 2013) enabled us to rapidly train and study training-driven neuroplasticity in both the blind and sighted groups. The five-day two-hour training taught participants to haptically explore, recognize, memorize raised-line images, and draw them free-hand from memory, in detail, including the fine facial characteristics of the face stimuli. Such drawings represent an externalization of the formed memory. Functional MRI was run before and after the training. Tactile-face perception activated the occipito-temporal cortex in all groups. However, the training led to a strong, predominantly left-hemispheric reorganization in the two blind groups, in contrast to right-hemispheric in blindfolded-sighted, i.e., the post-training response-change was stronger in the left hemisphere in the blind, but in the right in the blindfolded. This is the first study to discover interhemispheric differences in non-visual face processing. Remarkably, for face perception this learning-based change was positive in the CB and BF groups, but negative in the LB-group. Both the lateralization and inversed-sign learning effects were specific to face perception, but absent for the control nonface categories of small objects and houses. The unexpected inversed-sign training effect in CB vs LB suggests different stages of brain plasticity in the ventral pathway specific to the face category. Importantly, the fact that only after a very few days of our training, the totally-blind-from-birth CB manifested a very good (haptic) face perception, and even developed strong empathy to the explored faces, implies a preexisting face schema that can be "unmasked" and "tuned up" by a proper learning procedure. The Likova Cognitive-Kinesthetic Training is a powerful tool for driving brain plasticity, and providing deeper insights into non-visual learning, including emergence of perceptual categories. A rebound learning model and a neuro-Bayesian economy principle are proposed to explain the multidimensional learning effects. The results provide new insights into the Nature-vs-Nurture interplay in rapid brain plasticity and neurorehabilitation.


Electrophysiological evidence of illusory audiovisual speech percept in human infants.
How effortlessly and quickly infants acquire their native language remains one of the most intriguing questions of human development. Our study extends this question into the audiovisual domain, taking into consideration visual speech cues, which were recently shown to have more importance for young infants than previously anticipated [Weikum WM, Vouloumanos A, Navarra J, Soto-Faraco S, Sebastián-Gallés N, Werker JF (2007) Science 316:1159]. A particularly interesting phenomenon of audiovisual speech perception is the McGurk effect [McGurk H, MacDonald J (1976) Nature 264:746-748], an illusory speech percept resulting from integration of incongruent auditory and visual speech cues. For some phonemes, the human brain does not detect the mismatch between conflicting auditory and visual cues but automatically assimilates them into the closest legal phoneme, sometimes different from both auditory and visual ones. Measuring event-related brain potentials in 5-month-old infants, we demonstrate differential brain responses when conflicting auditory and visual speech cues can be integrated and when they cannot be fused into a single percept. This finding reveals a surprisingly early ability to perceive speech cross-modally and highlights the role of visual speech experience during early postnatal development in learning of the phonemes and phonotactics of the native language.


Radiographic patterns and associations of osteoarthritis of the hip.
A number of patterns of osteoarthritis of the hip are described, though studies are conflicting with respect to the frequency of such patterns and their associations. Two hundred and eleven patients (133 women, 78 men; mean age 66 years, range 29-86) referred to hospital with osteoarthritis of the hip were studied. Involvement was unilateral in 108 (51%) and bilateral in 89 (42%); 14 (7%) had undergone arthroplasty and were presenting with osteoarthritis hips). Sixty one per cent of hips had severe, 28% moderate, and 11% mild changes (Kellgren grade). Superior pole migration occurred in 82% (46% superolateral, 25% intermediate, 11% superomedial), medial/axial migration occurred in only 8%, and in 10% the pattern was indeterminate. In bilateral osteoarthritis of the hip the pattern was generally symmetrical. Superomedial and medial/axial patterns were proportionately more common in women, whereas superlateral osteoarthritis predominated in men. No association was found between multiple clinical nodes, radiographic polyarticular interphalangeal or first carpometacarpal osteoarthritis and any migration pattern. Any interphalangeal osteoarthritis was negatively associated with medial migration. Only 40% of hips could be categorised as hypertrophic or atrophic; chondrocalcinosis at any site was associated with atrophic osteoarthritis; no associations were seen with Forestier's disease. This large survey confirms the association between chondrocalcinosis and atrophic osteoarthritis of the hip. Importantly it suggests that gender, rather than associated osteoarthritis at other sites, is a major determinant of the pattern of osteoarthritis of the hip.


Effective osteoporosis education in the outpatient orthopaedic setting.
The orthopaedic surgeon may be the first medical specialist to interact with a patient with clinically important osteoporosis, providing an opportunity to educate that patient about this disease. The purpose of the present study was to investigate whether patients could be effectively educated with regard to osteoporosis and lifestyle modification during their outpatient visits to an orthopaedic surgeon's office. Eighty female patients ranging from fifteen to seventy-three years of age completed an eleven-question quiz that included items regarding their knowledge of osteoporosis, calcium intake, menopausal status, exercise, smoking, and whether or not they had had a bone mineral density scan. The quiz was completed during a visit to an outpatient sports medicine/general orthopaedic clinic. After the quiz, an educational intervention was performed by providing the patients with an informational handout. The patients were followed at an average interval of six months and were reassessed either in the office or over the telephone with use of the same quiz to evaluate increases in knowledge and modification of lifestyle. Fifty-four premenopausal and twenty-six postmenopausal patients were available for follow-up. The premenopausal and postmenopausal groups differed at the beginning of the study, with premenopausal patients having a higher daily calcium intake (p = 0.008) and a better ability to define osteoporosis (p = 0.004) and postmenopausal patients having a higher rate of having had a prior bone mineral density scan (p < 0.001). In response to the educational intervention, significant improvements were seen in terms of the patients' ability to define osteoporosis (p = 0.004), the ability to identify being female as a major risk factor (p < 0.001), and the understanding that females should begin adequate calcium intake at a young age (p < 0.001). Significant increases in daily calcium intake (p < 0.001) and exercise level also occurred (p < 0.003). The postmenopausal group demonstrated a less robust response to the educational intervention. The outpatient orthopaedic sports medicine office setting represents a prime opportunity for education regarding osteoporosis prevention and lifestyle modification that can be performed in an inexpensive fashion and that can be easily replicated in most offices both in the community and in academic settings.


Generation of three iPSC lines (XACHi007-A, XACHi008-A, XACHi009-A) from a Chinese family with long QT syndrome type 5 with heterozygous c.226G>A (p.D76N) mutation in KCNE1gene.
Induced pluripotent stem cell lines (iPSCs) were generated from peripheral blood mononuclear cells (PBMCs) isolated from the peripheral blood of an eight months-old boy and the parents. Long QT syndrome type 5 (LQT5) was diagnosed after identifying a heterozygous c.226G>A (p.D76N) variant in KCNE1 gene carried by the boy and inherited from his father who has a prolonged QT in ECG as well. PBMCs were reprogrammed using non-integrative Sendai viral vectors containing reprogramming factors OCT4, SOX2, KLF4 and C-MYC. iPSCs were shown to express pluripotent markers, have trilineage differentiation potential, carry KCNE1-D76N mutation, have a normal karyotype. Thus we established 2 new LQT5 iPSC lines and a related control line as useful tools for studying the pathophysiological mechanism of LQT5 and drug testing.


Disruption of iron homeostasis increases phosphine toxicity in Caenorhabditis elegans.
The aim of this study is to identify the biochemical mechanism of phosphine toxicity and resistance, using Caenorhabditis elegans as a model organism. To date, the precise mode of phosphine action is unclear. In this report, we demonstrate the following dose-dependent actions of phosphine, in vitro: (1) reduction of ferric iron (Fe3+) to ferrous iron (Fe2+), (2) release of iron from horse ferritin, (3) and the peroxidation of lipid as a result of iron release from ferritin. Using in situ hybridization, we show that the ferritin genes of C. elegans, both ferritin-1 and ferritin-2, are expressed along the digestive tract with greatest expression at the proximal and distal ends. Basal expression of the ferritin-2 gene, as determined by quantitative PCR, is approximately 80 times that of ferritin-1. However, transcript levels of ferritin-1 are induced at least 20-fold in response to phosphine, whereas there is no change in the level of ferritin-2. This resembles the reported pattern of ferritin gene regulation by iron, suggesting that phosphine toxicity may be related to an increase in the level of free iron. Indeed, iron overload increases phosphine toxicity in C. elegans at least threefold. Moreover, we demonstrate that suppression of ferritin-2 gene expression by RNAi, significantly increases sensitivity to phosphine. This study identifies similarities between phosphine toxicity and iron overload and demonstrates that phosphine can trigger iron release from storage proteins, increasing lipid peroxidation, leading to cell injury and/or cell death.


Vestibular and optokinetic nystagmus in ketamine-anesthetized rabbits.
The aim of this work has been to analyze the modification of vestibular and optokinetic nystagmus in animals after administration of therapeutic doses of ketamine. Three healthy rabbits (two reds and one white), weighing between 2.5 and 3 kg, were submitted to electronystagmography recording. The rabbits, head blocked, were placed on a Tönnies rotatory chair in the middle of a rotatory cylindrical chamber, the internal area of which was covered with 32 black vertical contrasts. All the rabbits underwent rotatory vestibular stimulation by stop test and optokinetic stimulation. After each test and a rest period for the animals, we administered 10 mg/kg of ketamine and performed the same ENG workup. In the first (red) rabbit, we collected eye-movement data at 3 minutes and 40 minutes after the intramuscular injection of a single dose of ketamine (10 mg/kg). In the second (white) rabbit, we performed ENG recording with the animal under anesthesia for the entire time of the test; in the third (red) rabbit, we analyzed the optokinetic response, from the administration of the drug until the end of its effects. Our data highlight the action of the drug on the structures that control the ocular movements and led to the conclusion of the presence of a second feedback integrator.


A S-adenosylmethionine methyltransferase-like domain within the essential, Fe-S-containing yeast protein Dre2.
Yeast Dre2 is an essential Fe-S cluster-containing protein that has been implicated in cytosolic Fe-S protein biogenesis and in cell death regulation in response to oxidative stress. Its absence in yeast can be complemented by the human homologous antiapoptotic protein cytokine-induced apoptosis inhibitor 1 (also known as anamorsin), suggesting at least one common function. Using complementary techniques, we have investigated the biochemical and biophysical properties of Dre2. We show that it contains an N-terminal domain whose structure in solution consists of a stable well-structured monomer with an overall typical S-adenosylmethionine methyltransferase fold lacking two α-helices and a β-strand. The highly conserved C-terminus of Dre2, containing two Fe-S clusters, influences the flexibility of the N-terminal domain. We discuss the hypotheses that the activity of the N-terminal domain could be modulated by the redox activity of Fe-S clusters containing the C-terminus domain in vivo.


A genome scan for renal function among hypertensives: the HyperGEN study.
Decreased renal function is often a complication of hypertension. Although it has been suggested that the response of the kidney to hypertension has an underlying genetic component, there is limited information suggesting that specific genetic regions or candidate genes contribute to the variability in creatinine clearance, a commonly used measure of kidney function. As part of the Hypertension Genetic Epidemiology Network (HyperGEN) study, creatinine clearance measurements were assessed in a large biracial sample of hypertensive siblings (466 African American subjects and 634 white subjects in 215 and 265 sibships, respectively). All participants were hypertensive before the age of 60 years, and the mean age of the siblings was 52 years among the African American subjects and 61 years among the white subjects. Two residual models were created for creatinine clearance: a minimally adjusted model (which included age and age(2)) and a fully adjusted model (which included age, age(2), lean body mass, pulse rate, pulse pressure, hormone-replacement therapy, educational status, and physical activity). Standardized residuals were calculated separately for men and women in both racial groups. The heritability of the residual creatinine clearance was 17% and 18% among the African American and white subjects, respectively. We conducted multipoint variance components linkage analysis using GENEHUNTER2 and 387 anonymous markers (Cooperative Human Linkage Center screening set 8). The best evidence for linkage in African American subjects was found on chromosome 3 (LOD = 3.61 at 214.6 cM, 3q27) with the fully adjusted model, and the best evidence in white subjects was found on chromosome 3 (LOD = 3.36 at 115.1 cM) with the minimally adjusted model. Positional candidate genes that are contained in and around the region on chromosome 3 (214.6 cM) that may contribute to renal function include enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase (EHHADH) and apolipoprotein D (ApoD). These findings suggest there may be genetic regions related to the variability of creatinine clearance among hypertensive individuals.


Rifampicin resistance in Mycobacterium tuberculosis--rapid detection and implications in chemotherapy.
Tuberculosis treatment and susceptibility testing are cumbersome, especially in the case of multidrug-resistant (MDR) Mycobacterium tuberculosis. It is known that mutations in the rpoB gene of M. tuberculosis lead to resistance to rifampicin (RMP). In this study, an attempt was made to apply molecular techniques for rapid detection of antibiotic resistance in clinical isolates of M. tuberculosis. DESIGN, SETTINGS AND SUBJECTS: RMP-resistant clinical isolates of M. tuberculosis from South Africa (N = 120) with unique resistant patterns were selected for calculation of resistance frequencies, and 74 MDR isolates of M. tuberculosis from different geographical origins were used for microbiological and molecular analysis. The polymerase chain reaction (PCR) technique was applied for amplification of a previously described region around a cluster of mutations in the rpoB gene, and single-stranded conformational polymorphism (SSCP) analysis was optimised to screen for mutations in the amplified region. The results showed that an optimised PCR-SSCP procedure could detect a cluster of mutations in the rpoB gene (for RMP resistance) in 95% of RMP-resistant isolates. This procedure could therefore be used in the prediction of RMP resistance. Evidence was obtained that these mutations can be screened for directly from BACTEC cultures or even directly from Ziehl-Neelsen-positive sputum samples. Statistical analysis also showed that this locus can be used to predict the presence of an MDR isolate, which may have important implications in decisions concerning chemotherapy. It is currently not feasible to test all tuberculosis cases, but application of the PCR-SSCP technology in the prediction of multidrug resistance in M. tuberculosis isolates may be important in patients, especially where frequencies are high for drug-resistant isolates This methodology could reduce the time required for sensitivity testing from approximately 6-12 weeks to a few days.


Small molecules and Alzheimer's disease: misfolding, metabolism and imaging.
Small molecule interactions with amyloid proteins have had a huge impact in Alzheimer's disease (AD), especially in three specific areas: amyloid folding, metabolism and brain imaging. Amyloid plaque amelioration or prevention have, until recently, driven drug development, and only a few drugs have been advanced for use in AD. Amyloid proteins undergo misfolding and oligomerization via intermediates, eventually forming protease resistant amyloid fibrils. These fibrils accumulate to form the hallmark amyloid plaques and tangles of AD. Amyloid binding compounds can be grouped into three categories, those that: i) prevent or reverse misfolding, ii) halt misfolding or trap intermediates, and iii) accelerate the formation of stable and inert amyloid fibrils. Such compounds include hydralazine, glycosaminoglycans, curcumin, beta sheet breakers, catecholamines, and ATP. The versatility of amyloid binding compounds suggests that the amyloid structure may serve as a scaffold for the future development of sensors to detect such compounds. Metabolic dysfunction is one of the earliest pathological features of AD. In fact, AD is often referred to as type 3 diabetes due to the presence of insulin resistance in the brain. A recent study indicates that altering metabolism improves cognitive function. While metabolic reprogramming is one therapeutic avenue for AD, it is more widely used in some cancer therapies. FDA approved drugs such as metformin, dichloroacetic acid (DCA), and methylene blue can alter metabolism. These drugs can therefore be potentially applied in alleviating metabolic dysfunction in AD. Brain imaging has made enormous strides over the past decade, offering a new window to the mind. Recently, there has been remarkable development of compounds that have the ability to image both types of pathological amyloids: tau and amyloid beta. We have focused on the low cost, simple to use, near infrared fluorescence (NIRF) imaging probes for amyloid beta (Aβ), with specific attention on recent developments to further improve contrast, specificity, and sensitivity. With advances in imaging technologies, such fluorescent imaging probes will open new diagnostic avenues.


Smoking concordance in lung and colorectal cancer patient-caregiver dyads and quality of life.
Distress may be heightened among members of cancer patient-caregiver dyads that are mismatched on smoking status (either the patient or caregiver smokes, but the other does not), negatively affecting quality of life (QoL). The purpose of this study was to examine associations between patient-caregiver smoking concordance, caregiver psychological adjustment, and caregiver and patient mental and physical QoL. Lung and colorectal patient-caregiver dyads (N = 742) were identified from the Cancer Care Outcomes Research and Surveillance (CanCORS) and CanCORS Caregiver studies. The majority of the cancer patients were male (67.0%) with local (45.6%) or regional (12.9%) disease. The majority of the informal caregivers were females (78.6%), under 65 years of age (69.6%), and often spouses (57.8%) of the patients. Lung and colorectal cancer caregivers, who were members of dyads where one or both members continued to smoke, reported worse mental health QoL than nonsmoking dyads. For colorectal cancer patients, continuing to smoke when the caregiver did not was associated with worse mental health QoL compared with nonsmoking dyads. Dyad smoking was less strongly associated with physical QoL for both caregivers and patients. Results highlight the importance of assessing smoking in both cancer patients and their caregivers and referring families to appropriate psychosocial and smoking cessation services. This is the first study to show associations between cancer patient-caregiver smoking status and QoL for both dyad members. Future studies will need to confirm these associations longitudinally and investigate potential mechanisms linking dyad smoking and QoL.


Ecosystem response persists after a prolonged marine heatwave.
Some of the longest and most comprehensive marine ecosystem monitoring programs were established in the Gulf of Alaska following the environmental disaster of the Exxon Valdez oil spill over 30 years ago. These monitoring programs have been successful in assessing recovery from oil spill impacts, and their continuation decades later has now provided an unparalleled assessment of ecosystem responses to another newly emerging global threat, marine heatwaves. The 2014-2016 northeast Pacific marine heatwave (PMH) in the Gulf of Alaska was the longest lasting heatwave globally over the past decade, with some cooling, but also continued warm conditions through 2019. Our analysis of 187 time series from primary production to commercial fisheries and nearshore intertidal to offshore oceanic domains demonstrate abrupt changes across trophic levels, with many responses persisting up to at least 5 years after the onset of the heatwave. Furthermore, our suite of metrics showed novel community-level groupings relative to at least a decade prior to the heatwave. Given anticipated increases in marine heatwaves under current climate projections, it remains uncertain when or if the Gulf of Alaska ecosystem will return to a pre-PMH state.


Large-scale functional networks connect differently for processing words and symbol strings.
Reconfigurations of synchronized large-scale networks are thought to be central neural mechanisms that support cognition and behavior in the human brain. Magnetoencephalography (MEG) recordings together with recent advances in network analysis now allow for sub-second snapshots of such networks. In the present study, we compared frequency-resolved functional connectivity patterns underlying reading of single words and visual recognition of symbol strings. Word reading emphasized coherence in a left-lateralized network with nodes in classical perisylvian language regions, whereas symbol processing recruited a bilateral network, including connections between frontal and parietal regions previously associated with spatial attention and visual working memory. Our results illustrate the flexible nature of functional networks, whereby processing of different form categories, written words vs. symbol strings, leads to the formation of large-scale functional networks that operate at distinct oscillatory frequencies and incorporate task-relevant regions. These results suggest that category-specific processing should be viewed not so much as a local process but as a distributed neural process implemented in signature networks. For words, increased coherence was detected particularly in the alpha (8-13 Hz) and high gamma (60-90 Hz) frequency bands, whereas increased coherence for symbol strings was observed in the high beta (21-29 Hz) and low gamma (30-45 Hz) frequency range. These findings attest to the role of coherence in specific frequency bands as a general mechanism for integrating stimulus-dependent information across brain regions.


Computational prediction and experimental validation associating FABP-1 and pancreatic adenocarcinoma with diabetes.
Pancreatic cancer, composed principally of pancreatic adenocarcinoma (PaC), is the fourth leading cause of cancer death in the United States. PaC-associated diabetes may be a marker of early disease. We sought to identify molecules associated with PaC and PaC with diabetes (PaC-DM) using a novel translational bioinformatics approach. We identified fatty acid binding protein-1 (FABP-1) as one of several candidates. The primary aim of this pilot study was to experimentally validate the predicted association between FABP-1 with PaC and PaC with diabetes. We searched public microarray measurements for genes that were specifically highly expressed in PaC. We then filtered for proteins with known involvement in diabetes. Validation of FABP-1 was performed via antibody immunohistochemistry on formalin-fixed paraffin embedded pancreatic tissue microarrays (FFPE TMA). FFPE TMA were constructed using 148 cores of pancreatic tissue from 134 patients collected between 1995 and 2002 from patients who underwent pancreatic surgery. Primary analysis was performed on 21 normal and 60 pancreatic adenocarcinoma samples, stratified for diabetes. Clinical data on samples was obtained via retrospective chart review. Serial sections were cut per standard protocol. Antibody staining was graded by an experienced pathologist on a scale of 0-3. Bivariate and multivariate analyses were conducted to assess FABP-1 staining and clinical characteristics. Normal samples were significantly more likely to come from younger patients. PaC samples were significantly more likely to stain for FABP-1, when FABP-1 staining was considered a binary variable. Compared to normals, there was significantly increased staining in diabetic PaC samples (p = 0.004) and there was a trend towards increased staining in the non-diabetic PaC group (p = 0.07). In logistic regression modeling, FABP-1 staining was significantly associated with diagnosis of PaC (OR 8.6 95% CI 1.1-68, p = 0.04), though age was a confounder. Compared to normal controls, there was a significant positive association between FABP-1 staining and PaC on FFPE-TMA, strengthened by the presence of diabetes. Further studies with closely phenotyped patient samples are required to understand the true relationship between FABP-1, PaC and PaC-associated diabetes. A translational bioinformatics approach has potential to identify novel disease associations and potential biomarkers in gastroenterology.


Assessment of agitation in Alzheimer's disease: the agitated behavior in dementia scale. Alzheimer's Disease Cooperative Study.
To develop and evaluate the psychometric properties of a new measure of agitation, the Agitated Behavior in Dementia scale (ABID). The ABID consists of 16 items designed specifically to evaluate frequency of and caregiver reaction to common agitated behaviors in community-residing dementia patients. The ABID was administered at the baseline assessment of a multi-site controlled treatment study to reduce agitation in Alzheimer's Disease (AD). Reliability was assessed by evaluating internal consistency and test-retest correlations. Validity was assessed by examining correlations with other constructs, including demographics, cognitive status, and overall behavioral disturbance. Twenty-one sites across the US, comprising the Alzheimer's Disease Cooperative Study, contributed subjects to the investigation. A total of 148 community-residing AD patients, living with a spouse or adult relative who acted as an informant. Mean age was 75 years, and mean Mini-Mental State Exam (MMSE) score was 13. Cognitive status was assessed using the MMSE. Behavioral disturbance was assessed using the Behavior Rating Scale for Dementia of the Consortium to Establish a Registry for Alzheimer's Disease, the Revised Memory and Behavior Problems Checklist, and the Cohen-Mansfield Agitation Inventory. Reliability of the ABID was excellent, with internal consistency of 0.70 and test-retest reliability of 0.60 to 0.73. Validity was confirmed by correlations with related measures and lack of correlation with unrelated constructs. The ABID is brief, easy to administer, and provides objectively anchored observations of problems. It is a promising measure for studies of community-residing AD patients.


LTR retroelements are intrinsic components of transcriptional networks in frogs.
LTR retroelements (LTR REs) constitute a major group of transposable elements widely distributed in eukaryotic genomes. Through their own mechanism of retrotranscription LTR REs enrich the genomic landscape by providing genetic variability, thus contributing to genome structure and organization. Nonetheless, transcriptomic activity of LTR REs still remains an obscure domain within cell, developmental, and organism biology. Here we present a first comparative analysis of LTR REs for anuran amphibians based on a full depth coverage transcriptome of the European pool frog, Pelophylax lessonae, the genome of the African clawed frog, Silurana tropicalis (release v7.1), and additional transcriptomes of S. tropicalis and Cyclorana alboguttata. We identified over 1000 copies of LTR REs from all four families (Bel/Pao, Ty1/Copia, Ty3/Gypsy, Retroviridae) in the genome of S. tropicalis and discovered transcripts of several of these elements in all RNA-seq datasets analyzed. Elements of the Ty3/Gypsy family were most active, especially Amn-san elements, which accounted for approximately 0.27% of the genome in Silurana. Some elements exhibited tissue specific expression patterns, for example Hydra1.1 and MuERV-like elements in Pelophylax. In S. tropicalis considerable transcription of LTR REs was observed during embryogenesis as soon as the embryonic genome became activated, i.e. at midblastula transition. In the course of embryonic development the spectrum of transcribed LTR REs changed; during gastrulation and neurulation MuERV-like and SnRV like retroviruses were abundantly transcribed while during organogenesis transcripts of the XEN1 retroviruses became much more active. The differential expression of LTR REs during embryogenesis in concert with their tissue-specificity and the protein domains they encode are evidence for the functional roles these elements play as integrative parts of complex regulatory networks. Our results support the meanwhile widely accepted concept that retroelements are not simple "junk DNA" or "harmful genomic parasites" but essential components of the transcriptomic machinery in vertebrates.


Rb1 and Pten Co-Deletion in Osteoblast Precursor Cells Causes Rapid Lipoma Formation in Mice.
The Rb and Pten tumor suppressor genes are important regulators of bone development and both are frequently mutated in the bone cancer osteosarcoma (OS). To determine if Rb1 and Pten synergize as tumor suppressor genes for osteosarcoma, we co-deleted them in osteoprogenitor cells. Surprisingly, we observed rapid development of adipogenic but not osteosarcoma tumors in the ΔRb1/Pten mice. ΔPten solo deleted mice also developed lipoma tumors but at a much reduced frequency and later onset than those co-deleted for Rb1. Pten deletion also led to a marked increase in adipocytes in the bone marrow. To better understand the function of Pten in bone development in vivo, we conditionally deleted Pten in OSX(+) osteoprogenitor cells using OSX-Cre mice. μCT analysis revealed a significant thickening of the calvaria and an increase in trabeculae volume and number in the femur, consistent with increased bone formation in these mice. To determine if Pten and Rb1 deletion actively promotes adipogenic differentiation, we isolated calvarial cells from Pten(fl/fl) and Pten(fl/fl); Rb1(fl/fl) mice, infected them with CRE or GFP expressing adenovirus, treated with differentiation media. We observed slightly increased adipogenic, and osteogenic differentiation in the ΔPten cells. Both phenotypes were greatly increased upon Rb1/Pten co-deletion. This was accompanied by an increase in expression of genes required for adipogenesis. These data indicate that Pten deletion in osteoblast precursors is sufficient to promote frequent adipogenic, but only rare osteogenic tumors. Rb1 hetero- or homo-zygous co-deletion greatly increases the incidence and the rapidity of onset of adipogenic tumors, again, with only rare osteosarcoma tumors.


Highly versatile antibody binding assay for the detection of SARS-CoV-2 infection and vaccination.
Monitoring the burden and spread of infection with the new coronavirus SARS-CoV-2, whether within small communities or in large geographical settings, is of paramount importance for public health purposes. Serology, which detects the host antibody response to the infection, is the most appropriate tool for this task, since virus-derived markers are most reliably detected during the acute phase of infection. Here we show that our ELISA protocol, which is based on antibody binding to the Receptor Binding Domain (RBD) of the S1 subunit of the viral Spike protein expressed as a novel fusion protein, detects antibody responses to SARS-CoV-2 infection and vaccination. We also show that our ELISA is accurate and versatile. It compares favorably with commercial assays widely used in clinical practice to determine exposure to SARS-CoV-2. Moreover, our protocol accommodates use of various blood- and non-blood-derived biospecimens, such as breast milk, as well as dried blood obtained with microsampling cartridges that are appropriate for remote collection. As a result, our RBD-based ELISA protocols are well suited for seroepidemiology and other large-scale studies requiring parsimonious sample collection outside of healthcare settings.


Trajectories of medical service use among girls and boys with and without early-onset conduct problems.
Children with conduct problems (CP) have been found to be heavy and costly medical service users in adulthood. However, there is little knowledge on how medical service use develops during childhood and adolescence among youth with and without childhood CP. Knowing whether differences in developmental trajectories of medical service use for specific types of problems (e.g., injuries) are predicted by childhood CP would help clinicians identify developmental periods during which they might intensify interventions for young people with CP in order to prevent later problems and associated increased service use. Participants were drawn from an ongoing longitudinal study of boys and girls with and without childhood CP as rated by parents and teachers. Medical service use was assessed using administrative data from a public single payer health plan. Latent growth modeling was used to estimate the mean trajectory of four types of medical visits (psychiatric, injury-related, preventative, total visits) across time and evaluate the effect of CP and other covariates. Support the hypothesis that early CP predicts higher medical service use at nine years old, and that this difference persists in a chronic manner over time, even when controlling the effects of ADHD and family income. Girls had fewer medical visits for psychiatric reasons than boys at baseline, but this difference diminished over time. Clinicians should be aware that childhood CP already predicts increased medical service use in elementary school. Issues specific to different contexts in which injuries might occur and sex differences are discussed.


A machine learning interpretation of the contribution of foliar fungicides to soybean yield in the north-central United States.
Foliar fungicide usage in soybeans in the north-central United States increased steadily over the past two decades. An agronomically-interpretable machine learning framework was used to understand the importance of foliar fungicides relative to other factors associated with realized soybean yields, as reported by growers surveyed from 2014 to 2016. A database of 2738 spatially referenced fields (of which 30% had been sprayed with foliar fungicides) was fit to a random forest model explaining soybean yield. Latitude (a proxy for unmeasured agronomic factors) and sowing date were the two most important factors associated with yield. Foliar fungicides ranked 7th out of 20 factors in terms of relative importance. Pairwise interactions between latitude, sowing date and foliar fungicide use indicated more yield benefit to using foliar fungicides in late-planted fields and in lower latitudes. There was a greater yield response to foliar fungicides in higher-yield environments, but less than a 100 kg/ha yield penalty for not using foliar fungicides in such environments. Except in a few production environments, yield gains due to foliar fungicides sufficiently offset the associated costs of the intervention when soybean prices are near-to-above average but do not negate the importance of disease scouting and fungicide resistance management.


Clinical features and survival among children with retinoblastoma in Uganda.
To characterise the clinical features, treatment and outcome of children diagnosed with retinoblastoma in Uganda. The study comprised a 6-year nationwide enrolment with follow-up. In total, 282 cases were enrolled, 26% (72) were bilateral; 6% were lost to follow-up. Almost all diagnoses in the first affected eye were International Classification of Retinoblastoma group E or worse. Histology was available for 92%; of those, 45%, had extraocular tumour at diagnosis. Enucleation of the first eye was done for 271; 94 received radiotherapy to the socket and in the last 2 years, 70 children received chemotherapy. At close of study, 139 children had died. Survival, as determined in a proportional hazards model adjusted for age, sex, laterality and treatment era (pre or post introduction of chemotherapy), varied by extent of the tumour (p<0.001); children with only intraocular involvement were 80% less likely to die (HR=0.21, 95% CI 0.12 to 0.35) compared with children with extraocular involvement. Diagnostic delay results in relatively high mortality among children with retinoblastoma in Uganda. There is an urgent need for more effective treatment modalities, particularly chemotherapy, and nationwide efforts to encourage earlier access to medical care.


HIV Prevention 2020: a framework for delivery and a call for action.
Although effective programmes are available and several countries have seen substantial declines in new HIV infections, progress in the reduction of adult HIV incidence has been slower than expected worldwide and many countries have not had large decreases in new infections in adults despite large reductions in paediatric infections. Reasons for slow progress include inadequate commitment, investment, focus, scale, and quality of implementation of prevention and treatment interventions. The UNAIDS-Lancet Commission on Defeating AIDS-Advancing Global Health reported that the provision of large-scale, effective HIV prevention programmes has failed and called on stakeholders to "get serious about HIV prevention". An ambitious worldwide target has been set by UNAIDS to reduce new infections below 500 000 by 2020-a 75% reduction from 2010. Models show that such a reduction requires a combination of primary prevention interventions and preventative effects of treatment. Achievement of the target will require more effective delivery of HIV prevention for sufficient coverage in populations at greatest risk of infection ensuring that interventions that have proved effective are made available, barriers to their uptake are overcome, demand is created, and use is consistent and occurs at the right scale with high coverage. This paper discusses how programmatic targets for prevention in a worldwide plan could be used to re-energise the HIV prevention approach. A management framework is proposed outlining global, regional, national, and subnational actions and is summarised in a call for action on HIV prevention for 2020.


Identification of human long noncoding RNAs associated with nonalcoholic fatty liver disease and metabolic homeostasis.
A growing number of long noncoding RNAs (lncRNAs) have emerged as vital metabolic regulators. However, most human lncRNAs are nonconserved and highly tissue specific, vastly limiting our ability to identify human lncRNA metabolic regulators (hLMRs). In this study, we established a pipeline to identify putative hLMRs that are metabolically sensitive, disease relevant, and population applicable. We first progressively processed multilevel human transcriptome data to select liver lncRNAs that exhibit highly dynamic expression in the general population, show differential expression in a nonalcoholic fatty liver disease (NAFLD) population, and respond to dietary intervention in a small NAFLD cohort. We then experimentally demonstrated the responsiveness of selected hepatic lncRNAs to defined metabolic milieus in a liver-specific humanized mouse model. Furthermore, by extracting a concise list of protein-coding genes that are persistently correlated with lncRNAs in general and NAFLD populations, we predicted the specific function for each hLMR. Using gain- and loss-of-function approaches in humanized mice as well as ectopic expression in conventional mice, we validated the regulatory role of one nonconserved hLMR in cholesterol metabolism by coordinating with an RNA-binding protein, PTBP1, to modulate the transcription of cholesterol synthesis genes. Our work overcame the heterogeneity intrinsic to human data to enable the efficient identification and functional definition of disease-relevant human lncRNAs in metabolic homeostasis.


Anakinra treatment in drug-resistant Behcet's disease: a case series.
The study objective was to report treatment with an interleukin (IL)-1 receptor antagonist, anakinra, in patients with multiorgan Behcet's disease (BD). Comparison of clinical manifestations, previous treatments, markers of inflammation, concomitant medications, treatment regimen modifications, relapses, and adverse events before and during anakinra administration among patients with BD were evaluated. Nine BD patients (mean age 34.55 ± 16.30 years) refractory to tumor necrosis factor blockers and standardized therapies are reported in our survey. Their mean age at disease onset was 25 ± 13.88 years and their overall disease duration was 9.55 ± 5.33 years. All patients were positive for the HLA-B51 allele. Within 1 or 2 weeks following the initiation of anakinra, eight out of nine patients promptly responded, and most of them were maintained on 100 mg of daily anakinra with low doses of prednisone. However, most patients experienced a relapse in one or more clinical manifestations over time (mean time to relapse 29 ± 21.65 weeks), and only one patient remained completely under control on anakinra monotherapy. Despite a relapse in one or more disease manifestations, treatment was continued in most patients for a mean period of 13.75 ± 6.49 months. No serious adverse events occurred. Eight out of nine refractory BD patients showed a prompt improvement after starting anakinra, supporting the concept that IL-1 plays a pathological role in this disease. Nevertheless, after several months, most patients experienced a relapse. It remains unclear whether increasing the dose of anakinra would have prevented the reoccurrence of disease activity.


Can homeostatic plasticity in deafferented primary auditory cortex lead to travelling waves of excitation?
Travelling waves of activity in neural circuits have been proposed as a mechanism underlying a variety of neurological disorders, including epileptic seizures, migraine auras and brain injury. The highly influential Wilson-Cowan cortical model describes the dynamics of a network of excitatory and inhibitory neurons. The Wilson-Cowan equations predict travelling waves of activity in rate-based models that have sufficiently reduced levels of lateral inhibition. Travelling waves of excitation may play a role in functional changes in the auditory cortex after hearing loss. We propose that down-regulation of lateral inhibition may be induced in deafferented cortex via homeostatic plasticity mechanisms. We use the Wilson-Cowan equations to construct a spiking model of the primary auditory cortex that includes a novel, mathematically formalized description of homeostatic plasticity. In our model, the homeostatic mechanisms respond to hearing loss by reducing inhibition and increasing excitation, producing conditions under which travelling waves of excitation can emerge. However, our model predicts that the presence of spontaneous activity prevents the development of long-range travelling waves of excitation. Rather, our simulations show short-duration excitatory waves that cancel each other out. We also describe changes in spontaneous firing, synchrony and tuning after simulated hearing loss. With the exception of shifts in characteristic frequency, changes after hearing loss were qualitatively the same as empirical findings. Finally, we discuss possible applications to tinnitus, the perception of sound without an external stimulus.


Prognostic Value of miRNAs in Head and Neck Cancers: A Comprehensive Systematic and Meta-Analysis.
Head and Neck Cancer (HNC) is the sixth most common type of cancer across the globe, with more than 300,000 deaths each year, globally. However, there are currently no standardised molecular markers that assist in determining HNC prognosis. The literature for this systematic review and meta-analysis were sourced from multiple bibliographic databases. This review followed PRISMA guidelines. The Hazard Ratio (HR) was selected as the effect size metric to independently assess overall survival (OS), disease-free survival (DFS), and prognosis. Subgroup analysis was performed for individual highly represented miRNA. A total of 6843 patients across 50 studies were included in the systematic review and 34 studies were included in the meta-analysis. Studies across 12 countries were assessed, with China representing 36.7% of all included studies. The analysis of the survival endpoints of OS and DFS were conducted separately, with the overall pooled effect size (HR) for each being 1.825 (95% CI 1.527-2.181; p < 0.05) and 2.596 (95% CI 1.917-3.515; p < 0.05), respectively. Subgroup analysis was conducted for impact of miR-21, 200b, 155, 18a, 34c-5p, 125b, 20a and 375 on OS, and miR-21 and 34a on DFS. The pooled results were found to be statistically significant for both OS and DFS. The meta-analysis indicated that miRNA alterations can account for an 82.5% decrease in OS probability and a 159.6% decrease in DFS probability. These results indicate that miRNAs have potential clinical value as prognostic biomarkers in HNC, with miR-21, 125b, 34c-5p and 18a, in particular, showing great potential as prognostic molecular markers. Further large scale cohort studies focusing on these miRNAs are recommended to verify the clinical utility of these markers individually and/or in combination.


The effects of hypoestrogenism on the vaginal wall: interference with the normal sexual response.
The sexual response depends on the adequate function of all systems related to the genital and extra-genital organs. Physiological conditions such as menopause can interfere with sexual expression because of central and peripheral changes. Genital effects of estrogen include vaginal trophism, lubrication, and local pleasure sensation in the sexual arousal phase. Hypoestrogenism causes changes in the four layers of the vaginal wall that may result in dyspareunia and a loss in the quality of the genital arousal response. The purpose of this review is to highlight the changes in the vaginal wall caused by hypoestrogenism, its possible relationship with dyspareunia, and its repercussions for genital arousal. Treatments for hypoestrogenism are also discussed. We evaluated the data available in PubMed (1982-2008) and surveyed the reference list for relevant studies. Two reviewers analyzed the data independently. A study was considered to be of high quality if it had all three of the following characteristics: (i) prospective design; (ii) valid data; and (iii) adequate sample size. Reviews and experimental animal studies were also considered. Normal genital morphology, hypoestrogenism and hormone replacement therapy were the focus of the studies reviewed in this paper. Atrophy of the vaginal wall may be associated with dyspareunia and genital sexual arousal disorder, but psychological and sociocultural aspects must also be considered. Regardless, however, local estrogen therapy is useful in improving vaginal wall trophism and, thus, in improving the sexual response. There are many possible alterations in the structure of the vaginal wall that are related to estrogen deficiency that may require medical intervention beyond the usual strategies used to attain adequate sexual function. Physicians should attempt to treat these alterations, and more research is needed to elucidate the physiopathology of dyspareunia and genital sexual arousal physiology.


Bacillus glycinifermentans sp. nov., isolated from fermented soybean paste.
Two independent isolates of a Gram-stain-positive, facultatively anaerobic, motile, rod-shaped bacterium were recovered from cheonggukjang, a Korean fermented soybean paste food product. Preliminary sequencing analysis of the 16S rRNA gene indicated that these strains were related most closely to Bacillus sonorensis KCTC-13918T and Bacillus licheniformis DSM 13T. In phenotypic characterization, the novel strains were found to grow between 15 and 55 °C and to tolerate up to 8 % (w/v) NaCl. Furthermore, the strains grew in media of pH 5-10 (optimal growth at pH 7.0). The predominant cellular fatty acids were anteiso-C15 : 0 and iso-C15 : 0.The isoprenoid quinone was menaquinone 7 (MK-7). The cell-wall peptidoglycan contained meso-diaminopimelic acid. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and an unknown glycolipid. Draft genomes of the two strains were determined and in silico DNA-DNA hybridizations with their nearest neighbour (B. sonorensis KCTC-13918T) revealed 29.9 % relatedness for both strains. Phylogenomic analysis of the genomes was conducted with the core genome (799 genes) of all strains in the Bacillus subtilis group and the two strains formed a distinct monophyletic cluster. In addition, the strains differed from the two most closely related species in that they did not metabolize maltose, d-galactose, d-sorbitol or d-gluconic acid. The DNA G+C content was 45.9 mol%. Based upon the consensus of phylogenetic and phenotypic analyses, these strains represent a novel species of the genus Bacillus, for which the name Bacillus glycinifermentans sp. nov. is proposed. The type strain is GO-13T ( = KACC 18425T = NRRL B-65291T).


Alternatives to polysomnography (PSG): a validation of wrist actigraphy and a partial-PSG system.
The objective of this study was to assess the validity of a sleep/wake activity monitor, an energy expenditure activity monitor, and a partial-polysomnography system at measuring sleep and wake under identical conditions. Secondary aims were to evaluate the sleep/wake thresholds for each activity monitor and to compare the three devices. To achieve these aims, two nights of sleep were recorded simultaneously with polysomnography (PSG), two activity monitors, and a partial-PSG system in a sleep laboratory. Agreement with PSG was evaluated epoch by epoch and with summary measures including total sleep time (TST) and wake after sleep onset (WASO). All of the devices had high agreement rates for identifying sleep and wake, but the partial-PSG system was the best, with an agreement of 91.6% ± 5.1%. At their best thresholds, the sleep/wake monitor (medium threshold, 87.7% ± 7.6%) and the energy expenditure monitor (very low threshold, 86.8% ± 8.6%) had similarly high rates of agreement. The summary measures were similar to those determined by PSG, but the partial-PSG system provided the most consistent estimates. Although the partial-PSG system was the most accurate device, both activity monitors were also valid for sleep estimation, provided that appropriate thresholds were selected. Each device has advantages, so the primary consideration for researchers will be to determine which best suits a given research design.


The role of L(u)ck in T cell triggering.
T cells use a highly complex signaling apparatus to discriminate between a diverse array of foreign antigens and a myriad of self molecules. The precise mechanism whereby signals are communicated from the antigen-binding T cell receptor to the intracellular signal transduction machinery remains a source of intense debate. This Journal Club article highlights recent research elucidating the role of the Src family kinase Lck in T cell triggering. Resting T cells contain a newly described form of preactivated Lck that is both necessary and sufficient for T cell activation but remains uncoupled from the T cell receptor in the absence of antigen. This research allows a reappraisal of the mechanisms underlying T cell triggering.


Size-dependent coupling between localized surface plasmons and excitons in silicon nitride matrix.
The size-dependent coupling between localized surface plasmons (LSPs) and excitons within a silicon nitride (SiN(x)) matrix is investigated. A strong correlation between the photoluminescence (PL) enhancement and this resonance coupling is observed. From the analysis of the relationship between the dipolar resonance peaks of Ag nanostructures with various sizes and those of PL enhancement, we ascribe the enhancement of PL from the SiN(x) matrix by the addition of Ag nanostructures mainly to the LSP resonance coupling.


Recovery of infrastructure networks after localised attacks.
The stability of infrastructure network is always a critical issue studied by researchers in different fields. A lot of works have been devoted to reveal the robustness of the infrastructure networks against random and malicious attacks. However, real attack scenarios such as earthquakes and typhoons are instead localised attacks which are investigated only recently. Unlike previous studies, we examine in this paper the resilience of infrastructure networks by focusing on the recovery process from localised attacks. We introduce various preferential repair strategies and found that they facilitate and improve network recovery compared to that of random repairs, especially when population size is uneven at different locations. Moreover, our strategic repair methods show similar effectiveness as the greedy repair. The validations are conducted on simulated networks, and on real networks with real disasters. Our method is meaningful in practice as it can largely enhance network resilience and contribute to network risk reduction.


Mesalazine pharmacokinetics and NAT2 phenotype.
Mesalazine undergoes extensive metabolism by N-acetylation. While there is some evidence for an involvement of N-acetyltransferase (NAT) type 1, a potential role of NAT type 2 (NAT2) in vivo has not been tested. In two studies in healthy young Caucasians, NAT2 phenotyping was carried out using a caffeine metabolic ratio in urine 4-6 h postdose. In study A, 1,000 mg mesalazine doses were given thrice daily for 5 days, and urine and blood samples were drawn during the last dosing interval. In study B, a 1,000 mg single dose was given, and samples were taken for 48 h postdose. Pharmacokinetics of mesalazine and N-acetylmesalazine (LC-MS/MS) were calculated by noncompartmental methods. NAT2 phenotype could be allocated unequivocally in 21 slow and 5 rapid acetylators in study A, and in 9 slow and 8 rapid acetylators in study B. Geometric mean (CV%) values in study A for slow [rapid] acetylators were as follows: mesalazine AUC 11.1 microg/mL.h (51%) [12.0 microg/mL.h (52%)], N-acetylmesalazine AUC 27.7 microg/mL.h (32%) [30.5 microg/mL.h (27%)], mesalazine Ae 8.53% (89%) [9.03% (52%)], N-acetylmesalazine Ae 31.4% (46%) [32.2 (41%)]. Values in study B were as follows: mesalazine AUC 3.45 microg/mL.h (113%) [2.36 microg/mL.h (87%)], N-acetylmesalazine AUC 21.3 microg/mL.h (29%) [18.0 microg/mL.h (39%)], mesalazine Ae 0.2% (256%) [0.1% (359%)], N-acetylmesalazine Ae 30.9% (44%) [18.1% (84%)]. Higher AUC and Ae values for mesalazine in steady state study indicate saturation of mesalazine metabolism. Statistics provided no evidence for a true difference in mesalazine pharmacokinetics between slow and rapid acetylators, and no significant correlation between NAT2 activity and any mesalazine pharmacokinetic parameter was found. NAT2 has no major role in human metabolism of mesalazine in vivo.


A predictable conserved DNA base composition signature defines human core DNA replication origins.
DNA replication initiates from multiple genomic locations called replication origins. In metazoa, DNA sequence elements involved in origin specification remain elusive. Here, we examine pluripotent, primary, differentiating, and immortalized human cells, and demonstrate that a class of origins, termed core origins, is shared by different cell types and host ~80% of all DNA replication initiation events in any cell population. We detect a shared G-rich DNA sequence signature that coincides with most core origins in both human and mouse genomes. Transcription and G-rich elements can independently associate with replication origin activity. Computational algorithms show that core origins can be predicted, based solely on DNA sequence patterns but not on consensus motifs. Our results demonstrate that, despite an attributed stochasticity, core origins are chosen from a limited pool of genomic regions. Immortalization through oncogenic gene expression, but not normal cellular differentiation, results in increased stochastic firing from heterochromatin and decreased origin density at TAD borders.


Epigenetics: The New Frontier in the Landscape of Asthma.
Over the years, on a global scale, asthma has continued to remain one of the leading causes of morbidity, irrespective of age, sex, or social bearings. This is despite the prevalence of varied therapeutic options to counter the pathogenesis of asthma. Asthma, as a disease per se, is a very complex one. Scientists all over the world have been trying to obtain a lucid understanding of the machinations behind asthma. This has led to many theories and conjectures. However, none of the scientific disciplines have been able to provide the missing links in the chain of asthma pathogenesis. This was until epigenetics stepped into the picture. Though epigenetic research in asthma is in its nascent stages, it has led to very exciting results, especially with regard to explaining the massive influence of environment on development of asthma and its varied phenotypes. However, there remains a lot of work to be done, especially with regard to understanding how the interactions between immune system, epigenome, and environment lead to asthma. But introduction of epigenetics has infused a fresh lease of life in research into asthma and the mood among the scientific community is that of cautious optimism.


Expression of major histocompatibility complex antigens and adhesion molecules in hearts of patients with chronic Chagas' disease.
We have previously reported that heart lesions in patients with chronic cardiac Chagas' disease are composed predominantly of granzyme A+, cytolytic CD8+ T lymphocytes. We now pursue this study in the immunopathology of chronic chagasic cardiomyopathy by investigation of the expression of HLA antigens, and adhesion molecules in the hearts of seven chagasic patients with cardiac disease, two asymptomatic chagasic patients, and seven normal controls. Comparative immunohistochemical analyses show that HLA-ABC antigen expression is enhanced on the myocardial cells of chagasic patients with chronic cardiomyopathy, suggesting a possible role for these cells as targets for the CD8+ cytolytic lymphocytes dominant in these lesions. The HLA-DR antigens are not observed on myocardial cells, but are consistently upregulated on the endothelial cells in the hearts of patients with chronic chagasic cardiomyopathy. Intercellular adhesion molecule is expressed by endothelial cells of both chagasic and nonchagasic individuals, but E-selectin was detected only on vessels of hearts from chagasic patients who had chronic cardiomyopathy. Most of the lymphocytes in these lesions express lymphocyte function antigen-1 (LFA-1), CD44, and very late antigen-4, and a few display weak expression of LFA-3. We propose that the expression of these adhesion molecules and major histocompatibility complex antigens by endothelial cells, myocardial cells, and lymphoid cells in these lesions contribute to the pathogenesis of chronic chagasic cardiomyopathy.