Comparison of pre-operative and post-operative (varicocelectomy) sperm parameters in patients suffering varicocle with and without reflux in Doppler ultrasonography.
Varicocele can cause progressive testicular damage and infertility. Severe retrograde blood flow to the internal spermatic vein has been suggested as a risk factor for infertility or progressive/stable varicocele. We have aimed to Compared th pre-operative and post-operative (varicocelectomy) sperm parameters in patients suffering varicocle with and without reflux in Doppler ultrasonography. This descriptive-analytic study was carried out at the Imaging Center of Ahwaz University of Medical Sciences in Imam and Golestan Hospitals. The parameters assessed included the presence or absence of internal spermatic vein reflux in both sided. Patients were divided into three groups based on the presence of testicular reflux: no reflux, left-sided reflux, and both sides reflux. The reflux longer than 1 second was considered pathologic. All patients were also referred to the laboratory for semen analysis, including semen volume, sperm morphology, sperm counts, and motility. Semen analysis was repeated 2 months after varicocelectomy. In this study, a total of 70 patients were evaluated. Forty-three patients (61.4%) did not have any reflux, 23 patients (32.9%) had left testicular reflux, and 4 (5.7%) had reflux in both testicles. Semen volume, number of sperms, number of motile sperm, and sperm morphology increased significantly after Varicocelectomy. We did not find any significant correlation between testicular reflux and improvement index of semen analysis factor was found. The findings of this study indicate that the presence of testicular reflux has no effect on semen analysis parameters, but also does not predict the consequences of varicocelectomy and therefore is not a suitable prognosis factor in varicocele patients.


Update on the pathogenesis and immunotherapy of esophageal squamous cell carcinoma.
The esophageal squamous cell carcinoma (ESCC) is the prevailing histology subtype of esophageal cancer and is distinguished by its high mortality and its geographic differences in regards to its incidence. The exact cause of this neoplasia is still unknown in spite of all the research made in this area. Our understanding about pathogenesis, epidemiology and behaviour of the ESCC is still in progress thanks to the advances on the field of molecular biology. Some of these advances include the research of etiopathogenesis (virus, as the human papillomavirus, and the genes susceptible to cancer), genes associated with tumors (oncogenes, tumor suppressor genes), as well as new forms of neoadjuvant immunotherapy for the treatment of this neoplasia.


Depth of cure efficacy of high-power curing devices vs traditional halogen lamps.
To determine the depth of cure resulting from three different curing devices in a photoactivated microhybrid composite through high-performance liquid chromatography (HPLC) analysis of leachable monomers. Three different curing units, a halogen lamp (Heliolux, Vivadent), a xenon lamp (Kreative Kuring, Allyn Welch), and a plasma-arc lamp (Apollo 95, DMDS) were investigated using a universal microhybrid composite (P 60, 3M) as the test material. To assess the effect of curing device variation, a flexural strength test was performed. In addition, samples of composite were prepared and cured "in contact" (0 mm between the sample surface and light-guide tip) and through a specific thickness of composite (1, 2, or 3 mm). The monomers (bis-GMA and UDMA) eluted from the samples were detected by HPLC. No significant differences were found in the mechanical properties of composite cured with different light sources. In contrast, the concentration of eluted monomers (bis-GMA, UDMA) at a depth of 2 mm and more was significantly higher for the specimens cured with the high-power curing devices than those cured with the traditional halogen lamp. Under these experimental conditions, high-power curing devices were shown to be inferior in the deep polymerization of resin composite when compared to a traditional halogen lamp.


Mars: change in axial tilt due to climate?
The average tilt of Mars' equator with respect to its orbital plane may have increased significantly over the age of the solar system. Obliquity oscillations might have induced changes in the climate, which altered the mass distribution and hence the solar torque on the planet. Viscous deformation attributable to loading by the large polar caps expected at low obliquity may have induced secular changes in the axial tilt. Earth-like effective viscosities can account for virtually the entire present obliquity of 24.4 degrees. Thus the present average tilt of Mars may not be primordial.


Contribution of post-mortem examination to cancer registries.
In developed countries, the post-mortem examination may not be critical to the identification of patients with cancer, since diagnostic sophistication and histological verification are readily available. The autopsy should be considered of increasing importance, however, to epidemiologists and other investigators who use the data generated by cancer registries. The contribution of post-mortem examinations to etiological studies, to documentation of the natural history of disease in a changing environment and to evaluating diagnostic and therapeutic modalities should, in fact, be recognized as essential to the practice of modern medicine and to research. In the less developed countries, cancer registration must depend to a much greater degree on necropsy for identification of cancer patients, since surgical biopsy may be limited or selected and often specimens are not even submitted for examination. The primary site and histology of a tumour are frequently not available from clinical records, which may carry significant inaccuracies. Most of the important observations and contributions relating to the geographical pathology of cancer have made substantial use of post-mortem material. All of the investigative approaches that are dependent on reliable cancer registry data and that involve use of information derived from autopsies are equally applicable to developed and less developed countries. Such information is of enormous importance to public health planning, and the potential for disease prevention cannot be overestimated.


Demineralization effects of hydrogen peroxide on bovine enamel and relation to shear bond strength of brackets.
To measure the demineralization capacity of 37% phosphoric acid and shear bond strength (SBS) of brackets attached on bovine enamel at different times after bleaching with 30% hydrogen peroxide. Four equally-sized pieces of each crown from 18 bovine incisors were randomly distributed among 7 groups (n = 10). After bleaching with 30% hydrogen peroxide for 1 h, specimens were stored in artificial saliva for 0 h, 24 h, or 1, 2, 3, or 4 weeks before bonding specimens to brackets. An unbleached group of specimens served as controls. Shear bond strength (SBS in MPa) was measured with a universal testing machine. Adhesive Remnant Index (ARI) scores were determined after failure of bracket bonds. To measure demineralized Ca2+, four 4 x 4 mm sections from each of 15 bovine incisors were randomly distributed among 4 groups (n = 15). Specimens were stored in artificial saliva for 0 h, 24 h or 7 days after bleaching and then immersed in 37% phosphoric acid solution. After 15 s, 30 s, and 60 s, 5-ml aliquots of solution were removed for spectrophotometry. Unbleached specimens served as controls. Larger amounts of Ca2+ were extracted from the enamel by phosphoric acid up to 24 h after application of hydrogen peroxide, when there was also a significant decrease in bracket-enamel SBS. After 1 week, there were no changes in amounts of Ca2+ extracted, and SBS values returned towards unbleached values. Lower bracket-enamel SBS values at 24 h after bleaching are closely correlated with the larger amounts of Ca2+ extracted from the enamel.


Similar proportions of stool specimens from hospitalized children with and without diarrhea test positive for Clostridium difficile.
Many laboratories use polymerase chain reaction (PCR)-based assays to detect the Clostridium difficile toxin B gene (tcdB) in stool. However, PCR testing experience in pediatric patients is limited. We compared the detection of C. difficile by PCR in hospitalized children with and without diarrhea. Stool samples from patients aged 1-18 years with diarrhea (symptomatic) and from patients without diarrhea (asymptomatic) were tested for C. difficile tcdB using a commercial PCR assay. Samples were cultured for C. difficile using standard techniques with tcdB PCR and cytotoxicity assays performed on C. difficile isolates. Demographic, clinical and laboratory data were abstracted. Categorical and continuous variables were compared between the 2 groups using Fisher Exact test and the Mann-Whitney test, respectively. Thirty-five of 188 (19%) stool samples from symptomatic patients and 18 of 74 (24%) samples from asymptomatic patients were positive by PCR (P=0.31). Among PCR-positive patients, symptomatic patients had a significantly higher proportion of subjects who received antimicrobials in the preceding 30 days (P=0.04) and a greater number of preceding antimicrobial days than did asymptomatic patients (P=0.02) but were comparable with respect to the other variables analyzed. C. difficile PCR assays are frequently positive in hospitalized children both with and without diarrhea. As we observed a high level of toxigenic C. difficile colonization in children, our findings suggest that a positive C. difficile PCR result in a child with diarrhea should be interpreted with caution.


Risk of preterm birth in a twin pregnancy after an early-term birth in the preceding singleton pregnancy: a retrospective cohort study.
To evaluate whether a history of spontaneous early-term birth (37+0 -38+6 weeks of gestation) in the previous singleton pregnancy is a risk factor for preterm birth (PTB) in a subsequent twin pregnancy. Retrospective cohort study. Two French university hospitals (2006-2016). All women who delivered twins from 24+0 weeks after a preceding singleton pregnancy birth at 37+0 to 41+6 weeks. Multivariate logistic regression analysis of association between twin PTB and a previous spontaneous singleton early-term birth. Twin PTB rate before 37, 34 and 32 weeks of gestation. Among 618 twin pregnancies, 270 were born preterm, 92 of them with a preceding spontaneous singleton early-term birth. The univariate analysis showed a significantly higher risk of twin PTB before 37, 34 and 32 weeks among those 92 women compared with those with a full- or late-term birth in their previous singleton pregnancy. This association remained significant after logistic regression (odds ratio [OR] between 2.42 and 3.88). The secondary analysis, restricted to the twin pregnancies with spontaneous PTB found similar results, with a risk of PTB before 37, 34 and 32 weeks significantly higher among women with a previous spontaneous singleton early-term birth, including after logistic regression analysis (OR between 3.51 and 3.56). A preceding spontaneous singleton early-term birth is a strong and easily identified risk factor for PTB in twin pregnancies. Spontaneous 'early-term' birth of a singleton is a significant risk factor for future preterm births in twin pregnancies.


A review of the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.
Hypertension is a major modifiable risk factor for cardiovascular diseases. After decades of improvement, population surveys demonstrate disturbing downward trends in the rates of awareness, treatment, and control of this disorder in recent years. Over this same time period, there has been a slight increase in the incidence of strokes, and a steady rise in the incidence of end-stage renal disease and the prevalence of congestive heart failure, conditions in which hypertension plays a prominent role. Results of recent studies support the possibility that lifestyle modifications may be effective for prevention of hypertension. Treatment of established hypertension involves lifestyle modifications and drug therapies designed to control blood pressure and reduce overall cardiovascular risk. Both threshold blood pressure levels for initiating drug therapy and goal blood pressure levels with treatment are individually determined based on the presence or absence of additional cardiovascular risk factors and hypertension target organ injury or clinical cardiovascular disease. Recent clinical trials support the value of lower goal blood pressures for patients with diabetes, heart failure, and renal disease. The presence or absence of comorbid conditions often determines specific drug choices. Diuretics and beta-blockers remain the drugs of choice in uncomplicated hypertension. Additional studies confirm the benefits of treating isolated systolic hypertension in the elderly. The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure provides a practical, evidence-based resource to help health care providers meet the public health challenges of preventing and controlling hypertension.


Tissue-specific splicing factor gene expression signatures.
The alternative splicing code that controls and coordinates the transcriptome in complex multicellular organisms remains poorly understood. It has long been argued that regulation of alternative splicing relies on combinatorial interactions between multiple proteins, and that tissue-specific splicing decisions most likely result from differences in the concentration and/or activity of these proteins. However, large-scale data to systematically address this issue have just recently started to become available. Here we show that splicing factor gene expression signatures can be identified that reflect cell type and tissue-specific patterns of alternative splicing. We used a computational approach to analyze microarray-based gene expression profiles of splicing factors from mouse, chimpanzee and human tissues. Our results show that brain and testis, the two tissues with highest levels of alternative splicing events, have the largest number of splicing factor genes that are most highly differentially expressed. We further identified SR protein kinases and small nuclear ribonucleoprotein particle (snRNP) proteins among the splicing factor genes that are most highly differentially expressed in a particular tissue. These results indicate the power of generating signature-based predictions as an initial computational approach into a global view of tissue-specific alternative splicing regulation.


Identification of Novel Inhibitors of the Type I Interferon Induction Pathway Using Cell-Based High-Throughput Screening.
Production of type I interferon (IFN) is an essential component of the innate immune response against invading pathogens. However, its production must be tightly regulated to avoid harmful effects. Compounds that modulate the IFN response are potentially valuable for a variety of applications due to IFN's beneficial and detrimental roles. We developed and executed a cell-based high-throughput screen (HTS) targeting components that participate in and/or regulate the IRF3 and nuclear factor (NF)-κB branches of the IFN induction pathway. The assay detects activation of the IFN induction pathway via an enhanced green fluorescent protein (eGFP) reporter gene under the control of the IFNβ promoter and was optimized, miniaturized, and demonstrated suitable for HTS as robust Z' factor scores of >0.6 were consistently achieved. A diversity screening set of 15,667 small molecules was assayed and two novel hit compounds validated that specifically inhibit the IFN induction pathway. We demonstrate that one of these compounds acts at or upstream of IRF3 phosphorylation. A second cell-based assay to detect activation of the IFN signaling (Jak-Stat) pathway via an eGFP reporter gene under the control of an IFN-stimulated response element (ISRE) containing MxA promoter also performed well (robust Z' factor >0.7) and may therefore be similarly used to identify small molecules that modulate the IFN signaling pathway.


Mono- and biallelic germline variants of DNA glycosylase genes in colon adenomatous polyposis families from two continents.
Recently, biallelic germline variants of the DNA glycosylase genes MUTYH and NTHL1 were linked to polyposis susceptibility. Significant fractions remain without a molecular explanation, warranting searches for underlying causes. We used exome sequencing to investigate clinically well-defined adenomatous polyposis cases and families from Finland (N=34), Chile (N=21), and Argentina (N=12), all with known susceptibility genes excluded. Nine index cases (13%) revealed germline variants with proven or possible pathogenicity in the DNA glycosylase genes, involving NEIL1 (mono- or biallelic) in 3 cases, MUTYH (monoallelic) in 3 cases, NTHL1 (biallelic) in 1 case, and OGG1 (monoallelic) in 2 cases. NTHL1 was affected with the well-established, pathogenic c.268C>T, p.(Gln90Ter) variant. A recurrent heterozygous NEIL1 c.506G>A, p.(Gly169Asp) variant was observed in two families. In a Finnish family, the variant occurred in trans with a truncating NEIL1 variant (c.821delT). In an Argentine family, the variant co-occurred with a genomic deletion of exons 2 - 11 of PMS2. Mutational signatures in tumor tissues complied with biological functions reported for NEIL1. Our results suggest that germline variants in DNA glycosylase genes may occur in a non-negligible proportion of unexplained colon polyposis cases and may predispose to tumor development.


TAGster: efficient selection of LD tag SNPs in single or multiple populations.
Genetic association studies increasingly rely on the use of linkage disequilibrium (LD) tag SNPs to reduce genotyping costs. We developed a software package TAGster to select, evaluate and visualize LD tag SNPs both for single and multiple populations. We implement several strategies to improve the efficiency of current LD tag SNP selection algorithms: (1) we modify the tag SNP selection procedure of Carlson et al. to improve selection efficiency and further generalize it to multiple populations. (2) We propose a redundant SNP elimination step to speed up the exhaustive tag SNP search algorithm proposed by Qin et al. (3) We present an additional multiple population tag SNP selection algorithm based on the framework of Howie et al., but using our modified exhaustive search procedure. We evaluate these methods using resequenced candidate gene data from the Environmental Genome Project and show improvements in both computational and tagging efficiency. The software Package TAGster is freely available at http://www.niehs.nih.gov/research/resources/software/tagster/


Feed sorting in dairy cattle: Causes, consequences, and management.
Dairy cattle commonly sort total mixed rations, a behavior that influences individual nutrient intake and reduces the nutritive value of the ration left in the bunk across the day. Typical patterns of feed sorting in lactating dairy cows, against longer forage particles, result in greater intake of highly-fermentable carbohydrates and lesser intake of effective fiber than intended, and are associated with reduced rumen pH and altered milk composition. To understand the reason for this behavior and reduce it on-farm, numerous studies have explored the influences of ration characteristics, feeding strategies, and management factors on the expression of feed sorting. In mature cows and young calves, feed sorting is influenced by forage inclusion rate, particle size, and dry matter content. Feeding strategies that increase the time available to manipulate feed-including decreased feeding frequency and increased feeding level-may result in increased feed sorting. The extent of feed sorting is also influenced by a variety of herd-level factors, but variability between individuals in the extent of feed sorting suggests that this behavior may be subject to additional factors, including previous experience and internal state. The development of feed sorting in young calves has been explored in several recent studies, suggesting that early opportunities to sort feed, as provided by access to mixed diets, may encourage the early onset of this behavior and help it persist beyond weaning. Evidence also supports the role of feedback mechanisms that influence this behavior at the individual level. In calves and adult cows, selective consumption of higher-energy ration components may be linked to energy demands, as influenced by the availability of supplemental feed or changing metabolic status. Further, considerable evidence suggests that cattle will adjust patterns of feed sorting in favor of physically effective fiber to attenuate low rumen pH, providing evidence for the role of postingestive feedback in feed sorting. In general, as long as cattle are provided with mixed diets that satisfy the average nutrient requirements of the group, feed sorting needs to be reduced, either through direct management or by discouraging the early development of the behavior. However, feed sorting may be functional in some scenarios, and continued research is needed to understand the feedback mechanisms that influence feed selection and sorting in young calves, replacement heifers, and mature cows.


Hepatitis B virus genotyping: current methods and clinical implications.
Hepatitis B virus (HBV) is a major cause of liver cirrhosis and hepatocellular carcinoma (HCC). Eight different HBV genotypes have been identified with distinct geographical distributions. Different genotyping methods exist including sequencing, INNO-LiPA, restriction fragment polymorphism (RFLP), multiplex PCR, serotyping, oligonucleotide microarray chips, reverse dot blot, restriction fragment mass polymorphism (RFMP), invader assay, and real-time PCR. Several investigators have studied the influence of HBV genotypes on clinical outcomes in chronic HBV patients. This review describes the current genotyping techniques, as well as their advantages and limitations. It also presents the clinical evidence that correlates HBV genotypes to clinical outcomes including disease severity, HCC development, response to therapy, disease chronicity, transplantation outcomes, and occult infection.


Cost-effectiveness analysis of colorectal cancer screening with stool DNA testing in intermediate-incidence countries.
The aim of this study is to compare the cost-effectiveness of screening with stool DNA testing with that of screening with other tools (annual fecal occult blood testing, flexible sigmoidoscopy every 5 years, and colonoscopy every 10 years) or not screening at all. We developed a Markov model to evaluate the above screening strategies in the general population 50 to 75 years of age in Taiwan. Sensitivity analyses were performed to assess the influence of various parameters on the cost-effectiveness of screening. A third-party payer perspective was adopted and the cost of dollar 13,000 per life-year saved (which is roughly the per capita GNP of Taiwan in 2003) was chosen as the ceiling ratio for assessing whether the program is cost-effective. Stool DNA testing every three, five, and ten years can reduce colorectal cancer mortality by 22%, 15%, and 9%, respectively. The associated incremental costs were dollar 9,794, dollar 9,335, and dollar 7,717, per life-year saved when compared with no screening. Stool DNA testing strategies were the least cost-effective with the cost per stool DNA test, referral rate with diagnostic colonoscopy, prevalence of large adenoma, and discount rate being the most influential parameters. In countries with a low or intermediate incidence of colorectal cancer, stool DNA testing is less cost-effective than the other currently recommended strategies for population-based screening, particularly targeting at asymptomatic subjects.


How muscle fiber lengths and velocities affect muscle force generation as humans walk and run at different speeds.
The lengths and velocities of muscle fibers have a dramatic effect on muscle force generation. It is unknown, however, whether the lengths and velocities of lower limb muscle fibers substantially affect the ability of muscles to generate force during walking and running. We examined this issue by developing simulations of muscle-tendon dynamics to calculate the lengths and velocities of muscle fibers from electromyographic recordings of 11 lower limb muscles and kinematic measurements of the hip, knee and ankle made as five subjects walked at speeds of 1.0-1.75 m s(-1) and ran at speeds of 2.0-5.0 m s(-1). We analyzed the simulated fiber lengths, fiber velocities and forces to evaluate the influence of force-length and force-velocity properties on force generation at different walking and running speeds. The simulations revealed that force generation ability (i.e. the force generated per unit of activation) of eight of the 11 muscles was significantly affected by walking or running speed. Soleus force generation ability decreased with increasing walking speed, but the transition from walking to running increased the force generation ability by reducing fiber velocities. Our results demonstrate the influence of soleus muscle architecture on the walk-to-run transition and the effects of muscle-tendon compliance on the plantarflexors' ability to generate ankle moment and power. The study presents data that permit lower limb muscles to be studied in unprecedented detail by relating muscle fiber dynamics and force generation to the mechanical demands of walking and running.


Morphologic and molecular backgrounds for personalized management of genito-urinary cancers: an overview.
This contribution gives an overview of recent insights and emerging strategies for individualized therapeutic approaches based on genomic and cancer molecular profiles in patients with a morphological diagnosis of renal, bladder and prostate tumors. Significant advances have been made in molecular biology technologies, such as next-generation sequencing and whole-exome sequencing. The rise of such novel techniques has increased our knowledge on tumor cell biology and cancer development, thus allowing us to identify complex genomic abnormalities. These findings have paved the way to provide healthcare from an individual perspective. An emerging strategy to individualize therapeutic interventions is focused on stem cells. Because of their unique characteristics, they are among the most promising candidates as potential vectors carrying suicide genes into different types of cancer, including genitourinary tumors. Another emerging strategy could be based on prostate specific membrane antigen (PSMA), a unique membrane-bound glycoprotein, which is overexpressed manifold in prostate cancer. PSMA can serve as target for delivering therapeutic agents such as cytotoxins or radionuclides.


Immune microenvironment of basal cell carcinoma and tumor regression following combined PD-1/LAG-3 blockade.
Systemic treatment options for patients with locally advanced or metastatic basal cell carcinoma (BCC) are limited, particularly when tumors are refractory to anti-programmed cell death protein-1 (PD-1). A better understanding of immune checkpoint expression within the BCC tumor microenvironment may inform combinatorial treatment strategies to optimize response rates. CD3, PD-1, programmed death ligand-1 (PD-L1), lymphocyte activation gene 3 (LAG-3), and T-cell immunoglobulin domain and mucin domain 3 (TIM-3)+ cell densities within the tumor microenvironment of 34 archival, histologically aggressive BCCs were assessed. Tumor infiltrating lymphocyte (TIL) expression of PD-1, PD-L1, and LAG-3, and to a lesser degree TIM-3, correlated with increasing CD3+ T-cell densities (Pearson's r=0.89, 0.72, 0.87, and 0.63, respectively). 100% of BCCs (34/34) demonstrated LAG-3 and PD-1 expression in >1% TIL; and the correlation between PD-1 and LAG-3 densities was high (Pearson's r=0.89). LAG-3 was expressed at ~50% of the level of PD-1. Additionally, we present a patient with locally-advanced BCC who experienced stable disease during and after 45 weeks of first-line anti-PD-1 (nivolumab), followed by a partial response after the addition of anti-LAG-3 (relatlimab). Longitudinal biopsies throughout the treatment course showed a graduated increase in LAG-3 expression after anti-PD-1 therapy, lending support for coordinated immunosuppression and suggesting LAG-3 as a co-target for combination therapy to augment the clinical impact of anti-PD-(L)1.


Hormetic modulation of aging and longevity by mild heat stress.
Aging is characterized by a stochastic accumulation of molecular damage, progressive failure of maintenance and repair, and consequent onset of age-related diseases. Applying hormesis in aging research and therapy is based on the principle of stimulation of maintenance and repair pathways by repeated exposure to mild stress. In a series of experimental studies we have shown that repetitive mild heat stress has anti-aging hormetic effects on growth and various other cellular and biochemical characteristics of human skin fibroblasts undergoing aging in vitro. These effects include the maintenance of stress protein profiles, reduction in the accumulation of oxidatively and glycoxidatively damaged proteins, stimulation of the proteasomal activities for the degradation of abnormal proteins, improved cellular resistance to ethanol, hydrogen peroxide and ultraviolet-B rays, and enhanced levels of various antioxidant enzymes. Anti-aging hormetic effects of mild heat shock appear to be facilitated by reducing protein damage and protein aggregation by activating internal antioxidant, repair and degradation processes.


Causes of death in people with liver cirrhosis in England compared with the general population: a population-based cohort study.
There is a need for unbiased estimates of cause-specific mortality by etiology in patients with liver cirrhosis. The aim of this study is to use nationwide linked electronic routine healthcare data from primary and secondary care alongside the national death registry data to report such estimates. We identified from the linked Clinical Practice Research Datalink (CPRD) and English Hospital Episode Statistics adults with an incident diagnosis of liver cirrhosis linked to the Office for National Statistics between 1998 and 2009. Age-matched controls from the CPRD general population were selected. We calculated the cumulative incidence (adjusting for competing risks) and excess risk of death by 5 years from diagnosis for different causes of death, stratified by etiology and stage of disease. Five thousand one hundred and eighteen patients with cirrhosis were matched to 152,903 controls. Among compensated patients, the 5-year excess risk of liver-related death was higher than that of any other cause of death for all patients, except those of unspecified etiology. For example, those of alcohol etiology had 30.8% excess risk of liver-related death (95% confidence interval (CI): 27.9%, 33.1%) compared with 9.9% excess risk of non-liver-related death. However, patients of unspecified etiology had a higher excess risk of non-liver-related compared with liver-related death (10.7% vs. 6.7%). This was due to a high excess risk of non-liver neoplasm death (7.7%, 95% CI: 5.9%, 9.5%). All decompensated patients had a higher excess of liver-related mortality than any other cause. In order to reduce associated mortality among people with liver cirrhosis, patients' care pathways need to be tailored depending on the etiology and stage of the disease.


Hollow hydroxyapatite microspheres as a device for controlled delivery of proteins.
Hollow hydroxyapatite (HA) microspheres were prepared by reacting solid microspheres of Li(2)O-CaO-B(2)O(3) glass (106-150 μm) in K(2)HPO(4) solution, and evaluated as a controlled delivery device for a model protein, bovine serum albumin (BSA). Reaction of the glass microspheres for 2 days in 0.02 M K(2)HPO(4) solution (pH = 9) at 37°C resulted in the formation of biocompatible HA microspheres with a hollow core diameter equal to 0.6 the external diameter, high surface area (~100 m(2)/g), and a mesoporous shell wall (pore size ≈ 13 nm). After loading with a solution of BSA in phosphate-buffered saline (PBS) (5 mg BSA/ml), the release kinetics of BSA from the HA microspheres into a PBS medium were measured using a micro bicinchoninic acid (BCA) protein assay. Release of BSA initially increased linearly with time, but almost ceased after 24-48 h. Modification of the BSA release kinetics was achieved by modifying the microstructure of the as-prepared HA microspheres using a controlled heat treatment (1-24 h at 600-900°C). Sustained release of BSA was achieved over 7-14 days from HA microspheres heated for 5 h at 600°C. The amount of BSA released at a given time was dependent on the concentration of BSA initially loaded into the HA microspheres. These hollow HA microspheres could provide a novel inorganic device for controlled local delivery of proteins and drugs.


CCR2(+)CCR5(+) T cells produce matrix metalloproteinase-9 and osteopontin in the pathogenesis of multiple sclerosis.
Multiple sclerosis (MS) is a demyelinating disease of the CNS that is presumably mediated by CD4(+) autoimmune T cells. Although both Th1 and Th17 cells have the potential to cause inflammatory CNS pathology in rodents, the identity of pathogenic T cells remains unclear in human MS. Given that each Th cell subset preferentially expresses specific chemokine receptors, we were interested to know whether T cells defined by a particular chemokine receptor profile play an active role in the pathogenesis of MS. In this article, we report that CCR2(+)CCR5(+) T cells constitute a unique population selectively enriched in the cerebrospinal fluid of MS patients during relapse but not in patients with other neurologic diseases. After polyclonal stimulation, the CCR2(+)CCR5(+) T cells exhibited a distinct ability to produce matrix metalloproteinase-9 and osteopontin, which are involved in the CNS pathology of MS. Furthermore, after TCR stimulation, the CCR2(+)CCR5(+) T cells showed a higher invasive potential across an in vitro blood-brain barrier model compared with other T cells. Of note, the CCR2(+)CCR5(+) T cells from MS patients in relapse are reactive to myelin basic protein, as assessed by production of IFN-γ. We also demonstrated that the CCR6(-), but not the CCR6(+), population within CCR2(+)CCR5(+) T cells was highly enriched in the cerebrospinal fluid during MS relapse (p < 0.0005) and expressed higher levels of IFN-γ and matrix metalloproteinase-9. Taken together, we propose that autoimmune CCR2(+)CCR5(+)CCR6(-) Th1 cells play a crucial role in the pathogenesis of MS.


Residual inflammation after rituximab treatment is associated with sustained synovial plasma cell infiltration and enhanced B cell repopulation.
To investigate the clinical effects of rituximab treatment in relation to immunological effects of rituximab on tissue-derived B lineage cells and repopulation of circulating B cells. A total of 24 patients with rheumatoid arthritis (RA) were treated with 2x1000 mg rituximab and assessed clinically at 4, 12, 18 and 24 weeks using a 44-joint Disease Activity Score (DAS(44)). Synovial biopsies were analysed with immunohistochemistry at baseline and 12 weeks after treatment. Peripheral blood mononuclear cells were analysed by high sensitivity flow cytometry at all timepoints. In this study, a cohort of patients was dichotomised according to those who achieved a low disease activity score (DAS(44)<2.4: LoA group) and those with persistent disease activity (DAS(44)>2.4: HiA group) at any time after rituximab treatment. At baseline, the low activity (LoA) group had significantly lower DAS(44) scores (median 3.33, range 2.84 to 4.23) than the high activity (HiA) group (median 3.73, range 3.03 to 5.23; p = 0.022) and significantly less histological inflammation in synovium (median 6.7, range 1 to 15 vs 16.6, range 4 to 22; p = 0.036). DAS(44) scores before and after rituximab treatment were associated with synovial infiltration of CD79a+ CD20- B cells, morphologically resembling plasma cells. Following treatment with rituximab, the LoA group had significantly reduced repopulation of circulating pre-switched IgD+ B cells (median 0.044%, range 0.002 to 0.66 vs 0.45%, range 0.07 to 9.47; p = 0.006) and post-switched CD27+ B cells (median 0.17%, range 0.04 to 0.39 vs 0.67, range 0.08 to 2.05; p = 0.005) compared to the HiA group. The present study demonstrated that a low disease activity state following rituximab was associated with reduced infiltration of CD79a+ CD20- plasma cells in synovium and reduced B cell repopulation.


Chemotaxis of Zoospores for Root Exudates.
A chemotactic response of the zoospores of a soil-inhabiting plant pathogenic fungus, Phytophthora cinnamomi, for roots of avocado seedlings was observed. The chemotaxis of the zoospores and chemotropy of their germ tubes were directly related to infection and disease production. Indications were obtained of specificity of the pathogen-attracting root exudate, and interesting implications are evident with regard to mechanisms of invasion and pathogenicity, and to disease resistance.


High serum and urine lysozyme levels in a dog with acute myeloid leukemia.
A 2-year-old, female German Shepherd Dog with facial nerve paralysis was diagnosed with acute myelomonocytic leukemia based on clinical, cytologic, and immunologic findings. Proteinuria (urine proteincreatinine ratio = 1.5) occurred in the absence of renal failure. Qualitative assessment of proteinuria by sodium dodecyl sulfate-agarose gel electrophoresis revealed a broad band with a molecular weight of approximately 15 kDa that was compatible with lysozyme (LZM). A diagnosis of tubular proteinuria was made, and a chemical evaluation of LZM in serum and urine samples was performed using a turbidimetric assay. The LZM concentrations were 24.5 mg/l (reference interval: 2.5-8.0 mg/l) and 274.5 mg/l (reference interval: <2 mg/l) in serum and urine, respectively.


Pseudomonas aeruginosa cleaves the decoding center of Caenorhabditis elegans ribosomes.
Pathogens such as Pseudomonas aeruginosa advantageously modify animal host physiology, for example, by inhibiting host protein synthesis. Translational inhibition of insects and mammalian hosts by P. aeruginosa utilizes the well-known exotoxin A effector. However, for the infection of Caenorhabditis elegans by P. aeruginosa, the precise pathways and mechanism(s) of translational inhibition are not well understood. We found that upon exposure to P. aeruginosa PA14, C. elegans undergoes a rapid loss of intact ribosomes accompanied by the accumulation of ribosomes cleaved at helix 69 (H69) of the 26S ribosomal RNA (rRNA), a key part of ribosome decoding center. H69 cleavage is elicited by certain virulent P. aeruginosa isolates in a quorum sensing (QS)-dependent manner and independently of exotoxin A-mediated translational repression. H69 cleavage is antagonized by the 3 major host defense pathways defined by the pmk-1, fshr-1, and zip-2 genes. The level of H69 cleavage increases with the bacterial exposure time, and it is predominantly localized in the worm's intestinal tissue. Genetic and genomic analysis suggests that H69 cleavage leads to the activation of the worm's zip-2-mediated defense response pathway, consistent with translational inhibition. Taken together, our observations suggest that P. aeruginosa deploys a virulence mechanism to induce ribosome degradation and H69 cleavage of host ribosomes. In this manner, P. aeruginosa would impair host translation and block antibacterial responses.


Hypothesis: soluble aβ oligomers in association with redox-active metal ions are the optimal generators of reactive oxygen species in Alzheimer's disease.
Considerable evidence points to oxidative stress in the brain as an important event in the early stages of Alzheimer's disease (AD). The transition metal ions of Cu, Fe, and Zn are all enriched in the amyloid cores of senile plaques in AD. Those of Cu and Fe are redox active and bind to Aβ in vitro. When bound, they can facilitate the reduction of oxygen to hydrogen peroxide, and of the latter to the hydroxyl radical. This radical is very aggressive and can cause considerable oxidative damage. Recent research favours the involvement of small, soluble oligomers as the aggregating species responsible for Aβ neurotoxicity. We propose that the generation of reactive oxygen species (i.e., hydrogen peroxide and hydroxyl radicals) by these oligomers, in association with redox-active metal ions, is a key molecular mechanism underlying the pathogenesis of AD and some other neurodegenerative disorders.


Structured Exercise in Obese Diabetic Patients with Chronic Kidney Disease: A Randomized Controlled Trial.
Patients with type 2 diabetes mellitus (DM), obesity, and chronic kidney disease (CKD) are generally physically inactive and may benefit from exercise. Our objective was to determine the effects of structured exercise on physical fitness, kidney function, endothelial function, inflammation, and body composition in such patients. In this randomized, controlled trial, 36 male patients (age 49-81) were randomly assigned to exercise + diet management (n = 18) or diet alone (n = 18). Participants were eligible if they had type 2 DM, body mass index >30 kg/m2, CKD stages 2-4, and persistent proteinuria (>200 mg/g creatinine for >3 months). The exercise intervention was a 12-week (3 days per week) program of aerobic and resistance training followed by 40 weeks of home exercise. The primary outcome measure was change from baseline in urine protein to creatinine ratio (UPCR) at 12 and 52 weeks. Thirty-two participants completed the study (14 exercise + diet, 18 diet-alone group). The change from baseline in UPCR was slightly greater in the diet-alone group at 12 weeks but not at 52 weeks. Changes in both symptom-limited and constant-workrate treadmill times were significantly higher in the exercise + diet group at 12 weeks but not at 52 weeks. There were no significant differences in urine albumin to creatinine ratio, estimated glomerular filtration rate, endothelial function, inflammation, or body composition between the groups. In obese diabetic subjects with CKD, structured exercise improved exercise capacity but not body composition or renal function. This is a work of the US Government and is not subject to copyright protection in the USA. Foreign copyrights may apply. Published by S. Karger AG, Basel.


Regulation of p53 by hypoxia: dissociation of transcriptional repression and apoptosis from p53-dependent transactivation.
Hypoxic stress, like DNA damage, induces p53 protein accumulation and p53-dependent apoptosis in oncogenically transformed cells. Unlike DNA damage, hypoxia does not induce p53-dependent cell cycle arrest, suggesting that p53 activity is differentially regulated by these two stresses. Here we report that hypoxia induces p53 protein accumulation, but in contrast to DNA damage, hypoxia fails to induce endogenous downstream p53 effector mRNAs and proteins. Hypoxia does not inhibit the induction of p53 target genes by ionizing radiation, indicating that p53-dependent transactivation requires a DNA damage-inducible signal that is lacking under hypoxic treatment alone. At the molecular level, DNA damage induces the interaction of p53 with the transcriptional activator p300 as well as with the transcriptional corepressor mSin3A. In contrast, hypoxia primarily induces an interaction of p53 with mSin3A, but not with p300. Pretreatment of cells with an inhibitor of histone deacetylases that relieves transcriptional repression resulted in a significant reduction of p53-dependent transrepression and hypoxia-induced apoptosis. These results led us to propose a model in which different cellular pools of p53 can modulate transcriptional activity through interactions with transcriptional coactivators or corepressors. Genotoxic stress induces both kinds of interactions, whereas stresses that lack a DNA damage component as exemplified by hypoxia primarily induce interaction with corepressors. However, inhibition of either type of interaction can result in diminished apoptotic activity.


Proteomic analysis and biochemical alterations in marine mussel gills after exposure to the organophosphate flame retardant TDCPP.
Organophosphate flame retardants (OPFRs) are (re-)emergent environmental pollutants increasingly being used because of the restriction of other flame retardants. The chlorinated OPFR, tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is among those of highest environmental concern, but its potential effects in the marine environment have rarely been investigated. We exposed a widely used sentinel marine mussel species, Mytilus galloprovincialis, to 10 μg L-1 of TDCPP during 28 days and studied: (i) the kinetics of bioaccumulation and elimination of the compound, (ii) the effect on two molecular biomarkers, glutathione S-transferase (GST) and acetylcholinesterase (AChE) activities, and (iii) proteomic alterations in the gills, following an isobaric labeling quantitative shotgun proteomic approach, at two exposure times (7 and 28 days). Uptake and elimination of TDCPP by mussels were very fast, and the bioconcentration factor of this compound in mussels was 147 L kgww-1, confirming that this compound is not very bioaccumulative, as predicted by its chemical properties. GST activity was not affected by TDCPP exposure, but AChE activity was inhibited by TDCPP at both 7 and 28 days of exposure. Proteomic analysis revealed subtle effects of TDCPP in mussel gills, since few proteins (less than 2 % of the analysed proteome) were significantly affected by TDCPP, and effect sizes were low. The most relevant effects detected were the up-regulation of epimerase family protein SDR39U1, an enzyme that could be involved in detoxification processes, at both exposure times, and the down-regulation of receptor-type tyrosine-protein phosphatase N2-like (PTPRN2) after 7 days of exposure, which is involved in neurotransmitter secretion and might be related to the neurotoxicity described for this compound. Exposure time rather than TDCPP exposure was the most important driver of protein abundance changes, with 33 % of the proteome being affected by this factor, suggesting that stress caused by laboratory conditions could be an important confounding factor that needs to be controlled in similar ecotoxicology studies. Proteomic data are available via ProteomeXchange with identifier PXD019720.


Influence of agitation and aeration in xanthan production by Xanthomonas campestris pv pruni strain 101.
Production, viscosity, and chemical composition of xanthan synthesized by bacterium Xanthomonas campestris pv pruni strain 101 were evaluated in bioreactor systems. During the process, the volumetric oxygen mass transfer coefficient (k(L)a) and the biomass were determined and the pH was monitored. The cultures were grown in a 3 I bioreactor, with aeration and agitation varying as follows: conditions (A) 300 rpm, 3 vvm and (B) 200 rpm, 2 vvm, at 28 degrees C. Our results showed that gum production was dependent on k(L)a, with a maximum yield of 8.15 g/l at 300 rpm, 3 vvm, 54 h of fermentation, k(L)a 21.4/h, while biomass was not affected. All aqueous solutions of 3% (w/v) xanthans synthesized showed a pseudoplastic behavior. The highest viscosity was reached under the strongest aeration/agitation conditions. All xanthan samples contained glucose, mannose, rhamnose, and glucuronic acid as their main components. The highest agitation and aeration rates used under condition A (300 rpm and 3 vvm) favorably influenced the yield and viscosity of the xanthan produced by bacterium X. campestris pv pruni 101 at different fermentation times.


A comparison between artificial and natural water oxidation.
Two artificial water oxidation catalysts, the blue dimer and the Llobet catalyst, have been studied using hybrid DFT methods. The results are compared to those for water oxidation in the natural photosystem II enzyme. Studies on the latter system have now reached a high level of understanding, at present much higher than the one for the artificial systems. A recent high resolution X-ray structural investigation of PSII has confirmed the main features of the structure of the oxygen evolving complex (OEC) suggested by previous DFT cluster studies. The O-O bond formation mechanism suggested is of direct coupling (DC) type between an oxygen radical and a bridging oxo ligand. A similar DC mechanism is found for the Llobet catalyst, while an acid-base (AB) mechanism is preferred for the blue dimer. All of them require at least one oxygen radical. Full energy diagrams, including both redox and chemical steps, have been constructed illustrating similarities and differences to the natural system. Unlike previous DFT studies, the results of the present study suggest that the blue dimer is rate-limited by the initial redox steps, and the Llobet catalyst by O(2) release. The results could be useful for further improvement of the artificial systems.


Site-specific blockade of RAGE-Vd prevents amyloid-beta oligomer neurotoxicity.
In the genesis of Alzheimer's disease (AD), converging lines of evidence suggest that amyloid-beta peptide (Abeta) triggers a pathogenic cascade leading to neuronal loss. It was long assumed that Abeta had to be assembled into extracellular amyloid fibrils or aggregates to exert its cytotoxic effects. Over the past decade, characterization of soluble oligomeric Abeta species in the brains of AD patients and in transgenic models has raised the possibility that different conformations of Abeta may contribute to AD pathology via different mechanisms. The receptor for advanced glycation end products (RAGE), a member of the Ig superfamily, is a cellular binding site for Abeta. Here, we investigate the role of RAGE in apoptosis induced by distinct well characterized Abeta conformations: Abeta oligomers (AbetaOs), Abeta fibrils (AbetaFs), and Abeta aggregates (AbetaAs). In our in vitro system, treatment with polyclonal anti-RAGE antibodies significantly improves SHSY-5Y cell and neuronal survival exposed to either AbetaOs or AbetaAs but does not affect AbetaF toxicity. Interestingly, using site-specific antibodies, we demonstrate that targeting of the V(d) domain of RAGE attenuates AbetaO-induced toxicity in both SHSY-5Y cells and rat cortical neurons, whereas inhibition of AbetaA-induced apoptosis requires the neutralization of the C(1d) domain of the receptor. Thus, our data indicate that distinct regions of RAGE are involved in Abeta-induced cellular and neuronal toxicity with respect to the Abeta aggregation state, and they suggest the blockage of particular sites of the receptor as a potential therapeutic strategy to attenuate neuronal death.


Prior victimization: a risk factor for child sexual abuse and for PTSD-related symptomatology among sexually abused youth.
The experience of prior victimization (sexual and nonsexual) was found to increase children's risk for experiencing later child sexual abuse (CSA) in a national random sample of 2,000 American children aged 10-16 years. Prior victimization predicted subsequent CSA even when background variables (child's gender, race, age, geographic location, quality of relationship with parents, and relative level of violence in the home community) were controlled for. In addition, the prior victimization of a family member also predicted later CSA. Among children who experienced CSA, prior victimization increased the level of post-traumatic stress symptomatology, even after demographic factors and characteristics of the CSA episode (e.g., severity of the assault, severity of injury, fear of death or serious injury) were included in the model. These results suggest that prior victimization is a factor that needs to be addressed by educators who design CSA prevention interventions and by mental health professionals who counsel child victims of sexual abuse.


CD4-directed peptide vaccination augments an antitumor response, but efficacy is limited by the number of CD8+ T cell precursors.
Peptide vaccination is an immunotherapeutic strategy being pursued as a method of enhancing Ag-specific antitumor responses. To date, most studies have focused on the use of MHC class I-restricted peptides, and have not shown a correlation between Ag-specific CD8(+) T cell expansion and the generation of protective immune responses. We investigated the effects of CD4-directed peptide vaccination on the ability of CD8(+) T cells to mount protective antitumor responses in the DUC18/CMS5 tumor model system. To accomplish this, we extended the amino acid sequence of the known MHC class I-restricted DUC18 rejection epitope from CMS5 to allow binding to MHC class II molecules. Immunization with this peptide (tumor-derived extracellular signal-regulated kinase-II (tERK-II)) induced Ag-specific CD4(+) T cell effector function, but did not directly prime CD8(+) T cells. Approximately 31% of BALB/c mice immunized with tERK-II were protected from subsequent tumor challenge in a CD40-dependent manner. Priming of endogenous CD8(+) T cells in immunized mice was detected only after CMS5 challenge. Heightened CD4(+) Th cell function in response to tERK II vaccination allowed a 12-fold reduction in the number of adoptively transferred CD8(+) DUC18 T cells needed to protect recipients against tumor challenge as compared with previous studies using unimmunized mice. Furthermore, tERK-II immunization led to a more rapid and transient expansion of transferred DUC18 T cells than was seen in unimmunized mice. These findings illustrate that CD4-directed peptide vaccination augments antitumor immunity, but that the number of tumor-specific precursor CD8(+) T cells will ultimately dictate the success of immunotherapy.


Shyness and Vocabulary: The Roles of Executive Functioning and Home Environmental Stimulation.
Although shyness has often been found to be negatively related to vocabulary, few studies have examined the processes that produce or modify this relation. The present study examined executive functioning skills and home environmental stimulation as potential mediating and moderating mechanisms. A sample of 3.5-year-old children (N=254) were administered executive functioning tasks and a vocabulary test during a laboratory visit. Mothers completed questionnaires assessing child shyness and home environmental stimulation. Our primary hypothesis was that executive functioning mediates the association between shyness and vocabulary, and home environmental stimulation moderates the relation between executive functioning and vocabulary. Alternative hypotheses were also tested. Results indicated that children with better executive functioning skills developed stronger vocabularies when reared in more, versus less, stimulating environments. Implications of these results are discussed in terms of the role of shyness, executive functioning, and home environmental stimulation in early vocabulary development.


Decreased protein synthesis of Hsp27 associated with cellular toxicity in a cell model of Machado-Joseph disease.
Machado-Joseph disease is an autosomal dominant spinocerebellar degeneration caused by the expansion of a polyglutamine tract within the gene product, ataxin-3. We have previously shown that increased oxidative stress and decreased expression of Hsp27 may be contributory factors to the disease progression. In this study, we utilized neuroblastoma SK-N-SH cells stably transfected with full-length expanded ataxin-3 to further investigate the mechanism(s) resulting in the decreased expression of Hsp27. Results from 35S-methionine pulse-chase labeling and protein degradation assays revealed that decreased Hsp27 in mutant MJD cells is due to defects in protein synthesis. Our results further demonstrated that Hsp27 degradation is independent of the proteasome degradation pathway. In addition, we showed that overexpression of Hsp27 desensitizes mutant MJD cells to apoptotic stress. Taken together, these findings provide the first evidence that expanded ataxin-3 interferes with Hsp27 synthesis, which may contribute to the impairment of the cells' ability to respond to stresses and trigger the progression of this late-onset disease.


PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma.
Phosphatidylinositol-3-kinase delta (PI3Kδ) mediates B-cell receptor signaling and microenvironmental support signals that promote the growth and survival of malignant B lymphocytes. In a phase 1 study, idelalisib, an orally active selective PI3Kδ inhibitor, showed antitumor activity in patients with previously treated indolent non-Hodgkin's lymphomas. In this single-group, open-label, phase 2 study, 125 patients with indolent non-Hodgkin's lymphomas who had not had a response to rituximab and an alkylating agent or had had a relapse within 6 months after receipt of those therapies were administered idelalisib, 150 mg twice daily, until the disease progressed or the patient withdrew from the study. The primary end point was the overall rate of response; secondary end points included the duration of response, progression-free survival, and safety. The median age of the patients was 64 years (range, 33 to 87); patients had received a median of four prior therapies (range, 2 to 12). Subtypes of indolent non-Hodgkin's lymphoma included follicular lymphoma (72 patients), small lymphocytic lymphoma (28), marginal-zone lymphoma (15), and lymphoplasmacytic lymphoma with or without Waldenström's macroglobulinemia (10). The response rate was 57% (71 of 125 patients), with 6% meeting the criteria for a complete response. The median time to a response was 1.9 months, the median duration of response was 12.5 months, and the median progression-free survival was 11 months. Similar response rates were observed across all subtypes of indolent non-Hodgkin's lymphoma, though the numbers were small for some categories. The most common adverse events of grade 3 or higher were neutropenia (in 27% of the patients), elevations in aminotransferase levels (in 13%), diarrhea (in 13%), and pneumonia (in 7%). In this single-group study, idelalisib showed antitumor activity with an acceptable safety profile in patients with indolent non-Hodgkin's lymphoma who had received extensive prior treatment. (Funded by Gilead Sciences and others; ClinicalTrials.gov number, NCT01282424.).


Estimation of Dog-Bite Risk and Related Morbidity Among Personnel Working With Military Dogs.
Soldiers serving in the Israel Defense Force Military Working Dogs (MWD) Unit spend many hours taming dogs' special skills, taking them on combat missions, and performing various dogkeeping activities. During this intensive work with the aggressive military dogs, bites are common, and some of them result in permanent disability. However, this phenomenon has not been quantified or reported as an occupational hazard. This was a retrospective cohort study based on self-administered questionnaires. Information was collected about soldiers' baseline demographics, duration of the experience of working with dogs, total number of bites they had, circumstances of bite events, and complications and medical treatment of each bite. Bite risk was quantified by incidence, mean time to first bite, and a Cox proportional hazards model. Rates of complications and the medical burden of bites were compared between combat soldiers and noncombat dogkeepers. Bite locations were presented graphically. Seventy-eight soldiers participated and reported on 139 bites. Mean time of working with dogs was 16 months (standard deviation, ±9.4 months). Overall bite incidence was 11 bites per 100 person-months; the mean time to first bite event was 6.3 months. The Cox proportional hazards model showed that none of baseline characteristics significantly increased bite hazard. About 90% of bites occurred during routine activities, and 3.3% occurred on combat missions. Only in 9% of bite events did soldiers observed the safety precautions code. Bite complications included fractures, need for intravenous antibiotic treatment and surgical repair, prominent scarring, diminished sensation, and stiffness of proximal joints. Bite complications were similar between combat soldiers and dogkeepers. Most bites (57%) were located on hands and arms. MWD bites are an occupational hazard resulting in significant medical burden. Hands and arms were most common bite locations. Observance of safety precautions may be the most appropriate first-line preventive intervention. Barrier protection of upper extremities may reduce bite severity and complication rates.


Veno-arterial extracorporeal membrane oxygenation for high-risk cardiac catheterisation procedures.
Extracorporeal membrane oxygenation (ECMO) provides circulatory or respiratory support, or both, to patients with severe but potentially reversible cardiac or respiratory failure refractory to standard therapy. The use of ECMO in the paediatric cardiac surgical population is established. Likewise, the use of ECMO for severe adult respiratory failure has recently been established and has been the subject of recent clinical trials. However, its use as a means of cardiac support in the adult population is not routine in clinical practice. We herein review the indications, technical procedure, complications and outcomes of extracorporeal membrane oxygenation as pertinent to cardiac disease in general, and specifically, to catheter-based interventions. We describe two cases of high-risk cardiac catheterisation laboratory procedures performed with veno-arterial ECMO support in adult patients who were deemed to be at unacceptably high risk for conventional open-heart surgery and cardiopulmonary bypass.


Infant feeding practices and prevalence of obesity in eight European countries - the IDEFICS study.
To assess the association between exclusive breast-feeding and childhood overweight. Cross-sectional data are from the baseline survey of the longitudinal cohort study IDEFICS. Exclusive rather than partial breast-feeding is the focus of the study due to the theoretical relationship between exclusive breast-feeding and development of dietary self-regulation. Children's measured heights and weights were used to calculate weight status, while waist-to-height ratio (WtHR) and skinfold measures were examined as alternative indicators of adiposity and fat patterning. Examination centres in eight European countries (Italy, Estonia, Cyprus, Belgium, Sweden, Hungary, Germany and Spain). The analysis included 14 726 children aged 2-9 years for whom early feeding practices were reported by parents in standardized questionnaires. After controlling for education, income and other potential confounders, breast-feeding exclusively for 4-6 months was protective of overweight (including obesity) when compared with children never exclusively breast-fed (OR = 0·73; 95 % CI 0·63, 0·85) across all measures of overweight. Exclusively breast-feeding for 6 months offered slightly more protection than for 4 and 5 months combined (OR = 0·71; 95 % CI 0·58, 0·85). The associations could not be explained by socio-economic characteristics or maternal overweight. This multi-country investigation indicated that exclusive breast-feeding for 4-6 months may confer protection against overweight in addition to other known benefits. There was no demonstrated benefit of exclusive breast-feeding for more than 6 months or combination feeding for any duration across all measures of overweight examined.


An AXL/LRP-1/RANBP9 complex mediates DC efferocytosis and antigen cross-presentation in vivo.
The phagocytosis of apoptotic cells (ACs), or efferocytosis, by DCs is critical for self-tolerance and host defense. Although many efferocytosis-associated receptors have been described in vitro, the functionality of these receptors in vivo has not been explored in depth. Using a spleen efferocytosis assay and targeted genetic deletion in mice, we identified a multiprotein complex--composed of the receptor tyrosine kinase AXL, LDL receptor-related protein-1 (LRP-1), and RAN-binding protein 9 (RANBP9)--that mediates DC efferocytosis and antigen cross-presentation. We found that AXL bound ACs, but required LRP-1 to trigger internalization, in murine CD8α+ DCs and human-derived DCs. AXL and LRP-1 did not interact directly, but relied on RANBP9, which bound both AXL and LRP-1, to form the complex. In a coculture model of antigen presentation, the AXL/LRP-1/RANBP9 complex was used by DCs to cross-present AC-associated antigens to T cells. Furthermore, in a murine model of herpes simplex virus-1 infection, mice lacking DC-specific LRP-1, AXL, or RANBP9 had increased AC accumulation, defective viral antigen-specific CD8+ T cell activation, enhanced viral load, and decreased survival. The discovery of this multiprotein complex that mediates functionally important DC efferocytosis in vivo may have implications for future studies related to host defense and DC-based vaccines.


Effect of Aging and Weathering on the Physical Properties of Maxillofacial Silicone Elastomers: A Systematic Review and Meta-Analysis.
This systematic review aims to identify and interpret results of studies that evaluated the changes in the physical properties of maxillofacial prosthetic materials (1) without aging, (2) after natural or artificial accelerated aging, and (3) after outdoor weathering. Relevant articles written in English only, before January 15, 2017, were identified using an electronic search in the PubMed, Scopus, and Google Scholar databases. Furthermore, a manual search of the related major journals was also conducted to identify more pertinent articles. The relevancy of the articles was verified by screening the title, abstract, and full text if they met the inclusion criteria. A total of 37 articles satisfied the criteria, from which data were extracted for qualitative synthesis. Among the 37 included articles, 14 were without aging, 15 were natural or artificial accelerated aging, 7 were outdoor weathering, and 1 contained both artificial aging and outdoor weathering. Only 4 studies out of the 14 without aging had significant observations; whereas 9 articles with natural or artificial aging published significant results, and 3 out of 7 outdoor weathering articles showed significant changes in the evaluated silicone elastomers. Despite the varying research, it seems that the single "ideal" maxillofacial prosthetic material that can provide sufficient resistance against different aging conditions is yet to be identified. Therefore, it is imperative for standardization organizations, the scientific community, and academia to develop modified prosthetic silicones possessing improved physical properties and color stability, limiting the clinical problems regarding degradation of maxillofacial prostheses.


Relationship between Toxoplasma gondii seropositivity and depression in children and adolescents.
Identification of the structural causes of depression is important for the treatment process, and toxoplasmosis may be related to psychiatric disorders. The aim of this study was to evaluate the relationship between Toxoplasma gondii (T. gondii) seropositivity and depression in children and adolescents. This case-control study included 37 children and adolescents aged 11-18 years diagnosed with depression who were followed by the Manisa Celal Bayar University Child and Adolescent Mental Health Service and 36 children and adolescents aged 11-18 years with no history of depressive episodes or psychiatric disorder treated by the Pediatric Outpatient Department. The T. gondii serology of these two groups was evaluated and compared. There were no statistically significant age or sex differences between the 37 participants with depression and the 36 healthy controls. Eight patients and two controls were seropositive for T. gondii, a statistically significant difference (p = 0.046). Seropositivity was significantly higher in patients with suicidal ideation (p = 0.005) than in those without suicidal ideation. The seropositivity of seven of the nine participants who attempted suicide was significantly higher (p < 0.001) than that of participants who did not. Thus, T. gondii infection may affect the predisposition for and severity of depression.


Separation of antigens by immunological specificity. Studies on the desorption of homologous antigen from disulphide-linked antibody immunosorbents.
1. Glycine-hydrochloric acid buffer, pH2.2, desorbed (131)I-labelled human serum albumin (100%), lysozyme (100%), ovalbumin (90%), fluorescent ovalbumin (50-60%) and fluorescent human gamma-globulin (20%) from their respective homologous disulphide-linked antibody immunosorbents; reasons are suggested for the low recoveries of the fluorescently labelled proteins. 2. Approx. 40% of the recovered (131)I-labelled human serum albumin and fluorescent ovalbumin was desorbed above pH6.0, but lysozyme was not eluted until the pH was 3.0 or below. 3. In all cases where high recoveries of antigen were obtained, the immunosorbents could be regenerated and recycled at least four times with full retention of specificity and minimal diminution of capacity. 4. The desorbed antigens were unchanged when compared with the original antigens by quantitative precipitin, specificradioactivity, fluorescent and enzymic analyses and by cellulose acetate electrophoresis. 5. Desorption of antigen with a variety of reagents was investigated. These reagents were less satisfactory than glycine-hydrochloric acid.


Early diagnosis of abnormal development of preterm newborns: assessment instruments.
To review the literature regarding screening psychomotor tests for the early identification of developmental problems. A search on SciELO, PubMed and Google Scholar was performed using the terms "prematurity," "developmental delay," "cerebral palsy," "early diagnosis" and "evaluation tests." A total of 455 references were listed, and 174 studies were selected for this review based on title, relevance, and abstract. Only original and electronically available material, from 1985 forward, with information on design, applicability, and psychometric properties of those tests was included. Screening tests are important to speed the beginning of treatment measures in order to allow for better developmental outcome. Among the many tests that can be employed for this purpose, the DENVER II and the Alberta Infant Motor Scale are the most often used in Brazilian studies. The Movement Assessment of Infants is starting to be used in our country. Two other tests are recommended in the literature due to their high sensibility and specificity: the Test of Infant Motor Performance and the General Movements.


The pressure/volume relationship during dobutamine stress echocardiography in transplanted heart: comparison with quality of life and coronary anatomy.
Cardiac allograft vasculopathy (CAV) is a major late complication in cardiac transplant recipients and has a relevant impact on outcome of these patients. to compare, in cardiac transplant recipients patients, the diagnostic value of pressure/volume relationship (ESPVR) during dobutamine stress echocardiography (DSE) for coronary artery disease, assessed by Multislice Computed Tomography (MSCT), and by coronary angiography (CA). We also analyzed any possible relationship between ESPVR and the Health Related Quality of Life of the patients (HRQoL), evaluated by SF-36 questionnaire. 25 consecutive patients underwent DSE within 24 hours after MSCT coronary angiogram and then they underwent CA. The HRQoL questionnaire was administered to the patients in the settings of DSE. They were followed-up for 6 months. DSE has a sensitivity in detecting CAV of 67%, specificity of 95%, positive predictive value of 67% and negative predictive value of 95%; DSE with ESPVR has a sensitivity of 100%, specificity of 95%, positive predictive value of 75%, negative predictive value of 100%; MSCT has a sensitivity of 100%; specificity of 82%; positive predictive value of 43%; negative predictive value of 100%. Htx recipients with a flat-biphasic ESPVR, although asymptomatic, perceived a worst HRQoL compared with the up-sloping ESPVR population, and this is statistically significant for the general health (p 0.0004), the vitality (p 0.0013) and the mental health (p 0.021) SF-36 subscale. Evaluation with DSE and ESPVR is accurate in the clinical control of heart transplant recipients reserving invasive evaluation only for patients with abnormal contractility indexes.


Hospital doctors' attitudes towards older people.
Ageism among health professionals is increasingly recognized, but few studies investigated hospital doctors' attitudes towards older people. The aims of this study were to investigate hospital doctors' attitudes towards older people and to determine whether factors, which were identified in studies on other health professionals, influence hospital doctors' attitudes. Hospital doctors who worked in General Medicine or Aged Care units in two tertiary public hospitals in metropolitan Victoria, Australia, in 2008 were surveyed with Fraboni's Scale of Ageism (FSA), a validated instrument used to investigate attitudes towards older people. Demographic data from participants were collected. Of the 235 questionnaires distributed, 122 were returned (overall response rate 51.9%). Response rate was highest among consultants (80.4%), followed by registrars (64.1%) and lowest among interns and residents (35.2%). The mean FSA score attained by the respondents was 61.5 (SD 11.0), representing a point between a neutral and a positive disposition. Doctors' characteristics that were associated with more positive attitudes towards older people included age of 30years or older (P < 0.001), female gender (P= 0.003), more senior in position (P < 0.001), postgraduate years of 10 or more (P < 0.001), previous working experience in Aged Care (P < 0.001), interest in Aged Care (P < 0.001) and more frequent social contacts with healthy older people (P < 0.001). Hospital doctors of different demographic features and background characteristics display different attitudes towards older people. These findings can be used to inform future development of undergraduate and postgraduate medical curricula and form a basis for future studies on the effectiveness of these interventions in improving doctors' attitudes.


Automated muscle segmentation from CT images of the hip and thigh using a hierarchical multi-atlas method.
Patient-specific quantitative assessments of muscle mass and biomechanical musculoskeletal simulations require segmentation of the muscles from medical images. The objective of this work is to automate muscle segmentation from CT data of the hip and thigh. We propose a hierarchical multi-atlas method in which each hierarchy includes spatial normalization using simpler pre-segmented structures in order to reduce the inter-patient variability of more complex target structures. The proposed hierarchical method was evaluated with 19 muscles from 20 CT images of the hip and thigh using the manual segmentation by expert orthopedic surgeons as ground truth. The average symmetric surface distance was significantly reduced in the proposed method (1.53 mm) in comparison with the conventional method (2.65 mm). We demonstrated that the proposed hierarchical multi-atlas method improved the accuracy of muscle segmentation from CT images, in which large inter-patient variability and insufficient contrast were involved.


Cocaine-mediated impairment of cardiac conduction in the dog: a potential mechanism for sudden death after cocaine.
Deaths from cocaine abuse continue to increase, while the mechanism of lethality remains unclear. Previous investigations have focused on potential ventricular dysrhythmias and myocardial ischemic events from enhanced autonomic tone or seizure activity from central stimulation. However, cocaine is a local anesthetic and may impair cardiac conduction. To evaluate this, 16 conscious dogs received i.v. cocaine over 30 sec to mimic "recreational" use in doses of 3 mg/kg (n = 6), 5 mg/kg (n = 6) or 7 mg/kg (n = 4). Another group of anesthetized dogs (n = 6) received two infusions of cocaine (5 mg/kg) 1 hr apart. Plasma cocaine levels and His bundle electrograms were obtained at control and at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, 10 and 15 min after cocaine administration. At 0.5 min, plasma cocaine reached peak levels of 30.0, 45.0 and 59.6 micrograms/ml with increasing dose. Cocaine rapidly produced severe prolongation of His to ventricle interval and widening of the R wave. Slowing of conduction was dose-dependent, with maximal increases in His to venticle interval of 37 to 56% (P = .0299) and R wave duration of 34 to 77% (P less than .025). Furthermore, significant conduction impairment developed at cocaine levels that did not produce seizures. Conduction effects were equally pronounced during repeated administration of cocaine. These data indicate that cocaine causes marked conduction slowing, which could play an important role in cocaine death.


The NCI All Ireland Cancer Conference.
The National Cancer Institute (NCI) has recently decided to embark on an international partnership with the developing cancer programs on the Island of Ireland (Northern Ireland and the Republic of Ireland) in an attempt to further improve the quality and range of cancer services available for patients. This Transatlantic Partnership called the All Ireland-NCI Cancer Consortium offers exciting opportunities in cancer treatment, education and research as the cancer-caring communities from both the Republic of Ireland and Northern Ireland prepare to join with the U.S. NCI in this major endeavor. The inaugural event of the partnership will be the NCI All Ireland Cancer Conference to be held in Belfast, October 3-6, 1999. (See www.allirelandcancer.com, for information on the conference.) Cancer is a significant cause of mortality and morbidity on the Island of Ireland. There are approximately 28,000 new cases and approximately 11,000 deaths from cancer each year. Therefore, Northern Ireland and the Republic of Ireland have among the highest cancer incidence and mortality rates in the Western World. In recent years there has been a major restructuring of cancer services in both parts of the Island. This is the result of several government reports such as the Campbell Report in Northern Ireland and the National Strategy Document for Cancer in the Republic of Ireland. The National Strategy Document proposes that cancer treatment services should be centered around primary care services, regional services, supra-regional centers and a national coordinating structure whereby the supra-regional centers deliver specialist surgery, medical and radiation oncology, rehabilitation and specialist palliative care. Three supra-regional cancer centers are being established in the cities of Dublin, Cork and Galway and a National Cancer Forum, which has served as a multidisciplinary advisory board to the Government, has pushed the development and implementation of this plan. This has already resulted in a major expansion in the number of medical oncologists practicing in Ireland but further development is required to facilitate multidisciplinary care, to establish programs of education and training and to harness the scientific talent available to engage in the international effort against cancer. In Northern Ireland the Chief Medical Officer commissioned a report entitled "Cancer Services-Investing for the Future" whose key recommendations were that Northern Ireland should have one cancer center in Belfast and four smaller cancer units. This report also recommended the implementation of a multidisciplinary approach to cancer diagnosis, treatment and palliative care. As in the Republic, all the recommendations of the Report have been accepted and the planning and implementation of this plan are now well under way. Therefore, development of services for cancer patients is a top priority for both governments on the Island and, given the process of cancer service development, it is timely to bring international expertise such as the NCI on board as partners in this effort. The decision by the NCI to develop an agreement for cancer research and service development in Ireland is a major boost for those involved in cancer care and research and will, no doubt, help speed the process of redevelopment. There have already been several visits from senior NCI personnel to Ireland including Dr. Klausner, the Director of the NCI, to determine the potential impact of this agreement and to identify the most productive areas of interaction between the NCI and the Irish Cancer Community. As a result of these visits, the NCI has decided to focus on several areas of strategic importance whose objectives will be to enhance clinical services, improve patient care, promote North South collaboration and cement strategic Ireland-U.S. collaboration in cancer research and development. The agreement will build on existing informal links in U.S.-Irish scientific, medical education and training and also promote clinical trials and cancer epidemiology programs. Major components of the NCI Ireland Agreement will include some of the following: EDUCATION AND EXCHANGE OF SCHOLARS: Education will form one of the major platforms of this agreement through the support of educational programs for medical, nursing and scientific staff. These will include the exchange of scholars, including Ph.D., M.D. and nursing students. Particular emphasis will be given to the exchange of medical and nursing trainees focused on clinical research. This will have an immediate clinical impact and will naturally extend the support that has already been given to the training of medical and scientific trainees from the Island of Ireland. Further exchanges would include Ph.D. students, laboratory-based M.D.s in training, clinical visiting professors and investigators from the U.S. wishing to extend their studies in Ireland. CLINICAL TRIALS: Another major area for partnership will be the enhancement of a clinical trials infrastructure and clinical trial development. Modernization of cancer care requires that delivery of care should be in the context of evidence-based medicine. This requires a vigorous and contemporary clinical trials infrastructure which would center around the clinical trials infrastructure already established at the Northern Ireland Cancer Centre and the Irish Clinical Oncology Research Group (ICORG) in the Republic of Ireland. The NCI has already commissioned the development of a new Clinical Trials Information System (CTIS) which seeks as its goal to set international standards in the clinical trials process, and it has already committed significant resources to its implementation. The outcome of this element of partnership will be that clinical trials performed in Irish institutions will immediately be compatible for collation, analysis and presentation with studies performed in the U.S. Moreover, this system will allow participating centers to immediately conform to international standards. This proposal therefore permits participating institutions in Northern Ireland and the Republic of Ireland to quickly achieve data management standards of the highest quality. TELECONFERENCING: Teleconferencing capabilities are already established in both the NCI and in Ireland and indeed limited teleconferencing linkages have already been established between the partners. Further investment in this infrastructure will be vital to the success of major elements of this partnership. It will facilitate clinical trial development, education programs, patient services development and exchange of clinical and scientific ideas. Communication between sites will be essential to the success of this partnership. TUMOR REGISTRIES: Another area for major collaboration and partnership will be in the use of the Cancer Tumor Registries in both Northern Ireland and the Republic of Ireland. The monitoring of improvements in cancer care can only be undertaken with a reliable tumor registry that tracks population-based cancer incidence and mortality. These data are now available in both Northern Ireland and the Republic of Ireland, and both Governments recognize their importance. The NCI proposes to assist both Tumor Registries by developing a common database that can assist in consultation, informatic tools and quality control. Consolidation of the Registries, North and South, will improve the overall quality of data collection and provide information on a genetically stable population. This therefore will act as a major tool for epidemiological investigations and programs focused on screening and prevention. DEVELOPMENTS IN CANCER CLINICAL SERVICES: The NCI Ireland partnership also proposes to assist the further development of clinical service programs on the Island of Ireland. These will include the improvement and standardization of Radiation Oncology practice and the development of a consolidated Radiation Oncology program for research. There are a limited number of radiation facilities on the Island of Ireland and there are significant needs in terms of linking practice elements and the implementation of uniform standards of practice. Assistance in standardizing and driving the development of clinical services will also extend to elements of medical and surgical oncology practice as well as palliative care. The development of palliative care services is already at an advanced stage on the Island of Ireland and is one that the NCI will carefully evaluate in terms of its own developing programs. THE NCI ALL IRELAND CANCER CONFERENCE: An important event to highlight the commencement of this special relationship will be the NCI All Ireland Cancer Conference to be held in Belfast October 3-6, 1999. This Conference will address clinical, laboratory, epidemiological and political issues that are pertinent to the care of cancer patients. It will highlight important work by Irish, American and European scientists with further input from well-known international academic and biotechnology investigators from across the world. These international experts will not only be asked to speak on their areas of expertise but also to comment on clinical and scientific programs that may help improve North and South interaction and Transatlantic collaboration. Finally, it is hoped that the Conference will be a marker of a very special interaction on the Island of Ireland focused on the overall development of cancer services for patients. It will also signal the start of an important partnership between the NCI and those involved in cancer care and research in Ireland. This tripartite cooperative agreement is a most exciting venture and it will hopefully be an example of how an effort focused on a human problem common to all societies can generate a spirit of cooperation and help to eliminate strife.


Fifteen minutes of chair-based yoga postures or guided meditation performed in the office can elicit a relaxation response.
This study compared acute (15 min) yoga posture and guided meditation practice, performed seated in a typical office workspace, on physiological and psychological markers of stress. Twenty participants (39.6 ± 9.5 yr) completed three conditions: yoga, meditation, and control (i.e., usual work) separated by ≥24 hrs. Yoga and meditation significantly reduced perceived stress versus control, and this effect was maintained postintervention. Yoga increased heart rate while meditation reduced heart rate versus control (P < 0.05). Respiration rate was reduced during yoga and meditation versus control (P < 0.05). Domains of heart rate variability (e.g., SDNN and Total Power) were significantly reduced during control versus yoga and meditation. Systolic and diastolic blood pressure were reduced secondary to meditation versus control only (P < 0.05). Physiological adaptations generally regressed toward baseline postintervention. In conclusion, yoga postures or meditation performed in the office can acutely improve several physiological and psychological markers of stress. These effects may be at least partially mediated by reduced respiration rate.


Metabolic profiling of angiopoietin-like protein 3 and 4 inhibition: a drug-target Mendelian randomization analysis.
Angiopoietin-like protein 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase (LPL) and represent emerging drug targets to lower circulating triglycerides and reduce cardiovascular risk. To investigate the molecular effects of genetic mimicry of ANGPTL3 and ANGPTL4 inhibition and compare them to the effects of genetic mimicry of LPL enhancement. Associations of genetic variants in ANGPTL3 (rs11207977-T), ANGPTL4 (rs116843064-A), and LPL (rs115849089-A) with an extensive serum lipid and metabolite profile (208 measures) were characterized in six cohorts of up to 61 240 participants. Genetic associations with anthropometric measures, glucose-insulin metabolism, blood pressure, markers of kidney function, and cardiometabolic endpoints via genome-wide summary data were also explored. ANGPTL4 rs116843064-A and LPL rs115849089-A displayed a strikingly similar pattern of associations across the lipoprotein and lipid measures. However, the corresponding associations with ANGPTL3 rs11207977-T differed, including those for low-density lipoprotein and high-density lipoprotein particle concentrations and compositions. All three genotypes associated with lower concentrations of an inflammatory biomarker glycoprotein acetyls and genetic mimicry of ANGPTL3 inhibition and LPL enhancement were also associated with lower C-reactive protein. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower waist-to-hip ratio, improved insulin-glucose metabolism, and lower risk of coronary heart disease and type 2 diabetes, whilst genetic mimicry of ANGPTL3 was associated with improved kidney function. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement have very similar systemic metabolic effects, whereas genetic mimicry of ANGPTL3 inhibition showed differing metabolic effects, suggesting potential involvement of pathways independent of LPL. Genetic mimicry of ANGPTL4 inhibition and LPL enhancement were associated with a lower risk of coronary heart disease and type 2 diabetes. These findings reinforce evidence that enhancing LPL activity (either directly or via upstream effects) through pharmacological approaches is likely to yield benefits to human health.


Making short-term climate forecasts useful: Linking science and action.
This paper discusses the evolution of scientific and social understanding that has led to the development of knowledge systems supporting the application of El Niño-Southern Oscillation (ENSO) forecasts, including the development of successful efforts to connect climate predictions with sectoral applications and actions "on the ground". The evolution of "boundary-spanning" activities to connect science and decisionmaking is then discussed, setting the stage for a report of outcomes from an international workshop comprised of producers, translators, and users of climate predictions. The workshop, which focused on identifying critical boundary-spanning features of successful boundary organizations, included participants from Australia, Hawaii, and the Pacific Islands, the US Pacific Northwest, and the state of Ceará in northwestern Brazil. Workshop participants agreed that boundary organizations have multiple roles including those of information broker, convenor of forums for engagement, translator of scientific information, arbiter of access to knowledge, and exemplar of adaptive behavior. Through these roles, boundary organizations will ensure the stability of the knowledge system in a changing political, economic, and climatic context. The international examples reviewed in this workshop demonstrated an interesting case of convergent evolution, where organizations that were very different in origin evolved toward similar structures and individuals engaged in them had similar experiences to share. These examples provide evidence that boundary organizations and boundary-spanners fill some social/institutional roles that are independent of culture.


Self-mixing laser Doppler flow sensor: an optofluidic implementation.
We present the miniaturization of self-mixing interferometry (SMI) into a microfluidic circuit using an optical fiber, forming an optofluidic device that can be used as a component in lab on a chip systems. We characterize the performance of the device as a fluid velocity (and hence flow) sensor, showing it to produce good accuracy and correlation with theory over a range of velocities from 0.5 to 60 mm/s and almost four decades of scatterer concentration. SMI in an optofluidic system has the advantage that only a single path to the optical inspection point is needed, as the laser source is also the receiver of light. In addition, the same system that is used for measuring fluid velocity can be used to measure other quantities such as particle size. The configuration presented is inherently easy to optically align due to the self-aligned property of SMI and divergent nature of light exiting the embedded optical fiber, providing for low-cost manufacturing.


Dust exposure in coeliac disease: a case-referent study.
Case series of coeliac disease show that chronic allergic alveolitis (farmers' lung) and fever reactions due to exposure to organic dust (organic dust toxic syndrome) commonly occur among subjects with coeliac disease and dermatitis herpetiformis, these being related disorders. In this case-referent study 105 cases of coeliac disease and dermatitis herpetiformis were compared with 237 referents from the general population by means of a mail inquiry regarding exposure to various environmental factors. Increased odds ratios were obtained with exposure to various farm animals and more clearly for cotton dust, although numbers were few. Animal husbandry in Sweden invariably means heavy exposure to organic dust. The fact that comparatively few persons reported dust exposure may be of doubtful validity in view of the high frequency of exposure to farm animals reported by the cases.


Nuclear medicine in diagnosis of prosthetic valve endocarditis: an update.
Over the past decades cardiovascular disease management has been substantially improved by the increasing introduction of medical devices as prosthetic valves. The yearly rate of infective endocarditis (IE) in patient with a prosthetic valve is approximately 3 cases per 1,000 patients. The fatality rate of prosthetic valve endocarditis (PVE) remains stable over the years, in part due to the aging of the population. The diagnostic value of echocardiography in diagnosis is operator-dependent and its sensitivity can decrease in presence of intracardiac devices and valvular prosthesis. The modified Duke criteria are considered the gold standard for diagnosing IE; their sensibility is 80%, but in clinical practice their diagnostic accuracy in PVE is lower, resulting inconclusively in nearly 30% of cases. In the last years, these new imaging modalities have gained an increasing attention because they make it possible to diagnose an IE earlier than the structural alterations occurring. Several studies have been conducted in order to assess the diagnostic accuracy of various nuclear medicine techniques in diagnosis of PVE. We performed a review of the literature to assess the available evidence on the role of nuclear medicine techniques in the diagnosis of PVE.


A constructivist grounded theory study to explore compassion through the perceptions of individuals who have experienced nursing care.
To explore compassion from the perceptions of individuals with personal experience of nursing care. Although compassion is considered integral to professional nursing, increasing reports of care experiences illustrating a lack of compassion have challenged this. Despite political and professional guidance to reaffirm compassion as an underpinning philosophy of contemporary nursing practice, this provides limited insight into what compassion may involve. Contemporary evidence to inform understanding of compassion predominately arises from the professional perspective. This knowledge gap supported the rationale to explore compassion from the individual perspective. Constructivist grounded theory, underpinned by the theoretical perspectives of symbolic interactionism and social constructionism. Data were collected via 11 individual interviews, a focus group discussion and three additional individual interviews during 2013-2015. Initial and focused coding, constant comparative analysis, conceptual mapping, theoretical memos and diagrams supported data analysis until theoretical sufficiency was determined. Inter-related data categories emerged: Self-Propensity for Compassion, Attributes for Compassion, Socialising for Compassion, Conditions for Compassion; and Humanising for Compassion (core category). Compassion is a complex phenomenon, constructed by individuals through their personal experiences of nursing care and life experiences in the social world. In this study, participants perceived that compassion was fundamentally embodied by experiences of a humanising approach to nursing care. These humanising experiences were thought to be influenced by biological, psychological and socio-contextual factors. The study provides additional insight into compassion that requires further investigation with individuals in other care contexts, nurses and healthcare professionals.


ROCKET AF adds more concerns about Digoxin safety in patients with atrial fibrillation.
In a recent article in the Journal, we have reviewed the adverse cardiovascular outcomes observed with digoxin use in the PALLAS study.(1) The PALLAS study was designed to determine if dronedarone would reduce major vascular events in patients with permanent atrial fibrillation (AF).(2) However the study was stopped early because of safety reasons, as a significant number of patients on the dronedarone arm reached the co-primary end point composite of stroke, myocardial infarction, systemic embolism, or cardiovascular death. Data sub-analyses suggested that digoxin-dronedarone interaction was responsible for the higher arrhythmic death rate observed in the trial. These observations are consistent with several other studies that demonstrate the potential hazard of the use of digoxin in heart failure and/or atrial fibrillation. A more recent article published in the Lancet studied the use and outcomes of digoxin in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism in Atrial Fibrillation (ROCKET AF) trial.(3) The investigators concluded that digoxin treatment was associated with a significant increase in all-cause mortality, vascular death, and sudden death in patients with AF.