Incident Cardiovascular Disease Among Adults With Blood Pressure <140/90 mm Hg.
Data from before the 2000s indicate that the majority of incident cardiovascular disease (CVD) events occur among US adults with systolic and diastolic blood pressure (SBP/DBP) ≥140/90 mm Hg. Over the past several decades, BP has declined and hypertension control has improved. We estimated the percentage of incident CVD events that occur at SBP/DBP <140/90 mm Hg in a pooled analysis of 3 contemporary US cohorts: the REGARDS study (Reasons for Geographic and Racial Differences in Stroke), the MESA (Multi-Ethnic Study of Atherosclerosis), and the JHS (Jackson Heart Study) (n=31 856; REGARDS=21 208; MESA=6779; JHS=3869). Baseline study visits were conducted in 2003 to 2007 for REGARDS, 2000 to 2002 for MESA, and 2000 to 2004 for JHS. BP was measured by trained staff using standardized methods. Antihypertensive medication use was self-reported. The primary outcome was incident CVD, defined by the first occurrence of fatal or nonfatal stroke, nonfatal myocardial infarction, fatal coronary heart disease, or heart failure. Events were adjudicated in each study. Over a mean follow-up of 7.7 years, 2584 participants had incident CVD events. Overall, 63.0% (95% confidence interval [CI], 54.9-71.1) of events occurred in participants with SBP/DBP <140/90 mm Hg; 58.4% (95% CI, 47.7-69.2) and 68.1% (95% CI, 60.1-76.0) among those taking and not taking antihypertensive medication, respectively. The majority of events occurred in participants with SBP/DBP <140/90 mm Hg among those <65 years of age (66.7%; 95% CI, 60.5-73.0) and ≥65 years of age (60.3%; 95% CI, 51.0-69.5), women (61.4%; 95% CI, 49.9-72.9) and men (63.8%; 95% CI, 58.4-69.1), and for whites (68.7%; 95% CI, 66.1-71.3), blacks (59.0%; 95% CI, 49.5-68.6), Hispanics (52.7%; 95% CI, 45.1-60.4), and Chinese-Americans (58.5%; 95% CI, 45.2-71.8). Among participants taking antihypertensive medication with SBP/DBP <140/90 mm Hg, 76.6% (95% CI, 75.8-77.5) were eligible for statin treatment, but only 33.2% (95% CI, 32.1-34.3) were taking one, and 19.5% (95% CI, 18.5-20.5) met the SPRINT (Systolic Blood Pressure Intervention Trial) eligibility criteria and may benefit from a SBP target goal of 120 mm Hg. Although higher BP levels are associated with increased CVD risk, in the modern era, the majority of incident CVD events occur in US adults with SBP/DBP <140/90 mm Hg. While absolute risk and cost-effectiveness should be considered, additional CVD risk-reduction measures for adults with SBP/DBP <140/90 mm Hg at high risk for CVD may be warranted.


Addressing care-seeking as well as insurance-seeking selection biases in estimating the impact of health insurance on out-of-pocket expenditure.
Health Insurance (HI) programmes in low-income countries aim to reduce the burden of out-of-pocket (OOP) health care expenditure. However, if the decisions to purchase insurance and to seek care when ill are correlated with the expected health care expenditure, the use of naïve regression models may produce biased estimates of the impact of insurance membership on OOP expenditure. Whilst many studies in the literature have accounted for the endogeneity of the insurance decision, the potential selection bias due to the care-seeking decision has not been taken into account. We extend the Heckman selection model to account simultaneously for both care-seeking and insurance-seeking selection biases in the health care expenditure regression model. The proposed model is illustrated in the context of a Vietnamese HI programme using data from a household survey of 1,192 individuals conducted in 1999. Results were compared with those of alternative econometric models making no or partial allowance for selection bias. In this illustrative example, the impact of insurance membership on reducing OOP expenditures was underestimated by 21 percentage points when selection biases were not taken into account. We believe this is an important methodological contribution that will be relevant to future empirical work.


Comparison of germline mosaics of genes in the Polycomb group of Drosophila melanogaster.
The genes of the Polycomb group (PcG) repress the genes of the bithorax and Antennapedia complexes, among others. To observe a null phenotype for a PcG gene, one must remove its maternal as well as zygotic contribution to the embryo. Five members of the PcG group are compared here: Enhancer of Polycomb [E(Pc)], Additional sex combs (Asx), Posterior sex combs (Psc), Suppressor of zeste 2 [Su (z) 2] and Polycomblike (Pcl). The yeast recombinase (FLP) system was used to induce mitotic recombination in the maternal germline. Mutant embryos were analyzed by staining with antibodies against six target genes of the PcG. The loss of the maternal component leads to enhanced homeotic phenotypes and to unique patterns of misexpression. E(Pc) and Su(z) 2 mutations had only subtle effects on the target genes, even when the maternal contributions were removed. Asx and Pcl mutants show derepression of the targets only in specific cell types. Psc shows unusual effects on two of the targets, Ultrabithorax and abdominal-A. These results show that the PcG genes do not act only in a common complex or pathway; they must have some independent functions.


Virus discovery in all three major lineages of terrestrial arthropods highlights the diversity of single-stranded DNA viruses associated with invertebrates.
Viruses encoding a replication-associated protein (Rep) within a covalently closed, single-stranded (ss)DNA genome are among the smallest viruses known to infect eukaryotic organisms, including economically valuable agricultural crops and livestock. Although circular Rep-encoding ssDNA (CRESS DNA) viruses are a widespread group for which our knowledge is rapidly expanding, biased sampling toward vertebrates and land plants has limited our understanding of their diversity and evolution. Here, we screened terrestrial arthropods for CRESS DNA viruses and report the identification of 44 viral genomes and replicons associated with specimens representing all three major terrestrial arthropod lineages, namely Euchelicerata (spiders), Hexapoda (insects), and Myriapoda (millipedes). We identified virus genomes belonging to three established CRESS DNA viral families (Circoviridae, Genomoviridae, and Smacoviridae); however, over half of the arthropod-associated viral genomes are only distantly related to currently classified CRESS DNA viral sequences. Although members of viral and satellite families known to infect plants (Geminiviridae, Nanoviridae, Alphasatellitidae) were not identified in this study, these plant-infecting CRESS DNA viruses and replicons are transmitted by hemipterans. Therefore, members from six out of the seven established CRESS DNA viral families circulate among arthropods. Furthermore, a phylogenetic analysis of Reps, including endogenous viral sequences, reported to date from a wide array of organisms revealed that most of the known CRESS DNA viral diversity circulates among invertebrates. Our results highlight the vast and unexplored diversity of CRESS DNA viruses among invertebrates and parallel findings from RNA viral discovery efforts in undersampled taxa.


Evolutionary establishment of moral and double moral standards through spatial interactions.
Situations where individuals have to contribute to joint efforts or share scarce resources are ubiquitous. Yet, without proper mechanisms to ensure cooperation, the evolutionary pressure to maximize individual success tends to create a tragedy of the commons (such as over-fishing or the destruction of our environment). This contribution addresses a number of related puzzles of human behavior with an evolutionary game theoretical approach as it has been successfully used to explain the behavior of other biological species many times, from bacteria to vertebrates. Our agent-based model distinguishes individuals applying four different behavioral strategies: non-cooperative individuals ("defectors"), cooperative individuals abstaining from punishment efforts (called "cooperators" or "second-order free-riders"), cooperators who punish non-cooperative behavior ("moralists"), and defectors, who punish other defectors despite being non-cooperative themselves ("immoralists"). By considering spatial interactions with neighboring individuals, our model reveals several interesting effects: First, moralists can fully eliminate cooperators. This spreading of punishing behavior requires a segregation of behavioral strategies and solves the "second-order free-rider problem". Second, the system behavior changes its character significantly even after very long times ("who laughs last laughs best effect"). Third, the presence of a number of defectors can largely accelerate the victory of moralists over non-punishing cooperators. Fourth, in order to succeed, moralists may profit from immoralists in a way that appears like an "unholy collaboration". Our findings suggest that the consideration of punishment strategies allows one to understand the establishment and spreading of "moral behavior" by means of game-theoretical concepts. This demonstrates that quantitative biological modeling approaches are powerful even in domains that have been addressed with non-mathematical concepts so far. The complex dynamics of certain social behaviors become understandable as the result of an evolutionary competition between different behavioral strategies.


Anti-diabetic and renoprotective effects of aliskiren in streptozotocin-induced diabetic nephropathy in female rats.
Since chronic kidney disease due to diabetic nephropathy (DN) is becoming an ever larger health burden worldwide, more effective therapies are desperately needed. In the present study, the anti-diabetic and renoprotective effects of aliskiren have been evaluated in streptozotocin (STZ)-induced DN in rats. DN was induced by a single intraperitoneal injection of STZ (65 mg/kg). Three weeks after STZ, rats were divided into four groups; normal, diabetic, diabetic treated with gliclazide (10 mg/kg/day) for 1 month, and diabetic treated with aliskiren (50 mg/kg/day) for 1 month. At the end of the experiment, mean arterial blood pressure and heart rate were recorded. Rats were then euthanized and serum was separated for determination of glucose, insulin, kidney function tests, superoxide dismutase activity (SOD), adiponectin, and tumor necrosis factor-alpha (TNF-α). One kidney was used for estimation of malondialdehyde (MDA), reduced glutathione (GSH), and nitric oxide (NO) contents. Other kidney was used for histopathological study and immunohistochemical measurement of caspase-3 and transforming growth factor beta (TGF-β). In addition, islets of Langerhans were isolated from normal rats by collagenase digestion technique for in vitro study. Aliskiren normalized STZ-induced hyperglycemia, increased insulin level both in vivo and in vitro, normalized kidney function tests and blood pressure, and alleviated STZ-induced kidney histopathological changes. This could be related to the ability of aliskiren toward preserving hemodynamic changes and alleviating oxidative stress and inflammatory and apoptotic markers induced by STZ in rats. However, aliskiren was more effective than gliclazide in relieving STZ-induced DN. These findings support the beneficial effect of aliskiren treatment in DN which could be attributed to its anti-diabetic, renoprotective, antioxidant, anti-inflammatory, and anti-apoptotic effects. Moreover, clinical studies are required to establish the effectiveness of aliskiren treatment in patients suffering from hypertension and diabetes.


The effect of frequent hemodialysis on self-reported sleep quality: Frequent Hemodialysis Network Trials.
Many patients who receive maintenance hemodialysis experience poor sleep. Uncontrolled studies suggest frequent hemodialysis improves sleep quality, which is a strong motivation for some patients to undertake the treatment. We studied the effects of frequent in-center ('daily') and nocturnal home hemodialysis on self-reported sleep quality in two randomized trials. Participants were randomly assigned to frequent (six times per week) or conventional (three times per week) hemodialysis in the Frequent Hemodialysis Network Daily (n = 245) and Nocturnal (n = 87) Trials. We used the Medical Outcomes Study Sleep Problems Index II (SPI II), a validated and reliable instrument in patients with end-stage renal disease, to measure self-reported sleep quality. The SPI II is scored from 0-100, with a higher value indicating poorer quality of sleep. A mean relative decline in SPI II would suggest improved sleep quality. The primary sleep outcome was the change in the SPI II score over 12 months. In the Daily Trial, after adjustment for baseline SPI II, subjects randomized to frequent as compared with conventional in-center hemodialysis experienced a 4.2 [95% confidence interval (CI) 0.4-8.0] point adjusted mean relative decline in SPI II at 4 months and a 2.6 (95% CI -2.3-7.5) point adjusted mean relative decline at 12 months. In the Nocturnal Trial, subjects randomized to frequent nocturnal as compared with conventional home hemodialysis experienced 2.9 (95% CI -3.4-9.3) and 4.5 (95% CI -3.2-12.2) point mean relative declines at Months 4 and 12, respectively. Although a possible benefit of frequent in-center hemodialysis was observed at 4 months, neither frequent in-center hemodialysis nor home nocturnal hemodialysis demonstrated significant improvements in self-reported sleep quality compared with conventional hemodialysis at 12 months.


Multiple wheat genomes reveal global variation in modern breeding.
Advances in genomics have expedited the improvement of several agriculturally important crops but similar efforts in wheat (Triticum spp.) have been more challenging. This is largely owing to the size and complexity of the wheat genome1, and the lack of genome-assembly data for multiple wheat lines2,3. Here we generated ten chromosome pseudomolecule and five scaffold assemblies of hexaploid wheat to explore the genomic diversity among wheat lines from global breeding programs. Comparative analysis revealed extensive structural rearrangements, introgressions from wild relatives and differences in gene content resulting from complex breeding histories aimed at improving adaptation to diverse environments, grain yield and quality, and resistance to stresses4,5. We provide examples outlining the utility of these genomes, including a detailed multi-genome-derived nucleotide-binding leucine-rich repeat protein repertoire involved in disease resistance and the characterization of Sm16, a gene associated with insect resistance. These genome assemblies will provide a basis for functional gene discovery and breeding to deliver the next generation of modern wheat cultivars.


31P nuclear magnetic resonance study of steady-state adenosine 5'-triphosphate levels during graded hypoxia in the isolated perfused rat kidney.
1. A model of controlled hypoxia in the isolated perfused rat kidney has been used to compare the extent of reduction in the steady-state level of adenosine 5'-triphosphate (ATP) from that initially observed with alterations in renal function and with the development of tubular cell injury. 2. ATP depletion was observed in response to decreased total oxygen delivery even when delivery greatly exceeded consumption and the venous oxygen tension remained in excess of 150 mmHg. 3. Increases in the fractional excretion of sodium occurred progressively below an apparent threshold value of whole kidney ATP of approximately 80% of the baseline. 4. With modestly decreased oxygen delivery, cellular injury was confined to deep proximal tubule and medullary thick ascending limb of Henle's loop. Severely decreased oxygen delivery rates were associated with cellular damage spreading throughout the cortex. 5. Even the smallest reductions in whole kidney ATP were associated with morphological damage to tubular cells. The extent of reduction in whole kidney ATP was closely correlated and approximately equivalent to the calculated volume of injured cells. 6. Our results indicate that reduction in whole kidney ATP during decreased oxygen delivery is a valid marker of the extent of injurious cellular hypoxia and are consistent with the view that cellular ATP concentrations in hypoxia are markedly inhomogeneous. They support the hypothesis that specific regions of the perfused kidney become critically hypoxic and develop cellular injury while overall oxygen delivery remains high. Areas at risk include deep proximal tubule as well as the medullary thick ascending limb of Henle's loop.


Real-world safety and efficacy of WATCHMAN LAA closure at one year in patients on dual antiplatelet therapy: results of the DAPT subgroup from the EWOLUTION all-comers study.
The study aimed to confirm the efficacy and safety of WATCHMAN LAA closure in atrial fibrillation patients unsuitable for oral anticoagulation. The EWOLUTION registry prospectively collects all clinical data on 1,005 European patients implanted with a WATCHMAN device. Following the procedure, 605 patients (60.2%) received dual antiplatelet therapy according to the local standard; DAPT was discontinued in 85% of patients within one year. CHA2DS2-VASc and HAS-BLED scores were 4.61.6 and 2.41.2, respectively. The periprocedural SAE rate was 3.3% (2.0% major adverse cardiac events), mostly resolving without sequelae. Device embolisation or pericardial effusion occurred in one (0.2%) and two (0.3%) patients, respectively. TEE (median 62 days post implant, IQR: 47-97) confirmed effective sealing (no leak >5 mm) in 99.2% of patients. Device thrombus was present in 22 patients (4.0%), one patient developed a stroke. One-year mortality in the DAPT group was 9.6% (N=58) reflecting the advanced age and comorbidities in this population. The ischaemic stroke rate at one year was 1.4% (expected based on CHA2DS2-VASc: 7.5%), none fatal. The major bleeding rate was 2.5%, or 2.1% excluding periprocedural events (expected rate on VKA based on HAS-BLED: 5.1%). LAA closure with the WATCHMAN device followed by DAPT therapy in a high-risk patient population is safe. At one year, the intervention is associated with a substantial risk reduction regarding ischaemic stroke and major bleeding compared to the expected rate based on CHA2DS2-VASc and HAS-BLED scores.


Identification and Treatment Optimization of Comorbid Depression in Rheumatoid Arthritis.
Patients with rheumatoid arthritis (RA) suffer from high rates of depression but depression often remains undiagnosed and untreated among RA patients. Because of its high prevalence and its profound impact on functional disability and health-related quality of life, prompt recognition and management of comorbid depression is urgently needed in patients with RA. Rheumatologists face the challenge of addressing depression in their clinical interactions with patients. The purpose of this paper is to present the prevalence of comorbid depression in RA, to delineate the consequences of depression among RA patients, to discuss the barriers to the identification of depression among RA patients, and to outline a set of recommendations to identify and treat comorbid depression that could be implemented within the rheumatology clinic setting. A comprehensive approach to the management of both physical and mental health needs of RA patients can aid in improving patient overall quality of life. New clinical protocols should be developed to include routine depression screening as part of the rheumatology visit. Patient education to address misconceptions, knowledge gaps, and destigmatize depression is also recommended. More counseling resources, including emotional support groups, are necessary to provide treatment for those suffering from depression. Such interventions could help mitigate disability, improve quality of life, patient function, and overall satisfaction.


A phyloclimatic study of Cyclamen.
The impact of global climate change on plant distribution, speciation and extinction is of current concern. Examining species climatic preferences via bioclimatic niche modelling is a key tool to study this impact. There is an established link between bioclimatic niche models and phylogenetic diversification. A next step is to examine future distribution predictions from a phylogenetic perspective. We present such a study using Cyclamen (Myrsinaceae), a group which demonstrates morphological and phenological adaptations to its seasonal Mediterranean-type climate. How will the predicted climate change affect future distribution of this popular genus of garden plants? We demonstrate phylogenetic structure for some climatic characteristics, and show that most Cyclamen have distinct climatic niches, with the exception of several wide-ranging, geographically expansive, species. We reconstruct climate preferences for hypothetical ancestral Cyclamen. The ancestral Cyclamen lineage has a preference for the seasonal Mediterranean climate characteristic of dry summers and wet winters. Future bioclimatic niches, based on BIOCLIM and Maxent models, are examined with reference to a future climate scenario for the 2050s. Over the next 50 years we predict a northward shift in the area of climatic suitability, with many areas of current distribution becoming climatically unsuitable. The area of climatic suitability for every Cyclamen species is predicted to decrease. For many species, there may be no areas with a suitable climate regardless of dispersal ability, these species are considered to be at high risk of extinction. This risk is examined from a phylogenetic perspective. Examining bioclimatic niches from a phylogenetic perspective permits novel interpretations of these models. In particular, reconstruction of ancestral niches can provide testable hypothesis about the historical development of lineages. In the future we can expect a northwards shift in climatic suitability for the genus Cyclamen. If this proves to be the case then dispersal is the best chance of survival, which seems highly unlikely for ant-dispersed Cyclamen. Human-assisted establishment of Cyclamen species well outside their native ranges offers hope and could provide the only means of dispersal to potentially suitable future environments. Even without human intervention the phylogenetic perspective demonstrates that major lineages could survive climate change even if many species are lost.


Development of immunoprecipitation - two-dimensional liquid chromatography - mass spectrometry methodology as biomarker read-out to quantify phosphorylated tau in cerebrospinal fluid from Alzheimer disease patients.
In Alzheimer's disease (AD) brain, one of the histopathological hallmarks is the neurofibrillary tangles consisting of aggregated and hyperphosphorylated tau. Currently many tau binding antibodies are under development to target the extracellular species responsible for the spreading of the disease in the brain. As such, an in-house developed antibody JNJ-63733657 with picomolar affinity towards tau phosphorylated at both T212 and T217 (further named p217+tau) was recently tested in phase I clinical trial NCT03375697. Following multiple dose administration in healthy subjects and subjects with AD, there were dose dependant reductions in free p217+tau fragments in cerebrospinal fluid (CSF) following antibody administration, as measured with a novel single molecule ELISA assay (Simoa PT3 x PT82 assay), demonstrating epitope engagement of the therapeutic antibody [Galpern, Haeverans, Janssens, Triana-Baltzer, Kolb, Li, Nandy, Mercken, Van Kolen, Sun, Van Nueten, 2020]. Total p217+tau levels also were reduced in CSF as measured with the Simoa PT3 x PT82 assay. In this study we developed an orthogonal immunoprecipitation - liquid chromatography - triple quadrupole mass spectrometry (IP-LC-TQMS) assay to verify the observed reductions in total p217+ tau levels. In this assay, an excess of JNJ-63733657 is added to the clinical CSF to ensure all p217+tau is bound by the antibody instead of having a pool of bound and unbound antigen and to immunoprecipitate all p217+tau, which is followed by on-bead digestion with trypsin to release surrogate peptides. Tryptic peptides with missed cleavages were monitored when phosphorylation occurred close to the cleavage site as this induced miscleavages. Compared with acidified mobile phases typically used for peptide analysis, reversed phase LC with mobile phase at basic pH resulted in sharper peaks and improved selectivity and sensitivity for the target peptides. With this setup a diphospho-tau tryptic peptide SRTPSLPTPPTREPK*2 could be measured with pT217 accounting for at least one of the phospho-sites. This is the first time that the presence of a diphopsho-tau peptide is reported to be present in human CSF. A two-dimensional LC-TQMS method was developed to remove matrix interferences. Selective trapping of diphospho-peptides via a metal oxide chromatography mechanism was achieved in a first dimension with a conventional reversed phase stationary phase and acidified mobile phase. Subsequent elution at basic pH enabled detection of low picomolar p217+tau levels in human CSF (lower limit of quantification: 2 pM), resulting in an approximate 5-fold increase in sensitivity. This enabled the quantification of total p217+tau in CSF leading to the confirmation that in addition to reductions in free p217+tau levels total p217+tau levels were also reduced following administration of the tau mAb JNJ-63733657, correlating with the previous measurement with the PT3 x PT82 Simoa assay. An orthogonal sample clean-up using offline TiO2/ZrO2 combined with 1DLC-TQMS was developed to confirm the presence of mono-ptau (pT217) tryptic peptides in CSF.


Non-neuronal release of ATP and inositol 1,4,5-trisphosphate accumulation evoked by P2- and M-receptor stimulation in guinea pig ileal segments.
Intracellular signal transduction involved in non-neuronal ATP release evoked by alpha, beta-methylene ATP and bethanechol was evaluated in guinea pig ileal longitudinal muscle segments. alpha, beta-methylene ATP (100 microM) and bethanechol (10 microM) evoked ATP released that reached a peak about 3 min after administration. The evoked release of ATP was markedly inhibited by neomycin and spermine, inhibitors of phospholipase C, but not by treatment with pertussis toxin. In addition, the release of ATP was almost completely suppressed by 1 mM Li+, an inhibitor of inositol monophosphatase. These inhibitors, however, did not affect the contractions of the tissue evoked by these agonists. Forskolin and phorbol 12-myristate 13-acetate, activators of adenylate cyclase and protein kinase C, respectively, failed to enhance the evoked release. The accumulation of inositol 1,4,5-triphosphate [Ins(1,4,5)P3] in the muscle segments were enhanced about 2 min after the administration of alpha, beta-methylene ATP. In the presence of 1 mM Li+, however, the enhancement of Ins(1,4,5)P3 accumulation by the P2 agonist was no longer elicited. These findings suggest that the release of ATP by receptor stimulation may result mainly from the activation of phospholipase C, which is coupled to a pertussis toxin-insensitive G-protein and subsequent accumulation of Ins(1,4,5)P3 in the smooth muscles. However, the discrepancy between the inhibitory effects of Li+ on the release of ATP and the accumulation of Ins(1,4,5)P3 to be clarified in future studies.


Nav1.7 is required for normal C-low threshold mechanoreceptor function in humans and mice.
Patients with bi-allelic loss of function mutations in the voltage-gated sodium channel Nav1.7 present with congenital insensitivity to pain (CIP), whilst low threshold mechanosensation is reportedly normal. Using psychophysics (n = 6 CIP participants and n = 86 healthy controls) and facial electromyography (n = 3 CIP participants and n = 8 healthy controls), we found that these patients also have abnormalities in the encoding of affective touch, which is mediated by the specialized afferents C-low threshold mechanoreceptors (C-LTMRs). In the mouse, we found that C-LTMRs express high levels of Nav1.7. Genetic loss or selective pharmacological inhibition of Nav1.7 in C-LTMRs resulted in a significant reduction in the total sodium current density, an increased mechanical threshold and reduced sensitivity to non-noxious cooling. The behavioural consequence of loss of Nav1.7 in C-LTMRs in mice was an elevation in the von Frey mechanical threshold and less sensitivity to cooling on a thermal gradient. Nav1.7 is therefore not only essential for normal pain perception but also for normal C-LTMR function, cool sensitivity and affective touch.


Phosphorylation of endothelin converting enzyme-1 isoforms: relevance to subcellular localization.
Endothelin-converting enzyme (ECE)-1 is a metalloenzyme with four subisoforms, which differ only in their amino-terminal domain. ECE-1a and c are the most common isoforms and are found at the plasma membrane and in the Golgi complex, whereas ECE-1b displays lysosomal localization. We have recently shown that ECE-1a but not ECE-1b also colocalizes with nuclear membrane markers, and that maintenance of cells in high glucose (25 mM) promotes relocalization of ECE-1a from the membrane to the intracellular compartment. To investigate the mechanisms involved in this process, we conducted a search for potential phosphorylation sites, which yielded a different number of putative sites for protein kinase (PK)-C and PKA in the amino-terminal region. Stimulation of Chinese hamster ovary (CHO) cells expressing a green fluorescent protein (GFP)-tagged human ECE-1a or ECE-1b with 100 nM phorbol myristate acetate (PMA) resulted in phosphorylation of ECE-1a, as determined by immunoprecipitation with an antibody to GFP followed by immunoblotting with an antibody to phosphoserine. Stimulation of cells with PMA also promoted intracellular relocalization, as seen in cells grown under high-glucose conditions. Incubation of cells grown in 25 mM glucose with the PKC inhibitor, calphostin C (100 nM), partially prevented the relocalization of ECE-1a from the plasma membrane to intracellular compartments. Stimulation of cells with 100 nM forskolin caused phosphorylation of ECE-1b and not ECE-1a, which is consistent with the lack of a putative PKA site in the ECE-1a amino-terminal sequence. Although phosphorylation is not required for ECE-1 enzymatic activity, these results suggest that ECE-1 isoforms are phosphorylated and that phosphorylation might play an important role in the regulation of intracellular trafficking of ECE-1 subisoforms.


Cortical thickness analysis in autism with heat kernel smoothing.
We present a novel data smoothing and analysis framework for cortical thickness data defined on the brain cortical manifold. Gaussian kernel smoothing, which weights neighboring observations according to their 3D Euclidean distance, has been widely used in 3D brain images to increase the signal-to-noise ratio. When the observations lie on a convoluted brain surface, however, it is more natural to assign the weights based on the geodesic distance along the surface. We therefore develop a framework for geodesic distance-based kernel smoothing and statistical analysis on the cortical manifolds. As an illustration, we apply our methods in detecting the regions of abnormal cortical thickness in 16 high functioning autistic children via random field based multiple comparison correction that utilizes the new smoothing technique.


Fbxw7β resides in the endoplasmic reticulum membrane and protects cells from oxidative stress.
Oxidative stress has been implicated in cancer initiation and progression. Fbxw7 (also known as Fbw7, SEL-10, hCdc4, or hAgo) is the F-box protein subunit of an Skp1-Cul1-F-box (SCF)-type ubiquitin ligase complex that plays a central role in the degradation of oncoproteins such as c-Myc, c-Jun, Notch, and cyclin E. Fbxw7 is therefore thought to function as a tumor suppressor, and indeed the Fbxw7 gene is frequently mutated in many human malignancies. The Fbxw7 gene locus encodes three protein isoforms: Fbxw7α, Fbxw7β, and Fbxw7γ. Whereas Fbxw7α and Fbxw7γ are resident in the nucleus, Fbxw7β shows a cytoplasmic distribution suggestive of localization to the endoplasmic reticulum (ER). The specific function of Fbxw7β has remained unknown, however. We now show that Fbxw7β contains a putative transmembrane domain near its NH(2) -terminus, and topological analysis revealed that Fbxw7β is inserted in the ER membrane. Fbxw7β assembled with Skp1, Cul1, and Rbx1 to form an SCF complex, although the efficiency of this process appeared lower than that for Fbxw7α or Fbxw7γ. To explore the physiological role of Fbxw7β, we generated mice specifically lacking this isoform of Fbxw7. Although these animals did not exhibit any apparent abnormalities in development, primary cultures of neurons prepared from the mutant mice were more vulnerable to oxidative stress than were those prepared from wild-type mice. Conversely, overexpression of Fbxw7β rendered cells resistant to oxidative stress, without affecting sensitivity to ER stress or other apoptosis-inducing agents. Our results thus suggest that Fbxw7β contributes to the protection of cells from oxidative stress.


Recommendations for Preventing Child Sexual Abuse in Youth-Serving Organizations: Implications From an Australian Royal Commission Review of the Literature.
Evidence suggests that tens of millions of children and adolescents are involved in youth-serving organizations (YSOs) outside of their homes on a daily basis. Children's involvement with YSOs clearly offers a broad array of emotional, social, and personal development benefits. This involvement can, however, also be associated with a variety of safety risks, including the potential for child sexual abuse (CSA) victimization and the myriad short- and long-term consequences to its victims and their families. Recognizing the significance of CSA within YSOs, the Australian Royal Commission into Institutional Responses to Child Sexual Abuse funded a comprehensive review of the literature on risk and protective factors related to CSA in institutions. This yielded more than 400 primarily research articles from the United States, United Kingdom, and Australia, examining institutional CSA victims, perpetrators, and settings. Findings were provided regarding six specific types of institutional settings, including faith-based, early childhood education, childcare and schools, health care, out-of-home/foster care, and sport. This article is based on the findings of Kaufman and Erooga's comprehensive literature review and Royal Commission findings. It provides a brief review of critical risks associated with CSA victims, perpetrators, and organizational settings, as well as highlights risks particular to specific types of YSOs and risks that are present across these organizations. Optimal prevention directions and strategies are outlined in response to identified patterns of organizational risk. Recommendations for YSO policy enhancements are also provided to complement the article's prevention focus. Finally, suggestions are offered for future research directions to foster the development of an evidence-based foundation for work in this area.


A Comparison of Three Frailty Indices in Predicting Morbidity and Mortality After On-Pump Aortic Valve Replacement.
Aortic valve replacement is a high-risk surgery (3%-5%, 30-day mortality) performed on approximately 30,000 elderly patients a year in the United States. Currently, preoperative risk assessment is based on a composite of medical examination and a subjective evaluation for frailty ("eyeball test"). Objective frailty assessment using validated indices has the potential to improve risk stratification. The purpose of this study was to (1) establish whether frailty can predict 30-day mortality and composite morbidity in patients undergoing aortic valve replacement and (2) compare the predictive ability of 3 frailty indices in this population. This study was a retrospective cohort study of 3088 patients 65 years old and older undergoing aortic valve replacement surgery (based on current procedure terminology codes) between the years 2006 and 2012 extracted from the American College of Surgeons National Surgical Quality Improvement Program database. Frailty was assessed using the modified frailty index, risk analysis index, and Ganapathi indices. Outcomes measured were 30-day mortality and composite morbidity (myocardial infarction, cardiac arrest, pulmonary embolism, pneumonia, reintubation, renal insufficiency, coma >24 hours, urinary tract infections, sepsis, deep vein thrombosis, deep wound surgical site infection, superficial site infection, and reoperation). Frailty was a better predictor of mortality than morbidity, and it was not markedly different among any of the 3 indices. Frailty was associated with an increased risk of 30-day mortality and longer lengths of stay. Frailty can predict mortality in patients undergoing aortic valve replacement. Choice of frailty index does not make a difference in this patient population.


Nutritional Outcomes of patients Undergoing Resection for upper gastroIntestinal cancer in AuStralian Hospitals (NOURISH): protocol for a multicentre point prevalence study.
Nutritional intervention and prevention of malnutrition is significantly important for patients with upper gastrointestinal oesophageal, pancreatic and gastric cancer. However, there is limited information regarding nutritional status, and perioperative nutritional interventions that patients receive when undergoing curative surgery. Patients diagnosed with upper gastrointestinal cancer, planned for curative intent resection across 27 Australian hospitals will be eligible to participate in this point prevalence study. The primary aim is to determine the prevalence of malnutrition in patients with upper gastrointestinal cancer at the time of surgery using subjective global assessment. Secondary aims are to determine the type and frequency of perioperative nutritional intervention received, the prevalence of clinically important weight loss and low muscle strength, and to investigate associations between the use of an evidence-based nutrition care pathway or protocol for the nutritional management of upper gastrointestinal surgical oncology patients and malnutrition prevalence. Data collection will be completed using a purpose-built data collection tool. Ethical approval was granted in May 2019 (LNR/51107/PMCC-2019). The design and reporting of this study comply with the Strengthening the Reporting of Observational Studies in Epidemiology checklist for reporting of observational cohort studies. Findings will be published in peer-reviewed scholarly journals and presented at relevant conferences. Results will assist in defining priority areas for research to improve patient outcomes.


Point mutational inactivation of the retinoblastoma antioncogene.
The retinoblastoma (Rb) antioncogene encodes a nuclear phosphoprotein, p105-Rb, that forms protein complexes with the adenovirus E1A and SV40 large T oncoproteins. A novel, aberrant Rb protein detected in J82 bladder carcinoma cells was not able to form a complex with E1A and was less stable than p105-Rb. By means of a rapid method for the detection of mutations in Rb mRNA, this defective Rb protein was observed to result from a single point mutation within a splice acceptor sequence in J82 genomic DNA. This mutation eliminates a single exon and 35 amino acids from its encoded protein product.


Readiness for the Patient-Centered Medical Home: structural capabilities of Massachusetts primary care practices.
The Patient-Centered Medical Home (PCMH), a popular model for primary care reorganization, includes several structural capabilities intended to enhance quality of care. The extent to which different types of primary care practices have adopted these capabilities has not been previously studied. To measure the prevalence of recommended structural capabilities among primary care practices and to determine whether prevalence varies among practices of different size (number of physicians) and administrative affiliation with networks of practices. Cross-sectional analysis. One physician chosen at random from each of 412 primary care practices in Massachusetts was surveyed about practice capabilities during 2007. Practice size and network affiliation were obtained from an existing database. Presence of 13 structural capabilities representing 4 domains relevant to quality: patient assistance and reminders, culture of quality, enhanced access, and electronic health records (EHRs). Three hundred eight (75%) physicians responded, representing practices with a median size of 4 physicians (range 2-74). Among these practices, 64% were affiliated with 1 of 9 networks. The prevalence of surveyed capabilities ranged from 24% to 88%. Larger practice size was associated with higher prevalence for 9 of the 13 capabilities spanning all 4 domains (P < 0.05). Network affiliation was associated with higher prevalence of 5 capabilities (P < 0.05) in 3 domains. Associations were not substantively altered by statistical adjustment for other practice characteristics. Larger and network-affiliated primary care practices are more likely than smaller, non-affiliated practices to have adopted several recommended capabilities. In order to achieve PCMH designation, smaller non-affiliated practices may require the greatest investments.


Is primary care a neglected piece of the jigsaw in ensuring optimal stroke care? Results of a national study.
Stroke is a major cause of mortality and morbidity with potential for improved care and prevention through general practice. A national survey was undertaken to determine current resources and needs for optimal stroke prevention and care. Postal survey of random sample of general practitioners undertaken (N = 204; 46% response). Topics included practice organisation, primary prevention, acute management, secondary prevention, long-term care and rehabilitation. Service organisation for both primary and secondary prevention was poor. Home management of acute stroke patients was used at some stage by 50% of responders, accounting for 7.3% of all stroke patients. Being in a structured cardiovascular management scheme, a training practice, a larger practice, or a practice employing a practice nurse were associated with structures and processes likely to support stroke prevention and care. General practices were not fulfilling their potential to provide stroke prevention and long-term management. Systems of structured stroke management in general practice are essential to comprehensive national programmes of stroke care.


Cinryze (C1-inhibitor) for the treatment of hereditary angioedema.
Cinryze is a pasteurized, nanofiltered plasma derived concentrate of C1-inhibitor (pdC1-INH) licensed for the prophylactic treatment of hereditary angioedema. In a double-blind placebo-controlled crossover trial to evaluate Cinryze as prophylaxis, the frequency of attacks was halved (6.26 per 12 weeks on Cinryze versus 12.73 per 12 weeks on placebo). Furthermore, attacks were generally milder and of shorter duration. For treatment of acute attacks in patients receiving Cinryze, 1000 units, within 4 h of the start of an attack, the estimated time to the onset of unequivocal relief was reduced to 2 h, compared with more than 4 h in those treated with placebo. Cinryze and other similar products are going to change the future management of hereditary angioedema and have potential in other areas of medicine.


Assessment of transparency indicators across the biomedical literature: How open is open?
Recent concerns about the reproducibility of science have led to several calls for more open and transparent research practices and for the monitoring of potential improvements over time. However, with tens of thousands of new biomedical articles published per week, manually mapping and monitoring changes in transparency is unrealistic. We present an open-source, automated approach to identify 5 indicators of transparency (data sharing, code sharing, conflicts of interest disclosures, funding disclosures, and protocol registration) and apply it across the entire open access biomedical literature of 2.75 million articles on PubMed Central (PMC). Our results indicate remarkable improvements in some (e.g., conflict of interest [COI] disclosures and funding disclosures), but not other (e.g., protocol registration and code sharing) areas of transparency over time, and map transparency across fields of science, countries, journals, and publishers. This work has enabled the creation of a large, integrated, and openly available database to expedite further efforts to monitor, understand, and promote transparency and reproducibility in science.


A Cross-Sectional Comparison of Health Literacy Deficits Among Patients With Chronic Kidney Disease.
Inadequate health literacy in people with chronic kidney disease (CKD) is associated with poorer disease management and greater complications. There are limited data on the health literacy deficits of people with CKD. The aim of this study was to investigate the types and extent of health literacy deficits in patients with CKD using the multidimensional Health Literacy Management Scale (HeLMS) and to identify associations between patient characteristics and the domains of health literacy measured by the HeLMS. Invitations to participate were sent to patients with CKD attending the renal unit of a regional Australian hospital. These patients included predialysis, dialysis (peritoneal and hemodialysis), and kidney transplant patients. This study identified that inadequate health literacy--especially in the domains relating to attending to one's health needs, understanding health information, social support, and socioeconomic factors--was common. Male gender and education level were significantly associated with inadequate health literacy. The type and extent of health literacy deficits varied among CKD groups, and transplant patients had more deficits than other CKD patient groups. This study provides useful information for health professionals treating patients with CKD, especially with regard to the design of self-management interventions and health information.


Risk factors of post-discharge under-five mortality among Danish children 1997-2016: A register-based study.
Estimating associations between somatic and socioeconomic risk factors and post-discharge under-five mortality. Register-based national cohort study using multiple Cox regression. The population of 1,263,795 Danish children live-born 1997-2016 who survived until date of first discharge to the home after birth was followed from that date until death, emigration, 5 years of age or 31 December 2016. (A) Mortality hazard ratios (HRs) among all children, (B) mortality HRs among children without severe chronic disease, and (C) mortality HRs among children without severe chronic disease or asthma. In the total population (1,947 deaths) severe chronic disease was associated with mortality HR = 15.28 (95% CI: 13.77-16.95). In children without severe chronic-disease (719 deaths) other somatic risk factors were immature birth HR = 3.40 (1.92-6.02), maternal smoking HR = 1.84 (1.55-2.18) and low birth weight HR = 1.74 (1.21-2.51). Socioeconomic risk factors for mortality included: maternal age < 25 years HR = 1.91 (1.38-2.64) compared to > 35 years (similar for 30-35 years and 25-29 years), lowest vs. highest family income tertile HR = 1.76 (1.23-2.51), not living with both parents HR = 1.63 (1.25-2.13), maternal unemployment HR = 1.54 (1.12-2.12), presence of siblings HR = 1.44 (1.20-1.71) and secondary vs. tertiary parental education HR = 1.33 (1.07-1.65) for fathers and HR = 1.23 (1.01-1.52) for mothers. Factors not found to be associated with child mortality in this population included presence of asthma HR = 1.29 (0.83-1.98) and non-Danish ethnicity HR = 0.98 (0.70-1.37). Childhood death after discharge to the home after birth and before 5 years of age is a very rare event in Denmark. This 'post-discharge' mortality was heavily associated with severe chronic disease. In children without severe chronic disease, immature birth, maternal smoking and certain socioeconomic characteristics were noticeable risk factors. Mortality may possibly be decreased by focusing on vulnerable groups.


Laser-assisted positron-impact ionization of atomic hydrogen.
We study the ionization of atomic hydrogen by a fast positron in the presence of an external linearly polarized laser field. We concentrate on the limit of a small momentum transfer and describe the fast positron's continuum states by Volkov wave functions. The ejected electron is described by a Coulomb-Volkov wave function. We are limited to small laser intensities such that the dressed state of the target is treatable within the time-dependent perturbation theory, even though the laser intensity is still quite high by laboratory standards. Numerical results for the triply differential cross sections and their dependencies on laser-field parameters are discussed and compared with the results of laser-assisted ionization by electron impact.


Child Appraisals of Interparental Conflict: The Effects of Intimate Partner Violence and Parent-Child Relationship Quality.
Children's appraisals of interparental violence, including appraisals of high threat and low coping efficacy, are robust predictors of behavioral and emotional problems. However, few studies have examined the factors that account for children's use of these maladaptive appraisals, particularly among children exposed to more severe forms of interparental conflict. The current study examines parent-child relationship quality as a mediator of the effect of intimate partner violence (IPV) exposure on children's appraisals of conflict. Participants were 118 mother-child dyads (54 girls and 64 boys), recruited from three Midwestern counties. Consistent with previous reports, child exposure to IPV, as reported by children's mothers, predicted higher threat and lower coping efficacy appraisals. In addition, mediation analyses showed child reports of parent-child relationship quality mediated the association between IPV and coping efficacy, but not the effects of IPV on threat appraisals. The role of parent-child relationships in shaping cognitive appraisals in the context of IPV exposure can have implications for prevention and intervention efforts as well as public policy.


The impact of victimization and mental health symptoms on recidivism for early system-involved juvenile offenders.
Although research has linked mental health symptoms and prior victimization to recidivism for youth on probation or in detention, little attention has been given to these risk factors for early system-involved youth. We conducted a survival/hazard model to estimate the impact of official records of abuse/neglect, crime victimization, and mental health issues (mood, anxiety, disruptive, and substance use disorders) on recidivism in a sample of 2,792 youth in a large Midwestern diversion program. Results indicated that youth with official records of abuse/neglect, person crime victimization, and property crime victimization were more likely to recidivate sooner than those without these victimization experiences (hazard ratio: 1.37, 1.42, and 1.52, respectively). Findings from the present study also demonstrated that substance use disorder was the only mental health cluster that predicted quicker time to recidivism. As one of the earliest points of entry into the juvenile justice system, diversion programs are in a unique position to address trauma from multiple types of victimization and adapt diversion programming to be responsive to each juvenile's mental health needs. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Cord blood metabolic markers are strong mediators of the effect of maternal adiposity on fetal growth in pregnancies across the glucose tolerance spectrum: the PANDORA study.
We aimed to assess associations between cord blood metabolic markers and fetal overgrowth, and whether cord markers mediated the impact of maternal adiposity on neonatal anthropometric outcomes among children born to Indigenous and Non-Indigenous Australian women with normal glucose tolerance (NGT), gestational diabetes mellitus (GDM) and pregestational type 2 diabetes mellitus. From the Pregnancy and Neonatal Outcomes in Remote Australia (PANDORA) study, an observational cohort of 1135 mother-baby pairs, venous cord blood was available for 645 singleton babies (49% Indigenous Australian) of women with NGT (n = 129), GDM (n = 419) and type 2 diabetes (n = 97). Cord glucose, triacylglycerol, HDL-cholesterol, C-reactive protein (CRP) and C-peptide were measured. Multivariable logistic and linear regression were used to assess the associations between cord blood metabolic markers and the outcomes of birthweight z score, sum of skinfold thickness (SSF), being large for gestational age (LGA) and percentage of body fat. Pathway analysis assessed whether cord markers mediated the associations between maternal and neonatal adiposity. Elevated cord C-peptide was significantly associated with increasing birthweight z score (β 0.57 [95% CI 0.42, 0.71]), SSF (β 0.83 [95% CI 0.41, 1.25]), percentage of body fat (β 1.20 [95% CI 0.69, 1.71]) and risk for LGA [OR 3.14 [95% CI 2.11, 4.68]), after adjusting for age, ethnicity and diabetes type. Cord triacylglycerol was negatively associated with birthweight z score for Indigenous Australian women only. No associations between cord glucose, HDL-cholesterol and CRP >0.3 mg/l (2.9 nmol/l) with neonatal outcomes were observed. C-peptide mediated 18% (95% CI 13, 36) of the association of maternal BMI with LGA and 11% (95% CI 8, 17) of the association with per cent neonatal fat. Cord blood C-peptide is an important mediator of the association between maternal and infant adiposity, across the spectrum of maternal glucose tolerance.


Role of a registered dietitian in pediatric type 1 and type 2 diabetes.
Type 1 and type 2 diabetes are complex, chronic diseases that are best managed by a multidisciplinary care team. Type 1 diabetes is most commonly diagnosed in the pediatric population, although the prevalence of type 2 diabetes in youth is increasing rapidly. A registered dietitian (RD) is a critical member of the diabetes team who provides focused nutrition education from diagnosis and throughout routine follow-up care. Specifically in the pediatric population, the RD also assesses growth and development, as well as eating behaviors, food choices and meal patterns. Based on a review of research, ongoing support from an RD improves glycemic control and delays onset of diabetes complications. In addition, dietitian-led nutrition education helps better manage lipid levels and aids in weight management. A sample model describing RD involvement in a pediatric diabetes care team is discussed in further detail.


Developing practice in breastfeeding.
This paper reports on an approach to practice development in breastfeeding as part of a national programme of work to address inequalities in maternal and child nutrition. The production and dissemination of evidence and guidelines is necessary but not sufficient on its own to effect change in practice, particularly when dealing with complex public health issues. In the case of breastfeeding, review evidence and national guidance have shown that multifaceted changes are essential if policy aspirations are to be realized. The objectives of the programme described here were to (1) inform and enable practice development in breastfeeding in low-income areas; (2) evaluate the impact of approaches used; and (3) develop robust approaches and appropriate material for use nationally. A conceptual framework was established, and a six-stage process is outlined. The recruitment of four sentinel sites across whole health economies, involving professionals and the voluntary sector, was an essential component of the programme. The strength of the model is that it provides a structured, cross-sectoral approach to practice development in public health. A key challenge is to identify whose responsibility it is to resource practice development when a number of disciplines and sectors are involved. This question needs to be addressed if public health guidance is to be of sustained benefit.


Steatotic and nonsteatotic scirrhous hepatocellular carcinomas reveal distinct clinicopathological features.
We investigated the clinicopathological and molecular characteristics of scirrhous hepatocellular carcinoma (HCC) to elucidate its uniqueness. Samples from 120 resected HCC cases underwent immunohistochemical analysis. Tumor area containing fibrous stroma and the percentage of steatotic cells within the tumor were evaluated. In our previous report, tumors were immunohistochemically subclassified as biliary/stem cell markers-positive (B/S) (cytokeratin 19 and/or sal-like protein 4 and/or epithelial cell adhesion molecule positive), Wnt/β-catenin signaling-related markers-positive (W/B) (β-catenin and/or glutamine synthetase positive), or all markers-negative (-/-) groups. Thirty-seven cases (31%) with fibrous stroma making up ≥50% of the largest tumor area were defined as scirrhous HCC (sHCC); the other 83 cases (69%) were categorized as common HCC (cHCC). Clinicopathologically, sHCC had fewer poorly differentiated tumors (P = .037) and a higher percentage of cases with steatosis (P = .025) than cHCC. sHCC cases were further divided into two subgroups: those with ≥5% steatotic cells (steatotic sHCC) and those with <5% steatotic cells (nonsteatotic sHCC). Hepatitis B virus infection was more frequent in nonsteatotic sHCC (P = .029), and non-B, non-C cases were more frequent in steatotic sHCC (P = .006). Steatotic sHCC tended to have a longer time to recurrence than nonsteatotic sHCC and cHCC. Most nonsteatotic sHCC cases belonged to B/S group, whereas most steatotic sHCC belonged to -/- group. The same tendency in sHCC was shown in another cohort. Distinct features were seen in steatotic and nonsteatotic sHCC, and both sHCC subgroups exhibited different clinicopathological and molecular features from cHCC. These findings support the hypothesis that sHCC is an independent entity.


Position of the Academy of Nutrition and Dietetics: Health Implications of Dietary Fiber.
It is the position of the Academy of Nutrition and Dietetics that the public should consume adequate amounts of dietary fiber from a variety of plant foods. Dietary fiber is defined by the Institute of Medicine Food Nutrition Board as "nondigestible carbohydrates and lignin that are intrinsic and intact in plants." Populations that consume more dietary fiber have less chronic disease. Higher intakes of dietary fiber reduce the risk of developing several chronic diseases, including cardiovascular disease, type 2 diabetes, and some cancers, and have been associated with lower body weights. The Adequate Intake for fiber is 14 g total fiber per 1,000 kcal, or 25 g for adult women and 38 g for adult men, based on research demonstrating protection against coronary heart disease. Properties of dietary fiber, such as fermentability and viscosity, are thought to be important parameters influencing the risk of disease. Plant components associated with dietary fiber may also contribute to reduced disease risk. The mean intake of dietary fiber in the United States is 17 g/day with only 5% of the population meeting the Adequate Intake. Healthy adults and children can achieve adequate dietary fiber intakes by increasing their intake of plant foods while concurrently decreasing energy from foods high in added sugar and fat, and low in fiber. Dietary messages to increase consumption of whole grains, legumes, vegetables, fruits, and nuts should be broadly supported by food and nutrition practitioners.


[Brain and spinal cord magnetic resonance imaging in spastic paraparesis associated to human T-lymphotropic virus].
The spastic paraparesis associated to HTLV-1 causes degenerative pyramidal tract lesions of the spinal cord and affects cortical-nuclear connections in the brain. To report the findings of magnetic resonance imaging in patients with spastic paraparesis. A magnetic resonance imaging of the brain and spinal cord was performed in 30 patients (24 females), mean age and evolution of 56 and 12 years respectively, with a clinical and virological diagnosis of tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM). No patient had abnormal signals in the spinal cord parenchyma. However, an atrophy of the dorsal segment was observed in 87% of patients. Patients with the highest degree of atrophy showed a higher degree of functional impairment. Eleven patients had spinal cord conus atrophy, associated to neurogenic bladder or impotency. In 80% of patients, hyperintense subcortical white matter images in DP, T2 and Flair, mostly bi frontal, were detected. In half of them, small rounded and isolated images were observed. In the other half, eight or more images, generally larger and occasionally confluent, were found. Ten of 12 patients with confluent brain lesions showed different degrees of cognitive impairment. No patient had lesions in the corpus callosus, periventricular white matter, pons, medulla oblongata or cerebellum. Most patients with tropical spastic paraparesis have alterations in brain or spinal cord magnetic resonance imaging. The magnetic resonance lesions are concordant with functional impairment. The characteristics of the imaging in TSP/HAM patients can be helpful in the differential diagnosis of patients with paraparesis.


Laparostomy for severe intra-abdominal infection complicating colorectal disease.
The aim of this study was to evaluate the use of laparostomy in the management of patients with severe intra-abdominal infection resulting from colorectal disease. Seven patients, four with inflammatory bowel disease, two with colorectal carcinoma, and one with diverticular perforation, underwent laparostomy during a six-year period for postoperative, severe, intra-abdominal infection. The median age was 42 years, the mean Acute Physiology and Chronic Health Evaluation II score was 22.7, and the observed mortality was 28.6 percent (2/7 patients). In one patient the laparostomy was closed at 11 days; in all the others the wound was left to heal by granulation and contraction, and two of these later required reconstructive surgery. The median follow-up was three years and seven months. Laparostomy is an effective and practical method of managing patients with severe intra-abdominal infection as a result of colorectal disease.


[Xanthones from Tibetan medicine Halenia elliptica and their antioxidant activity].
To investigate the xanthones from Tibetan medicine Halenia elliptica and their antioxidant activity. Column chromatography over normal phase silica gel, reversed phase silica gel, Sephadex LH-20, and recrystallization techniques were used to isolate and purify constituents from Halenia elliptica. Infrared spectrometry, mass spectrometry, and nuclear magnetic resonance spectrometry were used to identify the structure of compounds. The antioxidant activity was evaluated by measuring the content of malondialdehyde product in mice liver cell microsomal induced by ferrous-cysteine. Eight xanthones (compound I-VIII) were isolated and identified from the ethyl acetate extract of Halenia elliptica, among which 1,7-dihydroxy-2,3,5-trimethoxyxanthone was a novel compound. Compound I, III at 10 microg/ml and 100 microg/ml could inhibit the production of malondialdehyde in mouse liver microsomes in vitro. Eight xanthones were isolated and they have certain antioxidant activity.


Aortic outflow cannula tip design and orientation impacts cerebral perfusion during pediatric cardiopulmonary bypass procedures.
Poor perfusion of the aortic arch is a suspected cause for peri- and post-operative neurological complications associated with cardiopulmonary bypass (CPB). High-speed jets from 8 to 10FR pediatric/neonatal cannulae delivering ~1 L/min of blood can accrue sub-lethal hemolytic damage while also subjecting the aorta to non-physiologic flow conditions that compromise cerebral perfusion. Therefore, we emphasize the importance of cannulation strategy and hypothesize engineering better CPB perfusion through a redesigned aortic cannula tip. This study employs computational fluid dynamics to investigate novel diffuser-tipped aortic cannulae for shape sensitivity to cerebral perfusion, in an in silico cross-clamped aortic arch model modeled with fixed outflow resistances. 17 parametrically altered configurations of an 8FR end-hole and several diffuser cone angled tips in combination with jet incidence angles toward or away from the head-neck vessels were studied. Experimental pressure-flow characterizations were also conducted on these cannula tip designs. An 8FR end-hole aortic cannula delivering 1 L/min along the transverse aortic arch was found to give rise to backflow from the brachicephalic artery (BCA), irrespective of angular orientation, for the chosen ascending aortic insertion location. Parametric alteration of the cannula tip to include a diffuser cone angle (tested up to 7°) eliminated BCA backflow for any tested angle of jet incidence. Experiments revealed that a 1 cm long 10° diffuser cone tip demonstrated the best pressure-flow performance improvement in contrast with either an end-hole tip or diffuser cone angles greater than 10°. Performance further improved when the diffuser was preceded by an expanded four-lobe swirl inducer attachment-a novel component. In conclusion, aortic cannula orientation is crucial in determining net head-neck perfusion but precise angulations and insertion-depths are difficult to achieve practically. Altering the cannula tip to include a diffuser cone angle has been shown for the first time to have potential in ensuring a net positive outflow at the BCA. Cannula insertion distanced from the BCA inlet may also avoid backflow owing to the Venturi effect, but the diffuser tipped cannula design presents a promising solution to mitigate this issue irrespective of in vivo cannula tip orientation.


Potential therapeutic applications of multifunctional host-defense peptides from frog skin as anti-cancer, anti-viral, immunomodulatory, and anti-diabetic agents.
Frog skin constitutes a rich source of peptides with a wide range of biological properties. These include host-defense peptides with cytotoxic activities against bacteria, fungi, protozoa, viruses, and mammalian cells. Several hundred such peptides from diverse species have been described. Although attention has been focused mainly on antimicrobial activity, the therapeutic potential of frog skin peptides as anti-infective agents remains to be realized and no compound based upon their structures has yet been adopted in clinical practice. Consequently, alternative applications are being explored. Certain naturally occurring frog skin peptides, and analogs with improved therapeutic properties, show selective cytotoxicity against tumor cells and viruses and so have potential for development into anti-cancer and anti-viral agents. Some peptides display complex cytokine-mediated immunomodulatory properties. Effects on the production of both pro-inflammatory and anti-inflammatory cytokines by peritoneal macrophages and peripheral blood mononuclear cells have been observed so that clinical applications as anti-inflammatory, immunosuppressive, and immunostimulatory agents are possible. Several frog skin peptides, first identified on the basis of antimicrobial activity, have been shown to stimulate insulin release both in vitro and in vivo and so show potential as incretin-based therapies for treatment of patients with Type 2 diabetes mellitus. This review assesses the therapeutic possibilities of peptides from frogs belonging to the Ascaphidae, Alytidae, Pipidae, Dicroglossidae, Leptodactylidae, Hylidae, and Ranidae families that complement their potential role as anti-infectives for use against multidrug-resistant microorganisms.


Termination of pregnancy as emergency obstetric care: the interpretation of Catholic health policy and the consequences for pregnant women: an analysis of the death of Savita Halappanavar in Ireland and similar cases.
Issues arising from the death of Savita Halappanavar in Ireland in October 2012 include the question of whether it is unethical to refuse to terminate a non-viable pregnancy when the woman's life may be at risk. In Catholic maternity services, this decision intersects with health professionals' interpretation of Catholic health policy on treatment of miscarriage as well as the law on abortion. This paper explores how these issues came together around Savita's death and the consequences for pregnant women and maternity services worldwide. It discusses cases not only in Ireland but also the Americas. Many of the events presented are recent, and most of the sources are media and individual reports. However, there is a very worrying common thread across countries and continents. If further research unearths more cases like Savita's, any Catholic health professionals and/or hospitals refusing to terminate a pregnancy as emergency obstetric care should be stripped of their right to provide maternity services. In some countries these are the main or only existing maternity services. Even so, governments should refuse to fund these services, and either replace them with non-religious services or require that non-religious staff are available at all times specifically to take charge of such cases to prevent unnecessary deaths. At issue is whether a woman's life comes first or not at all.


Elephant APOBEC3A cytidine deaminase induces massive double-stranded DNA breaks and apoptosis.
The incidence of developing cancer should increase with the body mass, yet is not the case, a conundrum referred to as Peto's paradox. Elephants have a lower incidence of cancer suggesting that these animals have probably evolved different ways to protect themselves against the disease. The paradox is worth revisiting with the realization that most mammals encode an endogenous APOBEC3 cytidine deaminase capable of mutating single stranded DNA. Indeed, the mutagenic activity of some APOBEC3 enzymes has been shown to introduce somatic mutations into genomic DNA. These enzymes are now recognized as causal agent responsible for the accumulation of CG- > TA transitions and DNA breaks leading to chromosomal rearrangements in human cancer genomes. Here, we identified an elephant A3Z1 gene, related to human APOBEC3A and showed that it could efficiently deaminate cytidine, 5-methylcytidine and produce DNA breaks leading to massive apoptosis, similar to other mammalian APOBEC3A enzymes where body mass varies by up to four orders of magnitude. Consequently, it could be considered that eAZ1 might contribute to cancer in elephants in a manner similar to their proposed role in humans. If so, eAZ1 might be particularly well regulated to counter Peto's paradox.


Trends in the risks and benefits to patients with cancer participating in phase 1 clinical trials.
In the past, cancer patients entering phase 1 studies confronted the prospects of high risk and unlikely benefit. Over the last decade, cancer drugs under development have become more targeted, and the clinical research environment has become more scrutinized. The impact of these changes on the risks and benefits to patients who participate in phase 1 cancer trials is unknown. To determine trends in the rates of treatment-related (toxic) death, objective response, and serious toxicity and to identify factors associated with these outcomes. We searched abstracts and journal articles reporting the results of phase 1 cancer treatment trials originally submitted to annual meetings of the American Society of Clinical Oncology (ASCO) from 1991 through 2002. We focused on published single-agent trials that enrolled patients with advanced solid tumors and excluded studies testing agents already approved by the US Food and Drug Administration at the time of the ASCO presentation. Multiple observers independently extracted information on trial design, location, sponsorship, types of tumors treated, drug class, route of administration, and clinical outcomes. The overall toxic death rate for 213 studies (involving 6474 cancer patients) published in peer-reviewed journals was 0.54%, while the overall objective response rate was 3.8%. Toxic death rates decreased over the study period, from 1.1% over the first 4 years of the study (1991-1994) to 0.06% over the most recent 4-year period (1999-2002) (P<.01). Response rates also decreased but by proportionally much less. After adjusting for characteristics of the experimental trials and the investigational agents, the odds of a patient dying from an experimental treatment while participating in a trial submitted during the most recent 4-year period were less than one tenth those of a patient participating in a trial submitted during the first 4-year period (odds ratio, 0.09; 95% confidence interval, 0.01-0.67; P = .009). In comparison, the adjusted odds of a patient experiencing an objective response over the same time periods decreased by approximately half (odds ratio, 0.46; 95% confidence interval, 0.32-0.66; P<.001). The level of risk experienced by cancer patients who participate in phase 1 treatment trials appears to have improved over the 12-year period from 1991 through 2002. Because toxic death rates have decreased more quickly than have objective response rates, the ratio of risk to benefit may have also improved. These changes relate in part to the targeted and less-toxic nature of newer cancer drugs and are coincident with the increased attention that has been paid to the safety of clinical research over the time period we analyzed.


Autonomous vehicles and cycling: Policy implications and management issues.
Cycling as a form of active transport has great benefits for individuals and society, yet prevalence rates in many countries are low. The advent of autonomous vehicles (AVs) is likely to have substantial implications for cyclists, however little is known about the nature and magnitude of the likely impacts and the resulting implications for government planning and policy. The aim of this exploratory study was to consult with a range of stakeholder groups to identify relevant issues and stimulate debate about future efforts to maximize the benefits of vehicle autonomy for cycling outcomes. Interviews were conducted with key stakeholders representing government (local, state, and federal departments responsible for transport, health, and/or infrastructure), cycling organizations, technology firms, AV manufacturing/servicing companies, trade unions, the law, insurers (public and private), transport policy consortia, and academia. The results suggest that AVs have the potential to increase cycling prevalence while reducing cycling accidents, but that a range of issues will need to be addressed to optimize these outcomes. In particular, informed decisions need to be made about the infrastructure and equipment investments that could encourage larger numbers of commuters to select cycling as their primary form of transport.


Relation between lymphopenia and bacteraemia in UK adults with medical emergencies.
To determine the relevance of lymphopenia to the diagnosis of bacteraemia in patients admitted with medical emergencies, relative to peripheral blood white cell count and neutrophilia. A two year cohort study carried out in a teaching hospital in Oxford, UK of 21,495 consecutive adult emergency admissions to general medical or infectious disease wards. Full blood data were available in 21,372 cases; 41 cases with extreme full blood count results (neutrophil count, > 75 x 10(9)/litre; lymphocyte count, > 10 x 10(9)/litre) were excluded, leaving 21,331 cases for analysis. The association between the admission lymphocyte and neutrophil counts and the risk of bacteraemia was assessed. Neutrophilia and lymphopenia were both associated with bacteraemia. Lymphopenia was the better predictor in this cohort. Both neutrophilia and lymphopenia were more predictive of bacteraemia than the total white blood cell count. Both lymphocyte and neutrophil counts, rather than total white blood cell count, should be considered in adult medical admissions with suspected bacteraemia.


Family Religiosity and Oral Health Related Quality of Life: a Multilevel Analysis in Brazilian Schoolchildren.
Religiosity has been associated with a better dental condition and positive self-perception of health, but there are no studies on the relationship between religious practice and oral health-related quality of life (OHRQoL), especially among schoolchildren. Thus, the aim of this study was to evaluate the association between family religiosity and OHRQoL in 12-year-old schoolchildren. We conducted a cross-sectional study in a representative sample of 12-year-old schoolchildren from Santa Maria, a city in southern Brazil. A total of 1,134 schoolchildren were assessed in a randomly selected in 20 public schools in the city. Participants were examined by 4 calibrated dentists (minimum Kappa-value for intra and inter-examiner agreement were 0.79 and 0.77, respectively) according to dental caries (Decayed, Missed, Filled Teeth Index), and gingival bleeding (Community Periodontal Index criteria). OHRQoL was assessed by the Brazilian short version of Child Perceptions for Questionnaire (CPQ11-14). Parents or guardians answered a structured questionnaire regarding their socioeconomic status and religious practice. Data were analyzed using multilevel Poisson regression analysis to assess the association of religiosity and overall and domain-specific CPQ 11-14 scores. Religious practice less than once a week was associated with higher mean symptoms domain scores and higher mean CPQ 11-14 overall scores in schoolchildren. In conclusion, our findings demonstrate that family religiosity was positively associated with schoolchildren's OHRQoL.


Long-term follow-up of R403WMYH7 and R92WTNNT2 HCM families: mutations determine left ventricular dimensions but not wall thickness during disease progression.
The clinical profile and prognosis of patients with hypertrophic cardiomyopathy, a primary cardiac muscle disease caused mostly by mutations in sarcomeric protein-encoding genes, have been linked to particular disease-causing mutations in the past. However, such associations are often based on cross-sectional observations, as longitudinal studies of the progression of the disease in genotypically defined patients are sparse. Most importantly, the relative contribution of age, gender and genetic cause to disease profile and progression has not yet been reported, and the question remains whether one or more of these factors could mask the effect of the other(s). We previously described cross-sectional family studies of two hypertrophic cardiomyopathy (HCM)-causing mutations, R92W(TNNT2) and R403W(MYH7), both associated with minimal hypertrophy, but with widely different life expectancies. We re-investigated 22 and 26 R92W(TNNT2) and R403W(MYH7) mutation carriers in these and additional South African R92W(TNNT2) families after a mean 11.08 +/- 2.79 years, and compared the influence of the two mutations, in the context of age and gender, on disease progression. We demonstrated a positive correlation between age and interventricular septal thickness for both mutations, with more than a third of all mutation carriers developing clinically recognised hypertrophy only after the age of 35 years. This period of hypertrophically silent HCM also coincided with the years in which most sudden cardiac deaths occurred, particularly in male R92W(TNNT2) carriers. Statistical analyses indicated that the particular mutation was the strongest determinant of left ventricular remodelling; particularly, LVESD increased and EF reduction was noted in the majority of R403W(MYH7) carriers, which may require clinical follow-up over the longer term. Statistical modelling of follow-up data suggests that an interplay between unidentified, possibly gender-associated factors, and the causal mutation are the determinants of eventual cardiac function and survival, but not of the extent of hypertrophy, and emphasises the need for long-term follow-up even in individuals with apparently mild disease.


Configuring a context-aware middleware for Wireless Sensor Networks.
In the Future Internet, applications based on Wireless Sensor Networks will have to support reconfiguration with minimum human intervention, depending on dynamic context changes in their environment. These situations create a need for building these applications as adaptive software and including techniques that allow the context acquisition and decisions about adaptation. However, contexts use to be made up of complex information acquired from heterogeneous devices and user characteristics, making them difficult to manage. So, instead of building context-aware applications from scratch, we propose to use FamiWare, a family of middleware for Ambient Intelligence specifically designed to be aware of contexts in sensor and smartphone devices. It provides both, several monitoring services to acquire contexts from devices and users, and a context-awareness service to analyze and detect context changes. However, the current version of FamiWare does not allow the automatic incorporation related to the management of new contexts into the FamiWare family. To overcome this shortcoming, in this work, we first present how to model the context using a metamodel to define the contexts that must to be taken into account in an instantiation of FamiWare for a certain Ambient Intelligence system. Then, to configure a new context-aware version of FamiWare and to generate code ready-to-install within heterogeneous devices, we define a mapping that automatically transforms metamodel elements defining contexts into elements of the FamiWare family, and we also use the FamiWare configuration process to customize the new context-aware variant. Finally, we evaluate the benefits of our process, and we analyze both that the new version of the middleware works as expected and that it manages the contexts in an efficient way.


Endoscopic transgastric drainage of a gastric wall abscess after endoscopic submucosal dissection.
A 63-year-old woman was referred to our hospital for further examination because of an incidental finding of early gastric cancer. Endoscopic submucosal dissection (ESD) was successfully performed for complete resection of the tumor. On the first post-ESD day, the patient suddenly complained of abdominal pain after an episode of vomiting. Abdominal computed tomography (CT) showed delayed perforation after ESD. The patient was conservatively treated with an intravenous proton pump inhibitor and antibiotics. On the fifth post-ESD day, CT revealed a gastric wall abscess in the gastric body. Gastroscopy revealed a gastric fistula at the edge of the post-ESD ulcer, and pus was found flowing into the stomach. An intradrainage stent and an extradrainage nasocystic catheter were successfully inserted into the abscess for endoscopic transgastric drainage. After the procedure, the clinical symptoms and laboratory test results improved quickly. Two months later, a follow-up CT scan showed no collection of pus. Consequently, the intradrainage stent was removed. Although the gastric wall abscess recurred 2 wk after stent removal, it recovered soon after endoscopic transgastric drainage. Finally, after stent removal and oral antibiotic treatment for 1 mo, no recurrence of the gastric wall abscess was found.


Estimation of temporal changes in oxidation rates of sulphides in copper mine tailings at Laver, Northern Sweden.
Tailings containing pyrrhotite were deposited in an impoundment at a copper mine at Laver, Northern Sweden, which operated between 1936 and 1946. Since then the oxidation of sulphides has acidified recipient water courses and contaminated them with metals. Measurements from surface water sampled in 1993, 2001 and 2004-05 from a brook into which the tailing impoundment drains indicate that the amounts of sulphide-associated elements such as Cu, S and Zn released into the brook have decreased over time, while pH has increased. The mass transport of S in the brook during 1993 and 2001 corresponded well with the amount of S estimated to be released from the tailings by oxidation. Secondary precipitates such as covellite and gypsum, which can trap sulphur, were shown in earlier studies to be present in only low amounts. The annual release of elements from the tailings was estimated from the volume of tailings assumed to oxidise each year, which depends on movement of the oxidation front with time. The results indicate that the oxidation rate in the tailings has decreased over time, which may be due to the increased distance over which oxygen needs to diffuse to reach unoxidised sulphide grains, or their cores, in the tailings.


Effects of Distant Green Space on Physical Activity in Sydney, Australia.
The aim was to investigate the association between distant green space and physical activity modified by local green space. Information about physical activity, demographic and socioeconomic background at the individual level was extracted from the New South Wales Population Health Survey. The proportion of a postcode that was parkland was used as a proxy measure for access to parklands and was calculated for each individual. There was a significant relationship between distant green space and engaging in moderate-to-vigorous physical activity (MVPA) at least once a week. No significant relationship was found between adequate physical activity and distant green space. No significant relationships were found between adequate physical activity, engaging in MVPA, and local green space. However, if respondents lived in greater local green space (≥25%), there was a significant relationship between engaging in MVPA at least once a week and distance green space of ≥20%. This study highlights the important effect of distant green space on physical activity. Our findings also suggest that moderate size of local green space together with moderate size of distant green space are important levers for participation of physical activity.


The social norms of birth cohorts and adolescent marijuana use in the United States, 1976-2007.
Studies of the relationship between social norms and marijuana use have generally focused on individual attitudes, leaving the influence of larger societal-level attitudes unknown. The present study investigated societal-level disapproval of marijuana use defined by birth cohort or by time-period. Combined analysis of nationally representative annual surveys of secondary school students in the United States conducted from 1976 to 2007 as part of the Monitoring the Future study. In-school surveys completed by adolescents in the United States. A total of 986 003 adolescents in grades 8, 10 and 12. Main predictors included the percentage of students who disapproved of marijuana in each birth cohort and time-period. Multi-level models with individuals clustered in time-periods of observation and birth cohorts were modeled, with past-year marijuana use as the outcome. Results indicated a significant and strong effect of birth cohort disapproval of marijuana use in predicting individual risk of marijuana use, after controlling for individual-level disapproval, perceived norms towards marijuana and other characteristics. Compared to birth cohorts in which most (87-90.9%) adolescents disapproved of marijuana use, odds of marijuana use were 3.53 times higher in cohorts where fewer than half (42-46.9%) disapproved (99% confidence interval: 2.75, 4.53). Individuals in birth cohorts that are more disapproving of marijuana use are less likely to use, independent of their personal attitudes towards marijuana use. Social norms and attitudes regarding marijuana use cluster in birth cohorts, and this clustering has a direct effect on marijuana use even after controlling for individual attitudes and perceptions of norms.


A gene trap mutagenesis screen for genes underlying cellular response to the mood stabilizer lithium.
Identifying the biological pathways mediating the action of a therapeutic compound may help the development of more specific treatments while also increasing our understanding of the underlying disease pathology. Salts of the metal lithium are commonly used as a front-line mood stabilizing treatment for bipolar disorder. Lithium's action has been variously linked to inositol phosphate metabolism and the WNT/Glycogen Synthase Kinase 3β (GSK3β)/β-Catenin signalling cascade, but, to date, little is known about which of these provides the principal therapeutic benefit for patients and, more specifically, which constituent genes, through presumed sequence variation, determine differences in patient response to treatment. Here, we describe a functional screen in which SH-SY5Y neuroblastoma cells were randomly mutated through genomic integration of the pMS1 poly A 'gene trap' plasmid vector. Lithium normally induces differentiation of neuroblastoma cells, but a small proportion of mutated cells continued to proliferate and formed colonies. Rapid amplification of cDNA ends (RACE)-PCR was used to identify the 'trapped' gene in each of these lithium-resistant colonies. Heterozygous, gene trap integrations were identified within ten genes, eight of which are likely to produce loss-of-function mutations including MED10, MSI2 and three long intergenic non-coding (LINC) RNAs. Both MED10 and MSI2 have been previously linked with WNT/GSK3β/β-Catenin pathway function suggesting that this is an important mediator of lithium action in this screen. The methodology applied here provides a rapid, objective and economic approach to define the genetic contribution to drug action, but could also be readily adapted to any desired in vitro functional selection/screening paradigm.


Heavy vs Light Load Single-Joint Exercise Performance with Different Rest Intervals.
The aim of the study was to compare the effect of three distinct rest period lengths between sets of upper body single-joint exercise with different load zones and volume designed for either endurance or hypertrophy (50% or 80% of 1-RM). Sixteen trained men (20.75 ± 2.54 years; 76.35 ± 5.03 kg; 176.75 ± 3.33 cm, 24.53 ± 1.47 kg/m2) performed a test and retest of 1-RM on non-consecutive days. Forty-eight hours after load testing, the participants were randomly assigned to six sessions consisting of four sets of the triceps pull-down, combining different intensities with distinct rest periods between sets. The shorter 1 minute rest promoted a significant reduction in the total repetition number compared to 3 minute rest for both workloads. There was a difference between 3 and 5 minute conditions for the 50% of 1-RM that did not occur for the 80% of 1-RM condition. Both intensities presented significant interaction values for the rest conditions vs. each set (50% p = 0.0001; 80% p = 0.0001). Additionally, significant values were found for the main effect of the performance of subsequent sets (50% p = 0.003; 80% p = 0.001) and rest conditions (50% p = 0.0001; 80% p = 0.0001). In conclusion, for heavier loads (80%) to fatigue, longer rest of 3 to 5 minutes seems to allow for better recovery between sets and thus, promotes a greater volume. However, when training with lighter loads (50%), the magnitude of the rest seems to directly affect the performance of subsequent sets, and also presents a correlation with total volume achieved for the upper body single-joint exercise scheme.


Ultradeep single-molecule real-time sequencing of HIV envelope reveals complete compartmentalization of highly macrophage-tropic R5 proviral variants in brain and CXCR4-using variants in immune and peripheral tissues.
Despite combined antiretroviral therapy (cART), HIV+ patients still develop neurological disorders, which may be due to persistent HIV infection and selective evolution in brain tissues. Single-molecule real-time (SMRT) sequencing technology offers an improved opportunity to study the relationship among HIV isolates in the brain and lymphoid tissues because it is capable of generating thousands of long sequence reads in a single run. Here, we used SMRT sequencing to generate ~ 50,000 high-quality full-length HIV envelope sequences (> 2200 bp) from seven autopsy tissues from an HIV+/cART+ subject, including three brain and four non-brain sites. Sanger sequencing was used for comparison with SMRT data and to clone functional pseudoviruses for in vitro tropism assays. Phylogenetic analysis demonstrated that brain-derived HIV was compartmentalized from HIV outside the brain and that the variants from each of the three brain tissues grouped independently. Variants from all peripheral tissues were intermixed on the tree but independent of the brain clades. Due to the large number of sequences, a clustering analysis at three similarity thresholds (99, 99.5, and 99.9%) was also performed. All brain sequences clustered exclusive of any non-brain sequences at all thresholds; however, frontal lobe sequences clustered independently of occipital and parietal lobes. Translated sequences revealed potentially functional differences between brain and non-brain sequences in the location of putative N-linked glycosylation sites (N-sites), V1 length, V3 charge, and the number of V4 N-sites. All brain sequences were predicted to use the CCR5 co-receptor, while most non-brain sequences were predicted to use CXCR4 co-receptor. Tropism results were confirmed by in vitro infection assays. The study is the first to use a SMRT sequencing approach to study HIV compartmentalization in tissues and supports other reports of limited trafficking between brain and non-brain sequences during cART. Due to the long sequence length, we could observe changes along the entire envelope gene, likely caused by differential selective pressure in the brain that may contribute to neurological disease.


Do body mass index, hormone profile and testicular volume effect sperm retrieval rates of microsurgical sperm extraction in the patients with nonobstructive azoospermia?
We aimed to evaluate the effect of body mass index (BMI), follicle stimulating hormone (FSH), and luteinizing hormone (LH) levels and the mean testicular volume on sperm retrieval rates in microsurgical sperm extraction (microTESE) in the patients with nonobstructive azoospermia (NOA). The data of 282 infertile patients with NOA were analysed retrospectively. The patients with normal karyotype and no Y microdeletions were included in the study. The patients were classified according to their BMI scores and the medical history, physical examination and hormonal parameters were evaluated. The overall data were processed statistically with chi-square and logistic regression analysis and the relation between preoperative findings and sperm retrieval rates was investigated. The sperm retrieval rate of 282 patients after microTESE was found as 41.1%. There was no statistically significant difference in sperm retrieval rates among the subgroups classified according to BMI. FSH and LH levels and the mean testicular volume and pathologic findings were significantly correlated with sperm retrieval rates. Finally significant correlation was determined between sperm retrieval rates and FSH, and LH levels and testicular volumes but no statistically significant difference was found in sperm retrieval rates among BMI groups.


Microbial aspects of accelerated degradation of metam sodium in soil.
Preplant soil fumigation with metam sodium is used worldwide to control soilborne diseases. The development of accelerated degradation of pesticides in soil, including metam sodium, results in reduced pesticide efficacy. Therefore, we studied microbial involvement in accelerated degradation of methyl isothiocyanate (MITC) following repeated soil applications of the parent compound, metam sodium. MITC degradation was reduced in soil with a history of metam sodium applications following sterilization, indicating the key role of microorganisms in accelerated degradation. Accelerated degradation of MITC was induced by inoculation of soil with no previous application of metam sodium with soil with a history of metam sodium applications. We developed a method to extract the active microbial fraction responsible for MITC degradation from soil with a history of metam sodium applications. This concentrated soil extract induced accelerated degradation of MITC when added to two different soils with no previous application of metam sodium. An extensive shift in total bacterial community composition in concentrated soil extracts occurred after a single metam sodium application. Two Oxalobacteraceae strains, MDB3 and MDB10, isolated from Rehovot soil following triple application of metam sodium rapidly degraded MITC in soil with no previous application of metam sodium. Polymerase chain reaction-denaturing gradient gel electrophoresis analysis of bacterial community composition showed relative enrichment of MDB3 following metam sodium application, suggesting its potential in situ involvement in accelerated degradation development in Rehovot soil. Responses of resident Oxalobacteraceae community members to metam sodium applications differed between Rehovot and En Tamar soils. Isolate MDB10 did not induce accelerated degradation of MITC in En Tamar soil and, with the slow dissipation of MITC, soil suppressiveness of accelerated degradation is suggested. The isolation and identification of MITC-degrading bacteria might be helpful in developing tools for managing accelerated degradation.