Proximal renal tubular acidosis in pregnancy. A case report and literature review.
Renal tubular acidosis is usually associated with chronic renal conditions and is rarely encountered in pregnancy. It may be inherited causing osteomalacia and rickets in children or acquired following autoimmune diseases or following exposure to nephrotoxic agents. It is known to worsen during pregnancy and if left untreated may cause maternal and foetal morbidity or death. We report a 28-year-old woman, gravida 3 para 2, who presented at 30 weeks gestation with lethargy, weakness and generalized myalgia. Investigation revealed severe hypokalaemia and a systemic metabolic acidosis due to proximal renal tubular acidosis. Her previous pregnancies were both complicated by foetal losses at term. Following prompt correction of her electrolyte disturbance and metabolic acidosis, she went on to deliver a healthy female infant at term. Regular evaluation up to 1 year post-partum revealed mild persistence of her hypokalaemia. At 1 year, the infant showed no signs of the disorder and is growing normally.


Targeted disruption of Gb3/CD77 synthase gene resulted in the complete deletion of globo-series glycosphingolipids and loss of sensitivity to verotoxins.
To examine whether globotriaosylceramide (Gb3/CD77) is a receptor for verotoxins (VTs) in vivo, sensitivity of Gb3/CD77 synthase null mutant mice to VT-2 and VT-1 was analyzed. Although wild-type mice died after administration of 0.02 microg of VT-2 or 1.0 microg of VT-1, the mutant mice showed no reaction to doses as much as 100 times that administered to wild types. Expression analysis of Gb3/CD77 in mouse tissues with antibody revealed that low, but definite, levels of Gb3/CD77 were expressed in the microvascular endothelial cells of the brain cortex and pia mater and in renal tubular capillaries. Corresponding to the Gb3/CD77 expression, tissue damage with edema, congestion, and cytopathic changes was observed, indicating that Gb3/CD77 (and its derivatives) exclusively function as a receptor for VTs in vivo. The lethal kinetics were similar regardless of lipopolysaccharide elimination in VT preparation, suggesting that basal Gb3/CD77 levels are sufficient for lethal effects of VTs.


DNA targeting polyaza macrobicyclic dizinc(II) complexes promoting high in vitro caspase dependent anti-proliferative activity against human carcinoma cancer cells.
A series of macrobicyclic dizinc(II) complexes [Zn(2)L(1-2)B](ClO(4))(4) (1-6) have been synthesized and characterized (L(1-2) are polyaza macrobicyclic binucleating ligands, and B is the N,N-donor heterocyclic base (viz. 2,2'-bipyridine (bipy) and 1,10-phenanthroline (phen)). The DNA and protein binding, DNA hydrolysis and anticancer activity of these complexes were investigated. The interactions of complexes 1-6 with calf thymus DNA were studied by spectroscopic techniques, including absorption, fluorescence and CD spectroscopy. The DNA binding constant values of the complexes were found to range from 2.80 × 10(5) to 5.25 × 10(5) M(-1), and the binding affinities are in the following order: 3 > 6 > 2 > 5 > 1 > 4. All the dizinc(II) complexes 1-6 are found to effectively promote the hydrolytic cleavage of plasmid pBR322 DNA under anaerobic and aerobic conditions. Kinetic data for DNA hydrolysis promoted by 3 and 6 under physiological conditions give observed rate constants (k(obs)) of 5.56 ± 0.1 and 5.12 ± 0.2 h(-1), respectively, showing a 10(7)-fold rate acceleration over the uncatalyzed reaction of dsDNA. Remarkably, the macrobicyclic dizinc(II) complexes 1-6 bind and cleave bovine serum albumin (BSA), and effectively promote the caspase-3 and caspase-9 dependent deaths of HeLa and BeWo cancer cells. The cytotoxicity of the complexes was further confirmed by lactate dehydrogenase enzyme levels in cancer cell lysate and content media.


Retinol concentrations after birth are inversely associated with atopic manifestations in children and young adults.
Vitamin A has anti-inflammatory and immunomodulatory effects, and its deficiency results in impaired specific and innate immunity. Vitamin A is essential for inducing the gut-homing specificity on T cells. As an impaired gut immune response in early infancy may contribute to the development of atopic sensitization, we looked for an association of plasma retinol concentrations and the subsequent development of allergic symptoms in healthy infants. A cohort of 200 unselected, full-term newborns were followed up from birth to age 20 years. The plasma retinol concentration was determined in cord blood (n=97), at ages of 2, 4 and 12 months (n=95), and at ages 5 years (n=155) and 11 years (n=151). The subjects were re-examined at the ages of 5, 11 and 20 years with assessment of the occurrence of allergic symptoms during the preceding year, skin prick testing and measurement of serum total IgE. subjects with allergic symptoms or a positive skin prick test (SPT) in childhood or adolescence had lower retinol concentrations in infancy and childhood than symptom-free subjects. The difference was most pronounced at age 2 months. Retinol concentration at 2 months correlated inversely with positive SPT at ages of 5 and 20 years, and with allergic symptoms at age 20 years. Retinol concentration in young infants is inversely associated with the subsequent development of allergic symptoms. We propose that an inborn regulation of retinol may play a role in atopic sensitization, possibly through regulating the intestinal T cell responses.


Cryo-SOFI enabling low-dose super-resolution correlative light and electron cryo-microscopy.
Correlative light and electron cryo-microscopy (cryo-CLEM) combines information from the specific labeling of fluorescence cryo-microscopy (cryo-FM) with the high resolution in environmental context of electron cryo-microscopy (cryo-EM). Exploiting super-resolution methods for cryo-FM is advantageous, as it enables the identification of rare events within the environmental background of cryo-EM at a sensitivity and resolution beyond that of conventional methods. However, due to the need for relatively high laser intensities, current super-resolution cryo-CLEM methods require cryo-protectants or support films which can severely reduce image quality in cryo-EM and are not compatible with many samples, such as mammalian cells. Here, we introduce cryogenic super-resolution optical fluctuation imaging (cryo-SOFI), a low-dose super-resolution imaging scheme based on the SOFI principle. As cryo-SOFI does not require special sample preparation, it is fully compatible with conventional cryo-EM specimens, and importantly, it does not affect the quality of cryo-EM imaging. By applying cryo-SOFI to a variety of biological application examples, we demonstrate resolutions up to ∼135 nm, an improvement of up to three times compared with conventional cryo-FM, while maintaining the specimen in a vitrified state for subsequent cryo-EM. Cryo-SOFI presents a general solution to the problem of specimen devitrification in super-resolution cryo-CLEM. It does not require a complex optical setup and can easily be implemented in any existing cryo-FM system.


Body size, physical activity, and risk of triple-negative and estrogen receptor-positive breast cancer.
Triple-negative breast cancer, characterized by a lack of hormone receptor and HER2 expression, is associated with a particularly poor prognosis. Focusing on potentially modifiable breast cancer risk factors, we examined the relationship between body size, physical activity, and triple-negative disease risk. Using data from 155,723 women enrolled in the Women's Health Initiative (median follow-up, 7.9 years), we assessed associations between baseline body mass index (BMI), BMI in earlier adulthood, waist and hip circumference, waist-hip ratio, recreational physical activity, and risk of triple-negative (n=307) and estrogen receptor-positive (ER+, n=2,610) breast cancers. Women in the highest versus lowest BMI quartile had 1.35-fold (95% CI, 0.92-1.99) and 1.39-fold (95% CI, 1.22-1.58) increased risks of triple-negative and ER+ breast cancers, respectively. Waist and hip circumferences were positively associated with risk of ER+ breast cancer (Ptrend=0.01 for both measures) but were not associated with triple-negative breast cancer. Compared with women who reported no recreational physical activity, women in the highest activity tertile had similarly lower risks of triple-negative and ER+ breast cancers (HR=0.77; 95% CI, 0.51-1.13; and HR=0.85; 95% CI, 0.74-0.98, respectively). Despite biological and clinical differences, triple-negative and ER+ breast cancers are similarly associated with BMI and recreational physical activity in postmenopausal women. The biological mechanisms underlying these similarities are uncertain and these modest associations require further investigation. If confirmed, these results suggest potential ways postmenopausal women might modify their risk of both ER+ and triple-negative breast cancers.


Effects of regular exercise combined with ingestion of vespa amino acid mixture on aerobic fitness and cardiovascular disease risk factors in sedentary older women: a preliminary study.
Vespa amino acid mixture (VAAM) is a nutrient liquid with an amino acid composition that is similar to that produced by hornet (Vespa mandarina) larvae. Animal studies have shown that VAAM may enhance fat metabolism and exercise tolerance. Whether these effects are evident in humans, however, remains to be fully elucidated, especially in older women. The purpose of this study was to investigate whether regular exercise combined with oral ingestion of VAAM improves aerobic fitness and cardiovascular disease risk factors in sedentary older women. Twenty-four older women (aged 63.5±2.6 years) were randomly assigned to either the VAAM ingestion (3000 mg/day, n=12) or placebo (n=12) group. Subjects in both groups participated in 90-min exercise sessions consisting of aerobic exercise and light resistance training on a regular basis two times per week for 12 weeks. After the 12-week exercise regimen, maximal oxygen uptake was significantly increased in those who ingested VAAM (from 25.3 to 27.7 mL/kg per min), but not in those who ingested the placebo (from 25.4 to 26.9 mL/kg per min). Intra-abdominal fat estimated by computed tomography was significantly reduced in those who ingested VAAM (from 102.0 to 83.3 cm2), but not in those who ingested the placebo (from 92.1 to 82.6 cm2). Total cholesterol, low-density lipoprotein cholesterol and triglyceride levels remained unchanged in both groups. Regular exercise combined with VAAM ingestion may slightly increase aerobic fitness and decrease intra-abdominal fat in sedentary older women. Further investigations with a large sample, however, would be warranted.


Progress, challenges, and new opportunities for the prevention of mother-to-child transmission of HIV under the US President's Emergency Plan for AIDS Relief.
In June 2011, the Joint United Nations Programme on HIV/AIDS, the US President's Emergency Plan for AIDS Relief (PEPFAR), and other collaborators outlined a transformative plan to virtually eliminate pediatric AIDS worldwide. The ambitious targets of this initiative included a 90% reduction in new pediatric HIV infections and a 50% reduction in HIV-related maternal mortality--all by 2015. PEPFAR has made an unprecedented commitment to the expansion and improvement of prevention of mother-to-child HIV transmission (PMTCT) services globally and is expected to play a critical role in reaching the virtual elimination target. To date, PEPFAR has been instrumental in the success of many national programs, including expanded coverage of PMTCT services, an enhanced continuum of care between PMTCT and HIV care and treatment, provision of more efficacious regimens for antiretroviral prophylaxis, design of innovative but simplified PMTCT approaches, and development of new strategies to evaluate program effectiveness. These accomplishments have been made through collaborative efforts with host governments, United Nations agencies, other donors (eg, the Global Fund for AIDS, Tuberculosis, and Malaria), nongovernmental organizations, and private sector partners. To successfully meet the ambitious global targets to prevent new infant HIV infections, PEPFAR must continue to leverage the existing PMTCT platform, while developing innovative approaches to rapidly expand quality HIV services. PEPFAR must also carefully integrate PMTCT into the broader combination prevention agenda for HIV, so that real progress can be made toward an "AIDS-free generation" worldwide.


Effects of nanopolystyrene on the feeding behavior of the blue mussel (Mytilus edulis L.).
As the industrial production of nanoplastic and the degradation of microplastic into smaller particles at sea increase, the potential amount of nanoplastics in the marine environment rises. It has been reported that mussels uptake 100-nm polystyrene (PS) beads; to date, however, the effects of this uptake on the organism are unknown. In the present study, the authors investigated the effects of 30-nm PS on the feeding behavior of the blue mussel (Mytilus edulis) by exposing the organism to different nano PS and different algae (Pavlova lutheri) concentrations. The state of nano PS aggregation in the exposure medium was assessed using dynamic light scattering. In all treatments that contained nano PS, M. edulis produced pseudofeces. The total weight of the feces and pseudofeces increased with increasing nano PS and increasing algae concentration. Furthermore, M. edulis reduced its filtering activity when nano PS was present but still caused a decrease in the apparent nano PS concentration in the water. The presence of nano PS around the foot of M. edulis after the bioassay confirmed that the organism removed nano PS from the water. Chronic effect studies are therefore needed to investigate the effects of nanoplastics in M. edulis and possible consequences for its predators, including humans.


Ruthenium isotope vestige of Earth's pre-late-veneer mantle preserved in Archaean rocks.
The accretion of volatile-rich material from the outer Solar System represents a crucial prerequisite for Earth to develop oceans and become a habitable planet1-4. However, the timing of this accretion remains controversial5-8. It has been proposed that volatile elements were added to Earth by the late accretion of a late veneer consisting of carbonaceous-chondrite-like material after core formation had ceased6,9,10. This view could not be reconciled with the ruthenium (Ru) isotope composition of carbonaceous chondrites5,11, which is distinct from that of the modern mantle12, or of any known meteorite group5. As a possible solution, Earth's pre-late-veneer mantle could already have contained a fraction of Ru that was not fully extracted by core formation13. The presence of such pre-late-veneer Ru can only be established if its isotope composition is distinct from that of the modern mantle. Here we report the first high-precision, mass-independent Ru isotope compositions for Eoarchaean ultramafic rocks from southwest Greenland, which display a relative 100Ru excess of 22 parts per million compared with the modern mantle value. This 100Ru excess indicates that the source of the Eoarchaean rocks already contained a substantial fraction of Ru before the accretion of the late veneer. By 3.7 billion years ago, the mantle beneath southwest Greenland had not yet fully equilibrated with late accreted material. Otherwise, no Ru isotopic difference relative to the modern mantle would be observed. If constraints from other highly siderophile elements besides Ru are also considered14, the composition of the modern mantle can only be reconciled if the late veneer contained substantial amounts of carbonaceous-chondrite-like materials with their characteristic 100Ru deficits. These data therefore relax previous constraints on the late veneer and are consistent with volatile-rich material from the outer Solar System being delivered to Earth during late accretion.


Catalytic activity of three variants (Ile, Leu, and Thr) at amino acid residue 359 in human CYP2C9 gene and simultaneous detection using single-strand conformation polymorphism analysis.
This study evaluated the catalytic activity of three variants (Ile, Leu, and Thr) at codon 359 of CYP2C9 enzymes expressed in a yeast cDNA expression system, and then established single-strand conformation polymorphism (PCR-SSCP) analysis for simultaneous detection as a screening method. Diclofenac was used for the in vitro experiment, and its hydroxy metabolite (4'-hydroxydiclofenac) was measured by HPLC. To discuss the in vivo effect of the Thr359 variant on the pharmacokinetics of phenytoin, a case report is presented. The efficiency of the SSCP method was evaluated by analyzing DNA samples from a homozygote for Ile359 and a heterozygote for Leu359 or Thr359. To evaluate the interaction between the P450 level and reductase activity, two batches of the Thr359 variant with a different P450:reductase activity ratio (1:4.0 and 1:1.4) were used. The in vitro study revealed that recombinant Ile359, Leu359, and Thr359 (2 batches) possessed a mean Km of 2.0, 16.5 and (3.8 and 2.9) micromol and Vmax of 12.4, 17.9 and (4.4 and 5.1) nmol/min/nmol P450, respectively. Although the magnitude of the change in catalytic efficiency for the Thr359 variant was close to that of the Leu359 variant, the effect of the two variants on diclofenac 4'-hydroxylation appears to be different because Leu359 variant was associated with a high Km, and Thr359 with a low Vmax. No significant differences in the kinetic data were observed between the two Thr359 enzymes, suggesting that low reductase activity in the Thr359 enzyme was not a major determinant in the present in vitro experiment. Estimated pharmacokinetic parameters of phenytoin obtained by the Bayesian method in an epileptic patient who was a heterozygote carrier for Thr359 variant were: Km = 6.45 microg/mL, Vmax = 5.77 mg/kg/d, and Vmax/Km = 0.89 L/kg/day. The Vmax/Km value in this patient was similar to the population mean value (0.90 L/kg/day) in Japanese heterozygotes for the Leu359 variant. Results for PCR-SSCP were in complete agreement with those obtained using established methods. Thus, the PCR-SSCP approach is useful for identifying these three variants of the CYP2C9 gene.


Artificial Intelligence Techniques for Automated Diagnosis of Neurological Disorders.
Authors have been advocating the research ideology that a computer-aided diagnosis (CAD) system trained using lots of patient data and physiological signals and images based on adroit integration of advanced signal processing and artificial intelligence (AI)/machine learning techniques in an automated fashion can assist neurologists, neurosurgeons, radiologists, and other medical providers to make better clinical decisions. This paper presents a state-of-the-art review of research on automated diagnosis of 5 neurological disorders in the past 2 decades using AI techniques: epilepsy, Parkinson's disease, Alzheimer's disease, multiple sclerosis, and ischemic brain stroke using physiological signals and images. Recent research articles on different feature extraction methods, dimensionality reduction techniques, feature selection, and classification techniques are reviewed. Key Message: CAD systems using AI and advanced signal processing techniques can assist clinicians in analyzing and interpreting physiological signals and images more effectively.


The effects of chronic hypoxia on human auditory system sensitivity.
We have examined the effects of prolonged periods of hypoxia produced at high altitudes on the latency of the auditory brain-stem evoked response (ABER) in 9 subjects at around sea level, 3,500 m, and 4,370 m. Following an ascent from 1,300 m to 3,500 m over 24 h, the mean blood O2 saturation fell to 86.5 +/- 1.2% (+/- S.E.M.) and was associated with a mean prolongation of latency of wave V of the ABER of 0.34 +/- 0.10 ms (p = 0.011 two-tailed paired t-test). Using the stimulus-level/response latency relation determined at around sea-level for each subject, this prolongation of wave V corresponded to a mean reduction in sensitivity of 9.1 dB +/- 1.6 dB. Over a period of 72 h, blood O2 saturation improved slightly (mean 88.1% +/- 1.8%) and mean wave V latency returned to control values. A second rapid ascent to 4,370 m reduced blood O2 to below prerecovery levels (82.5% +/- 1.7%), but in this case there were no significant changes in auditory sensitivity (p = 0.79 two-tailed paired t-test). These data show that mild hypoxia results in an initial decrease in auditory sensitivity. However, the recovery of sensitivity with more prolonged exposure suggests that the auditory system can compensate for chronic mild hypoxia.


Modulation of Endothelial Bone Morphogenetic Protein Receptor Type 2 Activity by Vascular Endothelial Growth Factor Receptor 3 in Pulmonary Arterial Hypertension.
Bone morphogenetic protein (BMP) signaling has multiple roles in the development and function of the blood vessels. In humans, mutations in BMP receptor type 2 (BMPR2), a key component of BMP signaling, have been identified in the majority of patients with familial pulmonary arterial hypertension (PAH). However, only a small subset of individuals with BMPR2 mutation develops PAH, suggesting that additional modifiers of BMPR2 function play an important role in the onset and progression of PAH. We used a combination of studies in zebrafish embryos and genetically engineered mice lacking endothelial expression of Vegfr3 to determine the interaction between vascular endothelial growth factor receptor 3 (VEGFR3) and BMPR2. Additional in vitro studies were performed by using human endothelial cells, including primary lung endothelial cells from subjects with PAH. Attenuation of Vegfr3 in zebrafish embryos abrogated Bmp2b-induced ectopic angiogenesis. Endothelial cells with disrupted VEGFR3 expression failed to respond to exogenous BMP stimulation. Mechanistically, VEGFR3 is physically associated with BMPR2 and facilitates ligand-induced endocytosis of BMPR2 to promote phosphorylation of SMADs and transcription of ID genes. Conditional, endothelial-specific deletion of Vegfr3 in mice resulted in impaired BMP signaling responses, and significantly worsened hypoxia-induced pulmonary hypertension. Consistent with these data, we found significant decrease in VEGFR3 expression in pulmonary arterial endothelial cells from human PAH subjects, and reconstitution of VEGFR3 expression in PAH pulmonary arterial endothelial cells restored BMP signaling responses. Our findings identify VEGFR3 as a key regulator of endothelial BMPR2 signaling and a potential determinant of PAH penetrance in humans.


Minimal hepatic encephalopathy matters in daily life.
Minimal hepatic encephalopathy is a neuro-cognitive dysfunction which occurs in an epidemic proportion of cirrhotic patients, estimated as high as 80% of the population tested. It is characterized by a specific, complex cognitive dysfunction which is independent of sleep dysfunction or problems with overall intelligence. Although named "minimal", minimal hepatic encephalopathy (MHE) can have a far-reaching impact on quality of life, ability to function in daily life and progression to overt hepatic encephalopathy. Importantly, MHE has a profound negative impact on the ability to drive a car and may be a significant factor behind motor vehicle accidents. A crucial aspect of the clinical care of MHE patients is their driving history, which is often ignored in routine care and can add a vital dimension to the overall disease assessment. Driving history should be an integral part of care in patients with MHE. The lack of specific signs and symptoms, the preserved communication skills and lack of insight make MHE a difficult condition to diagnose. Diagnostic strategies for MHE abound, but are usually limited by financial, normative or time constraints. Recent studies into the inhibitory control and critical flicker frequency tests are encouraging since these tests can increase the rates of MHE diagnosis without requiring a psychologist. Although testing for MHE and subsequent therapy is not standard of care at this time, it is important to consider this in cirrhotics in order to improve their ability to live their life to the fullest.


Promoter exchange between ompF and ompC, genes for osmoregulated major outer membrane proteins of Escherichia coli K-12.
Expression of the ompF and ompC genes coding for major outer membrane proteins OmpF and OmpC is regulated in opposite directions by medium osmolarity. Chimera genes were constructed by a reciprocal exchange of the promoter-signal sequence region between the two genes. The chimera gene construction was designed so that the proteins synthesized by these genes were essentially the same as the OmpC and OmpF proteins. Studies with the chimera genes demonstrated that the osmoregulation of the OmpF-OmpC synthesis was promoter dependent. They also showed that cells grew normally even when the osmoregulation took place in opposite directions. The effects of the ompR2 and envZ mutations, which suppress ompC and ompF expression, respectively, also became reversed. The reduced expression was still subject to the promoter-controlled osmoregulation. Based on these observations, the mechanism of regulation of the ompF-ompC gene expression and its physiological importance are discussed.


Evaluation of the first 3 years of the Fast Track prevention trial with children at high risk for adolescent conduct problems.
Fast Track is a conduct-problem prevention trial that derives its intervention from longitudinal research on how serious and chronic adolescent problem behaviors develop. Over 9,000 kindergarten children at 4 sites in 3 cohorts were screened, and 891 were identified as high risk and then randomly assigned to intervention or control groups. Beginning in Grade 1, high-risk children and their parents were asked to participate in a combination of social skills and anger-control training, academic tutoring, parent training, and home visiting. A multiyear universal classroom program was delivered to the core schools attended by these high-risk children. By the end of third grade, 37% of the intervention group was determined to be free of serious conduct-problem dysfunction, in contrast with 27% of the control group. Teacher ratings of conduct problems and official records of use of special education resources gave modest effect-size evidence that the intervention was preventing conduct problem behavior at school. Parent ratings provided additional support for prevention of conduct problems at home. Parenting behavior and children's social cognitive skills that had previously emerged as proximal outcomes at the end of the 1st year of intervention continued to show positive effects of the intervention at the end of third grade.


Final Analysis of a Trial of M72/AS01E Vaccine to Prevent Tuberculosis.
Results of an earlier analysis of a trial of the M72/AS01E candidate vaccine against Mycobacterium tuberculosis showed that in infected adults, the vaccine provided 54.0% protection against active pulmonary tuberculosis disease, without evident safety concerns. We now report the results of the 3-year final analysis of efficacy, safety, and immunogenicity. From August 2014 through November 2015, we enrolled adults 18 to 50 years of age with M. tuberculosis infection (defined by positive results on interferon-γ release assay) without evidence of active tuberculosis disease at centers in Kenya, South Africa, and Zambia. Participants were randomly assigned in a 1:1 ratio to receive two doses of either M72/AS01E or placebo, administered 1 month apart. The primary objective was to evaluate the efficacy of M72/AS01E to prevent active pulmonary tuberculosis disease according to the first case definition (bacteriologically confirmed pulmonary tuberculosis not associated with human immunodeficiency virus infection). Participants were followed for 3 years after the second dose. Participants with clinical suspicion of tuberculosis provided sputum samples for polymerase-chain-reaction assay, mycobacterial culture, or both. Humoral and cell-mediated immune responses were evaluated until month 36 in a subgroup of 300 participants. Safety was assessed in all participants who received at least one dose of M72/AS01E or placebo. A total of 3575 participants underwent randomization, of whom 3573 received at least one dose of M72/AS01E or placebo, and 3330 received both planned doses. Among the 3289 participants in the according-to-protocol efficacy cohort, 13 of the 1626 participants in the M72/AS01E group, as compared with 26 of the 1663 participants in the placebo group, had cases of tuberculosis that met the first case definition (incidence, 0.3 vs. 0.6 cases per 100 person-years). The vaccine efficacy at month 36 was 49.7% (90% confidence interval [CI], 12.1 to 71.2; 95% CI, 2.1 to 74.2). Among participants in the M72/AS01E group, the concentrations of M72-specific antibodies and the frequencies of M72-specific CD4+ T cells increased after the first dose and were sustained throughout the follow-up period. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups. Among adults infected with M. tuberculosis, vaccination with M72/AS01E elicited an immune response and provided protection against progression to pulmonary tuberculosis disease for at least 3 years. (Funded by GlaxoSmithKline Biologicals and Aeras; ClinicalTrials.gov number, NCT01755598.).


Signals trigger state-specific transcriptional programs to support diversity and homeostasis in immune cells.
Macrophages play key roles in the immune systems of humans and other mammals. Here, we performed single-cell analyses of the mRNAs and proteins of human macrophages to compare their responses to the signaling molecules lipopolysaccharide (LPS), a component of Gram-negative bacteria, and palmitate (PAL), a free fatty acid. We found that, although both molecules signal through the cell surface protein Toll-like receptor 4 (TLR4), they stimulated the expression of different genes, resulting in specific pro- and anti-inflammatory cellular states for each signal. The effects of the glucocorticoid receptor, which antagonizes LPS signaling, and cyclic AMP-dependent transcription factor 3, which inhibits PAL-induced inflammation, on inflammatory response seemed largely determined by digital on-off events. Furthermore, the quantification of transcriptional variance and signaling entropy enabled the identification of cell state-specific deregulated molecular pathways. These data suggest that the preservation of signaling in distinct cells might confer diversity on macrophage populations essential to maintaining major cellular functions.


Use of breath hydrogen measurement to evaluate orocecal transit time in cats before and after treatment for hyperthyroidism.
Orocecal transit time was evaluated in 13 cats diagnosed with hyperthyroidism. Transit was determined by measuring the change in breath hydrogen and methane concentrations following oral administration of a nonabsorbable carbohydrate (lactulose). Transit times before and three to four weeks after treatment of the hyperthyroidism with radioactive iodine were compared. There was a significant prolongation of transit time, as determined by a change in hydrogen concentration, following correction of the hyperthyroidism (p = 0.034). Average transit times and standard errors were 27.7 +/- 3.7 minutes before treatment and 56.5 +/- 12.1 minutes after treatment. Methane was not detected in any of the samples. Hyperthyroidism appears to be associated with an accelerated small intestinal transit time in cats.


Towards visualisation of central-cell-effects in scanning tunnelling microscope images of subsurface dopant qubits in silicon.
Atomic-scale understanding of phosphorus donor wave functions underpins the design and optimisation of silicon based quantum devices. The accuracy of large-scale theoretical methods to compute donor wave functions is dependent on descriptions of central-cell corrections, which are empirically fitted to match experimental binding energies, or other quantities associated with the global properties of the wave function. Direct approaches to understanding such effects in donor wave functions are of great interest. Here, we apply a comprehensive atomistic theoretical framework to compute scanning tunnelling microscopy (STM) images of subsurface donor wave functions with two central-cell correction formalisms previously employed in the literature. The comparison between central-cell models based on real-space image features and the Fourier transform profiles indicates that the central-cell effects are visible in the simulated STM images up to ten monolayers below the silicon surface. Our study motivates a future experimental investigation of the central-cell effects via the STM imaging technique with potential of fine tuning theoretical models, which could play a vital role in the design of donor-based quantum systems in scalable quantum computer architectures.


Preserving axosomatic spiking features despite diverse dendritic morphology.
Throughout the nervous system, cells belonging to a certain electrical class (e-class)-sharing high similarity in firing response properties-may nevertheless have widely variable dendritic morphologies. To quantify the effect of this morphological variability on the firing of layer 5 thick-tufted pyramidal cells (TTCs), a detailed conductance-based model was constructed for a three-dimensional reconstructed exemplar TTC. The model exhibited spike initiation in the axon and reproduced the characteristic features of individual spikes, as well as of the firing properties at the soma, as recorded in a population of TTCs in young Wistar rats. When using these model parameters over the population of 28 three-dimensional reconstructed TTCs, both axonal and somatic ion channel densities had to be scaled linearly with the conductance load imposed on each of these compartments. Otherwise, the firing of model cells deviated, sometimes very significantly, from the experimental variability of the TTC e-class. The study provides experimentally testable predictions regarding the coregulation of axosomatic membrane ion channels density for cells with different dendritic conductance load, together with a simple and systematic method for generating reliable conductance-based models for the whole population of modeled neurons belonging to a particular e-class, with variable morphology as found experimentally.


Complementary and alternative medicine for cancer patients: results of the EPAAC survey on integrative oncology centres in Europe.
The Region of Tuscany Health Department was included as an associated member in WP7 "Healthcare" of the European Partnership for Action Against Cancer (EPAAC), initiated by the EU Commission in 2009. The principal aim was to map centres across Europe prioritizing those that provide public health services and operating within the national health system in integrative oncology (IO). A cross-sectional descriptive survey design was used to collect data. A questionnaire was elaborated concerning integrative oncology therapies to be administered to all the national health system oncology centres or hospitals in each European country. These institutes were identified by convenience sampling, searching on oncology websites and forums. The official websites of these structures were analysed to obtain more information about their activities and contacts. Information was received from 123 (52.1 %) out of the 236 centres contacted until 31 December 2013. Forty-seven out of 99 responding centres meeting inclusion criteria (47.5 %) provided integrative oncology treatments, 24 from Italy and 23 from other European countries. The number of patients seen per year was on average 301.2 ± 337. Among the centres providing these kinds of therapies, 33 (70.2 %) use fixed protocols and 35 (74.5 %) use systems for the evaluation of results. Thirty-two centres (68.1 %) had research in progress or carried out until the deadline of the survey. The complementary and alternative medicines (CAMs) more frequently provided to cancer patients were acupuncture 26 (55.3 %), homeopathy 19 (40.4 %), herbal medicine 18 (38.3 %) and traditional Chinese medicine 17 (36.2 %); anthroposophic medicine 10 (21.3 %); homotoxicology 6 (12.8 %); and other therapies 30 (63.8 %). Treatments are mainly directed to reduce adverse reactions to chemo-radiotherapy (23.9 %), in particular nausea and vomiting (13.4 %) and leucopenia (5 %). The CAMs were also used to reduce pain and fatigue (10.9 %), to reduce side effects of iatrogenic menopause (8.8 %) and to improve anxiety and depression (5.9 %), gastrointestinal disorders (5 %), sleep disturbances and neuropathy (3.8 %). Mapping of the centres across Europe is an essential step in the process of creating a European network of centres, experts and professionals constantly engaged in the field of integrative oncology, in order to increase, share and disseminate the knowledge in this field and provide evidence-based practice.


Pyronaridine-artesunate versus chloroquine in patients with acute Plasmodium vivax malaria: a randomized, double-blind, non-inferiority trial.
New antimalarials are needed for P. vivax and P. falciparum malaria. This study compared the efficacy and safety of pyronaridine-artesunate with that of chloroquine for the treatment of uncomplicated P. vivax malaria. This phase III randomized, double-blind, non-inferiority trial included five centers across Cambodia, Thailand, India, and Indonesia. In a double-dummy design, patients (aged >3-≤ 60 years) with microscopically confirmed P. vivax mono-infection were randomized (1:1) to receive pyronaridine-artesunate (target dose 7.2:2.4 mg/kg to 13.8:4.6 mg/kg) or chloroquine (standard dose) once daily for three days. Each treatment group included 228 randomized patients. Outcomes for the primary endpoint, Day-14 cure rate in the per-protocol population, were 99.5%, (217/218; 95%CI 97.5, 100) with pyronaridine-artesunate and 100% (209/209; 95%CI 98.3, 100) with chloroquine. Pyronaridine was non-inferior to chloroquine: treatment difference -0.5% (95%CI -2.6, 1.4), i.e., the lower limit of the 2-sided 95%CI for the treatment difference was greater than -10%. Pyronaridine-artesunate cure rates were non-inferior to chloroquine for Days 21, 28, 35 and 42. Parasite clearance time was shorter with pyronaridine-artesunate (median 23.0 h) versus chloroquine (32.0 h; p<0.0001), as was fever clearance time (median 15.9 h and 23.8 h, respectively; p = 0.0017). Kaplan-Meier estimates of post-baseline P. falciparum infection incidence until Day 42 were 2.5% with pyronaridine-artesunate, 6.1% with chloroquine (p = 0.048, log-rank test). Post-baseline P. vivax or P. falciparum infection incidence until Day 42 was 6.8% and 12.4%, respectively (p = 0.022, log rank test). There were no deaths. Adverse events occurred in 92/228 (40.4%) patients with pyronaridine-artesunate and 72/228 (31.6%) with chloroquine. Mild and transient increases in hepatic enzymes were observed for pyronaridine-artesunate. Pyronaridine-artesunate efficacy in acute uncomplicated P. vivax malaria was at least that of chloroquine. As pyronaridine-artesunate is also efficacious against P. falciparum malaria, this combination has potential utility as a global antimalarial drug. Clinicaltrials.gov NCT00440999.


Obtaining telephone numbers for a rural Medicaid population: issues for outreach and research.
This study examined the accuracy and costs of determining whether rural, low-income Medicaid recipients did or did not have a phone, and of obtaining phone numbers for those who did. For a random sample of 209 families, we compared phone information obtained from phone books and directory assistance with information obtained from department of social services (DSS) records. DSS records identified 51% of the sample as having phones, compared with 19%-25% for phone books and directory assistance. For identifying families as having no home phone or a phone with a number that matched the one in the DSS record, phone books or directory assistance corresponded with DSS records in 52%-57% of the sample. Using phone books or directory assistance was up to 3.2 times more costly than using DSS records. The study highlighted the need to establish policies to promote the exchange of information between social services and public health agencies and researchers.


Glycosphingolipids and kidney disease.
Glycosphingolipids, derived from the addition of sugar-moieties to the sphingolipid ceramide, are highly abundant in the kidney. Glycosphingolipids are known to play an important role in organ function at least in part from inherited lipid storage diseases such as Anderson-Fabry disease (Fabry's disease; FD) that results from a mutation in alpha-galactosidase a (α-GLA or α-Gal A), the enzyme responsible for catalyzing the removal of terminal galactose residues from glycosphingolipids. The inactivation in α-GLA in FD results in the accumulation of glycosphingolipids, including globosides and lactosylceramides, which manifests as several common pathologies including end-stage kidney disease. More recently, glycosphingolipids and other sphingolipids have become increasingly recognized for their roles in a variety of other kidney diseases including polycystic kidney disease, acute kidney injury, glomerulonephritis, diabetic nephropathy and kidney cancer. This chapter reviews evidence supporting a mechanistic role for glycosphingolipids in kidney disease and discusses data implicating a role for these lipids in kidney disease resulting from metabolic syndrome. Importantly, inhibitors of glycosphingolipid synthesis are well tolerated in animal models as well as in humans. Thus, an increased understanding of the mechanisms by which altered renal glycosphingolipid metabolism leads to kidney disease has great therapeutic potential.


Burden of cardiovascular risk factors and disease in five Asian groups in Catalonia: a disaggregated, population-based analysis of 121 000 first-generation Asian immigrants.
To evaluate the burden of cardiovascular risk factors and disease (CVD) among five Asian groups living in Catalonia (Spain): Indian, Pakistani, Bangladeshi, Filipino, and Chinese. Retrospective cohort study using the Catalan Health Surveillance System database including 42 488 Pakistanis, 40 745 Chinese, 21 705 Indians, 9544 Filipinos, and 6907 Bangladeshis; and 5.3 million native individuals ('locals'). We estimated the age-adjusted prevalence (as of 31 December 2019) and incidence (during 2019) of diabetes, hypertension, hyperlipidaemia, obesity, tobacco use, coronary heart disease (CHD), cerebrovascular disease, atrial fibrillation, and heart failure (HF). Bangladeshis had the highest prevalence of diabetes (17.4% men, 22.6% women) followed by Pakistanis. Bangladeshis also had the highest prevalence of hyperlipidaemia (23.6% men, 18.3% women), hypertension among women (24%), and incident tobacco use among men. Pakistani women had the highest prevalence of obesity (28%). For CHD, Bangladeshi men had the highest prevalence (7.3%), followed by Pakistanis (6.3%); and Pakistanis had the highest prevalence among women (3.2%). For HF, the prevalence in Pakistani and Bangladeshi women was more than twice that of locals. Indians had the lowest prevalence of diabetes across South Asians, and of CHD across South Asian men, while the prevalence of CHD among Indian women was twice that of local women (2.6% vs. 1.3%). Filipinos had the highest prevalence of hypertension among men (21.8%). Chinese men and women had the lowest prevalence of risk factors and CVD. In Catalonia, preventive interventions adapted to the risk profile of different Asian immigrant groups are needed, particularly for Bangladeshis and Pakistanis.


Immunoresponse of Coho salmon immunized with a gene expression library from Piscirickettsia salmonis.
We have used the expression library immunization technology to study the protection of Coho salmon Oncorhynchus kisutch to the infection with Piscirickettsia salmonis. Purified DNA from this bacterium was sonicated and the fragments were cloned in the expression vector pCMV-Bios. Two libraries were obtained containing 22,000 and 28,000 colonies and corresponding to approximately 8 and 10 times the genome of the pathogen, respectively. On average, the size of the inserts ranged between 300 and 1,000 bp. The plasmid DNA isolated from one of these libraries was purified and 20 micrograms were injected intramuscularly into 60 fish followed by a second dose of 10 micrograms applied 40 days later. As control, fish were injected with the same amount of DNA of the vector pCMV-Bios without insert. The titer of IgM anti-P. salmonis of vaccinated fish, evaluated 60 days post-injection, was significantly higher than that of the control group injected with the vector alone. Moreover, this response was specific against P. salmonis antigens, since no cross reaction was detected with Renibacterium salmoninarum and Yersinia ruckeri. The vaccinated and control fish were challenged 60 days after the second dose of DNA with 2.5 x 10(7) P. salmonis corresponding to 7.5 times the LD50. At 30 days post-challenge, 100% mortality was obtained with the control fish while 20% of the vaccinated animals survived. All surviving fish exhibited a lower bacterial load in the kidney than control fish. The expression library was also tested in Balb/c mice and it was found that the humoral immune response was specific to P. salmonis and it was dependent on the amount of DNA injected.


Depression among older adults after traumatic brain injury: a national analysis.
Sequelae of traumatic brain injury (TBI) include depression, which could exacerbate the poorer cognitive and functional recovery experienced by older adults. The objective of this study was to estimate incidence rates of depression after hospital discharge for TBI among Medicare beneficiaries aged at least 65 years, quantify the increase in risk of depression after TBI, and evaluate risk factors for incident depression post-TBI. Using a retrospective analysis, the authors studied Medicare beneficiaries at least 65 years old hospitalized for TBI during 2006 to 2010 who survived to hospital discharge and had no documented diagnosis of depression before the study period (N = 67,347). The annualized incidence rate of depression per 1,000 beneficiaries was 62.8 (95% confidence interval [CI]: 61.6, 64.1) pre-TBI and 123.9 (95% CI: 121.6, 126.2) post-TBI. Annualized incidence rates were highest immediately after hospital discharge and declined over the 12 months post-TBI. TBI increased the risk of incident depression in men (hazard ratio: 1.95; 95% CI: 1.84, 2.06; Wald χ(2) = 511.4, df = 1, p <0.001) and in women (hazard ratio: 1.69; 95% CI: 1.62, 1.77; Wald χ(2) = 589.3, df = 1, p <0.001). The strongest predictor of depression post-TBI for both men and women was discharge to a skilled nursing facility (men: odds ratio, 1.91; 95% CI, 1.77, 2.06; Wald χ(2) = 277.1, df = 1, p <0.001; women: odds ratio, 1.72; 95% CI, 1.63, 1.83; Wald χ(2) = 324.2, df = 1, p <0.001). TBI significantly increased the risk of depression among older adults, especially among men and those discharged to a skilled nursing facility. Results from this study will help increase awareness of the risk of depression post-TBI among older adults.


T lymphocyte activation initiates the degradation of the CD62L encoding mRNA and increases the transcription of the corresponding gene.
Following T-cell activation, CD62L, a member of the selectin family of cell adhesion molecules, is proteolytically cleaved by a constitutive endoprotease and subsequently re-expressed. To define whether the cleavage regulates CD62L gene transcription, we have analyzed the outcome of T-cell activation on the level of CD62L gene transcription and mRNA stability. Here, we report that CD62L shedding correlates with the concomitant upregulation of CD62L gene transcription and the rapid degradation of the corresponding mRNA. Novel protein synthesis is not required for CD62L gene upregulation, mRNA degradation or protein shedding. The three events are insensitive to cyclosporin A (CSA) and, thus, do not depend on the calcineurin signaling pathway. Activation of T cells in presence of a metallo-protease inhibitor, that protects CD62L shedding, does not prevent CD62L gene upregulation or mRNA degradation. In contrast induction of CD62L shedding by the chemically-induced dissociation of calmodulin from the CD62L cytosolic tail, in absence of T-cell activation, has no consequences on the levels of CD62L gene transcription or mRNA accumulation. These data demonstrate that the transcriptional and post-transcriptional events are exclusively regulated by T-cell activation and not by the CD62L density on cell membrane.


Blood pressure targets for prevention of cognitive decline in patients with diabetes and hypertension: Design of the Blood Pressure Control Target in Diabetes (BPROAD) Cognitive Study.
Both hypertension and diabetes are risk factors of dementia. Proper management of blood pressure (BP) and blood glucose is critical in delaying cognitive decline in the elderly. However, little is known regarding the optimal BP target in type 2 diabetes (T2DM) for the management of cognitive decline. The Blood Pressure Control Target in Diabetes (BPROAD) study is a nationwide, multicenter, randomized controlled trial that will enroll 12 702 T2DM patients with elevated systolic BP and increased cardiovascular risk from approximately 150 study centers across mainland China to undergo randomly antihypertensive treatment achieving systolic BP <120 mm Hg or systolic BP <140 mm Hg for up to 5 years. All BPROAD participants will take part in the BPROAD Cognitive Study for the assessment of cognitive function at baseline and annual visits by blinded outcome assessors to determine whether intensive BP treatment reduces risk of dementia and mild cognitive impairment (MCI) compared with standard BP treatment in patients with T2DM. In addition, approximately 1000 BPROAD participants will be enrolled in the magnetic resonance imaging (MRI) substudy to receive brain MRI at baseline and at closeout. The primary outcome of BPROAD Cognitive Study is a composite of all-cause dementia and MCI. The BPROAD Cognitive Study will provide crucial clinical trial data on the possible benefit of an intensive systolic BP lowering strategy in reducing dementia and MCI in patients with T2DM.


Assessing nuclear and mitochondrial DNA sequence variation within steinernema (rhabditida: steinernematidae).
DNA sequence analysis was used to characterize the nuclear ribosomal DNA ITS1 region and a portion of the COII and 16S rDNA genes of the mitochondrial genome from Steinernema entomopathogenic nematodes. Nuclear ITS1 nucleotide divergence among seven Steinernema spp. ranged from 6 to 22%, and mtDNA divergence among five species ranged from 12 to 20%. No intraspecific variation was observed among three S. feltiae strains. Phylogenetic analysis of both nuclear and mitochondrial DNA sequences confirms the existing morphological relationships of several Steinernema species. Both the rDNA ITS1 and mtDNA sequences were useful for resolving relationships among Steinernema taxa.


Impact of age and gender matching on long-term graft function and actual graft survival in live-related renal transplantation: Retrospective study from Sindh Institute of Urology and transplantation, Pakistan.
In renal transplantation, donor and allograft age are known to have an important influence on the outcome of the graft, reflecting functional renal mass. We evaluated the impact of gender and age matching in living-donor renal transplantation on long-term graft survival and actual graft function over five years from the day of transplantation. We retrospectively analyzed 500 primary live-related donor renal transplants performed from August 2007 to December 2008 at Sindh Institute of Urology and Transplantation, Karachi, Pakistan. Donors and recipients were divided into two age groups [young (YD) and elderly (ER)] with 40 years as cutoff line. Four donor recipient groups according to age match and age mismatch: YD/YR - ED/ER - YD/ER - ED/YR and four groups according to donor-recipient gender combinations: male recipients of male donors (MR/MD)-female recipients of male donors (FR/MD)-female recipients of female donors (FR/FD)-male recipients of female donors MR/FD) were studied. Serum creatinine was used to assess graft function after transplantation. The Kaplan-Meier method with the log-rank test was used to assess actual graft survival at five years. Actual graft function of four study groups based on age difference had no statistically significant difference at five years (P = 0.094). Regarding the actual graft survival, the best results were seen in young donor to elderly recipient group as compared to all other age combination groups. At five-year post-transplant, MD/MR had significantly better graft function than MR/FD and FR/MD had significantly better graft function than FD/FR and FD/MR. The actual graft survival was best in male-to-male (86%) compared to the lowest in female-to-female transplants (75%). The graft function at five years was better in elderly recipients of young donor kidneys. The actual graft survival was influenced positively by young donor age and negatively influenced by pre-transplant hepatitis C positivity of recipients.


Ran-binding protein 3 links Crm1 to the Ran guanine nucleotide exchange factor.
Ran-binding protein 3 (RanBP3) is an approximately 55-kDa protein that functions as a cofactor for Crm1-mediated nuclear export. RanBP3 stimulates export by enhancing the affinity of Crm1 for Ran.GTP and cargo. However, important additional functions for this cofactor may exist. We now report that RanBP3 associates with the Ran-specific guanine nucleotide exchange factor, regulator of chromosome condensation 1 (RCC1). This interaction was stimulated by the addition of Ran; moreover, Ran.GDP, Ran.GTP, and Ran without nucleotide could all stimulate complex formation between RanBP3 and RCC1 even though binding of Ran.GDP to RanBP3 alone was undetectable. RanBP3 could also promote binding of Crm1 to RCC1 in the presence of Ran. Binding of RanBP3 to RCC1 increased the catalytic activity of RCC1 toward Ran, and importantly, the ability of RanBP3 to stimulate RCC1 was not affected by the presence of Crm1. These data indicate that RanBP3 acts as a scaffold protein to promote the efficient assembly of export complexes. By tethering Crm1 to catalytically enhanced RCC1, RanBP3 may lower the entropic barrier for the loading of Ran.GTP onto Crm1. We propose that this provides an additional mechanism by which RanBP3 facilitates export.


Plasmacytoid dendritic cells in autoimmune diabetes - potential tools for immunotherapy.
Type 1 diabetes (T1D) is an autoimmune disease in which a T-cell-mediated attack destroys the insulin-producing cells of the pancreatic islets. Despite insulin supplementation severe complications ask for novel treatments that aim at cure or delay of the onset of the disease. In spontaneous animal models for diabetes like the nonobese diabetic (NOD) mouse, distinct steps in the pathogenesis of the disease can be distinguished. In the past 10 years it became evident that DC and macrophages play an important role in all three phases of the pathogenesis of T1D. In phase 1, dendritic cells (DC) and macrophages accumulate at the islet edges. In phase 2, DC and macrophages are involved in the activation of autoreactive T cells that accumulate in the pancreas. In the third phase the islets are invaded by macrophages, DC and NK cells followed by the destruction of the beta-cells. Recent data suggest a role for a new member of the DC family: the plasmacytoid DC (pDC). pDC have been found to induce tolerance in experimental models of asthma. Several studies in humans and the NOD mouse support a similar role for pDC in diabetes. Mechanisms found to be involved in tolerance induction by pDC are inhibition of effector T cells, induction of regulatory T cells, production of cytokines and indoleamine 2,3-dioxygenase (IDO). The exact mechanism of tolerance induction by pDC in diabetes remains to be established but the intrinsic tolerogenic properties of pDC provide a promising, yet underestimated target for therapeutic intervention.


Effect of brimonidine on retinal and choroidal neovascularization in a mouse model of retinopathy of prematurity and laser-treated rats.
To determine whether chronic treatment with brimonidine (BRI) attenuates retinal vascular leakage and neovascularization in neonatal mice after exposure to high oxygen in a mouse model of retinopathy of prematurity (ROP), and choroidal neovascularization (CNV) in rats after laser treatment. Experimental CNV was induced by laser treatment in Brown Norway (BN) rats. BRI or vehicle (VEH) was administered by osmotic minipumps, and CNV formation was measured 11 days after laser treatment. Oxygen-induced retinopathy was generated in neonatal mice by exposure to 75% oxygen from postnatal day (P)7 to P12. BRI or VEH was administered by gavage, and vitreoretinal vascular endothelial growth factor (VEGF) concentrations and retinal vascular leakage, neovascularization, and vaso-obliteration were measured on P17. Experimental CNV was induced in rabbits by subretinal lipopolysaccharide/fibroblast growth factor-2 injection. Systemic BRI treatment significantly attenuated laser-induced CNV formation in BN rats when initiated 3 days before or within 1 hour after laser treatment. BRI treatment initiated during exposure to high oxygen significantly attenuated vitreoretinal VEGF concentrations, retinal vascular leakage, and retinal neovascularization in P17 mice subjected to oxygen-induced retinopathy. Intravitreal treatment with BRI had no effect on CNV formation in a rabbit model of nonischemic angiogenesis. BRI treatment significantly attenuated vitreoretinal VEGF concentrations, retinal vascular leakage, and retinal and choroidal neovascularization in animal models of ROP and CNV. BRI may inhibit underlying event(s) of ischemia responsible for upregulation of vitreoretinal VEGF and thus reduce vascular leakage and retinal-choroidal neovascularization.


The uses and properties of almond oil.
Almond oil [Oleum amygdalae] has long been used in complementary medicine circles for its numerous health benefits. Although no conclusive scientific data exists currently, almonds and almond oil have many properties including anti-inflammatory, immunity-boosting and anti-hepatotoxicity effects. Further, associations between almond oil and improved bowel transit have been made, which consequently reduces irritable bowel syndrome symptoms. Further, some studies show a reduced incidence of colonic cancer. Moreover, cardiovascular benefits have also been identified with almond oil elevating the levels of so-called 'good cholesterol', high-density lipoproteins (HDL), whilst it reduces low-density lipoproteins (LDL). Historically, almond oil had been used in Ancient Chinese, Ayurvedic and Greco-Persian schools of Medicine to treat dry skin conditions such as psoriasis and eczema. Further, it is through anecdotal evidence and clinical experiences that almond oil seemingly reduces hypertrophic scarring post-operatively, smoothes and rejuvenates skin. Almond oil has emollient and sclerosant properties and, therefore, has been used to improve complexion and skin tone. Further studies looking into the use of almond oil post-operatively for the reduction of scarring are suggested.


Adverse events, toxicity and post-mortem data on duloxetine: case reports and literature survey.
Duloxetine, a dual acting norepinephrine serotonin reuptake inhibitor, is a relatively new pharmacologic agent utilized in the treatment of depression, as well as diabetic neuropathic pain, fibromyalgia, and female stress urinary incontinence. This expanding scope of usage will inevitably lead to its eventual appearance during routine post-mortem toxicologic assays. Currently there is a paucity of post-mortem toxicologic data concerning duloxetine. The current report provides six additional case reports of post-mortem duloxetine levels, along with a review of duloxetine's pharmacokinetics, and the toxicologic manifestations which have been reported in the literature. The post-mortem levels reported, including the highest level recorded to date, are integrated with previously published reports to generate a foundation for a nascent guide to the interpretation of post-mortem duloxetine levels that could be encountered during routine post-mortem toxicologic analyses, and establish a basis upon which the establishment of toxic and lethal thresholds for this compound can be further elucidated with greater clarity.


Prognostic microRNAs in upper tract urothelial carcinoma: multicenter and international validation study.
To validate previously discovered miRNAs (miR-31-5p and miR-149-5p) as prognostic factors for UTUC in an independent cohort of UTUC patients. Multicenter, international and retrospective study of formalin-fixed paraffin-embedded tissue samples from 103 UTUC patients (45 progressing and 58 non-progressing) who underwent radical nephroureterectomy. Total RNA was isolated and reverse transcribed. The expression of target miRNAs (miR-31-5p and miR-149-5p) and the endogenous control miR-218-5p was evaluated in all samples by reverse transcription quantitative PCR. Normalized miRNA expression values were evaluated by multivariate forward stepwise Cox regression analysis. Kaplan Meier curves were used to discriminate between two groups of patients with a different probability of tumour progression. The mean age (range) of the series was 67 (33-94) years. Overall, 45 patients (43.7%) developed tumour progression and 32 patients (31.2%) died, 20 of these (62.5%) due to their UTUC, after a median follow-up of 36 months. The mean time for tumour progression and cancer-specific survival were 15 and 20 months, respectively. Five year tumour progression free survival and cancer-specific survival were 58% for ≤ pT2, 36% for pT3 and 0% for pT4 and 67.8% for ≤ pT2, 50.6% for pT3 and 0% for pT4, respectively. In the multivariate analysis, expression of miR-31-5p was found to be an independent prognostic factor of tumour progression (HR 1.1; 95% CI 1.039-1.273; p=0.02). Kaplan Meier curve shows that miR-31-5p expression values are able to discriminate between two groups of UTUC patients with a different probability of tumour progression (p=0.007). We have been able to validate our previous results in an independent multicentre international cohort of UTUC patients, suggesting that miRNA-31-5p could be a useful prognostic marker of UTUC progression. The application of miRNA expression values to clinical practice could refine the currently used clinicopathological-based approach for predicting UTUC patients' outcome.


On the Temperature Dependence of the Piezoelectric Response of Prepoled Poly(vinylidene fluoride) Films.
There is growing interest in integrating piezoelectric materials with complementary metal-oxide-semiconductor (CMOS) technology to enable expanded applications. A promising material for ultrasound transducer applications is polyvinylidene fluoride (PVDF), a piezoelectric polymer. One of the challenges with PVDF is that its piezoelectric properties can deteriorate when exposed to temperatures in excess of 70 °C for extended periods of time during fabrication. Here, we report on the effects of both shortening annealing times and providing this heating non-uniformly, as is characteristic of some processing conditions, on the piezoelectric coefficient (d 33) of PVDF films for various thicknesses. In this case, no degradation in the d 33 was observed at temperatures below 100 °C for anneal times of under one minute when this heating is applied through one side of the film, making PVDF compatible with many bonding and photolithographic processing steps required for CMOS integration. More surprisingly, for one-sided heating to temperatures between 90 °C and 110 °C, we observed a transient enhancement of the d 33 by nearly 40% that lasted for several hours after these anneals. We attribute this effect to induced strain in these films.


Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.
Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10-6, 1.7 × 10-9, 3.5 × 10-12 and 1.0 × 10-4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.


Iodine Concentration in Spectral CT: Assessment of Prognostic Determinants in Patients With Gastric Adenocarcinoma.
The purpose of this study was to use virtual monochromatic spectral CT to investigate the usefulness of iodine concentration (IC) and its correlation with clinicopathologically determined prognostic factors in gastric adenocarcinoma. From June 2012 to March 2015, 34 patients with gastric adenocarcinoma underwent arterial and portal venous phase spectral CT. The ICs in the arterial and portal venous phases were calculated and then normalized with the aorta as normalized IC (NIC). The surgical specimen was evaluated with CD34 staining to determine microvessel density (MVD). The correlation between imaging results and clinicopathologic findings was investigated for histologic grading, lymph node metastasis, serosal involvement, distant metastasis, pathologic TNM stage, and MVD. The mean arterial phase NIC value of tumors was 0.12 ± 0.03, portal venous phase NIC value was 0.39 ± 0.06, and MVD was 26.94 ± 7.87 vessels per high-power field (×400). Both arterial phase and portal venous phase NIC values were significantly higher in poorly differentiated gastric adenocarcinomas (p = 0.005) than in moderately differentiated tumors (p = 0.013). There was no significant correlation between NIC and serosal involvement or distant metastasis. There was significant correlation between the NIC and MVD in gastric adenocarcinoma (arterial phase NIC, p = 0.013; portal venous phase NIC, p = 0.001). However, neither the arterial nor the portal venous phase NIC of gastric adenocarcinoma had a significant relation to lymphatic metastasis or pathologic TNM stage. There was a significant difference between the high and low MVD groups with respect to portal venous phase NIC (p = 0.045). NIC can serve as a useful predictor of angiogenesis and degree of differentiation of moderately and poorly differentiated gastric adenocarcinomas.


Bertolotti's syndrome in low-backache population: Classification and imaging findings.
Lumbosacral transition vertebrae (LSTVs) are associated with alterations in biomechanics and anatomy of spinal and paraspinal structures, which have important implications on surgical approaches and techniques. LSTVs are often inaccurately detected and classified on standard anteroposterior radiographs and magnetic resonance imaging. The use of whole-spine images as well as geometric relationships between the sacrum and lumbar vertebra increases accuracy. The diagnosis of symptomatic LSTV is considered with appropriate patient history and imaging studies. This study aimed to classify the anatomical variations in LSTV and determine, by plain radiography, if there exists a relationship between sacralization and low backache (LBP). Five hundred lumbosacral radiographs of LBP patients were examined after obtaining prior consent from the patient and approval from the "institutional ethics committee." Data collection consisted of the patient's age at the time of imaging gender and number of lumbar vertebral bodies. Dysplastic transverse processes were classified according to the Castellvi radiographic classification system. The incidence of sacralization in patients and the control groups was reported, and the anomaly was compared according to the groups. Of these patient groups, 134 were classified as positive for sacralization, which resulted in an incidence of 26.8%. The most common anatomical variant was Castellvi Type IA (7.6%). There were no statistically significant differences between men and women who had anomaly (P = 0.9256). Higher incidences of Type IB and Type IIB were found in men, but those results were not statistically significant (P = 0.133 and P = 0.581, respectively) when compared with the female group. Daily frequency and intensity of LBP were assessed in patients using visual analog scale (VAS) scores. The patients with LBP and no malformation reported an average pain level on the VAS for pain of 2.2 versus 5.2 in patients with LBP and a transitional vertebra, respectively. Based on our data, we conclude that lumbosacral transitional segments are a common cause in the low-backache population. However, no relationship was found between age and genders in this study. However, in comparison with the nonspecific low-backache group, the VAS scores were significantly higher and the pain duration was significantly longer in the LSTV group.


Multinational evidence of the applicability and robustness of discrete choice modeling for deriving EQ-5D-5L health-state values.
To investigate the feasibility of discrete choice experiments for valuing EQ-5D-5L states using computer-based data collection, the consistency of the estimated regression coefficients produced after modeling the preference data, and to examine the similarity of the values derived across countries. Data were collected in Canada, England, The Netherlands, and the United States (US). Interactive software was developed to standardize the format of the choice tasks across countries, except for face-to-face interviewing in England. The choice task required respondents to choose between 2 suboptimal health states. A Bayesian design was used to generate 200 pairs of states that were randomly grouped into 20 blocks. Each respondent completed 1 block of 10 pairs. A main-effects probit model was used to estimate regression coefficients and to derive values. Approximately 400 respondents participated from each country. The mean time to perform 1 choice task was between 29.2 (US) and 45.2 (England) seconds. All regression coefficients were statistically significant, except level 2 for Usual Activities in The Netherlands (P=0.51). Predictions for the complete set of 3125 EQ-5D-5L health states were similar for the 4 countries. Intraclass correlation coefficients between the countries were high: from 0.80 (England vs. US) through 0.98 (Canada vs. Derivation of value sets from the general population using computer-based choice tasks for the EQ-5D-5L is feasible. Parameter estimates were generally consistent and logical, and health-state values were similar across the 4 countries.


Literacy after cerebral hemispherectomy: Can the isolated right hemisphere read?
Cerebral hemispherectomy, a surgical procedure undergone to control intractable seizures, is becoming a standard procedure with more cases identified and treated early in life [33]. While the effect of the dominant hemisphere resection on spoken language has been extensively researched, little is known about reading abilities in individuals after left-sided resection. Left-lateralized phonological abilities are the key components of reading, i.e., grapheme-phoneme conversion skills [1]. These skills are critical for the acquisition of word-specific orthographic knowledge and have been shown to predict reading levels in average readers as well as in readers with mild cognitive disability [26]. Furthermore, impaired phonological processing has been implicated as the cognitive basis in struggling readers. Here, we explored the reading skills in participants who have undergone left cerebral hemispherectomy. Seven individuals who have undergone left cerebral hemispherectomy to control intractable seizures associated with perinatal infarct have been recruited for this study. We examined if components of phonological processing that are shown to reliably separate average readers from struggling readers, i.e., phonological awareness, verbal memory, speed of retrieval, and size of vocabulary, show the same relationship to reading levels when they are mediated by the right hemisphere [2]. We found that about 60% of our group developed both word reading and paragraph reading in the average range. Phonological processing measured by both phonological awareness and nonword reading was unexpectedly spared in the majority of participants. Phonological awareness levels strongly correlated with word reading. Verbal memory, a component of phonological processing skills, together with receptive vocabulary size, positively correlated with reading levels similar to those reported in average readers. Receptive vocabulary, a bilateral function, was preserved to a certain degree similar to that of strongly left-lateralized phonological skills [3]. Later seizure onset was associated with better reading levels. When cerebral hemispherectomy is performed to control seizures associated with very early (in utero) insult, it has been found that the remaining right hemisphere is still able to support reading and phonological processing skills that are normally mediated by the left hemisphere. Our results also suggest the existence of variability in individuals after hemispherectomy, even within groups having the same etiology and similar timing of insult.


Preferential loss of IL-2-secreting CD4+ T helper cells in chronic HCV infection.
Hepatitis C virus (HCV) becomes persistent in the majority of infected individuals. In doing so, the virus evades host adaptive immune responses, although the mechanisms responsible in this evasion are not clear. Several groups have demonstrated weak or absent HCV-specific CD4+ T cell responses during chronic HCV infection using proliferation assays and, more recently, class II tetramers. However, the functional status of HCV-specific CD4+ T cells in resolved and persistent infection is poorly understood. Using interferon gamma (IFN-gamma) and interleukin 2 (IL-2) enzyme-linked immunospot assays, we analyzed cytokine secretion patterns in chronically infected patients and compared them with those with resolved infection. In the spontaneous resolver group, strong IL-2 secretion in relation to IFN-gamma secretion was observed. However, in the persistently infected group, a consistent and significant loss of IL-2-secreting cells, compared with IFN-gamma-secreting cells, was identified. In vitro addition of IL-2 had a substantial effect in restoring CD4+ T cell activity. In conclusion, failure of IL-2 secretion, as opposed to physical deletion or complete functional unresponsiveness, appears to be an important determinant of the status of CD4+ T cell populations in chronic HCV infection. Loss of IL-2 secretory capacity may lead to disruption of IFN-gamma and proliferative function in vivo-a status that characterizes the cellular immune response in both CD4+ and CD8+ compartments in chronic disease.


Near-Field Enhanced Photochemistry of Single Molecules in a Scanning Tunneling Microscope Junction.
Optical near-field excitation of metallic nanostructures can be used to enhance photochemical reactions. The enhancement under visible light illumination is of particular interest because it can facilitate the use of sunlight to promote photocatalytic chemical and energy conversion. However, few studies have yet addressed optical near-field induced chemistry, in particular at the single-molecule level. In this Letter, we report the near-field enhanced tautomerization of porphycene on a Cu(111) surface in a scanning tunneling microscope (STM) junction. The light-induced tautomerization is mediated by photogenerated carriers in the Cu substrate. It is revealed that the reaction cross section is significantly enhanced in the presence of a Au tip compared to the far-field induced process. The strong enhancement occurs in the red and near-infrared spectral range for Au tips, whereas a W tip shows a much weaker enhancement, suggesting that excitation of the localized plasmon resonance contributes to the process. Additionally, using the precise tip-surface distance control of the STM, the near-field enhanced tautomerization is examined in and out of the tunneling regime. Our results suggest that the enhancement is attributed to the increased carrier generation rate via decay of the excited near-field in the STM junction. Additionally, optically excited tunneling electrons also contribute to the process in the tunneling regime.


Flavone acetic acid (FAA) with recombinant interleukin-2 (rIL-2) in advanced malignant melanoma. III: Cytokine studies.
Twelve patients undergoing IL-2 and flavone acetic acid (FAA) combination immunotherapy for advanced melanoma were studied throughout treatment for the induction of measurable levels of bioactive TNF, GM-CSF and IL-6 in their serum. This was to assess the extent of secondary cytokine induction in these patients and the possible role of such cytokines in both the toxic and therapeutic responses. The nature of the treatment schedule enabled these cytokines to be measured in response to FAA alone, FAA/IL-2 and FAA alone following IL-2/FAA activation of target cells. A small rise in the serum levels of these cytokines was seen on the initial course of FAA/IL-2 but this was minor compared to the marked elevation in levels 2-8 h following the initiation of the third course of FAA given with or without IL-2 and at a time point which coincided with maximum toxicity in those patients who experienced it. These results show that FAA alone can induce cytokine release from primed target cells. This may be associated with the therapeutic effect and/or toxicity of the agent.


Thoracic computed tomography, angiographic computed tomography, and pathology findings in six cats experimentally infected with Aelurostrongylus abstrusus.
Aelurostrongylus abstrusus infection is common in endemic areas and may cause severe respiratory clinical signs. Computed tomography (CT) is an important tool to diagnose pulmonary disease, because it allows detection of small lesions and discrimination of superimposed structures. The purpose of this study was to characterize by CT and angiographic CT the pulmonary lesions in six cats before, and 48 and 81 days after inoculation with 100 or 800 A. abstrusus infective larvae. Histological examination of the accessory lung lobe was performed to determine the microscopic, pathomorphologic correlate of the CT findings. The predominant CT lesion consisted of multiple nodules of varying size distributed throughout the lungs, severity depending on infectious dose. The histological correlate of the nodular lesions was multifocal dense granulomatous to mixed inflammatory cell infiltrates, including eosinophils distributed in the parenchyma and obliterating the alveoli. Marked, multifocal, dose-dependent thickening of the bronchi and adjacent interstitial changes blurred the margins of the outer serosal surface of the bronchi and vessels. Histologically, this was due to peribronchial mixed cell inflammation. During the course of infection some of the nodular and peribronchial changes were replaced by areas of ground-glass opacity. In addition to providing detailed depiction of pulmonary lesions resulting from an infectious cause and clearly defining lesions with respect to time and severity of infection, CT allowed quantitative assessment of bronchial thickness and lymph node size during the course of disease. Findings indicated that CT characteristics of this disease are consistent with pathologic findings.


Universal properties of dark matter halos.
We discuss the universal relation between density and size of observed dark matter halos that was recently shown to hold on a wide range of scales, from dwarf galaxies to galaxy clusters. Predictions of cold dark matter (ΛCDM) N-body simulations are consistent with this relation. We demonstrate that this property of ΛCDM can be understood analytically in the secondary infall model. Qualitative understanding given by this model provides a new way to predict which deviations from ΛCDM or large-scale modifications of gravity can affect universal behavior and, therefore, to constrain them observationally.


Highly sensitive real-time in vivo imaging of an influenza reporter virus reveals dynamics of replication and spread.
The continual public health threat posed by the emergence of novel influenza viruses necessitates the ability to rapidly monitor infection and spread in experimental systems. To analyze real-time infection dynamics, we have created a replication-competent influenza reporter virus suitable for in vivo imaging. The reporter virus encodes the small and bright NanoLuc luciferase whose activity serves as an extremely sensitive readout of viral infection. This virus stably maintains the reporter construct and replicates in culture and in mice with near-native properties. Bioluminescent imaging of the reporter virus permits serial observations of viral load and dissemination in infected animals, even following clearance of a sublethal challenge. We further show that the reporter virus recapitulates known restrictions due to host range and antiviral treatment, suggesting that this technology can be applied to studying emerging influenza viruses and the impact of antiviral interventions on infections in vivo. These results describe a generalizable method to quickly determine the replication and pathogenicity potential of diverse influenza strains in animals.


Patterns of Trypanosoma vivax and T. congolense infection differ in young N'Dama cattle and their dams.
Trypanosome infection was detected by the dark ground/phase contrast buffy coat microscopic technique in N'Dama cattle in a high natural tsetse challenge situation in Zaire. The data were used to compare the pattern of infection in very young animals and in their dams, and to evaluate how the pattern evolved in calves from birth to maturity, and thereafter in the different age groups represented by their dams. Five hundred and fourteen calves were evaluated at 3 week intervals for an average of 26 months each, over varying periods between birth and 42 months of age. Two hundred and sixty nine dams had matching records from parturition to calf weaning at 10 months. One month after weaning, animals were equally infected with Trypanosoma vivax and Trypanosoma congolense. From then until 42 months, the proportion of time an animal was infected with T. vivax relative to T. congolense gradually decreased. In the dams this trend continued from 4 years to at least 8 years of age by which time T. vivax infection was only one-third that of T. congolense infection. This finding is regarded as strong evidence of the ability of N'Dama cattle, in this region of Africa, to acquire significant control of the development of parasitaemia following T. vivax infection but apparently not following T. congolense infection. Pre-weaner calves, grazing with their dams, appeared to have considerable protection from, or be more resistant to, both T. vivax and T. congolense infections compared with their dams and to their own immediate post-weaning situations.(ABSTRACT TRUNCATED AT 250 WORDS)


Alcohol consumption and self-reported (SF12) physical and mental health among working-aged men in a typical Russian city: a cross-sectional study.
To investigate the association between patterns of alcohol consumption and self-reported physical and mental health in a population with a high prevalence of hazardous drinking. Cross-sectional study of an age-stratified random sample of a population register. SETTING : The city of Izhevsk, The Russian Federation, 2008-09. A total of 1031 men aged 25-60 years (68% response rate). MEASUREMENTS : Self-reported health was evaluated with the SF12 physical (PCS) and mental (MCS) component summaries. Measures of hazardous drinking (based on frequency of adverse effects of alcohol intake including hangover, excessive drunkenness and extended episodes of intoxication lasting 2 or more days) were used in addition to frequency of alcohol consumption and total volume of beverage ethanol per year. Information on smoking and socio-demographic factors were obtained. FINDINGS : Compared with abstainers, those drinking 10-19 litres of beverage ethanol per year had a PCS score 2.66 [95% confidence interval (CI) = 0.76; 4.56] higher. Hazardous beverage drinking was associated with a lower PCS score [mean diff: -2.95 (95% CI = -5.28; -0.62)] and even more strongly with a lower MCS score [mean diff: -4.29 (95% CI = -6.87; -1.70)] compared to non-hazardous drinkers, with frequent non-beverage alcohol drinking being associated with a particularly low MCS score [-7.23 (95% CI = -11.16; -3.29)]. Adjustment for smoking and socio-demographic factors attenuated these associations slightly, but the same patterns persisted. Adjustment for employment status attenuated the associations with PCS considerably. CONCLUSION : Among working-aged male adults in Russia, hazardous patterns of alcohol drinking are associated with poorer self-reported physical health, and even more strongly with poorer self-reported mental health. Physical health appears to be lower in those reporting complete abstinence from alcohol compared with those drinking 10-19 litres per year.


Differential display of eukaryotic messenger RNA by means of the polymerase chain reaction.
Effective methods are needed to identify and isolate those genes that are differentially expressed in various cells or under altered conditions. This report describes a method to separate and clone individual messenger RNAs (mRNAs) by means of the polymerase chain reaction. The key element is to use a set of oligonucleotide primers, one being anchored to the polyadenylate tail of a subset of mRNAs, the other being short and arbitrary in sequence so that it anneals at different positions relative to the first primer. The mRNA subpopulations defined by these primer pairs were amplified after reverse transcription and resolved on a DNA sequencing gel. When multiple primer sets were used, reproducible patterns of amplified complementary DNA fragments were obtained that showed strong dependence on sequence specificity of either primer.


Synthetic sex pheromone in a long-lasting lure attracts the visceral leishmaniasis vector, Lutzomyia longipalpis, for up to 12 weeks in Brazil.
Current control methodologies have not prevented the spread of visceral leishmaniasis (VL) across Brazil. Here, we describe the development of a new tool for controlling the sand fly vector of the disease: a long-lasting lure, which releases a synthetic male sex pheromone, attractive to both sexes of Lutzomyia longipalpis. This device could be used to improve the effectiveness of residual insecticide spraying as a means of sand fly control, attracting L. longipalpis to insecticide-treated animal houses, where they could be killed in potentially large numbers over a number of weeks. Different lure designs releasing the synthetic pheromone (±)-9-methylgermacrene-B (CAS 183158-38-5) were field-tested in Araçatuba, São Paulo (SP). Experiments compared numbers of sand flies caught overnight in experimental chicken sheds with pheromone lures, to numbers caught in control sheds without pheromone. Prototype lures, designed to last one night, were first used to confirm the attractiveness of the pheromone in SP, and shown to attract significantly more flies to test sheds than controls. Longer-lasting lures were tested when new, and at fortnightly intervals. Lures loaded with 1 mg of pheromone did not attract sand flies for more than two weeks. However, lures loaded with 10 mg of pheromone, with a releasing surface of 15 cm2 or 7.5 cm2, attracted female L. longipalpis for up to ten weeks, and males for up to twelve weeks. Approximately five times more sand flies were caught with 7.5 cm2 10 mg lures when first used than occurred naturally in non-experimental chicken resting sites. These results demonstrate that these lures are suitably long-lasting and attractive for use in sand fly control programmes in SP. To our knowledge, this is the first sex pheromone-based technology targeting an insect vector of a neglected human disease. Further studies should explore the general applicability of this approach for combating other insect-borne diseases.


Identification of a transactivation activity in the COOH-terminal region of p73 which is impaired in the naturally occurring mutants found in human neuroblastomas.
p73 is a recently cloned tumor suppressor gene that is highly homologous to p53, and the products of both possess similar functions in inhibiting cell growth and inducing apoptosis. Interestingly, the COOH-terminal region of p53 displays no significant homology with that of p73. Moreover, p73 has an additional segment at its COOH terminus. Recently, we have found two mutations of p73 with amino acid substitution (P405R and P425L) in primary neuroblastomas. Because the region (amino acid residues 382-491) contains a glutamine- and proline-rich domain, we hypothesized that it has a transactivation function, and the mutations found in tumors result in loss of function. To test it, we used the yeast GAL4 DNA-binding fusion system. Yeast transformants expressing a GAL4-p73(1-112) or a GAL4-p73alpha(380-513) fusion protein were grown in SD medium lacking histidine and tryptophan and exhibited a significant induction of beta-galactosidase activity. Transient transfection experiments revealed that both of fusion proteins could induce the chloramphenicol acetyltransferase activity in mammalian cells, indicating that the COOH-terminal as well as NH2-terminal regions of p73 had significantly high levels of transactivation activity. Furthermore, the former activity was severely impaired in two naturally occurring mutant forms found in neuroblastomas. These suggest that, unlike p53, p73 has two domains with transactivation function, one in the NH2-terminal region and the other in the COOH-terminal region. Loss of function mutation in the latter might be involved in tumorigenesis and/or tumor progression.


The Magnaporthe oryzae avirulence gene AvrPiz-t encodes a predicted secreted protein that triggers the immunity in rice mediated by the blast resistance gene Piz-t.
The Magnaporthe oryzae avirulence gene AvrPiz-t activates immunity in a gene-for-gene fashion to rice mediated by the blast resistance gene Piz-t. To dissect the molecular mechanism underlying their recognition, we initiated the cloning of AvrPiz-t using a map-based cloning strategy. The AvrPiz-t gene was delimited to an approximately 21-kb genomic fragment, in which six genes were predicted. Complementation tests of each of these six candidate genes led to the final identification of AvrPiz-t, which encodes a 108-amino-acid predicted secreted protein with unknown function and no homologues in M. oryzae or in other sequenced fungi. We found that AvrPiz-t is present in the virulent isolate GUY11 but contains a Pot3 insertion at a position 462 bp upstream from the start codon. Complementation tests of AvrPiz-t genes driven by promoters of varying length revealed that a promoter larger than 462 bp is essential to maintain the AvrPiz-t function. These results suggest that a Pot3 insertion in GUY11 might interfere with the proper function of AvrPiz-t. Additionally, we found that AvrPiz-t can suppress the programmed cell death triggered by mouse BAX protein in Nicotiana benthamiana, identifying a mechanism by which AvrPiz-t may contribute virulence of M. oryzae.


Nectar secretion requires sucrose phosphate synthases and the sugar transporter SWEET9.
Angiosperms developed floral nectaries that reward pollinating insects. Although nectar function and composition have been characterized, the mechanism of nectar secretion has remained unclear. Here we identify SWEET9 as a nectary-specific sugar transporter in three eudicot species: Arabidopsis thaliana, Brassica rapa (extrastaminal nectaries) and Nicotiana attenuata (gynoecial nectaries). We show that SWEET9 is essential for nectar production and can function as an efflux transporter. We also show that sucrose phosphate synthase genes, encoding key enzymes for sucrose biosynthesis, are highly expressed in nectaries and that their expression is also essential for nectar secretion. Together these data are consistent with a model in which sucrose is synthesized in the nectary parenchyma and subsequently secreted into the extracellular space via SWEET9, where sucrose is hydrolysed by an apoplasmic invertase to produce a mixture of sucrose, glucose and fructose. The recruitment of SWEET9 for sucrose export may have been a key innovation, and could have coincided with the evolution of core eudicots and contributed to the evolution of nectar secretion to reward pollinators.


Divine intuition: cognitive style influences belief in God.
Some have argued that belief in God is intuitive, a natural (by-)product of the human mind given its cognitive structure and social context. If this is true, the extent to which one believes in God may be influenced by one's more general tendency to rely on intuition versus reflection. Three studies support this hypothesis, linking intuitive cognitive style to belief in God. Study 1 showed that individual differences in cognitive style predict belief in God. Participants completed the Cognitive Reflection Test (CRT; Frederick, 2005), which employs math problems that, although easily solvable, have intuitively compelling incorrect answers. Participants who gave more intuitive answers on the CRT reported stronger belief in God. This effect was not mediated by education level, income, political orientation, or other demographic variables. Study 2 showed that the correlation between CRT scores and belief in God also holds when cognitive ability (IQ) and aspects of personality were controlled. Moreover, both studies demonstrated that intuitive CRT responses predicted the degree to which individuals reported having strengthened their belief in God since childhood, but not their familial religiosity during childhood, suggesting a causal relationship between cognitive style and change in belief over time. Study 3 revealed such a causal relationship over the short term: Experimentally inducing a mindset that favors intuition over reflection increases self-reported belief in God.


NUTRITIONAL SUPPORT FOR FULMINANT HEPATITIS.
fulminant hepatitis (FH) is associated with exacerbated hypercatabolism, hypoglycemia and hyperammonemia that are accompanied by the release of proinflammatory cytokines and catabolic hormones into the systemic circulation worsening patient's clinical condition. Nutritional support is a crucial element for the recovery of these patients. the aim of this review is to update Nutritional Support for Fulminant Hepatitis. the review was performed using electronic search on Medline-PubMed using Mesh-terms. there are not many data available on nutritional support to fulminant hepatitis or acute liver failure. Strategies for initial nutritional intervention are focused on the control of the previously described FH metabolic derangements, and should be individualized according to the severity of patient's clinical condition. Energy and protein can be provided in amounts of 25‑40 kcal/kg/day and 0.8-1.2 g/kg/day, respectively. Enteral nutrition therapy is indicated for patients with advancing encephalopathy or for those who cannot be properly fed orally. Euglycemia must be achieved and protein intake can be based on BCAA formulae. Lipids can be administered as energy supplementation with caution. Adequate nutrition therapy can potentially reduce morbidity and mortality of FH patients.


Disease-modifying effects of an SCAF4 structural variant in a predominantly SOD1 ALS cohort.
To test the hypothesis that rs573116164 will have disease-modifying effects in patients with superoxide dismutase 1 (SOD1) familial amyotrophic lateral sclerosis (fALS), we characterized rs573116164 within a cohort of 190 patients with fALS and 560 healthy age-matched controls to assess the variant for association with various measures of disease. Using a previously described bioinformatics evaluation algorithm, a polymorphic short structural variant associated with SOD1 was identified according to its theoretical effect on gene expression. An 12-18 poly-T repeat (rs573116164) within the 3' untranslated region of serine and arginine rich proteins-related carboxy terminal domain associated factor 4 (SCAF4), a gene that is adjacent to SOD1, was assessed for disease association and influence on survival and age at onset in an fALS cohort using PCR, Sanger sequencing, and capillary separation techniques for allele detection. In a North American cohort of predominantly SOD1 fALS patients (n =190) and age-matched healthy controls (n = 560), we showed that carriage of an 18T SCAF4 allele was associated with disease within this cohort (odds ratio [OR] 6.6; 95% confidence interval [CI] 3.9-11.2; p = 4.0e-11), but also within non-SOD1 cases (n = 27; OR 5.3; 95% CI 1.9-14.5; p = 0.0014). This finding suggests genetically SOD1-independent effects of SCAF4 on fALS susceptibility. Furthermore, carriage of an 18T allele was associated with a 26-month reduction in survival time (95% CI 6.6-40.8; p = 0.014), but did not affect age at onset of disease. The findings in this fALS cohort suggest that rs573116164 could have SOD1-independent and broader relevance in ALS, warranting further investigation in other fALS and sporadic ALS cohorts, as well as studies of functional effects of the 18T variant on gene expression.