Are introduced species better dispersers than native species? A global comparative study of seed dispersal distance.
We provide the first global test of the idea that introduced species have greater seed dispersal distances than do native species, using data for 51 introduced and 360 native species from the global literature. Counter to our expectations, there was no significant difference in mean or maximum dispersal distance between introduced and native species. Next, we asked whether differences in dispersal distance might have been obscured by differences in seed mass, plant height and dispersal syndrome, all traits that affect dispersal distance and which can differ between native and introduced species. When we included all three variables in the model, there was no clear difference in dispersal distance between introduced and native species. These results remained consistent when we performed analyses including a random effect for site. Analyses also showed that the lack of a significant difference in dispersal distance was not due to differences in biome, taxonomic composition, growth form, nitrogen fixation, our inclusion of non-invasive introduced species, or our exclusion of species with human-assisted dispersal. Thus, if introduced species do have higher spread rates, it seems likely that these are driven by differences in post-dispersal processes such as germination, seedling survival, and survival to reproduction.


Reduced perception-action dissociation in children with amblyopia.
The functional distinction between vision-for-perception and vision-for-action is a key aspect of understanding the primate visual system. While this dissociation has been well-established in adulthood, its development and dependence on typical visual experience remain unclear. To address these questions, we examined two groups of children: typically developed children and those with amblyopia, who presumably have a sub-optimal visual experience. The Ponzo illusion, known to impact perception but not visuomotor behaviors across age groups, was employed to assess the extent of dissociation. Participants engaged in two tasks involving the Ponzo illusion: a grasping task (vision-for-action) and a manual estimation task (vision-for-perception), with objects placed on the "close" and "far" surfaces of the illusion. Typically developed children displayed grasping movements that were unaffected by the illusion, as their grasping apertures were scaled based on object size, independent of its location. In contrast, children with amblyopia exhibited a clear susceptibility to the illusion, showing larger apertures for objects placed on the 'far' surface of the illusion, and smaller apertures for objects placed on the 'close' surface. Interestingly, both groups of children demonstrated similar susceptibility to the illusion during the perceptual task, with objects placed on the far surface being perceived as longer compared to objects placed on the close surface. These findings shed light on the impact of atypical visual development on the emergence of the dissociation between perception and action, highlighting the crucial role of typical visual experience in establishing this distinction.


Rapid soil production and weathering in the Southern Alps, New Zealand.
Evaluating conflicting theories about the influence of mountains on carbon dioxide cycling and climate requires understanding weathering fluxes from tectonically uplifting landscapes. The lack of soil production and weathering rate measurements in Earth's most rapidly uplifting mountains has made it difficult to determine whether weathering rates increase or decline in response to rapid erosion. Beryllium-10 concentrations in soils from the western Southern Alps, New Zealand, demonstrate that soil is produced from bedrock more rapidly than previously recognized, at rates up to 2.5 millimeters per year. Weathering intensity data further indicate that soil chemical denudation rates increase proportionally with erosion rates. These high weathering rates support the view that mountains play a key role in global-scale chemical weathering and thus have potentially important implications for the global carbon cycle.


Assembly and forward trafficking of NMDA receptors (Review).
N-Methyl-D-aspartate (NMDA) receptors are a subclass of the excitatory, ionotropic L-glutamate neurotransmitter receptors. They are important for normal brain function being both primary candidates for the molecular basis of learning and memory and in the establishment of synaptic connections during the development of the central nervous system. NMDA receptors are also implicated in neurological and psychiatric disorders. Their dysfunction which is primarily due to either hypo- or hyper-activity is pivotal to these pathological conditions. There is thus a fine balance between NMDA receptor-mediated mechanisms in normal brain and those in diseased states where receptor homeostasis is perturbed. Receptor activity is due in part to the number of surface expressed receptors. Understanding the assembly and trafficking of this complex, heteromeric, neurotransmitter receptor family may therefore, be pivotal to understanding diseases in which their altered activity is evident. This article will review the current understanding of the mechanisms of NMDA receptor assembly, how this assembly is regulated and how assembled receptors are trafficked to their appropriate sites in post-synaptic membranes where they are integral components of a macromolecular signalling complex.


American foreign medical graduates. Performance after a year of supervised clinical clerkships (fifth pathway).
The performance during graduate medical education of Americans who have studied medicine abroad and who have taken a year of intense and closely supervised clinical clerkships (fifth pathway program) was assessed. Only 14% of such house officers were given inadequate or below-average ratings in overall clinical performance by residency program directors. Ninety percent or more received average, good, very good, or excellent evaluations in their ability to take medical histories and perform physical examinations, in their response to instruction, in behavior and interpersonal relationships, and in appearance and emotional stability. Seventy percent were said to be as good as or better than house staff in general. Carefully selected and properly motivated Americans who have studied medicine in a foreign country can become good physicians following a well-organized, comprehensive closely supervised year of clinical clerkship education.


Real-world outcomes with immuno-oncology therapies in advanced melanoma: final results of the OPTIMIzE registry study.
Aim: The OPTIMIzE registry study evaluated real-world outcomes in patients with advanced melanoma receiving immuno-oncology therapies. Materials and methods: Data were collected for patients treated with anti-programmed death 1 (PD-1) monotherapy (nivolumab or pembrolizumab; n = 147) or nivolumab plus ipilimumab (n = 81) from 2015-2017 and followed for ≥3 years. Results: Nivolumab plus ipilimumab versus anti-PD-1 monotherapy was associated with a nonsignificantly lower risk of death (adjusted HR: 0.83; 95% CI: 0.54-1.28; p = 0.41), higher disease control rate (72 vs 56%; p = 0.04), and stable quality of life, but more grade 3-4 treatment-related adverse events (54 vs 26%; p < 0.0001). Conclusion: These results support the use of immuno-oncology therapy in advanced melanoma.


Therapy with 2'-O-Me Phosphorothioate Antisense Oligonucleotides Causes Reversible Proteinuria by Inhibiting Renal Protein Reabsorption.
Antisense oligonucleotide therapy has been reported to be associated with renal injury. Here, the mechanism of reversible proteinuria was investigated by combining clinical, pre-clinical, and in vitro data. Urine samples were obtained from Duchenne muscular dystrophy (DMD) patients treated with drisapersen, a modified 2'O-methyl phosphorothioate antisense oligonucleotide (6 mg/kg). Urine and kidney tissue samples were collected from cynomolgus monkeys (Macaca fascicularis) dosed with drisapersen (39 weeks). Cell viability and protein uptake were evaluated in vitro using human conditionally immortalized proximal tubule epithelial cells (ciPTECs). Oligonucleotide treatment in DMD patients was associated with an increase in urinary alpha-1-microglobulin (A1M), which returned to baseline following treatment interruptions. In monkeys, increased urinary A1M correlated with dose-dependent accumulation of oligonucleotide in kidney tissue without evidence of tubular damage. Furthermore, oligonucleotides accumulated in the lysosomes of ciPTECs and reduced the absorption of A1M, albumin, and receptor-associated protein, but did not affect cell viability when incubated for up to 7 days. In conclusion, phosphorothioate oligonucleotides appear to directly compete for receptor-mediated endocytosis in proximal tubules. We postulate that oligonucleotide-induced low molecular weight proteinuria in patients is therefore a transient functional change and not indicative of tubular damage.


Circumventricular organs and fever.
We have examined the roles of three circumventricular organs, the area postrema, the subfornical organ, and the organum vasculosum of the lamina terminalis (OVLT), as possible access points for circulating pyrogens to cause fever. In conscious, unrestrained rats prepared with telemetry devices, intracerebroventricular cannulas, and intravenous catheters, body temperature was monitored after intravenously administered lipopolysaccharide and, on a different occasion, after intracerebroventricular prostaglandin E1. Lipopolysaccharide-induced fevers in sham control lesioned rats were indistinguishable from those observed in animals with lesions of the area postrema, the OVLT, or the tissue immediately adjacent to this structure (peri-OVLT). In contrast, rats with lesions of the subfornical organ displayed reduced fevers. In none of the groups of lesioned animals were prostaglandin E1 fevers reduced. Thus lesions did not interfere with central thermogenic pathways responsive to prostaglandin. Our results indicate that subfornical organ neurons respond to circulating pyrogens and through their efferent projections activate central pathways involved in fever.


Decisional balance regarding substance use among persons with schizophrenia.
State-of-the-science treatment of substance abuse relies on decisional balance activities (weighing pros and cons of continued substance use) to enhance motivation for change. Few data are available regarding the feasibility of these activities among persons dually diagnosed with schizophrenia and substance use disorder. To address this lacuna in the literature, we completed focus groups with 21 participants, all of whom had a schizophrenia-spectrum diagnosis and lifetime substance abuse or dependence. These key informants discussed the pros and cons of substance use as well as the pros and cons of quitting in response to a structured group interview. Our qualitative data indicate that persons living with schizophrenia can generate rich and diverse decisional balance information. We describe salient themes, contrast complementary perspectives (i.e., the pros of using and cons of quitting), and suggest treatment implications based on these findings.


Behavioral and neuroanatomical analyses in a genetic mouse model of 2q13 duplication.
Duplications of human chromosome 2q13 have been reported in patients with neurodevelopmental disorder including autism spectrum disorder. Nephronophthisis-1 (NPHP1) was identified as a causative gene in the minimal deletion on chromosome 2q13 for familial juvenile type 1 nephronophthisis and Joubert syndrome, an autosomal recessive neurodevelopmental disorder characterized by a cerebellar and brain stem malformation, hypotonia, developmental delay, ataxia, and sometimes associated with cognitive impairment. NPHP1 encodes a ciliary protein, nephrocystin-1, which is expressed in the brain, yet its function in the brain remains largely unknown. In this study, we generated bacterial artificial chromosome-based transgenic mice, called 2q13 dup, that recapitulate human chromosome 2q13 duplication and contain one extra copy of the Nphp1 transgene. To analyze any behavioral alterations in 2q13 dup mice, we conducted a battery of behavioral tests. Although 2q13 dup mice show no significant differences in social behavior, they show deficits in spontaneous alternation behavior and fear memory. We also carried out magnetic resonance imaging to confirm whether copy number gain in this locus affects the neuroanatomy. There was a trend toward a decrease in the cerebellar paraflocculus of 2q13 dup mice. This is the first report of a genetic mouse model for human 2q13 duplication.


Nucleoporins nup98 and nup214 participate in nuclear export of human immunodeficiency virus type 1 Rev.
Human immunodeficiency virus type 1 (HIV-1) Rev contains a leucine-rich nuclear export signal that is essential for its nucleocytoplasmic export mediated by hCRM1. We examined the role of selected nucleoporins, which are located in peripheral structures of the nuclear pore complex and are thought to be involved in export, in Rev function in human cells. First, we found that upon actinomycin D treatment, Nup98, but not Nup214 or Nup153, is able to translocate to the cytoplasm of HeLa cells, demonstrating that Nup98 may act as a soluble factor. We further showed that Rev can recruit Nup98 and Nup214, but not Nup153, to the nucleolus. We also found that the isolated FG-containing repeat domains of Nup98 and Nup214, but not those of Nup153, competitively inhibit the Rev/RRE-mediated expression of HIV. Taken together, the recruitment of Nup98 and Nup214 by Rev and the competitive inhibition exhibited by their NP domains demonstrate direct participation of Nup98 and Nup214 in the Rev-hCRM1-mediated export.


Recombinant Bacillus subtilis expressing the Clostridium perfringens alpha toxoid is a candidate orally delivered vaccine against necrotic enteritis.
Recombinant Bacillus subtilis endospores have been used to vaccinate against tetanus and anthrax. In this work, we have developed spores that could be used to vaccinate against Clostridium perfringens alpha toxin and that could be used to protect against gas gangrene in humans and necrotic enteritis in poultry. The primary active agent in both cases is alpha toxin. A carboxy-terminal segment of the alpha toxin gene (cpa) fused to the glutathione-S-transferase (GST) gene was cloned in B. subtilis such that the encoded GST-Cpa(247-370) polypeptide had been expressed in the following three different ways: expression in the vegetative cell, expression on the surface of the spore coat (fused to the CotB spore coat protein), and a combined approach of spore coat expression coupled with expression in the vegetative cell. Mice immunized orally or nasally with three doses of recombinant spores that carried GST-Cpa(247-370) on the spore surface showed the most striking responses. This included seroconversion with anti-Cpa(247-370)-specific immunoglobulin G (IgG) responses in their sera, a Th2 bias, and secretory IgA responses in saliva, feces, and lung samples. Neutralizing IgG antibodies to alpha toxin were detected using in vitro and in vivo assays, and a toxin challenge established protection. Mice immunized nasally or orally with recombinant spores were protected against a challenge with 12 median lethal doses of alpha toxin. Existing use of spores as competitive exclusion agents in animal feeds supports their use as a potentially economical and heat-stable vaccine for the poultry industry.


Effects of indomethacin on energy metabolism in rat jejunal tissue in vivo.
The non-steroidal anti-inflammatory drugs (NSAIDs) are a widely used group of drugs in clinical medicine. However, their propensity to cause gastrointestinal damage limits their clinical utility. The pathogenesis of this toxicity is not well established. It has been postulated that an early event in the development of damage is an effect of these drugs on mitochondrial function. The present paper sets out to evaluate the effects of indomethacin, a commonly used NSAID, on energy metabolism in vivo. Indomethacin was administered to male Sprague-Dawley rats, either intrajejunally or orally, and indices of mitochondrial function were determined. The parameters chosen for this purpose were oxygen uptake by, lactate levels in and the energy charge of jejunal tissue. Oxygen uptake by and energy charge in jejunal tissue were unaffected at 1 and 3 h after dosing by gavage with indomethacin. The drug significantly affected the tissue lactate/pyruvate ratio at 3 h (but not at 1 h) after oral dosing. Effects of indomethacin on jejunum incubated ex vivo were found to be reversible. The data suggest that indomethacin affects mitochondrial function in vivo, but that compensatory changes in glycolytic rate maintain energy charge.


Glecaprevir/pibrentasvir for the treatment of chronic hepatitis C: design, development, and place in therapy.
Direct-acting antiviral (DAA) therapy has changed the landscape of hepatitis C virus (HCV) management and has changed the focus to the possibility of HCV elimination in the near future. Glecaprevir, an NS3/4A protease inhibitor, and pibrentasvir, an HCV NS5A inhibitor, have addressed many of the existing shortcomings in the DAA therapy spectrum. This combination has proven to be a highly efficacious pan-genotypic DAA with a high barrier to resistance as a once-daily, all-oral medication. This review explores the design and development of glecaprevir and pibrentasvir, its place in current HCV management in the midst of a myriad of DAA therapy options, and also remaining challenges.


Comparison of plasminogen activator inhibitor-1, tissue type plasminogen activator antigen, fibrinogen, and D-dimer levels in various age decades in patients with type 2 diabetes mellitus and stable coronary artery disease (from the BARI 2D trial).
Advancing age is associated with downregulation of fibrinolysis in normal subjects. This is reflected by high concentrations of plasminogen activator inhibitor-1 (PAI-1) in the blood, which has been implicated in the increasing cardiovascular morbidity and mortality with age. We sought to delineate the relation of PAI-1 to several factors, including age, gender, and ethnicity in patients with type 2 diabetes mellitus (DM) and stable coronary artery disease enrolled in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. A total of 2,321 patients with DM and stable coronary artery disease in the BARI 2D trial were grouped by age (<50, 50 to 59, 60 to 69, and > or =70 years). Tissue-type plasminogen activator antigen, PAI-1 antigen and activity, fibrinogen, and D-dimer were quantified at baseline. The PAI-1 antigen (p <0.001) and its activity (p <0.001) and their ratios to tissue-type plasminogen activator (p <0.001) were all paradoxically lower with advancing age. In contrast, D-dimer (p <0.0001) was elevated. The fibrinogen level was greatest in the oldest age group (p = 0.01). The level of tissue-type plasminogen activator antigen did not vary with age. These age-related differences were observed primarily in men and non-Hispanic white and Asian/other participants. In conclusion, PAI-1 is inversely related to age in patients with DM and stable coronary artery disease and is associated with elevation of D-dimer, reflecting augmented fibrinolysis. The unexpected profibrinolytic state seen with advancing age and DM might reflect a protective phenomenon resulting from enhanced survival of some older patients with DM that endowed the older patients with longevity sufficient to enable them to participate in the BARI 2D trial. Targeting the factors that led to the downregulation of PAI-1 in older patients with type 2 DM might offer an attractive strategy for reducing cardiovascular risk.


Practices countering resident-to-resident aggression and promoting wellness care for older adults in congregate residential facilities: results from a systematic review.
Resident-to-resident aggression (RRA) is an important issue in congregate residential facilities (CRFs) for older adults and has devastating effects. This study aimed to provide an inventory and content analysis of the practices used to counter RRA and promote wellness care for older adults in CRFs. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, original, peer-reviewed research and systematic reviews published in 14 electronic databases and two gray literature sources were examined. Of the 6196 articles identified, 28 met the inclusion criteria. Practices aimed to prevent, track or intervene in RRA, mostly in long-term care centers, but few were evidence-based and ready for widespread implementation. It emerges that continuous training of staff is necessary and that it should prioritize a person-centered approach. CRFs' managers must promote a culture of wellness care and policymakers should consider the prevention practices to improve the quality of life of older adults in CRFs.


The impact of smoking on thromboembolism and mortality in patients with incident atrial fibrillation: insights from the Danish Diet, Cancer, and Health study.
Smoking and atrial fibrillation (AF) are major health problems worldwide and are responsible for substantial health-care costs. Our aim was to investigate whether smoking impacts the risk of stroke and death in patients with AF. To test this hypothesis, we analyzed data from a large Danish cohort: the Diet, Cancer, and Health study. This was a cohort study of 57,053 people (27,178 men; 29,876 women) aged 50 to 64 years. The risk of thromboembolism (ischemic stroke/arterial thromboembolism) or death according to smoking habits among 3,161 patients with incident AF (mean age, 66.9 years; 2,032 men, 1,129 women) was assessed using Cox proportional hazard models after a median follow-up of 4.9 years. Of those with AF, 34% were current smokers and 37% former smokers. After adjustment for vitamin K antagonist treatment, the hazard ratios (HRs) (95% CI) of thromboembolism or death were 3.13 (1.72-6.37) and 2.73 (2.02-3.70) among women and men who currently were heavy smokers (>25 g/d), respectively. The associations remained after adjustment for well-established risk factors with HRs of 3.64 (1.88-7.07) and 2.17 (1.59-2.95) among women and men, respectively. In a sensitivity analysis, smoking was still strongly associated with thromboembolism or death after censoring people with a cancer diagnosis during follow-up. Smoking is associated with a higher risk of thromboembolism or death in patients with AF even after adjusting for well-recognized risk factors used in stroke risk stratification schemes. The associations may be modified by sex, as the associations were strongest among women.


The incidence of T2-weighted MR imaging signal abnormalities in the brain of cocaine-dependent patients is age-related and region-specific.
Cocaine and its metabolites can produce vasospasm, and cocaine-dependent patients are at increased risk for stroke. Based on previous case reports, we hypothesized that the incidence of hyperintense brain lesions observed on T2-weighted MR images would also be increased in asymptomatic cocaine-dependent individuals. Sixty-two male "crack" (smoked) cocaine-dependent participants ranging in age from 25 to 66 years were compared with 116 normal male control participants ranging in age from 25 to 80 years. Those with histories of neurologic symptoms or illnesses were excluded. The severity of hyperintense lesions was rated on a 0- to 3-point scale, and ratings of 3 were used in the data analysis as an indicator of a probable pathologic process. Three regions were separately rated: the cerebral white matter, insular subcortex white matter, and subcortical gray matter (basal ganglia and thalamus region). Significantly increased risk of severe lesions was observed in the two white matter regions of the cocaine-dependent group (odds ratio of 16.7 and 20.3) but not in the subcortial gray matter region (odds ratio of 1.4). In the insula subcortex white matter, the risk of lesions increased with age in the cocaine-dependant sample, but remained essentially absent among normal controls through the age of 80 years. In the cerebral white matter, the relationship of age and risk of lesion among normal participants was similar in shape to that in cocaine-dependent participants, but equivalent risk was seen 20 years earlier among cocaine-dependent participants. Cocaine-dependent participants had a significantly increased age-related risk of white matter damage. The possible clinical implications of this damage are discussed.


Direct and indirect costs of pain therapy for osteoarthritis in an insured population in the United States.
To assess the health care utilization and cost of illness for osteoarthritis (OA) patients taking pain medications. Specifically, the goals were to estimate the direct health care and indirect costs of OA. A claims database of privately insured patients was used to identify OA patients. Prescription drug pain treatments included tramadol, cyclooxygenase-II inhibitors, and nonsteroidal anti-inflammatory drugs. Mean annual per patient costs were calculated from an employer's perspective. OA patients were prescribed multiple drugs simultaneously and/or sequentially to manage pain. OA patients had a number of prevalent comorbid conditions. Average annual direct medical, drug, and indirect work loss costs were $8601, $2941, and $4603, respectively. There was a substantial payer burden associated with OA resulting from the drug, medical, and disability costs and OA-related comorbidities and high concomitant medication utilization.


Feeding Strategies Before and at Mixing: The Effect on Sow Aggression and Behavior.
Hierarchy formation in domestic sows results in aggression and stress, which might be ameliorated through nutritional satiety. The effect on aggression in group housed, gestating sows provided a standard or high volume of a "standard" diet, or diet enhanced with lignocellulose before, at, and after mixing was studied. Ninety-six Large White cross Landrace weaned sows were allocated to: control diet (CON), high volume diet (HI), and lignocellulose-enhanced diet before and at mixing (LC), and after mixing (LCM) (24 sows per treatment). Sows were housed in stalls for 10 days before mixing, when the CON, HI, and LCM groups were fed a standard diet, and in the LC group, a diet enhanced with lignocellulose at 2.5% was given. At mixing, the CON group continued on a standard diet at 2.5 kg/sow per day, HI were fed the standard diet at 4 kg/sow per day for the first four days and 2.5 kg/sow per day thereafter, and LC and LCM were fed the lignocellulose-enhanced diet at 2.5 kg/sow per day. Behavior, salivary cortisol concentrations, lesion number, and condition were recorded on M0, M1, M6, and M14. Reproduction was assessed using pregnancy rate and progesterone measurements. There were several treatment effects on aggression in the sows following mixing. There were significantly lower fight numbers (CON = 0.34 ± 0.03 Log (1 + x) transformed mean and SEM (1.49 untransformed adjusted mean), LC = 0.31 ± 0.04 (1.14), LCM = 0.42 ± 0.04 (0.28), HI = 0.35 ± 0.04 (1.64); p = 0.001) and longer individual fight durations in the LCM group compared to the CON and LC group (CON = 0.88 s ± 0.07 Log transformed mean and SEM (10.31 s, untransformed adjusted mean), LC = 0.89 ± 0.09 (13.51), LCM = 1.16 ± 0.07 (21.43), HI = 01.03 ± 0.07 (16.42); p = 0.04), and overall higher injury numbers in the LC and LCM groups than the HI. Time spent eating was significantly lower in the CON group than both HI and LC (CON = 7.79 ± 0.37, LC = 8.91 ± 0.38, LCM = 8.49 ± 0.42, HI = 9.55 ± 0.39; p = 0.007). The time spent drinking was also affected by treatment, with more time spent drinking in CON than LC (p = 0.024). The condition score of the sows was affected by diet, with higher condition scores in the HI group than LCM and LC (CON = 2.98 ± 0.11, LC = 2.75 ± 0.10, LCM = 2.74 ± 0.10, HI = 3.12 ± 0.10; p = 0.017). These results suggest that feeding a diet containing 2.5% lignocellulose and a standard diet at a high feeding level for four days post-mixing may affect overall aggression and possibly satiety levels. Our data found decreased fight numbers and increased fight duration in the LCM compared to the LC treatment, and therefore, feeding the fiber source before mixing affects aggression levels differently than when fed just after mixing. A further understanding of different fiber sources and how their physiochemical properties affect digestion and sow satiety would enable critical evaluation and use of fiber sources for benefits in reducing aggression at mixing.


Comparative evaluation of the cerebral and cerebellar white matter development in pediatric age group using quantitative diffusion tensor imaging.
Age-dependent changes in the normal cerebral white matter have been reported; however, there is no study on normal cerebellar white matter maturation in developing brain using diffusion tensor imaging (DTI). We performed DTI in 21 children who had normal neurological assessment along with no evidence of any abnormality on imaging. The aim of this study was to compare the age-related changes in fractional anisotropy (FA) and mean diffusivity (MD) quantified from cerebral white matter (splenium and genu of the corpus callosum and posterior limb of the internal capsule) and cerebellar white matter (middle cerebellar peduncles, superior cerebellar peduncles, and inferior cerebellar peduncles) regions in healthy children ranging in age from birth to 132 months. Log-linear regression model showed best fit to describe the age-related changes in FA and MD both for cerebral and cerebellar white matter. In cerebral white matter, an initial sharp increase in FA was observed up to the age of 24 months followed by a gradual increase up to 132 months. In cerebellar white matter, sharp increase in FA was observed up to 36 months, which then followed a gradual increase. However, MD showed a sharp decrease in cerebral white matter up to 24 months followed by a more gradual decrease thereafter, while in cerebellar white matter after an initial decrease (6 months), it followed a stable pattern. This study provides normative database of brain white matter development from neonates to childhood. This quantitative information may be useful for assessing brain maturation in patients with developmental delay of the cerebral and cerebellar white matter.


Normal lung development needs self-eating.
Autophagy is a Greek-derived concept that means "self-eating" and is increasingly recognized as an important regulator of homeostasis and disease. In this issue of the JCI, Yeganeh et al. report the important finding that intrinsic autophagy is required for normal progression of lung development. Conditional deletion of the beclin 1-encoding gene (Becn1) specifically within lung epithelial cells of embryonic mice resulted in neonatal lethal respiratory distress that was associated with negative impacts on airway branching and differentiation of airway epithelial cell lineages. The authors draw speculative parallels with the alveolar simplification phenotype of bronchopulmonary dysplasia in premature human infants and suggest that stimulation of autophagy by cAMP-dependent kinase activation might conceivably rescue these phenotypes.


Polymorphisms of the NCF4 Gene Increase the Risk of Chronic Heart Failure in Patients with Type 2 Diabetes Mellitus.
We showed for the first time that polymorphisms rs2075938 and rs2075938 of the NCF4 gene are associated with the risk of chronic heart failure in patients with type 2 diabetes mellitus (n=1310). In particular, haplotypes ATGTCTAT (OR=1.74, 95%CI=1.23-2.47; p=0.0017) and ATATTCAC (OR=2.83, 95%CI=1.33-6.03; p=0.0072) of NCF4 increase the risk of chronic heart failure in type 2 diabetes mellitus patients. The results show that NADPH oxidase subunit NCF4 is involved in the molecular mechanisms of myocardial damage in type 2 diabetes mellitus.


Host diversity affects the abundance of the extraradical arbuscular mycorrhizal network.
Arbuscular mycorrhizal fungi (AMF) can form complex networks in the soil that connect different host plants. Previous studies have focused on the effects of these networks on individual hosts and host communities. However, very little is known about how different host species affect the success of the fungal network itself. Given the potentially strong selection pressure against hosts that invest in a fungal network which benefits their competitors, we predict that the presence of multiple host species negatively affects the growth of the extraradical network. We designed an experiment using an in vitro culture approach to investigate the effect of different hosts (carrot, chichory and medicago) on the formation of a common mycelial network. In vitro root cultures, each inoculated with their own fungal network, were grown in a double split plate design with two host compartments and a common central compartment where fungal networks could form. We found that the size of fungal networks differs depending on the social environment of the host. When host species were propagated in a mixed species environment, the fungal abundance was significantly reduced compared to monoculture predictions. Our work demonstrates how host-to-host conflict can influence the abundance of the fungal partner.


Phase II trial of anastrozole plus goserelin in the treatment of hormone receptor-positive, metastatic carcinoma of the breast in premenopausal women.
To explore the antitumor activity of the aromatase inhibitor, anastrozole, in the treatment of premenopausal women with hormone receptor-positive, metastatic breast cancer who have been rendered functionally postmenopausal with the use of the luteinizing hormone-releasing hormone agonist, goserelin. Premenopausal women with estrogen and/or progesterone receptor-positive, metastatic or recurrent breast cancer were enrolled in this prospective, single-arm, multicenter phase II trial. Patients were treated with goserelin 3.6 mg subcutaneous monthly and began anastrozole 1-mg daily 21 days after the first injection of goserelin. Patients continued on treatment until disease progression or unacceptable toxicity. Thirty-five patients were enrolled of which 32 were evaluable for response and toxicity. Estradiol suppression was assessed, with mean estradiol levels of 18.7 pg/mL at 3 months and 14.8 pg/mL at 6 months. One participant (3.1%) experienced a complete response, 11 (34.4%) experienced partial response, and 11 (34.4%) experienced stable disease for 6 months or longer for a clinical benefit rate of 71.9%. Median time to progression was 8.3 months (range, 2.1 to 63+) and median survival was not been reached (range, 11.1 to 63+). The most common adverse events were fatigue (50%), arthralgias (53%), and hot flashes (59%). There were no grade 4 to 5 toxicities. The combination of goserelin plus anastrozole has substantial antitumor activity in the treatment of premenopausal women with hormone receptor-positive metastatic breast cancer.


Randomised, double-blind, placebo-controlled trial of pindolol in combination with fluoxetine antidepressant treatment.
Major depression affects more than 5% of the population and is a serious health and economic problem. Antidepressants have a slow onset of action and are effective in less than two-thirds of patients. The biochemical effects of selective serotonin reuptake inhibitors may be limited by the negative feedback from serotonin autoreceptors. Pindolol is an antagonist of both serotonin autoreceptors and beta-adrenoceptors. We studied the effect of the addition of pindolol to fluoxetine antidepressant treatment. Of 132 eligible patients with major depression, 111 were randomly assigned to treatment with fluoxetine (20 mg daily) and either placebo or pindolol (7.5 mg daily). Patients were assessed twice a week for the first 3 weeks of active treatment and then once a week until the end of the study (42 days). Hamilton and Montgomery-Asberg depression-rating scales were used to assess depression severity. The proportion of patients who responded to treatment with fluoxetine and pindolol was greater than that with fluoxetine and placebo (41/55 [75%] vs 33/56 [59%], [90% CI 1.1-30.1], p = 0.04). The proportion of patients who achieved a sustained response was also greater in the fluoxetine and pindolol group than in the fluoxetine and placebo group (38/55 [69%] vs 27/56 [48%] [5.9-35.9], p = 0.03). The number of days to reach a sustained response was lower in the fluoxetine and pindolol group than in the fluoxetine and placebo group (median 19 vs 29 days, p = 0.01), however, there was no difference in the time-to-onset of clinical improvement when stringent conditions were used (15 vs 18 days, p = 0.20). The addition of pindolol to fluoxetine antidepressant treatment increases the effectiveness of fluoxetine therapy. Further work is needed to resolve whether the time to clinical improvement benefits from this combination and whether the increase in efficacy occurs with other antidepressants.


Superfluid motion and drag-force cancellation in a fluid of light.
Quantum fluids of light merge many-body physics and nonlinear optics, revealing quantum hydrodynamic features of light when it propagates in nonlinear media. One of the most outstanding evidence of light behaving as an interacting fluid is its ability to carry itself as a superfluid. Here, we report a direct experimental detection of the transition to superfluidity in the flow of a fluid of light past an obstacle in a bulk nonlinear crystal. In this cavityless all-optical system, we extract a direct optical analog of the drag force exerted by the fluid of light and measure the associated displacement of the obstacle. Both quantities drop to zero in the superfluid regime characterized by a suppression of long-range radiation from the obstacle. The experimental capability to shape both the flow and the potential landscape paves the way for simulation of quantum transport in complex systems.


Response to "Built and Natural Environment Barriers and Facilitators to Physical Activity in Rural, Suburban, and Small Urban Neighborhoods".
DeGuzman et al. (2019) should be commended for their article "Built and Natural Environment Barriers and Facilitators to Physical Activity in Rural, Suburban, and Small Urban Neighborhoods." The work is a meaningful contribution to the oncology field, given the health disparity among patients with cancer living in rural and suburban communities. Nurses need to be part of the larger conversation and advocate for patients through policy reform that supports access to an equitable built environment. DeGuzman et al.'s (2019) article starts this conversation. In this letter, I wish to build on that initial conversation by deepening the discussion of built environment and costs as significant barriers to physical activity in cancer survivors.


Regional distribution of Sonic Hedgehog, patched, and smoothened mRNA in the adult rat brain.
In vertebrates, Sonic Hedgehog (Shh), Desert Hedgehog (Dhh), and Indian Hedgehog (Ihh) genes encode a family of morphogen proteins that are implicated in a wide range of signaling activities, particularly during embryonic development. These secreted proteins are proposed to mediate their effects on target cells by interacting with their putative receptor, Patched (Ptc), and with a seven-pass transmembrane protein, Smoothened (Smo). However, the roles that these signaling molecules may play in adult tissues, particularly in brain, are not yet clearly defined. Therefore, we investigated the expression of these genes in adult rat tissues. Northern blot analysis revealed expression of Shh, Dhh, and Ihh genes in peripheral tissues, whereas Shh transcript was also identified in brain. It is interesting that northern blot analysis with probes derived from the mouse Ptc and Smo genes revealed the expression of a 7.9-kb and a 3.7-kb transcript, respectively, in all brain tissues examined. In situ hybridization experiments using specific digoxigenin-labeled riboprobes showed expression of Ptc and Smo transcripts in discrete brain areas. Shh-positive cells were observed in restricted regions of the brain. Within the cerebellum, Shh, Ptc, and Smo transcripts were colocalized in the Purkinje cell layer. These data suggest that, besides its roles in determining cell fate and patterning during embryogenesis, the hedgehog signaling pathway may have also important roles in the adult brain.


Spatio-temporal analyses of West Nile virus transmission in Culex mosquitoes in northern Illinois, USA, 2004.
After a severe outbreak of West Nile virus (WNV) in Cook County, Illinois, in 2002, detections of WNV in mosquitoes were frequent across the state in the following years despite small numbers of human cases. We conducted a spatio-temporal analysis of Culex (subgenus Culex) mosquitoes collected in 2004 in three mosquito abatement districts (MAD) in Cook County by calculating monthly estimates of mosquito density, prevalence of infected mosquitoes, and exposure intensity, which in turn is a product of mosquito density and infection rates. Mosquito infections were detected early at three sites in late May and were widely detected throughout the three MADs in the summer with infection rates as high as 13 per 1000 in August. Exposure intensities were higher at sites adjacent to the Des Plaines River, especially in August and September. The aggregated pattern of WNV transmission along the river might be related to the existence of substantial forest preserves and wetlands that might produce ecological conditions favorable for mosquito proliferation and interactions between mosquitoes and birds.


ITER: Image-to-pixel Representation for Weakly Supervised HSI Classification.
Recent years have witnessed the superiority of deep learning-based algorithms in the field of HSI classification. However, a prerequisite for the favorable performance of these methods is a large number of refined pixel-level annotations. Due to atmospheric changes, sensor differences, and complex land cover distribution, pixel-level labeling of high-dimensional hyperspectral image (HSI) is extremely difficult, time-consuming, and laborious. To overcome the above hurdle, an Image-To-pixEl Representation (ITER) approach is proposed in this paper. To the best of our knowledge, this is the first time that image-level annotation is introduced to predict pixel-level classification maps for HSI. The proposed model is along the lines of subject modeling to boundary refinement, corresponding to pseudo-label generation and pixel-level prediction. Concretely, in the pseudo-label generation part, the spectral/spatial activation, spectral-spatial alignment loss, and geographic element enhancement are sequentially designed to locate discriminate regions of each category, optimize multi-domain class activation map (CAM) collaborative training, and refine labels, respectively. For the pixel-level prediction portion, a high frequency-aware self-attention in a high-enhanced transformer is put forward to achieve detailed feature representation. With the two-stage pipeline, ITER explores weakly supervised HSI classification with image-level tags, bridging the gap between image-level annotation and dense prediction. Extensive experiments in three benchmark datasets with state-of-the-art (SOTA) works show the performance of the proposed approach.


Single-shot color digital holography based on the fractional Talbot effect.
We present a method for recording on-axis color digital holograms in a single shot. Our system performs parallel phase-shifting interferometry by using the fractional Talbot effect for every chromatic channel simultaneously. A two-dimensional binary amplitude grating is used to generate Talbot periodic phase distributions in the reference beam. The interference patterns corresponding to the three chromatic channels are captured at once at different axial distances. In this scheme, one-shot recording and digital reconstruction allow for real-time measurement. Computer simulations and experimental results confirm the validity of our method.


Effect of Nocardia rubra cell wall skeleton on T-cell-mediated cytotoxicity in mice bearing syngeneic sarcoma.
Cell-mediated cytotoxicity against syngeneic MC104 fibrosarcoma cells was detected in C57BL/6N mice 7 days after tumor inoculation in the hind foot. This cytotoxicity was undetectable by Day 14 in the Winn test using spleen and draining popliteal lymph node (DPLN) cells. Similar results were obtained with the 51Cr release assay following in vitro activation of these lymphoid cells with mitomycin C-treated tumor cells. The antitumor cytotoxicity was shown to be mediated by T-cells. Spleen but not DPLN cells from 14-day tumor bearers enhanced tumor growth in the Winn test, suggesting the presence of immunosuppressor cells in the spleen. Two intralesional injections of 50 microgram of cell wall skeleton (CWS) of Nocardia rubra on Days 2 and 7 resulted in apparent tumor growth inhibition and prolongation of the survival period of tumor bearers. DPLN cells from tumor bearers treated with N. rubra CWS exhibited significant recovery in the cytotoxicity tested on Day 14, whereas the recovery in that of spleen cells was not apparent. The cytotoxicity augmented by N. rubra CWS was specific to MC104 tumor cells and was shown to be mediated by T-cells. These cytotoxic T-cells were shown to be able to localize not only in DPLN but also in the spleen and tumor in mice receiving the intralesional immunotherapy with N. rubra CWS. These results suggest that T-cell-mediated cytotoxicity against syngeneic tumor can be augmented by N. rubra CWS and might play an important role in the systemic development of its antitumor effect, although the effector cell increase in the spleen might be suppressed by splenic suppressor cells during tumor growth.


Adapting evidence-based interventions to accommodate cultural differences: where does this leave effectiveness?
Evidence-based interventions are an essential part of delivering contemporary mental health services. Many such interventions, however, are developed with and for mainstream population groups. Practitioners and researchers alike will often adapt tools, practices, processes or programmes to meet the needs of culturally diverse populations groups, but wonder if and how such adaptations will affect outcomes. This paper considers the processes by which evidence-based interventions can be adapted by health professionals in any context; and includes an example of a successful cultural adaptation to an evidence-based intervention. The successful implementation of the Aboriginal Mental Health First Aid programme in Australia illustrates the potential for adapted interventions to support improvements in the health outcomes of people from culturally diverse backgrounds. The paper concludes by outlining the steps mental health professionals can take when adapting evidence-based interventions for use in their own workplace settings.


Angiogenin and hemoxygenase in pregnancy: influence of hypertension.
The pathophysiology of hypertension and preeclampsia involves angiogenesis and endothelial damage/dysfunction, as shown by abnormal growth factors (vascular endothelial growth factor [VEGF], and its receptor sFlt-1) and von Willebrand factor (vWf) in the plasma. Angiogenin and hemoxygenase are abnormal in hypertension and angiogenesis but data on pregnancy are scant. We hypothesized altered angiogenin and hemoxygenase in 38 hypertensive pregnant women (HTPW) compared to 38 normotensive pregnant women (NTPW) and 50 nonpregnant controls (NonPCs). Plasma markers were measured by enzyme-linked immunosorbent assay (ELISA). Hypertensive pregnant women had lower VEGF than NonPCs (P < .01), vWf was raised in both pregnant groups (P < .01), but sFlt-1 was no different. Both angiogenin and hemoxygenase were lower in NTPW compared to NonPCs (both p<0.02). In both pregnancy groups, angiogenin correlated with vWf (r > .33, P < .05), but in NonPCs this was not significant (r = .13, P = .367). These changes may reflect differences in endothelial cell physiology and pathology in the hypertension in pregnancy.


Legislation for trial registration and data transparency.
Public confidence in clinical trials has been eroded by data suppression, misrepresentation and manipulation. Although various attempts have been made to achieve universal trial registration- e.g., Declaration of Helsinki, WHO clinical Trial Registry Platform (WHO ICTRP), the International Committee of Medical Journal Editors requirement- they have not succeeded, probably because they lack the enough power of enforcement.Legislation appears to be the most efficient and effective means to ensure that all researchers register their trials and disseminate their data accurately and in a timely manner. We propose that a global network be established. This could be accomplished in two steps. The first step is to legislate about trial registration and data transparency, such as USA's FDAAA Act 2007; and the second step to establish a global network to ensure uniform, international consistency in policy and enforcement of trial registration and data transparency.


Effect of carnitine administration on glycine metabolism in patients with isovaleric acidemia: significance of acetylcarnitine determination to estimate the proper carnitine dose.
In isovaleric acidemia (IVA), accumulated isovaleryl-CoA in the mitochondrion induces variable metabolic disturbances. To remove intramitochondrial isovaleryl groups, glycine therapy has been advocated primarily. On the other hand, secondary carnitine deficiency has been documented in this disorder and carnitine supplementation alone has been reported to be effective. In the present study, we administered carnitine and glycine to patients with IVA, and investigated serum carnitine and urinary excretion of total and free carnitine, acylcarnitine profile (i.e., isovalerylcarnitine and acetylcarnitine), and isovalerylglycine. By adding carnitine to glycine supplementation, more isovalerylglycine, not only isovalerylcarnitine, was excreted in the urine. Acetylcarnitine was detected in the urine only when sufficient carnitine was supplemented. We concluded that combined therapy of glycine and carnitine is more effective and safer to eliminate isovaleryl-CoA in IVA than conventional therapy using either glycine or carnitine. Urinary acetylcarnitine concentration might be a good marker indicating the optimal dose of L-carnitine supplementation.


Chiral Alkyl Amine Synthesis via Catalytic Enantioselective Hydroalkylation of Enecarbamates.
Chiral alkyl amines are omnipresent as bioactive molecules and synthetic intermediates. The catalytic and enantioselective synthesis of alkyl amines from readily accessible precursors is challenging. Here we develop a nickel-catalyzed hydroalkylation method to assemble a wide range of chiral alkyl amines from enecarbamates (N-Cbz-protected enamines) and alkyl halides with high regio- and enantioselectivity. The method works for both nonactivated and activated alkyl halides and is able to produce enantiomerically enriched amines with two minimally differentiated α-alkyl substituents. The mild conditions lead to high functional group tolerance, which is demonstrated in the postproduct functionalization of many natural products and drug molecules, as well as the synthesis of chiral building blocks and key intermediates to bioactive compounds.


The correlation between serum inflammatory, antioxidant, glucose handling biomarkers, and Dietary Antioxidant Index (DAI) and the role of DAI in obesity/overweight causation: population-based case-control study.
Obesity is a multifactorial disease, and about 40% of world adults are overweight, and about 20% are obese. Diet is one of the most important factors in the causality of obesity. The interactions between the diet and gut microbiota or chronic inflammation pathways highlight the importance of its various aspects in the incidence and prevalence of obesity. At the same time, diet is a combination of several antioxidants that are needed together for the body's antioxidant system. The Dietary Antioxidant Index (DAI) is a valid nutritional tool, and its correlation has been studied concerning total antioxidant capacity and malondialdehyde. The study aimed to examine the relationship between the DAI and the odds of obesity. We hypothesized that a higher DAI score indicating a predominantly antioxidant diet has a protective effect against odds of obesity. In this population-based case-control study, 812 participants with a higher body mass index (BMI) than 25 were selected as the case group. Also, 793 participants with BMI in the range of 17.9-24.9 were selected as the control group. A valid and reliable 124-item food frequency questionnaire (FFQ) was used to assess dietary intake. Based on FFQ data, we summed up the standardized intake of the major dietary antioxidants, including vitamin A, E, C, selenium, zinc, and manganese, to calculate DAI. In a multivariable adjusting model, there was a significant association between DAI (as a continuous variable) and BMI (odds ratio (OR) = 0.95; 95% CI: 0.92-0.99; P value = 0.02). Also, there was a significant association between DAI (as a categorized variable) and body surface area with multivariable adjusting model (OR = 0.79; 95% CI: 0.64-0.98; P value = 0.04). In conclusion, the DAI can accurately predict some serum antioxidant and anti-inflammatory levels along with glucose handling markers.


Immunohistochemical Study of Apoptosis of Lens Epithelial Cells in Human and Diabetic Rat Cataracts.
Purpose: An immunohistochemical evalution of lens epithelial cell apoptosis.Methods: We performed terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assays on capsulotomy specimens (68 eyes in 53 patients) from patients who had undergone cataract surgery and an epithelium of diabetic cataracts in rats (144 eyes in 72 rats). The animal model of diabetic cataracts was prepared by injection of streptozotocin in three-week old rats. The rats were also examined using the proliferating cell nuclear antigen (PCNA) immunohistochemical staining method.Results: Although some TUNEL-positive cells were detected in capsulotomy specimens, we recognized little correlation between its distribution and morphological classification of cataracts. In the animal model of diabetic cataracts, TUNEL-positive cells were seen around the region where epithelial cells had accumulated. In the accumulated region, PCNA labeled cells undergoing DNA synthesis were also detected.Conclusion: These results suggest the possibility that apoptosis occurs in human lens epithelial cells and apoptosis and proliferation may be induced by factors such as hyperglycemia.


Mitochondrial cytochrome c release and caspase-3-like protease activation during indomethacin-induced apoptosis in rat gastric mucosal cells.
Indomethacin (IND), a nonsteroidal anti-inflammatory drug, has been known to cause gastric mucosal injury as a side effect. Using a rat gastric mucosal cell line, RGM1, we determined whether apoptosis is involved in IND-mediated gastropathy, and whether caspase activation and mitochondrial cytochrome c release play an important role in producing apoptosis of IND-treated RGM1 cells in the presence of serum. IND caused caspase-3-like protease activation followed by apoptosis in a dose- and time-dependent manner. Caspase-1-like protease activity did not change during IND-induced apoptosis. IND also increased mitochondrial cytochrome c release in a time-dependent fashion. Mitochondrial cytochrome c efflux occurred just before or at the same time as caspase-3-like protease activation, and preceded the increase in apoptotic cell numbers. Z-VAD-FMK, a caspase inhibitor, inhibited both the increase in caspase-3-like protease activity and apoptosis in IND-treated RGM1 cells but did not affect caspase-1-like protease activity or mitochondrial cytochrome c release. These observations suggest that the apoptosis of gastric mucosal cells could be involved in IND-induced gastropathy, that cytochrome c is released from mitochondria into the cytosol during the early phase of IND-mediated apoptosis, and that subsequent activation of caspase-3-like protease, but not caspase-1-like protease, is required for the execution of apoptosis.


Effects of nurses' practice of a sedation protocol on sedation and consciousness levels of patients on mechanical ventilation.
Providing high-quality care in the intensive care units (ICUs) is a major goal of every medical system. Nurses play a crucial role in achieving this goal. One of the most important responsibilities of nurses is sedation and pain control of patients. The present study tried to assess the effect of nurses' practice of a sedation protocol on sedation and consciousness levels and the doses of sedatives and analgesics in the ICU patients. This clinical trial was conducted on 132 ICU patients on mechanical ventilation. The patients were randomly allocated to two groups. While the control group received the ICU's routine care, the intervention group was sedated by ICU nurses based on Jacob's modified sedation protocol. The subjects' sedation and consciousness levels were evaluated by the Richmond Agitation Sedation Scale (RASS) and the Glasgow Coma Scale (GCS), respectively. Doses of administered midazolam and morphine were also recorded. The mean RASS score of the intervention group was closer to the ideal range (-1 to +1), compared to the control group (-0.95 ± 0.3 vs. -1.88 ± 0.4). Consciousness level of the control group was lower than that of the intervention group (8.4 ± 0.4 vs. 8.8 ± 0.4). Finally, higher doses of midazolam and morphine were administered in the control group than in the intervention group. As nurses are in constant contact with the ICU patients, their practice of a sedation protocol can result in better sedation and pain control in the patients and reduce the administered doses of sedatives and analgesics.


Ionic liquids and deep eutectics as a transformative platform for the synthesis of nanomaterials.
Ionic liquids (ILs) are becoming a revolutionary synthesis medium for inorganic nanomaterials, permitting more efficient, safer and environmentally benign preparation of high quality products. A smart combination of ILs and unconventional synthesis methods allows added value to be drawn from the broad matrix of available property combinations. Mixed systems such as Deep Eutectic Solvents (DES) offer a similarly broad combinatorial playground, which is also beginning to translate into applications. Approached holistically, these liquids therefore enable new universal manufacturing techniques that provide solutions to the existing problems of nanomanufacturing, and beyond that will open completely new horizons and possibilities for controlling the growth and assembly of nanostructures. Examples that illustrate the power of ILs in the improved manufacturing of nanomaterials are explored, such as the synthesis of light phosphors with exceptional quantum yields, record-figure-of merit thermoelectrics, and efficient photocatalysts, alongside developments in DES nanostructure and deep eutectic-solvothermal and ionothermal techniques.


Aqueous solutions of binary ionic liquids: insight into structure, dynamics, and interface properties by molecular dynamics simulations and DFT methods.
The behavior of aqueous solutions of mixtures of ionic liquids (ILs) is of special interest because of their amphiphilic character, from both a fundamental and application viewpoint. In this work, we conducted molecular dynamics (MD) simulations and density functional theory (DFT) calculations to understand the effect of water on the intermolecular interactions in three IL binary mixtures [C4mim]/[Cl]/[BF4], [C4mim]/[Cl]/[PF6] and [C4mim]/[BF4]/[PF6] containing the well-characterized cation, 1-n-butyl-3-methylimidazolium [C4mim]+ and the anions chloride [Cl]-, tetrafluoroborate [BF4]-, and hexafluorophosphate [PF6]-. The perturbation of the structures in the binary IL mixture by water molecules was analyzed in the bulk and at the liquid/vacuum interface using distribution functions, hydrogen-bond statistics, and density profiles. Interactions between anions and cations change drastically when the IL mixtures are dissolved in water. In particular, anion-water interactions are stronger than anion-cation interactions. H-Bonds are the dominant interactions. They are prevalently electrostatic and strong for the two [Cl]-containing systems in both the water-free and the water-containing systems. The very hydrophobic [C4mim]/[BF4]/[PF6] system gains stability from dispersive interactions and consequently segregates water markedly when admixed. The most probable orientations of IL cations in the bulk and at the vicinity of the interface were examined using bivariate distribution calculations and show [PF6]- segregating to the surface in keeping with its highly hydrophobic nature. DFT calculated structures, energies, dipole moments, global hardness and solvation energies using model ion pairs [C4mim][X] or complexes [C4mim]2[X][Y], with [X/Y]- = [Cl]-, [BF4]-, or [PF6]- are completely consistent with the findings for the bulk.


Automatic and intentional influences on saccade landing.
Saccadic eye movements enable us to rapidly direct our high-resolution fovea onto relevant parts of the visual world. However, while we can intentionally select a location as a saccade target, the wider visual scene also influences our executed movements. In the presence of multiple objects, eye movements may be "captured" to the location of a distractor object, or be biased toward the intermediate position between objects (the "global effect"). Here we examined how the relative strengths of the global effect and visual object capture changed with saccade latency, the separation between visual items and stimulus contrast. Importantly, while many previous studies have omitted giving observers explicit instructions, we instructed participants to either saccade to a specified target object or to the midpoint between two stimuli. This allowed us to examine how their explicit movement goal influenced the likelihood that their saccades terminated at either the target, distractor, or intermediate locations. Using a probabilistic mixture model, we found evidence that both visual object capture and the global effect co-occurred at short latencies and declined as latency increased. As object separation increased, capture came to dominate the landing positions of fast saccades, with reduced global effect. Using the mixture model fits, we dissociated the proportion of unavoidably captured saccades to each location from those intentionally directed to the task goal. From this we could extract the time course of competition between automatic capture and intentional targeting. We show that task instructions substantially altered the distribution of saccade landing points, even at the shortest latencies.NEW & NOTEWORTHY When making an eye movement to a target location, the presence of a nearby distractor can cause the saccade to unintentionally terminate at the distractor itself or the average position in between stimuli. With probabilistic mixture models, we quantified how both unavoidable capture and goal-directed targeting were influenced by changing the task and the target-distractor separation. Using this novel technique, we could extract the time course over which automatic and intentional processes compete for control of saccades.


[Prolactin modulation of theophylline inhibitory action on maturation of bovine oocyte-cumulus complexes in vitro].
The comparative investigation of the individual and joint impact of prolactin (PRL, 50 ng/ml) and theophylline (TP), a nonselective inhibitor of phosphodiesterases, on nuclear maturation of bovine oocytes and the expansion of cumulus cells enclosing the oocytes was carried out using a model of in vitro culturing. It has been shown that TP (5 mM) exerts a short-term inhibitory action on oocyte meiosis reinitiation and blocks it at diakinesis and metaphase I stages as well as inhibits the cumulus expansion. The addition of PRL to the medium containing TP caused the decrease in the rate of oocytes at diplotene stage after 6 h of culturing and the increase in the rate of oocytes attained the closing stages of maturation after 24 h of culturing. Furthermore, PRL suppressed partly the inhibitory impact of TP on the expansion of cumulus cells. The data obtained suggest the signal cascade induced by PRL in bovine oocyte-cumulus complexes to be compled with cAMP-dependent intracellular pathway.


Stunted scale-up of a performance-based financing program on HIV and maternal-child health services in Mozambique - a policy analysis.
A performance-based financing (PBF) program was implemented for services for HIV, prevention of mother-to-child transmission (PMTCT) and maternal/child health (MCH) in two provinces of Mozambique. This study investigates the determinants of policy scale-up to help accelerate the expansion of PBF in Mozambique and globally from pilot projects to national policies. A retrospective policy programme analysis was carried out using in-depth key informant interviews. A total of 24 interviews were conducted with stakeholders from donor agencies, the implementing NGO, district and provincial health offices, and the Ministry of Health. Stakeholders reported that the scale-up process of PBF was influenced by three key determinants: political power, financial sustainability, and available capacity and evidence. In Mozambique, PBF scaled-up provincially but not nationally due to these determinants. The adoption of PBF in Mozambique involved a restricted range of policy actors at the central level and was strongly driven by the donor and a PBF champion. Provincial scale-up was fostered by political support and increasing capacity over time. There was a generalised ambivalence and lack of incentive to scale-up PBF from the implementing NGO. Coupled with the lack of evidence of a positive effect, and of cost-effectiveness in comparison with other models to improve health service delivery and health system strengthening, it is difficult to argue for the need to scale up the PBF programme studied. Care needs to be taken to base the adoption of health policies, including PBF, on a situational analysis and on evidence of intervention effectiveness, cost-benefits and contextual fit.


[Effects of (-), (+)clausenamide on anisodine-induced acetylcholine decrease and associated memory deficits in the mouse brain].
The effect of a new cognition enhancer clausenamide on regional acetylcholine (ACh) levels and anisodine-induced ACh decrease were examined in mice of memory deficits. In the mean time, the effect of (-)clausenamide on ACh was compared with that of (+)clausenamide. Animal amnesia model was induced by i.p. anisodine, brain acetylcholine content was measured by high performance liquid chromatography with electrochemical detection. It was found that single administration of (-)clausenamide or (+)clausenamide(10, 20, 50 mg.kg-1, ig) showed no effect on the ACh level in the frontal cortex, hippocampus and striatum in normal condition. However, pretreatment with (-)clausenamide (10, 20, 50 mg.kg-1, ig) significantly ameliorated the reduction of ACh in these regions induced by anisodine (10 mg.kg-1, i.p.) in a dose-dependent manner. In the meantime, (-) clausenamide ameliorate anisodine-induced memory deficits in step-through test in mice. In contrast, (+)clausenamide showed no effect on these sides. The results indicate that there is significant difference between the actions of (-)clausenamide and (+)clausenamide; The protective action of (-)clausenamide against anisodine-induced amnesia is due to its ability to reverse ACh reduction.


The majority of the matrix protein TapA is dispensable for Bacillus subtilis colony biofilm architecture.
Biofilm formation is a co-operative behaviour, where microbial cells become embedded in an extracellular matrix. This biomolecular matrix helps manifest the beneficial or detrimental outcome mediated by the collective of cells. Bacillus subtilis is an important bacterium for understanding the principles of biofilm formation. The protein components of the B. subtilis matrix include the secreted proteins BslA, which forms a hydrophobic coat over the biofilm, and TasA, which forms protease-resistant fibres needed for structuring. TapA is a secreted protein also needed for biofilm formation and helps in vivo TasA-fibre formation but is dispensable for in vitro TasA-fibre assembly. We show that TapA is subjected to proteolytic cleavage in the colony biofilm and that only the first 57 amino acids of the 253-amino acid protein are required for colony biofilm architecture. Through the construction of a strain which lacks all eight extracellular proteases, we show that proteolytic cleavage by these enzymes is not a prerequisite for TapA function. It remains unknown why TapA is synthesised at 253 amino acids when the first 57 are sufficient for colony biofilm structuring; the findings do not exclude the core conserved region of TapA having a second role beyond structuring the B. subtilis colony biofilm.


Morphological and molecular characteristics of living human fetuses between Carnegie stages 7 and 23: immunolocalization of inhibin alpha and beta a subunits.
Transforming growth factor (TGF) is known to have the ability to modify mitogenic responses of tissues to other peptide growth factors and therefore may contribute to the rapid growth rate of an embryo. Throughout the TGF superfamily there is a similar fundamental molecular architecture. Included in this superfamily are inhibin A, activin A and activin B. It has been shown that activin is a powerful mesodermal inducing factor in the early embryo. The human embryo has shown localization of inhibin in the gonads after 16 weeks gestation but it has not been previously identified in earlier embryos. The inhibin-activin protein was found in a range of tissues including the liver stages 19-21 (alpha) and stages 19-22 (beta); oesophagus stages 19-22 (alpha and beta); stomach stages 21 and 22 (alpha and beta); gut stages 16-22 (alpha) and 21 and 22 (beta); pericardium stages 12-22 (alpha and beta); gonad stages 21 and 22 (beta) stage 22 (alpha); adrenal stages 19-22 (alpha and beta); urogenital system stages 21 and 22 (alpha and beta); yolk sac stage 12 (alpha and beta); mesenchyme stages 16-22 (alpha); surface ectoderm stages 13-22 (alpha) and stages 16-22 (beta a); notocord stages 13-22 (beta) and stages 21 and 22 (alpha); nasal, trachea and bronchi stages 19-22 (alpha and beta) leading to speculation of the role of both subunits.


Does milk intake promote prostate cancer initiation or progression via effects on insulin-like growth factors (IGFs)? A systematic review and meta-analysis.
To establish whether the association between milk intake and prostate cancer operates via the insulin-like growth factor (IGF) pathway (including IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3). Systematic review, collating data from all relevant studies examining associations of milk with IGF, and those examining associations of IGF with prostate cancer risk and progression. Data were extracted from experimental and observational studies conducted in either humans or animals, and analyzed using meta-analysis where possible, with summary data presented otherwise. One hundred and seventy-two studies met the inclusion criteria: 31 examining the milk-IGF relationship; 132 examining the IGF-prostate cancer relationship in humans; and 10 animal studies examining the IGF-prostate cancer relationship. There was moderate evidence that circulating IGF-I and IGFBP-3 increase with milk (and dairy protein) intake (an estimated standardized effect size of 0.10 SD increase in IGF-I and 0.05 SD in IGFBP-3 per 1 SD increase in milk intake). There was moderate evidence that prostate cancer risk increased with IGF-I (Random effects meta-analysis OR per SD increase in IGF-I 1.09; 95% CI 1.03, 1.16; n = 51 studies) and decreased with IGFBP-3 (OR 0.90; 0.83, 0.98; n = 39 studies), but not with other growth factors. The IGFBP-3 -202A/C single nucleotide polymorphism was positively associated with prostate cancer (pooled OR for A/C vs. AA = 1.22; 95% CI 0.84, 1.79; OR for C/C vs. AA = 1.51; 1.03, 2.21, n = 8 studies). No strong associations were observed for IGF-II, IGFBP-1 or IGFBP-2 with either milk intake or prostate cancer risk. There was little consistency within the data extracted from the small number of animal studies. There was additional evidence to suggest that the suppression of IGF-II can reduce tumor size, and contradictory evidence with regards to the effect of IGFBP-3 suppression on tumor progression. IGF-I is a potential mechanism underlying the observed associations between milk intake and prostate cancer risk.


Sub-therapeutic exposure to polyene antimycotics elicits a post-antifungal effect (PAFE) and depresses the cell surface hydrophobicity of oral Candida albicans isolates.
Post-antifungal effect (PAFE) is defined as the suppression of growth that persists following limited exposure of fungi to antimycotics and subsequent removal of the drug. The fungal pathogen Candida albicans is the major aetiologic agent of oral candidosis, and the cell surface hydrophobicity (CSH) of this yeast is considered a critical factor contributing to its colonisation potential. As the concentration of topically prescribed antifungals reach sub-therapeutic levels at dosage intervals, the study of the polyene-induced PAFE and its impact on the CSH of oral C. albicans should be of clinical relevance. Hence the aims of this investigation were to measure the PAFE and CSH of 12 isolates of C. albicans following limited exposure (1 h) to nystatin and amphotericin B and also to investigate the ultrastructural features of yeast cells following such antifungal exposure. The yeasts were exposed to sub-lethal concentrations of nystatin (x2 MIC) and amphotericin B (x2 MIC) for a period of 1 h. Following subsequent removal of the drug, the PAFE and the CSH of the isolates were assessed by a turbidometric measurement of growth and a biphasic aqueous-hydrocarbon assay, respectively. The mean duration of PAFE of nystatin and amphotericin B were 5.99 (+/-0.49) h and 8.73 (+/-0.93) h, respectively, while the reduction in CSH following exposure to these drugs were 17.32% (P<0.05 for 83% of the isolates) and 14.26% (P<0.05 for 66% of the isolates), respectively. On scanning electron microscopy the exposed cells were seen to undergo collapse of the internal cell membrane, leaving an intact cell wall, while a proportion of cells were deflated. Some cells showed intense puckering of the cell wall, resulting in a mulberry appearance. Taken together, these data elucidate additional mechanisms by which polyene antimycotics may operate in vivo to suppress candidal pathogenicity.


Evaluating health-care: the perspectives of sufferers with upper limb pain.
There is considerable uncertainty over the diagnosis, treatment and management of upper limb pain, which has implications for patient care. Research into patient experiences and evaluation of health-care has been neglected and the study presented here aims to fill this gap. A two-staged, mixed methodology was adopted. Phase 1 involved a postal survey of a random sample (n = 2781) of the working age population (25-64) of an area in south-west England. Phase 2 consisted of follow-up, informal face-to-face interviews with a purposive sample of 47 informants identified, according to pre-defined criteria, from the survey sample. Our data showed that concerns about the effectiveness of treatments for alleviating pain were fundamental to users' evaluations of both orthodox and non-orthodox health-care. This took priority over the need for a diagnosis and other information. There was a general recognition that the treatments available were, at least, only partially effective and the pragmatic approach led some to eventually withdraw from both orthodox care and complementary and alternative medicines (CAM). Patients' priorities for health-care, in this context, were perceived to involve the provision of treatments which alleviated pain and were safe and painless. Orthodox and non-orthodox care needed to be more closely integrated into primary care services.


[Hemorrhage after endoscopic polypectomy of the stomach].
46 endoscopic electroexcisions of gastric polyps were performed in one case this procedure was complicated with bleeding, that would not be arrested via an endofibroscope. This operative procedure is described, and also some considerations concerning endoscopic electroexcision of gastric polyps are given.


Computing with phase locked loops: choosing gains and delays.
We simulate a four-node fully connected phase-locked loop (PLL) network with an architecture similar to the neural network proposed by Hoppensteadt and Izhikevich (1999, 2000), using second-order PLLs. The idea is to complement their work analyzing some engineering questions like:how the individual gain of the nodes affects the synchronous state of whole network; how the individual gain of the nodes affects the acquisition time of the whole network; how close the free-running frequencies of the nodes need to be in order to the network be able to acquire the synchronous state; how the delays between nodes affect the synchronous state frequency. The computational results show that the Hoppensteadt-Izhikevich network is robust to the variation of these parameters and their effects are described through graphics showing the dependence of the synchronous state frequency and acquisition time with gains, free-running frequencies, and delays.


[Eye banks and available transplants].
Eye banks have procured, processed and stored donor corneas for decades. In parallel, new techniques have emerged employing allogeneic transplantation of various cells and tissues from the eye banks. This progress is a consequence of increased knowledge of stem cells, cell kinetics and immunological aspects and improved techniques for cell culturing, tissue storage and microsurgery. Review article on available transplants for treating eye diseases, based on experience with eye banking, clinical ophthalmological practice, own research and literature retrieved from PubMed, Medline and www.google.com. Treatment techniques for eye diseases, which require biological material for grafting, need efficient eye banks for continuous supply of donor material of high quality. New Norwegian legislation, based on implementation of EU Directive 2004/23/EC, demands authorization of all eye banks. The EU Directive sets high and rigorous standards for quality and safety for donation, procurement, testing, processing, storage and distribution of tissues and cells. Well-run eye banks are of great importance for modern treatment of patients suffering from eye diseases and for progress and research in ophthalmology.


DNA binding properties of simian virus 40 temperature-sensitive A proteins.
Wild-type simian virus 40 A protein (large T antigen) bound to three tandem regions of simian virus 40 DNA. The binding regions were defined by the ability of A protein to protect simian virus 40 DNA from digestion with limited (footprint assay) or excess (fragment assay) amounts of DNase I. At low concentrations, protein first bound to region I, which maps 30 to 45 base pairs to the early side of the origin of replication. At higher concentrations, A protein also protected region II and then region III. Region II spanned approximately 65 base pairs and corresponded in location to the functional origin of replication that contains a unique BglI site along with an adjacent adenine-thymine-rich region. Region III was adjacent to the late boundary of region II, but its distal limit was not well defined. Twelve distinct temperature-sensitive (ts) A proteins were purified and examined for their ability to bind in regions I to III. Three classes of tsA protein were defined on the basis of thermal stability. Class I tsA protein displayed wild-type binding either with or without a heat shock. Unheated class II tsA protein exhibited wild-type binding, but after a heat shock bound very poorly to the origin of replication. Class III tsA protein was defective in its binding even without a heat shock and only protected region I. Classes II and III were coded by mutants mapping in two distinct regions of the genome. For all of the tsA proteins examined, there was a positive correlation between the thermolability of origin binding in vitro and the temperature sensitivity of these mutants for DNA replication and transcriptional autoregulation in vivo. This correlation adds support to the essential role of origin binding by A protein in viral DNA replication and early transcription repression.


Measuring Satisfaction with Amplification in Daily Life: the SADL scale.
To develop a self-report inventory to quantify satisfaction with hearing aids. The inventory was developed in several stages. To determine the elements that are most important to satisfaction for most people, we conducted structured interviews and then designed a questionnaire. Hearing aid owners responded to the questionnaire, indicating the relative importance of 14 different elements in their hearing aid satisfaction. Analyses indicated that the elements could be placed into four importance content areas. Trial satisfaction items were designed for each content area and submitted to focus groups to identify highly salient items as well as ambiguous items. A 25-item satisfaction questionnaire then was developed and disseminated to hearing aid owners. Results were obtained from 257 individuals. These data were analyzed to generate the final questionnaire. Fifteen items, divided into four subscales, were selected for the final Satisfaction with Amplification in Daily Life (SADL) questionnaire. The questionnaire yields a Global satisfaction score and a profile of subscale scores, which address Positive Effects, Service and Cost, Negative Features, and Personal Image. A preliminary evaluation of retest stability was conducted with 104 subjects. Ninety percent critical differences for the various scores ranged from 0.9 to 2.0 score intervals on a 7 point scale. The SADL scale is both brief enough to be clinically acceptable and comprehensive enough to provide a valid assessment of an inherently multidimensional variable. Additional assessment is necessary to refine understanding of its test-retest properties, explore validity issues, and determine clinical, research, and administrative applications of the data.


Perspectives of mothers with substance use problems on father involvement.
A number of complex factors contribute to pregnant and parenting women's alcohol and substance use. To date, little research has focused on the implications, meaning and experiences of father involvement on mothers with substance use problems. The current study explores the experiences of mothers with substance use problems with respect to the role, impact and meaning of father involvement. This study conducted two focus groups utilizing a phenomenological approach. Mothers receiving clinical services at a comprehensive, community based program serving pregnant and parenting women with substance use problems were recruited to participate in this research. The meaning of father involvement among this group of women centered on four dimensions: emotional support, financial contributions to the family, amount and quality of time spent with the children and the family, and was dependent upon the particular expectations of the mother involved. Barriers and influences of father involvement were identified. The nature of father involvement had negative and positive impacts on participants. Maternal use of alcohol is a complex issue, one factor often ignored in father involvement. For mothers with substance use problems father involvement has a number of implications, both positive and negative.


Road to recovery: drugs used in stroke rehabilitation.
The practice of neurorehabilitation is unique in that it supplements treatments with medications which complement and expedite the rehabilitation process. In stroke rehabilitation, medications can be used not only to treat poststroke secondary complications but also to facilitate recovery. Since only thrombolytics have been demonstrated to be effective in minimizing brain damage and maximizing functional outcome, intensive rehabilitation remains the most significant and important means by which stroke survivors possibly may maximize stroke recovery. There is an opportunity to complement intensive rehabilitation with pharmacologic interventions that facilitate the recovery of damaged neurons as well as plastic responses in underutilized and unused brain tissue. However, few of these medications have been approved for these indications or have been subjected to large randomized clinical trials. Nonetheless, this review identifies areas in stroke rehabilitation that can be addressed with neuropharmacologic agents, lists specific medications currently used to treat these conditions and describes the evidence that supports the recommendations for these medications.


Particulate matter-attributable mortality and relationships with carbon dioxide in 250 urban areas worldwide.
Urban air pollution is high on global health and sustainability agendas, but information is limited on associated city-level disease burdens. We estimated fine particulate matter (PM2.5) mortality in the 250 most populous cities worldwide using PM2.5 concentrations, population, disease rates, and concentration-response relationships from the Global Burden of Disease 2016 Study. Only 8% of these cities had population-weighted mean concentrations below the World Health Organization guideline for annual average PM2.5. City-level PM2.5-attributable mortality rates ranged from 13-125 deaths per 100,000 people. PM2.5 mortality rates and carbon dioxide (CO2) emission rates were weakly positively correlated, with regional influences apparent from clustering of cities within each region. Across 82 cities globally, PM2.5 concentrations and mortality rates were negatively associated with city gross domestic product (GDP) per capita, but we found no relationship between GDP per capita and CO2 emissions rates. While results provide only a cross-sectional snapshot of cities worldwide, they point to opportunities for cities to realize climate, air quality, and health co-benefits through low-carbon development. Future work should examine drivers of the relationships (e.g. development stage, fuel mix for electricity generation and transportation, sector-specific PM2.5 and CO2 emissions) uncovered here and explore uncertainties to test the robustness of our conclusions.


Results of an Ocean Trial of the Symbiotic Machine for Ocean uRanium Extraction.
Amidoxime-based adsorbents have become highly promising for seawater uranium extraction. However, current deployment schemes are stand-alone, intermittent operation systems that have significant practical and economic challenges. This paper presents two 1:10 scale prototypes of a Symbiotic Machine for Ocean uRanium Extraction (SMORE) which pairs with an existing offshore structure. This pairing reduces mooring and deployment costs while enabling continuous, autonomous uranium extraction. Utilizing a shell enclosure to decouple the mechanical and chemical requirements of the adsorbent, one design concept prototyped continuously moves the shells through the water while the other keeps them stationary. Water flow in the shells on each prototype was determined using the measurement of radium adsorbed by MnO2 impregnated acrylic fibers contained within each enclosure. The results from a nine-week ocean trial show that while movement of the shells through the water may not have an effect on uranium adsorption by the fibers encased, it could help reduce biofouling if above a certain threshold speed (resulting in increased uptake), while also allowing for the incorporation of design elements to further mitigate biofouling such as bristle brushes and UV lamps. The trace metal uptake by the AI8 adsorbents in this trial also varied greatly from previous marine deployments, suggesting that uranium uptake may depend greatly upon the seawater concentrations of other elements such as vanadium and copper. The results from this study will be used to inform future work on the seawater uranium production cost from a full-scale SMORE system.


Testing a Method for Evaluation of the Viability of Biofilm-Forming Bacteria after Exposure to Disinfectants.
A method for determining the viability of opportunistic pathogenic bacteria at the stage of biofilm formation after exposure to disinfectants with different active components was tested. The method is based on oxidation of tetrazolium salts by metabolically active cells with the formation of colored formazan derivatives and their quantitative spectrophotometry. The cell viability in the biofilm decreased after exposure to quaternary ammonium compounds and chlorine-containing disinfectants, but their effect was reversible. Dissemination of cells that had retained viability from the biofilm occurred after 24 h. The algorithm of testing, necessary controls, counting, and data interpretation are specified. The method can be recommended for use in laboratory diagnostics and clinical practice.


Development of isolation-induced vocal behavior in normal-hearing and deafened guinea pig infants.
Infants in many different animal species require auditory information from conspecifics to learn appropriate responses to important environmental and social cues. Isolation calls are emitted by infant guinea pigs in contexts of social separation from their mothers. The aim of the present study was to examine the ontogeny of the isolation calls in normal-hearing and deafened infant guinea pigs, from 2 to 40 days postpartum and to determine the role of hearing maternal vocalization in infant guinea pig vocal responses in contexts of social proximity and isolation. Female newborn pigmented guinea pigs (Cavia porcellus) were housed with their birth mother and siblings. Water and dry food were available ad libitum. One day postpartum, the cochlea of infants in the experimental group was destroyed. The control group consisted of normal-hearing female siblings. Vocalizations from infants in the experimental and control groups were recorded for 6 minutes when with the mother before isolation, 6 minutes when alone, and then 6 minutes when with the mother after reunion. Recordings were made 5 days per week from 2 to 40 days after birth. The duration of calling was calculated for each 6-minute period of recording. Results demonstrated that deaf infants vocalize more than normal-hearing infants during social isolation from their mothers. Vocal activity of isolated deaf and normal-hearing infants decreased substantially over development, almost disappearing by the end of the study period. These results indicate that maternal vocal behavior modulates the vocal responses of guinea pigs early in infant development and supports other evidence that the guinea pig offers a viable model for investigating audition in deaf and normal-hearing human infants.


Step initiation in Parkinson's disease: influence of initial stance conditions.
In this study, we investigated how the size of preparatory postural adjustments prior to step initiation, and step length and velocity depend on initial stance width in patients with Parkinson's disease (PD) both in the ON and OFF levodopa states and in healthy elderly subjects. Twenty-one subjects with idiopathic PD and 24 age-matched healthy control subjects took two steps starting with feet on a two-plate force-platform, from either narrow or wide stance width. We measured how the magnitude of anticipatory postural adjustments (APA) and step characteristics scaled with stance width. Results showed that preparation for step initiation from wide stance was associated with a larger lateral and backward center of pressure (CoP) displacement than from narrow stance. Velocity and length of the first step were also sensitive to initial stance conditions, probably in relation with the differences in the corresponding APA. On the contrary, the duration of APA was not significantly affected by initial stance width, but it was longer in PD compared to healthy subjects, and speeded up by levodopa. Although subjects with PD did scale up the size of their APA with stance width, they had much more difficulty initiating a step from a wide stance than from a narrow stance, as shown by the greater differences from control subjects in the magnitude of the APA. Our results support the hypothesis that PD subjects maintain a narrow stance as a compensation for their inability to sufficiently increase the size of their lateral APA to allow fast step initiation in wide stance.


Clinicopathologic differences of gastric neoplasms between Helicobacter pylori-infected and -naïve patients: a multicenter retrospective analysis.
The incidence of gastric neoplasms in Helicobacter pylori (Hp)-naïve patients has recently increased due to a remarkable decrease in the Hp-infected population in Japan. We investigated the clinicopathologic differences between Hp-infected gastric neoplasms (HpIGNs) and Hp-naïve gastric neoplasms (HpNGNs) that have not been fully elucidated so far. This retrospective multicenter study investigated 966 consecutive patients with 1131 gastric dysplasia or cancers who underwent endoscopic or surgical treatment for the recent decade. Clinicopathologic features were compared between HpIGN and HpNGN cases. One thousand and sixty-eight HpIGNs in 916 patients included 877 differentiated types and 191 undifferentiated types. Sixty-three HpNGNs in 50 patients included 57 differentiated types (35 foveolar types, 15 intestinal types, 6 fundic-gland types, and 1 other differentiated type) and 6 undifferentiated types. HpNGNs occurred in younger (59.5 vs. 71.8 years, p < 0.05) and female patients (40.0% vs. 26.5%, p < 0.05), were found more frequently in the proximal compartment (p < 0.05), and had smaller size (median 4.0 vs. 20.0 mm, p < 0.05). Histologically, HpNGNs and HpIGNs both primarily consisted of differentiated type (90.5% vs. 82.1%, p = 0.089) and HpNGNs showed lower prevalence of invasive cancer (11.1% vs. 37.6%, p < 0.05) and lymphovascular invasion (1.6% vs. 31.6%, p < 0.05). Nearly all HpNGNs (62/63, 98.4%) were diagnosed in early pathological stage, while 16.1% (172/1068) of HpIGNs were diagnosed in advanced stage (p < 0.05). HpNGNs is recently on the increase but shows lower malignant nature regardless of histologic type than HpIGN. Endoscopic gastric cancer screening will be reviewed via cost effectiveness for Hp-naïve individuals in future.


Patterns of triangular fibrocartilage complex (TFCC) injury associated with severely dorsally displaced extra-articular distal radius fractures.
The aim of the study was to examine triangular fibrocartilage (TFCC) injury patterns associated with unstable, extra-articular dorsally displaced distal radius fractures. Twenty adult patients with an Arbeitsgemeinschaft für Osteosynthesefragen (AO), type A2 or A3, distal radius fracture with an initial dorsal angulation greater than 20° were included. Nine had a tip fracture (distal to the base) of the ulnar styloid and 11 had no such fracture. They were all openly explored from an ulnopalmar approach and TFCC injuries were documented. Eleven patients also underwent arthroscopy and intra-articular pathology was recorded. All patients had TFCC lesions of varying severity, having an extensor carpi ulnaris subsheath avulsion in common. Eighteen out of 20 also displayed deep foveal radioulnar ligament lesions, with decreasingly dorsal fibres remaining. The extent of this foveal injury could not be appreciated by radiocarpal arthroscopy. Severe displacement of an extra-articular radius fracture suggests an ulnar-sided ligament injury to the TFCC. The observed lesions concur with findings in a previous cadaver study. The lesions follow a distinct pattern affecting both radioulnar as well as ulnocarpal stabilisers.


Carnival: A Graph-Based Data Integration and Query Tool to Support Patient Cohort Generation for Clinical Research.
Clinical research studies often leverage various heterogeneous data sources including patient electronic health record, online survey, and genomic data. We introduce a graph-based, data integration and query tool called Carnival. We demonstrate its powerful ability to unify data from these disparate data sources to create datasets for two studies: prevalence and incidence case/control matches for coronary artery disease and controls for Marfan syndrome. We conclude with future directions for Carnival development.


Enhancement of endogenous xenotropic murine retrovirus expression by tuftsin.
The exposure of a high-passage clone of Kirsten sarcoma virus transformed Balb/c (K-Balb) mouse cells to tuftsin (Thr-Lys-Pro-Arg) enhanced the expression of endogenous xenotropic retrovirus. The tetrapeptide increased the expression of virus that was infectious for rat, but not mouse, cells in a concentration-dependent fashion (0.001-1000 micrograms/ml). Increased virus expression could be achieved during short-term incubations (3-4 hr), with maximum enhancement occurring over longer time periods (16-18 hr). The enhancement of virus expression by tuftsin was proportional to the spontaneous release of virus. The infectivity of the enhanced virus was neutralized by goat anti-RLV gp 70 serum. Actinomycin D inhibited the induction of virus, suggesting that enhanced expression required de novo RNA synthesis. Tuftsin stimulated DNA, RNA, and protein synthesis in K-Balb cells during 16-hr incubations. Increased cellular proliferation was also seen at various time periods. The effects observed using K-Balb cells offer an opportunity to study the modulation of gene expression by tuftsin in a fibroblast culture system.