HIV, injecting drug use and harm reduction: a public health response.
Injecting drug use is driving HIV epidemics in many countries around the world. There is evidence that such epidemics can be averted, halted and reversed if comprehensive HIV programmes targeting drug users are put into place. The term 'harm reduction' is used widely to describe the goals, policies and interventions of such programmes. However, despite its rapidly expanding use, the term has no universally accepted definition. This paper aims to describe the evolution and branding of the term 'harm reduction' and the adoption of the concept across a wide range of countries. It highlights a range of issues that remain controversial in the harm reduction discourse related to HIV and injecting drug use, including: the definition of 'harm reduction' and related terms; the scope of harm reduction; the promotion of a public health versus drug control dichotomy; the feasibility and appropriateness of harm reduction in low- and middle-income countries; and the strength of evidence on harm reduction interventions. The paper argues that harm reduction should be a core element of a public health response to HIV/AIDS where injecting drug use exists. The effectiveness of policies and programmes targeting drug users should be measured against public health outcomes. This requires the alignment of drug control measures with public health goals. A 'model package' for harm reduction is proposed, which provides guidance to countries on the selection of evidence-based policies and interventions, including: interventions for reducing HIV transmission; treatment of HIV/AIDS and associated comorbidities; appropriate models of service delivery; creation of supportive policy, legal and social environments; and strengthening of strategic information systems to better guide responses.


MicroRNA-449b-5p promotes the progression of osteoporosis by inhibiting osteogenic differentiation of BMSCs via targeting Satb2.
We aimed to explore the role of microRNA-449b-5p in osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and its mechanism of action. Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) assay was used to detect the expression levels of microRNA-449b-5p and osteogenic markers including RUNX2, OCN during BMSCs differentiation. The microRNA-449b-5p mimic and microRNA-449b-5p inhibitors were transfected into BMSCs to achieve microRNA-449b-5p overexpression and knockdown, then the expressions of osteogenic markers were detected by qRT-PCR. The ALP activity staining and the alizarin red staining were used to detect the activity of ALP and the mineralization ability of cells after overexpression and knockdown of microRNA-449b-5p. Binding sites for microRNA-449b-5p and Satb2 were predicted by TargetScan, the PicTar and microRNAanda programs, and confirmed by dual-luciferase reporter gene assay. The relationship between microRNA-449b-5p and Satb2 was analyzed by QRT-PCR and Western blot. The microRNA-449b-5p inhibitor and shSATB2 lentivirus were simultaneously transfected in BMSCs, and the expression levels of RUNX2, OCN and ALP were detected by qRT-PCR and ALP activity assays. microRNA-449b-5p expression gradually decreased during osteogenic differentiation. Overexpression of microRNA-449b-5p inhibited BMSCs differentiation by down-regulating ALP activity, RUNX2, and OCN expression, while the opposite result was observed after knockdown of microRNA-449b-5p. MicroRNA-449b-5p can bind to the 3'UTR end of Satb2, which was involved in the osteogenic differentiation of microRNA-449b-5p-regulated BMSCs, and silencing of Satb2 can abolish the positive effect of the microRNA-449b-5p inhibitor on osteoblasts differentiation. microRNA-449b-5p could aggravate osteoporosis by inhibiting osteogenic differentiation of BMSCs through targeting Satb2.


False-positive EUS-guided FNA cytology for solid pancreatic lesions.
The currently accepted paradigm is that the false-positive (FP) rate for EUS-guided fine-needle aspiration (EUS-FNA) cytologic analysis of a pancreatic lesion is less than 1%. To assess the FP rate of EUS-FNA in patients who underwent surgical resection for presumed pancreatic cancer. Retrospective study. Tertiary-care referral center. This study involved 367 patients with solid pancreatic lesions in whom EUS-FNA cytology results were interpreted as positive or suspicious for malignancy, which resulted in subsequent surgical resection. Surgical resection. The FP diagnosis was defined as EUS-FNA cytology specimens being reported as "positive" or "suspicious for malignancy" but that were later proven to be benign on surgical pathology. The FP rate for EUS-FNA was 4 of 367 (1.1%) when only "positive" cytology findings were interpreted as malignant and 14 of 367 (3.8%) when both suspicious and positive cytology findings were interpreted as malignant. Among the 4 cases falsely interpreted as positive, 1 was falsely diagnosed cytologically as a neuroendocrine tumor and 3 as adenocarcinomas. All FP specimens showed chronic pancreatitis on surgical pathology. The incidence of discordance between cytology and surgical pathology did not change over time (2000-2006: 8/188 [4.3%] vs 2007-2010: 6/179 [3.4%]; P = .79). Retrospective study at a single center. In a retrospective cohort trial, the FP rate for EUS-FNA of solid pancreatic lesions was 1.1%. Findings of the current study are in line with previous studies that have evaluated the FP cytology rates with EUS-FNA of solid lesions. FP cases transpired primarily as a result of cytologic misinterpretation in the setting of chronic pancreatitis.


Tree crickets optimize the acoustics of baffles to exaggerate their mate-attraction signal.
Object manufacture in insects is typically inherited, and believed to be highly stereotyped. Optimization, the ability to select the functionally best material and modify it appropriately for a specific function, implies flexibility and is usually thought to be incompatible with inherited behaviour. Here, we show that tree-crickets optimize acoustic baffles, objects that are used to increase the effective loudness of mate-attraction calls. We quantified the acoustic efficiency of all baffles within the naturally feasible design space using finite-element modelling and found that design affects efficiency significantly. We tested the baffle-making behaviour of tree crickets in a series of experimental contexts. We found that given the opportunity, tree crickets optimised baffle acoustics; they selected the best sized object and modified it appropriately to make a near optimal baffle. Surprisingly, optimization could be achieved in a single attempt, and is likely to be achieved through an inherited yet highly accurate behavioural heuristic.


Penicillamine-induced polymyositis-dermatomyositis.
Two patients with classical rheumatoid arthritis developed myopathy during treatment with penicillamine. In both patients, electromyography and muscle biopsies were indicative of polymyositis. In one patient, muscle enzymes were not examined at the appropriate time; in the other patient muscle enzymes were raised. This latter patient also had a rash and, in the dermal epidermal junction of pathological skin, granular deposits of immunoglobulin and complement were found. The myopathy subsided in both patients after withdrawal of penicillamine.


Acute hepatitis associated with mouse leukemia. V. The neurotropic properties of the causal virus.
Observations on the behavior of MHV (Pr) in the cerebral tissue of Princeton and Swiss weanling mice indicated a limited neurotropism. The virus migrated to the brain on intraperitoneal injection and was established there by cranial passage, though with difficulty in Swiss mice. Intracerebral multiplication was rarely followed by outward signs of nervous disorder. A slight pathologic reaction occurred in the brains of intracerebrally injected Princeton mice, but it was negligible compared with that of the ensuing hepatitis. In Swiss mice, injected intracerebrally with a mixture of MHV (Pr) and Eperythrozoon coccoides, a related virus with restricted pathogenicity and host range, possibly a mutant, was isolated from the liver and brain. MHV (C), an actively hepatotropic virus recovered from leukemic Balb C mice, was much more neurotropic than MHV (Pr). Intracerebral injection of Balb C and Swiss weanling mice was attended by marked leptomeningeal and encephalitic lesions. Paralysis of the extremities occurred in some of the animals. The virus was essentially inactive in Princeton mice. During the intracerebral passage of MHV (C) in Swiss mice a pleuropneumonia-like organism was isolated from the brain. In conjunction with the virus this organism produced a vigorous leukocytic reaction.


Enamel evaluation by scanning electron microscopy after debonding brackets and removal of adhesive remnants.
The bonding of accessories in the dental crown during the orthodontic treatment creates microporosities, thus promoting micromechanical retention of the adhesive to the enamel structure. After debonding brackets, at the end of the active orthodontic treatment, a certain amount of adhesive remnants must be mechanically removed from the enamel. The objective of this study was to compare, by means of scanning electron microscopy, three different methods to remove the adhesive remnants after orthodontic bracket removal. An experimental analytical study was conducted on human premolar specimens, extracted within a year or less. The preparation of the enamel was carried out with the application of 35% phosphoric acid and Transbond XT Light Cure Adhesive Primer® adhesive. Edgwise Standart prescription brackets, slot .022 "(Morelli Orthodontia) were glued to the enamel using Transbond XT® bonding resin. The brackets were placed on the center of the vestibular face of the clinical crown, and a 300-gram pressure was exerted against the surface of the enamel, measured with an orthodontic dynamometer. The brackets were debonded with adhesive removing pliers, and the samples were divided into groups, according to the protocol used for adhesive remnant removal: high-speed multi-laminated drill bit, low-speed multi-laminated drill bit, and low-speed glass fiber. After removal of the adhesive remnants, the samples went through scanning electron microscopy, obtaining electro micrographs with a magnification range of 150 X, 500 X, and 2,000 X. The tested method showed that the best effectiveness for the removal of the adhesive remnants after bracket debonding was the use of a tungsten carbide multi-laminated high speed, followed by the use of a tungsten carbide multi-laminated, low-rotation drill. The use of fiberglass drill alone has proved to be inefficient for clinical use, given the large amounts of adhesive remnants it leaves on the enamel. All methods evaluated in this study proved to be inefficient for total removal of adhesive remnants from the enamel. Key words:Dental enamel, microscopy, orthodontics.


An alternating treatments comparison of oral and total communication training with minimally verbal retarded children.
This study was a comparison of the effects of oral speech with total communication (speech plus sign language) training on the ability of mentally retarded children to repeat 4-word sentences. Three children were chosen who used single words to communicate but who did not combine words into complete sentences. Three sentence pairs were trained, with each pair having one sentence trained using oral methods and an equivalent one trained using the total communication approach. Both training procedures involved chaining sentence parts, reinforcement, and prompting. Oral methods involved presenting vocal stimuli and requiring vocal responses whereas total communication methods involved presenting vocal and signed stimuli and requiring vocal and signed responses. For the initial sentence pair with each child, an alternating treatments design was used to determine the relative efficacy of the two language training approaches. This was repeated with a second and third sentence pair using a multiprobe technique within a multiple baseline design. Results pointed to the superiority of the total communication approach in facilitating sentence repetition. Possible explanations of these results are offered and the utility of the alternating treatments experimental design is discussed.


Bimetallics in a Nutshell: Complexes Supported by Chelating Naphthyridine-Based Ligands.
Bimetallic motifs are a structural feature common to some of the most effective and synthetically useful catalysts known, including in the active sites of many metalloenzymes and on the surfaces of industrially relevant heterogeneous materials. However, the complexity of these systems often hampers detailed studies of their fundamental properties. To glean valuable mechanistic insight into how these catalysts function, this research group has prepared a family of dinucleating 1,8-naphthyridine ligands that bind two first-row transition metals in close proximity, originally designed to help mimic the proposed active site of metal oxide surfaces. Of the various bimetallic combinations examined, dicopper(I) is particularly versatile, as neutral bridging ligands adopt a variety of different binding modes depending on the configuration of frontier orbitals available to interact with the Cu centers. Organodicopper complexes are readily accessible, either through the traditional route of salt metathesis or via the activation of tetraarylborate anions through aryl group abstraction by a dicopper(I) unit. The resulting bridging aryl complexes engage in C-H bond activations, notably with terminal alkynes to afford bridging alkynyl species. The μ-hydrocarbyl complexes are surprisingly tolerant of water and elevated temperatures. This stability was leveraged to isolate a species that typically represents a fleeting intermediate in Cu-catalyzed azide-alkyne coupling (CuAAC); reaction of a bridging alkynyl complex with an organic azide afforded the first example of a well-defined, symmetrically bridged dicopper triazolide. This complex was shown to be an intermediate during CuAAC, providing support for a proposed bimetallic mechanism. These platforms are not limited to formally low oxidation states; chemical oxidation of the hydrocarbyl complexes cleanly results in formation of mixed valence CuICuII complexes with varying degrees of distortion in both the bridging moiety and the dicopper core. Higher oxidation states, e.g., dicopper(II), are easily accessed via oxidation of a dicopper(I) compound with air to give a CuII2(μ-OH)2 complex. Reduction of this compound with silanes resulted in the unexpected formation of pentametallic copper(I) dihydride clusters or trimetallic monohydride complexes, depending on the nature of the silane. Finally, development of an unsymmetrical naphthyridine ligand with mixed donor side-arms enables selective synthesis of an isostructural series of six heterobimetallic complexes, demonstrating the power of ligand design in the preparation of heterometallic assemblies.


Comprehensive smoking bans and acute myocardial infarction among Medicare enrollees in 387 US counties: 1999-2008.
Restrictions on smoking in public places have become increasingly widespread in the United States, particularly since the year 2005. National-scale studies in Europe and local-scale studies in the United States have found decreases in hospital admissions for acute myocardial infarction (AMI) following smoking bans. The authors analyzed AMI admission rates for the years 1999-2008 in 387 US counties that enacted comprehensive smoking bans across 9 US states, using a study population of approximately 6 million Medicare enrollees aged 65 years or older. Effects of smoking bans on AMI admissions were estimated by using Poisson regression with linear and nonlinear adjustment for secular trend and random effects at the county level. Under the assumption of linearity in the secular trend of declining AMI, smoking bans were associated with a statistically significant ban-associated decrease in admissions for AMI in the 12 months following the ban. However, the estimated effect was attenuated to nearly zero when the assumption of linearity in the underlying trend was relaxed. This analysis demonstrates that estimation of potential health benefits associated with comprehensive smoking bans is challenged by the need to adjust for nonlinearity in secular trend.


The influence of age and sex on asthma admissions.
To describe demographic data from a large population of asthmatic patients to define the role of age and sex as risk factors for asthma admission. A retrospective review of all asthma admissions as defined by International Classification of Diseases, Ninth Revision, code 493.0. All medical-surgical admissions from 67 hospitals in five counties of southeastern Pennsylvania from 1986 through 1989. Patients admitted for asthma treatment (33,269) were reviewed. In the 0- to 5-year-old and 6- to 10-year-old age groups, males were admitted nearly twice as often as age-identical females. In the 11- to 20-year-old age group, admissions for males and females were nearly identical. Between 20 and 50 years of age, the female-to-male ratio was nearly 3:1. Thereafter, females were admitted for asthma at a rate of about 2.5:1 when compared with their age-equivalent male counterparts. Length of stay increased proportionally as the patient age increased. After 30 years of age, the length of stay was slightly greater for females than males. There is a much higher rate of admission for prepubertal males than females. However, there is a higher incidence of asthma admissions for adult females than adult male asthmatic patients, and female asthmatic patients experience longer hospital stays per admission as well. These data indicate that adult females are more severely affected by asthma and raise the possibility that hormonal or biochemical differences related to sex may play a role in the pathophysiology of asthma.


Gut epithelial cell-derived exosomes trigger posttrauma immune dysfunction.
Exosomes are extracellular vesicles that act as endogenous mediators of the immune response. We have previously shown that exosomes released into mesenteric lymph (ML) following trauma (T)/hemorrhagic shock (HS) induce proinflammatory cytokine production in macrophages and are involved in the pathogenesis of postshock acute lung injury. However, the cellular origin of ML exosomes and their role in the posttrauma immune response remains unclear. We hypothesized that exosomes released from damaged-intestinal epithelial cells contribute to posttrauma immune dysfunction by altering the function of dendritic cells (DCs), key regulators of the adaptive immunity. Male rats underwent cannulation of the femoral artery, jugular vein and ML duct. T/HS was induced by laparotomy and 60 minutes of hemorrhagic shock followed by resuscitation. The ML was collected before (preshock) and after T/HS (post-T/HS) for isolation of exosomes. Surface epitopes of exosomes isolated from ML were assessed by flow cytometry to determine their cellular origin and phenotypic changes. The immunomodulatory effects of ML exosomes on DCs were assessed by Annexin V apoptosis assay, expression of costimulatory molecules, and antigen-presenting capacity to lymphocytes. Exosomes isolated from ML highly expressed CD63 (exosome marker) and epithelial cell-specific marker, suggesting their derivation from intestinal epithelial cells. The expression of immunomodulatory molecules, such as major histocompatibility complex class II and Fas ligand on ML exosomes, was significantly increased after T/HS. Coincubation of DCs with exosomes isolated from ML after T/HS increased DC apoptosis twofold compared with preshock ML exosomes. Furthermore, post-T/HS ML exosomes significantly suppressed lipopolysaccharide-mediated expression of CD80 and CD86 on DCs as well as decreased their antigen-presenting capacity to induce lymphocytes proliferation. Gut epithelial cells release immunomodulatory exosomes into the ML after T/HS and resuscitation. Mesenteric lymph exosomes may be critical mediators of posttraumatic immunosuppression causing depletion and dysfunction of DCs.


Inhibition of type I and type III interferons by a secreted glycoprotein from Yaba-like disease virus.
Type I (IFN-alpha/beta) and type III (IFN-lambdas) IFNs are important components of the host antiviral response. Although type III IFNs possess intrinsic antiviral activity similar to that of type I IFNs, they signal through a specific unique receptor complex, and their functional importance for antiviral resistance is largely uncharacterized. Here, we report the first virus defense mechanism that directly targets type III IFNs. Y136 from Yaba-like disease virus, a yatapoxvirus, is a secreted glycoprotein related to protein B18 from Vaccinia virus, a known type I IFN-binding protein and a member of the Ig superfamily. Surprisingly, whereas B18 inhibits only type I IFNs, Y136 inhibits both type I and type III IFNs. Y136 inhibits IFN-induced signaling and suppresses IFN-mediated biological activities including up-regulation of MHC class I antigen expression and induction of the antiviral state. These data demonstrate that poxviruses have developed unique strategies to counteract IFN-mediated antiviral protection and highlight the importance of type III IFNs in antiviral defense. These results suggest that type III IFNs may be an effective treatment for some poxviral infections.


Vital signs: Unintentional injury deaths among persons aged 0-19 years - United States, 2000-2009.
Unintentional injuries are the leading cause of death in the United States for persons aged 1-19 years and the fifth leading cause of death for newborns and infants aged <1 year. This report describes 10-year trends in unintentional injury deaths among persons aged 0-19 years. CDC analyzed 2000-2009 mortality data from the National Vital Statistics System by age group, sex, race/ethnicity, injury mechanism, and state. From 2000 to 2009, the overall annual unintentional injury death rate decreased 29%, from 15.5 to 11.0 per 100,000 population, accounting for 9,143 deaths in 2009. The rate decreased among all age groups except newborns and infants aged <1 year; in this age group, rates increased from 23.1 to 27.7 per 100,000 primarily as a result of an increase in reported suffocations. The poisoning death rate among teens aged 15-19 years nearly doubled, from 1.7 to 3.3 per 100,000, in part because of an increase in prescription drug overdoses (e.g., opioid pain relievers). Childhood motor vehicle traffic-related death rates declined 41%; however, these deaths remain the leading cause of unintentional injury death. Among states, unintentional injury death rates varied widely, from 4.0 to 25.1 per 100,000 in 2009. CONCLUSIONS AND IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Although the annual rate is declining, unintentional injury remains the leading cause of death among children and adolescents in the United States, led by motor vehicle traffic-related deaths. Death rates from infant suffocation and teen poisoning are increasing. The 2012 National Action Plan for Child Injury Prevention provides actions in surveillance, research, communication, education, health care, and public policy to guide efforts in saving lives by reducing injuries.


The activity levels and quality of life of physically disabled children who continued or did not continue rehabilitation during the COVID-19 pandemic.
Social isolation during the COVID-19 pandemic had a harmful impact on the psychological and physical health of children and teenagers. It is known that interruptions in rehabilitation can cause soft tissue contractures, bone deformities and a decline in motor functions among other complications. The aim of this study was to compare the quality of life and physical activity levels of physically disabled children who continued and did not continue rehabilitation during the COVID-19 pandemic. The gross motor levels of 18 children who continued special education and rehabilitation during the COVID-19 pandemic and 18 children who did not continue were determined with the Gross Motor Function Classification System (GMFCS). The International Physical Activity Questionnaire Short Form (IPAQ) and Children's Quality of Life Scale (PedsQL) questionnaires were administered. The study participants comprised 54.1% females and 45.9% males with a mean age of 9.02 years. No significant differences were detected between the two groups in respect of demographic, clinical and functional characteristics (p > 0.05). The walking parameters of PedsQL (p = 0.02) and IPAQ-SF scores (p = 0.03) were determined to be statistically significantly better in the group that continued rehabilitation. The results of this study demonstrated that the quality of life and walking capacity of children who continued rehabilitation during the COVID-19 pandemic were better. Methods should be developed to ensure that rehabilitation is not interrupted during isolation periods of any future pandemic.


Inter-individual variability of in vivo CYP2D6 activity in different genotypes.
Cytochrome P450 2D6 (CYP2D6), which has a large number of genetic polymorphisms, is involved in the metabolism of a wide range of substrates. Dextromethorphan (DM) is a well-known probe drug for CYP2D6 and metabolic ratio (MR) is often used to measure the enzyme activity in vivo. Using the literature values of DM MR, we estimated the inter-individual variability of CYP2D6 hepatic intrinsic clearance (CL(int,h,2D6)) in each genotype by Monte Carlo simulation and found that the homozygote of CYP2D6*1 and the heterozygote of CYP2D6*1 and null alleles had a coefficient of variation (CV) of 43% and 56%, respectively. The variability of homozygotes of CYP2D6*2 and CYP2D6*10 was 63% and 66%, while that of the heterozygotes of CYP2D6*2 and null alleles and CYP2D6*10 and null alleles was 125% and 109%, respectively. Based on the variability and reported frequency of the CYP2D6 genotype in Asians and Caucasians, the inter-individual variability of CL(int,h,2D6) of extensive metabolizers was estimated at 60-70%, which provided comparable variability of AUC with the literature values of DM, tolterodine, risperidone and atomoxetine. It is suggested that the produced inter-individual variability of CL(int,h,2D6) in each genotype is useful for estimating AUC variability of the CYP2D6 substrates in the regional population.


Isolation, stability, and characteristics of high-pressure superdormant Bacillus subtilis spores.
Bacterial spores are a major challenge in industrial decontamination processes owing to their extreme resistance. High-pressure (HP) of 150 MPa at 37 °C can trigger the germination of spores, making them lose their extreme resistance. Once their resistance is lost, germinated spores can easily be inactivated by a mild decontamination step. The implementation of this gentle germination-inactivation strategy is hindered by the presence of a subpopulation of so-called high-pressure superdormant (HPSD) spores, which resist germination or germinate only very slowly in response to HP. It is essential to understand the properties of HPSD spores and the underlying causes of superdormancy to tackle superdormant spores and further develop germination-inactivation strategies involving HP. This study investigated factors influencing the prevalence of HPSD spores and successfully isolated them by combining buoyant density centrifugation and fluorescence-activated cell sorting, which allowed further characterisation of HPSD spores for the first time. The prevalence of HPSD spores was shown to be strongly dependent on the HP dwell time, with increasing treatment times reducing their prevalence. Spore mutants lacking major germinant receptors further showed a highly increased prevalence of HPSD spores; 93% of the spores remained dormant even after a prolonged HP dwell time of 40 min. In contrast to nutrient germination, sublethal heat treatment of 75 °C for 30 min prior to pressure treatment did not induce spore activation and increase germination. The isolated HPSD spores did not show visible structural differences compared to the initial dormant spores when investigated with transmission electron microscopy. Re-sporulated HPSD spores showed similar germination capacity compared to the initial dormant spores, indicating that HPSD spores are most likely not genetically different from the rest of the population. Moreover, the majority of HPSD spores germinated when exposed a second time to the same germination treatment; however, the germination capacity was lower than that of the initial population. The fact that the majority of spores lost superdormancy when exposed a second time to the same trigger makes it unlikely that there is one factor that determines whether a spore germinates with a certain HP treatment or not. Instead, it seems possible that there are other reversible or cumulative causes. This study investigated the factors influencing spore HP superdormancy to improve the understanding of HPSD spores with regard to their stability, germination capacity, and potential underlying causes of spore HP superdormancy. This knowledge will contribute to the development of HP-based germination-inactivation strategies for gentle but effective spore control.


Medical devices and public policy: the pharmaceuticals analogy.
In much of the world, public health policy regarding medical devices and the need to ensure their safety is poorly defined and much less developed than that regarding pharmaceuticals. A small number of countries have now established systems to monitor risk and to ensure some form of assessment and approval of medical equipment, at least where an element of risk could be involved. In view of the very large number of medical devices and current evidence of their unwanted effects there is a reason for the extension of such monitoring and licensing systems, complemented by self-regulatory mechanisms. Measures are also needed to ensure that when they enter the field devices are properly used and maintained. In various respects, the close analogy of pharmaceutical regulation can be applied.


Genetic risk score for prediction of newborn adiposity and large-for-gestational-age birth.
Macrosomic infants are at increased risk for adverse metabolic outcomes. Improving prediction of large-for-gestational-age (LGA) birth may help prevent these outcomes. This study sought to determine whether genes associated with obesity-related traits in adults are associated with newborn size, and whether a genetic risk score (GRS) predicts LGA birth. Single nucleotide polymorphisms (SNPs) in 40 regions associated with adult obesity-related traits were tested for association with newborn size. GRS's for birth weight and sum of skinfolds (SSF) specific to ancestry were calculated using the most highly associated SNP for each ancestry in genomic regions with one or more SNPs associated with birth weight and/or SSF in at least one ancestry group or meta-analyses. Newborns from the Hyperglycemia Adverse Pregnancy Outcomes Study were studied (942 Afro-Caribbean, 1294 Northern European, 573 Mexican-American, and 1182 Thai). Birth weight >90th percentile (LGA) and newborn SSF >90th percentile were primary outcomes. After adjustment for ancestry, sex, gestational age at delivery, parity, maternal genotype, maternal smoking/alcohol intake, age, body mass index, height, blood pressure and glucose, 25 and 23 SNPs were associated (P < .001) with birth weight and newborn SSF, respectively. The GRS was highly associated with both phenotypes as continuous variables across all ancestries (P ≤ 1.6 × 10(-19)) and improved prediction of birth weight and SSF >90th percentile when added to a baseline model incorporating the covariates listed above. A GRS comprised of SNPs associated with adult obesity-related traits may provide an approach for predicting LGA birth and newborn adiposity beyond established risk factors.


Evaluation of Electromechanical Properties and Conversion Efficiency of Piezoelectric Nanocomposites with Carbon-Fiber-Reinforced Polymer Electrodes for Stress Sensing and Energy Harvesting.
Wireless sensor networks are the future development direction for realizing an Internet of Things society and have been applied in bridges, buildings, spacecraft, and other areas. Nevertheless, with application expansion, the requirements for material performance also increase. Although the development of carbon-fiber-reinforced polymer (CFRP) to achieve these functions is challenging, it has attracted attention because of its excellent performance. This study combined the CFRP electrode with epoxy resin containing potassium sodium niobate piezoelectric nanoparticles and successfully polarized the composite sample. Furthermore, a three-point bending method was applied to compare the bending behavior of the samples. The peak output voltage produced by the maximum bending stress of 98.4 MPa was estimated to be 0.51 mV. Additionally, a conversion efficiency of 0.01546% was obtained. The results showed that the piezoelectric resin with CFRPs as the electrode exhibited stress self-inductance characteristics. This study is expected to be applied in manufacturing self-sensing piezoelectric resin/CFRP composite materials, paving the way for developing stable and efficient self-sensing structures and applications.


An ascochlorin derivative, AS-6, reduces insulin resistance in the genetically obese diabetic mouse, db/db.
An ascochlorin derivative, AS-6, is a new hypoglycemic agent orally active in both obese hyperinsulinemic and insulin-deficient diabetic animal models. AS-6, when given as a 0.025-0.2% admixture in the diet, dose-dependently ameliorated polydipsia, polyuria, and glycosuria in the genetically obese diabetic mouse, C57BL/KsJ db/db, while neither insulin nor tolbutamide showed any beneficial effects. The amelioration by AS-6 was associated with a marked decrease in serum glucose and triglyceride. The effects persisted at least 10 wk, accompanied by a steady decrease in drinking water consumption. The chronic treatment prevented pancreatic islet degeneration, e.g., degranulation of the beta-cells, basophilic appearance of the exocrine border around the islets, and small round cell infiltration. The isolated islets from AS-6-treated mice released much more insulin in response to glucose than those from untreated controls. A significant correlation between serum immunoreactive insulin and glucose/triglyceride from both treated and untreated mice suggests that AS-6 restores sensitivity and responsiveness to insulin to the mice. In fact, the combined treatment with insulin synergistically decreased serum glucose by 50% below AS-6 treatment alone. Furthermore, the epididymal fat pad slices from AS-6-treated db/db mice increased CO2 generation and lipogenesis over the untreated controls, and the glucose metabolic rate (CO2 generation plus lipogenesis from U-[14C]-glucose) in the slices and the serum glucose level inversely correlated at r = 0.8799.(ABSTRACT TRUNCATED AT 250 WORDS)


Heavy metal induced oxidative stress & its possible reversal by chelation therapy.
Exposure to heavy metals is a common phenomenon due to their environmental pervasiveness. Metal intoxication particularly neurotoxicity, genotoxicity, or carcinogenicity is widely known. This review summarizes our current understanding about the mechanism by which metalloids or heavy metals (particularly arsenic, lead, cadmium and mercury) induce their toxic effects. The unifying factor in determining toxicity and carcinogenicity for all these metals is the generation of reactive oxygen and nitrogen species. The toxic manifestations of these metals are caused primarily due to imbalance between pro-oxidant and antioxidant homeostasis which is termed as oxidative stress. Besides these metals have high affinity for thiol groups containing enzymes and proteins, which are responsible for normal cellular defense mechanism. Long term exposure to these metals could lead to apoptosis. Signaling components affected by metals include growth factor receptors, G-proteins, MAP kinases and transcription factors. Chelation therapy with chelating agents like calcium disodium ethylenediamine tetra acetic acid (CaNa(2)EDTA), British Anti Lewisite (BAL), sodium 2,3-dimercaptopropane 1-sulfonate (DMPS), meso 2,3-dimercaptosuccinic acid (DMSA) etc., is considered to be the best known treatment against metal poisoning. Despite many years of research we are still far away from effective treatment against toxicity caused due to exposure to heavy metals/metalloids. The treatment with these chelating agents is compromised with number of serious side-effects. Studies show that supplementation of antioxidants along-with a chelating agent prove to be a better treatment regimen than monotherapy with chelating agents. This review attempts a comprehensive account of recent developments in the research on heavy metal poisoning particularly the role of oxidative stress/free radicals in the toxic manifestation, an update about the recent strategies for the treatment with chelating agents and a possible beneficial role of antioxidants supplementation to achieve the optimum effects. We have selected only arsenic, lead, mercury and cadmium for this article keeping in view current concerns and literature available.


Gastro-oesophageal reflux and severity of pulmonary disease in cystic fibrosis.
The correlation between oesophageal dysfunction (OD), pathologic gastro-oesophageal reflux (GOR), and severity of pulmonary disease was studied in 12 patients with cystic fibrosis (CF). They were interviewed about symptoms of OD and underwent 24-h pH recording in the oesophagus, oesophageal manometry combined with reflux provocation tests, the acid perfusion test, the acid clearance test, lung function tests, and scoring of the chest radiograph. Six of the 12 patients reported symptoms of OD. Abnormal GOR, as shown by 24-h pH monitoring of the oesophagus, was found in eight of them. Altogether 9 of the 12 participants had at least one pathologic oesophagus test result. Results of radiologic examinations of the oesophagus, performed in six patients, were pathologic. The four patients with the best chest radiograph scores and the best lung function had significantly less signs and symptoms of OD and GOR than the other eight patients. We conclude that OD, GOR, and pulmonary disease covariate in CF.


Decreasing glycerol content by co-supplementation of trehalose and taxifolin hydrate in ram semen extender: Microscopic, oxidative stress, and gene expression analyses.
This study aimed to evaluate the comparative effects of taxifolin hydrate and trehalose on the quality of frozen-thawed ram spermatozoa for the first time. Ejaculates collected from six mature rams were pooled, and divided to eight equal aliquots to extend them with different concentrations of glycerol (%5 and %3), taxifolin hydrate (10, 100, and 500 μM), and trehalose (60 mM) as eight groups (G5T0, G5T10, G5T100, G5T500, G3T0, G3T10, G3T100, and G3T500). After freeze-thawing process of cryopreservation, microscopic and oxidative stress parameters, and gene expression levels were investigated for understanding of possible impacts of taxifolin hydrate and trehalose. The study showed that G3T10 resulted in the highest post-thawed viability and mitochondrial activity. Moreover, all extenders with taxifolin hydrate reduced DNA fragmentation in comparison to G5T0, but DNA damage was prevented at the highest rate in presence of G5T10. The level of LPO significantly decreased in the groups G5T500 and G3T100, and the expression levels of NQO1, GCLC, and GSTP1 genes significantly increased in the groups G5T100, G5T500, G3T10, and G3T100 compared to the group G5T0. Finally, co-supplementation of tris-based extender having 3% glycerol with 60 mM trehalose and 10 μM taxifolin hydrate in cryopreservation extender may be recommended to improve the quality of post-thawed ram spermatozoa. However, further in vivo and in vitro studies are suggested to evaluate fertility rates of frozen-thawed ram spermatozoa co-supplemented with trehalose and taxifolin hydrate.


Measuring and modeling the social and geographic context of trauma: a multilevel modeling approach.
Increasingly it is recognized that health and illness are products of individual level risk and protective factors, as well as forces operating at contextual levels. In this article, we present the motivation and rationale for understanding trauma within its context. We use the example of the concept of social capital to illustrate the relevance of the contextual approach for trauma research and outline a multilevel modeling approach to examining contextual influences on trauma outcomes.


Inhibition of Adenosine Pathway Alters Atrial Electrophysiology and Prevents Atrial Fibrillation.
Adenosine leads to atrial action potential (AP) shortening through activation of adenosine 1 receptors (A1-R) and subsequent opening of G-protein-coupled inwardly rectifying K+ channels. Extracellular production of adenosine is drastically increased during stress and ischemia. The aim of this study was to address whether the pharmacological blockade of endogenous production of adenosine and of its signaling prevents atrial fibrillation (AF). The role of A1-R activation on atrial action potential duration, refractoriness, and AF vulnerability was investigated in rat isolated beating heart preparations (Langendorff) with an A1-R agonist [2-chloro-N 6-cyclopentyladenosine (CCPA), 50 nM] and antagonist [1-butyl-3-(3-hydroxypropyl)-8-(3-noradamantyl)xanthine (PSB36), 40 nM]. Furthermore, to interfere with the endogenous adenosine release, the ecto-5'-nucleotidase (CD73) inhibitor was applied [5'-(α,β-methylene) diphosphate sodium salt (AMPCP), 500 μM]. Isolated trabeculae from human right atrial appendages (hRAAs) were used for comparison. As expected, CCPA shortened AP duration at 90% of repolarization (APD90) and effective refractory period (ERP) in rat atria. PSB36 prolonged APD90 and ERP in rat atria, and CD73 inhibition with AMPCP prolonged ERP in rats, confirming that endogenously produced amount of adenosine is sufficiently high to alter atrial electrophysiology. In human atrial appendages, CCPA shortened APD90, while PSB36 prolonged it. Rat hearts treated with CCPA are prone to AF. In contrast, PSB36 and AMPCP prevented AF events and reduced AF duration (vehicle, 11.5 ± 2.6 s; CCPA, 40.6 ± 16.1 s; PSB36, 6.5 ± 3.7 s; AMPCP, 3.0 ± 1.4 s; P < 0.0001). A1-R activation by intrinsic adenosine release alters atrial electrophysiology and promotes AF. Inhibition of adenosine pathway protects atria from arrhythmic events.


De novo discovery of serotonin N-acetyltransferase inhibitors.
Serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AANAT) is a member of the GCN5 N-acetyltransferase (GNAT) superfamily and catalyzes the penultimate step in the biosynthesis of melatonin; a large daily rhythm in AANAT activity drives the daily rhythm in circulating melatonin. We have used a structure-based computational approach to identify the first druglike and selective inhibitors of AANAT. Approximately 1.2 million compounds were virtually screened by 3D high-throughput docking into the active site of X-ray structures for AANAT, and in total 241 compounds were tested as inhibitors. One compound class, containing a rhodanine scaffold, exhibited low micromolar competitive inhibition against acetyl-CoA (AcCoA) and proved to be effective in blocking melatonin production in pineal cells. Compounds from this class are predicted to bind as bisubstrate inhibitors through interactions with the AcCoA and serotonin binding sites. Overall, this study demonstrates the feasibility of using virtual screening to identify small molecules that are selective inhibitors of AANAT.


JBEAM: multiscale curve coding via beamlets.
A multiscale coder for curves and boundaries is presented. It utilizes a multiscale structure--beamlets--that is designed primarily for linear and curvilinear features. The coder is composed of three main components: 1) a rate-distortion optimized beamlet-based representation, 2) a tree-based coding from a beamlet representation to a symbol stream, and 3) an entropy coder. This coder is named "JBEAM." Taking advantage of its multiscale property, we utilized tree-based coding to make it progressive. The derived coder has a low order of computational complexity. Simulations demonstrate an advantage over the state-of-the-art industrial standard: JBIG 2. A software package, which includes an implementation of JBEAM, is made available. Variations and potential improvements of this method will be discussed. This work may inspire more activities in this line of research, improving curve coding.


A special case of Wellens' syndrome.
Wellens' syndrome is a pattern of electrocardiographic T-wave changes associated with critical stenosis of proximal left anterior descending artery (LAD). T-waves abnormalities were found in precordial leads, especially in V2-V3 during pain-free periods, and ECG obtained during episodes of pain demonstrates upright T-waves with possible elevated or isoelectric ST segments. Early recognition and appropriate intervention carries significant diagnostic and prognostic value. We reported a case of Wellens' syndrome with different etiology and prognosis. Although the ECG showed typical T-wave changes in V2-V5 leads, patient's coronary angiography revealed moderate stenosis in proximal LAD, and coronary artery spasm was suggested. Unlike the classic Wellens' syndrome, which needs aggressive coronary intervention, our patient fared well with conservative medical therapy (diltiazem and nitrates) and showed favorable prognosis.


[Intensive care - palliative care. Contradiction or supplement? Considerations on ethical issues and principles in the treatment of dying patients].
Over the last five decades the progress in intensive care has extended the limitations of controlling the process of dying and given doctors more influence in determining the time of death. More recently, palliative care has emerged as a new approach in response to the ethical dilemmas of modern medicine, which accepts that dying is a natural process that should not be hastened or delayed through medical interventions. While in Germany in 1999 more than 50 000 people have died in intensive care units, only a small number of 8000 patients have died in palliative care. In comparison to the highly-developed intensive care sector, palliative care is a much neglected area. The public debate following the legalisation of euthanasia in the Netherlands has highlighted concerns in Germany that intensive care has the potential of inappropriately prolonging life and raised expectations about the alternative therapies offered by palliative care. Doctors in intensive care and in palliative care face similar ethical dilemmas, though with a different weighting: the dilemma between professional judgement and patient autonomy, between traditional medical roles and patient self-determination and the dilemma of extending the span of life at the expense of quality of life. The approach of palliative care with its strong focus on alleviating the suffering of the terminally ill, has influenced the ethical debate of dying in intensive care. Although intensive care and palliative care have different aims and priorities, there are common problems of decision-making which could benefit from a shared orientation and interdisciplinary debate. Both the interpretation of a dying parent's will as well as withdrawing or withholding treatment in patients who are unable to decide for themselves should not merely be guided by the debate on active and passive euthanasia, but rather take into account the appropriateness or inappropriateness of medical actions in the specific situation.


Health literacy, self-efficacy, and patients' assessment of medical disclosure and consent documentation.
Informed consent documents are designed to convey the risks of medical procedures to patients, yet they are often difficult to understand; this is especially true for individuals with limited health literacy. An important opportunity for advancing knowledge about health literacy and informed consent involves examining the theoretical pathways that help to explain how health literacy relates to information processing when patients read consent forms. In this study, we proposed and tested a model that positioned self-efficacy as a mediator of the association between health literacy and patients' comprehension and assessment of informed consent documentation. Findings from structured interviews with patients (n = 254) indicated that lower health literacy predicted lower self-efficacy, which predicted feeling less well informed and less prepared, being more confused about the procedure and its hazards, and wanting more information about risks. Incorporating awareness of self-efficacy into disclosure documents and consent conversations may be a useful means of prompting patients to ask questions that can help them make informed decisions about care.


Intensity-modulated radiotherapy and chemotherapy for canine right atrial tumors: A retrospective study of seven dogs.
Most primary cardiac tumors in dogs are located in the right atrium/atrial appendage, with hemangiosarcoma being the most common. The aims of this retrospective, case series were to describe outcomes for seven dogs with right atrial tumors treated with hypofractionated intensity-modulated radiotherapy and concurrent vinblastine and propranolol. One dog had a complete response, four dogs had partial responses and two dogs had stable disease after treatment. Effusions resolved in all dogs. Median progression-free survival was 290 days. Five dogs died from metastatic disease, one dog from unrelated neoplasia, and one dog is alive. Median overall survival was 326 days. Three dogs with confirmed hemangiosarcoma survived 244, 326, and 445 days. Two dogs developed clinically significant, but nonfatal, cardiac arrhythmias. One dog that received three courses of radiation had subclinical myocardial and arterial fibrosis at necropsy. Hypofractionated chemoradiotherapy was well tolerated and may provide clinical benefit in dogs with right atrial tumors.


Measurement of the trapping efficiency of an elliptical optical trap with rigid and elastic objects.
Optical tweezers and their various modifications offer a sophisticated way to perform noncontact cell manipulation. In this paper, we quantify forces existing in an elliptical trap formed by two cylindrical lenses and compare the results with a point optical trap case. The trapping efficiency of point and elliptical traps was analyzed by measuring the Q values of both traps. Polystyrene microspheres and red blood cells (RBCs) were used as samples. Stretching of the RBC was taken into account in the Q value measurements. Although the Q value of a point optical trap is larger than that of an elliptical trap when measured for a single RBC, we can manipulate the orientation of an RBC in a point trap with the elliptical trap and can also trap several RBCs simultaneously in the elliptical trap far from the cuvette surfaces by using a long-working-distance water immersion objective. This opens new possibilities for studying light-matter interactions at the cellular level.


Integrated analysis of regulatory and metabolic networks reveals novel regulatory mechanisms in Saccharomyces cerevisiae.
We describe the use of model-driven analysis of multiple data types relevant to transcriptional regulation of metabolism to discover novel regulatory mechanisms in Saccharomyces cerevisiae. We have reconstructed the nutrient-controlled transcriptional regulatory network controlling metabolism in S. cerevisiae consisting of 55 transcription factors regulating 750 metabolic genes, based on information in the primary literature. This reconstructed regulatory network coupled with an existing genome-scale metabolic network model allows in silico prediction of growth phenotypes of regulatory gene deletions as well as gene expression profiles. We compared model predictions of gene expression changes in response to genetic and environmental perturbations to experimental data to identify potential novel targets for transcription factors. We then identified regulatory cascades connecting transcription factors to the potential targets through a systematic model expansion strategy using published genome-wide chromatin immunoprecipitation and binding-site-motif data sets. Finally, we show the ability of an integrated metabolic and regulatory network model to predict growth phenotypes of transcription factor knockout strains. These studies illustrate the potential of model-driven data integration to systematically discover novel components and interactions in regulatory and metabolic networks in eukaryotic cells.


Synergistic effect of afatinib with su11274 in non-small cell lung cancer cells resistant to gefitinib or erlotinib.
Epidermal growth factor receptor (EGFR) and c-MET receptors are expressed on many non-small cell lung cancer (NSCLC) cells. Current single agent therapeutic targeting of a mutant EGFR has a high efficacy in the clinic, but is not curative. Here, we investigated the combination of targeting EGFR and c-MET pathways in NSCLC cells resistant to receptor tyrosine kinase inhibitors (TKIs), using RNA interference and inhibition by TKIs. Different NSCLC cell lines with various genomic characteristics (H358, H1650 and H1975) were transfected with EGFR-specific-siRNA, T790M-specific-siRNA, c-MET siRNA or the combination. Subsequently EGFR TKIs (gefitinib, erlotinib or afatinib) or monoclonal antibody cetuximab were combined respectively with the c-MET-specific TKI su11274 in NSCLC cell lines. The cell proliferation, viability, caspase-3/7 activity and apoptotic morphology were monitored by spectrophotometry, fluorimetry and fluorescence microscopy. The combined effect of EGFR TKIs, or cetuximab and su11274, was evaluated using a combination index. The results showed that the cell lines that were relatively resistant to EGFR TKIs, especially the H1975 cell line containing the resistance T790M mutation, were found to be more sensitive to EGFR-specific-siRNA. The combination of EGFR siRNA plus c-MET siRNA enhanced cell growth inhibition, apoptosis induction and inhibition of downstream signaling in EGFR TKI resistant H358, H1650 and H1975 cells, despite the absence of activity of the c-MET siRNA alone. EGFR TKIs or cetuximab plus su11274 were also consistently superior to either agent alone. The strongest biological effect was observed when afatinib, an irreversible pan-HER blocker was combined with su11274, which achieved a synergistic effect in the T790M mutant H1975 cells. In a conclusion, our findings offer preclinical proof of principle for combined inhibition as a promising treatment strategy for NSCLC, especially for patients in whom current EGFR-targeted treatments fail due to the presence of the T790M-EGFR-mutation or high c-MET expression.


Graphene nanodots with intrinsically magnetic protrusions.
The three step auf bau of a triangular polyaromatic protrusion attached to a larger parent hexagonal shaped graphene nanodot (GND) is described and the dichotomy between intrinsic protrusion localized magnetism and parent extended zigzag edge magnetism is explored using ab initio density functional theory calculations of spin and charge distributions and geometry. Comparison of a three ring with a ten-ring protrusion-GND establishes a pattern for the magnetization of GNDs with larger protrusions and different morphology. The magnetism of the isolated protrusions arises from the mismatch in numbers of sublattice (alternant hydrocarbon) carbon atoms. In the parent, the sublattices are equivalent providing a singlet ground state and the magnetization appears only on long zigzag edges due to exchange interactions operating in a regime of reduced coulombic interactions. We demonstrate that a small protrusion can quench the magnetism of the edge to which it is attached. Concomitantly, the adjacent edges exhibit a small magnetic enhancement, while the remote edges are unperturbed. With size the protrusion can dominate its edge and exert control over the magnetization of other edges. Different multiplicities of the parent moiety were not found. These calculations provide guidance in understanding how the magnetism changes with system shape and in designing nanodots with a specific magnetization.


Children's perception of interpersonal coordination during joint painting.
Interpersonal coordination is important for many joint activities. A special case of interpersonal coordination is synchronization, which is required for the performance of many activities, but is also associated with diverse positive social and emotional attributes. The extent to which these effects are due to the reliance on synchrony for task performance or to its specific rhythmic characteristics, is not clear. To address these questions, we considered a more general form of interpersonal coordination, implemented during joint artmaking. This is a non-typical context for interpersonal coordination, not required for task success, and smoother and more loosely-structured than more standard forms of synchronous coordination. Therefore, comparing interpersonal coordination with non-coordination during shared painting, could help reveal general social-emotional reactions to coordination. To gain a more 'naïve' perspective we focused on children, and staged coordinated and non-coordinated art interactions between an adult and a child, asking child observers to judge various variables reflecting the perceived bond between the painters. We found an overall stronger perceived bond for the coordination condition. These results demonstrate that even a non-typical form of interpersonal coordination could be attributed with positive social and emotional qualities, a capacity revealed already in childhood, with possible implications for development.


Shiitake mushroom (Lentinus edodes): a poorly known allergen in Western countries responsible for severe work-related asthma.
The aim of this study was to investigate the IgE-mediated pathogenesis of severe asthma presented by a patient only after handling shiitake (Lentinus edodes) mushrooms (SM). Skin tests were performed using in-house extracts from mushrooms that the patient usually handled, i.e., shiitake, porcini, oyster and black fungus mushroom varieties. Specific IgE to champignons and various molds were determined. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) immunoblotting was performed to detect IgE-binding components. Four negative controls were included in the study. Skin prick tests performed with in-house mushroom extracts from varieties other than shiitake were completely negative, in contrast to the positive test obtained for shiitake mushrooms. Serum specific IgE levels for common molds and champignons were all negative. SDS-PAGE revealed many protein bands in the four mushroom extracts. Immunoblotting using the patient's serum showed allergenic bands at about 15 and 24 kDa exclusively for SM that were not shared with negative controls. Another faint band was detectable at approximately 37 kDa for SM and porcini varieties. Here, we present the first European case of SM-induced occupational asthma, a disease more frequently occurring in Asia. Asthma attacks stopped when the patient avoided contact with shiitake mushrooms. No skin reactions and no IgE-binding proteins by immunoblotting were detectable with the other mushrooms tested. The positive skin test with shiitake mushrooms and IgE-binding components in the shiitake extract confirmed the IgE-mediated etiology of the reaction.


Host-related Risk Factors for Adherent Perinephric Fat in Healthy Individuals Undergoing Laparoscopic Living-donor Nephrectomy.
The purpose of this study is to assess the risk factors and characteristics of adherent perinephric fat (APF) in healthy individuals. Men who underwent laparoscopic donor nephrectomy were included. Video review was used to divide patients on the basis of APF severity. Relationship between APF scores and clinical and radiographic features was evaluated. Of the 92 patients, 43 (46.7%) and 8 (8.7%) were categorized as APF and severe APF, respectively. The median total operative time was significantly associated with APF severity. Sex, body mass index, and perinephric fat area, stranding, and thickness were significantly associated with severe APF. In the multivariate analysis, perinephric fat areas and stranding were independent risk factors for severe APF (HR, 1.189 and 14.450, respectively). In the 44 analyzed cytokines, levels of sIL-6R in the perinephric adipose tissue-conditioned medium were significantly higher for APF group than that for non-APF group (P=0.049). Host-related risk factors for APF could predict surgical difficulty in patients undergoing partial nephrectomy.


Does wound healing contribute to the eradication of basal cell carcinoma following curettage and electrodessication?
Histologic studies indicate that C&D fails to mechanically remove all the tumor in a percentage of cases that far exceeds the 5-year recurrence rate. This raises the question that if C&D does not mechanically remove the tumor in a significant number of patients, why don't we observe tumor recurrence in most of these patients? Our previous study indicates that inflammation occurring over 1 month following C&D does not clear residual tumor. It may be some other process, requiring more time, that clears the residual tumor. Perhaps the proliferative or maturation phase of wound healing or, alternatively, a slow-acting process such as a low-grade immune response set in motion earlier, clears the residual tumor. To test the hypothesis that wound healing and maturation following C&D clear residual tumor that has not mechanically removed by the procedure. The frequency of residual BCC detected histologically immediately following C&D was compared with the frequency 3 months after the C&D, an amount of time in which the maturation phase of wound healing is well under way. Twenty-two of 29 primary BCC less than 1 cm in size were tumor-free immediately following the procedure (clearance rate 75.9%). Twelve primary BCC <1 cm were treated by C&D, allowed to heal for 3 months, and then excised and checked histologically. Ten of the twelve BCC were free of tumor, for a clearance rate of 83.3%, which is not a statistically significant difference (p = 0.7187). By 3 months, the proliferative phase of wound healing is complete, and our study indicates that this phase has no effect on clearing the tumor. The maturation phase is well under way three months following C&D, and no statistically significant effect was observed.


Evolution of electroencephalogram in infants with tuberous sclerosis complex and neurodevelopmental outcome: a prospective cohort study.
To describe the evolution of electroencephalogram (EEG) characteristics in infants with tuberous sclerosis complex (TSC) and the relationship with neurodevelopmental outcome at 24 months. Eighty-three infants were enrolled in the EPISTOP trial and underwent serial EEG follow-up until the age of 24 months (males n=45, females n=37, median age at enrolment 28d, interquartile range 14-54d). Maturation of the EEG background and epileptiform discharges were compared between the TSC1 and TSC2 variants and between preventive and conventional groups respectively. Children with TSC2 more frequently had a slower posterior dominant rhythm (PDR) at 24 months (51% vs 11%, p=0.002), a higher number of epileptiform foci (median=8 vs 4, p=0.003), and a lower fraction of EEGs without epileptiform discharges (18% vs 61%, p=0.001) at follow-up. A slower PDR at 24 months was significantly associated with lower cognitive (median=70 vs 80, p=0.028) and motor developmental quotients (median=70 vs 79, p=0.008). A higher fraction of EEGs without epileptiform discharges was associated with a lower probability of autism spectrum disorder symptoms (odds ratio=0.092, 95% confidence interval=0.009-0.912, p=0.042) and higher cognitive (p=0.004), language (p=0.002), and motor (p=0.001) developmental quotients at 24 months. TSC2 is associated with more abnormal EEG characteristics compared to TSC1, which are predictive for neurodevelopmental outcome.


Breast Cancer Screening Trials: Endpoints and Overdiagnosis.
Screening mammography was assessed in 9 randomized trials initiated between 1963 and 1990, with breast cancer-specific mortality as the primary endpoint. In contrast, breast cancer detection has been the primary endpoint in most screening trials initiated during the past decade. These trials have evaluated digital breast tomosynthesis, magnetic resonance imaging, and ultrasound, and novel screening strategies have been recommended solely on the basis of improvements in breast cancer detection rates. Yet, the assumption that increases in tumor detection produce reductions in cancer mortality has not been validated, and tumor-detection endpoints may exacerbate the problem of overdiagnosis. Indeed, the detection of greater numbers of early stage breast cancers in the absence of a subsequent decline in rates of metastatic cancers and cancer-related mortality is the hallmark of overdiagnosis. There is now evidence to suggest that both ductal carcinoma in situ and invasive cancers are overdiagnosed as a consequence of screening. For each patient who is overdiagnosed with breast cancer, the adverse consequences include unnecessary anxiety, financial hardships, and a small risk of morbidity and mortality from unnecessary treatments. Moreover, the overtreatment of breast cancer, as a consequence of overdiagnosis, is costly and contributes to waste in health-care spending. In this article, we argue that there is a need to establish better endpoints in breast cancer screening trials, including quality of life and composite endpoints. Tumor-detection endpoints should be abandoned, because they may lead to the implementation of screening strategies that increase the risk of overdiagnosis.


The state of clinical research in neurology.
To study and provide an update on the state of clinical research in neurology in the United States. US American Academy of Neurology members and chairs of departments of neurology were surveyed regarding clinical research in 2016. NIH data on the neuroscience pipeline and extramural grant funding were also collected. The response rate was 32% (n = 254) for nonchair researchers and 58% (n = 67) for department chairs. Researcher respondents were on average 50 years old, 66% were men, and 81% were actively conducting clinical research, with phase II/III clinical trials and outcome measure studies being the most common type of research conducted. Time to conduct research, recruitment, and administrative burden were the major barriers reported. According to department chairs, funding and training opportunities in patient-oriented research have increased over the last 10 years. Overall, applicants to neuroscience-specific NIH institutes for extramural funding have decreased over the same time period. The state of clinical research in neurology has remained relatively stable over the last 10 years, but neurologists still have barriers in conducting clinical research. There has been an interval decrease in neuroscience applicants for NIH funding, which raises concerns about the pipeline and future of clinical research in neurology. These results will serve as a reference for the development of solutions to these issues.


Clostridium difficile toxin A-induced microvascular dysfunction. Role of histamine.
Clostridium difficile toxin A (Tx-A) mediates secretion and inflammation in experimental enterocolitis. Intravital video microscopy was used to define the mechanisms that underlie the inflammatory reactions elicited by direct exposure of the microvasculature to Tx-A. Leukocyte adherence and emigration, leukocyte-platelet aggregation, and extravasation of FITC-albumin were monitored in rat mesenteric venules exposed to Tx-A. Significant increases in leukocyte adherence and emigration (LAE) and albumin leakage were noted within 15-30 min of Tx-A exposure. These responses were accompanied by mast cell degranulation and the formation of platelet-leukocyte aggregates. The Tx-A-induced increases in LAE and albumin leakage were significantly attenuated by pretreatment with either monoclonal antibodies (mAbs) directed against the leukocyte adhesion glycoproteins, CD11/CD18, intercellular adhesion molecule-1, and P-selectin (but not E-selectin) or with sialyl Lewis x, a counter-receptor for P-selectin. The mast cell stabilizer, lodoxamide, an H1- (but not an H2-) receptor antagonist, and diamine oxidase (histaminase) were also effective in reducing the LAE and albumin leakage elicited by Tx-A. The platelet-leukocyte aggregation response was blunted by an mAb against P-selectin, sialyl Lewis x, and the H1-receptor antagonist. These observations indicate that Tx-A induces a leukocyte-dependent leakage of albumin from postcapillary venules. Mast cell-derived histamine appears to mediate at least part of the leukocyte-endothelial cell adhesion and platelet-leukocyte aggregation by engaging H1-receptors on endothelial cells and platelets to increase the expression of P-selectin. The adhesion glycoproteins CD11/CD18 and intercellular adhesion molecule-1 also contribute to the inflammatory responses elicited by toxin A.


Arabinogalactan blockade of experimental metastases to liver by murine hepatoma.
Blocking of organ-specific experimental metastasis was investigated in a syngeneic tumor-host system using a new tumor which primarily colonizes the liver upon intravenous injection. The study included systemic treatment with D-galactose and arabinogalactan as well as cell pretreatment with arabinogalactan and two other glycoconjugates. Treatment with arabinogalactan reduced the amount of liver metastases and prolonged the survival times of the animals in both studies. Host treatment was more effective than tumor cell pretreatment. This could be an effect of arabinogalactan blockade of potential liver receptors by covering of galactose-specific binding sites.


[RNA-dependent DNA polymerase from rat liver].
RNA-dependent DNA-polymerase was isolated from rat liver, and its characteristics were studied. Wistar rat livers were homogenized in the disruptive buffer, centrifuged at 100,000 g and the supernatant was freed of the nucleic acids by DEAE-cellulose (DE-23) chromatography. The further chromatography of the eluate on DEAE-cellulose (DE-52) and phosphocellulose P-11 resulted in the obtaining of 300-400-fold purified RNA-dependent DNA-polymerase. Even more purified enzyme 1500-fold was isolated from the 165,000 g pellet of postmitochondrial rat liver fraction. The main properties of the purified enzyme are characteristic for the retroviral reverse transcriptase. The enzyme catalyzes DNA synthesis when poly(A)+mRNA is used as a template-primer. Its sedimentation constant amounts to 4.6 S. Mg2+ is preferable to Mn2+ as an activator of the enzyme. The optimal pH is 7.8. Among the products of the enzymic reaction hybrid RNA X DNA molecules were identified.


Metaplastic effect of apamin on LTP and paired-pulse facilitation.
In area CA1 of hippocampal slices, a single 1-sec train of 100-Hz stimulation generally triggers a short-lasting long-term potentiation (S-LTP) of 1-2 h. Here, we found that when such a train was applied 45 min after application of the small conductance Ca(2+)-activated K(+ )(SK) channel blocker apamin, it induced a long-lasting LTP (L-LTP) of several hours, instead of an S-LTP. Apamin-induced SK channel blockage is known to resist washing. Nevertheless, the aforementioned effect is not a mere delayed effect; it is metaplastic. Indeed, when a single train was delivered to the Schaffer's collaterals during apamin application, it induced an S-LTP, like in the control situation. At the moment of this LTP induction (15th min of apamin application), the SK channel blockage was nevertheless complete. Indeed, at that time, under the influence of apamin, the amplitude of the series of field excitatory postsynaptic potentials (fEPSPs) triggered by a stimulation train was increased. We found that the metaplastic effect of apamin on LTP was crucially dependent on the NO-synthase pathway, whereas the efficacy of the NMDA receptors was not modified at the time of its occurrence. We also found that apamin produced an increase in paired-pulse facilitation not during, but after, the application of the drug. Finally, we found that the induction of each of these two metaplastic phenomena was mediated by NMDA receptors. A speculative unitary hypothesis to explain these phenomena is proposed.


Bradykinin 2 receptor antagonist LF 16-0687Ms reduces posttraumatic brain edema.
Activation of the kallikrein-kinin system contributes to traumatic brain edema formation. Inhibition of bradykinin 2 (B2) receptors has been shown to successfully reduce brain edema formation. The purpose of this study was to investigate the protective effect of the novel nonpeptide B2 receptor antagonist LF 16-0687Ms in brain-injured rats. Contusion was produced in forty rats by controlled cortical impact injury. Five minutes after trauma rats received a single dose of 0, 3, or 30 mg/kg of LF 16-0687Ms. After 24 hours brain swelling and hemispheric water content were determined. Brain swelling was significantly decreased by 25% in the low and 27% in the high dose group compared to controls (p < 0.03). Water content of the traumatized hemisphere tended to be decreased (80.2 +/- 0.1 vs. 80.4 +/- 0.1%) while water content of the non-traumatized hemispheres tended to be increased after administering LF 16.0687Ms (79.3 +/- 0.1 vs. 79.0 +/- 0.1%). Single administration of the novel nonpeptide B2 receptor antagonist LF 16-0687Ms significantly reduces brain swelling. The missing significant reduction in water content of the traumatized hemisphere, however, could be related to an unspecific increase in water content due to LF 16.0687Ms as suggested by increased water content in the non-traumatized hemisphere.


Effect of teaching on students' attitudes to self-poisoning.
The attitudes of students, resident house physicians, and medical social workers towards 10 medical conditions were assessed in relation to both personal attitudes and the opinions expressed of the attitudes of the medical profession. Final-year students and house physicians showed unfavourable attitudes towards self-poisoning in contrast to fourth-year students and medical social workers. The fourth-year students were given the opportunity to admit patients referred to hospital with self-poisoning and visited the family doctor and the patient after discharge. After this exposure there was a subjective impression that the students became more interested in the problems of use self-poisoned patients, and this was supported by a review of their attitudes at the end of the teaching project.


Acoustic neuromas. Diagnostic efficiency of various test combinations.
In the majority of diagnostic tests usually used in the search for acoustic tumors, there is a large difference in the outcome between patients with and without tumors. Because of a possible coherence between the tests applied, a statistical analysis of this connection was performed with the aid of a logistic model. The best single investigation used to differentiate between patients with and without tumors was tomography of the internal acoustic meatus. This examination was used in combination with the differential caloric test and the alternate binaural loudness balance recruitment test to differentiate completely between patients with and without tumors. Results of other examinations did not contribute significantly to the differentiation between patients with and without tumors. This factor did not render the other examinations superfluous because the analysis was valuable only in patients with a hearing level better or equal to 80 dB. By applying the other tests, information was obtained on pressure conditions in the internal acoustic meatus and possible difficulties at surgery, as well as information about the size of the tumor.


Drivers of stunting reduction in Nepal: a country case study.
Chronic child malnutrition represents a serious global health concern. Over the last several decades, Nepal has seen a significant decline in linear growth stunting - a physical manifestation of chronic malnutrition - despite only modest economic growth and significant political instability. This study aimed to conduct an in-depth assessment of the determinants of stunting reduction in Nepal from 1996 to 2016, with specific attention paid to national-, community-, household-, and individual-level factors, as well as relevant nutrition-specific and -sensitive initiatives rolled out within the country. Using a mixed-methods approach, 4 types of inquiry were employed: 1) a systematic review of published peer-reviewed and gray literature; 2) retrospective quantitative data analyses using Demographic and Health Surveys from 1996 to 2016; 3) a review of key nutrition-specific and -sensitive policies and programs; and 4) retrospective qualitative data collection and analyses. Mean height-for-age z-scores (HAZ) improved by 0.94 SDs from 1996 to 2016. Subnational variation and socioeconomic inequalities in stunting outcomes persisted, with the latter widening over time. Decomposition analysis for children aged under 5 y explained 90.9% of the predicted change in HAZ, with key factors including parental education (24.7%), maternal nutrition (19.3%), reduced open defecation (12.3%), maternal and newborn health care (11.5%), and economic improvement (9.0%). Key initiatives focused on decentralizing the health system and mobilizing community health workers to increase accessibility; long-standing nationwide provision of basic health interventions; targeted efforts to improve maternal and child health; and the prioritization of nutrition-sensitive initiatives by both government and donors. National and community stakeholders and mothers at village level highlighted a mixture of poverty reduction, access to health services, improved education, and increased access to water, sanitation, and hygiene as drivers of stunting reduction. Improvements in both nutrition-specific and nutrition-sensitive sectors have been critical to Nepal's stunting decline, particularly in the areas of poverty reduction, health, education, and sanitation.


Lifetime prevalence of DSM-III-R psychiatric disorders among urban and rural Mexican Americans in California.
The Mexican American Prevalence and Services Survey presents lifetime prevalence rates for 12 DSM-III-R psychiatric disorders in a sample of 3012 adults of Mexican origin by place of residence and nativity, and compares these results with those of population surveys conducted in the United States and Mexico. The stratified random sample included non-institutionalized persons aged 18 to 59 years of Mexican origin, who were residents of Fresno County, California. Psychiatric disorders were assessed using a modified version of the World Health Organization Composite International Diagnostic Interview in face-to-face interviews. Mexican immigrants had lifetime rates similar to those of Mexican citizens, while rates for Mexican Americans were similar to those of the national population of the United States. This difference is attributable to a prevalence rate for any disorder among immigrants of 24.9%, compared with 48.1% among US-born respondents. A higher prevalence for any disorder was reported in urban (35.7%) compared with town (32.1%) or rural (29.8%) areas. Multivariate analyses showed an adjusted effect of country of birth, but not of urban residence. Despite very low education and income levels, Mexican Americans had lower rates of lifetime psychiatric disorders compared with rates reported for the US population by the National Comorbidity Survey. Psychiatric morbidity among Mexican Americans is primarily influenced by cultural variance rather than socioeconomic status or urban vs rural residence.


Misuse of DeLong test to compare AUCs for nested models.
The area under the receiver operating characteristics curve (AUC of ROC) is a widely used measure of discrimination in risk prediction models. Routinely, the Mann-Whitney statistics is used as an estimator of AUC, while the change in AUC is tested by the DeLong test. However, very often, in settings where the model is developed and tested on the same dataset, the added predictor is statistically significantly associated with the outcome but fails to produce a significant improvement in the AUC. No conclusive resolution exists to explain this finding. In this paper, we will show that the reason lies in the inappropriate application of the DeLong test in the setting of nested models. Using numerical simulations and a theoretical argument based on generalized U-statistics, we show that if the added predictor is not statistically significantly associated with the outcome, the null distribution is non-normal, contrary to the assumption of DeLong test. Our simulations of different scenarios show that the loss of power because of such a misuse of the DeLong test leads to a conservative test for small and moderate effect sizes. This problem does not exist in cases of predictors that are associated with the outcome and for non-nested models. We suggest that for nested models, only the test of association be performed for the new predictors, and if the result is significant, change in AUC be estimated with an appropriate confidence interval, which can be based on the DeLong approach.


Effect of cellulose synthesis inhibition on growth and the integration of xyloglucan into pea internode cell walls.
2,6-Dichlorobenzonitrile (DCB, 100 mum) inhibited by 80 to 85% the incorporation of [(3)H]glucose into cellulose in stem segments of etiolated pea (Pisum sativum) seedlings. The inhibition lasted for at least 24 h. In the period 1 to 4 h after the excision of the segments, DCB did not influence elongation in the presence or absence of 2,4-dichlorophenoxyacetic acid (2,4-D). However, during the period 1 to 24 h after excision, DCB enhanced endogenous and 2,4-D-stimulated elongation by 65 and 34%, respectively. DCB did not affect the incorporation of (3)H from [(3)H]arabinose into xyloglucan, and did not change the ability of the [(3)H]xyloglucan formed in vivo to bind strongly to the cell wall. Therefore, at least 80 to 85% of newly synthesized cellulose was excess to the requirements for tight wall binding of newly synthesized xyloglucan. This conflicts with the hypothesis that xyloglucan is held in the cell wall solely by direct hydrogen bonding to the surfaces of cellulosic microfibrils.


Bioaerosol emissions associated with pit latrine emptying operations.
Pit latrines are the most common sanitation option in the developing world. They are simple to build but require periodic emptying which results in widespread dispersion of fecal pathogens in the environment. While much is known about the health risks of fecal-oral exposure, little is known about those resulting from the aerosolization of pathogens from fecal material. Bioaerosols were sampled around seven pit latrines before, after, and during emptying in Blantyre, Malawi. Bioaerosols were collected directly onto nutrient and selective medium agar plates using an impact sampler. DNA was extracted from some plates and analyzed for selected enteric pathogens. Total heterotrophic bacteria in the air during active emptying ranged from 198 to >13,000 colony forming units (CFU) per m3, and generally increased above background levels during pit emptying. At about one meter from the pit latrine emptying, E. coli and total coliforms concentrations in air reached up to 350 and 790 CFU m-3, respectively. Additionally, at four out of the seven pit latrines sites sampled, enterotoxigenic E. coli (ETEC) LT/ST was confirmed to be present in bioaerosols. This work demonstrates the potential for airborne dispersion of enteric pathogens during pit latrine emptying operations.


The evening complex coordinates environmental and endogenous signals in Arabidopsis.
Plants maximize their fitness by adjusting their growth and development in response to signals such as light and temperature. The circadian clock provides a mechanism for plants to anticipate events such as sunrise and adjust their transcriptional programmes. However, the underlying mechanisms by which plants coordinate environmental signals with endogenous pathways are not fully understood. Using RNA-sequencing and chromatin immunoprecipitation sequencing experiments, we show that the evening complex (EC) of the circadian clock plays a major role in directly coordinating the expression of hundreds of key regulators of photosynthesis, the circadian clock, phytohormone signalling, growth and response to the environment. We find that the ability of the EC to bind targets genome-wide depends on temperature. In addition, co-occurrence of phytochrome B (phyB) at multiple sites where the EC is bound provides a mechanism for integrating environmental information. Hence, our results show that the EC plays a central role in coordinating endogenous and environmental signals in Arabidopsis.


Decreased expression of Small glutamine-rich tetratricopeptide repeat-containing protein (SGT) correlated with prognosis of Hepatocellular carcinoma.
Small glutamine-rich tetratricopeptide repeat-containing protein (SGT) is an ubiquitously expressed cochaperone of heat shock cognate protein of 70 kDa (Hsc70). SGT binds to the C terminus of Hsc70 to recruit Hsc70 into complexes of diverse function. SGTB was identified as an isoform of SGT with 60% amino acid sequence homology. To investigate the expression of SGTB in hepatocellular carcinoma (HCC) and determine its correlation with tumor progression and prognosis, we evaluated the expression levels of SGTB in HCCs and corresponding adjacent non-tumor liver tissues. We also assessed the association between their expression and clinicopathologic parameters. The expression of SGTB was absent or low in HCCs while it was notable in paracancerous tissues from 108 patients by western blotting and immunochemistry (P < 0.05). Among the 108 HCCs, low expression of SGTB was associated with gender, histological grade (P<0.001) and HBsAg expression (P=0.002). Univariate analysis showed that the low SGTB expression was associated with poor prognosis (P<0.001). Thus, decreased expression of SGTB may be a favorable independent poor prognostic parameter for hepatocellular carcinoma.


When to use the projection assumption and the weak-phase object approximation in phase contrast cryo-EM.
The projection assumption (PA) and the weak-phase object approximation (WPOA) are commonly used to model image formation in cryo-electron microscopy. For simulating the next step in resolution improvement we show that it is important to revisit these two approximations as well as their limitations. Here we start off by inspecting both approximations separately to derive their respective conditions of applicability. The thick-phase grating approximation (TPGA) imposes less strict conditions on the interaction potential than PA or WPOA and gives comparable exit waves as a multislice calculation. We suggest the ranges of applicability for four models (PA, PA+WPOA, WPOA, and TPGA) given different interaction potentials using exit wave simulations. The conditions of applicability for the models are based on two measures, a worst-case (safest) and an average criterion. This allows us to present a practical guideline for when to use each image formation model depending on the spatial frequency, thickness and strength of the interaction potential of a macromolecular complex.


Quality of life of patients who have undergone the minimally invasive repair of pectus carinatum.
Several studies previously demonstrated an improvement in the quality of life (QoL) of the patients undergoing a minimally invasive repair of pectus excavatum, but there are no data about such improvement following the minimally invasive repair of pectus carinatum (PC) deformity. The purpose of this study was to investigate the effects of the minimally invasive repair of PC deformity on the psychosocial and physical functioning of the patients. Among 40 patients who underwent minimally invasive repair for PC deformity from July 2008 to March 2011, 35 patients accepted to answer the QoL questionnaires, and 30 of them who had completed the postoperative 6th month were evaluated in this study. The modified two-step Nuss questionnaire was used for the QoL assessment. All patients and their parents completed the appropriate questionnaires regarding the patients' preoperative psychosocial and physical functioning, and they were asked to answer the same questions on the postoperative 6th month. The results from these questionnaires were analysed using Wilcoxon signed rank test to investigate the effects of the minimally invasive repair of PC deformity on psychosocial and physical functioning of the patients. The questionnaires used in the study confirmed the positive impact of the surgical correction on psychosocial and physical well-being in the patients and their parents. Spearman's ρ correlation coefficient determined how well the answers to the same question at two different times correlated with each other, and Cronbach's alpha demonstrated the internal consistency of these answers. These two parameters showed that the statistical results of the study were reliable enough. Statistical analysis of the scoring of the individual questions and the total scoring of individual patients revealed a statistically significant improvement (P < 0.05) following surgery. Similar significant improvements were observed in the total scoring of individual parents and in most scoring of the individual questions (10 of 13, 77%) in the parental questionnaire (P < 0.05). The results of this study confirm for the first time that minimally invasive repair of PC deformity has a positive impact on both psychosocial and physical functioning of the patient, which is supported by parental assessment.


Perceived structural vulnerabilities among detained noncitizen immigrants in Minnesota.
Across several decades there has been an unprecedented increase in immigration enforcement including detention and deportation. Immigration detention profoundly impacts those experiencing detention and their family members. An emerging area of research has found that immigrants experience a number of challenges which constrain and limit their decisions, choices, and options for security and integration in the United States due to social, political and structural determinants. These determinants lead to greater structural vulnerabilities among immigrants. The purpose of the current study was to illuminate the perceived vulnerabilities of detained noncitizen immigrants as they are raised and described while attending case hearings at the Bloomington, Minnesota immigration court. Through conducting a thematic analysis of notes derived from third party immigration court observers, three areas of perceived vulnerability were identified. These perceived vulnerabilities include 1) migration and motivations to migrate, 2) structural vulnerabilities (e.g., discrimination, financial insecurity, social ties and family support, stable or fixed residence, English language proficiency, health and mental health) in the US, and 3) challenges in navigating immigration detention. These findings demonstrate that noncitizen immigrants who are undergoing immigration detention are experiencing multiple intersecting vulnerabilities which profoundly impact their lives. Collaborative efforts across sectors are needed to work towards comprehensive immigration reforms including both short-term and long-term solutions to address pressing issues for noncitizens undergoing immigration detention.


Association of Copeptin, a Surrogate Marker of Arginine Vasopressin, with Decreased Kidney Function in Sugarcane Workers in Guatemala.
Vasopressin is elevated in response to heat and dehydration and has been postulated to have a role in the chronic kidney disease of unknown origin being observed in Central America. The aims of this study were to examine whether the vasopressin pathway, as measured by copeptin, is associated with the presence of kidney dysfunction, and to examine whether higher fluid intake is associated with lower circulating copeptin and thereby preserves kidney health among sugarcane workers exposed to hot conditions. Utilizing a longitudinal study of 105 workers in Guatemala, we examined relationships between hydration indices, plasma copeptin concentrations, and kidney function markers at 3 times during the 6-month harvest. We also examined whether baseline copeptin concentrations increased the odds of developing an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. Copeptin concentrations were positively associated with serum creatinine (β 1.41, 95% CI 0.88-2.03) and negatively associated with eGFR (β -1.07, 95% CI -1.43 to -0.70). In addition, as workers improved their hydration (measured by increases in fluid balance), copeptin concentrations were reduced, and this reduction was associated with an improvement in kidney function. Results suggest that copeptin should be studied as a potential prognostic biomarker.


Relationship of meeting physical activity guidelines with health-related utility.
Health-related utility measures overall health status and quality of life and is commonly incorporated into cost-effectiveness analyses. This study investigates whether attainment of federal physical activity guidelines translates into better health-related utility in adults with or at risk for knee osteoarthritis (OA). Cross-sectional data from 1,908 adults with or at risk for knee OA participating in the accelerometer ancillary study of the Osteoarthritis Initiative were assessed. Physical activity was measured using 7 days of accelerometer monitoring and was classified as 1) meeting guidelines (≥150 bouted moderate-to-vigorous [MV] minutes per week); 2) insufficiently active (≥1 MV bout[s] per week but below guidelines); or 3) inactive (zero MV bouts per week). A Short Form 6D health-related utility score was derived from patient-reported health status. Relationship of physical activity levels to median health-related utility adjusted for socioeconomic and health factors was tested using quantile regression. Only 13% of participants met physical activity guidelines, and 45% were inactive. Relative to the inactive group, median health-related utility scores were significantly greater for the meeting guidelines group (0.063; 95% confidence interval [95% CI] 0.055, 0.071) and the insufficiently active group (0.059; 95% CI 0.054, 0.064). These differences showed a statistically significant linear trend and strong cross-sectional relationship with physical activity level even after adjusting for socioeconomic and health factors. We found a significant positive relationship between physical activity level and health-related utility. Interventions that encourage adults, including persons with knee OA, to increase physical activity even if recommended levels are not attained may improve their quality of life.


Referral practices are associated with a delay in treatment of symptomatic cholelithiasis and cholecystitis.
The project was performed to determine if referrals to non-surgical providers after an initial presentation of symptomatic cholelithiasis are associated with a delay in surgical management. A single institution chart review of all adult patients who underwent a cholecystectomy from 2015 to 2019 was completed. Quantitative data was analyzed using independent t-tests. Of 574 reviewed, 482 patients met criteria. Following initial presentation, 295 (61.2%) received a referral to surgery and 187 (38.8%) received follow up with a non-surgical provider. Those in the latter group had a significantly longer time from initial symptom presentation to surgical evaluation (65.7 days vs. 10.3 days, p < 0.001) and cholecystectomy (102.0 days vs 39.1 days, p < 0.001) when compared to the surgery referral group. This study demonstrated that cholecystectomy was significantly delayed for patients who had been referred to non-surgical providers after initial presentation, prolonging symptoms and increasing use of healthcare resources.


A naturally occurring nonapeptide functionally compensates for the CP1 domain of leucyl-tRNA synthetase to modulate aminoacylation activity.
aaRSs (aminoacyl-tRNA synthetases) establish the rules of the genetic code by catalysing the formation of aminoacyl-tRNA. The quality control for aminoacylation is achieved by editing activity, which is usually carried out by a discrete editing domain. For LeuRS (leucyl-tRNA synthetase), the CP1 (connective peptide 1) domain is the editing domain responsible for hydrolysing mischarged tRNA. The CP1 domain is universally present in LeuRSs, except MmLeuRS (Mycoplasma mobile LeuRS). The substitute of CP1 in MmLeuRS is a nonapeptide (MmLinker). In the present study, we show that the MmLinker, which is critical for the aminoacylation activity of MmLeuRS, could confer remarkable tRNA-charging activity on the inactive CP1-deleted LeuRS from Escherichia coli (EcLeuRS) and Aquifex aeolicus (AaLeuRS). Furthermore, CP1 from EcLeuRS could functionally compensate for the MmLinker and endow MmLeuRS with post-transfer editing capability. These investigations provide a mechanistic framework for the modular construction of aaRSs and their co-ordination to achieve catalytic efficiency and fidelity. These results also show that the pre-transfer editing function of LeuRS originates from its conserved synthetic domain and shed light on future study of the mechanism.