Ability of Nonswelling Polyethylene Glycol-Based Vitreous Hydrogel to Maintain Transparency in the Presence of Vitreous Hemorrhage.
Postoperative vitreous hemorrhage is a vision-impacting complication of vitrectomy. This preclinical in vitro study assessed the potential ability of a nonswelling polyethylene glycol-based artificial vitreous hydrogel to maintain transparency in the vitreous cavity in the presence of vitreous hemorrhage. Samples (1 mL) of diluted blood at concentrations of 0.1%, 0.25%, 0.5%, and 1.25% were added to 1 mL samples of polymerized hydrogel in cuvettes (gel + blood group); 2 mL samples of diluted blood at the same concentrations were prepared as controls (blood only group). Spectral transmission curves for the hydrogel (gel + blood group) and diluted blood (blood only group) were obtained before and on days 1, 2, 5, 7, 14, and 28 of the experiment. Between-group comparisons were made using the Student's t-test. The percentage of transmittance in the visible light spectrum (400-700 nm) was measured at each time point. Mean light transmittance was maintained at >90% until day 7 in the gel + blood group and was significantly greater in the gel + blood than in the blood only groups in samples containing blood diluted to 0.25%, 0.5%, and 1.25% during the 28-day study period (P < 0.05). A nonswelling polyethylene glycol-based artificial vitreous hydrogel maintained high optical transparency in the presence of blood through the study period. Injection of this hydrogel into the vitreous cavity at the end of surgery might help to prevent or mitigate vitreous hemorrhage-associated postoperative visual loss. The hydrogel may prevent visual loss due to postoperative vitreous hemorrhage.


Prenatal brain MRI of fetuses with Zika virus infection.
An outbreak of Zika virus was observed in French Polynesia in 2013-2014. Maternal Zika virus infection has been associated with fetal microcephaly and severe cerebral damage. To analyze the MRI cerebral findings in fetuses with intrauterine Zika virus infection. We retrospectively analyzed prospectively collected data. Inclusion criteria comprised cases with (1) estimated conception date between June 2013 and May 2014, (2) available US and MRI scans revealing severe fetal brain lesions and (3) positive polymerase chain reaction for Zika virus in the amniotic fluid. We recorded pregnancy history of Zika virus infection and analyzed US and MRI scans. Three out of 12 cases of severe cerebral lesions fulfilled all inclusion criteria. History of maternal Zika virus infection had been documented in two cases. Calcifications and ventriculomegaly were present at US in all cases. MRI showed micrencephaly (n = 3), low cerebellar biometry (n = 2), occipital subependymal pseudocysts (n = 2), polymicrogyria with laminar necrosis and opercular dysplasia (n = 3), absent (n = 1) or hypoplastic (n = 1) corpus callosum and hypoplastic brainstem (n = 1). Severe cerebral damage was observed in our series, with indirect findings suggesting that the germinal matrix is the principal target for Zika virus. The lesions are very similar to severe forms of congenital cytomegalovirus and lymphocytic choriomeningitis virus infections.


Profiling of gene expression in rat liver and rat primary cultured hepatocytes treated with peroxisome proliferators.
The Toxicogenomics project has been constructing a large-scale database of about 150 compounds exposed to rat (single dose, 3, 6, 9, 24 hrs and repeated dose for 3, 7, 14 28 days with 3 dose levels) and rat hepatocytes (2, 8, 24 hr with 3 concentrations) and data of transcriptome in liver using GeneChip, and the related toxicological measures are being accumulated. In the present study, the data of three ligands of peroxisome proliferator activated receptor alpha (PPARalpha), i.e., clofibrate, WY-14643 and gemfibrozil in our database were analyzed. Many of the beta-oxidation-related genes were commonly induced in vivo and in vitro, whereas expression changes in genes related to cell proliferation, apoptosis, were detected in vivo (single and repeated dose) but not in vitro. Changes in those related to the immune response, coagulation and the stress response were also detectable exclusively in vivo. Using the genes mobilized in two or three PPARalpha agonists, hierarchical clustering was performed on 32 compounds stored in our database. In the profiling of an in vivo single dose, benzbromarone and aspirin were located in the same cluster of the three PPARalpha agonists. The clustering of in vitro data revealed that benzbromarone, three NSAIDs (aspirin, indomethacin and diclofenac sodium) and valproic acid belonged to the same cluster of PPARalpha agonists, supporting the reports that benzbromarone,valproic acid and some NSAIDs were reported to be PPARalpha agonists. Using the genes commonly up-regulated both in vivo and in vitro, principal component analysis was performed in 32 compounds, and principal component 1 was found to be the convenient parameter to extract PPARalpha agonist-like compounds from the database.


Pathways family intervention for third-grade American Indian children.
The goal of the feasibility phase of the Pathways family intervention was to work with families of third-grade American Indian children to reinforce health behaviors being promoted by the curriculum, food service, and physical activity components of this school-based obesity prevention intervention. Family behaviors regarding food choices and physical activity were identified and ranked according to priority by using formative assessment and a literature review of school-based programs that included a family component. The family intervention involved 3 primary strategies designed to create an informed home environment supportive of behavioral change: 1) giving the children "family packs" containing worksheets, interactive assignments, healthful snacks, and low-fat tips and recipes to take home to share with their families; 2) implementing family events at the school to provide a fun atmosphere in which health education concepts could be introduced and reinforced; and 3) forming school-based family advisory councils composed of family members and community volunteers who provided feedback on Pathways strategies, helped negotiate barriers, and explored ideas for continued family participation. For strategy 2, a kick-off Family Fun Night provided a series of learning booths that presented the healthful behaviors taught by Pathways. At an end-of-year Family Celebration, a healthy meal was served, students demonstrated newly learned Pathways activities, and certificates were presented in recognition of completion of the Pathways curriculum. Based on evaluation forms and attendance rosters, strategies 1 and 2 were more easily implemented and better received than strategy 3. Implications for developing family involvement strategies for intervention programs are discussed.


Y1767C, a novel SCN5A mutation, induces a persistent Na+ current and potentiates ranolazine inhibition of Nav1.5 channels.
Long QT syndrome type 3 (LQT3) has been traced to mutations of the cardiac Na(+) channel (Na(v)1.5) that produce persistent Na(+) currents leading to delayed ventricular repolarization and torsades de pointes. We performed mutational analyses of patients suffering from LQTS and characterized the biophysical properties of the mutations that we uncovered. One LQT3 patient carried a mutation in the SCN5A gene in which the cysteine was substituted for a highly conserved tyrosine (Y1767C) located near the cytoplasmic entrance of the Na(v)1.5 channel pore. The wild-type and mutant channels were transiently expressed in tsA201 cells, and Na(+) currents were recorded using the patch-clamp technique. The Y1767C channel produced a persistent Na(+) current, more rapid inactivation, faster recovery from inactivation, and an increased window current. The persistent Na(+) current of the Y1767C channel was blocked by ranolazine but not by many class I antiarrhythmic drugs. The incomplete inactivation, along with the persistent activation of Na(+) channels caused by an overlap of voltage-dependent activation and inactivation, known as window currents, appeared to contribute to the LQTS phenotype in this patient. The blocking effect of ranolazine on the persistent Na(+) current suggested that ranolazine may be an effective therapeutic treatment for patients with this mutation. Our data also revealed the unique role for the Y1767 residue in inactivating and forming the intracellular pore of the Na(v)1.5 channel.


The Contribution of Race to Breast Tumor Microenvironment Composition and Disease Progression.
Breast cancer is the second most commonly diagnosed cancer in American women following skin cancer. Despite overall decrease in breast cancer mortality due to advances in treatment and earlier screening, black patients continue to have 40% higher risk of breast cancer related death compared to white patients. This disparity in outcome persists even when controlled for access to care and stage at presentation and has been attributed to differences in tumor subtypes or gene expression profiles. There is emerging evidence that the tumor microenvironment (TME) may contribute to the racial disparities in outcome as well. Here, we provide a comprehensive review of current literature available regarding race-dependent differences in the TME. Notably, black patients tend to have a higher density of pro-tumorigenic immune cells (e.g., M2 macrophages, regulatory T cells) and microvasculature. Although immune cells are classically thought to be anti-tumorigenic, increase in M2 macrophages and angiogenesis may lead to a paradoxical increase in metastasis by forming doorways of tumor cell intravasation called tumor microenvironment of metastasis (TMEM). Furthermore, black patients also have higher serum levels of inflammatory cytokines, which provide a positive feedback loop in creating a pro-metastatic TME. Lastly, we propose that the higher density of immune cells and angiogenesis observed in the TME of black patients may be a result of evolutionary selection for a more robust immune response in patients of African geographic ancestry. Better understanding of race-dependent differences in the TME will aid in overcoming the racial disparity in breast cancer mortality.


X-ray micro-CT scanning reveals temporal separation of male harm and female kicking during traumatic mating in seed beetles.
In the seed beetle Callosobruchus maculatus, the male intromittent organ is covered in sharp spines that pierce the female copulatory tract wall during mating. Although the fitness consequences of traumatic mating are well studied in this species, we know much less about how the male and female genitalia interact during mating. This is partly due to the fact that genital interactions occur primarily inside the female, and so are difficult to observe. In this study, we use X-ray micro-CT scanning to examine the proximate mechanisms of traumatic mating in C. maculatus in unprecedented detail. We show that this technique can be used to identify female tissue damage before the melanization of wound sites. We visualize the positioning of the male intromittent organ inside the female copulatory tract during mating, and show how this relates to tract wounding in three dimensions. By scanning pairs flash-frozen at different times during mating, we show that significant tract wounding occurs before the onset of female kicking. There is thus some degree of temporal separation between the onset of wounding and the onset of kicking, which supports recent suggestions that kicking is not an effective female counter-adaptation to reduce copulatory wounding in this species. We also present evidence that the sharp teeth protruding from the female tract wall are able to pierce the spermatophore as it is deposited, and may thus function to aid sperm release.


Toxigenic clostridia.
Toxigenic clostridia belonging to 13 recognized species are discussed in this review. Each species or group of organisms is, in general, introduced by presenting the historical aspects of its discovery by early investigators of human and animal diseases. The diseases caused by each species or group are described and usually discussed in relation to the toxins involved in the pathology. Morphological and physiological characteristics of the organisms are described. Finally, the toxins produced by each organism are listed, with a presentation of their biological activities and physical and biochemical characteristics. The complete amino acid sequences for some are known, and some of the genes have been cloned. The term toxin is used loosely to include the various antigenic protein products of these organisms with biological and serological activities which have served as distinguishing characteristics for differentiation and classification. Some of these factors are not truly toxic and have no known role in pathogenicity. Some of the interesting factors common to more than one species or group are the following: neurotoxins, lethal toxins, lecithinases, oxygen-labile hemolysins, binary toxins, and ADP-ribosyltransferases. Problems in bacterial nomenclature and designation of biologically active factors are noted.


Single-walled carbon nanotubes promote rat vascular adventitial fibroblasts to transform into myofibroblasts by SM22-α expression.
The aim of this study was to explore whether single-wall carbon nanotubes (SWCNTs) can be used as artery tissue-engineering materials by promoting vascular adventitial fibroblasts (VAFs) to transform into myofibroblasts (MFs) and to find the signal pathway involved in this process. VAFs were primary cultured and incubated with various doses of SWCNTs suspension (0, 0.8, 3.2, 12.5, 50, and 200 μg/mL). In the present study, we used three methods (MTT, WST-1, and WST-8) at the same time to detect the cell viability and immunofluorescence probe technology to investigate the effects of oxidative injury after VAFs incubated with SWCNTs. Immunocytochemical staining was used to detect SM(22)-α expression to confirm whether VAFs transformed into MFs. The protein levels were detected by western blotting. The results of immunocytochemical staining showed that SM(22)-α was expressed after incubation with 50 μg/mL SWCNTs for 96 hours, but with oxidative damage. The mRNA and protein levels of SM(22)-α, C-Jun N-terminal kinase, TGF-β(1), and TGF-β receptor II in VAFs increased with the dose of SWCNTs. The expression of the p-Smad2/3 protein was upregulated while the Smad7 protein was significantly down-regulated. Smad4 was translocated to the nucleus to regulate SM(22)-α gene expression. In conclusion, SWCNTs promoted VAFs to transform into MFs with SM(22)-α expression by the C-Jun N-terminal kinase/Smads signal pathway at the early stage (48 hours) but weakened quickly. SWCNTs also promoted the transformation by the TGF-β(l)/Smads signal pathway at the advanced stage in a persistent manner. These results indicate that SWCNTs can possibly be used as artery tissue-engineering materials.


Recommendations on vaccination for Latin American small animal practitioners: a report of the WSAVA Vaccination Guidelines Group.
The World Small Animal Veterinary Association Vaccination Guidelines Group has produced global guidelines for small companion animal practitioners on best practice in canine and feline vaccination. Recognising that there are unique aspects of veterinary practice in certain geographical regions of the world, the Vaccination Guidelines Group undertook a regional project in Latin America between 2016 and 2019, culminating in the present document. The Vaccination Guidelines Group gathered scientific and demographic data during visits to Argentina, Brazil and Mexico, by discussion with national key opinion leaders, visiting veterinary practices and review of the scientific literature. A questionnaire survey was completed by 1390 veterinarians in five Latin American countries and the Vaccination Guidelines Group delivered continuing education at seven events attended by over 3500 veterinarians. The Vaccination Guidelines Group recognised numerous challenges in Latin America, for example: (1) lack of national oversight of the veterinary profession, (2) extraordinary growth in private veterinary schools of undetermined quality, (3) socioeconomic constraints on client engagement with preventive health care, (4) high regional prevalence of some key infectious diseases (e.g. feline leukaemia virus infection, canine visceral leishmaniosis), (5) almost complete lack of minimal antigen vaccine products as available in other markets, (6) relative lack of vaccine products with extended duration of immunity as available in other markets, (7) availability of vaccine products withdrawn from other markets (e.g. Giardia vaccine) or unique to Latin America (e.g. some Leishmania vaccines), (8) accessibility of vaccines directly by pet owners or breeders such that vaccination is not delivered under veterinary supervision, (9) limited availability of continuing education in veterinary vaccinology and lack of compulsion for continuing professional development and (10) limited peer-reviewed published scientific data on small companion animal infectious diseases (with the exception of leishmaniosis) and lack of support for such academic research. In this document, the Vaccination Guidelines Group summarises the findings of this project and assesses in evidence-based fashion the scientific literature pertaining to companion animal vaccine-preventable diseases in Latin America. The Vaccination Guidelines Group makes some recommendations on undergraduate and postgraduate education and academic research. Recognising that current product availability in Latin America does not permit veterinarians in these countries to vaccinate according to the global World Small Animal Veterinary Association guidelines, the Vaccination Guidelines Group makes a series of "pragmatic" recommendations as to what might be currently achievable, and a series of "aspirational" recommendations as to what might be desirable for the future. The concept of "vaccine husbandry" is addressed via some simple guidelines for the management of vaccine products in the practice. Finally, the Vaccination Guidelines Group emphasises the global trend towards delivery of vaccination as one part of an "annual health check" or "health care plan" that reviews holistically the preventive health care needs of the individual pet animal. Latin American practitioners should transition towards these important new practices that are now well embedded in more developed veterinary markets. The document also includes 70 frequently asked questions and their answers; these were posed to the Vaccination Guidelines Group during our continuing education events and small group discussions and should address many of the issues surrounding delivery of vaccination in the Latin American countries. Spanish and Portuguese translations of this document will be made freely available from the on-line resource pages of the Vaccination Guidelines Group.


MR-self Noise2Noise: self-supervised deep learning-based image quality improvement of submillimeter resolution 3D MR images.
The study aimed to develop a deep neural network (DNN)-based noise reduction and image quality improvement by only using routine clinical scans and evaluate its performance in 3D high-resolution MRI. This retrospective study included T1-weighted magnetization-prepared rapid gradient-echo (MP-RAGE) images from 185 clinical scans: 135 for DNN training, 11 for DNN validation, 20 for qualitative evaluation, and 19 for quantitative evaluation. Additionally, 18 vessel wall imaging (VWI) data were included to evaluate generalization. In each scan of the DNN training set, two noise-independent images were generated from the k-space data, resulting in an input-label pair. 2.5D U-net architecture was utilized for the DNN model. Qualitative evaluation between conventional MP-RAGE and DNN-based MP-RAGE was performed by two radiologists in image quality, fine structure delineation, and lesion conspicuity. Quantitative evaluation was performed with full sampled data as a reference by measuring quantitative error metrics and volumetry at 7 different simulated noise levels. DNN application on VWI was evaluated by two radiologists in image quality. Our DNN-based MP-RAGE outperformed conventional MP-RAGE in all image quality parameters (average scores = 3.7 vs. 4.9, p < 0.001). In the quantitative evaluation, DNN showed better error metrics (p < 0.001) and comparable (p > 0.09) or better (p < 0.02) volumetry results than conventional MP-RAGE. DNN application to VWI also revealed improved image quality (3.5 vs. 4.6, p < 0.001). The proposed DNN model successfully denoises 3D MR image and improves its image quality by using routine clinical scans only. • Our deep learning framework successfully improved conventional 3D high-resolution MRI in all image quality parameters, fine structure delineation, and lesion conspicuity. • Compared to conventional MRI, the proposed deep neural network-based MRI revealed better quantitative error metrics and comparable or better volumetry results. • Deep neural network application to 3D MRI whose pulse sequences and parameters were different from the training data showed improvement in image quality, revealing the potential to generalize on various clinical MRI.


The prostate cancer journey: results of an online survey of men and their partners.
The initial impact of treatments for men with prostate cancer is well reported in the literature. Less is known about the psychosocial needs of these men as their journey after diagnosis and treatment continues into the months and years. The objective of this study was to examine and understand the supportive care needs of men diagnosed and treated for prostate cancer at key identifiable periods of their cancer journey. An international Web-based survey was conducted in 2012, investigating men's prostate cancer pathways. The survey was based on substantial qualitative research and assessed for validity and reliability before piloting. To provide a unique insight into men living with prostate cancer, the views of partners were also elicited. Completed questionnaires were obtained from 193 men and 40 partners from 6 nations. The physical and psychosocial impact of treatment and need for support varied along the cancer journey. Fear, distress, loss, regret, anxiety, low self-esteem, depression, changes in sexuality, masculinity, and relationships were also described by both men and partners as adverse effects of the diagnosis and treatment for prostate cancer. Wives and partners are a key psychosocial support to men with prostate cancer. They may also provide valuable insight into men's supportive care needs that men are often unable to recognize themselves. Findings suggest that wives and partners of men with prostate cancer can provide nurses and healthcare authorities with a powerful and unique resource in providing supportive care for men who are challenged by prostate cancer.


A Coccidioides posadasii CPS1 Deletion Mutant Is Avirulent and Protects Mice from Lethal Infection.
The CPS1 gene was identified as a virulence factor in the maize pathogen Cochliobolus heterostrophus Hypothesizing that the homologous gene in Coccidioides posadasii could be important for virulence, we created a Δcps1 deletion mutant which was unable to cause disease in three strains of mice (C57BL/6, BALB/c, or the severely immunodeficient NOD-scid,γc(null) [NSG]). Only a single colony was recovered from 1 of 60 C57BL/6 mice following intranasal infections of up to 4,400 spores. Following administration of very high doses (10,000 to 2.5 × 10(7) spores) to NSG and BALB/c mice, spherules were observed in lung sections at time points from day 3 to day 10 postinfection, but nearly all appeared degraded with infrequent endosporulation. Although the role of CPS1 in virulence is not understood, phenotypic alterations and transcription differences of at least 33 genes in the Δcps1 strain versus C. posadasii is consistent with both metabolic and regulatory functions for the gene. The in vitro phenotype of the Δcps1 strain showed slower growth of mycelia with delayed and lower spore production than C. posadasii, and in vitro spherules were smaller. Vaccination of C57BL/6 or BALB/c mice with live Δcps1 spores either intranasally, intraperitoneally, or subcutaneously resulted in over 95% survival with mean residual lung fungal burdens of <1,000 CFU from an otherwise lethal C. posadasii intranasal infection. Considering its apparently complete attenuation of virulence and the high degree of resistance to C. posadasii infection when used as a vaccine, the Δcps1 strain is a promising vaccine candidate for preventing coccidioidomycosis in humans or other animals.


Gendering inequality: a note on Piketty's Capital in the twenty-first century.
Thomas Piketty's Capital in the Twenty-First Century is remarkable for moving inequality from the margins to mainstream debate through detailed analysis of longitudinal statistics and, for an economist, by advocating an interdisciplinary perspective and writing in a witty and accessible style. With reference to the post 1970 period, when wage increases are largely responsible for the increase in inequality, Piketty shows how patrimonial capitalists (elite managers) in the top decile and centile of the distribution appropriate a growing share of social wealth as a consequence of their 'power to set their own remuneration' in the context of tolerant social norms rather than through their productive contributions. Piketty raises but defers the question of where these social norms come from to other disciplines. A Feminist Economics perspective indicates that these questions are central to a more inclusive form of economic analysis and such an approach would enrich Piketty's analysis in two main ways. First, by paying greater attention to the processes and social norms through which inequalities are produced and justified and second by highlighting the ways in which inequality is experienced differently depending not only on class, but also on other aspects of identity including gender. This approach also suggests that it is necessary to supplement the ex-post redistributive policies recommended by Piketty: a global wealth tax and more steeply progressive income tax, with ex-ante measures to stop the rise in wage inequality in the first place, especially by bridging the huge gulf that exists between those who care for people and those who manage money.


Signs Indicative of Central Sensitization Are Present but Not Associated with the Central Sensitization Inventory in Patients with Focal Nerve Injury.
Carpal tunnel syndrome (CTS) is the most common focal nerve injury. People with CTS may show alterations in central processing of nociceptive information. It remains unclear whether the central sensitization inventory (CSI) is capable of detecting such altered central pain processing. Thirty healthy volunteers were matched with 30 people with unilateral CTS from the orthopaedic waitlist. Changes to central pain processing were established through psychophysical sensory testing (bilateral pressure pain thresholds (PPT), conditioned pain modulation, temporal summation) and pain distribution on body charts. Patients also completed pain severity and function questionnaires, psychological questionnaires and the CSI. Compared to healthy volunteers, patients with CTS have lower PPTs over the carpal tunnel bilaterally (t = -4.06, p < 0.0001 ipsilateral and t = -4.58, p < 0.0001 contralateral) and reduced conditioned pain modulation efficacy (t = -7.31, p <0.0001) but no differences in temporal summation (t = 0.52, p = 0.60). The CSI was not associated with psychophysical measures or pain distributions indicative of altered central pain processing. However, there was a correlation of the CSI with the Beck Depression Inventory (r = 0.426; p = 0.019). Patients with CTS show signs of altered central pain mechanisms. The CSI seems unsuitable to detect changes in central pain processing but is rather associated with psychological factors in people with focal nerve injuries.


Modulation of androgen receptor transactivation by gelsolin: a newly identified androgen receptor coregulator.
The partial agonist effect of antiandrogens has been well documented, and such effect is amplified by derived mutant androgen receptors (ARs) in prostate cancer cells. Here we report the identification of gelsolin (GSN) as an AR-associated protein. Hydroxyflutamide (HF), as well as androgens, can promote the interaction between AR and GSN in a dose-dependent manner. GSN interacts with AR DNA-binding domain and ligand-binding domain via its COOH-terminal domain. Immunolocalization studies show that GSN interacts with AR during nuclear translocation. Functional analyses additionally demonstrate that GSN enhances AR activity in the presence of either androgen or HF. Two peptides representing partial regions of the AR DNA-binding domain and the ligand-binding domain can block the GSN-enhanced AR activity. The expression of GSN is enhanced in LNCaP cells, LNCaP xenografts, and human prostate tumors after androgen depletion. Increasing expression of GSN enhances the AR activity in the presence of HF. Together, these data suggest that the weak androgenic effect of HF may be amplified by increasing the amount of GSN after androgen ablation treatment. Therefore, blockage of the interaction between AR and GSN could become a potential therapeutic target for the treatment of prostate cancer.


Effect of Trimetazidine Dihydrochloride Therapy on Exercise Capacity in Patients With Nonobstructive Hypertrophic Cardiomyopathy: A Randomized Clinical Trial.
Hypertrophic cardiomyopathy causes limiting symptoms in patients, mediated partly through inefficient myocardial energy use. There is conflicting evidence for therapy with inhibitors of myocardial fatty acid metabolism in patients with nonobstructive hypertrophic cardiomyopathy. To determine the effect of oral therapy with trimetazidine, a direct inhibitor of fatty acid β-oxidation, on exercise capacity in patients with symptomatic nonobstructive hypertrophic cardiomyopathy. This randomized, placebo-controlled, double-blind clinical trial at The Heart Hospital, University College London Hospitals, London, United Kingdom was performed between May 31, 2012, and September 8, 2014. The trial included 51 drug-refractory symptomatic (New York Heart Association class ≥2) patients aged 24 to 74 years with a maximum left ventricular outflow tract gradient 50 mm Hg or lower and a peak oxygen consumption during exercise of 80% or less predicted value for age and sex. Statistical analysis was performed from March 1, 2016 through July 4, 2018. Participants were randomly assigned to trimetazidine, 20 mg, 3 times daily (n = 27) or placebo (n = 24) for 3 months. The primary end point was peak oxygen consumption during upright bicycle ergometry. Secondary end points were 6-minute walk distance, quality of life (Minnesota Living with Heart Failure questionnaire), frequency of ventricular ectopic beats, diastolic function, serum N-terminal pro-brain natriuretic peptide level, and troponin T level. Of 49 participants who received trimetazidine (n = 26) or placebo (n = 23) and completed the study, 34 (70%) were male; the mean (SD) age was 50 (13) years. Trimetazidine therapy did not improve exercise capacity, with patients in the trimetazidine group walking 38.4 m (95% CI, 5.13 to 71.70 m) less than patients in the placebo group at 3 months after adjustment for their baseline walking distance measurements. After adjustment for baseline values, peak oxygen consumption was 1.35 mL/kg per minute lower (95% CI, -2.58 to -0.11 mL/kg per minute; P = .03) in the intervention group after 3 months. In symptomatic patients with nonobstructive hypertrophic cardiomyopathy, trimetazidine therapy does not improve exercise capacity. Pharmacologic therapy for this disease remains limited. ClinicalTrials.gov identifier: NCT01696370.


Host-Parasite Relationships in Fall-Sown Sugar Beets Infected by the Stem and Bulb Nematode, Ditylenchus dipsaci.
Stunted growth of fall-sown sugar beets (Beta vulgaris) associated with high incidence of crownroot infections and large soil infestations by Ditylenchus dipsaci were observed at the end of the crop growing season in southern Spain by early June 2005. The largest proportion (75%) of the nematode life-stages in plant and soil was the fourth-stage juvenile. The large number (up to 3,750 nematodes per gram of fresh tissue) of D. dipsaci individuals and severe anatomical alterations observed in storage sugar beet roots suggest that the stem and bulb nematode is the causal agent of the impaired growth of sugar beets observed in commercial fields. Observed morphological traits of nematode specimens and results of specific polymerase chain reaction (PCR) and phylogenetic analyses confirmed that the population of D. dipsaci infecting sugar beet belongs to the normal (nongiant) biological type of the nematode. Results of host-range bioassays indicated that the population of D. dipsaci infecting sugar beet in southern Spain reproduces on pea (including seeds and pods), onion, potato, spinach, and tomato, but not on bean, cotton, maize, and tobacco. These results indicate that D. dipsaci may be an important constraint for sugar beet crops in the affected area, but also for other important crops commonly used in rotation with them.


Analysis of antibodies to newly described Plasmodium falciparum merozoite antigens supports MSPDBL2 as a predicted target of naturally acquired immunity.
Prospective studies continue to identify malaria parasite genes with particular patterns of polymorphism which indicate they may be under immune selection, and the encoded proteins require investigation. Sixteen new recombinant protein reagents were designed to characterize three such polymorphic proteins expressed in Plasmodium falciparum schizonts and merozoites: MSPDBL1 (also termed MSP3.4) and MSPDBL2 (MSP3.8), which possess Duffy binding-like (DBL) domains, and SURFIN4.2, encoded by a member of the surface-associated interspersed (surf) multigene family. After testing the antigenicities of these reagents by murine immunization and parasite immunofluorescence, we analyzed naturally acquired antibody responses to the antigens in two cohorts in coastal Kenya in which the parasite was endemic (Chonyi [n = 497] and Ngerenya [n = 461]). As expected, the prevalence and levels of serum antibodies increased with age. We then investigated correlations with subsequent risk of clinical malaria among children <11 years of age during 6 months follow-up surveillance. Antibodies to the polymorphic central region of MSPDBL2 were associated with reduced risk of malaria in both cohorts, with statistical significance remaining for the 3D7 allelic type after adjustment for individuals' ages in years and antibody reactivity to whole-schizont extract (Chonyi, risk ratio, 0.51, and 95% confidence interval [CI], 0.28 to 0.93; Ngerenya, risk ratio, 0.38, and 95% CI, 0.18 to 0.82). For the MSPDBL1 Palo Alto allelic-type antigen, there was a protective association in one cohort (Ngerenya, risk ratio, 0.53, and 95% CI, 0.32 to 0.89), whereas the other antigens showed no protective associations after adjustment. These findings support the prediction that antibodies to the polymorphic region of MSPDBL2 contribute to protective immunity.


Foreign-Born Latinos Living in Rural Areas are more likely to Experience Health Care Discrimination: Results from Proyecto de Salud para Latinos.
Health care discrimination is increasingly considered a significant barrier to accessing health services among minority populations, including Latinos. However, little is known about the role of immigration status. The purpose of this study was to examine the association between immigration status and perceived health care discrimination among Latinos living in rural areas. Interviews were conducted among 349 young-adult Latinos (ages 18 to 25) living in rural Oregon, as part of Proyecto de Salud para Latinos. Over a third of participants experienced health care discrimination (39.5 %). Discrimination was higher among foreign-born (44.9 %) rather than US-born Latinos (31.9 %). Multivariate results showed that foreign-born Latinos were significantly more likely to experience health care discrimination, even after controlling for other relevant factors (OR = 2.10, 95 % CI 1.16-3.82). This study provides evidence that health care discrimination is prevalent among young-adult Latinos living in rural areas, particularly the foreign-born. Effective approaches towards reducing discrimination in health care settings should take into consideration the need to reform our broken immigration system.


Using comprehensive geriatric assessment for quality improvements in healthcare of older people in UK care homes: protocol for realist review within Proactive Healthcare of Older People in Care Homes (PEACH) study.
Care home residents are relatively high users of healthcare resources and may have complex needs. Comprehensive geriatric assessment (CGA) may benefit care home residents and improve efficiency of care delivery. This is an approach to care in which there is a thorough multidisciplinary assessment (physical and mental health, functioning and physical and social environments) and a care plan based on this assessment, usually delivered by a multidisciplinary team. The CGA process is known to improve outcomes for community-dwelling older people and those in receipt of hospital care, but less is known about its efficacy in care home residents. Realist review was selected as the most appropriate method to explore the complex nature of the care home setting and multidisciplinary delivery of care. The aim of the realist review is to identify and characterise a programme theory that underpins the CGA intervention. The realist review will extract data from research articles which describe the causal mechanisms through which the practice of CGA generates outcomes. The focus of the intervention is care homes, and the outcomes of interest are health-related quality of life and satisfaction with services; for both residents and staff. Further outcomes may include appropriate use of National Health Service services and resources of older care home residents. The review will proceed through three stages: (1) identifying the candidate programme theories that underpin CGA through interviews with key stakeholders, systematic search of the peer-reviewed and non-peer-reviewed evidence, (2) identifying the evidence relevant to CGA in UK care homes and refining the programme theories through refining and iterating the systematic search, lateral searches and seeking further information from study authors and (3) analysis and synthesis of evidence, involving the testing of the programme theories. The PEACH project was identified as service development following submission to the UK Health Research Authority and subsequent review by the University of Nottingham Research Ethics Committee. The study protocols have been reviewed as part of good governance by the Nottinghamshire Healthcare Foundation Trust. We aim to publish this realist review in a peer-reviewed journal with international readership. We will disseminate findings to public and stakeholders using knowledge mobilisation techniques. Stakeholders will include the Quality Improvement Collaboratives within PEACH study. National networks, such as British Society of Gerontology and National Care Association will be approached for wider dissemination. The realist review has been registered on International Prospective Register of Systematic Reviews (PROSPERO 2017: CRD42017062601).


Do group practices have lower caesarean rates than solo practice obstetric clinics? Evidence from Taiwan.
This study examined physicians' propensity for caesarean deliveries at solo versus group practice obstetrics/gynaecology (ob/gyn) clinics in Taiwan. We used population-based (National Health Insurance) claims data covering all 253 618 singleton deliveries conducted at ob/gyn clinics, during 2000-02. The dependent variable, delivery mode, was treated as dichotomous [caesarean section (CS) = 1, vaginal delivery (VD) = 0]. The independent variable of interest was practice size, classified into four categories: 1, 2, 3 and 4+ physicians. Multilevel logistic regression modelling, accounting for clinic-level variation in CS rates, was used to examine CS likelihood by practice size, among the total delivery sample and among the sub-samples disaggregated by obstetric complication status. Solo practices have 7% excess caesarean cases relative to large group practices. After controlling for patient's age, physician demographics, the clinic's geographic location and size of delivery service, and clinic-level random effect, solo practice physicians were 5.38 times as likely as 4+ physician practices to provide caesarean delivery (CI = 4.18 approximately 6.93), 2-physician practices were 3.87 times (CI = 2.99 approximately 5.01) and 3-physician practices 2.72 times (CI = 2.06 approximately 3.59) as likely as 4+ physician practices to provide caesarean delivery. This effect is driven by higher CS propensity among solo and small groups among cases with obstetrically less salient complications and the 'no complications' subset of patients. Wide confidence intervals for odds ratios in these sub-samples also attest to wide variations in clinic-level CS rates among these patient groups. Solo physicians are the most likely to provide caesarean delivery, and CS likelihood decreases with increasing number of physicians in the practice. Group practice support may reduce the CS likelihood, when it is not clinically indicated. Policy makers should consider initiatives to limit full service delivery privileges to group practice obstetric clinics, in order to reduce unnecessary CS. Solo practice clinics should, at best, be licensed as birthing centres, required to transfer patients needing CS to a larger facility.


Association analysis of IGF-I gene expression with growth and reproductive traits in Jinghai yellow chickens.
The insulin-like growth factor, IGF-I, plays an important role in the development of growth and reproductive traits. Single-strand conformation polymorphism analysis was used to detect and analyze polymorphisms and expression profiles of the IGF-I gene and its association with growth and reproductive traits of Jinghai yellow chickens. A point mutation g.295T>C was detected in the IGF-I gene with three genotypes CC, CT, and TT. The CT and TT genotypes were found to be significantly (P < 0.05) superior to the CC genotype in 8-, 10-, 12-, 14-, and 16-week-age weight of chickens (for growth traits) and in body weight at first egg-laying (for reproductive traits). Comparison of the expression level between males and females showed similarity in their expression curves, with females showing relatively higher IGF-I expression than males in all studied tissues. A similar IGF-I expression pattern was observed in the breast and leg muscles of both males and females, with the leg muscle showing relative higher IGF-I expression than the breast muscle. Our results indicate that, g.295T>C mutation in the IGF-I gene affects certain growth and reproductive traits, and it could be used to provide a theoretical basis as well as marker-assisted selection to upgrade the development of Jinghai yellow chickens in future.


The limits of elaboration: curved allometries reveal the constraints on mandible size in stag beetles.
Many studies have demonstrated the adaptive advantage of elaborate secondary sexual traits, but few if any have shown compelling evidence for the limits to the elaboration of these traits that must exist. We describe such evidence in the exaggerated mandibles of stag beetles. In 1932, Huxley showed that the slope of the allometric relationship between mandible length and body size in some stag beetles declines in the largest males. We show that this curvature is most pronounced in species with relatively long mandibles, consistent with the hypothesis that the decrease in slope is caused by the increasing costs of large mandibles, which ultimately limit their size. Increasing depletion of resources in the prepupa and pupa by the rapidly growing mandibles is the most likely way in which these costs are manifested. The curved allometries have two components: intraspecific mandible allometry is steepest among small males of the species with the longest mandibles, but shallowest among the largest males of those same species. These patterns suggest that selection continues to favour positive allometry in species that invest relatively more in weaponry despite the limits to mandible exaggeration being reached in the largest males.


Spatiotemporal energy models for the perception of motion.
A motion sequence may be represented as a single pattern in x-y-t space; a velocity of motion corresponds to a three-dimensional orientation in this space. Motion sinformation can be extracted by a system that responds to the oriented spatiotemporal energy. We discuss a class of models for human motion mechanisms in which the first stage consists of linear filters that are oriented in space-time and tuned in spatial frequency. The outputs of quadrature pairs of such filters are squared and summed to give a measure of motion energy. These responses are then fed into an opponent stage. Energy models can be built from elements that are consistent with known physiology and psychophysics, and they permit a qualitative understanding of a variety of motion phenomena.


Murine homolog of SALL1 is essential for ureteric bud invasion in kidney development.
SALL1 is a mammalian homolog of the Drosophila region-specific homeotic gene spalt (sal); heterozygous mutations in SALL1 in humans lead to Townes-Brocks syndrome. We have isolated a mouse homolog of SALL1 (Sall1) and found that mice deficient in Sall1 die in the perinatal period and that kidney agenesis or severe dysgenesis are present. Sall1 is expressed in the metanephric mesenchyme surrounding ureteric bud; homozygous deletion of Sall1 results in an incomplete ureteric bud outgrowth, a failure of tubule formation in the mesenchyme and an apoptosis of the mesenchyme. This phenotype is likely to be primarily caused by the absence of the inductive signal from the ureter, as the Sall1-deficient mesenchyme is competent with respect to epithelial differentiation. Sall1 is therefore essential for ureteric bud invasion, the initial key step for metanephros development.


Cigarette smoking and the lifetime alcohol involvement continuum.
Greater understanding of how alcohol use relates to the initiation, progression, and persistence of cigarette smoking is of great significance for efforts to prevent and treat smoking and excessive drinking and their substantial combined iatrogenic effects on health. Studies investigating the relationship between levels of alcohol involvement and smoking have typically been limited by analytic approaches that treat drinking behavior and alcohol use disorder diagnoses as separate phenomena rather than as indicators of a single latent alcohol involvement dimension. The purposes of the present study were (a) to create a lifetime index of alcohol involvement that integrates information about alcohol consumption and alcohol problems into a single measure and (b) to relate this index to initiation of smoking, progression from initiation to daily smoking, progression from initiation to dependence, and persistence of smoking. Rasch model analyses of data from 1508 middle-aged (34-44 years) adults showed that creating an additive index of lifetime alcohol involvement was psychometrically supported. Significant quadratic effects of alcohol involvement on initiation, progression, and persistence of smoking demonstrated that there were specific regions of the alcohol involvement continuum that were particularly strongly related to increased smoking. These results provide the most comprehensive depiction to date of the nature of the relationship between lifetime alcohol involvement and lifetime cigarette smoking and suggest potential avenues for research on the etiology and maintenance of smoking and tobacco dependence.


An extremely halophilic proteobacterium combines a highly acidic proteome with a low cytoplasmic potassium content.
Halophilic archaea accumulate molar concentrations of KCl in their cytoplasm as an osmoprotectant and have evolved highly acidic proteomes that function only at high salinity. We examined osmoprotection in the photosynthetic Proteobacteria Halorhodospira halophila and Halorhodospira halochloris. Genome sequencing and isoelectric focusing gel electrophoresis showed that the proteome of H. halophila is acidic. In line with this finding, H. halophila accumulated molar concentrations of KCl when grown in high salt medium as detected by x-ray microanalysis and plasma emission spectrometry. This result extends the taxonomic range of organisms using KCl as a main osmoprotectant to the Proteobacteria. The closely related organism H. halochloris does not exhibit an acidic proteome, matching its inability to accumulate K(+). This observation indicates recent evolutionary changes in the osmoprotection strategy of these organisms. Upon growth of H. halophila in low salt medium, its cytoplasmic K(+) content matches that of Escherichia coli, revealing an acidic proteome that can function in the absence of high cytoplasmic salt concentrations. These findings necessitate a reassessment of two central aspects of theories for understanding extreme halophiles. First, we conclude that proteome acidity is not driven by stabilizing interactions between K(+) ions and acidic side chains but by the need for maintaining sufficient solvation and hydration of the protein surface at high salinity through strongly hydrated carboxylates. Second, we propose that obligate protein halophilicity is a non-adaptive property resulting from genetic drift in which constructive neutral evolution progressively incorporates weakly stabilizing K(+)-binding sites on an increasingly acidic protein surface.


A hospital-wide quality-improvement collaborative to reduce catheter-associated bloodstream infections.
Catheter-associated bloodstream infections (CA BSIs) are associated with increased hospital length of stay, total hospital costs, and mortality. Quality-improvement collaboratives (QICs) are frequently used to improve health care quality. Our PICU was previously involved in a successful national QIC to reduce the incidence of CA BSI in critically ill children. We hypothesized that the formation of a hospital-wide QIC would reduce the incidence of CA BSI throughout our institution. We retrospectively reviewed the incidence of CA BSI from March 2006 to March 2010. The collaborative approach included hospital-wide implementation of central-line insertion and maintenance bundles that emphasized full sterile barrier precautions and chlorhexidine skin preparation during line insertion, daily discussion of catheter necessity, and meticulous site and tubing care. The hospital units involved were our 3 critical care units, the oncology unit, the bone marrow transplant unit, and wards. Each individual unit was responsible for collecting unit-specific data and performing event-cause analysis within 48 hours of identifying a CA BSI. These results were shared with the other hospital units during monthly meetings. Compliance with the insertion and maintenance bundles was monitored and reported to each unit monthly. The hospital-wide CA-BSI rate decreased from a baseline of 3.0 to <1.0 CA BSI per 1000 line-days after implementation of the QIC. Our hospital-wide QIC resulted in a significant reduction in the incidence of CA BSI at our children's hospital. A collaborative model based on improvement science methodology is both feasible and effective in reducing the incidence of CA BSI.


Transmitter inputs to different motoneuron subgroups in the oculomotor and trochlear nucleus in monkey.
In all vertebrates the eyes are moved by six pairs of extraocular muscles enabling horizontal, vertical and rotatory movements. Recent work showed that each extraocular muscle is controlled by two motoneuronal groups: (1) Motoneurons of singly-innervated muscle fibers (SIF) that lie within the boundaries of motonuclei mediating a fast muscle contraction; and (2) motoneurons of multiply-innervated muscle fibers (MIF) in the periphery of motonuclei mediating a tonic muscle contraction. Currently only limited data about the transmitter inputs to the SIF and MIF motoneurons are available. Here we performed a quantitative study on the transmitter inputs to SIF and MIF motoneurons of individual muscles in the oculomotor and trochlear nucleus in monkey. Pre-labeled motoneurons were immunostained for GABA, glutamate decarboxylase, GABA-A receptor, glycine transporter 2, glycine receptor 1, and vesicular glutamate transporters 1 and 2. The main findings were: (1) the inhibitory control of SIF motoneurons for horizontal and vertical eye movements differs. Unlike in previous primate studies a considerable GABAergic input was found to all SIF motoneuronal groups, whereas a glycinergic input was confined to motoneurons of the medial rectus (MR) muscle mediating horizontal eye movements and to those of the levator palpebrae (LP) muscle elevating the upper eyelid. Whereas SIF and MIF motoneurons of individual eye muscles do not differ numerically in their GABAergic, glycinergic and vGlut2 input, vGlut1 containing terminals densely covered the supraoculomotor area (SOA) targeting MR MIF motoneurons. It is reasonable to assume that the vGlut1 input affects the near response system in the SOA, which houses the preganglionic neurons mediating pupillary constriction and accommodation and the MR MIF motoneurones involved in vergence.


Is the true 'wisdom of the crowd' to copy successful individuals?
Diversity of expertise at an individual level can increase intelligence at a collective level-a type of swarm intelligence (SI) popularly known as the 'wisdom of the crowd'. However, this requires independent estimates (rare in the real world owing to the availability of public information) and contradicts people's bias for copying successful individuals. To explain these inconsistencies, 429 people took part in a 'guess the number of sweets' exercise. Guesses made with no public information were diverse, resulting in highly accurate SI. Individuals with access to the previous guess, mean guess or a randomly chosen guess, tended to over-estimate the number of sweets and this undermined SI. However, when people were provided with the current best guess, this prevented very large (inaccurate) guesses, resulting in convergence of guesses towards the true value and accurate SI across a range of group sizes. Thus, contrary to previous work, we show that social influence need not undermine SI, especially where individual decisions are made sequentially and then aggregated. Furthermore, we offer an explanation for why people have a bias to recruit and follow experts in team settings: copying successful individuals can enable accuracy at both the individual and group level, even at small group sizes.


Australian Football Athletes Lack Awareness of Current Sport Nutrition Guidelines.
Sports nutrition is an evolving field, but there is a lack of data on Australian athletes' knowledge of current sports nutrition guidelines. Additionally, several tools used to assess nutrition knowledge (NK) have not undergone adequate validation. The purpose of this study was to assess and compare the sports NK of elite and nonelite Australian football (AF) athletes using a newly validated questionnaire-The Nutrition for Sport Knowledge Questionnaire. Elite AF players (n = 46) were recruited directly from their club dietitian and nonelite AF players (n = 53) were invited to participate via e-mail from their club president or secretary. The mean NK score of elite and nonelite AF players was 46 ± 16% and 51 ± 11%, respectively (p = .041). In both groups, knowledge of macronutrients, weight management, and alcohol was better than knowledge of supplements, micronutrients, and sports nutrition. Nonelite athletes achieved statistically significantly higher scores on the questionnaire subsections testing weight management (elite: 48 ± 18; nonelite: 57 ± 19, p = .019), micronutrients (elite: 39 ± 19; nonelite: 50 ± 16, p = .004), and alcohol (elite: 52 ± 13; nonelite: 71 ± 17, p = .002). While overall NK of Australian athletes was poor, scores varied greatly among individuals (range: 10-70%) and across the six subsections (topics) being assessed. Professionals working with athletes should undertake an assessment of the athletes' NK so that they can provide targeted education programs.


Mitonuclear Ecology.
Eukaryotes were born of a chimeric union between two prokaryotes--the progenitors of the mitochondrial and nuclear genomes. Early in eukaryote evolution, most mitochondrial genes were lost or transferred to the nucleus, but a core set of genes that code exclusively for products associated with the electron transport system remained in the mitochondrion. The products of these mitochondrial genes work in intimate association with the products of nuclear genes to enable oxidative phosphorylation and core energy production. The need for coadaptation, the challenge of cotransmission, and the possibility of genomic conflict between mitochondrial and nuclear genes have profound consequences for the ecology and evolution of eukaryotic life. An emerging interdisciplinary field that I call "mitonuclear ecology" is reassessing core concepts in evolutionary ecology including sexual reproduction, two sexes, sexual selection, adaptation, and speciation in light of the interactions of mitochondrial and nuclear genomes.


CD14+CD16++ "nonclassical" monocytes are associated with endothelial dysfunction in patients with coronary artery disease.
Endothelial dysfunction and inflammation are key mechanisms of vascular disease. We hypothesised that heterogeneity of monocyte subpopulations may be related to the development of vascular dysfunction in coronary artery disease (CAD). Therefore, we examined the relationships between monocyte subsets (CD14++CD16- "classical - Mon1", CD14++CD16+ "intermediate - Mon2" and CD14+CD16++ "nonclassical - Mon3"), endothelial function and risk factor profiles in 130 patients with CAD undergoing coronary artery bypass grafting. This allowed for direct nitric oxide (NO) bioavailability assessment using isometric tension studies ex vivo (acetylcholine; ACh- and sodium-nitropruside; SNP-dependent) in segments of internal mammary arteries. The expression of CD14 and CD16 antigens and activation markers were determined in peripheral blood mononuclear cells using flow cytometry. Patients with high CD14+CD16++ "nonclassical" and low CD14++CD16- "classical" monocytes presented impaired endothelial function. High frequency of CD14+CD16++ "nonclassical" monocytes was associated with increased vascular superoxide production. Furthermore, endothelial dysfunction was associated with higher expression of activation marker CD11c selectively on CD14+CD16++ monocytes. Nonclassical and classical monocyte frequencies remained independent predictors of endothelial dysfunction when major risk factors for atherosclerosis were taken into account (β=0.18 p=0.04 and β=-0.19 p=0.03, respectively). In summary, our data indicate that CD14+CD16++ "nonclassical" monocytes are associated with more advanced vascular dysfunction measured as NO- bioavailability and vascular reactive oxygen species production.


[Anencephaly: the magnitude of the judicial authorization among medical doctors in Brazil].
This paper describes the magnitude of the medical care for pregnant women with an anencephalic fetus. Anencephaly is an abnormality incompatible with life. The right to abort in this case is under litigation at the Brazilian Supreme Court. This survey was conducted among 1,814 medical doctors, all of them affiliated to the Brazilian Federation of Gynecology and Obstetrics (Febrasgo), corresponding to 12% of the doctors within this federation. The results show that, in a group of 9,730 women cared by the physicians over the last 20 years, 85% preferred to interrupt pregnancy in case of anencephaly. This fact reveals how common the experience of assist women pregnant with an anencephalic fetus is in health care services, as well as the ethical challenge imposed by the restrictive Brazilian legislation on abortion.


Epidemiology of Lung Cancer in Oman: 20-Year Trends and Tumor Characteristics.
We sought to investigate the epidemiology of lung cancer and its trends in Oman over 20 years. We analyzed all cases of primary lung cancer reported to the Oman National Cancer Registry between 1996 and 2015. The World Standard Population was used to obtain age-standardized incidence rates (ASR) of lung cancer per 100 000. Analyses were conducted using univariate statistics. A total of 956 cases of primary lung cancer cases were registered in Oman between 1996 and 2015, with a male to female ratio of 3:1. In men, the ASR was 8.2 per 100 000, while in females it was 2.6 per 100 000 over the entire study period. There were no statistically significant differences in the ASR among men or women when the data was divided over three calendar periods (1996-2005, 2006-2015, and 1996-2015) (p = 0.332 and p = 0.577, respectively). There was also no increasing trend in the incidence of lung cancer. The risk of lung cancer onset commenced in the 30-34 year age group and the mean age at diagnosis was 60.0 years for men and 61.0 years for women. Adenocarcinoma was the most common type of lung cancer among Omanis with a higher proportion in females compared to males. Oman has one of the lowest incidence rates of lung cancer in the world with no evidence of an increasing trend of this cancer type. This could be attributed to low uptake of tobacco smoking among both sexes. National authorities should capitalize on this finding to avoid any future lung cancer epidemics especially those driven by tobacco use.


Reproductive factors and risk of esophageal squamous cell carcinoma in northern Iran: a case-control study in a high-risk area and literature review.
Several epidemiologic studies have suggested an inverse association between female reproductive factors and the risk of esophageal squamous cell carcinoma (ESCC), but the evidence is not conclusive. We examined the association of the number of pregnancies, live births, and miscarriages/stillbirths in women and the association of the number of children in both sexes with the risk of ESCC in Golestan Province, a high-risk area in Iran. Data from 297 histopathologically confirmed ESCC cases (149 women) and 568 controls (290 women) individually matched to cases for age, sex, and neighborhood of residence were included in this analysis. Conditional logistic regression was used to calculate odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). The average numbers of live births and miscarriages/stillbirths among the controls were 8.2 and 0.8, respectively. Women with six or more live births were at ~1/3 the risk of ESCC as those with 0-3 live births; the OR (95% CI) for having 6-7 live births was 0.33 (0.12-0.92). In contrast, the number of miscarriages/stillbirths was associated with an increase in the risk of ESCC. The OR (95% CI) for at least three versus no miscarriages/stillbirths was 4.43 (2.11-9.33). The number of children in women was suggestive of an inverse association with ESCC, but this association was not statistically significant; in men, no association was observed. The findings of this study support a protective influence of female hormonal factors on the risk of ESCC. However, further epidemiological and mechanistic studies are required to prove a protective association.


Encoding of natural sounds at multiple spectral and temporal resolutions in the human auditory cortex.
Functional neuroimaging research provides detailed observations of the response patterns that natural sounds (e.g. human voices and speech, animal cries, environmental sounds) evoke in the human brain. The computational and representational mechanisms underlying these observations, however, remain largely unknown. Here we combine high spatial resolution (3 and 7 Tesla) functional magnetic resonance imaging (fMRI) with computational modeling to reveal how natural sounds are represented in the human brain. We compare competing models of sound representations and select the model that most accurately predicts fMRI response patterns to natural sounds. Our results show that the cortical encoding of natural sounds entails the formation of multiple representations of sound spectrograms with different degrees of spectral and temporal resolution. The cortex derives these multi-resolution representations through frequency-specific neural processing channels and through the combined analysis of the spectral and temporal modulations in the spectrogram. Furthermore, our findings suggest that a spectral-temporal resolution trade-off may govern the modulation tuning of neuronal populations throughout the auditory cortex. Specifically, our fMRI results suggest that neuronal populations in posterior/dorsal auditory regions preferably encode coarse spectral information with high temporal precision. Vice-versa, neuronal populations in anterior/ventral auditory regions preferably encode fine-grained spectral information with low temporal precision. We propose that such a multi-resolution analysis may be crucially relevant for flexible and behaviorally-relevant sound processing and may constitute one of the computational underpinnings of functional specialization in auditory cortex.


Arctic complexity: a case study on diel vertical migration of zooplankton.
Diel vertical migration (DVM) of zooplankton is a global phenomenon, characteristic of both marine and limnic environments. At high latitudes, patterns of DVM have been documented, but rather little knowledge exists regarding which species perform this ecologically important behaviour. Also, in the Arctic, the vertically migrating components of the zooplankton community are usually regarded as a single sound scattering layer (SSL) performing synchronized patterns of migration directly controlled by ambient light. Here, we present evidence for hitherto unknown complexity of Arctic marine systems, where zooplankton form multiple aggregations through the water column seen via acoustics as distinct SSLs. We show that while the initiation of DVM during the autumnal equinox is light mediated, the vertical positioning of the migrants during day is linked more to the thermal characteristics of water masses than to irradiance. During night, phytoplankton biomass is shown to be the most important factor determining the vertical positioning of all migrating taxa. Further, we develop a novel way of representing acoustic data in the form of a Sound Image (SI) that enables a direct comparison of the relative importance of each potential scatterer based upon the theoretical contribution of their backscatter. Based on our comparison of locations with contrasting hydrography, we conclude that a continued warming of the Arctic is likely to result in more complex ecotones across the Arctic marine system.


Transplantation of induced pluripotent stem cells improves functional recovery in Huntington's disease rat model.
The purpose of this study was to determine the functional recovery of the transplanted induced pluripotent stem cells in a rat model of Huntington's disease with use of 18F-FDG microPET/CT imaging. In a quinolinic acid-induced rat model of striatal degeneration, induced pluripotent stem cells were transplanted into the ipsilateral lateral ventricle ten days after the quinolinic acid injection. The response to the treatment was evaluated by serial 18F-FDG PET/CT scans and Morris water maze test. Histological analyses and Western blotting were performed six weeks after stem cell transplantation. After induced pluripotent stem cells transplantation, higher 18F-FDG accumulation in the injured striatum was observed during the 4 to 6-weeks period compared with the quinolinic acid-injected group, suggesting the metabolic recovery of injured striatum. The induced pluripotent stem cells transplantation improved learning and memory function (and striatal atrophy) of the rat in six week in the comparison with the quinolinic acid-treated controls. In addition, immunohistochemical analysis demonstrated that transplanted stem cells survived and migrated into the lesioned area in striatum, and most of the stem cells expressed protein markers of neurons and glial cells. Our findings show that induced pluripotent stem cells can survive, differentiate to functional neurons and improve partial striatal function and metabolism after implantation in a rat Huntington's disease model.


Divergent requirements for fibroblast growth factor signaling in zebrafish maxillary barbel and caudal fin regeneration.
The zebrafish maxillary barbel is an integumentary organ containing skin, glands, pigment cells, taste buds, nerves, and endothelial vessels. The maxillary barbel can regenerate (LeClair & Topczewski 2010); however, little is known about its molecular regulation. We have studied fibroblast growth factor (FGF) pathway molecules during barbel regeneration, comparing this system to a well-known regenerating appendage, the zebrafish caudal fin. Multiple FGF ligands (fgf20a, fgf24), receptors (fgfr1-4) and downstream targets (pea3, il17d) are expressed in normal and regenerating barbel tissue, confirming FGF activation. To test if specific FGF pathways were required for barbel regeneration, we performed simultaneous barbel and caudal fin amputations in two temperature-dependent zebrafish lines. Zebrafish homozygous for a point mutation in fgf20a, a factor essential for caudal fin blastema formation, regrew maxillary barbels normally, indicating that the requirement for this ligand is appendage-specific. Global overexpression of a dominant negative FGF receptor, Tg(hsp70l:dn-fgfr1:EGFP)(pd1) completely blocked fin outgrowth but only partially inhibited barbel outgrowth, suggesting reduced requirements for FGFs in barbel tissue. Maxillary barbels expressing dn-fgfr1 regenerated peripheral nerves, dermal connective tissue, endothelial tubes, and a glandular epithelium; in contrast to a recent report in which dn-fgfr1 overexpression blocks pharyngeal taste bud formation in zebrafish larvae (Kapsimali et al. 2011), we observed robust formation of calretinin-positive tastebuds. These are the first experiments to explore the molecular mechanisms of maxillary barbel regeneration. Our results suggest heterogeneous requirements for FGF signaling in the regeneration of different zebrafish appendages (caudal fin versus maxillary barbel) and taste buds of different embryonic origin (pharyngeal endoderm versus barbel ectoderm).


Low case notification rates of childhood tuberculosis in southern Ethiopia.
Childhood tuberculosis (TB) is a public health concern causing considerable mortality. However, control of childhood TB receives little attention. The control efforts could be inadequate because of challenges associated with difficulties in diagnosing the disease in children. Understanding the burden of the disease among children is important to assess the ongoing transmission of the disease in a community and improving TB control efforts. This study was carried out to assess TB case notification rates (CNRs) and treatment outcomes in children aged less than 15 years over a ten-year period. Data were collected from unit TB registers from all health facilities providing TB treatment in the Sidama Zone in Ethiopia. We analysed the CNRs and treatment outcomes by age category, gender, and place of residence. We used logistic regression analysis to identify factors associated with treatment outcomes and to control for confounding. A total of 4,656 cases of children less than 15 years of age were notified as diagnosed and treated for TB, constituting 13% of all notified TB cases in the study area. The mean CNRs per 100,000 children less than 15 years were 30 for all new cases of TB, 28 for rural cases, 67 for urban cases, 28 in boys, and 32 in girls. The proportions of treatment success were 82% for new and 77% for retreatment cases for the entire study period and increased to 93% for new cases in 2012 (X(2) trend, P < 0.001). Children less than five years old had a lower treatment success [adjusted odds ratio (AOR) 0.64 (95% CI, 0.52-0.80)] and higher deaths [AOR 2 (95% CI, 1.27-3.12)]. The proportion of children who died during treatment among children in the less than 2-year-old age group was three times higher than children in the 2 year and above age groups [AOR 3.34 (95% CI, 1.92-5.82)]. The CNRs of childhood TB were low in Sidama. Children less than 5 years old had a higher proportion of deaths. Efforts need to be made to improve the diagnosis and treatment of TB among children.


Legitimacy in the 'secular church' of the United Nations.
This article argues that how the United Nations (UN) conceptualizes legitimacy is not only a matter of legalism or power politics. The UN's conception of legitimacy also utilizes concepts, language and symbolism from the religious realm. Understanding the entanglement between political and religious concepts and the ways of their verbalization at the agential level sheds light on how legitimacy became to be acknowledged as an integral part of the UN and how it changes. At the constitutional level, the article examines phrases and 'verbal symbols', enshrined in the Charter of the 'secular church' UN. They evoke intrinsic legitimacy claims based on religious concepts and discourse such as hope and salvation. At the agential level, the article illustrates how the Secretary-General verbalizes those abstract constitutional principles of legitimacy. Religious language and symbolism in the constitutional framework and agential practice of the UN does not necessarily produce an exclusive form of legitimacy. This article shows, however, that legitimacy as nested in the UN's constitutional setting cannot exist without religious templates because they remain a matter of a 'cultural frame'.


Insulin-like growth factor I (IGF-I) in a growth-enhanced transgenic (GH-overexpressing) bony fish, the tilapia (Oreochromis niloticus): indication for a higher impact of autocrine/paracrine than of endocrine IGF-I.
Several lines of growth hormone (GH)-overexpressing fish have been produced and analysed for growth and fertility parameters. However, only few data are available on the growth-promoting hormone insulin-like growth factor I (IGF-I) that mediates most effects of GH, and these are contradictory. Using quantitative real-time RT-PCR, radioimmunoassay, in situ hybridization, immunohistochemistry, and radiochromatography we investigated IGF-I and IGF binding proteins (IGFBPs) in an adult (17 months old) transgenic (GH-overexpressing) tilapia (Oreochromis niloticus). The transgenics showed an around 1.5-fold increase in length and an approximately 2.3-fold higher weight than the non-transgenics. Using radioimmunoassay, the serum IGF-I levels were lower (6.22 +/- 0.75 ng/ml) in transgenic than in wild-type (15.01 +/- 1.49 ng/ml) individuals (P = 0.0012). Radioimmunoassayable IGF-I in transgenic liver was 4.2-times higher than in wild-type (16.0 +/- 2.21 vs. 3.83 +/- 0.71 ng/g, P = 0.0017). No hepatocytes in wild-type but numerous hepatocytes in transgenic liver contained IGF-I-immunoreactivity. RT-PCR revealed a 1.4-times higher IGF-I mRNA expression in the liver of the transgenics (10.51 +/- 0.82 vs. 7.3 +/- 0.49 pg/microg total RNA, P = 0.0032). In correspondence, in situ hybridization showed more IGF-I mRNA containing hepatocytes in the transgenics. A twofold elevated IGF-I mRNA expression was determined in the skeletal muscle of transgenics (0.33 +/- 0.02 vs. 0.16 +/- 0.01 pg/microg total RNA, P < 0.0001). Both liver and serum of transgenics showed increased IGF-I binding. The increased IGFBP content in the liver may lead to retention of IGF-I, and/or the release of IGF-I into the circulation may be slower resulting in accumulation of IGF-I in the hepatocytes. Our results indicate that the enhanced growth of the transgenics likely is due to enhanced autocrine/paracrine action of IGF-I in extrahepatic sites, as shown here for skeletal muscle.


Change in symptom clusters in head and neck cancer patients undergoing postoperative radiotherapy: A longitudinal study.
Research on symptom clusters is a newly emerging field in oncology; however, little evidence regarding symptom clusters in head and neck cancer (HNC) is currently available. To clarify this under-researched area, we investigated symptom clusters among patients with HNC treated with surgery and postoperative radiotherapy. We also examined the pattern of symptom clusters throughout the treatment course. A convenience sample of 100 patients with HNC was recruited in the Ear, Nose, and Throat unit of a medical center in Taiwan. Before undergoing postoperative radiotherapy, patients were asked to complete the MD Anderson Symptom Inventory and a demographic sheet. Patients completed the same inventory questionnaire at week 1, 2, 3, 4, 5, and 6 of radiotherapy. Two symptom clusters were observed, and they were stable throughout the course of radiotherapy. Cluster 1, the HNC-specific cluster, comprised the symptoms of pain, dry mouth, lack of appetite, sleep disturbance, fatigue, drowsiness, distress, and sadness. Cluster 2, the gastrointestinal cluster, included nausea, vomiting, numbness, shortness of breath, and difficulty remembering. This study advanced our knowledge of symptom clusters in patients with HNC. The results are expected to contribute to the development of appropriate assessment and nursing interventions targeting multiple symptoms that may coexist in postoperative radiotherapy.


Hedgehog pathway inhibitors promote adaptive immune responses in basal cell carcinoma.
Basal cell carcinomas (BCCs) are tumors ignored by immune surveillance. Activated Hedgehog (Hh) signaling within primary cilia is a key driver in the pathogenesis of BCCs. We examined immune alterations during treatment with systemic Hh inhibitors. We investigated biopsies from patients with BCC before (23 patients) and after 4 weeks of treatment (5 patients) with Hh signaling inhibitor. Ber-Ep4, BCL-2, Ki-67, CD4, CD8, MHC class I, HLA-DR-class II, and SOX9 were analyzed by immunohistochemistry. Primary cilia were analyzed by double immunofluorescence of acetylated tubulin and SOX9. Differential gene expression for 84 cytokines and chemokines was analyzed in 3 patients. After 4 weeks of treatment, we found reduction of Ki-67, SOX9, Ber-EP4, and BCL-2 expression in tumors associated with morphologic signs of squamous differentiation. In addition, the number of cilia-positive BCC cells was significantly decreased. An upregulation of MHC I expression on the cell membranes of residual tumor cells and an influx of CD4(+), HLA-DR-class II(+), and CD8(+) cells with invasion into the tumor cell nests were found. Finally, qPCR arrays showed the differential expression of genes involved in modulating immune responses. We show that Hh pathway inhibitor-induced tumor regression is accompanied by a dynamic change of the microenvironment with a disruption of immune privilege involving an influx of cytotoxic T cells, activation of the adaptive immune functions, and a profound alteration of the local chemokine/cytokine network.


The natural rehabilitation of an anthropogenically acidified tropical Lake: two decades of monitoring.
The rehabilitation of a pond after approximately 20 years of strong acidified conditions due to industrial and domestic waste deposition in its catchment basin is reviewed. We describe in this study the acidification process that occurred in a tropical pond in Northeast Brazil (Dunas Lake), the rehabilitation plan for the pond and the subsequent monitoring conducted over two decades. After the contamination assessment by the late 80s, a rehabilitation plan was carried out in the early 90s, in which the contaminated soil and water have been removed and reduced, respectively. No further attempt to neutralize the water or any remediation has been carried out. A toxicity monitoring plan based on toxicity assays with the fish Poecilia reticulata was employed to verify the natural rehabilitation of the pond. The data on toxicity, pH, conductivity, sulphate and dissolved iron recorded from 1994 to 2010 were also compiled and discussed. The collected data in 2003 and 2004 indicated changes in water quality and from them complementary management actions, namely improvement in the containment plant, were conducted in 2005. Results for toxicity assays and pH results indicated interannual changes in the water quality similar to rainy-dry periods. Moving average approach using pH data clearly showed the recovery process of Dunas Lake as well as the importance of the containment plan to reduce the contamination. Finally, a summary of the recent situation after two decades of rehabilitation is provided.


Trends in Follow-Up of Patients Presenting to the Emergency Department with Symptomatic Cholelithiasis.
Fewer than 25% of Medicare beneficiaries presenting with symptomatic cholelithiasis undergo elective cholecystectomy. To better understand underuse of cholecystectomy, we examined physician follow-up patterns after emergency department (ED) visits for symptomatic gallstones. We used 100% Texas Medicare claims (2001 to 2010) to identify patients 66 years of age and older who presented to the ED with symptomatic cholelithiasis and were discharged home without cholecystectomy. Timing of outpatient physician visits after ED discharge and rates of emergent cholecystectomy based on physician follow-up patterns were compared. In total, 11,126 patients presented to the ED with symptomatic cholelithiasis and were discharged without cholecystectomy. After discharge, 5,327 patients (47.9%) had an outpatient surgeon visit, 29.0% saw another physician and never saw a surgeon, and 23.1% never saw a physician; 68.2% of patients who saw a surgeon underwent elective cholecystectomy; and 8.3% of patients who saw a surgeon, 14.6% of patients who saw other physicians and no surgeon, and 77.6% of patients who never saw any physician, required emergent hospitalization (p < 0.0001). For people who did not see a physician, mean time to emergent hospitalization was 7.5 days (median 2 days); 95.9% presented within 2 weeks after their initial presentation. Fewer than half of patients were evaluated by a surgeon after an initial ED visit for symptomatic gallstones. Patients who did not have physician follow-up were most likely to require emergent cholecystectomy, suggesting inappropriate ED discharge and highlighting the need for timely follow-up. Early outpatient surgical consultation is critical in determining appropriateness for cholecystectomy and avoiding emergent cholecystectomy in older patients with symptomatic gallstones.


Assessing abuse risk beyond self-report: analog task of acceptability of parent-child aggression.
The present investigation reports on the development and initial validation of a new analog task, the Parent-Child Aggression Acceptability Movie Task (P-CAAM), intended to assess respondents' acceptance of parent-child aggression, including both physical discipline and physical abuse. Two independent samples were utilized to develop and evaluate the P-CAAM: an undergraduate sample to initially pilot the task and a separate sample of normative parents for additional assessment of validity. Scores from the P-CAAM were compared to related measures, including measures of self-reported disciplinary attitudes, child abuse potential, harsh parenting style, and use and escalation of physical discipline practices on another analog parenting task. Across the studies, the P-CAAM demonstrated acceptable internal consistency and construct validity, evidencing mild to moderate associations with both self-report and analog measures. Participants demonstrating increased acceptance of physical discipline and physical abuse on the P-CAAM analog task also reported greater approval of physical discipline, greater use of and escalation of physical discipline, harsher parenting styles, and higher child abuse potential on two separate measures. The P-CAAM analog appears to offer a promising alternative and/or supplement to conventional self-report measures, assessing attitudes regarding the acceptability of parent-child aggression in a way that is less likely to be influenced by social desirability. Suggestions for future evaluations with alternative samples, as well as possible implications of the data for disciplinary reactions are discussed. The development of alternatives to self-report measurement may lead to clarification of theoretical models of abuse in ways that lead to improvements in intervention programming; analogs may also provide a useful means to assess intervention programming outcomes.


Comparison of EMG during passive stretching and shortening phases of each muscle for the investigation of parkinsonian rigidity.
The aim of this study was to test the hypothesis in the literature that torque resistance of parkinsonian rigidity is the difference between the independent contributions of stretched and shortened muscles. The hypothesis was tested using muscle-specific stretch-shortening (MSSS) EMG ratio in this study. Nineteen patients with idiopathic Parkinson's disease (PD) and 18 healthy subjects (the mean age comparable to that of patients) participated in this study. The EMG activity was measured in the four muscles involved in wrist joint movement, i.e. flexor carpi radialis, flexor carpi ulnaris, extensor carpi radialis and extensor carpi ulnaris. The passive flexion-extension movement with a range of ±30∘ was applied at wrist joint. Root mean squared (RMS) mean was calculated from the envelope of the EMG for each of stretching and shortening phases. MSSS EMG ratio was defined as the ratio of RMS EMG of stretching phase and RMS EMG of shortening phase of a single muscle, and it was calculated for each muscle. MSSS EMG ratios were smaller than one in all muscles. These results indicate that all wrist muscles generate greater mean EMG during shortening than during stretching. Therefore, the torque resistance of parkinsonian rigidity cannot be explained as the simple summation of independent antagonistic torque pair.


Whole-genome reconstruction and mutational signatures in gastric cancer.
Gastric cancer is the second highest cause of global cancer mortality. To explore the complete repertoire of somatic alterations in gastric cancer, we combined massively parallel short read and DNA paired-end tag sequencing to present the first whole-genome analysis of two gastric adenocarcinomas, one with chromosomal instability and the other with microsatellite instability. Integrative analysis and de novo assemblies revealed the architecture of a wild-type KRAS amplification, a common driver event in gastric cancer. We discovered three distinct mutational signatures in gastric cancer--against a genome-wide backdrop of oxidative and microsatellite instability-related mutational signatures, we identified the first exome-specific mutational signature. Further characterization of the impact of these signatures by combining sequencing data from 40 complete gastric cancer exomes and targeted screening of an additional 94 independent gastric tumors uncovered ACVR2A, RPL22 and LMAN1 as recurrently mutated genes in microsatellite instability-positive gastric cancer and PAPPA as a recurrently mutated gene in TP53 wild-type gastric cancer. These results highlight how whole-genome cancer sequencing can uncover information relevant to tissue-specific carcinogenesis that would otherwise be missed from exome-sequencing data.


The effects of neuregulin on cardiac Myosin light chain kinase gene-ablated hearts.
Activation of ErbB2/4 receptor tyrosine kinases in cardiomyocytes by neuregulin treatment is associated with improvement in cardiac function, supporting its use in human patients with heart failure despite the lack of a specific mechanism. Neuregulin infusion in rodents increases cardiac myosin light chain kinase (cMLCK) expression and cardiac myosin regulatory light chain (RLC) phosphorylation which may improve actin-myosin interactions for contraction. We generated a cMLCK knockout mouse to test the hypothesis that cMLCK is necessary for neuregulin-induced improvement in cardiac function by increasing RLC phosphorylation. The cMLCK knockout mice have attenuated RLC phosphorylation and decreased cardiac performance measured as fractional shortening. Neuregulin infusion for seven days in wildtype mice increased cardiac cMLCK protein expression and RLC phosphorylation while increasing Akt phosphorylation and decreasing phospholamban phosphorylation. There was no change in fractional shortening. In contrast, neuregulin infusion in cMLCK knockout animals increased cardiac performance in the absence of cMLCK without increasing RLC phosphorylation. In addition, CaMKII signaling appeared to be enhanced in neuregulin-treated knockout mice. Thus, Neuregulin may improve cardiac performance in the failing heart without increasing cMLCK and RLC phosphorylation by activating other signaling pathways.


Use of exosomes as vectors to carry advanced therapies.
Exosomes are microvesicles of nanometric size involved in the communication between cells and tissues. Inside their bilipidic membrane they carry nucleic acids such as cargos (DNA, miRNA, etc.). Some of the advantages that make exosomes very attractive therapeutic vehicles are (i) their tropism through different tissues, (ii) the ability to pass biological barriers and (iii) the protection of the encapsulated material from the immune system and degradation. Viruses are some of the most widely employed gene therapy vehicles; however, they are still facing many problems, such as inefficient tropism to damaged areas and their elimination by the immune system. One of the functions attributed to exosomes is the elimination of substances that could be harmful to the cell, including viruses. Recently it has been investigated whether complete viruses or part of them could be encapsulated in exosomes, for a new viral-exosome gene therapy approach. Moreover, nanotechnology is another type of advanced therapy (together with gene and cell therapies) that can be used, among other utilities, to transfer genetic material. Recently the field of encapsulation of nanomaterials in exosomes, with or without gene transfer, is increasing. In this review we will summarize all of those studies.


In Vitro Systems Toxicology Assessment of a Candidate Modified Risk Tobacco Product Shows Reduced Toxicity Compared to That of a Conventional Cigarette.
Cigarette smoke increases the risk for respiratory and other diseases. Although smoking prevalence has declined over the years, millions of adults choose to continue to smoke. Modified risk tobacco products (MRTPs) are potentially valuable tools for adult smokers that are unwilling to quit their habit. Here, we investigated the biological impact of a candidate MRTP, the tobacco-heating system (THS) 2.2, compared to that of the 3R4F reference cigarette in normal primary human bronchial epithelial cells. Chemical characterization of the THS 2.2 aerosol showed reduced levels of harmful constituents compared to those of a combustible cigarette. Multiparametric indicators of cellular toxicity were measured via real-time cellular analysis and high-content screening. The study was complemented by a whole transcriptome analysis, followed by computational approaches to identify and quantify perturbed molecular pathways. Exposure of cells to 3R4F cigarette smoke resulted in a dose-dependent response in most toxicity end points. Moreover, we found a significant level of perturbation in multiple biological pathways, particularly in those related to cellular stress. By contrast, exposure to THS 2.2 resulted in an overall lower biological impact. At 3R4F doses, no toxic effects were observed. A toxic response was observed for THS 2.2 in some functional end points, but the responses occurred at doses between 3 and 15 times higher than those of 3R4F. The level of biological network perturbation was also significantly reduced following THS 2.2 aerosol exposure compared to that of 3R4F cigarette smoke. Taken together, the data suggest that THS 2.2 aerosol is less toxic than combustible cigarette smoke and thus may have the potential to reduce the risk for smoke-related diseases.


Validation of Procedural Codes to Identify Infants Evaluated for Serious Bacterial Infection.
To validate a novel coding method using Current Procedural Terminology, Fourth Edition (CPT-4) codes for identifying infants who underwent a full evaluation for serious bacterial infection (SBI). We performed a multicenter, retrospective examination to determine the accuracy of a combination of CPT-4 codes for blood, cerebrospinal fluid (CSF), and urine cultures to identify previously healthy infants ≤90 days old admitted to a general care floor and fully evaluated for SBI. Full SBI evaluation was defined as blood, CSF, and urine cultures performed during the emergency department encounter or corresponding hospitalization. Cases were defined as infants who had codes for blood, CSF, and urine cultures (87040, 87070, and either 87086 or 87088), and these were compared with all other encounters. We validated these findings by comparing medical record documentation of blood, CSF, and urine cultures to the corresponding CPT-4 codes, with calculation of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). We identified 8548 qualifying encounters, and 347 (4%) had a combination of CPT-4 codes 87040, 87070, and either 87086 or 87088. This combination had a sensitivity of 100% (95% confidence interval, 98.9-100) and specificity of 98.2% (95% confidence interval, 97.3-98.8) for identifying infants who underwent full SBI evaluation for an unknown source. CPT-4 codes provide an accurate means to identify infants who underwent complete SBI evaluation.


Novel and recurrent mutations in the C1NH gene of Arab patients affected with hereditary angioedema.
Autosomal dominant hereditary angioedema (HAE) results in episodes of subcutaneous edema in any body part and/or submucosal edema of the upper respiratory or gastrointestinal tracts. This disorder is caused by mutations in the C1NH gene, many of which have been described primarily in European patients. However, the genetic cause of HAE in Middle Eastern Arab patients has not yet been determined. Four unrelated Arab families, in which 15 patients were diagnosed with HAE, were studied. DNA from 13 patients was analyzed for mutations in the C1NH gene by DNA sequencing. Three novel and 2 recurrent mutations were identified in the C1NH gene of HAE patients. In family 1, the patient was heterozygous for a novel c.856C>T and a recurrent c.1361T>A missense mutation encoding for p.Arg264Cys and p.Val432Glu, respectively. In patients from family 2, a novel c.509C>T missense mutation encoding for a p.Ser148Phe was identified. In patients from family 3, a novel c.1142delC nonsense mutation encoding for a p.Ala359AlafsX15 was discovered. In family 4, a recurrent c.1397G>A missense mutation encoding for a p.Arg444His was present. This is the first ever report of C1NH gene mutations in Middle Eastern Arab patients. Our study suggests that, despite the numerous existing mutations in the C1NH gene, there are novel and recurrent mutations in HAE patients of non-European origin. We conclude that the spectrum of C1NH gene mutations in HAE patients is wider due to the likely presence of novel and recurrent mutations in patients of other ethnicities.


Biomechanical evaluation of bone screw fixation with a novel bone cement.
Bone cement augmentation is commonly used to improve the fixation stability of orthopaedic implants in osteoporotic bone. The aim of this study was to evaluate the effect of novel bone cements on the stability of bone screw fixation by biomechanical testing and to compare them with a conventional Simplex(®)P bone cement and requirements of the standards. Basic biomechanical properties were compared with standard tests. Adhesion of bone cements were tested with polished, glass blasted and corundum blasted stainless steel surfaces. Screw pullout testing with/without cement was carried out using a synthetic bone model and cancellous and cortical bone screws. All the tested bone cements fulfilled the requirements of the standard for biomechanical properties and improved the screw fixation stability. Even a threefold increase in shear and tensile strength was achieved with increasing surface roughness. The augmentation improved the screw pullout force compared to fixation without augmentation, 1.2-5.7 times depending on the cement and the screw type. The good biomechanical properties of novel bone cement for osteoporotic bone were confirmed by experimental testing. Medium viscosity of the bone cements allowed easy handling and well-controlled penetration of bone cement into osteoporotic bone. By proper parameters and procedures it is possible to achieve biomechanically stable fixation in osteoporotic bone. Based on this study, novel biostable bone cements are very potential biomaterials to enhance bone screw fixation in osteoporotic bone. Novel bone cement is easy to use without hand mixing using a dual syringe and thus makes it possibility to use it as required during the operation.


Auxin dynamics after decapitation are not correlated with the initial growth of axillary buds.
One of the first and most enduring roles identified for the plant hormone auxin is the mediation of apical dominance. Many reports have claimed that reduced stem indole-3-acetic acid (IAA) levels and/or reduced basipetal IAA transport directly or indirectly initiate bud growth in decapitated plants. We have tested whether auxin inhibits the initial stage of bud release, or subsequent stages, in garden pea (Pisum sativum) by providing a rigorous examination of the dynamics of auxin level, auxin transport, and axillary bud growth. We demonstrate that after decapitation, initial bud growth occurs prior to changes in IAA level or transport in surrounding stem tissue and is not prevented by an acropetal supply of exogenous auxin. We also show that auxin transport inhibitors cause a similar auxin depletion as decapitation, but do not stimulate bud growth within our experimental time-frame. These results indicate that decapitation may trigger initial bud growth via an auxin-independent mechanism. We propose that auxin operates after this initial stage, mediating apical dominance via autoregulation of buds that are already in transition toward sustained growth.