Emotion regulation via the autonomic nervous system in children with attention-deficit/hyperactivity disorder (ADHD).
Despite growing interest in conceptualizing ADHD as involving disrupted emotion regulation, few studies have examined the physiological mechanisms related to emotion regulation in children with this disorder. This study examined parasympathetic and sympathetic nervous system reactivity via measures of respiratory sinus arrhythmia (RSA) and cardiac pre-ejection period (PEP) in children with ADHD (n=32) and typically developing controls (n=34), using a novel emotion task with four conditions: negative induction, negative suppression, positive induction, and positive suppression of affect. Both groups showed strong task-response effects in RSA. However, typically developing children showed systematic variation in parasympathetic activity (RSA) depending on both emotion valence (more activation for negative emotion, reduced activation for positive emotion) and task demand (more activation for suppression than induction). In contrast, children with ADHD displayed a stable pattern of elevated parasympathetic activity (RSA) across all task conditions compared to baseline. No group differences in sympathetic activity (PEP) were observed. It is concluded ADHD in childhood is associated with abnormal parasympathetic mechanisms involved in emotion regulation.


Molecular toxicology of polybrominated diphenyl ethers: nuclear hormone receptor mediated pathways.
Polybrominated diphenyl ethers (PBDEs) are used in large quantities as flame retardant additives in commercial products. Bio-monitoring data show that PBDE concentrations have increased rapidly in the bodies of wildlife and human over the last few decades. Based on the studies on experimental animals, the toxicological endpoints of exposure to PBDEs are likely to be thyroid homeostasis disruption, neuro-developmental deficits, reproductive ineffectiveness and even cancer. Unfortunately, the available molecular toxicological evidence for these endpoints is still very limited. This review focuses on the recent studies on the molecular mechanisms of PBDE toxicities carried out through the hormone receptor pathways, including thyroid hormone receptor, estrogen receptor, androgen receptor, progesterone receptor and aryl hydrocarbon receptor pathways. The general approach in the mechanistic investigation is to examine the in vitro direct binding of a PBDE with a receptor, the in vitro recruitment of a co-activator or co-repressor by the ligand-bound receptor, and the participation of the ligand in the receptor-mediated transcription pathways in cells. It is hoped that further studies in this area would provide more insights into the potential risks of PBDEs to human health.


Evidence-based approach of treatment options for postoperative knee pain.
Optimal pain management is critical after knee surgery to avoid adverse events and to improve surgical outcomes. Pain may affect surgical outcomes by contributing to limitations in range of motion, strength, and functional recovery. The causes of postoperative pain are multifactorial; therefore, an appropriate pain management strategy must take into account preoperative, intraoperative, and postoperative factors to create a comprehensive and individualized plan for the patient. Preoperative assessment includes management of patient expectations, recognition of conditions and early counseling for high-risk patients (ie, opioid dependence, psychiatric comorbidities), and use of preemptive analgesia techniques (ie, preoperative IV medications, peripheral nerve blocks, incisional field blocks). Intraoperative strategies include meticulous surgical technique, limiting the use of tourniquets (ie, duration and pressure), and using preventive analgesia methods (ie, postoperative field block, continuous nerve catheters, intra-articular injection). Postoperative analgesia may be facilitated by cryotherapy, early mobilization, bracing, and rehabilitation. Certain modalities (ie, continuous passive motion devices, transcutaneous electrical nerve stimulation units, iontophoresis) may be important adjuncts in the perioperative period as well. There may be an evolving role for alternative medicine strategies. Early recognition and treatment of exaggerated postoperative pain responses may mitigate the effects of complex regional pain syndrome or the development of chronic pain.


Coadaptation in mother and infant regulated by a paternally expressed imprinted gene.
This study investigates how a targeted mutation of a paternally expressed imprinted gene regulates multiple aspects of foetal and post-natal development including placental size, foetal growth, suckling and post-natal growth, weaning age and puberty onset. This same mutation in a mother impairs maternal reproductive success with reduced maternal care, reduced maternal food intake during pregnancy, and impaired milk let-down, which in turn reduces infant growth and delays weaning and onset of puberty. The significance of these coadaptive traits being synchronized in mother and offspring by the same paternally expressed imprinted gene ensures that offspring that have extracted 'good' maternal nurturing will themselves be both well provisioned and genetically predisposed towards 'good' mothering.


[Value of echography in the diagnosis of postoperative complications].
The results of ultrasonic investigation of 54 females with a variety of complications following uterine and adnexal surgery are reviewed. Echograms are presented, and echographic description of intraperitoneal hemorrhages, hematomas at various sites, peritonitis, infiltrations, abscesses, ligature fistulas, pelvic foreign bodies, etc. is made. Echography is shown to be a highly valuable method for the diagnosis of postoperative complications.


[Spatial and seasonal variation of soil culturable-bacterial functional groups in a Mexican tropical dry forest].
Microbial biomass and activity in soils are frequently studied in tropical dry forests, but scarce information is available about the relationships between functional bacterial groups and soil fertility, where relief interacts with rainfall seasonality. The culturable-bacterial groups and nutrients were studied during two consecutive years in soils from two topographic areas of different relief (hilltop vs hillslope) in a tropical dry forest from Chamela Jalisco, Mexico. We expected that seasonal and spatial variation in soil resources availability affects the abundance of functional culturable-bacterial groups. To evaluate this, fifteen soil cores (1kg), 0-5cm depth, were taken in the dry, early rainy and rainy seasons, from each of the ten replicate plots in hilltop and hillslope areas located in three microbasins. We found that hilltop soils were more organic and had higher concentration of labile C and total nutrient forms than hillslope soils, for which these soils had higher counts of colony-forming units (CFU) of total heterotrophic and P solubilizing bacteria. In both hilltop and hillslope soils, C and nutrient concentrations, as well as the counts of CFU of heterotrophic and P solubilizing bacteria generally decreased from the dry to the rainy season during the two study years. In contrast, the counts of CFU nitrifying and cellulolytic bacteria were higher at the hillslope than at the hilltop soils. The seasonal pattern of both groups was opposite to that of heterotrophic bacteria, presumably associated with a decrease in soil labile C and organic matter quality. In conclusion, our study suggests that available C appears to be the main factor that controls the structure of soil bacterial groups and soil fertility, where relief, rainfall seasonality and intra- and inter-annual variations are critical factors that interactively modify bacterial dynamics related to soil C availability in the tropical dry forest.


Electroencephalographic changes as prognostic indicators after psychosurgery.
Thirty-five patients were studied by EEG with recordings taken the day before, two weeks after, and six months after psychosurgery. Most showed a characteristic frontal slow activity of varying degrees after operation with varying enhancement of background activity. The amount and spread of the frontal slow waves two weeks after operation showed a significant positive correlation with the clinical outcome one year later, which suggests a relatively objective and very early indication of the subsequent clinical response to psychosurgery.


Engaging Communities in Commodity Stock Monitoring Using Telecommunication Technology in Primary Health Care Facilities in Rural Nigeria.
With several efforts being made by key stakeholders to bridge the gap between beneficiaries and their having full access to free supplies, frequent stock-out, pilfering, collection of user fees for health commodities, and poor community engagement continue to plague the delivery of health services at the primary health care (PHC) level in rural Nigeria. To assess the potential in the use of telecommunication technology as an effective way to engage members of the community in commodity stock monitoring, increase utilization of services, as well as promote accountability and community ownership. The pilot done in 8 PHCs from 4 locations within Nigeria utilized telecommunication technologies to exchange information on stock monitoring. A triangulated technique of data validation through cross verification from 3 subsets of respondents was used: 160 ward development committee (WDC) members, 8 officers-in-charge (OICs) of PHCs, and 383 beneficiaries (health facility users) participated. Data collection made through a call center over a period of 3 months from July to September 2014 focused on WDC participation in inventory of commodities and type and cost of maternal, neonatal, and child health services accessed by each beneficiary. Results showed that all WDCs involved in the pilot study became very active, and there was a strong cooperation between the OICs and the WDCs in monitoring commodity stock levels as the OICs participated in the monthly WDC meetings 96% of the time. A sharp decline in the collection of user fees was observed, and there was a 10% rise in overall access to free health care services by beneficiaries. This study reveals the effectiveness of mobile phones and indicates that telecommunication technologies can play an important role in engaging communities to monitor PHC stock levels as well as reduce the incidence of user fees collection and pilfering of commodities (PHC) level in rural communities.


Multivariate analysis of outcome of mental health care using graphical chain models. The South-Verona Outcome Project 1.
Short-term outcome of mental health care was assessed in a multidimensional perspective using graphical chain models, a new multivariate method that analyses the relationship between variables conditionally, i.e. taking into account the effect of antecedent and intervening variables. GAF, BPRS, DAS (at baseline and after 6 months), LQL and VSSS (at follow-up only) were administered to 194 patients attending the South-Verona community-based mental health service. Direct costs in the interval were also calculated. Graphical chain models were used to analyse: (1) the associations between predictors (psychopathology, disability, functioning, assessed at baseline); (2) the effects of predictors on costs; and (3) the effect of predictors and costs on outcomes (psychopathology, disability, functioning, quality of life and service satisfaction) as well as their correlation. Psychopathology, disability and functioning scores at baseline predicted the corresponding scores at 6-month follow-up, with greater improvement in the more severely ill. Higher psychopathology and poorer functioning at baseline predicted higher costs and, in turn, costs predicted poorer functioning at follow-up. Outcome indicators polarized in two groups: psychopathology, disability and functioning, which were highly correlated; and the dyad service satisfaction and quality of life. Service satisfaction was highly related to quality of life and was predicted by low disability and high dysfunctioning. No predictors for quality of life were found. Graphical chain models were demonstrated to be a useful methodology to analyse process and outcome data. The results of the present study help in formulating specific hypotheses for future studies on outcome.


Atrazine-induced hermaphroditism at 0.1 ppb in American leopard frogs (Rana pipiens): laboratory and field evidence.
Atrazine is the most commonly used herbicide in the United States and probably the world. Atrazine contamination is widespread and can be present in excess of 1.0 ppb even in precipitation and in areas where it is not used. In the current study, we showed that atrazine exposure (> or = to 0.1 ppb) resulted in retarded gonadal development (gonadal dysgenesis) and testicular oogenesis (hermaphroditism) in leopard frogs (Rana pipiens). Slower developing males even experienced oocyte growth (vitellogenesis). Furthermore, we observed gonadal dysgenesis and hermaphroditism in animals collected from atrazine-contaminated sites across the United States. These coordinated laboratory and field studies revealed the potential biological impact of atrazine contamination in the environment. Combined with reported similar effects in Xenopus laevis, the current data raise concern about the effects of atrazine on amphibians in general and the potential role of atrazine and other endocrine-disrupting pesticides in amphibian declines.


California mussels (Mytilus californianus) as sentinels for marine contamination with Sarcocystis neurona.
Sarcocystis neurona is a terrestrial parasite that can cause fatal encephalitis in the endangered Southern sea otter (Enhydra lutris nereis). To date, neither risk factors associated with marine contamination nor the route of S. neurona infection to marine mammals has been described. This study evaluated coastal S. neurona contamination using California mussels (Mytilus californianus) as sentinels for pathogen pollution. A field investigation was designed to test the hypotheses that (1) mussels can serve as sentinels for S. neurona contamination, and (2) S. neurona contamination in mussels would be highest during the rainy season and in mussels collected near freshwater. Initial validation of molecular assays through sporocyst spiking experiments revealed the ITS-1500 assay to be most sensitive for detection of S. neurona, consistently yielding parasite amplification at concentrations ⩾5 sporocysts/1 mL mussel haemolymph. Assays were then applied on 959 wild-caught mussels, with detection of S. neurona confirmed using sequence analysis in three mussels. Validated molecular assays for S. neurona detection in mussels provide a novel toolset for investigating marine contamination with this parasite, while confirmation of S. neurona in wild mussels suggests that uptake by invertebrates may serve as a route of transmission to susceptible marine animals.


Inner blood-retinal barrier mediates l-isomer-predominant transport of serine.
D-serine, a coagonist for N-methyl-D-aspartate-type glutamate receptors, which mediate visual signal transmission, is thought to be generated from L-serine via serine racemase in the retina. However, the source of L-serine and D-serine in the retina are yet to be determined. The purpose of the present study was to investigate the characteristics of the blood-to-retina transport of serine at the inner blood-retinal barrier (BRB). In vivo study revealed the blood-to-retina transport of [(3) H]L-serine with an influx clearance of 49.9 μL/(min·g retina), which is greater than that of [(3) H]D-serine. This was consistent with the L-isomer-predominant uptake of serine by conditionally immortalized rat retinal capillary endothelial cell line (TR-iBRB2 cells), an in vitro inner BRB model. [(3) H]L-Serine and [(3) H]D-serine uptake by TR-iBRB2 cells took place in an Na(+)-dependent and a concentration-dependent manner with Michaelis constant values of 97.5 μM and 9.63 mM, respectively. The uptake process of [(3) H]L-serine and [(3) H]D-serine was significantly inhibited by system ASC (alanine-serine-cysteine) substrates. Polymerase chain reaction analysis and immunocytochemistry revealed the expression of ASC transporters ASCT1 and ASCT2 in TR-iBRB2 cells. These results suggest that the system ASC at the inner BRB is a potent pathway for supplying serine in the form of the L-isomer from the circulating blood to the retina.


Overexpression of the cardiac Na+/Ca2+ exchanger increases susceptibility to ischemia/reperfusion injury in male, but not female, transgenic mice.
Influx of Ca2+ into myocytes via Na+/Ca2+ exchange may be stimulated by the high levels of intracellular Na+ and the changes in membrane potential known to occur during ischemia/reperfusion. This increased influx could, in turn, lead to Ca2+ overload and injury. Overexpression of the cardiac Na+/Ca2+ exchanger therefore may increase susceptibility to ischemia/reperfusion injury. To test this hypothesis, the hearts of male and female transgenic mice, overexpressing the Na+/Ca2+ exchange protein, and hearts of their wild-type littermates, were perfused with Krebs-Henseleit buffer and subjected to 20 minutes of ischemia and 40 minutes of reperfusion. Preischemic left ventricular developed pressures and +dP/dtmax, as well as -dP/dtmin, were higher in the male transgenic hearts compared with wild-type, implying a role for Na+/Ca2+ exchange in the contraction, as well as the relaxation, phases of the cardiac beat. Postischemic function was lower in male transgenic than in male wild-type hearts (7+/-2% versus 32+/-6% of preischemic function), but there was no difference between female transgenic and female wild-type hearts, both at approximately 30% of preischemic function. To assess whether this male/female difference was due to female-specific hormones such as estrogen, the hearts of bilaterally ovariectomized and sham-operated transgenic females were subjected to the same protocol. The functional recoveries of ovariectomized female transgenic hearts were lower (17+/-3% of preischemic function) than those of wild-type and sham-operated transgenic females. The lower postischemic functional recovery in the male transgenic and female ovariectomized transgenic hearts correlated with lower recoveries of the energy metabolites, ATP and phosphocreatine, as measured by 31P nuclear magnetic resonance spectroscopy. Alternans were observed during reperfusion in male transgenic and female ovariectomized transgenic hearts only, consistent with intracellular Ca2+ overload. Western analyses showed that alterations in the expression of the Na+/Ca2+ exchange or L-type Ca2+ channel proteins were not responsible for the protection observed in the female transgenic hearts. In conclusion, in males, overexpression of the Na+/Ca2+ exchanger reduced postischemic recovery of both contractile function and energy metabolites, indicating that the Na+/Ca2+ exchanger may play a role in ischemia/reperfusion injury. From the studies of females, however, it appears that this exacerbation of ischemia/reperfusion injury by overexpression of the Na+/Ca2+ exchanger can be overcome partially by female-specific hormones such as estrogen.


CaSiO₃ microstructure modulating the in vitro and in vivo bioactivity of poly(lactide-co-glycolide) microspheres.
Poly(lactide-co-glycolide) (PLGA) microspheres have been used for regenerative medicine due to their ability for drug delivery and generally good biocompatibility, but they lack adequate bioactivity for bone repair application. CaSiO₃ (CS) has been proposed as a new class of material suitable for bone tissue repair due to its excellent bioactivity. In this study, we set out to incorporate CS into PLGA microspheres to investigate how the phase structure (amorphous and crystal) of CS influences the in vitro and in vivo bioactivity of the composite microspheres, with a view to the application for bone regeneration. X-ray diffraction (XRD), N₂ adsorption-desorption analysis, and scanning electron microscopy (SEM) were used to analyze the phase structure, surface area/pore volume, and microstructure of amorphous CS (aCS) and crystal CS (cCS), as well as their composite microspheres. The in vitro bioactivity of aCS and cCS-PLGA microspheres was evaluated by investigating their apatite-mineralization ability in simulated body fluids (SBF) and the viability of human bone mesenchymal stem cells (BMSCs). The in vivo bioactivity was investigated by measuring their de novo bone-formation ability. The results showed that the incorporation of both aCS and cCS enhanced the in vitro and in vivo bioactivity of PLGA microspheres. cCS/PLGA microspheres improved better in vitro BMSC viability and de novo bone-formation ability in vivo, compared to aCS/PLGA microspheres. Our study indicates that controlling the phase structure of CS is a promising method to modulate the bioactivity of polymer microsphere system for potential bone tissue regeneration.


Divergent coronary flow responses to uridine adenosine tetraphosphate in atherosclerotic ApoE knockout mice.
Uridine adenosine tetraphosphate (Up4A) exerts potent relaxation in porcine coronary arteries that is reduced following myocardial infarction, suggesting a crucial role for Up4A in the regulation of coronary flow (CF) in cardiovascular disorders. We evaluated the vasoactive effects of Up4A on CF in atherosclerosis using ApoE knockout (KO) mice ex vivo and in vivo. Functional studies were conducted in isolated mouse hearts using the Langendorff technique. Immunofluorescence was performed to assess purinergic P2X1 receptor (P2X1R) expression in isolated mouse coronary arteries. In vivo effects of Up4A on coronary blood flow (CBF) were assessed using ultrasound. Infusion of Up4A (10-9-10-5 M) into isolated mouse hearts resulted in a concentration-dependent reduction in CF in WT and ApoE KO mice to a similar extent; this effect was exacerbated in ApoE KO mice fed a high-fat diet (HFD). The P2X1R antagonist MRS2159 restored Up4A-mediated decreases in CF more so in ApoE KO + HFD than ApoE KO mice. The smooth muscle to endothelial cell ratio of coronary P2X1R expression was greater in ApoE KO + HFD than ApoE KO or WT mice, suggesting a net vasoconstrictor potential of P2X1R in ApoE KO + HFD mice. In contrast, Up4A (1.6 mg/kg) increased CBF to a similar extent among the three groups. In conclusion, Up4A decreases CF more in ApoE KO + HFD mice, likely through a net upregulation of vasoconstrictor P2X1R. In contrast, Up4A increases CBF in vivo regardless of the atherosclerotic model.


HTLV-1 propels untransformed CD4 lymphocytes into the cell cycle while protecting CD8 cells from death.
Human T cell leukemia virus type 1 (HTLV-1) infects both CD4+ and CD8+ lymphocytes, yet it induces adult T cell leukemia/lymphoma (ATLL) that is regularly of the CD4+ phenotype. Here we show that in vivo infected CD4+ and CD8+ T cells displayed similar patterns of clonal expansion in carriers without malignancy. Cloned infected cells from individuals without malignancy had a dramatic increase in spontaneous proliferation, which predominated in CD8+ lymphocytes and depended on the amount of tax mRNA. In fact, the clonal expansion of HTLV-1-positive CD8+ and CD4+ lymphocytes relied on 2 distinct mechanisms--infection prevented cell death in the former while recruiting the latter into the cell cycle. Cell cycling, but not apoptosis, depended on the level of viral-encoded tax expression. Infected tax-expressing CD4+ lymphocytes accumulated cellular defects characteristic of genetic instability. Therefore, HTLV-1 infection establishes a preleukemic phenotype that is restricted to CD4+ infected clones.


Activation of latent papillomavirus genomes by chronic mechanical irritation.
The skin of animals of a laboratory strain of Mastomys natalensis carrying endogenous, latent papillomavirus genomes was irritated by scratching with glasspaper. Hyperproliferation of the epidermis and amplification of viral DNA followed this treatment, and in approximately 27% of the animals virus-producing papillomas were induced.


The Influence of Neurocognitive Impairment, Depression, and Alcohol Use Disorders on Health-Related Quality of Life among Incarcerated, HIV-Infected, Opioid Dependent Malaysian Men: A Moderated Mediation Analysis.
Prior research has widely recognized neurocognitive impairment (NCI), depression, and alcohol use disorders (AUDs) as important negative predictors of health-related quality of life (HRQoL) among people living with HIV (PLWH). No studies to date, however, have explored how these neuropsychological factors operate together and affect HRQoL. Incarcerated male PLWH (N = 301) meeting criteria for opioid dependence were recruited from Malaysia's largest prison. Standardized scales for NCI, depression, alcohol use disorders (AUDs) and HRQoL were used to conduct a moderated mediation model to explore the extent to which depression mediated the relationship between NCI, HRQoL, and AUDs using an ordinary least squares regression-based path analytic framework. Results showed that increasing levels of NCI (B = -0.1773, p < 0.001) and depression (B = -0.6147, p < 0.001) were negatively associated with HRQoL. The effect of NCI on HRQoL was significantly (Sobel z = -3.5600, p < 0.001) mediated via depression (B = -0.1230, p < 0.001). Furthermore, the conditional indirect effect of NCI on HRQoL via depression for individuals with AUDs was significant (B = -0.9099, p = 0.0087), suggesting a moderated mediation effect. The findings disentangle the complex relationship using a moderated mediation model, demonstrating that increasing levels of NCI, which can be reduced with HIV treatment, negatively influenced HRQoL via depression for individuals with AUDs. This highlights the need for future interventions to target these complex interplay between neuropsychological factors in order to improve HRQoL among PLWH, particularly incarcerated PLWH with AUDs.


Development, implementation, and effects of community-based diabetes prevention program for obese latino youth.
Obesity and type 2 diabetes have emerged as critical health issues among Latino youth. Although both conditions manifest early in life, very few diabetes prevention programs have been developed to specifically meet the needs of this population. The authors describe the development, implementation, and metabolic impact of a culturally informed, community-based diabetes prevention program for obese Latino youth. A lifestyle education program was developed to address the health needs of Latino youth served by a community-based medical clinic. The program consisted of group education sessions delivered to children and their families to address nutrition, physical activity, family roles and responsibilities, and self-esteem. The metabolic impact of the program was evaluated by assessing body mass index (BMI), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol, triglycerides, glucose, and insulin. On entry, the prevalence of risk factors among the 102 youth (mean BMI, 30.4 ± 4.9 kg/m(2)) was substantial (68.6% with low HDL cholesterol, 32.1% with elevated triglycerides, 9.4% with impaired fasting glucose, 39.4% with elevated total cholesterol, 43.0% with elevated LDL cholesterol, and 60.6% with hyperinsulinemia). The 50 youth who returned after the program for follow-up measurements exhibited significant health improvements, including a 3.8% reduction in BMI; 5.4% and 8.6% decreases in total and LDL cholesterol, respectively; a 9.3% increase in HDL cholesterol; and a 24.0% decrease in fasting insulin (all P values < .05). These promising findings suggest that a community-based diabetes prevention program for obese Latino youth is a feasible strategy for improving health in this high-risk population. Further studies are warranted to examine whether similar programs can be implemented in diverse communities and settings.


Natural product biosynthetic potential reflects macroevolutionary diversification within a widely distributed bacterial taxon.
This is the most comprehensive study performed thus far on the biosynthetic potential within the Flavobacteriaceae family. Our findings reveal intertwined taxonomic and natural product biosynthesis diversification within the family. We posit that the carbohydrate, peptide, and secondary metabolism triad synergistically shaped the evolution of this keystone bacterial taxon, acting as major forces underpinning the broad host range and opportunistic-to-pathogenic behavior encompassed by species in the family. This study further breaks new ground for future research on select Flavobacteriaceae spp. as reservoirs of novel drug leads.


SIG-1451, a Novel, Non-Steroidal Anti-Inflammatory Compound, Attenuates Light-Induced Photoreceptor Degeneration by Affecting the Inflammatory Process.
Age-related macular degeneration is a progressive retinal disease that is associated with factors such as oxidative stress and inflammation. In this study, we evaluated the protective effects of SIG-1451, a non-steroidal anti-inflammatory compound developed for treating atopic dermatitis and known to inhibit Toll-like receptor 4, in light-induced photoreceptor degeneration. SIG-1451 was intraperitoneally injected into rats once per day before exposure to 1000 lx light for 24 h; one day later, optical coherence tomography showed a decrease in retinal thickness, and electroretinogram (ERG) amplitude was also found to have decreased 3 d after light exposure. Moreover, SIG-1451 partially protected against this decrease in retinal thickness and increase in ERG amplitude. One day after light exposure, upregulation of inflammatory response-related genes was observed, and SIG-1451 was found to inhibit this upregulation. Iba-1, a microglial marker, was suppressed in SIG-1451-injected rats. To investigate the molecular mechanism underlying these effects, we used lipopolysaccharide (LPS)-stimulated rat immortalised Müller cells. The upregulation of C-C motif chemokine 2 by LPS stimulation was significantly inhibited by SIG-1451 treatment, and Western blot analysis revealed a decrease in phosphorylated I-κB levels. These results indicate that SIG-1451 indirectly protects photoreceptor cells by attenuating light damage progression, by affecting the inflammatory responses.


The IGF-1 Signaling Pathway in Viral Infections.
Insulin-like growth factor-1 (IGF-1) and the IGF-1 receptor (IGF-1R) belong to the insulin-like growth factor family, and IGF-1 activates intracellular signaling pathways by binding specifically to IGF-1R. The interaction between IGF-1 and IGF-1R transmits a signal through a number of intracellular substrates, including the insulin receptor substrate (IRS) and the Src homology collagen (Shc) proteins, which activate two major intracellular signaling pathways: the phosphatidylinositol 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) pathways, specifically the extracellular signal-regulated kinase (ERK) pathways. The PI3K/AKT kinase pathway regulates a variety of cellular processes, including cell proliferation and apoptosis. IGF1/IGF-1R signaling also promotes cell differentiation and proliferation via the Ras/MAPK pathway. Moreover, upon IGF-1R activation of the IRS and Shc adaptor proteins, Shc stimulates Raf through the GTPase Ras to activate the MAPKs ERK1 and ERK2, phosphorylate and several other proteins, and to stimulate cell proliferation. The IGF-1 signaling pathway is required for certain viral effects in oncogenic progression and may be induced as an effect of viral infection. The mechanisms of IGF signaling in animal viral infections need to be clarified, mainly because they are involved in multifactorial signaling pathways. The aim of this review is to summarize the current data obtained from virological studies and to increase our understanding of the complex role of the IGF-1 signaling axis in animal virus infections.


Extrapyramidal effects of acute organophosphate poisoning.
There is limited information on extrapyramidal symptoms in acute organophosphate (OP) poisoning. We describe the course and outcome of severely poisoned patients who develop extrapyramidal manifestations. In this prospective observational study, spanning 8 months (Apr-Nov 2013) adult patients (>18 years) admitted with OP poisoning were enrolled. Patients on anti-psychotic therapy, those refusing consent or presenting with co-ingestions were excluded. Treatment included atropine and supportive care (e.g. ventilation and inotropes as indicated); oximes were not administered. The presence of rigidity, tremors, dystonia and chorea were assessed daily till discharge using modifications of the Unified Parkinson's Disease rating scale and the Tremor rating scale. The presence of extrapyramidal manifestations was correlated with length of ventilation and hospital stay and mortality. Of the 77 patients admitted with OP poisoning, 32 were enrolled; 17 (53.1%) developed extrapyramidal manifestations which included rigidity (94.1%), tremors (58.8%) and dystonia (58.8%). None developed chorea. The median (inter-quartile range) time of symptom onset was 8 (5-11) days; extrapyramidal features resolved in 11 (6-17) days. The median duration of intensive care stay in patients not developing extrapyramidal symptoms was 6 (2-8) days, indicating that most of these patients had recovered even before symptom onset in patients who developed extrapyramidal manifestations. Overall, 27/32 (84%) were ventilated. Hospital mortality was 6.25% (2/32). When compared with patients not developing extrapyramidal signs, those with extrapyramidal manifestations had significantly prolonged ventilation (5 versus 16 median days; p = 0.001) and hospitalization (8 versus 21 days; p < 0.001), reduced ventilator-free days (23 versus 12 days; p = 0.023) and increased infections (p = 0.03). The need for ventilation and mortality were not significantly different (p > 0.6). Extrapyramidal symptoms were not observed in non-OP poisoned patients with prolonged ICU stay. In this small series of acute OP poisoning, extrapyramidal manifestations were common after 1 week of intensive care but self-limiting. They are significantly associated with longer duration of ventilation and hospital stay.


Bottom-up fabrication of artery-mimicking tubular co-cultures in collagen-based microchannel scaffolds.
We developed a robust bottom-up approach to construct open-ended, tubular co-culture constructs that simulate the human vascular morphology and microenvironment. By design, these three-dimensional artificial vessels mimic the basic architecture of an artery: a collagen-rich extracellular matrix (as the tunica externa), smooth muscle cells (SMCs) (as the tunica media), and an endothelial cell (EC) lining (as the tunica interna). A versatile needle-based fabrication technique was employed to achieve controllable arterial layouts within a PDMS-hosted collagen microchannel scaffold (330 ± 10 μm in diameter): (direct co-culture) a SMC/EC bilayer to follow the structure of an arteriole-like segment; and (encapsulated co-culture) a lateral SMC multilayer covered by an EC monolayer lining to simulate the architecture of a larger artery. Optical and fluorescence microscopy images clearly evidenced the progressive cell elongation and sprouting behavior of SMCs and ECs along the collagen gel contour and within the gel matrix under static co-culture conditions. The progressive cell growth patterns effectively led to the formation of a tubular co-culture with an internal endothelial lining expressing prominent CD31 (cluster of differentiation 31) intercellular junction markers. During a 4-day static maturation period, the artery constructs showed modest alteration in the luminal diameters (i.e. less than 10% changes from the initial measurements). This argues in favor of stable and predictable arterial architecture achieved via the proposed fabrication protocols. Both co-culture models showed a high glucose metabolic rate during the initial proliferation phase, followed by a temporary quiescent (and thus, mature) stage. These proof-of-concept models with a controllable architecture create an important foundation for advanced vessel manipulations such as the integration of relevant physiological functionality or remodeling into a vascular disease-mimicking tissue.


Identification of genes induced by interleukin-3 and erythropoietin via the Jak-Stat5 pathway using enhanced differential display-reverse southern.
Cytokines mediate their effects on growth and maturation of hematopoietic cells by binding to their cognate receptors and activating target genes. Interleukin-3 (IL-3) and erythropoietin (Epo) induce signal transduction via the Jak-Stat pathway. We report here on the identification of several known and novel genes induced by IL-3 and Epo, using a modified version of the PCR-based technique, enhanced differential display (EDD). We modified the technique to facilitate the screening and verification of the differential expression of the genes by using reverse Southern blotting (RS) and PCR-Southern blotting, and we called it EDD-RS. From the initial 110 genetags that were identified as differential expressed genes, 14 contained more than one gene. Among the differentially expressed genes, 24 are known genes and 39 are novel genes. Several of the known genes, such as IRF-1 and P21waf, were previously observed by others to be induced by IL-3 and Epo, but their dependence on Stat5 activation in cytokine-dependent cells was unknown. Other known genes, such as crp and Mssp2/1, were not described previously as target genes for cytokine induction. The results demonstrate that EDD-RS is an efficient method to identify cytokine-induced genes and can be productive in delineating the signal required for their induction.


[Arthroscopic minimally invasive treatment of tibial intercondylar eminence fractures in children].
To analyze the characteristics of children tibial intercondylar eminence fractures, and introduce arthroscopic minimally invasive techniques for the treatment of tibial intercondylar eminence fractures in children. From January 2004 to December 2008, 12 children with tibial intercondylar eminence fractures were treated with cross Kirschner wire fixation after arthroscopic reduction. According to Meyers-McKeever classification systems, there were 1 case of type I, 4 cases of type II, and 7 cases of type III. There were 10 fresh and 2 old fractures in all. Among the patients, 10 patients were boy and 2 patients were girl,ranging in age from 8 to 13 years, with an average of 10 years. All the patients underwent arthroscopic exploration, reduction and fixation. During follow-up ranging from 10 to 36 months, the union of fracture, range of motion and stabilization of the knee were assessed. One patient was combined with lesions of the menisci, 1 patient with femoral trochlea cartilage injury, and 5 patients with meniscal entrapment under the bone. The heeling time averaged 5 weeks. No knee laxity or instability and no intercondylar notch impingement was detected in all cases at 3 months postoperatively. At same time, full range of motion of the affected knee returned, and the average Lysholm knee score was (92.7 +/- 2.5), the average Lysholm knee score was (96.4 +/- 1.7) at 6 months postoperatively. The Lachman test and ADT test was negative. The type II and type III tibial intercondylar eminence fractures occur frequently in children. Lesions of the menisci and cartilage occur seldom. The method of arthroscopic cross Kirschner wire fixation for the treatment of tibial intercondylar eminence fracture is easy to operate. Simultaneously, this technique is less invasive and allows early recovery. Also it coincidences with the characteristic rapid bone growth of children.


Regulation of Dihydropyrimidinase-like 3 Gene Expression by MicroRNAs in PC12 Cells with Induced Ischaemia and Hypothermia.
Although hypothermic treatment has been reported to have some beneficial effects on ischaemia at the clinical level, the mechanism of ischaemia suppression by hypothermia remains unclear due to a lack of mechanism understanding and insufficient data. The aim of this study was to isolate and characterize microRNAs specifically expressed in ischaemia-hypothermia for the dihydropyrimidinase-like 3 (Dpysl3) gene. PC12 cells were induced with CoCl2 for chemical ischaemia and incubated at 32 ℃ for hypothermia. In ischaemia-hypothermia, four types of microRNAs (miR-106b-5p, miR-194-5p, miR-326-5p, and miR-497-5p) were highly related to the Dpysl3 gene based on exosomal microRNA analysis. Dpysl3 gene expression was up-regulated by miR-497-5p but down-regulated by miR-106b-5p, miR-194-5p and miR-326-5p. Our results suggest that these four microRNAs are involved in the regulation of Dpysl3 gene expression. These findings provide valuable clues that exosomal microRNAs could be used as therapeutic targets for effective treatment of ischaemia.


[Vesicular peroxidase transport by the epithelial cells of the small intestine in the adult rat].
Electron cytochemistry has shown that after administering horse radish peroxidase to the gastrointestinal tract of adult rats it penetrates the epithelial barrier of the small intestine and is transported functionally intact into the circulation. Peroxidase was largely absorbed on the apex of the villi, entered the enterocytes by pinocytosis and was transported via the cytoplasm within the pinocytotic vesicles. Peroxidase was not detected in cytosole or endoplasmic reticulum of the enterocytes. It is assumed that the disclosed functional heterogeneity of absorption depends on adsorption selectivity of the microvilli of the enterocyte apical membrane. It is concluded that the pinocytotic mechanism also functions in adult mammals, by which foreign protein is transported to the circulation, causing allergic reactions.


Use and perceived efficacy of complementary and alternative medicines after discontinuation of hormone therapy: a nested United Kingdom Collaborative Trial of Ovarian Cancer Screening cohort study.
Given that the Women's Health Initiative reported in 2002 increased risks of breast cancer and cardiovascular events with hormone therapy (HT) use and many women discontinued use, we assessed the use and perceived efficacy of complementary and alternative medicines (CAMs) for menopausal symptom relief after discontinuation of HT. Postmenopausal women aged 50 to 65 years within the United Kingdom Collaborative Trial of Ovarian Cancer Screening who were willing to take part in a secondary study were mailed a survey to evaluate menopausal symptom management. Use and perceived efficacy of CAMs for relief of vasomotor symptoms (VMS) upon discontinuation of HT were examined. The survey was sent to 15,000 women between July 2 and July 9, 2008. Seventy-one percent (10,662 of 15,000) responded, and 10,607 women with complete data were included. Ever use of HT was reported by 60.2% (6,383 of 10,607). At survey completion, 79.3% (5,060 of 6,383) had discontinued HT, with 89.7% (4,540 of 5,060) of the latter reporting using one or more CAMs for VMS relief. About 70.4% (3,561 of 5,060) used herbal remedies, with evening primrose oil (48.6%; 2,205 of 4,540) and black cohosh (30.3%;1,377 of 4,540) being most commonly used. Exercise was used by 68.2% (3,098 of 4,540), whereas other behavioral/lifestyle approaches were less frequently reported (13.9%; 629 of 4,540). Contrarily, more women (57%-72%) rated behavioral/lifestyle approaches as effective compared with herbal remedies (28%-46%; rating ≥4 on a "helpfulness" scale from 1-10). Among medical treatments, selective serotonin reuptake inhibitors were used by 10% and rated effective by 72.1%. Although more women use over-the-counter medicines, behavioral/lifestyle approaches seem to provide better relief of VMS. There is a pressing need for better evidence-based lay information to support decision-making on CAM use for relief of VMS.


[Capacity and exchange functions of the kidney blood vessels at various leveles of venous outflow].
In perfusion of the cat hemodynamically isolated kidney with a constant blood flow volume, responses of venous vessels to noradrenaline did not depend on the venous outflow pressure level and only involved a diminishing of the blood filling which distinguishes kidneys from other organs. The renal veins' capacity decreased in response to noradrenaline practically completely disappears in high values of the venous outflow pressure. The renal capillary filtration coefficient was shown to equal 0.21 +/- 0.11, whereas the effect of changes in renal vein's pressure on implementation of the microvessels' exchange function in determined by the shifts of capillary hydrostatic pressure.


Interactions between infections and immune-inflammatory cells in type 1 diabetes mellitus and inflammatory bowel diseases: evidences from animal models.
Type 1 diabetes mellitus (T1D) and inflammatory bowel diseases (IBD) are multifactorial disorders of autoimmune origin. Several microbial agents have been reported to be associated with the development of type 1 diabetes and inflammatory bowel diseases in animal models by different mechanisms. These models which resemble the phenotype of the human disease they mimic, can be very useful to identify important pathogenetic mechanisms, as well as therapeutical targets to treat the disease. This review is focused on the immune inflammatory pathways which are considered to be associated with the pathogenesis T1D and IBD in transgenic mice.


Isolated while heart calorimetry: energetics of length-dependent activation.
Myocardial energy expenditure measured by whole heart calorimetry has in the past been used to demonstrate that the thermal accompaniment of contractile activity is indicative of both force-related and force-independent activities. A mechanical technique for demonstrating the length dependence of activation in the right ventricular papillary muscle has been extended to the intact but isolated whole left ventricle of the heart. A functional relationship between the degree of length-dependent activation and force-independent energy expenditure has been observed. Potentiation of isovolumic cardiac mechanical activity by inotropic stimulation with extracellular calcium is thermally more economic than similar potentiation by length-dependent activation, particularly at large ventricular volumes (long muscle fiber lengths). A hypothesis is formulated that explains both the current myothermic observations and the aequorin calcium transients observed by Allen and Kurihara. Important analytic limitations of whole heart calorimetry are acknowledged.


Circulating Tumor DNA as a Prognostic Determinant in Small Cell Lung Cancer Patients Receiving Atezolizumab.
The IFCT-1603 trial evaluated atezolizumab in small cell lung cancer (SCLC). The purpose of the present study was to determine whether circulating tumor DNA (ctDNA), prospectively collected at treatment initiation, was associated with the prognosis of SCLC, and whether it identified patients who benefited from atezolizumab. 68 patients were included in this study: 46 patients were treated with atezolizumab and 22 with conventional chemotherapy. Circulating DNA was extracted from plasma and NGS (Next Generation Sequencing) looked for mutations in the TP53, RB1, NOTCH1, NOTCH2, and NOTCH3 genes. ctDNA was detectable when at least one somatic mutation was identified, and its relative abundance was quantified by the variant allele fraction (VAF) of the most represented mutation. We found that 49/68 patients (70.6%) had detectable baseline ctDNA. The most frequently identified mutations were TP53 (32/49; 65.3%) and RB1 (25/49; 51.0%). Patients with detectable ctDNA had a significantly lower disease control rate at week 6 compared with patients with no detectable ctDNA, regardless of the nature of the treatment. Detection of ctDNA was associated with a poor OS prognosis. The detection of ctDNA at a relative abundance greater than the median value was significantly associated with poor overall survival (OS) and progression free survival (PFS). Interestingly, the benefit in overall survival (OS) associated with low ctDNA was more pronounced in patients treated with atezolizumab than in patients receiving chemotherapy. Among patients whose relative ctDNA abundance was below the median, those treated with atezolizumab tended to have higher OS than those in the chemotherapy arm. ctDNA is strongly associated with the prognosis of SCLC patients treated with second-line immunotherapy. Its analysis seems justified for future SCLC clinical trials.


A Case of Kaposi's Sarcoma during Primary HIV-1 Infection.
The majority of cases of Kaposi's sarcoma (KS) occur at low CD4 counts during chronic HIV-1 infection. We present a case of KS which was diagnosed during primary HIV-1 infection. This report aims to draw attention that KS may occur early in the course of HIV-1 infection and that primary HIV-1 infection may rapidly progress to AIDS.


Clinical course of sepsis in children with acute leukemia admitted to the pediatric intensive care unit.
To describe the clinical course, resource use, and mortality of patients with leukemia admitted to the pediatric intensive care unit with sepsis and nonsepsis diagnoses over a 10-yr period. Retrospective analysis. Tertiary medical-surgical pediatric intensive care unit at C.S. Mott Children's Hospital, University of Michigan. All patients with leukemia admitted to the pediatric intensive care unit from January 1, 1998, to December 31, 2008. None; chart review. Clinical course was characterized by demographics, leukemia diagnosis, phase of therapy, leukocyte count on admission, presence of sepsis, steroid administration, intensity of care, and Pediatric Risk of Mortality score on admission to the pediatric intensive care unit. The primary outcome was survival to pediatric intensive care unit discharge. Among 68 single admissions to the pediatric intensive care unit with leukemia during the study period, 33 (48.5%) were admitted with sepsis. Admission to the pediatric intensive care unit for sepsis was associated with greater compromise of hemodynamic and renal function and use of stress dose steroids (p = .016), inotropic and/or vasopressor drugs (p = .01), and renal replacement therapy (p = .028) than nonsepsis admission. There was higher mortality among children with sepsis than other diagnoses (52% vs. 17%, p = .004). Also, mortality among children with sepsis was higher among those with acute lymphoblastic leukemia (60% vs. 44%) compared with acute myelogenous leukemia. Administration of stress dose steroids was associated with higher mortality (50% vs. 17%, p = .005) and neutropenia. Patients with acute lymphoblastic leukemia and sepsis showed the greatest mortality and resource use. Patients with acute leukemia and sepsis had a much higher mortality rate compared with previously described sepsis mortality rates for the general pediatric intensive care unit patient populations. Patients who received steroids had an increased mortality rate, but given the retrospective nature of this study, we maintain a position of equipoise with regard to this association. Variation in mortality and resource use by leukemia type suggests further research is needed to develop targeted intervention strategies to enhance patient outcomes.


Anxiety about food supply in cree women with infants in Quebec.
The objectives were to document the prevalence of maternal anxiety about food supply in Cree women who had 9-month-old infants, and to understand maternal and infant characteristics associated with anxiety. The design was descriptive and combined both cross-sectional and retrospective analyses. The study took place in nine Cree communities in northern Quebec. Data on maternal characteristics in pregnancy (age, parity, anemia, smoking status) and infant characteristics (gestational age, birth weight, weight and hemoglobin concentration at 9 months old) were obtained from medical records. At 9 months postpartum, mothers were asked about infant feeding practices, the health of their infant, and the question, "Do you ever worry you don't have enough money to buy your children food to eat?" Affirmative responses were considered evidence for anxiety about food supply. Pricing data was collected for commercial baby food, formula, milk and water in the communities and, for comparison, in the large urban city of Montreal. 245 woman-infant pairs participated. One-fifth (20.8%) of mothers were anxious about food supply. The prevalences of anxiety in women who had anemia, or smoked, during pregnancy, or who bottle-fed their 9-month-old infants, were 44.4%, 27.5% and 24.0%, respectively. The corresponding prevalences of anxiety in women who did not have anemia, who did not smoke, or who breastfed without bottle-feeding at 9-months postpartum, were 19.0%, 13.6% and 6.7%. The adjusted ORs for anxiety were 3.10 (95% CI, 1.11-8.65), 2.12 (95% CI, 1.05-4.29) and 3.87 (95% CI, 1.12-13.36) for anemia, smoking and bottle-feeding, respectively. Prevalences of anemia and infection were comparable between infants of mothers who did and did not express anxiety. However, infants whose mothers had anemia during pregnancy had higher prevalences of anemia (44.0% vs. 24.6%, p = 0.04) and infection (77.8% vs. 50.2%, p = 0.03) at 9 months old. Women who had anxiety about food supply for their children had characteristics that distinguished them from women who did not have anxiety. Anxiety was associated with anemia and smoking during pregnancy, and with bottle-feeding at 9 months postpartum.


[Various neurophysiological aspects of examination of children with Gilles de la Tourette's syndrome].
EEG mapping was used to study the ECG and brain electric activity in 45 normal children and in 33 patients with Gilles de la Tourette's syndrome. Significant differences were discovered in the test parameters in groups of patients and normal children as well as in subgroups of patients with different varieties of the syndrome. Analysis of the ECG has shown that 78% of children with typical Tourette's syndrome manifest neurovegetative regulation impairment in the form of bradycardia and cardiac arrhythmia. In tourette-like disorders within the framework of schizophrenia and encephalopathy and in normal test subjects, such alterations occur much more seldom. The data of the EEG mapping and analysis of spectral power of different rhythmic ranges attest to the existence of mainly nonspecific changes in the EEG common to all varieties of the syndrome. At the same time a tendency was recorded toward definite abnormalities in one or another patients' group. The data obtained can be of help for differential diagnosis of the syndrome under study.


[Neurofibromatosis: current clinical and molecular genetic aspects from the neurologic viewpoint].
Neurofibromatosis is one of the most frequent autosomal-dominant hereditary disorders. Neoplastic, dysplastic and dysraphic lesions characterize the disease from the viewpoint of a neurologist. Depression, suicide, emotional instability, learning disability and behavior disorder are important aspects for the neuropsychiatric evaluation. Treatment of the patients will be facilitated by following the diagnostic criteria and by an interdisciplinary approach to diagnosis. The gene-molecular differentiation of NF I and NF II provides a basis for a more profound understanding of the disease which allows for more than just the clinical description. Cloning of the gene of NF I will give the possibility of predictive diagnosis of NF I. At present an indirect prenatal diagnosis of the genetic disorder is possible by flanking markers of NF I.


Stress induces pain transition by potentiation of AMPA receptor phosphorylation.
Chronic postsurgical pain is a serious issue in clinical practice. After surgery, patients experience ongoing pain or become sensitive to incident, normally nonpainful stimulation. The intensity and duration of postsurgical pain vary. However, it is unclear how the transition from acute to chronic pain occurs. Here we showed that social defeat stress enhanced plantar incision-induced AMPA receptor GluA1 phosphorylation at the Ser831 site in the spinal cord and greatly prolonged plantar incision-induced pain. Interestingly, targeted mutation of the GluA1 phosphorylation site Ser831 significantly inhibited stress-induced prolongation of incisional pain. In addition, stress hormones enhanced GluA1 phosphorylation and AMPA receptor-mediated electrical activity in the spinal cord. Subthreshold stimulation induced spinal long-term potentiation in GluA1 phosphomimetic mutant mice, but not in wild-type mice. Therefore, spinal AMPA receptor phosphorylation contributes to the mechanisms underlying stress-induced pain transition.


Association of serum uric acid with proteinuria in type 2 diabetic patients.
Various findings suggest that uric acid is an inflammatory factor and may have a role in endothelial dysfunction and act as a mediator of diabetic nephropathy. The objective of this study was to evaluate the relationships between serum uric acid level and level of proteinuria in type 2 diabetic (T2D) patients. A cross-sectional analytical study was conducted in 60 patients with T2D without a history of gout. None was treated with allopurinol. Venous blood samples were obtained in fasting state for determinations of serum creatinine, uric acid, and hemoglobin A1c (HbA1c) (reference range 3.8-5.5%); 24-h urine proteinuria was also measured. Mean age of the patients was 57 ± 8.3 years. Mean ± standard error (SE) of serum creatinine was 0.98 ± 0.028 mg/dL, mean ± SE of serum uric acid was 4.5 ± 0.15 mg/dL, and mean ± SE of proteinuria was 388 ± 28.7 mg/day (median = 303.5 mg/day). There was no significant difference in serum uric acid, HbA1c, and creatinine level between males and females (P > 0.05). There was a significant positive association between body mass index (BMI) and serum uric acid levels (r = 0.428, P = 0.001). After adjustment for weight, a significant positive association of serum uric acid with level of proteinuria was seen (r = 0.47, P < 0.001). Serum uric acid had a significant positive association with diabetic nephropathy. It might be hypothesized that serum uric acid plays a role in diabetic nephropathy in T2D.


Mechanism for the postive inotropic effect of angiotensin II on isolated cardiac muscle.
Angiotensin II (A II) and analogues were tested for their ability to restore electrical and mechanical activity to cardiac muscle preparations in which the fast Na+ channels had been inactivated by partial depolarization (22-27 mM K+) or by tetrodotoxin (TTX). The partially depolarized or TTX-blocked preparations were chosen because under these conditions electrical and mechanical responses are primarily Ca2+ -dependent. In depolarized rabbit right atria, A II restored spontaneous mechanical and electrical activity (measured by both intracellular and extracellular recording techniques). The frequency of action potential discharge was concentration-dependent; the threshold concentration of A II was 10(-10) M, the ED50 was 8 X 10(-9) M, and the maximum effect was observed at 5 X 10(-8) M. In contrast, depolarized guinea pig atria were insensitive to A II, Sar1-angiotensin II, and des-Asp1-angiotensin II, even at concentrations as high as 10(-5) M. Rabbit papillary muscle (TTX-blocked), embryonic (18-day) chick heart (partially depolarized) and chick heart reaggregates (TTX-blocked) responded similarly to rabbit atria in that A II (9.6 X 10(-7) M) restored both electrical and mechanical activity. We found that in these preparations the action of A II was unaffected by propranolol (5.0 X 10(-6) M to 5.0 X 10(-5) M) but was blocked by Mn2+ (10(-3) M), D-600 (1 X 10(-7) g/ml) and the specific A II antagonists Sar1-Ala8-angiotensin II (P-113) (5.0 X 10(-5) M) and Sar1-Ile8-angiotensin II (5.28 X 10(-5) M). We conclude that the positive inotropic effect of A II on the myocardium is due to its ability to increase transmembrane ion movements in or through the cell membrane. The ability of Mn2+ and D-600 to block this effect suggests that this ion movement is via the so-called "slow channels."


High genetic diversity and distinctiveness of rear-edge climate relicts maintained by ancient tetraploidisation for Alnus glutinosa.
Populations located at the rear-edge of a species' distribution may have disproportionate ecological and evolutionary importance for biodiversity conservation in a changing global environment. Yet genetic studies of such populations remain rare. This study investigates the evolutionary history of North-African low latitude marginal populations of Alnus glutinosa Gaertn., a European tree species that plays a significant ecological role as a keystone of riparian ecosystems. We genotyped 551 adults from 19 populations located across North Africa at 12 microsatellite loci and applied a coalescent-based simulation approach to reconstruct the demographic and evolutionary history of these populations. Surprisingly, Moroccan trees were tetraploids demonstrating a strong distinctiveness of these populations within a species otherwise known as diploid. Best-fitting models of demographic reconstruction revealed the relict nature of Moroccan populations that were found to have withstood past climate change events and to be much older than Algerian and Tunisian populations. This study highlights the complex demographic history that can be encountered in rear-edge distribution margins that here consist of both old stable climate relict and more recent populations, distinctively diverse genetically both quantitatively and qualitatively. We emphasize the high evolutionary and conservation value of marginal rear-edge populations of a keystone riparian species in the context of on-going climate change in the Mediterranean region.


Healthy and sustainable diet: a narrative review of the challenges and perspectives.
Based on the principle that a non-sustainable food system is not capable of producing healthy food for consumption, food can only be considered healthy if it is also sustainable, going beyond the nutritional perspective. Therefore, a narrative review of the scientific literature on the sustainable and health food system was conducted, regarding aspects of production, processing, marketing and consumption, seeking to pinpoint the challenges and perspectives for its consolidation. Food systems needs to be related to a food production and consumption system which protects biodiversity and promote a diverse consumption, bringing back traditional dishes and preparation techniques. It should also be accessible and available for everyone, both in quantity and in quality, based on food that is locally produced by family farmers through agroecology and founded on fair trade, bringing production and consumption closer together. In addition, it must be free from physical, biological or chemical contaminants that cause damage to everyone involved, whether it be an isolated incident or chronically.


A brief report on the clinical trial on neural mobilization exercise for joint pain in patients with rheumatoid arthritis.
In rheumatoid arthritis (RA) synovitis, activation of synoviocytes and infiltration of adaptive immune cells leads to synovial hyperplasia and joint swelling. Under the elevated extra-neural pressure, free nerve endings release neuropeptides, calcitonin gene-related peptide, and substance P, thus promoting neurogenic inflammation. This study aimed to assess the effect of therapeutic neural mobilization (NM) exercises targeting the nervous system on disease impact in RA patients. A total of 21 RA patients were randomized into NM (n = 11) and control (n = 10) groups. NM group patients performed NM exercises targeting the median, musculocutaneous, femoral, and saphenous nerve, as well as the entire nervous system twice daily for 4-8 weeks. Control RA patients performed gentle joint mobilization exercises targeting the same joints. Primary outcome was the change in pre-/post-treatment score in the validated Rheumatoid Arthritis Impact of Disease (RAID). Secondary outcome was erythrocyte sedimentation rate (ESR). There were no significant differences between the groups at baseline. No adverse events were observed and compliance was over 90%. Post-treatment, favorable changes were observed in the NM group RAID score: -5.1 vs. -0.8; weighted RAID score: -0.79 vs. -0.15. ESR was reduced in the NM group, albeit non-significantly. Regarding the RAID score domains, the NM group demonstrated significant improvements in pain and coping. The current data indicate a beneficial effect of NM exercises on pain and self-efficacy in our RA patients. Larger clinical studies are warranted to determine the clinical effectiveness of NM as a treatment for pain for RA patients and simultaneously address immune and neuropeptide modulation through NM.


Four major antigenic sites of the coronavirus transmissible gastroenteritis virus are located on the amino-terminal half of spike glycoprotein S.
Four major antigenic sites have been delineated on the spike protein (S) of the porcine enteric coronavirus transmissible gastroenteritis virus (TGEV) in previous topological studies using monoclonal antibodies (MAbs). Correlation of these sites with the physical structure of the protein was achieved by use of different approaches. Recombinant pEX plasmids directing the synthesis of various fused S polypeptides were constructed. A hybrid protein containing nine S-specific residues (363 to 371) was shown to express site C epitopes. The other sites were localized through study of the antigenic activity of fragments generated by controlled cleavage of the native protein with different endopeptidases. Two identified cleavage products of 26K and 13K, immunoreactive to site A-B- and site D-specific MAbs respectively, could be aligned on the S primary structure according to N-terminal sequence data. This led us to propose that the major neutralization domain A-B is contained in a region of approximately 200 residues with residue 506 as its N boundary. Similarly, site D epitopes should be located within a stretch of 130 residues, starting at 82 residues from the N terminus. Point mutations identified by direct RNA sequencing of neutralization-resistant mutants were consistent with the proposed location of these sites.


Physical assault on a medical resident.
We report a physical assault on a 25-year-old male medical resident who was on-call in the emergency room. Causes of assault on physicians as well as how they can be avoided are discussed.


In vitro and in vivo biochemistry of olanzapine: a novel, atypical antipsychotic drug.
Classical (typical) antipsychotic drugs are in wide use clinically, but some patients do not respond at all to treatment, while in others, negative symptoms and cognitive deficits fail to respond. Also, these drugs often cause serious motor disturbances. Clozapine, an atypical antipsychotic, appears to correct many of these deficiencies, but has a significant incidence of potentially fatal agranulocytosis. Accordingly, we attempted to develop a prototype of a new generation of antipsychotics that is both more efficacious and safe. Our strategy was to create a compound that is not only active in behavioral tests that predict antipsychotic action but also shares the rich, multifaceted receptor pharmacology of clozapine without its side effects. To this end, Eli Lilly and Co. developed olanzapine. In this article we characterize the in vitro and in vivo receptor pharmacology of olanzapine. We evaluated olanzapine interactions with neuronal receptors using standard assays of radioreceptor binding in vitro and well-established in vivo (functional) assays. Binding studies showed that olanzapine interacts with key receptors of interest in schizophrenia, having a nanomolar affinity for dopaminergic, serotonergic, alpha 1-adrenergic, and muscarinic receptors. In vivo olanzapine is a potent antagonist at DA receptors (DOPAC levels; pergolide-stimulated increases in plasma corticosterone) and 5-HT receptors (quipazine-stimulated increases in corticosterone), but is weaker at alpha-adrenergic and muscarinic receptors. Olanzapine has little or no effect at other receptors, enzymes, or key proteins in neuronal function. Olanzapine has a receptor profile that is similar to that of clozapine: it is relatively nonselective at dopamine receptor subtypes and it shows selectivity for mesolimbic and mesocortical over striatal dopamine tracts (electrophysiology; Fos). The binding and functional profile of olanzapine (1) is similar to that of clozapine, (2) indicates that olanzapine is an atypical antipsychotic drug, and (3) is consistent with clinical efficacy. If olanzapine also proves to be safe, then it will have high potential to become a more ideal antipsychotic drug.


Family medicine: behavioral science contributions.
The trend in medicine has been towards specialization which promotes a philosophy that extensive knowledge of a limited field is necessary for competence. Little emphasis has been placed on behavioral sciences as an important aspect for assisting the specialty physician in dealing with patients. Family medicine reverses this trend by emphasizing a breadth of medical knowledge with inclusion of behavioral sciences as a part of training. Behavioral sciences contribute heavily to the education of the family physician in the areas of character, culture, and counseling. The results is a humanistic physician with excellent skills in patient management. The inclusion of behavioral sciences in family medicine places this specialty at the forefront of a new direction in medicine and may well be emulated by other medical specialties.


Targeting EPHA2 with Kinase Inhibitors in Colorectal Cancer.
The ephrin type-A 2 receptor tyrosine kinase (EPHA2) is involved in the development and progression of various cancer types, including colorectal cancer (CRC). There is also evidence that EPHA2 plays a key role in the development of resistance to the endothelial growth factor receptor (EGFR) monoclonal antibody Cetuximab used clinically in CRC. Despite the promising pharmacological potential of EPHA2, only a handful of specific inhibitors are currently available. In this concept paper, general strategies for EPHA2 inhibition with molecules of low molecular weight (small molecules) are described. Furthermore, available examples of inhibiting EPHA2 in CRC using small molecules are summarized, highlighting the potential of this approach.


Valorization of phosphate sludge and its bacterial biomass as a potential bioformulation for improving tomato growth.
Phosphorus (P) is a vital limiting nutrient element for plant growth and yield. In Morocco, the natural phosphate rock extractions generate significant amounts of phosphate wash sludge (PS), which could be reused productively, thus creating another added value for farmers. The present study aimed to demonstrate the combination effect of soil amendment by two different PS concentrations (1% and 5%) associated with three phosphate-solubilizing bacteria (PSB) consortia (C1, C2, and C3), isolated from phosphate mining sludge, on plant growth and nutrient uptake in tomato seedlings (Solanum lycopersicum). The results obtained showed that this bioformulation significantly improved P solubilization and plant growth compared to control conditions. Of all the combinations, C3-inoculated soil amended with 5% PS was the most effective in significantly improving plant height and dry and fresh biomass of shoots and roots. P solubilization and its availability for tomato seedlings uptake were maximal with the bioformulation (C3 + 5% PS). This latter enhanced P and potassium (K) uptake by 27.89 and 38.81% in shoots and 38.57% and 74.67% in roots, respectively, compared to non-inoculated soil amended with 5% PS. The highest flowering rate (200 %) was recorded in C3-inoculated soil amended with 5% PS. Supporting these results, the principal component analysis discriminated this bioformulation (C3 + 5% PS) from the other combinations. Our results open up prospects for upgrading phosphate sludge enriched with PSB consortia as a biofertilizer that can be used in ecofriendly agriculture integrated into the circular economy.


Predicting the rate and extent of fragrance chemical absorption into and through the skin.
The absorption of a chemical into the skin depends upon its physicochemical properties, the manner in which it is presented to the skin (i.e., the "vehicle" in which it is applied), the "skin environment", and the duration of exposure (t(exp)). There is value, therefore, in attempting to quantify the maximum percutaneous penetration of a chemical and then using this characteristic to evaluate exposure based upon the specific scenario involved (for example, when the chemical and/or the principal vehicle constituents are volatile). Chemicals may be classified by their maximum, theoretically calculated fluxes (J(max)), and the quantity (Q) absorbed per exposure may then be calculated from Q = J(max)t(exp)A, where A is the area of skin contact. This approach is conservative and assumes that (i) the compound is applied at its saturation concentration and (ii) no depletion of chemical from the applied phase occurs during t(exp). For a number of fragrance chemicals, agreement between predicted and experimental results for this extreme scenario is good. On the other hand, for smaller, finite "doses", particularly of highly volatile chemicals, theory largely overpredicts reality. A refined, "finite dose" model is therefore required to account for surface depletion due to skin uptake and/or evaporative loss.


Differences in the literacy skills of Danish dyslexic students in two types of higher education programmes.
Previous research has treated high-functioning dyslexic students as a homogeneous group. This study explores the clinical observation that dyslexic students attending university programmes differ from dyslexic students attending tertiary education professional programmes in some aspects of their literacy skills. Four groups, dyslexic university students (n = 32), dyslexic students attending professional programmes (n = 32), control university students (n = 31), and control students from professional programmes (n = 30), were assessed on measures of pseudoword reading, phonological choice, vocabulary, reading and spelling of morphologically complex single words, and reading aloud from a syntactically complex text. The results showed that the two dyslexic groups were comparable only on the phonological tasks, the dyslexic university students outperforming the professional programme students in all reading and spelling measures. Controlling vocabulary and number of semesters studied, the difference was no longer significant. Nevertheless, the analyses indicate that phonological deficits underlie the performance of professional programme students with dyslexia across a wide range of tasks, whereas university students with dyslexia may be able to limit the impact of phonological deficits to some extent by relying on some alternative cognitive attributes. Reading experience, orthographic learning, and working memory efficiency are discussed as possible explanations for this pattern of results.


Operative versus nonoperative management of acute odontoid Type II fractures: a meta-analysis.
The purpose of this study was to evaluate the feasibility of the criteria described in the literature as the indications for surgery for acute Type II odontoid fractures. The authors searched the PubMed database for studies in which the fusion rate of acute Type II odontoid fractures following external immobilization (halo vest or collar) or surgery (posterior C1-2 fusion or anterior screw fixation) was reported. The only studies included reported the fusion rate for either 1) groups of patients whose age was either more or less than a certain age range (45-55 years); or 2) groups of patients with a fracture displacement of either more or less than a certain odontoid fracture displacement (4-6 mm) or the direction of displacement (see Methods section of text for more details). A meta-analysis in which the random effect model was used was conducted to analyze the data. There was a statistically significantly higher fusion rate for operative management compared with external immobilization (85 vs 60%, p = 0.01) for the patients > 45-55 years. However, the overall fusion rate was > 80% for the patients whose age was < 45-55 years, regardless of treatment modality, and no significant differences were observed between surgically and nonsurgically treated patients (89 and 81%, respectively; p = 0.29). The result of operation (overall fusion rate 89%) was superior to external immobilization (44%) when the fracture was posteriorly displaced (p < 0.001), but for anteriorly displaced fractures, the results of operative and nonoperative management were identical (p = 0.15). The overall fusion rate of operative management of both anteriorly and posteriorly displaced fractures proved to be > 85%, and no statistically significant difference was observed (p = 0.50). For all degrees of displacement (either > or < 4-6 mm) the operation proved to provide significantly better results than conservative treatment. The fusion rate of conservatively treated fractures with < 4-6 mm displacement was significantly better than in fractures with > 4-6 mm displacement (76 vs 41%, p = 0.002). Operative treatment (posterior C1-2 fixation or anterior screw fixation) provides a better fusion rate than external immobilization for acute odontoid Type II fractures, although in certain situations, such as anterior displacement of the fracture and for younger (< 45-55 years of age) patients, conservative management (halo vest or collar immobilization) can be as effective as surgery. Operative management is recommended in older patients, in cases of posterior displacement of the fracture, and when there is displacement of > 4-6 mm.


Alpha-glucan synthesis on a protein primer. A reconstituted system for the formation of protein-bound alpha-glucan.
Reconstitution experiments with the DEAE-cellulose-treated enzymes, engaged in a two-step mechanism of synthesis of alpha-glucan bound to protein, are performed. Urea/sodium dodecyl sulfate/polyacrylamide gel electrophoretic analysis of the radioactive products synthesized by the reconstituted system shows highly glucosylated, labeled bands, whose apparent molecular masses change with the acrylamide concentration in the gels. The long carbohydrate chains synthesized during the second step arise from the sequential addition of glucosyl moieties to the glucoprotein formed during the first step. A deglucosylation experiment confirms that the product of the reconstituted system originates from the 38-kDa glucosylated component of the reaction 1 product by the addition of beta-amylase-sensitive glucosyl moieties. Our data suggest that specific phosphorylases and starch synthetases are found in potato tuber, which are capable of utilizing reaction 1 product as primer for the synthesis of protein-bound glucan.


COLORADO3D, a web server for the visual analysis of protein structures.
COLORADO3D is a World Wide Web server for the visual presentation of three-dimensional (3D) protein structures. COLORADO3D indicates the presence of potential errors (detected by ANOLEA, PROSAII, PROVE or VERIFY3D), identifies buried residues and depicts sequence conservations. As input, the server takes a file of Protein Data Bank (PDB) coordinates and, optionally, a multiple sequence alignment. As output, the server returns a PDB-formatted file, replacing the B-factor column with values of the chosen parameter (structure quality, residue burial or conservation). Thus, the coordinates of the analyzed protein 'colored' by COLORADO3D can be conveniently displayed with structure viewers such as RASMOL in order to visualize the 3D clusters of regions with common features, which may not necessarily be adjacent to each other at the amino acid sequence level. In particular, COLORADO3D may serve as a tool to judge a structure's quality at various stages of the modeling and refinement (during both experimental structure determination and homology modeling). The GeneSilico group used COLORADO3D in the fifth Critical Assessment of Techniques for Protein Structure Prediction (CASP5) to successfully identify well-folded parts of preliminary homology models and to guide the refinement of misthreaded protein sequences. COLORADO3D is freely available for academic use at http://asia.genesilico.pl/colorado3d/.


Polycystic ovarian syndrome is linked to increased oxidative stress in Omani women.
Literature emerging from Western countries has reported increased levels of serum oxidative stress markers among polycystic ovarian syndrome (PCOS) women. In the Arab region, there is limited research about the association between oxidative stress and PCOS. This study aimed to compare sociodemographic and clinical characteristics, sex hormones, and oxidative stress indices between PCOS women and non-PCOS women and to investigate the correlation between oxidative stress biomarkers and sex hormones. This hospital-based case-control study was conducted among reproductive-aged women. The study included 51 women diagnosed with PCOS (as per Rotterdam 2003 criteria) and 45 control women who were not diagnosed with PCOS. Serum samples were collected to measure the mean levels of the following sex hormones: total testosterone, dehydroepiandrosterone sulfate, estradiol and progesterone, as well as to measure biomarkers of oxidative stress including glutathione peroxidase (GPx), glutathione reductase (GR), glutathione (GSH), and total antioxidant capacity (TAC). PCOS women exhibited clinical characteristics including irregular menses, hirsutism, and acne compared to the control group (P≤0.05). Significant differences were observed in the waist-hip ratio of PCOS women compared to controls (P=0.004). GPx and GR activity levels appeared to be higher among PCOS women compared to controls; however, no statistically significant differences were observed between the two groups (P>0.05). PCOS women had lower GSH and TAC levels compared to controls with a statistically significant difference observed for GSH levels (P=0.006). Correlation analysis showed a significant negative correlation between estradiol and TAC in the total sample (r=-0.284, P=0.005). This study provides supportive evidence that oxidative stress might play a role in the pathogenesis of PCOS and, hence, oxidative stress parameters could be suggested as diagnostic markers for early diagnosis of high-risk groups. Also, the study provides supportive evidence that obesity and sex hormones, particularly estradiol, in PCOS may contribute to enhanced oxidative stress.


Extranucleosomal DNA enhances the activity of the LSD1/CoREST histone demethylase complex.
The promoter regions of active genes in the eukaryotic genome typically contain nucleosomes post-translationally modified with a trimethyl mark on histone H3 lysine 4 (H3K4), while transcriptional enhancers are marked with monomethylated H3K4. The flavin-dependent monoamine oxidase LSD1 (lysine-specific demethylase 1, also known as KDM1) demethylates mono- and dimethylated H3K4 in peptide substrates, but requires the corepressor protein, CoREST, to demethylate nucleosome substrates. The molecular basis for how the LSD1/CoREST complex interacts with its physiological nucleosome substrate remains largely unknown. We examine here the role of extranucleosomal DNA beyond the nucleosome core particle for LSD1/CoREST function. Our studies of LSD1/CoREST's enzyme activity and nucleosome binding show that extranucleosomal DNA dramatically enhances the activity of LSD1/CoREST, and that LSD1/CoREST binds to the nucleosome as a 1:1 complex. Our photocrosslinking experiments further indicate both LSD1 and CoREST subunits are in close contact with DNA around the nucleosome dyad as well as extranucleosomal DNA. Our results suggest that the LSD1/CoREST interacts with extranucleosomal DNA when it productively engages its nucleosome substrate.


Long term warfarin treatment in artery disease.
The long-term use of oral anticoagulants like warfarin in artery disease has long been controversial. Possible aims of treatment include the primary or secondary prevention of systemic embolism, preventing recurrence after myocardial infarction or the progression of transient cerebral ischemia to a complete stroke, and the prevention of artery graft occlusion. The value of long-term anticoagulation is generally accepted in the few situations where, as in patients with mechanical heart valve prostheses, mitral valve disease and atrial fibrillation, or idiopathic dilated cardiomyopathy, the risk of arterial thromboembolism without anticoagulation is known to be high and there is good evidence that anticoagulants are effective, so the benefit:risk balance strongly favours their use. In many settings, however, it is hard to justify long-term warfarin treatment as the benefit:risk balance remains unknown; either because the risk of thromboembolism without anticoagulation remains to be clearly defined (as in the case of patients with 'lone' atrial fibrillation), or because possible benefits have not been well documented (as after transient cerebral ischemia or peripheral vascular surgery). Finally, there is the difficult problem of estimating the benefit from long-term anticoagulation after myocardial infarction. It seems that warfarin can reduce the likelihood of non-fatal reinfarction with relative safety in highly selected patients, but whether it reduces mortality, and how its effect compares with that of other, more recent, therapies aimed at preventing reinfarction, remains unknown.


Further Understanding of Urokinase Plasminogen Activator Overexpression in Urothelial Bladder Cancer Progression, Clinical Outcomes and Potential Therapeutic Targets.
The Plasminogen Activation System (PAS) plays a role in tumor growth, invasion and metastasis and has been associated with oncological outcomes in urinary bladder carcinoma (UBC). The use of the different components of this system as molecular markers could improve our understanding of the heterogeneous behavior of UBC and might enable earlier disease detection, individual risk stratification, more accurate outcome prediction and be a rationale for new targeted therapies. A comprehensive literature search including relevant articles up to October 2020 was performed using the MEDLINE/PubMed database. The components of the PAS axis are involved in tumor progression through their signaling processes during angiogenesis, cell migration, metastasis and adhesion. The body of evidence shows an association of PAS component overexpression with adverse pathological features and clinical outcome in UBC. Overexpressed PAS components correlate with a higher pathological tumor grade and advanced tumor stage. In non-muscle-invasive bladder cancer (NMIBC), the PAS components were associated with disease outcome while in muscle-invasive bladder cancer (MIBC), it was associated with disease outcome and pathological features. Possible therapeutic approaches in the PAS for the treatment of UBC have only been sparsely investigated in in vitro and in vivo studies. Intravesical plasminogen activator inhibitor 1 (PAI-1) instillation in animal models yielded interesting results and warrant further exploration in Phase II studies. The overexpression of PAS components in UBC tumor tissue is associated with adverse pathological features and worse oncological outcomes. These findings are mainly based on preclinical studies and retrospective series, which requires further prospective studies to translate the PAS into clinically useful biomarkers and therapeutic targets.


[Taxonomic status of the Tyulek virus (TLKV) (Orthomyxoviridae, Quaranjavirus, Quaranfil group) isolated from the ticks Argas vulgaris Filippova, 1961 (Argasidae) from the birds burrow nest biotopes in the Kyrgyzstan].
The Tyulek virus (TLKV) was isolated from the ticks Argas vulgaris Filippova, 1961 (Argasidae), collected from the burrow biotopes in multispecies birds colony in the Aksu river floodplain near Tyulek village (northern part of Chu Valley, Kyrgyzstan). Recently, the TLKV was assigned to the Quaranfil group (including the Quaranfil virus (QRFV), Johnston Atoll virus (JAV), Lake Chad virus) that is a novel genus of the Quaranjavirus in the Orthomyxoviridae family. In his work, the complete genome (ID GenBank KJ438647-8) sequence of the TLKV was determined using next-generation sequencing (Illumina platform). Comparison of deduced amino acid sequences shows closed relationship of the TLKV with QRFV and JAV (86% and 84% identity for PB1 and about 70% for PB2 and PA, respectively). The identity level of the TLKV and QRFV in outer glycoprotein GP is 72% and 80% for nucleotide and amino acid sequences, respectively. The phylogenetic analysis showed that the TLKV belongs to the genus of the Quaranjavirus in the family Orthomyxoviridae.


Secretory leukocyte proteinase inhibitor-competent DNA deposits are potent stimulators of plasmacytoid dendritic cells: implication for psoriasis.
Secretory leukocyte proteinase inhibitor (SLPI) is a well-established inhibitor of serine proteases such as human neutrophil elastase (HNE) and a NF-κB regulatory agent in immune cells. In this paper, we report that SLPI plays a previously uncharacterized role in regulating activation of plasmacytoid dendritic cells (pDCs). As the main source of IFN type I (IFNI), pDCs are crucial contributors to inflammatory and likely wound-healing responses associated with psoriasis. The mechanisms responsible for activation of pDCs in psoriatic skin are therefore of substantial interest. We demonstrate that in lesional skin of psoriasis patients, SLPI together with its enzymatic target HNE and DNA, is a component of neutrophil extracellular traps (NETs). Whereas SLPI(+) neutrophils and NETs were found to colocalize with pDCs in psoriatic skin, a mixture of SLPI with neutrophil DNA and HNE induced a marked production of IFNI by pDCs. IFNI synthesis by stimulated pDCs was dependent on intracellular DNA receptor TLR9. Thus, SLPI may contribute to psoriasis by enabling pDCs to sense extracellular DNA and produce IFNI.


Optimal mating strategies to manage a heterozygous advantage major gene in sheep.
Some mutations (or 'major genes') have a desirable effect in heterozygous carriers but an undesirable effect in homozygous carriers. When these mutations affect a trait of significant economic importance, their eradication, depending on their effect and frequency, may be counterproductive. This is especially the case of major genes affecting the ovulation rate and thus the prolificacy in meat sheep populations. To manage such situations, a mating design based on the major genotypes of reproducers has to be optimized. Both the effect of the major gene and the cost of genotyping candidates at this locus influence the expected genetic progress and profitability of the breeding plan. The aim of this study was to determine the optimal combination of matings that maximizes profitability at the level of the whole population (nucleus + commercial flocks). A deterministic model was developed and, using sequential quadratic programming methodology, the optimal strategy (optimal combination of matings) that maximized the economic gain achieved by the population across a range of genotype effects and genotyping costs was determined. The optimal strategy was compared with simpler and more practical strategies based on a limited number of parental genotype mating types. Depending on the genotype effect and genotyping costs, the optimal strategy varied, such that either the heterozygous frequency and/or polygenic gain was maximized with a large number of animals genotyped, or when genotyping costs were higher, the optimization led to lower heterozygous frequency and/or polygenic gain with fewer animals genotyped. Comparisons showed that some simpler strategies were close to the optimal strategy. An overlapping model was then derived as an application of the real case of the French Lacaune meat sheep OVI-TEST breeding program. Results showed that a practical strategy based on mating non-carriers to heterozygous carriers was only slightly less effective than the optimal strategy, with a reduction in efficiency from 3% to 8%, depending on the genotyping costs. Based on only two different parental genotype mating types, this strategy would be easy to implement.


Concurrent Proximal Fractures Are Rare in Distal Forearm Fractures: A National Cross-sectional Study.
Distal forearm fractures (DFF) account for 1.5% of emergency department (ED) visits in the United States. Clinicians frequently obtain imaging above/below the location of injury to rule out additional injuries. We sought to determine the incidence of associated proximal fractures (APF) in the setting of DFF and to evaluate the imaging practices in a nationally representative sample of EDs. We queried the 2013 National Emergency Department Sample using International Classification of Diseases, 9th edition, diagnostic codes for DFF and APF. Current Procedural Technology codes identified associated imaging studies. We calculated national estimates using a weighted analysis of patient and hospital-level characteristics associated with APF and imaging practices. An analysis of costs estimated the financial impact of additional imaging in patients with DFF using Medicare reimbursement to approximate costs according to the 2018 Medicare Physician Fee Schedule. In 2013, an estimated 297,755 ED visits (weighted) were associated with a DFF, of which 1.6% (4836 cases) had an APF. The incidence of APF was lower among females (odds ratio [OR] (0.76); 95% confidence interval [CI], 0.64-0.91) but higher in metropolitan teaching hospitals compared to metropolitan non-teaching hospitals (OR [2.39]; 95% CI, 1.43-3.99) and Level 1 trauma centers (OR [3.9]; 95%, 1.91-7.96) compared to non-trauma centers. Approximately 40% (n = 117,948) of those with only DFF received non-wrist radiographs and 19% (n = 55,236) underwent non-wrist/non-forearm imaging. Factors independently associated with additional imaging included gender, payer, patient and hospital rurality, hospital region, teaching status, ownership, and trauma center level. Nearly $3.6 million (2018 U.S. dollars) was spent on the aforementioned additional imaging. Despite the frequency of proximal imaging in patients with DFF, the incidence of APF was low. Further study to identify risk factors for APF based on mechanism and physical examination factors may result in reduced imaging and decreased avoidable healthcare spending.


A role for an inhibitory connexin in testis?
Functional expression of gap junction proteins can be obtained conveniently with the paired oocyte cell--cell channel assay. So far all gap junction proteins (connexins), with the exception of one, have been found to make functional channels either by themselves or as hybrid channels (two hemichannels of different connexin composition). Connexin33 (cx33) appears not to follow this rule. Expression of cx33 in oocytes does not yield functional channels, and attempts to identify another connexin with which cx33 can form hybrid channels have failed so far. The observation was made that cx33 inhibits functional expression of other connexins in a connexin-specific way. While expression of cx32 remains unaffected by coinjection into oocytes of cx33 mRNA together with cx32 mRNA, junctional conductance obtained with cx43 is marginally reduced whereas coinjection of cx33 mRNA at equimolar concentrations almost completely abolishes functional cx37 expression. The fact that testis is the only tissue found to express significant levels of cx33 mRNA together with cx37 and cx43 suggests a possible functional role for an inhibitory connexin. A model is proposed where cx33 limits a cell's capability to make functional channels by allowing formation of heterotypic channels with other cells while formation of homotypic channels is disallowed. Such a mechanism would permit asynchronous maturation of germ cells while at the same time allowing communication between germ cells and Sertoli cells.


Influenza research in the Eastern Mediterranean Region: the current state and the way forward.
We searched published literature, surveillance data sources, and sequence databases to analyze the state of influenza virus research and to identify research gaps in the World Health Organization (WHO) Eastern Mediterranean Region. PubMed, Scopus, and other databases were searched for influenza publications and nucleotide sequences. WHO's FluNet was searched to determine virologic reporting from each country. We found that influenza research has increased in recent years with the emergence of H5N1 and pandemic H1N1. In some countries, influenza research is growing and is diversified, covering epidemiologic, veterinary, and basic science aspects. However, the volume and diversity of influenza research is low, especially in light of the burden of influenza in the region. To have contemporary and advanced research in the region, systematic surveillance in humans and animals, as well as at the human-animal interface, needs to be boosted. Surveillance data should then be used to answer more important epidemiologic, virologic, immunologic, and basic science questions.