Risk factors for urolithiasis in dogs with congenital extrahepatic portosystemic shunts: 95 cases (1999-2013).
To identify risk factors for urolithiasis in dogs with congenital extrahepatic portosystemic shunts (EHPSSs) and to determine whether portoazygos shunts were associated with increased risk of urolithiasis at the initial evaluation for EHPSS. Retrospective case series. Dogs (n = 95) with EHPSSs confirmed via CT angiography or surgery. Medical records from 1999 to 2013 were reviewed. Variables of interest included signalment, previous medical management, and results of urinalysis, urolith analyses, and diagnostic imaging. Univariable and multivariable logistic regression analyses for assessment of risk factors for urolithiasis at the time of initial EHPSS evaluation were performed. The dogs' median age was 0.9 years (range, 0.2 to 12.6 years). Among the 95 dogs, 27 (28.4%) and 68 (71.6%) had portoazygos and portocaval shunts, respectively. Urinalysis was performed for 79 (83.2%) dogs, 29 (36.7%) of which had crystalluria (mainly ammonium urate and struvite crystals). Uroliths were present in 34 of 95 (35.8%) dogs; 16 of 17 uroliths analyzed were composed of ammonium urate. Portoazygos shunts were not associated with significantly increased odds of urolithiasis at the time of the initial evaluation for EHPSS. However, the odds of urolithiasis was significantly increased for male dogs, older dogs, and dogs that received previous medical treatment. In dogs with EHPSS, shunt morphology was not associated with increased odds of urolithiasis at the initial evaluation. Male dogs, older dogs, and dogs having received medical management for EHPSS prior to initial evaluation should be considered at increased risk for development of urolithiasis.


Cost-effectiveness of carfilzomib plus dexamethasone compared with bortezomib plus dexamethasone for patients with relapsed or refractory multiple myeloma in the United States.
We assessed the economic value of carfilzomib 56 mg/m2 and dexamethasone (Kd56) vs. bortezomib and dexamethasone (Vd) for relapsed/refractory multiple myeloma (R/RMM) using ENDEAVOR trial results. Cost-effectiveness of Kd56 vs. Vd was assessed using a partitioned survival model by estimating progression-free survival, overall survival, and direct costs over a lifetime horizon. Surveillance Epidemiology and End Results (SEER) survival data were extrapolated after matching registry and ENDEAVOR patients. Utilities were sourced from the literature and mapped from patient-reported quality of life in ENDEAVOR to estimate quality-adjusted life-years (QALYs) from life-years (LYs). The model predicted an average gain of 1.66 LYs and 1.50 QALYs with Kd56 vs. Vd, and lifetime additional costs of $182,699, resulting in an incremental cost-effectiveness ratio (ICER) of $121,828/QALY gained. The ICER was $114,793/QALY in patients with 1 prior treatment; $99,263/QALY in those not transplanted, and <$150,000/QALY up to an 85% discount in bortezomib price. Kd56 is cost-effective for patients with R/RMM at a willingness-to-pay threshold of $150,000/QALY. Trial data in the model may limit generalizability; however, SEER registry data mitigates this challenge. Kd56 provides additional value in key subgroups, and remains cost-effective after steep comparator discounts.


Clinical and methodological confounders in assessing the cerebellar cognitive affective syndrome in adult patients with posterior fossa tumours.
The cerebellar cognitive affective syndrome (CCAS) was first described by Schmahmann and Sherman as a constellation of symptoms including dysexecutive syndrome, spatial cognitive deficit, linguistic deficits and behavioural abnormalities in patients with a lesion in the cerebellum with otherwise normal brain. Neurosurgical patients with cerebellar tumours constitute one of the cohorts in which the CCAS has been described. In this paper, we present a critical review of the literature of this syndrome in neurosurgical patients. Thereafter, we present a prospective clinical study of 10 patients who underwent posterior fossa tumour resection and had a detailed post-operative neuropsychological, neuropsychiatric and neuroradiological assessment. Because our findings revealed a large number of perioperative neuroradiological confounding variables, we reviewed the neuroimaging of a further 20 patients to determine their prevalence. Our literature review revealed that study design, methodological quality and sometimes both diagnostic criteria and findings were inconsistent. The neuroimaging study (pre-operative, n = 10; post-operative, n = 10) showed very frequent neuroradiological confounding complications (e.g. hydrocephalus; brainstem compression; supratentorial lesions and post-operative subdural hygroma); the impact of such features had largely been ignored in the literature. Findings from our clinical study showed various degree of deficits in neuropsychological testing (n = 1, memory; n = 3, verbal fluency; n = 3, attention; n = 2, spatial cognition deficits; and n = 1, behavioural changes), but no patient had full-blown features of CCAS. Our study, although limited, finds no robust evidence of the CCAS following surgery. This and our literature review highlight a need for guidelines regarding study design and methodology when attempting to evaluate neurosurgical cases with regard to the potential CCAS.


Anti-Caries Effects of Dental Adhesives Containing Quaternary Ammonium Methacrylates with Different Chain Lengths.
The objectives of this study were to investigate the effects of dental adhesives containing quaternary ammonium methacrylates (QAMs) with different alkyl chain lengths (CL) on ecological caries prevention in vitro. Five QAMs were synthesized with a CL = 3, 6, 9, 12, and 16 and incorporated into adhesives. Micro-tensile bond strength and surface charge density were used to measure the physical properties of the adhesives. The proportion change in three-species biofilms consisting of Streptococcus mutans, Streptococcus sanguinis, and Streptococcus gordonii was tested using the TaqMan real-time polymerase chain reaction. Lactic acid assay, MTT [3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, exopolysaccharide staining, live/dead staining, scanning electron microscopy (SEM), and transverse microradiography (TMR) were performed to study the anti-biofilm and anti-demineralization effects of the dental adhesives. The results showed that incorporating QAMs with different alkyl chain lengths into the adhesives had no obvious effect on the dentin bond strength. The adhesives containing QAMs with a longer alkyl chain developed healthier biofilms. The surface charge density, anti-biofilm, and anti-demineralization effects of the adhesives increased with a CL of the QAMs from 3 to 12, but decreased slightly with a CL from 12 to 16. In conclusion, adhesives containing QAMs with a tailored chain length are promising for preventing secondary caries in an "ecological way".


Benefits and costs of mutualism: demographic consequences in a pollinating seed-consumer interaction.
Interspecific interactions can affect population dynamics and the evolution of species traits by altering demographic rates such as reproduction and survival. The influence of mutualism on population processes is thought to depend on both the benefits and costs of the interaction. However, few studies have explicitly quantified both benefits and costs in terms of demographic rates; furthermore there has been little consideration as to how benefits and costs depend on the demographic effects of factors extrinsic to the interaction. I studied how benefits (pollination) and costs (larval fruit consumption) of pollinating seed-consumers (senita moths) affect the reproduction of senita cacti and how these effects may rely on extrinsic water limitation for reproduction. Fruit initiation was not limited by moth pollination, but survival of initiated fruit increased when moth eggs were removed from flowers. Watered cacti produced more flowers and initiated more fruit from hand-pollinated flowers than did unwatered cacti, but fruit initiation remained low despite excess pollen. Even though water, pollination and larvae each affected a component of cactus reproduction, when all of these factors were included in a factorial experiment, pollination and water determined rates of reproduction. Counter-intuitively, larval fruit consumption had a negligible effect on cactus reproduction. By quantifying both benefits and costs of mutualism in terms of demographic rates, this study demonstrates that benefits and costs can be differentially influential to population processes and that interpretation of their influences can depend on demographic effects of factors extrinsic to the interaction.


Modular Toolbox as Snap Jewelry for Biomimetic Synthesis of Multifunctional Amino Acid Surfactants Inspired by Melanin.
Amino acid surfactants have gained significant importance in overcoming the limitations of conventional surfactants, notably, their low biocompatibility and biodegradability. However, the current amino acid surfactants lack multifunctional properties due to the nonreactivity of their aliphatic chains, necessitating the development of a new type of amino acid surfactant. A novel melanin-like amino acid surfactant and a biomimetic synthesis route were devised by mimicking the biosynthesis of melanin. Renewable natural polyphenol compounds with catechol moieties were utilized as building blocks for the hydrophobic group. In a proof-of-concept experiment, ethyl protocatechuate was oxidized to o-quinone and subsequently covalently linked to the amino group of lysine via Michael addition. The chemical structure was verified using liquid chromatography-tandem mass spectroscopy. The melanin-like amino acid surfactant exhibited excellent surface-active properties, with a critical micelle concentration of 1.59 mN m-1. Furthermore, it demonstrated remarkable emulsifying, foaming, solubilizing, dispersing, and wetting capabilities. Notably, it also possessed multifunctionality, including antibacterial activity, antioxidant activity, robustness, and mildness. These outstanding properties indicate significant potential for various applications. This strategy offers innovative insights and a versatile, modular toolbox for synthesizing multifunctional amino acid surfactants that mimic melanin. The approach allows for the easy interchange of o-quinone building blocks, which is akin to snap jewelry.


Case-control studies of sporadic enteric infections: a review and discussion of studies conducted internationally from 1990 to 2009.
Epidemiologists have used case-control studies to investigate enteric disease outbreaks for many decades. Increasingly, case-control studies are also used to investigate risk factors for sporadic (not outbreak-associated) disease. While the same basic approach is used, there are important differences between outbreak and sporadic disease settings that need to be considered in the design and implementation of the case-control study for sporadic disease. Through the International Collaboration on Enteric Disease "Burden of Illness" Studies (the International Collaboration), we reviewed 79 case-control studies of sporadic enteric infections caused by nine pathogens that were conducted in 22 countries and published from 1990 through to 2009. We highlight important methodological and study design issues (including case definition, control selection, and exposure assessment) and discuss how approaches to the study of sporadic enteric disease have changed over the last 20 years (e.g., making use of more sensitive case definitions, databases of controls, and computer-assisted interviewing). As our understanding of sporadic enteric infections grows, methods and topics for case-control studies are expected to continue to evolve; for example, advances in understanding of the role of immunity can be used to improve control selection, the apparent protective effects of certain foods can be further explored, and case-control studies can be used to provide population-based measures of the burden of disease.


Genes and (auto)immunity in primary biliary cirrhosis.
Primary biliary cirrhosis (PBC) is a chronic autoimmune cholestatic liver disease most commonly encountered in postmenopausal women; it is characterized by high-titer serum autoantibodies to mitochondrial antigens, elevated serum IgM, progressive destruction of intrahepatic bile ducts, and ultimately liver cirrhosis and failure. The cytopathic mechanisms leading to the selective destruction of intrahepatic cholangiocytes are still largely unknown. The current theory on the pathogenesis of PBC indicated that environmental factors might trigger autoimmunity in genetically susceptible individuals. In fact, genetic predisposition is critical to disease onset and progression, yet peculiar among autoimmune diseases, as indicated by the lack of a strong association with major histocompatibility complex haplotypes. Further, the recently reported concordance rate among monozygotic twins strengthens the importance of genetic factors, while also indicating that additional factors, possibly infectious agents or xenobiotics, intervene to trigger the disease. In this review, the available data regarding the genetic factors associated with PBC susceptibility and progression, as well as the available evidence regarding the immunomediated pathogenesis of PBC, will be critically illustrated and discussed.


Ambient pressure XPS and IRRAS investigation of ethanol steam reforming on Ni-CeO2(111) catalysts: an in situ study of C-C and O-H bond scission.
Ambient-Pressure X-ray Photoelectron Spectroscopy (AP-XPS) and Infrared Reflection Absorption Spectroscopy (AP-IRRAS) have been used to elucidate the active sites and mechanistic steps associated with the ethanol steam reforming reaction (ESR) over Ni-CeO2(111) model catalysts. Our results reveal that surface layers of the ceria substrate are both highly reduced and hydroxylated under reaction conditions while the small supported Ni nanoparticles are present as Ni(0)/NixC. A multifunctional, synergistic role is highlighted in which Ni, CeOx and the interface provide an ensemble effect in the active chemistry that leads to H2. Ni(0) is the active phase leading to both C-C and C-H bond cleavage in ethanol and it is also responsible for carbon accumulation. On the other hand, CeOx is important for the deprotonation of ethanol/water to ethoxy and OH intermediates. The active state of CeOx is a Ce(3+)(OH)x compound that results from extensive reduction by ethanol and the efficient dissociation of water. Additionally, we gain an important insight into the stability and selectivity of the catalyst by its effective water dissociation, where the accumulation of surface carbon can be mitigated by the increased presence of surface OH groups. The co-existence and cooperative interplay of Ni(0) and Ce(3+)(OH)x through a metal-support interaction facilitate oxygen transfer, activation of ethanol/water as well as the removal of coke.


Homologous chromosome associations and nuclear order in meiotic and mitotically dividing cells of budding yeast.
This chapter discusses the relationship between nuclear order and the association of homologous DNA sequences in the budding yeast, Saccharomyces cerevisiae. Homologous chromosomes functionally interact with one another to repair DNA double-strand breaks (DSBs) introduced either environmentally (e.g., by gamma-irradiation) or deliberately by the cell (e. g., during meiosis). DNA homology recognition in these instances often involves the (RecA) homolog RAD51 and/or the related gene, DMC1. Evidence for interactions between homologous chromosomes occurring independent of DSB formation and (RecA) homolog function has also been described in meiotic, premeiotic, and mitotically dividing cells of yeast. These interactions presumably depend upon DNA homology but the molecular details of such associations are poorly understood. Both DSB-dependent and -independent homolog associations may be facilitated by the nonrandom organization of chromosomes in the nucleus, including centromere and telomere clustering, which are also discussed.


Efficacy of a mixed glycoprotein vaccine against pseudorabies in pregnant sows.
A pseudorabies virus (PRV) glycoprotein-mixed vaccine was prepared by heparin-affinity chromatography from PRV-infected PK-15 cell lysates. In our previous study, the trial vaccine was induced protection with suppression of virus shedding in one-month-old pigs and generation of cytotoxic T lymphocyte (CTL) response in mice. In this study, the effect of the trial vaccine on suppression of both virus shedding and reproductive failure in pregnant sows was examined. Three sows were vaccinated twice until one week before mating. Each of them was infected intranasally with 10(6) TCID50 of PRV on day 28, 54, or 85 after mating, respectively. Three other sows were also mated and challenged at the same time as the respective control. The vaccinated sows produced virus-neutralizing antibodies. Sows with high level of VN antibody lowered the level and period of virus shedding after challenge. The maximum level of shed-virus titers in vaccinated sows were 10(1.25) to 10(3) times lower than controls. Vaccinated sows shed virus for 1 or 5 days, while controls shed for 8, 9, or 12 days. No abortion or stillbirth was observed in vaccinated sows during pregnancy. On the other hand, control sow challenged at a late stage of pregnancy showed abortion and stillbirth. The results obtained here indicate that our trial vaccine is effective to prevent reproductive failure by pseudorabies virus.


Establishment of the chloroplast genetic system in rice during early leaf development and at low temperatures.
Chloroplasts are the central nodes of the metabolic network in leaf cells of higher plants, and the conversion of proplastids into chloroplasts is tightly coupled to leaf development. During early leaf development, the structure and function of the chloroplasts differ greatly from those in a mature leaf, suggesting the existence of a stage-specific mechanism regulating chloroplast development during this period. Here, we discuss the identification of the genes affected in low temperature-conditional mutants of rice (Oryza sativa). These genes encode factors involved in chloroplast rRNA regulation (NUS1), and nucleotide metabolism in mitochondria, chloroplasts, and cytosol (V2 , V3, ST1). These genes are all preferentially expressed in the early leaf developmental stage P4, and depleting them causes altered chloroplast transcription and translation, and ultimately leaf chlorosis. Therefore, it is suggested that regulation of cellular nucleotide pools and nucleotide metabolism is indispensable for chloroplast development under low temperatures at this stage. This review summarizes the current understanding of these factors and discusses their roles in chloroplast biogenesis.


Mendelian randomisation analysis of circulating adipokines and C-reactive protein on breast cancer risk.
Circulating adipokines and C-reactive protein (CRP) have been linked to breast cancer risk in observational epidemiological studies. The causal nature of these associations is unclear because of the susceptibility of conventional observational designs to residual confounding, reverse causation and other forms of bias. Mendelian randomisation (MR) uses genetic variants as proxies for risk factors to strengthen causal inference in observational settings. We performed a MR analysis to evaluate the causal relevance of six previously reported circulating adipokines [adiponectin, hepatocyte growth factor (HGF), interleukin-6, leptin receptor, plasminogen activator inhibitor-1 and resistin] and CRP in risk of overall and oestrogen receptor-stratified breast cancer in up to 122,977 cases and 105,974 controls of European ancestry. Genetic instruments were constructed from single-nucleotide polymorphisms robustly (p < 5 × 10-8 ) associated with risk factors in genome-wide association studies. Colocalisation was performed as a sensitivity analysis to examine whether findings reflected shared causal variants or genomic confounding. In MR analyses, there was evidence for an association of HGF with oestrogen receptor-negative cancer (odds ratio per standard deviation increase: 1.17, 95% confidence interval: 1.01-1.35; p = 0.035) but little evidence for associations of other adipokines or CRP with overall or oestrogen receptor-stratified breast cancer. Colocalisation analysis suggested that the association of HGF with oestrogen receptor-negative breast cancer was unlikely to reflect a causal association. Collectively, these findings do not support an important aetiological role of various adipokines or CRP in overall or oestrogen receptor-specific breast cancer risk.


Pulse low dose steroids attenuate post-cardiopulmonary bypass SIRS; SIRS I.
Cardiopulmonary bypass (CPB) initiates inflammation that contributes to multiorgan dysfunction (SIRS). Steroids have been demonstrated to attenuate this response; however, resistance to use steroids remains because of potential adverse effects of the high doses used. This study examines a lower dose steroid protocol for safety and attenuation of SIRS. Sixty patients undergoing CPB were randomized to pulse low doses of methylprednisolone (250 mg given twice IV) or placebo in this RCT. Outcomes pertaining to hemodynamics, ventilator requirement, arrhythmia, and metabolic derangements were recorded. Post-operative glucose control and gastrointestinal prohylaxis was instituted in all patients. IL-6 concentrations were lower in the steroid group at 4 and 8 h post-operatively (P < 0.0001). The steroid group demonstrated more normothermia (37.2 degrees C versus 37.6 degrees C, P = 0.002), better hemodynamic stability with less requirement for inotropes or vasopressors (0% versus 27.6%, P = 0.005), higher SVRIs (1840 versus 1340 DSm2/cm5, P = 0.002), and higher mean arterial pressures (79 versus 74 mmHg, P = 0.03). The steroid group had a shorter duration of intubation (7.7 versus 10.7 h, P = 0.02), a shorter length of ICU stay (1.0 versus 2.0 days, P = 0.03), and less blood loss (505 versus 690 ml, P = 0.04) with no difference in post-operative blood glucose levels or complications. Patients undergoing cardiopulmonary bypass receiving low pulse dose steroids had better hemodynamics, shorter mechanical ventilation times, less blood loss, and required less time in the ICU compared to those receiving placebo. Therefore, this study demonstrates that prophylactic low dose steroids attenuate the SIRS response to CPB without resulting in any untoward side-effects.


Abdominal Obesity is More Predictive of Advanced Colorectal Neoplasia Risk Than Overall Obesity in Men: A Cross-sectional Study.
We aimed to ascertain whether waist circumference (WC) is associated with risk of colorectal neoplasia (CRN), independent of body mass index (BMI). Although several studies have reported the association between abdominal obesity, measured by WC, and CRN, it remains unclear whether their association is biased by BMI. A cross-sectional study was performed on 154,552 asymptomatic examinees who underwent colonoscopy for a health check-up. The mean age was 42.6 years, and the proportion of males was 65.2%. The prevalence rate of CRN in subjects in WC quartiles 1, 2, 3, and 4 was 15.6%, 18.1%, 20.4%, and 22.0% among men and 7.8%, 9.4%, 12.2%, and 15.8% among women, respectively. WC and BMI were independent risk factors for overall CRN and nonadvanced CRN in both men and women. In men, the association of BMI with advanced CRN was attenuated to null after adjusting for WC [Q2, Q3, and Q4 vs. Q1; odds ratios (95% confidence intervals), 0.93 (0.79-1.10), 0.85 (0.71-1.03), and 0.99 (0.80-1.22), respectively; Ptrend=0.822], whereas the association of WC with advanced CRN significantly persisted even after adjusting for BMI [Q2, Q3, and Q4 vs. Q1; 1.20 (1.02-1.42), 1.45 (1.20-1.75), and 1.64 (1.32-2.04), respectively; Ptrend<0.001]. In women, neither WC nor BMI was associated with the risk of advanced CRN. Abdominal obesity is associated with an increased risk of advanced CRN, independent of overall obesity (BMI) in men. Our findings suggest that abdominal obesity is more strongly predictive of advanced CRN than overall obesity in men.


A new channel-forming antibiotic from Streptomyces coelicolor A3(2) which requires calcium for its activity.
A recently discovered antibiotic (CDA; calcium-dependent antibiotic) of Streptomyces coelicolor A3(2) was found to be effective against a wide range of Gram-positive bacteria only in the presence of calcium ions. Producer and non-producer strains were identified and several media tested for their ability to support antibiotic production. The action of calcium was not simulated by any of the other cations tested. The antibiotic was found to induce discrete conductance fluctuations in planar lipid bilayer consistent with a channel-forming action. The electrical potential difference caused by a concentration difference of various salts across the CDA-containing bilayer, showed the channel to be cation-selective but of a size that discriminated against tetramethyl ammonium and choline ions. The data indicate that the antibiotic activity of CDA is due to its action as a calcium-dependent ionophore.


Efficient gene delivery of primary human cells using peptide linked polyethylenimine polymer hybrid.
Polyethylenimine (PEI) based polymers are efficient agents for cell transfection. However, their use has been hampered due to high cell death associated with transfection thereby resulting in low efficiency of gene delivery within the cells. To circumvent the problem of cellular toxicity, metal binding peptides were linked to PEI. Eight peptide-PEI derivatives were synthesized to improve cell survival and transfection efficiency. TAT linked PEI was used as a control polymer. Peptides linked with PEI amines formed nanogels as shown by electron microscopy and atomic force microscopic measurements. Polymers were characterized by spectroscopic methods and their ability to form complexes with plasmids was tested using electrophoretic studies. These modifications improved polymer biocompatibility as well as cell survival markedly, when compared to PEI alone. A subset of the modified peptide-polymers also showed significantly higher transfection efficiency in primary human cells with respect to the widely used transfection agent, lipofectamine. Study of the underlying mechanism of the observed phenomena revealed lower levels of 'reactive oxygen species' (ROS) in the presence of the peptide-polymers when compared to PEI alone. This was further corroborated with global gene expression analysis which showed upregulation of multiple genes and pathways involved in regulating intracellular oxidative stress.


Advanced glycation end products, soluble receptor for advanced glycation end products, and risk of colorectal cancer.
Advanced glycation end products (AGE) accumulate in human tissue proteins during aging, particularly under hyperglycemia conditions. AGEs induce oxidative stress and inflammation via the receptor for AGEs (RAGE) and soluble RAGE (sRAGE) can neutralize the effects mediated by RAGE-ligand engagement. We examined the association between N(ε)-(carboxymethyl)lysine (CML), a prominent AGE, and sRAGE and colorectal cancer risk in a prospective case-cohort study nested within a cancer prevention trial among 29,133 Finnish male smokers. Among study subjects who were alive without cancer 5 years after baseline (1985-1988), we identified 483 incident colorectal cancer cases and randomly sampled 485 subcohort participants as the comparison group with the follow-up to April 2006. Baseline serum levels of CML-AGE, sRAGE, glucose and insulin were determined. Weighted Cox proportional hazard regression models were used to calculate relative risks (RR) and 95% CI. Comparing highest with lowest quintile of sRAGE, the RR for incident colorectal cancer was 0.65 (95% CI, 0.39-1.07; P(trend) = 0.03), adjusting for age, years of smoking, body mass index, and CML-AGE. Further adjustment for serum glucose strengthened the association (RR = 0.52; 95% CI, 0.30-0.89; P(trend) = 0.009). Highest quintile of CML-AGE was not associated with an increased risk of colorectal cancer (multivariate RR = 1.20; 95% CI, 0.64-2.26). Higher prediagnostic levels of serum sRAGE were associated with lower risk of colorectal cancer in male smokers. This is the first epidemiologic study to implicate the receptor for AGEs in colorectal cancer development.


Aerodynamic impact of total inferior turbinectomy versus inferior turbinoplasty - a computational fluid dynamics study.
The aim of this study was to investigate using computational fluid dynamics (CFD) the effects on nasal aerodynamics of two different techniques for reducing the inferior turbinate. This may assist in surgical planning to select the optimal procedure. Virtual surgery using two techniques of turbinate reduction was performed in eight nasal airway obstruction patients. Three bilateral nasal airway models for each patient were compared: 1) Pre-operative 2) Bilateral inferior turbinoplasty 3) Bilateral total inferior turbinate resection (ITR). Two representative healthy models were included. CFD modeling of airflow was performed under steady-state, laminar, inspiratory conditions. Nasal airway resistance was slightly more reduced following ITR compared to turbinoplasty due to loss of the pressure gradient at the head of the IT. Turbinoplasty resulted in ventilation, pressure and wall shear stress profiles closer to those of healthy models. A more prominent jet-like course of the main flow stream was observed inferiorly in the ITR group. Nasal air conditioning was significantly altered following IT surgery. Overall differences between the groups were small and are unlikely to bear influence on nasal function in normal environments. Further studies using a larger number of patients and healthy subjects are required, attempting to establish a clinical correlation with long-term outcomes such as the perception of nasal patency, mucosal crusting and drying, and air conditioning in different environments. Since a large proportion of IT mucosa remains following turbinoplasty, future dependence on topical therapy should also be considered.


Classic indicators and diel dissolved oxygen versus trend analysis in assessing eutrophication of potable-water reservoirs.
Potable source-water reservoirs are the main water supplies in many urbanizing regions, yet their long-term responses to cultural eutrophication are poorly documented in comparison with natural lakes, creating major management uncertainties. Here, long-term discrete data (June 2006-June 2018) for classical eutrophication water quality indicators, continuous depth-profile data for dissolved oxygen (DO), and an enhanced hybrid statistical trend analysis model were used to evaluate the eutrophication status of a potable source-water reservoir. Based on classical indicators (nitrogen, N and phosphorus, P concentrations and ratios; phytoplankton biomass as chlorophyll a, chl a; and trophic state indices), the reservoir was eutrophic to hypereutrophic and stoichiometrically imbalanced. Anoxia/hypoxia occurred for 7-8 months annually systemwide, even throughout the water column for days to weeks in some years; and elevated total ammonia (up to ~900 μg tNH3 L-1 ) in surface waters from late summer/fall through late winter/early spring suggested substantial internal legacy nutrient loading. These surprising DO and tNH3 phenomena may characterize many reservoirs in urbanizing areas, and the associated cascade of negative impacts may increasingly affect them under global warming. Total organic carbon (TOC), seasonally influenced by phytoplankton biomass, commonly exceeded 6 mg L-1 , which is problematic for potable-water treatment, and significantly trended up over time. Wet-year inflow dilution influenced an apparent decreasing trend in nutrients within the hypereutrophic upper reservoir, which receives most tributary inputs. Nevertheless, significant reservoirwide trends (increasing total phosphorus [TP], phytoplankton chl a, TOC) and mid- and/or lower region trends (increasing total nitrogen [TN], tNH3 , decreasing TN:TP ratios) suggest that water quality degradation from eutrophication has worsened over time. These findings support broadly applicable recommendations to strengthen protection of potable source-water reservoirs in urbanizing watersheds: (1) protective numeric water quality criteria are needed for TOC as well as TN, TP, and chl a; (2) continuous diel data capture more realistic DO conditions than traditional sampling, and can provide important insights for water treatment managers; and (3) assessment of reservoir eutrophication status to track management progress over time should emphasize classic indicators equally as statistical trends, which are highly sensitive to short-term meteorological forcing.


Jaundice following intravesical botulinum toxin - a previously unreported complication.
A 59-year-old woman presented 5 days after her third instillation of intravesical botulinum toxin with right upper quadrant pain and jaundice. Blood tests demonstrated deranged liver function tests. An abdominal ultrasound, radiograph, magnetic resonance cholangiopancreatography, serum hepatitis screen, immunoglobulins and autoantibody testing were normal. An ultrasound-guided liver biopsy was performed. The histological appearances were those of chronic active/lobular hepatitis. Following treatment with steroids, her jaundice improved over a period of about 3 weeks. Her serum liver function tests returned to normal in 3 months. The steroids were discontinued once her liver function tests normalised. The patient had no further recurrence of jaundice and serum liver function tests have been within normal limits after 6 months follow-up.


Assessment of the soft tissue volumetric changes following acellular dermal matrix grafts with cone beam computerized tomography.
The aim of this study was to use cone beam computerized tomography (CBCT), which consistently allowed the determination of the dimensions of the soft tissue, to evaluate acellular dermal matrix grafts (ADMG) used to increase gingival soft tissue thickness (GSTT). In total, 90 gingival defects were included in the study. Surgical procedures were performed to augment the gingival tissue with ADMG. While GSTT measurements were assessed at baseline and 6, 12, and 18 months post-surgery, ADMG measurements were performed with CBCT at 6, 12, and 18 months post-surgery. All parameters showed statistically significant differences between time intervals. In the ADMG-treated sites, the baseline GSTT was 1.00 ± 0.37 mm and the final thickness was 1.66 ± 0.34 mm. The 6-month measurement of ADMG was 0.79 ± 0.08 mm, and the final measurement was 0.11 ± 0.09 mm. High-quality images of the GSTT and ADMG can be consistently obtained with CBCT. The present findings indicate that soft tissue augmentation can be achieved in gingival defects with the use of ADMG.


A step towards tuning the jute fiber structure and properties by employing sodium periodate oxidation and coating with alginate.
This paper outlines a novel simple protocol for tuning the structure and properties of jute using sodium periodate (NaIO4) oxidation and coating with alginate. When compared to the raw jute, fabrics oxidized with a 0.2 or 0.4 % NaIO4 solution for 30-120 min exhibited an increased aldehyde group content (0.185 vs. 0.239-0.398 mmol/g), a significantly increased negative zeta potential (from -8.57 down to -20.12 mV), a slight disruption of fiber crystallinity, 15.1-37.5 % and 27.9-49.8 % lower fabric maximum force and stiffness, respectively. Owing to the removal of hydrophobic surface barrier, decreased crystallinity index and the presence of micropores on the fabrics' surfaces, oxidized fabrics have a 22.3-29.6 % improved ability for moisture sorption compared to raw fabric. Oxidized fabrics characterized by very long wetting times and excellent antioxidant activities (> 98 %), can find applications as hydrophobic packaging materials. To further extend the utilization of jute in biocarpet engineering such as water-binding geo-prebiotic supports, oxidized fabrics were coated with alginate resulting in 7.9-24.9 % higher moisture sorption and 352-660 times lower wetting times than their oxidized counterparts. This modification protocol has never been applied to lignocellulosic fibers and sheds new light on obtaining jute fabrics with tuned structure and properties intended for various applications.


Independent prognostic importance of a restrictive left ventricular filling pattern after myocardial infarction: an individual patient meta-analysis: Meta-Analysis Research Group in Echocardiography acute myocardial infarction.
Restrictive mitral filling pattern (RFP), the most severe form of diastolic dysfunction, is a predictor of outcome after acute myocardial infarction (AMI). Low power has precluded a definite conclusion on the independent importance of RFP, especially when overall systolic function is preserved. We undertook an individual patient meta-analysis to determine whether RFP is predictive of mortality independently of LV ejection fraction (LVEF), end-systolic volume index, and Killip class in patients after AMI. Twelve prospective studies (3396 patients) assessing the relationship between prognosis and Doppler echocardiographic LV filling pattern in patients after AMI were included. Individual patient data from each study were extracted and collated into a single database for analysis. RFP was associated with higher all-cause mortality (hazard ratio, 2.67; 95% CI, 2.23 to 3.20; P<0.001) and remained an independent predictor in multivariate analysis with age, gender, and LVEF. The overall prevalence of RFP was 20% but was highest (36%) in the quartile of patients with lowest LVEF (<39%) and lowest (9%) in patients with the highest LVEF (>53%; P<0.0001). RFP remained significant within each quartile of LVEF, and no interaction was found for RFP and LVEF (P=0.42). RFP also predicted mortality in patients with above- and below-median end-systolic volume index (1575 patients) and in different Killip classes (1746 patients). Importantly, when diabetes, current medication, and prior AMI were included in the model, RFP remained an independent predictor of outcome. Restrictive filling is an important independent predictor of mortality after AMI regardless of LVEF, end-systolic volume index, and Killip class.


Dissection of antibody specificities induced by yellow fever vaccination.
The live attenuated yellow fever (YF) vaccine has an excellent record of efficacy and one dose provides long-lasting immunity, which in many cases may last a lifetime. Vaccination stimulates strong innate and adaptive immune responses, and neutralizing antibodies are considered to be the major effectors that correlate with protection from disease. Similar to other flaviviruses, such antibodies are primarily induced by the viral envelope protein E, which consists of three distinct domains (DI, II, and III) and is presented at the surface of mature flavivirions in an icosahedral arrangement. In general, the dominance and individual variation of antibodies to different domains of viral surface proteins and their impact on neutralizing activity are aspects of humoral immunity that are not well understood. To gain insight into these phenomena, we established a platform of immunoassays using recombinant proteins and protein domains that allowed us to dissect and quantify fine specificities of the polyclonal antibody response after YF vaccination in a panel of 51 vaccinees as well as determine their contribution to virus neutralization by serum depletion analyses. Our data revealed a high degree of individual variation in antibody specificities present in post-vaccination sera and differences in the contribution of different antibody subsets to virus neutralization. Irrespective of individual variation, a substantial proportion of neutralizing activity appeared to be due to antibodies directed to complex quaternary epitopes displayed on the virion surface only but not on monomeric E. On the other hand, DIII-specific antibodies (presumed to have the highest neutralizing activity) as well as broadly flavivirus cross-reactive antibodies were absent or present at very low titers. These data provide new information on the fine specificity as well as variability of antibody responses after YF vaccination that are consistent with a strong influence of individual-specific factors on immunodominance in humoral immune responses.


Corticosteroids for pulmonary sarcoidosis.
Pulmonary sarcoidosis is a common condition with an unpredictable course. Oral or inhaled steroids are widely used in its treatment, but there is no consensus about when and in whom therapy should be initiated, what dose should be given and for how long. Corticosteroids given for several months have deleterious side-effects so it is important to know whether they have any maintained benefit in pulmonary sarcoidosis. To determine the randomised controlled trial (RCT) evidence for the benefit of corticosteroids (oral or inhaled) in the treatment of pulmonary sarcoidosis. The Cochrane Airways Group interstitial lung disease RCT register was searched using the terms: sarcoidosis and (steroid* OR corticosteroid* OR prednisolone OR prednisone OR beclomethasone OR budesonide OR fluticasone). Bibliographies of retrieved RCTs and reviews were searched for additional RCTs. Pharmaceutical companies and authors of identified RCTs were contacted for other published and unpublished studies. Two reviewers independently assessed full text articles for inclusion based upon the following criteria: the study had to be a RCT or controlled clinical trial in adults with histological evidence of pulmonary sarcoidosis. Study quality was assessed and data extracted independently by two reviewers. Outcomes were analysed as continuous and dichotomous outcomes, using standard statistical techniques. Nine RCTs were identified, two had insufficient data for any analysis. There were 516 patients in the five usable trials of oral steroids, and 66 patients in two trials of inhaled steroids. The oral steroid dose was equivalent to prednisolone 15-40 mg/day. The inhaled steroid was budesonide 0.8 - 1.2 mg/day. Outcomes were symptoms, chest X-ray (CXR) changes, lung function and global scores (a combination of all three outcomes). Oral steroids improved the CXR over 6-24 months. Two studies showed no improvement in lung function, in another there was an improvement in diffusing capacity in the treated group. Global scores improved in patients with Stage 2 and 3 disease but not with Stage 1 disease. There were no data on side-effects. Inhaled steroids had no effect on CXR. In one study diffusing capacity improved. In another, symptoms improved at the end of six months of treatment. Oral steroids improved the chest X-ray and a global score of CXR, symptoms and spirometry over 6-24 months., but there is little evidence of an improvement in lung function. There are no data beyond two years to indicate whether oral steroids have any modifying effect on long-term disease progression. Oral steroids are indicated for patients with Stage 2 and 3 disease with moderate - severe or progressive symptoms or CXR changes. The available data provide no guidance for the management of this disease after two years. Short term (less than six months) of inhaled steroids may improved symptoms, perhaps in patients who mainly have cough.


[Estimating accumulation and depletion of substances in a double osmotic-diffusive cell containing polymeric membranes].
In this paper there were presented the results of studying accumulation and depletion in an inter-membrane compartment (m) of double-membrane osmotic-diffusive cell. This cell was contained two (Ml and M(r)), microporous and symmetrical flat polymeric membranes (Nephrophane and Cellulose IMP-1), separating three compartments (l, m, r) containing the heterogeneous binary and ternary nonelectrolytic solutions. The inter-membrane compartment (m) consists of the infinitesimal layer of solution. The volumes of compartment m and external compartment (l and r) fulfill the conditions Vm-->0 and Vl = Vr-->infinity respectively. As binary solutions were used the aqueous glucose, and as ternary--the glucose solutions in 0.75 mole.l-1 aqueous ethanol solution. In this system the solution concentrations fulfill the condition Cls > Co(ms) > Crs. In the initial moment Co(ms) = 0.5 (Cls + Crs). The calculations of a concentration in a steady-state Ci(ms) for configurations A and B of double-membrane osmotic-diffusive cell were elaborated. In configuration A solution with concentration Cls was placed in compartment above membrane Ml and water below membrane M(r). In configuration B--the sequence of solution was reversed. In case of the accumulation of substance in compartment m Ci(ms) > Co(ms), and a case of depletion--Ci(ms) < Co(ms).


Nonprogrammed Vascular Access Is Associated With Greater Mortality in Patients Who Return to Hemodialysis With a Failing Renal Graft.
In incident hemodialysis (HD) patients, the use of catheters is associated with a worse prognosis when compared with those with an arteriovenous fistula, but the role of vascular access (VA) type in the morbidity and mortality of patients returning to HD with a failing renal allograft is unknown. We aimed to determine the associations between the type of VA and mortality in this population. This was a retrospective observational cohort study of 138 patients who initiated dialysis after kidney transplant failure between 1995 and 2014. We recorded access type, laboratory values at entry, stratified patients per risk, and determined the effect on mortality of programmed VA (PVA), (arteriovenous fistula or PTFE graft) and nonprogrammed VA (UPVA) (tunneled or nontunneled catheters) at the initiation of HD. Eighty-five (61.6%) and 53 (38.4%) patients initiated therapy with PVA and UPVA, respectively. Overall mortality was 14.6% at 1 year. Patients using catheters had greater mortality than those with a PVA (log rank P <0.0001). At 24 months, 7 patients died in PVA group versus 22 in UPVA group. Multivariate Cox analysis showed that initiation of HD with a catheter (hazard ratio, 5.90; 95%, confidence interval, 2.83-12.31) was independently associated with greater mortality after adjusting for confounders. Nonprogrammed VA with a catheter predicted all-cause mortality among patients with transplant failure reentering HD.


Positive parenting, family cohesion, and child social competence among immigrant Latino families.
The relation between positive parenting, family cohesion, and child social competence was examined among Latino families (predominantly from Mexico) who were recent immigrants to the United States. A mixed method study was conducted, including both pre- and post-test self-reported surveys (9-month interval) and qualitative data from focus groups. A total of 282 parents and 282 children (ages 9-12) participated in the survey study. Results at post-test follow-up indicated that family cohesion predicted improvements in child social problem-solving skills and social self-efficacy, and positive parenting predicted improvements in child social self-efficacy. A total of 12 mothers participated in the focus group study that was designed to explore barriers to positive parenting and family cohesion in this population. Results from focus groups revealed four major themes impacting parenting and family cohesion: (a) acculturation differences between parents and children and the resulting power imbalance; (b) difficulty getting involved in their child's education; (c) loss of extended family; and (d) discrimination against immigrants and legal status. The implications for family support programs for immigrant Latino families and their children are discussed.


Microphysics of the aqueous bulk counters the water activity driven rate acceleration of bromide oxidation by ozone from 289-245 K.
The reaction of ozone with bromide is an initiation process in bromine activation resulting in the formation of reactive bromine species with impacts on the fate of compounds in the lower atmosphere. Environmental halide sources often contain organics, which are known to influence aqueous bulk reactivity. Here, we present a study investigating the temperature dependence of bromide oxidation by ozone using a coated wall flow tube reactor coated with an aqueous mixture of citric acid, as a proxy for oxidized secondary organic matter, and sodium bromide. Using the resistor model formulation, we quantify changes in the properties of the aqueous bulk relevant for the observed reactivity. The reactive uptake coefficient decreased from 2 × 10-6 at 289 K to 0.5 × 10-6 at 245 K. Our analysis indicates that the humidity-driven increase in concentration with a corresponding increase in the pseudo-first order reaction rate was countered by the colligative change in ozone solubility and the effect of the organic fraction via increased viscosity and decreased diffusivity of ozone as the temperature decreased. From our parameterization, we provide an extension of the temperature dependence of the reaction rate coefficients driving the oxidation of bromide, and assess the temperature-dependent salting effects of citric acid on ozone solubility. This study shows the effects of the organic species at relatively mild temperatures, between the freezing point and eutectic temperature of sea as is typical for the Earth's cryosphere. Thus, this study may be relevant for atmospheric models at different scales describing halogen activation in the marine boundary layer or free troposphere including matrices such as sea-spray aerosol and brine in sea ice, snow, and around mid-latitude salt lakes.


Detection of herpesvirus-like DNA in the bronchoalveolar lavage fluid of patients with pulmonary Kaposi's sarcoma.
Pulmonary involvement is a clinically important form of visceral Kaposi's sarcoma in immunocompromised patients. Recently, herpesvirus-like deoxyribonucleic acid (DNA) sequences, defining a new herpesvirus termed "human herpesvirus 8" (HHV8) or "Kaposi's sarcoma-associated herpesvirus" (KSHV), were detected in Kaposi's sarcoma of acquired immune deficiency syndrome (AIDS) and non-AIDS patients. We describe the successful detection of HHV8 DNA in the bronchoalveolar lavage (BAL) fluid of patients with pulmonary Kaposi's sarcoma. Three immunocompromised patients, two HIV seropositive and one after kidney transplantation, suffered from respiratory symptoms and showed pulmonary infiltrates on chest radiography after development of biopsy proven Kaposi's sarcoma of the skin. Bronchoscopy revealed the typical Kaposi like livid endobronchial lesions. BAL fluid was analysed for the presence of HHV8 DNA using a nested polymerase chain reaction (PCR) assay. HHV8 DNA was detected in the BAL fluid of all three patients. In addition, HHV8 DNA could be detected in the skin biopsy tissue, lymph node, and peripheral blood mononuclear cells of these patients. Our data show that human herpesvirus 8 deoxyribonucleic acid can be detected in the bronchoalveolar lavage fluid of patients with pulmonary Kaposi's sarcoma. If further studies reveal a high specificity for human herpesvirus 8 deoxyribonucleic acid detection, this test will improve the tools for the diagnosis of pulmonary Kaposi's sarcoma without further need of biopsies.


Lipopolysaccharide neutralization by antimicrobial peptides: a gambit in the innate host defense strategy.
Antimicrobial peptides (AMPs) are nowadays understood as broad multifunctional tools of the innate immune system to fight microbial infections. In addition to its direct antimicrobial action, AMPs can modulate the host immune response by promoting or restraining the recruitment of cells and chemicals to the infection focus. Binding of AMPs to lipopolysaccharide is a critical step for both their antimicrobial action and their immunomodulatory properties. On the one hand, removal of Gram-negative bacteria by AMPs can be an effective strategy to prevent a worsened inflammatory response that may lead to septic shock. On the other hand, by neutralizing circulating endotoxins, AMPs can successfully reduce nitric oxide and tumor necrosis factor-α production, hence preventing severe tissue damage. Furthermore, AMPs can also interfere with the Toll-like receptor 4 recognition system, suppressing cytokine production and contributing to modulate the inflammatory response. Here, we review the immune system strategies devised by AMPs to avoid an exacerbated inflammatory response and thus prevent a fatal end to the host.


[Assessment of the diagnostic yield of cerebral CT in children].
In order to show if an excessive use of cerebral computed tomography of children (aged 0 to 15 years) existed, scans from 157 patients from a single X-ray-department was examined. The clinical information which was presented on referral of the patients was also investigated. No excessive use was proven, as 26.1% of the patients showed pathological changes on the scans. But the investigation also showed that the percentage could probably be higher if more (if not all) patients was examined by a neurologist before referral to the X-ray-department.


Time trends in social differences in nutrition habits of a Lithuanian population: 1994-2010.
During the post-communist transition period, political, economic, and social changes affected the lifestyles of the Lithuanian population, including their nutritional habits. However, people of lower socio-economic position were more vulnerable to these changes. The aim of the present study was to evaluate the trends in selected food habits of the Lithuanian adult population by their level of education and place of residence from 1994 to 2010. The data were obtained from nine biannual cross-sectional postal surveys of Lithuanian health behaviours, beginning in 1994. Each survey used a randomly selected nationally representative sample of 3000 inhabitants aged 20-64 drawn from the population register. In total, 7358 men and 9796 women participated in these surveys. Questions about food consumption were included within all health behaviour questionnaires. During the transition period, use of vegetable oil in cooking and the frequency of consumption of fresh vegetables increased, use of butter on bread decreased, and the proportion of women drinking high-fat milk declined. Lithuanians with higher education reported more frequent use of vegetable oil in cooking as well as daily consumption of fresh vegetables than those with a lower level of education. Consumption of high-fat milk was inversely associated with educational background. In addition, the proportion of persons spreading butter on bread increased with higher education level. The greatest urban-rural difference was observed in high-fat milk consumption. The increase in the use of vegetable oil in cooking, and the reduction of spreading butter on bread was more evident among less educated and rural inhabitants. Meanwhile, a greater proportion of the rural population, compared to urban, reduced their use of butter on bread. Daily consumption of fresh vegetables increased most among highly educated Lithuanians. The data from our study indicate beneficial dietary changes among the Lithuanian adult population. In general, those with a higher level of education had healthier food habits than those with low education. The educational gradient in analyzed food habits, except the use of vegetable oil, enlarged. A higher proportion of the rural population, compared to urban, reduced their usage of butter on bread. However, consumption of high-fat milk was greatest in the rural population. Our data highlight the need for future food and nutrition policies, as well as health promotion programmes, targeting the whole population, particularly those with lower education and living in rural areas.


Comparison of gray-level detectability on computer monitors among several dental specialties: A web-based study.
Diagnosis in dentistry begins with the correct reading and interpreting of the dental radiograph. The aim of the present study was to examine the effects of the imaging technique used, the dentistry specialty and the years of experience on the gray-level perception among dentists. A custom web application was developed. Dentomaxillofacial radiologists (DentRads), endodontists (Ends) and general dental practitioners (GDPs) were invited via e-mail to participate in the study. A total of 46 participants met the requirements of the test. The test comprised 2 webpages. On the 1st page, the participants were asked for information such as gender, specialty, the years of experience, and the imaging techniques they used. Then, on the 2nd page, they were welcomed with instructions and directions, and asked to rearrange 85 gray color tones represented by square bars of equal dimensions. These mixed gray bars were placed in 4 rows according to the principles of the FarnsworthMunsell 100-hue test (FM). Each clinician's test results were recorded in a database. The individual's level of recognition of gray tones was evaluated through the total error score (TES), which was calculated using a web-based independent scoring software program. Lower TES values were a desirable result, indicating fewer misplacement, while higher scores indicated more misplacements of gray tones. The testing time (TT) was recorded automatically. The years of the participants' experience as dentists or specialists did not affect TES or TT. The dentists who used the charge-coupled device-complementary metal oxide semiconductor (CCD-CMOS) had lower TES values than those who used analog radiographs (p < 0.05). While the specialty and the years of experience did not affect the clinicians' ability to recognize gray tones, the digital imaging techniques (photostimulable phosphor (PSP) and CCD/CMOS) could improve the clinicians' gray-level perception.


Neuropathic pain in cancer.
Cancer-related neuropathic pain is common; it can be disease related or related to the acute or chronic effects of cancer treatment. For example, chemotherapy-induced peripheral neuropathy occurs in 90% of patients receiving neurotoxic chemotherapy. Cancer treatments have become more effective; patients are living longer with cancer and there are more cancer survivors. However, side-effects (particularly neuropathy) have become more problematic. The key to management of cancer-related neuropathy is a considered assessment, remembering not to miss the opportunity of reversing the cause of the pain with appropriate oncological management. An increasing range of oncological therapies are available, including radiotherapy, chemotherapy, hormonal therapy, or one of the evolving approaches (e.g. immune therapies). Patients are often elderly and with comorbidities; therefore, all treatment decisions have to be made carefully and reviewed appropriately. Cancer pain is often of mixed aetiology or, if purely neuropathic, may be one of several pains experienced by a patient. For these reasons, opioids are used more frequently in patients with cancer-related neuropathic pain. Standard guidelines for the use of anticonvulsants (e.g. pregabalin and gabapentin), antidepressants (e.g. duloxetine and tricyclics), and topical treatments (e.g. capsaicin and lidocaine) may be applicable, but there is a lack of good-quality clinical trials in cancer-related neuropathic pain. Choice is dictated not just by age, drug interactions, and comorbidities, but also by the coexistence of many symptoms in patients with cancer. Treating more than one symptom with a particular neuropathic pain agent can avoid polypharmacy.


The tyrosine phosphorylation substrate p36 is developmentally regulated in embryonic avian limb and is induced in cell culture.
The 36-kD protein-tyrosine kinase substrate p36 has been variously postulated to be involved in membrane-cytoskeletal interactions, membrane traffic, and the regulation of phospholipase A2, and its phosphorylation may play some role in malignant transformation by avian sarcoma viruses. Because embryonic tissues are resistant to transformation by avian sarcoma viruses, we have examined the expression of p36 in the developing avian embryonic limb. The level of p36 increased progressively from day 5 to day 14 of development. It was largely absent from day-5 mesenchyme, and was induced during the differentiation of mesenchymal cells into connective tissue and cartilage, but was not induced in differentiating muscle. In contrast, p36 was detected in ectodermal cells at all developmental stages examined. When day-5 limbs were dissociated and cultured, p36 was induced in all adherent cells, beginning at 2-4 h after plating, and reaching levels comparable to those observed with intact day-14 limb tissue within 48 h. The accumulation of p36 in culture was dependent on substratum adherence, suggesting that its stability is regulated by cell attachment or spreading. These findings are consistent with a structural or mechanical role for p36.


[Effect of lateral position and chest percussion on pulmonary gas exchange in patients with decreased level of consciousness].
The purpose of this study is to verify the effect of lateral position and chest percussion on gas exchange in the decreased level of conscious patients. The Subjects for this study were 21 patients 'admitted in ICU of CNUH from Dec 18th, 1989 to Aug 4th, 1990. The Data was analyzed by paired t-test. The results of this study as follows: 1) In comparison of supine position, good-lung dependent position and good-lung dependent with chest percussion, the difference of PaO. was statistically significant (P less than 0.05). 2) In comparison of supine position, good-lung dependent position and good-lung dependent with chest percussion, the difference of A-a Do. was statistically significant (p less than 0.05). In conclusion, the use of good-lung dependent position and chest percussion was effective nursing intervention on decreased level of conscious patients in ICU.


Prognostic Usefulness Of Advanced Lung Cancer Inflammation Index In Locally-Advanced Pancreatic Carcinoma Patients Treated With Radical Chemoradiotherapy.
Previously advanced lung cancer inflammation index (ALI) has been demonstrated to have prognostic utility in the stratification of patients into distinctive survival groups, but the prognostic value of ALI has never been explored in the setting of locally advanced pancreatic carcinomas (LAPC) treated with concurrent chemoradiotherapy (CCRT). Hence, we aimed to investigate the prognostic value of pre-treatment ALI in LAPC patients who underwent radical CCRT. Present retrospective cohort analysis incorporated 141 LAPC patients who received radical CCRT. Accessibility of baseline ALI cutoff(s) impacting survival outcomes was sought by receiver operating characteristic (ROC) curve analysis. Interaction between the ALI and overall- (OS) and progression-free survival (PFS) comprised our primary and secondary endpoints, respectively. At a median follow-up of 14.4 months (range: 3.2-74.2), the median PFS and OS were 7.5 (%95 CI: 5.9-9.1) and 14.6 months (%95 CI: 11.6-17.6), respectively. ROC curve analyses set the ideal ALI cutoff value at 25.3 (AUC: 75.6%; sensitivity: 72.7%; specificity: 70.3%) that exhibited significant associations with both the OS and PFS results. Patient stratification into two groups per ALI [≤25.3 (N=75) versus>25.3 (N=66)] showed that the ALI>25.3 group had significantly superior median OS (25.8 versus 11.4 months; P<0.001) and PFS (15.9 versus 6.0 months; P<0.001) durations than its ALI≤25.3 counterpart. Other factors exhibiting significantly better OS and PFS rates were N0 stage (versus N1; P<0.05 for each endpoint) and CA 19-9 ≤90 U/mL (versus >90 U/mL; P<0.05 for each endpoint), respectively. These three factors were additionally asserted to be independent indicators of longer OS (P<0.05 for each) and PFS (P<0.05 for each) in multivariate analyses. Results of this hypothesis-generating research proposed the pre-CCRT ALI as a novel robust associate of OS and PFS outcomes for LAPC patients undergoing CCRT.


Regulation of astrocytic glutamate transporter expression by Akt: evidence for a selective transcriptional effect on the GLT-1/EAAT2 subtype.
In the nervous system, astrocytes express different ratios of the two glial glutamate transporters, glutamate transporter subtype 1 (GLT-1) and glutamate/aspartate transporter (GLAST), but little is known about the signaling pathways that independently regulate their expression. Treatment with dibutyryl-cAMP, epidermal growth factor (EGF) or other growth factors both induces expression of GLT-1 and increases expression of GLAST in astrocyte cultures. The induction of GLT-1 is correlated with morphological and biochemical changes that are consistent with astrocyte maturation. Pharmacological studies suggest that phosphatidylinositol 3-kinase (PI-3K) and the nuclear transcription factor-kappaB (NF-kappaB) may be involved in the induction of GLT-1 expression. In several signaling systems Akt, also known as protein kinase B (PKB), functions downstream of PI-3K. In these present studies we used lentiviral vectors engineered to express dominant-negative (DN), constitutively active (CA), or null variants of Akt to study the possible involvement of Akt in the regulation of GLT-1. Expression of DN-Akt attenuated the EGF-dependent induction of GLT-1. Expression of CA-Akt caused a dose- and time-dependent increase in GLT-1 protein, increased GLT-1 mRNA levels, increased dihydrokainate-sensitive (presumably GLT-1 mediated) transport activity, and caused a change in astrocyte morphology to a more stellate shape, but had no effect on GLAST protein levels. Finally, the expression of CA-Akt increased the expression of a reporter construct containing a putative promoter fragment from the human homolog of GLT-1, called EAAT2. From these studies, we conclude that Akt induces the expression of GLT-1 through increased transcription and that Akt can regulate GLT-1 expression without increasing GLAST expression in astrocytes.


Early mobilisation versus plaster immobilisation of simple elbow dislocations: results of the FuncSiE multicentre randomised clinical trial.
To compare outcome of early mobilisation and plaster immobilisation in patients with a simple elbow dislocation. We hypothesised that early mobilisation would result in earlier functional recovery. From August 2009 to September 2012, 100 adult patients with a simple elbow dislocation were enrolled in this multicentre randomised controlled trial. Patients were randomised to early mobilisation (n=48) or 3 weeks plaster immobilisation (n=52). Primary outcome measure was the Quick Disabilities of the Arm, Shoulder, and Hand (Quick-DASH) score. Secondary outcomes were the Oxford Elbow Score, Mayo Elbow Performance Index, pain, range of motion, complications and activity resumption. Patients were followed for 1 year. Quick-DASH scores at 1 year were 4.0 (95% CI 0.9 to 7.1) points in the early mobilisation group versus 4.2 (95% CI 1.2 to 7.2) in the plaster immobilisation group. At 6 weeks, early mobilised patients reported less disability (Quick-DASH 12 (95% CI 9 to 15) points vs 19 (95% CI 16 to 22); p<0.05) and had a larger arc of flexion and extension (121° (95% CI 115° to 127°) vs 102° (95% CI 96° to 108°); p<0.05). Patients returned to work sooner after early mobilisation (10 vs 18 days; p=0.020). Complications occurred in 12 patients; this was unrelated to treatment. No recurrent dislocations occurred. Early active mobilisation is a safe and effective treatment for simple elbow dislocations. Patients recovered faster and returned to work earlier without increasing the complication rate. No evidence was found supporting treatment benefit at 1 year. NTR 2025.


Virulence and antifungal susceptibility of microsatellite genotypes of Candida albicans from superficial and deep locations.
A set of 185 strains of Candida albicans from patients with vulvovaginal candidiasis (VVC) and from non-VVC clinical sources in southwest China was analysed. Strains were subjected to genotyping using CAI microsatellite typing and amplification of an intron-containing region of the 25S rRNA gene. Microsatellite genotypes of strains from non-VVC sources showed high polymorphism, whereas those of VVC were dominated by few, closely similar genotypes. However, among non-VVC strains, two genotypes were particularly prevalent in patients with lung cancer. 25S rDNA genotype A was dominant in VVC sources (86.7%), whereas genotypes A, B, and C were rather evenly distributed among non-VVC sources; known genotypes D and E were not found. In an experimental mouse model, isolates from lung cancer and AIDS patients proved to have higher virulence than VVC strains. Among 156 mice infected with C. albicans, 19 developed non-invasive urothelial carcinoma. No correlation could be established between parameters of virulence, source of infection, and incidence of carcinoma. C. albicans strains from VVC were less susceptible to itraconazole than the strains from non-VVC sources, whereas there was small difference in antifungal susceptibility between different 25S rDNA genotypes of C. albicans tested against amphotericin B, itraconazole, fluconazole, and flucytosine.


How to choose when implants of adjacent height both fit the disc space properly in single-level cervical artificial disc replacement.
In cervical artificial disc replacement (C-ADR), sometimes we encountered with such cases that implants of adjacent height both fit the target disc space properly. No study was available discussing the choice of implant height and the clinical outcomes under such circumstance. The purpose of this study was to evaluate the impact of different implant heights on the clinical outcomes and radiographic results when the implants of adjacent height both fit the disc space properly. This retrospective study included 34 patients underwent single-level C-ADR at the C5-C6 level at our institution. In these 34 patients, implant with either 5 mm height or 6 mm height fit the surgical level properly without overstretching the disc space or the facet joint space. Clinical outcomes were evaluated using the Japanese Orthopedic Association score, visual analog scale (VAS), and Neck Disability Index. Radiographic assessments were conducted on static and dynamic radiographs for the determination of the disc space height, intersegmental range of motion (ROM), and the ROM of the functional spinal unit (FSU) at the surgical level. The baseline information of the patients, such as age, gender, weight, follow-up time, and diagnosis, was similar between the 2 groups (P > .05). Postoperative mean VAS in group B was significantly lower than that in group A (2.1 ± 0.7 vs. 2.7 ± 1.0, P < .05). The mean VAS decrease in group B was significantly larger than that in group A (5.3 ± 0.8 vs. 4.6 ± 1.1, P < .05). Significant difference was found in the postoperative disc height of the surgical segment between the 2 groups (6.4 ± 0.4 mm vs. 7.5 ± 0.5 mm, P < .05). No significant differences were noted in the intersegmental ROM and ROM of the FSU between the 2 groups both before the surgery and at the last follow-up (P > .05). No hypermobility or instability was observed in these patients. Our results suggested that when implants of adjacent height both fit the disc space properly, using the larger implant could result in better pain relief without the risk of segmental hypermobility in patients underwent single-level C-ADR at the C5-C6 level.


Local and systemic induction of CD4+CD25+ regulatory T-cell population by non-Hodgkin lymphoma.
Regulatory T (Treg) cells contribute to immune evasion by malignancies. To investigate their importance in non-Hodgkin lymphoma (NHL), we enumerated Treg cells in peripheral blood mononuclear cells (PBMCs) and involved tissues from 30 patients. CD25(+)FoxP3(+)CD127(low)CD4(+) Treg cells were increased markedly in PBMCs (median = 20.4% CD4 T cells, n = 20) versus healthy controls (median = 3.2%, n = 13, P < .001) regardless of lymphoma subtype, and correlated with disease stage and serum lactate dehydrogenase (R(s) = 0.79, P < .001). T-cell hyporesponsiveness was reversed by depleting CD25(+) cells, or by adding anti-CTLA-4, supporting the view that Treg cells explain the systemic immunosuppression seen in NHL. A high proportion of Treg cells was also present in involved tissues (median = 38.8% CD4 T cells, n = 15) versus reactive nodes (median = 11.6%, n = 2, P = .02). When autologous CD25(-) PBMC fractions were incubated with tumor cells from patients (n = 6) in vitro, there was consistent strong induction and then expansion of cells with the CD4(+)CD25(+)FoxP3(+) phenotype of classic "natural" Treg cells. This population was confirmed to be suppressive in function. Direct cell-cell interaction of tumor cells with CD25(-) PBMCs was important in Treg induction, although there was heterogeneity in the mechanisms responsible. We conclude that NHL cells are powerful inducers of Treg cells, which may represent a new therapeutic target.


Brain computerized tomography reading in suspected acute ischemic stroke patients: what are essentials for medical students?
Few systematic methods prioritize the image education in medical students (MS). We hope to develop a checklist of brain computerized tomography (CT) reading in patients with suspected acute ischemic stroke (AIS) for MS and primary care (PC) physicians. Our pilot group generated the items indicating specific structures or signs for the checklist of brain CT reading in suspected AIS patients for MS and PC physicians. These items were used in a modified web-based Delphi process using the online software "SurveyMonkey". In total 15 panelists including neurologists, neurosurgeons, neuroradiologists, and emergency department physicians participated in the modified Delphi process. Each panelist was encouraged to express feedback, agreement or disagreement on the inclusion of each item using a 9-point Likert scale. Items with median scores of 7-9 were included in our final checklist. Fifty-two items were initially provided for the first round of the Delphi process. Of these, 35 achieved general agreement of being an essential item for the MS and PC physicians. The other 17 of the 52 items in this round and another two added items suggested by the panelists were further rated in the next round. Finally, 38 items were included in the essential checklist items of brain CT reading in suspected AIS patients for MS and PC physicians. We established a reference regarding the essential items of brain CT reading in suspected AIS patients. We hope this helps to minimize malpractice and a delayed diagnosis, and to improve competency-based medical education for MS and PC physicians.


Studies on the mechanisms responsible for inhibition of experimental metastasis of B16-F10 murine melanoma by pentoxifylline.
Pentoxifylline (PTX), a methylxanthine derivative widely used as a hemorheological agent in the treatment of peripheral vascular disease, was studied to unveil the mechanisms responsible for its inhibitory action on B16-F10 experimental metastasis. In vitro pretreatment of B16-F10 cells with noncytotoxic concentrations of PTX significantly inhibited their adhesion to reconstituted basement membrane Matrigel(R) and type IV collagen as well as the relative activity of secreted 92 kD metalloproteinase. However, PTX pretreatment of B16-F10 cells did not affect their in vitro invasiveness. Heterotypic organ adhesion assays carried out with B16-F10 cells and suspended organ tissues demonstrated that pretreatment with noncytotoxic concentrations of PTX of both, tumor cells or lung tissue, brought about a dose-dependent inhibition of melanoma cell adhesion to lung. Immunohistochemical studies using antibodies against CD31 adhesion molecule (PECAM-1) revealed that B16-F10 cells adhere to lung endothelial cells. Our results suggest that PTX may exert its inhibitory effect on tumor lodgment, and as a consequence of that on experimental metastases, through an inhibitory action on cell adhesion molecules.


Stridor in an 11-year-old child.
Stridor in older children can be due to diverse aetiology that includes infections, anaphylaxis and rarely systemic conditions leading to hypocalcaemia. We report the case of a previously asymptomatic 11-year-old girl who presented to the casualty with stridor due to hypocalcaemia. The aetiological investigations for hypocalcaemia uncovered previously undetected chronic renal failure, possibly due to a rare autosomal recessive condition called nephronophthisis. We report this case to highlight the importance of widening the diagnostic focus for children presenting with stridor, especially when they fall outside the usual age group for infections like croup, or when the history is atypical.


[Genetic variants of Mycobacterium tuberculosis isolated from patients of the Xth Region of Chile].
The emergence of new virulent and drug resistant strains of Mycobacterium tuberculosis has forced researchers to focus on the worldwide geographical distribution of the genetics variants of this pathogen. Mycobacterium bovis, a close related pathogen, contributes with human tuberculosis and therefore, it is particularly important in countries with significant bovine tuberculosis prevalence. Spoligotyping is currently one of the most widely used strategies for genotyping members of the M. tuberculosis complex. In this work, of a total of 41 isolates, 25 were from different patients from the Xth Region from Chile. These isolates formed 15 clusters of spoligotypes. Twenty four percent of the spoligotypes corresponded to the worldwide distributed spoligotype 53 (SpolDB4). A significant number of spoligotypes were identical to profiles found in Brazil followed by Argentina and Spain. Although the patients where from rural areas, no cases of zoonosis were observed. To establish the geographical distribution, persistence and routes of dissemination of the pathogen, a greater number of epidemiologically relevant isolates are being analyzed using the MIRUs-VNTRs.


Atypical speech versus non-speech detection and discrimination in 4- to 6- yr old children with autism spectrum disorder: An ERP study.
Previous event-related potential (ERP) research utilizing oddball stimulus paradigms suggests diminished processing of speech versus non-speech sounds in children with an Autism Spectrum Disorder (ASD). However, brain mechanisms underlying these speech processing abnormalities, and to what extent they are related to poor language abilities in this population remain unknown. In the current study, we utilized a novel paired repetition paradigm in order to investigate ERP responses associated with the detection and discrimination of speech and non-speech sounds in 4- to 6-year old children with ASD, compared with gender and verbal age matched controls. ERPs were recorded while children passively listened to pairs of stimuli that were either both speech sounds, both non-speech sounds, speech followed by non-speech, or non-speech followed by speech. Control participants exhibited N330 match/mismatch responses measured from temporal electrodes, reflecting speech versus non-speech detection, bilaterally, whereas children with ASD exhibited this effect only over temporal electrodes in the left hemisphere. Furthermore, while the control groups exhibited match/mismatch effects at approximately 600 ms (central N600, temporal P600) when a non-speech sound was followed by a speech sound, these effects were absent in the ASD group. These findings suggest that children with ASD fail to activate right hemisphere mechanisms, likely associated with social or emotional aspects of speech detection, when distinguishing non-speech from speech stimuli. Together, these results demonstrate the presence of atypical speech versus non-speech processing in children with ASD when compared with typically developing children matched on verbal age.


A dietary study of the elderly in the City of Roskilde 1988/89. Methodological aspects of the relative validity of the dietary history method.
In winter 1988/89, 194 elderly adults (96 men and 98 women, aged 70-75 years) were interviewed, using the dietary history method. The relative validity of a dietary history method used in this elderly population was assessed. The record of intake of energy and nutrients from the dietary history method was compared with that obtained in the same group by means of a 3-day food record completed during the same period. For daily intake of energy and nutrients, the differences in mean intake were generally below 15%. But mean differences were significant for energy, fat, dietary fiber, and calcium. The two dietary methods correlated well for energy and nutrients. Pearson's correlation coefficient varied from 0.80 (dietary fiber) to 0.24 (vitamin A). The two methods classified about half of the subjects similarly into tertiles for energy and most nutrients. Gross misclassification occurred for 2-17% of the subject. Agreement between the two methods were poorest for vitamin A. The results suggest that the dietary history method may be inadequate for determining the exact level of mean and distribution of dietary intake in a group or the precise intake of an individual. But the method could be used to test differences in means between groups and to rank subjects as to their dietary intake within the study.


Effects of an electric field and zero valent iron on anaerobic treatment of azo dye wastewater and microbial community structures.
A zero valent iron (ZVI) bed with a pair of electrodes was packed in an anaerobic reactor aiming at enhancing treatment of azo dye wastewater. The experiments were carried out in three reactors operated in parallel: an electric field enhanced ZVI-anaerobic reactor (R1), a ZVI-anaerobic reactor (R2) and a common anaerobic reactor (R3). R1 presented the highest performance in removal of COD and color. Raising voltage in R1 further improved its performance. Scanning electron microscopy images displayed that the structure of granular sludge from R1 was intact after being fed with the high dye concentration, while that of R3 was broken. Fluorescence in situ hybridization analysis indicated that the abundance of methanogens in R1 was significantly greater than that in the other two reactors. Denaturing gradient gel electrophoresis showed that the coupling of electric field and ZVI increased the diversity of microbial community and especially enhanced bacterial strains responsible for decolorization.


Variability of measurements of sweat sodium using the regional absorbent-patch method.
There is interest in including recommendations for the replacement of the sodium lost in sweat in individualized hydration plans for athletes. Although the regional absorbent-patch method provides a practical approach to measuring sweat sodium losses in field conditions, there is a need to understand the variability of estimates associated with this technique. Sweat samples were collected from the forearms, chest, scapula, and thigh of 12 cyclists during 2 standardized cycling time trials in the heat and 2 in temperate conditions. Single measure analysis of sodium concentration was conducted immediately by ion-selective electrodes (ISE). A subset of 30 samples was frozen for reanalysis of sodium concentration using ISE, flame photometry (FP), and conductivity (SC). Sweat samples collected in hot conditions produced higher sweat sodium concentrations than those from the temperate environment (P = .0032). A significant difference (P = .0048) in estimates of sweat sodium concentration was evident when calculated from the forearm average (mean ± 95% CL; 64 ± 12 mmol/L) compared with using a 4-site equation (70 ± 12 mmol/L). There was a high correlation between the values produced using different analytical techniques (r2 = .95), but mean values were different between treatments (frozen FP, frozen SC > immediate ISE > frozen ISE; P < .0001). Whole-body sweat sodium concentration estimates differed depending on the number of sites included in the calculation. Environmental testing conditions should be considered in the interpretation of results. The impact of sample freezing and subsequent analytical technique was small but statistically significant. Nevertheless, when undertaken using a standardized protocol, the regional absorbent-patch method appears to be a relatively robust field test.


Dietary supplementation with rumen-protected capsicum during the transition period improves the metabolic status of dairy cows.
In ruminants, it has been observed that capsicum oleoresin can alter insulin responses and that high-intensity artificial sweetener can increase glucose absorption from the small intestine. Because glucose metabolism and insulin responses are critical during early lactation, these supplements might have an effect on the metabolic status of dairy cows during the transition period. The objective of this experiment was to evaluate the effects of rumen-protected capsicum oleoresin fed alone or in combination with artificial sweetener during the transition period on lactational performance and susceptibility to subclinical ketosis in dairy cows. Fifteen primiparous and 30 multiparous Holstein cows (a total of 39 cows finished the study) were arranged in a randomized complete block design during d -21 to 60 relative to parturition. Cows within block were randomly assigned to one of the following treatments: no supplement (CON), supplementation with 100 mg of rumen-protected capsicum/cow per day (RPCap), or RPCap plus 2 g of high-intensity artificial sweetener/cow per day (RPCapS). For both the RPCap and RPCapS treatments, only rumen-protected capsicum was fed during the dry period. From d 8 to 11 of lactation, intake was limited to 70% of predicted dry matter intake to induce subclinical ketosis. Production variables were recorded daily, samples for milk composition were collected on wk 2, 4, 6, and 8, and blood samples were collected on wk -2, 1, 2, and 4 of the experiment for analysis of metabolic hormones and blood cell counts. Supplementation with rumen-protected capsicum increased serum insulin and decreased β-hydroxybutyrate concentrations precalving, indicating a decrease in lipolysis. During the lactation period, RPCap was associated with a trend for increased milk production and feed efficiency following the ketosis challenge. Supplementation with RPCapS appeared to negate the response to rumen-protected capsicum. All cows developed subclinical ketosis during the challenge, and this was not affected by treatment. We conclude that treatments did not decrease susceptibility to subclinical ketosis; however, dietary supplementation with rumen-protected capsicum was effective at improving energy status precalving and tended to increased milk production and feed efficiency. The mechanism underlying these responses is unclear.


Recall phenomenon or severe skin and muscle necrosis following Adriamycin extravasation in the hand.
A 56-year-old male, following pneumonectomy for oat cell carcinoma, was receiving Adriamycin intravenously. Early in his treatment schedule, the intravenous Adriamycin was alleged to have infiltrated, and was promptly stopped. However, treatment was continued through the veins of the other arm at three week intervals. The patient developed an extensive slough of the dorsum of the hand and forearm, including the extensor tendons and muscle, over a seven week period from the initial extravasation. Numerous debridements and skin grafting procedures were required to salvage the hand. It is suggested that the continued Adriamycin treatments had an additive effect in the already devitalized tissue, resulting in recall phenomenon, which further aggravated and enhanced the extent of necrosis. Ameliorative efforts to treat the extravasation in experimental and clinical settings have been ineffective. Care in the intravenous drug administration and dilution of Adriamycin are the best means of preventing the sequela of Adriamycin extravasation.


Histidine uptake in strains of Neurospora crassa with normal and mutant transport systems.
Kinetic parameters for three systems of active histidine uptake by germinated conidia of Neurospora crassa have been measured. Each system appears to follow typical Michaelis-Menten kinetics when studied separately from the other systems. Under the conditions studied, the general amino acid transport system was found to account for the major portion of histidine uptake from low concentrations. Three types of transport mutants with altered growth inhibition patterns were selected in a histidine auxotroph. Growth of one mutant, type bas(a), could be inhibited by the addition of methionine to a histidine-supplemented medium, and another type, neu(a), could be inhibited by the addition of arginine. These mutants were shown to be lacking active histidine uptake by the basic amino acid and neutral amino acid transport systems, respectively. Another type of double mutant (his-3, neu(r)) could be inhibited only by the addition of very high concentrations of methionine in the presence of arginine and histidine, and the mutation appeared to have altered the specificity of the neutral amino acid permease.


Gating of the vertex somatosensory and auditory evoked potential P50 and the correlation to skin conductance orienting response in healthy men.
A defect in auditory evoked potential (AEP) P50 gating supports the theory of information-processing deficits in schizophrenia. The relationship between gating of the mid-latency evoked potentials (EP) in the somatosensory and the auditory modalities has not been studied together before. In schizophrenia, we might expect the processing deficits to act on multiple modalities. We have examined the gating of median nerve somatosensory EP (SEP) following paired stimulation identical to the AEP P50 gating paradigm using interstimulus intervals (ISI) of 500, 750 and 1000 ms and the correlation of gating to the skin conductance orienting response (SCOR) in 20 healthy men. We measured mid-latency vertex components (SEP: P50, N65, P85 and N100; AEP: P30, N45, P50 and N80). The gating was most pronounced at ISI 500 ms where the SEP P50 and N100 gating were 0.59 and 0.37, respectively, as compared to a gating of 0.61 in P30, 0.33 in P50 and 0.45 in N80 in the AEP. Repetition effects in the two modalities were not correlated. AEP P50 gating was correlated to skin conductance level (SCL). The combination of recording repetition effects on the mid-latency EP in two modalities could provide a method for investigating if deficits of information processing in schizophrenia are cross-modal.


Activation of calcium-permeable cation channel by insulin in Chinese hamster ovary cells expressing human insulin receptors.
The present study was conducted to examine the ability of insulin receptor to activate the calcium signaling system in Chinese hamster ovary (CHO) cells expressing human insulin receptor (CHO-IR cells). In these cells, insulin evoked the elevation of cytoplasmic free calcium concentration, [Ca2+]c, measured by using fura-2. Insulin-induced increase in [Ca2+]c was blocked by reducing the extracellular calcium concentration to 1 microM or by adding nickel chloride, an inorganic inhibitor of calcium entry. Insulin did not elevate [Ca2+]c in parental CHO cells or in CHO cells expressing mutant insulin receptor lacking an ATP-binding site. When the transmembrane calcium current was measured by perforated whole-cell patch clamp, adding insulin to the bath solution markedly augmented the inward calcium current. In a cell-attached patch, a single channel activity appeared when insulin was included in the pipette. In contrast, insulin added outside the patch was ineffective. The current/voltage relationship demonstrated that insulin activated a voltage-independent calcium-permeable cation channel with a single-channel conductance of 10 pS. Exposing CHO-IR cells to pertussis toxin abolished the subsequent insulin effect on [Ca2+]c and activation of the calcium-permeable channel. Mastoparan activated the 10-pS calcium-permeable cation channel. In an inside-out patch, insulin activated the calcium-permeable channel when the bath solution contained both GTP and ATP. Nonhydrolyzable ATP could substitute for ATP. These results indicate that in CHO-IR cells, insulin elevates [Ca2+]c by activating the 10-pS calcium-permeable cation channel. Activation by the insulin receptor involves pertussis toxin-sensitive G protein.


Coronavirus disease 2019 (COVID-19) research agenda for healthcare epidemiology.
This SHEA white paper identifies knowledge gaps and challenges in healthcare epidemiology research related to coronavirus disease 2019 (COVID-19) with a focus on core principles of healthcare epidemiology. These gaps, revealed during the worst phases of the COVID-19 pandemic, are described in 10 sections: epidemiology, outbreak investigation, surveillance, isolation precaution practices, personal protective equipment (PPE), environmental contamination and disinfection, drug and supply shortages, antimicrobial stewardship, healthcare personnel (HCP) occupational safety, and return to work policies. Each section highlights three critical healthcare epidemiology research questions with detailed description provided in supplementary materials. This research agenda calls for translational studies from laboratory-based basic science research to well-designed, large-scale studies and health outcomes research. Research gaps and challenges related to nursing homes and social disparities are included. Collaborations across various disciplines, expertise and across diverse geographic locations will be critical.


The hepatitis C virus NS4A protein: interactions with the NS4B and NS5A proteins.
Hepatitis C virus encodes a large polyprotein precursor that is proteolytically processed into at least 10 distinct products, in the order NH2-C-E1-E2-p7-NS2-NS3-NS4A-NS4B-NS5A-NS5B -COOH. A serine proteinase encoded in the N-terminal 181 residues of the NS3 nonstructural protein is responsible for cleavage at four sites (3/4A, 4A/4B, 4B/5A, and 5A/5B) in the nonstructural region. NS4A, a 54-residue nonstructural protein which forms a stable complex with the NS3 proteinase, is required as a cofactor for cleavage at the 3/4A and 4B/5A sites and enhances processing at the 4A/4B and 5A/5B sites. Recently reported crystal structures demonstrated that NS4A forms an integral part of the NS3 serine proteinase. In this report, we present evidence that NS4A forms a nonionic-detergent-stable complex with the NS4B5A polyprotein substrate, which may explain the requirement of NS4A for the 4B/5A cleavage. Isoleucine-29 of NS4A, which has been previously shown to be essential for its proteinase cofactor activity and formation of the NS3 complex, was found to be important for the interaction between NS4A and the NS4B5A substrate. In addition, two more hydrophobic residues in the NS4A central region (valine-23 and isoleucine-25) were also shown to be essential for the cofactor activity and for the interaction with either the NS3 proteinase or the NS4B5A polyprotein substrate. Finally, the possible mechanisms by which these viral proteins interact with each other are discussed.


Concomitant PIK3CD and TNFRSF9 deficiencies cause chronic active Epstein-Barr virus infection of T cells.
Infection of T cells by Epstein-Barr virus (EBV) causes chronic active EBV infection (CAEBV) characterized by T cell lymphoproliferative disorders (T-LPD) of unclear etiology. Here, we identified two homozygous biallelic loss-of-function mutations in PIK3CD and TNFRSF9 in a patient who developed a fatal CAEBV. The mutation in TNFRSF9 gene coding CD137/4-1BB, a costimulatory molecule expressed by antigen-specific activated T cells, resulted in a complete loss of CD137 expression and impaired T cell expansion toward CD137 ligand-expressing cells. Isolated as observed in one sibling, CD137 deficiency resulted in persistent EBV-infected T cells but without clinical manifestations. The mutation in PIK3CD gene that encodes the catalytic subunit p110δ of the PI3K significantly reduced its kinase activity. Deficient T cells for PIK3CD exhibited reduced AKT signaling, while calcium flux, RAS-MAPK activation, and proliferation were increased, suggestive of an imbalance between the PLCγ1 and PI3K pathways. These skewed signals in T cells may sustain accumulation of EBV-infected T cells, a process controlled by the CD137-CD137L pathway, highlighting its critical role in immunity to EBV.


Tyrosines-740/751 of PDGFRβ contribute to the activation of Akt/Hif1α/TGFβ nexus to drive high glucose-induced glomerular mesangial cell hypertrophy.
Glomerular mesangial cell hypertrophy contributes to the complications of diabetic nephropathy. The mechanism by which high glucose induces mesangial cell hypertrophy is poorly understood. Here we explored the role of the platelet-derived growth factor receptor-β (PDGFRβ) tyrosine kinase in driving the high glucose-induced mesangial cell hypertrophy. We show that high glucose stimulates the association of the PDGFRβ with PI 3 kinase leading to tyrosine phosphorylation of the latter. High glucose-induced Akt kinase activation was also dependent upon PDGFRβ and its tyrosine phosphorylation at 740/751 residues. Inhibition of PDGFRβ activity, its downregulation and expression of its phospho-deficient (Y740/751F) mutant inhibited mesangial cell hypertrophy by high glucose. Interestingly, expression of constitutively active Akt reversed this inhibition, indicating a role of Akt kinase downstream of PDGFRβ phosphorylation in this process. The transcription factor Hif1α is a target of Akt kinase. siRNAs against Hif1α inhibited the high glucose-induced mesangial cell hypertrophy. In contrast, increased expression of Hif1α induced hypertrophy similar to high glucose. We found that inhibition of PDGFRβ and expression of PDGFRβ Y740/751F mutant significantly inhibited the high glucose-induced expression of Hif1α. Importantly, expression of Hif1α countered the inhibition of mesangial cell hypertrophy induced by siPDGFRβ or PDGFRβ Y740/751F mutant. Finally, we show that high glucose-stimulated PDGFRβ tyrosine phosphorylation at 740/751 residues and the tyrosine kinase activity of the receptor regulate the transforming growth factor-β (TGFβ) expression by Hif1α. Thus we define the cell surface PDGFRβ as a major link between high glucose and its effectors Hif1α and TGFβ for induction of diabetic mesangial cell hypertrophy.