[Factors predicting metallo-beta-lactamase-producing Acinetobacter baumannii in Iwate Medical University Hospital].
We conducted a decision tree analysis in which 6 isolates of metallo-beta-lactamase (MBL) -producing Acinetobacter baumannii detected by a sodium mercaptoacetic acid disk method and 38 isolates of MBL nonproducing A. baumannii were investigated from January 2003 to December 2003 in Iwate Medical University Hospital. Factors predicting MBL-producing A. baumannii were analyzed from the clinical backgrounds such as laboratory data, therapeutic histories and bacterial circumstances. In the decision tree analysis, seven significant rules were found for predicting MBL-producing A. baumannii; previous isolation of P. aeruginosa, administration period of 3rd generation cephem antibiotics > 11 days, both TP < or = 6.9 g/dl and Hb < or = 6.3 g/dl, both administration of anticancer drugs and a use of respirator, TP > 6.9 g/dl, CRP > 22.7 mg/dl, both CRP 8.7 mg/dl and body temperature > 36.6 degrees C. Two cases, which were matched with the rule of TP > 6.9 g/dl, were hospitalized in the same division, and their pulsed-field gel electrophoresis patterns were identical. In comparison with conventional statistical analysis, the decision tree analysis has advantages in explaining the tendencies and the relationships of the data. It is possible that, based on the rules extracted in this study, we could issue precautions in preventing nosocomial MBL-producing strains even in the earlier stages when the number of these isolates are still small.


The glucose/fatty acid cycle and physical exhaustion.
The energy required for sustained exercise is provided by the oxidation of two fuels, glucose and long-chain fatty acids, which are stored as liver and muscle glycogen and adipose tissue triglyceride. The latter provides the largest energy reserve in the body; there is sufficient energy for about five days of continuous marathon running. Glycogen reserves, in contrast, are very limited and, at most, could provide energy for 100 minutes. Evidence is presented of a metabolic limit in the rate of fatty acid utilization, so that sustained exercise at a high power output requires the utilization of both fat and carbohydrate simultaneously. There is a regulatory mechanism by which fatty acid oxidation reduces carbohydrate utilization in muscle--the glucose/fatty acid cycle. This plays an important part in ensuring that marathon runners can continue beyond the theoretical limit of 100 minutes. Triglyceride is mobilized from adipose tissue as long-chain fatty acids and the oxidation of these by muscle reduces the rate of glucose utilization. The availability of fatty acids for oxidation as early as possible in exercise will allow the use of both fuels (fatty acids and glucose) for a longer period of time. Since it appears that fatigue occurs when carbohydrate reserves are depleted, reduction in the rate of glucose utilization by the oxidation of fatty acids is obviously beneficial. The ability of ultra-distance runners to exceed these limits poses interesting metabolic questions relating to exhaustion.


A nuclear lncRNA Linc00839 as a Myc target to promote breast cancer chemoresistance via PI3K/AKT signaling pathway.
Chemoresistance has become a leading cause of mortality in breast cancer patients and is one of the major obstacles for improving the clinical outcome. Long noncoding RNAs play important roles in breast cancer tumorigenesis and chemoresistance. However, the involvement and regulation of lncRNAs in breast cancer chemoresistance are not completely understood. Here, we reported that Linc00839 was localized in the nucleus and upregulated in chemoresistant breast cancer cells and tissues, and high level of Linc00839 was associated with a poor prognosis. Knockdown of Linc00839 significantly suppressed proliferation, invasion, and migration, sensitized cells to paclitaxel in vitro and inhibited transplant tumor development in vivo. Mechanistically, we found that Myc could directly bind to the promoter region of Linc00839 and activate its transcription. Furthermore, Linc00839 overexpression increased the expression of Myc and the RNA-binding protein Lin28B and activated the PI3K/AKT signaling pathway. We also discovered that Lin28B positively interacted with Linc00839 and was upregulated in breast cancer tissues. Taken together, for the first time, we showed that Linc00839 was activated by Myc and promoted proliferation and chemoresistance in breast cancer through binding with Lin28B. These findings provide new insight into the regulatory mechanism of Linc00839 and propose a Myc/Linc00839/Lin28B feedback loop that could be used as a novel therapeutic target for breast cancer.


A Quantitative Analysis of Electrochemical CO2 Reduction on Copper in Organic Amide and Nitrile-Based Electrolytes.
Aqueous electrolytes used in CO2 electroreduction typically have a CO2 solubility of around 34 mM under ambient conditions, contributing to mass transfer limitations in the system. Non-aqueous electrolytes exhibit higher CO2 solubility (by 5-8-fold) and also provide possibilities to suppress the undesired hydrogen evolution reaction (HER). On the other hand, a proton donor is needed to produce many of the products commonly obtained with aqueous electrolytes. This work investigates the electrochemical CO2 reduction performance of copper in non-aqueous electrolytes based on dimethylformamide (DMF), n-methyl-2-pyrrolidone (NMP), and acetonitrile (ACN). The main objective is to analyze whether non-aqueous electrolytes are a viable alternative to aqueous electrolytes for hydrocarbon production. Additionally, the effects of aqueous/non-aqueous anolytes, membrane, and the selection of a potential window on the electrochemical CO2 reduction performance are addressed in this study. Experiments with pure DMF and NMP mainly produced oxalate with a faradaic efficiency (FE) reaching >80%; however, pure ACN mainly produced hydrogen and formate due to the presence of more residual water in the system. Addition of 5% (v/v) water to the non-aqueous electrolytes resulted in increased HER and formate production with negligible hydrocarbon production. Hence, we conclude that aqueous electrolytes remain a better choice for the production of hydrocarbons and alcohols on a copper electrode, while organic electrolytes based on DMF and NMP can be used to obtain a high selectivity toward oxalate and formate.


Tuning Gold Nanoparticles with Chelating Ligands for Highly Efficient Electrocatalytic CO2 Reduction.
Capped chelating organic molecules are presented as a design principle for tuning heterogeneous nanoparticles for electrochemical catalysis. Gold nanoparticles (AuNPs) functionalized with a chelating tetradentate porphyrin ligand show a 110-fold enhancement compared to the oleylamine-coated AuNP in current density for electrochemical reduction of CO2 to CO in water at an overpotential of 340 mV with Faradaic efficiencies (FEs) of 93 %. These catalysts also show excellent stability without deactivation (<5 % productivity loss) within 72 hours of electrolysis. DFT calculation results further confirm the chelation effect in stabilizing molecule/NP interface and tailoring catalytic activity. This general approach is thus anticipated to be complementary to current NP catalyst design approaches.


Proximity-induced pseudogap: evidence for preformed pairs.
The temperature evolution of the proximity effect in Au/La(2-x)Sr(x)CuO(4) and La(1.55)Sr(0.45)CuO(4)/La(2-x)Sr(x)CuO(4) bilayers was investigated using scanning tunneling microscopy. Proximity-induced gaps, centered at the chemical potential, were found to persist above the superconducting transition temperature, T(c), and up to nearly the pseudogap crossover temperature in both systems. Such independence of the spectra on the details of the normal-metal cap layer is incompatible with a density-wave order origin. However, our results can be accounted for by a penetration of incoherent Cooper pairs into the normal metal above T(c).


Omeprazole for severe reflux esophagitis in children.
Severe esophagitis is a rare complication of gastroesophageal reflux in children. In adults, omeprazole therapy of severe erosive esophagitis has become the gold standard short-term treatment of the disease. In children, data on its use are limited, and problems about the dosage are unresolved. The aim of this study was to evaluate the efficacy of a simplified, body-weight-based daily dosage of omeprazole in children with severe esophagitis. Ten children (median age 75.6 months; range 25-109 months) with severe esophagitis were prospectively investigated. All patients were evaluated by endoscopy, histology, and 24-h pH-metry study before and after 3 months of omeprazole. The starting dose of omeprazole was 20 mg as a single daily dose in children weighing less than 30 kg, and 40 mg daily for those weighing over 30 kg. A significant improvement in all the children was demonstrated after 3 months of treatment by clinical, endoscopic, and pH-metry assessment. However, histologic study failed to show significant improvement of both inflammatory and hyperplastic findings. Relapse occurred in six of 10 patients after discontinuation of therapy. Omeprazole is effective in the short-term treatment of severe oesophagitis in children. The daily dose of the drug could be easily based on the body weight. The persistence of histologic features of esophagitis in spite of clinical and endoscopic healing could be an indicator of poor outcome.


Prospective survey of use of therapeutic drugs, alcohol, and cigarettes during pregnancy.
Use of drugs during pregnancy was recorded prospectively in 2765 women attending the antenatal clinics of a general hospital from October 1982 to March 1984. Of these women, 2588 (93.6%) avoided exposure to drugs during the first trimester, 1802 (65.2%) took no drugs at any stage, 963 (34.8%) took a total of 154 different drugs from 35 groups of drugs, and 243 (8.8%) took a self administered drug. The most commonly used drugs were non-narcotic analgesics, usually self administered, and antibacterials. The last survey of use of drugs in pregnancy in the United Kingdom 20 years ago showed fewer women avoiding drugs throughout pregnancy (195 of 911 (21.4%), p less than 0.001) and in taking a self administered drug (586 (64.4%), p less than 0.001) than at present. Most women nowadays abstain totally from alcohol (1786 (64.6%) v 109 (12.0%) previously, p less than 0.001), but while more women are non-smokers compared with previously (1811 (65.5%) v 392 (43%), p less than 0.001) the trend has been far less dramatic than that for use of alcohol.


Performance of crosses among Hereford, Angus and Simmental cattle with different levels of Simmental breeding. II. Effect of calf breed on cow productivity.
Hereford cows were randomly bred to Hereford, Angus, Simmental X Hereford and Simmental sires. Each sire breed group was represented by nine or 10 sires. These matings produced approximately 100 calves in each sire breed group over 4 yr. The objective of this study was to determine the effect of calf breed on characteristics of the cow such as milk production, reproduction, measures of condition, weight and changes in condition and weight during lactation. All of the cows were contemporary Herefords that were raised and managed under similar environmental conditions. Hence, any detection of an important effect of calf breed on cow productivity should be a reflection of different levels of maternal requirement imposed on the cow by the different calf breed groups. Cows that raised crossbred calves gained less weight from precalving to weaning, had lower condition scores at weaning, had smaller gains in weight change per unit of height and experienced a lower pregnancy rate. All results consistently showed that crossbred calves challenged the maternal ability of their dams to a greater degree than the straightbred calves and that among the crossbred calves, those by Simmental sires challenged their dams the most. It appeared that calf breed group effects on cow traits were at least partially mediated through calf growth rate, but not through parturition stress. Therefore, benefits realized from crossbreeding need to be weighted against possible unfavorable results.


Synthesis of core/shell nanoparticles of Au/CdSe via Au-Cd bialloy precursor.
We present a novel method for the preparation of ultrasmall Au/CdSe core/shell particles. Au-Cd bialloy particles of 4.7 nm diameter were prepared as the precursor. The Cd component in the precursor reacted with the Se source at a temperature of 205 degrees C and was heated to 250 degrees C, leading to formation of a Au/CdSe core/shell structure. The sizes of Au/CdSe nanoparticles have a narrow distribution with an average size of 6.0 nm and Au core of 2.2 nm diameter. The X-ray diffraction pattern and the images of the high-resolution electron transmission microscopy show that the Au cores and the CdSe shells of Au/CdSe core/shell nanoparticles are both well crystallized, and the CdSe shells are in a cubic phase. The absorption spectrum of the Au/CdSe nanoparticles combines the absorption behaviors of the Au cores and the CdSe shells.


Development of a novel reciprocating cryogenic tribometer through deformations of measurement structure.
In this study, a novel reciprocating tribometer, in which the frictional pairs were immersed in liquid nitrogen directly, was developed to simulate the cryogenic fluid lubrication. To eliminate the negative influence of extremely low temperature on force sensors, a transfer structure of force-deformation, consisting of cantilever beams and measurement beams, was designed specially. It can transfer the structural deformations caused by the loading force and the friction force from the cryogenic zone to the room-temperature zone. The corresponding measurement principle was discussed in detail, and the linear relationship between the structural deformation and the applied force was verified theoretically. Through static calibration experiments, the fitting relationship between the deformations and the loading/friction force was acquired for the developed tribometer. In final, a preliminary investigation of graphite materials was conducted on the tribometer to compare the room-temperature and cryogenic tribological behaviors.


Social Eavesdropping: Can You Hear the Emotionality in a "Hello" That Is Not Meant for You?
The study examined third-party listeners' ability to detect the Hellos spoken to prevalidated happy, neutral, and sad facial expressions. The average detection accuracies from the happy and sad (HS), happy and neutral (HN), and sad and neutral (SN) listening tests followed the average vocal pitch differences between the two sets of Hellos in each of the tests; HS and HN detection accuracies were above chance reflecting the significant pitch differences between the respective Hellos. The SN detection accuracy was at chance reflecting the lack of pitch difference between sad and neutral Hellos. As expected, the SN detection accuracy positively correlated with theory of mind; participating in these tests has been likened to the act of eavesdropping, which has been discussed from an evolutionary perspective. An unexpected negative correlation between the HS detection accuracy and the empathy quotient has been discussed with respect to autism research on empathy and pitch discrimination.


Incidence and prevalence of asthma and allergic rhinitis: a cohort study of Finnish adolescents.
Only limited data are available about the incidence of asthma and allergic rhinitis based on prospective longitudinal studies throughout childhood into adult life. The main purpose of the study was to estimate the incidence rate of asthma and allergic rhinitis from birth to early adulthood. We also estimated the prevalences of these diseases at 16, 22, and 32 years of age. The data were drawn from a follow-up survey of a Finnish urban age cohort (1967 birth cohort, N = 2269) from age 16 to age 32 years. All data were based on self-report. The prevalence of asthma from age 16 to age 32 years changed from 3.0% to 5.0% (males from 3.3% to 4.9%; females from 2.7% to 5.1%); and that of allergic rhinitis from 17.5% to 26.0% (males from 18.7% to 27.8%; females 16.2% to 24.5%), respectively. The overall incidence rate of asthma was approximately 2.1 new cases per 1000 person-years (95% CI = 1.6-2.8). There was a tendency for boys to have a higher incidence rate of asthma than girls in childhood before 16 years of age: gender difference was reversed from period 17 to 22 years of age. In early adulthood (23-32 years), incidence rates were equal in both sexes. The incidence rate for allergic rhinitis in males was 13.4 per 1000 person-years (95% CI- 11.8-14.8), slightly greater than in females, 11.4 (95% CI = 10.1-12.8). Among both genders, the highest incidence rate of allergic rhinitis was between 17 and 22 years. Our study adds to the limited knowledge on the incidence rates of asthma and allergic rhinitis.


Choose Your Poison-Space-Use Strategy Influences Pollutant Exposure in Barents Sea Polar Bears.
Variation in space-use is common within mammal populations. In polar bears, Ursus maritimus, some individuals follow the sea ice (offshore bears) whereas others remain nearshore yearlong (coastal bears). We studied pollutant exposure in relation to space-use patterns (offshore vs coastal) in adult female polar bears from the Barents Sea equipped with satellite collars (2000-2014, n = 152). First, we examined the differences in home range (HR) size and position, body condition, and diet proxies (nitrogen and carbon stable isotopes, n = 116) between offshore and coastal space-use. Second, we investigated how HR, space-use, body condition, and diet were related to plasma concentrations of polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) ( n = 113), perfluoroalkyl substances (PFASs; n = 92), and hydroxylated-PCBs ( n = 109). Offshore females were in better condition and had a more specialized diet than did coastal females. PCBs, OCPs, and hydroxylated-PCB concentrations were not related to space-use strategy, yet PCB concentrations increased with increasing latitude, and hydroxylated-PCB concentrations were positively related to HR size. PFAS concentrations were 30-35% higher in offshore bears compared to coastal bears and also increased eastward. On the basis of the results we conclude that space-use of Barents Sea female polar bears influences their pollutant exposure, in particular plasma concentrations of PFAS.


C3 adsorbed to a polymer surface can form an initiating alternative pathway convertase.
Contact between blood and a biomaterial surface induces an immediate complement-mediated inflammatory response. Under these conditions, the alternative pathway of complement is often initiated and amplified on the biomaterial surface. Adsorption of a protein such as C3 to a polymer surface induces conformational changes in the protein. Based on the expression on adsorbed C3 of conformational neoepitopes specific for bound C3 fragments, we have hypothesized that adsorbed C3 is able to bind factor B and form a functional C3,Bb convertase. Using a quartz crystal microbalance to monitor binding of proteins to a polymer surface, we have demonstrated that a functional C3-containing alternative pathway convertase can be formed, in particular, in the presence of properdin. These data indicate that adsorption of C3 induces conformational changes that turn C3 into a C3b-like molecule that is able to participate in the functioning of the alternative convertase, and they suggest a new mechanism for complement activation on a biomaterial surface.


Clinical study of a new urine collection bag.
A pilot study of an innovative urine drainage bag that defines a new principle regarding dependent gravity drainage was conducted. Patients and caregivers found improvement in activities of daily living, comfort, convenience, safety, and cost savings as noted by the majority of evaluators.


Continual expression of Rab5(Q79L) causes a ligand-independent EGFR internalization and diminishes EGFR activity.
The amount of cell-surface Epidermal Growth Factor Receptor (EGFR) available to secreted ligand (EGF) dictates a cell's ability to mediate cell proliferation, differentiation or migration. Multiple factors regulate EGFR cell-surface expression including the rates of protein synthesis and protein degradation, and the endocytic trafficking of both stimulated and unstimulated EGFR. Rab5 is a 25 kDa protein that is localized to the plasma membrane and the early endosome. Its exact molecular function, however, remains controversial. We have used stable and transient expression systems in HeLa cells to examine the consequence of continual, overexpression of wild-type and activated mutants of rab5 on EGFR localization and signaling. Continual expression of constitutively activated mutants of rab5 causes a ligand-independent redistribution of EGFRs into intracellular vesicles that can not be blocked with an antagonistic antibody. The net result is a decrease in the level of cell-surface EGFRs available for ligand stimulation. Thus, rab5 activation regulates EGFR signaling by facilitating the internalization of the unliganded EGFR.


The Design of the Internet's Architecture by the Internet Engineering Task Force (IETF) and Human Rights.
The debate on whether and how the Internet can protect and foster human rights has become a defining issue of our time. This debate often focuses on Internet governance from a regulatory perspective, underestimating the influence and power of the governance of the Internet's architecture. The technical decisions made by Internet Standard Developing Organisations (SDOs) that build and maintain the technical infrastructure of the Internet influences how information flows. They rearrange the shape of the technically mediated public sphere, including which rights it protects and which practices it enables. In this article, we contribute to the debate on SDOs' ethical responsibility to bring their work in line with human rights. We defend three theses. First, SDOs' work is inherently political. Second, the Internet Engineering Task Force (IETF), one of the most influential SDOs, has a moral obligation to ensure its work is coherent with, and fosters, human rights. Third, the IETF should enable the actualisation of human rights through the protocols and standards it designs by implementing a responsibility-by-design approach to engineering. We conclude by presenting some initial recommendations on how to ensure that work carried out by the IETF may enable human rights.


Microbiome associations of therapeutic enteral nutrition.
One of the most effective forms of therapeutic enteral nutrition is designated as "exclusive enteral nutrition" (EEN). EEN constitutes the monotonous enteral delivery of complete liquid nutrition and has been most explored in the treatment Crohn's disease (CD), a form of inflammatory bowel disease. While EEN's mechanisms of action are not clearly understood, it has been shown to modify the composition of the intestinal microbiome, an important component of CD pathogenesis. The current literature on the intestinal microbiome in healthy individuals and CD patients is reviewed with respect to EEN therapy. Further investigations in this field are needed to better understand the role and potential for EEN in chronic human disorders.


High-throughput study of alpha-synuclein expression in yeast using microfluidics for control of local cellular microenvironment.
Microfluidics is an emerging technology which allows the miniaturization, integration, and automation of fluid handling processes. Microfluidic systems offer low sample consumption, significantly reduced processing time, and the prospect of massive parallelization. A microfluidic platform was developed for the control of the soluble cellular microenvironment of Saccharomyces cerevisiae cells, which enabled high-throughput monitoring of the controlled expression of alpha-synuclein (aSyn), a protein involved in Parkinson's disease. Y-shaped structures were fabricated using particle desorption mass spectrometry-based soft-lithography techniques to generate biomolecular gradients along a microchannel. Cell traps integrated along the microchannel allowed the positioning and monitoring of cells in precise locations, where different, well-controlled chemical environments were established. S. cerevisiae cells genetically engineered to encode the fusion protein aSyn-GFP (green fluorescent protein) under the control of GAL1, a galactose inducible promoter, were loaded in the microfluidic structure. A galactose concentration gradient was established in the channel and a time-dependent aSyn-GFP expression was obtained as a function of the positioning of cells along the galactose gradient. Our results demonstrate the applicability of this microfluidic platform to the spatiotemporal control of cellular microenvironment and open a range of possibilities for the study of cellular processes based on single-cell analysis.


Histopathological findings of the pancreas, liver, and carbohydrate metabolizing enzymes in STZ-induced diabetic rats improved by administration of myrtenal.
This study aims to evaluate the efficacy of myrtenal, a natural monoterpene, for its antihyperglycemic effects and β cell protective properties in streptozotocin (STZ)-induced diabetic rats. Oral administration of myrtenal at doses of 20, 40, and 80 mg/kg body weight to diabetic rats for 28 days resulted in a significant reduction (P < 0.05) in the levels of plasma glucose, glycosylated hemoglobin (HbA1c), and an increase in the levels of insulin and hemoglobin (Hb). Protection of body weight loss of diabetic rats by myrtenal was noted. The altered activities of the key metabolic enzymes involved in carbohydrate metabolism such as hexokinase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, and hepatic enzymes AST, ALT, and ALP levels of diabetic rats were significantly improved by the administration of myrtenal in STZ-induced diabetic rats. Moreover, myrtenal treatment improved hepatic and muscle glycogen content in diabetic rats. Histopathological studies further revealed that the reduced islet cells were restored to near-normal conditions on treatment with myrtenal in STZ-induced diabetic rats. An alteration in liver architecture was also prevented by myrtenal treatment. Our results suggest that myrtenal possess antihyperglycemic and β cell protective effects. Hence, myrtenal could be considered as a potent phytochemical for development as a new antidiabetic agent.


Dysphagia due to thoracic aortic aneurysm, relieved by thoracic endovascular aneurysm repair: a case report and review of the literature.
Thoracic aortic aneurysm is a rare clinical entity that is usually asymptomatic. Failure to treat this type of aneurysm can prove fatal. Here, the authors report a case of thoracic aortic aneurysm causing chronically worsening compressive symptoms including dysphagia. This was diagnosed following a suspicious chest radiograph, and confirmed with thoracic CT angiogram. These symptoms remitted over a period of months following thoracic endovascular repair of the aneurysm. Aneurysmal compression and deviation of the oesophagus is noticeably reduced following repair. This is one of few cases in the literature of a remittance of dysphagia following endovascular aneurysm repair, and highlights that rare causes of dysphagia ought not to be disregarded.


A Bayesian meta-analysis of multiple treatment comparisons of systemic regimens for advanced pancreatic cancer.
For advanced pancreatic cancer, many regimens have been compared with gemcitabine (G) as the standard arm in randomized controlled trials. Few regimens have been directly compared with each other in randomized controlled trials and the relative efficacy and safety among them remains unclear. A systematic review was performed through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ASCO meeting abstracts up to May 2013 to identify randomized controlled trials that included advanced pancreatic cancer comparing the following regimens: G, G+5-fluorouracil, G+ capecitabine, G+S1, G+ cisplatin, G+ oxaliplatin, G+ erlotinib, G+ nab-paclitaxel, and FOLFIRINOX. Overall survival and progression-free survival with 95% credible regions were extracted using the Parmar method. A Bayesian multiple treatment comparisons was performed to compare all regimens simultaneously. Twenty-two studies were identified and 16 were included in the meta-analysis. Median overall survival, progression free survival, and response rates for G arms from all trials were similar, suggesting no significant clinical heterogeneity. For overall survival, the mixed treatment comparisons found that the probability that FOLFIRINOX was the best regimen was 83%, while it was 11% for G+ nab-paclitaxel and 3% for G+ S1 and G+ erlotinib, respectively. The overall survival hazard ratio for FOLFIRINOX versus G+ nab-paclitaxel was 0.79 [0.50-1.24], with no obvious difference in toxicities. The hazard ratios from direct pairwise comparisons were consistent with the mixed treatment comparisons results. FOLFIRINOX appeared to be the best regimen for advanced pancreatic cancer probabilistically, with a trend towards improvement in survival when compared with other regimens by indirect comparisons.


Permeation of antigen protein-conjugated nanoparticles and live bacteria through microneedle-treated mouse skin.
The present study was designed to evaluate the extent to which pretreatment with microneedles can enhance skin permeation of nanoparticles in vitro and in vivo. Permeation of live bacteria, which are physically nanoparticles or microparticles, through mouse skin pretreated with microneedles was also studied to evaluate the potential risk of microbial infection. It was found that pretreatment of mouse skin with microneedles allowed permeation of solid lipid nanoparticles, size 230 nm, with ovalbumin conjugated on their surface. Transcutaneous immunization in a mouse skin area pretreated with microneedles with ovalbumin nanoparticles induced a stronger antiovalbumin antibody response than using ovalbumin alone. The dose of ovalbumin antigen determined whether microneedle-mediated transcutaneous immunization with ovalbumin nanoparticles induced a stronger immune response than subcutaneous injection of the same ovalbumin nanoparticles. Microneedle treatment permitted skin permeation of live Escherichia coli, but the extent of the permeation was not greater than that enabled by hypodermic injection. Transcutaneous immunization on a microneedle-treated skin area with antigens carried by nanoparticles can potentially induce a strong immune response, and the risk of bacterial infection associated with microneedle treatment is no greater than that with a hypodermic injection.


Hyaluronidase dissolves a component in the hamster zona pellucida.
Mammalian sperm must pass between cumulus cells and corona radiata cells before reaching the surface of the zona pellucida which surrounds the oocyte. The cumulus and corona radiata cells are separated from each other by an extracellular matrix (ECM) containing hyaluronic acid. The structure of this ECM and of the zona pellucida was investigated in the hamster oocyte-cumulus complex (OCC) using transmission electron microscopy (TEM) following processing in ruthenium red. When fixed in the presence of ruthenium red, the ECM of the OCC and the zona pellucida were well preserved and highly structured. The ECM between corona radiata cells was comprised of a network of granules and filaments which resembled hyaluronic acid containing matrices described in other systems. The outer one-third to one-half of the zona pellucida was porous; the ECM of the corona radiata extended into these pores. Bovine testicular hyaluronidase, Streptomyces hyaluronidase, and hamster sperm extracts containing hyaluronidase each dispersed the cumulus cells and most of the corona radiata cells. TEM examination revealed that brief (5-10 min) hyaluronidase treatment of OCCs removed the matrix filaments and caused clumping of the granules in both the corona radiata and zona pellucida. Longer hyaluronidase treatments (15-30 min) removed both filaments and granules. Our observations are consistent with the ideas that: 1) the ECM between corona radiata cells contains hyaluronic acid, and 2) hyaluronic acid is present in the outer one-third to one-half of the zona pellucida.(ABSTRACT TRUNCATED AT 250 WORDS)


Near-complete Humerus Reconstruction in the Pediatric Patient with Vascularized Free Fibula Transfer.
Vascularized free fibula transfer remains the gold standard for reconstruction of large segmental diaphyseal defects of the upper extremity. In the pediatric patient, before skeletal maturity, free fibula transfer with the fibular head provides an active physis for growth and an articular interface for glenohumeral joint reconstruction. Clinical and cadaveric studies have demonstrated that the vascular supply to the fibular head originates, in most cases, from the anterior tibial system. However, anatomical variation exists, and we report a case in which a vascularized fibula autograft including the physis was transferred on the peroneal artery in a 5-year-old patient with Ewing's sarcoma. At 15-month follow-up, the patient has functional range of motion of the shoulder.


Identification of nucleolar organizer regions in non-neoplastic and neoplastic hepatocytes by the silver-staining technique.
The silver staining technique to demonstrate nucleolar organizer region (NOR)-associated proteins (AgNORs) was applied to a variety of liver tissues, including chronic persistent hepatitis (CPH), chronic active hepatitis (CAH), liver cirrhosis (LC), liver cell dysplasia (LCD), focal nodular hyperplasia (FNH), adenomatous hyperplasia (AH) and hepatocellular carcinoma (HCC). In the present study, only discrete, easily counted black dots within nuclei and silver-stained nucleolus were counted under a magnification of x400 without oil-immersion objectives. The mean AgNOR counts of HCC and LCD were significantly higher than that of normal hepatocytes, and 77% of cases of LCD and 56% of HCC had mean AgNOR counts more than 2, whereas those in CPH, CAH, LC, FNH and AH were always less than 2 and were not different from that of normal hepatocytes. Among HCC, the mean number of AgNORs increased with the grade of the tumor. However, the AgNOR counts of grade I HCC were always less than 2 and overlapped with those of normal hepatocytes and other benign categories. All cases with mean AgNOR counts of more than 2 turned out to be HCC, except LCD which exhibited characteristic histologic appearances easily distinguished from HCC. These findings suggest that AgNORs could be quantitatively useful in evaluating the grade of HCC, even under routine microscopic examination without oil-immersion objectives, and mean AgNOR counts of more than 2 per nucleus are hallmarks of HCC.


MicroRNA-Dependent Control of Sensory Neuron Function Regulates Posture Behavior in Drosophila.
All what we see, touch, hear, taste, or smell must first be detected by the sensory elements of our nervous system. Sensory neurons, therefore, represent a critical component in all neural circuits and their correct function is essential for the generation of behavior and adaptation to the environment. Here, we report that the evolutionarily-conserved microRNA (miRNA) miR-263b plays a key behavioral role in Drosophila melanogaster through effects on the function of larval sensory neurons. Several independent experiments (in 50:50 male:female populations) support this finding: first, miRNA expression analysis, via reporter expression and fluorescent-activated cell sorting (FACS)-quantitative PCR (qPCR) analysis, demonstrate miR-263b expression in larval sensory neurons. Second, behavioral tests in miR-263b null mutants show defects in self-righting, an innate and evolutionarily conserved posture-control behavior that allows larvae to rectify their position if turned upside-down. Third, competitive inhibition of miR-263b in sensory neurons using a miR-263b "sponge" leads to self-righting defects. Fourth, systematic analysis of sensory neurons in miR-263b mutants shows no detectable morphologic defects in their stereotypic pattern, while genetically-encoded calcium sensors expressed in the sensory domain reveal a reduction in neural activity in miR-263b mutants. Fifth, miR-263b null mutants show reduced "touch-response" behavior and a compromised response to sound, both characteristic of larval sensory deficits. Furthermore, bioinformatic miRNA target analysis, gene expression assays, and behavioral phenocopy experiments suggest that miR-263b might exert its effects, at least in part, through repression of the basic helix-loop-helix (bHLH) transcription factor Atonal Altogether, our study suggests a model in which miRNA-dependent control of transcription factor expression affects sensory function and behavior.SIGNIFICANCE STATEMENT Sensory neurons are key to neural circuit function, but how these neurons acquire their specific properties is not well understood. Here, we examine this problem, focusing on the roles played by microRNAs (miRNAs). Using Drosophila, we demonstrate that the evolutionarily-conserved miRNA miR-263b controls sensory neuron function allowing the animal to perform an adaptive, elaborate three-dimensional movement. Our work thus shows that microRNAs can control complex motor behaviors by modulating sensory neuron physiology, and suggests that similar miRNA-dependent mechanisms may operate in other species. The work contributes to advance the understanding of the molecular basis of behavior and the biological roles of microRNAs within the nervous system.


Antimicrobials for reduction of Salmonella contamination in uncooked, surface-browned breaded chicken products.
Surface-browned but uncooked frozen breaded chicken products have been associated with salmonellosis outbreaks due to inadequate or no cooking of the products before consumption. This study was conducted to evaluate the effect of three antimicrobials against Salmonella during manufacture of a surface-browned, uncooked frozen breaded chicken meat product. Fresh chicken breast meat portions (5 by 5 by 5 cm) were inoculated (4 to 5 log CFU/g) with Salmonella and mixed with caprylic acid (CAA; 0.5 and 1.0%), carvacrol (CAR; 0.3 and 0.5%), ε-polylysine (POL; 0.125 and 0.25%), or distilled water (control). Sodium chloride (1.2%) and sodium tripolyphosphate (0.3%) were added to all treatments, and the mixtures were ground (5% total moisture enhancement level) and formed into portions (9 by 5 by 3 cm). The products were breaded and surface browned by baking in an oven (208°C for 15 min) or deep frying in vegetable oil (190°C for 15 s), packaged in polyethylene bags, and stored at -20°C for 7 days. Total reductions of inoculated Salmonella in untreated control oven- or fryer-browned products after frozen storage were 1.2 and 0.8 log CFU/g, respectively. In comparison, treatment with CAA, CAR, or POL reduced initial pathogen counts by 3.3 to >4.5, 4.1 to >4.7, and 1.1 to 1.6 log CFU/g, respectively, regardless of the antimicrobial concentration and browning method. Treatment with 1.0% CAA (oven browned) or 0.5% CAR (oven or fryer browned) reduced Salmonella to nondetectable levels (<0.3 log CFU/g) in stored frozen products. These data may be useful for development of suitable antimicrobial treatments to reduce the risk of Salmonella contamination in surface-browned, uncooked frozen breaded chicken products.


Fate of oligosaccharide-lipid intermediates synthesized by resting rat-spleen lymphocytes.
Using conditions to avoid the utilization of labelled precursors by intracellular glycosyltransferases, experiments are described demonstrating that intact rat-spleen lymphocytes are capable of utilizing exogenous GDP-mannose and UDP-N-acetylglucosamine to synthesize dolichyl monophosphate mannose and dolichyl diphosphate oligosaccharides. Kinetic and chase experiments show that dolichyl diphosphate oligosaccharides are either utilized for the transfer of their carbohydrate moieties to protein acceptors or further degraded. Since glycosylation of proteins is limited in resting lymphocytes, the degradation pathway appears as a major event in the fate of the dolichyl diphosphate oligosaccharides synthesized in vitro. These dolichyl diphosphate oligosaccharides are degraded into phospho-oligosaccharides and oligosaccharides which are released in the medium. This enzymatic cleavage of the phosphodiester bond is inhibited by bacitracin. The phospho-oligosaccharides are susceptible to alkaline phosphatase giving neutral oligosaccharides and they are cleaved by endo-N-acetyl-beta-D-glucosaminidase H leaving N-acetylglucosamine 1-phosphate and neutral oligosaccharides. These data suggest that splitting of the phosphodiester bond of colichyl diphosphate oligosaccharides, dephosphorylation and/or endo-N-acetyl-beta-D-glucosaminidase hydrolysis of the phosphorylated oligosaccharides could represent the beginning of the catabolic pathway of dolichyl diphosphate oligosaccharides.


Autonomic function in children with congenital central hypoventilation syndrome and their families.
Congenital central hypoventilation syndrome (CCHS) is a genetic disorder characterized by failure of automatic control of breathing in the absence of obvious anatomic lesions. There have been several reports suggesting that CCHS patients display autonomic dysregulation. Pulse arterial tonometry (PAT) is a novel technique that provides noninvasive moment-to-moment measurements of sympathetic tone changes to the cutaneous vascular bed. We hypothesized that autonomic function as measured by PAT would be altered in children with CCHS. Prospective study. CCHS Family Conference, Orlando, FL, and the local community in Louisville, KY. Nineteen CCHS patients and 31 parents as well as 24 control children and 15 adult control subjects. Children with CCHS and their parents underwent sympathetic challenges (vital capacity sigh and cold hand pressor test) and a test of reactive hyperemia (brachial artery occlusion) while PAT was continuously monitored from the right hand. Control children and control adults underwent the same procedure. The maximal change of the PAT signal compared to the preceding baseline was averaged and expressed as percentage change for each of the challenges. The magnitude of sympathetic discharge-induced attenuation of PAT signal following a sigh was reduced in CCHS children compared to control subjects for both the vital capacity sighs and the cold hand pressor test. There were no differences observed in the magnitude of PAT attenuation between parents of children with CCHS and control adults. No differences were observed between either CCHS and control subjects or CCHS parents and adult control subjects for the brachial artery occlusion test. CCHS patients show an attenuated response to endogenous sympathetic stimulation, supporting the presence of autonomic nervous system dysfunction as a consistent feature of this condition. No differences were found in parents of children with CCHS compared to control adults, consistent with the finding that CCHS is primarily the result of a de novo gene mutation.


[Horizontal canal benign paroxysmal positional vertigo (HC-BPPV) with direction-changing apogeotropic nystagmus: a case with the more-triggering side altering over a short-term].
We report a 44-year-old man who had apogeotropic nystagmus with the rotation of his head to either side from the supine position. His nystagmus lasted more than 2 minutes and was difficult to treat with. There were no neurological abnormalities except for the nystagmus and no findings suggesting intracranial disease on MRI. The head-position in which more intense nystagmus was evoked changed again and again in a short term. We diagnosed his illness as cupulolithiasis of horizontal canal, however, the affected ear could not be explained by any of the previously supposed mechanisms. In our case, we speculate the following mechanism. Otoliths were located on the right utricular side of the cupula. All of them were attached on the cupula at the beginning(attached phase) and then, some of them were detached from it(detached phase). The extent of the cupular deviation differed in each phase when the otoliths were beneath the cupula with his head turned to the left lateral position. According to Ewald's second law, more intense nystagmus is evoked when the cupula deviates toward the utricle than away from it. The patient's head-position in which more intense nystagmus was evoked changed according to the balance between the effect of Ewald's second law and the amount of otoliths detached from cupula. Our case showed that, in HC-BPPV with direction-changing apogeotropic nystagmus, we could not be certain about which ear was diseased. Therefore, it may be difficult to apply exercise therapy by determining the affected ear based on the head-position in which more intense nystagmus is evoked.


Immunoreactive insulin-like growth factor II in urine.
Insulin-like growth factor II and insulin-like growth factor binding protein-1 were identified and quantified in the urine of 23 healthy subjects between 17 and 76 years of age. IGF-II was measured after separation by gel chromatography at low pH and compared with IGF-I levels in the same samples, whereas IGF binding protein-1 was measured in dialysed urine. Urinary IGF-II was found at much higher concentrations than IGF-I (mean +/- SEM: 717 +/- 69 vs 110 +/- 5 ng/mmol creatinine). The chromatographic profile indicates that pro-IGF-II may also be present. The concentrations of IGF-II appear to be less variable than the other reported parameters. The mean IGF binding protein-1 concentrations in these urine samples was 414 +/- 83 ng/mmol creatinine. IGFs in the urine are in part bound to binding proteins.


Genotoxicity studies in semiconductor industry. 1. In vitro mutagenicity and genotoxicity studies of waste samples resulting from plasma etching.
Solid waste samples taken from the etching reactor, the turbo pump, and the waste air system of a plasma etching technology line in semiconductor production were studied as to their genotoxic properties in a bacterial repair test, in the Ames/Salmonella microsome assay, in the SOS chromotest, in primary mouse hepatocytes, and in Chinese hamster V79 cell cultures. All three waste samples were found to be active by inducing of unscheduled DNA-synthesis in mouse hepatocytes in vitro. In the bacterial rec-type repair test with Proteus mirabilis, waste samples taken from the turbo pump and the vacuum pipe system were not genotoxic. The waste sample taken from the chlorine-mediated plasma reactor was clearly positive in the bacterial repair assay and in the SOS chromotest wit Escherichia coli. Mutagenic activity was demonstrated for all samples in the presence and absence of S9 mix made from mouse liver homogenate. Again, highest mutagenic activity was recorded for the waste sample taken from the plasma reactor, while samples collected from the turbo pump and from the waste air system before dilution and liberation of the air were less mutagenic. For all samples chromosomal damage in V79 cells was not detected, indicating absence of clastogenic activity in vitro. Altogether, these results indicate generation of genotoxic and mutagenic products as a consequence of chlorine-mediated plasma etching in the microelectronics industry and the presence of genotoxins even in places distant from the plasma reactor. Occupational exposure can be expected both from the precipitated wastes and from chemicals reaching the environment with the air stream.


Milestones in CT: Past, Present, and Future.
In 1971, the first patient CT examination by Ambrose and Hounsfield paved the way for not only volumetric imaging of the brain but of the entire body. From the initial 5-minute scan for a 180° rotation to today's 0.24-second scan for a 360° rotation, CT technology continues to reinvent itself. This article describes key historical milestones in CT technology from the earliest days of CT to the present, with a look toward the future of this essential imaging modality. After a review of the beginnings of CT and its early adoption, the technical steps taken to decrease scan times-both per image and per examination-are reviewed. Novel geometries such as electron-beam CT and dual-source CT have also been developed in the quest for ever-faster scans and better in-plane temporal resolution. The focus of the past 2 decades on radiation dose optimization and management led to changes in how exposure parameters such as tube current and tube potential are prescribed such that today, examinations are more customized to the specific patient and diagnostic task than ever before. In the mid-2000s, CT expanded its reach from gray-scale to color with the clinical introduction of dual-energy CT. Today's most recent technical innovation-photon-counting CT-offers greater capabilities in multienergy CT as well as spatial resolution as good as 125 μm. Finally, artificial intelligence is poised to impact both the creation and processing of CT images, as well as automating many tasks to provide greater accuracy and reproducibility in quantitative applications.


Cutaneous Leishmaniasis - Dermoscopic Findings And Cryotherapy.
We present a 60-year-old male patient who, three months after a holiday in Southern Greece, found a small 'pimple' on his back, which gradually got as big as a small walnut, the central part becoming ulcerated and scabby. Dermatological examination found an erythematous-to-livid nodular lesion on the right shoulder; it was 16 mm in diameter with central ulceration, covered with brownish crust which discharged pus-like secretion upon pressure. Microscope examination of Romanowsky-Giemsa stained lesion material detected amastigote forms of Leishmania tropica. The culture investigation and serological tests for leishmaniasis were negative. Dermoscopy of the lesion found the following features: erythema, hyperkeratosis, central ulceration covered with brownish crust, "yellow tears-like" structures and "white starburst-like" patterns, and various vascular structures (including dotted vessels, comma-shaped vessels, hairpin- and glomerular-like vessels). The patient was diagnosed with cutaneous leishmaniasis and underwent four cryotherapy sessions every other week with excellent therapeutic results - complete resolution of infiltrate with subsequent gentle hypopigmented scarring. In conclusion, dermoscopy is an easily accessible non-invasive method which can be useful for the diagnosis of cutaneous leishmaniasis. Cryotherapy is the treatment of choice for single skin lesions.


Measurement of theophylline in dried blood spots by spectrophotometric enzyme immunoassay.
A widely-used enzyme immunoassay for the measurement of theophylline in plasma (EMIT) has been adapted for use with dried blood spots. Potential interference from haemoglobin in eluates of the spots was avoided by autoclaving them prior to analysis. The method was investigated in terms of the recovery of theophylline added to samples, precision, and the correlation of results in DBS with those in plasma samples. The recoveries of some other drugs from eluates of autoclaved DBS were also investigated.


Constitutive turnover of inositol-containing phospholipids in B220+ T cells from autoimmune-prone MRL-lpr/lpr mice.
B220+ T cells from mice that are homozygous for the lpr gene exhibit profound defects in their capacity to produce and respond to IL-2 and provide a cellular model for investigating the basic requirements for effective transmembrane signal transduction in immunologically normal T cells. A correlation between defective lectin-stimulated proliferation and deficient hydrolysis of inositol-containing phospholipids (PI) has recently been demonstrated in B220+ T cells. The finding has been postulated to explain abnormal expression of protein kinase C (PKC) activity in these cells. In a previous study, we found that the constitutive turnover of [3H]arachidonyl-PI was markedly increased in B220+ T cells from lpr-bearing MRL mice relative to that in controls. This observation suggested that an inability to metabolize PI and to generate second messengers putatively necessary for transmembrane signaling might not be responsible for aberrant PKC activity in B220+ T cells. To clarify this issue, the constitutive turnover of phosphoinositides in B220+ T cells from autoimmune-prone MRL-lpr/lpr mice was investigated. We found that in the absence of stimulation with exogenous Ag, B220+ T cells exhibited greatly increased 1) incorporation of labeled myoinositol into PI, 2) production of inositol phosphates in cells prelabeled with [3H]myoinositol, and 3) formation of diacylglycerol in [3H]arachidonic acid-labeled cells. Increased spontaneous PI turnover in B220+ cells was associated with normal phosphatidyl inositol-4,5-biphosphate-phospholipase C activity in membrane homogenates, normal levels of membrane PI, and normal resting and mitogen-stimulated levels of intracellular free-ionized Ca2+. The results suggest that an incomplete form of the PI cycle, one unassociated with PKC activation, is constitutively expressed in B220+ T cells.


Systemic Delivery of Dysferlin Overlap Vectors Provides Long-Term Gene Expression and Functional Improvement for Dysferlinopathy.
Dysferlinopathies comprise a family of disorders caused by mutations in the dysferlin (DYSF) gene, leading to a progressive dystrophy characterized by chronic muscle fiber loss, fat replacement, and fibrosis. To correct the underlying histopathology and function, expression of full-length DYSF is required. Dual adeno-associated virus vectors have been developed, defined by a region of homology, to serve as a substrate for reconstitution of the full 6.5 kb dysferlin cDNA. Previous work studied the efficacy of this treatment through intramuscular and regional delivery routes. To maximize clinical efficacy, dysferlin-deficient mice were treated systemically to target all muscles through the vasculature for efficacy and safety studies. Mice were evaluated at multiple time points between 4 and 13 months post treatment for dysferlin expression and functional improvement using magnetic resonance imaging and magnetic resonance spectroscopy and membrane repair. A systemic dose of 6 × 1012 vector genomes resulted in widespread gene expression in the muscles. Treated muscles showed a significant decrease in central nucleation, collagen deposition, and improvement of membrane repair to wild-type levels. Treated gluteus muscles were significantly improved compared to placebo-treated muscles and were equivalent to wild type in volume, intra- and extramyocellular lipid accumulation, and fat percentage using magnetic resonance imaging and magnetic resonance spectroscopy. Dual-vector treatment allows for production of full-length functional dysferlin with no toxicity. This confirms previous safety data and validates translation of systemic gene delivery for dysferlinopathy patients.


Mutational topography reflects clinical neuroblastoma heterogeneity.
Neuroblastoma is a pediatric solid tumor characterized by strong clinical heterogeneity. Although clinical risk-defining genomic alterations exist in neuroblastomas, the mutational processes involved in their generation remain largely unclear. By examining the topography and mutational signatures derived from all variant classes, we identified co-occurring mutational footprints, which we termed mutational scenarios. We demonstrate that clinical neuroblastoma heterogeneity is associated with differences in the mutational processes driving these scenarios, linking risk-defining pathognomonic variants to distinct molecular processes. Whereas high-risk MYCN-amplified neuroblastomas were characterized by signs of replication slippage and stress, homologous recombination-associated signatures defined high-risk non-MYCN-amplified patients. Non-high-risk neuroblastomas were marked by footprints of chromosome mis-segregation and TOP1 mutational activity. Furthermore, analysis of subclonal mutations uncovered differential activity of these processes through neuroblastoma evolution. Thus, clinical heterogeneity of neuroblastoma patients can be linked to differences in the mutational processes that are active in their tumors.


R12-calibrated H2O-H2 interaction: full dimensional and vibrationally averaged potential energy surfaces.
The potential energy surface of H(2)O-H(2) is of great importance for quantum chemistry as a test case for H(2)O-molecule interactions. It is also required for a detailed understanding of important astrophysical processes, namely, the collisional excitation of water, including the pumping of water masers and the formation of molecular hydrogen on icy interstellar dust grains. We have calculated the interaction for H(2)O-H(2) by performing both rigid-rotor (five-dimensional) and non-rigid-rotor (nine-dimensional) calculations using the coupled-cluster theory at the level of singles and doubles with perturbative corrections for triple excitations [CCSD(T)] with moderately large but thoroughly selected basis set. The resulting surface was further calibrated using high precision explicitly correlated CCSD(T)-R12 calculations on a subset of the rigid-rotor intermolecular geometries. The vibrationally averaged potential is presented in some details and is compared with the most recent rigid-rotor calculations. We explain, in particular, as to why vibrationally averaged rigid-rotor geometries are a better choice than equilibrium geometries. Our fit of the vibrationally averaged surface provides for the first time an accuracy of approximately 3 cm(-1) in the van der Waals minimum region of the interaction. The overall accuracy of the nine-dimensional surface and fit is lower but remains of the order of 3%-4% of the anisotropy in the domain spanned by the vibrational functions.


Correlation of induced sputum eosinophil levels with clinical parameters in mild and moderate persistent asthma in children aged 7-18 years.
Treatment decisions in asthma are currently based on clinical assessment and spirometry. Sputum eosinophil, being a marker of airway inflammation, can serve as a tool for assessing severity and response to treatment in asthma patients. To measure eosinophil percentage in induced sputum in children with asthma and correlate it with clinical asthma parameters. A prospective observational study was performed at tertiary care hospital on 91 children aged 7-18 years with newly diagnosed mild or moderate persistent asthma. Theinduced sputum eosinophil percentage was obtained at the time of enrollment and three months after treatment with inhaled budesonide. Patients were specifically evaluated for five clinical parameters of asthma, i.e., days of acute exacerbations, use of salbutamol as rescue medication, emergency visits, nighttime cough and days of school absence. Sputum eosinophil percentage was high (3.1 ± 0.515%) at the time of enrollment which reduced significantly after three months of inhaled budesonide therapy [0.06 ± 0.164% (p < 0.0005)]. Children with moderate persistent asthma had significantly higher values of sputum eosinophil levels than children with mild persistent asthma at the time of enrollment (3.38 ± 0.64% vs. 2.99 ± 0.42%, p = 0.001) but the difference was not significant after three months of inhaled steroid therapy (0.07 ± 0.18 vs. 0.04 ± 0.12, p = 0.5104). A significant negative correlation was found between reduction in sputum eosinophil levels and improvement in FEV1 (r = -0.400, p = 0.0001). All the clinical asthma parameters also correlated significantly with the reduction in sputum eosinophil levels after three months of inhaled steroid therapy. Eosinophil levels in induced sputum correlate well with clinical asthma parameters and asthma severity in children. It is a simple, noninvasive and cheap method which can be used for the monitoring of asthma in a resource-limited setting.


Impact of lifestyle choices on female infertility.
To inform physicians who are involved in the primary care of reproductive-age women of the specific relationships between lifestyle choices and infertility so that they can use this knowledge to educate their patients and encourage changes in behavior. A review of the relevant literature, performed via Medline search. Prevention of chlamydial and gonorrheal infections; maintenance of the proper body weight; increased individual awareness about the effects of age on fecundity; and reduced intake of caffeine, tobacco and alcohol are all possible avenues for primary prevention of infertility. Lifestyle choices can be made that influence the reproductive capability of women. It may be worthwhile for primary care physicians to use information on lifestyle to encourage their patients to improve their overall health while positively affecting their ability to reproduce.


Caenorhabditis elegans Predation on Bacillus anthracis: Decontamination of Spore Contaminated Soil with Germinants and Nematodes.
Remediation of Bacillus anthracis-contaminated soil is challenging and approaches to reduce overall spore levels in environmentally contaminated soil or after intentional release of the infectious disease agent in a safe, low-cost manner are needed. B. anthracis spores are highly resistant to biocides, but once germinated they become susceptible to traditional biocides or potentially even natural predators such as nematodes in the soil environment. Here, we describe a two-step approach to reducing B. anthracis spore load in soil during laboratory trials, whereby germinants and Caenorhabditis elegans nematodes are applied concurrently. While the application of germinants reduced B. anthracis spore load by up to four logs depending on soil type, the addition of nematodes achieved a further log reduction in spore count. These laboratory based results suggest that the combined use of nematodes and germinants could represent a promising approach for the remediation of B. anthracis spore contaminated soil. Originality-Significance Statement: This study demonstrates for the first time the successful use of environmentally friendly decontamination methods to inactivate Bacillus anthracis spores in soil using natural predators of the bacterium, nematode worms.


Improving Outcomes in INTERMACS Category 1 Patients with Pre-LVAD, Awake Venous-Arterial Extracorporeal Membrane Oxygenation Support.
Effective strategies to optimize Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS 1) patients are in much need. A novel awake venous-arterial extracorporeal membrane oxygenation (aVA ECMO) allows for clinical assessments while temporarily supporting biventricular function and stabilizing end-organ functions. The aim of the study was to assess outcomes of patients with aVA ECMO support before durable left ventricular assist device (LVAD) implantation. We evaluated 83 patients who received durable LVAD in 2012-2015, of whom 19 received aVA ECMO support before durable LVAD. Kaplan-Meier and Cox proportional hazards analyses were conducted to assess post-LVAD survival. No complications were observed during the mean aVA ECMO support of 2.7 days. Unadjusted survival of aVA ECMO-supported patients and non-aVA ECMO INTERMACS 1 patients at 1 year were 84.2% and 66.7%, respectively (p = 0.15). Survival of aVA ECMO patients was comparable with that of non-aVA ECMO INTERMACS 2 cohort (84.2% vs. 80.8%) at 1 year. Multivariate analysis demonstrated a significant reduction in the risk of death in aVA ECMO group compared with INTERMACS 1 non-aVA ECMO group (hazard ratio [HR]: 0.17; p = 0.035). Awake venous-arterial (VA) ECMO allows bridge to next therapy and improves outcomes in INTERMACS category 1 patients with an effect comparable with downgrading the disease severity on the INTERMACS scale.


Effects of Chronic Musculoskeletal Pain on Fertility Potential in Lean and Overweight Male Patients.
Both chronic pain and obesity are known to affect reproductive hormone profiles in male patients. However, the effect of these conditions, alone or in combination, on male fertility potential has received less attention. 20 chronic musculoskeletal pain patients and 20 healthy controls were divided into lean and overweight subgroups according to their BMI. Current level of chronic pain (visual analogue scale) and pressure pain thresholds (PPTs) in 16 predefined sites, classically described and tested as painful points on the lower body, were measured. Levels of reproductive hormone and lipid profiles were assessed by ELISA. Sperm concentration and motility parameters were analyzed using a computer-aided sperm analysis system. Sperm concentration, progressive motility, and percentage of hyperactivated sperm were generally lower in the chronic pain patients in both lean and overweight groups. The overweight control and the lean chronic pain groups demonstrated a significantly lower percentage of progressively motile sperm compared with the lean control group, suggesting that musculoskeletal chronic pain may have a negative influence on sperm quality in lean patients. However, due to the potential great negative influence of obesity on the sperm parameters, it is difficult to propose if musculoskeletal chronic pain also influenced sperm quality in overweight patients. Further research in chronic pain patients is required to test this hypothesis.


An exploration into study design for biomarker identification: issues and recommendations.
Genomic profiling produces large amounts of data and a challenge remains in identifying relevant biological processes associated with clinical outcome. Many candidate biomarkers have been identified but few have been successfully validated and make an impact clinically. This review focuses on some of the study design issues encountered in data mining for biomarker identification with illustrations of how study design may influence the final results. This includes issues of clinical endpoint use and selection, power, statistical, biological and clinical significance. We give particular attention to study design for the application of supervised clustering methods for identification of gene networks associated with clinical outcome and provide recommendations for future work to increase the success of identification of clinically relevant biomarkers.


The utility of enlarging symptomatic nasal septal perforations.
Nasal septal perforations cause a subset of patients to suffer with significant impairments in quality of life. While smaller perforations can often be surgically repaired, perforations exceeding 2 cm are challenging to close. These repairs are highly technical, and there is a lack of consensus regarding the most effective means to do so. The authors performed a retrospective chart review of patients with perforation enlargements and have found that, in select patients, enlarging the septal perforation's edge posterior to the head of the middle turbinates has proven effective in relieving symptoms.


Brain imaging predictors and the international study to predict optimized treatment for depression: study protocol for a randomized controlled trial.
Approximately 50% of patients with major depressive disorder (MDD) do not respond optimally to antidepressant treatments. Given this is a large proportion of the patient population, pretreatment tests that predict which patients will respond to which types of treatment could save time, money and patient burden. Brain imaging offers a means to identify treatment predictors that are grounded in the neurobiology of the treatment and the pathophysiology of MDD. The international Study to Predict Optimized Treatment in Depression is a multi-center, parallel model, randomized clinical trial with an embedded imaging sub-study to identify such predictors. We focus on brain circuits implicated in major depressive disorder and its treatment. In the full trial, depressed participants are randomized to receive escitalopram, sertraline or venlafaxine-XR (open-label). They are assessed using standardized multiple clinical, cognitive-emotional behavioral, electroencephalographic and genetic measures at baseline and at eight weeks post-treatment. Overall, 2,016 depressed participants (18 to 65 years old) will enter the study, of whom a target of 10% will be recruited into the brain imaging sub-study (approximately 67 participants in each treatment arm) and 67 controls. The imaging sub-study is conducted at the University of Sydney and at Stanford University. Structural studies include high-resolution three-dimensional T1-weighted, diffusion tensor and T2/Proton Density scans. Functional studies include standardized functional magnetic resonance imaging (MRI) with three cognitive tasks (auditory oddball, a continuous performance task, and Go-NoGo) and two emotion tasks (unmasked conscious and masked non-conscious emotion processing tasks). After eight weeks of treatment, the functional MRI is repeated with the above tasks. We will establish the methods in the first 30 patients. Then we will identify predictors in the first half (n=102), test the findings in the second half, and then extend the analyses to the total sample. International Study to Predict Optimized Treatment--in Depression (iSPOT-D). ClinicalTrials.gov, NCT00693849.


Mediastinal seminoma with florid follicular lymphoid hyperplasia: a clinicopathological and immunohistochemical study of six cases.
Seminomas are unusual primary tumors of the anterior mediastinum. Morphologically, they are indistinguishable from their testicular counterparts; however, in the mediastinum, the occurrence of secondary changes such as cyst formation is not uncommon. We now describe six cases associated with florid follicular hyperplasia. The patients were male with an age range from 24 to 31 years. Clinically, symptoms included cough, dyspnea, and chest pain. Anterior mediastinal masses were detected on imaging and all patients underwent thymectomy. Macroscopically, all tumors had a fleshy, lobulated cut surface. Histologically, the tumors were composed of round to polygonal cells with indistinct cell borders, clear cytoplasm, and prominent nucleoli. Striking follicular hyperplasia was evident in all cases to a degree whereby the tumor component was nearly obscured. Immunohistochemical studies demonstrated that the germinal centers were largely composed of B lymphocytes, and T cells were the predominant component of the interfollicular areas. Scattered Langerhans cells were noted in between tumor cells, and dendritic cells were seen in the mantle zones. All cases failed to show light chain restriction. Follow-up showed that five patients were alive and well 1-5 years after diagnosis, while one was lost to follow-up. Thymic seminomas can be associated with striking lymphoid follicular hyperplasia, likely as a response to specific tumor antigens. Familiarity with this variant of thymic seminoma is important in order not to misdiagnose these cases for reactive conditions or other tumors such as lymphoproliferative neoplasms which may require a different treatment approach.


Gastrointestinal complaints related to eating and drinking habits and work life of intensive care nurses in Zonguldak, Turkey.
The purpose of this descriptive study was to determine the effect of self-reported work life and nutritional habits of intensive care unit nurses in the incidence of gastrointestinal complaints. This study of 110 nurses found that long work hours at night and incorrect eating and drinking habits affect their gastrointestinal system.


Cryoelectron microscopy of protein IX-modified adenoviruses suggests a new position for the C terminus of protein IX.
Recombinant human adenovirus is a useful gene delivery vector for clinical gene therapy. Minor capsid protein IX of adenovirus has been of recent interest since multiple studies have shown that modifications can be made to its C terminus to alter viral tropism or add molecular tags and/or reporter proteins. We examined the structure of an engineered adenovirus displaying the enhanced green fluorescent protein (EGFP) fused to the C terminus of protein IX. Cryoelectron microscopy and reconstruction localized the C-terminal EGFP fusion between the H2 hexon and the H4 hexon, positioned between adjacent facets, directly above the density previously assigned as protein IIIa. The original assignment of IIIa was based largely on indirect evidence, and the data presented herein support the reassignment of the IIIa density as protein IX.


Predictors of depression symptoms in patients with diabetes in Slovakia.
The patterns of relationships between diabetes and depression in countries of central and eastern Europe (CEE) might differ from those in countries of western Europe and the United States. Among the reasons are specifics of transitioning healthcare systems (including mental health) and the general social, cultural, and economic background of these countries. The aim of this article is to analyze the prevalence of depression symptoms in patients with diabetes in Slovakia and to identify its predictors. Diabetes patients (N= 1043) from two diabetes outpatient-care offices were recruited for the study. The Patient Health Questionnaire 9 (PHQ-9) was applied to screen for depression symptoms. Patients were categorized into four categories based on depression symptom severity. Demographic and disease-related factors were analyzed as predictors of depression symptoms. In the univariate analysis, a number of factors were associated with increasing severity of depression symptoms. In the multivariate analysis, lower education (OR 0.52; Cl 95% 0.33-0.81), and high degree of self-perceived severity of illness (OR 5.33; CI 95% 2.47-12.12) were confirmed as independent predictors of depression symptoms in our patients. Demographic and psychological factors have an important role in developing depression symptoms in patients with diabetes in our population. Further studies into the topic are needed to gain further clues on this topic throughout the Central European region. The findings of this study should be considered by mental health service providers and public health authorities to raise awareness about this important issue.


[Detection of sexually transmitted pathogens in patients with hematospermia].
Although the current literature attributes most cases of hematospermia to an infectious agent, identification of the specific pathogens involved has been limited. To determine the prevalence of different pathogens, in patients presenting with hematospermia to our sexually transmitted disease clinic. We retrospectively examined the laboratory results of 30 patients who presented to our clinic with hematospermia after other non-infectious pathologies had been excluded by a referring physician. Firstly, void urine samples as well as genitourinary and serum specimens were tested for Herpes simplex, Chlamydia trachomatis and Ureaplasma urealyticum. Standard bacterial cultures were also performed. In 12 of the 18 patients a possible pathogenic cause for the hematospermia was found. Evidence for Herpes simplex virus (Type 2) was found in 5 of the patients (16.6%), for Chlamydia trachomatis in 3 patients (10%) and for Ureaplasma urealyticum in 2 of the patients. Enterococcus fecalis was detected in 2 (6.6%) of the patients and in 1 patient Herpes simplex virus (Type 1) antigen and antibodies were detected. In all cases in which evidence of a pathogen was identified, the appropriate antimicrobial agent was administered, with recurrence in two patients only. Recent advances in microbiologic diagnostic techniques have facilitated the detection of pathogens in patients with hematospermia, thereby enhancing the efficacy of treatment.


An improved method for describing the effects of heat radiation on men.
At industrial workplaces radiant heat load is often the dominant heat stress factor. Based on 900 climatic chamber experiments on humans, this study was conducted to develop a physiologically validated index-method to evaluate climates with intensified heat radiation. A comparison shows that the international recommended heat stress indices are not suitable to evaluate such climates correctly. By application of the new index-method into the commonly used indices, the improvement for the prediction of thermal stress effects in view of climates with increased heat radiation is discussed.


A new neutrosophic sign test: An application to COVID-19 data.
The Sign test is a famous nonparametric test from classical statistics used to assess the one or two sample averages. The test is practical when the sample size is small, or the distributional assumption under a parametric test does not satisfy. One of the limitations of the Sign test is the exact form of the data, and the existing methodology of the test does not cover the interval-valued data. The interval-valued data often comes from the fuzzy logic where the experiment's information is not sure and possesses some kind of vagueness, uncertainty or indeterminacy. This research proposed a modified version of the Sign test by considering the indeterminate state and the exact form of the data-the newly proposed sign test methodology is designed for both one-sample and two-sample hypothesis testing problems. The performance of the proposed modified versions of the Sign test is evaluated through two real-life data examples comprised of covid-19 reproduction rate and covid-positive daily occupancy in ICU in Pakistan. The findings of the study suggested that our proposed methodologies are suitable in nonparametric decision-making problems with an interval-valued data. Therefore, applying the new neutrosophic sign test is explicitly recommended in biomedical sciences, engineering, and other statistical fields under an indeterminate environment.


Food Allergies and Parasites in Children.
The dynamically growing incidence of food allergies forces the scientific community to develop new methods for their diagnosis, differentiation, and effective treatment. Parasitoses appear much less frequently in the scientific literature, as well as among the presumed causes of numerous conditions. The similarity of inflammatory mechanisms in allergies and parasitosis necessitates a revision of current diagnostic standards. A lack of specificity and the coincidence of symptoms at an early stage of disease can lead to misdiagnosis. In this paper, we attempted to perform a comparative analysis of the similarities and differences in symptoms for these two types of diseases. We described the molecular mechanisms and metabolic pathways of food allergy and parasitosis. We presented the available research methods and directions of ongoing studies aimed at implementing precise medical techniques for differential diagnosis. We discussed the allergenic properties of certain parasite proteins, using the example of myofibrillar tropomyosins from the nematode Anisakis simplex. The literature in the fields of allergology and parasitology leads to the conclusion that it is reasonable to run parallel allergological and parasitological diagnostics in patients with non-specific symptoms. This approach will facilitate accurate and early diagnosis and implementation of effective therapy.


Genetic variation in transforming growth factor beta 1 and mammographic density in Singapore Chinese women.
TGF-β plays a critical role in normal mammary development and morphogenesis. Decreased TGF-β signaling has been associated with increased mammographic density. Percent mammographic density (PMD) adjusted for age and body mass index (BMI) is a strong risk factor and predictor of breast cancer risk. PMD is highly heritable, but few genetic determinants have been identified. We investigated the association between genetic variation in TGFB1 and PMD using a cross-sectional study of 2,038 women who were members of the population-based Singapore Chinese Health Study cohort. We assessed PMD using a computer-assisted method. We used linear regression to examine the association between nine tagging single-nucleotide polymorphisms (SNP) of TGFB1 and PMD and their interaction with parity, adjusting for age, BMI, and dialect group. We calculated P values adjusted for correlated tests (P(ACT)) to account for multiple testing. The strongest association was observed for rs2241716. Adjusted PMD was higher by 1.5% per minor allele (P(ACT) = 0.04). When stratifying by parity, this association was limited to nulliparous women. For nulliparous women, adjusted PMD was higher by 8.6% per minor allele (P(ACT) = 0.003; P for interaction with parity = 0.002). Three additional TGFB1 tagging SNPs, which were in linkage disequilibrium with rs2241716, were statistically significantly associated with adjusted PMD (P(ACT) < 0.05) for nulliparous women. However, none of these three SNPs showed statistically significant association after adjusting for rs2241716. Our data support that TGFB1 genetic variation may be an important genetic determinant of mammographic density measure that predicts breast cancer risk, particularly in nulliparous women.


Nontypeable Haemophilus influenzae and chronic obstructive pulmonary disease: a review for clinicians.
Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of morbidity and mortality worldwide. In the lower airways of COPD patients, bacterial infection is a common phenomenon and Haemophilus influenzae is the most commonly identified bacteria. Haemophilus influenzae is divided into typeable and nontypeable (NTHi) strains based on the presence or absence of a polysaccharide capsule. While NTHi is a common commensal in the human nasopharynx, it is associated with considerable inflammation when it is present in the lower airways of COPD patients, resulting in morbidity due to worsening symptoms and increased frequency of COPD exacerbations. Treatment of lower airway NTHi infection with antibiotics, though successful in the short term, does not offer long-term protection against reinfection, nor does it change the course of the disease. Hence, there has been much interest in the development of an effective NTHi vaccine. This review will summarize the current literature concerning the role of NTHi infections in COPD patients and the consequences of using prophylactic antibiotics in patients with COPD. There is particular focus on the rationale, findings of clinical studies and possible future directions of NTHi vaccines in patients with COPD.


Public health, induced abortion, and spontaneous abortion.
Bruce P. Blackshaw and Daniel Rodger contend that if we assume fetuses are persons, then abortion is a public health crisis that justifies overriding a gestational mother's rights and compelling her to carry the fetus to term, but dawdle addressing greater public health crises like spontaneous abortion and hunger. They draw a distinction between deliberate and indeliberate harm to justify restricting rights in the former, but not the latter; but such distinction fails to justify restricting rights in most public health crises. Furthermore, it fails to justify curtailing abortion rights as unwilling gestational mothers might deliberately induce abortion in self-defense, merely indeliberately harming the fetus.


Flowers under pressure: ins and outs of turgor regulation in development.
Turgor pressure is an essential feature of plants; however, whereas its physiological importance is unequivocally recognized, its relevance to development is often reduced to a role in cell elongation. This review surveys the roles of turgor in development, the molecular mechanisms of turgor regulation and the methods used to measure turgor and related quantities, while also covering the basic concepts associated with water potential and water flow in plants. Three key processes in flower development are then considered more specifically: flower opening, anther dehiscence and pollen tube growth. Many molecular determinants of turgor and its regulation have been characterized, while a number of methods are now available to quantify water potential, turgor and hydraulic conductivity. Data on flower opening, anther dehiscence and lateral root emergence suggest that turgor needs to be finely tuned during development, both spatially and temporally. It is anticipated that a combination of biological experiments and physical measurements will reinforce the existing data and reveal unexpected roles of turgor in development.


Navigating the care between two distinct cultures: a qualitative study of the experiences of Arabic-speaking immigrants in Norwegian hospitals.
During the past decades, there has been an increase in the number of immigrants to European and Scandinavian countries. This has challenged the health-care systems, which cater to the needs of patients despite their cultural and linguistic barriers, in these countries. Most studies on this topic have focused on the perspectives of health-care providers in delivering their service. The purpose of this qualitative study was to explore how hospitalized Arabic-speaking patients experienced their interaction with the Norwegian health-care system. In-depth interviews with 20 participants and researcher's participant observation were conducted to explore the idiosyncratic details and ascribed meanings that foreign-born patients attach to their everyday experience of the Norwegian health-care system. Thematic analysis was performed on the transcribed and translated versions of the in-depth interviews. The findings of this study indicated three interrelated core themes. Firstly, there exist challenges in understanding and being understood because of linguistic and cultural differences of newly migrated patients. Secondly, some patients missed the holistic and direct care available in their home countries. Finally, patients were satisfied with the Norwegian health-care system because of its compassion, care, and respect toward them as well as advanced health-care equipment. Arabic-speaking patients in Norwegian hospitals experienced long waiting times and linguistic problems. Hence, a better and specialized interpreter service may resolve problems emanating from communication within the system and the subsequent delays in treatment. Compassionate care and the feeling of respect and love is the core strength of the Norwegian system as perceived by the patients.


The PINOID protein kinase regulates organ development in Arabidopsis by enhancing polar auxin transport.
Arabidopsis pinoid mutants show a strong phenotypic resemblance to the pin-formed mutant that is disrupted in polar auxin transport. The PINOID gene was recently cloned and found to encode a protein-serine/threonine kinase. Here we show that the PINOID gene is inducible by auxin and that the protein kinase is present in the primordia of cotyledons, leaves and floral organs and in vascular tissue in developing organs or proximal to meristems. Overexpression of PINOID under the control of the constitutive CaMV 35S promoter (35S::PID) resulted in phenotypes also observed in mutants with altered sensitivity to or transport of auxin. A remarkable characteristic of high expressing 35S::PID seedlings was a frequent collapse of the primary root meristem. This event triggered lateral root formation, a process that was initially inhibited in these seedlings. Both meristem organisation and growth of the primary root were rescued when seedlings were grown in the presence of polar auxin transport inhibitors, such as naphthylphtalamic acid (NPA). Moreover, ectopic expression of PINOID cDNA under control of the epidermis-specific LTP1 promoter provided further evidence for the NPA-sensitive action of PINOID. The results presented here indicate that PINOID functions as a positive regulator of polar auxin transport. We propose that PINOID is involved in the fine-tuning of polar auxin transport during organ formation in response to local auxin concentrations.


MRI of the lung (3/3)-current applications and future perspectives.
MRI of the lung is recommended in a number of clinical indications. Having a non-radiation alternative is particularly attractive in children and young subjects, or pregnant women. Provided there is sufficient expertise, magnetic resonance imaging (MRI) may be considered as the preferential modality in specific clinical conditions such as cystic fibrosis and acute pulmonary embolism, since additional functional information on respiratory mechanics and regional lung perfusion is provided. In other cases, such as tumours and pneumonia in children, lung MRI may be considered an alternative or adjunct to other modalities with at least similar diagnostic value. In interstitial lung disease, the clinical utility of MRI remains to be proven, but it could provide additional information that will be beneficial in research, or at some stage in clinical practice. Customised protocols for chest imaging combine fast breath-hold acquisitions from a "buffet" of sequences. Having introduced details of imaging protocols in previous articles, the aim of this manuscript is to discuss the advantages and limitations of lung MRI in current clinical practice. New developments and future perspectives such as motion-compensated imaging with self-navigated sequences or fast Fourier decomposition MRI for non-contrast enhanced ventilation- and perfusion-weighted imaging of the lung are discussed. Main Messages • MRI evolves as a third lung imaging modality, combining morphological and functional information. • It may be considered first choice in cystic fibrosis and pulmonary embolism of young and pregnant patients. • In other cases (tumours, pneumonia in children), it is an alternative or adjunct to X-ray and CT. • In interstitial lung disease, it serves for research, but the clinical value remains to be proven. • New users are advised to make themselves familiar with the particular advantages and limitations.


RNA-binding protein HuR enhances mineralocorticoid signaling in renal KC3AC1 cells under hypotonicity.
Mineralocorticoid receptor (MR) mediates the sodium-retaining action of aldosterone in the distal nephron. Herein, we decipher mechanisms by which hypotonicity increases MR expression in renal principal cells. We identify HuR (human antigen R), an mRNA-stabilizing protein, as an important posttranscriptional regulator of MR expression. Hypotonicity triggers a rapid and reversible nuclear export of HuR in renal KC3AC1 cells, as quantified by high-throughput microscopy. We also identify a key hairpin motif in the 3'-untranslated region of MR transcript, pivotal for the interaction with HuR and its stabilizing function. Next, we show that hypotonicity increases MR recruitment onto Sgk1 promoter, a well-known MR target gene, thereby enhancing aldosterone responsiveness. Our data shed new light on the crucial role of HuR as a stabilizing factor for the MR transcript and provide evidence for a short autoregulatory loop in which expression of a nuclear receptor transcriptionally regulating water and sodium balance is controlled by osmotic tone.


Viscoelastic properties of pressure overload hypertrophied myocardium: effect of serine protease treatment.
To determine whether and to what extent one component of the extracellular matrix, fibrillar collagen, contributes causally to abnormalities in viscoelasticity, collagen was acutely degraded by activation of endogenous matrix metalloproteinases (MMPs) with the serine protease plasmin. Papillary muscles were isolated from normal cats and cats with right ventricular pressure overload hypertrophy (POH) induced by pulmonary artery banding. Plasmin treatment caused MMP activation, collagen degradation, decreased the elastic stiffness constant, and decreased the viscosity constant in both normal and POH muscles. Thus, whereas many mechanisms may contribute to the abnormalities in myocardial viscoelasticity in the POH myocardium, changes in fibrillar collagen appear to play a predominant role.


[Measurement of the oncotic pressure of blood (methodology and analysis of errors)].
The authors give their practical recommendations on improving the accuracy of the blood plasma colloid osmometry by standardizing the methods for the collection, treatment, and storage of the samples and the oncometry procedure per se. The recommendations are based on literature data and the authors' experience.


[Impact of erlotinib treatment on symptoms and quality of life in patients with advanced non-small-cell lung cancer].
To investigate the impact of erlotinib as a second or third line treatment on the symptoms and quality of life (QOL) in patients with advanced non-small cell lung cancer (NSCLC). Fifty patients with stage III b and IV NSCLC, treated previously with at least one regimen of platinum-based chemotherapy, received 150 mg of erlotinib orally, once a day till disease progression. QOL was assessed by European Organization for Research and Treatment of Cancer QLQ-C30 and the lung cancer module (QLQ-LC13). The primary end points for QOL analysis were time to deterioration of three common lung cancer symptoms: cough, dyspnea and pain. Among 47 evaluable cases, there were partial remission (PR) in 18 cases, stable disease (SD) in 21 cases, and progressive disease (PD) in 8 cases. After two cycles of treatment, the mean scores of global QOL and all 5 functioning scales except the cognitive function increased significantly (P < 0.05). Mean scores of major general symptoms, hypodynamia and anorexia, and disease-related symptoms alleviated significantly. Both response rates of five functioning and global QOL were more than 44% after erlotinib treatment. Response rates of major general symptoms and disease-related symptoms varied from 14% to 76%. Patients with complete or partial response likely had improvement in the QOL response (P < 0.05), and the time to major symptom deterioration in those were significantly longer (P < 0.001) than that in patients with stable or even progressive disease. Erlotinib is effective to improve not only survival, but also tumor-related symptoms and quality of life in patients with advanced NSCLC previously treated with cisplatin-contained regimens. The improvement in the quality of life is positively correlated with objective tumor response.


Provider Feedback about Imaging Appropriateness by Using Scores from Order Entry Decision Support: Raw Rates Misclassify Outliers.
To determine the relevant physician- and practice-related factors that jointly affect the rate of low-utility imaging examinations (score of 1-3 out of 9) ordered by means of an order entry system that provides normative appropriateness feedback. This HIPAA-compliant study was approved by the institutional review board under an expedited protocol for analyzing anonymous aggregated administrative data. This is a retrospective study of approximately 250 000 consecutive scheduled outpatient advanced imaging examinations (computed tomography, magnetic resonance imaging, nuclear medicine) ordered by 164 primary care and 379 medical specialty physicians from 2008 to 2012. A hierarchical logistic regression model was used to identify multiple predictors of the probability that an examination received a low utility score. Physician- and practice-specific random effects were estimated to articulate (odds ratio) and quantify (intraclass correlation) interphysician variation. Fixed effects found to be statistically significant predictors of low-utility imaging included examination type, whether the examination was cancelled, status of the person entering the order, and the total number of examinations ordered by the clinician. Neither patient age nor sex had any effect, and there were no secular trends (year of study). The remaining amount of interphysician variation was moderate (intraclass correlation, 22%), whereas the variation between medical specialties and primary care practices was low (intraclass correlation, 5%). The estimated physician-specific effects had reliability of 70%, which makes them just suitable for identifying outliers. The authors found that 22% of the variation in the rate of low-utility examinations is attributable to ordering providers and 5% to their specialty or clinic.


Interactions of Alphavirus nsP3 Protein with Host Proteins.
Alphaviruses are members of the Togaviridae family and are grouped into two categories: arthritogenic and encephalitic. Arthritogenic alphavirus infections, as the name implies, are associated with arthritic outcomes while encephalitic alphavirus infections can lead to encephalitic outcomes in the infected host. Of the non-structural proteins (nsPs) that the viruses code for, nsP3 is the least understood in terms of function. Alphavirus nsP3s are characterized by regions with significantly conserved domain structure along with regions of high variability. Interactions of nsP3 with several host proteins have been documented including, stress granule-related proteins, dead box proteins, heat shock proteins, and kinases. In some cases, in addition to the interaction, requirement of the interaction to support infection has been demonstrated. An understanding of the proteomic network of nsP3 and the mechanisms by which these interactions support the establishment of a productive infection would make alphavirus nsP3 an interesting target for design of effective medical countermeasures.


Impulsivity and compulsivity in bulimia nervosa.
A primary objective of the current article is to investigate the relationship between impulsivity and compulsivity in patients with bulimia nervosa (BN). A second goal is to explore the relationship between impulsivity and compulsivity and related psychiatric problems. Two-hundred four females with BN completed several measures of impulsivity and compulsivity as well as measures of personality, substance use, eating pathology, and depression. Participants reported considerable variability on measures of impulsivity and compulsivity and these scores were positively correlated with each other. Impulsive-compulsive groups differed in personality, substance use, eating, and depression. These findings suggest that impulsivity and compulsivity can coexist in BN patients and that both traits may provide useful information about comorbid problems in women with BN.