Type II pneumocyte proliferation in vitro: problems and future directions.
In adult animals, the type II pneumocyte is progenitor of both the type I and type II alveolar epithelium. In primary culture, however, the fate of this cell is uncertain. Type II cells in culture lose their differentiated properties and eventually resemble type I cells, but a lack of specific markers has complicated the characterization of the phenotype acquired in vitro. Furthermore, limited proliferation of these cells in vitro has precluded definition of the relationship between type II cell proliferation and differentiation. Recent work in this laboratory has involved the correlation of flow cytometric cell cycle analysis with phenotype markers. Initial results indicate that isolation of type II cells induces cell cycle block similar to that sustained by other cell types in response to stress. In addition, preliminary evaluation of phenotype suggests that traditional markers become ambiguous beyond the 1st day of primary culture. These results raise concern related to the interpretation of experiments conducted in vitro. This report discusses the implications of these findings and directions for future work.


[Effect of ulinastatin on perioperative glycocalyx and lung function in patients undergoing mitral valve replacement surgery].
To explore the effect of ulinastatin on perioperative glycocalyx and lung function in patients undergoing mitral valve replacement surgery. Methods: Fourty patients, undergoing mitral valve replacement, were randomly allocated into a control group and an ulinastatin group, which were administrated 50 mL normal saline or 2×104 U/kg ulinastatin at the beginning of cardiopulmonary bypass (CPB), respectively. The radical artery blood was collected at 4 time points: After induction of anesthesia (T0), at 10 min after the start of CPB (T1), 1 h after the end of CPB (T2), and 8 h after operation. The concentration of syndecan-1 and TNF-α in blood was measured. Moreover, the blood gas analysis was preformed and the oxygen index (OI) and difference in alveolar arterial oxygen partial pressure (PA-aO2) were calculated at T0, T2, and T3. Results: There were no significant difference between the 2 groups in OI, PA-aO2, and the concentration of syndecan-1 and TNF-α at T0 (P>0.05). The concentration of syndecan-1 and TNF-α was significantly increased at T1 and T2 in the 2 groups, and reached peak at T2. Compared with the control group, the concentration of syndecan-1 and TNF-α was decreased in the ulinastatin group at T1, T2, and T3 (P<0.05). Compared with T0, OI was lower and PA-aO2 was higher at T2 and T3 in both groups, but the 2 indexes were improved in the ulinastatin group compared with those in the control group (P<0.05). Conclusion: Ulinastatin can improve the post-operative pulmonary ventilation function in patients with mitral valve replacement. The mechanism may be associated with the inhibition of TNF-α release and the reduction of glycocalyx shedding induced by ulinastatin.


Safety evaluation of a novel muramidase for feed application.
Safety evaluation of a muramidase produced by a Trichoderma reesei strain (safe lineage), expressing a muramidase gene isolated from Acremonium alcalophilum is presented. Intended use in feed of this enzyme is as digestive aid in broiler chickens. Muramidase 007, was non-mutagenic and non-clastogenic in vitro, and no adverse effects were observed in 90-day subchronic toxicity studies in rats at doses up to 1132 mg TOS/kg body weight/day. The enzyme did not exhibit, in vitro, skin, nor eye irritation potential. Acute aquatic toxicity evaluated on daphnia and algae showed absence of effect of the enzyme at the standard doses tested. Muramidase 007 was fully tolerated by broiler chickens in a 6-weeks tolerance study showing no adverse effects in any of the dietary treatments (0, 1×, 5× and 10× maximum recommended dose). In conclusion, Muramidase 007 is found to be toxicologically inert, and there are no worker's safety concerns if standard precautions are instituted and a non-dusty formulation is employed. Muramidase 007 is well tolerated by the target species (broiler chickens) and cause no harm to the environment. The beneficial safety evaluation of Muramidase 007 is in line with this type of enzyme that is found ubiquitously in nature.


Adenovirus-mediated suicide gene therapy for experimental bladder cancer.
To determine the feasibility, safety, and efficacy of suicide gene therapy using adenoviral-mediated herpes simplex virus thymidine kinase gene (HSV-tk) and the prodrug ganciclovir (GCV) in a murine model of human transitional cell carcinoma. We used a replication-defective adenoviral construct containing the beta-galactosidase gene (ADV/Rous sarcoma virus [RSV]-beta-gal) as a control or ADV/RSV-tk as the therapeutic vector under the transcriptional control of the RSV long-terminal repeat promoter. Transduction efficiency was assessed in vitro by infection of MBT-2 cells with ADV/RSV-beta-gal at various multiplicities of infection (MOI) utilizing 5-bromo-4-chlor-3-indolyl-beta-D-galactoside (X-gal) staining. Sensitivity of MBT-2 cells to the therapeutic vector was determined after infection with ADV/RSV-tk with or without GCV. Subcutaneous tumors were established in syngeneic C3H/He female mice with 5 x 10(5) MBT-2 cells. Optimal dosing of ADV/RSV-tk was determined by direct percutaneous tumor injection with increasing viral doses and treatment with GCV. Treatment efficacy, long-term survival, and toxicity were determined in separate, similar, controlled experiments. In vitro studies indicated greater than 95% transduction 96 hours after inoculation at an MOI of 3000 and a greater than 95% cell death rate with RSV-tk + GCV at an MOI of 61 or greater. In vivo experiments demonstrated an optimal viral dose of 3 x 10(8) plaque-forming units (pfu) and a greater than fourfold reduction in tumor growth for the animals treated with ADV/RSV-tk compared with control animals (P = 0.0013). Toxicity was limited to histologic evidence of hepatitis with ADV/RSV-tk doses greater than 3 x 10(8) pfu + GCV. Long-term survival of treatment animals was significantly increased over that of control animals (59%, P = 0.0001). ADV/RSV-tk with GCV treatment results in efficient gene transfer in vitro and provides effective therapy in experimental murine bladder cancer by significantly inhibiting tumor growth and improving host survival.


Stroke in Saudi Arabia: a review of the recent literature.
Stroke is a major cerebrovascular disease resulting in high mortality and persistent disability in adults across the world. Besides coronary heart disease and cancer, stroke is the commonest cause of death in most industrialized countries. Survivors of stroke are often left with severe mental and physical disabilities, which create a major social and economic burden, ranking as the second most common cause of death worldwide and a major source of morbidity. The Kingdom of Saudi Arabia (KSA) is the largest country in the Middle East occupying approximately four-fifths of the Arabian Peninsula supporting a population of more than 28 million. Stroke is becoming a rapidly increasing problem and an important cause of illness and deaths in Saudi Arabia. However, compared with the developed countries, research regarding the incidence, prevalence and their socio-demographic properties of stroke is still insufficient due to lack of appropriate studies being conducted in these specified areas. This review aims to discuss the range of the aspect of stroke in Saudi Arabia from the literature published.


Fasting enhances the response of arcuate neuropeptide Y-glucose-inhibited neurons to decreased extracellular glucose.
Fasting increases neuropeptide Y (NPY) expression, peptide levels, and the excitability of NPY-expressing neurons in the hypothalamic arcuate (ARC) nucleus. A subpopulation of ARC-NPY neurons ( approximately 40%) are glucose-inhibited (GI)-type glucose-sensing neurons. Hence, they depolarize in response to decreased glucose. Because fasting enhances NPY neurotransmission, we propose that during fasting, GI neurons depolarize in response to smaller decreases in glucose. This increased excitation in response to glucose decreases would increase NPY-GI neuronal excitability and enhance NPY neurotransmission. Using an in vitro hypothalamic explant system, we show that fasting enhances NPY release in response to decreased glucose concentration. By measuring relative changes in membrane potential using a membrane potential-sensitive dye, we demonstrate that during fasting, a smaller decrease in glucose depolarizes NPY-GI neurons. Furthermore, incubation in low (0.7 mM) glucose enhanced while leptin (10 nM) blocked depolarization of GI neurons in response to decreased glucose. Fasting, leptin, and glucose-induced changes in NPY-GI neuron glucose sensing were mediated by 5'-AMP-activated protein kinase (AMPK). We conclude that during energy sufficiency, leptin reduces the ability of NPY-GI neurons to sense decreased glucose. However, after a fast, decreased leptin and glucose activate AMPK in NPY-GI neurons. As a result, NPY-GI neurons become depolarized in response to smaller glucose fluctuations. Increased excitation of NPY-GI neurons enhances NPY release. NPY, in turn, shifts energy homeostasis toward increased food intake and decreased energy expenditure to restore energy balance.


Zonal ultracentrifuge for the separation of ribosomal subunits.
Ribosomal subunits were prepared by means of the Anderson zonal ultracentrifuge. With this technique it is possible to separate more than 300 milligrams of subunits with complete resolution in a single run, as compared with about 2 milligrams with conventional rotors. Superior resolution is achieved in the zonal ultracentrifuge, affording possibilities for the detection and preparation of minor ribosomal components.


Pregnancy and offspring after the appearance of breast cancer.
The objective of this study was to investigate the influence of pregnancy in breast cancer prognosis of women under the age of 35 years. Two hundred and forty-three women with breast cancer, from three oncology departments in Athens, were investigated. Twenty-one got pregnant (7.91%) 7-100 months after breast cancer diagnosis and in a median time period of 31 months. All women had mastectomy apart from 2 who had only lumpectomy as surgical procedure. Thirteen of 21 were treated with radiotherapy and 17 of 21 had also adjuvant chemotherapy mainly with CMF for 6 cycles. Sixteen children from 14 mothers were born and the rest of the patients underwent an abortion between the 2nd and 5th month of pregnancy. All children were healthy and grew up normally up to the age of 12-142 months (end of the study) and their median age of 51 months. Only 2 patients had stage III disease at diagnosis while the remaining 19 had stage I-IIb. Three cancer recurrences were observed (14.3%) after 7-84 months. One patient had a second primary-ovarian cancer 60 months after mastectomy. Recurrence rate and survival compared with those of nonpregnant women of the same age and the stages of disease were not different. To conclude: the present study indicates that healthy offsprings can be delivered from breast cancer patients, and pregnancy does not seem to play any role in tumor recurrence.


Cost-effectiveness analysis of ureteroscopic laser lithotripsy and shock wave lithotripsy in the management of ureteral calculi in eastern China.
It was the aim of this study to compare the efficiency and safety between shock wave lithotripsy (SWL) and ureteroscopic holmium laser lithotripsy (URL) methods for ureteral calculi while also determining which option is more cost-effective. During January 2008 to September 2009, a prospective randomized study was conducted to compare both modalities for the management of solitary radiopaque ureteral stones. Patient and stone characteristics, treatment outcome and charges were documented. Both options were compared using univariate statistical tests to identify the efficiency quotient and cost-effectiveness for ureteral calculi according to the stone location. A total of 257 patients were in the SWL group, while 269 were in the URL group. The efficiency quotients for SWL and URL were 0.81 and 0.88, respectively. The initial stone-free rate of URL for lower ureteral calculi was higher (p = 0.002), while the complication rate of SWL for upper ureteral calculi was lower (p = 0.027). The SWL group required lower hospitalization charges (USD 440 vs. 1,221; p < 0.001), lower total charges (USD 454 vs. 1,284; p < 0.001) and a shorter period of hospitalization (5.4 vs. 6.6 days; p < 0.001) compared with the URL group for all ureteral locations. For mid and lower ureteral calculi, the postoperative office visits of the URL group were fewer (1.03 vs. 1.1 times; p = 0.001). Primary in situ SWL for upper and middle ureteral calculi showed lower complication rates compared to URL and was more cost-effective in Eastern China. However, primary URL was a better option for treating lower ureteral stones with a higher stone-free rate but was more expensive.


A conformational change in PBX1A is necessary for its nuclear localization.
The fly homeodomain (HD) protein EXTRADENTICLE (EXD) is dependent on a second HD protein, HOMOTHORAX (HTH), for nuclear localization. We show here that in insect cells the mammalian homolog of EXD, PBX1A, shows a similar dependence on the HTH homologs MEIS1, 2, and 3 and the MEIS-like protein PREP1. Paradoxically, removal of residues N-terminal to the PBX1A HD abolishes interactions with MEIS/PREP but allows nuclear accumulation of PBX1A. We use deletion mapping and fusion to green fluorescent protein to map two cooperative nuclear localization signals (NLSs) in the PBX HD. The results of DNA-binding assays and pull-down experiments are consistent with a model whereby the PBX N-terminus binds to the HD and masks the two NLSs. In support of the model, a mutation in the PBX HD that disrupts contact with the N-terminus leads to constitutive nuclear localization. The HD mutation also increases sensitivity to protease digestion, consistent with a change in conformation. We propose that MEIS family proteins induce a conformational change in PBX that unmasks the NLS, leading to nuclear localization and increased DNA-binding activity. Consistent with this, PBX1 is nuclear only where Meis1 is expressed in the mouse limb bud.


Expression, localization, and regulation of aquaporin-1 to -3 in rat urothelia.
Although mammalian urothelia are generally considered impermeable to constituents of urine, in vivo studies in several species indicate urothelial transport of water and solutes under certain conditions. This study investigates the expression, localization, and regulation of aquaporin (AQP)-1, -2, and -3 in ureteral and bladder tissues in 48-h dehydrated and water-loaded female Wistar rats. Immunoblots of homogenates of whole ureter and bladder identified characteristic approximately 28- and 35- to 44-kDa bands for AQP-1, -2, and -3. AQP-1 was localized to capillary and arteriole endothelial cells, whereas AQP-2 and -3 circumferentially lined the epithelial cell membranes except for the apical membrane of the epithelial cells adjacent to the lumens of both ureter and bladder. AQP-2 was also present in epithelial cell cytoplasm. Dehydration resulted in 160-200% increases of AQP-3 signal and 24-49% increases of AQP-2 signal but no change in AQP-1 signal on immunoblots of homogenates of ureters and bladders. AQPs in genitourinary tract urothelia likely play a role in the regulation of epithelial cell volume and osmolality and may play a role in bulk water movement across urothelia.


Racial variations in interfacial behavior of lipids extracted from worn soft contact lenses.
To explore interfacial behaviors and effects of temperature and dilatation on dynamic properties of multilayered human tear lipids extracted from silicone hydrogel (SiH) lenses worn by asymptomatic Asian and white subjects. Interfacial properties of lipids extracted from Focus N&D lenses worn by 14 subjects continuously for 1 month were studied. The lipids were deposited on an air bubble immersed in a model tear electrolyte (MTE) solution to form 100 ± 20-nm-thick films. Surface pressure was recorded during slow expansion/contraction cycles to evaluate compressibility and hysteresis of lipid films. Films were also subjected to fast step-strain dilatations at temperatures of 22 to 45°C for their viscoelastic property assessment. Isocycles for Asian and white lipids were similar at low surface pressures but had distinctly different compressibility and hysteresis at dynamic pressures exceeding 30 mN/m. Rheological parameters of reconstituted lipids were also dissimilar between Asian and white. The elastic modulus E∞ for white lipids was 1.5 times higher than that for Asian lipids, whereas relaxation time (t) was on average 1.3 times higher for Asian. No significant changes were observed in rheological properties of both Asian and white lipids when temperature increased from 22.0 to 36.5°C. However, for white lipids, E∞ reduced considerably at temperatures higher than 42.0°C, whereas t remained unchanged. For Asian lipids, both E∞ and t started to decline as temperature increased to 38°C and higher. Higher elastic modulus of white lipids and elasticity threshold at certain deformations indicate stronger structure and intermolecular interactions as compared with more viscous Asian lipids. The differences in interfacial behaviors between Asian and white lipids may be associated with the differences in their chemical compositions.


The impact of HIV and antiretroviral therapy on TB risk in children: a systematic review and meta-analysis.
Children (<15 years) are vulnerable to TB disease following infection, but no systematic review or meta-analysis has quantified the effects of HIV-related immunosuppression or antiretroviral therapy (ART) on their TB incidence. Determine the impact of HIV infection and ART on risk of incident TB disease in children. We searched MEDLINE and Embase for studies measuring HIV prevalence in paediatric TB cases ('TB cohorts') and paediatric HIV cohorts reporting TB incidence ('HIV cohorts'). Study quality was assessed using the Newcastle-Ottawa tool. TB cohorts with controls were meta-analysed to determine the incidence rate ratio (IRR) for TB given HIV. HIV cohort data were meta-analysed to estimate the trend in log-IRR versus CD4%, relative incidence by immunological stage and ART-associated protection from TB. 42 TB cohorts and 22 HIV cohorts were included. In the eight TB cohorts with controls, the IRR for TB was 7.9 (95% CI 4.5 to 13.7). HIV-infected children exhibited a reduction in IRR of 0.94 (95% credible interval: 0.83-1.07) per percentage point increase in CD4%. TB incidence was 5.0 (95% CI 4.0 to 6.0) times higher in children with severe compared with non-significant immunosuppression. TB incidence was lower in HIV-infected children on ART (HR: 0.30; 95% CI 0.21 to 0.39). Following initiation of ART, TB incidence declined rapidly over 12 months towards a HR of 0.10 (95% CI 0.04 to 0.25). HIV is a potent risk factor for paediatric TB, and ART is strongly protective. In HIV-infected children, early diagnosis and ART initiation reduces TB risk. CRD42014014276.


Transition-metal-catalyzed laboratory-scale carbon-carbon bond-forming reactions of ethylene.
Ethylene, the simplest alkene, is the most abundantly synthesized organic molecule by volume. It is readily incorporated into transition-metal-catalyzed carbon-carbon bond-forming reactions through migratory insertions into alkylmetal intermediates. Because of its D2h symmetry, only one insertion outcome is possible. This limits byproduct formation and greatly simplifies analysis. As described within this Minireview, many carbon-carbon bond-forming reactions incorporate a molecule (or more) of ethylene at ambient pressure and temperature. In many cases, a useful substituted alkene is incorporated into the product.


Multifaceted radiomics for distant metastasis prediction in head & neck cancer.
Accurately predicting distant metastasis in head & neck cancer has the potential to improve patient survival by allowing early treatment intensification with systemic therapy for high-risk patients. By extracting large amounts of quantitative features and mining them, radiomics has achieved success in predicting treatment outcomes for various diseases. However, there are several challenges associated with conventional radiomic approaches, including: (1) how to optimally combine information extracted from multiple modalities; (2) how to construct models emphasizing different objectives for different clinical applications; and (3) how to utilize and fuse output obtained by multiple classifiers. To overcome these challenges, we propose a unified model termed as multifaceted radiomics (M-radiomics). In M-radiomics, a deep learning with stacked sparse autoencoder is first utilized to fuse features extracted from different modalities into one representation feature set. A multi-objective optimization model is then introduced into M-radiomics where probability-based objective functions are designed to maximize the similarity between the probability output and the true label vector. Finally, M-radiomics employs multiple base classifiers to get a diverse Pareto-optimal model set and then fuses the output probabilities of all the Pareto-optimal models through an evidential reasoning rule fusion (ERRF) strategy in the testing stage to obtain the final output probability. Experimental results show that M-radiomics with the stacked autoencoder outperforms the model without the autoencoder. M-radiomics obtained more accurate results with a better balance between sensitivity and specificity than other single-objective or single-classifier-based models.


CT-based pleural effusion volume estimation formula demonstrates low accuracy and reproducibility for traumatic hemothorax.
We aimed to evaluate the accuracy and reproducibility of the CT-based volume estimation formula V = d2 * h, where d and h represent the maximum depth and height of the effusion, for acute traumatic hemothorax. Prospectively identified patients with CT showing acute traumatic hemothorax were considered. Volumes were retrospectively estimated using d2 * h, then manually measured on axial images. Subgroup analysis was performed on borderline-sized hemothorax (200-400 mL). Measurements were repeated by three non-radiologists. Bland-Altman analysis was used to assess agreement between the two methods and agreement between raters for each method. A total of 46 patients (median age 34; 36 men) with hemothorax volume 23-1622 mL (median 191 mL, IQR 99-324 mL) were evaluated. Limits of agreement between estimates and measured volumes were -718 - +842 mL (± 202 mL). Borderline-sized hemothorax (n = 13) limits of agreement were -300 - +121 mL (± 114 mL). Of all hemothorax, 85 % (n = 39/46) were correctly stratified as over or under 300 mL, and of borderline-sized hemothorax, 54 % (n = 7/13). Inter-rater limits of agreement were -251 - +350, -694 - +1019, and -696 - +957 for the estimation formula, respectively, and -124 - +190, -97 - +111, and -96 - +46 for the measured volume. An estimation formula varies with actual hemothorax volume by hundreds of mL. There is low accuracy in stratifying hemothorax volumes close to 300 mL. Variability between raters was substantially higher with the estimation formula than with manual measurements.


Bacteria isolated from Bengal cat (Felis catus × Prionailurus bengalensis) anal sac secretions produce volatile compounds potentially associated with animal signaling.
In social animals, scent secretions and marking behaviors play critical roles in communication, including intraspecific signals, such as identifying individuals and group membership, as well as interspecific signaling. Anal sacs are an important odor producing organ found across the carnivorans (species in the mammalian Order Carnivora). Secretions from the anal sac may be used as chemical signals by animals for behaviors ranging from defense to species recognition to signaling reproductive status. In addition, a recent study suggests that domestic cats utilize short-chain free fatty acids in anal sac secretions for individual recognition. The fermentation hypothesis is the idea that symbiotic microorganisms living in association with animals contribute to odor profiles used in chemical communication and that variation in these chemical signals reflects variation in the microbial community. Here we examine the fermentation hypothesis by characterizing volatile organic compounds (VOC) and bacteria isolated from anal sac secretions collected from a male Bengal cat (Felis catus × Prionailurus bengalensis), a cross between the domestic cat and the leopard cat. Both left and right anal sacs of a male Bengal cat were manually expressed (emptied) and collected. Half of the material was used to culture bacteria or to extract bacterial DNA and the other half was used for VOC analysis. DNA was extracted from the anal sac secretions and used for a 16S rRNA gene PCR amplification and sequencing based characterization of the microbial community. Additionally, some of the material was plated out in order to isolate bacterial colonies. Three taxa (Bacteroides fragilis, Tessaracoccus, and Finegoldia magna) were relatively abundant in the 16S rRNA gene sequence data and also isolated by culturing. Using Solid Phase Microextraction (SPME) gas chromatography-mass spectrometry (GC-MS), we tentatively identified 52 compounds from the Bengal cat anal sac secretions and 67 compounds from cultures of the three bacterial isolates chosen for further analysis. Among 67 compounds tentatively identified from bacterial isolates, 51 were also found in the anal sac secretion. We show that the bacterial community in the anal sac consists primarily of only a few abundant taxa and that isolates of these taxa produce numerous volatiles that are found in the combined anal sac volatile profile. Several of these volatiles are found in anal sac secretions from other carnivorans, and are also associated with known bacterial biosynthesis pathways. This is consistent with the fermentation hypothesis and the possibility that the anal sac is maintained at least in part to house bacteria that produce volatiles for the host.


Characterization of a chorismate mutase from the potato cyst nematode Globodera pallida.
SUMMARY Some plant endoparasitic nematodes are biotrophic and induce remarkable changes in their hosts in order to ensure a continuous supply of food. Proteins secreted from oesophageal gland cells have been implicated in this pathogenic process. A potentially secreted chorismate mutase has been isolated from the potato cyst nematode Globodera pallida. The gene encoding this protein is expressed in the subventral oesophageal gland cells of the nematode, and the mRNA derived from this gene is only present in the early parasitic stages. Sequence analysis of this gene shows that, like other genes involved in the host-parasite interaction of plant parasitic nematodes, it is likely to have been acquired by horizontal gene transfer from bacteria. The presence of a signal peptide in the deduced amino acid sequence of the G. pallida chorismate mutase and its expression in the subventral oesophageal gland cells suggest that it is secreted from the nematode, pointing to a role for the protein in the host-parasite interaction. The shikimate pathway, of which chorismate mutase is normally a part, is not found in animals but is present in plants and bacteria. In plants it gives rise to a variety of compounds which are important in amino acid synthesis and defence signalling pathways, as well as auxins, which have been implicated in the early development of nematode feeding sites. The potential roles of a nematode chorismate mutase are discussed.


Investigational drug therapies for the treatment of gastroparesis.
Gastroparesis is defined by nausea, vomiting, pain, early satiety and bloating, and characterized by delayed gastric emptying without obvious structural abnormalities. Metoclopramide is widely used, increasing gastric emptying and inhibiting nausea and vomiting. Other drugs are available in certain countries and some are used 'off-label' because they increase gastric emptying or inhibit emesis. However, correlation between gastroparesis symptoms and rates of gastric emptying is poor. For anti-emetic drugs, dose-ranging and Phase III trials in gastroparesis are lacking. Areas covered: Gastric motility may still be disordered, leading to nausea, even though gastric emptying is unchanged. One hypothesis is that interstitial cells of Cajal (ICC) are damaged by diabetes leading to gastric dysrhythmia and nausea. Novel approaches to treatment of nausea also include the use of ghrelin receptor agonists, highlighting a link between appetite and nausea. Expert opinion: There is an urgent need to diversify away from historical drug targets. In particular, there is a need to control nausea by regulating ICC functions and/or by facilitating appetite via ghrelin receptor agonists. It is also important to note that different upper gastrointestinal disorders (gastroparesis, chronic unexplained nausea and vomiting, functional dyspepsia) are difficult to distinguish apart, suggesting wider therapeutic opportunity.


Structural and electrical properties of ZnO films deposited with low-temperature facing targets magnetron sputtering (FTS) system with changes in H2 and O2 flow rate.
ZnO has been studied as a strong candidate for high-quality TCO in accordance with increasing demand to replace ITO. The origin of n-doping in ZnO is not clearly understood, but recently, the H2 effect has received attention due to the role it plays in O-rich and O-poor conditions. In spite of recent rapid developments, controlling the electrical conductivity of ZnO has remained a major challenge. To control the electrical conductivity of ZnO, this study was performed using an FTS system with H2 and O2 addition at low processing temperature. The structural and electrical properties of ZnO thin films deposited at various H2 and O2 flow rates were investigated using XRD and a sheet resistance meter. In response to changes in H2 and O2 flow rates, the crystallization and related grain size of the ZnO films were somewhat changed. The sheet resistance increased from approximately 10(-1) to approximately 10(4) M ohm/sq. when the O2 flow rate was increased, and the resistance decreased from approximately 10(-1) to approximately 10(-4) M ohm/sq. when the H2 flow rate was increased. The increase of sheet resistance with O2 flow rates could be explained by decrease of oxygen vacancies. The decrease of sheet resistance with H2 flow rates could be explained by increase of the electrons from interstitial hydrogen atoms. The plasma characteristics were analyzed using optical emission spectroscopy (OES). But, the overall spectrum did not change with the H2 and O2 gas flow rates. So, the dramatic changes in the electrical properties of ZnO thin films could be considered to be a result of changes in chemical composition of the thin films rather than the plasma status.


Research Status of Dendrimer Micelles in Tumor Therapy for Drug Delivery.
Dendrimers are a family of polymers with highly branched structure, well-defined composition, and extensive functional groups, which have attracted great attention in biomedical applications. Micelles formed by dendrimers are ideal nanocarriers for delivering anticancer agents due to the explicit study of their characteristics of particle size, charge, and biological properties such as toxicity, blood circulation time, biodistribution, and cellular internalization. Here, the classification, preparation, and structure of dendrimer micelles are reviewed, and the specific functional groups modified on the surface of dendrimers for tumor active targeting, stimuli-responsive drug release, reduced toxicity, and prolonged blood circulation time are discussed. In addition, their applications are summarized as various platforms for biomedical applications related to cancer therapy including drug delivery, gene transfection, nano-contrast for imaging, and combined therapy. Other applications such as tissue engineering and biosensor are also involved. Finally, the possible challenges and perspectives of dendrimer micelles for their further applications are discussed.


Phenotypic flexibility in metabolic adjustments and digestive function in white-shouldered starlings: responses to short-term temperature acclimation.
Changing the intrinsic rate of metabolic heat production is the main adaptive strategy for small birds to cope with different ambient temperatures. In this experiment, we tested the hypothesis that the small passerine, white-shouldered starlings (Sturnus sinensis), can modulate basal metabolism under temperature acclimation by changing the morphological, physiological and biochemical states of their tissues and organs. We measured the effects of temperature on body mass, basal metabolic rate (BMR), wet mass of various internal organs, state 4 respiration (S4R) and cytochrome c oxidase (CCO) activities in the pectoral muscle and organs, metabolites in the pectoral muscle, energy intake, histological dynamics and the activities of duodenal digestive enzymes. Warm acclimation decreased BMR to a greater extent than cold acclimation. At the organ level, birds in the cold-acclimated group had significantly heavier intestines but significantly lighter pectoral muscles. At the cellular level, birds in the cold-acclimated group showed significantly higher S4R in the liver and heart and CCO activity in the liver and kidney at both the mass-specific and whole-organ levels. A metabolomic analysis of the pectoral tissue revealed significantly higher lipid decomposition, amino acid degradation, ATP hydrolysis, and GTP and biotin synthesis in cold-acclimated birds. Acclimation to cold significantly increased the gross energy intake (GEI), feces energy (FE) and digestive energy intake (DEI) but significantly decreased the digestive efficiency of these birds. Furthermore, cold-acclimated birds had a higher maltase activity and longer villi in the duodenum. Taken together, these data showed that white-shouldered starlings exhibited high phenotypic flexibility in metabolic adjustments and digestive function under temperature acclimation, consistent with the notion that small birds cope with the energy challenges presented by a cold environment by modulating tissue function in a way that would affect BMR.


An open-label phase I pilot study of continuous intrapleural infusion of escalated doses of methotrexate in malignant pleural mesothelioma.
The aim of this study was to evaluate the toxicity from escalated methotrexate (MTX) doses infused intrapleural over 5 days and to determine pleural and systemic drug levels with this chemotherapeutic approach. Five patients with malignant pleural mesothelioma were treated with 3 cycles of intrapleural MTX infused through a pigtail catheter inserted in the pleural space. MTX levels were estimated in the pleural fluid and serum once daily throughout the treatment cycles. Fourteen days between cycles were calculated from the last day of the previous one. The total dose for each cycle was infused over 5 days with simultaneous intravenous calcium folinate. The total cycle dose for the first, second, and third cycles were: 300, 501, and 750.5 mg/m, respectively. The mean serum MTX level was 1.72 µmole/L, whereas that of the pleural fluid was 503.224 µmole/L. The mean serum/pleural ratio was 0.00396, whereas the pleural/serum ratio was 396.21. No remarkable toxicity was observed in the 5 patients except for patient 1 who developed fluid leakage around the puncture site. Patient 2 developed grade I hepatotoxicity and both patients developed grade I pleuritic chest pain and dry irritative cough. This study demonstrates no grade II toxicity from 750.5 mg/m of MTX infused intrapleural over 5 days. This approach allows attaining MTX pleural levels that are 95 to 3000 times higher than systemic serum levels, with minimal toxicity. The results mandate performing this trial on a wider scale as a preliminary step for a formal phase II study.


Metabolic Compensation of Fitness Costs Is a General Outcome for Antibiotic-Resistant Pseudomonas aeruginosa Mutants Overexpressing Efflux Pumps.
It is generally assumed that the acquisition of antibiotic resistance is associated with a fitness cost. We have shown that overexpression of the MexEF-OprN efflux pump does not decrease the fitness of a resistant Pseudomonas aeruginosa strain compared to its wild-type counterpart. This lack of fitness cost was associated with a metabolic rewiring that includes increased expression of the anaerobic nitrate respiratory chain when cells are growing under fully aerobic conditions. It was not clear whether this metabolic compensation was exclusive to strains overexpressing MexEF-OprN or if it extended to other resistant strains that overexpress similar systems. To answer this question, we studied a set of P. aeruginosa mutants that independently overexpress the MexAB-OprM, MexCD-OprJ, or MexXY efflux pumps. We observed increased expression of the anaerobic nitrate respiratory chain in all cases, with a concomitant increase in NO3 consumption and NO production. These efflux pumps are proton/substrate antiporters, and their overexpression may lead to intracellular H+ accumulation, which may in turn offset the pH homeostasis. Indeed, all studied mutants showed a decrease in intracellular pH under anaerobic conditions. The fastest way to eliminate the excess of protons is by increasing oxygen consumption, a feature also displayed by all analyzed mutants. Taken together, our results support metabolic rewiring as a general mechanism to avoid the fitness costs derived from overexpression of P. aeruginosa multidrug efflux pumps. The development of drugs that block this metabolic "reaccommodation" might help in reducing the persistence and spread of antibiotic resistance elements among bacterial populations.IMPORTANCE It is widely accepted that the acquisition of resistance confers a fitness cost in such a way that in the absence of antibiotics, resistant populations will be outcompeted by susceptible ones. Based on this assumption, antibiotic cycling regimes have been proposed in the belief that they will reduce the persistence and spread of resistance among bacterial pathogens. Unfortunately, trials testing this possibility have frequently failed, indicating that resistant microorganisms are not always outcompeted by susceptible ones. Indeed, some mutations do not result in a fitness cost, and in case they do, the cost may be compensated for by a secondary mutation. Here we describe an alternative nonmutational mechanism for compensating for fitness costs, which consists of the metabolic rewiring of resistant mutants. Deciphering the mechanisms involved in the compensation of fitness costs of antibiotic-resistant mutants may help in the development of drugs that will reduce the persistence of resistance by increasing said costs.


[The characteristics of the clinical course and diagnosis of acute cholecystitis complicated by jaundice].
The clinical picture of acute cholecystitis complicated by jaundice has four main types: with the prevailing syndrome of inflammation of the gallbladder, of the pancreatic syndrome, of the cholangitis syndrome and of the profound pain syndrome by the type of renal colic. Echography is thought to be an informative preoperative method of diagnostics of the cause of jaundice, its significance being increased when combined with the percutaneous transhepatic cholangiography (94.4%). The patients must be operated upon within 24-28 hours. The intervention volume must be adequate to the type of the injury independent of the patient's age and of the degree of concomitant diseases.


Single Na+ channels activated by veratridine and batrachotoxin.
Voltage-sensitive Na+ channels from rat skeletal muscle plasma membrane vesicles were inserted into planar lipid bilayers in the presence of either of the alkaloid toxins veratridine (VT) or batrachotoxin (BTX). Both of these toxins are known to cause persistent activation of Na+ channels. With BTX as the channel activator, single channels remain open nearly all the time. Channels activated with VT open and close on a time scale of 1-10 s. Increasing the VT concentration enhances the probability of channel opening, primarily by increasing the rate constant of opening. The kinetics and voltage dependence of channel block by 21-sulfo-11-alpha-hydroxysaxitoxin are identical for VT and BTX, as is the ionic selectivity sequence determined by bi-ionic reversal potential (Na+ approximately Li+ greater than K+ greater than Rb+ greater than Cs+). However, there are striking quantitative differences in open channel conduction for channels in the presence of the two activators. Under symmetrical solution conditions, the single channel conductance for Na+ is about twice as high with BTX as with VT. Furthermore, the symmetrical solution single channel conductances show a different selectivity for BTX (Na+ greater than Li+ greater than K+) than for VT (Na+ greater than K+ greater than Li+). Open channel current-voltage curves in symmetrical Na+ and Li+ are roughly linear, while those in symmetrical K+ are inwardly rectifying. Na+ currents are blocked asymmetrically by K+ with both BTX and VT, but the voltage dependence of K+ block is stronger with BTX than with VT. The results show that the alkaloid neurotoxins not only alter the gating process of the Na+ channel, but also affect the structure of the open channel. We further conclude that the rate-determining step for conduction by Na+ does not occur at the channel's "selectivity filter," where poorly permeating ions like K+ are excluded.


The BioFilm Ring Test: a Rapid Method for Routine Analysis of Pseudomonas aeruginosa Biofilm Formation Kinetics.
Currently, few techniques are available for the evaluation of bacterial biofilm adhesion. These detection tools generally require time for culture and/or arduous handling steps. In this work, the BioFilm Ring Test (BRT), a new technology, was used to estimate the biofilm formation kinetics of 25 strains of Pseudomonas aeruginosa, isolated from the sputum of cystic fibrosis (CF) patients. The principle of the new assay is based on the mobility measurement of magnetic microbeads mixed with a bacterial suspension in a polystyrene microplate. If free to move under the magnetic action, particles gather to a visible central spot in the well bottom. Therefore, the absence of spot formation in the plate reflects the bead immobilization by a biofilm in formation. The BRT device allowed us to classify the bacterial strains into three general adhesion profiles. Group 1 consists of bacteria, which are able to form a solid biofilm in <2 h. Group 2 comprises the strains that progressively set up a biofilm during 24 h. Lastly, group 3 includes the strains that stay in a planktonic form. The grouping of our strains did not differ according to culture conditions, i.e., the use of different sets of beads or culture media. The BRT is shown to be an informative tool for the characterization of biofilm-forming bacteria. Various application perspectives may be investigated for this device, such as the addition of antibiotics to the bacterial suspension to select which would have the ability to inhibit the biofilm formation.


Projected inhibition of platelet aggregation with ticagrelor twice daily vs. clopidogrel once daily based on patient adherence data (the TWICE project).
Twice daily dosing is often perceived as inferior to once daily dosing due to a higher likelihood of missing a dose. However, more important is the extent to which drug action is maintained when doses are delayed or missed. We compared the estimated inhibition of platelet aggregation (eIPA) for ticagrelor twice daily and clopidogrel once daily, based on their pharmacokinetic/ pharmacodynamic relationships and patient dosing history data. Drug dosing histories of 5014 patients prescribed cardiovascular medications (primarily antihypertensive medicines) were extracted from an electronically compiled dosing history database. eIPA levels were simulated for 677 twice daily and 677 once daily dosing histories over a 30 day period, based on published onset/offset models for ticagrelor and clopidogrel IPA characteristics. While many patients treated twice daily missed at least one dose in 30 days, only 25.7% missed two consecutive doses. By comparison, 46.8% of patients treated once daily missed at least one dose. Simulations based on patient adherence over time showed that the average mean eIPA for ticagrelor twice daily remained significantly higher than for clopidogrel once daily (81.1% vs. 55.0%, P < 0.001). Ticagrelor twice daily patients had an eIPA below 10% for 0.20% of the 30 day period compared with 2.05% for clopidogrel once daily (P = 0.0001). The projected level of platelet inhibition remained higher for ticagrelor twice daily than clopidogrel once daily, mainly due to the higher eIPA level achieved with ticagrelor and the relatively low likelihood of missing two consecutive twice daily doses. This modelling and simulation study suggests a therapeutic benefit of ticagrelor over clopidogrel when taking into account the most common dosing omissions.


Effect of barium on cell volume regulation in rabbit proximal straight tubules.
Rabbit proximal straight tubules swell abruptly when exposed to hypotonic medium but then shrink in a few minutes as they approach their base-line volume following loss of solute and water. Potassium, the major intracellular cation, as well as sodium, is lost during this process. In the present experiments, we studied hypotonic cell volume regulation in the presence of barium, an agent reported to decrease potassium permeability. Exposure to BaCl2 significantly prolonged hypotonic volume recovery in a dose-dependent manner. Tubules depleted of potassium and loaded with sodium chloride by exposure to 10(-4) M ouabain for 1 h swelled osmometrically and subsequently volume regulated in dilute medium. Volume regulation in such tubules is a consequence of transbasement membrane hydrostatic forces. By contrast, tubules similarly loaded with sodium, but also exposed to 10(-3) M BaCl2, volume regulated only minimally in dilute medium, suggesting BaCl2 might also affect sodium movement. However, hypotonic volume regulation was restored in sodium-loaded BaCl2-treated tubules when cells were more effectively depleted of potassium by incubation in 0-mM potassium medium. We conclude that barium retards hypotonic volume regulation primarily because of its effect on potassium movement.


Inkjet-printed multicolor arrays of highly luminescent nanocrystal-based nanocomposites.
Inkjet technology is a compelling method for the flexible and cost-effective printing of functional inks. We show that nanocomposite solutions based on polystyrene and differently sized core/shell-type nanocrystals (NCs) formed by a CdSe core coated with a shell of ZnS (CdSe@ZnS) in a single solvent, chloroform, can be reliably dispensed into luminescent, multicolor pixel arrays. This study demonstrates the relevance of parameters like polymer concentration and nozzle diameter, highlighting how the optimal conditions to print NCs embedded in 5 wt% polystyrene nanocomposite are given by a 70-microm-diameter nozzle. The obtained structures show that the bright size-dependent emission of the NCs in the nanocomposite is retained in the printed pixels.


Iodine Biofortification of Apples and Pears in an Orchard Using Foliar Sprays of Different Composition.
Many people across the world suffer from iodine (I) deficiency and related diseases. The I content in plant-based foods is particularly low, but can be enhanced by agronomic biofortification. Therefore, in this study two field experiments were conducted under orchard conditions to assess the potential of I biofortification of apples and pears by foliar fertilization. Fruit trees were sprayed at various times during the growing season with solutions containing I in different concentrations and forms. In addition, tests were carried out to establish whether the effect of I sprays can be improved by co-application of potassium nitrate (KNO3) and sodium selenate (Na2SeO4). Iodine accumulation in apple and pear fruits was dose-dependent, with a stronger response to potassium iodide (KI) than potassium iodate (KIO3). In freshly harvested apple and pear fruits, 51% and 75% of the biofortified iodine was localized in the fruit peel, respectively. The remaining I was translocated into the fruit flesh, with a maximum of 3% reaching the core. Washing apples and pears with running deionized water reduced their I content by 14%. To achieve the targeted accumulation level of 50-100 μg I per 100 g fresh mass in washed and unpeeled fruits, foliar fertilization of 1.5 kg I per hectare and meter canopy height was required when KIO3 was applied. The addition of KNO3 and Na2SeO4 to I-containing spray solutions did not affect the I content in fruits. However, the application of KNO3 increased the total soluble solids content of the fruits by up to 1.0 °Brix compared to the control, and Na2SeO4 in the spray solution increased the fruit selenium (Se) content. Iodine sprays caused leaf necrosis, but without affecting the development and marketing quality of the fruits. Even after three months of cold storage, no adverse effects of I fertilization on general fruit characteristics were observed, however, I content of apples decreased by 20%.


Prions of fungi: inherited structures and biological roles.
The term 'prion' means an infectious protein that does not need an accompanying nucleic acid. There are six fungal prions, including four self-propagating amyloids and two enzymes that are necessary to activate their inactive precursors. Here we explore the scope of the prion phenomenon, the biological and evolutionary roles of prions, the structural basis of the amyloid prions and the prominent role of chaperones (proteins that affect the folding of other proteins) and other cellular components in prion generation and propagation.


[Effect of nitroglycerin on vasodilation at high altitude].
After more than centenary successful use of nitroglycerin in clinical practice, scientists revealed that its medicinal effect is based on release of potent vasodilator nitric oxide (NO). Moreover, the experiments showed that NO plays an important role in hypoxia vasodilator mechanisms. Since nitroglycerin is an exogenous NO donor and moderate hypoxia facilitates release of endogenous NO, we suggested that nitroglycerin effects are changed in high altitude. To examine this suggestion, we have carried out a standard nitroglycerin test for healthy volunteers living in high and low altitude areas. Comparison of obtained results showed that the use of oral nitroglycerin in high altitude areas is accompanied with significant prolonged decrease in blood pressure and total vascular resistance. So, we first found that high altitude hypoxia strengthens and extends nitroglycerin-induced peripheral vasodilation in healthy subjects. This effect might be caused by additive vasodilator effect of nitroglycerin and moderate hypoxia. This data should be taken into account when prescribing exogenous and endogenous NO donors to treat patients in high altitude areas.


"They Kept Going for Answers": Knowledge, Capacity, and Environmental Health Literacy in Michigan's PBB Contamination.
The Michigan PBB Oral History Project documented community residents' descriptions of a large-scale chemical contamination-the PBB contamination-that occurred in Michigan in 1973. These oral histories document residents' and others' experiences during and after the contamination. We conducted a grounded theory qualitative analysis of 31 oral histories to examine the experiences of community members, researchers, lawyers, and others who actively sought out and contributed essential information about the contamination and its impacts. Our findings highlight several challenges encountered in the development of this knowledge including four central themes-contested knowledge, community skills, inaction, and uncertainty. Integrating environmental health literacy, community capacity, and contested illness frameworks, we examine the contributions of community residents, scientists (from inside and outside the community), and others to the development of knowledge to inform decisions and sustain action regarding this large-scale contamination. We close with a discussion of lessons learned regarding efforts to build environmental health knowledge within uncertain and often contested contexts and for promoting environmental health and action related to large-scale chemical contaminations. Our findings suggest the importance of integrated frameworks for examining and promoting the critical role of community skills, leadership, participation, sense of community, and community power in promoting environmental health.


Dose-Banding of Intravenous Piperacillin-Tazobactam in Pediatric Surgical Inpatients.
Antimicrobial doses in children are often prescribed by using an individually calculated dose per weight (e.g., mg/kg) or based on body surface area. Dosing errors are the most commonly reported medication errors in children. A "dose-banding" strategy is frequently used for some over-the-counter drugs to prevent dosing errors. It could also lead to efficiencies by enabling batch preparation of intravenous (IV) medications in hospitals. To evaluate whether use of dose-banding for IV piperacillin-tazobactam results in acceptable dose variation from standard practice of individualized prescription of 100 mg/kg in children. We conducted a historically controlled intervention study comparing prescriptions of IV piperacillin-tazobactam before vs. after introduction of dose-banding prescribing guidance for surgical inpatients weighing >5 kg and <16 years of age at the tertiary referral pediatric hospital in Western Australia. Dose-banding of IV piperacillin-tazobactam (with a maximum of 15% departure from the recommended milligram-per-weight dose of 100 mg/kg) resulted in similar overall variation of prescribed dose in comparison to individualized milligram-per-weight (non-dose-banded) prescribing. There was a trend toward fewer prescriptions with large variance (>30% variation from the 100-mg/kg dose) in the dose-banded compared to the non-dose-banded group (1/140 vs. 5/105; p = 0.09). Our study showed dose-banding of IV piperacillin-tazobactam resulted in acceptable variation when compared to individualized milligram-per-weight dosing in children. Prospectively designed controlled trials are warranted to determine whether dose-banding could reduce medication errors and optimize use of hospital resources. Implications for future practice could include faster batch preparation, shorter checking and dispensing time, and reduction in drug wastage.


Combining Metabolomics and Experimental Evolution Reveals Key Mechanisms Underlying Longevity Differences in Laboratory Evolved Drosophila melanogaster Populations.
Experimental evolution with Drosophila melanogaster has been used extensively for decades to study aging and longevity. In recent years, the addition of DNA and RNA sequencing to this framework has allowed researchers to leverage the statistical power inherent to experimental evolution to study the genetic basis of longevity itself. Here, we incorporated metabolomic data into to this framework to generate even deeper insights into the physiological and genetic mechanisms underlying longevity differences in three groups of experimentally evolved D. melanogaster populations with different aging and longevity patterns. Our metabolomic analysis found that aging alters mitochondrial metabolism through increased consumption of NAD+ and increased usage of the TCA cycle. Combining our genomic and metabolomic data produced a list of biologically relevant candidate genes. Among these candidates, we found significant enrichment for genes and pathways associated with neurological development and function, and carbohydrate metabolism. While we do not explicitly find enrichment for aging canonical genes, neurological dysregulation and carbohydrate metabolism are both known to be associated with accelerated aging and reduced longevity. Taken together, our results provide plausible genetic mechanisms for what might be driving longevity differences in this experimental system. More broadly, our findings demonstrate the value of combining multiple types of omic data with experimental evolution when attempting to dissect mechanisms underlying complex and highly polygenic traits such as aging.


Preference for Shelters at Different Developmental Stages of Chinese Mitten Crab (Eriocheir sinensis).
A shelter is a good habitat for aquatic organisms, which could aid in avoiding cannibalism and facilitate predation. Chinese Mitten Crab (Eriocheir sinensis) is an important aquaculture species with troglodytism and nocturnal habit. To clarify the preference for shelters at different developmental stages of E. sinensis, different shelters (mud, sand, grass and rocks) were selected for comparison. These results indicated that juvenile crabs had a significant preference for grass; button-sized crabs preferred to hide in mud; and the favorite shelters for parent crabs were rocks, followed by mud. E. sinensis in three stages all showed concealing behavior. The concealing behavior of juvenile crabs was the most significant, followed by button-sized and parent crabs. Additionally, E. sinensis held a low hiding rate at night but a high hiding rate during the daytime due to nocturnal habits. These findings will help to better understand the habits of E. sinensis and provide a reference for resource restoration, habitat construction and the restoration of E. sinensis.


Immunological changes in acute myocardial infarction.
This study was undertaken to investigate troponin and lymphocyte subset changes in acute myocardial infarctions (AMI) and to correlate these changes with disease variables. Forty-five patients with AMI admitted to the Coronary Care Unit, Jordan University Hospital and Queen Alia Heart Institute at King Hussein Medical Center, Amman, Jordan during the period November 1999 through to April 2000 were included in the study. Forty-five patients with non cardiac conditions were selected as a control group. Tests performed include; determination of the percentages of B-lymphocytes, T-lymphocytes and T-lymphocyte subsets by flow cytometry, measurements of serum cardiac troponin I (cTnI) by microparticle enzyme immunoassay and determination of minor blood groups by the gel test. A significant increase in the percentages of CD8+ and CD19+ cells combined with a significant decrease in the percentages of CD3+ and CD4+ cells as well as a decrease of CD4+/CD8+ ratio were documented in patients with AMI 24 hours after admission to the hospital. Except for CD19+ cells, all of cell types assayed for returned to their normal percentages before discharge of patients. Very low CD4+ cell percentages and CD4+/CD8+ ratio were found to be poor prognostic signs of AMI. Serum cTnI levels which were elevated in all patients correlate very well with the decreased CD4+ cell percentages, and the decreased CD4+/CD8+ cell ratio and they seem to correlate with the extensiveness of infarction. Troponin and lymphocyte subset changes, on the other hand, did not correlate with the number of vessels diseased or the risk factors for AMI. Finally, a statistically significant association was observed between the Le (a-b-) phenotype and AMI. Immunologic change seem to accompany or follow AMI and changes in T-lymphocyte subsets and cTnI can be regarded as prognostic markers in AMI but these changes are independent of risk factors and the number of vessels diseased.


Evaluating restoration trajectories using DNA metabarcoding of ground-dwelling and airborne invertebrates and associated plant communities.
Invertebrates are important for restoration processes as they are key drivers of many landscape-scale ecosystem functions; including pollination, nutrient cycling and soil formation. However, invertebrates are often overlooked in restoration monitoring because they are highly diverse, poorly described, and time-consuming to survey, and require increasingly scarce taxonomic expertise to enable identification. DNA metabarcoding is a relatively new tool for rapid survey that is able to address some of these concerns, and provide information about the taxa with which invertebrates are interacting via food webs and habitat. Here, we evaluate how invertebrate communities may be used to determine ecosystem trajectories during restoration. We collected ground-dwelling and airborne invertebrates across chronosequences of mine-site restoration in three ecologically disparate locations in Western Australia and identified invertebrate and plant communities using DNA metabarcoding. Ground-dwelling invertebrates showed the clearest restoration signals, with communities becoming more similar to reference communities over time. These patterns were weaker in airborne invertebrates, which have higher dispersal abilities and therefore less local fidelity to environmental conditions. Although we detected directional changes in community composition indicative of invertebrate recovery, patterns observed were inconsistent between study locations. The inclusion of plant assays allowed identification of plant species, as well as potential food sources and habitat. We demonstrate that DNA metabarcoding of invertebrate communities can be used to evaluate restoration trajectories. Testing and incorporating new monitoring techniques such as DNA metabarcoding is critical to improving restoration outcomes.


Specific killing of Rb mutant cancer cells by inactivating TSC2.
The retinoblastoma (Rb) tumor suppressor is often inactivated in cancers. To identify genes that can be used to specifically target such cancers, we carried out a genetic screen in Drosophila. We identified gig (fly TSC2) and found that inactivation of rbf (fly Rb) and gig synergistically induced cell death. Interestingly, inactivation of TSC2 specifically kills Rb mutant cancer cells under stress conditions, which is correlated with an inhibition of tumor growth. We show that cancer cell killing induced by concomitant inactivation of Rb and TSC2 is mediated by increased cellular stress, including oxidative stress. Inactivation of TSC2 and Rb synergistically induce oxidative stress via increased protein synthesis, inhibited de novo lipid synthesis, and decreased reactive oxygen species scavenger enzyme SOD2 induction.


Resource stability and geographic isolation are associated with genome divergence in western Palearctic crossbills.
While many conifers produce annually variable seed crops, serotinous species (which hold seeds in cones for multiple years) represent unusually stable food resources for seed predators. Such stability is conducive to residency and potentially population divergence of consumers as exemplified by the Cassia crossbill (Loxia sinesciuris) in North America. We used genotyping by sequencing (GBS) to test whether three Mediterranean subspecies of common crossbills (L. curvirostra) associated with the serotinous Aleppo pine (Pinus halepensis) were more genetically distinct than European crossbills associated with nonserotinous conifers. We assembled a Cassia crossbill draft genome as a reference for mapping GBS reads and as a first step towards a more contiguous genome assembly. We found clear patterns of genetic divergence for each of the P. halepensis-associated subspecies. Geographic isolation, as promoted by resource stability and residency, is associated with genetic divergence of two of these subspecies. However, geographic isolation cannot account for divergence of L. c. hispana. Instead, resource stability likely contributed to divergence by reducing dispersal and increasing resource competition that may limit breeding by immigrants. In contrast, we found no differentiation among common crossbills associated with less stable resources, and only slight differentiation between common crossbills and parrot crossbills (L. pytyopsittacus). The substantial morphological divergence between common and parrot crossbills has likely originated or been maintained by selection despite gene flow generated by spatiotemporal resource fluctuation. Our results indicate that phenological as well as morphological characteristics of conifers have influenced crossbill diversification, and suggest a possible link between resource stability and population divergence.


[Experience with the use of parlodel in the treatment of Parkinson patients].
The dopamine agonist parlodel was given to 42 patients with parkinsonism for several months. The drug proved effective in more than one-third of the patients. Different side-effects were observed in almost half of the patients. Parlodel may be used alone in mild cases but generally it is used as an adjunct to L-DOPA therapy. The optimum dose of parlodel is individual and varies within a wide range.


Vocal Symptoms and Voice Quality in Children With Allergy and Asthma.
The background for dysphonia is multifactorial, and health-related factors have been listed among the factors affecting voice. In previous studies with adult participants, allergy and asthma have been indicated to have a connection to vocal symptoms. With the majority of previous research being studies involving adult participants, it is unclear what the effect of allergy and asthma on children's voices is. The aim of this study was to investigate if allergies and asthma are risk factors for having vocal symptoms. The material was collected through paper questionnaires distributed to the parents of new pediatric patients at an allergy clinic. The participants were 108 children aged 9 months to 17 years and 1 month. Of the children whose parents had filled in the questions on vocal symptoms, 18.2% (n = 18) had frequently occurring vocal symptoms, which was defined as having two or more vocal symptoms every week or more often. The most common vocal symptoms were throat clearing and coughing. There was a significant connection between inhalant allergy and having frequently occurring vocal symptoms. The connection between cough that lasted for more than 4 weeks and having frequently occurring vocal symptoms was also significant. In this study, we found no significant connection between having an asthma diagnosis and having frequently occurring vocal symptoms. Based on the results of this study, voice screening for children with inhalant allergy would be advisable. Prolonged cough should be taken seriously and be treated, as the mechanical trauma caused by cough seems to have a connection to vocal symptoms.


Single subject task-related BOLD signal artifact in a real-time fMRI feedback paradigm.
Real-time functional magnetic resonance imaging (rtfMRI) has been proposed as a method of providing feedback to develop a participant's ability to control his or her own neuronal activity. However, this BOLD signal is vulnerable to contamination from nonneuronal sources that can also be shaped by the feedback provided. Here we illustrate an artifact found while training participants to control signal from an ROI in the insula. As the artifact was directly behind the eye and the experiment used an echo-planar imaging (EPI) sequence with phase encoding direction that included the orbits and the insula in the same line, we hypothesized that the artifact was due to eye motion. We demonstrate a reduced training effect when eyeball signal is regressed out of the data and reproduce the artifact with block design voluntary eye movement. Further, using independent components analysis on historical data, we find the artifact is common in BOLD data, but typically not task-correlated, even in tasks where one might expect differing amounts of eye movement in the active task blocks. The artifact, thus, does not significantly impact group results in typical fMRI experiments. Finally, we demonstrate this particular artifact can be avoided in rtfMRI experiments by ensuring that the phase encoding direction does not project any eye movement related artifact onto the ROI being used for feedback training. Our findings underscore the importance of taking great care in designing rtfMRI feedback procedures to avoid contamination with nonneuronal sources of BOLD signal alteration.


Association of human papillomavirus type 16 long control region mutation and cervical cancer.
The variation of human papillomavirus (HPV) genes or HPV variants demonstrates different risks of cervical cancer. Mutation in the long control region (LCR) at YY1-motifs is one of the mechanisms for enhancing viral oncogene expression during the course of cancer cell progression. In Thai women, cervical cancers are almost always associated with HPV16 variant sub-lineage Asian (HPV16As); however, the mechanism involved remains elusive. The aim of this study was to understand further the oncogenic potential of HPV16As. A total of 82 HPV16-positive specimens from Thai women were selected from formalin-fixed paraffin-embedded cervical tissues, and the full length E6 gene of each specimen was amplified and sequenced. LCRs of the HPV16As-positive cases were amplified and sequenced to analyze their polymorphisms. Transcriptional activities of the HPV16As LCRs were then compared with sub-lineage European (EUR), sub-lineage Asian-American 1 (AA1) and HPV16 prototype by insertion of the LCRs into the pGL3-Basic vector. The HPV16 DNA sequences were classified as HPV16 prototype (18.3%), Asian (As, 61%), Asian American-1 (AA1, 8.5%), European (EUR, 7.3%), Asian African-2 (AFR2, 3.7%) and Java-135C (J135C, 1.2%). The prevalence of HPV16As was 30% in low-grade squamous intraepithelial lesion (LSIL), while that in high-grade squamous intraepithelial lesion (HSIL) and squamous cell cervical carcinoma (SCC) were 63.9% and 66.7%, respectively, which demonstrates a significant association of HPV16As with the disease severity. LCR polymorphisms from 43 HPV16As positive cases were analyzed by PCR-sequencing. Thirty-eight nucleotide variation positions spanned nucleotide positions 7157-82. Ten new mutations found in the HPV16As LCRs were located predominantly at the enhancer and proximal to the 3'-end of the early promoter. The LCRs of the common HPV16As, EUR and AA1 showed 5, 13 and 23-fold higher activity than the HPV16 prototype LCR, while those of the new nucleotide variations of As showed 19 (As-sv1) and 30 (As-sv14) -fold higher activity than the HPV16 prototype. HPV16As DNA sequence variation, especially at the proximal to early promoter in the LCR, enhances transcriptional activity. This could be one of the possible mechanisms for HPV16As-associated cervical cancer development.


Multicenter Study of the Risk Factors for Colonization or Infection with Carbapenem-Resistant Enterobacteriaceae in Children.
Carbapenem-resistant Enterobacteriaceae (CRE) are increasingly identified in children in the United States, but data on the epidemiology of CRE in this population are limited. The objectives of this study were to characterize the risk factors for colonization or infection with CRE and describe the microbiologic characteristics of pediatric CRE isolates. We performed a multicenter matched case-control study from January 2011 to October 2015 at three tertiary care pediatric centers. Case patients were hospitalized children with CRE isolated from clinical cultures and were matched in a 2:1 ratio to control patients with carbapenem-susceptible Enterobacteriaceae (CSE). Risk factors for colonization or infection with CRE were then evaluated using a multivariable conditional logistic regression. Additionally, we comprehensively reported the antimicrobial susceptibility pattern for CRE isolates. Sixty-three case patients were identified and matched to 126 control patients. On multivariable analysis, antipseudomonal antibiotic exposure within the previous 3 months (odds ratio [OR], 5.20; 95% confidence interval [CI], 1.71 to 15.9; P = 0.004), prior surgery (OR, 6.30; 95% CI, 1.83 to 21.6; P = 0.003), and mechanical ventilation (OR, 12.4; 95% CI, 1.26 to 122; P = 0.031) were identified as risk factors for colonization or infection with CRE. Pediatric CRE isolates demonstrated relatively low rates of resistance to amikacin (5%) and ciprofloxacin (25%). Our findings support an important role for antibiotic stewardship interventions limiting the unnecessary use of antipseudomonal antibiotics as a strategy to prevent widespread emergence of CRE in children. Future studies should further characterize molecular determinants of antibiotic resistance among pediatric CRE isolates.


Effect of prolonged acquisition intervals for CT-perfusion analysis methods in patients with ischemic stroke.
The limited axial coverage of many computed tomography (CT) scanners poses a high risk on false negative findings in cerebral CT-perfusion (CTP) imaging. Axial coverage may be increased by moving the table back and forth during image acquisition. However, this method often increases the acquisition interval between CT frames, which may influence the CTP analysis. In this study, we evaluated the influence of different acquisition intervals on quantitative perfusion maps and infarct volumes by analyzing patient data with three CTP analysis methods. CT-perfusion data from 25 patients with ischemic stroke were used for this study. The acquisition interval was synthetically reduced from 1 to 5 s before calculating perfusion values, which included cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT). The color scaling of the perfusion was scaled such that the mean perfusion value had the same color-coding as the mean perfusion in the 1 s reference. Also, infarct core and penumbra volumes (summary map) were calculated using default thresholds of CBV and relative MTT (rMTT). The original, 1 s acquisition interval scan served as the reference standard. A commercial block-circulant singular value decomposition (bSVD) based method (ISP; Philips Healthcare), a non-commercial bSVD method, and a non-linear regression (NLR) model-based method were evaluated. Cerebral blood volume values generated with bSVD and NLR were not significantly different from the reference standard, while ISP showed significant differences for acquisition intervals of 3 and 4 s. MTT and CBF values generated with bSVD and ISP were significantly different for all acquisition intervals, whereas NLR did not show any significant differences. Calibrated perfusion maps were able to distinguish healthy from infarcted tissue up to an acquisition interval of 5 s for all methods. The infarct core volumes were significantly different for acquisition intervals of 2 (NLR) and 3 s (bSVD and ISP) or greater. For the penumbra volumes, NLR showed no significant differences, while bSVD and ISP showed significant differences for the 5 s interval and for all intervals, respectively. Visual inspection of the summary maps indicated minor differences between the reference standard and acquisition intervals of 4 s or less (ISP) and 5 s or less (bSVD and NLR). Altering the acquisition interval may introduce a bias in the perfusion parameters. Calibration of the visualization of the perfusion maps with increasing acquisition intervals allowed distinction between healthy and infarcted tissue. Infarct volumes based on relative MTT can be influenced by the acquisition interval, but visual inspection of the summary maps indicated minor differences between the reference standard and acquisition intervals up to 4 (ISP) and 5 s (bSVD and NLR). Taken together, axial coverage can be increased by prolonging the acquisition interval up to 5 s depending on the perfusion analysis.


Toca 511 gene transfer and treatment with the prodrug, 5-fluorocytosine, promotes durable antitumor immunity in a mouse glioma model.
Toca 511 (vocimagene amiretrorepvec) is a retroviral replicating vector encoding an optimized yeast cytosine deaminase (CD). Tumor-selective expression of CD converts the prodrug, 5-fluorocytosine (5-FC), into the active chemotherapeutic, 5-fluorouracil (5-FU). This therapeutic approach is being tested in a randomized phase II/III trial in recurrent glioblastoma and anaplastic astrocytoma (NCT0241416). The aim of this study was to identify the immune cell subsets contributing to antitumor immune responses following treatment with 5-FC in Toca 511-expressing gliomas in a syngeneic mouse model. Flow cytometry was utilized to monitor and characterize the immune cell infiltrate in subcutaneous Tu-2449 gliomas in B6C3F1 mice treated with Toca 511 and 5-FC. Tumor-bearing animals treated with Toca 511 and 5-FC display alterations in immune cell populations within the tumor that result in antitumor immune protection. Attenuated immune subsets were exclusive to immunosuppressive cells of myeloid origin. Depletion of immunosuppressive cells temporally preceded a second event which included expansion of T cells which were polarized away from Th2 and Th17 in the CD4+ T cell compartment with concomitant expansion of interferon gamma-expressing CD8+ T cells. Immune alterations correlated with clearance of Tu-2449 subcutaneous tumors and T cell-dependent protection from future tumor challenge. Treatment with Toca 511 and 5-FC has a concentrated effect at the site of the tumor which causes direct tumor cell death and alterations in immune cell infiltrate, resulting in a tumor microenvironment that is more permissive to establishment of a T cell mediated antitumor immune response.


Food security status of patients with type 2 diabetes and their adherence to dietary counselling from selected hospitals in Addis Ababa, Ethiopia: A cross-sectional study.
Even though adherence to dietary counselling for patients with diabetes is essential for improving health and preventing complications, access to an adequate and quality diet is challenging for patients living in a food-insecure household. The availability of data in this regard is limited in Ethiopia. Thus, this study assessed the food security status of patients with type 2 diabetes, their adherence to dietary counselling, and contributing factors at public hospitals in Addis Ababa, Ethiopia. This was a facility-based cross-sectional study among 602 patients with Type 2 diabetes in Addis Ababa, Ethiopia, from July to August 2019. Patients were selected randomly after the total number of samples was proportionally allocated to four public hospitals. Relevant information was collected by trained data collectors using a pre-tested questionnaire. Data were entered into Epi-info version 7 and exported to SPSS version 24 for data analysis. Logistic regression analysis was employed to identify factors associated with adherence to dietary counselling. The proportion of nonadherence to dietary counselling among patients with type 2 diabetes was 67.3% (95%CI: 63.5%-71.1%). Nearly half (50.7%) of the respondents were food insecure. Of these, mildly food insecure, moderately food insecure, and severely food insecure were 8.5%, 29.2%, and 13%, respectively. Physical activity (AOR = 1.7; 95%CI: 1.1-2.9); diabetes knowledge (AOR = 1.8; 95%CI: 1.2-2.6); lack of access to information (AOR = 1.6; 95%CI: 1.1-2.6); moderately food insecure (AOR = 2.2; 95%CI: 1.3-3.7); and severely food insecure (AOR = 5.6; 95%CI: 2.1-15.0) were the major significant factors associated with nonadherence to dietary counselling. Over two-thirds of patients with diabetes did not adhere to dietary counselling, which appears high. As a result, improving diabetes education, information access, and food security status should be considered to ensure dietary counselling adherence among type 2 diabetes patients.


2-D echocardiography: emergent use in the evaluation of penetrating precordial trauma.
Diagnosis of cardiac injury in stable patients suffering penetrating precordial trauma has relied on observation, subxiphoid window, or exploratory thoracotomy. Previous reports have stressed the need for an alternative noninvasive diagnostic test. Although the use of echocardiography (ECHO) in this patient population has been suggested, to our knowledge no report thus far has presented extensive experience with this technique. We present our experience over 3 years with 36 patients in whom emergent ECHO was used as part of their initial work-up. Injuries included single stab wounds (17), multiple stab wounds (14), and gunshot wounds (5). Four patients (11%) had jugular venous distention, and 12 (33%) were tachycardic. None had a systolic blood pressure below 90 mm Hg. Four ECHOs (11%) were positive for pericardial effusion. No valvular abnormalities were detected. Three of the effusions were small and these patients were triaged to monitored beds and observed. All three effusions resolved on serial echocardiography. The fourth patient underwent an uneventful operative repair of a left ventricular laceration. Although the yield is low, emergent 2-D ECHO is a valuable tool in the triage of stable penetrating trauma patients when cardiac injury is suspected. Patients without effusion can be discharged or triaged to a ward bed. Small effusions can be observed in a monitored setting with serial examinations, while large effusions should be treated surgically. Echocardiography is less expensive than ICU admission and less invasive than either subxiphoid window or thoracotomy. There are no known complications associated with the procedure and it is recommended for emergent use when available.


Azathioprine Maintenance Therapy to Prevent Relapses in Autoimmune Pancreatitis.
Steroids are used to induce remission in autoimmune pancreatitis (AIP). Low-dosage steroid therapy or immunosuppressant (IMs) has been proposed as maintenance therapy to prevent AIP relapse. Few and conflicting data have been published on the efficacy of azathioprine (AZA) in preventing AIP relapse. The aim of this study was to evaluate the indication and efficacy of AZA as maintenance therapy to prevent disease relapse in AIP. Patients suffering from AIP diagnosed according to the ICDC in type 1, type 2, and not otherwise specified (NOS) were divided in those treated with AZA (AZA+ group) as maintenance therapy and not treated with maintenance therapy (AZA- group). Exclusion criteria were: previous pancreatic surgery, other autoimmune diseases as indication for AZA treatment, and use of IMs different from AZA. Drug safety, clinical and instrumental outcome of AZA+ patients were evaluated. A total of 23 patients (18 Males and 5 Females, mean age 54±11 years) in AZA+ group and 97 (58 Males and 39 Females, mean age 45±18 years) in AZA- group were compared. In AZA+ group, patients were significantly older (P=0.043), type 1 AIP was more frequently diagnosed (87 vs. 51%, P=0.006), sIgG4 higher (758±625 vs. 311±409 mg/dl, P<0.001), other organ involvement (OOI) more frequently observed (83 vs. 48%, P=0.002), with higher frequency of relapse before AZA treatment (78 vs. 14%, P<0.001). Three patients in AZA+ group required drug discontinuation because of adverse events. Twenty patients were therefore evaluated for outcome. Six out of 20 patients (30%) relapsed after 24±15 months (5 in pancreas and 1 on biliary tract). They were retreated with steroids and continued AZA. Two out of 6 patients (33%) had a second relapse,after respectively 11 months (in pancreas and kidney) and 22 months (in kidney). AZA is an effective and safe treatment to prevent AIP relapses.


Bioclimatic zonation and potential distribution of Spodoptera frugiperda (Lepidoptera: Noctuidae) in South Kivu Province, DR Congo.
The fall Armyworm (FAW) Spodoptera frugiperda (JE Smith), is currently a devastating pest throughout the world due to its dispersal capacity and voracious feeding behaviour on several crops. A MaxEnt species distributions model (SDM) was developed based on collected FAW occurrence and environmental data's. Bioclimatic zones were identified and the potential distribution of FAW in South Kivu, eastern DR Congo, was predicted. Mean annual temperature (bio1), annual rainfall (bio12), temperature seasonality (bio4) and longest dry season duration (llds) mainly affected the FAW potential distribution. The average area under the curve value of the model was 0.827 demonstrating the model efficient accuracy. According to Jackknife test of variable importance, the annual rainfall was found to correspond to the highest gain when used in isolation. FAWs' suitable areas where this pest is likely to be present in South Kivu province are divided into two corridors. The Eastern corridor covering the Eastern areas of Kalehe, Kabare, Walungu, Uvira and Fizi territories and the Western corridor covering the Western areas of Kalehe, Kabare, Walungu and Mwenga. This research provides important information on the distribution of FAW and bioclimatic zones in South Kivu. Given the rapid spread of the insect and the climatic variability observed in the region that favor its development and dispersal, it would be planned in the future to develop a monitoring system and effective management strategies to limit it spread and crop damage.


Discontinuation of beta-blockers in cardiovascular disease: UK primary care cohort study.
The present study aims to investigate patterns of beta-blocker usage in a national primary care cohort. This is a retrospective cohort study utilising the UK General Practice Research Database from 2004 to 2008. Inclusion criteria were (i) a first diagnosis of chronic heart failure (CHF), myocardial infarction (MI) or angina, and (ii) first-ever prescription of beta-blocker on or after 1st April 2004. Outcome measures were discontinuation of beta-blockers over time, initiation dosages, titration patterns, incidence of adverse events (AEs) and associated prescribing actions. A total of 12,493 patients (68.0% male; mean age 58.0 ± SD 17.6 years) were included. Of these, 27% had discontinued beta-blockers within 1 year of initiation, increasing to 39% by 2 years and 50% by 3 years. Persistence appeared to be greater in the MI cohort compared with angina or CHF cohorts. Beta-blocker dose at initiation averaged approximately 33% of guideline recommended target, rising to 40% in those who continued with therapy. Dyspnoea, fatigue and dizziness were the most common incident AEs at 98, 53 and 49 per 1000 patient years, with little difference between indications. A quarter of patients with cardiovascular disease who are commenced on a beta-blocker are no longer taking the drug by one year. This rises to 50% by three years, a finding that is consistent irrespective of whether the prescription is for prognostic (CHF or post MI) or symptomatic (angina) benefit. There is an urgent need to understand and address the prescribing difficulties of beta-blockers in these at-risk patients.


Maternal and gestational risk factors for hypospadias.
An increase in the prevalence of hypospadias has been reported, but the environmental causes remain virtually unknown. Our goal was to assess the association between risk of hypospadias and indicators of placental function and endogenous hormone levels, exposure to exogenous hormones, maternal diet during pregnancy, and other environmental factors. We conducted a case-control study in Sweden and Denmark from 2000 through 2005 using self-administered questionnaires completed by mothers of hypospadias cases and matched controls. The response rate was 88% and 81% among mothers of cases and controls, respectively. The analyses included 292 cases and 427 controls. A diet during pregnancy lacking both fish and meat was associated with a more than 4-fold increased risk of hypospadias [odds ratio (OR) = 4.6; 95% confidence interval (CI), 1.6-13.3]. Boys born to obese [body mass index (BMI) > or = 30] women had a more than 2-fold increased risk of hypospadias (OR = 2.6; 95% CI, 1.2-5.7) compared with boys born to mothers with a normal weight (BMI = 20-24). Maternal hypertension during pregnancy and absence of maternal nausea increased a boy's risk of hypospadias 2.0-fold (95% CI, 1.1-3.7) and 1.8-fold (95% CI, 1.2-2.8), respectively. Nausea in late pregnancy also appeared to be positively associated with hypospadias risk (OR = 7.6; 95% CI, 1.1-53). A pregnancy diet lacking meat and fish appears to increase the risk of hypospadias in the offspring. Other risk associations were compatible with a role for placental insufficiency in the etiology of hypospadias.


Doppler echocardiography in the diagnosis of pulmonary hypertension.
Review of the current state of knowledge about Doppler diagnosis of pulmonary hypertension is presented. The authors compare the findings of numerous studies with their own data and analyse the causes of discrepancies and controversies that have remained to date. Doppler estimation of mean pulmonary artery pressure (PAP) using acceleration time (ACT) measurement in the right ventricular outflow tract or main pulmonary artery has been shown to correlate closely with simultaneously measured values of PAP both at rest and during exercise (r = -0.92 and -0.94, respectively). ACT values show sufficient sensitivity for the detection of pulmonary hypertension (89%), at maximum (100%) specificity. However, Doppler values not obtained simultaneously do not necessarily correlate with PAP in view of rapid physiological variations of PAP. For everyday diagnostic practice in cardiology, prediction based upon mere qualitative estimation of the type of velocity curve seems sufficient. Doppler diagnosis of pulmonary hypertension, little demanding on both technical skills and equipment, is gaining a priority status among the non-invasive methods available.


Is Traumatic Brain Injury Associated with Reduced Inter-Hemispheric Functional Connectivity? A Study of Large-Scale Resting State Networks following Traumatic Brain Injury.
Traumatic brain injury (TBI) often has long-term debilitating sequelae in cognitive and behavioral domains. Understanding how TBI impacts functional integrity of brain networks that underlie these domains is key to guiding future approaches to TBI rehabilitation. In the current study, we investigated the differences in inter-hemispheric functional connectivity (FC) of resting state networks (RSNs) between chronic mild-to-severe TBI patients and normal comparisons (NC), focusing on two externally oriented networks (i.e., the fronto-parietal network [FPN] and the executive control network [ECN]), one internally oriented network (i.e., the default mode network [DMN]), and one somato-motor network (SMN). Seed voxel correlation analysis revealed that TBI patients displayed significantly less FC between lateralized seeds and both homologous and non-homologous regions in the opposite hemisphere for externally oriented networks but not for DMN or SMN; conversely, TBI patients showed increased FC within regions of the DMN, especially precuneus and parahippocampal gyrus. Region of interest correlation analyses confirmed the presence of significantly higher inter-hemispheric FC in NC for the FPN (p < 0.01), and ECN (p < 0.05), but not for the DMN (p > 0.05) or SMN (p > 0.05). Further analysis revealed that performance on a neuropsychological test measuring organizational skills and visuo-spatial abilities administered to the TBI group, the Rey-Osterrieth Complex Figure Test, positively correlated with FC between the right FPN and homologous regions. Our findings suggest that distinct RSNs display specific patterns of aberrant FC following TBI; this represents a step forward in the search for biomarkers useful for early diagnosis and treatment of TBI-related cognitive impairment.


T cell lymphoma involving the graft of a multivisceral organ recipient.
Posttransplant lymphoproliferative disorders are typically of B cell origin, whereas T cell lymphomas have been rarely documented. We present a case of a non-Hodgkin's T cell lymphoma involving the intestinal graft of a multivisceral transplant patient. The patient was a 7-year-old girl who underwent at age 5 a multivisceral transplant secondary to short gut syndrome. Baseline immunosuppressive therapy consisted of FK506, methylprednisone, and mycophenolate mofetil. At 2 years posttransplant she presented with fever, diarrhea, nausea, and vomiting. Multiple endoscopic biopsies revealed a severe intensity, diffuse and focally nodular lymphocytic infiltrate composed predominantly of small, monomorphic lymphoid cells with scattered plasma cells and abundant eosinophils. Immunohistochemically, the majority of the lymphoid cells expressed the pan T cell marker CD3. Southern blot analysis revealed rearrangement of the T cell receptor beta chain gene, with germline configuration of the heavy immunoglobulin chain gene, confirming a clonal T cell genotype. In situ hybridization for Epstein Barr virus revealed rare positive lymphoid cells, that were negative with CD3 by immunohistochemical staining. A detailed clinico-radiological work-up revealed no other sites of involvement by the lymphomatous process. After the diagnosis of posttransplant lymphoproliferative disorder, immunosuppression was reduced with a subsequent partial improvement in the endoscopic appearance of the graft and a focal decrease in the lymphocytic infiltrate seen in the follow-up biopsies. Repeat gene rearrangement studies demonstrated germline configuration of both the T cell receptor beta chain gene and the heavy chain immunoglobulin. gene. To our knowledge, this represents the first description of a T cell lymphoma affecting the intestinal allograft of a multivisceral transplant patient.


"Life is so easy on ART, once you accept it": Acceptance, denial and linkage to HIV care in Shiselweni, Swaziland.
Timely uptake of antiretroviral therapy, adherence and retention in care for people living with HIV (PLHIV) can improve health outcomes and reduce transmission. Médecins Sans Frontières and the Swaziland Ministry of Health provide community-based HIV testing services (HTS) in Shiselweni, Swaziland, with high HTS coverage but sub-optimal linkage to HIV care. This qualitative study examined factors influencing linkage to HIV care for PLHIV diagnosed by community-based HTS. Participants were sampled purposively, exploring linkage experiences among both genders and different age groups. Interviews were conducted with 28 PLHIV (linked and not linked) and 11 health practitioners. Data were thematically analysed to identify emergent patterns and categories using NVivo 10. Principles of grounded theory were applied, including constant comparison of findings, raising codes to a conceptual level, and inductively generating theory from participant accounts. The process of HIV status acceptance or denial influenced the accounts of patients' health seeking and linkage to care. This process was non-linear and varied temporally, with some experiencing non-acceptance for an extended period of time. Non-acceptance was linked to perceptions of HIV risk, with those not identifying as at risk less likely to expect and therefore be prepared for a positive result. Status disclosure was seen to support linkage, reportedly occurring after the acceptance of HIV status. HIV status acceptance motivated health seeking and tended to be accompanied by a perceived need for, and positive value placed on, HIV health care. The manner in which PLHIV process a positive result can influence their engagement with HIV treatment and care. Thus, there is a need for individually tailored approaches to HTS, including the potential for counselling over multiple sessions if required, supporting status acceptance, and disclosure. This is particularly relevant considering 90-90-90 targets and the need to better support PLHIV to engage with HIV treatment and care following diagnosis.


Hierarchical prosody modeling for Mandarin spontaneous speech.
In this paper, a hierarchical prosody model (HPM)-based method for Mandarin spontaneous speech is proposed. First, an HPM is designed for describing relations among acoustic features of utterances, linguistic features of texts, and prosodic tags representing the underlying hierarchical prosodic structures of utterances. Subsequently, a sequential optimization algorithm is employed to train the HPM based on a large conversational speech corpus, the Mandarin Conversational Dialogue Corpus (MCDC), which features orthographic transcriptions and prosodic event annotations. In this unsupervised training method, all utterances of the MCDC are labeled with two types of prosodic tags, namely, break and prosodic states, automatically and simultaneously. After training, the HPM parameters are examined to identify critical prosodic properties of Mandarin spontaneous speech, which are then compared with their counterparts in the read-speech HPM. The prosodic tags on the studied utterances enable mapping of various prosodic events onto the hierarchical prosodic structures of the utterances. Prosodic analyses of some disfluent events are conducted using the prosodic tags affixed to the MCDC. Finally, an application of the HPM to assist in Mandarin spontaneous-speech recognition is discussed. Significant relative error rate reductions of 9.0%, 9.2%, 15.6%, and 7.3% are obtained for base-syllable, character, tone, and word recognition, respectively.


Clinton's tooth-fairy financing.
Even President Clinton's supporters say his proposal to finance health reform is politically unrealistic. It's that--and more. His plan to raise $441 billion over five years would reduce services to elderly and poor Americans, assumes savings unmatched anywhere in the Western world, and ignores the federal government's dismal track record in forecasting what new benefits will cost.