Syncope: current diagnosis and treatment.
The patient with syncope often poses a formidable diagnostic challenge. A large number of underlying causes must be considered, ranging in severity from benign to life-threatening. A careful, systematic clinical evaluation beginning with a history, physical examination, and ECG will establish the diagnosis in most patients, and the judicious use of specialized testing will confirm or uncover the cause in many of the remaining cases. Further basic and clinical research into the pathogenesis and treatment of neurocardiogenic syncope, the role of HUT testing in neurally mediated syncope, and the optimal use of EPS in patients with cardiac disease will markedly improve our management of these patients in the future.


Multicentric Glioblastoma Multiforme Mimicking Optic Neuritis.
A 49-year-old previously healthy woman presented with acute painless visual loss in the right eye, a right relative afferent pupillary defect, and a normal fundus examination. She was diagnosed with retrobulbar "optic neuritis" and given a course of intravenous steroids. Despite treatment, however, she continued to lose vision and serial visual field testing confirmed a junctional scotoma in the fellow eye. Cranial magnetic resonance imaging (MRI) showed a mass at the junction between the right optic nerve and the anterior aspect of the chiasm and a right frontal lesion that proved to be multicentric glioblastoma multiforme. Clinicians should be aware of the possibility of aggressive neoplasm in the differential diagnosis of retrobulbar optic neuritis.


CRISPR/Cas9-mediated excision of ALS/FTD-causing hexanucleotide repeat expansion in C9ORF72 rescues major disease mechanisms in vivo and in vitro.
A GGGGCC24+ hexanucleotide repeat expansion (HRE) in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), fatal neurodegenerative diseases with no cure or approved treatments that substantially slow disease progression or extend survival. Mechanistic underpinnings of neuronal death include C9ORF72 haploinsufficiency, sequestration of RNA-binding proteins in the nucleus, and production of dipeptide repeat proteins. Here, we used an adeno-associated viral vector system to deliver CRISPR/Cas9 gene-editing machineries to effectuate the removal of the HRE from the C9ORF72 genomic locus. We demonstrate successful excision of the HRE in primary cortical neurons and brains of three mouse models containing the expansion (500-600 repeats) as well as in patient-derived iPSC motor neurons and brain organoids (450 repeats). This resulted in a reduction of RNA foci, poly-dipeptides and haploinsufficiency, major hallmarks of C9-ALS/FTD, making this a promising therapeutic approach to these diseases.


The (Non)Impact of the 2015 Paris Terrorist Attacks on Political Attitudes.
Previous research has consistently found widespread attitudinal impacts of terrorist attacks. Using data from the European Social Survey, which was conducting interviews in 11 countries when the Charlie Hebdo attacks happened in January 2015, I compare respondents from before and after the shootings to test whether the event shifted public opinion on several topics. There is no evidence of average impacts across a range of issues, from xenophobia to ideological self-placement and immigration policy preferences. Data collected when the Paris November 2015 shootings happened also present no evidence of public opinion change on immigration and refugee policy matters in France, but there appears to be an effect in other countries-which varies according to contextual vulnerability. Results suggest that views on immigration and immigrants have, to a certain extent, stabilized in Europe and are less susceptible to shifts from dramatic events.


Binding curve of the beryllium dimer using similarity-transformed FCIQMC: Spectroscopic accuracy with triple-zeta basis sets.
We demonstrate how similarity-transformed full configuration interaction quantum Monte Carlo (FCIQMC) based on the transcorrelated Hamiltonian can be applied to make highly accurate predictions for the binding curve of the beryllium dimer, marking the first case study of a molecular system with this method. In this context, the non-Hermitian transcorrelated Hamiltonian, resulting from a similarity transformation with a Jastrow factor, serves the purpose to effectively address dynamic correlation beyond the used basis set and thus allows for obtaining energies close to the complete basis set limit from FCIQMC already with moderate basis sets and computational effort. Building on results from other explicitly correlated methods, we discuss the role of the Jastrow factor and its functional form, as well as potential sources for size consistency errors, and arrive at Jastrow forms that allow for high accuracy calculations of the vibrational spectrum of the beryllium dimer.


Determination of Sudan IV in hot chilli powder with luminol/dissolved oxygen chemiluminescence system.
A green, simple and sensitive flow injection chemiluminescence (CL) procedure is proposed for the determination of Sudan dyes. The method is based on the finding that Sudan I, II, III and IV markedly enhance the CL intensity of the luminol/dissolved oxygen reaction. The increment in CL intensity was proportional to the concentration of Sudan I, II, III and IV, giving calibration graphs linear over the ranges 0.007-1, 0.5-30, 1-10 and 0.7-300 ng mL(-1) respectively (R(2) >or= 0.9981), with limits of detection of 0.002, 0.2, 0.3 and 0.2 ng mL(-1) respectively. At a flow rate of 2 mL min(-1), complete determination of Sudan dyes, including sampling and washing, could be accomplished in 40 s, with relative standard deviations of less than 5% (n = 7). The proposed method was successfully applied to the determination of Sudan IV in contaminated hot chilli powder, with recoveries ranging from 89.3 to 108.4%. The possible mechanism of enhancement of the luminol/dissolved oxygen CL reaction by Sudan IV can be attributed to the acceleration of electron transfer. Compared with other procedures, the proposed CL method offers the highest sensitivity and the least reagent consumption for the determination of Sudan IV.


Protein engineering.
The techniques of protein engineering are proving to be a revolutionary experimental tool for understanding protein structure-function relationships. Even at this early stage, proteins of improved characteristics for specific industrial and therapeutic uses have already been produced. Tailoring enzymatic properties for non-physiological substrate conditions, altering pH optima, changing substrate specificity, and improving stability have already been demonstrated to be feasible. Nevertheless, the ability to make useful proteins which radically differ from a natural structure or designing altogether new structures exceeds present understanding.


Opposite regulation of endothelial NO synthase by HSP90 and caveolin in liver and lungs of rats with hepatopulmonary syndrome.
The hepatopulmonary syndrome is a complication of cirrhosis that associates an overproduction of nitric oxide (NO) in lungs and a NO defect in the liver. Because endothelial NO synthase (eNOS) is regulated by caveolin that decreases and heat shock protein 90 (HSP90) that increases NO production, we hypothesized that an opposite regulation of eNOS by caveolin and HSP90 might explain the opposite NO production in both organs. Cirrhosis was induced by a chronic bile duct ligation (CBDL) performed 15, 30, and 60 days before sample collection and pharmacological tests. eNOS, caveolin, and HSP90 expression were measured in hepatic and lung tissues. Pharmacological tests to assess NO released by shear stress and by acetylcholine were performed in livers (n = 28) and lungs (n = 28) isolated from normal and CBDL rats. In lungs from CBDL rats, indirect evidence of high NO production induced by shear stress was associated with a high binding of HSP90 and a low binding of caveolin to eNOS. Opposite results were observed in livers from CBDL rats. Our study shows an opposite posttranslational regulation of eNOS by HSP90 and caveolin in lungs and liver from rats with CBDL. Such opposite posttranslational regulation of eNOS by regulatory proteins may explain in part the pulmonary overproduction of NO and the hepatic NO defect in rats with hepatopulmonary syndrome.


Oxidation of erythrocyte glutathione by monocytes stimulated with interleukin-6. Analysis by 1H spin echo NMR.
1H spin echo NMR was used to follow the release of reactive oxygen species (ROS) from human monocytes by monitoring erythrocyte glutathione status, which is sensitive to applied oxidative stress. This allowed the ability of the cytokine interleukin-6 (IL-6) to stimulate release of ROS from monocytes to be assessed in terms of oxidative damage to other cells, providing an estimation of its importance in vivo. It was found that incubation of monocytes with erythrocytes in the presence of IL-6 resulted in oxidation of the erythrocyte glutathione pool, indicating that oxidants are released in sufficient amounts to cause oxidative stress. High levels of IL-6 occurring in plasma of women with severe pre-eclampsia could therefore be responsible for depleted plasma antioxidants and haemolysis. The oxidation of erythrocyte glutathione was inhibited by the presence of the cyclooxygenase inhibitor indomethacin, suggesting that this may be of value in the treatment of oxidative pathologies.


Beta-rolls, beta-helices, and other beta-solenoid proteins.
Beta-rolls and beta-helices belong to a larger group of topologically similar proteins with solenoid folds: because their regular secondary structure elements are exclusively beta-strands, they are referred to as beta-solenoids. The number of beta-solenoids whose structures are known is now large enough to support a systematic analysis. Here we survey the distinguishing structural features of beta-solenoids, also documenting their notable diversity. Appraisal of these structures suggests a classification based on handedness, twist, oligomerization state, and coil shape. In addition, beta-solenoids are distinguished by the number of chains that wind around a common axis: the majority are single-stranded but there is a recently discovered subset of triple-stranded beta-solenoids. This survey has revealed some relationships of the amino acid sequences of beta-solenoids with their structures and functions-in particular, the repetitive character of the coil sequences and conformations that recur in tracts of tandem repeats. We have proposed the term beta-arc for the distinctive turns found in beta-solenoids and beta-arch for the corresponding strand-turn-strand motifs. The evolutionary mechanisms underlying these proteins are also discussed. This analysis has direct implications for sequence-based detection, structural prediction, and de novo design of other beta-solenoid proteins. The abundance of virulence factors, toxins and allergens among beta-solenoids, as well as commonalities of beta-solenoids with amyloid fibrils, imply that this class of folds may have a broader role in human diseases than was previously recognized. Thus, identification of genes with putative beta-solenoid domains promises to be a fertile direction in the search for viable targets in the development of new antibiotics and vaccines.


Clinical presentation and radiographic identification of small bowel rupture following blunt trauma in children.
The incidence of significant intraabdominal injuries from blunt trauma in children is low (1-8%); however, a missed intestinal laceration may result in a devastating, if not morbid, consequence. We present retrospective case studies of eight children with intestinal lacerations following blunt trauma. Each patient has a unique anatomic defect with misleading initial laboratory and radiographic studies. We did not find a single laboratory or roentgenographic study to be consistently reliable for diagnosis of hollow viscus laceration. The combination of a high index of suspicion and serial abdominal examinations, coupled with subsequent comparative laboratory and radiographic evaluations, proved most reliable in identifying patients with intestinal injury.


Investigation and assessment of heavy metals in surface sediments of Ganjiang River, China.
Surface sediment samples were collected from four sampling areas (Ganzhou nonferrous metal processing zones (GZ), Jian city sewage discharge areas (JA), Non city areas (NC) and Zhangshu middle-city areas (ZS)) to investigate the degree and chemical partitioning of heavy metals. Samples were analyzed for Cu, Zn, Pb, Cd, Cr, As and Ni using sequential extraction scheme. Based on geo-statistics analyses, the results showed maximum values of Cu (131.84 μg g(-1)), Zn (290.68 μg g(-1)), Cd (99.57 μg g(-1)), Cr (53.75 μg g(-1)), As (25.58 μg g(-1)) and Ni (64.75 μg g(11)) were in sediments dated at GZ areas, while ZS areas had the highest concentrations of Pb (128.51 μg g(-1)). Almost all metal values were higher than their corresponding background values in the following order: Ni < Cr < Zn < Pb < As < Cu < Cd. Meanwhile, sediments showed that heavy metals were predominantly occured in Fe-Mn oxide, residual, organic, exchangeable and carbonate fractions respectively. It was found that concentration in carbonate fractions were generally low for most of the studied metals. The geo-accumulation index and sediment quality values were used to determine the potential risk of heavy metal contamination. The results of geo-accumulation index indicated that contamination degree ranged from uncontaminated to extremely contaminated degrees. When metal partitioning characteristics were also considered, over 60% of metals showed potential bioavailability and toxic effects were probable.


Contribution of Epidemiological Predictors in Unraveling the Phylogeographic History of HIV-1 Subtype C in Brazil.
The phylogeographic history of the Brazilian HIV-1 subtype C (HIV-1C) epidemic is still unclear. Previous studies have mainly focused on the capital cities of Brazilian federal states, and the fact that HIV-1C infections increase at a higher rate than subtype B infections in Brazil calls for a better understanding of the process of spatial spread. A comprehensive sequence data set sampled across 22 Brazilian locations was assembled and analyzed. A Bayesian phylogeographic generalized linear model approach was used to reconstruct the spatiotemporal history of HIV-1C in Brazil, considering several potential explanatory predictors of the viral diffusion process. Analyses were performed on several subsampled data sets in order to mitigate potential sample biases. We reveal a central role for the city of Porto Alegre, the capital of the southernmost state, in the Brazilian HIV-1C epidemic (HIV-1C_BR), and the northward expansion of HIV-1C_BR could be linked to source populations with higher HIV-1 burdens and larger proportions of HIV-1C infections. The results presented here bring new insights to the continuing discussion about the HIV-1C epidemic in Brazil and raise an alternative hypothesis for its spatiotemporal history. The current work also highlights how sampling bias can confound phylogeographic analyses and demonstrates the importance of incorporating external information to protect against this. Subtype C is responsible for the largest HIV infection burden worldwide, but our understanding of its transmission dynamics remains incomplete. Brazil witnessed a relatively recent introduction of HIV-1C compared to HIV-1B, but it swiftly spread throughout the south, where it now circulates as the dominant variant. The northward spread has been comparatively slow, and HIV-1B still prevails in that region. While epidemiological data and viral genetic analyses have both independently shed light on the dynamics of spread in isolation, their combination has not yet been explored. Here, we complement publically available sequences and new genetic data from 13 cities with epidemiological data to reconstruct the history of HIV-1C spread in Brazil. The combined approach results in more robust reconstructions and can protect against sampling bias. We found evidence for an alternative view of the HIV-1C spatiotemporal history in Brazil that, contrary to previous explanations, integrates seamlessly with other observational data.


Effects of iron-chelators on ion-channels and HIF-1alpha in the carotid body.
Acute hypoxia instantaneously increases the chemosensory discharge from the carotid body, increasing ventilation mostly by inhibiting the oxygen sensitive ion channels and exciting the mitochondrial functions in the glomus cells. On the other hand, Fe2+-chelation mimics hypoxia by inhibiting the prolyl hydroxylases and the degradation of HIF-1alpha in non-excitable cells. Whether Fe2+-chelation can inhibit the ion channels giving rise to the sensory responses in excitable cells was the question. We characterized the responses to Fe2+-chelators on excitable glomus cells of the rat, and found that they instantaneously blocked the ion-channels, exciting the chemosensory discharge, and later causing a gradual accumulation of HIF-1alpha. Although initiated by the same stimuli, the two effects (on ion channels and cytosolic HIF-1alpha) possibly occurred by two different mechanisms.


A case of aseptic meningitis due to Japanese encephalitis virus in a traveller returning from the Philippines.
We here report the case of Japanese encephalitis virus (JEV) meningitis in a previously healthy young women returning from a trip to the Philippines. JEV is a mosquito-borne encephalitic flavivirus pathogen, which is endemic in South East and Eastern Asia. Our patient presented with aseptic meningitis and recovered well under supportive therapy. Although the chance of a traveller getting symptomatic JEV infection is extremely low, clinicians and microbiologist should be aware of patients contracting this emerging infectious disease, especially in the light of the increasing international travel.


Status of lifestyle modifications in hypertension.
Hypertension is essentially the elevation of arterial blood pressure beyond an arbitrary cut off point, though the dividing line between normal and elevated BP is lacking. Hypertension can be classified into primary, essential or idiopathic hypertension on one hand, and secondary one due to some disease itself. In treating hypertension, antihypertensives have their role, but attention may be directed towards some lifestyle modifications. As regarding dietary interventions, calorie restriction may influence the minimisation of BP. Body weight reduction, less alcohol consumption, salt restriction, potassium and calcium supplementation can enhance the process of lowering BP. The role of magnesium in hypertension is debatable. Serum cholesterol level is commonly elevated in hypertensive patients and its reduction reduces the risk of non-fatal coronary events. Diet rich in plant fibres either alone or with a low fat, low sodium could lower the BP by about 5 mm Hg in hypertensives. The omega-3-polyunsaturated fatty acids found in highest concentrations in cold water fishes have a modest antihypertensive effect. Caffeine contained in two cups of coffee may raise the BP by 5 mm Hg in infrequent users but in habitual users, caffeine has no role. Deficiency of vitamin C might lead to hypertension. As regarding behavioural changes, stopping smoking, regular physical exercise, relaxation therapies like yoga, etc, have definite beneficial effect on hypertensives. The antihypertensive effect of lifestyle modifications may obviate drug therapy. For this one or more of the lifestyle modifications should be tried initially in all hypertensive patients.


Wheat bran components modulate intestinal bacteria and gene expression of barrier function relevant proteins in a piglet model.
The objective of this study was to determine the impact of wheat bran and its main polysaccharides on intestinal bacteria and gene expression of intestinal barrier function relevant proteins. Thirty freshly weaned male piglets were assigned randomly to five dietary treatment groups with six piglets per group. Accordingly, five synthetic diets including a basal control diet without fiber components (CON), wheat bran diet (10% wheat bran, WB), arabinoxylan diet (AX), cellulose diet (CEL) and combined diet of arabinoxylan and cellulose (CB) were studied. The piglets were fed ad libitum for 30 d. Lower Escherichia coli (E. coli) populations in WB group and higher probiotic (Lactobacillus and Bifidobacterium) populations in groups fed diets containing arabinoxylan (WB, AX and CB) were observed and compared with CON group. Compared with CON group, the gene expressions of cystic fibrosis transmembrane conductance regulator (CFTR), calcium-activated chloride channel regulator 1 (CLCA1) and voltage-gated chloride channel 2 (CIC2) were suppressed in the WB group. And wheat bran down-regulated gene expression of pro-inflammation (TNF-α, IL-1β, IL-6) and TLRs/MyD88/NF-κB pathway compared with CON group. In conclusion, wheat bran and its main polysaccharides could change intestinal microflora and down-regulate the gene expression of intestinal barrier function relevant proteins in the distal small intestinal mucosa.


betaII-tubulin and GAP 43 mRNA expression in chronically injured neurons of the red nucleus after a second spinal cord injury.
Regeneration by chronically injured supraspinal neurons is enhanced by treatment of a spinal cord lesion site with a variety of neurotrophic and growth factors. The removal of scar tissue, with subsequent reinjury of the spinal cord, is necessary for injured axons to access tissue transplants placed into the lesion to support axon regrowth. The present study examined chronically injured and reinjured rubrospinal tract (RST) neurons to determine if changes in gene expression could explain the failure of these neurons to regenerate without exogenous trophic factor support. Adult female rats were subjected to a right full hemisection lesion via aspiration of the cervical level 3 spinal cord. Using radioactive cDNA probes and in situ hybridization, RST neurons in the contralateral red nucleus were examined for changes in mRNA levels of betaII-tubulin and GAP 43 in an acute injury period (6 h-3 days), a chronic injury period (28 days after spinal cord injury (SCI)) and following a second lesion of the chronic injury site (6 h-7 days). Based upon the analysis of gene expression in single cells, GAP-43 mRNA levels were increased as early as 1 day following the initial SCI, but were no different than uninjured control levels at 28 days postoperative (dpo). The response to relesion was more rapid and higher than that detected after the initial injury with a significant increase in GAP 43 mRNA at 6 h that was maintained for at least 7 days. betaII-tubulin mRNA levels remained unchanged until 3 days after an acute injury followed by a decrease in expression to 30% below uninjured control values at 28 dpo. The expression of betaII-tubulin mRNA was significantly higher within 6 h after a second injury, where it remained stable for 5 days before a second increase occurred at 7 days after reinjury of the spinal cord. Thus, neurons in a chronic injury state retain the ability to respond to a traumatic injury and, in fact, neurons subjected to a second injury exhibit a significantly heightened expression of regeneration-associated genes.


Developing a marker of exposure to xenoestrogen mixtures in human serum.
It has been hypothesized that environmental estrogens may play a role in the increasing incidence of breast cancer, testicular cancer, and other problems of the reproductive system. While a single causal agent can be identified in cases in which humans have had occupational exposures, wildlife showing signs of reproductive damage have usually been exposed to a combination of endocrine disruptors that may act cumulatively. The development of appropriate biomarkers of cumulative exposure, and their measurement at developmental points where exposure is critical, are required to test the environmental estrogen hypothesis. Measuring levels of each of the xenoestrogens in blood is a better approximation of real exposure at the target organ level than inferring cumulative exposure by estimating from mass balance of dietary levels. However, the cumulative estrogenicity of mixtures cannot be directly concluded from individual xenoestrogen plasma levels. Two approaches may be used to assess total load: a) the development of methods to study mixtures of these xenoestrogens, to quantify their cumulative effects, and to begin to understand their interactions (i.e., additivity, synergy, antagonism, or independent action), so that plasma concentrations may be translated into units of activity such as "estradiol equivalents"; and b) the development of methods to separate xenoestrogens from ovarian estrogens in blood and to directly measure the estrogenic activity of the xenoestrogen extract using a bioassay. The cumulative activity may be used as a marker of exposure to xenoestrogens. This article reports the development of a method to extract and separate xenoestrogens from ovarian estrogens using human serum as a source, followed by using a bioassay for determination of the cumulative xenoestrogen load as "estradiol equivalents."


Multiple genotypes of Crimean-Congo hemorrhagic fever virus detected in ticks during a one health survey in Agnam, Northeastern Senegal.
A Crimean-Congo Hemorrhagic Fever Virus (CCHFV) survey in Agnam (North Senegal) permits the detection of three isolates in ticks. These isolates belong genetically to multiple genotypes (I, II, III) and clustered with strains from Uganda, Sudan, Mauritania, and Senegal. The role of ticks in CCHF emergence and widespread is highlighted.


Hydroxyurea accelerates loss of extrachromosomally amplified genes from tumor cells.
Gene amplification is one mechanism mediating the resistance of tumor cells to antineoplastic agents and the overexpression of a variety of oncogenes in diverse tumor types. There is mounting evidence that acentric extrachromosomal elements such as double minute chromosomes are common intermediates in the amplification process. These acentric structures partition unequally at mitosis and can be lost in the absence of selection. In the present study, we used human and hamster cell lines documented to contain extrachromosomally amplified drug resistance genes to investigate the feasibility of enhancing the loss rate of the extrachromosomally amplified genes to make the cells more sensitive to drug treatment. The results show that treatment of each of these lines with hydroxyurea accelerates the loss of the extrachromosomally amplified drug resistance genes. Loss of these extrachromosomal genes was associated with a corresponding increase in the drug sensitivity in the cases examined. The mechanism of accelerated loss does not appear to involve a differential effect on the replication of extrachromosomal DNA sequences. The results suggest that hydroxyurea treatment may provide a valuable tool for the general accelerated elimination of extrachromosomally amplified genes.


In Vivo Tracking of Chemokine Receptor CXCR4-Engineered Mesenchymal Stem Cell Migration by Optical Molecular Imaging.
CXCR4, the stromal cell-derived factor-1 receptor, plays an important role in the migration of hematopoietic progenitor/stem cells to injured and inflamed areas. Noninvasive cell tracking methods could be useful for monitoring cell fate. Therefore, in this study, we evaluated the efficacy of an intravenous infusion of genetically engineered mesenchymal stem cells (MSCs) overexpressing CXC chemokine receptor 4 (CXCR4) to home to the tumor, by optical imaging. We constructed a retroviral vector containing CXCR with dual reporter genes, eGFP and Fluc2, under the control of an EF1α promoter (pBABE-EF1α-CXCR4-eGFP-IRES-Fluc2). We also developed an eGFP-Fluc2 construct in the Retro-X retroviral vector (Retro-X-eGFP-Fluc2). MSCs were transduced with retroviruses to generate CXCR4-overexpressing MSCs (MSC-CXCR4/Fluc2) and MSCs (MSC/Fluc2). CXCR4 mRNA and protein expression was confirmed by RT-PCR and Western blotting, respectively, and it was higher in MSC-CXCR4/Fluc2 than in naive MSCs. eGFP expression was confirmed by confocal microscopy. The transfected MSC-CXCR4/Fluc2 cells showed higher migratory capacity than naive MSCs observed in Transwell migration assay. The in vivo migration of CXCR4-overexpressing MSCs to MDAMB231/Rluc tumor model by BLI imaging was also confirmed. Intravenous delivery of genetically modified MSCs overexpressing CXCR4 with a Fluc2 reporter gene may be a useful, noninvasive BLI imaging tool for tracking cell fate.


Triple therapy and incidence of de novo cancer in renal transplant recipients.
Some 27 (5.5 per cent) of 492 renal transplant recipients developed de novo cancer between January 1975 and December 1991. Patients administered triple therapy of prednisolone, cyclosporin A and azathioprine had a significantly higher incidence of cancer (seven of 40 patients; 17.5 per cent) than those given prednisolone with cyclosporin (14 of 319; 4.4 per cent) and azathioprine with prednisolone (six of 133; 4.5 per cent) (P = 0.005). In a prospective study between January 1989 and December 1992, 110 renal transplant patients were randomized into three immunosuppressive regimens at the time of transplantation. The incidence of cancer in patients receiving low-dose cyclosporin, azathioprine and prednisolone was three of 45, in those given high-dose cyclosporin and prednisolone none of 23 and in those administered high-dose cyclosporin, nifedipine and prednisolone one of 29. The addition of azathioprine to ongoing maintenance cyclosporin and prednisolone therapy is useful in a subgroup of patients with graft dysfunction, but there are possibly higher risks in the development of de novo carcinoma.


Gene carriers based on hexanediol diacrylate linked oligoethylenimine: effect of chemical structure of polymer on biological properties.
Two biodegradable polycations based on hexanediol diacrylate linked oligoethylenimine (OEI) were synthesized by applying different reaction temperatures, 20 degrees C (LT-OEI-HD) and 60 degrees C (HT-OEI-HD). Their structural properties were analyzed by NMR, FTIR, and SEC/MALLS (size exclusion chromatography coupled with multiangle laser light scattering detection). Reaction temperature strongly influenced molecular weight and ester/amide ratio and thus resulted in polycations with different biological activities and degradation profiles. LT-OEI-HD was an ester-based polycation of 8.7 kDa which degraded rapidly at pH 7 and pH 9 respectively. HT-OEI-HD had a molecular weight of 26.6 kDa, was mainly based on amides, and degraded more slowly than LT-OEI-HD. Both polymers mediated gene transfer as efficiently as linear polyethylenimine of 22 kDa in two cell lines while being less toxic at their optimal conjugate/plasmid (C/P) ratios. LT-OEI-HD needed higher C/P ratios for gene delivery; however, it was significantly less toxic than HT-OEI-HD.


Off-Label Use of Phosphodiesterase Type 5 Inhibitor Erectile Dysfunction Medication to Enhance Sex Among Gay and Bisexual Men in Australia: Results From the FLUX Study.
Gay and bisexual men (GBM) use oral erectile dysfunction medications (EDMs) often with little evidence of medical indication necessitating their use. To investigate the prevalence, contexts, and motivations for oral EDM use and its relation to sexual risk behavior. A total of 2,250 Australian GBM completed an online survey of licit and illicit drug use and their associated behaviors. Multivariate logistic regression analysis identified factors associated with use of EDMs in the previous 6 months and, for those who had used EDMs, factors associated with use on a weekly basis. Any EDM use and at least weekly use in the previous 6 months. The median age of the sample was 33.0 years (range = 16-81). Two thirds (67.7%) reported no lifetime history of EDM use. Approximately 1 in 10 participants (11.1%) had last used an EDM more than 6 months previously. In the previous 6 months, 11.5% reported using EDMs less than monthly, 5.3% reported using EDMs approximately monthly, and 4.5% reported using EDMs at least weekly. Of men who had used EDMs in the previous 6 months, common reasons cited for its use were to maintain an erection for longer (73.3%), to make it easier to "get hard" (67.3%), and difficulty in attaining or maintain an erection (53.5%). Use of EDMs in the previous 6 months was associated with illicit drug use and higher rates of sexual risk behavior. Weekly users were more likely to have severe anxiety than less frequent users. The use of EDMs in the context of intensive sex partying, with the associated potential for increased risk of HIV transmission and illicit drug use, indicates a need to consider the use of EDMs among GBM in HIV prevention and minimizing harm. This large-scale study of drug use among GBMs includes comprehensive detailed data on their history of use and rationales for use. Our online methodology potentially decreases social desirability bias in reporting illegal or stigmatized behaviors. This volunteer online convenience sample might not be representative of all GBMs in Australia. GBMs who used an oral EDM in the previous 6 months often used it for recreational purposes, but many of those who used it on a weekly basis also might have used it for therapeutic reasons. GBMs often use EDMs to enhance their sexual experiences often in the context of intensive sex partying (which can include risky sexual behavior). Hammoud MA, Jin F, Lea T, et al. Off-Label Use of Phosphodiesterase Type 5 Inhibitor Erectile Dysfunction Medication to Enhance Sex Among Gay and Bisexual Men in Australia: Results From the FLUX Study. J Sex Med 2017;14:774-784.


Phrenic and hypoglossal nerve activity during respiratory response to hypoxia in 6-OHDA unilateral model of Parkinson's disease.
Parkinson's disease (PD) patients apart from motor dysfunctions exhibit respiratory disturbances. Their mechanism is still unknown and requires investigation. Our research was designed to examine the activity of phrenic (PHR) and hypoglossal (HG) nerves activity during a hypoxic respiratory response in the 6-hydroxydopamine (6-OHDA) model of PD. Male adult Wistar rats were injected unilaterally with 6-OHDA (20μg) or the vehicle into the right medial forebrain bundle (MFB). Two weeks after the surgery the activity of the phrenic and hypoglossal nerve was registered in anesthetized, vagotomized, paralyzed, and mechanically ventilated rats under normoxic and hypoxic conditions. Lesion effectiveness was confirmed by the cylinder test, performed before the MFB injection and 14days after, before the respiratory experiment. 6-OHDA lesioned animals showed a significant increase in normoxic inspiratory time. Expiratory time and total time of the respiratory cycle were prolonged in PD rats after hypoxia. The amplitude of the PHR activity and its minute activity were increased in comparison to the sham group at recovery time and during 30s of hypoxia. The amplitude of the HG activity was increased in response to hypoxia in 6-OHDA lesioned animals. The degeneration of dopaminergic neurons decreased the pre-inspiratory/inspiratory ratio of the hypoglossal burst amplitude during and after hypoxia. Unilateral MFB lesion changed the activity of the phrenic and hypoglossal nerves. The altered pre-inspiratory hypoglossal nerve activity indicates modifications to the central mechanisms controlling the activity of the HG nerve and may explain respiratory disorders seen in PD, i.e. apnea.


Serosurveillance of hepatitis A in a region which adopted the universal mass vaccination.
Hepatitis A is a common infectious disease worldwide that was endemic in many regions of Southern Italy, such as Apulia region. After a large hepatitis A outbreak occurred between 1996 and 1997, in Apulia an active-free immunization program that was targeted to new-borns and adolescents was started. The aim of this study is to investigate the hepatitis A seroprevalence in the adult Apulian population 18 years after the immunization program introduction, in order to evaluate the risk of new epidemics onset.The study was carried out from May 2011 to June 2012 among blood donors from Department of Transfusion Medicine and Blood Bank of Policlinico General Hospital in Bari. Participants signed a written consent and filled out a questionnaire including items on demographic characteristics, risk factors, disease memory, and raw food consumption. Serum samples, collected from each patient, were tested for anti-HAV using the chemiluminescent microparticle immunoassay. Vaccination status against hepatitis A was checked on Regional Digital Immunization Registry (GIAVA).In total 1827 donors agreed to participate (77.7% male) with a mean age of 38.4 ± 11.7 years. However, 1172 (64.1%) donors were seropositive with no difference by sex. The highest proportion of seronegative subjects was in the 27 to 35 years age group. 91.8% of 1-dose vaccinated subjects (n = 190/207; 95%CI = 87.2-95.1) and 96.1% (n = 171/178; 95%CI = 92.1-98.1) of 2-doses vaccinated subjects were immune to the disease. Sensitivity of disease memory in unvaccinated subjects was 14.4% (95%CI = 12.2-16.7), specificity was 97.8% (95%CI = 96.3-98.8), positive predictive value was 91% (95%CI = 85.3-95), and negative predictive value was 42.6% (95%CI = 40-45.2). Raw seafood consumption in unvaccinated subjects was associated with the anti-HAV IgG positivity (OR = 2.1; 95%CI = 1.7-2.7; z = 7.4; P < 0.0001).The vaccination program seems to have changed the virus circulation pattern, with a higher seronegativity rate among subjects not included in the vaccination strategy: 67% of susceptible subjects were among younger people aged 27 to 35 years. Immunization program implementation with a catch-up strategy may be needed to avoid a possible increase of hepatitis A incidence and outbreaks in Apulia. Epidemiological surveillance should be continued and vaccination should actively be offer for free to all the cases contacts, in order to prevent new outbreaks onset.


New bifunctional antioxidant/σ1 agonist ligands: Preliminary chemico-physical and biological evaluation.
We previously reported bifunctional sigma-1 (σ1) ligands endowed with antioxidant activity (1 and 2). In the present paper, pure enantiomers (R)-1 and (R)-2 along with the corresponding p-methoxy (6, 11), p-fluoro derivatives (7, 12) were synthesized. σ1 and σ2 affinities, antioxidant properties, and chemico-physical profiles were evaluated. Para derivatives, while maintaining strong σ1 affinity, displayed improved σ1 selectivity compared to the parent compounds 1 and 2. In vivo evaluation of compounds 1, 2, (R)-1, 7, and 12 showed σ1 agonist pharmacological profile. Chemico-physical studies revealed that amides 2, 11 and 12 were more stable than corresponding esters 1, 6 and 7 under our experimental conditions. Antioxidant properties were exhibited by fluoro derivatives 7 and 12 being able to increase total antioxidant capacity (TAC). Our results underline that p-substituents have an important role on σ1 selectivity, TAC, chemical and enzymatic stabilities. In particular, our data suggest that new very selective compounds 7 and 12 could be promising tools to investigate the disorders in which σ1 receptor dysfunction and oxidative stress are contemporarily involved.


[Self-care and demand for social support in women with infertility].
The prevalence of infertility among married couples is growing. It is estimated that every fifth married couple in Poland is infertile. Infertility is often a source of significant stress for the spouses. It is therefore important to provide professional support, demonstrate interest, listen to the problem, and be present in difficult moments. Social support considerably reduces the feeling of abandonment, fosters self-care, accelerates recovery, strengthens coping, and helps modify views and habits or attitudes towards treatment. The aim of this study was to assess self-care in women with infertility and to identify the most common sources of social support. The study group consisted of 100 women diagnosed or treated for infertility at the Department of Reproduction and Gynecology, Pomeranian Medical University in Szczecin. The diagnostic poll was done with the aid of a standardised research tool--the Social Support Scale Questionnaire by Danuta Zarzycka. The study protocol was approved by the Bioethics Committee of the Pomeranian Medical University. The study was performed between July 2005 and March 2007. (1) Self-care in women with infertility is adequate. (2) Women with infertility usually expect professional support from a physician; the role of the nurse is undervalued. Thus, the role of the nurse and midwife needs further promotion.


Evaluation of clinical assessments of social abilities for use in autism clinical trials by the autism biomarkers consortium for clinical trials.
Clinical trials in autism spectrum disorder (ASD) often rely on clinician rating scales and parent surveys to measure autism-related features and social behaviors. To aid in the selection of these assessments for future clinical trials, the Autism Biomarkers Consortium for Clinical Trials (ABC-CT) directly compared eight common instruments with respect to acquisition rates, sensitivity to group differences, equivalence across demographic sub-groups, convergent validity, and stability over a 6-week period. The sample included 280 children diagnosed with ASD (65 girls) and 119 neurotypical children (36 girls) aged from 6 to 11 years. Full scale IQ for ASD ranged from 60 to 150 and for neurotypical ranged from 86 to 150. Instruments measured clinician global assessment and autism-related behaviors, social communication abilities, adaptive function, and social withdrawal behavior. For each instrument, we examined only the scales that measured social or communication functioning. Data acquisition rates were at least 97.5% at T1 and 95.7% at T2. All scales distinguished diagnostic groups. Some scales significantly differed by participant and/or family demographic characteristics. Within the ASD group, most clinical instruments exhibited weak (≥ |0.1|) to moderate (≥ |0.4|) intercorrelations. Short-term stability was moderate (ICC: 0.5-0.75) to excellent (ICC: >0.9) within the ASD group. Variations in the degree of stability may inform viability for different contexts of use, such as identifying clinical subgroups for trials versus serving as a modifiable clinical outcome. All instruments were evaluated in terms of their advantages and potential concerns for use in clinical trials.


Interventions with families of people with schizophrenia in India.
Although families have traditionally been the caregivers for mentally ill relatives in India, this situation is changing, creating a need for more structured interventions with families. Interventions appropriate to families in India are discussed here.


Crohn's disease of the gall bladder.
A 64 year old man with known enteric Crohn's disease developed a granulomatous cholecystitis in which the histological features were identical to those seen in sites conventionally affected by this disease. Extraintestinal granulomatous lesions are rare in Crohn's disease and the present case is reported because of its apparent uniqueness.


[Crimean-Congo Hemorrhagic Fever].
Crimean-Congo Hemorrhagic Fever (CCHF) virus is a tick-borne virus, which is a member of Bunyaviridae family, Nairovirus genus. CCHF virus has been isolated from 31 different tick species so far, and genus Hyalomma includes the basic vectors of which H. anatolicum, H. marginatum, H. detritum, H. dromedarii, H. excavatum and H. turanicum are frequently found in the geography in which Turkey takes place. The virus is transmitted via the bite of infected ticks or direct contact with CCHF infected patients and the products of infected animals. Following 2-9 days incubation period, the disease abruptly starts with fever, feeling cold, shivering, headache, muscle and joint aches. After a few days hemorrhage develops at various parts of the body. Since an effective vaccine and a specific antiviral therapy have not been found yet, the high mortality rate which may reach to 10-60%, and a wide geography affecting approximately 40 countries including Turkey, CCHF attracts the attention of both scientific and mediatic world, in recent years. In this article, the structure, vectors and reservoirs of CCHF virus, together with the epidemiology, clinical features, laboratory diagnosis and strategies of treatment and prevention, have been reviewed.


Cerebrospinal fluid amine metabolites in delirium tremens.
Cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5HIAA), homovanillic acid (HVA) and tryptophan (TRY) were measured in 14 male alcohol-dependent patients with delirium tremens. Lumbar punctures were performed immediately after admission following a standardized psychiatric examination and symptom rating in a drug-free state. Results were compared with a control group consisting of 32 neurological patients with only peripheral disorders, excluding spinal processes and abnormal routine CSF findings. All three substances were significantly increased in delirium tremens; 5HIAA showed the most marked and TRY the least pronounced increase. The statistical correction for age, height and body weight did not decrease but somewhat increased the differences. Duration of alcohol abuse did not account for the observed metabolic changes; severity of delirium tremens, however, correlated significantly with the 5HIAA and to a lesser degree with the HVA level. The further analysis revealed a differential relationship of the amine metabolite concentrations to some prominent symptoms: agitation was significantly dependent only on the HVA level while disorientation and hallucination seemed to be determined mostly by the serotonin metabolite 5HIAA in the CSF. TRY concentration proved to be unrelated to either global severity or any of these symptoms.


Wellness spirituality in homosexual men with HIV infection.
The concept of wellness as a spiritual process is examined in this grounded theory study on the role of human relationships in the well-being of gay men with HIV infection. The sample included 29 homosexual men in various stages of HIV illness. Findings reveal a description of the construct, wellness spirituality, in which the elements of human connectedness, meaning, and self-acceptance are discussed. This study confirms the findings of other researchers who demonstrated the importance of spirituality in the health and well-being of terminally ill people.


Child Loss, Social Capital, and Depressive Symptoms Among Elderly Adults in Urban and Rural China.
The purpose of this study was to examine the moderating effects of individual and community social capital on the relationship between child loss and depressive symptoms among elderly adults in China. A sample of 2,581 elderly adults in 272 rural communities and 826 elderly adults in 116 urban communities was drawn from Chinese Health and Retirement Longitudinal Studies. Hierarchical linear modeling was applied in the analysis. Social participation as an indicator of individual social capital has a buffering effect on depressive symptoms among rural bereaved parents while it is not beneficial for urban bereaved parents. In contrast, community social capital may be a protective factor for the mental health of urban bereaved parents, but no so for those in rural areas. These findings highlight the complex interplay of social capital and broader socio-cultural contexts in rural and urban China and suggest policy implications.


Clinical activity of a cytotoxic fusion protein in the treatment of cutaneous T-cell lymphoma.
A phase I trial in patients with refractory hematologic malignancies was performed at our institution to test the clinical relevance of the selective cytotoxic activity of the interleukin-2 (IL-2)-diphtheria toxin fusion protein, DAB486IL-2. A subset of five patients from this trial, all with cutaneous T-cell lymphomas (CTCL), forms the basis of this report. Two treatment schedules were used. One patient received DAB486IL-2 at a dose of 0.075 mg/kg/d intravenous (i.v.) bolus over 15 minutes daily for 5 consecutive days. The other four patients received DAB486IL-2 at a dose of 0.1 mg/kg as an i.v. infusion over 180 minutes weekly for 5 consecutive weeks. Three of the five CTCL patients achieved significant tumor responses. One patient attained a complete clinical and pathologic response (CR), which has been sustained without any interval treatment for 33+ months. Two other patients achieved partial responses (PRs) of 17+ and 4 months' duration, respectively. Treatment was well tolerated. The most common adverse effect was a transient increase in hepatic transaminases experienced by all five patients. The growth factor-cytotoxin fusion protein DAB486IL-2 demonstrated significant clinical activity with acceptable toxicity in a group of heavily pretreated patients with CTCL.


HBsAg seropositivity among multi-transfused thalassemic children.
Thalassemia major patients are transfusion dependent; they are at high risk of post transfusion viral infections including Hepatitis B virus (HBV). The present study was undertaken to find out the proportion of HBV infection among multiple transfused patients. This cross-sectional study was conducted among thalassemic children of either sex between 2 to 13 years of age, who attended the tertiary care hospital (G. G. Hospital, Jamnagar). Subjects were divided according to number of transfusions and the immunization status. HBsAg was detected by ELISA. Of 90 patients 6 (6.6%) were positive for HBsAg. Of 29 patients who had received above hundred transfusions 3 (10.34%) were sero-positive for HBV. Un-immunized patients were at double risk for acquiring HBV infection. This study suggests that the screening of blood of donors for HBV should be strictly followed and implementation of immunization against HBV is a must, especially in a high-risk group like thallasemic patients.


Genetic variation in wild and cultivated rhizoma corydalis revealed by ISSRs markers.
Rhizoma Corydalis is an important Chinese medicinal herb. In this paper, we employed ISSR data to explore the genetic variation in domesticated populations and wild populations of the species. The average of within-population ISSR diversity in cultivated populations (PPF=25.32%, Hpop=0.094) was lower than that in wild populations (PPF=47.70%, Hpop=0.144). Cultivated populations (PhiST=0.515, GST=0.429) have a greater proportion of their genetic variability distributed among populations than wild populations (PhiST=0.277, GST=0.226). Based on hierarchical estimates of variance components, significant statistical differences (57.77%, P<0.001) were found between the wild and cultivated groups. The low levels of genetic diversity within cultivated populations and high levels of genetic differentiation among populations/groups may result from artificial selection, the mode of clonal propagation, and only limited exchange of material among localities. Finally, some suggestions for conservation and efficient management of the genetic resources of this important medicinal herb are proposed.


Subtotal Cervical Esophagectomy and Anastomosis in an Ostrich (Struthio camelus domesticus).
An adult, female, captive ostrich (Struthio camelus domesticus) was referred to a veterinary teaching hospital for a 2-week history of lethargy and a mass effect in the proximal cervical region. Physical examination revealed a fistula in the middle cervical esophagus surrounded by devitalized and necrotic tissue; feed material was found leaking from the site. Cervical radiography identified an esophageal stricture with anterior dilation due to the accumulation of feed. After receiving supportive care for 48 hours, the patient's overall status improved, allowing partial esophagectomy and resection of the affected tissues with end-to-end anastomosis. Postoperative management included fasting for 24 hours, followed by the administration of a liquid hand-rearing formula prepared with commercially available ostrich feed and administered via a feeding tube for 15 days. Proper healing of the surgical site was confirmed by esophagoscopy using a flexible endoscope 17 days after surgery. The ostrich was discharged after 27 days, with no complications recorded within the 180 days of the follow-up period. Partial cervical esophagectomy with end-to-end anastomosis along with pre- and postoperative management provided a successful outcome for the treatment of a fistulated esophageal stricture in a captive ostrich, resulting in full recovery without surgical complications.


A prospective pilot study of genome-wide exome and transcriptome profiling in patients with small cell lung cancer progressing after first-line therapy.
Small cell lung cancer (SCLC) that has progressed after first-line therapy is an aggressive disease with few effective therapeutic strategies. In this prospective study, we employed next-generation sequencing (NGS) to identify therapeutically actionable alterations to guide treatment for advanced SCLC patients. Twelve patients with SCLC were enrolled after failing platinum-based chemotherapy. Following informed consent, genome-wide exome and RNA-sequencing was performed in a CLIA-certified, CAP-accredited environment. Actionable targets were identified and therapeutic recommendations made from a pharmacopeia of FDA-approved drugs. Clinical response to genomically-guided treatment was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The study completed its accrual goal of 12 evaluable patients. The minimum tumor content for successful NGS was 20%, with a median turnaround time from sample collection to genomics-based treatment recommendation of 27 days. At least two clinically actionable targets were identified in each patient, and six patients (50%) received treatment identified by NGS. Two had partial responses by RECIST 1.1 on a clinical trial involving a PD-1 inhibitor + irinotecan (indicated by MLH1 alteration). The remaining patients had clinical deterioration before NGS recommended therapy could be initiated. Comprehensive genomic profiling using NGS identified clinically-actionable alterations in SCLC patients who progressed on initial therapy. Recommended PD-1 therapy generated partial responses in two patients. Earlier access to NGS guided therapy, along with improved understanding of those SCLC patients likely to respond to immune-based therapies, should help to extend survival in these cases with poor outcomes.


Splanchnic Nerve Modulation Effects on Surrogate Measures of Venous Capacitance.
Background Splanchnic nerve modulation (SNM) is an emerging procedure to reduce cardiac filling pressures in heart failure. Although the main contributor to reduction in cardiac preload is thought to be increased venous capacitance in the splanchnic circulation, supporting evidence is limited. We examined changes in venous capacitance surrogates pre- and post-SNM. Methods and Results This is a prespecified analysis of a prospective, open-label, single-arm interventional study evaluating the effects of percutaneous SNM with ropivacaine in chronic heart failure with elevated filling pressures at rest and with exercise. Patients underwent cardiopulmonary exercise testing with invasive hemodynamic assessment pre- and post-SNM. Blood pressure changes with modified Valsalva maneuver and hemoconcentration, pre- and post-SNM were compared using a repeated measures model. Inferior vena cava diameter and collapsibility (>50% decrease in size with inspiration), and presence of bendopnea pre- and post-SNM were also compared. Fifteen patients undergoing SNM (age 58 years, 47% women, 93% with left ventricular ejection fraction ≤35%) were included. After SNM, changes in systolic blood pressure during Valsalva (peak-to-trough) were greater (41 versus 48 mm Hg, P=0.025). Exercise-induced hemoconcentration was unchanged (0.63 versus 0.43 g/dL, P=0.115). Inferior vena cava diameter was reduced (1.59 versus 1.30 cm, P=0.034) with higher collapsibility (33% versus 73%, P=0.014). Bendopnea was less (47% versus 13%, P=0.025). Conclusions SNM resulted in increased venous capacitance, associated decreased cardiac preload, and decreased bendopnea. Minimally invasive measures of venous capacitance could serve as markers of successful SNM. Long-term effects of SNM on venous capacitance warrant further investigation for heart failure management. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03453151.


Thoracic paravertebral block for percutaneous transhepatic biliary drainage.
Percutaneous transhepatic biliary drainage is a painful procedure most commonly performed after intravenous sedation. Despite systemic opiates and benzodiazepines, most patients experience significant pain during the procedure and in the recovery period. Paravertebral blocks allow the spinal nerve roots and sympathetic chain in the paravertebral space to be anesthetized, and their role in providing analgesia for thoracic and upper abdominal surgical procedures is well-established. Herein a case is described in which thoracic paravertebral blockade dramatically reduced standard intra- and postprocedural analgesic needs and provided superior pain control.


Preexisting immunity to adenovirus in rhesus monkeys fails to prevent vector-induced toxicity.
In an earlier study we evaluated innate immune responses to a first-generation adenoviral vector infused into the portal vein of rhesus monkeys who had never been exposed to adenovirus previously. In these animals, the systemic administration of E1/E3-deleted adenoviral vectors resulted in immediate activation of innate immunity and serious toxicity caused by targeting of vector to antigen-presenting cells and systemic inflammation. We analyze here how these responses are affected by vector-specific preexisting immunity that was induced by intramuscular immunization 6 months prior to evaluation. Our results show that preexposure to the vector substantially diminishes the transgene expression in most tissues but has little effect on gene transfer. Significantly, preimmunization does not eliminate systemic vector-induced toxicity. These conclusions are based on the presence of clinical features of coagulopathy and elevated levels of proinflammatory cytokine interleukin-6 in the serum of animals treated with vector after intramuscular immunization. Furthermore, preexisting immunity appears to induce a vector-specific inhibitory effect on erythroid progenitor development in the bone marrow that is not found when naive animals are challenged with vector.


Nucleoplasmic lamins define growth-regulating functions of lamina-associated polypeptide 2α in progeria cells.
A-type lamins are components of the peripheral nuclear lamina but also localize in the nuclear interior in a complex with lamina-associated polypeptide (LAP) 2α. Loss of LAP2α and nucleoplasmic lamins in wild-type cells increases cell proliferation, but in cells expressing progerin (a mutant lamin A that causes Hutchinson-Gilford progeria syndrome), low LAP2α levels result in proliferation defects. Here, the aim was to understand the molecular mechanism governing how relative levels of LAP2α, progerin and nucleoplasmic lamins affect cell proliferation. Cells from progeria patients and inducible progerin-expressing cells expressing low levels of progerin proliferate faster than wild-type or lamin A-expressing control cells, and ectopic expression of LAP2α impairs proliferation. In contrast, cells expressing high levels of progerin and lacking lamins in the nuclear interior proliferate more slowly, and ectopic LAP2α expression enhances proliferation. However, simultaneous expression of LAP2α and wild-type lamin A or an assembly-deficient lamin A mutant restored the nucleoplasmic lamin A pool in these cells and abolished the growth-promoting effect of LAP2α. Our data show that LAP2α promotes or inhibits proliferation of progeria cells depending on the level of A-type lamins in the nuclear interior.This article has an associated First Person interview with the first author of the paper.


Does moist wound healing influence the rate of infection?
Wound infections account for 9% of all healthcare-associated infection. Traditional wound dressings have been shown to give limited protection against microbes in comparison with modern dressings, yet they remain the main dressings of choice. While modern dressings facilitate a moist wound healing environment, which may increase the rate of healing, there is growing concern that it will increase the rate of infection. To review the evidence relating to moist wound healing and its influence on infection rates. Fourteen studies were reviewed from 36 studies found. Methodological issues identified included: differences in the measurement of wound infection, small sample groups, inappropriate dressing selection and limited comparability between studies. The rate of wound infection was not increased with the use of modern dressings when compared with traditional dressings. No statistical significance was found to suggest there were fewer infections under the modern dressings. The barrier effect of some dressings cannot be generalized to include all modern dressings.


[Separation and quantitative analysis of the composition of low molecular weight sulfated polysaccharides by size exclusion chromatography].
As the composition of low molecular weight sulfated polysaccharides is very complex, the quantitative analysis of their compositions is very important for understanding their bioactivity and the purpose of the quality control. A method was developed for the separation and quantitative analysis of the composition of low molecular weight sulfated polysaccharides. The effects of the parameters, such as the mobile phase constitution including ionic strength and pH, column length and temperature, flow rate of the mobile phase on the separation were systematically investigated. The obtained optimal conditions were as follows: two TSK-GEL G2000 SWxl columns (300 mm x 7.8 mm) coupled together; mobile phase, 100 mmol/L Na2HPO4-NaH2PO4(pH 7.0); flow rate, 0.5 mL/min; column temperature, 35 degrees C; injection volume, 5 microL; sample concentration, 10 g/L. The method was validated in terms of its reproducibility and robustness. Under the optimized chromatographic separation conditions, each composition of the low molecular weight sulfated polysaccharide can be clearly separated, and their distribution ratios were quantitatively analyzed. The composition profilings of the samples from United States pharmacopoeia (USP), the two commercial available samples and two home-made samples were quantitatively compared. The method can be used for the quality control of the drugs based on low molecular weight sulfated polysaccharides.


[Hemodynamic Predictors of Clinical Deterioration in Patients With Pulmonary Arterial Hypertension Associated With Systemic Scleroderma].
to elucidate hemodynamic predictors of clinical deterioration (CD) in patients with pulmonary arterial hypertension (PAH) associated with systemic scleroderma (SSD). We included into this study 48 patients with PAH-SSD consecutively admitted in 2004-2014. At inclusion all patients underwent right heart catheterization (RHC) and thereafter were under dynamic observation. CD deterioration was diagnosed in the presence of the following: >15% decline in 6-minute walk test distance; worsening of PAH functional class; intensification of symptoms of right ventricular failure; necessity in administration of parenteral diuretics. RHC was used for confirmation of CD. Relative risk (RR) of events was calculated for identification of significant predictors of CD. Cut points were determined with the help of construction of characteristic curves, statistical significance was estimated in Kaplan-Meier analysis. During follow-up (duration 46 [23;91] months) 21 patients had 24 CDs confirmed by RHC. Calculation of RR identified a number of hemodynamic parameters related to CD development. ROC analysis confirmed significance of initial right atrial pressure (RAP) 6.5 mm Hg (95% confidence interval [CI] 0.59-0.89, sensitivity 71%, specificity 63%, p<0.004) and dynamics of pulmonary vascular resistance (PVR) -1.06 Wood units (95%CI 0.790.99; sensitivity 76%, specificity 80%, <0.0001). Kaplan-Meier analysis revealed significant differences in times to CD (median 31.5 and 10 months in patients with RAP <6.5 and more or equal 6.5 mm Hg, respectively, p=0.01; 37 and 17months in patients with PVR lowering >1.06 Wood units and no PVR lowering, respectively, p=0.009. We identified prognostic levels of key hemodynamic predictors of CD in patients with SSD and PAH (RAP 6.5 mm Hg, PVR - 1. 06 Wood units) which can be used for individualization and optimization of therapy.


Adenosine inhibits renin release from juxtaglomerular cells via an A1 receptor-TRPC-mediated pathway.
Renin is synthesized and released from juxtaglomerular (JG) cells. Adenosine inhibits renin release via an adenosine A1 receptor (A1R) calcium-mediated pathway. How this occurs is unknown. In cardiomyocytes, adenosine increases intracellular calcium via transient receptor potential canonical (TRPC) channels. We hypothesized that adenosine inhibits renin release via A1R activation, opening TRPC channels. However, higher concentrations of adenosine may stimulate renin release through A2R activation. Using primary cultures of isolated mouse JG cells, immunolabeling demonstrated renin and A1R in JG cells, but not A2R subtypes, although RT-PCR indicated the presence of mRNA of both A2AR and A2BR. Incubating JG cells with increasing concentrations of adenosine decreased renin release. Different concentrations of the adenosine receptor agonist N-ethylcarboxamide adenosine (NECA) did not change renin. Activating A1R with 0.5 μM N6-cyclohexyladenosine (CHA) decreased basal renin release from 0.22 ± 0.05 to 0.14 ± 0.03 μg of angiotensin I generated per milliliter of sample per hour of incubation (AngI/ml/mg prot) (P < 0.03), and higher concentrations also inhibited renin. Reducing extracellular calcium with EGTA increased renin release (0.35 ± 0.08 μg AngI/ml/mg prot; P < 0.01), and blocked renin inhibition by CHA (0.28 ± 0.06 μg AngI/ml/mg prot; P < 0. 005 vs. CHA alone). The intracellular calcium chelator BAPTA-AM increased renin release by 55%, and blocked the inhibitory effect of CHA. Repeating these experiments in JG cells from A1R knockout mice using CHA or NECA demonstrated no effect on renin release. However, RT-PCR showed mRNA from TRPC isoforms 3 and 6 in isolated JG cells. Adding the TRPC blocker SKF-96365 reversed CHA-mediated inhibition of renin release. Thus A1R activation results in a calcium-dependent inhibition of renin release via TRPC-mediated calcium entry, but A2 receptors do not regulate renin release.


Epstein-Barr virus, cytomegalovirus, and other viral infections in children after liver transplantation.
We studied 51 consecutive pediatric patients for the frequency and morbidity of viral infections after liver transplantation. The incidence of primary (67%) and reactivation (48%) Epstein-Barr virus (EBV) infections and reactivation (88%) cytomegalovirus (CMV) infection was comparable to that seen in adult transplant recipients. However, fewer pediatric than adult transplant recipients experienced primary CMV infection (P less than .01). Five (38%) of 13 CMV infections were symptomatic and included hepatitis, pneumonitis, enteritis, and mononucleosis. Two of 14 patients with primary EBV infection subsequently developed, at two months and two years after initial infection, an EBV-associated lymphoproliferative syndrome, and one of 10 patients with reactivated EBV infection developed a possible EBV-associated febrile encephalopathy. Other viruses causing infection in these children included herpes simplex virus, varicella-zoster virus, adenovirus, parainfluenza virus, respiratory syncytial virus, and rotavirus.


Fentanyl and a Novel Synthetic Opioid U-47700 Masquerading as Street "Norco" in Central California: A Case Report.
In 2013 and 2014, more than 700 deaths were attributed to fentanyl and fentanyl analogues in the United States. Of recent concern is the cluster of unintentional fentanyl overdoses because of tablets thought to be "Norco" purchased on the street in Northern California. U-47700 (trans-3,4-dichloro-N-[2-(dimethyl-amino)cyclohexyl]-N-methylbenz-amide) is a nonfentanyl-based synthetic opioid with 7.5 times the binding affinity of morphine to μ-opioid. We report a case of fentanyl and U-47700 intoxication from what was thought to be illicitly purchased Norco. A 41-year-old woman presented to the emergency department (ED) for altered mental status shortly after ingesting 3 beige Norco pills bearing a Watson imprint. She had pinpoint pupils and respiratory depression, which reversed after 0.4 mg naloxone administration intravenously. She had complete recovery and was discharged from the ED after a 4-hour observation period. Serum testing with liquid chromatography-quadrupole time-of-flight mass spectrometry (LC 1260 QTOF/MS 6550; Agilent, Santa Clara, CA) confirmed the presence of the medications the patient reported receiving, and additionally fentanyl (15.2 ng/mL) and U-47700 (7.6 ng/mL). In this case report, street Norco purchased in Central California resulted in altered mental status requiring naloxone reversal because of fentanyl and the novel synthetic opioid U-47700. Because these compounds are not detected by routine urine drug testing and physical examination findings are similar to those of a traditional opioid toxidrome, emergency providers should use the patient's history and other circumstantial details to aid in diagnosis. In cases with suspicion of opioid or opioid analogue cause, we recommend that emergency providers contact their local poison control center, medical toxicologist, or public health department to aid in the investigation.


Nonparametric estimation of the distribution of time to onset for specific diseases in survival/sacrifice experiments.
This paper concerns the analysis of an animal survival/sacrifice experiment designed to investigate the incidence of a particular disease of interest. The disease is assumed to be irreversible, and detectable only at death, for example by a necropsy. Each observation can be of one of three types: (i) death caused by the disease, (ii) death from a competing cause such as sacrifice, with the disease present, or (iii) death with the disease absent. A two-dimensional EM algorithm is proposed for the nonparametric maximum likelihood estimation of the distributions of the time to onset and of the time to death from the disease. These can be compared with nonparametric estimators recently proposed by Kodell , Shaw and Johnson (1982, Biometrics 38, 43-58) and by Dinse and Lagakos (1982, Biometrics 38, 921-932). A slight modification of the algorithm permits the construction of likelihood-based interval estimates of quantiles of the distributions. Some extensions and generalizations are indicated.


[Fournier gangrene following prostatic puncture].
Authors report a case of Fournier's gangrene developed after prostatic puncture to draw attention to this rare condition, which can develop rapidly and jeopardize patient's life. They recommend an urgent and aggressive surgical intervention including temporary urinary and bowel diversion, if it is required.


High-energy Q-switched 16-core tapered rod-type fiber laser system.
High-energy Q-switched master oscillator power amplifier systems based on rod-type 4 × 4 multicore fibers are demonstrated, achieving energy up to 49 mJ in ns-class pulses. A tapered fiber geometry is tested that maintains low mode order in large multimode output cores, improving beam quality in comparison to a similar fiber with no taper. The tapered fiber design can be scaled both in the number of amplifying cores and in the dimensions of the cores themselves, providing a potential route toward joule-class fiber lasers systems.


Isobaric bupivacaine for spinal anaesthesia in acute war injuries.
Twenty nine patients with acute war injuries of the lower limbs or perineum were anaesthetised with intrathecal bupivacaine. Eleven patients (38%) were shocked on arrival with systolic arterial blood pressures less than 90 mmHg; in three the blood pressure was unrecordable . All patients were resuscitated and ready for surgery within 30 minutes of arrival at the field hospital. Hypotension occurred two minutes after injection of bupivacaine in three of the eleven shocked patients, but was corrected with fluids and metaraminol without difficulty. Patients with a fever were found to be less likely to develop hypotension. The early onset of hypotension and the necessity for a head-down tilt gives bupivacaine a significant advantage over hyperbaric agents, and the technique can be recommended.


Increased carotid intima-media thickness in the physiologic range is associated with impaired postprandial glucose metabolism, insulin resistance and beta cell dysfunction.
Carotid Intima-Media Thickness (C-IMT) is a reliable predictor of cardiovascular events. We examined if increased C-IMT was associated with defects in glucose metabolism in non-diabetic subjects independently of age. In 366 Caucasian non-diabetic subjects of the CARAMERIS study, we measured glucose response during a 75 g-Oral Glucose Tolerance Test (OGTT), insulin sensitivity index (ISI, by Matsuda Index), Liver Insulin Resistance Index (Liver-IR), insulin secretion by ΔAUC Ins0-120/Glu0-120 (ΔI/ΔG) and beta cell function (Disposition Index, DI). Subjects were divided in two groups according to the median age (AGE1 ≤ 45 y; AGE2 > 45 y). Only 5 subjects in AGE1 and 32 in AGE2 had C-IMT > 0.9 mm. Compared to AGE1, AGE2 had a worse cardio-metabolic profile, increased cholesterol, glucose and insulin concentrations, blood pressure and C-IMT. Both ΔI/ΔG ratio and DI were significantly reduced in AGE2. By considering tertiles of C-IMT in each AGE group (G1-G3, where G3 comprised the highest C-IMT), we found that G3 showed increased OGTT glucose profiles and Liver IR, decreased ISI and DI, compared to G1 in each AGE group. Increased C-IMT, but within normal ranges, is associated independently of age with altered postprandial glucose profile, increased peripheral and hepatic insulin resistance, decreased b-cell function. C-IMT measurement should become a routine analysis even in younger subjects to predict the risk of cardio-metabolic disease.


Mitochondrial calcium overload triggers complement-dependent superoxide-mediated programmed cell death in Trypanosoma cruzi.
The epimastigote stage of Trypanosoma cruzi undergoes PCD (programmed cell death) when exposed to FHS (fresh human serum). Although it has been known for over 30 years that complement is responsible for FHS-induced death, the link between complement activation and triggering of PCD has not been established. We have previously shown that the mitochondrion participates in the orchestration of PCD in this model. Several changes in mitochondrial function were described, and in particular it was shown that mitochondrion-derived O(2)(*-) (superoxide radical) is necessary for PCD. In the present study, we establish mitochondrial Ca(2+) overload as the link between complement deposition and the observed changes in mitochondrial physiology and the triggering of PCD. We show that complement activation ends with the assembly of the MAC (membrane attack complex), which allows influx of Ca(2+) and release of respiratory substrates to the medium. Direct consequences of these events are accumulation of Ca(2+) in the mitochondrion and decrease in cell respiration. Mitochondrial Ca(2+) causes partial dissipation of the inner membrane potential and consequent mitochondrial uncoupling. Moreover, we provide evidence that mitochondrial Ca(2+) overload is responsible for the increased O(2)(*-) production, and that if cytosolic Ca(2+) rise is not accompanied by the accumulation of the cation in the mitochondrion and consequent production of O(2)(*-), epimastigotes die by necrosis instead of PCD. Thus our results suggest a model in which MAC assembly on the parasite surface allows Ca(2+) entry and its accumulation in the mitochondrion, leading to O(2)(*-) production, which in turn constitutes a PCD signal.


Exserohilum turcicum Race Population Distribution in the North Central United States.
Northern leaf blight (NLB) of corn, caused by Exserohilum turcicum, is a foliar disease common across corn production regions of the world, including those in the north central United States. Previous race population distribution studies identified five physiological races present in the United States, prior to 1995. For this study, 156 E. turcicum isolates were screened on corn differential lines containing Ht1, Ht2, Ht3, Htm1, and Htn1 resistance genes. Isolates were collected from fields in Iowa, Illinois, Indiana, Minnesota, North Carolina, Ohio, and Wisconsin, which included 143 isolates collected between 2007 and 2014 and 13 isolates collected between 1979 and 1985. Twenty different physiological races were observed based on the symptom response of the differential corn lines. E. turcicum race 0, 1, and 1mn were the most prevalent races, comprising 21, 27, and 13% of the 156 isolates, respectively. Race populations were diverse within states and years. Virulence to multiple Ht resistance genes within individual isolates was observed in 47% of those tested, with 3% of the isolates conferring virulence to all Ht resistance genes. Virulence to the Ht1, Ht2, Ht3, Htm1, and Htn1 resistance genes was present in 64, 20, 18, 32, and 27% of the E. turcicum isolates, respectively. Virulence to Ht resistance genes was fairly evenly distributed across states, in isolates collected after 2008. Virulence to Ht2, Ht3, Htm1, and Htn1 decreased after 2010. Variations in race population diversity are difficult to explain without knowing the level of selection pressure present in fields, and information regarding Ht resistance gene deployment in commercial varieties is not publicly available. Although virulence was observed against all Ht resistance genes, qualitative Ht resistance genes could be used in conjunction with quantitative resistance to increase NLB control.


Insect cuticle and insecticide development.
Insecticide resistance poses a significant challenge, diminishing the effectiveness of chemical insecticides. To address this global concern, the development of novel and efficient pest management technologies based on chemical insecticides is an ongoing necessity. The insect cuticle, a highly complex and continuously renewing organ, plays a crucial role in this context. On one hand, as the most vital structure, it serves as a suitable target for insecticides. On the other hand, it acts as the outermost barrier, isolating the insect's inner organs from the environment, and thus offering resistance to contact with insecticides, preventing their entry into insect bodies. Our work focuses on key targets concerning cuticle formation and the interaction between the cuticle and contact insecticides. Deeper studying insect cuticles and understanding their structure-function relationship, formation process, and regulatory mechanisms during cuticle development, as well as investigating insecticide resistance related to the barrier properties of insect cuticles, are promising strategies not only for developing novel insecticides but also for discovering general synergists for contact insecticides. With this comprehensive review, we hope to contribute valuable insights into the development of effective pest management solutions and the mitigation of insecticide resistance.


Association of Glyburide and Subcutaneous Insulin With Perinatal Complications Among Women With Gestational Diabetes.
Nearly 30% of individuals with gestational diabetes (GDM) do not achieve glycemic control with lifestyle modification alone and require medication treatment. Oral agents, such as glyburide, have several advantages over insulin for the treatment of GDM, including greater patient acceptance; however, the effectiveness of glyburide for the treatment of GDM remains controversial. To compare the perinatal and neonatal outcomes associated with glyburide vs insulin using causal inference methods in a clinical setting with information on glycemic control. The population-based cohort study included patients with GDM who required medication treatment from 2007 to 2017 in Kaiser Permanente Northern California. Machine learning and rigorous casual inference methods with time-varying exposures were used to evaluate associations of exposure to glyburide vs insulin with perinatal outcomes. Data analysis was conducted from March 2018 to July 2017. Time-varying exposure to glyburide vs insulin during pregnancy. Outcomes evaluated separately included neonatal hypoglycemia, jaundice, shoulder dystocia, respiratory distress syndrome (RDS), neonatal intensive care unit (NICU) admission, size-for-gestational age, and cesarean delivery. Inverse probability weighting (IPW) estimation was used to separately compare perinatal outcomes between those initiating glyburide and insulin. This approach was combined with Super Learning for propensity score estimation to account for both baseline and time-dependent confounding in both per-protocol (primary) and intention-to-treat (secondary) analyses to evaluate sustained exposure to the same therapy. From 2007 to 2017, 11 321 patients with GDM (mean [SD] age, 32.9 [4.9] years) initiated glyburide or insulin during pregnancy. In multivariate models, the risk of neonatal respiratory distress was 2.03 (95% CI, 0.13-3.92) per 100 births lower and the risk of NICU admission was 3.32 (95% CI, 0.20-6.45) per 100 births lower after continuous exposure to glyburide compared with insulin. There were no statistically significant differences in glyburide vs insulin initiation in risk for neonatal hypoglycemia (0.85 [95% CI, -1.17 to 2.86] per 100 births), jaundice (0.02 [95% CI, -1.46 to 1.51] per 100 births), shoulder dystocia (-1.05 [95% CI, -2.71 to 0.62] per 100 births), or large-for-gestational age categories (-2.75 [95% CI, -6.31 to 0.80] per 100 births). Using data from a clinical setting and contemporary causal inference methods, our findings do not provide evidence of a difference in the outcomes examined between patients with GDM initiating glyburide compared with those initiating insulin.


A Simple Vitamin Deficiency With Life-Threatening Complications: A Case of B12 Deficiency and Hyperhomocysteinemia-Induced Thrombosis.
While macrocytic anemia is common in vitamin B12 deficiency, rarely, pancytopenia and hemolytic anemia can occur. Homocysteine levels are elevated in severe B12 deficiency, and this is linked to thrombus formation with potentially life-threatening complications. We present a patient with severe vitamin B12 deficiency complicated by hyperhomocysteinemia and obstructive shock from pulmonary embolism. A 56-year-old male with no medical history presented to the hospital with altered mentation. The patient's family stated he was experiencing bilateral paresthesias of his lower extremities, progressive depression, anxiety, and insomnia. Initial vitals were blood pressure of 76/36, heart rate of 70 beats per minute, respiratory rate of 14, and temperature of 36.3 degrees Celsius. He was intubated due to severe encephalopathy. Relevant labs indicated severe macrocytic anemia, thrombocytopenia, decreased B12 levels, elevated methylmalonic acid, and elevated homocysteine. Imaging demonstrated a right common femoral vein thrombosis and subsegmental pulmonary emboli. Peripheral blood smear revealed schistocytes, anisopoikilocytosis, and decreased platelet count. The patient required fluid resuscitation, antibiotics, and multiple blood products. Vitamin B12 was administered intramuscularly, which improved the anemia. Esophagogastroduodenoscopy (EGD) demonstrated gastritis. Gastric and duodenal biopsies were negative for Helicobacter pylori and celiac disease. He was negative for intrinsic factor (IF) antibodies but had elevated gastrin levels. An intravenous unfractionated heparin infusion was started when the platelet count was above 50000. The patient was extubated after seven days. Heparin was transitioned to apixaban and an inferior vena cava (IVC) filter was placed. Hyperhomocysteinemia is a known pro-thrombotic factor that can lead to the development of venous thromboembolism. B12 malabsorption can stem from inflammatory bowel disease, celiac disease, gastritis, pancreatic insufficiency, gastrectomy, gastric bypass surgery, or antibodies to IF. While this case showed gastritis and negative IF antibodies, gastrin levels were elevated, indicating a mixed picture. This highlights the challenge of definitively diagnosing pernicious anemia as the cause of vitamin B12 deficiency. Vitamin B12 deficiency may lead to critical illness in which thromboembolism develops secondary to hyperhomocysteinemia.


Mechanisms of accumulation of small particles of iron oxide in experimentally induced osteosarcomas of rats: a correlation of magnetic resonance imaging and histology. Preliminary results.
This study was conducted to investigate the distribution and kinetics of small particles of iron oxide in osteosarcoma-like tumors. Magnetic resonance (MR) imaging was performed in eight athymic nude rats with an experimentally induced osteosarcoma of the right hind leg immediately after intravenous injection of a superparamagnetic iron oxide preparation. Five animals received 150 mumol iron oxide/ kg and three received 50 mumol iron oxide/kg. The iron oxide preparation consisted of polythylenglycol-coated particles with a core diameter of 6 to 8 nm. The MR images were correlated with histologic slices of the tumors. The tumors accumulated iron oxide rapidly. A marked decrease in signal intensity, preferentially along the periphery of the tumor, was followed by a partial return of the signal intensity within the first minute. The maximum signal decrement throughout the entire tumor exceeded 41% and 21% with one dose each of 150 mumol iron/kg and 50 mumol iron/kg, respectively. The rate of return depended on the injected dose and tumor area, with the signal intensity approaching the initial value before the injection of iron oxide after 45 minutes. Histologic correlation only showed deposition of contrast medium in the proliferative areas of the tumors, mainly confined to the tumor margin. In addition to a predominantly extracellular deposition, intracellular storage could be detected. The findings help to advance the understanding of the distribution and kinetics of intravenous-injected small particles of iron oxide in osteosarcoma-like tumors. A first-pass accumulation of iron oxide could be documented by MR imaging in the periphery of osteosarcomas. Due to sieving of iron oxide particles by liver, spleen, and bone marrow, the signal intensity at 45 minutes after the injection of iron oxide returned to 89% (150 mumol iron oxide/kg) and 95% (50 mumol iron oxide/kg) of the preinjection intensity.


Identification and mapping QTL for high-temperature adult-plant resistance to stripe rust in winter wheat (Triticum aestivum L.) cultivar 'Stephens'.
High-temperature adult-plant (HTAP) resistance from the winter wheat (Triticum aestivum) cultivar 'Stephens' has protected wheat crops from stripe rust caused by Puccinia striiformis f. sp. tritici for 30 years. The objectives of this study were to identify quantitative trait loci (QTL) for HTAP resistance in Stephens through genetic linkage analysis and identify DNA markers linked to the QTL for use in marker-assisted breeding. Mapping populations consisted of 101 recombinant inbred lines (RILs) through single-seed descent from 'Stephens' (resistant) x 'Michigan Amber' (susceptible). F(5), F(6) and F(7) RILs were evaluated for stripe rust resistance at Pullman, WA in 1996, 1997 and 1998, respectively, whereas F(8) RILs were evaluated at Mt Vernon, WA, USA in 2005. The 101 F(8) RILs were evaluated with 250 resistance gene analog polymorphism (RGAP), 245 simple sequence repeat (SSR) and 1 sequence tagged site (STS) markers for genetic linkage map construction. Two QTL, which explained 48-61% of the total phenotypic variation of the HTAP resistance in Stephens, were identified. QYrst.wgp-6BS.1 was within a 3.9-cM region flanked by Xbarc101 and Xbarc136. QYrst.wgp-6BS.2 was mapped in a 17.5-cM region flanked by Xgwm132 and Xgdm113. Both two QTL were physically mapped to the short arm of chromosome 6B, but in different bins. Validation and polymorphism tests of the flanking markers in 43 wheat genotypes indicated that the molecular markers associated with these QTL should be useful in marker-assisted breeding programs to efficiently incorporate HTAP resistance into new wheat cultivars.


Mandibular symphysis morphology in different skeletal malocclusions and its correlation with uvulo-glossopharyngeal structures.
Objective: The aim of the present study was to evaluate mandibular symphyseal morphology and its relationship with uvulo-glossopharyngeal structures in patients who had a range of sagittal malocclusions.Methods: The study sample consisted of 100 patients who presented with Class I, Class II div. 1, Class II div. 2, or Class III malocclusions. Skeletal, dental, symphyseal, and uvulo-glossopharyngeal measurements were evaluated on cephalograms.Results: As the vertical growth of the mandibular symphysis increased, the ANB angle and the IMPA and soft palate length and thickness decreased, whereas, the SNB angle and RgnH increased significantly. In addition, as the symphysis inclination in relation to the mandibular plane increased, the IMPA and ANB angles increased, while tongue height decreased.Conclusion: Based on the findings of the present study, it can be concluded that there are relationships between mandibular symphysis morphology and the uvulo-glossopharyngeal structures and differences between sagittal skeletal malocclusions.


Pelvic exenteration for locally advanced colorectal carcinoma.
Pelvic exenteration provided worthwhile palliation and achieved a cumulative five-year survival rate of 38.8% in 49 patients who had carcinoma of the lower colon or rectum infiltrating adjoining pelvic viscera. Survival and the disease-free period were not significantly different after total or posterior exenteration. The stage of disease was the major determinant of outcome: five-year survival rates averaged 51.8% and 28.8% for Stages II and III, respectively. Hospital mortality (26.9%) after total exenteration was chiefly due to technical mishaps, and the inclusion of many high-risk but symptomatic elderly patients. Complete clearance of locally advanced colorectal cancer by pelvic exenteration is indicated in fit patients, especially those with Stage II disease.


Sympathetic nervous system activity and pain-related response indexed by electrodermal activity during the earliest postnatal life in healthy term neonates.
Sympathetic nervous system (SNS) undergoes a prolonged period of fetal and neonatal development and maturation during which is vulnerable to a variety of influences (e.g. painful experiences). Thus, we aimed to evaluate SNS activity at rest and in response to stressful stimulus (pain) within the earliest postnatal life in healthy term neonates using electrodermal activity (EDA) measures. In twenty eutrophic healthy term neonates EDA was recorded within the first two hours after birth (measurement 1 - M1) and 72 h after birth (measurement 2 - M2) at rest and in response to pain (M1 - intramuscular K vitamin administration; M2 - heel stick). Evaluated parameters were skin conductance level (SCL), non-specific skin conductance responses (NS.SCRs), skin SCL 10 s before pain stimulus (SCL_10 before pain), skin conductance response (SCR) peak after pain stimulus, SCL 10 s after pain stimulus (SCL_10 after pain), SCR magnitude, latency, SCR rise/decline time, SCR half recovery time. SCL was significantly decreased at rest during M2 compared to M1 (p=0.010). SCL_10 before pain, SCR peak after pain, and SCL_10 after pain stimulus were significantly decreased in M2 compared to M1 (p=0.014, p=0.020, p=0.011, respectively). SCL was significantly decreased and NS.SCRs were significantly higher in the recovery period after the pain stimulus during M2 compared to M1 (p=0.015, p=0.032, respectively). Our results indicate EDA parameters sensitive to detect sympathetic changes during the earliest postnatal life reflecting its potential in early diagnosis of the autonomic maturation - linked pathological states in neonates.


Urinary catecholamine responses in F-15 pilots: evaluation of the stress induced by long-distance flights.
Included in the Cooperative Cope Thunder exercises from Japan to Alaska is one of the longest distance flight missions carried out by Japan Air-Self Defense Force F-15 pilots. The magnitude of the flight stress of these pilots is considered to be quite high. The purpose of this study was to evaluate the flight stress induced by the long-distance flights. The subjects were eight pilots who participated on a volunteer basis. Samples of urine were collected approximately 30 minutes before (preflight) and 20 minutes after (postflight) the flights. The ratios (post-:preflight) of noradrenaline levels were 1.20 +/- 0.09 (Japan-Alaska) and 1.32 +/- 0.12 (Alaska-Japan), and those of adrenaline were 4.03 +/- 1.06 and 3.68 +/- 0.98. These results strongly suggest that psychological stress during the long-distance flights is increased in the fighter pilots.


Selection rule for cavity configurations to generate cylindrical vector beams with low beam quality factor.
Considering the birefringence of the gain medium, we propose a selection rule for designing cavity configurations that enable the generation of radially and azimuthally polarized laser beams with a low beam quality factor, i.e., high beam quality. Using this rule, all stable regions can support cylindrical vector (CV) beams by using the position of the end mirror as the tuning parameter to vary the cavity configuration. Such cavity configurations tend to sustain the fundamental or lowest-order CV beam, and radially or azimuthally polarized beams can be obtained simply by varying the tuning parameter. Based on experimental measurements of the beam quality factor and polarization characteristics, we verified our analyses and simulations for a four-element laser system.


Cerebral toxoplasmosis in HIV/AIDS: a case report.
This is a case of HIV infection with cerebral toxoplasmosis. Cerebral toxoplasmosis is an AIDS- related infection and is one of the causes of CNS mass lesions in AIDS. A 36-year-old male was admitted at Komfo Anokye Teaching Hospital (KATH) for a week. He had focal seizures for which he was treated as an "epileptic" with herbal preparations. A computerized tomography (CT) head scan revealed the characteristic scan findings in CNS toxoplasmosis.


A single-valent long-acting human CD47 antagonist enhances antibody directed phagocytic activities.
Many cancer cells express CD47 as a 'don't eat me' signal to mask their presences from immune recognition and destruction. Such a signal is transmitted when CD47 binds to the signal regulatory protein-α (SIRPα) on macrophages to cut the phagocytic reaction. Most recent studies have focused on developing CD47 blocking agents with different affinities and avidities in order to optimize the therapeutic window between efficacy and toxicities involving normal cells expressing CD47. We described in this study a new design to fuse one CD47 binding domain of SIRPα with a pharmacokinetics modifying domain F8. The resulted single valent long-acting CD47 antagonist SIRPα-F8 was able to bind to CD47 and disrupt CD47-SIRPα axis. However, by itself it cannot trigger endocytosis and has no effect on tumor growth. Only when used in combination with the anti-CD20 mAbs, there were greatly improved phagocytic activities towards CD20 positive cancer cells. In vivo the combination also resulted in better tumor growth inhibition comparing to the vehicle control group. In addition, we showed that the F8 fusion bound to hFcRn only inside endosomes at pH 6.0, enabled hFcRn mediated recycling and thus greatly extended the circulation half-life in hFcRn knock-in mice. Taken together, the SIRPα-F8 design may suggest a new option to improve the therapeutic index of antibody treatment in clinical use towards tumors.


Mouse vitamin D-24-hydroxylase: molecular cloning, tissue distribution, and transcriptional regulation by 1alpha,25-dihydroxyvitamin D3.
Vitamin D-24-hydroxylase (24-OHase) is a cytochrome P-450 enzyme that catalyzes the conversion of 25-hydroxyvitamin D3 (25OHD3) and 1alpha,25-dihydroxyvitamin D3 [1,25-(OH)2D3] to 24,25-dihydroxyvitamin D3 and 1,24,25-trihydroxyvitamin D3, respectively. A full-length complementary DNA for mouse 24-OHase has now been characterized. The complementary DNA consists of 3309 bp and encodes a protein of 514 amino acids that shows 82% and 95% sequence identity with the human and rat enzymes, respectively. Northern blot analysis of tissues from mice injected with 1,25-(OH)2D3 (24 pmol/g) revealed that the 3.4-kb 24-OHase messenger RNA (mRNA) is most abundant in kidney and intestine, with smaller amounts present in skin, thymus, and bone. RT-PCR and Southern blot analysis detected 24-OHase mRNA in several other tissues including lung, testis, spleen, pancreas, and heart. Intraperitoneal injection of 1,25-(OH)2D3 induced dose- and time-dependent increases in both 24-OHase mRNA abundance and enzyme activity in mouse kidney. Similarly, 1,25-(OH)2D3-induced increases in both 24-OHase mRNA and activity were apparent in the duodenum. Although 1,25-(OH)2D3 increased the amount of 24-OHase mRNA in skin, enzyme activity was not detected in this tissue. Pretreatment of mice with cycloheximide (400 microg/g), an inhibitor of protein synthesis, potentiated the increase in 24-OHase mRNA abundance, but blocked the increase in 24-OHase activity, induced by 1,25-(OH)2D3 in kidney and duodenum, suggesting that 24-OHase gene expression may be regulated not only by the vitamin D receptor but also by a short-lived repressor protein.