A high speed CMOS image sensor with a novel digital correlated double sampling and a differential difference amplifier.
In order to increase the operating speed of a CMOS image sensor (CIS), a new technique of digital correlated double sampling (CDS) is described. In general, the fixed pattern noise (FPN) of a CIS has been reduced with the subtraction algorithm between the reset signal and pixel signal. This is because a single-slope analog-to-digital converter (ADC) has been normally adopted in the conventional digital CDS with the reset ramp and signal ramp. Thus, the operating speed of a digital CDS is much slower than that of an analog CDS. In order to improve the operating speed, we propose a novel digital CDS based on a differential difference amplifier (DDA) that compares the reset signal and the pixel signal using only one ramp. The prototype CIS has been fabricated with 0.13 µm CIS technology and it has the VGA resolution of 640 × 480. The measured conversion time is 16 µs, and a high frame rate of 131 fps is achieved at the VGA resolution.


Genomic analysis of the ecdysone steroid signal at metamorphosis onset using ecdysoneless and EcRnullDrosophila melanogaster mutants.
Steroid hormone gene regulation is often depicted as a linear transduction of the signal, from molecule release to the gene level, by activation of a receptor protein after being bound by its steroid ligand. Such an action would require that the hormone be present and bound to the receptor in order to have target gene response. Here, we present data that presents a novel perspective of hormone gene regulation, where the hormone molecule and its receptor have exclusive target gene regulation function, in addition to the traditional direct target genes. Our study is the first genome-wide analysis of conditional mutants simultaneously modeling the steroid and steroid receptor gene expression regulation. We have integrated classical genetic mutant experiments with functional genomics techniques in the Drosophila melanogaster model organism, where we interrogate the 20-hydroxyecdysone signaling response at the onset of metamorphosis. Our novel catalog of ecdysone target genes illustrates the separable transcriptional responses among the hormone, the pre-hormone receptor and the post-hormone receptor. We successfully detected traditional ecdysone target genes as common targets and also identified novel sets of target genes which where exclusive to each mutant condition. Around 12 % of the genome responds to the ecdysone hormone signal at the onset of metamorphosis and over half of these are independent of the receptor. In addition, a significant portion of receptor regulated genes are differentially regulated by the receptor, depending on its ligand state. Gene ontology enrichment analyses confirm known ecdysone regulated biological functions and also validate implicated pathways that have been indirectly associated with ecdysone signaling.


Novel diagnostic approaches in Bing-Neel syndrome.
The central nervous system (CNS) manifestations of Waldenström's macroglobulinemia (WM) are known as the Bing-Neel syndrome (BNS). Patients with BNS can be classified into Group A and Group B based on the presence of lymphoplasmacytoid (LMP) cells within the brain parenchyma, leptomeninges, dura, and/or cerebrospinal fluid (CSF). To identify characteristic imaging findings for both Group A and Group B patients, we reviewed all 36 cases (26 referenced, 10 unreported) of proven WM with CNS symptoms, CSF analysis and/or biopsy, and magnetic resonance imaging (MRI) of the brain and/or spinal cord. Enhancement on MRI suggests invasion of the central neuraxis by LMP cells, and can help distinguish between Group A and Group B patients. In addition to differentiating true WM lesions in the CNS from ischemia, hyperviscosity events, and demyelinating lesions, evaluation of brain and spinal cord with gadolinium-enhanced MRI has the potential to guide management.


Mapping eQTLs in the Norfolk Island genetic isolate identifies candidate genes for CVD risk traits.
Cardiovascular disease (CVD) affects millions of people worldwide and is influenced by numerous factors, including lifestyle and genetics. Expression quantitative trait loci (eQTLs) influence gene expression and are good candidates for CVD risk. Founder-effect pedigrees can provide additional power to map genes associated with disease risk. Therefore, we identified eQTLs in the genetic isolate of Norfolk Island (NI) and tested for associations between these and CVD risk factors. We measured genome-wide transcript levels of blood lymphocytes in 330 individuals and used pedigree-based heritability analysis to identify heritable transcripts. eQTLs were identified by genome-wide association testing of these transcripts. Testing for association between CVD risk factors (i.e., blood lipids, blood pressure, and body fat indices) and eQTLs revealed 1,712 heritable transcripts (p < 0.05) with heritability values ranging from 0.18 to 0.84. From these, we identified 200 cis-acting and 70 trans-acting eQTLs (p < 1.84 × 10(-7)) An eQTL-centric analysis of CVD risk traits revealed multiple associations, including 12 previously associated with CVD-related traits. Trait versus eQTL regression modeling identified four CVD risk candidates (NAAA, PAPSS1, NME1, and PRDX1), all of which have known biological roles in disease. In addition, we implicated several genes previously associated with CVD risk traits, including MTHFR and FN3KRP. We have successfully identified a panel of eQTLs in the NI pedigree and used this to implicate several genes in CVD risk. Future studies are required for further assessing the functional importance of these eQTLs and whether the findings here also relate to outbred populations.


Eyeing the ED's open door.
More than one-third of all hospital admissions originate from the emergency department (ED). ED case managers maximize the quality of care and control ED admissions by verifying admission criteria, finding alternatives to inappropriate or social admissions, and identifying high-risk discharge factors.


Changes of the transverse diameter and volume and dosimetry before the 25th fraction during the course of intensity-modulated radiation therapy (IMRT) for patients with nasopharyngeal carcinoma.
To quantify changes of the transverse diameter and volume and dosimetry, and to illustrate the inferiority of non-replanning during intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC) patients. Fifty-three NPC patients who received IMRT in 33 fractions were enrolled in this prospective trial. Before the 25th fraction, a new simulation computed tomography (CT) scan was acquired for all patients. The dose-volume histograms of the phantom plan were compared with the initial plan. Significant reduction of the transverse diameter of the nasopharyngeal, the neck, and 2 parotid glands volume was observed on second CT compared with the first CT (mean reduction 7.48 ± 4.45 mm, 6.80 ± 15.14 mm, 5.70 ± 6.26 mL, and 5.04 ± 5.85 mL, respectively; p < 0.01). The maximum dose and V-40 of the spinal cord, mean dose, and V30 of the left and right parotid, and V-50 of the brain stem were increased significantly in the phantom plan compared with the initial plan (mean increase 4.75 ± 5.55 Gy, 7.18 ± 10.07%, 4.51 ± 8.55 Gy, 6.59 ± 17.82%, 5.33 ± 8.55 Gy, 11.68 ± 17.11% and 1.48 ± 3.67%, respectively; p < 0.01). On the basis of dose constraint criterion in the RTOG0225 protocol, the dose of the normal critical structures for 52.83% (28/53) of the phantom plans were out of limit compared with 1.89% (1/53) of the initial plans (p < 0.0001). Because of the significant change in anatomy and dose before the 25th fraction during IMRT, replanning should be necessary during IMRT with NPC.


Interleukin-15 promotes intestinal dysbiosis with butyrate deficiency associated with increased susceptibility to colitis.
Dysbiosis resulting in gut-microbiome alterations with reduced butyrate production are thought to disrupt intestinal immune homeostasis and promote complex immune disorders. However, whether and how dysbiosis develops before the onset of overt pathology remains poorly defined. Interleukin-15 (IL-15) is upregulated in distressed tissue and its overexpression is thought to predispose susceptible individuals to and have a role in the pathogenesis of celiac disease and inflammatory bowel disease (IBD). Although the immunological roles of IL-15 have been largely studied, its potential impact on the microbiota remains unexplored. Analysis of 16S ribosomal RNA-based inventories of bacterial communities in mice overexpressing IL-15 in the intestinal epithelium (villin-IL-15 transgenic (v-IL-15tg) mice) shows distinct changes in the composition of the intestinal bacteria. Although some alterations are specific to individual intestinal compartments, others are found across the ileum, cecum and feces. In particular, IL-15 overexpression restructures the composition of the microbiota with a decrease in butyrate-producing bacteria that is associated with a reduction in luminal butyrate levels across all intestinal compartments. Fecal microbiota transplant experiments of wild-type and v-IL-15tg microbiota into germ-free mice further indicate that diminishing butyrate concentration observed in the intestinal lumen of v-IL-15tg mice is the result of intrinsic alterations in the microbiota induced by IL-15. This reconfiguration of the microbiota is associated with increased susceptibility to dextran sodium sulfate-induced colitis. Altogether, this study reveals that IL-15 impacts butyrate-producing bacteria and lowers butyrate levels in the absence of overt pathology, which represent events that precede and promote intestinal inflammatory diseases.


Beyond Atherosclerosis and Fibromuscular Dysplasia: Rare Causes of Renovascular Hypertension.
Renovascular hypertension is one of the most common forms of secondary hypertension. Over 95% of cases of renovascular hypertension are due either to atherosclerosis of the main renal artery trunks or to fibromuscular dysplasia. These two causes of renal artery stenosis have been extensively discussed in recent reviews and consensus. The aim of the current article is to provide comprehensive and up-to-date information on the remaining causes. While these causes are rare or extremely rare, etiologic and differential diagnosis matters both for prognosis and management. Therefore, the clinician cannot ignore them. For didactic reasons, we have grouped these different entities into stenotic lesions (neurofibromatosis type 1 and other rare syndromes, dissection, arteritis, and segmental arterial mediolysis) often associated with aortic coarctation and other arterial abnormalities, and nonstenotic lesions, where hypertension is secondary to compression of adjacent arteries and changes in arterial pulsatility (aneurysm) or to the formation of a shunt, leading to kidney ischemia (arteriovenous fistula). Finally, thrombotic disorders of the renal artery may also be responsible for renovascular hypertension. Although thrombotic/embolic lesions do not represent primary vessel wall disease, they are characterized by frequent macrovascular involvement. In this review, we illustrate the most characteristic aspects of these different entities responsible for renovascular hypertension and discuss their prevalence, pathophysiology, clinical presentation, management, and prognosis.


Planning and studying improvement in patient care: the use of theoretical perspectives.
A consistent finding in articles on quality improvement in health care is that change is difficult to achieve. According to the research literature, the majority of interventions are targeted at health care professionals. But success in achieving change may be influenced by factors other than those relating to individual professionals, and theories may help explain whether change is possible. This article argues for a more systematic use of theories in planning and evaluating quality-improvement interventions in clinical practice. It demonstrates how different theories can be used to generate testable hypotheses regarding factors that influence the implementation of change, and it shows how different theoretical assumptions lead to different quality-improvement strategies.


Postlicensure safety surveillance for 7-valent pneumococcal conjugate vaccine.
Clinical trials evaluate a vaccine's safety before approval, but some risks may escape detection or adequate characterization until larger population exposures occur after licensure. To summarize reports of events occurring after vaccination with 7-valent pneumococcal conjugate vaccine (PCV), including those that may warrant further investigation to assess possible causation by PCV. Descriptive epidemiology of reports submitted to the Vaccine Adverse Event Reporting System (VAERS), a national passive surveillance database. United States during first 2 years after licensure of PCV (February 2000 through February 2002). Reports studied were for children younger than 18 years and vaccinated with PCV. Numbers and proportional distributions of reports. A total of 4154 reports of events following PCV were submitted to VAERS, for a rate of 13.2 reports per 100,000 doses distributed. Multiple vaccines were given in 74.3% of reports. The most frequently reported symptoms and signs included fever, injection site reactions, fussiness, rashes, and urticaria. Serious events were described in 14.6% of reports. There were 117 deaths, 23 reports of positive rechallenges, and 34 cases of invasive pneumococcal infections possibly representing vaccine failure. Immune-mediated events occurred in 31.3% of reports. All 14 patients with anaphylactic or anaphylactoid reactions survived. Thrombocytopenia developed in 14 patients and serum sickness in 6 others. Neurologic symptoms occurred in 38% of reports. Seizures described in 393 reports included 94 febrile seizures. The majority of reports to VAERS in the first 2 years after licensure of PCV described generally minor adverse events previously identified in clinical trials. The proportion of reports portraying serious events was similar to that for other vaccines. Although there are important limitations in passive surveillance data, and caution in their interpretation is necessary, symptoms experienced by a few children more than once after successive PCV doses, including allergic reactions, prolonged or abnormal crying, fussiness, dyspnea, and gastrointestinal distress, warrant continued surveillance, as do reports of rare but potentially serious events, such as seizures, anaphylactic or anaphylactoid reactions, serum sickness, and thrombocytopenia.


Early vs late tracheotomy for prevention of pneumonia in mechanically ventilated adult ICU patients: a randomized controlled trial.
Tracheotomy is used to replace endotracheal intubation in patients requiring prolonged ventilation; however, there is considerable variability in the time considered optimal for performing tracheotomy. This is of clinical importance because timing is a key criterion for performing a tracheotomy and patients who receive one require a large amount of health care resources. To determine the effectiveness of early tracheotomy (after 6-8 days of laryngeal intubation) compared with late tracheotomy (after 13-15 days of laryngeal intubation) in reducing the incidence of pneumonia and increasing the number of ventilator-free and intensive care unit (ICU)-free days. Randomized controlled trial performed in 12 Italian ICUs from June 2004 to June 2008 of 600 adult patients enrolled without lung infection, who had been ventilated for 24 hours, had a Simplified Acute Physiology Score II between 35 and 65, and had a sequential organ failure assessment score of 5 or greater. Patients who had worsening of respiratory conditions, unchanged or worse sequential organ failure assessment score, and no pneumonia 48 hours after inclusion were randomized to early tracheotomy (n = 209; 145 received tracheotomy) or late tracheotomy (n = 210; 119 received tracheotomy). The primary endpoint was incidence of ventilator-associated pneumonia; secondary endpoints during the 28 days immediately following randomization were number of ventilator-free days, number of ICU-free days, and number of patients in each group who were still alive. Ventilator-associated pneumonia was observed in 30 patients in the early tracheotomy group (14%; 95% confidence interval [CI], 10%-19%) and in 44 patients in the late tracheotomy group (21%; 95% CI, 15%-26%) (P = .07). During the 28 days immediately following randomization, the hazard ratio of developing ventilator-associated pneumonia was 0.66 (95% CI, 0.42-1.04), remaining connected to the ventilator was 0.70 (95% CI, 0.56-0.87), remaining in the ICU was 0.73 (95% CI, 0.55-0.97), and dying was 0.80 (95% CI, 0.56-1.15). Among mechanically ventilated adult ICU patients, early tracheotomy compared with late tracheotomy did not result in statistically significant improvement in incidence of ventilator-associated pneumonia. clinicaltrials.gov Identifier: NCT00262431.


Parallel evolution of novelties: extremely long intromittent organs in the leaf beetle subfamily Criocerinae.
Extreme elongation of a part of the intromittent organ, the flagellum, has occurred several times in Criocerinae (Chrysomelidae). These leaf beetles have acquired a specialized pocket to store the flagellum in the abdominal cavity, at the same time allowing a quick control of movements of this structure during copulation. We investigated the morphogenesis of the intromittent organs of species with and without a flagellum to discuss the evolutionary background of parallel evolution of novel structures. We found that the specialized pocket is formed by the invagination of an epidermal layer and a resultant rotation of the primary gonopore. Invagination itself is a well-known phenomenon in morphogenetic processes, which leads us to hypothesize that the novelty is formed by co-opting a previously acquired genetic system. A large open-space is present within the intromittent organ during the entire morphogenesis in species without a flagellum, and the invagination in the species with a flagellum grows in the corresponding area. This means that there are no physical impediments for the growth of a large pocket. In addition the sites of muscular attachments in the species with a flagellum are also different from those without it. The differentiation of muscles is completed immediately before adult emergence, which means the muscles are adjustable during the entire morphogenesis in this group. Simple modifications probably based on a co-option of previously acquired genetic systems, the potential space for adding a new element, and an adjustable factor in morphogenesis of the intromittent organ facilitate the parallel evolution of the extreme elongation.


Birthsize, gestational age and adrenal function in adult life: studies of dexamethasone suppression and ACTH1-24 stimulation.
Several studies show that low birthweight is associated with long-term alterations in the function of the hypothalamic-pituitary-adrenal axis (HPAA). We recently reported that the relationship between birthweight and fasting serum cortisol concentrations differed according to the gestational age of the babies, suggesting that both hypercortisolism and hypocortisolism could be a consequence of impaired fetal growth. We have now extended these findings by examining the relationship between birthweight, gestational age and tests of adrenal suppression and stimulation. Prospective birth cohort study. We studied 165 women (mean age 71.3 Years) born at term in Helsinki, Finland, between 1924 and 1933, whose body size and gestational age at birth were recorded. These women underwent an overnight 0.25 mg dexamethasone suppression test followed by a 1 microg ACTH(1-24) stimulation test. In all women combined, low birthweight was associated with lower total (P=0.03) and free (P=0.02) cortisol concentrations following dexamethasone. However, these relationships were dependent on gestational age at birth, interactions between the effects of birth size and gestational age on dexamethasone responsiveness being statistically significant. To demonstrate these interactions, we divided the study population into two groups according to gestational age. In subjects born at 40 weeks of gestation or more, low birthweight was strongly associated with enhanced dexamethasone suppression (P=0.003 for total and P=0.0004 for free cortisol), while in subjects born before 40 weeks of gestation there was no association. There was, however, no correlation between birth size and the adrenal response to ACTH(1-24). These findings reinforce our suggestions that events during prenatal life may lead to both up-regulation and down-regulation of the HPAA.


Less is more in mammalian phylogenomics: AT-rich genes minimize tree conflicts and unravel the root of placental mammals.
Despite the rapid increase of size in phylogenomic data sets, a number of important nodes on animal phylogeny are still unresolved. Among these, the rooting of the placental mammal tree is still a controversial issue. One difficulty lies in the pervasive phylogenetic conflicts among genes, with each one telling its own story, which may be reliable or not. Here, we identified a simple criterion, that is, the GC content, which substantially helps in determining which gene trees best reflect the species tree. We assessed the ability of 13,111 coding sequence alignments to correctly reconstruct the placental phylogeny. We found that GC-rich genes induced a higher amount of conflict among gene trees and performed worse than AT-rich genes in retrieving well-supported, consensual nodes on the placental tree. We interpret this GC effect mainly as a consequence of genome-wide variations in recombination rate. Indeed, recombination is known to drive GC-content evolution through GC-biased gene conversion and might be problematic for phylogenetic reconstruction, for instance, in an incomplete lineage sorting context. When we focused on the AT-richest fraction of the data set, the resolution level of the placental phylogeny was greatly increased, and a strong support was obtained in favor of an Afrotheria rooting, that is, Afrotheria as the sister group of all other placentals. We show that in mammals most conflicts among gene trees, which have so far hampered the resolution of the placental tree, are concentrated in the GC-rich regions of the genome. We argue that the GC content-because it is a reliable indicator of the long-term recombination rate-is an informative criterion that could help in identifying the most reliable molecular markers for species tree inference.


Clofarabine in the treatment of myelodysplastic syndromes.
Clofarabine is a second-generation purine nucleoside analog approved in 2004 for the treatment of pediatric patients with relapsed or refractory acute lymphocytic leukemia (ALL) following failure of at least two prior regimens. Clofarabine is a hybrid of fludarabine and cladribine, designed to overcome the pharmacologic limitations associated with its predecessors, while retaining their beneficial properties. In addition to providing a valuable treatment option for pediatric patients with ALL, clofarabine alone and in combination with cytarabine (Ara-C) has demonstrated substantial activity against myelodysplastic syndrome (MDS), thus rendering this agent a potential therapeutic option for MDS. This review focuses on the pharmacology and clinical activity of clofarabine in MDS, as well as its emerging role in the treatment of MDS. Publications in English were selected from the MEDLINE (PubMed) database, as well articles of interest from bibliographies and abstracts based on the publication of meeting materials. DNA-methyltransferase inhibitors are the mainstay of therapy for many patients with MDS who require treatment. Although these agents are very well tolerated and represent a significant advancement in the treatment of MDS by improving transfusion requirements and prolonging survival in various subgroups of patients, response rates are modest and the duration of response is short. In addition to providing a valuable treatment option for pediatric ALL patients, clofarabine has substantial activity against MDS and is well tolerated by elderly patients, thus rendering it a potential therapeutic option.


Cell immobilization in kappa-carrageenan for ethanol production.
A combination of extended Monod kinetics and the diffusional equation was used for evaluating the effectiveness factor of entrapped immobilized cells. Based on the kinetics of Zymomonas mobilis reported in the literature, the numerical results have revealed that the problem of mass transfer diffusional restrictions can be neglected by using small beads (1 mm in diameter) with a corresponding cell loading up to 276 g/L gel. On the basis of the numerical results obtained, the application of immobilized cells for continuous ethanol production was investigated. The kappa-carrageenan method was utilized to entrap Z. mobilis CP4, a potential ethanol producer. A two stage fermentation process has also been developed for ethanol production by the Z. mobilis carrageenan-bound cells. About 90 g/L ethanol was produced by immobilized cells at a total residence time of 1.56 h. The ethanol yield was estimated to be 93% of theoretical. The results obtained in this study also indicated that the control of optimum pH in an immobilized cell column is necessary to enhance the rate of ethanol production.


Association of microRNA biosynthesis genes XPO5 and RAN polymorphisms with cancer susceptibility: Bayesian hierarchical meta-analysis.
XPO5/RAN-GTP complex mediates the nuclear transport of pre-miRNAs in the miRNA processing system, its altered expression is indicated to be correlated with cancer risk. Several studies have inspected the association between XPO5 or RAN polymorphisms and the risk of various cancers, but the findings remain controversial. A Bayesian hierarchical meta-analysis was carried out to review and analyze the effect of XPO5 and RAN polymorphisms on cancer risk. The association was estimated by calculating the logarithm of odds ratio (Log OR) and 95% credible interval (95% CrI). The expression quantitative trait loci (eQTL) analysis was used for in silico functional validation of the identified significant susceptibility loci. Consequently, 38 case-control studies (from 27 citations) with 27,459 cancer cases and 25,151controls were included in the meta-analysis of the five most prevalent SNPs (rs11077 A/C, rs2257082 G/A, rs3803012 A/G, rs14035 C/T, rs3809142 C/T). In the XPO5 gene rs11077 SNP, the minor C allele significantly increased the risk of cancer (Log OR = 0.120, 95% CrI = 0.013, 0.241), and a strong association between rs11077 SNP and cancer risk was also found in the dominant model (CC + AC vs. AA: Log OR = 0.132, 95% CrI = 0.009, 0.275). In addition, the minor GG genotype allele of the RAN gene rs3803012 SNP significantly increased the cancer risk (Log OR = 0.707, 95% CrI = 0.059, 1.385). Statistically significant associations between rs3803012 SNP and cancer risk were also observed in the recessive model (GG vs. AG + AA: Log OR = 0.708, 95% CrI = 0.059, 1.359). Furthermore, the eQTL analysis revealed that rs11077 SNP was significantly correlated with XPO5 mRNA expression, which provided additional biological basis for the observed positive association. Our results suggest that XPO5 rs11077 may be a possible functional susceptibility locus for cancer risk.


Quantum chemical modeling of the kinetic isotope effect of the carboxylation step in RuBisCO.
Ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO), the most important enzyme for the assimilation of carbon into biomass, features a well-known isotope effect with regards to the CO(2) carbon atom. This kinetic isotope effect α = k(12)/k(13) for the carboxylation step of the RuBisCO reaction sequence, and its microscopic origin, was investigated with the help of cluster models and quantum chemical methods [B3LYP/6-31G(d,p)]. We use a recently proposed model for the RuBisCO active site, in which a water molecule remains close to the reaction center during carboxylation of ribulose-1,5-bisphosphate [B. Kannappan, J.E. Gready, J. Am. Chem. Soc. 130 (2008), 15063]. Alternative active-site models and/or computational approaches were also tested. An isotope effect alpha for carboxylation is found, which is reasonably close to the one measured for the overall reaction, and which originates from a simple frequency shift of the bending vibration of (12)CO(2) compared to (13)CO(2). The latter is the dominant mode for the product formation at the transition state.


Molecular basis of deficient IL-2 production in T cells from patients with systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease characterized by diverse cellular and biochemical aberrations, including decreased production of IL-2. Here we show that nuclear extracts from unstimulated SLE T cells, unlike extracts from normal T cells, express increased amounts of phosphorylated cAMP-responsive element modulator (p-CREM) that binds the -180 site of the IL-2 promoter. Nuclear extracts from stimulated normal T cells display increased binding of phosphorylated cAMP-responsive element binding protein (p-CREB) to the -180 site of the IL-2 promoter, whereas nuclear extracts from stimulated SLE T cells display primarily p-CREM and decreased p-CREB binding. In SLE T cells, p-CREM bound to the transcriptional coactivators, CREB binding protein and p300. Increased expression of p-CREM correlated with decreased production of IL-2. The transcription of a reporter gene driven by the -180 site was enhanced in normal T cells, but was suppressed in SLE T cells. These experiments demonstrate that transcriptional repression is responsible for the decreased production of IL-2 by SLE T cells.


Simultaneous assay of immunoreactive beta-lipotropin, gamma-lipotropin, and beta-endorphin in plasma of normal human subjects, patients with ACTH/lipotropin hypersecretory syndromes, and patients undergoing chronic hemodialysis.
We have studied the relative concentrations of the human immunoreactive (IR) peptides gamma-lipotropin (hgammaLPH, [1-58]hbetaLPH), beta-lipotropin (hbetaLPH), and beta-endorphin (hbetaEND, [61-91]hbetaLPH) using gel exclusion chromatography together with a specific radio-immunoassay (RIA) for hgammaLPH and a RIA that (because hbetaEND is the COOH-terminus of the hbetaLPH molecule) measures both hbetaEND and hbetaLPH on an equimolar basis. In normal subjects, basal plasma IR-hgammaLPH was often undetectable (<12.5 fmol/ml), but ranged up to 21 fmol/ml, and IR-hbetaEND/hbetaLPH was 10.8+/-0.7 fmol/ml; previous studies by others suggest that most of the IR-hbetaEND/hbetaLPH was probably hbetaLPH. Both IR-hgammaLPH and IR-hbetaEND/hbetaLPH were significantly elevated (P < 0.001) in patients undergoing chronic hemodialysis (101.5+/-12.7 and 23.8+/-2.0 fmol/ml, respectively). Their IR-hgammaLPH coeluted with standard hgammaLPH as a single peak, and IR-hbetaEND/hbetaLPH coeluted with hbetaLPH; no distinct peak of IR-hbetaEND was observed. In patients with ACTH/LPH hypersecretion due to Addison's disease, Nelson's syndrome, or ectopic ACTH syndrome, IR-hgammaLPH and IR-hbetaEND/hbetaLPH were both elevated, and IR-hbetaEND/hbetaLPH eluted as two peaks, one coeluting with hbetaLPH and the other with hbetaEND. The molar concentrations of all three peptides were significantly correlated with one another. The lower concentrations of endogenous IR-hbetaEND observed may be due in part to its apparent shorter plasma half-life, as estimated in an Addison's patient given a cortisol infusion. The biologic significance of these three peptides in circulating blood is still unknown. The increased levels of hbetaLPH and hgammaLPH in plasma of patients with chronic renal failure suggest that the kidney may be an important organ for their metabolism.


Ecological Role of Bacteria Involved in the Biogeochemical Cycles of Mangroves Based on Functional Genes Detected through GeoChip 5.0.
Mangroves provide a variety of ecosystem services and contribute greatly to the global biogeochemical cycle. Microorganisms play important roles in biogeochemical cycles and maintain the dynamic balance of mangroves. However, the roles of bacteria in the biogeochemical cycles of mangroves and their ecological distribution and functions remain largely uncharacterized. This study thus sought to analyze and compare the ecological distributions and potential roles of bacteria in typical mangroves using 16S rRNA gene amplicon sequencing and GeoChip. Interestingly, the bacterial community compositions were largely similar in the studied mangroves, including Shenzhen, Yunxiao, Zhanjiang, Hainan, Hongkong, Fangchenggang, and Beihai mangroves. Moreover, gamma-proteobacterium_uncultured and Woeseia were the most abundant microorganisms in the mangroves. Furthermore, most of the bacterial communities were significantly correlated with phosphorus levels (P < 0.05; -0.93 < R < 0.93), suggesting that this nutrient is a vital driver of bacterial community composition. Additionally, GeoChip analysis indicated that the functional genes amyA, narG, dsrA, and ppx were highly abundant in the studied mangroves, suggesting that carbon degradation, denitrification, sulfite reduction, and polyphosphate degradation are crucial processes in typical mangroves. Moreover, several genera were found to synergistically participate in biogeochemical cycles in mangroves. For instance, Neisseria, Ruegeria, Rhodococcus, Desulfotomaculum, and Gordonia were synergistically involved in the carbon, nitrogen, and sulfur cycles, whereas Neisseria and Treponema were synergistically involved in the nitrogen cycle and the sulfur cycle. Taken together, our findings provide novel insights into the ecological roles of bacteria in the biogeochemical cycles of mangroves. IMPORTANCE Bacteria have important functions in biogeochemical cycles, but studies on their function in an important ecosystem, mangroves, are still limited. Here, we investigated the ecological role of bacteria involved in biogeochemical cycles in seven representative mangroves of southern China. Furthermore, various functional genes from bacteria involved in biogeochemical cycles were identified by GeoChip 5.0. The functional genes associated with the carbon cycle (particularly carbon degradation) were the most abundant, suggesting that carbon degradation is the most active process in mangroves. Additionally, some high-abundance bacterial populations were found to synergistically mediate key biogeochemical cycles in the mangroves, including Neisseria, Pseudomonas, Treponema, Desulfotomaculum, and Nitrosospira. In a word, our study gives novel insights into the function of bacteria in biogeochemical cycles in mangroves.


Clinical Characteristics, Risk Factors, and Outcomes Associated With Neonatal Hemorrhagic Stroke: A Population-Based Case-Control Study.
Hemorrhage into the brain of term newborns often results in major injury and lifelong disability. The clinical epidemiology of neonatal hemorrhagic stroke (NHS) remains undefined, hindering the development of strategies to improve outcomes. To characterize the incidence, types, presentations, associated factors, and outcomes of neonatal hemorrhagic stroke. Population-based, nested case-control study. The Alberta Perinatal Stroke Project, a provincial registry, ascertained NHS cases using exhaustive diagnostic code searching (1992-2010, >2500 medical record reviews). Prospective cases were captured through the Calgary Pediatric Stroke Program (2007-2014). Participants included term neonates with magnetic resonance imaging-confirmed NHS including primary and secondary intracerebral hemorrhage, hemorrhagic transformation of ischemic injury, and presumed perinatal hemorrhagic stroke. Control infants with common data were recruited from a population-based study (4 to 1 ratio). Infants with NHS underwent structured medical record review using data-capture forms and blinded scoring of neuroimaging. Clinical risk factor common data elements were explored using logistic regression. Provincial live births were obtained from Statistics Canada. Outcomes were extrapolated to the Pediatric Stroke Outcome Measure. We identified 86 cases: 51 infants (59%) with NHS, of which 32 (67%) were idiopathic, 30 (35%) were hemorrhagic transformation of primary ischemic injuries (14 with neonatal cerebral sinovenous thrombosis, 11 with hypoxic ischemic encephalopathy, and 5 with neonatal arterial ischemic stroke), and 5 were presumed perinatal hemorrhagic stroke. Sixty-two percent were male. Incidence of pure NHS was 1 in 9500 live births and 1 in 6300 for all forms. Most presented in the first week of life with seizures and encephalopathy. Acute neurosurgical intervention was rare (3 of 86 total cases; 3.5%). Temporal lobe was the most common NHS location (16 of 51 pure NHS cases; 31%). A primary cause was evident in 19 of the 51 cases of non-hemorrhagic transformation NHS (37%). Idiopathic NHS was independently associated with lower maternal age (odds ratio [OR], 0.87; 95% CI, 0.78-0.94), primiparity (OR, 2.98; 95% CI, 1.18-7.50), prior spontaneous abortion (OR, 0.11; 95% CI, 0.02-0.53), difficult fetal transition (bradycardia [OR, 15.0; 95% CI, 2.19-101.9] and low Apgar [OR, 14.3; 95% CI, 2.77-73.5]), and small for gestational age (OR, 14.3; 95% CI, 1.62-126.1). Follow-up of 50 cases at a median of 37 months demonstrated poor neurological outcomes in 21 patients (44%). Neonatal hemorrhagic stroke is more common than previously reported, occurring in at least 1 in 6300 live births. Etiologies are approximately equally distributed between idiopathic, secondary, and hemorrhagic transformation. Clinical associations do not suggest a common mechanism or predictability of NHS. Recurrence is rare. Outcomes are often poor, mandating attention to prevention and rehabilitation.


"It's like texting at the dinner table": A qualitative analysis of the impact of electronic health records on patient-physician interaction in hospitals.
nBACKGROUND: Electronic health records (EHRs) may reduce medical errors and improve care, but can complicate clinical encounters. To describe hospital-based physicians' perceptions of the impact of EHRs on patient-physician interactions and contrast these findings against office-based physicians' perceptionsMethods: We performed a qualitative analysis of comments submitted in response to the 2014 Rhode Island Health Information Technology Survey. Office- and hospital-based physicians licensed in Rhode Island, in active practice, and located in Rhode Island or neighboring states completed the survey about their Electronic Health Record use. The survey's response rate was 68.3% and 2,236 (87.1%) respondents had EHRs. Among survey respondents, 27.3% of hospital-based and 37.8% of office-based physicians with EHRs responded to the question about patient interaction. Five main themes emerged for hospital-based physicians, with respondents generally perceiving EHRs as negatively altering patient interactions. We noted the same five themes among office-based physicians, but the rank-order of the top two responses differed by setting: hospital-based physicians commented most frequently that they spend less time with patients because they have to spend more time on computers; office-based physicians commented most frequently on EHRs worsening the quality of their interactions and relationships with patients. In our analysis of a large sample of physicians, hospital-based physicians generally perceived EHRs as negatively altering patient interactions, although they emphasized different reasons than their office-based counterparts. These findings add to the prior literature, which focuses on outpatient physicians, and can shape interventions to improve how EHRs are used in inpatient settings.


ENDS, cigarettes, and respiratory illness: Longitudinal associations among US youth.
Electronic nicotine delivery system (ENDS) use is highly prevalent among U.S. youth, and there is concern about its respiratory health effects. However, evidence from nationally representative longitudinal data is limited. Using youth data (ages 12-17) from waves 1-5 (2013-2019) of the Population Assessment of Tobacco and Health (PATH) Study, multilevel Poisson regression models were estimated to examine the association between ENDS use, cigarettes, and diagnosed bronchitis, pneumonia, or chronic cough. Current product use was lagged by one wave and categorized as: (a) never/non-current use; (b) exclusive cigarette use; (c) exclusive ENDS use; and (d) dual ENDS/cigarette use. Multivariable models adjusted for age, sex, race and ethnicity, parental educational, asthma, body mass index, cannabis use, secondhand smoke exposure, and household use of combustible products. Data analysis was conducted in 2022-2023. 7.4% of respondents were diagnosed with bronchitis, pneumonia, or chronic cough at follow-up. In the multivariable model, exclusive cigarette use (IRR = 1.85; 95% CI 1.29-2.65), exclusive ENDS use (IRR = 1.49; 95% CI 1.06-2.08), and dual use (IRR = 2.70, 95% CI 1.61-3.50) were associated with a higher risk of diagnosed bronchitis, pneumonia, or chronic cough, compared to never/non-current use. These results suggest that ENDS and cigarettes, used exclusively or jointly, increased the risk of diagnosed bronchitis, pneumonia, or chronic cough among U.S. youth. However, dual use was associated with the highest risk. Targeted policies aimed at continuing to reduce cigarette smoking and ENDS use among youth, especially among those with dual use, are needed.


Sequence of the 11 beta-hydroxylase gene from the Cape baboon (Papio ursinus).
We investigated the nucleotide sequence of the steroid 11 beta-hydroxylase gene (CYP11B1) from the Cape baboon (Papio ursinus). Six primers, previously used in studies on human CYP11B1, were utilised to amplify three overlapping fragments (A, B and C) of the baboon CYP11B1 by the polymerase chain reaction (PCR). Sequence analysis of the three fragments yielded the sequence of all the exons of baboon CYP11B1. The open reading frame of 1509 bases shows 57 nucleotide exchanges when compared to the human resulting in 18 amino acid substitutions. For eight of these exchanges we found the amino acid which is common for human aldosterone synthase at the corresponding position. Most of the remaining 10 amino acid substitutions were conservative. Eight of the substitutions were located in the first four exons with a cluster in the second half of exon 3. One substitution was in exon 5 (F280L) and the 10th was C494F at the end of the protein.


[Gastroesophageal reflux and Helicobacter pylori].
The relationship between Helicobacter pylori (H. pylori) infection and gastroesophageal reflux disease (GERD) is not well known yet, and has some controversial issues. There is indirect epidemiological evident, not yet proven, that H. pylori may have a protective role against GERD. Hypochlorhydria caused by gastritis located mainly at corpus would be the principal physiopathological protector mechanism against GERD. Even knowing that more studies are needed, the risk of developing GERD after the H. pylori eradication seems to be increased in some groups of patients. In the presence of the microorganism, the efficacy of acid suppression therapy may decrease, and its long-term use could favour the progression to corpus atrophic gastritis. Specialized intestinal metaplasia in an endoscopically normal-appearing cardia may precede adenocarcinoma, and its prevention would vary, depending on its controversial origin, secondary to carditis, H. pylori or GERD.


[Specificity of the anaerobic bacterial infections in the surgical and orthopedic wards].
The aim of this study was to estimate the contribution strictly anaerobic bacteria in the etiology of infections in patients on surgery and orthopedic wards. We examined 159 samples taken from patients hospitalized in surgical wards and 179 clinical specimens taken from orthopedic patients. Clinical strains of obligate anaerobes were identified by API 20A biochemical tests (ATB Expression, bioMerieux S.A., France). Susceptibility of the clinical strains was examined by ATB ANA (bioMerieux S.A., France) system. The MIC values were determined by the gradient diffusion method, Etest (AB BIODISK, Sweden i bioMerieux S.A., France). Gram-negative bacteria predominant in the samples taken from surgical patients, Most frequently we isolated rods of the genus Bacteroides (26%): B. fragilis, B. ovatus/B. thetaiotaomicron, and B. distasonis. In 44 samples (28%) we identified only anaerobic bacteria. Multibacterial isolations, with the participation of anaerobic and aerobic flora, dominated among patients in the study. Overall 238 strictly anaerobic bacteria were cultured from patients hospitalized in orthopedic wards. Gram-positive bacteria accounted for 78%. The most frequently were isolated Peptostreptococcus (56%), Propionibacterium (10%) species. In this study all Bacteroides strains were resistant to penicillin G. Some species were resistant to clindamycin, as well. Overall 40% of Bacteroides strains taken from surgical and 50% isolated from orthopedic wards showed no sensitivity to this antibiotic. A similar phenomenon was observed among bacteria of the genus Prevotella. In samples taken from orthopedic patients we observed the predominance of Gram-positive anaerobic bacteria. Some of them were part of the normal flora but they should not be excluded as an etiology agents of infection. The specimens taken from patients treated in surgical wards showed the presence of a mixed microflora, which included aerobic and anaerobic bacteria, primarily Gram-negative rods. Rational empirical therapy of infections with anaerobes should be mainly based on the resistance pattern in each ward and hospital. In view of the increasing in the number of resistant strains is necessary to monitor drug resistance of anaerobic bacteria.


Supporting the role of the nurse consultant -- an exercise in leadership development via an interactive learning opportunity.
This paper discusses how a group of consultant nurses were supported over a period of three years by a process of interactive learning. The purpose of this learning was to help them develop the personal and professional abilities necessary for them to achieve success in the role. These personal and professional abilities are not new clinical skills, but the skills of leadership, self-awareness, confidence, self-belief and value clarification and a clear mental model of what it is they want to be within healthcare. An evaluation of the action learning methods reveals their success in helping the participants to achieve some competence and awareness in these personal and professional abilities, to reach a comfort zone in the role. However, the analysis also reveals the polarities and paradoxes such practitioners will have to negotiate if they are to achieve success and establish themselves within the role.


Surgical outcomes in choroid plexus papillomas: an institutional experience.
Choroid plexus papillomas (CPPs) are rare, indolent lesions that comprise less than 0.5 % of intracranial tumors. We sought to assess the long-term outcomes and associated surgical complications at our institution. A review of the University of California, San Francisco (UCSF) Brain Tumor Research Center (BTRC) database was performed to identify a cohort of patients treated for CPP from 1997 to 2011. Patients were grouped based on tumor location and extent of resection. Outcomes including progression-free survival and surgical complications were assessed. We identified 24 patients (16 female, 8 male) ranging in age from 6 months to 55 years (median 29 years) treated at our institution. Tumors were found in the following locations: 16 (67 %) fourth ventricle/cerebellopontine angle; 7 (29 %) lateral ventricle; 1 (4 %) third ventricle. Gross total resection (GTR) was achieved in 20 patients (83 %) with subtotal resection (STR) in 4 (17 %). Median follow-up time was 2.8 years with 3 recurrences identified at 1.6, 3.3, and 8.5 years. Extent of resection and tumor location were not associated with recurrence. There was one new permanent neurologic deficit detected after surgery. All patients were alive at most recent follow-up. Attempted gross total resection is the standard treatment for CPPs and generally associated with excellent outcomes. Since recurrences are rare, even among patients who undergo STR, radiation may be reserved for cases of tumor progression. This modern experience at a tertiary care center performed exclusively during the MRI-era demonstrates that CPPs can be safely removed with minimal morbidity and good tumor control.


5-Hydroxymethylcytosine-mediated alteration of transposon activity associated with the exposure to adverse in utero environments in human.
Preeclampsia and gestational diabetes mellitus (GDM) are the most common clinical conditions in pregnancy that could result in adverse in utero environments. Fetal exposure to poor environments may raise the long-term risk of postnatal disorders, while epigenetic modifications could be involved. Recent research has implicated involvement of 5-hydroxymethylcytosine (5hmC), a DNA base derived from 5-methylcytosine, via oxidation by ten-eleven translocation (TET) enzymes, in DNA methylation-related plasticity. Here, we show that the TET2 expression and 5hmC abundance are significantly altered in the umbilical veins of GDM and preeclampsia. Genome-wide profiling of 5hmC revealed its specific reduction on intragenic regions from both GDM and preeclampsia compared to healthy controls. Gene Ontology analysis using loci bearing unique GDM- and preeclampsia-specific loss-of-5hmC indicated its impact on several critical biological pathways. Interestingly, the substantial alteration of 5hmC on several transposons and repetitive elements led to their differential expression. The alteration of TET expression, 5hmC levels and 5hmC-mediated transposon activity was further confirmed using established hypoxia cell culture model, which could be rescued by vitamin C, a known activator of TET proteins. Together, these results suggest that adverse pregnancy environments could influence 5hmC-mediated epigenetic profile and contribute to abnormal development of fetal vascular systems that may lead to postnatal diseases.


Human polyomavirus BK monitoring by quantitative PCR in renal transplant recipients.
To study the relation between human polyomavirus BK (BKV) infection and the risk of developing nephropathy, we monthly investigated the BKV load in urine and serum samples from 15 renal transplant recipients during 6 months in relation with immunosuppressive treatment and renal function. BKV-DNA in serum samples was detected by nested PCR. BKV-DNA in urine and positive serum samples was quantified by a PCR protocol developed in our laboratory. Fifty-three percent of the patients had quantifiable BKV-DNA both in urine and serum samples but there was no relation between viruria and viraemia. Seventy-five percent of the patients on FK506 therapy and 71.4% of those on CyA therapy showed activation of BKV infection. No patients developed interstitial nephritis during the study. In ten patients serum creatinine levels were <2 mg/dl for the whole study, even if 80% presented BKV viruria and/ or viraemia. On the other hand, in 4 patients serum creatinine levels reached higher values, but they were BKV viruria and/or viraemia negative during the study. Our results suggest that viruria and viraemia may reflect independent BKV reactivation in different tissues. The activation of the infection does not seem to be related to the type of immunosuppressive treatment nor to impairment of renal function. To better understand the pathogenetic role of BKV infection in renal transplant recipients further investigations are needed.


Surgical approaches to facial nerve deficits.
The facial nerve is one of the most commonly injured cranial nerves. Once injured, the effects on form, function, and psyche are profound. We review the anatomy of the facial nerve from the brain stem to its terminal branches. We also discuss the physical exam findings of facial nerve injury at various levels. Finally, we describe various reconstructive options for reanimating the face and restoring both form and function.


Interaction between the DNA polymerase and single-stranded DNA-binding protein (infected cell protein 8) of herpes simplex virus 1.
The herpes virus-encoded DNA replication protein, infected cell protein 8 (ICP8), binds specifically to single-stranded DNA with a stoichiometry of one ICP8 molecule/12 nucleotides. In the absence of single-stranded DNA, it assembles into long filamentous structures. Binding of ICP8 inhibits DNA synthesis by the herpes-induced DNA polymerase on singly primed single-stranded DNA circles. In contrast, ICP8 greatly stimulates replication of circular duplex DNA by the polymerase. Stimulation occurs only in the presence of a nuclear extract from herpes-infected cells. Appearance of the stimulatory activity in nuclear extracts coincides closely with the time of appearance of herpes-induced DNA replication proteins including ICP8 and DNA polymerase. A viral factor(s) may therefore be required to mediate ICP8 function in DNA replication.


Leveraging the Tools Available: Using the Hyde Amendment to Preserve Minimum Abortion Access and Mitigate Harms in Restrictive States.
The overturn of Roe v. Wade has resulted in fewer rights and resources for people seeking abortion care, particularly in the South. The Hyde Amendment has historically restricted abortion access for those enrolled in Medicaid. We argue here that its guarantees of minimum abortion coverage should be leveraged to offset harms where possible.


Effect of apolipoprotein E polymorphism on serum lipid, lipoproteins, and atherosclerosis in hemodialysis patients.
Atherosclerosis and cardiovascular disease are the main causes of death in hemodialysis patients. Possession of the apolipoprotein E4 (ApoE4) allele has been associated with increased levels of serum lipids and with coronary and carotid artery atherosclerosis. We investigated the possible relationship between ApoE polymorphism and atherosclerosis risk factors in hemodialysis patients. Two hundred sixty-nine hemodialysis patients (115 women, 154 men) were included in our study. The mean patient age and mean hemodialysis duration were 45.8 +/- 15.3 years and 52.6 +/- 40.6 months, respectively. Testing was done on all patients to determine ApoE genotype and serum levels of total cholesterol (T-Cho), low-density lipoprotein (LDL-C), high-density cholesterol (HDL-C), triglyceride (TG), lipoprotein (a) (Lp[a]), intact parathormone (iPTH), and fibrinogen. ApoE genotype was identified with the polymerase chain reaction. Ultrasonographic measurement of carotid artery intima media thickness (IMT) was used to diagnose atherosclerosis. We also analyzed ApoE polymorphism and risk factors such as age, gender, duration of hemodialysis, smoking, and hypertension in relation to the presence of atherosclerosis. Serum T-Cho and LDL-C levels were higher in patients with the ApoE4/3 phenotype than in those with ApoE3/3 and ApoE3/2 phenotypes (P < 0.05). However, there was no statistically significant link between ApoE polymorphism and serum levels of TG, HDL-C, or Lp(a) (P > 0.05). Apart from a relationship with age and duration of hemodialysis (P < 0.05), we found no significant association between atherosclerosis and ApoE polymorphism or the other risk factors analyzed (P > 0.05). In conclusion, although ApoE polymorphism significantly affects serum levels of T-Cho and LDL-C in hemodialysis patients, this study indicates that ApoE polymorphism is not associated with the presence of atherosclerosis in these individuals. The high incidence of atherosclerosis in these patients underlines the need for further research on other possible causative factors.


Modeling the effect of time and temperature on respiration rate of pomegranate arils (cv. "Acco" and "Herskawitz").
Understanding the effect of time and temperature on the respiration rate (RR) of fresh-cut produce, towards the design of a suitable modified atmosphere packaging (MAP) system, requires an adequate mathematical model for prediction of RR as a function of both time and temperature. This study investigated the effect of temperature (5, 10, and 15 °C) and storage time (1 to 5 d) on the RR (R(O2) and R(CO2)) of 2 pomegranate cultivars (cv. "Acco" and "Herskawitz") fresh arils. R(O2) and R(CO2) were 3 to 4 folds significantly higher with increased temperature from 5 to 15 °C and were within the range of 2.51 to 7.59 mL/kg h and 2.72 to 9.01 mL/kg h, respectively, for both cultivars. At 15 °C R(CO2) increased significantly from 8.4 to 25.96 mL/kg h from day 1 to 5, respectively, while at 5 °C R(CO2) changed from 2.9 to 2.05 mL/kg h from day 1 to 5. Temperature had the greatest influence on RR and the interaction of time and temperature also significantly affected R(O2) and R(CO2). The respiratory quotient (RQ) estimated by linear regression was 0.98 at 95% significant level. The dependence of RR on temperature and time was accurately described with a combination of an Arrhenius-type and power equation model for and of fresh pomegranate arils.


Global exploration of the metabolic requirements of gallid alphaherpesvirus 1.
Although therapeutics targeting viral metabolic processes have been considered as promising strategies to treat herpesvirus infection, the metabolic requirements of gallid alphaherpesvirus 1 (ILTV), which is economically important to the poultry industry worldwide, remain largely unknown. Using the ILTV-susceptible but nonpermissive chicken cell line DF-1 and the ILTV-permissive chicken cell line LMH as models, the present study explored the metabolic requirements of ILTV by global transcriptome analysis and metabolome assays of ILTV infected cell lines in combination with a set of functional validations. The extensive metabolic exploration demonstrated that ILTV infection tended to promote a metabolic shift from glycolysis to fatty acid (FA) and nucleotide biosynthesis and utilizes glutamine independently of glutaminolysis, without significant general effect on the TCA cycle. In addition, different metabolic pathways were found to be required for distinct stages of ILTV replication. Glucose and glutamine were required for the transcription of viral immediate early gene ICP4 and subsequent steps of viral replication. However, FA synthesis was essential for assembly but not required for other upstream steps of ILTV replication. Moreover, the metabolic requirements of ILTV infection revealed in chicken cell lines were further validated in chicken primary cells isolated from chicken embryo kidneys and chicken embryo livers. The present study, to the best of our knowledge, provides the first global metabolic profile of animal herpesviruses and illustrates the main characteristics of the metabolic program of ILTV.


Suppression of the AvrBs1-specific hypersensitive response by the YopJ effector homolog AvrBsT from Xanthomonas depends on a SNF1-related kinase.
*Pathogenicity of the Gram-negative plant pathogen Xanthomonas campestris pv. vesicatoria (Xcv) depends on a type III secretion system that translocates a cocktail of > 25 type III effector proteins into the plant cell. *In this study, we identified the effector AvrBsT as a suppressor of specific plant defense. AvrBsT belongs to the YopJ/AvrRxv protein family, members of which are predicted to act as proteases and/or acetyltransferases. *AvrBsT suppresses the hypersensitive response (HR) that is elicited by the effector protein AvrBs1 from Xcv in resistant pepper plants. HR suppression occurs inside the plant cell and depends on a conserved predicted catalytic residue of AvrBsT. Yeast two-hybrid based analyses identified plant interaction partners of AvrBs1 and AvrBsT, including a putative regulator of sugar metabolism, SNF1-related kinase 1 (SnRK1), as interactor of AvrBsT. Intriguingly, gene silencing experiments revealed that SnRK1 is required for the induction of the AvrBs1-specific HR. *We therefore speculate that SnRK1 is involved in the AvrBsT-mediated suppression of the AvrBs1-specific HR.


Risk of liver injury among methotrexate users: A meta-analysis of randomised controlled trials.
Methotrexate is an effective treatment for a variety of inflammatory diseases. Robust evidence on the risk of serious liver injury is lacking. The aim of this study was to evaluate the relative risk and severity of liver disease among patients treated with methotrexate. We searched PubMed and the Cochrane Central Register of Controlled Trials from 1 January 1990 to 24 April 2014 for double-blind randomised controlled trials of methotrexate versus comparator agents in adults with rheumatoid arthritis, psoriasis, psoriatic arthritis or inflammatory bowel disease. Studies with less than 100 subjects or of less than 24 weeks' duration were excluded. Two investigators independently searched both the databases. All authors reviewed the selected studies. We compared relative risk (RR) differences using the Mantel-Haenszel random effects method to assess total liver adverse events, minor liver enzyme abnormalities (≤ 3 ULN), major liver enzyme abnormalities (>3 ULN or treatment withdrawal) and a composite outcome of liver failure, fibrosis, cirrhosis or death. A total of 32 studies with 13,177 participants met our inclusion criteria. Methotrexate was associated with an increased risk of total adverse liver events, RR = 2.19 (95% CI: 1.73-2.77, I(2) = 68%), as well as minor and major liver enzyme abnormalities, RR = 2.16 (95% CI: 1.67-2.79, I(2) = 68%) and RR = 2.63 (95% CI: 1.90-3.64, I(2) = 10%), respectively. Patients treated with methotrexate were not at increased risk of liver failure, cirrhosis or death, RR = 0.12 (95% CI: 0.01-1.09, I(2) = 0%). Our study found an increased risk of elevated transaminases but not liver failure, cirrhosis or death with methotrexate compared to other agents. We were unable to assess long-term liver toxicity due to the short duration of included clinical trials.


Willingness to take long-acting injectable pre-exposure prophylaxis among men who have sex with men who participated in the CROPrEP study: a cross-sectional online study.
Evidence on the willingness of men who have sex with men (MSM) with oral pre-exposure prophylaxis (PrEP) experience, especially those with suboptimal adherence, to take long-acting injectable PrEP (LAI-PrEP) is critical to guide future LAI-PrEP implementation. The objective was to assess the willingness of MSM with oral PrEP experience to take LAI-PrEP. MSM who participated in the China Real-world Study of Oral PrEP (CROPrEP) were enrolled in this study. Information on the willingness of MSM to take LAI-PrEP and potential correlates was collected using a structured online questionnaire. The main outcomes were the willingness of MSM to take LAI-PrEP and its association with HIV-related behaviours, sexually transmitted infections, and oral PrEP history. Logistic regression was used to identify correlates of the willingness of MSM to take LAI-PrEP. A total of 612 former CROPrEP participants (FCPs) were included in this study. There were 315 (51.5%) daily oral PrEP (D-PrEP) users and 297 (48.5%) event-driven oral PrEP (ED-PrEP) users at the last follow-up. Most FCPs (77.8%) were willing to take free LAI-PrEP. FCPs with no less than two sexual male partners (aOR = 1.54, [95% CI: 1.04, 2.29], P = 0.031), those with male partners with unknown HIV statuses (aOR = 2.04, [95% CI: 1.31, 3.18], P = 0.002), those with recreational drug use (aOR = 1.58, [95% CI: 1.05, 2.40], P = 0.030), and those with HSV-2 positivity (aOR = 2.15, [95% CI: 1.30, 3.57], P = 0.003) were more willing to take LAI-PrEP, while ED-PrEP users (aOR = 0.66, [95% CI: 0.45, 0.98], P = 0.037) and FCPs with suboptimal oral PrEP adherence (aOR = 0.58, [95% CI: 0.36, 0.94], P = 0.026) were less willing to take LAI-PrEP. LAI-PrEP has good prospects for expanding PrEP coverage. However, FCPs with suboptimal oral PrEP adherence are less likely to take LAI-PrEP. Further intervention and implementation efforts are needed to improve the willingness of MSM to use LAI-PrEP, and sexual health should be considered during the discussion about PrEP initiation.


A Cerasus humilis transcription factor, ChDREB2C, enhances salt tolerance in transgenic Arabidopsis.
DREB transcription factors play important roles in plant responses to various abiotic and biotic stresses. We conducted bioinformatics analysis of ChDREB2C, explored subcellular localization, transcription activation activity, and heterologous expression in Arabidopsis, and measured expression of related physiological indicators and genes under salt stress. A transcription factor of the DREB family was cloned and named ChDREB2C. ChDREB2C protein was localized in the nucleus, and its C-terminal domain exhibited transcriptional activation activity. ChDREB2C formed a homologous dimer in yeast. Arabidopsis plants overexpressing ChDREB2C were more tolerant to salt stress than WT plants, through increased scavenging capacity of ROS and accumulation of proline. Overexpression of ChDREB2C resulted in increased expression of AtSOS1, AtNHX1, AtRD29A, AtRD29B, AtKIN1, AtABA4, and AtABF2 genes. The interaction between ChABF2 (ABA response element binding factor 2) and ChDREB2C was verified using yeast two-hybrid and firefly luciferase assays. The results suggest that ChDREB2C could have a positive role in mediating the abiotic response.


High-content analysis to leverage a robust phenotypic profiling approach to vascular modulation.
Phenotypic screening seeks to identify substances that modulate phenotypes in a desired manner with the aim of progressing first-in-class agents. Successful campaigns require physiological relevance, robust screening, and an ability to deconvolute perturbed pathways. High-content analysis (HCA) is increasingly used in cell biology and offers one approach to prosecution of phenotypic screens, but challenges exist in exploitation where data generated are high volume and complex. We combine development of an organotypic model with novel HCA tools to map phenotypic responses to pharmacological perturbations. We describe implementation for angiogenesis, a process that has long been a focus for therapeutic intervention but has lacked robust models that recapitulate more completely mechanisms involved. The study used human primary endothelial cells in co-culture with stromal fibroblasts to model multiple aspects of angiogenic signaling: cell interactions, proliferation, migration, and differentiation. Multiple quantitative descriptors were derived from automated microscopy using custom-designed algorithms. Data were extracted using a bespoke informatics platform that integrates processing, statistics, and feature display into a streamlined workflow for building and interrogating fingerprints. Ninety compounds were characterized, defining mode of action by phenotype. Our approach for assessing phenotypic outcomes in complex assay models is robust and capable of supporting a range of phenotypic screens at scale.


Early tracheal intubation with thiopentone in elective surgery.
We have studied tracheal intubating conditions within 30 s of administration of thiopentone in 24 patients and compared this with our usual method of tracheal intubation, which involves 3 min of manual ventilation in 29 patients. All patients received papaveretum 10 mg 3 min before induction and alcuronium at induction of anaesthesia. Satisfactory intubating conditions were observed in 83% of patients in both groups. There were no difficult or failed intubations and no patient had laryngospasm. The duration of laryngoscopy in the control group was 14.1 (SD 8.6) s (range 7-50 s), compared with 12.4 (3.1) s (range 6-20 s), in the early intubation group (ns). In the control group there was a significant decrease in systolic pressure before tracheal intubation and a significant increase in heart rate after intubation, compared with baseline values. The average systolic pressure in the early intubation group increased only minimally: from a pre-intubation value of 143.3 (21.2) mm Hg to 145.5 (25.1) mm Hg after intubation. Our results demonstrate that early tracheal intubation under thiopentone supplemented with an opioid and a non-depolarizing neuromuscular block is feasible, associated with minimal changes in arterial pressure and not accompanied by an increased incidence of side effects.


Most frequent tumors in maxillofacial area rehabilitated through surgical reconstruction and prostheses.
Cancer is regarded as the abnormal cellular multiplication; it is not controlled by the organism; and its cells present a differentiated DNA. Initially, the disease does not show clinical signs, but it can be diagnosed by laboratorial examinations. When tumors are present in the maxillofacial area, they can entail the loss of these area organs, which become responsible for the carrier's social environment exclusion. This paper aimed at showing, through a literature review, the cancers that more commonly happen in the face and the possibilities of regenerating in the patient mutilated through surgical reconstruction and prostheses.


A study of human resource competencies required to implement community rehabilitation in less resourced settings.
It is estimated that over one billion persons worldwide have some form of disability. However, there is lack of knowledge and prioritisation of how to serve the needs and provide opportunities for people with disabilities. The community-based rehabilitation (CBR) guidelines, with sufficient and sustained support, can assist in providing access to rehabilitation services, especially in less resourced settings with low resources for rehabilitation. In line with strengthening the implementation of the health-related CBR guidelines, this study aimed to determine what workforce characteristics at the community level enable quality rehabilitation services, with a focus primarily on less resourced settings. This was a two-phase review study using (1) a relevant literature review informed by realist synthesis methodology and (2) Delphi survey of the opinions of relevant stakeholders regarding the findings of the review. It focused on individuals (health professionals, lay health workers, community rehabilitation workers) providing services for persons with disabilities in less resourced settings. Thirty-three articles were included in this review. Three Delphi iterations with 19 participants were completed. Taken together, these produced 33 recommendations for developing health-related rehabilitation services. Several general principles for configuring the community rehabilitation workforce emerged: community-based initiatives can allow services to reach more vulnerable populations; the need for supportive and structured supervision at the facility level; core skills likely include case management, social protection, monitoring and record keeping, counselling skills and mechanisms for referral; community ownership; training in CBR matrix and advocacy; a tiered/teamwork system of service delivery; and training should take a rights-based approach, include practical components, and involve persons with disabilities in the delivery and planning. This research can contribute to implementing the WHO guidelines on the interaction between the health sector and CBR, particularly in the context of the Framework for Action for Strengthening Health Systems, in which human resources is one of six components. Realist syntheses can provide policy makers with detailed and practical information regarding complex health interventions, which may be valuable when planning and implementing programmes.


Low back pain beliefs are associated to age, location of work, education and pain-related disability in Chinese healthcare professionals working in China: a cross sectional survey.
Low back pain (LBP) is the leading cause of disability worldwide. Evidence pointing towards a more efficacious model of care using a biopsychosocial approach for LBP management highlights the need to understand the pain-related beliefs of patients and those who treat them. The beliefs held by healthcare professionals (HCPs) are known to influence the treatment advice given to patients and consequently management outcomes. Back pain beliefs are known to be influenced by factors such as culture, education, health literacy, place of work, personal experience of LBP and the sequelae of LBP such as disability. There is currently a knowledge gap among these relationships in non-western countries. The aim of this study was to examine the associations between LBP-related beliefs among Chinese HCPs and characteristics of these HCPs. A convenience sample of 432 HCPs working in various health settings in Shanghai, China, completed a series of questionnaires assessing their demographic characteristics, LBP status, pain-related disability and their beliefs about their own LBP experience, using the Back beliefs Questionnaire (BBQ) and the Fear Avoidance Beliefs Questionnaire (FABQ). Younger Chinese HCPs (20-29 years) held more negative beliefs and attitudes related to LBP compared to older HCPs (>40years; BBQ mean difference [95% CI]: 2.4 [0.9 - 3.9], p = 0.001). HCPs working outside tertiary hospitals had poorer beliefs concerning the inevitable consequences of LBP (BBQ mean difference [95% CI]: -2.4 [-3.8 - -1.0], p = 0.001). HCPs who experienced LBP had higher level of fear avoidance beliefs when experiencing high LBP-related disability (FABQ-physical mean difference [95% CI]: 2.8 [1.5 - 4.1], p < 0.001; FABQ-work mean difference [95% CI]: 6.2 [4.0 - 8.4], p < 0.001)) and had lower level of fear avoidance beliefs if they had completed postgraduate study (FABQ-physical mean difference [95% CI]: 2.9 [-5.8 - 0.0], p = 0.049). This study suggests that LBP-related beliefs and attitudes among Chinese HCPs are influenced by age, location of work, level of LBP-related disability and education level. Understanding back pain beliefs of Chinese HCPs forms an important foundation for future studies into the condition and its management in China.


Multilocus sequence typing of Chlamydia trachomatis among men who have sex with men reveals cocirculating strains not associated with specific subpopulations.
Previous studies identified specific Chlamydia trachomatis strains circulating among men who have sex with men (MSM). This study investigates whether distinct C. trachomatis strains circulate among subpopulations within the MSM community. Participants were recruited at the sexually transmitted infection clinic of the Public Health Service of Amsterdam from 2008 to 2009. C. trachomatis samples were typed using multilocus sequence typing. Epidemiological and clinical data were derived from questionnaires and patient records. Typing of 277 samples from 260 MSM identified distinct C. trachomatis strains circulating concurrently over time. Men with lymphogranuloma venereum (LGV)-inducing strains were more likely to be infected with human immunodeficiency virus, more often had a history of STI, and had a higher frequency of risky sexual behavior. No such associations were found for non-LGV-inducing strains. MSM infected with heterosexual-associated strains were often younger (P = .04) and more often reported sex with women (P = .03), compared with men infected with MSM-associated strains. With the exception of LGV-inducing strains, no evidence was found that different C. trachomatis strains circulated in distinct subpopulations of MSM. This indicates that no separate transmission networks for C. trachomatis among MSM existed. However, younger MSM and bisexuals were more often infected with heterosexual-associated C. trachomatis strains.


The Practical Application of Bio-Inspired PMA for the Detection of Partial Discharges in High Voltage Equipment.
In this paper, the practical application of a bio-inspired antenna for partial discharge (PD) detection in high voltage equipment was evaluated in order to validate the efficiency of using this technology for PD monitoring purposes. For this, PD measurements using the bio-inspired antenna were performed on operational 69 kV potential transformers (PT) in a real substation. After the field experiment, laboratory measurements using the IEC 60270 standard method and a bio-inspired antenna were performed, simultaneously, over the evaluated PT. The results obtained at the substation indicated suspicious frequencies of partial discharge activity in two out of three evaluated potential transformers, mainly for the frequencies of 461 MHz, 1366 MHz, 1550 MHz and 1960 MHz. During the laboratory tests, the presence of partial discharge activity over the suspicious potential transformers was confirmed with the detection of PD apparent charge levels above 20 pC. Finally, the frequency spectrum obtained from the PD signals detected by the bio-inspired antenna in the laboratory presented similar frequency values to those obtained during the practical application at the substation, making it a promising indicator for future defect classification studies using artificial intelligence.


Hippocampal atrophy rates in Alzheimer's disease: automated segmentation variability analysis.
Hippocampal (HC) atrophy and atrophy rates are putative clinical markers of progression to Alzheimer's disease (AD). We compared results given by two different automated HC segmentation techniques in the Alzheimer's Disease Neuroimaging Initiative dataset between two time intervals. We used HC volumetric automated segmentation data for a total of 683 patients at baseline (198 controls, 331 with mild cognitive impairment (MCI) and 154 with AD), 684 at 6 months (198 controls, 332 with MCI and 154 with AD) and 587 at 12 months (176 controls, 280 with MCI and 131 with AD). Segmentation techniques included FreeSurfer and SNT. We calculated HC monthly atrophy rates between baseline and 6 months and between 6 and 12 months, and used a multiple-way ANOVA for repeated measures. Mean HC volumes decrease with time. The only significant (p<0.05) main effect was diagnosis. We measured strong interaction between technique and scan interval and weak interaction between diagnoses and scan interval. When compared to mean rates from largely manual segmentation, automated segmentation results show increased atrophy rates for both SNT and FreeSurfer techniques. While sensitive, there remains substantial technique variability, likely due to differences in methodological approaches and especially neuroanatomical HC definitions. These fundamental metrological problems need to be resolved before concluding with certainty on the accuracy and reliability of automated techniques.


Targeted disruption of the orphanin FQ/nociceptin gene increases stress susceptibility and impairs stress adaptation in mice.
The neuropeptide orphanin FQ (also known as nociceptin; OFQ/N) has been implicated in modulating stress-related behavior. OFQ/N was demonstrated to reverse stress-induced analgesia and possess anxiolytic-like activity after central administration. To further study physiological functions of OFQ/N, we have generated OFQ/N-deficient mice by targeted disruption of the OFQ/N gene. Homozygous mice display increased anxiety-like behavior when exposed to a novel and threatening environment. OFQ/N-null mice show elevated basal pain threshold but develop normal stress-induced analgesia. Interestingly, these mice show impaired adaptation to repeated stress when compared with wild-type mice, whereas their performance in spatial learning remained unaffected. Basal and poststress plasma corticosterone levels were found to be elevated in OFQ/N-deficient animals. Thus, OFQ/N appears to be crucially involved in the neurobiological regulation of stress-coping behavior and fear.


[(125)I]orphanin FQ/nociceptin binding in Raji cells.
Western blots using an antibody which recognizes the orphanin FQ/nociceptin (OFQ/N) receptor reveals a band at approximately 69 kD in several cell lines, including the Raji human B cell lymphoma cell line. RT-PCR confirms the presence of this receptor in the Raji cells. Binding studies revealed a high affinity [(125)I][Tyr(14)]OFQ/N site in the Raji cells. The affinity of [(125)I][Tyr(14)]OFQ/N in the Raji cells (K(D) 68.4 pM) was similar to that in the transfected receptor (K(D) 36.7 pM). Its selectivity profile also was quite similar. OFQ/N competed binding quite potently (K(i) 65 pM), as did [Tyr(14)]OFQ/N (K(i) 33 pM). Traditional opioids displayed no appreciable affinity for the binding at any concentration examined, with the exception of naloxone benzoylhydrazone, which had only a very modest affinity. The receptors in the Raji cells were functionally active. OFQ/N inhibited forskolin-stimulated cyclase by 72% with an IC(50) value of approximately 1 nM.


Heritable changes in chromatin contacts linked to transgenerational obesity.
Burgeoning evidence demonstrates that effects of environmental exposures can be transmitted to subsequent generations through the germline without DNA mutations 1,2 . This phenomenon remains controversial because underlying mechanisms have not been identified. Therefore, understanding how effects of environmental exposures are transmitted to unexposed generations without DNA mutations is a fundamental unanswered question in biology. Here, we used an established murine model of male-specific transgenerational obesity to show that exposure to the obesogen tributyltin (TBT) elicited heritable changes in chromatin interactions (CIs) in primordial germ cells (PGCs). New CIs were formed within the Ide gene encoding Insulin Degrading Enzyme in the directly exposed PGCs, then stably maintained in PGCs of the subsequent (unexposed) two generations. Concomitantly, Ide mRNA expression was decreased in livers of male descendants from the exposed dams. These males were hyperinsulinemic and hyperglycemic, phenocopying Ide -deficient mice that are predisposed to adult-onset, diet-induced obesity. Creation of new CIs in PGCs, suppression of hepatic Ide mRNA, increased fat mass, hyperinsulinemia and hyperglycemia were male-specific. Our results provide a plausible molecular mechanism underlying transmission of the transgenerational predisposition to obesity caused by gestational exposure to an environmental obesogen. They also provide an entry point for future studies aimed at understanding how environmental exposures alter chromatin structure to influence physiology across multiple generations in mammals.


Soilless cultivation of soybean for Bioregenerative Life-Support Systems: a literature review and the experience of the MELiSSA Project - Food characterisation Phase I.
Higher plants play a key role in Bioregenerative Life-Support Systems (BLSS) for long-term missions in space, by regenerating air through photosynthetic CO2 absorption and O2 emission, recovering water through transpiration and recycling waste products through mineral nutrition. In addition, plants could provide fresh food to integrate into the crew diet and help to preserve astronauts' wellbeing. The ESA programme Micro-Ecological Life-Support System Alternative (MELiSSA) aims to conceive an artificial bioregenerative ecosystem for resources regeneration, based on both microorganisms and higher plants. Soybean [Glycine max (L.) Merr.] is one of the four candidate species studied for soilless (hydroponic) cultivation in MELiSSA, because of the high nutritional value of the seeds. Within the MELiSSA programme - Food characterisation Phase I, the aim of the research carried out on soybean at the University of Naples was to select the most suitable European cultivars for cultivation in BLSS. In this context, a concise review on the state-of-the-art of soybean cultivation in space-oriented experiments and a summary of research activity for the preliminary theoretical selection and subsequent agronomical evaluation of four cultivars will be presented in this paper.


Protein intake per day and at each daily meal and skeletal muscle mass declines among older community dwellers in Japan.
To examine associations between protein intake per day and at different meals and skeletal muscle mass declines. Two-year prospective cohort study among older community dwellers. National Institute for Longevity Sciences-Longitudinal Study of Aging (NILS-LSA) in Japan. Older men (n 292) and women (n 363) aged 60-87 years who participated in the baseline (2006-2008) and follow-up studies (2008-2010) of NILS-LSA and did not exhibit low skeletal muscle mass at baseline. Muscle mass was assessed using dual-energy X-ray absorptiometry at baseline and follow-up. Low muscle mass was defined as skeletal muscle mass index <7·0 kg/m2 for men and <5·4 kg/m2 for women at follow-up. Daily protein intake and protein intake at each meal were calculated from 3 d dietary records at baseline and sex-stratified tertiles were determined. Mean (sd) protein intake at breakfast, lunch and dinner was 22·7 (7·8), 26·7 (9·3) and 37·4 (10·5) g for men and 19·3 (6·3), 23·2 (7·3) and 28·5 (7·0) g for women, respectively. After adjusting for age, baseline skeletal muscle mass and other confounders in logistic modelling, greater total protein intake was associated with lower prevalence of skeletal muscle mass decline among men at follow-up (P = 0·024). Particularly, the OR (95 % CI) for high lunchtime protein intake was low (0·11 (0·02, 0·61); P = 0·01). No significant association between total protein intake and prevalence of skeletal muscle mass decline was found among women. High total protein intake, particularly at lunchtime, is associated with retention of skeletal muscle mass in men.


Maternal-fetal pharmacokinetics and dynamics of a single intrapartum dose of maraviroc in rhesus macaques.
Single-dose nevirapine (NVP) is effective in reducing mother-to-child transmission (MTCT) of HIV; however, the subsequent development of drug resistance is problematic. The pharmacokinetic profile of the HIV entry inhibitor maraviroc after a single intrapartum dose in rhesus macaques was studied to determine whether maraviroc could serve as an alternative to NVP in a single-dose strategy. Four pregnant macaques received an oral dose of maraviroc 2 h before delivery, and both infant and maternal plasma maraviroc concentrations and CCR5 receptor occupancy on CD4(+) lymphocytes were measured over time. Maximum plasma maraviroc concentrations were found at delivery (2-h-postintrapartum dose) in both the mothers and infants, with median concentrations of 974 ng/ml (range, 86 to 2,830 ng/ml) and 22 ng/ml (range, 4 to 99 ng/ml), respectively. Maraviroc was detected in the plasma of mothers up to 48 h after dosing but only as long as 3.5 h in the infants. The median fetal-maternal area under the concentration-time curve (AUC) ratio was 0.009 (range, 0.000 to 0.015). Maraviroc receptor occupancy data showed evidence of unprotected CCR5 receptors on CD4(+) cells in the mothers 24 to 48 h after dosing. Extremely low CCR5 expression on CD4(+) cells of newborn macaques prevented determination of receptor occupancy in the infants. In rhesus macaques, maraviroc was poorly transferred across the placenta and was quickly cleared from the infants' blood. The low concentrations of fetal maraviroc and short pharmacokinetic profile in infants suggest that a single maternal intrapartum dose of maraviroc would not be effective in reducing the risk of MTCT of HIV.


Attachment Styles, Condomless Sex, and Drugs in HIV-Positive Gay and Bisexual Men.
This study evaluated whether attachment styles might be related to condomless sex, use of drugs, and adherence to antiretroviral treatment (ART) in 400 HIV-positive gay and bisexual men (GBM). With the Relationship Questionnaire, 160 men were classified as securely attached and 240 as insecurely attached (88 dismissive, 79 preoccupied, and 73 fearful). Insecurely attached GBM had more condomless sex (p = 0.04), and used more cocaine (p = 0.001), ecstasy (p = 0.03), GHB (p = 0.04), and ketamine (p = 0.04). No differences were observed in adherence to ART. Dismissively attached GBM reported more condomless sex and use of drugs than preoccupied and fearfully attached GBM. The perspective of attachment might enrich the interventions to promote heath care in GBM.


The relative efficiency of altering pulse frequency or train duration when determining seizure threshold.
In 12 depressed inpatients referred for bilateral electroconvulsive therapy (ECT), each patient was titrated at the first treatment session by using an ascending method-of-limits procedure with a step-wise increase in pulse frequency (frequency titration) or train duration (duration titration). At the second treatment session, seizure threshold was redetermined by using the method (frequency or duration titration) not used at the first treatment. Frequency or duration was maintained at the lowest level when the other parameter was titrated. Seizure threshold was significantly lower with duration titration (mean, 90 mC; SD, 27.3) than frequency titration (mean, 114 mC; SD, 35.6; p = 0.03). On average, patients in the duration-titration group required 1.2 (SD, 0.6) subconvulsive stimulations before a seizure was elicited, and patients in the frequency-titration group required 1.7 (SD, 0.9) subconvulsive stimulations before a seizure was elicited, a nonsignificant difference. These findings suggest that to elicit a seizure during ECT, increasing train duration may be slightly more efficient than increasing frequency. Basic and other clinical research findings indicate that increasing pulse width may be an inefficient way to elicit a seizure. Therefore the following sequence in the determination of seizure threshold is worth considering when using dose-titration or related techniques: the train duration should be increased first before increasing pulse frequency, and the decision to increase pulse width should be reserved for patients who do not seize at the maximal duration and frequency settings. Further empiric research is needed to establish the utility of this approach.


Contribution to the Evaluation of Physicochemical Properties, Total Phenolic Content, Antioxidant Potential, and Antimicrobial Activity of Vinegar Commercialized in Morocco.
Vinegar is a natural product widely used in food and traditional medicine thanks to its physicochemical properties and its richness in bioactive molecules. However, its direct use by consumers can have complications and undesirable effects. Therefore, this study contributes to investigating the physicochemical and biological properties of eleven vinegars marketed in Morocco. Determination of pH, acetic acid, conductivity, total soluble solids and alcohol content in vinegar was carried out. The polyphenols (TP), flavonoids (TF), and condensed tannins (CT) content was determined, and their antioxidant activities were evaluated using 2,2-diphenyl-1-picryl Hydrazyl (DPPH), Ferric Reducing Antioxidant Power (FRAP) and Phosphomolybdenum Reduction Assay (TAC). Then, the antimicrobial activity was studied against four pathogenic bacteria and two fungal strains, using the disk diffusion and the microdilution method. This study showed a wide range of acetic acid values from 0.65 ± 0.29 to 5.15 ± 0.20%. The high value of TP, TF, and CT in our samples V10, V9, and V4 was 655.00 ± 22.2 µgGAE/mL, 244.53 ± 11.32 µgQE/mL and 84.63 ± 1.00 µgTAE/mL, respectively. The tested strains showed variable sensitivities to the different samples with inhibition zones ranging from 6.33 ± 2.08 to 34.33 ± 0.58 mm. The lowest minimum inhibition concentrations were recorded against Staphylococcus aureus ATCC29213 ranging from 1.95 to 7.81 µL/mL. While Aspergillus niger ATCC16404 showed resistance against all of the analyzed samples. In general, vinegar commercialized in Morocco presents a variable range of products with variable properties. Indeed, must take into account this diversity when using it. A future study is needed to identify the phytochemical composition that will further the comprehension of this variability and contribute to its valorization.


Modulation of neglect hemianesthesia by transcutaneous electrical stimulation.
The effects of transcutaneous electrical stimulation on deficits of tactile perception contralateral to a hemispheric lesion were investigated in 10 right brain-damaged patients and in four left brain-damaged patients. The somatosensory deficit recovered, transiently and in part, after stimulation of the side of the neck contralateral to the side of the lesion, in all 10 patients with lesions in the right hemisphere, both with (six cases) and without (four cases) left visuo-spatial hemineglect, and in one left brain-damaged patient with right hemineglect. In three left brain-damaged patients without hemineglect, the treatment had no detectable effects. In one right brain-damaged patient, the stimulation of the side of the neck ipsilateral to the side of the lesion temporarily worsened the somatosensory deficit. These effects of transcutaneous electrical stimulation are similar to those of vestibular stimulation. The suggestion is made that these treatments modulate, through afferent sensory pathways, higher-order spatial representations of the body, which are pathologically distorted toward the side of the lesion. The modulatory effect is direction-specific: the defective internal representation of the contralesional side may be either partly restored, improving the disorder of tactile perception, or further impoverished, worsening the deficit. The possible neural basis of this modulation is discussed.


Successful Treatment of Severe Gamma-Hydroxybutyric Acid Withdrawal Syndrome With Dantrolene.
The prevalence of gamma-butyrolactone/gamma-hydroxybutyric acid (GBL/GHB) use is increasing. The gravity and number of incidents with this drug are relatively high. A feared complication is addiction and its withdrawal syndrome, which can be life-threatening and is difficult to treat. We present the case of a 31-year-old man, admitted to the ICU because of accidental GBL withdrawal. The patient was tachycardic, sweaty, extremely agitated, and showed signs of psychosis. High doses of benzodiazepines, propofol, sufentanil, and quetiapine could not sedate the patient sufficiently. Dosing with pharmaceutical GHB was challenging due to severe gastric retention. As the patient developed hyperthermia and rhabdomyolysis, signs of a neuroleptic malignant syndrome (NMS), he was treated with dantrolene. After 14 days, the patient was discharged to a psychiatric clinic for further treatment. GHB affects multiple neurotransmitters and chronic use causes the up- or down-regulation of several receptors. During GHB withdrawal, the patient developed a hyperexcitable state, in which there was insufficient gamma-aminobutyric acid (GABA) (the most important inhibiting neurotransmitter) and an abundance of glutamate (the most important excitatory neurotransmitter). High-dose benzodiazepines are often advocated as the first-line treatment, but benzodiazepine resistance has frequently been reported. Therefore, treatment with pharmaceutical GHB is advised. Patients with GHB-withdrawal who have clinical signs of NMS can be treated with dantrolene because it regulates the distorted calcium secretion and affects the serotonin and cholinergic system.


Serotonin receptor, SERT mRNA and correlations with symptoms in males with alcohol dependence and suicide.
This study tested the hypothesis that abnormalities in components of the serotonin (5HT) system in the prefrontal cortex are associated with suicide in alcohol-dependent subjects. Second, we assessed the relationship of lifetime impulsivity and mood symptoms with prefrontal cortex 5-HT measures. Tissue was obtained from Brodmann's areas (BA) 9 and 24 in postmortem samples of individuals who were alcohol dependent with suicide (n = 5), alcohol dependent without suicide (n = 9) and normal controls (n = 5). Serotonin receptor (5HT) and serotonin reuptake transporter (SERT) mRNA were measured. Interviews with next of kin estimated lifetime impulsivity and mood symptoms in the last week of life. Serotonin receptor 1A (5HT1A) mRNA in BA 9 was elevated in the alcohol dependence without suicide group compared with controls. In the alcohol dependence with suicide group, anxiety symptoms were associated with decreased BA 24 SERT mRNA and depressive symptoms with BA 9 5HT1A mRNA expression. In the alcohol dependent only group impulsivity is correlated with increased BA 9, and BA 24 serotonin receptor 2A mRNA. Our data suggest region-specific change, rather than global serotonin blunting is involved in alcohol dependence and suicide. It also suggests that symptoms are differentially influenced by prefrontal cortex serotonin receptor mRNA levels.


Selective covalent immobilization of ferritin on alumina.
Selective and specific covalent immobilization and simultaneous suppression of nonspecific adsorption of the protein ferritin (FN) on the surfaces of polycrystalline α-alumina colloidal particles and single α-alumina crystals is demonstrated. FN immobilization is obtained by using a classical immobilization route and by combining either the organic silane 3-(triethoxysilyl)propylsuccinic anhydride (TESPSA) or (3-aminopropyl)triethoxysilane (APTES) with the zero-length cross linking system N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC)/N-hydroxysuccinimide (NHS). The combination of APTES or TESPSA with EDC/NHS leads to a stable FN binding via amide bonds. However, the authors demonstrate that the TESPSA-EDC/NHS system enables an overall higher amount of covalent immobilization and a simultaneous suppression of nonspecific FN adsorption. After TESPSA functionalization negatively charged carboxylic groups are formed and can at the same time both electrostatically repel the overall negatively charged FN proteins and react with EDC/NHS for FN covalent immobilization. Moreover, the authors show that by specifically controlling the FN concentration during the immobilization reaction, the molecule distribution and density of bound FN can be easily tuned. The approach presented enables to selectively immobilize FN at mild conditions on substrates with different geometries and is therefore relevant for the fabrication of biomimetic nanomaterials and two-dimensional FN arrays.