Identification of nitric oxide as an endogenous inhibitor of 26S proteasomes in vascular endothelial cells.
The 26S proteasome plays a fundamental role in almost all eukaryotic cells, including vascular endothelial cells. However, it remains largely unknown how proteasome functionality is regulated in the vasculature. Endothelial nitric oxide (NO) synthase (eNOS)-derived NO is known to be essential to maintain endothelial homeostasis. The aim of the present study was to establish the connection between endothelial NO and 26S proteasome functionality in vascular endothelial cells. The 26S proteasome reporter protein levels, 26S proteasome activity, and the O-GlcNAcylation of Rpt2, a key subunit of the proteasome regulatory complex, were assayed in 26S proteasome reporter cells, human umbilical vein endothelial cells (HUVEC), and mouse aortic tissues isolated from 26S proteasome reporter and eNOS knockout mice. Like the other selective NO donors, NO derived from activated eNOS (by pharmacological and genetic approach) increased O-GlcNAc modification of Rpt2, reduced proteasome chymotrypsin-like activity, and caused 26S proteasome reporter protein accumulation. Conversely, inactivation of eNOS reversed all the effects. SiRNA knockdown of O-GlcNAc transferase (OGT), the key enzyme that catalyzes protein O-GlcNAcylation, abolished NO-induced effects. Consistently, adenoviral overexpression of O-GlcNAcase (OGA), the enzyme catalyzing the removal of the O-GlcNAc group, mimicked the effects of OGT knockdown. Finally, compared to eNOS wild type aortic tissues, 26S proteasome reporter mice lacking eNOS exhibited elevated 26S proteasome functionality in parallel with decreased Rpt2 O-GlcNAcylation, without changing the levels of Rpt2 protein. In conclusion, the eNOS-derived NO functions as a physiological suppressor of the 26S proteasome in vascular endothelial cells.


[Residues of organochlorine insecticides in human and bovine milk in Colombia].
Studies carried out in various countries have determined the presence of organochlorine insecticides in human and cow's milk. To quantify this contamination in Colombia, the concentrations of these insecticides were measured in 170 samples of milk from lactating mothers in Bogotá (105 samples) and three agricultural areas where fumigation is done frequently (65 samples). Also, for purposes of comparison, the study included 75 samples of fresh cow's milk, 10 samples of pasteurized milk, and 10 samples of whole powdered milk. In all the samples of human or cow's milk, high concentrations of total DDT were found. In some samples there were also appreciable amounts of benzene hexachloride (BHC) and other insecticides not included in the study. The samples of cow's milk contained lower concentrations of sufficient total DDT. In a comparison of the means, the samples of human milk showed contamination several times greater than the cow's milk. The pasteurized and powdered milk had lower levels of contamination. The average amount of total DDT in the samples of human milk (0.075 ppm, or micrograms/ml) far exceeded the DDT contamination limit established for milk by FAO/WHO (0.050 ppm). However, there was a wide range in the levels found (the lowest being 0.002, and the highest, 0.680), which means that in some of the samples the concentrations of total DDT were more than 10 times greater than the maximum set by FAO/WHO while in many other cases they were close to the recommended limit.


Influence of cell proliferation on initiating activity of pure polychlorinated biphenyls and complex mixtures in resistant hepatocyte in vivo assays for carcinogenicity.
The abilities of various pure polychlorinated biphenyls (PCB) and complex mixtures to generate resistant gamma-glutamyltransferase (GGT)-positive hepatocellular nodules was evaluated in F344 rats in which hepatocytes were proliferating. The PCB examined were 2,2',4,4',5,5'-hexachlorobiphenyl (CAS: 35065-27-1), 2,2',4,4'-tetrachlorobiphenyl, 2,2',5,5'-tetrachlorobiphenyl, Aroclor 1254 (CAS: 11097-69-1), and a prepared mixture of pure PCB isomers and congeners similar to those found in human breast milk. The PCB were administered either to male and female suckling rats (weekly for 3 wk) during liver growth or to adult male rats (150-160 g body wt) previously subjected to two-thirds partial hepatectomy (PH). Rats were subsequently given a selection regimen consisting of 3 daily doses (20 mg/kg) of 2-acetylamino-fluorene (2-FAA; CAS: 53-96-3) followed by either PH or necrotizing carbon tetrachloride (CAS: 56-23-5) in adult rats that previously underwent PH. None of the PCB exposures generated GGT-positive nodules after selection, whereas known initiators such as diethylnitrosamine (CAS: 55-18-5), 3-methylcholanthrene (CAS: 56-49-5), benzo[a]pyrene (CAS: 50-32-8), and 2-FAA were active initiators of nodules in suckling or hepatectomized rats. These findings indicate that short-term exposures to these PCB during liver cell proliferation do not show initiating action in an in vivo assay that detects both hepatic and nonhepatic initiating carcinogens.


Predicting school uptake of The Daily Mile in Northern Ireland- a data linkage study with School Census Data and Multiple Deprivation Measures.
Participating in physical activity benefits health, yet a majority of children remain inactive. The Daily Mile™ (TDM) originated in Scotland in 2012 with the aim of increasing primary school children's physical fitness. Despite being a practically feasible and popular initiative, it remains unclear the extent to which schools implement TDM, and whether TDM core principles are adhered to (i.e., run or jog at least 3-days per week). In Northern Ireland it is unknown how many schools regularly participate in TDM, and whether there is an association between TDM participation with school type, school location, size, total number of children attending the school, school deprivation level, and/or motivation as measured by the COM-B model (Capabilities, Opportunities, Motivation model of behaviour). Therefore, this study aimed to quantify the uptake of TDM in Northern Ireland, assess whether schools are following the core principles, and analyse if there is an association between aforesaid demographic factors and TDM participation. An online cross-sectional survey was sent to all primary and special education schools in Northern Ireland with the support of the Education Authority for Northern Ireland and the Public Health Agency for Northern Ireland. The survey was completed by the school principal or teacher, and was available from 31st August until 16th December 2022. Survey results were linked with the 2021/2022 Northern Ireland School Census Data and Northern Ireland Multiple Deprivation Measure 2017. Quantitative and qualitative questions were included in the survey to assess participation and implementation of TDM. The survey received 609 school responses. After data cleaning, and removal of duplicates from schools a sample of 358 primary schools (45%) and 19 special education schools (47.5%) was analysed. Over half (54.7%) of primary schools and 36.8% of special education schools reported taking part in TDM. More special education needs schools reported taking part in their own version of an 'active mile' rather than TDM formally, and qualitative findings showed TDM was not perceived as appropriate for many children in special educational settings. There was wide variation in adherence to TDM core principles. A multivariate binary logistic regression model was fitted to the data, but it was not statistically significant (χ2(17) = 22.689, p = .160). However, univariate effects showed that increasing levels on COM-B (Capability) was associated with increased likelihood of TDM participation (OR = 2.506), and Catholic Maintained schools were almost twice as likely as Controlled schools to be delivering TDM (OR = 1.919). There was no association found between deprivation and TDM uptake. Encouragingly over 50% of schools in Northern Ireland reported taking part in TDM. However, despite being a low-cost and practically feasible physical activity initiative, further intervention work with sound research methodology is needed to promote adherence to TDM core principles to maximise benefits to children's health. Furthermore, concerted efforts are required to adjust TDM so that it is inclusive for all educational settings, and children's abilities.


Central versus lateral presentation in hemispheric sentence processing: a paradoxical finding.
There is considerable current interest in the question of the contribution of the right cerebral hemisphere to the comprehension of complex linguistic entities such as sentences and scripts. A problem in this field has been the difficulty of distinguishing between the consequences of lexical and message-level activation. The present study used a cross-modal lexical priming (CMLP) procedure to visually sample activation of word concepts at three different points during the auditory presentation of a sentence. Our aim was to contrast direct lexical activation following presentation of a word in the sentence with syntactic reactivation triggered by a subsequent anaphor. Visual word probes were presented to the right, left, and central visual fields, in order to permit hemispheric performance to be evaluated in relation to previous research confined to central presentations. The results were surprising. LVF probes revealed activation immediately following the target word, RVF probes exhibited activation three words downstream from the target, and centrally presented probes exhibited activation at all three sampling points. The most puzzling aspect of these results was the paradoxical finding that central presentations showed strong activation upon encountering an anaphor of the target, while neither lateral probe revealed any activation at all. We relate these results to recent research on the hemispheric implications of split-foveal word presentation, and suggest that simultaneous stimulation of the two hemispheres may be critical in evoking responses mediated by high-level integrative mechanisms requiring collaborative hemispheric processing.


After infection with Leishmania infantum, Golden Hamsters (Mesocricetus auratus) become more attractive to female sand flies (Lutzomyia longipalpis).
In Brazil, human and canine visceral leishmaniasis is caused by infection with Leishmania infantum, a Protist parasite transmitted by blood-feeding female Lutzomyia longipalpis sand flies. The objective of this study was to determine if the odour of hamsters, infected with Le. infantum, was more attractive than the odour of the same hamsters, before they were infected. The attractiveness of odour collected from individual hamsters (n = 13), before they were infected, was compared in a longitudinal study, with the attractiveness of the odour of the same hamster in a Y-tube olfactometer bioassay, at a late stage of infection. The odour of six of the golden hamsters was significantly more attractive to 50% of the female sand flies at the end of infection compared to before infection and the odour of four of the golden hamsters was significantly more attractive to 75% of the female sand flies at the end of infection. These results strongly indicate that hamsters infected with Le. infantum become significantly more attractive to a greater proportion of female sand flies as the infection progresses.


12-lead surface electrocardiogram reconstruction from implanted device electrograms.
Reconstruction of the surface electrocardiogram (EKG) from voltage recordings from implanted leads is not performed by current pacemakers or cardioverter-defibrillators. We investigated the feasibility and accuracy of reconstruction of a full 12-lead surface EKG from an implanted biventricular device. We applied three techniques for surface EKG reconstruction from multiple intracardiac (IC) vector recordings from implanted cardiac leads: single fixed dipole modelling via exact solution, exhaustive best-fit solution, and time-independent association using a transfer matrix. Recordings were performed at biventricular generator change in 10 patients. Overdetermined projection transformation resulted in high fidelity surface EKG reproduction for left-sided implanted devices (correlation coefficient 0.84+/-0.13) with computationally lightweight reconstruction. After individual post-implantation correlation with the surface EKG, reconstruction using a time-independent transfer matrix accurately reproduces the surface EKG, is free from gating requirements, and retains validity during aberrant depolarization. These findings have significant implications for further study relating IC electrogram to surface tracings. The techniques may be used for real-time or remote monitoring and diagnosis of rhythm disturbances, cardiac ischaemia, and lead integrity and stability.


Recent advances in plant endomembrane research and new microscopical techniques.
The endomembrane system consists of various membrane-bound organelles including the endoplasmic reticulum (ER), Golgi apparatus, trans-Golgi network (TGN), endosomes, and the lysosome/vacuole. Membrane trafficking between distinct compartments is mainly achieved by vesicular transport. As the endomembrane compartments and the machineries regulating the membrane trafficking are largely conserved across all eukaryotes, our current knowledge on organelle biogenesis and endomembrane trafficking in plants has mainly been shaped by corresponding studies in mammals and yeast. However, unique perspectives have emerged from plant cell biology research through the characterization of plant-specific regulators as well as the development and application of the state-of-the-art microscopical techniques. In this review, we summarize our current knowledge on the plant endomembrane system, with a focus on several distinct pathways: ER-to-Golgi transport, protein sorting at the TGN, endosomal sorting on multivesicular bodies, vacuolar trafficking/vacuole biogenesis, and the autophagy pathway. We also give an update on advanced imaging techniques for the plant cell biology research.


Casting inorganic structures with DNA molds.
We report a general strategy for designing and synthesizing inorganic nanostructures with arbitrarily prescribed three-dimensional shapes. Computationally designed DNA strands self-assemble into a stiff "nanomold" that contains a user-specified three-dimensional cavity and encloses a nucleating gold "seed." Under mild conditions, this seed grows into a larger cast structure that fills and thus replicates the cavity. We synthesized a variety of nanoparticles with 3-nanometer resolution: three distinct silver cuboids with three independently tunable dimensions, silver and gold nanoparticles with diverse cross sections, and composite structures with homo- and heterogeneous components. The designer equilateral silver triangular and spherical nanoparticles exhibited plasmonic properties consistent with electromagnetism-based simulations. Our framework is generalizable to more complex geometries and diverse inorganic materials, offering a range of applications in biosensing, photonics, and nanoelectronics.


Mechanistic Basis of Cabotegravir-Glucuronide Disposition in Humans.
Cabotegravir, a novel integrase inhibitor under development for treatment and prevention of HIV, is primarily metabolized by UDP-glucuronosyltransferase (UGT)1A1 and UGT1A9 to a direct ether glucuronide metabolite. The aim of these studies was to elucidate the mechanistic basis of cabotegravir-glucuronide disposition in humans. Cabotegravir glucuronidation was predominantly hepatic (>95%) with minimal intestinal and renal contribution. Rat liver perfusions demonstrated that cabotegravir-glucuronide formed in the liver undergoes comparable biliary and sinusoidal excretion, consistent with high concentrations of the glucuronide in human bile and urine. Cabotegravir-glucuronide biliary excretion was mediated by multidrug resistance-associated protein (MRP)2 (not transported by breast cancer resistance protein or P-glycoprotein), whereas hepatic basolateral excretion into sinusoidal blood was via both MRP3 [fraction transport (Ft) = 0.81] and MRP4 (Ft = 0.19). Surprisingly, despite high urinary recovery of hepatically-formed cabotegravir-glucuronide, metabolite levels in circulation were negligible, a phenomenon consistent with rapid metabolite clearance. Cabotegravir-glucuronide was transported by hepatic uptake transporters organic anion-transporting (OAT) polypeptide (OATP)1B1 and OATP1B3; however, metabolite clearance by hepatic uptake from circulation was low (2.7% of hepatic blood flow) and unable to explain the minimal systemic exposure. Instead, circulating cabotegravir-glucuronide undergoes efficient renal clearance, where uptake into the proximal tubule would be mediated by OAT3 (not transported by OAT1), and subsequent secretion into urine by MRP2 (Ft = 0.66) and MRP4 (Ft = 0.34). These studies provide mechanistic insight into the disposition of cabotegravir-glucuronide, a hepatically-formed metabolite with appreciable urinary recovery and minimal systemic exposure, including fractional contribution of redundant transporters to any given process based on quantitative proteomics. SIGNIFICANCE STATEMENT: The role of membrane transporters in metabolite disposition, especially glucuronides, and as sites of unexpected drug-drug interactions, which alter drug efficacy and safety, has been established. Cabotegravir-glucuronide, formed predominantly by direct glucuronidation of parent drug in liver, was the major metabolite recovered in human urine (27% of oral dose) but was surprisingly not detected in systemic circulation. To our knowledge, this is the first mechanistic description of this phenomenon for a major hepatically-formed metabolite to be excreted in the urine to a large extent, but not circulate at detectable levels. The present study elucidates the mechanistic basis of cabotegravir-glucuronide disposition in humans. Specific hepatic and renal transporters involved in the disposition of cabotegravir-glucuronide, with their fractional contribution, have been provided.


Are traditional body fat equations and anthropometry valid to estimate body fat in children and adolescents living with HIV?
The aim of this study was to assess the validity of traditional anthropometric equations and to develop predictive equations of total body and trunk fat for children and adolescents living with HIV based on anthropometric measurements. Forty-eight children and adolescents of both sexes (24 boys) aged 7-17 years, living in Santa Catarina, Brazil, participated in the study. Dual-energy X-ray absorptiometry was used as the reference method to evaluate total body and trunk fat. Height, body weight, circumferences and triceps, subscapular, abdominal and calf skinfolds were measured. The traditional equations of Lohman and Slaughter were used to estimate body fat. Multiple regression models were fitted to predict total body fat (Model 1) and trunk fat (Model 2) using a backward selection procedure. Model 1 had an R2=0.85 and a standard error of the estimate of 1.43. Model 2 had an R2=0.80 and standard error of the estimate=0.49. The traditional equations of Lohman and Slaughter showed poor performance in estimating body fat in children and adolescents living with HIV. The prediction models using anthropometry provided reliable estimates and can be used by clinicians and healthcare professionals to monitor total body and trunk fat in children and adolescents living with HIV.


Validation of a food frequency questionnaire for assessing dietary soy isoflavone intake among midlife Chinese women in Hong Kong.
Substantial evidence suggests that soy isoflavones may protect against certain chronic diseases. This study aims to assess the reproducibility and validity of a 47-item semiquantitative soy FFQ (SFFQ) designed to measure the usual intake of soy isoflavones among 145 Chinese mid-life women in Hong Kong. Reproducibility of the SFFQ was assessed by the stability of dietary intake obtained at baseline (SFFQ0) and at 13-mo follow-up (SFFQ1). Relative validity was measured by comparing data collected from SFFQ1 with those derived from 23-d, 24-h dietary recalls (DR) collected during the same 1-y validation period. Isoflavone intake was calculated using analytical values from the Chinese University of Hong Kong Soy Isoflavone Database. A total of 3,217 DR were successfully obtained. The median (interquartile range) absolute intake estimated by the SFFQ1 was 0.91 (-2.7 to 6.8) mg aglucon equivalents/d higher than the 6.3 (3.7-10.7) mg aglucon equivalents/d measured by the DR (P < 0.0057; Wilcoxon's Signed Rank test). Bland-Altman analysis further demonstrated the presence of significant proportional bias between methods among Cantonese women with above-median intake (Spearman correlation coefficient; r = 0.44; P = 0.0005). Nonetheless, the intraclass and Pearson correlation coefficients, respectively, were 0.84 and 0.72 for non-Cantonese and 0.65 and 0.50 for Cantonese, showing moderate to good levels of reproducibility and validity of the SFFQ (difference between 2 intraclass correlation coefficients, P = 0.09; difference between 2 Pearson r, P = 0.16). The unadjusted and BMI-adjusted correlations were of similar magnitude. The SFFQ is a reasonably valid instrument for assessing dietary soy isoflavone exposure in Hong Kong Chinese mid-life women.


[Decreased fetal movement and a sinusoidal pattern on the cardiotocogram: 2 alarm signals].
A 24-year-old primigravida was referred at 35 weeks of gestation due to decreased foetal movement. External monitoring demonstrated a sinusoidal foetal heart rate pattern accompanied by late decelerations. A hydropic and severely anaemic infant with clinical signs of thrombocytopenia was delivered by emergency caesarean section. He failed to breath spontaneously and required positive pressure ventilation. Cranial ultrasound and computerised tomography of the brain revealed a massive intraparenchymal haemorrhage. After the infant had died, post mortem studies revealed the presence of maternal antibodies to the human platelet antigen (HPA) 1a which suggested neonatal isoimmune thrombocytopenia as cause of the intracranial haemorrhage. A sinusoidal foetal heart rate pattern is an alarm signal--it is not necessarily significant but is often associated with mortality or serious morbidity and is therefore a reason for quickly investigating the condition of the foetus.


Comparison of Amyloid β and Tau Spread Models in Alzheimer's Disease.
Tau and amyloid β (Aβ), 2 key pathogenic proteins in Alzheimer's disease (AD), reportedly spread throughout the brain as the disease progresses. Models of how these pathogenic proteins spread from affected to unaffected areas had been proposed based on the observation that these proteins could transmit to other regions either through neural fibers (transneuronal spread model) or through extracellular space (local spread model). In this study, we modeled the spread of tau and Aβ using a graph theoretical approach based on resting-state functional magnetic resonance imaging. We tested whether these models predict the distribution of tau and Aβ in the brains of AD spectrum patients. To assess the models' performance, we calculated spatial correlation between the model-predicted map and the actual map from tau and amyloid positron emission tomography. The transneuronal spread model predicted the distribution of tau and Aβ deposition with significantly higher accuracy than the local spread model. Compared with tau, the local spread model also predicted a comparable portion of Aβ deposition. These findings provide evidence of transneuronal spread of AD pathogenic proteins in a large-scale brain network and furthermore suggest different contributions of spread models for tau and Aβ in AD.


Analysis of Mechanoreceptors and Free Nerve Endings of the Transverse Carpal Ligament.
Background: The treatment of carpal tunnel syndrome (CTS) by sectioning the transverse carpal ligament (TCL) is not exempt from complications. Some nerve branches may be damaged by the incision. The aim of this study is to identify and map the TCL nerve endings, serving as a guide for sectioning this structure in a zone with less nerve ending density. Methods: Ten TCLs were obtained from fresh frozen cadavers. The TCLs were measured, divided into 3 equal bands (radial, central, and ulnar), and submitted to cryostat sectioning. The sections were subjected to immunofluorescence with the protein gene product (PGP) 9.5 and confocal microscopy analysis. Results: All the specimens contained type I and type IV mechanoreceptors. Neural elements occupied 0.695 ± 0.056% of the ligament area. The density of the neural elements was greater in the radial, followed by the ulnar and central bands, with 0.730 ± 0.083%, 0.686 ± 0.009%, and 0.669 ± 0.031%, respectively. Conclusion: The present findings suggest that the region with the least potential for neural element injury during TCL release is the central third near the transition with the ulnar third. When performed distally to proximally with a slight inclination from the radial to the ulnar, this release compromises the lowest nerve element density. Topographically, the proximal limit of the release is the distal wrist crease, while the distal limit is the intersection of Kaplan cardinal line and the axis of the third webspace.


Age differences in everyday stressor-related negative affect: A coordinated analysis.
Advancing age is often characterized by preserved or even enhanced emotion regulation, which is thought to manifest in terms of age-related reductions in the within-person association between stressors and negative affect. Existing research from ecological momentary assessment and end-of-day daily diary studies examining such age-related benefits have yielded mixed results, potentially due to differences in samples, design, and measurement of everyday stressors and negative affect. We conducted a coordinated analysis of 5 ecological momentary assessments and 2 end-of-day daily diary studies to examine adult age differences in the within-person association between everyday stressors and negative affect. Reported stressor occurrences are robustly associated with higher negative affect, regardless of study design and sample characteristics. Across studies, interactions between age and everyday stressors predicting negative affect revealed a pattern of age-related decreases in the stressor-negative affect association, but this interaction was only significant for 2 studies. Further, examination of statistical power of the included studies suggests that, despite differences in the number of repeated assessments, power to detect within-person stressor-negative affect associations is quite good. In contrast, despite possessing wider age ranges, observed age differences were relatively small in magnitude, and studies are potentially underpowered to detect age differences in these within-person associations. We discuss the importance of study design, interval of repeated assessments and number of participants for examining age differences in everyday stressors and negative affect, as well as the virtue of coordinated analyses for detecting consistent direction of associations, but inconsistent patterns of statistical significance. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


[Continuous subcutaneous deferoxamine treatment in thalassemia major. Decrease of hemosiderosis and improvement of liver function].
Liver function during continuous subcutaneous deferoxamine therapy was investigated in 29 patients with homozygotic beta-thalassaemia. Average duration of treatment was 26 months (range 8-51 months). A decrease in haemosiderosis and an improvement in liver function was observed in 27 patients: Mean liver density, determined by computed tomography, decreased from 98 to 84 HU, mean serum ferritin concentration fell from 8028 to 3661 ng/ml, mean serum GOT activity from 44 to 13 U/l and GPT from 51 to 16 U/l. Mean cholinesterase activity, reflecting the improved synthetic activity of the liver, increased from 4063 to 4530 U/l.


Development of a rectal nicotine delivery system for the treatment of ulcerative colitis.
The aims of this investigation were: i. to develop a rectal nicotine delivery system with bioadhesives for the treatment of ulcerative colitis and ii. to evaluate nicotine transport and cytotoxicity of the delivery system using Caco-2 cell culture systems. Rectal nicotine suppository formulations were prepared in semi-synthetic glyceride bases (Suppocire AM and AI, Gattefosse Inc.) by fusion method. The in vitro release of nicotine was carried out in modified USP dissolution apparatus 1. Differential scanning calorimetry (DSC) and powder X-ray diffraction were used to study the polymorphic changes if any in the formulations. An LC method was used for the assay of nicotine. The effect of bioadhesives (glyceryl monooleate (GMO), and Carbopol) on the nicotine flux was evaluated using Caco-2 cell permeability studies and Caco-2 cell viability was determined using the MTT toxicity assay. In vitro release studies indicated that the low melting AI base was superior to that of the AM base. Presence of GMO in the formulation enhanced the release of nicotine whereas Carbopol showed an opposite effect. The enhanced release of nicotine in the presence of GMO was found to be partly due to the melting point lowering effect of this compound. Caco-2 cell absorption studies showed that there was a decrease in the flux of nicotine in the presence of both the bioadhesives. The flux of the fluorescein marker which is used to study the integrity of the cell monolayers was found to be slightly higher only in the presence of 10% (w/w) Carbopol. Nicotine, Carbopol, and GMO do not have any cytotoxic effect on these cell monolayers within the concentration range used in the formulations. Rectal nicotine formulations containing bioadhesives were developed and characterized. Both in vitro release and cell culture studies have indicated that one can manipulate the nicotine release from these rectal delivery systems by incorporation of various bioadhesives or the use of different bases in the formulation. Nicotine concentration below 2% (w/v) and bioadhesive concentration below 10% (w/w) do not have any cytotoxic effect on Caco-2 cells.


Comparative Molecular Dynamics Simulations Provide Insight Into Antibiotic Interactions: A Case Study Using the Enzyme L,L-Diaminopimelate Aminotransferase (DapL).
The L,L-diaminopimelate aminotransferase (DapL) pathway, a recently discovered variant of the lysine biosynthetic pathway, is an attractive pipeline to identify targets for the development of novel antibiotic compounds. DapL is a homodimer that catalyzes the conversion of tetrahydrodipicolinate to L,L-diaminopimelate in a single transamination reaction. The penultimate and ultimate products of the lysine biosynthesis pathway, meso-diaminopimelate and lysine, are key components of the Gram-negative and Gram-positive bacterial peptidoglycan cell wall. Humans are not able to synthesize lysine, and DapL has been identified in 13% of bacteria whose genomes have been sequenced and annotated to date, thus it is an attractive target for the development of narrow spectrum antibiotics through the prevention of both lysine biosynthesis and peptidoglycan crosslinking. To address the common lack of structural information when conducting compound screening experiments and provide support for the use of modeled structures, our analyses utilized inferred structures from related homologous enzymes. Using a comprehensive and comparative molecular dynamics (MD) software package-DROIDS (Detecting Relative Outlier Impacts in Dynamic Simulations) 2.0, we investigated the binding dynamics of four previously identified antagonistic ligands of DapL from Verrucomicrobium spinosum, a non-pathogenic relative of Chlamydia trachomatis. Here, we present putative docking positions of the four ligands and provide confirmatory comparative molecular dynamics simulations supporting the conformations. The simulations performed in this study can be applied to evaluate putative targets to predict compound effectiveness prior to in vivo and in vitro experimentation. Moreover, this approach has the potential to streamline the process of antibiotic development.


[The status of cerebral hemodynamics in patients with vertebro-basilar insufficiency syndrome].
The state of venous and arterial cerebral hemodynamics was studied using ultrasonic dopplerography with application of hypo- and hypercapnia, angioencephaloscintigraphy with pertecnetate Tc-99m in 48 patients with syndrome of vertebrobasilar insufficiency. Estimation was performed in patients by the results of neurological and otoneurologic evidence, the data of nistagmography and registration of the truncal evoked potentials. It was found that at early stages of the development of vertebrobasilar insufficiency's syndrome disorders of vasomotor reactivity and disturbances in venous hemodynamics play a leading role in its pathogenesis. Stenosis damages of extra- and intracranial arteries become dominating in subsequent clinical picture.


Neonatal thrombosis: are we doing the right studies?
Although neonatal thrombosis may be fatal or cause serious morbidity in survivors, strong clinical recommendations on the management of affected infants could not be made in the 1980s because of the lack of sound data from high-quality studies. To determine whether the "right" studies are now being done, a Medline search (exp infant, newborn, and exp thrombosis) for English language articles 1991-1994, was done and 135 citations were found. After exclusion of 59 nonrelevant articles (such as thrombosis in pregnant women or in vitro studies), plus nine letters to the editor, two reviews, and one consensus report, 64 original articles remained. Eighty-four percent of those (54 citations) were case reports and small case series. Experimental designs (prospective or retrospective cohort and case-control studies) were used in only 10 reports. The recently published literature on neonatal thrombosis continues to show an overabundance of anecdotal reports and a shortage of well-designed collaborative studies. The latter are sorely needed to improve the management of affected infants.


Focusing properties of fractal zone plates: experimental implementation with a liquid-crystal display.
We report the first experimental results, to our knowledge, with fractal zone plates implemented in a liquid-crystal display. Our results largely agree with theory for the axial irradiance distribution of these lenses. The dependence of the shape and size of the focus points on critical design parameters is discussed. Additional unpredicted features are also described.


Perceptions of aging among middle-aged offspring of traumatized parents: the effects of parental Holocaust-related communication and secondary traumatization.
Traumatized parents may transmit anxieties of physical deterioration and demise to their offspring. These anxieties can amplify negative perceptions of the aging process when the offspring enter old age. The current study examined how middle-aged offspring of Holocaust survivors (OHS) recount trauma-related communication by their parents, and how these reports are related to offspring's perceptions of their aging process. The study included 450 respondents at the age range of 50-67 (mean age = 57.5, SD = 4.6): 300 OHS and 150 comparisons. Participants reported parental communication of the Holocaust, completed measures of subjective successful aging, aging and death anxieties, and reported secondary traumatization assessing symptoms, developed as a result of a close and continuous relationship with a traumatized parent. Latent profile analysis identified two profiles of parental Holocaust-related communication: intrusive and informative. Offspring who reported intrusive parental communication about the Holocaust perceived themselves as aging less successfully and were more anxious of aging and death than comparisons. Offspring who reported informative parental communication and comparisons did not differ in perceptions of aging. Secondary traumatization mediated these group differences, meaning, intrusive parental communication was related to higher secondary traumatization, which in turn was related to less favorable perceptions of aging. These findings allude to the possibility that secondary traumatization mold negative perceptions of the aging process among middle-aged offspring of traumatized parents. Mental health practitioners may help OHS process fragmented and intrusive remnants of parental trauma, thereby diminishing secondary traumatization, and promoting more adaptive perceptions of aging.


The malaria parasite Plasmodium relictum in the endemic avifauna of eastern Cuba.
Island populations are vulnerable to introduced pathogens, as evidenced by extinction or population decline of several endemic Hawaiian birds caused by the malaria parasite, Plasmodium relictum (order Haemosporida). We analyzed blood samples from 363 birds caught near Guantánamo Bay, Cuba, for the presence of haemosporidian infections. We characterized parasite lineages by determining nucleotide variation of the parasite's mitochondrial cyt b gene. Fifty-nine individuals were infected, and we identified 7 lineages of haemosporidian parasites. Fifty individuals were infected by 6 Haemoproteus sp. lineages, including a newly characterized lineage of Haem. (Parahaemoproteus) sp. CUH01. Nine individuals carried the P. relictum lineage GRW4, including 5 endemic Cuban Grassquits (Tiaris canorus) and 1 migratory Cape May Warbler (Setophaga tigrina). A sequence of the merozoite surface protein gene from one Cuban Grassquit infected with GRW4 matched that of the Hawaiian haplotype Pr9. Our results indicate that resident and migratory Cuban birds are infected with a malaria lineage that has severely affected populations of several endemic Hawaiian birds. We suggest GRW4 may be associated with the lack of several bird species on Cuba that are ubiquitous elsewhere in the West Indies. From the standpoint of avian conservation in the Caribbean Basin, it will be important to determine the distribution of haemosporidian parasites, especially P. relictum GRW4, in Cuba as well as the pathogenicity of this lineage in species that occur and are absent from Cuba.


Visual Analysis of Displacement Processes in Porous Media using Spatio-Temporal Flow Graphs.
We developed a new approach comprised of different visualizations for the comparative spatio-temporal analysis of displacement processes in porous media. We aim to analyze and compare ensemble datasets from experiments to gain insight into the influence of different parameters on fluid flow. To capture the displacement of a defending fluid by an invading fluid, we first condense an input image series to a single time map. From this map, we generate a spatio-temporal flow graph covering the whole process. This graph is further simplified to only reflect topological changes in the movement of the invading fluid. Our interactive tools allow the visual analysis of these processes by visualizing the graph structure and the context of the experimental setup, as well as by providing charts for multiple metrics. We apply our approach to analyze and compare ensemble datasets jointly with domain experts, where we vary either fluid properties or the solid structure of the porous medium. We finally report the generated insights from the domain experts and discuss our contribution's advantages, generality, and limitations.


Computational Toxicology Methods in Chemical Library Design and High-Throughput Screening Hit Validation.
The discovery of molecular toxicity in a clinical drug candidate can have a significant impact on both the cost and timeline of the drug discovery process. Early identification of potentially toxic compounds during screening library preparation or, alternatively, during the hit validation process, is critical to ensure that valuable time and resources are not spent pursuing compounds that may possess a high propensity for human toxicity. This chapter focuses on the application of computational molecular filters, applied either prescreening or postscreening, to identify and remove known reactive and/or potentially toxic compounds from consideration in drug discovery campaigns.


Fasting rapidly increases fatty acid oxidation in white adipose tissue of young broiler chickens.
Upregulating the fatty acid oxidation capacity of white adipose tissue in mice protects against diet-induced obesity, inflammation and insulin resistance. Part of this capacity results from induction of brown-like adipocytes within classical white depots, making it difficult to determine the oxidative contribution of the more abundant white adipocytes. Avian genomes lack a gene for uncoupling protein 1 and are devoid of brown adipose cells, making them a useful model in which to study white adipocyte metabolism in vivo. We recently reported that a brief (5 hour) period of fasting significantly upregulated many genes involved in mitochondrial and peroxisomal fatty acid oxidation pathways in white adipose tissue of young broiler chickens. The objective of this study was to determine if the effects on gene expression manifested in increased rates of fatty acid oxidation. Abdominal adipose tissue was collected from 21 day-old broiler chicks that were fasted for 3, 5 or 7 hours or fed ad libitum (controls). Fatty acid oxidation was determined by measuring and summing 14CO2 production and 14C-labeled acid-soluble metabolites from the oxidation of [1-14C] palmitic acid. Fasting induced a progressive increase in complete fatty acid oxidation and citrate synthase activity relative to controls. These results confirm that fatty acid oxidation in white adipose tissue is dynamically controlled by nutritional status. Identifying the underlying mechanism may provide new therapeutic targets through which to increase fatty acid oxidation in situ and protect against the detrimental effects of excess free fatty acids on adipocyte insulin sensitivity.


Barriers and Facilitators to Implementation of Health System Interventions Aiming to Welcome and Protect Immigrant Patients: a Qualitative Study.
At the same time that federal policymakers have enforced restrictive immigration policies, healthcare systems across the USA are developing, and have implemented, interventions aimed at addressing immigration-related stressors faced by immigrant communities. Yet, little is known about the contextual determinants that influence their implementation success. Using the Consolidated Framework for Implementation Research (CFIR), this study identifies factors enabling or challenging the implementation of interventions aimed at mitigating immigration-related stressors in the healthcare context. We used a qualitative research design to conduct 38 semi-structured interviews with stakeholders involved in implementation of interventions at 25 healthcare facilities across 5 states with the highest undocumented immigrant populations (California, Texas, New York, Florida, and Illinois). Interviews were conducted from May through August 2018. Constant comparative analysis was used to identify barrier and facilitator themes. Deductive coding was thereafter used to categorize themes according to CFIR domain. Barriers to implementation included perceptions of legal complexity and challenges to adopting such systemic strategies. Facilitators included a national policy climate that had brought immigrant health to the forefront, allowing for leveraging momentum towards institutional change; communication among healthcare personnel; existing community partnerships with immigrant rights and service organizations; and a shared sense of mission centering health equity. Local variation in immigration-related policies (e.g., local law agencies enforcing federal immigration laws) and heterogeneity of local immigrant communities also impacted implementation. Champions and informal leaders were integral to institutional efforts but not sufficient for sustainability. Perceived urgency to act superseded evaluation considerations, with all interventions in initial phases of implementation. Future iterations and evaluations of these interventions are needed to establish best practices and implementation determinants. This is the first systematic study describing implementation determinants of immigration-related interventions across health systems. Identifying these determinants provides guidance to other healthcare organizations to effectively strategize and ensure implementation success.


[Growth of Clostridium botulinum in media with garlic (Allium sativum)].
The effect of garlic on the growth and toxin formation of Clostridium botulinum (GT) was studied in A) crude juice obtained from a pool of cloves by i) crushing, ii) pressing out and iii) filtration, and B) minced garlic (6 to 8 pieces per clove). For both, "white" and "red" garlic varieties were used. The juice (pH 5.7 to 6.0, for different batches) was activated 30 min at 37 degrees C and diluted (log 2) in PGY broth (g%: peptone (Difco) 1.0; glucose 0.5; yeast extract (Difco) 0.5; pH 7.3). A small drop from a 18 h at 37 degrees C chopped meat medium culture of a highly toxigenic autochthonous strain (110) of C. botulinum type A, was transferred to the juice dilutions, incubating anaerobically 15d at 37 degrees C. As a control of the inhibitory effect of the juice, four microorganisms were cultured 48 h at 37 degrees C in the juice dilutions (Table 1). Clove pieces were suspended to 50% (w/v) either in PGY broth or distilled water without pH adjustment. Aliquots were heated in water bath 15 min at 100 degrees C. After seeded with the A 110 strain, duplicate tubes and their controls were incubated 15 d at 37 degrees C in aerated and anaerobic conditions (Table 2). Titers of botulinum toxin were empirically estimated by the time to death of a pair of mice injected with 0.5 ml each, via IP, observed 72 h. Results are shown in tables 1 and 2. Garlic reduces (in undiluted juice, traces or 3 to 5 DL50/ml were recorded in separate experiments) but not inhibit GT.(ABSTRACT TRUNCATED AT 250 WORDS)


Facilitators and Barriers to Contraceptive Use Among U.S. Servicewomen Who Had an Abortion.
Despite evidence that the unintended pregnancy rate is higher among U.S. servicewomen than the general population and that servicewomen may face barriers to contraceptive use, there is little research about contraceptive access and use experiences of non-deployed active duty servicewomen. This qualitative study aimed to explore the experiences of accessing contraception while in the U.S. military among active duty servicewomen who had an abortion. From January 2015 to July 2016, we conducted qualitative in-depth interviews with 21 servicewomen who had obtained an abortion within the prior two years while active duty. The interviews included questions about participants' experiences accessing and using contraception while in the military. Interviews were transcribed and analyzed thematically using inductive and deductive coding. Ethical approval was obtained from the Allendale Investigational Review Board. Over half of the respondents had ever obtained contraception from the military and had positive feelings about the military's contraceptive services; however, the vast majority of participants described barriers to contraceptive access in the military. Many identified barriers that were related to the military health care system, including inadequate counseling, challenges getting a preferred contraceptive method, and the structure and functioning of the military health system, or were a result of the demands of military service. In addition to these factors that were directly related to being in the military, respondents identified barriers not directly related to service, including contraceptive adherence, product concerns, and side effects; although not directly related to their service, in some cases, these barriers were exacerbated by their career. Active duty servicewomen who had an abortion experienced many barriers to accessing contraception while in the military. These findings highlight the need to improve contraceptive counseling and access in the U.S. military. Results support the need to implement mandatory yearly and pre-deployment contraceptive counseling as required by the 2016 National Defense Authorization Act, offer contraceptive counseling in multiple settings, ensure military providers receive training to avoid contraceptive coercion, expand military clinic and pharmacy hours, increase the number of female military health care providers and providers able to administer all forms of contraception, and expand the contraceptive methods included under the Basic Core Formulary. Limitations to this study include that participants were self-selected and were asked to recall experiences up to several years in the past. Future studies should evaluate representative samples to understand the proportion of servicewomen with unmet contraceptive need.


Two-dimensional gel analysis of HSV type 1-induced polypeptides and glycoprotein processing.
Two hundred and thirty virus-induced polypeptides have been detected in BHK cells infected with herpes simplex virus type 1 (HSV-1; strain 17) by means of two-dimensional gel electrophoresis. The polypeptides have been characterized by both relative mobility following isoelectric focusing and apparent mol. wt. in SDS-polyacrylamide gels. Some polypeptides, visualized as a single band on a one-dimensional SDS-polyacrylamide gel, were resolved into several spots. Three were identified in Vmw43, the band thought to contain thymidine kinase activity. Not all the observed polypeptides are unique species: some appear to be related and have altered mobilities as a consequence of post-translational modification events. Pulse-chase experiments and treatment of infected cells with neuraminidase suggested that glycoproteins gB, gC and gD contain sialic acid and that synthesis of gB and gD occurs by at least 15 and 10 discrete steps respectively.


Isolation and characterization of the sucrose 6-phosphate hydrolase gene from Streptococcus mutans.
The Streptococcus mutans GS-5 gene, scrB, coding for sucrose 6-phosphate hydrolase activity has been cloned into Escherichia coli utilizing the bacteriophage replacement vector lambda L47.1. DNA sequences containing the gene were initially subcloned into the moderate-copy-number plasmid vector pLG339 to yield active subclones. However, due to the instability of the resultant chimeric plasmids, the gene was subsequently subcloned into the low-copy-number vector pOU61 to yield the stable hybrid plasmid pMH613. Both plasmids contain a 6.6-kilobase EcoRI fragment from strain GS-5 and express both hydrolase and sucrase activities. The relative position of the gene in the insert has been determined after Tn5 mutagenesis and deletion analysis. The cloned enzyme was purified to near homogeneity after gel filtration and anion-exchange chromatography, chromatofocusing, and preparative polyacrylamide gel electrophoresis. The purified enzyme displayed a molecular mass of 58 kilodaltons, which is significantly higher than the 48-kilodalton enzyme previously purified from S. mutans GS-5. These results suggest that processing of the hydrolase occurs in S. mutans.


Association between the Dietary Inflammatory Index and All-Cause Mortality in Adults with Obesity.
The dietary inflammatory index (DII) is associated with numerous chronic noncommunicable diseases. Previous studies have shown that the pro-inflammatory DII categories are associated with abdominal and simple obesity. However, the association between DII and mortality in patients with abdominal obesity and simple overweight or obesity remains unclear. We used data from the US National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018. A DII >0 (positive DII) was defined as a pro-inflammatory diet. A restricted cubic spline curve was used to describe the trend between DII and all-cause mortality. We then examined the association between DII and all-cause mortality in different body types using a Cox regression analysis and investigated the differences between sexes. Finally, the mediating effects of systemic inflammation were explored. A pro-inflammatory diet increased all-cause mortality in adults with abdominal obesity (aHR: 1.31, 95% confidence interval [CI]: 1.11-1.54; p < 0.001) and with simple overweight or obesity (aHR: 1.30, 95% CI: 1.11-1.53; p < 0.001). In addition, the most pro-inflammatory DII increased the risk of mortality by 43% (hazard ratio [HR]: Q4 vs. Q1 = 1.43, 95% CI = 1.14-1.79; p = 0.002; p for trend = 0.003) and 39% (HR: Q4 vs. Q1 = 1.39, 95% CI = 1.13-1.74; p = 0.003; p for trend = 0.009) in participants with abdominal obesity and with simple overweight or obesity, respectively. However, this association was not present in normal-sized participants. Compared with men, women resisted the effects of a pro-inflammatory diet. Mediation analysis showed that white blood cell and neutrophil were mediators of the association between DII and all-cause mortality (p < 0.001). A pro-inflammatory diet is associated with all-cause mortality in adults with abdominal obesity and simple overweight or obesity, and this effect differs between men and women. Systemic inflammation may mediate the association between DII and all-cause mortality.


AHRA survey. Staff utilization: Part III.
Part III is the final installment of the 1993 AHRA membership survey on staff utilization and includes results for radiation therapy, nuclear medicine, interventional/angiography and cardiac catheterization. The information includes the volume of procedures and numbers of FTEs in departmental areas and comparisons with results reported from a similar survey of AHRA members conducted in 1989.


Increased expression of renal cyclooxygenase-2 and neuronal nitric oxide synthase in hypertensive Cx40-deficient mice.
Cx40-deficient mice (Cx40-/-) are hypertensive due to increased renin secretion. We evaluated the renal expression of neuronal nitric oxide synthase (nNOS) and cyclooxygenases COX-1 and COX-2, three macula densa enzymes. The levels of nNOS were increased in kidneys of Cx40-/- mice, as well as in those of wild-type (WT) mice subjected to the two-kidney one-clip model of hypertension. In contrast, the levels of COX-2 expression were only increased in the hypoperfused kidney of Cx40-/- mice. Treatment with indomethacin lowered blood pressure and renin mRNA in Cx40-/- mice without affecting renin levels, indicating that changes in COX-2 do not cause the altered secretion of renin. Suppression of NOS activity by N(G)-nitro-L-arginine methyl ester (L-NAME) decreased renin levels in Cx40-/- animals, indicating that NO regulates renin expression in the absence of Cx40. Treatment with candesartan normalized blood pressure in Cx40-/- mice, and decreased the levels of both COX-2 and nNOS. After a treatment combining candesartan and L-NAME, the blood pressure of Cx40-/- mice was higher than that of WT mice, showing that NO may counterbalance the vasoconstrictor effects of angiotensin II in Cx40-/- mice. These data document that renal COX-2 and nNOS are differentially regulated due to the elevation of renin-dependent blood pressure in mice lacking Cx40.


In search of a face: childbearing decisions among couples living with HIV from rural southern Malawi.
In the context of increasing access to antiretroviral therapy (ART), the issue of childbearing among people living with HIV is important. The little that is known originates from either studies conducted before widespread availability of highly active ART or has focused on women's or men's reproductive behaviours and experiences. This paper therefore explores factors that influence childbearing decisions of married couples living with HIV in patrilineal and matrilineal kinship communities in rural Malawi. Qualitative exploratory research was conducted in two rural districts in the southern part of Malawi. Data were collected using in-depth interviews from 20 couples purposively sampled in matrilineal (Chiradzulu) and patrilineal (Chikhwawa) communities from July to December 2010 and was analysed using the content analysis method. The research findings show that couples living with HIV continue having children despite knowledge of the risk associated with childbearing and resistance from others in the community. Furthermore, the findings suggest that men are driven to have children by the need to cement relationships (patrilineal and matrilineal communities) and to secure position (matrilineal communities) while women do not want to have children because they are afraid of the risks and a heavier childcare burden. Finally, the findings suggest that outcomes of the decisions are dominated by husbands' desires in both communities. This paper therefore extends the discourse on the value of childbearing beyond the question of adulthood expressed in varying ways according to gender and kinship organisation. We therefore recommend that intervention strategies for both reproductive health and HIV and AIDS must focus on husbands and be sensitive to local culture. The antiretroviral clinics must integrate family planning services in their routine activities and condom use must be complemented with other effective family planning methods to prevent future pregnancies.


Ultraviolet photolysis studies on XeO4 in noble-gas and F2 matrices and the formation and characterization of a new Xe(VIII) oxide, (η(2) -O2 )XeO3.
The photolytic behavior of the thermochemically unstable xenon(VIII) oxide XeO4 was investigated by UV irradiation in noble-gas and F2 matrices. Photolysis of Xe(16) O4 or Xe(18) O4 in noble-gas matrices at 365 nm yielded XeO3 and a new xenon(VIII) oxide, namely, (η(2) -O2 )XeO3 , which, along with XeO4 , was characterized by matrix-isolation IR spectroscopy and quantum-chemical calculations. Calculations of the UV spectrum showed that the photodecomposition is induced by an n→σ* transition, but the nature of the excitation differs when different light sources are used. There is strong evidence for the formation of mobile (1) D excited O atoms in the case of excitation at 365 nm, which led to the formation of (η(2) -O2 )XeO3 by reaction with XeO4 . Matrix-isolation IR spectroscopy in Ne and Ar matrices afforded the natural-abundance xenon isotopic pattern for the ν3 (T2 ) stretching mode of Xe(16) O4 , and (18) O enrichment provided the (16) O/(18) O isotopic shifts of XeO4 and (η(2) -O2 )XeO3 .


Hyperbaric oxygen therapy for acute ischaemic stroke.
Most cases of stroke are caused by impairment of blood flow to the brain (ischaemia) which results in a reduction in oxygen available and subsequent cell death. It has been postulated that hyperbaric oxygen therapy (HBOT) may reduce the volume of brain that will die by greatly increasing the oxygen available, and it may further improve outcome by reducing brain swelling. Some centres are using HBOT routinely to treat stroke. To assess the effectiveness and safety of adjunctive HBOT in the treatment of acute ischaemic stroke. We searched the Cochrane Stroke Group Trials Register (last searched 9 January 2004), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 3, 2004), MEDLINE (1966 to July 2004), EMBASE (1980 to July 2004), CINAHL (1982 to July 2004), and DORCTHIM (Database of Randomised Controlled Trials in Hyperbaric Medicine) (from inception to 2004). We handsearched journals and conference proceedings, searched reference lists of articles, and contacted researchers in an effort to identify additional published and unpublished studies. We included all randomised controlled trials that compared the effect of adjunctive HBOT with no HBOT (no treatment or sham). Two authors used standardised forms to extract the data independently. Each trial was assessed for internal validity with differences resolved by discussion. Data were extracted and entered into RevMan 4.2. Three randomised controlled trials (106 participants) satisfied the inclusion criteria. The methodological quality of the trials varied but was generally high. Data could be pooled for a limited number of clinically important outcomes. There were no significant differences in mortality rate at six months in those receiving HBOT compared to the control group (relative risk 0.61, 95% confidence interval (CI) 0.17 to 2.2, P value 0.45). Two of 15 scale measures of disability and functional indicated an improvement following HBOT, both at one year follow up: the mean Trouillas Disability Scale was lower with HBOT (mean difference (MD) 2.2 points reduction with HBOT, 95% CI 0.15 to 4.3, P value 0.04) and the mean Orgogozo Scale was higher (MD 27.9 points, 95% CI 4.0 to 51.8, P value 0.02). These improvements were not reflected in other trials or functional scales. This systematic review has not found evidence to show that HBOT improves clinical outcomes when applied during the acute presentation of ischaemic stroke. While evidence from the three randomised controlled trials is insufficient to provide clear guidelines for practice, clinical benefit does not seem likely. Further research is required to better define the role of HBOT in this condition.


A ventilation strategy during general anaesthesia to reduce postoperative atelectasis.
Atelectasis is common during and after general anaesthesia. We hypothesized that a ventilation strategy, without recruitment manoeuvres, using a combination of continuous positive airway pressure (CPAP) or positive end-expiratory pressure (PEEP) and a reduced end-expiratory oxygen fraction (FETO2) before ending mask ventilation with CPAP after extubation would reduce the area of postoperative atelectasis. Thirty patients were randomized into three groups. During induction and emergence, inspiratory oxygen fractions (FIO2) were 1.0 in the control group and 1.0 or 0.8 in the intervention groups. No CPAP/PEEP was used in the control group, whereas CPAP/PEEP of 6 cmH2O was used in the intervention groups. After extubation, FIO2 was set to 0.30 in the intervention groups and CPAP was applied, aiming at FETO2 < 0.30. Atelectasis was studied by computed tomography 25 min postoperatively. The median area of atelectasis was 5.2 cm(2) (range 1.6-12.2 cm(2)) and 8.5 cm(2) (3-23.1 cm(2)) in the groups given FIO2 1.0 with or without CPAP/PEEP, respectively. After correction for body mass index the difference between medians (2.9 cm(2)) was statistically significant (confidence interval 0.2-7.6 cm(2), p = 0.04). In the group given FIO2 0.8, in which seven patients were ex- or current smokers, the median area of atelectasis was 8.2 cm(2) (1.8-14.7 cm(2)). Compared with conventional ventilation, after correction for obesity, this ventilation strategy reduced the area of postoperative atelectasis in one of the intervention groups but not in the other group, which included a higher proportion of smokers.


Reassortant H9N2 canine influenza viruses containing the pandemic H1N1/2009 ribonucleoprotein complex circulating in pigs acquired enhanced virulence in mice.
The reassortment between avian H9N2 and Eurasian avian-like (EA) H1N1 viruses may have potentially changed from avian-to-mammals adaptation. This study generated 20 reassortant viruses with the introduction of H1N1/2009 internal genes from EA H1N1 virus into H9N2 virus. 12 of these recovered the replication capability both in the lungs and turbinate samples. 10 of 12 obtained PA gene segments from the ribonucleoprotein (RNP) complexes of the EA H1N1 virus, and 3 exhibited extreme virulence. Specially, the combination of PB2, PA and NP genes could overcome the species-specific restriction in human cells. Analysis of the polymerase activities found that introduction of the PA gene resulted in increased polymerase activity. These findings indicated that RNP complexes from EA H1N1 virus could confer an adaptation advantage and high compatibility to avian H9N2 virus. This raises new concerns for public health due to the possible coexistence of H9N2 and EA H1N1 viruses in dogs.


Identification of surrogate measures of diesel exhaust exposure in a controlled chamber study.
Exposure to diesel exhaust (DE) has been associated with acute cardiopulmonary and vascular responses, chronic noncancer health effects, and respiratory cancers in humans. To better understand DE exposures and eventually their related health effects, we established a controlled chamber experiment wherein human volunteer subjects were exposed to approximately 100 microg/m3 DE. In general, human exposure assessment for DE is based on ambient air measurements of surrogates such as elemental carbon (EC) or total organic carbon (OC) collected on filters. As specific health effect mechanisms and dose-response are obscured bythe complex composition of DE, the linkage from exposure to internal dose can presumably be improved by use of specific biomarkers and metabolites in blood, breath, or urine. Because EC and OC are not suitable as biomarkers, in this study, we focus on identifying compounds that are demonstrated indicators of DE and can also be found in biological fluids. We measured an assortment of volatile, semivolatile, and particle-bound aromatic compounds in the chamber air and report their airborne concentrations in DE and purified air, as well as the estimated values of the corresponding exposure ratios (mean DE air concentration:mean purified air concentration). These estimated exposure ratios were used to identify naphthalene (Nap) and phenanthrene (Phe) as potentially useful surrogates for DE exposure that could also serve as biomarkers. Estimated mean levels of Nap and Phe associated with the nominal 100 microg/m3 DE were 2600 and 765 ng/m3 with estimated exposure ratios of 252 and 92.4, respectively. Nap levels were significantly correlated with OC and total particle-bound polycyclic aromatic hydrocarbons (PAHs); Phe levels were significantly correlated with total volatile + semivolatile PAHs. These results suggest that Nap and Phe may be particularly useful surrogates for DE concentrations. While Nap and Phe are not validated here as internal biomarkers of DE exposure, we are currently assessing human biological specimens collected during this study and will discuss those results in ensuing papers.


Cardioplegia: the protection of the myocardium during open heart surgery: a review.
Cold chemical cardioplegia is currently the method of choice for providing a still, relaxed and unobstructed operating field during open heart surgery. This procedure involves aortic cross clamping, with the resulting tissue ischemia being modified by coronary infusion of cold chemical solutions, together with the application of topical hypothermia. This paper defines some of the detrimental cellular changes which occur as a result of the induced ischemia, and considers the mechanisms by which cardioplegia can afford extensive protection. Three components of protection are defined and discussed: firstly, energy conservation through the rapid induction of diastolic arrest; secondly, slowing metabolic and degenerative processes through the use of hypothermia; thirdly, selective prevention or reversal of various unfavourable ischemic changes. On the basis of these three components, it is possible to derive a number of guide lines for the formulation and use of safe and effective cardioplegic solutions.


Cellular mechanisms involved in the stenosis and obliteration of the cerebral aqueduct of hyh mutant mice developing congenital hydrocephalus.
Two phases may be recognized in the development of congenital hydrocephalus in the hyh mutant mouse. During embryonic life the detachment of the ventral ependyma is followed by a moderate hydrocephalus. During the first postnatal week the cerebral aqueduct becomes obliterated and a severe hydrocephalus develops. The aim of the present investigation was to elucidate the cellular phenomena occurring at the site of aqueduct obliteration and the probable participation of the subcommissural organ in this process. Electron microscopy, immunocytochemistry, and lectin histochemistry were used to investigate the aqueduct of normal and hydrocephalic hyh mice from embryonic day 14 (E-14) to postnatal day 7 (PN-7). In the normal hyh mouse, the aqueduct is an irregularly shaped cavity with 3 distinct regions (rostral, middle, and caudal) lined by various types of ependyma. In the hydrocephalic mouse, these 3 regions behave differently; the rostral end becomes stenosed, the middle third dilates, and the caudal end obliterates. The findings indicate that the following sequence of events lead to hydrocephalus: 1) denudation of the ventral ependyma (embryonic life); 2) denudation of dorsal ependyma and failure of the subcommissural organ to form Reissner fiber (first postnatal week); 3) obliteration of distal end of aqueduct; and 4) severe hydrocephalus. No evidence was obtained that NCAM is involved in the detachment of ependymal cells. The process of ependymal denudation would involve alterations of the surface sialoglycoproteins of the ependymal cells and the interaction of the latter with macrophages.


Biopsy follow-up in patients with isolated atypical small acinar proliferation (ASAP) in prostate biopsy.
The incidence of prostate cancer (PCA) was evaluated in 155 patients with isolated Atypical Small Acinar Proliferation (ASAP) found on initial prostate biopsy, after a medium-term follow-up (40 months) with at least one re-biopsy. Clinical and histological data were analysed. Cancer was detected in 81 of 155 (52.3%). The cancer detection rate was 71.6%, 91.3%, 97.5%, 100% at the 1st re-biopsy, 2nd, 3rd, and 4th rebiopsy respectively. At the uni- and multivariate analyses, prostate volume (≤ 30 cc), transition zone volume (≤ 10 cc), small core length at the initial biopsy (≤ 10 mm) and few number of cores at initial biopsy (≤ 8) are predictive of cancer. Furthermore, tumour characteristics on the whole surgical specimens was assessed in 30 men: 13 of 30 (43 %) had clinically relevant cancer (volume > 0.5 ml or/and Gleason score ≥ 7, or pT3). Most of relevant cancers were detected in the distal apex, anterior gland and midline. These anatomical sites could be under-sampled at the initial biopsy using the transrectal approach. Our data suggest that follow-up biopsy is recommended in all cases of isolated ASAP detected after biopsy using endfire transrectal probe. The re-biopsy strategy should increase the number of cores (or a saturation biopsy), focusing on area of ASAP in the initial biopsy, but also including the under-sampled areas (anterior gland, distal apex and midline) to detect clinically relevant cancers.


Cancer mortality following in utero exposure among offspring of female Mayak Worker Cohort members.
Little is known about long-term cancer risks following in utero radiation exposure. We evaluated the association between in utero radiation exposure and risk of solid cancer and leukemia mortality among 8,000 offspring, born from 1948-1988, of female workers at the Mayak Nuclear Facility in Ozyorsk, Russia. Mother's cumulative gamma radiation uterine dose during pregnancy served as a surrogate for fetal dose. We used Poisson regression methods to estimate relative risks (RRs) and 95% confidence intervals (CIs) of solid cancer and leukemia mortality associated with in utero radiation exposure and to quantify excess relative risks (ERRs) as a function of dose. Using currently available dosimetry information, 3,226 (40%) offspring were exposed in utero (mean dose = 54.5 mGy). Based on 75 deaths from solid cancers (28 exposed) and 12 (6 exposed) deaths from leukemia, in utero exposure status was not significantly associated with solid cancer: RR = 0.94, 95% CI 0.58 to 1.49; ERR/Gy = -0.1 (95% CI < -0.1 to 4.1), or leukemia mortality; RR = 1.65, 95% CI 0.52 to 5.27; ERR/Gy = -0.8 (95% CI < -0.8 to 46.9). These initial results provide no evidence that low-dose gamma in utero radiation exposure increases solid cancer or leukemia mortality risk, but the data are not inconsistent with such an increase. As the offspring cohort is relatively young, subsequent analyses based on larger case numbers are expected to provide more precise estimates of adult cancer mortality risk following in utero exposure to ionizing radiation.


Elevated plasma homocysteine level in patients with Parkinson disease: motor, affective, and cognitive associations.
An elevated plasma homocysteine (Hcy) level has been prospectively associated with an increased risk of vascular and degenerative dementias. An Hcy elevation is prevalent in patients with Parkinson disease (PD) in part because levodopa metabolism produces Hcy. The clinical relevance of an elevated Hcy level in patients with PD is unknown. To determine if hyperhomocysteinemia in patients with PD is associated with depression or with cognitive or physical impairments. Ninety-seven people with a mean (SD) PD duration of 3.6 (1.6) years completed the Beck Depression Inventory, a battery of 11 cognitive tests, and the motor and function components of the Unified Parkinson's Disease Rating Scale. Normalized scores for the affective, cognitive, and physical measures were compared between those with a normal Hcy level (n = 66) and those with hyperhomocysteinemia (n = 31) (Hcy level, >1.89 mg/L [>14 micro mol/L]), controlling for age, sex, disease duration, and treatment. Subjects with an elevated Hcy level were slightly older (68 vs 62 years), but had similar plasma concentrations of vitamin B(12) and folate. Hyperhomocysteinemic patients were more depressed (P =.02) and had worse cognition (P<.01), but the physical measure did not differ. Patients with PD and hyperhomocysteinemia are more likely to be depressed and to perform worse on neuropsychometric tasks compared with normohomocysteinemic patients. Further research is warranted to see if hyperhomocysteinemia is a reversible risk factor for neuropsychiatric burden in patients with PD.


Intestinal anion exchange in marine teleosts is involved in osmoregulation and contributes to the oceanic inorganic carbon cycle.
Marine teleost fish osmoregulation involves seawater ingestion and intestinal fluid absorption. Solute coupled fluid absorption by the marine teleost fish intestine has long been believed to be the product of Na(+) and Cl(-) absorption via the Na(+) :K(+) :2Cl(-) co-transporter (NKCC2). However, the past decade has revealed that intestinal anion exchange contributes significantly to Cl(-) absorption, in exchange for HCO(3) (-) secretion, and that this process is important for intestinal water absorption. In addition to contributing to solute coupled water absorption intestinal anion exchange results in luminal precipitation of CaCO(3) which acts to reduce luminal osmotic pressure and thus assist water absorption. Most recently, activity of apical H(+) -pumps, especially in distal segments of the intestine have been suggested to not only promote anion exchange, but also to reduce luminal osmotic pressure by preventing excess HCO(3)(-) concentrations from accumulating in intestinal fluids, thereby aiding water absorption. The present review summarizes and synthesizes the most recent advances in our view of marine teleosts osmoregulation, including our emerging understanding of epithelial transport of acid-base equivalents in the intestine, the consequences for whole organism acid-base balance and finally the impact of piscine CaCO(3) formation on the global oceanic carbon cycle.


Assessment of the correlation between TIMP4 SNPs and schizophrenia and autism spectrum disorders.
Tissue inhibitors of metalloproteinases (TIMPs) are involved in synaptic plasticity, neuronal cell differentiation and neuroprotection in the central nervous system. To investigate whether TIMP4 polymorphisms are associated with schizophrenia and autism spectrum disorders (ASDs), 480 patients (schizophrenia, n=287; ASDs, n=193) and 296 controls were enrolled. Clinical symptoms of schizophrenia and ASDs were assessed using the operation criteria checklist for psychotic illness (OPCRIT) and Childhood Autism Rating Scale (CARS), respectively. One promoter single nucleotide polymorphism (SNP; rs3755724, -55C/T) and one exonic SNP (rs17035945, 3'-untranslated region) were selected. SNPStats and SNPAnalyzer Pro programs were used to calculate odds ratios. Multiple logistic regression models were performed to analyze the genetic data. Based on the results, these two SNPs were not associated with schizophrenia and ASD. In the analysis of clinical features of schizophrenia, rs3755724 was nominally associated with schizophrenia with poor concentration (P=0.044 in the codominant2 model, P=0.041 in the log-additive model and P=0.043 in allele frequency). These results suggest that TIMP4 is not associated with the development of schizophrenia and ASD in the population studied.


[The prognostication of development of peri-apical abscess under chronic periodontitis by blood parameters and cell immunity in children].
The chronic periodontitis in children is frequently complicated by development of periapical abscess under inadequate conservative therapy. However, prognostic models of estimation of probability of its development are lacking. The purpose of study is to develop regression models of prognostication of periapical abscess under chronic periodontitis in children according indices of peripheral blood and systemic cellular immunity. The chronic periodontitis complicated with periapical abscess is analyzed in 120 children aged from 8 to 15 years. The prognostication of periapical abscess was implemented by stepwise regression technique using parameters of blood and systemic cellular immunity. The mathematical models are developed for prognostication of periapical abscess in children with chronic periodontitis on the basis of indices of peripheral blood and systemic cellular immunity permitting to prognosticate development of the given complication with needed quality. The prognostication periapical abscess requires using the given models, absolute number of lymphocytes, percentage of stab bond neutrophils, ESR, absolute number of T-lymphocytes in blood, T-helpers, T-suppressors and relative content of T-suppressors.


Neural regulation of muscle acetylcholine receptor epsilon- and alpha-subunit gene promoters in transgenic mice.
The effects of denervation were investigated in mice with transgenes containing promoter elements from the muscle acetylcholine receptor epsilon- and alpha-subunit genes. The promoter sequences were coupled to a nuclear localization signal-beta-galactosidase fusion gene (nlacZ) as a reporter. While many postsynaptic specializations form in the embryo, expression of the epsilon subunit is induced during the first two postnatal weeks. When muscles were denervated at birth, before the onset of epsilon expression, epsilon nlacZ still appeared at the former synaptic sites on schedule. This result suggests that the nerve leaves a localized "trace" in the muscle that can continue to regulate transcription. An additional finding was that epsilon nlacZ expression was much stronger in denervated than in intact muscles. This suggests that the epsilon promoter is similar to the other subunits in containing elements that are activated on cessation of neural activity. However, even after denervation, epsilon nlacZ expression was always confined to the synaptic region whereas alpha nlacZ expression increased in nuclei along the entire length of the fiber. This suggests that while the epsilon gene is similar in its activity dependence to other subunit genes, it is unique in that local nerve-derived signals are essential for its expression. Consequently, inactivity enhances epsilon expression only in synaptic nuclei where such signals are present, but enhances expression throughout the muscle fiber. Truncations and an internal deletion of the epsilon promoter indicate that cis-elements essential for the response to synaptic signals are contained within 280 bp of the transcription start site. In contrast to these results in young animals, denervation in older animals leads to an unexpected reduction in nlacZ activity. However, mRNA measurements indicated that transgene expression was increased in these animals. This discordance between nlacZ mRNA and enzyme activity, demonstrates a previously unknown limitation of nlacZ as a reporter gene in transgenic animals.


[Pharmacokinetics of antimalarials: quinine and mefloquine, halofantrine, qinghaosu, amino-4-quinolines].
The development of new sensitive and specific assays (HPLC) have enabled the pharmacokinetics of antimalarial drugs to be studied. Parameters such as half-life distribution volume, clearance and bioavailability, are defined. In healthy subjects, quinine is rapidly eliminated (t1/2 beta: 6-12 h). Hepatic biotransformation accounts for approximately 80% of its total clearance. In malaria, the pharmacokinetic properties of quinine (decrease in the apparent volume of distribution, prolongation of the t1/2 beta, reduction in systemic clearance), are altered in proportion to the severity of infection. Red cell concentrations and plasma binding are increased. Parenteral quinine should be given by slow intravenous infusion and a loading dose is recommended in severe infections. Chloroquine (t1/2 beta: 6-50 days) and mefloquine (t1/2 beta: 6-33 days) have extensive tissue distribution and prolonged activity after a single dose. Both drugs are concentrated in erythrocytes and are bound considerably to plasma proteins. Amodiaquine is not found in the blood after oral administration. Hepatic biotransformation accounts for almost all orally administered drug. Its antiplasmodial activity is thus almost entirely due to monodesethylamodiaquine, the main metabolite. In healthy subjects, the t1/2 beta of this metabolite is 9 to 18 days in plasma. Amodiaquine is concentrated in erythrocytes. The protein binding of this drug has not been studied to date. For prophylaxis, it has been suggested that the dosage of 10 mg/kg/wk should be spread over the week (3.5 mg/kg every other day, or 1.5 every day). Halofantrine has an elimination half-life of between 1.3 and 6.6 days. This drug has been suggested as a single-dose treatment. No pharmacokinetic studies of qinghaosu have been reported in humans. In rabbits, the elimination half-life in plasma was found to be 40 min. Although rapidly eliminated, this drug appears to be highly effective. More information is required on the pharmacokinetics of these drugs in malaria, during pregnancy, in children and in renal and hepatic failure.


Global exponential stability of neural networks with globally Lipschitz continuous activations and its application to linear variational inequality problem.
This paper investigates the existence, uniqueness, and global exponential stability (GES) of the equilibrium point for a large class of neural networks with globally Lipschitz continuous activations including the widely used sigmoidal activations and the piecewise linear activations. The provided sufficient condition for GES is mild and some conditions easily examined in practice are also presented. The GES of neural networks in the case of locally Lipschitz continuous activations is also obtained under an appropriate condition. The analysis results given in the paper extend substantially the existing relevant stability results in the literature, and therefore expand significantly the application range of neural networks in solving optimization problems. As a demonstration, we apply the obtained analysis results to the design of a recurrent neural network (RNN) for solving the linear variational inequality problem (VIP) defined on any nonempty and closed box set, which includes the box constrained quadratic programming and the linear complementarity problem as the special cases. It can be inferred that the linear VIP has a unique solution for the class of Lyapunov diagonally stable matrices, and that the synthesized RNN is globally exponentially convergent to the unique solution. Some illustrative simulation examples are also given.


Combination therapy of amlodipine and atorvastatin has more beneficial vascular effects than monotherapy in salt-sensitive hypertension.
Current treatment for the secondary prevention of cardiovascular diseases frequently involves the prescription of several combination therapies, particularly antihypertensive medications and HMG-CoA reductase inhibitor. We have previously shown that in salt-sensitive hypertension either a statin or the calcium channel blocker amlodipine (Aml) have vasoprotective effects. Here, we investigated in aortas from Dahl salt-sensitive (DS) rats the effects of Aml, the statin atorvastatin (AT), and their combination on endothelial function, superoxide (O2 (-)) production, and the expression of endothelial nitric oxide synthase (eNOS), chemokine monocyte chemoattractant protein-1 (MCP-1), and lectin-like oxidized LDL receptor-1 (LOX-1). Groups of DS rats were fed either normal-salt (NS, 0.5% NaCl) or high-salt (HS, 4% NaCl) diet or a HS diet with AT (15mg/kg/day), Aml (5mg/kg/day) or combination of AT/Aml for 6 weeks. Rats on the HS diet developed hypertension, aortic hypertrophy, accompanied by increased plasma C-reactive protein (CRP), aortic O2 (-), MCP-1 (80%), and LOX-1 (55%) expression and reduced eNOS and endothelial-dependent relaxation to acetylcholine (EDR). Aml reduced systolic blood pressure (SBP), aortic hypertrophy, plasma CRP, vascular O2 (-), and MCP-1 expression and improved eNOS and EDR. AT reduced aortic hypertrophy and plasma CRP, improved EDR, and normalized vascular O2 (-), eNOS, and proinflammatory gene expression with mild reduction in SBP. Combination therapy further reduced the SBP and normalized aortic hypertrophy, EDR, and plasma CRP. The combination therapy of Aml/AT has an additive beneficial effect on the vasculature. These novel findings may provide scientific basis for the combination therapy of statins with antihypertensive agents to reduce and prevent cardiovascular diseases.


Mouse adult hematopoietic stem cells actively synthesize ribosomal RNA.
The contribution of basal cellular processes to the regulation of tissue homeostasis has just started to be appreciated. However, our knowledge of the modulation of ribosome biogenesis activity in situ within specific lineages remains very limited. This is largely due to the lack of assays that enable quantitation of ribosome biogenesis in small numbers of cells in vivo. We used a technique, named Flow-FISH, combining cell surface antibody staining and flow cytometry with intracellular ribosomal RNA (rRNA) FISH, to measure the levels of pre-rRNAs of hematopoietic cells in vivo. Here, we show that Flow-FISH reports and quantifies ribosome biogenesis activity in hematopoietic cell populations, thereby providing original data on this fundamental process notably in rare populations such as hematopoietic stem and progenitor cells. We unravel variations in pre-rRNA levels between different hematopoietic progenitor compartments and during erythroid differentiation. In particular, our data indicate that, contrary to what may be anticipated from their quiescent state, hematopoietic stem cells have significant ribosome biogenesis activity. Moreover, variations in pre-rRNA levels do not correlate with proliferation rates, suggesting that cell type-specific mechanisms might regulate ribosome biogenesis in hematopoietic stem cells and progenitors. Our study contributes to a better understanding of the cellular physiology of the hematopoietic system in vivo in unperturbed situations.


Unrelated cord blood transplantation for thalassaemia: a single-institution experience of 35 patients.
Our study was designed to prospectively determine whether or not unrelated cord blood transplantation (CBT) can produce outcomes comparable to related donor transplantation for children with β-thalassaemia. In 35 patients, 40 transplants were performed between October 2003 and September 2009. HLA matching at enrolment was 6/6 (n=8), 5/6 (n=16), 4/6 (n=27), or 3/6 (n=1) by low-resolution HLA-A, -B, and high-resolution DRB1. These patients received non-manipulated grafts without ex vivo expansion or T-cell depletion. The median number of nucleated and CD34+ cells infused was 7.8 × 10(7)/kg (range, 2.8-14.7 × 10(7)/kg) and 4.0 × 10(5)/kg (range, 1.7-19.9 × 10(5)/kg), respectively. The 5-year OS and thalassaemia-free survival after the first transplant were 88.3 and 73.9%, respectively. The cumulative incidence of TRM at 2 years was 11.7%. Fourteen patients developed chronic skin GVHD. Thirty patients were alive and transfusion-independent with a Lansky performance score ≥80% achieved between 6 and 76 months post transplant (median, 36 months). These data compare acceptably with the survival rates of related-donor BMT for thalassaemia and suggest that patients without an available HLA-compatible sibling but who have well-matched unrelated donors should also be considered for CBT.


Somatosensory input in the context of transcranial magnetic stimulation coupled with electroencephalography: An evidence-based overview.
The transcranial evoked potential (TEP) is a powerful technique to investigate brain dynamics, but some methodological issues limit its interpretation. A possible contamination of the TEP by electroencephalographic (EEG) responses evoked by the somatosensory input generated by transcranial magnetic stimulation (TMS) has been postulated; nonetheless, a characterization of these responses is lacking. The aim of this work was to review current evidence about possible somatosensory evoked potentials (SEP) induced by sources of somatosensory input in the craniofacial region. Among these, only contraction of craniofacial muscle and stimulation of free cutaneous nerve endings may be able to induce EEG responses, but direct evidence is lacking due to experimental difficulties in isolating these inputs. Notably, EEG evoked activity in this context is represented by a N100/P200 complex, reflecting a saliency-related multimodal response, rather than specific activation of the primary somatosensory cortex. Strategies to minimize or remove these responses by EEG processing still yield uncertain results; therefore, data inspection is of paramount importance to judge a possible contamination of the TEP by multimodal potentials caused by somatosensory input.


Microleakage of dentin/amalgam alloy bonding agents: results after 1 year.
The purpose of this study was to evaluate the 1-year results of the dentin bond (DBS)/viscous resin liner combinations Amalgambond Plus, Tenure/Panavia, Syntac/Dual Cem, and All-Bond 2/Liner F in reducing microleakage in class 5 cavity preparations restored with an admixed or a spherical amalgam alloy and to compare these results to the previously reported short-term (4-day) data from this same study. Class 5 cavity preparations with occlusal margins in enamel and gingival margins in cementum were prepared on extracted human molar teeth. Prepared teeth were distributed randomly into 12 treatment groups (n = 10) consisting of the various DBS/ liners, Copalite, and no liner for each alloy. Samples were stored in saline for 12 months, thermocycled, and stained with dye. Restorations were sectioned and microleakage scored. The DBS/liner combinations, with the exception of Syntac/Dual Cem, had significantly less microleakage with both alloys than Copalite or no liner. Comparing short-term to long-term results within the DBS/liners, only Tenure/ Panavia with Tytin had a significant increase in microleakage scores. These data indicate DBS/ liner combinations can provide significant protection against microleakage under high-copper amalgam alloys for up to 1 year.


Comparative accuracy of several published formulae for the estimation of serum osmolality in cats.
To determine the osmole gap utilizing 18 previously published formulae for the estimation of serum osmolality in cats. Serum samples were frozen at -80°C after routine biochemical analysis. An Advanced Micro Osmometer 3300 was used to measure serum osmolality. Eighteen previously reported formulae were used to calculate osmolality from biochemical analysis results. The calculated osmolality was subtracted from the measured osmolality to determine the osmole gap. Osmole gaps for azotaemic and hyperglycaemic cats were compared to those from cats without azotaemia or hyperglycaemia using each formula. The osmole gaps varied dependent on the formula used and the presence or absence of hyperglycaemia or azotaemia. Eleven formulae led to calculated osmolality and osmole gaps that were not statistically different when hyperglycaemia, azotaemia or both were present. Four of these 11 formulae resulted in osmole gaps near zero. For each formula used, the osmole gap increased with increasing osmolality. Multiple formulae to calculate serum osmolality can be used, but they result in significantly different osmole gaps. Clinicians should be aware of the specific reference interval for the formula being used. The formula [2(Na(+) ) + glucose + BUN] is recommended as it is easy to use and reliable even in the presence of hyperglycaemia and/or azotaemia.


A Natural Fungal Gene Drive Enacts Killing via DNA Disruption.
Fungal spore killers are a class of selfish genetic elements that positively bias their own inheritance by killing non-inheriting gametes following meiosis. As killing takes place specifically within the developing fungal ascus, a tissue which is experimentally difficult to isolate, our understanding of the mechanisms underlying spore killers are limited. In particular, how these loci kill other spores within the fungal ascus is largely unknown. Here, we overcome these experimental barriers by developing model systems in 2 evolutionary distant organisms, Escherichia coli (bacterium) and Saccharomyces cerevisiae (yeast), similar to previous approaches taken to examine the wtf spore killers. Using these systems, we show that the Podospora anserina spore killer protein SPOK1 enacts killing through targeting DNA. IMPORTANCE Natural gene drives have shaped the genomes of many eukaryotes and recently have been considered for applications to control undesirable species. In fungi, these loci are called spore killers. Despite their importance in evolutionary processes and possible applications, our understanding of how they enact killing is limited. We show that the spore killer protein Spok1, which has homologues throughout the fungal tree of life, acts via DNA disruption. Spok1 is only the second spore killer locus in which the cellular target of killing has been identified and is the first known to target DNA. We also show that the DNA disrupting activity of Spok1 is functional in both bacteria and yeast suggesting a highly conserved mode of action.


Fundamental differences in the neural invasion behavior of pancreatic endocrine tumors: relevance for local recurrence rates?
Neural invasion represents an important prognostic factor in pancreatic cancer, and it is thought to be one of the main causes for the high rate of postoperative local recurrences in pancreatic ductal adenocarcinomas. In contrast to the latter, systematic investigations of the mode and extent of neural invasion in pancreatic endocrine tumors have not yet been carried out, although this process represents an important feature in the classification of these tumors. In the present study, a total of 48 pancreatic endocrine tumors were analyzed including 10 well-differentiated endocrine tumors of uncertain behavior, 33 well-differentiated endocrine carcinomas, and 5 poorly differentiated endocrine carcinomas. Neural invasion was found in a large subset (73%) of pancreatic endocrine tumors. The frequency of neural invasion correlated with the grade of malignancy but occurred irrespective of functional activity, hormone phenotype, or histomorphology. Analogous to pancreatic ductal adenocarcinoma, the expression of epidermal growth factor receptor and nerve growth factor, which were expressed in 50% and 100% of the tumors, respectively, seemed to be associated with the frequency of neural invasion. However, in contrast to pancreatic ductal adenocarcinoma, neural invasion in pancreatic endocrine tumors was only detected within the tumor boundaries and did not reach beyond the tumor invasion front. This phenomenon may explain the low rate of local relapses after tumor resection in pancreatic endocrine tumors despite the high frequency of neural invasion.


Metabolic clearance rate of ketone bodies in dogs following Escherichia coli endotoxin administration.
The metabolic clearance rates of ketone bodies were determined in anesthetized dogs following the intravenous administration of either Escherichia coli endotoxin or saline, in order to examine the influence of endotoxin on the efficiency of peripheral ketone body removal. A nonisotopic method was employed for these studies consisting of a stepwise infusion of beta-hydroxybutyrate at three different rates. At each infusion rate, a steady-state arterial concentration was reached, at which time the rate of appearance of ketone bodies equaled their removal rates. Rates of infusion were plotted against the steady-state arterial concentrations, and the reciprocal of the slope of this linear relationship represented the metabolic clearance rate. Administration of endotoxin did not alter the metabolic clearance rate of ketone bodies. The uptake of ketone bodies by the thigh muscles was also unaffected by endotoxin administration. It is concluded, that E. coli endotoxin does not influence the efficiency of peripheral ketone body removal.