Adult T-cell leukemia/lymphoma development in HTLV-1-infected humanized SCID mice.
The molecular and genetic factors induced by human T-lymphotropic virus type-1 (HTLV-1) that initiate adult T-cell leukemia/lymphoma (ATLL) remain unclear, in part from the lack of an animal model that accurately recapitulates leukemogenesis. HTLV-1-infected humanized nonobese diabetic severe combined immunodeficiency (HU-NOD/SCID) mice were generated by inoculation of NOD/SCID mice with CD34(+) hematopoietic progenitor and stem cells (CD34(+) HP/HSCs) infected ex vivo with HTLV-1. HTLV-1-HU-NOD/SCID mice exclusively developed CD4(+) T-cell lymphomas with characteristics similar to ATLL and elevated proliferation of infected human stem cells (CD34(+)CD38(-)) in the bone marrow were observed in mice developing malignancies. Purified CD34(+) HP/HSCs from HTLV-1-infected patient peripheral blood mononuclear cells revealed proviral integrations suggesting viral infection of human bone marrow-derived stem cells. NOD/SCID mice reconstituted with CD34(+) HP/HSCs transduced with a lentivirus vector expressing the HTLV-1 oncoprotein (Tax1) also developed CD4(+) lymphomas. The recapitulation of a CD4(+) T-cell lymphoma in HU-NOD/SCID mice suggests that HSCs provide a viral reservoir in vivo and act as cellular targets for cell transformation in humans. This animal model of ATLL will provide an important tool for the identification of molecular and cellular events that control the initiation and progression of the lymphoma and potential therapeutic targets to block tumor development.


Hb S-β-thalassemia: molecular, hematological and clinical comparisons.
Clinical and hematological features are presented for 261 patients with identified β-thalassemia (β-thal) mutations. Mutations causing Hb S [β6(A3)Glu→Val]-β(0)-thal were IVS-II-849 (A>G) in 44%, frameshift codon (FSC) 6 (-A) in 14%, Hb Monroe [β30(B12)Arg→Thr] in 14%, and IVS-II-1 (G>A) in 10%. Mutations causing Hb S-β(+)-thal with 14-25% Hb A (type III) were -29 (A>G) mutation in 60%, -88 (C>T) in 22% and the polyadenylation signal site (polyA) (T>C) mutation in 14%, and in Hb S-β(+)-thal with 1-7% Hb A (type I), all had the IVS-I-5 (G>C) mutation. Hematologically, only minor differences occurred between the four Hb S-β(0)-thal mutations, but among the three mutations causing Hb S-β(+)-thal type III, levels of Hb A(2), Hb F, hemoglobin (Hb), MCV and MCH were highest in the -88 and lowest in the polyA mutations. Clinically, Hb S-β(0)-thal and Hb S-β(+)-thal type I were generally severe, and Hb S-β(+)-thal type III disease with the -88 mutation was milder than that caused by the polyA mutation.


How grooves reflect and confine surfaceplasmon polaritons.
The reflection of surface plasmon polaritons by deep linear grooves structured into gold surfaces is investigated with numerical finite-difference-in-time-domain as well as boundary-element-method calculations. Groove widths of 25 and 100 nm are studied, with depths as large as 500 nm. The reflection depends strongly on wavelength, groove depth, and width. By systematically varying these parameters and studying the field profiles in the grooves as well as mode dispersion, we relate the resonances of the reflectivity to resonant coupling of propagating planar plasmon modes to cavity modes inside the grooves. By careful design of the groove width and depth the reflectivity can be tuned to values up to at least 30% for either a narrow or wide band of wavelengths.


Results of a genomewide linkage scan: support for chromosomes 9 and 11 loci increasing risk for cigarette smoking.
Cigarette smoking is highly destructive to individuals and society, and is moderately heritable. We completed a genomewide linkage scan to map loci increasing risk for cigarette smoking in a set of families originally identified because they segregate panic disorder (PD). One hundred forty two genotyped individuals in a total of 12 families were studied (214 subjects analyzed, including non-genotyped individuals). Of these individuals, 69 were "affected" with habitual cigarette smoking (i.e., they smoked more than one pack per day for at least a year, or at least 1/2 pack per day for at least 10 years), 49 were "unaffected" (i.e., they smoked less than 1/2 pack per day for less than 1 year), and 24 were scored as "unknown." Nine families from the panic series were excluded from these analyses because they lacked multiple affected individuals with habitual cigarette smoking. In an initial genomewide scan, we genotyped a total of 416 markers (398 autosomal, 18 X-chromosome) with an average spacing of less than 10 cM, spanning the genome. Linkage analysis (pairwise, or single-point, and multi-point) was performed using ALLEGRO. An additional 14 markers were genotyped in a high-density panel to follow-up on an identified region of interest on chromosome 11p. The three highest multi-point Zlr scores (3.43, 3.04, and 3.01; P = 0.0003, P = 0.0012, and P = 0.0013, respectively), which each reflect "suggestive" evidence for linkage, were observed in multi-point linkage analyses using Allegro on chromosomes 11p and 9, near markers D11S4046, D9S283, and D9S1677, respectively. D11S4046 is in a region where linkage to alcohol dependence and linkage disequilibrium to substance dependence have previously been identified. The chromosome 9 region we identified as possibly linked to cigarette smoking in anxiety families, was previously identified as significantly linked to PD in Icelandic pedigrees. We also identified evidence supporting linkage (Zlr score > 2.3, P < 0.01) to regions of chromosomes 14, 16, and X. There was a significant phenotypic association between PD and cigarette smoking (P < 0.001). We identified evidence for two loci increasing risk for cigarette smoking that map to chromosomes 9 and 11. There is now evidence supporting linkage or association of chromosome 11 markers with alcohol dependence, illegal drug abuse and dependence, and cigarette smoking. Interestingly, one of our most promising linkage regions, includes a region previously identified as linked to PD.


Relapse recovery: The forgotten variable in multiple sclerosis clinical trials.
To determine whether basing the decision to initiate immediate vs delayed disease-modifying therapy (DMT) on extent of recovery after initial relapse affects long-term disability accumulation in a multiple sclerosis (MS) evidence-based setting. We analyzed the double-blind, placebo-controlled interferon beta-1a 30 mc once a week in clinically isolated syndrome and 10-year-follow-up extension trial. Good recovery after presenting relapse was defined as (1) full early recovery within 28 days of symptom onset (Expanded Disability Status Scale [EDSS] score of 0 at enrollment maintained ≥6 months) and (2) delayed good recovery (EDSS score > 0 at enrollment and improvement from peak deficit to 6th-month or 1-year visit ≥ median). Time from recovery assignment to future disability (EDSS score ≥ 2.5 or ≥4.0) was studied on a relapse-recovery-stratified age axis and immediate vs 3-year delayed treatment initiation with Kaplan-Meier statistics and hazard ratios (HRs). One hundred seventy-five/328 patients had good recovery (94 immediate and 81 delayed treatment); 153 did not have good recovery (77 immediate and 76 delayed treatment). HRs for EDSS score ≥2.5 outcome were: delayed treatment without good recovery as reference (HR = 1.0), delayed treatment with good recovery (HR6th-month: 0.67, p = 0.207; HR1st-year: 0.40, p = 0.027), immediate treatment without good recovery (HR6th-month: 0.56, p = 0.061; HR1st-year: 0.40, p = 0.011), and immediate treatment with good recovery (HR6th-month: 0.43, p = 0.014; HR1st-year: 0.48, p = 0.034). Placebo patients were switched to long-term treatment after 3 years, and insufficient EDSS score ≥4.0 outcome events were available to study. In patients with MS presenting without good recovery after the initial relapse, immediate DMT initiation favorably influences the likelihood of more ambulatory-benign disease akin to patients with good recovery after the initial relapse. This study provides Class III evidence that for patients with MS without good recovery after the initial relapse, immediate DMT initiation increases the likelihood of a benign disease course.


Radiomic Signatures Associated with CD8+ Tumour-Infiltrating Lymphocytes: A Systematic Review and Quality Assessment Study.
The tumour immune microenvironment influences the efficacy of immune checkpoint inhibitors. Within this microenvironment are CD8-expressing tumour-infiltrating lymphocytes (CD8+ TILs), which are an important mediator and marker of anti-tumour response. In practice, the assessment of CD8+ TILs via tissue sampling involves logistical challenges. Radiomics, the high-throughput extraction of features from medical images, may offer a novel and non-invasive alternative. We performed a systematic review of the available literature reporting radiomic signatures associated with CD8+ TILs. We also aimed to evaluate the methodological quality of the identified studies using the Radiomics Quality Score (RQS) tool, and the risk of bias and applicability with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Articles were searched from inception until 31 December 2021, in three electronic databases, and screened against eligibility criteria. Twenty-seven articles were included. A wide variety of cancers have been studied. The reported radiomic signatures were heterogeneous, with very limited reproducibility between studies of the same cancer group. The overall quality of studies was found to be less than desirable (mean RQS = 33.3%), indicating a need for technical maturation. Some potential avenues for further investigation are also discussed.


Physical and functional interactions between Escherichia coli MutY and endonuclease VIII.
Both GO (7,8-dihydro-8-oxoguanine) and hoU (5-hydroxyuracil) are highly mutagenic because DNA polymerase frequently misincorporates adenine opposite these damaged bases. In Escherichia coli, MutY DNA glycosylase can remove misincorporated adenine opposite G or GO on the template strand during DNA replication. MutY remains bound to the product that contains an AP (apurinic/apyrimidinic) site. Endo VIII (endonuclease VIII) can remove oxidized pyrimidine and weakly remove GO by its DNA glycosylase and beta/delta-elimination activities. In the present paper, we demonstrate that Endo VIII can promote MutY dissociation from AP/G, but not from AP/GO, and can promote beta/delta-elimination on the products of MutY. MutY interacts physically with Endo VIII through its C-terminal domain. MutY has a moderate affinity for DNA containing a hoU/A mismatch, which is a substrate of Endo VIII. MutY competes with Endo VIII and inhibits Endo VIII activity on DNA that contains a hoU/A mismatch. Moreover, MutY has a weak adenine glycosylase activity on hoU/A mismatches. These results suggest that MutY may have some role in reducing the mutagenic effects of hoU.


Density-dependent decay in HIV-1 dynamics.
The decay of HIV-1-infected cell populations after treatment with antiretroviral therapy has been measured using simple exponential decay models. These models are unlikely to be realistic over periods longer than a few months, however, because the population dynamics of HIV are complex. We considered an alternate model developed by Perelson and colleagues that extends the standard model for biphasic viral load decline and allows for nonlinear log decay of infected cell populations. Using data from 6 children on highly active antiretroviral therapy (HAART) and a single parameter in the new model, the assumption of log linear decay of infected cell populations is tested. Our analysis indicates that the short-lived and long-lived infected cell populations do not decay according to a simple exponential model. Furthermore, the resulting estimates of time to eradication of infected cell compartments are dramatically longer than those previously reported (eg, decades vs. years for long-lived infected cell populations and years vs. weeks for short-lived infected cell populations). Furthermore, estimates of the second-phase decay rates are significantly different than 0 for most children when obtained using the Perelson biphasic decay model. In contrast, this rate is not significantly different than 0 when the density-dependent decay model is used for parameter estimation and inference. Thus, the density-dependent decay model but not the simple exponential decay model is consistent with recent data showing that even under consistent HAART-mediated suppression of viral replication, decay rates of infected cell reservoirs decay little over several years. This suggests that conclusions about long-term viral dynamics of HIV infection based on simple exponential decay models should be carefully re-evaluated.


Sharing of a conserved haplotype suggests a susceptibility gene for multiple sclerosis at chromosome 17p11.
Multiple sclerosis (MS) is a chronic inflammatory disease resulting in demyelination in the central nervous system (CNS). Increasing evidence supports that genetic factors confer susceptibility to MS. One locus, the HLA complex (6p21), has been identified as important in MS, but no other loci have been clearly implicated, neither by a candidate gene approach, nor by a genomic screen strategy. Here, we studied a genetically isolated population in the northern-most part of Sweden, which demonstrates a high incidence of MS, using haplotype sharing analysis. Genealogical analysis demonstrated that 22 MS patients originate from a single common ancestral couple in the eighteenth century. Five affected individuals from four nuclear families were selected for an initial genomic screen with 390 microsatellite markers. Seven shared haplotypes in six different chromosomal regions were observed. After genotyping for these haplotypes with the same and additional markers in 15 MS patients and healthy relatives, some portion of a conserved haplotype spanning 10 cM at 17p11 was found to be shared by 12 of 15 affected individuals. The statistical analysis revealed a significant excess of transmission of alleles of three markers to affected individuals (P<0.05) by the transmission/disequilibrium test (TDT). An identical four-marker haplotype was shared by six of 15 patients (40%; P<0.01). Surprisingly, DR-typing revealed no significant sharing of the HLA region. In conclusion, our data suggests a novel susceptibility gene for MS in chromosome 17p11.


An other perspective on personality: meta-analytic integration of observers' accuracy and predictive validity.
The bulk of personality research has been built from self-report measures of personality. However, collecting personality ratings from other-raters, such as family, friends, and even strangers, is a dramatically underutilized method that allows better explanation and prediction of personality's role in many domains of psychology. Drawing hypotheses from D. C. Funder's (1995) realistic accuracy model about trait and information moderators of accuracy, we offer 3 meta-analyses to help researchers and applied psychologists understand and interpret both consistencies and unique insights afforded by other-ratings of personality. These meta-analyses integrate findings based on 44,178 target individuals rated across 263 independent samples. Each meta-analysis assessed the accuracy of observer ratings, as indexed by interrater consensus/reliability (Study 1), self-other correlations (Study 2), and predictions of behavior (Study 3). The results show that although increased frequency of interacting with targets does improve accuracy in rating personality, informants' interpersonal intimacy with the target is necessary for substantial increases in other-rating accuracy. Interpersonal intimacy improved accuracy especially for traits low in visibility (e.g., Emotional Stability) but only minimally for traits high in evaluativeness (e.g., Agreeableness). In addition, observer ratings were strong predictors of behaviors. When the criterion was academic achievement or job performance, other-ratings yielded predictive validities substantially greater than and incremental to self-ratings. These findings indicate that extraordinary value can gained by using other-reports to measure personality, and these findings provide guidelines toward enriching personality theory. Various subfields of psychology in which personality variables are systematically assessed and utilized in research and practice can benefit tremendously from use of others' ratings to measure personality variables.


A Ca(2+)-mobilising carbohydrate-based polyphosphate: synthesis of 2-hydroxyethyl alpha-D-glucopyranoside 2',3,4-trisphosphate.
Two routes to a glucose-based mimic of the second messenger 1D-myo-inositol 1,4,5-trisphosphate related to adenophostin A are described. Fischer glycosidation of D-glucose with allyl alcohol in the presence of a strong cation-exchange resin gave a 7:3 alpha: beta-anomeric mixture of allyl glucopyranosides (5ab) from which the pure alpha anomer 5a was isolated by crystallisation. Treatment of 5ab with 1.05 equiv of dibutyltin oxide followed by 2.1 equiv of benzoyl chloride gave allyl 2,6-di-O-benzoyl-alpha-D-glucopyranoside, which was converted in 3 steps into allyl 2,6-di-O-benzyl-3,4-O-isopropylidene-alpha-D-glucopyranoside (4). Alternatively, treatment of 5a with 2.5 equiv of dibutyltin oxide followed by benzyl bromide gave allyl 2,6-di-O-benzyl-alpha-D-glucopyranoside (9) which was also converted into 4. Compound 4 was elaborated to the phosphorylation precursor 2-hydroxyethyl 2,6-di-O-benzyl-alpha-D-glucopyranoside (12) in a convenient one-pot reaction, and 12 was phosphorylated and deblocked to afford 2-hydroxyethyl alpha-D-glucopyranoside 2',3,4-trisphosphate. The 2,6-di-O-benzyl derivative 9 was converted in high yield into 2,6-di-O-benzyl-3,4-di-O-(p-methoxybenzyl)-D-glucopyranose, a useful intermediate for the synthesis of adenophostin A and related compounds.


Factors affecting pharmacists' recommendation of complementary medicines - a qualitative pilot study of Australian pharmacists.
Complementary medicines (CMs) are widely used by the Australian public, and pharmacies are major suppliers of these medicines. The integration of CMs into pharmacy practice is well documented, but the behaviours of pharmacists in recommending CMs to customers are less well studied. This study reports on factors that influence whether or not pharmacists in Australia recommend CMs to their customers. Data were collected from semi-structured interviews with twelve practicing pharmacists based in Brisbane, Australia. The qualitative data were analysed by thematic analysis. The primary driver of the recommendation of CMs was a desire to provide a health benefit to the customer. Other important drivers were an awareness of evidence of efficacy, customer feedback and pharmacy protocols to recommend a CM alongside a particular pharmaceutical medication. The primary barrier to the recommendation of CMs was safety concerns around patients on multiple medications or with complex health issues. Also, a lack of knowledge of CMs, a perceived lack of evidence or a lack of time to counsel patients were identified as barriers. There was a desire to see a greater integration of CM into formal pharmacy education. Additionally, the provision of good quality educational materials was seen as important to allow pharmacists to assess levels of evidence for CMs and educate them on their safe and appropriate use. Pharmacists who frequently recommend CMs identify many potential benefits for patients and see it as an important part of providing a 'healthcare solution'. To encourage the informed use of CMs in pharmacy there is a need for the development of accessible, quality resources on CMs. In addition, incorporation of CM education into pharmacy curricula would better prepare graduate pharmacists for community practice. Ultimately, such moves would contribute to the safe and effective use of CMs to the benefit of consumers.


The impact of contact with suicide-related behavior in prison on young offenders.
Prison suicide rates are high, and suicide-related behaviors (SRBs) higher, but effects of contact with such behaviors in prison have not previously been examined. To compare the mental state of young men witnessing a peer's suicide-related behavior in prison with that of men without such experience, and to test for factors associated with morbidity. Forty-six male prisoners (age 16-21 years) reporting contact with another's suicide-related behavior in prison were interviewed 6 months after the incident, with validated questionnaires, as were 44 without such contact at least 6 months into their imprisonment. Significantly higher levels of psychiatric morbidity and own suicide-related behaviors were found in the witness group, even after controlling for their higher levels of family mental illness and pre-exposure experience of in-prison bullying. Some personal factors were associated with higher morbidity; incident and institutional factors were not. Findings of heightened vulnerabilities among young men exposed to suicide-related behaviors in prison suggest a need for longitudinal study to clarify temporal relationships and inform strategies to prevent or limit development of morbidity and further harm.


Pathogenesis of listeria-infected Drosophila wntD mutants is associated with elevated levels of the novel immunity gene edin.
Drosophila melanogaster mount an effective innate immune response against invading microorganisms, but can eventually succumb to persistent pathogenic infections. Understanding of this pathogenesis is limited, but it appears that host factors, induced by microbes, can have a direct cost to the host organism. Mutations in wntD cause susceptibility to Listeria monocytogenes infection, apparently through the derepression of Toll-Dorsal target genes, some of which are deleterious to survival. Here, we use gene expression profiling to identify genes that may mediate the observed susceptibility of wntD mutants to lethal infection. These genes include the TNF family member eiger and the novel immunity gene edin (elevated during infection; synonym CG32185), both of which are more strongly induced by infection of wntD mutants compared to controls. edin is also expressed more highly during infection of wild-type flies with wild-type Salmonella typhimurium than with a less pathogenic mutant strain, and its expression is regulated in part by the Imd pathway. Furthermore, overexpression of edin can induce age-dependent lethality, while loss of function in edin renders flies more susceptible to Listeria infection. These results are consistent with a model in which the regulation of host factors, including edin, must be tightly controlled to avoid the detrimental consequences of having too much or too little activity.


A highly K(+)-selective phenylaza-[18]crown-6-lariat-ether-based fluoroionophore and its application in the sensing of K+ ions with an optical sensor film and in cells.
Herein, we report the synthesis of two phenylaza-[18]crown-6 lariat ethers with a coumarin fluorophore (1 and 2) and we reveal that compound 1 is an excellent probe for K(+) ions under simulated physiological conditions. The presence of a 2-methoxyethoxy lariat group at the ortho position of the anilino moiety is crucial to the substantially increased stability of compounds 1 and 2 over their lariat-free phenylaza-[18]crown-6 ether analogues. Probe 1 shows a high K(+)/Na(+) selectivity and a 2.5-fold fluorescence enhancement was observed in the presence of 100 mM K(+) ions. A fluorescent membrane sensor, which was prepared by incorporating probe 1 into a hydrogel, showed a fully reversible response, a response time of 150 s, and a signal change of 7.8% per 1 mM K(+) within the range 1-10 mM K(+). The membrane was easily fabricated (only a single sensing layer on a solid polyester support), yet no leaching was observed. Moreover, compound 1 rapidly permeated into cells, was cytocompatible, and was suitable for the fluorescent imaging of K(+) ions on both the extracellular and intracellular levels.


Spreading dead zones and consequences for marine ecosystems.
Dead zones in the coastal oceans have spread exponentially since the 1960s and have serious consequences for ecosystem functioning. The formation of dead zones has been exacerbated by the increase in primary production and consequent worldwide coastal eutrophication fueled by riverine runoff of fertilizers and the burning of fossil fuels. Enhanced primary production results in an accumulation of particulate organic matter, which encourages microbial activity and the consumption of dissolved oxygen in bottom waters. Dead zones have now been reported from more than 400 systems, affecting a total area of more than 245,000 square kilometers, and are probably a key stressor on marine ecosystems.


Comparing Spatial Contrast Sensitivity Functions Measured With Digit and Grating Stimuli.
The contrast sensitivity function (CSF) is measured traditionally with grating stimuli. Recently, we introduced a new set of digit stimuli to improve the efficiency of CSF tests for people unfamiliar with the Latin alphabet. Given the significant differences between grating and digit stimuli, we conducted this study to evaluate whether the estimated CSFs from the digit test are equivalent to those from the grating test. The CSFs of five young (with Psi) and five older (with quick CSF [qCSF]) participants were measured with a two-alternative forced choice (2AFC) grating orientation identification task and a 10-digit identification task. The CSFs obtained from the two tasks were compared. The estimated CSFs from the two tasks matched well after controlling for stimulus types and performance levels. The root mean square error (RMSE) between the CSFs from the two tasks was 0.093 ± 0.029 (300 trials) and 0.131 ± 0.016 (100 trials) log10 units for young and older observers, respectively. To reach the same standard deviation (0.1 log10 units), the digit CSF test required fewer trials/less time than the classic grating CSF for young (60 vs. 90 trials) and older (15 vs. 21 trials) observers. The complicated behavioral responses of the observer in the 10-AFC digit identification task can be accounted by a model that consists of digit similarity and one single parameter of sensory noise (χ2[99] = 3.42, P = 0.999). The estimated CSFs from the digit test highly matched those obtained from the grating test; however, the digit test is much more efficient. The digit CSF test provides a compatible assessment of the CSF as the traditional grating CSF test with more efficiency.


Severe cerebral congophilic angiopathy coincident with increased brain aluminium in a resident of Camelford, Cornwall, UK.
In July 1988, 20 tonnes of aluminium sulphate was discharged by the South West Water Authority into the drinking water supplied to a large region of North Cornwall. Up to 20,000 people were exposed to concentrations of aluminium which were 500-3000 times the acceptable limit under European Union legislation (0.200 mg/l). Although this incident is currently the topic of a government inquiry, nothing is known about its longer-term repercussions on human health. The first neuropathological examination of a person who was exposed and died of an unspecified neurological condition was carried out. A rare form of sporadic early-onset beta amyloid angiopathy in cerebral cortical and leptomeningeal vessels, and in leptomeningeal vessels over the cerebellum was identified. In addition, high concentrations of aluminium were found coincident with the severely affected regions of the cortex. Although the presence of aluminium is highly unlikely to be adventitious, determining its role in the observed neuropathology is impossible. A clearer understanding of aluminium's role in this rare form of Alzheimer's related disease should be provided by future research on other people from the exposed population as well as similar neuropathologies in people within or outside this group.


Sound level measurements using smartphone "apps": useful or inaccurate?
Many recreational activities are accompanied by loud concurrent sounds and decisions regarding the hearing hazards associated with these activities depend on accurate sound measurements. Sound level meters (SLMs) are designed for this purpose, but these are technical instruments that are not typically available in recreational settings and require training to use properly. Mobile technology has made such sound level measurements more feasible for even inexperienced users. Here, we assessed the accuracy of sound level measurements made using five mobile phone applications or "apps" on an Apple iPhone 4S, one of the most widely used mobile phones. Accuracy was assessed by comparing application-based measurements to measurements made using a calibrated SLM. Whereas most apps erred by reporting higher sound levels, one application measured levels within 5 dB of a calibrated SLM across all frequencies tested.


Direct, noninvasive measurement of brain glycogen metabolism in humans.
The concentration and metabolism of the primary carbohydrate store in the brain, glycogen, is unknown in the conscious human brain. This study reports the first direct detection and measurement of glycogen metabolism in the human brain, which was achieved using localized 13C NMR spectroscopy. To enhance the NMR signal, the isotopic enrichment of the glucosyl moieties was increased by administration of 80 g of 99% enriched [1-13C]glucose in four subjects. 3 h after the start of the label administration, the 13C NMR signal of brain glycogen C1 was detected (0.36+/-0.07 micromol/g, mean+/-S.D., n=4). Based on the rate of 13C label incorporation into glycogen and the isotopic enrichment of plasma glucose, the flux through glycogen synthase was estimated at 0.17+/-0.05 micromol/(gh). This study establishes that brain glycogen can be measured in humans and indicates that its metabolism is very slow in the conscious human. The noninvasive detection of human brain glycogen opens the prospect of understanding the role and function of this important energy reserve under various physiological and pathophysiological conditions.


Dedicated health systems strengthening of the Global Fund to Fight AIDS, Tuberculosis, and Malaria: an analysis of grants.
This study aims to understand the determinants of the Global Fund to Fight AIDS, Tuberculosis, and Malaria's dedicated channel for health systems strengthening (HSS) funding across countries and to analyze their health system priorities expressed in budgets and performance indicators. We obtained publicly available data for disease-specific and HSS grants from the Global Fund over 2004-2013 prior to the new funding model. Regression analysis was employed to assess the determinants of dedicated HSS funding across 111 countries. Documents for 27 dedicated HSS grants including budgets and performance indicators were collected, and activities were analyzed by health system functions. HSS funding per capita is significantly associated with TB and HIV funding per capita, but not per capita income and health worker density. Of 27 dedicated HSS grants, 11 had line-item budgets publicly available, in which health workforce and medical products form the majority (89% or US$132 million of US$148 million) of funds. Yet these areas accounted for 41.7% (215) of total 516 performance indicators. Health worker densities were not correlated with HSS funding, despite the emphasis on health workforce in budgets and performance indicators. Priorities in health systems in line-item budgets differ from the numbers of indicators used.


Sexually transmitted diseases and the increased risk for HIV transmission: implications for cost-effectiveness analyses of sexually transmitted disease prevention interventions.
We estimated the annual number and cost of new HIV infections in the United States attributable to other sexually transmitted diseases (STDs). We used a mathematical model of HIV transmission to estimate the probability that a given STD infection would facilitate HIV transmission from an HIV-infected person to his or her partner and to calculate the number of HIV infections due to these facilitative effects. In 1996, an estimated 5,052 new HIV cases were attributable to the four STDs considered here: chlamydia (3,249 cases), syphilis (1,002 cases), gonorrhea (430 cases), and genital herpes (371 cases). These new HIV cases account for approximately $985 million U.S. in direct HIV treatment costs. The model suggested that syphilis is far more likely than the other STDs (on a per-case basis) to facilitate HIV transmission. This analysis provides a framework for incorporating STD-attributable HIV treatment costs into cost-effectiveness analyses of STD prevention programs.


Factors influencing the length of the incision and the operating time for total thyroidectomy.
The incision used for thyroid surgery has become shorter over time, from the classical 10 cm long Kocher incision to the shortest 15 mm access achieved with Minimally Invasive Video-Assisted Thyroidectomy. This rather large interval encompasses many different possible technical choices, even if we just consider open surgery.The aim of the study was to assess the correlation between incision length and operation duration with a set of biometric and clinical factors and establish a rationale for the decision on the length of incision in open surgery. Ninety-seven consecutive patients scheduled for total thyroidectomy were prospectively evaluated. All operations were performed by the same team and the surgeon decided the length of the incision according to his personal judgement. Patients who had previously undergone neck surgery were excluded. The length of the incision was strongly correlated with gender, thyroid volume, neck circumference and clinical diagnosis and weakly correlated with the body mass index. Operation duration was only weakly correlated with gender and neck circumference. Multiple linear regression revealed that the set of factors assessed explained almost 60 % of the variance in incision length but only 20 % of the variance in operation duration. When patients were classified according to the distribution of their thyroid volume, cases within one standard deviation of the mean did not show a significant difference in terms of operation duration with incisions of various lengths. Although thyroid volume was a major factor in driving the decision with respect to the length of the incision, our study shows that it had only minor effect on the duration of the operation. Many more open thyroidectomies could therefore be safely performed with shorter incisions, especially in women. Duration of the operation is probably more closely linked to the inherent technical difficulty of each case.


Bilateral normal filtering for mesh denoising.
Decoupling local geometric features from the spatial location of a mesh is crucial for feature-preserving mesh denoising. This paper focuses on first order features, i.e., facet normals, and presents a simple yet effective anisotropic mesh denoising framework via normal field denoising. Unlike previous denoising methods based on normal filtering, which process normals defined on the Gauss sphere, our method considers normals as a surface signal defined over the original mesh. This allows the design of a novel bilateral normal filter that depends on both spatial distance and signal distance. Our bilateral filter is a more natural extension of the elegant bilateral filter for image denoising than those used in previous bilateral mesh denoising methods. Besides applying this bilateral normal filter in a local, iterative scheme, as common in most of previous works, we present for the first time a global, noniterative scheme for an isotropic denoising. We show that the former scheme is faster and more effective for denoising extremely noisy meshes while the latter scheme is more robust to irregular surface sampling. We demonstrate that both our feature-preserving schemes generally produce visually and numerically better denoising results than previous methods, especially at challenging regions with sharp features or irregular sampling.


HaloTag-based conjugation of proteins to barcoding-oligonucleotides.
Highly sensitive protein quantification enables the detection of a small number of protein molecules that serve as markers/triggers for various biological phenomena, such as cancer. Here, we describe the development of a highly sensitive protein quantification system called HaloTag protein barcoding. The method involves covalent linking of a target protein to a unique molecule counting oligonucleotide at a 1:1 conjugation ratio based on an azido-cycloalkyne click reaction. The sensitivity of the HaloTag-based barcoding was remarkably higher than that of a conventional luciferase assay. The HaloTag system was successfully validated by analyzing a set of protein-protein interactions, with the identification rate of 44% protein interactions between positive reference pairs reported in the literature. Desmoglein 3, the target antigen of pemphigus vulgaris, an IgG-mediated autoimmune blistering disease, was used in a HaloTag protein barcode assay to detect the anti-DSG3 antibody. The dynamic range of the assay was over 104-times wider than that of a conventional enzyme-linked immunosorbent assay (ELISA). The technology was used to detect anti-DSG3 antibody in patient samples with much higher sensitivity compared to conventional ELISA. Our detection system, with its superior sensitivity, enables earlier detection of diseases possibly allowing the initiation of care/treatment at an early disease stage.


Biological features of herpes simplex virus type 1 latency in mice according to experimental conditions and type of neurones.
To compare the biological patterns of viral transcripts during herpes simplex virus type 1 (HSV1) latent infection according to experimental conditions. Two types of murine models of HSV1 infection were used: the corneal scarification model, often used in studies of HSV1 latency, and the oro-ocular murine model. Two strains of HSV1 were used for the inoculation: SC16, a wild type strain considered as highly neuroinvasive, and KOS, previously described as poorly neurovirulent. The amounts of viral genomes, and those of four types of viral transcripts (immediate-early, early and late, together with latency-associated transcripts [LATs]), were measured by quantitative PCR and RT-PCR in the main sites of HSV1 latent infection at 6 days, 1 and 3 months post inoculation, and the number of LAT-expressing neurons was assessed by in-situ hybridization on histological sections of trigeminal ganglia (TG). Using the SC16 strain of HSV1 in the oro-ocular model, immediate-early transcripts were still present at 1 month post inoculation (early stage of latent infection), but were not detected at 3 months (late stage of latent infection). In both cases, early and late viral genes transcripts were not detected, demonstrating the latent nature of the infection with this combination of experimental conditions. In contrast, such progress in the viral gene expression was not observed in the corneal scarification model, particularly when the KOS strain of HSV1 was used. These results highlight that the behavior of the virus in the nervous system depends on the method inoculation, and the viral strain. All these parameters are likely to influence the establishment of latent infection.


Perceived agricultural runoff impact on drinking water.
Agricultural runoff into surface water is a problem in Australia, as it is in arguably all agriculturally active countries. While farm practices and resource management measures are employed to reduce downstream effects, they are often either technically insufficient or practically unsustainable. Therefore, consumers may still be exposed to agrichemicals whenever they turn on the tap. For rural residents surrounded by agriculture, the link between agriculture and water quality is easy to make and thus informed decisions about water consumption are possible. Urban residents, however, are removed from agricultural activity and indeed drinking water sources. Urban and rural residents were interviewed to identify perceptions of agriculture's impact on drinking water. Rural residents thought agriculture could impact their water quality and, in many cases, actively avoided it, often preferring tank to surface water sources. Urban residents generally did not perceive agriculture to pose health risks to their drinking water. Although there are more agricultural contaminants recognised in the latest Australian Drinking Water Guidelines than previously, we argue this is insufficient to enhance consumer protection. Health authorities may better serve the public by improving their proactivity and providing communities and water utilities with the capacity to effectively monitor and address agricultural runoff.


Proresolving and cartilage-protective actions of resolvin D1 in inflammatory arthritis.
Rheumatoid arthritis (RA) is a debilitating disease characterized by persistent accumulation of leukocytes within the articular cavity and synovial tissue. Metabololipidomic profiling of arthritic joints from omega-3 supplemented mice identified elevated levels of specialized proresolving lipid mediators (SPM) including resolvin D1 (RvD1). Profiling of human RA synovial fluid revealed physiological levels of RvD1, which - once applied to human neutrophils - attenuated chemotaxis. These results prompted analyses of the antiarthritic properties of RvD1 in a model of murine inflammatory arthritis. The stable epimer 17R-RvD1 (100 ng/day) significantly attenuated arthritis severity, cachexia, hind-paw edema, and paw leukocyte infiltration and shortened the remission interval. Metabololipidomic profiling in arthritic joints revealed 17R-RvD1 significantly reduced PGE2 biosynthesis, while increasing levels of protective SPM. Molecular analyses indicated that 17R-RvD1 enhanced expression of genes associated with cartilage matrix synthesis, and direct intraarticular treatment induced chondroprotection. Joint protective actions of 17R-RvD1 were abolished in RvD1 receptor-deficient mice termed ALX/fpr2/3-/- . These investigations open new therapeutic avenues for inflammatory joint diseases, providing mechanistic substance for the benefits of omega-3 supplementation in RA.


Neutrophils roll on adherent neutrophils bound to cytokine-induced endothelial cells via L-selectin on the rolling cells.
Specific arrest of neutrophils in venules is central to their rapid accumulation during local inflammatory responses. Initial neutrophil rolling on endothelium is mediated by leukocyte L-selectin and the inducible vascular adhesion proteins P- and E-selectin. This rolling is a prerequisite for endothelial-dependent neutrophil arrest. Here we describe rolling of neutrophils on the surface of previously arrested neutrophils and demonstrate that this interaction involves L-selectin exclusively on rolling cells. The adherent neutrophil support of L-selectin-dependent neutrophil rolling in vivo can promote continuous and augmented leukocyte recruitment at sites of previous neutrophil accumulation.


Runtime Analysis of Restricted Tournament Selection for Bimodal Optimisation.
Niching methods have been developed to maintain the population diversity, to investigate many peaks in parallel, and to reduce the effect of genetic drift. We present the first rigorous runtime analyses of restricted tournament selection (RTS), embedded in a (μ+1) EA, and analyse its effectiveness at finding both optima of the bimodal function TwoMax. In RTS, an offspring competes against the closest individual, with respect to some distance measure, amongst w (window size) population members (chosen uniformly at random with replacement), to encourage competition within the same niche. We prove that RTS finds both optima on TwoMax efficiently if the window size w is large enough. However, if w is too small, RTS fails to find both optima even in exponential time, with high probability. We further consider a variant of RTS selecting individuals for the tournament without replacement. It yields a more diverse tournament and is more effective at preventing one niche from taking over the other. However, this comes at the expense of a slower progress towards optima when a niche collapses to a single individual. Our theoretical results are accompanied by experimental studies that shed light on parameters not covered by the theoretical results and support a conjectured lower runtime bound.


Antibiotics create a shift from mutualism to competition in human gut communities with a longer-lasting impact on fungi than bacteria.
Antibiotic treatment has a well-established detrimental effect on the gut bacterial composition, but effects on the fungal community are less clear. Bacteria in the lumen of the gastrointestinal tract may limit fungal colonization and invasion. Antibiotic drugs targeting bacteria are therefore seen as an important risk factor for fungal infections and induced allergies. However, antibiotic effects on gut bacterial-fungal interactions, including disruption and resilience of fungal community compositions, were not investigated in humans. We analysed stool samples collected from 14 healthy human participants over 3 months following a 6-day antibiotic administration. We integrated data from shotgun metagenomics, metatranscriptomics, metabolomics, and fungal ITS2 sequencing. While the bacterial community recovered mostly over 3 months post treatment, the fungal community was shifted from mutualism at baseline to competition. Half of the bacterial-fungal interactions present before drug intervention had disappeared 3 months later. During treatment, fungal abundances were associated with the expression of bacterial genes with functions for cell growth and repair. By extending the metagenomic species approach, we revealed bacterial strains inhibiting the opportunistic fungal pathogen Candida albicans. We demonstrated in vitro how C. albicans pathogenicity and host cell damage might be controlled naturally in the human gut by bacterial metabolites such as propionate or 5-dodecenoate. We demonstrated that antibacterial drugs have long-term influence on the human gut mycobiome. While bacterial communities recovered mostly 30-days post antibacterial treatment, the fungal community was shifted from mutualism towards competition. Video abstract.


Marked Up-Regulation of ACE2 in Hearts of Patients With Obstructive Hypertrophic Cardiomyopathy: Implications for SARS-CoV-2-Mediated COVID-19.
To explore the transcriptomic differences between patients with hypertrophic cardiomyopathy (HCM) and controls. RNA was extracted from cardiac tissue flash frozen at therapeutic surgical septal myectomy for 106 patients with HCM and 39 healthy donor hearts. Expression profiling of 37,846 genes was performed using the Illumina Human HT-12v3 Expression BeadChip. All patients with HCM were genotyped for pathogenic variants causing HCM. Technical validation was performed using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. This study was started on January 1, 1999, and final analysis was completed on April 20, 2020. Overall, 22% of the transcriptome (8443 of 37,846 genes) was expressed differentially between HCM and control tissues. Analysis by genotype revealed that gene expression changes were similar among genotypic subgroups of HCM, with only 4% (1502 of 37,846) to 6% (2336 of 37,846) of the transcriptome exhibiting differential expression between genotypic subgroups. The qRT-PCR confirmed differential expression in 92% (11 of 12 genes) of tested transcripts. Notably, in the context of coronavirus disease 2019 (COVID-19), the transcript for angiotensin I converting enzyme 2 (ACE2), a negative regulator of the angiotensin system, was the single most up-regulated gene in HCM (fold-change, 3.53; q-value =1.30×10-23), which was confirmed by qRT-PCR in triplicate (fold change, 3.78; P=5.22×10-4), and Western blot confirmed greater than 5-fold overexpression of ACE2 protein (fold change, 5.34; P=1.66×10-6). More than 20% of the transcriptome is expressed differentially between HCM and control tissues. Importantly, ACE2 was the most up-regulated gene in HCM, indicating perhaps the heart's compensatory effort to mount an antihypertrophic, antifibrotic response. However, given that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses ACE2 for viral entry, this 5-fold increase in ACE2 protein may confer increased risk for COVID-19 manifestations and outcomes in patients with increased ACE2 transcript expression and protein levels in the heart.


Genetic architecture of pollination syndrome transition between hummingbird-specialist and generalist species in the genus Rhytidophyllum (Gesneriaceae).
Adaptation to pollinators is a key factor of diversification in angiosperms. The Caribbean sister genera Rhytidophyllum and Gesneria present an important diversification of floral characters. Most of their species can be divided in two major pollination syndromes. Large-open flowers with pale colours and great amount of nectar represent the generalist syndrome, while the hummingbird-specialist syndrome corresponds to red tubular flowers with a less important nectar volume. Repeated convergent evolution toward the generalist syndrome in this group suggests that such transitions rely on few genes of moderate to large effect. To test this hypothesis, we built a linkage map and performed a QTL detection for divergent pollination syndrome traits by crossing one specimen of the generalist species Rhytidophyllum auriculatum with one specimen of the hummingbird pollinated R. rupincola. Using geometric morphometrics and univariate traits measurements, we found that floral shape among the second-generation hybrids is correlated with morphological variation observed between generalist and hummingbird-specialist species at the genus level. The QTL analysis showed that colour and nectar volume variation between syndromes involve each one major QTL while floral shape has a more complex genetic basis and rely on few genes of moderate effect. Finally, we did not detect any genetic linkage between the QTLs underlying those traits. This genetic independence of traits could have facilitated evolution toward optimal syndromes.


Markers of intestinal inflammation in patients with ankylosing spondylitis: a pilot study.
Inflammatory bowel disease (IBD) and ankylosing spondylitis (AS) are similar chronic inflammatory diseases whose definitive etiology is unknown. Following recent clinical and genetic evidence supporting an intertwined pathogenic relationship, we conducted a pilot study to measure fecal calprotectin (fCAL) and IBD-related serologies in AS patients. Consecutive AS patients were recruited from a long-term prospectively collected longitudinal AS cohort at Cedars-Sinai Medical Center. Controls were recruited from Cedars-Sinai Medical Center employees or spouses of patients with AS. Sera were tested by ELISA for IBD-associated serologies (antineutrophil cytoplasmic antibodies (ANCA), anti-Saccharomyces cerevisiae antibody IgG and IgA, anti-I2, anti-OmpC, and anti-CBir1). The Bath Ankylosing Spondylitis Disease Activity Index, the Bath Ankylosing Spondylitis Functional Index, and the Bath Ankylosing Spondylitis Radiology Index were completed for AS patients. A total of 81 subjects (39 AS patients and 42 controls) were included for analysis. The average age of AS patients was 47 years and the average disease duration was 22 years. AS patients were predominantly male; 76% were HLA-B27-positive. Median fCAL levels were 42 μg/g and 17 μg/g in the AS group and controls, respectively (P < 0.001). When using the manufacturer's recommended cutoff value for positivity of 50 μg/g, stool samples of 41% of AS patients and 10% of controls were positive for fCAL (P = 0.0016). With the exception of ANCA, there were no significant differences in antibody levels between patients and controls. Median ANCA was 6.9 ELISA units in AS patients and 4.3 ELISA units in the controls. Among AS patients stratified by fCAL level, there were statistically significant differences between patients and controls for multiple IBD-associated antibodies. Calprotectin levels were elevated in 41% of patients with AS with a cutoff value for positivity of 50 μg/g. fCAL-positive AS patients displayed higher medians of most IBD-specific antibodies when compared with healthy controls or fCAL-negative AS patients. Further studies are needed to determine whether fCAL can be used to identify and characterize a subgroup of AS patients whose disease might be driven by subclinical bowel inflammation.


Diagonal chromatographic selection of cysteinyl peptides modified with benzoquinones.
The derivatization of cysteine-containing peptides with benzoquinone compounds is rapid, quantitative and specific in acidic media. The conversion of cysteines into hydrophobic benzoquinone-adducted residues in peptides is used here to alter the chromatographic properties of cysteinyl peptides during liquid chromatography separation. The benzoquinone derivatization is shown to allow the accurate selection of cysteine-containing peptides of bovine serum albumin tryptic digest by diagonal reversed-phase chromatography, which consists of one primary and a series of secondary identical liquid chromatographic separations, before and after a cysteinyl-targeted modification of the peptides by benzoquinone compounds.


AIDS-related and non-AIDS-related mortality in the Asia-Pacific region in the era of combination antiretroviral treatment.
Although studies have shown reductions in mortality from AIDS after the introduction of combination antiretroviral treatment (cART), little is known about cause-specific mortality in low-income settings in the cART era. We explored predictors of AIDS and non-AIDS mortality and compared cause-specific mortality across high-income and low-income settings in the Asia-Pacific region. We followed patients in the Asia Pacific HIV Observational Database from the date they started cART (or cohort enrolment if cART initiation was identified retrospectively), until the date of death or last follow-up visit. Competing risks methods were used to estimate the cumulative incidence, and to investigate predictors, of AIDS and non-AIDS mortality. Of 4252 patients, 215 died; 89 from AIDS, 97 from non-AIDS causes and 29 from unknown causes. Age more than 50 years [hazard ratio 4.29; 95% confidence interval (CI) 2.10-8.79] and CD4 cell counts less than or equal to 100 cells/microl (hazard ratio 8.59; 95% CI 5.66-13.03) were associated with an increased risk of non-AIDS mortality. Risk factors for AIDS mortality included CD4 cell counts less than or equal to 100 cells/microl (hazard ratio 34.97; 95% CI 18.01-67.90) and HIV RNA 10 001 or more (hazard ratio 4.21; 95% CI 2.07-8.55). There was some indication of a lower risk of non-AIDS mortality in Asian high-income, and possibly low-income, countries compared to Australia. Immune deficiency is associated with an increased risk of AIDS and non-AIDS mortality. Older age predicts non-AIDS mortality in the cART era. Less conclusive was the association between country-income level and cause-specific mortality because of the relatively high proportion of unknown causes of death in low-income settings.


Cerebrospinal fluid monoamine levels in central disorders of hypersomnolence.
Whether the cause of daytime sleepiness in narcolepsy type 1 (NT1) is a direct consequence of the loss of orexin (ORX) neurons or whether low orexin reduces the efficacy of the monoaminergic systems to promote wakefulness is unclear. The neurobiology underlying sleepiness in other central hypersomnolence disorders, narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH), is currently unknown. Eleven biogenic amines including the monoaminergic neurotransmitters and their metabolites and five trace amines were measured in the cerebrospinal fluid (CSF) of 94 drug-free subjects evaluated at the French National Reference Center for Narcolepsy: 39 NT1(orexin-deficient) patients, 31 patients with objective sleepiness non orexin-deficient (NT2 and IH), and 24 patients without objective sleepiness. Three trace amines were undetectable in the sample: tryptamine, octopamine, and 3-iodothyronamine. No significant differences were found among the three groups for quantified monoamines and their metabolites in crude and adjusted models; however, CSF 5-hydroxyindoleacetic acid (5-HIAA) levels tended to increase in NT1 compared to other patients after adjustment. Most of the biomarkers were not associated with ORX-A levels, clinical or neurophysiological parameters, but a few biomarkers (e.g. 3-methoxy-4-hydroxyphenylglycol and norepinephrine) correlated with daytime sleepiness and high rapid eye movement (REM) sleep propensity. We found no striking differences among CSF monoamines, their metabolites and trace amine levels, and few associations between them and key clinical or neurophysiological parameters in NT1, NT2/IH, and patients without objective sleepiness. Although mostly negative, these findings are a significant contribution to our understanding of the neurobiology of hypersomnolence in these disorders that remain mysterious and deserve further exploration.


Microarray-based characterization of Staphylococcus aureus isolates obtained from chicken carcasses.
A total of 34 Staphylococcus aureus isolates from flock-wise pooled chicken neck skin samples collected at two abattoirs during slaughter were characterized with DNA microarray analysis and spa typing. The 20 isolates from abattoir A all belonged to clonal complex (CC) 12 and spa type t160. Of the 14 isolates from abattoir B, 7 belonged to CC5-t3478, 5 to CC12-t160, 1 to CC45-t040, and 1 to CC101-t056. Of the various resistance-associated genes tested, only blaZ/R/I (6 isolates of CC12 and CC101 from abattoir B), sdrM (n = 34), fosB (n = 33), and qacC (n = 22) were detected. None of the isolates harbored genes conferring methicillin resistance. In terms of genes encoding enterotoxins, seb (all isolates of CC12), egc (seg, sei, selm, seln, selo, selu; all isolates of CC5 and CC45), and sea (14 isolates of CC12 and 1 isolate of CC5) were found. In addition, all isolates harbored genes for intracellular adhesion proteins (icaA/C/D) and were positive for cap5 or cap8 (capsule type 5 or 8). Comparison of DNA microarray profiles identified four categories comprising (i) all isolates of CC12, (ii) all isolates of CC5, (iii) the CC45 isolate, and (iv) the CC101 isolate. The high similarity of the isolates from abattoir A could indicate contamination of chicken carcasses with S. aureus persisting on the slaughter equipment, but further investigations are required to elucidate potential contamination routes.


Choledocho-choledochostomy: the natural history of healing in pigs.
Aiming to investigate the natural history of the healing of choledocho-choledochostomies. Fifty-five female pigs of 57 kg median weight were used for the experiments. The gallbladder was removed and the common bile duct transected. Continuity was re-established by standardized single-line, interrupted, and inverted sutures. The pigs had a planned postoperative survival of up to 14 days with a subsequent laparotomy for evaluation. Blood samples were drawn prior to the first and the final operations. During laparotomy the animals were investigated for signs of cholascos, and an intraoperative cholangiography was performed. The excised anastomosis was examined for breaking strength and collagen content. Standard liver parameters were not significantly affected by the surgery, and cholangiography showed no signs of extrahepatic stenosis or intrahepatic dilatation. Breaking strength showed a decrease for the initial 3 postoperative days (PODs), then an increase to a stable level on PODs 6 to 14. Collagen content per volume showed a rise on PODs 0 to 1, then no change until POD 4, followed by a gradual rise until day 6. Subsequently a stable level was reached until POD 14. Two pigs were excluded due to minor cholascos. The present study on pigs shows that choledocho-choledochostomies, judged by breaking strength and collagen content, regain a stable level of strength 6 days after operation.


Brief wakeful resting boosts new memories over the long term.
A brief wakeful rest after new verbal learning enhances memory for several minutes. In the research reported here, we explored the possibility of extending this rest-induced memory enhancement over much longer periods. Participants were presented with two stories; one story was followed by a 10-min period of wakeful resting, and the other was followed by a 10-min period during which participants played a spot-the-difference game. In Experiment 1, wakeful resting led to significant enhancement of memory after a 15- to 30-min period and also after 7 days. In experiment 2, this striking enhancement of memory 7 days after learning was demonstrated even when no retrievals were imposed in the interim. The degree to which people can remember prose after 7 days is significantly affected by the cognitive activity that they engage in shortly after new learning takes place. We propose that wakeful resting after new learning allows new memory traces to be consolidated better and hence to be retained for much longer.


Prevention of learning deficit in a Down syndrome model.
To evaluate whether peptides given to adult mice with Down syndrome prevent learning deficits, and to delineate the mechanisms behind the protective effect. Ts65Dn mice were treated for 9 days with peptides D-NAPVSIPQ (NAP)+D-SALLRSIPA (SAL) or placebo, and wild-type animals were treated with placebo. Beginning on treatment day 4, the mice were tested for learning using the Morris watermaze. Probe tests for long-term memory were performed on treatment day 9 and 10 days after treatment stopped. Open-field testing was performed before and after the treatment. Calibrator-normalized relative real-time polymerase chain reaction (PCR) with glyceraldehyde-3-phosphate dehydrogenase (GAPD) standardization was performed on the whole brain and hippocampus for activity-dependent neuroprotective protein, vasoactive intestinal peptide (VIP), glial fibrillary acidic protein (GFAP), NR2B, NR2A, and γ-aminobutyric acid type A (GABAA)-α5. Statistics included analysis of variance and the Fisher protected least significant difference, with P<.05 significant. The Ts65Dn plus placebo animals did not learn over the 5-day period compared with the controls (P<.001). The Ts65Dn +(D-NAP+D-SAL) learned significantly better than the Ts65Dn plus placebo (P<.05), and they retained learning similar to controls on treatment day 9, but not after 10 days of no treatment. Treatment with D-NAP+D-SAL prevented the Ts65Dn hyperactivity. Adult administration of D-NAP+D-SAL prevented changes in activity-dependent neuroprotective protein, intestinal peptide, and NR2B with levels similar to controls (all P<.05). Adult treatment with D-NAP+D-SAL prevented learning deficit in Ts65Dn, a model of Down syndrome. Possible mechanisms of action include reversal of vasoactive intestinal peptide and activity-dependent neuroprotective protein dysregulation, as well as increasing expression of NR2B, thus facilitating learning.


Angiotensin-converting enzyme and male fertility.
The angiotensin-converting enzyme (ACE; EC 220.127.116.11) gene (Ace) encodes both a somatic isozyme found in blood and several other tissues, including the epididymis, and a testis-specific isozyme (testis ACE) found only in developing spermatids and mature sperm. We recently used gene targeting to disrupt the gene coding for both ACE isozymes in mice and reported that male homozygous mutants mate normally but have reduced fertility; the mutant females are fertile. Here we explore the male fertility defect. We demonstrate that ACE is important for achieving in vivo fertilization and that sperm from mice lacking both ACE isozymes show defects in transport within the oviducts and in binding to zonae pellucidae. Males generated by gene targeting that lack somatic ACE but retain testis ACE are normally fertile, establishing that somatic ACE in males is not essential for their fertility. Furthermore, male and female mice lacking angiotensinogen have normal fertility, indicating that angiotensin I is not a necessary substrate for testis ACE. Males heterozygous for the mutation inactivating both ACE isozymes sire wild-type and heterozygous offspring at an indistinguishable frequency, indicating no selection against sperm carrying the mutation.


Acquired appetitive responding to intravenous nicotine reflects a Pavlovian conditioned association.
Recent research examining Pavlovian appetitive conditioning has extended the associative properties of nicotine from the unconditioned stimulus or reward to include the role of a conditional stimulus (CS), capable of acquiring the ability to evoke a conditioned response. To date, published research has used presession extravascular injections to examine nicotine as a contextual CS in that appetitive Pavlovian drug discrimination task. Two studies in the current research examined whether a nicotine CS can function discretely, multiple times within a session using passive iv infusions. In Experiment 1, rats readily acquired a discrimination in conditioned responding between nicotine and saline infusions when nicotine was selectively paired with sucrose presentations. In Experiment 2, rats were either trained with nicotine paired with sucrose or explicitly unpaired with sucrose. The results showed that rats trained with explicitly unpaired nicotine and sucrose did not increase dipper entries after the infusions. Nicotine was required to be reliably paired with sucrose for control of conditioned responding to develop. Implications of these findings are discussed in relation to tobacco addiction, learning theory, and pharmacology.


Optimizing nanophotonic cavity designs with the gravitational search algorithm.
Designing photonic crystal cavities with high quality factors and low mode volumes is of great importance for maximizing interactions of light and matter in metamaterials. Previous work on photonic crystal cavities has revealed dramatic improvements in performance by fine-tuning the device design. In L3 cavities, slight shifts of the holes on the edge of the cavity have been found to greatly increase quality factors without significantly altering the mode volume. Here we demonstrate utilizing a nature inspired search algorithm to efficiently explore a large parameter space. The results converge upon a new cavity model with a high quality factor to mode volume ratio (Q/V = 798,000 (λ/n)(-3)).


Identification of amino acid determinants in CYP4B1 for optimal catalytic processing of 4-ipomeanol.
Mammalian CYP4B1 enzymes are cytochrome P450 mono-oxygenases that are responsible for the bioactivation of several exogenous pro-toxins including 4-ipomeanol (4-IPO). In contrast with the orthologous rabbit enzyme, we show here that native human CYP4B1 with a serine residue at position 427 is unable to bioactivate 4-IPO and does not cause cytotoxicity in HepG2 cells and primary human T-cells that overexpress these enzymes. We also demonstrate that a proline residue in the meander region at position 427 in human CYP4B1 and 422 in rabbit CYP4B1 is important for protein stability and rescues the 4-IPO bioactivation of the human enzyme, but is not essential for the catalytic activity of the rabbit CYP4B1 protein. Systematic substitution of native and p.S427P human CYP4B1 with peptide regions from the highly active rabbit enzyme reveals that 18 amino acids in the wild-type rabbit CYP4B1 protein are key for conferring high 4-IPO metabolizing activity. Introduction of 12 of the 18 amino acids that are also present at corresponding positions in other human CYP4 family members into the p.S427P human CYP4B1 protein results in a mutant human enzyme (P+12) that is as stable and as active as the rabbit wild-type CYP4B1 protein. These 12 mutations cluster in the predicted B-C loop through F-helix regions and reveal new amino acid regions important to P450 enzyme stability. Finally, by minimally re-engineering the human CYP4B1 enzyme for efficient activation of 4-IPO, we have developed a novel human suicide gene system that is a candidate for adoptive cellular therapies in humans.


Morphological Requirements for Nanoscale Electric Field Buildup in a Bulk Heterojunction Solar Cell.
The morphology of organic semiconductors is critical to their function in optoelectronic devices and is particularly crucial in the donor-acceptor mixture that comprises the bulk heterojunction of organic solar cells. Here, energy landscapes can play integral roles in charge photogeneration, and recently have been shown to drive the accumulation of charge carriers away from the interface, resulting in the buildup of large nanoscale electric fields, much like a capacitor. In this work we combine morphological and spectroscopic data to outline the requirements for this interdomain charge accumulation, finding that this effect is driven by a three-phase morphology that creates an energetic cascade for charge carriers. By adjusting annealing conditions, we show that domain purity, but not size, is critical for an electro-absorption feature to grow-in. This demonstrates that the energy landscape around the interface shapes the movement of charges and that pure domains are required for charge carrier buildup that results in reduced recombination and large interdomain nanoscale electric fields.


The crystal structure of the ligand binding module of axonin-1/TAG-1 suggests a zipper mechanism for neural cell adhesion.
We have determined the crystal structure of the ligand binding fragment of the neural cell adhesion molecule axonin-1/TAG-1 comprising the first four immunoglobulin (Ig) domains. The overall structure of axonin-1(Ig1-4) is U-shaped due to contacts between domains 1 and 4 and domains 2 and 3. In the crystals, these molecules are aligned in a string with adjacent molecules oriented in an anti-parallel fashion and their C termini perpendicular to the string. This arrangement suggests that cell adhesion by homophilic axonin-1 interaction occurs by the formation of a linear zipper-like array in which the axonin-1 molecules are alternately provided by the two apposed membranes. In accordance with this model, mutations in a loop critical for the formation of the zipper resulted in the loss of the homophilic binding capacity of axonin-1.


Epidemiology of Burkholderia cepacia infection in patients with cystic fibrosis: analysis by randomly amplified polymorphic DNA fingerprinting.
We fingerprinted a collection of 627 Burkholderia cepacia isolates from 255 patients with cystic fibrosis (CF) and 43 patients without CF and from the environment, by a PCR-based randomly amplified polymorphic DNA (RAPD) method with primers selected for their ability to produce discriminatory polymorphisms. The RAPD typing method was found to be reproducible and discriminatory, more sensitive than PCR ribotyping, and able to group epidemiologically related B. cepacia strains previously typed by both pulsed-field gel electrophoresis and conventional ribotyping. Seven strain types infecting multiple CF patients were found at several different CF treatment centers in Canada, the United States, the United Kingdom, France, and Australia, indicating the presence of epidemic strain types. Most CF patients were each colonized with a single strain type, and several patients harbored the same strain type for 5 or more years. B. cepacia isolates recovered from other clinical sources (44 isolates examined) and from the environment (58 isolates examined) possessed RAPD fingerprints that were generally distinct from CF-associated strain types (525 isolates examined). RAPD is a versatile fingerprinting method for studying the epidemiology of B. cepacia.


Comparative Genomics and Proteomic Analysis of Four Non-tuberculous Mycobacterium Species and Mycobacterium tuberculosis Complex: Occurrence of Shared Immunogenic Proteins.
The Esx and PE/PPE families of proteins are among the most immunodominant mycobacterial antigens and have thus been the focus of research to develop vaccines and immunological tests for diagnosis of bovine and human tuberculosis, mainly caused by Mycobacterium bovis and Mycobacterium tuberculosis, respectively. In non-tuberculous mycobacteria (NTM), multiple copies of genes encoding homologous proteins have mainly been identified in pathogenic Mycobacterium species phylogenically related to Mycobacterium tuberculosis and Mycobacterium bovis. Only ancestral copies of these genes have been identified in nonpathogenic NTM species like Mycobacterium smegmatis, Mycobacterium sp. KMS, Mycobacterium sp. MCS, and Mycobacterium sp. JLS. In this study we elucidated the genomes of four nonpathogenic NTM species, viz Mycobacterium komanii sp. nov., Mycobacterium malmesburii sp. nov., Mycobacterium nonchromogenicum, and Mycobacterium fortuitum ATCC 6841. These genomes were investigated for genes encoding for the Esx and PE/PPE (situated in the esx cluster) family of proteins as well as adjacent genes situated in the ESX-1 to ESX-5 regions. To identify proteins actually expressed, comparative proteomic analyses of purified protein derivatives from three of the NTM as well as Mycobacterium kansasii ATCC 12478 and the commercially available purified protein derivatives from Mycobacterium bovis and Mycobacterium avium was performed. The genomic analysis revealed the occurrence in each of the four NTM, orthologs of the genes encoding for the Esx family, the PE and PPE family proteins in M. bovis and M. tuberculosis. The identification of genes of the ESX-1, ESX-3, and ESX-4 region including esxA, esxB, ppe68, pe5, and pe35 adds to earlier reports of these genes in nonpathogenic NTM like M. smegmatis, Mycobacterium sp. JLS and Mycobacterium KMS. This report is also the first to identify esxN gene situated within the ESX-5 locus in M. nonchromogenicum. Our proteomics analysis identified a total of 609 proteins in the six PPDs and 22 of these were identified as shared between PPD of M.bovis and one or more of the NTM PPDs. Previously characterized M tuberculosis/M. bovis homologous immunogenic proteins detected in one or more of the nonpathogenic NTM in this study included CFP-10 (detected in M. malmesburii sp. nov. PPD), GroES (detected in all NTM PPDs but M. malmesburii sp. nov.), DnaK (detected in all NTM PPDs), and GroEL (detected in all NTM PPDs). This study confirms reports that the ESX-1, ESX-3, and ESX-4 regions are ancestral regions and thus found in the genomes of most mycobacteria. Identification of NTM homologs of immunogenic proteins warrants further investigation of their ability to cause cross-reactive immune responses with MTBC antigens.


Systemic Scedosporium prolificans infection in an 11-month-old Border collie with cobalamin deficiency secondary to selective cobalamin malabsorption (canine Imerslund-Gräsbeck syndrome).
An 11-month-old Border collie presented collapsed and continued to deteriorate rapidly despite supportive treatment. The dog had a history of failure to thrive and recurring respiratory infection. Laboratory abnormalities included neutrophilic leucocytosis, Heinz body anaemia, hyperammonaemia, hyperbilirubinaemia, proteinuria and hypocobalaminaemia. Post-mortem examination revealed multi-focal necrosis within the heart, kidneys, pancreas, liver, meninges and cerebral cortex. Fungal hyphae in lesions were identified as Scedosporium prolificans following culture. Subsequent genotyping confirmed that the dog carried the CUBN:c.8392delC mutation in a homozygous state, verifying hereditary cobalamin deficiency (a.k.a. Imerslund-Gräsbeck syndrome). Cobalamin deficiency may have been a predisposing factor for the development of systemic fungal infection in this dog.


Calcium as a Key Player in Arrhythmogenic Cardiomyopathy: Adhesion Disorder or Intracellular Alteration?
Arrhythmogenic cardiomyopathy (ACM) is an inherited heart disease characterized by sudden death in young people and featured by fibro-adipose myocardium replacement, malignant arrhythmias, and heart failure. To date, no etiological therapies are available. Mutations in desmosomal genes cause abnormal mechanical coupling, trigger pro-apoptotic signaling pathways, and induce fibro-adipose replacement. Here, we discuss the hypothesis that the ACM causative mechanism involves a defect in the expression and/or activity of the cardiac Ca2+ handling machinery, focusing on the available data supporting this hypothesis. The Ca2+ toolkit is heavily remodeled in cardiomyocytes derived from a mouse model of ACM defective of the desmosomal protein plakophilin-2. Furthermore, ACM-related mutations were found in genes encoding for proteins involved in excitation‒contraction coupling, e.g., type 2 ryanodine receptor and phospholamban. As a consequence, the sarcoplasmic reticulum becomes more eager to release Ca2+, thereby inducing delayed afterdepolarizations and impairing cardiac contractility. These data are supported by preliminary observations from patient induced pluripotent stem-cell-derived cardiomyocytes. Assessing the involvement of Ca2+ signaling in the pathogenesis of ACM could be beneficial in the treatment of this life-threatening disease.


Social cohesion, condom use, and sexually transmitted infections among female sex workers living with HIV in the Dominican Republic.
This cross-sectional study examines the relationship between social cohesion with consistent condom use (CCU) and sexually transmitted infections (STIs) among the Abriendo Puertas (Opening Doors) cohort of female sex workers (FSWs) living with human immunodeficiency virus (HIV) in the Dominican Republic (n = 228). Using data from the follow-up survey of the cohort, we conducted multivariate logistic regression to explore these dynamics. Social cohesion was significantly associated with CCU between FSWs living with HIV and their clients in the last month (adjusted odds ratio [AOR] = 1.65, 95% confidence interval [CI]: 1.11-2.45) and STI prevalence among FSWs (AOR: 3.76, CI: 1.159-12.162). Social cohesion was not associated with CCU between FSWs living with HIV and their steady partners. However, both illicit drug use in the past six months (AOR = 0.11, CI: 0.023-0.57) and pregnancy intentions (AOR = 0.11; CI: 0.02-0.42) were significantly associated with CCU with steady partners. Findings highlight the differential role of social cohesion on condom use outcomes between FSWs living with HIV and their paying clients versus steady partners. Research on the pathways via which cohesion influences condom use among sex workers and their clients is merited, as is research regarding the role of drug use and pregnancy intentions on condom use with steady partners.


Effect of recombinant vascular endothelial growth factor on experimental otitis media with effusion.
This study demonstrates that rVEGF in the middle ear cavity contributes significantly to the development of OME by increasing the vascular permeability of the middle ear mucosa. Vascular endothelial growth factor (VEGF) has been detected in otitis media with effusion (OME). It has a very strong effect on increasing vascular permeability, and is much more potent than platelet-activating factor, arachidonic acid metabolites or histamine. The purpose of this study was to investigate whether recombinant VEGF (rVEGF) can increase vascular permeability in the middle ear mucosa of rats. rVEGF was injected transtympanically at doses of 0.01, 0.1 and 1.0 microg in the experimental groups; normal saline was injected in the control group. Twenty-four h after the injection of rVEGF, middle ear fluid was aspirated and the vascular permeability of the middle ear mucosa was measured by means of the Evans Blue vital dye technique. Extravasation of Evans Blue dye was found in all specimens injected with rVEGF, and was quantified using a spectrophotometer. Middle ear fluid developed in all ears injected with 0.1 or 1.0 microg of rVEGF and histopathology of the middle ear mucosa revealed severe inflammatory cellular infiltration, subepithelial edema and vascular dilatation. Rats injected with 1.0 microg of rVEGF showed a significant increase in middle ear vascular permeability in comparison with the control group (p < 0.05).


Food insufficiency is associated with high-risk sexual behavior among women in Botswana and Swaziland.
Both food insufficiency and HIV infection are major public health problems in sub-Saharan Africa, yet the impact of food insufficiency on HIV risk behavior has not been systematically investigated. We tested the hypothesis that food insufficiency is associated with HIV transmission behavior. We studied the association between food insufficiency (not having enough food to eat over the previous 12 months) and inconsistent condom use, sex exchange, and other measures of risky sex in a cross-sectional population-based study of 1,255 adults in Botswana and 796 adults in Swaziland using a stratified two-stage probability design. Associations were examined using multivariable logistic regression analyses, clustered by country and stratified by gender. Food insufficiency was reported by 32% of women and 22% of men over the previous 12 months. Among 1,050 women in both countries, after controlling for respondent characteristics including income and education, HIV knowledge, and alcohol use, food insufficiency was associated with inconsistent condom use with a nonprimary partner (adjusted odds ratio [AOR] 1.73, 95% confidence interval [CI] 1.27-2.36), sex exchange (AOR 1.84, 95% CI 1.74-1.93), intergenerational sexual relationships (AOR 1.46, 95% CI 1.03-2.08), and lack of control in sexual relationships (AOR 1.68, 95% CI 1.24-2.28). Associations between food insufficiency and risky sex were much attenuated among men. Food insufficiency is an important risk factor for increased sexual risk-taking among women in Botswana and Swaziland. Targeted food assistance and income generation programs in conjunction with efforts to enhance women's legal and social rights may play an important role in decreasing HIV transmission risk for women.


Primary hyperparathyroidism in young patients in Russia: high frequency of hyperparathyroidism-jaw tumor syndrome.
Primary hyperparathyroidism (PHPT) is a relatively rare disorder among children, adolescents and young adults. Its development at an early age is suspicious for hereditary causes, though the need for routine genetic testing remains controversial. To identify and describe hereditary forms of PHPT in patients with manifestation of the disease under 40 years of age. We enrolled 65 patients with PHPT diagnosed before 40 years of age. Ten of them had MEN1 mutation, and PHPT in them was the first manifestation of multiple endocrine neoplasia type 1 syndrome. The other fifty-five patients underwent next-generation sequencing (NGS) of a custom-designed panel of genes, associated with PHPT (MEN1, CASR, CDC73, CDKN1A, CDKN1B, CDKN1C, CDKN2A, CDKN2C, CDKN2D). In cases suspicious for gross CDC73 deletions multiplex ligation-dependent probe amplification was performed. NGS revealed six pathogenic or likely pathogenic germline sequence variants: four in CDC73 c.271C>T (p.Arg91*), c.496C>T (p.Gln166*), c.685A>T (p.Arg229*) and c.787C>T (p.Arg263Cys); one in CASR c.3145G>T (p.Glu1049*) and one in MEN1 c.784-9G>A. In two patients, MLPA confirmed gross CDC73 deletions. In total, 44 sporadic and 21 hereditary PHPT cases were identified. Parathyroid carcinomas and atypical parathyroid adenomas were present in 8/65 of young patients, in whom CDC73 mutations were found in 5/8. Hereditary forms of PHPT can be identified in up to 1/3 of young patients with manifestation of the disease at <40 years of age. Parathyroid carcinomas or atypical parathyroid adenomas in young patients are frequently associated with CDC73 mutations.


Clinical and biochemical markers of visceral adipose tissue activity: Body mass index, visceral adiposity index, leptin, adiponectin, and matrix metalloproteinase-3. Correlation with Gleason patterns 4 and 5 at prostate biopsy.
The correlation between aggressive prostate cancer and obesity mainly based on body mass index (BMI) and pathology after surgery remains controversial. The aim of the study was to correlate BMI, visceral adiposity index (VAI), and the plasmatic levels of leptin, adiponectin, and matrix metalloproteinase-3 (MMP-3), and biomarkers of adipose tissue function, with the detection of Gleason patterns 4 and 5 at biopsy. Consecutive patients with prostate cancer at 12-core transrectal biopsy were enrolled. BMI, waist circumference (WC), blood samples to evaluate the plasmatic levels of triglycerides (TG) and high-density lipoproteins (HDL), adiponectin, leptin, and MMP-3 were obtained immediately before biopsy. The VAI was calculated according to the formula: WC/(39.68 + [1.88 × BMI]) × TG/1.03 × 1.31/HDL. One hundred and forty-nine patients were entered. The median PSA, BMI, and VAI were 10.0 ng/ml, 27.6 kg/m2, and 4.6, respectively. Gleason patterns 4 or 5 were detected in 68 (45.6%) patients; in 15 (41.7%), 31 (44.9%), and 22 (50.0%) among normal weight, overweight, and obese patients, respectively (P = 0.55). The statistical analysis did not show any significant correlation between BMI, VAI, the plasmatic levels of leptin, adiponectin, MMP-3, and the detection of Gleason patterns 4 and 5 at biopsy. A statistically significant association emerged with older age (P = 0.017) and higher PSA values (P = 0.02). We did not find any association between BMI, VAI, the plasmatic levels of adiponectin, leptin, and MMP-3 and the detection of Gleason patterns 4 and 5 at prostate biopsy.


Cardiopulmonary resuscitation (CPR) plus delayed defibrillation versus immediate defibrillation for out-of-hospital cardiac arrest.
Sudden cardiac arrest (SCA) is a common health problem associated with high levels of mortality. Cardiac arrest is caused by three groups of dysrhythmias: ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT), pulseless electric activity (PEA) and asystole. The most common dysrhythmia found in out-of-hospital cardiac arrest (OHCA) is VF. During VF or VT, cardiopulmonary resuscitation (CPR) provides perfusion and oxygenation to the tissues, whilst defibrillation restores a viable cardiac rhythm. Early successful defibrillation is known to improve outcomes in VF/VT. However, it has been hypothesized that a period of CPR before defibrillation creates a more conducive physiological environment, increasing the likelihood of successful defibrillation. The order of priority of CPR versus defibrillation therefore remains in contention. As previous studies have remained inconclusive, we conducted a systematic review of available evidence in an attempt to draw conclusions on whether CPR plus delayed defibrillation or immediate defibrillation resulted in better outcomes in OHCA. To examine whether an initial one and one-half to three minutes of CPR administered by paramedics before defibrillation versus immediate defibrillation on arrival influenced survival rates, neurological outcomes or rates of return of spontaneous circulation (ROSC) in OHCA. We searched the following databases: the Cochrane Central Register of Controlled trials (CENTRAL) (2013, Issue 6); MEDLINE (Ovid) (1948 to May 2013); EMBASE (1980 to May 2013); the Institute for Scientific Information (ISI) Web of Science (1980 to May 2013) and the China Academic Journal Network Publishing Database (China National Knowledge Infrastructure (CNKI), 1980 to May 2013). We included studies published in all languages. We also searched the Current Controlled Trials and Clinical Trials databases for ongoing trials. We screened the references lists of studies included in our review against the reference lists of relevant International Liaison Committee on Resuscitation (ILCOR) evidence worksheets. Our participant group consisted of adults over 18 years of age presenting with OHCA who were in VF or pulseless VT at the time of emergency medical service (EMS) paramedic arrival. We included randomized controlled trials (RCTs) and quasi-randomized controlled trials that evaluated the effects of one and one-half to three minutes of CPR versus defibrillation as initial therapy on survival and neurological outcomes of these participants. We excluded observational and cross-over design studies. Two review authors independently extracted the data. We contacted study authors to ask for additional data when required. The risk ratio (RR) for each outcome was calculated and summarized in the meta-analysis after heterogeneity was considered. We used Review Manager software for all analyses. We included four RCTs with a total of 3090 enrolled participants (one study used a cluster-randomized design). Three trials were considered to have a relatively low risk of bias, and one trial was considered to have a relatively high risk. When survival to hospital discharge was compared, 38 of 320 (11.88%) participants survived to discharge in the initial CPR plus delayed defibrillation group compared with 39 of 338 participants (11.54%) in the immediate defibrillation group (RR 1.09, 95% CI 0.54 to 2.20, Chi(2) = 10.78, degrees of freedom (df) = 5, P value 0.06, I(2) = 54%, low-quality evidence).When we compared the neurological outcome at hospital discharge (RR 1.12, 95% CI 0.65 to 1.93, low-quality evidence), the rate of return of spontaneous circulation (ROSC) (RR 0.94, 95% CI 0.77 to 1.15,low-quality evidence) and survival at one year (RR 0.77, 95% CI 0.24 to 2.49, low-quality evidence), we could not rule out the superiority of either treatment.Adverse effects were not associated with either treatment. Owing to the low quality of available evidence, we have been unable to determine conclusively whether immediate defibrillation and one and one-half to three minutes of CPR as initial therapy before defibrillation have similar effects on rates of return of spontaneous circulation, survival to discharge or neurological insult.We have also been unable to conclude whether either treatment approach provides a degree of superiority in OHCA.We propose that this is an area that needs further rigorous research through additional high-quality RCTs, including larger sample sizes and proper subgroup analysis.


Molecular analysis of the ovine cystic fibrosis transmembrane conductance regulator gene.
There is a need for a large-animal model to investigate the etiology and biology of cystic fibrosis (CF) lung disease and to study potential therapies. The development and electrophysiology of the sheep airway have been shown to exhibit close functional parallels with the human airway, particularly with respect to the respiratory epithelium. We have cloned and sequenced the ovine cystic fibrosis transmembrane conductance regulator (CFTR) cDNA. It shows a high degree of conservation at the DNA coding and predicted polypeptide levels with human CFTR: at the nucleic acid level there is a 90% conservation (compared with 80% between human and mouse CFTR cDNA); at the polypeptide level, the degree of similarity is 95% (compared with 88% between human and mouse). Northern blot analysis and reverse transcription-PCR have shown that the patterns of expression of the ovine CFTR gene are very similar to those seen in humans. Further, the developmental expression of CFTR in the sheep is equivalent to that observed in humans. Thus, overall a CF sheep should show lung pathology similar to that of humans with CF.


Decoloration rates of a photomerocyanine dye as a visual probe into hydrogen bonding interactions.
We have developed a visual marker for the investigation of hydrogen bonding (HB) effects. The decoloration rate of a photochromic dye that incorporates a latent intra-molecular HB feature can be linked to the HB character of the media. Kinetic and thermodynamic parameters of this simple decoloration approach for HB sensing are investigated both experimentally and by high level theoretical studies. This principle has been applied for the detection of changes in the HB character of stationary and fluidic systems. A major finding is the observation of a shear-related perturbation of the balance between intra- and inter-molecular HB within a dynamic thin film.


Clustered voltage-gated Na+ channels in Aplysia axons.
Clustering of voltage-gated Na+ channels is critical for the fast saltatory conduction of action potentials in vertebrate myelinated axons. However, the mechanisms responsible for the generation and maintenance of Na+ channel clustering are not well understood. In this study we have raised an antibody against the cloned SCAP-1 voltage-gated Na+ channel of the marine invertebrate Aplysia californica and used it to examine Na+ channel localization in Aplysia ganglia and in cultured Aplysia sensory neurons. Our results show that there is a large cytoplasmic pool of Na+ channels in the soma of Aplysia neurons. Furthermore, we show that Na+ channels in Aplysia axons are not homogeneously distributed but, rather, are present in distinct clusters. Theoretical considerations indicate that Na+ channel clustering may enhance action potential conduction. We propose that clustered Na+ channels may be a fundamental property of many axons, and perhaps of many membranes that conduct Na(+)-dependent action potentials.


Magnesium Hydride Nanoparticles Self-Assembled on Graphene as Anode Material for High-Performance Lithium-Ion Batteries.
MgH2 nanoparticles (NPs) uniformly anchored on graphene (GR) are fabricated based on a bottom-up self-assembly strategy as anode materials for lithium-ion batteries (LIBs). Monodisperse MgH2 NPs with an average particle size of ∼13.8 nm are self-assembled on the flexible GR, forming interleaved MgH2/GR (GMH) composite architectures. Such nanoarchitecture could effectively constrain the aggregation of active materials, buffer the strain of volume changes, and facilitate the electron/lithium ion transfer of the whole electrode, leading to a significant enhancement of the lithium storage capacity of the GMH composite. Furthermore, the performances of GMH composite as anode materials for LIBs are enabled largely through robust interfacial interactions with poly(methyl methacrylate) (PMMA) binder, which plays multifunctional roles in forming a favorable solid-electrolyte interphase (SEI) film, alleviating the volume expansion and detachment of active materials, and maintaining the structural integrity of the whole electrode. As a result, these synergistic effects endow the obtained GMH composite with a significantly enhanced reversible capacity and cyclability as well as a good rate capability. The GMH composite with 50 wt % MgH2 delivers a high reversible capacity of 946 mA h g-1 at 100 mA g -1 after 100 cycles and a capacity of 395 mAh g-1 at a high current density of 2000 mA g-1 after 1000 cycles.


Radiological and functional comparison of single-bundle anterior cruciate ligament reconstruction: transtibial versus anteromedial technique
Background/aim: This study aimed to compare radiological and functional outcomes of patients who had single-bundle anterior cruciate ligament (ACL) reconstruction with autologous hamstring tendon grafts using transtibial (TT) versus anteromedial (AM) femoral tunnel drilling techniques. Materials and methods: Sixty patients who had been operated on between 2010 and 2013 were enrolled in this study. Tunnel positions and widenings in the femur and tibia were evaluated with radiographs, arthrometric measurements with a Rolimeter arthrometer (Aircast, Summit, NJ, USA), stability assessment with Lachman and reverse pivot shift tests, and functional assessment with the International Knee Documentation Committee and Tegner and Lysholm scoring systems. Results: Tunnel enlargement in the sagittal and coronal planes of the femur was higher with the TT technique (P < 0.0001) and that of the coronal planes of the tibia was also higher with the TT technique (P = 0.01). During the assessment with the Rolimeter, the difference between sides was significant with the TT technique (P = 0.013). Positive results of the Lachman and reverse pivot shift tests were more frequent with the TT technique (P < 0.05), and the Lysholm scores were higher with the AM technique (P = 0.001). Conclusion: ACL reconstruction with hamstring autografts by either TT or AM technique demonstrated similar and excellent results in terms of functional outcomes at the end of the first postoperative year. The TT group had increased tunnel enlargement, which may have uncertain long-term outcomes, compared with the AM group.


Classification of small lesions in dynamic breast MRI: Eliminating the need for precise lesion segmentation through spatio-temporal analysis of contrast enhancement over time.
Characterizing the dignity of breast lesions as benign or malignant is specifically difficult for small lesions; they don't exhibit typical characteristics of malignancy and are harder to segment since margins are harder to visualize. Previous attempts at using dynamic or morphologic criteria to classify small lesions (mean lesion diameter of about 1 cm) have not yielded satisfactory results. The goal of this work was to improve the classification performance in such small diagnostically challenging lesions while concurrently eliminating the need for precise lesion segmentation. To this end, we introduce a method for topological characterization of lesion enhancement patterns over time. Three Minkowski Functionals were extracted from all five post-contrast images of sixty annotated lesions on dynamic breast MRI exams. For each Minkowski Functional, topological features extracted from each post-contrast image of the lesions were combined into a high-dimensional texture feature vector. These feature vectors were classified in a machine learning task with support vector regression. For comparison, conventional Haralick texture features derived from gray-level co-occurrence matrices (GLCM) were also used. A new method for extracting thresholded GLCM features was also introduced and investigated here. The best classification performance was observed with Minkowski Functionals area and perimeter, thresholded GLCM features f8 and f9, and conventional GLCM features f4 and f6. However, both Minkowski Functionals and thresholded GLCM achieved such results without lesion segmentation while the performance of GLCM features significantly deteriorated when lesions were not segmented (p < 0.05). This suggests that such advanced spatio-temporal characterization can improve the classification performance achieved in such small lesions, while simultaneously eliminating the need for precise segmentation.