Vibrational overtone spectroscopy of jet-cooled methanol from 5000 to 14 000 cm(-1).
Spectra of jet-cooled methanol in the overtone and combination region from 5000 to 14 000 cm(-1) have been obtained by means of infrared laser-assisted photofragment spectroscopy. Many of the observed features are assigned to combination bands of the type nnu(1)+nu(6), nnu(1)+nu(8), and nnu(1)+nu(6)+nu(8) (n=1,2,3), where nu(1) is the OH stretch, nu(6) is the OH bend, and nu(8) is the CO stretch. These bands show sharp torsion-rotation structure with features as narrow as 0.1 cm(-1). We also observe CH stretch overtones that are weaker than the OH containing combination bands and lack distinct torsion-rotation structure above v(CH)=2. The extent of observed structure on these bands allows us to place limits on the intramolecular vibrational energy redistribution decay rates in the upper vibrational states. We report a global fit of the observed band centers to a simple expression involving low-order anharmonicity constants.


Are developing beta-adrenoceptors able to desensitize? Acute and chronic effects of beta-agonists in neonatal heart and liver.
During fetal and neonatal development, beta-adrenergic receptors (beta-ARs) appear to be resistant to desensitization by beta-agonist drugs. To determine the mechanisms underlying the regulatory differences between adults and neonates, we administered isoproterenol, a mixed beta(1)/beta(2)-AR agonist, and terbutaline, a beta(2)-selective agonist. Effects were examined in the ensuing 4 h after a single injection, or after the last of four daily injections. We prepared cell membranes from heart (predominantly beta(1)-ARs) and liver (predominantly beta(2)-ARs) and assessed signal transduction in the adenylyl cyclase (AC) pathway. In the first few hours after a single administration of isoproterenol to adult rats, cardiac beta-ARs showed activation of G proteins (elevated AC response to forskolin) and desensitization of beta-AR-mediated responses; after the fourth injection, heterologous desensitization emerged, characterized by a loss of signaling mediated either through beta-ARs or glucagon receptors. Terbutaline evoked an increase in the forskolin response but no desensitization of receptor-mediated responses. When we gave the same treatments to neonatal rats, we observed cardiac G protein activation, but there was neither homologous nor heterologous desensitization of beta-ARs or glucagon receptors. In the adult liver, isoproterenol and terbutaline both failed to evoke desensitization, regardless of whether the drugs were given once or for 4 days. In neonates, however, acute or chronic treatment elicited homologous desensitization of beta-AR-mediated AC signaling, while sensitizing the response to glucagon. These results show that neonatal beta-ARs are inherently capable of desensitization in some, but not all, cell types; cellular responses can be maintained through heterologous sensitization of signaling proteins downstream from the receptor. Differences from adult patterns of response are highly tissue selective and are likely to depend on ontogenetic differences in subtypes of beta-ARs and AC.


Breast-feeding and a subsequent diagnosis of measles.
Breast-feeding protects against many infectious diseases and may also influence immunization outcomes. This study investigated if breast-feeding protects against clinical measles and if it modified the effect of immunization. We used logistic regression with data for 10 207 individuals from the 1970 British Cohort study (BCS70). Breast-feeding data were collected at five years of age, and information on clinical measles infection, as well as socio-economic measures was collected at the age of ten years. Breast feeding was categorized as: breast-fed <1 month (n = 1611), breast-fed for 1-3 months (n = 1016), breast-fed for more than three months (n = 1108), breast-feeding of uncertain duration (n = 21) and never breast-fed (n = 6451). Breast-feeding for more than three months was negatively associated with a diagnosis of clinical measles infection after adjustment for crowding, social class, measles vaccination, parity and sex with an odds ratio (95% confidence interval) of 0.69 (0.60-0.81) compared with those who never breast-fed. Measles vaccination was highly associated with low risk for measles with: 0.14 (0.13-0.16). Age at acute measles infection was not associated with breastfeeding. Breast-feeding did not notably alter measles immunization efficacy. Immunization against measles provides effective protection against the disease. A more modest reduction in the risk of a measles diagnosis is associated with breast-feeding. The associations with a diagnosis of measles for breast-feeding and measles immunization are independent of each other.


An association between organophosphate pesticides exposure and Parkinsonism amongst people in an agricultural area in Ubon Ratchathani Province, Thailand.
Parkinson's disease (PD) is a ubiquitous disease. However, PDs prevalence in the population of agricultural communities lacks understanding and there has been no epidemiological study on the association between pesticides exposure factors and risk for PD. To investigate the potential association between organophosphate pesticides exposure and Parkinsonism by using a screening questionnaire in agricultural areas. Ninety elderly people living in agricultural areas participated in a cross-sectional study conducted at Tambon Hua-Rua Health Promoting Hospital in April 2014. Screening questionnaires for Parkinson's disease, Test-mate ChE (Model 400) for blood cholinesterase (ChE) levels of both blood enzymes erythrocyte cholinesterase (AChE), and plasma cholinesterase (PChE) were used as measurement tools. Descriptive statistics for frequencies and percentage distributions were used primarily to summarize and describe the data. Sensitivity, specificity, positive and negative predictive values were calculated. The age range of the participants was 50 to 59 years old, with an average age of 53.9±2.87 years. The majority of the participants were female (62.2%), 82.2% of respondents were farmers. Most of participants (76.7%) reported that they applied insecticides in their farms. Ninety persons participated and completed the 11-item questionnaire. Of these, 17 (18.9%) felt that they lost balance when turning or that they needed to take a few steps to turn right around and 16.7% of participants indicated that they felt the need to move slowly or stiffly. The study found the prevalence of abnormal AChE levels was 28.9% (95%CI=19.81-39.40) and 17.8% of PChE levels (95%CI=10.52-27.26). To predict Parkinsonism, AChE, and PChE level, with a cutoff score of 5 or higher there had to be a sensitivity of 0.31, specificity of 1.00, positive predictive value (PPV) of 1.00 and negative predictive value (NPV) of 0.78 for AChE. While PChE, the score value of 5 or more had a sensitivity of 0.19, specificity of 0.93, PPV of 0.38 and NPV of 0.84. This study described an association between pesticides exposure and Parkinsonism. The questionnaire appears to be useful for Thai agriculturists as a screening tool for Parkinsonism and cholinesterase levels regarding to pesticides exposure.


Epigenetic Activation of Antibacterial Property of an Endophytic Streptomyces coelicolor Strain AZRA 37 and Identification of the Induced Protein Using MALDI TOF MS/MS.
The endophytic Streptomyces coelicolor strain AZRA 37 was isolated from the surface sterilized root of Azadirachta indica A. Juss., commonly known as neem plant in India. Since only a few reports are available regarding epigenetic modulations of microbial entities, S. coelicolor was treated with different concentrations of 5-azacytidine for this purpose and evaluated for its antibacterial potential against five human pathogenic bacteria (Aeromonas hydrophila IMS/GN11, Enterococcus faecalis IMS/GN7, Salmonella typhi MTCC 3216, Shigella flexneri ATCC 12022 and Staphylococcus aureus ATCC 25923). The crude extract obtained from cultures treated with 25 μM concentration of 5-azacytidine, was found effective against all five pathogenic bacteria tested while the untreated control was only active against 3 pathogenic bacteria. HPLC analysis of crude compounds from treated cultures showed a greater number of compounds than that of the control. Extraction of whole cell protein and its SDS PAGE analysis showed an additional major protein band in 25 μM 5-azacytidine treated culture and MALDI TOF MS/MS analysis revealed that this protein belongs to the porin family.


Vision of embodied rubber hands enhances tactile distractor processing.
Previous research has demonstrated that viewing one's hand can induce tactile response compatibility effects at the hands. Here, we investigated the question of whether vision of one's own hand is actually necessary. The Eriksen flanker task was combined with the rubber hand illusion in order to determine whether tactile distractors presented to the hand would be processed up to the level of response selection when a pair of rubber hands was seen (while one's own hands were not). Our results demonstrate that only if the rubber hands are perceived as belonging to one's own body, is enhanced distractor processing (up to the level of response selection) observed at the hands. In conclusion, vision of a pair of fake hands enhances tactile distractor processing at the hands if, and only if, it happens to be incorporated into the body representation.


Effects of whole-grain wheat, rye, and lignan supplementation on cardiometabolic risk factors in men with metabolic syndrome: a randomized crossover trial.
A whole-grain (WG)-rich diet has shown to have potential for both prevention and treatment of the metabolic syndrome (MetS), which is a cluster of risk factors that increase the risk of type 2 diabetes and cardiovascular disease. Different WGs may have different health effects. WG rye, in particular, may improve glucose homeostasis and blood lipids, possibly mediated through fermentable dietary fiber and lignans. Recent studies have also suggested a crucial role of the gut microbiota in response to WG. The aim was to investigate WG rye, alone and with lignan supplements [secoisolariciresinol diglucoside (SDG)], and WG wheat diets on glucose tolerance [oral-glucose-tolerance test (OGTT)], other cardiometabolic outcomes, enterolignans, and microbiota composition. Moreover, we exploratively evaluated the role of gut microbiota enterotypes in response to intervention diets. Forty men with MetS risk profile were randomly assigned to WG diets in an 8-wk crossover study. The rye diet was supplemented with 280 mg SDG at weeks 4-8. Effects of treatment were evaluated by mixed-effects modeling, and effects on microbiota composition and the role of gut microbiota as a predictor of response to treatment were analyzed by random forest plots. The WG rye diet (± SDG supplements) did not affect the OGTT compared with WG wheat. Total and LDL cholesterol were lowered (-0.06 and -0.09 mmol/L, respectively; P < 0.05) after WG rye compared with WG wheat after 4 wk but not after 8 wk. WG rye resulted in higher abundance of Bifidobacterium [fold-change (FC) = 2.58, P < 0.001] compared with baseline and lower abundance of Clostridium genus compared with WG wheat (FC = 0.54, P = 0.02). The explorative analyses suggest that baseline enterotype is associated with total and LDL-cholesterol response to diet. WG rye, alone or with SDG supplementation, compared with WG wheat did not affect glucose metabolism but caused transient LDL-cholesterol reduction. The effect of WG diets appeared to differ according to enterotype. This trial was registered at www.clinicaltrials.gov as NCT02987595.


Four-dimensional in vivo X-ray microscopy with projection-guided gating.
Visualizing fast micrometer scale internal movements of small animals is a key challenge for functional anatomy, physiology and biomechanics. We combine phase contrast tomographic microscopy (down to 3.3 μm voxel size) with retrospective, projection-based gating (in the order of hundreds of microseconds) to improve the spatiotemporal resolution by an order of magnitude over previous studies. We demonstrate our method by visualizing 20 three-dimensional snapshots through the 150 Hz oscillations of the blowfly flight motor.


CTLA-4: a negative regulator of autoimmune disease.
CTLA-4, a CD28 homologue expressed on activated T cells, binds with high affinity to the CD28 ligands, B7-1 (CD80) and B7-2 (CD86). This study was designed to examine the role of CTLA-4 in regulating autoimmune disease. Murine relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE) is a demyelinating disease mediated by PLP139-151-specific CD4+ T cells in SJL/J mice. Anti-CTLA-4 mAbs (or their F(ab) fragments) enhanced in vitro proliferation and pro-inflammatory cytokine production by PLP139-151-primed lymph node cells. Addition of either reagent to in vitro activation cultures potentiated the ability of T cells to adoptively transfer disease to naive recipients. In vivo administration of anti-CTLA-4 mAb to recipients of PLP139-151-specific T cells resulted in accelerated and exacerbated disease. Finally, anti-CTLA-4 treatment of mice during disease remission resulted in the exacerbation of relapses. Collectively, these results suggest that CTLA-4 mediates the downregulation of ongoing immune responses and plays a major role in regulating autoimmunity.


A robust penalized method for the analysis of noisy DNA copy number data.
Deletions and amplifications of the human genomic DNA copy number are the causes of numerous diseases, such as, various forms of cancer. Therefore, the detection of DNA copy number variations (CNV) is important in understanding the genetic basis of many diseases. Various techniques and platforms have been developed for genome-wide analysis of DNA copy number, such as, array-based comparative genomic hybridization (aCGH) and high-resolution mapping with high-density tiling oligonucleotide arrays. Since complicated biological and experimental processes are often associated with these platforms, data can be potentially contaminated by outliers. We propose a penalized LAD regression model with the adaptive fused lasso penalty for detecting CNV. This method contains robust properties and incorporates both the spatial dependence and sparsity of CNV into the analysis. Our simulation studies and real data analysis indicate that the proposed method can correctly detect the numbers and locations of the true breakpoints while appropriately controlling the false positives. The proposed method has three advantages for detecting CNV change points: it contains robustness properties; incorporates both spatial dependence and sparsity; and estimates the true values at each marker accurately.


Control of extracellular dopamine at dendrite and axon terminals.
Midbrain dopamine neurons release dopamine from both axons and dendrites. The mechanism underlying release at these different sites has been proposed to differ. This study used electrochemical and electrophysiological methods to compare the time course and calcium dependence of somatodendritic dopamine release in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) to that of axonal dopamine release in the dorsal striatum. The amount of dopamine released in the striatum was approximately 20-fold greater than in cell body regions of the VTA or SNc. However, the calcium dependence and time to peak of the dopamine transients were similar. These results illustrate an unexpected overall similarity in the mechanisms of dopamine release in the striatum and cell body regions. To examine how diffusion regulates the time course of dopamine following release, dextran was added to the extracellular solution to slow diffusion. In the VTA, dextran slowed the rate of rise and fall of the extracellular dopamine transient as measured by fast-scan cyclic voltammetry yet did not alter the kinetics of the dopamine-dependent IPSC. Dextran failed to significantly alter the time course of the rise and fall of the dopamine transient in the striatum, suggesting a more influential role for reuptake in the striatum. The conclusion is that the time course of dopamine within the extracellular space of the VTA is dependent on both diffusion and reuptake, whereas the activation of D(2) receptors on dopamine neurons is primarily limited by reuptake.


Smartphone App Using Mindfulness Meditation for Women With Chronic Pelvic Pain (MEMPHIS): Protocol for a Randomized Feasibility Trial.
Female chronic pelvic pain (CPP) is defined as intermittent or constant pelvic or lower abdominal pain occurring in a woman for at least 6 months. Up to a quarter of women are estimated to be affected by CPP worldwide and it is responsible for one fifth of specialist gynecological referrals in the United Kingdom. Psychological interventions are commonly utilized. As waiting times and funding capacity impede access to face-to-face consultations, supported self-management (SSM) has emerged as a viable alternative. Mindfulness meditation is a potentially valuable SSM tool, and in the era of mobile technology, this can be delivered to the individual user via a smartphone app. To assess the feasibility of conducting a trial of a mindfulness meditation intervention delivered by a mobile phone app for patients with CPP. The main feasibility objectives were to assess patient recruitment and app adherence, to obtain information to be used in the sample size estimate of a future trial, and to receive feedback on usability of the app. Mindfulness Meditation for Women With Chronic Pelvic Pain (MEMPHIS) is a three-arm feasibility trial, that took place in two hospitals in the United Kingdom. Eligible participants were randomized in a 1:1:1 ratio to one of three treatment arms: (1) the intervention arm, consisting of a guided, spoken mindfulness meditation app; (2) an active control arm, consisting of a progressive muscle relaxation app; and (3) usual care (no app). Participants were followed-up for 6 months. Key feasibility outcomes included the time taken to recruit all patients for the study, adherence, and estimates to be used in the sample size calculation for a subsequent full-scale trial. Upon completion of the feasibility trial we will conduct focus groups to explore app usability and reasons for noncompliance. Recruitment for MEMPHIS took place between May 2016 and September 2016. The study was closed March 2017 and the report was submitted to the NIHR on October 26, 2017. This feasibility trial will inform the design of a large multicentered trial to assess the clinical effectiveness of mindfulness meditation delivered via a smartphone app for the treatment of CPP. ClinicalTrials.gov: NCT02721108; https://clinicaltrials.gov/ct2/show/NCT02721108 (Archived by WebCite at http://www.webcitation.org/6wLMAkuaU); BioMed Central: ISRCTN10925965; https://www.isrctn.com/ISRCTN10925965 (Archived by WebCite at http://www.webcitation.org/6wLMVLuys).


Computerized map of risk to manage wildlife species in urban areas.
For the last 20 years, human-wildlife conflicts have been rapidly increasing in towns. Although people want "greener" cities, the expansion of disliked species causes problems that are difficult to manage and to reduce. The complexity of the numerous factors involved in these human-wildlife relations needs the development of a comprehensive tool for urban planners. Today, with the development of computers and geographical information systems, it is easier to analyze and combine different spatial data as methods used for the management of risks in studies of natural hazards. Here we present a method for assessing and mapping the risk in cases of human-wildlife conflict. An application to starling management in a town in western France will show the efficiency of our methods to combine information given by a network of experts and to highlight higher risk sites. The map of risk provides a spatial result useful for comprehension, communication between people and agencies, and public education.


Regulation of the xylan-degrading apparatus of Cellvibrio japonicus by a novel two-component system.
The microbial degradation of lignocellulose biomass is not only an important biological process but is of increasing industrial significance in the bioenergy sector. The mechanism by which the plant cell wall, an insoluble composite structure, activates the extensive repertoire of microbial hydrolytic enzymes required to catalyze its degradation is poorly understood. Here we have used a transposon mutagenesis strategy to identify a genetic locus, consisting of two genes that modulate the expression of xylan side chain-degrading enzymes in the saprophytic bacterium Cellvibrio japonicus. Significantly, the locus encodes a two-component signaling system, designated AbfS (sensor histidine kinase) and AbfR (response regulator). The AbfR/S two-component system is required to activate the expression of the suite of enzymes that remove the numerous side chains from xylan, but not the xylanases that hydrolyze the beta1,4-linked xylose polymeric backbone of this polysaccharide. Studies on the recombinant sensor domain of AbfS (AbfS(SD)) showed that it bound to decorated xylans and arabinoxylo-oligosaccharides, but not to undecorated xylo-oligosaccharides or other plant structural polysaccharides/oligosaccharides. The crystal structure of AbfS(SD) was determined to a resolution of 2.6A(.) The overall fold of AbfS(SD) is that of a classical Per Arndt Sim domain with a central antiparallel four-stranded beta-sheet flanked by alpha-helices. Our data expand the number of molecules known to bind to the sensor domain of two-component histidine kinases to include complex carbohydrates. The biological rationale for a regulatory system that induces enzymes that remove the side chains of xylan, but not the hydrolases that cleave the backbone of the polysaccharide, is discussed.


TAK1-TAB2 signaling contributes to bone destruction by breast carcinoma cells.
Advanced-stage breast cancers frequently metastasize to the bones and cause bone destruction, but the underlying mechanism is not fully understood. This study presents evidence that TGF-β-activated protein kinase 1 (TAK1) signaling in tumor cells promotes bone destruction by metastatic breast carcinoma cells, controlling expression of prometastatic factors including matrix metalloproteinase (MMP) 9 and COX2. Suppression of TAK1 signaling by dominant-negative TAK1 (dn-TAK1) in breast carcinoma MDA-MB-231 cells impairs bone colonization by carcinoma cells and bone osteolysis in the intracardiac injection model. Mechanistic studies showed that inhibition of TAK1 by dn-TAK1 or siRNA blocked expression of factors implicated in bone metastasis, such as MMP-9, COX2/PTGS2, parathyroid hormone-related protein (PTHrP) and interleukin 8 (IL-8), but did not affect activation of p38MAPK by TGF-β. TAK1 signaling is mediated by TAK1-binding partners TAB1, TAB2, and TAB3. Carcinoma cells express elevated mRNA levels of TAB2 and TAB3, whereas the TAB1 expression is noticeably low. Accordingly, depletion of TAB2 by siRNA reduced expression of MMP-9 and COX2. Together, these studies show that the TAK1-TAB2-TAB3 signaling axis is critical for carcinoma-induced bone lesions, mediating expression of proinvasive and osteolytic factors. These findings identify the TAK1-TAB2 axis as a potential therapeutic target in bone metastasis.


Authorship representation in global emergency medicine: a bibliometric analysis from 2016 to 2020.
High-income country (HIC) authors are disproportionately represented in authorship bylines compared with those affiliated with low and middle-income countries (LMICs) in global health research. An assessment of authorship representation in the global emergency medicine (GEM) literature is lacking but may inform equitable academic collaborations in this relatively new field. We conducted a bibliometric analysis of original research articles reporting studies conducted in LMICs from the annual GEM Literature Review from 2016 to 2020. Data extracted included study topic, journal, study country(s) and region, country income classification, author order, country(s) of authors' affiliations and funding sources. We compared the proportion of authors affiliated with each income bracket using Χ2 analysis. We conducted logistic regression to identify factors associated with first or last authorship affiliated with the study country. There were 14 113 authors in 1751 articles. Nearly half (45.5%) of the articles reported work conducted in lower middle-income countries (MICs), 23.6% in upper MICs, 22.5% in low-income countries (LICs). Authors affiliated with HICs were most represented (40.7%); 26.4% were affiliated with lower MICs, 17.4% with upper MICs, 10.3% with LICs and 5.1% with mixed affiliations. Among single-country studies, those without any local authors (8.7%) were most common among those conducted in LICs (14.4%). Only 31.0% of first authors and 21.3% of last authors were affiliated with LIC study countries. Studies in upper MICs (adjusted OR (aOR) 3.6, 95% CI 2.46 to 5.26) and those funded by the study country (aOR 2.94, 95% CI 2.05 to 4.20) had greater odds of having a local first author. There were significant disparities in authorship representation. Authors affiliated with HICs more commonly occupied the most prominent authorship positions. Recognising and addressing power imbalances in international, collaborative emergency medicine (EM) research is warranted. Innovative methods are needed to increase funding opportunities and other support for EM researchers in LMICs, particularly in LICs.


Using SERVQUAL for assessing and improving patient satisfaction at a rural health facility in Pakistan.
A cross-sectional study of patient satisfaction with care was conducted over a period of 1 year from March 2004 to March 2005 in a secondary-level hospital in a peri-urban area of Karachi, Pakistan. Using the SERVQUAL tool and exit interviews, data were collected quarterly from a total of 1533 patients. Results sharing and capacity-building workshops were arranged during the 4 phases of the survey to sensitize the staff of the hospital to work towards improving patient satisfaction. The level of satisfaction of the patients with the outpatient health services provided showed a gradual increase from 34.4% to 82.0% over the 1-year period.


Methionine-dependent histone methylation at developmentally important gene loci in mouse preimplantation embryos.
The involvement of specific nutrients in epigenetic gene regulation is a possible mechanism underlying nutrition-directed phenotypic alteration. However, the involvement of nutrients in gene-specific epigenetic regulation remains poorly understood. Methionine has been received attention as a possible nutrient involved in epigenetic modifications, as it is a precursor of the universal methyl donor for epigenetic methylation of DNA and histones. In the present study, the disruption of methionine metabolism by ethionine, an antimetabolite of methionine, induced abnormally higher expression of genes related to cell lineage differentiation and resulted in impaired blastocyst development of mouse preimplantation embryos in vitro. These effects were mitigated by the presence of methionine. Importantly, ethionine treatment induced lower trimethylation of histone H3 lysine 9 but did not affect methylation of DNA in the promoter regions of the examined genes. These results demonstrated that intact methionine metabolism is required for proper epigenetic histone modifications and normal expression of developmentally important genes during preimplantation development.


Endovascular stent grafting and open surgical replacement for chronic thoracic aortic aneurysms: a systematic review and prospective cohort study.
The management of chronic thoracic aortic aneurysms includes conservative management, watchful waiting, endovascular stent grafting and open surgical replacement. The Effective Treatments for Thoracic Aortic Aneurysms (ETTAA) study investigates timing and intervention choice. To describe pre- and post-intervention management of and outcomes for chronic thoracic aortic aneurysms. A systematic review of intervention effects; a Delphi study of 360 case scenarios based on aneurysm size, location, age, operative risk and connective tissue disorders; and a prospective cohort study of growth, clinical outcomes, costs and quality of life. Thirty NHS vascular/cardiothoracic units. Patients aged > 17 years who had existing or new aneurysms of ≥ 4 cm in diameter in the arch, descending or thoracoabdominal aorta. Endovascular stent grafting and open surgical replacement. Pre-intervention aneurysm growth, pre-/post-intervention survival, clinical events, readmissions and quality of life; and descriptive statistics for costs and quality-adjusted life-years over 12 months and value of information using a propensity score-matched subsample. The review identified five comparative cohort studies (endovascular stent grafting patients, n = 3955; open surgical replacement patients, n = 21,197). Pooled short-term all-cause mortality favoured endovascular stent grafting (odds ratio 0.71, 95% confidence interval 0.51 to 0.98; no heterogeneity). Data on survival beyond 30 days were mixed. Fewer short-term complications were reported with endovascular stent grafting. The Delphi study included 20 experts (13 centres). For patients with aneurysms of ≤ 6.0 cm in diameter, watchful waiting was preferred. For patients with aneurysms of > 6.0 cm, open surgical replacement was preferred in the arch, except for elderly or high-risk patients, and in the descending aorta if patients had connective tissue disorders. Otherwise endovascular stent grafting was preferred. Between 2014 and 2018, 886 patients were recruited (watchful waiting, n = 489; conservative management, n = 112; endovascular stent grafting, n = 150; open surgical replacement, n = 135). Pre-intervention death rate was 8.6% per patient-year; 49.6% of deaths were aneurysm related. Death rates were higher for women (hazard ratio 1.79, 95% confidence interval 1.25 to 2.57; p = 0.001) and older patients (age 61-70 years: hazard ratio 2.50, 95% confidence interval 0.76 to 5.43; age 71-80 years: hazard ratio 3.49, 95% confidence interval 1.26 to 9.66; age > 80 years: hazard ratio 7.01, 95% confidence interval 2.50 to 19.62; all compared with age < 60 years, p < 0.001) and per 1-cm increase in diameter (hazard ratio 1.90, 95% confidence interval 1.65 to 2.18; p = 0.001). The results were similar for aneurysm-related deaths. Decline per year in quality of life was greater for older patients (additional change -0.013 per decade increase in age, 95% confidence interval -0.019 to -0.007; p < 0.001) and smokers (additional change for ex-smokers compared with non-smokers 0.003, 95% confidence interval -0.026 to 0.032; additional change for current smokers compared with non-smokers -0.034, 95% confidence interval -0.057 to -0.01; p = 0.004). At the time of intervention, endovascular stent grafting patients were older (age difference 7.1 years; 95% confidence interval 4.7 to 9.5 years; p < 0.001) and more likely to be smokers (75.8% vs. 66.4%; p = 0.080), have valve disease (89.9% vs. 71.6%; p < 0.0001), have chronic obstructive pulmonary disease (21.3% vs. 13.3%; p = 0.087), be at New York Heart Association stage III/IV (22.3% vs. 16.0%; p = 0.217), have lower levels of haemoglobin (difference -6.8 g/l, 95% confidence interval -11.2 to -2.4 g/l; p = 0.003) and take statins (69.3% vs. 42.2%; p < 0.0001). Ten (6.7%) endovascular stent grafting and 15 (11.1%) open surgical replacement patients died within 30 days of the procedure (p = 0.2107). One-year overall survival was 82.5% (95% confidence interval 75.2% to 87.8%) after endovascular stent grafting and 79.3% (95% confidence interval 71.1% to 85.4%) after open surgical replacement. Variables affecting survival were aneurysm site, age, New York Heart Association stage and time waiting for procedure. For endovascular stent grafting, utility decreased slightly, by -0.017 (95% confidence interval -0.062 to 0.027), in the first 6 weeks. For open surgical replacement, there was a substantial decrease of -0.160 (95% confidence interval -0.199 to -0.121; p < 0.001) up to 6 weeks after the procedure. Over 12 months endovascular stent grafting was less costly, with higher quality-adjusted life-years. Formal economic analysis was unfeasible. The study was limited by small numbers of patients receiving interventions and because only 53% of patients were suitable for both interventions. Small (4-6 cm) aneurysms require close observation. Larger (> 6 cm) aneurysms require intervention without delay. Endovascular stent grafting and open surgical replacement were successful for carefully selected patients, but cost comparisons were unfeasible. The choice of intervention is well established, but the timing of intervention remains challenging. Further research should include an analysis of the risk factors for growth/rupture and long-term outcomes. Current Controlled Trials ISRCTN04044627 and NCT02010892. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 6. See the NIHR Journals Library website for further project information.


Urinary cytokines and steroid responsiveness in idiopathic nephrotic syndrome of childhood.
Steroid-resistant nephrotic syndrome (SRNS) has been associated with activation of TGF-beta(1) and progression to chronic kidney disease. Steroid-sensitive nephrotic syndrome (SSNS) has been associated with activation of T-cells and favorable outcome. Our objective was to distinguish SRNS from SSNS and focal segmental glomerulosclerosis (FSGS) from minimal change disease (MCD) on the basis of urinary cytokine profile. We used a high-throughput cytokine array. ICAM-1 and TGF-beta(1) in urine and kidney tissue were evaluated by ELISA and immunohistochemistry (IHC), respectively. Age, gender, race, body mass index, and glomerular filtration rate were similar among groups. There were no statistically significant differences between SRNS (n = 12) and SSNS (n = 12) in regard to the presence of hypertension, treatment with ACE inhibitors, and renal histology. Arrays detected a 1- to 5.5-fold increase in urinary cytokine expression in subjects with idiopathic nephrotic syndrome (INS) as compared to controls. Using ELISA, urinary excretion of ICAM-1 was significantly higher in INS subjects than in controls (control group, n = 12; p = 0.005), but it did not differentiate SRNS from SSNS, or FSGS from MCD. IHC failed to reveal differences in renal tissue expression of ICAM-1 among controls, SRNS and SSNS. There were no significant differences among controls, and patients with SRNS and SSNS in the urinary excretion of TGF-beta(1) (p = 0.21). However, urinary TGF-beta(1) levels were significantly higher in FSGS than in MCD (p = 0.03), and IHC showed increased immunoreactivity in FSGS. Our data indicate that urinary TGF-beta(1) was able to differentiate between FSGS and MCD but was not a biomarker of steroid responsiveness.


NIMA-related kinases 6, 4, and 5 interact with each other to regulate microtubule organization during epidermal cell expansion in Arabidopsis thaliana.
NimA-related kinase 6 (NEK6) has been implicated in microtubule regulation to suppress the ectopic outgrowth of epidermal cells; however, its molecular functions remain to be elucidated. Here, we analyze the function of NEK6 and other members of the NEK family with regard to epidermal cell expansion and cortical microtubule organization. The functional NEK6-green fluorescent protein fusion localizes to cortical microtubules, predominantly in particles that exhibit dynamic movement along microtubules. The kinase-dead mutant of NEK6 (ibo1-1) exhibits a disturbance of the cortical microtubule array at the site of ectopic protrusions in epidermal cells. Pharmacological studies with microtubule inhibitors and quantitative analysis of microtubule dynamics indicate excessive stabilization of cortical microtubules in ibo1/nek6 mutants. In addition, NEK6 directly binds to microtubules in vitro and phosphorylates β-tubulin. NEK6 interacts and co-localizes with NEK4 and NEK5 in a transient expression assay. The ibo1-3 mutation markedly reduces the interaction between NEK6 and NEK4 and increases the interaction between NEK6 and NEK5. NEK4 and NEK5 are required for the ibo1/nek6 ectopic outgrowth phenotype in epidermal cells. These results demonstrate that NEK6 homodimerizes and forms heterodimers with NEK4 and NEK5 to regulate cortical microtubule organization possibly through the phosphorylation of β-tubulins.


The role of prenatal maternal stress in the development of childhood anxiety symptomatology: The QF2011 Queensland Flood Study.
It is possible that findings suggesting a link between prenatal maternal stress (PNMS) and anxiety symptoms in offspring are confounded by postnatal and/or shared mother-child heritability effects. Following exposure to a natural disaster, the Queensland Flood Study investigated the unique and additive effects of various types of disaster-related PNMS (objective hardship, cognitive appraisal, and subjective distress) on childhood anxiety symptomatology (internalizing and/or anxiety symptom measures). Timing of flood exposure during pregnancy and child sex were examined as potential moderators. After controlling for maternal psychosocial factors, greater objective hardship as a result of the floods was significantly associated with greater anxiety symptoms (N = 114) and marginally associated with greater internalizing behaviors (N = 115). Earlier timing of the flood in pregnancy was associated with greater anxiety symptoms. No such associations were found between any PNMS measure and teacher-rated child internalizing behaviors (N = 90). Sex and timing did not moderate associations. Our findings suggest that, in isolation, increased maternal hardship due to exposure to an independent stressor, during pregnancy, may have a programming effect on childhood anxiety symptoms.


Biomechanical effects of cervical lesions and restoration on periodontally compromised teeth.
The purpose of this study was to photoelastically evaluate the effects of cervical root lesions and their restoration on stress distribution in periodontally compromised teeth. Three-dimensional composite photoelastic models of a maxillary first premolar with buccal cervical root lesions were fabricated. Two different lesion configurations, wedge- and shallow saucer-shaped, at 20% alveolar bone height reduction were tested. A 35% reduction model was given a wedge-shaped lesion. The lesions were restored with microfine resin composite. Vertical loads of 7.5 lbs were applied to the unrestored and restored models at the tip of the buccal cusp and the tip of the lingual cusp. The resulting stresses within the tooth models were monitored and recorded photographically in the field of a circular polariscope arrangement. For buccal cusp loading of the unrestored models, stress concentrated at the apex of the lesion regardless of the lesion shape or periodontal support conditions. The highest stress concentration was observed around the apex of the wedge-shaped lesion on the 35% reduction model. Restoring the lesions changed stress distribution. Restoration of the lesions resulted in a marked stress reduction at the lesion apex. Stress along the gingival restoration-model interface was characteristic for the restored situation. The interfacial stress followed the contour of the restoration most closely for the wedge-shaped lesion on the 20% support reduction model. The shape and dimension of the lesion as well as periodontal support status has considerable influence on stress distribution, especially around the lesion, restored or not restored.


Structural studies by proton magnetic relaxation of stereochemical probes. II. Allosteric effects in human methaemoglobin.
The haem-iron accessibility to solvent molecules in human aquomet- and fluoromethaemoglobin was studied by the magnetic relaxation of protons from a stereochemical probe (methanol in deuterated solutions) in its dependence on allosteric effects induced by inositol hexaphosphate and pH between 5.5 and 8.5. The exchange of methanol with bulk solvent was observed only when inositol hexaphosphate was bound to aquomethaemoglobin, which is consistent with a widening of the haemcrevice compared to the conformation in the absence of inositol hexaphosphate. An increase in alkalinity in the physiological range of the Bohr effect results in a gradual impedence of the solvent dynamics inside the haem-pocket. The fast-relaxation phase of methyl protons indicates that a large number of methanol molecules are under the strong influence of the protein; this effect is considerably smaller with inositol hexaphosphate bound to aquomethaemoglobin. The hypothesis which implies a proton from the coordinated water molecule is responsible for the observed relaxation rates has been critically discussed. The model with a water molecule exchanging between a position next to the sixth-ligand site of the haem-iron and the bulk solvent is further substantiated experimentally. This model has been found to be the simplest and most self consistent in the interpretation of all these proton magnetic relaxation data.


An Analysis Pipeline with Statistical and Visualization-Guided Knowledge Discovery for Michigan-Style Learning Classifier Systems.
Michigan-style learning classifier systems (M-LCSs) represent an adaptive and powerful class of evolutionary algorithms which distribute the learned solution over a sizable population of rules. However their application to complex real world data mining problems, such as genetic association studies, has been limited. Traditional knowledge discovery strategies for M-LCS rule populations involve sorting and manual rule inspection. While this approach may be sufficient for simpler problems, the confounding influence of noise and the need to discriminate between predictive and non-predictive attributes calls for additional strategies. Additionally, tests of significance must be adapted to M-LCS analyses in order to make them a viable option within fields that require such analyses to assess confidence. In this work we introduce an M-LCS analysis pipeline that combines uniquely applied visualizations with objective statistical evaluation for the identification of predictive attributes, and reliable rule generalizations in noisy single-step data mining problems. This work considers an alternative paradigm for knowledge discovery in M-LCSs, shifting the focus from individual rules to a global, population-wide perspective. We demonstrate the efficacy of this pipeline applied to the identification of epistasis (i.e., attribute interaction) and heterogeneity in noisy simulated genetic association data.


Construction of 3D micropatterned surfaces with wormlike and superhydrophilic PEG brushes to detect dysfunctional cells.
Detection of dysfunctional and apoptotic cells plays an important role in clinical diagnosis and therapy. To develop a portable and user-friendly platform for dysfunctional and aging cell detection, we present a facile method to construct 3D patterns on the surface of styrene-b-(ethylene-co-butylene)-b-styrene elastomer (SEBS) with poly(ethylene glycol) brushes. Normal red blood cells (RBCs) and lysed RBCs (dysfunctional cells) are used as model cells. The strategy is based on the fact that poly(ethylene glycol) brushes tend to interact with phosphatidylserine, which is in the inner leaflet of normal cell membranes but becomes exposed in abnormal or apoptotic cell membranes. We demonstrate that varied patterned surfaces can be obtained by selectively patterning atom transfer radical polymerization (ATRP) initiators on the SEBS surface via an aqueous-based method and growing PEG brushes through surface-initiated atom transfer radical polymerization. The relatively high initiator density and polymerization temperature facilitate formation of PEG brushes in high density, which gives brushes worm-like morphology and superhydrophilic property; the tendency of dysfunctional cells adhered on the patterned surfaces is completely different from well-defined arrays of normal cells on the patterned surfaces, providing a facile method to detect dysfunctional cells effectively. The PEG-patterned surfaces are also applicable to detect apoptotic HeLa cells. The simplicity and easy handling of the described technique shows the potential application in microdiagnostic devices.


Treatment of active tuberculosis in HIV-coinfected patients: a systematic review and meta-analysis.
Patients with human immunodeficiency virus (HIV) infection and tuberculosis have an increased risk of death, treatment failure, and relapse. A systematic review and meta-analysis of randomized, controlled trials and cohort studies was conducted to evaluate the impact of duration and dosing schedule of rifamycin and use of antiretroviral therapy in the treatment of active tuberculosis in HIV-positive patients. In included studies, the initial tuberculosis diagnosis, failure, and/or relapse were microbiologically confirmed, and patients received standardized rifampin- or rifabutin-containing regimens. Pooled cumulative incidence of treatment failure, death during treatment, and relapse were calculated using random-effects models. Multivariable meta-regression was performed using negative binomial regression. After screening 5158 citations, 6 randomized trials and 21 cohort studies were included. Relapse was more common with regimens using 2 months rifamycin (adjusted risk ratio, 3.6; 95% confidence interval, 1.1-11.7) than with regimens using rifamycin for at least 8 months. Compared with daily therapy in the initial phase (n=3352 patients from 35 study arms), thrice-weekly therapy (n=211 patients from 5 study arms) was associated with higher rates of failure (adjusted risk ratio, 4.0; 95% confidence interval, 1.5-10.4) and relapse [adjusted risk ratio, 4.8; 95% confidence interval, 1.8-12.8). There were trends toward higher relapse rates if rifamycins were used for only 6 months, compared with > or =8 months, or if antiretroviral therapy was not used. This review raises serious concerns regarding current recommendations for treatment of HIV-tuberculosis coinfection. The data suggest that at least 8 months duration of rifamycin therapy, initial daily dosing, and concurrent antiretroviral therapy might be associated with better outcomes, but adequately powered randomized trials are urgently needed to confirm this.


Genome recoding by tRNA modifications.
RNA modifications are emerging as an additional regulatory layer on top of the primary RNA sequence. These modifications are particularly enriched in tRNAs where they can regulate not only global protein translation, but also protein translation at the codon level. Modifications located in or in the vicinity of tRNA anticodons are highly conserved in eukaryotes and have been identified as potential regulators of mRNA decoding. Recent studies have provided novel insights into how these modifications orchestrate the speed and fidelity of translation to ensure proper protein homeostasis. This review highlights the prominent modifications in the tRNA anticodon loop: queuosine, inosine, 5-methoxycarbonylmethyl-2-thiouridine, wybutosine, threonyl-carbamoyl-adenosine and 5-methylcytosine. We discuss the functional relevance of these modifications in protein translation and their emerging role in eukaryotic genome recoding during cellular adaptation and disease.


A comparison of cancer detection rates achieved by breast cancer screening programmes by number of readers, for one and two view mammography: results from the UK National Health Service breast screening programme.
To determine the increased cancer detection rate, if any, of programmes in the UK National Health Service breast screening programme (NHSBSP) using more than single reading of mammograms. Information on the detection of cancers by individual screening programmes from annual (KC62) returns, supplemented by questionnaire information about the number of readers. The 87 NHSBSP programmes from England and Wales for the screening year 1 April 1996 to 31 March 1997. The study includes all programmes for prevalent screens where two views are mandatory, but excludes the four programmes using two view mammography for incident screening. Cancer detection, invasive cancer detection, and small (< 15 mm) invasive cancer detection by mammographic reading protocol using single reading as the reference level. Programmes collectively using single reading detected the lowest rate of cancers at both prevalent (first) and incident (subsequent) screening. The highest rate of age standardised cancer detection was achieved by programmes using double reading with arbitration. At prevalent screens, where all programmes used two views, those programmes using double reading with arbitration detected 32% (95% confidence interval (CI) 3% to 69%) more small (< 15 mm) invasive cancers than programmes using single reading. At incident screens, where all programmes analysed used one view this increased to 73% (95% CI 40% to 113%). Recall rates showed no obvious difference between single reading and the double reading protocols, being around 7% for prevalent screens and 3.5% for incident screens. The results suggest that the increase in cancer detection resulting from increasing the number of readers depends on the number of views, and is higher for one view than two views. Single reading of one view results in a low detection rate of small invasive cancers for most individual programmes. It is, however, recognised that a small number of individual readers may achieve high detection rates with such a protocol. All groups of programmes using different reader/view protocols are on average close to or above target cancer detection rates, except those using single reading of one view (mediolateral oblique) at incident screens.


Integration of Novel Materials and Advanced Genomic Technologies into New Vaccine Design.
Designing new vaccines is one of the most challenging tasks for public health to prevent both infectious and chronic diseases. Even though many research scientists have spent great efforts in improving the specificity, sensitivity and safety of current available vaccines, there are still much space on how to effectively combine different biomaterials and technologies to design universal or personalized vaccines. Traditionally, vaccines were made based on empirical approaches designed to mimic immunity induced by natural infection. Either live attenuated or killed whole microorganisms were used as vaccines. With the development of biomaterial science, DNA/RNA, recombinant vector, adjuvant and nanoparticles greatly expand the category of vaccines. More importantly, with the tremendous advances of new technologies including genomics, proteomics and immunomics, the paradigm of vaccine design has shifted from microbiological to sequence-based approaches. This ever-growing large amount of genomic data and new genomic approaches such as comparative genomics, reverse vaccinology and pan-genomics, will play critical roles in novel vaccine design and enable development of more effective vaccines to cure and control both chronic and infectious diseases. In this review, we summarize current various vaccine materials, advanced technologies and combinational strategies to integrate biomaterials and advanced technologies for vaccine design, which we hope will provide some very useful guidelines and perspectives for the vaccine design.


Anterior approaches to fusion of the cervical spine: a metaanalysis of fusion rates.
Anterior cervical discectomy (ACD), ACD with interbody fusion (ACDF), ACDF with placement of an anterior plate system (ACDFP), corpectomy, and corpectomy with plate placement are used to fuse the cervical spine. The authors conducted a metaanalysis of studies published after 1990 in which fusion rates achieved with each procedure were reported for patients with degenerative disease at one, two, and three disc levels. Twenty-one papers each included data on at least 25 patients. In each of the 21 studies the average clinical follow up was more than 12 months, and the results were evaluated according to radiographic evidence of fusion and delineated by the number of levels fused. Chi-square and Fisher exact tests were used for comparisons. The mean age of the patients was 46.7 years, 46.6% were female, and the mean follow-up period was 39.6 months. The studies included 2682 patients and the overall fusion rate was 89.5%. For single disc-level disease, fusion rates were 84.9% for ACD, 92.1% for ACDF, and 97.1% for ACDFP (p = 0.0002). For two disc-level disease, fusion rates were 79.9% for ACDF, 94.6% for ACDFP, 95.9% for corpectomy, and 92.9% for corpectomy with plate placement (p = 0.0001). For three disc-level disease, fusion rates were 65.0% for ACDF, 82.5% for ACDFP, 89.8% for corpectomy, and 96.2% for corpectomy with plate placement (p = 0.0001). The use of anterior plates significantly improved fusion for one-level (p < 0.0001), two-level (p < 0.0001), and three-level (p < 0.05) ACDF. There was no significant difference in fusion rates between two-level ACDF and corpectomy with plate placement. The anticipated fusion rate is one of several factors that may guide surgical decision making. Anterior cervical decompression and fusion results in high fusion rates. The results of the authors' study show that regardless of the number of levels fused, the use of an anterior cervical plate system significantly increases the fusion rate. For two-disc-level disease, there was no significant difference between ACD with a plate system or corpectomy with a plate system. For three-disc-level disease, however, the evidence suggests that corpectomy with plate placement is associated with higher fusion rates than discectomy with plate placement.


Bridge Centrality: A Network Approach to Understanding Comorbidity.
Recently, researchers in clinical psychology have endeavored to create network models of the relationships between symptoms, both within and across mental disorders. Symptoms that connect two mental disorders are called "bridge symptoms." Unfortunately, no formal quantitative methods for identifying these bridge symptoms exist. Accordingly, we developed four network statistics to identify bridge symptoms: bridge strength, bridge betweenness, bridge closeness, and bridge expected influence. These statistics are nonspecific to the type of network estimated, making them potentially useful in individual-level psychometric networks, group-level psychometric networks, and networks outside the field of psychopathology such as social networks. We first tested the fidelity of our statistics in predicting bridge nodes in a series of simulations. Averaged across all conditions, the statistics achieved a sensitivity of 92.7% and a specificity of 84.9%. By simulating datasets of varying sample sizes, we tested the robustness of our statistics, confirming their suitability for network psychometrics. Furthermore, we simulated the contagion of one mental disorder to another, showing that deactivating bridge nodes prevents the spread of comorbidity (i.e., one disorder activating another). Eliminating nodes based on bridge statistics was more effective than eliminating nodes high on traditional centrality statistics in preventing comorbidity. Finally, we applied our algorithms to 18 group-level empirical comorbidity networks from published studies and discussed the implications of this analysis.


CCR4/NOT complex associates with the proteasome and regulates histone methylation.
The proteasome regulates histone lysine methylation and gene transcription, but how it does so is poorly understood. To better understand this process, we used the epistatic miniarray profile (E-MAP) approach to identify factors that genetically interact with proteasomal subunits. In addition to members of the Set1 complex that mediate histone H3 lysine 4 methylation (H3K4me), we found that deleting members of the CCR4/NOT mRNA processing complex exhibit synthetic phenotypes when combined with proteasome mutants. Further biochemical analyses revealed physical associations between CCR4/NOT and the proteasome in vivo. Consistent with the genetic and biochemical interactions linking CCR4/NOT with proteasome and Set1-mediated methylation, we find that loss of Not4 decreases global and gene-specific H3K4 trimethylation (H3K4me3) and decreases 19S proteasome recruitment to the PMA1 gene. Similar to proteasome regulation of histone methylation, loss of CCR4/NOT members does not affect ubiquitinated H2B. Mapping of Not4 identified the RING finger domain as essential for H3K4me3, suggesting a role for ubiquitin in this process. Consistent with this idea, loss of the Not4-interacting protein Ubc4, a known ubiquitin-conjugating enzyme, decreases H3K4me3. These studies implicate CCR4/NOT in the regulation of H3K4me3 through a ubiquitin-dependent pathway that likely involves the proteasome.


Predicting adult obesity from measures in earlier life.
As most obese adults were not overweight as children, the prediction of adult obesity from childhood body size alone is limited. We constructed a two-way, multifactor risk assessment framework for predicting adult obesity during childhood using the Foresight Obesity System Map and tested it against longitudinal data from the 1958 National Child Development Study. The framework divided study participants according to two categories of risk: 'conditioning factors' (past/fixed events and conditions) and 'intervention factors' (present and modifiable). At the age of 11 years, conditioning factors were 'low/high birth weight' and 'absence of breastfeeding', and intervention factors were 'low childhood activity level' and 'having at least one obese parent'. From a composite score of all four variables, study participants were assigned to one of the four risk groups: low risk, past 'conditioning' risk only, present 'intervention' risk only and high combined risk. ORs and relative risks for the development of future overweight/obesity at ages 23, 33 and 42 years were calculated for each risk group. Those identified in the highest risk category at the age of 11 were around twice as likely to become overweight (body mass index (BMI)≥25 kg/m(2)) by the age of 23 years, and obese (BMI≥30 kg/m(2)) by ages 33 and 42 years, in comparison to their low-risk peers (total sample, N=11 752). Increased prevalence of future obesity was also observed for high-risk children who were not already overweight at the age of 11 (filtered sample, N=9549). This framework identifies a greater proportion of the population that is at risk for future obesity than does childhood weight assessment alone.


Optical materials research.
There are eras in research when days are filled with excitement because unique materials are being produced and researchers "think what nobody else has thought" (Albert von Szent Gyorgyi). Such were the periods when many new optical glasses emerged from the laboratories of the Eastman Kodak Company and when the hot pressing technology was applied to produce new polycrystalline materials. This paper discusses the people and accomplishments of those periods.


A genetic and molecular analysis of the 46C chromosomal region surrounding the FMRFamide neuropeptide gene in Drosophila melanogaster.
We have analyzed the FMRFamide neuropeptide gene region of Drosophila melanogaster. This gene maps to the 46C region of chromosome 2R; this interval previously was not well characterized. For this genetic and molecular analysis, we have used X-ray mutagenesis, EMS mutagenesis, and the recently reported local P element transposition method. We identified four overlapping deletions, two of which have proximal breakpoints that define a 50-60-kb region surrounding the FMRFamide gene in 46C. To this small region, we mapped three lethal complementation groups; 10 additional lethal complementation groups were mapped to more distal regions of 46CD. One of these groups corresponds to even-skipped, the other 12 are previously unidentified. Using various lines of evidence we excluded the possibility that FMRFamide corresponds to any of the three lethal complementation groups mapping to its immediate 50-60-kb vicinity. The positions of two of the three lethal complementation groups were identified with P elements using a local transposition scheme. The third lethal complementation group was excluded as being FMRFamide mutants by sequence analysis and by immunocytochemistry with proFMRFamide precursor-specific antibodies. This analysis has (1) provided a genetic map of the 46CD chromosomal region and a detailed molecular map of a portion of the 46C region and (2) provided additional evidence of the utility of local transposition for targeting nearby genes.


Interval prevalence of and factors associated with colic in horses hospitalized for ocular or orthopedic disease.
OBJECTIVE To determine interval (1-year) prevalence of and factors associated with colic in horses hospitalized for ocular or orthopedic disease. DESIGN Cross-sectional study. ANIMALS 105 horses with ocular disease and 197 horses with orthopedic disease admitted to a veterinary teaching hospital between July 1, 2011, and June 30, 2012. PROCEDURES Medical records were reviewed to determine whether colic (abnormal behavior prompting abdominal palpation per rectum or nasogastric intubation) was observed during hospitalization. Data were collected on putative risk factors for colic, including reason for admission, signalment, and medical or surgical interventions received. RESULTS No significant difference in interval prevalence of colic was identified between horses with ocular disease (8/105 [8%]) or orthopedic disease (9/197 [5%]). However, horses with ocular disease differed significantly from other horses in median age (10 vs 3 years, respectively); proportions of sexually intact males (3% vs 30%), Thoroughbreds (28% vs 62%), and those receiving general anesthesia (65% vs 80%); and median duration of hospitalization (3 vs 2 days). For every 1 mg/kg increase in daily NSAID dose, the odds of colic increased by 98%. No difference between groups was identified in median duration of colic (1 day), hospitalization (7 vs 3 days), or systemic NSAID administration (7 vs 5 days). Colic in both groups resolved with medical management for all but 1 horse with ocular disease. CONCLUSIONS AND CLINICAL RELEVANCE Horses hospitalized for ocular disease were at no greater odds for colic than were horses hospitalized for orthopedic disease. Medical management of colic appeared adequate for most horses.


Jarid2 binds mono-ubiquitylated H2A lysine 119 to mediate crosstalk between Polycomb complexes PRC1 and PRC2.
The Polycomb repressive complexes PRC1 and PRC2 play a central role in developmental gene regulation in multicellular organisms. PRC1 and PRC2 modify chromatin by catalysing histone H2A lysine 119 ubiquitylation (H2AK119u1), and H3 lysine 27 methylation (H3K27me3), respectively. Reciprocal crosstalk between these modifications is critical for the formation of stable Polycomb domains at target gene loci. While the molecular mechanism for recognition of H3K27me3 by PRC1 is well defined, the interaction of PRC2 with H2AK119u1 is poorly understood. Here we demonstrate a critical role for the PRC2 cofactor Jarid2 in mediating the interaction of PRC2 with H2AK119u1. We identify a ubiquitin interaction motif at the amino-terminus of Jarid2, and demonstrate that this domain facilitates PRC2 localization to H2AK119u1 both in vivo and in vitro. Our findings ascribe a critical function to Jarid2 and define a key mechanism that links PRC1 and PRC2 in the establishment of Polycomb domains.


Fructose, exercise, and health.
The large daily energy intake common among athletes can be associated with a large daily intake of fructose, a simple sugar that has been linked to metabolic disorders. Fructose commonly is found in foods and beverages as a natural component (e.g., in fruits) or as an added ingredient (as sucrose or high fructose corn syrup [HFCS]). A growing body of research suggests that excessive intake of fructose (e.g., >50 g.d(-1)) may be linked to development of the metabolic syndrome (obesity, dyslipidemia, hypertension, insulin resistance, proinflammatory state, prothrombosis). The rapid metabolism of fructose in the liver and resultant drop in hepatic adenosine triphosphate (ATP) levels have been linked with mitochondrial and endothelial dysfunction, alterations that could predispose to obesity, diabetes, and hypertension. However, for athletes, a positive aspect of fructose metabolism is that, in combination with other simple sugars, fructose stimulates rapid fluid and solute absorption in the small intestine and helps increase exogenous carbohydrate oxidation during exercise, an important response for improving exercise performance. Although additional research is required to clarify the possible health-related implications of long-term intake of large amounts of dietary fructose among athletes, regular exercise training and consequent high daily energy expenditure may protect athletes from the negative metabolic responses associated with chronically high dietary fructose intake.


Lawsonia inermis L. leaves aqueous extract as a natural antioxidant and antibacterial product.
This study was carried out to investigate the biomedicinal potential of aqueous extract (1.25 and 2.5%) of three henna ecotypes (Shahdad, Roodbar and Bam) against Two types of Gram positive and negative bacteria, Staphylococcus aureus (ATCC 25923), Streptococcus agalactiae (ATCC 29933), Bacillus cereus (ATCC 14579), Corynebacterium pseudotuberculosis (ATCC 19410), Klebsiella pneumonia (ATCC 700603), Escherichia coli (ATCC 25922) and Salmonella enterica serovar typhi (ATCC 19430). Henna extract prevent the growth of bacteria in a dose dependent manner. The species of K. pneumonia and B. cereus showed higher resistant to henna aqueous extract compared with other bacteria species. Leaves aqueous extract of Shahdad ecotype had the highest antioxidant activity compared with those of the other ecotypes. The highest amount of 2-hydroxy-1,4-naphthoquinone as an antibacterial compound was obtained in Bam ecotype. The results also implies that other phytochemical compounds may have contributed in antibacterial and antioxidant activity of henna and thus further study needs to be done to explore them.[Formula: see text].


Methamphetamine abuse affects gene expression in brain-derived microglia of SIV-infected macaques to enhance inflammation and promote virus targets.
Methamphetamine (Meth) abuse is a major health problem linked to the aggravation of HIV- associated complications, especially within the Central Nervous System (CNS). Within the CNS, Meth has the ability to modify the activity/function of innate immune cells and increase brain viral loads. Here, we examined changes in the gene expression profile of neuron-free microglial cell preparations isolated from the brain of macaques infected with the Simian Immunodeficiency Virus (SIV), a model of neuroAIDS, and exposed to Meth. We aimed to identify molecular patterns triggered by Meth that could explain the detection of higher brain viral loads and the development of a pro-inflammatory CNS environment in the brain of infected drug abusers. We found that Meth alone has a strong effect on the transcription of genes associated with immune pathways, particularly inflammation and chemotaxis. Systems analysis led to a strong correlation between Meth exposure and enhancement of molecules associated with chemokines and chemokine receptors, especially CXCR4 and CCR5, which function as co-receptors for viral entry. The increase in CCR5 expression was confirmed in the brain in correlation with increased brain viral load. Meth enhances the availability of CCR5-expressing cells for SIV in the brain, in correlation with increased viral load. This suggests that Meth is an important factor in the susceptibility to the infection and to the aggravated CNS inflammatory pathology associated with SIV in macaques and HIV in humans.


Influence of PEGylation of Vitamin-K-Loaded Mixed Micelles on the Uptake by and Transport through Caco-2 Cells.
The aim of the study is to investigate the uptake by and transport through Caco-2 cells of two mixed micelle formulations (based on egg phosphatidylcholine and glycocholic acid) of vitamin K, i.e., with and without DSPE-PEG2000. The uptake of vitamin K and fluorescently labeled mixed micelles with and without PEG coating showed similar kinetics and their uptake ratio remained constant over time. Together with the fact that an inhibitor of scavenger receptor B1 (BLT-1) decreased cellular uptake of vitamin K by ∼80% compared to the uptake in the absence of this inhibitor, we conclude that both types of micelles loaded with vitamin K can be taken up intactly by Caco-2 cells via this scavenger receptor. The amount of vitamin K in chylomicrons fraction from Caco-2 cell monolayers further indicates that mixed micelles (with or without PEGylation) are likely packed into chylomicrons after internalization by Caco-2 cells. Uptake of vitamin K from PEGylated mixed micelles increased four- to five-fold at simulated gastrointestinal conditions. In conclusion, PEGylated mixed micelles are stable upon exposure to simulated gastric conditions, and as a result, they do show overall a higher cellular uptake efficiency of vitamin K as compared to mixed micelles without PEG coating.


Role of Toll-Like Receptor 5 (TLR5) in Experimental Melioidosis.
The Gram-negative intracellular pathogen Burkholderia pseudomallei is the causative agent of melioidosis, an important cause of sepsis in Southeast Asia. Recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) is essential for an appropriate immune response during pathogen invasion. In patients with melioidosis, TLR5 is the most abundantly expressed TLR, and a hypofunctional TLR5 variant has been associated with improved survival. Here, we studied the functional role of TLR5 and its ligand flagellin in experimental melioidosis. First, we observed differential TLR5 expression in the pulmonary and hepatic compartments upon infection with B. pseudomallei Next, we found that B. pseudomallei-challenged TLR5-deficient (Tlr5-/- ) mice were more susceptible to infection than wild-type (WT) mice, as demonstrated by higher systemic bacterial loads, increased organ injury, and impaired survival. Lung bacterial loads were not different between the two groups. The phenotype was flagellin independent; no difference in in vivo virulence was observed for the flagellin-lacking mutant MM36 compared to the wild-type B. pseudomallei strain 1026b. Tlr5-/- mice showed a similar impaired antibacterial defense when infected with MM36 or 1026b. Ex vivo experiments showed that TLR5-deficient macrophages display markedly impaired phagocytosis of B. pseudomallei In conclusion, these data suggest that TLR5 deficiency has a detrimental flagellin-independent effect on the host response against pulmonary B. pseudomallei infection.


Therapeutic applications of pomegranate (Punica granatum L.): a review.
The pomegranate, Punica granatum L., is an ancient, mystical, unique fruit borne on a small, long-living tree cultivated throughout the Mediterranean region, as far north as the Himalayas, in Southeast Asia, and in California and Arizona in the United States. In addition to its ancient historical uses, pomegranate is used in several systems of medicine for a variety of ailments. The synergistic action of the pomegranate constituents appears to be superior to that of single constituents. In the past decade, numerous studies on the antioxidant, anticarcinogenic, and anti-inflammatory properties of pomegranate constituents have been published, focusing on treatment and prevention of cancer, cardiovascular disease, diabetes, dental conditions, erectile dysfunction, bacterial infections and antibiotic resistance, and ultraviolet radiation-induced skin damage. Other potential applications include infant brain ischemia, male infertility, Alzheimer's disease, arthritis, and obesity.


Lipid vesicles and other colloids as drug carriers on the skin.
Colloids from an aqueous suspension can cross the skin barrier only through hydrophilic pathways. Various colloids have a different ability to do this by penetrating narrow pores of fixed size in the skin, or the relevant nano-pores in barriers modelling the skin. Such ability is governed by colloid adaptability, which must be high enough to allow penetrant deformation to the size of a pore in such barrier: for a 100 nm colloid trespassing the skin this means at least 5-fold deformation/elongation. (Lipid) Bilayer vesicles are normally more adaptable than the comparably large (lipid coated) fluid droplets. One of the reasons for this, and an essential condition for achieving a high bilayer adaptability and pore penetration, is a high bilayer membrane elasticity. The other reason is the relaxation of changing colloid's volume-to-surface constraint during pore penetration; it stands to reason that such relaxation requires a concurrent, but only transient and local, bilayer permeabilisation. Both these phenomena are reflected in bilayer composition sensitivity, which implies non-linear pressure dependency of the apparent barrier penetrability, for example. Amphipats that acceptably weaken a membrane (surfactants, (co)solvents, such as certain alcohols, etc.) consequently facilitate controlled, local bilayer destabilisation and increase lipid bilayer flexibility. When used in the right quantity, such additives thus lower the energetic expense for elastic bilayer deformation, associated with pore penetration. Another prerequisite for aggregate transport through the skin is the colloid-induced opening of the originally very narrow ( approximately 0.4 nm) gaps between cells in the barrier to pores with diameter above 30 nm. Colloids incapable of enforcing such widening-and simultaneously of self-adapting to the size of 20-30 nm without destruction-are confined to the skin surface. All relatively compact colloids seem to fall in this latter category. This includes mixed lipid micelles, solid (nano)particles, nano-droplets, biphasic vesicles, etc. Such colloids, therefore, merely enter the skin through the rare wide gaps between groups of skin cells near the organ surface. Transdermal drug delivery systems based on corresponding drug formulations, therefore, rely on simple drug diffusion through the skin; the colloid then, at best, can modulate drug transport through the barrier. In contrast, the adaptability-and stability-optimised mixed lipid vesicles (Transfersomes, a trademark of IDEA AG) can trespass much narrower pathways between most cells in the skin; such highly adaptable colloids thus mediate drug transport through the skin. Sufficiently stable ultra-adaptable carriers, therefore, can ensure targeted drug delivery deep below the application site. This has already been shown in numerous preclinical tests and several phase I and phase II clinical studies. Drug delivery by means of highly adaptable drug carriers, moreover, allows highly efficient and well-tolerated drug targeting into the skin proper. Sustained drug release through the skin into systemic blood circulation is another field of ultradeformable drug carrier application.


Methicillin-resistant Staphylococcus aureus in hospitals and the community: stealth dynamics and control catastrophes.
Methicillin-resistant Staphylococcus aureus (MRSA) represents a serious threat to the health of hospitalized patients. Attempts to reduce the spread of MRSA have largely depended on hospital hygiene and patient isolation. These measures have met with mixed success: although some countries have almost eliminated MRSA or remained largely free of the organism, others have seen substantial increases despite rigorous control policies. We use a mathematical model to show how these increases can be explained by considering both hospital and community reservoirs of MRSA colonization. We show how the timing of the intervention, the level of resource provision, and chance combine to determine whether control measures succeed or fail. We find that even control measures able to repeatedly prevent sustained outbreaks in the short-term can result in long-term control failure resulting from gradual increases in the community reservoir. If resources do not scale with MRSA prevalence, isolation policies can fail "catastrophically."


Outcomes of Active Surveillance for Ductal Carcinoma in Situ: A Computational Risk Analysis.
Ductal carcinoma in situ (DCIS) is a noninvasive breast lesion with uncertain risk for invasive progression. Usual care (UC) for DCIS consists of treatment upon diagnosis, thus potentially overtreating patients with low propensity for progression. One strategy to reduce overtreatment is active surveillance (AS), whereby DCIS is treated only upon detection of invasive disease. Our goal was to perform a quantitative evaluation of outcomes following an AS strategy for DCIS. Age-stratified, 10-year disease-specific cumulative mortality (DSCM) for AS was calculated using a computational risk projection model based upon published estimates for natural history parameters, and Surveillance, Epidemiology, and End Results data for outcomes. AS projections were compared with the DSCM for patients who received UC. To quantify the propagation of parameter uncertainty, a 95% projection range (PR) was computed, and sensitivity analyses were performed. Under the assumption that AS cannot outperform UC, the projected median differences in 10-year DSCM between AS and UC when diagnosed at ages 40, 55, and 70 years were 2.6% (PR = 1.4%-5.1%), 1.5% (PR = 0.5%-3.5%), and 0.6% (PR = 0.0%-2.4), respectively. Corresponding median numbers of patients needed to treat to avert one breast cancer death were 38.3 (PR = 19.7-69.9), 67.3 (PR = 28.7-211.4), and 157.2 (PR = 41.1-3872.8), respectively. Sensitivity analyses showed that the parameter with greatest impact on DSCM was the probability of understaging invasive cancer at diagnosis. AS could be a viable management strategy for carefully selected DCIS patients, particularly among older age groups and those with substantial competing mortality risks. The effectiveness of AS could be markedly improved by reducing the rate of understaging.


The Trw type IV secretion system of Bartonella mediates host-specific adhesion to erythrocytes.
Bacterial pathogens typically infect only a limited range of hosts; however, the genetic mechanisms governing host-specificity are poorly understood. The alpha-proteobacterial genus Bartonella comprises 21 species that cause host-specific intraerythrocytic bacteremia as hallmark of infection in their respective mammalian reservoirs, including the human-specific pathogens Bartonella quintana and Bartonella bacilliformis that cause trench fever and Oroya fever, respectively. Here, we have identified bacterial factors that mediate host-specific erythrocyte colonization in the mammalian reservoirs. Using mouse-specific Bartonella birtlesii, human-specific Bartonella quintana, cat-specific Bartonella henselae and rat-specific Bartonella tribocorum, we established in vitro adhesion and invasion assays with isolated erythrocytes that fully reproduce the host-specificity of erythrocyte infection as observed in vivo. By signature-tagged mutagenesis of B. birtlesii and mutant selection in a mouse infection model we identified mutants impaired in establishing intraerythrocytic bacteremia. Among 45 abacteremic mutants, five failed to adhere to and invade mouse erythrocytes in vitro. The corresponding genes encode components of the type IV secretion system (T4SS) Trw, demonstrating that this virulence factor laterally acquired by the Bartonella lineage is directly involved in adherence to erythrocytes. Strikingly, ectopic expression of Trw of rat-specific B. tribocorum in cat-specific B. henselae or human-specific B. quintana expanded their host range for erythrocyte infection to rat, demonstrating that Trw mediates host-specific erythrocyte infection. A molecular evolutionary analysis of the trw locus further indicated that the variable, surface-located TrwL and TrwJ might represent the T4SS components that determine host-specificity of erythrocyte parasitism. In conclusion, we show that the laterally acquired Trw T4SS diversified in the Bartonella lineage to facilitate host-restricted adhesion to erythrocytes in a wide range of mammals.


Evaluating an Electronic Measure of Colorectal Cancer Screening at Indian Health Service Facilities, 2008-2010.
Colorectal cancer (CRC) is a leading cause of cancer mortality in American Indian and Alaska Native (AIAN) people, and incidence rates vary considerably among AIAN populations throughout the United States. Screening has the potential to prevent CRC deaths by detection and treatment of early disease or removal of precancerous polyps. Surveillance of CRC screening is critical to efforts to improve delivery of this preventive service, but existing CRC screening surveillance methods for AIAN are limited. The Government Performance and Results Act (GPRA) CRC screening clinical care measure provides data on CRC screening among AIAN populations. The aim of this study was to evaluate the accuracy of the GPRA measure for CRC screening (sensitivity, specificity, positive predictive value and negative predictive value), determine reasons for CRC screening misclassification (procedures noted as screening when they were actually diagnostic exams), and to suggest opportunities for improving surveillance for CRC screening nationwide for AIAN populations. Medical record reviews (paper and electronic) were compared to the GPRA-reported CRC screening status for 1,071 patients receiving care at tribal health facilities. A total of 8 tribal health facilities (2 small, 3 medium, and 3 large) participated in the study from the Pacific Coast, the Southwest, the Southern Plains, and Alaska IHS regions. Screening-eligible patients were identified using queries of the local electronic health record from January 2007 to December 2008, and medical chart reviews were completed at participating facilities from September 2008 to June 2010. Among 545 patients classified as screened by the GPRA measure, 305 (56%, CI: 52%-60%) had a false positive for screening as compared with medical record review. The overall sensitivity of the GPRA measure for CRC screening was 93% (CI=89%-95%) while specificity was 62% (CI: 59%-66%). The most common reasons for misclassification were for diagnostic or surveillance tests to be recorded as screening (67%), as well as medical record miscoding (18%) due to miscoding, charting errors, screenings performed outside the IHS, testing for a non-screening purpose, and categorization of patients as screened when a test had been ordered but not actually completed. This study found that the GPRA CRC screening clinical measure overestimates the true screening rate due to the inclusion of diagnostic and surveillance exams, especially colonoscopy, as well as misclassification errors. The results of this study suggest a need to more accurately use the ICD-9 diagnostic code V76.51, which was associated with frequent coding errors. In combination with other programmatic efforts that focus on screening average- risk, asymptomatic American Indian and Alaska Native persons, improving the coding used for CRC screening may help to more accurately detect decreases in AIAN CRC incidence and mortality.


An insight into the role of the surfactant CTAB in the formation of microporous molecular sieves.
Quaternary ammonium salts are well-known zeolite structure-directing agents. However, cationic surfactants with quaternary ammonium head groups are known to fail to function as SDAs of zeolites because their long surfactant chains disrupt the ordered growth of the zeolite crystals. In this study, we found that ZSM-5 and silicalite-1 can be formed very easily with appropriate synthesis compositions over a large temperature range of 100-200 °C. The (13)C CP/MAS data for surfactants in ZSM-5 combined with elemental analysis indicated that the surfactants were in more rigid, isolated environments and did not undergo decomposition. The surfactant head groups can serve as structure-directing agents for zeolites, and the long chains become isolated and occupy the micropores. Our findings provide a new insight into the molecular factors governing the formation of inorganic-organic microporous materials, which opens up new possibilities for the elaborate fabrication of mesoporous zeolites.


The impact of COVID-19 pandemic on cardiac surgery in Israel.
Ever since the coronavirus disease 2019 (COVID-19) has become a pandemic, worldwide efforts are being made to "flatten the curve". Israel was amongst the first countries to impose significant restrictions. As a result, cardiac surgeons have been required to scale down their routine practice, resulting in a significant reduction in the number of cardiac surgeries. The aim of this study is to characterize the impact of COVID-19 on cardiac surgery in Israel. This is a retrospective observational study performed in two cardiac surgery departments in Israel and includes all patients who underwent cardiac surgery in March and April during the years 2019 and 2020. The patient cohort was divided into two groups based on the year of operation. Analysis of the patients' baseline characteristics, operative data, and postoperative outcome, was performed. The 2019 group (n = 173), and the 2020 group (n = 108) were similar regarding their baseline characteristics, previous medical history, and rates of previous revascularization interventions. However, compared to the 2019 group, patients in the 2020 group were found to be more symptomatic (NYHA class IV; 2.4% vs. 6.2%, p = 0.007). While all patients underwent similar procedures, patients in the 2020 group had significantly longer procedural time (p < 0.001). In-hospital mortality rate was found to be significantly higher in group 2020 (13% vs. 5.2%, p = 0.037). While the number of patients undergoing cardiac surgery declined during the outbreak period, the rate of surgical mortality increased. One explanation for this might be delayed hospital arrival.


Scaling of the dynamics of flexible Lennard-Jones chains.
The isomorph theory provides an explanation for the so-called power law density scaling which has been observed in many molecular and polymeric glass formers, both experimentally and in simulations. Power law density scaling (relaxation times and transport coefficients being functions of ρ(γ(S)), where ρ is density, T is temperature, and γ(S) is a material specific scaling exponent) is an approximation to a more general scaling predicted by the isomorph theory. Furthermore, the isomorph theory provides an explanation for Rosenfeld scaling (relaxation times and transport coefficients being functions of excess entropy) which has been observed in simulations of both molecular and polymeric systems. Doing molecular dynamics simulations of flexible Lennard-Jones chains (LJC) with rigid bonds, we here provide the first detailed test of the isomorph theory applied to flexible chain molecules. We confirm the existence of isomorphs, which are curves in the phase diagram along which the dynamics is invariant in the appropriate reduced units. This holds not only for the relaxation times but also for the full time dependence of the dynamics, including chain specific dynamics such as the end-to-end vector autocorrelation function and the relaxation of the Rouse modes. As predicted by the isomorph theory, jumps between different state points on the same isomorph happen instantaneously without any slow relaxation. Since the LJC is a simple coarse-grained model for alkanes and polymers, our results provide a possible explanation for why power-law density scaling is observed experimentally in alkanes and many polymeric systems. The theory provides an independent method of determining the scaling exponent, which is usually treated as an empirical scaling parameter.


Predictors of discordant tuberculin skin test and QuantiFERON®-TB Gold In-Tube results in various high-risk groups.
Persons in whom targeted testing for latent tuberculosis infection (LTBI) is recommended in Seattle, Washington; Atlanta, Georgia; and central North Carolina, United States. To compare the performance of an interferon-gamma release assay (QuantiFERON®-TB Gold In-Tube [QFT-GIT]) with the tuberculin skin test (TST) among foreign-born, homeless, human immunodeficiency virus (HIV) infected and substance abuse persons tested for LTBI. A cross-sectional study requiring participants to have a blood test, a TST and data collected. Of 1653 persons, 19.5% were TST-positive and 14.0% were QFT-GIT-positive. Overall concordance was moderate (kappa 0.53; 95%CI 0.47-0.58). Compared to concordant positive results, TST+/QFT-GIT- discordance was associated with HIV infection and sex, while TST-/QFT-GIT+ discordance was associated with HIV and inversely associated with foreign birth. Compared to concordant negative results, TST-/QFT-GIT+ discordance was associated with foreign birth and age ≥50 years, while TST+/QFT-GIT-discordance was associated with foreign birth, age 30-49 years, being Black and inversely associated with HIV. HIV infection was significantly associated with indeterminate QFT-GIT results. QFT-GIT may be an improvement over the TST for diagnosing LTBI in foreign-born and older persons, and may be as useful as the TST in HIV-infected persons. The sensitivity of both tests may be low in HIV-infected persons.


Contrast-enhanced ultrasound assessment of tissue response to high-intensity focused ultrasound.
We report the use of contrast-enhanced ultrasonography as an immediate means of assessing the clinical response to high-intensity focused ultrasound (US) or HIFU treatment of liver tumours. HIFU is a noninvasive transcutaneous technique for the ablation of tumours that has been shown to destroy tumour vasculature, as well as to cause coagulative necrosis of tumour cells. As a dynamic indicator of tissue perfusion, microbubble contrast agents have already been reported to increase the diagnostic sensitivity of ultrasonography in the detection of liver tumours. This report documents the ability of one i.v. microbubble contrast agent (SonoVue, Bracco, Italy) to delineate the extent of HIFU ablation by comparison of pre- and immediately posttreatment perfusion within the target tumour. Observed changes were seen to correlate well with the ablated volume on histologic evaluation of the treated volume. This is the first time that this imaging technique has been reported in this setting.


Nerve growth factor-induced alteration in the response of PC12 pheochromocytoma cells to epidermal growth factor.
PC12 cells, which differentiate morphologically and biochemically into sympathetic neruonlike cells in response to nerve growth fact, also respond to epidermal growth factor. The response to epidermal growth factor is similar in certain respects to the response to nerve growth fact. Both peptides produce rapid increases in cellular adhesion and 2-deoxyglucose uptake and both induce ornithine decarboxylase. But nerve growth factor causes a decreased cell proliferation and a marked hypertrophy of the cells. In contrast, epidermal growth factor enhances cell proliferation and does not cause hypertrophy. Nerve growth factor induces the formation of neuritis; epidermal growth factor does not. When both factors are presented simultaneously, the cells form neurites. Furthermore, the biological response to epidermal growth fact, as exemplified by the induction of ornithine decarboxylase, is attenuated by prior treatment of the cells with nerve growth factor. PC12 cells have epidermal growth factor receptors. The binding of epidermal growth factor to these receptors is rapid and specific, and exhibits an equilibrium constant of 1.9 x 10(-9) M. Approximately 80,000 receptors are present per cell, and this number is independent of cell density. Treatment of the cells with nerve growth factor reduces the amount of epidermal growth factor binding by at least 80 percent. The decrease in receptor binding begins after approximately 12-18 h of nerve growth factor treatment and is complete within 3 d. Scratchard plots indicate that the number of binding sites decreases, not the affinity of the binding sites for epidermal growth factor.


Immunosensor towards low-cost, rapid diagnosis of tuberculosis.
A rapid, accurate tuberculosis diagnostic tool that is compatible with the needs of tuberculosis-endemic settings is a long-sought goal. An immunofluorescence microtip sensor is described that detects Mycobacterium tuberculosis complex cells in sputum in 25 minutes. Concentration mechanisms based on flow circulation and electric field are combined at different scales to concentrate target bacteria in 1 mL samples onto the surfaces of microscale tips. Specificity is conferred by genus-specific antibodies on the microtip surface. Immunofluorescence is then used to detect the captured cells on the microtip. The detection limit in sputum is 200 CFU mL(-1) with a success rate of 96%, which is comparable to PCR.


Role of cardiorespiratory abnormalities, smoking and dive characteristics in the manifestations of neurological decompression illness.
1. Blind analysis of contrast echocardiograms to detect intracardiac shunts, blind analysis of lung function tests for evidence of small airways disease, smoking history and dive characteristics were examined in an attempt to explain neurological symptoms that occurred within 5 min of surfacing from unprovocative dives. 2. Pulmonary abnormalities were significantly more frequent in those divers without intracardiac shunts (50%) than in those with shunts (0%). Smoking was more common in those divers without shunts (55% versus 15%), although this just failed to reach conventional significance levels. Divers without shunts experienced cerebral rather than spinal symptoms after significantly shallower dives with lower tissue nitrogen loads. Depths of dives, tissue nitrogen loads and clinical manifestations in those divers without shunts were similar to the findings in divers who had symptoms after rapid ascents. Despite conservative dive profiles, clinical manifestations in divers with shunts resembled those observed after missed decompression stops. 3. The findings suggest that occult lung disease, and probably smoking, increase the risk of neurological symptoms, even after unprovocative dives, and the similarity of the dive profiles and clinical manifestations to cases with rapid ascents suggest that pulmonary barotrauma and arterial gas embolism are responsible. In divers with intracardiac shunts the different dive profiles and clinical manifestations imply that there is another mechanism, involving different tissue and bubble nitrogen kinetics resulting in venous gas liberation and peripheral amplification in embolized tissues, rather than paradoxical embolism per se.


In situ classification and image cytometry of pelagic bacteria from a high mountain lake (gossenkollesee, austria).
We describe a procedure to measure the cell sizes of pelagic bacteria after determinative hybridization with rRNA-targeted fluorescently labeled oligonucleotide probes. Our approach is based on established image analysis techniques modified for objects simultaneously stained with two fluorescent dyes. It allows the estimation of biomass and cell size distribution and the morphological characterization of different bacterial taxa in plankton samples. The protocol was tested in a study of the bacterioplankton community of a high mountain lake during and after the ice break period. Cells that hybridized with a probe for the domain Bacteria accounted for 70% of the bacterial abundance (range, 49 to 83%) as determined by 4(prm1),6(prm1)-diamidino-2-phenylindole staining (K. G. Porter and Y. S. Feig, Limnol. Oceanogr. 25:943-948, 1980), but for >85% of the total biomass (range, 78 to 99%). The size distribution for members of the beta subclass of the Proteobacteria shifted toward larger cells and clearly distinguished this group from the total bacterial assemblage. In the surface water layer beneath the winter cover, bacteria belonging to the beta 1 subgroup constituted about one-half of the beta subclass abundance. The mean cell volume of the beta 1 subgroup bacteria was significantly less than that of the beta subclass proteobacteria, and the beta 1 subgroup accounted for less than 30% of the total beta subclass biovolume. Two weeks later, the biovolume of the beta Proteobacteria had decreased to the level of the beta 1 subgroup, and both the biovolume size distributions and cell morphologies of the beta Proteobacteria and the beta 1 subgroup were very similar. We could thus quantify the disappearance of large, morphologically distinct beta subclass proteobacteria which were not members of the beta 1 subgroup during the ice break period. Our results demonstrate that changes in biovolumes and cell size distributions of different bacterial taxa, and eventually of individual populations, reveal hitherto unknown processes within aquatic bacterial assemblages and may open new perspectives for the study of microbial food webs.