Men's media use, sexual cognitions, and sexual risk behavior: testing a mediational model.
Efforts to link media use to adolescents' sexual initiation have produced somewhat inconsistent results, perhaps as a result of the limited framing of the question. This study sought to expand current approaches by sampling college students instead of high school students, by investigating a range of sexual behaviors and media formats, and by testing a model that featured sexual cognitions as mediators. We tested our model with a sample of 796 heterosexual, male college students who reported on their regular consumption of 4 media (prime-time TV programs, music videos, movies, and men's magazines); their attitudes toward abstinence, the male sexual role, and nonrelational sex; their perceptions of peer sexual behavior; and several aspects of their sexual behavior (e.g., number of sexual partners). Findings revealed strong support for our mediated model, with exposure to men's magazines and movies contributing most strongly to their sexual cognitions, and with men's cognitions, in turn, contributing heavily to their sexual behavior. Some direct connections from media use to sexual behavior also emerged. Together, the findings provide insight into both potential mechanisms for and new approaches to addressing this issue.


Isolation and killing of candidate chronic myeloid leukemia stem cells by antibody targeting of IL-1 receptor accessory protein.
Chronic myeloid leukemia (CML) is genetically characterized by the Philadelphia (Ph) chromosome, formed through a reciprocal translocation between chromosomes 9 and 22 and giving rise to the constitutively active tyrosine kinase P210 BCR/ABL1. Therapeutic strategies aiming for a cure of CML will require full eradication of Ph chromosome-positive (Ph(+)) CML stem cells. Here we used gene-expression profiling to identify IL-1 receptor accessory protein (IL1RAP) as up-regulated in CML CD34(+) cells and also in cord blood CD34(+) cells as a consequence of retroviral BCR/ABL1 expression. To test whether IL1RAP expression distinguishes normal (Ph(-)) and leukemic (Ph(+)) cells within the CML CD34(+)CD38(-) cell compartment, we established a unique protocol for conducting FISH on small numbers of sorted cells. By using this method, we sorted cells directly into drops on slides to investigate their Ph-chromosome status. Interestingly, we found that the CML CD34(+)CD38(-)IL1RAP(+) cells were Ph(+), whereas CML CD34(+)CD38(-)IL1RAP(-) cells were almost exclusively Ph(-). By performing long-term culture-initiating cell assays on the two cell populations, we found that Ph(+) and Ph(-) candidate CML stem cells could be prospectively separated. In addition, by generating an anti-IL1RAP antibody, we provide proof of concept that IL1RAP can be used as a target on CML CD34(+)CD38(-) cells to induce antibody-dependent cell-mediated cytotoxicity. This study thus identifies IL1RAP as a unique cell surface biomarker distinguishing Ph(+) from Ph(-) candidate CML stem cells and opens up a previously unexplored avenue for therapy of CML.


Comparing ion-pairing reagents and sample dissolution solvents for ion-pairing reversed-phase liquid chromatography/electrospray ionization mass spectrometry analysis of oligonucleotides.
A sensitive and selective liquid chromatography/mass spectrometry (LC/MS) method is essential for quality control of synthetic oligonucleotides. However, researchers are still searching for improvements to ion-pairing reagents for ion-pairing reversed-phase LC/MS. This study performed a comprehensive comparison of six ion-pairing reagents to determine their performance as mobile phase modifiers for oligonucleotide LC/MS. The study was performed using a Waters ultra-performance liquid chromatography (UPLC®) system coupled to a Waters LCT premier XE ESI-TOF mass spectrometer by using a UPLC® OST column (2.1 mm × 100 mm, 1.7 µm). Buffer systems containing ion-pairing reagents (triethylamine, tripropylamine, hexylamine, N,N-dimethylbutylamine, dibutylamine, N,N-diisopropylethylamine) and hexafluoro-2-propanol were compared by measuring the adduct ion formation, chromatographic separation, and MS signal intensity of four oligonucleotides (10mer to 40mer). The effect of dissolution solvents on MS signal intensity and adduct ion formation was also investigated. Results showed that the type of dissolution solvent can have a signficiant impact on adduct ion formation with oligonucleotides. Results also showed that the maximum separation for small, medium and large oligonucleotides occured when using tripropylamine, N,N-dimethylbutylamine, and dibutylamine, respectively. However, on average 15 mM hexylamine and 50 mM hexafluoro-2-propanol provided the best chromtatographic performance (resolution values: 14.1 ± 0.34, 11.0 ± 0.17, and 6.4 ± 0.11 for the pairs of oligonucleotides T10 & T15, T15 & T25, and T25 & T40, respectively (3 replicates)). The impact of dissolution solvent on the MS signal of oligonucleotides depends on the type of ion-pairing reagent. Buffer combining 15 mM hexylamine and 50 mM hexafluoro-2-propanol produced the highest overall performance for oligonucleotides (10mer to 40mer) with respect to chromatographic resolution and mass detection.


Molecular velocity imaging of supersonic flows using pulsed planar laser-induced fluorescence of NO.
A technique is described for imaging components of velocity in a gaseous flow field by using pulsed planar laser-induced fluorescence. The technique is based on the fluorescence detection of Doppler-shifted absorption that results when a spectrally narrow absorption line is excited with a broadband laser. Results obtained in a Mach 7 underexpanded supersonic jet, seeded with NO, are presented. The practical extension of this technique to single-shot measurements of two velocity components is discussed.


Psychosocial factors and their association with reflux oesophagitis, Barrett's oesophagus and oesophageal adenocarcinoma.
To investigate the role of psychological characteristics as risk factors for oesophageal adenocarcinoma (OAC), as well as the reflux-mediated precursor pathway. An all-Ireland population-based case-control study recruited 230 reflux oesophagitis (RO), 224 Barrett's oesophagus (BO) and 227 OAC patients and 260 controls. Each case/control group completed measures of stress, depression, self-efficacy, self-esteem, repression and social support. A comparative analysis was undertaken using polytomous logistic regression adjusted for potential confounders. Compared to controls, OAC patients were almost half as likely to report high stress levels over their lifetime (P = 0.010, OR 0.51; 95%CI: 0.29-0.90) and 36% less likely to report having experienced depression (OR 0.64; 95%CI: 0.42-0.98). RO patients reported significantly higher stress than controls particularly during middle- and senior-years (P for trends < 0.001). RO patients were 37% less likely to report having been highly emotionally repressed (OR 0.63; 95%CI: 0.41-0.95). All case groups (OAC, RO and BO) were more likely than controls to report having had substantial amounts of social support (OR 2.84; 95%CI: 1.63-4.97; OR 1.97; 95%CI: 1.13-3.44 and OR 1.83; 95%CI: 1.03-3.24, respectively). The improved psychological profile of OAC patients may be explained by response shift. The role of psychological factors in the development of OAC requires further investigation.


A newly developed bioartificial pancreas successfully controls blood glucose in totally pancreatectomized diabetic pigs.
Construction of a safe and functional bioartificial pancreas (BAP) that provides an adequate environment for islet cells may be an important approach to treating diabetic patients. Various types of BAP devices have been developed, but most of them involve extravascular implantation of islets in microcapsules or diffusion chambers. These devices have poor diffusive exchange between the islets and blood, and often rupture. To overcome these problems, we developed a new type of BAP composed of polyethylene-vinyl alcohol (EVAL) hollow fibers that are permeable to glucose and insulin and a poly-amino-urethane-coated, non-woven polytetrafluoroethylene (PTFE) fabric that allows cell adhesion. Porcine islets attached to the surface of the PTFE fabric, but not to the surface of the EVAL hollow fibers, allowing nutrient and oxygen exchange between blood flowing inside the fibers and cells outside. We inoculated this BAP with porcine islets and connected it to the circulation of totally pancreatectomized diabetic pigs. We found that blood glucose levels were reduced to a normal range and general health was improved, resulting in longer survival times. In addition, regulation of insulin secretion from the BAP was properly controlled in response to glucose both in vitro and in vivo. These results indicate that our newly developed BAP may be a potential therapy for the treatment of diabetes in humans.


Chloroquine encapsulated in malaria-infected erythrocyte-specific antibody-bearing liposomes effectively controls chloroquine-resistant Plasmodium berghei infections in mice.
The suitability of liposomes as drug carriers in the treatment of drug-resistant rodent malaria was examined after covalently attaching F(ab')2 fragments of a mouse monoclonal antibody (MAb), MAb F10, raised against the host cell membranes isolated from the Plasmodium berghei-infected mouse erythrocytes, to the liposome surface. The antibody-bearing liposomes thus formed specifically recognized the P. berghei-infected mouse erythrocytes under both in vitro and in vivo conditions. No such specific binding of the liposomes with the infected cells was observed when MAb F10 was replaced by another mouse monoclonal antibody, MAb D2. Upon loading with the antimalarial drug chloroquine, the MAb F10-bearing liposomes effectively controlled not only the chloroquine-susceptible but also the chloroquine-resistant P. berghei infections in mice. The chloroquine delivered in these liposomes intravenously at a dosage of 5 mg/kg of body weight per day on days 4 and 6 postinfection completely cured the animals (75 to 90%) of chloroquine-resistant P. berghei infections. These results indicate that selective homing of chloroquine to malaria-infected erythrocytes may help to cure the chloroquine-resistant malarial infections with low doses of chloroquine.


A grounded theory of how social support influences physical activity in adolescent girls.
Adolescent girls are not sufficiently active to achieve health benefits. Social support from friends and family has been positively associated with physical activity in adolescent girls; however it is unclear how social support influences physical activity behaviour. This study aimed to develop a grounded theory of how social support influences physical activity in adolescent girls. A qualitative, constructivist grounded theory approach was adopted. Individual interviews explored adolescent girls' perspectives of how significant others' influenced their physical activity through providing social support, and through modelling physical activity. Participants perceived social support to influence physical activity behaviour through performance improvements, self-efficacy, enjoyment, motivation and by enabling physical activity. Improvements in performance and self-efficacy were also linked to motivation to be active. Girls perceived modelling to influence behaviour through providing opportunities for them to be physically active, and by inspiring them to be active. The grounded theory outlines adolescent girls' perceptions of how significant others influence their physical activity and provides a framework for future research examining the role of social support on physical activity.


Mutation patterns of amino acid tandem repeats in the human proteome.
Amino acid tandem repeats are found in nearly one-fifth of human proteins. Abnormal expansion of these regions is associated with several human disorders. To gain further insight into the mutational mechanisms that operate in this type of sequence, we have analyzed a large number of mutation variants derived from human expressed sequence tags (ESTs). We identified 137 polymorphic variants in 115 different amino acid tandem repeats. Of these, 77 contained amino acid substitutions and 60 contained gaps (expansions or contractions of the repeat unit). The analysis showed that at least about 21% of the repeats might be polymorphic in humans. We compared the mutations found in different types of amino acid repeats and in adjacent regions. Overall, repeats showed a five-fold increase in the number of gap mutations compared to adjacent regions, reflecting the action of slippage within the repetitive structures. Gap and substitution mutations were very differently distributed between different amino acid repeat types. Among repeats containing gap variants we identified several disease and candidate disease genes. This is the first report at a genome-wide scale of the types of mutations occurring in the amino acid repeat component of the human proteome. We show that the mutational dynamics of different amino acid repeat types are very diverse. We provide a list of loci with highly variable repeat structures, some of which may be potentially involved in disease.


Interaction between polymorphisms in the renin-angiotensin-system and angiotensin-converting enzyme inhibitor or beta-blocker use and the risk of myocardial infarction and stroke.
This study investigates whether the interaction between angiotensin-converting enzyme (ACE) inhibitors or beta-blockers and the ACE insertion/deletion (I/D) polymorphism or angiotensin receptor II type 1 (AGTR1) 573C/T polymorphism modifies the risk of myocardial infarction (MI) or stroke. In total, 4097 subjects with hypertension were included in this study. The drug-gene interaction on the risk of MI or stroke was determined with a Cox proportional hazard model. The risk of MI was reduced in current users of ACE inhibitors with the AGTR1 573CT or CC genotype compared to ACE inhibitors with the AGTR1 573TT genotype (synergy index (SI):0.32; 95% confidence interval (CI): 0.14-0.70). No significant drug-gene interaction was found on the risk of stroke (SI:0.82; 95% CI: 0.44-1.52) or in beta-blocker users. Also, no significant drug-gene interaction was found with the ACE I/D polymorphism. In conclusion, subjects with at least one copy of the AGTR1 573C allele might have more benefit from ACE inhibitor therapy.


Ocean Research Priorities: Similarities and Differences among Scientists, Policymakers, and Fishermen in the United States.
Understanding and solving complex ocean conservation problems requires cooperation not just among scientific disciplines but also across sectors. A recently published survey that probed research priorities of marine scientists, when provided to ocean stakeholders, revealed some agreement on priorities but also illuminated key differences. Ocean acidification, cumulative impacts, bycatch effects, and restoration effectiveness were in the top 10 priorities for scientists and stakeholder groups. Significant priority differences were that scientists favored research questions about ocean acidification and marine protected areas; policymakers prioritized questions about habitat restoration, bycatch, and precaution; and fisheries sector resource users called for the inclusion of local ecological knowledge in policymaking. These results quantitatively demonstrate how different stakeholder groups approach ocean issues and highlight the need to incorporate other types of knowledge in the codesign of solutions-oriented research, which may facilitate cross-sectoral collaboration.


Total colony-forming units are a strong, independent predictor of neutrophil and platelet engraftment after unrelated umbilical cord blood transplantation: a single-center analysis of 435 cord blood transplants.
Graft failure occurs in approximately 20% of patients after unrelated umbilical cord blood transplantation (UCBT). This could be because of inadequate potency of the cord blood unit (CBU). To this end, we investigated the impact of graft characteristics on engraftment and survival of 435 primarily pediatric (median age: 5.3 years) patients receiving a single-unit unrelated UCBT after myeloablative conditioning from 2000 to 2008. Pre-cryopreservation (pre-cryo) graft characteristics were provided by the banks. Post-thaw parameters were measured on dextran/albumin-washed grafts. Post-thaw recovery of the colony-forming unit (CFU), a biological assay reflecting functional viability of the cord blood cells was the lowest percent age (median 21.2%, mean 36.5%) of the pre-cryo value, regardless of the bank of origin. The cumulative incidences of neutrophil and platelet engraftment were 76.9% (95%, confidence interval [CI], 71.3%-82.5%) and 55% (95% CI, 49.3%-60.7%), respectively. Univariate and separate multivariate models using pre-cryo and post-thaw datasets including clinical parameters identified predictors of engraftment and survival. In multivariate modeling, higher CFU dosing was the only pre-cryo graft characteristic predictive of neutrophil (P = .0024) and platelet engraftment (P = .0063). In the post-thaw model, CFU dose best predicted neutrophil and platelet engraftment (both P < .0001). Comparatively, CD34(+) and total nucleated cell (TNC) were only weakly predictive in post-thaw neutrophil and platelet engraftment models, respectively. In conclusion, CFU dose is a strong independent predictor of engraftment after unrelated UCBT and should be used to assess potency when selecting CBUs for transplantation.


3-D imaging mass spectrometry of protein distributions in mouse Neurofibromatosis 1 (NF1)-associated optic glioma.
Neurofibromatosis type 1 (NF1) is a common neurogenetic disorder, in which affected individuals develop tumors of the nervous system. Children with NF1 are particularly prone to brain tumors (gliomas) involving the optic pathway that can result in impaired vision. Since tumor formation and expansion requires a cooperative tumor microenvironment, it is important to identify the cellular and acellular components associated with glioma development and growth. In this study, we used 3-D matrix assisted laser desorption ionization imaging mass spectrometry (MALDI IMS) to measure the distributions of multiple molecular species throughout optic nerve tissue in mice with and without glioma, and to explore their spatial relationships within the 3-D volume of the optic nerve and chiasm. 3-D IMS studies often involve extensive workflows due to the high volume of sections required to generate high quality 3-D images. Herein, we present a workflow for 3-D data acquisition and volume reconstruction using mouse optic nerve tissue. The resulting 3-D IMS data yield both molecular similarities and differences between glioma-bearing and wild-type (WT) tissues, including protein distributions localizing to different anatomical subregions. The current work addresses a number of challenges in 3-D MALDI IMS, driven by the small size of the mouse optic nerve and the need to maintain consistency across multiple 2-D IMS experiments. The 3-D IMS data yield both molecular similarities and differences between glioma-bearing and wild-type (WT) tissues, including protein distributions localizing to different anatomical subregions, which could then be targeted for identification and related back to the biology observed in gliomas of the optic nerve.


Underdiagnosed asthma in South Australia.
The prevalence of undiagnosed asthma in the general population and the clinical and demographic characteristics of these patients compared with those with diagnosed asthma are unclear. The North West Adelaide Health Survey (NWAHS) is a population household interview survey of adults (age>18 years) in the north western suburbs of Adelaide, South Australia (regional population 0.6 million). Data obtained were weighted to the closest census data to provide population representative estimates. Positive answers to: "Have you ever had asthma?"; "Has it been confirmed by a doctor?"; "Do you still have asthma?" determined current physician diagnosed asthma. A positive bronchodilator response on spirometric testing according to ATS criteria without a physician's diagnosis determined undiagnosed asthma. Other measures included the SF-12 health survey questionnaire, the Selim index of severity of chronic lung disease, skin allergy tests, and demographic data. Of the 3422 individuals interviewed, 2523 (74%) agreed to participate in the clinical assessment. Of these, 292 (11.6%) had asthma, 236 (9.3%) with a doctor's diagnosis of asthma and 56 (2.3%) with undiagnosed asthma defined on spirometric criteria; thus, 19.2% of the total asthma group were undiagnosed. Those undiagnosed were more likely (p<0.05) to be >40 years old, on government benefits, with an income <AUD$40,000. Symptom frequency was similar in the two asthma groups, but mean spirometric values were lower in the undiagnosed group (p<0.05) while positive skin allergy tests were more common in the diagnosed group (p<0.05). SF-12 component summary scores were significantly lower in both asthma groups than in the non-asthma population. Undiagnosed asthma was frequent in men and in those aged >65 years. Health service use over the previous year was similar for both asthma groups. Undiagnosed asthma is common among the Australian population, with a similar clinical spectrum to those with diagnosed asthma.


Fine mapping of quantitative trait loci for meat color on Sus scrofa chromosome 6: analysis of the swine NUDT7 gene.
In the livestock industry, meat color has become important because consumer acceptance is subject to the appearance of the product in the marketplace. Our previous analyses of a whole genome QTL scan for various meat qualities using 2 F(2) families from Japanese wild boar (known as a red meat) x Large White and from Duroc x Chinese Jinhua suggested that a meat color (heme content) QTL is located on SSC6. The objective of this study was to fine-map this SSC6 meat color QTL and subsequently investigate positional candidate genes for polymorphisms that may cause changes in meat color. Therefore, we conducted interval mapping on SSC6 using an additional 9 gene markers through combined analyses of the 2 F(2) families of Japanese wild boar x Large White (353 progeny) and Duroc x Chinese Jinhua (204 progeny). Comparative analysis with humans, mice, and cattle suggested that there were 10 functional genes in the region. Among these genes, we suggested that a novel pig gene encoding a nudix (nucleoside diphosphate linked moiety X)-type motif 7 (NUDT7, a member of the nudix hydrolases) is a strong candidate for the QTL because the mouse Nudt7 is reported to hydrolyze succinyl-CoA, a substrate of the reaction limiting the rate of heme biosynthesis. We therefore determined the pig NUDT7 gene sequence including the 5' promoter region and explored genetic polymorphisms between Japanese wild boar and Large White. We identified 116 polymorphisms within the NUDT7 CDS or in the 5' region. None of the AA substitutions were associated with the meat color QTL; however, 3 polymorphisms were found in putative transcription factor recognition sites. We then investigated the differential expression of NUDT7 in Japanese wild boar and Large White by allele-specific quantitative real-time PCR. The expression level of the Large White type allele was greater than that of the Japanese wild-boar-type allele. Consequently, we speculated that the difference in meat color between Japanese wild boar and Large White is caused partly by differential expression of this candidate gene. Upregulation of NUDT7 expression in muscle may reduce succinyl-CoA content and thus reduce the level of heme biosynthesis.


Reaction rate reconstruction from biomass concentration measurement in bioreactors using modified second-order sliding mode algorithms.
This paper deals with the estimation of unknown signals in bioreactors using sliding observers. Particular attention is drawn to estimate the specific growth rate of microorganisms from measurement of biomass concentration. In a recent article, notions of high-order sliding modes have been used to derive a growth rate observer for batch processes. In this paper we generalize and refine these preliminary results. We develop a new observer with a different error structure to cope with other types of processes. Furthermore, we show that these observers are equivalent, under coordinate transformations and time scaling, to the classical super-twisting differentiator algorithm, thus inheriting all its distinctive features. The new observers' family achieves convergence to time-varying unknown signals in finite time, and presents the best attainable estimation error order in the presence of noise. In addition, the observers are robust to modeling and parameter uncertainties since they are based on minimal assumptions on bioprocess dynamics. In addition, they have interesting applications in fault detection and monitoring. The observers performance in batch, fed-batch and continuous bioreactors is assessed by experimental data obtained from the fermentation of Saccharomyces Cerevisiae on glucose.


Clinical aspects of the use of clopidogrel, a new antiplatelet agent.
Clopidogrel, a new platelet ADP receptor antagonist, is more effective than aspirin in reducing the risk of subsequent vascular ischemic events in patients with a broad spectrum of symptomatic atherosclerosis (recent ischemic stroke, recent myocardial infarction, or symptomatic peripheral arterial disease). In CAPRIE (clopidogrel versus aspirin in patients at risk of ischemic events), a randomized, blinded, active control trial in 19,185 high-risk patients, clopidogrel reduced the combined risk of ischemic stroke, myocardial infarction or vascular death by 8.7% compared with aspirin (p = 0.043). The CAPRIE cohort had a mean age of 62.5 years, which was reflected in the high proportion of patients who had medical conditions other than symptomatic atherosclerosis, and in the extensive use of concurrent therapies, including commonly used cardiovascular drugs. For all concomitant medications analysed, there was no evidence of statistically or clinically significant interactions with clopidogrel. The CAPRIE data confirm the findings of earlier clinical studies, which suggested that clinically significant drug interactions with clopidogrel are rare, that it can safely be prescribed with a range of other drugs (including phenobarbital, cimetidine, estrogen, digoxin, theophylline, atenolol, nifedipine, or nifedipine-atenolol in combination), and that the clinically proven dose of 75 mg once daily is suitable for all age groups studied. Moreover, CAPRIE demonstrated that there is no need for an adjustment of clopidogrel dose on the basis of gender, weight or race, and that there is no need for routine hematological monitoring. Additional clinical pharmacology studies have shown that the absorption of clopidogrel is unaffected by food or antacids, and that no dose adjustment is necessary in patients with renal impairment or with mild-to-moderate hepatic impairment. Due to pharmacologic considerations and limited clinical data, clopidogrel should be used cautiously with heparin, warfarin or non-steroidal anti-inflammatory drugs. With a simple regimen of 75 mg once daily indicated for all patients, clopidogrel combines a favorable risk/benefit ratio with ease of use in clinical practice.


Millimeter wave-induced suppression of B16 F10 melanoma growth in mice: involvement of endogenous opioids.
Millimeter wave treatment (MMWT) is widely used in Eastern European countries, but is virtually unknown in Western medicine. Among reported MMWT effects is suppression of tumor growth. The main aim of the present "blind" and dosimetrically controlled experiments was to evaluate quantitatively the ability of MMWT to influence tumor growth and to assess whether endogenous opioids are involved. The murine experimental model of B16 F10 melanoma subcutaneous growth was used. MMWT characteristics were: frequency, 61.22 GHz; average incident power density, 13.3 x 10(-3) W/cm2; single exposure duration, 15 min; and exposure area, nose. Naloxone (1 mg/kg, intraperitoneally, 30 min prior to MMWT) was used as a nonspecific blocker of opioid receptors. Five daily MMW exposures, if applied starting at the fifth day following B16 melanoma cell injection, suppressed subcutaneous tumor growth. Pretreatment with naloxone completely abolished the MMWT-induced suppression of melanoma growth. The same course of 5 MMW treatments, if started on day 1 or day 10 following tumor inoculations, was ineffective. We concluded that MMWT has an anticancer therapeutic potential and that endogenous opioids are involved in MMWT-induced suppression of melanoma growth in mice. However, appropriate indications and contraindications have to be developed experimentally before recommending MMWT for clinical usage.


Co-transmitting interneurons in the mouse olfactory bulb regulate olfactory detection and discrimination.
Co-transmission of multiple neurotransmitters from a single neuron increases the complexity of signaling information within defined neuronal circuits. Superficial short-axon cells in the olfactory bulb release both dopamine and γ-aminobutyric acid (GABA), yet the specific targets of these neurotransmitters and their respective roles in olfaction have remained unknown. Here, we implement intersectional genetics in mice to selectively block GABA or dopamine release from superficial short-axon cells to identify their distinct cellular targets, impact on circuit function, and behavioral contribution of each neurotransmitter toward olfactory behaviors. We provide functional and anatomical evidence for divergent superficial short-axon cell signaling onto downstream neurons to shape patterns of mitral cell firing that contribute to olfactory-related behaviors.


[The role of health care providers in the late diagnosis of pulmonary tuberculosis among adults in Medellín, Colombia].
To describe the role of health care providers in the delayed diagnosis of pulmonary tuberculosis (PTB) among the adult population in a city in Colombia. A case study of PTB diagnosis among adults in the city of Medellín, Colombia, in 2007. Quantitative and qualitative data were collected through in-depth interviews with 19 patients (11 with early diagnosis and 8 with late diagnosis), from medical records, and by a survey of PTB-related knowledge and practices among 89 doctors and nurses at health care clinics. A research workshop was held with patients to share the results and validate new categories. A lack of PTB knowledge and patient stereotyping were found to lead to misinterpretation of symptoms and the use of symptomatic treatments. The lack of knowledge regarding risk factors and clinical protocols made diagnosis difficult when the patient did not match the stereotype or presented with a more well-known illness. Misinformation on PTB transmission and inappropriate measures led to discriminatory practices and social isolation and only reinforced stereotypes and stigma, which in turn discouraged the quest for medical attention. Health care providers played a large part in the late diagnosis of PTB in the adults studied. Beliefs regarding social stigma and a lack of knowledge about the disease-shared by providers and patients-contributed to stereotyping of the illness and the disease-carrier, and limited the probability of an early diagnosis of PTB.


A case for implementation of adult pneumococcal vaccine program in Africa: review and expert opinion.
Vaccines are considered as a therapeutic area for children; the scientific community focuses mainly on managing chronic disease when it comes to adults. There currently is an increase in the burden of vaccine preventable illnesses in adults. Adult vaccination has been shown to dramatically increase the health and quality of life of older populations. Therefore, adult vaccinations need to be approached as a public health issue, similar to smoking cessation programs, for example. According to the Kenya Non-Communicable Diseases and injuries poverty commission report, 2018. Kenya has a high percentage of disability adjusted life years (DALYs) from communicable diseases at 63%, while non-communicable diseases (NCDs) contribute 30% of the DALYs. Specific to pneumococcal pneumonia (PP) in adults, the Global burden of disease (GBD) study in 2016 found that 2,377,697 people of all ages died from lower respiratory tract infections (LRTI) in 2016. Of these, more people died from Streptococcus pneumonia(SP) than from all other studied respiratory pathogens combined. While the incidence of LRTIs in children under five years old was reducing, partly as a result of well-established vaccination programs in children, the incidence, morbidity and mortality of PP was increasing in older populations. The expert recommendations included the following; i) all individuals 65 years of age and above, and individuals with a predisposing comorbidity regardless of age, should receive the pneumococcal vaccine; ii) several systemic modules can be emulated from the successful childhood vaccines programs onto an adult vaccine program; iii) formulation of an effective vaccine program will require collaboration from the public, the government, healthcare providers, and the media, to create awareness; iv) stakeholders who need to be involved in vaccine policy development and implementation include medical professional associations, nurses, pharmacists, clinical officers, payers (private and public insurances), government, medical learning institutions and faith-based medical organizations.


Cellularized cylindrical fiber/hydrogel composites for ligament tissue engineering.
Electrospun meshes suffer from poor cell infiltration and limited thickness, which restrict their use to thin tissue applications. Herein, we demonstrate two complementary processes to overcome these limitations and achieve elastomeric composites that may be suitable for ligament repair. First, C3H10T1/2 mesenchymal stem cells were incorporated into electrospun meshes using a hybrid electrospinning/electrospraying process. Second, electrospun meshes were rolled and formed into composites with an interpenetrating polyethylene glycol (PEG) hydrogel network. Stiffer composites were formed from poly(lactic-co-glycolic acid) (PLGA) meshes, while softer and more elastic composites were formed from poly(ester-urethane urea) (PEUUR) meshes. As-spun PLGA and PEUUR rolled meshes had tensile moduli of 19.2 ± 1.9 and 0.86 ± 0.34 MPa, respectively, which changed to 11.6 ± 4.8 and 1.05 ± 0.39 MPa with the incorporation of a PEG hydrogel phase. In addition, cyclic tensile testing indicated that PEUUR-based composites deformed elastically to at least 10%. Finally, C3H10T1/2 cells incorporated into electrospun meshes survived the addition of the PEG phase and remained viable for up to 5 days. These results indicate that the fabricated cellularized composites are support cyclic mechanical conditioning, and have potential application in ligament repair.


Criminalizing Health-Related Behaviors Dangerous to Others? Disease Transmission, Transmission-Facilitation, and the Importance of Trust.
Statutes criminalizing behavior that risks transmission of HIV/AIDS exemplify use of the criminal law against individuals who are victims of infectious disease. These statutes, despite their frequency, are misguided in terms of the goals of the criminal law and the public health aim of reducing overall burdens of disease, for at least three important reasons. First, they identify individual offenders for punishment, a paradigm that is misplaced in the most typical contexts of transmission of infectious disease and even for HIV/AIDS, despite claims of AIDS exceptionalism. Second, although there are examples of individuals who transmit infectious disease in a manner that fits the criminal law paradigm of identification of individual offenders for deterrence or retribution, these examples are limited and can be accommodated by existing criminal laws not devoted specifically to infectious disease. Third, and most importantly, the current criminal laws regarding HIV/AIDS, like many other criminal laws applied to infectious disease transmission, have been misguided in focusing on punishment of the diseased individual as a wrongful transmitter. Instead of individual offenders, activities that enhance the scale of disease transmission-behaviors that might be characterized as 'transmission facilitation'-are a more appropriate target for the criminal law. Examples are trafficking in human beings (including sex trafficking, organ trafficking, and labor trafficking), suppression of information about the emergence of infection in circumstances in which there is a legally established obligation to disclose, and intentional or reckless activities to discourage disease treatment or prevention. Difficulties remain with justifications for criminalizing even these behaviors, however, most importantly the need for trust in reducing overall burdens of disease, problems in identifying individual responsible offenders, and potential misalignment between static criminal law and the changing nature of infectious disease.


HOIL-1L interacting protein (HOIP) as an NF-kappaB regulating component of the CD40 signaling complex.
The tumor necrosis factor receptor (TNFR) superfamily mediates signals critical for regulation of the immune system. One family member, CD40, is important for the efficient activation of antibody-producing B cells and other antigen-presenting cells. The molecules and mechanisms that mediate CD40 signaling are only partially characterized. Proteins known to interact with the cytoplasmic domain of CD40 include members of the TNF receptor-associated factor (TRAF) family, which regulate signaling and serve as links to other signaling molecules. To identify additional proteins important for CD40 signaling, we used a combined stimulation/immunoprecipitation procedure to isolate CD40 signaling complexes from B cells and characterized the associated proteins by mass spectrometry. In addition to known CD40-interacting proteins, we detected SMAC/DIABLO, HTRA2/Omi, and HOIP/RNF31/PAUL/ZIBRA. We found that these previously unknown CD40-interacting partners were recruited in a TRAF2-dependent manner. HOIP is a ubiquitin ligase capable of mediating NF-kappaB activation through the ubiquitin-dependent activation of IKKgamma. We found that a mutant HOIP molecule engineered to lack ubiquitin ligase activity inhibited the CD40-mediated activation of NF-kappaB. Together, our results demonstrate a powerful approach for the identification of signaling molecules associated with cell surface receptors and indicate an important role for the ubiquitin ligase activity of HOIP in proximal CD40 signaling.


Effect of the entero-pancreatic hormones, gastric inhibitory polypeptide and glucagon-like polypeptide-1(7-36) amide, on fatty acid synthesis in explants of rat adipose tissue.
The effect of gastric inhibitory polypeptide (GIP), glucagon-like peptide-1(7-36) amide, (GLP-1(7-36) amide), glucagon-like peptide-2 (GLP-2), glucagon and insulin on fatty acid synthesis in explants of rat adipose tissue from various sites was investigated. GIP, GLP-1(7-36) amide and insulin stimulated fatty acid synthesis, as determined by measuring the incorporation of [14C]acetate into saponifiable fat, in a dose-dependent manner, over the concentration range 5-15 ng/ml (0.87-2.61 nmol/l) for insulin and 0.5-7.5 ng/ml for GIP (0.10-1.50 nmol/l) and GLP-1(7-36) amide (0.15-2.27 nmol/l). Insulin and GIP caused a significantly greater stimulation of [14C]acetate incorporation into fatty acids in omental adipose tissue than in either epididymal or subcutaneous adipose tissue. Both GIP and GLP-1(7-36) amide had the ability to stimulate fatty acid synthesis within the physiological range of the circulating hormones. At lower concentrations of the hormones, GLP-1(7-36) amide was a more potent stimulator of fatty acid synthesis than GIP in omental adipose tissue culture; the basal rate of fatty acid synthesis was 0.41 +/- 0.03 pmol acetate incorporated/mg wet weight tissue per 2 h; at 0.10 nmol hormone/1 1.15 +/- 0.10 and 3.40 +/- 0.12 pmol acetate incorporated/mg wet weight tissue per 2 h for GIP and GLP-1(7-36) amide respectively (P less than 0.01). GLP-2 and glucagon were without effect on fatty acid synthesis in omental adipose tissue. The study indicates that GIP and GLP-1(7-36)amide, in addition to stimulating insulin secretion, may play a direct physiological role in vivo, in common with insulin, in promoting fatty acid synthesis in adipose tissue.


Regulation of KCNQ2/KCNQ3 current by G protein cycling: the kinetics of receptor-mediated signaling by Gq.
Receptor-mediated modulation of KCNQ channels regulates neuronal excitability. This study concerns the kinetics and mechanism of M1 muscarinic receptor-mediated regulation of the cloned neuronal M channel, KCNQ2/KCNQ3 (Kv7.2/Kv7.3). Receptors, channels, various mutated G-protein subunits, and an optical probe for phosphatidylinositol 4,5-bisphosphate (PIP2) were coexpressed by transfection in tsA-201 cells, and the cells were studied by whole-cell patch clamp and by confocal microscopy. Constitutively active forms of Galphaq and Galpha11, but not Galpha13, caused a loss of the plasma membrane PIP2 and a total tonic inhibition of the KCNQ current. There were no further changes upon addition of the muscarinic agonist oxotremorine-M (oxo-M). Expression of the regulator of G-protein signaling, RGS2, blocked PIP2 hydrolysis and current suppression by muscarinic stimulation, confirming that the Gq family of G-proteins is necessary. Dialysis with the competitive inhibitor GDPbetaS (1 mM) lengthened the time constant of inhibition sixfold, decreased the suppression of current, and decreased agonist sensitivity. Removal of intracellular Mg2+ slowed both the development and the recovery from muscarinic suppression. When combined with GDPbetaS, low intracellular Mg2+ nearly eliminated muscarinic inhibition. With nonhydrolyzable GTP analogs, current suppression developed spontaneously and muscarinic inhibition was enhanced. Such spontaneous suppression was antagonized by GDPbetaS or GTP or by expression of RGS2. These observations were successfully described by a kinetic model representing biochemical steps of the signaling cascade using published rate constants where available. The model supports the following sequence of events for this Gq-coupled signaling: A classical G-protein cycle, including competition for nucleotide-free G-protein by all nucleotide forms and an activation step requiring Mg2+, followed by G-protein-stimulated phospholipase C and hydrolysis of PIP2, and finally PIP2 dissociation from binding sites for inositol lipid on the channels so that KCNQ current was suppressed. Further experiments will be needed to refine some untested assumptions.


Microscopic anatomy of a femoral head after resurfacing arthroplasty: a case report.
The femoral head was removed after delayed sepsis in a resurfacing arthroplasty in a 50-year-old woman 12 months postoperation. Histologic sections showed intimate bonding between the femoral cup, cement and subjacent bone without evidence of excessive resorptive activity. The femoral head appeared viable within the cup and showed osteoblastic activity. The layers of fibrous tissue interposed between cement and bone appear to be a stage in the reparative process leading to effective anchoring of the cup rather than being a step toward bone resorption and loosening of the cup. A viable femoral head with an adequate blood supply is essential for healing of resurfacing arthroplasty. Osteogenesis in the resurfaced femoral head may be the important factor in the long-term success of an arthroplasty. Adequate blood supply may prevent avascular necrosis and subsequent "collapse".


Magnesium intake and mortality due to liver diseases: Results from the Third National Health and Nutrition Examination Survey Cohort.
People with fatty liver disease are at high risk of magnesium deficiency. Meanwhile, low magnesium status is linked to both chronic inflammation and insulin resistance. However, no study has investigated the association between intake of magnesium and risk of mortality due to liver diseases. We evaluated the association between total magnesium intake and mortality due to liver diseases in the Third National Health and Nutrition Examination Study (NHANES III) cohort, which included 13,504 participants who completed liver ultrasound examination for hepatic steatosis. Overall magnesium intake was associated with a reduced risk of mortality due to liver disease at borderline significance (P = 0.05). In fully-adjusted analyses, every 100 mg increase in intake of magnesium was associated with a 49% reduction in the risk for mortality due to liver diseases. Although interactions between magnesium intake and alcohol use and hepatic steatosis at baseline were not significant (P > 0.05), inverse associations between magnesium intake and liver disease mortality were stronger among alcohol drinkers and those with hepatic steatosis. Our findings suggest higher intakes of magnesium may be associated with a reduced risk of mortality due to liver disease particularly among alcohol drinkers and those with hepatic steatosis. Further studies are warranted to confirm the findings.


Hypoglycemic effect and protein nutritive quality of soy and methionine-supplemented whole durum pasta products.
New low cost, high-protein and high-fiber pasta products processed from whole durum meal (WD) solely, WD supplemented with 7% or 12% defatted soy flour (SF), or 12% SF plus 0.3% methionine were evaluated in comparison with the regular pasta made of pure durum semolina (DS). Their protein nutritive quality was biologically evaluated by rat growth studies using diets containing 9% protein, through the parameters: food efficiency ratio (FER), protein efficiency ratio (PER), net protein utilization (NPU), digestibility coefficient (DC) and biological value (BV). The original products were administered to diabetic hypercholesterolemic albino rats, (injected with alloxane) to study their effects on the levels of blood glucose and plasma lipid fractions. The results indicate that diets based on pasta made of WD supplemented with SE or SF plus methionine had superior protein quality and succeeded in supporting normal growth of rats in contrast to the diets based on pasta made of unsupplemented WD or DS. These assays demonstrated that the values of FER, PER, NPU and BV of WD-pasta increased with increasing SF supplementation. However, high-fiber pasta made of unrefined WD solely or with SF had lower DC values compared to that of the regular DS-pasta. DC values decreased as the added SF increased. Adding methionine evidently affected FER, PER, BV and NPU values. Administration of high-protein and high-fiber pasta samples made of WD solely, supplemented with SF or SF plus methionine significantly reduced the elevated blood glucose as well as plasma cholesterol and plasma lipid fractions in hypercholesterolemic diabetic rats. Overall, considering nutritional evaluation, protein cost as well as hypoglycemic and hypocholesterolemic effects the pasta composed of 12% SF-WD and supplemented with 0.3% methionine represented the best high-fiber; high-protein and high-quality product.


Phosphorylation of p27Kip1 regulates assembly and activation of cyclin D1-Cdk4.
p27 mediates Cdk2 inhibition and is also found in cyclin D1-Cdk4 complexes. The present data support a role for p27 in the assembly of D-type cyclin-Cdk complexes and indicate that both cyclin D1-Cdk4-p27 assembly and kinase activation are regulated by p27 phosphorylation. Prior work showed that p27 can be phosphorylated by protein kinase B/Akt (PKB/Akt) at T157 and T198. Here we show that PKB activation and the appearance of p27pT157 and p27pT198 precede p27-cyclin D1-Cdk4 assembly in early G(1). PI3K/PKB inhibition rapidly reduced p27pT157 and p27pT198 and dissociated cellular p27-cyclin D1-Cdk4. Mutant p27 allele products lacking phosphorylation at T157 and T198 bound poorly to cellular cyclin D1 and Cdk4. Cellular p27pT157 and p27pT198 coprecipitated with Cdk4 but were not detected in Cdk2 complexes. The addition of p27 to recombinant cyclin D1 and Cdk4 led to cyclin D1-Cdk4-p27 complex formation in vitro. p27 phosphorylation by PKB increased p27-cyclin D1-Cdk4 assembly in vitro but yielded inactive Cdk4. In contrast, Src pretreatment of p27 did not affect p27-cyclin D1-Cdk4 complex formation. However, Src treatment led to tyrosine phosphorylation of p27 and catalytic activation of assembled cyclin D1-Cdk4-p27 complexes. Thus, while PKB-dependent p27 phosphorylation appears to increase cyclin D1-Cdk4-p27 assembly or stabilize these complexes in vitro, cyclin D1-Cdk4-p27 activation requires the tyrosine phosphorylation of p27. Constitutive activation of PKB and Abl or Src family kinases in cancers would drive p27 phosphorylation, increase cyclin D1-Cdk4 assembly and activation, and reduce the cyclin E-Cdk2 inhibitory function of p27. Combined therapy with both Src and PI3K/PKB inhibitors may reverse this process.


Dimerization of dendrimeric lanthanide complexes: thermodynamic, thermal, and liquid-crystalline properties.
A series of 10 different mesomorphic semidendrimeric tridentate ligands L5-L14 grafted with terminal cyanobiphenyl groups have been synthesized. Upon reaction with Ln(NO(3))(3) (Ln = trivalent lanthanide), the central 2,6-bis(N-ethylbenzimidazol-2-yl)pyridine unit is meridionally tricoordinated to the metal to give rodlike monomeric [Ln(Lk)(NO(3))(3)] and H-shaped dimeric [Ln(2)(Lk)(2)(NO(3))(6)] complexes. For the small Lu(III) cation, the monomeric complexes are quantitatively formed in a noncoordinating CD(2)Cl(2) solution. For larger cations (Ln = Eu, Pr), the thermodynamic equilibrium 2[Ln(Lk)(NO(3))(3)] ↔ [Ln(2)(Lk)(2)(NO(3))(6)] can be evidenced across the complete ligand series. Detailed thermodynamic studies show that the dimeric complexes result from the formation of primary intermetallic nitrate bridges whose strength depends on the metallic size. For each complex, secondary nonspecific interstrand van der Waals interactions produce nonartifactual enthalpy/entropy compensation. In the absence of solvent, only the complexes with the most extended ligands L5 and L6 produce thermotropic mesophases. Layered organizations are dominant (smectic A) with the induction of nematogenic behavior at high temperature when interstrand interactions are modulated by methyl substitutions. Correlations between the trend of dimerization and the sequences of thermotropic mesophases are attempted.


Cryo-EM structure of aerolysin variants reveals a novel protein fold and the pore-formation process.
Owing to their pathogenical role and unique ability to exist both as soluble proteins and transmembrane complexes, pore-forming toxins (PFTs) have been a focus of microbiologists and structural biologists for decades. PFTs are generally secreted as water-soluble monomers and subsequently bind the membrane of target cells. Then, they assemble into circular oligomers, which undergo conformational changes that allow membrane insertion leading to pore formation and potentially cell death. Aerolysin, produced by the human pathogen Aeromonas hydrophila, is the founding member of a major PFT family found throughout all kingdoms of life. We report cryo-electron microscopy structures of three conformational intermediates and of the final aerolysin pore, jointly providing insight into the conformational changes that allow pore formation. Moreover, the structures reveal a protein fold consisting of two concentric β-barrels, tightly kept together by hydrophobic interactions. This fold suggests a basis for the prion-like ultrastability of aerolysin pore and its stoichiometry.


Gastroprotective effects of sulforaphane and thymoquinone against acetylsalicylic acid-induced gastric ulcer in rats.
Nonsteroidal anti-inflammatory drugs (NSAIDs) commonly cause gastric ulcers (GUs). We investigated the effects of sulforaphane (SF) and thymoquinone (TQ) in rats with acetylsalicylic acid (ASA)-induced GUs. Thirty-five male Wistar-Albino rats were divided into five groups: control; ASA; ASA with vehicle; ASA + SF; and ASA + TQ. Compounds were administered by oral gavage before GU induction. GUs were induced by intragastric administration of ASA. Four hours after GU induction, rats were killed and stomachs excised. Total oxidant status, total antioxidant status, total thiol, nitric oxide, asymmetric dimethylarginine, tumor necrosis factor-alpha levels, superoxide dismutase activity, and glutathione peroxidase activity in tissue were measured. Messenger RNA expression of dimethylarginine dimethylaminohydrolases, heme oxygenase-1 (HO-1), nuclear factor erythroid 2-related factor 2, and nuclear factor kappa-light-chain-enhancer of activated B cells were analyzed. Renal tissues were evaluated by histopathologic and immunohistochemical means. SF and TQ reduced GU indices, apoptosis, total oxidant status, asymmetric dimethylarginine, and tumor necrosis factor-alpha levels, nuclear factor kappa-light-chain-enhancer of activated B cells, and inducible nitric oxide synthase expressions (P < 0.001, P = 0.001). Both examined compounds increased superoxide dismutase activity, glutathione peroxidase activity, total antioxidant status, total thiol, nitric oxide levels, endothelial nitric oxide synthase, dimethylarginine dimethylaminohydrolases, HO-1, nuclear factor erythroid 2-related factor 2, and HO-1 expressions (P < 0.001). These results suggest that pretreatment with SF or TQ can reduce ASA-induced GUs via anti-inflammatory, antioxidant, and antiapoptotic effects. These compounds may be useful therapeutic strategies to prevent the gastrointestinal adverse effects that limit nonsteroidal anti-inflammatory drugs use.


Chemically contaminated casualties: different problems and possible solutions.
The initial response to mass casualty incidents is usually informal as uninjured and injured survivors and passersby assist the injured and take them to medical centers. This creates some problems, for example, most victims go to one or two hospitals and the least injured arrive first; but, on the whole, it works. However, the same response does not work when victims are contaminated, and some of the solutions that work when victims are only injured do not work when victims are contaminated. This article suggests an approach that accepts the reality of what happens-the first receiving hospital becomes contaminated--and suggests how planning can begin with that as a starting point. It stressed that current plans are based on false assumptions and that this can lead to inadequate preparation.


Award for Distinguished Scientific Applications of Psychology.
The Award for Distinguished Scientific Applications of Psychology is presented to a person who, in the opinion of the Committee on Scientific Awards, has made distinguished theoretical or empirical advances leading to the understanding or amelioration of important practical problems. The 2018 recipients of the APA Scientific Contribution Awards were recognized by the 2017 Board of Scientific Affairs and selected by the 2017 Committee on Scientific Awards. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Impact of TCFA on Unanticipated Ischemic Events in Medically Treated Diabetes Mellitus: Insights From the PROSPECT Study.
This study sought to investigate the relationship between thin-cap fibroatheromas (TCFAs) on major adverse cardiac events (MACEs) arising from medically treated nonculprit lesions (NCLs) in patients with acute coronary syndromes (ACS) with and without diabetes mellitus (DM). MACEs occur frequently in patients with DM and ACS. The impact of plaque composition on subsequent MACEs in DM patients with ACS is unknown. In the PROSPECT (Providing Regional Observations Study Predictors of Events in the Coronary Tree) study, using 3-vessel radiofrequency intravascular ultrasound, we analyzed the incidence of NCL-MACE in 2 propensity-matched groups according to the presence of DM and TCFA. Among 697 patients, 119 (17.7%) had DM. The 3-year total MACE rate (29.4% vs. 18.8%; p = 0.01) was significantly higher in patients with versus without DM, driven by a higher rate of NCL-MACE in DM (18.7% vs. 10.4%; p = 0.02). Propensity score matching generated 2 balanced groups with and without DM of 82 patients each. Among DM patients, the presence of ≥1 TCFA was associated with higher NCL-MACE at 3 years (27.8% vs. 8.9% in patients without a TCFA, hazard ratio: 3.56; 95% confidence interval: 0.98 to 12.96; p = 0.04). DM patients without a TCFA had a similar 3-year rate of NCL-MACE as patients without DM (8.9% vs. 8.9%; hazard ratio: 1.09; 95% confidence interval: 0.27 to 4.41; p = 0.90). ACS patients with DM and ≥1 TCFA have a high rate of NCL-MACE at 3 years. In contrast, the prognosis of ACS patients with DM but no TCFAs is favorable and similar to patients without DM.


Childhood Cognition and Age-Related Change in Standing Balance Performance From Mid to Later Life: Findings From a British Birth Cohort.
Cognitive processing plays a crucial role in the integration of sensory input and motor output that facilitates balance. However, whether balance ability in adulthood is influenced by cognitive pathways established in childhood is unclear, especially as no study has examined if these relationships change with age. We aimed to investigate associations between childhood cognition and age-related change in standing balance between mid and later life. Data on 2,380 participants from the MRC National Survey of Health and Development were included in analyses. Repeated measures multilevel models estimated the association between childhood cognition, assessed at age 15, and log-transformed balance time, assessed at ages 53, 60-64, and 69 using the one-legged stand with eyes closed. Adjustments were made for sex, death, attrition, anthropometric measures, health conditions, health behaviors, education, other indicators of socioeconomic position (SEP), and adult verbal memory. In a sex-adjusted model, 1 standard deviation increase in childhood cognition was associated with a 13% (95% confidence interval: 10, 16; p < .001) increase in balance time at age 53, and this association got smaller with age (cognition × age interaction: p < .001). Adjustments for education, adult verbal memory, and SEP largely explained these associations. Higher childhood cognition was associated with better balance performance in midlife, with diminishing associations with increasing age. The impact of adjustment for education, cognition and other indicators of SEP suggested a common pathway through which cognition is associated with balance across life. Further research is needed to understand underlying mechanisms, which may have important implications for falls risk and maintenance of physical capability.


Knowledge and use of measures to reduce health risks by corporate expatriate employees in western Ghana.
Expatriate corporate workers stationed in remote regions of developing countries with limited health care resources are at substantial risk for a variety of infectious diseases. A survey was carried out among expatriates working at a large power plant construction site in western Ghana in 1998 to evaluate their use of pretravel medical services, current knowledge, and behavioral practices in relation to food- and waterborne disease prevention, diarrhea, malaria, respiratory infections, alcohol use, and high-risk sexual activity. An anonymous, structured, and pretested questionnaire was used. The response rate was 42 of 60 (70%). Most respondents were men (39 of 42, 93%) with previous international construction experience. Adherence to food and water safety recommendations decreased with time. Expatriates (15 of 23, 65%) from developed countries reported at least one episode of diarrhea, whereas no expatriates (0 of 9) from resource-poor countries reported diarrhea (p < 0.001). Use of malaria chemoprophylaxis deteriorated with increasing duration of time on the job site. None of the expatriates (0 of 9) who had been on the site for more than a year was still taking an antimalarial compared to those who had been there for 3 months or less (13 of 16) (p < 0.01). Forty-three percent (18 of 42) of the respondents reported having had a respiratory infection in the past 3 months. Only 38% (15 of 39) received preplacement education on human immunodeficiency virus (HIV) risk. A higher proportion of those who received pretravel HIV education used condoms always (4 of 5) than those who did not receive HIV education (1 of 5). The use of health advice and preventive measures was generally low among the expatriate corporate survey respondents. Adherence to preventive measures declined with the increase in length of stay. Corporations need to develop appropriate health promotion strategies targeting their expatriates in developing countries.


Accuracy of direct gradient sensing by cell-surface receptors.
Chemotactic cells of eukaryotic organisms are able to accurately sense shallow chemical concentration gradients using cell-surface receptors. This sensing ability is remarkable as cells must be able to spatially resolve small fractional differences in the numbers of particles randomly arriving at cell-surface receptors by diffusion. An additional challenge and source of uncertainty is that particles, once bound and released, may rebind the same or a different receptor, which adds to noise without providing any new information about the environment. We recently derived the fundamental physical limits of gradient sensing using a simple spherical-cell model, but not including explicit particle-receptor kinetics. Here, we use a method based on the fluctuation-dissipation theorem (FDT) to calculate the accuracy of gradient sensing by realistic receptors. We derive analytical results for two receptors, as well as two coaxial rings of receptors, e.g. one at each cell pole. For realistic receptors, we find that particle rebinding lowers the accuracy of gradient sensing, in line with our previous results.


Allergic disease and atopic sensitization in children in relation to measles vaccination and measles infection.
Our aim was to investigate the role of measles vaccination and measles infection in the development of allergic disease and atopic sensitization. A total of 14 893 children were included from the cross-sectional, multicenter Prevention of Allergy-Risk Factors for Sensitization in Children Related to Farming and Anthroposophic Lifestyle study, conducted in 5 European countries (Austria, Germany, the Netherlands, Sweden, and Switzerland). The children were between 5 and 13 years of age and represented farm children, Steiner-school children, and 2 reference groups. Children attending Steiner schools often have an anthroposophic (holistic) lifestyle in which some immunizations are avoided or postponed. Parental questionnaires provided information on exposure and lifestyle factors as well as symptoms and diagnoses in the children. A sample of the children was invited for additional tests, and 4049 children provided a blood sample for immunoglobulin E analyses. Only children with complete information on measles vaccination and infection were included in the analyses (84%). In the whole group of children, atopic sensitization was inversely associated with measles infection, and a similar tendency was seen for measles vaccination. To reduce risks of disease-related modification of exposure, children who reported symptoms of wheezing and/or eczema debuting during first year of life were excluded from some analyses. After this exclusion, inverse associations were observed between measles infection and "any allergic symptom" and "any diagnosis of allergy by a physician." However, no associations were found between measles vaccination and allergic disease. Our data suggest that measles infection may protect against allergic disease in children.


Effects of an expanded Uber-like transport system on access to and use of maternal and newborn health services: findings of a prospective cohort study in Homa Bay, Kenya.
Kenya's progress towards reducing maternal and neonatal deaths is at present 'insufficient'. These deaths could be prevented if the three delays, that is, in deciding to seek healthcare (delay 1), in accessing formal healthcare (delay 2) and in receiving quality healthcare (delay 3), are comprehensively addressed. We designed a mobile phone enhanced 24 hours Uber-like transport navigation system coupled with personalised and interactive gestation-based text messages to address these delays. Our main objective was to evaluate the impact of this intervention on women's adherence to recommended antenatal (ANC) and postnatal care (PNC) regimes and facility birth. We conducted a prospective cohort study. Women were eligible to participate in the study if they were 15 years or older and less than 28 weeks gestation. We defined cases as those who received the standard of care plus the intervention and the control group as those who received the standard of care only. For analysis, we used logistic regression analysis and report crude and adjusted OR (aOR) and 95 % CI. Cases (women who received the intervention) had five times higher odds of having four or more ANC visits (aOR=4.7, 95% CI 3.20 to 7.09), three times higher odds of taking between 30 and 60 min to reach a health facility for delivery (aOR=3.14, 95% CI 2.37 to 4.15) and four times higher odds of undergoing at least four PNC visits (aOR=4.10, 95% CI 3.11 to 5.36). An enhanced community-based Uber-like transport navigation system coupled with personalised and interactive gestation-based text messages significantly increased the utilisation of ANC and PNC services as well as shortened the time taken to reach an appropriate facility for delivery compared with standard care.


Ancient DNA reveals a multistep spread of the first herders into sub-Saharan Africa.
How food production first entered eastern Africa ~5000 years ago and the extent to which people moved with livestock is unclear. We present genome-wide data from 41 individuals associated with Later Stone Age, Pastoral Neolithic (PN), and Iron Age contexts in what are now Kenya and Tanzania to examine the genetic impacts of the spreads of herding and farming. Our results support a multiphase model in which admixture between northeastern African-related peoples and eastern African foragers formed multiple pastoralist groups, including a genetically homogeneous PN cluster. Additional admixture with northeastern and western African-related groups occurred by the Iron Age. These findings support several movements of food producers while rejecting models of minimal admixture with foragers and of genetic differentiation between makers of distinct PN artifacts.


Bif-1 regulates Atg9 trafficking by mediating the fission of Golgi membranes during autophagy.
Atg9 is a transmembrane protein essential for autophagy which cycles between the Golgi network, late endosomes and LC3-positive autophagosomes in mammalian cells during starvation through a mechanism that is dependent on ULK1 and requires the activity of the class III phosphatidylinositol-3-kinase (PI3KC3). In this study, we demonstrate that the N-BAR-containing protein, Bif-1, is required for Atg9 trafficking and the fission of Golgi membranes during the induction of autophagy. Upon starvation, Atg9-positive membranes undergo continuous tubulation and fragmentation to produce cytoplasmic punctate structures that are positive for Rab5, Atg16L and LC3. Loss of Bif-1 or inhibition of the PI3KC3 complex II suppresses starvation-induced fission of Golgi membranes and peripheral cytoplasmic redistribution of Atg9. Moreover, Bif-1 mutants, which lack the functional regions of the N-BAR domain that are responsible for membrane binding and/or bending activity, fail to restore the fission of Golgi membranes as well as the formation of Atg9 foci and autophagosomes in Bif-1-deficient cells starved of nutrients. Taken together, these findings suggest that Bif-1 acts as a critical regulator of Atg9 puncta formation presumably by mediating Golgi fission for autophagosome biogenesis during starvation.


The Fourth-Revolution in the Water Sector Encounters the Digital Revolution.
The so-called fourth revolution in the water sector will encounter the Big data and Artificial Intelligence (AI) revolution. The current data surplus stemming from all types of devices together with the relentless increase in computer capacity is revolutionizing almost all existing sectors, and the water sector will not be an exception. Combining the power of Big data analytics (including AI) with existing and future urban water infrastructure represents a significant untapped opportunity for the operation, maintenance, and rehabilitation of urban water infrastructure to achieve economic and environmental sustainability. However, such progress may catalyze socio-economic changes and cross sector boundaries (e.g., water service, health, business) as the appearance of new needs and business models will influence the job market. Such progress will impact the academic sector as new forms of research based on large amounts of data will be possible, and new research needs will be requested by the technology industrial sector. Research and development enabling new technological approaches and more effective management strategies are needed to ensure that the emerging framework for the water sector will meet future societal needs. The feature further elucidates the complexities and possibilities associated with such collaborations.


Strategizing Safety: Theoretical Frameworks to Understand Women's Decision Making in the Face of Partner Violence and Social Inequities.
Women in physically and psychologically abusive relationships face numerous decisions related to their safety: decisions that historically have been viewed by researchers and human service practitioners as related to individual or interpersonal factors, such as how they feel about their partner, what they (or those they are close to) think is best for their children, or whether they have a safe place to go to. Social and structural factors, such as poverty, sexism, and barriers related to disability, are either left out or viewed at their individual-level consequence, such as a woman's employment status. Using interview data and case studies from a larger study on housing instability, partner violence, and health, the authors apply ecological and macro-level theoretical models that go beyond the individual level to the stories of women who struggled with partner violence, arguing that it is critical to examine the large social and structural forces that impact women's lives if we are to understand the decisions women make when facing a violent partner.


Prevalence of hepatitis B and C serological markers among first-time blood donors in Brazil: a multi-center serosurvey.
Little data are available on the seroprevalence of, and risk factors for hepatitis B and C viruses (HBV and HCV) infection in Latin American countries. A multi-center serosurvey was conducted among 3,598 first-time blood donors (65% men) from Sao Paulo, Salvador and Manaus in Brazil. The gender-specific seroprevalences of antibodies against hepatitis B core antigen (anti-HBc) and of the hepatitis B surface antigen (HBsAg) in anti-HBc-positive sera were measured, and risk factors analyzed by gender. The gender-specific seroprevalences of antibodies against HCV (anti-HCV) were measured, but risk factors for HCV were not determined. Anti-HBc and HBsAg seroprevalences were not significantly different in men [101/2,341 (4.31%) and 4/2,229 (0.18%), respectively] and women [65/1,237 (5.25%) and 8/1,169 (0.68%), respectively], whereas the seroprevalence of anti-HCV was higher in women (12/1,238 [0.97%] vs. 9/2,353 [0.38%]; odds ratio [OR] = 2.49; 95% confidence interval [CI]: 1.0-6.0). No significant difference for HBV infection was found across the three study sites or by ethnic group. The seroprevalence of anti-HBc increased with age, but decreased with education level in both genders. Lifetime number of sexual partners was associated with anti-HBc prevalence among men (OR = 1.95; 95% CI: 1.2-3.1), but not women. The seroprevalence of HBV and HCV was low among Brazilian blood donors, and exposure increased with age in both genders.


Harmonic modulation of light by means of collinear acousto-optic interaction.
The collinear anisotropic interaction of light with a standing acoustic wave generated in a lithium niobate crystal is discussed. Diffraction may be applied for harmonic modulation of laser light. The analysis of the light modulation is based on the concept of vector diagrams. A set of differential equations is derived to describe up to five interacting optic waves in the material. It is shown that solution of the equations by the method of successive approximations yields amplitudes of electric fields corresponding to diffracted and transmitted optical beams at the output of the crystal. Dependences of the amplitudes of the interacting waves on the acoustic frequency and length of the acousto-optic interaction are also discussed.


Mitonuclear protein imbalance as a conserved longevity mechanism.
Longevity is regulated by a network of closely linked metabolic systems. We used a combination of mouse population genetics and RNA interference in Caenorhabditis elegans to identify mitochondrial ribosomal protein S5 (Mrps5) and other mitochondrial ribosomal proteins as metabolic and longevity regulators. MRP knockdown triggers mitonuclear protein imbalance, reducing mitochondrial respiration and activating the mitochondrial unfolded protein response. Specific antibiotics targeting mitochondrial translation and ethidium bromide (which impairs mitochondrial DNA transcription) pharmacologically mimic mrp knockdown and extend worm lifespan by inducing mitonuclear protein imbalance, a stoichiometric imbalance between nuclear and mitochondrially encoded proteins. This mechanism was also conserved in mammalian cells. In addition, resveratrol and rapamycin, longevity compounds acting on different molecular targets, similarly induced mitonuclear protein imbalance, the mitochondrial unfolded protein response and lifespan extension in C. elegans. Collectively these data demonstrate that MRPs represent an evolutionarily conserved protein family that ties the mitochondrial ribosome and mitonuclear protein imbalance to the mitochondrial unfolded protein response, an overarching longevity pathway across many species.


Factors Affecting Survival in Surgically Salvaged Locoregional Recurrences of Squamous Cell Carcinoma of the Tongue.
To determine the factors affecting outcomes in surgically salvaged, locoregionally recurrent squamous cell carcinoma of the tongue (SCCT). In a retrospective cohort of patients who underwent successful salvage of locoregionally recurrent SCCT, we performed this observational analytical study to determine survival and its determinants. Details extracted from our database were patient characteristics (age, gender, tobacco use), treatment characteristics, and characteristics of recurrent disease (stage and adverse pathologic features [APFs] such as grade, perineural invasion, and lymphovascular invasion). Overall survival (OS) curves were plotted using the Kaplan-Meier method. A Cox proportional hazards model was used to determine the impact of patient, disease, and treatment characteristics on OS. Of 52 patients with locoregional recurrences of surgically treated SCCT, 25 (48.1%) underwent surgical salvage with curative intent. The median overall OS for this cohort was 26 months. Factors predictive of worse OS were previous adjuvant therapy (P = .016) and increasing APFs in recurrent tumor histology (P = .008). Lymphovascular invasion in recurrent tumor histology and patients with a disease-free interval of less than 6 months showed worse survival (P = .008 and P = .058, respectively). Among patients with locoregional recurrence, the number who are eligible for curative-intent surgical salvage is small. Those who received previous adjuvant therapy and those with increasing APFs in recurrent tumors had poor outcomes despite attempts at surgical salvage, particularly patients with early recurrence.


Influence of ATP-Binding Cassette Transporters in Root Exudation of Phytoalexins, Signals, and in Disease Resistance.
The roots of plants secrete compounds as a way to exchange information with organisms living in the soil. Here, we report the involvement of seven root-expressed ATP-binding cassette (ABC) transporters corresponding to both full and half-size molecules (Atabcg36, Atabcg37, Atabcc5, Atabcf1, Atabcf3, Atnap5, and Atath10) in root exudation processes using Arabidopsis thaliana. Root exuded phytochemicals were analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS) and gas chromatography-mass spectrometry (GC-MS), and it was determined that some of the root exudates from the corresponding ABC transporter mutants were significantly different compared to the wild type. For example, Atabcg37 and Atabcc5 secreted higher levels of the phytoalexin camalexin, and Atabcg36 secreted higher levels of organic acids, specifically salicylic acid (SA). Furthermore, we analyzed the root tissue metabolites of these seven ABC transporter mutants and found that the levels of SA, quercetin, and kaempferol glucosides were higher in Atabcg36, which was correlated with higher expression levels of defense genes in the root tissues compared with the wild type. We did not observe significant changes in the root exudates of the half-size transporters except for Atabcf1 that showed lower levels of few organic acids. In summary, full-size transporters are involved in root secretion of phytochemicals.


A 7-week-old female infant with a left thigh swelling.
This case is presented to illustrate the imaging and clinical findings of a condition of interest to orthopedic surgeons. The initial findings are noted on this page. The clinical and imaging diagnoses are presented on the following pages.


Establishing stable test performance in tests from the Behavioral Assessment and Research System (BARS).
Research to identify adverse effects in humans chronically exposed to neurotoxic substances in the workplace or environment typically assesses people at one point in time in a cross-sectional study. The most widely used strategy employs performance measures taken from a single point in time and compares these with either performance of a control group or established normative data. However, multiple comparison points of the same people on the same test allow the dissection of acute--from chronic--exposure effects, among other important questions. When performance measures are used from multiple points in time, within-subject deviations are examined. For either research design, the goal is to minimize the effects of practice and to obtain stable performance on a test. Demographic variables such as age, education, and cultural background or ethnicity influence performance on neurobehavioral tests. These variables may also influence the development of stable performance. Different populations may have different learning curves so that stable performance on a test is achieved with different amounts of practice. This is especially important when making comparisons across groups that may not have equivalent backgrounds. The performance of three groups, English-speaking adults, Spanish-speaking adolescents, and Spanish-speaking migrant adolescents, was examined. Each group completed a battery of neurobehavioral tests from the Behavioral Assessment and Research System (BARS) during four sessions. Repeated measures ANOVAs were used to investigate performance across time. Tests measuring motor performance produced stable performance from the first session. More complex tasks that involved attention and memory showed a practice effect across sessions.


Functional antigen-presenting leucocytes derived from human embryonic stem cells in vitro.
Differentiated cells derived from pluripotent human embryonic stem (hES) cells offer the opportunity for new transplantation therapies. However, hES cells and their differentiated progeny express highly polymorphic MHC molecules that serve as major graft rejection antigens to the immune system of allogeneic hosts. To achieve sustained engraftment of donor cells, strategies must be developed to overcome graft rejection without broadly suppressing host immunity. One approach entails induction of donor-specific immune tolerance by establishing chimeric engraftment in hosts with haemopoietic cells derived from an existing hES cell line. We aimed to develop methods to efficiently differentiate hES cells to haemopoietic cells, including immune-modulating leucocytes, a prerequisite of the tolerance induction strategies applying to hES cell-mediated transplantation. We developed a method to generate a broad range of haemopoietic cells from hES-generated embryonic bodies in the absence of murine stromal feeder cells. Embryonic bodies were further cultured in the presence of haemopoietic cytokines. In addition to flow cytometric analyses of haemopoietic cell markers, we analysed the hES cell-derived haemopoietic cells by colony-forming assays (for erythroid and myeloid progenitor cells), cytochemical staining, and mixed leucocyte reactions to determine the functional capacity of the generated antigen-presenting cells. 12 independent experiments were done. When selected growth factors were added, leucocytes expressing CD45 were generated and released into culture media for 6-7 weeks. Under the condition used, both erythroid and myeloid progenitor cells were generated. About 25% of the generated leucocytes acquired MHC class II and costimulatory molecule expression. These hES-derived, MHC class II+ leucocytes resembled dendritic cells and macrophages, and they functioned as antigen-presenting cells capable of eliciting allogeneic CD4 and CD8 T-cell responses in culture. The hES cell-derived antigen-presenting cells could be used to regulate alloreactive T cells and induce immune tolerance for improvement of the transplant acceptance of hES-cell derivatives.


Implementing achievable benchmarks in preventive health: a controlled trial in residency education.
To evaluate the Preventive Health Achievable Benchmarks Curriculum, a multifaceted improvement intervention that included an objective, practice-based performance evaluation of internal medicine and pediatric residents' delivery of preventive services. The authors conducted a nonrandomized experiment of intervention versus control group residents with baseline and follow-up of performance audited for 2001-2004. All 130 internal medicine and 78 pediatric residents at two continuity clinics at the University of Alabama School of Medicine, Birmingham, participated. Performance of preventive care was assessed by structured chart review. The multifaceted feedback curriculum included individualized performance feedback, academic detailing by faculty, and collective didactic sessions. The main outcome was difference in receipt of preventive care for patients seen by intervention and control residents, comparing baseline and follow-up. Charts were reviewed for 3,958 patients. Receipt of preventive care increased for patients of intervention residents, but not for patients of control residents. For the intervention group, significant increases occurred for five of six indicators in internal medicine: smoking screening, quit smoking advice, colon cancer screening, pneumonia vaccine, and lipid screening; and four of six in pediatrics: parental quit smoking advice, car seats, car restraints, and eye alignment (p < .05 for all). For control residents, no consistent improvements were seen. There was greater improvement for intervention than for control residents for four of six indicators in internal medicine, and two of six in pediatrics. Using a multifaceted feedback curriculum, the authors taught residents about the care they provide and improved documented patient care.


Studying the effects of dietary body weight-adjusted acute tryptophan depletion on punishment-related behavioral inhibition.
Alterations in serotonergic (5-HT) neurotransmission are thought to play a decisive role in affective disorders and impulse control. This study aims to reproduce and extend previous findings on the effects of acute tryptophan depletion (ATD) and subsequently diminished central 5-HT synthesis in a reinforced categorization task using a refined body weight-adjusted depletion protocol. Twenty-four young healthy adults (12 females, mean age [SD]=25.3 [2.1] years) were subjected to a double-blind within-subject crossover design. Each subject was administered both an ATD challenge and a balanced amino acid load (BAL) in two separate sessions in randomized order. Punishment-related behavioral inhibition was assessed using a forced choice go/no-go task that incorporated a variable payoff schedule. Administration of ATD resulted in significant reductions in TRP measured in peripheral blood samples, indicating reductions of TRP influx across the blood-brain barrier and related brain 5-HT synthesis. Overall accuracy and response time performance were improved after ATD administration. The ability to adjust behavioral responses to aversive outcome magnitudes and behavioral adjustments following error contingent punishment remained intact after decreased brain 5-HT synthesis. A previously observed dissociation effect of ATD on punishment-induced inhibition was not observed. Our results suggest that neurodietary challenges with ATD Moja-De have no detrimental effects on task performance and punishment-related inhibition in healthy adults.


Intestinal epithelial HuR modulates distinct pathways of proliferation and apoptosis and attenuates small intestinal and colonic tumor development.
HuR is a ubiquitous nucleocytoplasmic RNA-binding protein that exerts pleiotropic effects on cell growth and tumorigenesis. In this study, we explored the impact of conditional, tissue-specific genetic deletion of HuR on intestinal growth and tumorigenesis in mice. Mice lacking intestinal expression of HuR (Hur (IKO) mice) displayed reduced levels of cell proliferation in the small intestine and increased sensitivity to doxorubicin-induced acute intestinal injury, as evidenced by decreased villus height and a compensatory shift in proliferating cells. In the context of Apc(min/+) mice, a transgenic model of intestinal tumorigenesis, intestinal deletion of the HuR gene caused a three-fold decrease in tumor burden characterized by reduced proliferation, increased apoptosis, and decreased expression of transcripts encoding antiapoptotic HuR target RNAs. Similarly, Hur(IKO) mice subjected to an inflammatory colon carcinogenesis protocol [azoxymethane and dextran sodium sulfate (AOM-DSS) administration] exhibited a two-fold decrease in tumor burden. Hur(IKO) mice showed no change in ileal Asbt expression, fecal bile acid excretion, or enterohepatic pool size that might explain the phenotype. Moreover, none of the HuR targets identified in Apc(min/+)Hur(IKO) were altered in AOM-DSS-treated Hur(IKO) mice, the latter of which exhibited increased apoptosis of colonic epithelial cells, where elevation of a unique set of HuR-targeted proapoptotic factors was documented. Taken together, our results promote the concept of epithelial HuR as a contextual modifier of proapoptotic gene expression in intestinal cancers, acting independently of bile acid metabolism to promote cancer. In the small intestine, epithelial HuR promotes expression of prosurvival transcripts that support Wnt-dependent tumorigenesis, whereas in the large intestine epithelial HuR indirectly downregulates certain proapoptotic RNAs to attenuate colitis-associated cancer. Cancer Res; 74(18); 5322-35. ©2014 AACR.


Rat brain DNA transcript profile of halothane and isoflurane exposure.
Inhaled anesthetics produce many effects and bind to a large number of brain proteins, but it is not yet clear if this is accompanied by widespread changes in gene expression of the biological targets. Such changes in expression might implicate functionally important targets from the large pool of binding targets. Both rats and isolated primary cortical neurons were exposed to anesthetics and DNA oligonucleotide microarrays were used to detect and quantify transcriptional changes in neural tissue. Using analysis of variance with multiple testing correction, multiple exposures of rats to 0.8 MAC (minimum alveolar concentration) halothane only produced significant changes in a few metabolic genes. No significant in-vivo gene transcriptional response to 0.8 MAC isoflurane was detected. The use of primary cortical neurons allowed exposure to 3 MAC anesthetics without evidence of toxicity. Isoflurane altered several genes involved with neurotransmitter transport, signaling and cellular structure, whereas halothane produced few detectable changes in these cultured cells. Selected genes were confirmed by quantitative reverse transcription-polymerase chain reaction. Although indicating only a small degree of transcriptional regulation, these data implicate several plausible targets, including synaptic vesicle handling, that might contribute to drug action. In addition, the data show different gene expression profiles for the two inhaled anesthetics, suggesting unique pharmacological targets and mechanisms in each case.


Virulence of Mycobacterium tuberculosis Clinical Isolates Is Associated With Sputum Pre-treatment Bacterial Load, Lineage, Survival in Macrophages, and Cytokine Response.
It is uncertain whether differences in Mycobacterium tuberculosis (Mtb) virulence defined in vitro influence clinical tuberculosis pathogenesis, transmission, and mortality. We primarily used a macrophage lysis model to characterize the virulence of Mtb isolates collected from 153 Vietnamese adults with pulmonary tuberculosis. The virulence phenotypes were then investigated for their relationship with sputum bacterial load, bacterial lineages, bacterial growth, and cytokine responses in macrophages. Over 6 days of infection, 34 isolates (22.2%) showed low virulence (< 5% macrophages lysed), 46 isolates (30.1%) showed high virulence (≥90% lysis of macrophages), and 73 isolates (47.7%) were of intermediate virulence (5-90% macrophages lysed). Highly virulent isolates were associated with an increased bacterial load in patients' sputum before anti-tuberculosis therapy (P = 0.02). Isolate-dependent virulence phenotype was consistent in both THP-1 and human monocyte-derived macrophages. High virulence isolates survived better and replicated in macrophages one hundred fold faster than those with low virulence. Macrophages infected with high virulence isolates produced lower concentrations of TNF-α and IL-6 (P = 0.002 and 0.0005, respectively), but higher concentration of IL-1β (P = 5.1 × 10-5) compared to those infected with low virulence isolates. High virulence was strongly associated with East Asian/Beijing lineage [P = 0.002, Odd ratio (OR) = 4.32, 95% confident intervals (CI) 1.68-11.13]. The association between virulence phenotypes, bacterial growth, and proinflammatory cytokines in macrophages suggest the suppression of certain proinflammatory cytokines (TNF-α and IL-6) but not IL-1β allows better intracellular survival of highly virulent Mtb. This could result in rapid macrophage lysis and higher bacterial load in sputum of patients infected with high virulence isolates, which may contribute to the pathogenesis and success of the Beijing lineage.


Management of diabetic dyslipidemia: An update.
Diabetic dyslipidemia is a cluster of lipoprotein abnormalities characterized by increased triglyceride level, decreased high-density lipoprotein-cholesterol levels and increase in small dense low-density lipoprotein (LDL) particles. It is extremely common in type 2 diabetes (T2DM) affecting around 70 % of patients. Diabetic is a significant risk factor for atherosclerotic cardiovascular disease (ASCVD) which is the most common cause of death in the United States and LDL-cholesterol is the number 1 predictor of ASCVD events in T2DM. The purpose of this review is to discuss the pathophysiology and treatment of diabetic dyslipidemia. In this review, we have discussed both non-pharmacological and pharmacological treatment modalities including major treatment trials which have impacted the cardiovascular outcomes in patients with diabetes. Statin therapy is the mainstay of treatment to reduce ASCVD by decreasing LDL-C by 30%-49% or at least 50% depending on risk level. Attractive adjunctive therapies include Ezetimibe which is more cost effective and PCSK9 inhibitors which display potent LDL-cholesterol lowering and ASCVD event reduction. For severe hypertriglyceridemia, to avert the risk of pancreatitis, both fish oil and fenofibrate in concert with diet is the best strategy.


Budget Impact of Cryoablation Versus Radiofrequency Ablation of Atrial Fibrillation in the Brazilian Public Healthcare System.
Cryoablation is a new technology for ablation of atrial fibrillation (AF), effective and safe when compared with standard radiofrequency (RF) ablation. Nevertheless, the economic impact of its incorporation is unknown, especially considering the public health system of a developing country. This study analyzed the budget impact of cryoablation incorporation for treatment of paroxysmal AF in the Brazilian public health system. The budget impact was calculated as the cost difference between the current scenario (RF ablation guided by electroanatomic mapping) and the new scenario (cryoablation). The cost of each intervention was obtained by multiplying the price of a single procedure by the number of candidates for it. Other technologies (RF ablation guided by intracardiac echocardiography or with a nonirrigated catheter) were considered in a sensitivity analysis. The budget impact showed savings of $43 097 096.84 with cryoablation. In the sensitivity analysis, cryoablation resulted in cost savings compared with RF ablation guided by intracardiac echocardiography, whereas in comparison to RF ablation with the nonirrigated catheter, cryoablation was more expensive. A market share assessment, performed using an incorporation rate of 3% per year, indicated savings of approximately $800 000 per 5 years. Cryoablation of AF resulted in cost savings compared with the current scenario (RF ablation guided by electroanatomic mapping). When alternative technologies were considered, cryoablation was more expensive than RF ablation with a nonirrigated catheter, but it also resulted in savings compared with RF ablation guided by intracardiac echocardiography. Overall, cryoablation of AF may reduce expenditures in the Brazilian public health system.


Reliable and precise neuronal firing during sensory plasticity in superficial layers of primary somatosensory cortex.
Neocortical neurons show astonishing variation in the presence and timing of action potentials across stimulus trials, a phenomenon whose function and significance has been the subject of great interest. Here we present data showing that this response variability can be significantly reduced by altered sensory experience. Removal of all but one whisker from the side of the mouse face results in the rapid (within 24 h) potentiation of mean firing rates within the cortical representation of the spared whisker in young postnatal animals (postnatal days 13-16). Analysis of single-unit responses from whisker-spared animals shows that this potentiation can be attributed to an enhancement of trial-to-trial reliability (i.e., reduced response failures), as well as an increase in the mean number of spikes evoked within a successful trial. Changes were confined to superficial layers 2/3 and were not observed in the input layer of the cortex, layer 4. In addition to these changes in firing rates, we also observed profound changes in the precise timing of sensory-evoked responses. Trial-to-trial temporal precision was enhanced and the absolute latency of responses was reduced after single-whisker experience. Enhanced spike-timing precision and trial-to-trial reliability could also be triggered in adolescent animals with longer periods (7 d) of single-whisker experience. These experiments provide a quantitative analysis of how sensory experience can enhance both reliability and temporal precision in neocortical neurons and provide a framework for testing specific hypotheses about the role of response variability in cortical function and the molecular mechanisms underlying this phenomenon.


Comparison of three-view thoracic radiography and computed tomography for detection of pulmonary nodules in dogs with neoplasia.
To compare the detection of pulmonary nodules by use of 3-view thoracic radiography and CT in dogs with confirmed neoplasia. Prospective case series. 33 dogs of various breeds. 3 interpreters independently evaluated 3-view thoracic radiography images. The location and size of pulmonary nodules were recorded. Computed tomographic scans of the thorax were obtained and evaluated by a single interpreter. The location, size, margin, internal architecture, and density of pulmonary nodules were recorded. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for thoracic radiography (with CT as the gold standard). 21 of 33 (64%) dogs had pulmonary nodules or masses detected on CT. Of the dogs that had positive CT findings, 17 of 21 (81%) had pulmonary nodules or masses detected on radiographs by at least 1 interpreter. Sensitivity of radiography ranged from 71% to 95%, and specificity ranged from 67% to 92%. Radiography had a positive predictive value of 83% to 94% and a negative predictive value of 65% to 89%. The 4 dogs that were negative for nodules on thoracic radiography but positive on CT were all large-breed to giant-breed dogs with osteosarcoma. CT was more sensitive than radiography for detection of pulmonary nodules. This was particularly evident in large-breed to giant-breed dogs. Thoracic CT is recommended in large-breed to giant-breed dogs with osteosarcoma if the detection of pulmonary nodules will change treatment.