Risk factors and clinical outcomes in chronic coronary and peripheral artery disease: An analysis of the randomized, double-blind COMPASS trial.
Secondary prevention in patients with coronary artery disease and peripheral artery disease involves antithrombotic therapy and optimal control of cardiovascular risk factors. In the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) study, adding low-dose rivaroxaban on top of aspirin lowered cardiovascular events, but there is limited data about risk factor control in secondary prevention. We studied the association between risk factor status and outcomes, and the impact of risk factor status on the treatment effect of rivaroxaban, in a large contemporary population of patients with coronary artery disease or peripheral artery disease. We reported ischemic events (cardiovascular death, stroke, or myocardial infarction) in participants from the randomized, double-blind COMPASS study by individual risk factor (blood pressure, smoking status, cholesterol level, presence of diabetes, body mass index, and level of physical activity), and by number of risk factors. We compared rates and hazard ratios of patients treated with rivaroxaban plus aspirin vs aspirin alone within each risk factor category and tested for interaction between risk factor status and antithrombotic regimen. Complete baseline risk factor status was available in 27,117 (99%) patients. Status and number of risk factors were both associated with increased risk of ischemic events. Rates of ischemic events (hazard ratio 2.2; 95% confidence interval 1.8-2.6) and cardiovascular death (hazard ratio 2.0; 1.5-2.7) were more than twofold higher in patients with 4-6 compared with 0-1 risk factors (p < 0.0001 for both). Rivaroxaban reduced event rates independently of the number of risk factors (p interaction 0.93), with the largest absolute benefit in patients with the highest number of risk factors. More favorable risk factor status and low-dose rivaroxaban were independently associated with lower risk of cardiovascular events.


Early cerebral perfusion pressure augmentation with phenylephrine after traumatic brain injury may be neuroprotective in a pediatric swine model.
Cerebral perfusion pressure<40 mm Hg following pediatric traumatic brain injury has been associated with increased mortality independent of age, and current guidelines recommend maintaining cerebral perfusion pressure between 40 mm Hg-60 mm Hg. Although adult traumatic brain injury studies have observed an increased risk of complications associated with targeting a cerebral perfusion pressure>70, we hypothesize that targeting a cerebral perfusion pressure of 70 mm Hg with the use of phenylephrine early after injury in the immature brain will be neuroprotective. Animals were randomly assigned to injury with a cerebral perfusion pressure of 70 mm Hg or 40 mm Hg. Diffuse traumatic brain injury was produced by a single rapid rotation of the head in the axial plane. Cerebral microdialysis, brain tissue oxygen, intracranial pressure, and cerebral blood flow were measured 30 min-6 hrs postinjury. One hour after injury, cerebral perfusion pressure was manipulated with the vasoconstrictor phenylephrine. Animals were euthanized 6 hrs posttraumatic brain injury, brains fixed, and stained to assess regions of cell injury and axonal dysfunction. University center. Twenty-one 4-wk-old female swine. Augmentation of cerebral perfusion pressure to 70 mm Hg resulted in no change in axonal dysfunction, but significantly smaller cell injury volumes at 6 hrs postinjury compared to cerebral perfusion pressure 40 (1.1% vs. 7.4%, p<.05). Microdialysis lactate/pyruvate ratios were improved at cerebral perfusion pressure 70 compared to cerebral perfusion pressure 40. Cerebral blood flow was higher in the cerebral perfusion pressure 70 group but did not reach statistical significance. Phenylephrine was well tolerated and there were no observed increases in serum lactate or intracranial pressure in either group. Targeting a cerebral perfusion pressure of 70 mm Hg resulted in a greater reduction in metabolic crisis and cell injury volumes compared to a cerebral perfusion pressure of 40 mm Hg in an immature swine model. Early aggressive cerebral perfusion pressure augmentation to a cerebral perfusion pressure of 70 mm Hg in pediatric traumatic brain injury before severe intracranial hypertension has the potential to be neuroprotective, and further investigations are needed.


Yeast cells depleted of the frataxin homolog Yfh1 redistribute cellular iron: Studies using Mössbauer spectroscopy and mathematical modeling.
The neurodegenerative disease Friedreich's ataxia arises from a deficiency of frataxin, a protein that promotes iron-sulfur cluster (ISC) assembly in mitochondria. Here, primarily using Mössbauer spectroscopy, we investigated the iron content of a yeast strain in which expression of yeast frataxin homolog 1 (Yfh1), oxygenation conditions, iron concentrations, and metabolic modes were varied. We found that aerobic fermenting Yfh1-depleted cells grew slowly and accumulated FeIII nanoparticles, unlike WT cells. Under hypoxic conditions, the same mutant cells grew at rates similar to WT cells, had similar iron content, and were dominated by FeII rather than FeIII nanoparticles. Furthermore, mitochondria from mutant hypoxic cells contained approximately the same levels of ISCs as WT cells, confirming that Yfh1 is not required for ISC assembly. These cells also did not accumulate excessive iron, indicating that iron accumulation into yfh1-deficient mitochondria is stimulated by O2. In addition, in aerobic WT cells, we found that vacuoles stored FeIII, whereas under hypoxic fermenting conditions, vacuolar iron was reduced to FeII. Under respiring conditions, vacuoles of Yfh1-deficient cells contained FeIII, and nanoparticles accumulated only under aerobic conditions. Taken together, these results informed a mathematical model of iron trafficking and regulation in cells that could semiquantitatively simulate the Yfh1-deficiency phenotype. Simulations suggested partially independent regulation in which cellular iron import is regulated by ISC activity in mitochondria, mitochondrial iron import is regulated by a mitochondrial FeII pool, and vacuolar iron import is regulated by cytosolic FeII and mitochondrial ISC activity.


Changes in Renal Function in Patients With Chronic HBV Infection Treated With Tenofovir Disoproxil Fumarate vs Entecavir.
It is unclear whether drugs used to treat chronic hepatitis B virus (HBV) infection cause significant renal impairment. We compare adjusted mean estimated glomerular filtration rates (eGFR; mL/min/1.73 m2) of patients with chronic HBV infection treated with tenofovir disoproxil fumarate (TDF) vs patients treated with entecavir. We performed a retrospective study of patients with chronic HBV infections treated with TDF (n = 239) or entecavir (n = 171), from 2000 through 2016, followed for a mean time of 43-46 months. Levels of serum creatinine were measured ≥12 months while patients received treatment. Patients did not have prior exposure to adefovir or HCV, HDV, or HIV co-infection. We performed propensity score matching (PSM) for age, sex, presence of hypertension, diabetes mellitus, baseline eGFR, cirrhosis, and follow-up duration. We performed multivariate generalized linear modeling, adjusting for cirrhosis, diabetes, and hypertension, to estimate adjusted mean eGFR for matched and unmatched cohorts. Cox regression was used to identify predictors of renal impairment. eGFRs were ≥60, after PSM, in 116 patients given entecavir and in 116 patients given TDF; eGFRs were <60 in 32 patients given entecavir and 26 patients given TDF. Multivariate generalized linear modeling of the unmatched overall and <60 eGFR cohorts revealed significantly lower adjusted mean eGFRs in patients given TDF (all P < .001). However, in the eGFR ≥60 PSM cohort, the adjusted mean eGFR was similar between patients receiving either treatment. In Cox regression analysis, TDF was not associated with mild or moderate renal impairment compared with entecavir. In a retrospective study of patients with chronic HBV infections treated with TDF vs entecavir, we found that TDF was not associated with higher risk of worsening renal function during short- or intermediate-term follow-up periods, among patients without significant renal impairment. Additional studies, with longer follow-up periods, are needed because treatment for chronic HBV infection is generally long term or life-long. For patients with baseline renal impairment, significant renal decline was among patients given TDF compared to patients given entecavir.


Cytologic diagnosis of acinic cell carcinoma of minor salivary gland: a distinct rarely described entity.
A rare case of acinic cell carcinoma of minor salivary gland with cervical lymph node metastasis in a 50-year-old man is reported and the literature regarding this type of tumor is reviewed. These tumors arise from either an intercalated duct stem cell or the reserve cell of the salivary gland terminal tubule but not from both simultaneously. Rarely these neoplasms arise from more mature acinar cells. It is clear that these tumors behave ominously. The 25 year determinate survival rate is 50%, with a 20% incidence of metastasis. Surgical excision is the treatment of choice. Radiotherapy, especially neutron therapy, has a place in the treatment of this tumor but the role of chemotherapy is not exactly known at this time.


Analysis of amyotrophic lateral sclerosis as a multistep process: a population-based modelling study.
Amyotrophic lateral sclerosis shares characteristics with some cancers, such as onset being more common in later life, progression usually being rapid, the disease affecting a particular cell type, and showing complex inheritance. We used a model originally applied to cancer epidemiology to investigate the hypothesis that amyotrophic lateral sclerosis is a multistep process. We generated incidence data by age and sex from amyotrophic lateral sclerosis population registers in Ireland (registration dates 1995-2012), the Netherlands (2006-12), Italy (1995-2004), Scotland (1989-98), and England (2002-09), and calculated age and sex-adjusted incidences for each register. We regressed the log of age-specific incidence against the log of age with least squares regression. We did the analyses within each register, and also did a combined analysis, adjusting for register. We identified 6274 cases of amyotrophic lateral sclerosis from a catchment population of about 34 million people. We noted a linear relationship between log incidence and log age in all five registers: England r(2)=0·95, Ireland r(2)=0·99, Italy r(2)=0·95, the Netherlands r(2)=0·99, and Scotland r(2)=0·97; overall r(2)=0·99. All five registers gave similar estimates of the linear slope ranging from 4·5 to 5·1, with overlapping confidence intervals. The combination of all five registers gave an overall slope of 4·8 (95% CI 4·5-5·0), with similar estimates for men (4·6, 4·3-4·9) and women (5·0, 4·5-5·5). A linear relationship between the log incidence and log age of onset of amyotrophic lateral sclerosis is consistent with a multistage model of disease. The slope estimate suggests that amyotrophic lateral sclerosis is a six-step process. Identification of these steps could lead to preventive and therapeutic avenues. UK Medical Research Council; UK Economic and Social Research Council; Ireland Health Research Board; The Netherlands Organisation for Health Research and Development (ZonMw); the Ministry of Health and Ministry of Education, University, and Research in Italy; the Motor Neurone Disease Association of England, Wales, and Northern Ireland; and the European Commission (Seventh Framework Programme).


Computer-facilitated review of electronic medical records reliably identifies emergency department interventions in older adults.
An estimated 14% to 25% of all scientific studies in peer-reviewed emergency medicine (EM) journals are medical records reviews. The majority of the chart reviews in these studies are performed manually, a process that is both time-consuming and error-prone. Computer-based text search engines have the potential to enhance chart reviews of electronic emergency department (ED) medical records. The authors compared the efficiency and accuracy of a computer-facilitated medical record review of ED clinical records of geriatric patients with a traditional manual review of the same data and describe the process by which this computer-facilitated review was completed. Clinical data from consecutive ED patients age 65 years or older were collected retrospectively by manual and computer-facilitated medical record review. The frequency of three significant ED interventions in older adults was determined using each method. Performance characteristics of each search method, including sensitivity and positive predictive value, were determined, and the overall sensitivities of the two search methods were compared using McNemar's test. For 665 patient visits, there were 49 (7.4%) Foley catheters placed, 36 (5.4%) sedative medications administered, and 15 (2.3%) patients who received positive pressure ventilation. The computer-facilitated review identified more of the targeted procedures (99 of 100, 99%), compared to manual review (74 of 100 procedures, 74%; p < 0.0001). A practical, non-resource-intensive, computer-facilitated free-text medical record review was completed and was more efficient and accurate than manually reviewing ED records.


How to improve allocation of support service costs.
Better accounting for support service costs at outpatient facilities involves distinguishing between fixed and variable expenses, then creating separate budgets for them. To simplify this step, financial managers can create a surrogate, such as the number of patient visits, to represent service activity. Once this is completed, separated costs are allocated by using criteria that recognize short-term and long-term service use.


Robust Design of a Particle-Free Silver-Organo-Complex Ink with High Conductivity and Inkjet Stability for Flexible Electronics.
Currently, silver-nanoparticle-based inkjet ink is commercially available. This type of ink has several serious problems such as a complex synthesis protocol, high cost, high sintering temperatures (∼200 °C), particle aggregation, nozzle clogging, poor shelf life, and jetting instability. For the emerging field of printed electronics, these shortcomings in conductive inks are barriers for their widespread use in practical applications. Formulating particle-free silver inks has potential to solve these issues and requires careful design of the silver complexation. The ink complex must meet various requirements, such as in situ reduction, optimum viscosity, storage and jetting stability, smooth uniform sintered films, excellent adhesion, and high conductivity. This study presents a robust formulation of silver-organo-complex (SOC) ink, where complexing molecules act as reducing agents. The 17 wt % silver loaded ink was printed and sintered on a wide range of substrates with uniform surface morphology and excellent adhesion. The jetting stability was monitored for 5 months to confirm that the ink was robust and highly stable with consistent jetting performance. Radio frequency inductors, which are highly sensitive to metal quality, were demonstrated as a proof of concept on flexible PEN substrate. This is a major step toward producing high-quality electronic components with a robust inkjet printing process.


The acetylase/deacetylase couple CREB-binding protein/Sirtuin 1 controls hypoxia-inducible factor 2 signaling.
Hypoxia-inducible factors (HIFs) are oxygen-sensitive transcription factors. HIF-1α plays a prominent role in hypoxic gene induction. HIF-2α target genes are more restricted but include erythropoietin (Epo), one of the most highly hypoxia-inducible genes in mammals. We previously reported that HIF-2α is acetylated during hypoxia but is rapidly deacetylated by the stress-responsive deacetylase Sirtuin 1. We now demonstrate that the lysine acetyltransferases cAMP-response element-binding protein-binding protein (CBP) and p300 are required for efficient Epo induction during hypoxia. However, despite close structural similarity, the roles of CBP and p300 differ in HIF signaling. CBP acetylates HIF-2α, is a major coactivator for HIF-2-mediated Epo induction, and is required for Sirt1 augmentation of HIF-2 signaling during hypoxia in Hep3B cells. In comparison, p300 is a major contributor for HIF-1 signaling as indicated by induction of Pgk1. Whereas CBP can bind with HIF-2α independent of the HIF-2α C-terminal activation domain via enzyme/substrate interactions, p300 only complexes with HIF-2α through the C-terminal activation domain. Maximal CBP/HIF-2 signaling requires intact CBP acetyltransferase activity in both Hep3B cells as well as in mice.


[Intoxicated women: A study into gender differences in substance abuse in forensic psychiatric patients].
Substance abuse is an important risk factor for (violent) offending, but is mostly studied in male populations. More knowledge about women is needed.
 AIM: To gain insight into possible gender differences in substance abuse and offending in forensic psychiatric patients.
 METHOD: Files were analysed of 275 women and 275 men who have been admitted between 1984 and 2014 to one of four Dutch forensic psychiatric facilities and related to incidents of violence during treatment or recidivism after discharge (for 78 women).
 RESULTS: Although substance abuse was common in women (57%), it was significantly more prevalent in men (68%). Men were more often diagnosed with substance dependency and more often committed the index-offense whilst intoxicated. Predictive accuracy for violent incidents during treatment was better for men. Both women and men with substance abuse had significantly more historical risk factors compared to those without substance abuse. A history of substance abuse was not a significant predictor for recidivism after discharge in women.
 CONCLUSION: There are gender differences in substance abuse and the relationship with offending was stronger for men. These differences may have implications for substance use treatment in forensic mental health services.


Association between childhood obesity and subsequent Type 1 diabetes: a systematic review and meta-analysis.
To review and synthesize the published evidence on the possible association between childhood obesity and the subsequent risk of Type 1 diabetes. The PubMed database was systematically searched for studies using childhood obesity, BMI or %weight-for-height as the exposure variable and subsequent Type 1 diabetes as the outcome. Studies were only included if assessment of obesity preceded the diagnosis of Type 1 diabetes. Eight case-control studies and one cohort study were included, comprising a total of 2658 cases. Of these nine studies, seven reported a significant association between childhood obesity, BMI or %weight-for-height and increased risk for Type 1 diabetes. Meta-analysis of the four studies that reported childhood obesity as a categorical exposure produced a pooled odds ratio of 2.03 (95% CI 1.46-2.80) for subsequent Type 1 diabetes; however, in those studies, age at obesity assessment varied from age 1 to 12 years. A dose-response relationship was supported by a continuous association between childhood BMI and subsequent Type 1 diabetes in a meta-analysis of five studies (pooled odds ratio 1.25 (95%CI 1.04-1.51) per 1 sd higher BMI). There is overall evidence for an association between childhood obesity, or higher BMI, and increased risk of subsequent Type 1 diabetes. Several theories have been proposed for a causal relationship. Reduction in Type 1 diabetes should be considered as a potential additional benefit of preventing childhood obesity.


Gender differences in TBT accumulation and transformation in Thais clavigera after aqueous and dietary exposure.
In this study, female and male Thais clavigera whelks were exposed to aqueous and dietary (using oysters as the prey) tributyltin (TBT) for up to 45 days, followed by a 30-day depuration, in order to examine the gender differences in TBT accumulation and transformation. The metabolites of TBT [dibutyltin (DBT) and monobutyltin (MBT)] were also measured in different tissues of the whelks (digestive, reproductive and remaining organs) during the exposure and depuration periods. By the end of the exposure period, all of the female whelks developed imposex after TBT exposure, and both the relative penis size index and the vas deferens sequence index were positively correlated with the tissue burden of TBT. However, biomagnification of TBT did not occur in the whelks. TBT was rapidly accumulated in their digestive and reproductive organs from both routes of exposure, and both elimination and biotransformation of TBT were also rapid. The redistribution of TBT among tissues was obvious during the exposure period but negligible during depuration. MBT was generally the major metabolite in each tissue, indicating a significant metabolism of TBT by the whelks. Accumulation, transformation, as well as elimination, were more significant following dietary exposure than following aqueous exposure. In particular, we observed gender-related differences in the biokinetics of TBT. Rapid biotransformation and elimination of TBT were detected in the male whelks, while the female whelks had higher bioaccumulation but lower elimination of TBT in their reproductive organs. Internal remobilization of TBT from digestive to reproductive organs was also more obvious in the females, indicating that the reproductive organs of females were the main targets of TBT accumulation.


[Involvement of monoamine oxidases in formation of 4-hydroxyphenylethanol, major component of tribulin A].
Pathways of 4-hydroxyphenylethanol formation were studied in the bovine brain. Incubation of brain homogenates with tyramine or tyrosine increased 4-hydroxyphenylethanol content only in the presence of NADH. Tyramine produced more pronounced augmentation of 4-hydroxyphenylethanol content than tyrosine. Tyrosine preparations were not contamined with tyramine. This suggests that 4-hydroxyphenylethanol may be formed from tyramine and tyrosine in NADH-dependent process. Preincubation of homogenates with 0.1 mM pargyline completely inhibited monoamine oxidases A and B and prevented NADH-dependent formation of 4-hydroxyphenylethanol from tyramine. The latter suggests that MAO is involved in formation of 4-hydroxyphenylethanol.


Kinetics of the metal components of intratracheally instilled stainless steel welding fume suspensions in rats.
The kinetics of iron, chromium, nickel, and cobalt from manual metal arc and metal inert gas stainless steel welding fumes were studied. Neutron activated welding fumes, in aqueous suspensions, were instilled intratracheally into rats. The follow up continued for up to 106 days. From both fumes, approximately 10% of the injection bolus was immediately lost into the gastrointestinal tract, to be recovered in the faeces within three days. Thereafter, a pronounced difference was seen in the kinetics of the two types of fumes. After the first day, chromium, nickel, and iron were lost from the lungs with half times of about 53, 49, and 73 days after exposure to MMA/SS fumes, whereas practically no loss could be seen in the metal components of the metal inert gas welding fumes within two months. The disposition of chromium from MMA/SS fumes closely resembled that of intratracheally instilled water soluble chromates. On the other hand, the disappearance of trivalent chromium from MIS/SS fumes was considerably slower than that of the practically water insoluble chromates, or even of trivalent chromium salts. Thus the physical characteristics of the fume appreciably affect the kinetics of the clearance of chromium compounds from the lungs.


Response-based selection of barley cultivars and legume species for complementarity: Root morphology and exudation in relation to nutrient source.
Phosphorus (P) and nitrogen (N) use efficiency may be improved through increased biodiversity in agroecosystems. Phenotypic variation in plants' response to nutrient deficiency may influence positive complementarity in intercropping systems. A multicomponent screening approach was used to assess the influence of P supply and N source on the phenotypic plasticity of nutrient foraging traits in barley (H. vulgare L.) and legume species. Root morphology and exudation were determined in six plant nutrient treatments. A clear divergence in the response of barley and legumes to the nutrient treatments was observed. Root morphology varied most among legumes, whereas exudate citrate and phytase activity were most variable in barley. Changes in root morphology were minimized in plants provided with ammonium in comparison to nitrate but increased under P deficiency. Exudate phytase activity and pH varied with legume species, whereas citrate efflux, specific root length, and root diameter lengths were more variable among barley cultivars. Three legume species and four barley cultivars were identified as the most responsive to P deficiency and the most contrasting of the cultivars and species tested. Phenotypic response to nutrient availability may be a promising approach for the selection of plant combinations for minimal input cropping systems.


Examining the construct validity of the Eating Disorder Inventory.
The construct validity of the Eating Disorder Inventory (EDI) was examined in 3 samples. An archival clinic sample (n = 318) of women completed the EDI, a structured interview, and the Millon Clinical Multiaxial Inventory-II (MCMI-II). Confirmatory factor analyses (CFAs) indicated that neither null nor 1-factor models of the EDI fit item-level or item-parcel data. The proposed 8-factor model did not fit at the item level but did fit item-parcel data. Reliability estimates of the 8 scales ranged from .82 to .93, and low-to-moderate interscale correlations among the eating and weight-related scales provided partial support for convergent validity. EDI personality scales showed moderate interscale correlations and were associated with MCMI-II scales. A final CFA of the EDI scales supported a 2-factor model (Eating and Weight, Personality) of the 8 EDI scales. Strong associations between depression and several EDI scale scores were found in a treatment study sample (n = 50). The archival clinic sample scored significantly higher on the 8 EDI scales than the nonpatient college comparison sample (n = 487).


Evidence-based psychosocial treatment in the community: considerations for dissemination and implementation.
In psycho-oncology care, steps toward dissemination and implementation of evidence-based treatments (EBTs) have not been made. For this to change, factors associated with real-world dissemination and implementation must be identified. In the community, providers, their organizations, and patients are key stakeholders. A focused review of literatures in continuing education, dissemination, and implementation of mental health services is provided. Early-career providers are most ready to implement as they have greater openness and more positive attitudes toward EBTs. Current continuing education practices to teach EBTs have limited effectiveness. Instruction using interactive strategies tailored to therapists' clinical needs and the provision of post-education consultation is needed. There is tension between EBT delivery with fidelity and the necessity for adaptation. EBT service provision is the key outcome of implementation, and documenting such is important to patients, providers, and organizations. A multilevel conceptual framework, Setting, Therapist, Education, imPlementation, and Sustainability, is offered and provides directions for dissemination and sustainable implementation. Guidelines from the Commission on Cancer of the American College of Surgeons and the American Society of Clinical Oncology underscore the timeliness of the proposed framework to move EBTs from the research settings where they were developed to the practice settings where they are needed.


Early and delayed shut-off of host protein synthesis in cells infected with herpes simplex virus.
A mutant of herpes simplex virus type 1 [HSV-1(HFEM)], tsB7, appears to have two temperature-sensitive functions. One is required during the first hour of infecting a cell (suggesting that it is performed by a virion protein) and the other is the non-essential function of "early shut-off" of cellular protein synthesis, which is mediated by a virion protein. The latter function remained temperature-sensitive in a revertant virus (RC2) grown at the non-permissive temperature (39 degrees C). However, under these conditions RC2 did cause inhibition of host synthesis, showing that "delayed shut-off", requiring virus protein synthesis, can occur independently of early shut-off, which is mediated by a virion protein. Early shut-off by u.v.-irradiated tsB7 was reversed when the temperature was raised, whereas delayed shut-off by intact tsB7 was not. Of two wild-type strains of virus examined, HSV-1(F) also exhibited temperature-sensitive early shut-off, but HSV-2(G) did not.


Macrophage damage in relation to the pathogenesis of lung diseases.
Pulmonary macrophages are important since their migratory patterns and behavior are often pivotal events in the pathogenesis of pulmonary disease. Alveolar macrophages act to decrease the probability of particle penetration through epithelial barriers, and their phagocytic and lytic potentials provide most of the known bactericadal properties of the lung. Macrophages are also involved in immune responses and in defense against neoplasms. Increased inert or infectious particles stimulate the recruitment of additional macrophages. Most free cells containing particles eventually reach the airways and are quickly carried to the pharynx and swallowed. In addition, evidence has now accumulated that macrophages play a part in the pathogenesis of pulmonary diseases. For example, the ingestion of some particles by macrophages causes a release of lysosomal enzymes into the macrophage cytoplasm. These enzymes may kill the macrophage, and dead or dying macrophages release a substance with attracts fibroblasts that elicit fibrogenic responses. Other toxic particles, such as cigarette smoke, my lead to a release of proteases and other toxic enzymes. All particles are capable of competitive inhibition of phagocytosis in macrophages and many may be cytotoxic and further depress phagocytosis. In addition, connective tissue macrophages may contribute to lung disease by concentrating and storing potent carcinogens or other toxic particles close to a reactive bronchial epithelium for long periods. Thus, even through macrophages serve as a first line of defense for the alveolar surface, they may also be capable of injuring the host while exercising their defensive role.


Evolution of transposons: natural selection for Tn5 in Escherichia coli K12.
A novel in vivo effect of the transposable element Tn5 has been observed in chemostats when certain isogenic Tn5 and non-Tn5 strains of Escherichia coli compete for a limiting carbon source in the absence of kanamycin. The Tn5-bearing strain has a more rapid growth rate and increases in frequency from 50% to 90% within the first 15 to 20 generations. The effect occurs when Tn5 is inserted at a variety of chromosomal locations or when the element is carried by an episome, but it is strain specific, having been observed in two out of three strains examined. (For reasons unknown, the effect has not been observed with derivatives of strain CSH12.) Although the growth-rate advantage of Tn5 is independent of nutrient concentration and generation time, it can be reduced by prior adaptation of the strains to limiting conditions, and the amount of reduction is proportional to the length of prior adaptation. The growth-rate effect is evidently not caused by beneficial mutations induced by Tn5 transposition, as Tn5-bearing strains selected in chemostats retain their initial Tn5 position and copy number. However, the effect does not occur in Tn5-112, a transpositionless deletion mutation missing the transposase-coding region of the right-hand IS sequence flanking the element. Since Tn5-112 retains a functional kanamycin-phosphotransferase gene, this gene is not responsible for the growth-rate effect. Thus, the effect evidently requires transposase function, but it does not involve actual transposition of the intact element. Altogether, these data provide a mechanism for the maintenance of Tn5 in bacterial populations in the absence of kanamycin, and they suggest a model for the proliferation and the maintenance of IS sequences and transposable elements in the absence of other identifiable selection pressures.


Equality according to whom? Debating an age-related restriction in the upcoming disability legislation reform in Finland.
Within many countries, the policies of disability and old age have been developing on distinct paths. Even though the prevalence of disability is higher in older populations, older persons tend to be excluded from disability discourses. Taking Finland's disability service legislation reform as an example, this article elaborates on the justifications for excluding or including older persons from disability policies. The paper analyses the public statements given in 2017 to a proposal that introduced an age-related restriction to disability services in order to understand how the restriction is argued for and against, and what kind of conceptualisations of old age and disability the statements portray. This study found that although equality is the most important principle underlying the reform, the conceptualisation of equality varies. Depending on who is included in the disability discourse, the idea of what is fair differs. Hence, it is necessary to recognise the differing understandings of equality in the debate regarding the age-related restriction. In addition, I argue that equality research can be helpful in assessing the fairness of public policies at the intersection of ageing and disability.


Does Attending Worship Mitigate Racial/Ethnic Discrimination in Influencing Health Behaviors? Results From an Analysis of the California Health Interview Survey.
Existing research suggests that religious institutions play a significant role in improving the health of communities, particularly those coping with racial and ethnic discrimination. Using the California Health Interview Survey, this article examines the relationship of self-reported experiences of racial/ethnic discrimination, worship attendance, and several health behaviors. Supporting existing research, higher self-reported racial/ethnic discrimination is associated with worse health behaviors. Logistic regression models indicate that the odds of engaging in healthy lifestyle behaviors significantly increase for those who report attending worship, compared with those who do not attend worship, with variations by race/ethnicity. Worship attendance moderates the association between discrimination and binge drinking, but does not moderate the association for smoking, walking, or being obese. Findings suggest that religious attendance plays an important role in the health and well-being of all population groups. More research is needed to ascertain the reasons why attending worship may have the ability to mitigate the relationship between racial/ethnic discrimination and health.


The effect of larval density on pre-imaginal development in two species of desert fleas.
We studied the effect of density of larvae on pre-imaginal development in 2 flea species (Xenopsylla conformis and Xenopsylla ramesis) parasitic on 2 desert rodent species (Dipodillus dasyurus, adult body mass 20 g and Meriones crassus, 80 g). We predicted a decrease in duration of development with an increase in density of larvae. In general, in both flea species, duration of larva-to-pupa development decreased with an increasing larval density. In addition, this stage of development was longer in male fleas and in fleas from parents fed on D. dasyurus. The effect of larval density on larval development was manifested mainly when parent fleas fed on D. dasyurus. Duration of pupation decreased with increasing larval density only in offspring of fleas fed on G. dasyurus. In both fleas, pupation was longer in males. The effect of parent host on duration of pupation was found in X. ramesis only (longer if the host was M. crassus). Resistance of newly emerged fleas to starvation depended mainly on parent host species. Young X. conformis survived longer if their parents fed on D. dasyurus, whereas young X. ramesis survived longer if their parents fed on M. crassus. It was also found that (a) an individual flea that spent more time as a larva also spent more time as a pupa and (b) longer larval development resulted in a shorter time that a newly emerged flea was able to survive when starved.


Retrospectively ECG-gated multi-detector row CT of the chest: does ECG-gating improve three-dimensional visualization of the bronchial tree?
To determine the impact of retrospectively ECG-gated multi-detector row CT (MDCT) on three-dimensional (3D) visualization of the bronchial tree and virtual bronchoscopy (VB) as compared to non-ECG-gated data acquisition. Contrast-enhanced retrospectively ECG-gated and non-ECG-gated MDCT of the chest was performed in 25 consecutive patients referred for assessment of coronary artery bypass grafts and pathology of the ascending aorta. ECG-gated MDCT data were reconstructed in diastole using an absolute reverse delay of - 400 msec in all patients. In 10 patients additional reconstructions at - 200 msec, - 300 msec, and - 500 msec prior to the R-wave were performed. Shaded surface display (SSD) and virtual bronchoscopy (VB) for visualization of the bronchial segments was performed with ECG-gated and non-ECG-gated MDCT data. The visualization of the bronchial tree underwent blinded scoring. Effective radiation dose and signal-to-noise ratio (SNR) for both techniques were compared. There was no significant difference in visualizing single bronchial segments using ECG-gated compared to non-ECG-gated MDCT data. However, the total sum of scores for all bronchial segments visualized with non-ECG-gated MDCT was significantly higher compared to ECG-gated MDCT (P < 0.05). The summary scores for visualization of bronchial segments for different diastolic reconstructions did not differ significantly. The effective radiation dose and the SNR were significantly higher with the ECG-gated acquisition technique (P < 0.05). The bronchial tree is significantly better visualized when using non-ECG-gated MDCT compared to ECG-gated MDCT. Additionally, non-ECG-gated techniques require less radiation exposure. Thus, the current retrospective ECG-gating technique does not provide any additional benefit for 3D visualization of the bronchial tree and VB.


The Arabidopsis thaliana Med25 mediator subunit integrates environmental cues to control plant development.
Development in plants is controlled by abiotic environmental cues such as day length, light quality, temperature, drought, and salinity. These signals are sensed by a variety of systems and transmitted by different signal transduction pathways. Ultimately, these pathways are integrated to control expression of specific target genes, which encode proteins that regulate development and differentiation. The molecular mechanisms for such integration have remained elusive. We here show that a linear 130-amino-acids-long sequence in the Med25 subunit of the Arabidopsis thaliana Mediator is a common target for the drought response element binding protein 2A, zinc finger homeodomain 1, and Myb-like transcription factors which are involved in different stress response pathways. In addition, our results show that Med25 together with drought response element binding protein 2A also function in repression of PhyB-mediated light signaling and thus integrate signals from different regulatory pathways.


[Gender inequalities for cardiovascular diseases].
Cardiovascular diseases are the primary cause of death in women. Cardiovascular risk is specific and often underestimated in women. At equal age, women have more cardiovascular risk factors than men. Some of them such as smoking and diabetes are associated with greater increase of cardiovascular risk and poorer prognosis in women as compared to men. In addition, women have a specific hormonal risk linked to contraception, pregnancy and menopause. Prevention, screening and diagnosis are generally implemented both at later stages and less frequently than in men because of particularities in clinical presentation, and treatments are not optimal in women. All these specificities must be considered for an optimized evaluation of cardiovascular risk and an improvement of management in women.


Calibration of optical traps by dual trapping of one bead.
We introduce a method for optical trap calibration that is suitable for viscoelastic material. The method is designed for use on experimental setups with two optical tweezers and is based on pulling a trapped particle with one trap while holding it with the other. No piezo stage is needed, and only one optical trap must be movable with galvo mirrors, piezo mirrors, or acousto-optical deflectors. The method combines advantages of commonly known PSD-fitting and fast-sweeping methods, allowing calibration of a completely fixed trap in a fluid of unknown viscosity/viscoelasticity. A detailed method description, a theoretical derivation, and an experimental comparison to other methods are reported.


The Possible Influence of Non-synonymous Point Mutations within the FimA Adhesin of Non-typhoidal Salmonella (NTS) Isolates in the Process of Host Adaptation.
Non-typhoidal Salmonella (NTS) remains a global pathogen that affects a wide range of animal species. We analyzed a large number of NTS isolates of different host origins, including Salmonella Heidelberg (n = 80, avian), S. Dublin (50, bovine), S. Typhimurium var 5- (n = 40, porcine), S. 4,5,12,:i:- (n = 40, porcine), S. Cerro (n = 16, bovine), and S. Montevideo (n = 14, bovine), using virulence profiling of the bcfC, mgtC, ssaC, invE, pefA, stn, sopB, and siiE virulence-associated genes, a biofilm production assay, pulsed field gel electrophoresis, and the full-length sequencing of the fimA (adhesin) and iroN (receptor) genes. We determined a key amino acid substitution, A169 (i.e., threonine changed to alanine at position 169), in the FimA protein that changed ligand affinity of FimA toward N-acetyl-D-glucosamine. This finding clearly indicates the important role of non-synonymous single nucleotide polymorphism (nsSNPs) in adhesin functionality that may impact the host tropism of NTS. This nsSNP was found in S. Heidelberg and S. Cerro isolates. Although this was not the case for the IroN receptor, the phylogeny of this receptor and different host origins of NTS isolates were positively correlated, suggesting existence of specific host immune selective pressures on this unique receptor in S. enterica. We found that pefA, a gene encoding major fimbrial subunit, was the most-segregative virulence factor. It was associated with S. Heidelberg, S. Typhimurium var 5- and S. 4,5,12,:i:- but not with the rest of NTS strains. Further, we observed a significantly higher frequency of non-biofilm producers among NTS strains that do not carry pefA (42.5%) compared to S. Heidelberg (2.5%) and S. Typhimurium var 5- (7.5%) and S. 4,5,12,:i:- (0%). This study provides new insights into the host adaptation of avian and mammalian NTS isolates that are based on the bacterial antigens FimA and IroN as well as the interrelationships between host adaptation, overall genetic relatedness, and virulence potential in these NTS isolates.


The use of platelet-rich plasma in oral surgery: a systematic review and meta-analysis.
The aim of this systematic review and meta-analysis was to evaluate the benefit of platelet rich plasma (PRP) in oral surgery. We performed a systematic search of the literature. The GRADE system was used to assess the certainty of the body of evidence. We found 21 randomised controlled trials that met our inclusion criteria: 12 studies included patients with periodontal defects, five studies focused on healing of extraction sockets, three studies on sinus lift augmentation, and one study on periapical osseous defects. However, for the quantitative synthesis (meta-analysis), we evaluated "periodontal defects" studies only, since for other clinical contexts the number of studies were too low and the procedural heterogeneity was too high to allow pooling of data. PRP-containing regimens were compared to non-PRP-containing regimens. Primary outcomes for the evaluation of periodontal defects were probing depths, clinical attachment level, gingival recession, and radiographic bone defect. It is not usually clear whether or not the use of PRP compared to controls affects "probing depth" at long-term follow up; the between group differences were small and unlikely to be of clinical importance (i.e., very low quality of evidence). For the other outcomes analysed ("clinical attachment levels", "gingival recession", "bony defect"), we observed a very slight marginal clinical benefit of PRP compared to controls. The available evidence for these comparisons was rated as low quality as most of the studies selected showed inconsistency, imprecision, and risk of bias. Evidence from a comparison between the use in oral surgery of PRP-containing regimens compared to other regimens not-containing PRP was of low quality. The results of the meta-analysis, limited to studies in patients with periodontal defects, document that PRP was slightly more effective compared to controls not-containing PRP.


Hemodynamic adaptations to stress with advancing age.
With advancing adult aging an increase in vascular stiffness, an increase in systolic, pulse and mean arterial pressure, modest left ventricular hypertrophy, and a moderate decline in early diastolic filling rate have uniformly been observed. In some individuals these changes are not associated with enhanced systemic resistance if arterial pressure remains within the normotensive range. End-systolic volume, stroke volume, ejection fraction, velocity of ejection, and cardiac output are preserved in these elderly subjects. In other individuals both aortic impedance and peripheral vascular resistance are increased with age and modest declines in resting stroke volume and cardiac output have been observed. During maximal exercise a diminished heart rate and a diminished reduction of end-systolic volume occur in elderly subjects. In some, an enhanced end-diastolic volume prevents a reduction in or enhances stroke volume (Starling mechanism); this adaptation bears a striking resemblance to that observed during exercise when the beta-adrenergic system is pharmacologically inhibited. In other elderly subjects, stroke volume during exercise does not increase to the extent that it does in younger subjects. Even in these subjects in whom peak cardiac output during exercise declines, however, it is not entirely clear that the central circulation limits peak oxygen consumption (VO2). The nonuniformity of results of studies that have investigated the effect of aging on cardiac function and vascular resistance suggests that variables that impact on cardiovascular function other than aging per se, i.e. life style variables, e.g. nutrition, smoking, physical conditioning status, or the prevalence of occult coronary disease, differed among the various subjects studied.


Long-term digoxin treatment in general practice.
A questionnaire was sent to several general practitioners and specialists in an attempt to obtain a consensus on standards of care for patients receiving long-term digoxin treatment. The consultants' suggested standards were slightly more stringent than those of the general practitioners. The records of 42 patients taking digoxin under the care of two general practitioners were studied to see how far their actual care matched up to the suggested standards. The models of management proposed by these patients' doctors were only slightly different from those suggested by other practitioners, but measured against these models the patients' care was in some cases inadequate. Nevertheless, there was little relationship between the recorded levels of care and the health of the patient, and it may have been the standard of recording rather than the care that was inadequate. Measuring plasma digoxin levels in these patients proved to be of little value. Medical audit is thus a useful tool in helping the general practitioner to review his work and improve his knowledge, but it may not be a practical or true way of measuring the quality of care.


Low risk of attrition among adults on antiretroviral therapy in the Rwandan national program: a retrospective cohort analysis of 6, 12, and 18 month outcomes.
We report levels and determinants of attrition in Rwanda, one of the few African countries with universal ART access. We analyzed data abstracted from health facility records of a nationally representative sample of adults [≥ 18 years] who initiated ART 6, 12, and 18 months prior to data collection; and collected facility characteristics with a health facility assessment questionnaire. Weighted proportions and rates of attrition [loss to follow-up or death] were calculated, and patient- and health facility-level factors associated with attrition examined using Cox proportional hazard models. 1678 adults initiated ART 6, 12 and 18 months prior to data collection, with 1508 person-years [PY] on ART. Attrition was 6.8% [95% confidence interval [CI] 6.0-7.8]: 2.9% [2.4-3.5] recorded deaths and 3.9% [3.4-4.5] lost to follow-up. Population attrition rate was 7.5/100 PY [6.1-9.3]. Adjusted hazard ratio [aHR] for attrition was 4.2 [3.0-5.7] among adults enrolled from in-patient wards [vs 2.2 [1.6-3.0] from PMTCT, ref: VCT]. Compared to adults who initiated ART 18 months earlier, aHR for adults who initiated ART 12 and 6 months earlier was 1.8 [1.3-2.5] and 1.3 [0.9-1.9] respectively. Male aHR was 1.4 [1.0-1.8]. AHR of adults enrolled at urban health facilities was 1.4 [1.1-1.8, ref: rural health facilities]. AHR for adults with CD4+ ≥ 200 cells/μL vs <200 cells/μL was 0.8 [0.6-1.0]; and adults attending facilities with performance-based financing since 2004-2006 [vs. 2007-2008] had aHR 0.8 [0.6-0.9]. Attrition was low in the Rwandan national program. The above patient and facility correlates of attrition can be the focus of interventions to sustain high retention.


Testicular protein synthesis during the response to subtoxic levels of cadmium.
Male rats received one injection of a 'subtoxic' amount of Cd2+ (9.2 mumol/kg body weight) as cadmium chloride and the testes were removed 24 h later. Homogenate fractions of tests that had been freed of ribosomes were tested for their activity in cell-free protein-synthesizing systems using excess exogenous rat liver ribosomes and mRNA. A marked decrease in the incorporation of free [14C]-phenylalanine into peptide was observed with the testes preparations from the cadmium-treated rats. The results indicated that about half of the effect of cadmium was due to decreased aminoacyl-tRNA synthetase activity and the other half was due to decreased binding of [14C]-phenylalanyl-tRNA to ribosomes. The results are discussed relative to the contrasting results obtained in kidney and liver preparations.


Biochar derived from fruit by-products using pyrolysis process for the elimination of Pb(II) ion: An updated review.
Water pollution is one of the most concerning global environmental problems in this century with the severity and complexity of the issue increases every day. One of the major contributors to water pollution is the discharge of harmful heavy metal wastes into the rivers and water bodies. Without proper treatment, the release of these harmful inorganic waste would endanger the environment by contaminating the food chains of living organisms, hence, leading to potential health risks to humans. The adsorption method has become one of the cost-effective alternative treatments to eliminate heavy metal ions. Since the type of adsorbent material is the most vital factor that determines the effectiveness of the adsorption, continuous efforts have been made in search of cheap adsorbents derived from a variety of waste materials. Fruit waste can be transformed into valuable products, such as biochar, as they are composed of many functional groups, including carboxylic groups and lignin, which is effective in metal binding. The main objective of this study was to review the potential of various types of fruit wastes as an alternative adsorbent for Pb(II) removal. Following a brief overview of the properties and effects of Pb(II), this study discussed the equilibrium isotherms and adsorption kinetic by various adsorption models. The possible adsorption mechanisms and regeneration study for Pb(II) removal were also elaborated in detail to provide a clear understanding of biochar produced using the pyrolysis technique. The future prospects of fruit waste as an adsorbent for the removal of Pb(II) was also highlighted.


Evaluation of patients' knowledge about anticoagulant treatment.
To develop a questionnaire to evaluate patients' knowledge of anticoagulation. Anonymous self completed questionnaire study based on hospital anticoagulant guidelines. Anticoagulant clinic in a 580 bed district general hospital in London. 70 consecutive patients newly referred to the anticoagulant clinic over six months. Information received by patients on six items of anticoagulation counselling (mode of action of warfarin, adverse effects of over or under anticoagulation, drugs to avoid, action if bleeding or bruising occurs, and alcohol consumption), the source of such information, and patients' knowledge about anticoagulation. Of the recruits, 36 (51%) were male; 38(54%) were aged below 46 years, 22(31%) 46-60, and 10(14%) over 75. 50 (71%) questionnaires were returned. In all, 40 respondents spoke English at home and six another language. Most patients reported being clearly advised on five of the six items, but knowledge about anticoagulation was poor. Few patients could correctly identify adverse conditions associated with poor control of anticoagulation: bleeding was identified by only 30(60%), bruising by 23(56%), and thrombosis by 18(36%). Only 26(52%) patients could identify an excessive level of alcohol consumption, and only seven (14%) could identify three or more self prescribed agents which may interfere with warfarin. The questionnaire provided a simple method of determining patients' knowledge of anticoagulation, and its results indicated that this requires improvement. Patients' responses suggested that advice was not always given by medical staff, and use of counselling checklists is recommended. Reinforcement of advice by non-medical counsellors and with educational guides such as posters or leaflets should be considered. Such initiatives are currently being evaluated in a repeat survey.


Number and mode of inheritance of QTL influencing backfat thickness on SSC2p in Sino-European pig pedigrees.
In the pig, multiple QTL associated with growth and fatness traits have been mapped to chromosome 2 (SSC2) and among these, at least one shows paternal expression due to the IGF2-intron3-G3072A substitution. Previously published results on the position and imprinting status of this QTL disagree between analyses from French and Dutch F2 crossbred pig populations obtained with the same breeds (Meishan crossed with Large White or Landrace). To study the role of paternal and maternal alleles at the IGF2 locus and to test the hypothesis of a second QTL affecting backfat thickness on the short arm of SSC2 (SSC2p), a QTL mapping analysis was carried out on a combined pedigree including both the French and Dutch F2 populations, on the progeny of F1 males that were heterozygous (A/G) and homozygous (G/G) at the IGF2 locus. Simulations were performed to clarify the relations between the two QTL and to understand to what extent they can explain the discrepancies previously reported. The QTL analyses showed the segregation of at least two QTL on chromosome 2 in both pedigrees, i.e. the IGF2 locus and a second QTL segregating at least in the G/G F1 males and located between positions 30 and 51 cM. Statistical analyses highlighted that the maternally inherited allele at the IGF2 locus had a significant effect but simulation studies showed that this is probably a spurious effect due to the segregation of the second QTL. Our results show that two QTL on SSC2p affect backfat thickness. Differences in the pedigree structures and in the number of heterozygous females at the IGF2 locus result in different imprinting statuses in the two pedigrees studied. The spurious effect observed when a maternally allele is present at the IGF2 locus, is in fact due to the presence of a second closely located QTL. This work confirms that pig chromosome 2 is a major region associated with fattening traits.


A novel loss-of-function DDAH1 promoter polymorphism is associated with increased susceptibility to thrombosis stroke and coronary heart disease.
Asymmetrical dimethylarginine (ADMA), an endogenous arginine analogue, inhibits nitric oxide synthases and plays an important role in endothelial dysfunction. In the present study, we tested whether a novel genetic variant in dimethylarginine dimethylaminohydrolase 1 (DDAH1), an important ADMA hydrolyzing gene, was associated with stroke and coronary heart disease (CHD) susceptibility in the Chinese Han population. By resequencing, we identified a novel 4-nucleotide deletion/insertion variant in the DDAH1 promoter. The insertion allele disrupted binding of metal-regulatory transcription factor 1, which resulted in significant reduction of in vitro DDAH1 transcriptional activity and in vivo DDAH1 mRNA level, and in turn, increased plasma ADMA level and the ratio of ADMA to L-arginine. We initially genotyped the polymorphism in 1388 stroke patients and 1027 controls as well as 576 CHD patients and 557 controls and then replicated our study in additional independent case-control cohorts comprising 961 stroke patients and 822 controls and 482 CHD patients and 1072 controls. We identified that the -396 4N ins allele was significantly associated with increased risk of thrombosis stroke and CHD after adjusting for environmental factors in both samples for both diseases (thrombosis stroke discovery set: odds ratio [OR]=1.35, P=0.032; replication set: OR=1.51, P=0.006; CHD discovery set: OR=1.45, P=0.035; replication set: OR=1.47, P=0.003). Our results suggest that the DDAH1 loss-of-function polymorphism is associated with both increased risk of thrombosis stroke and CHD.


Cystic lesions of the pituitary: clinicopathological features distinguishing craniopharyngioma, Rathke's cleft cyst, and arachnoid cyst.
The distinction among craniopharyngioma (CR), Rathke's cleft cyst (RCC), and intrasellar arachnoid cyst (AC) remains a difficult preoperative problem. Accurate diagnosis of these rare pituitary lesions is important to determine the type of treatment and predict prognostic outcome. The majority of the literature describes the clinical manifestations and management of only one of CR, RCC, or AC, rendering comparisons difficult. We conducted a study to 1) investigate distinguishing preoperative clinical, biochemical, and radiographic features of patients with CR, RCC, and AC; and 2) identify clinicopathological features that independently predict recurrence in CR and RCC in adults. Fifty-two adult patients included 21 patients with CR (mean age at initial surgery, 35 +/- 14 yr), 26 patients with RCC (mean age, 37 +/- 14 yr), and 5 patients with AC (mean age, 53 +/- 12 yr). Mean follow-up duration was 70 +/- 13 months. Patients with CR presented with hypopituitarism in 95% of cases and hyperprolactinemia in 38%. These patients also had more preoperative neurological deficits (67%), ophthalmological complaints (67%), and significantly higher psychiatric manifestations (33%; P = 0.003) than those with RCC or AC. Patients with AC presented with headaches (60%), visual field deficits (60%), or impotence (50%) in the absence of other specific endocrine dysfunction symptoms. Using biochemical criteria, the percentage of patients with two or more pituitary hormonal axes impaired preoperatively was 67% for CR and 62% for RCC, significantly greater (P = 0.03) than that for the AC patients who had pituitary dysfunction of only one axis. The composition of CR lesions was cystic (38%), solid (10%), or mixed solid and cystic (43%). Patients with RCC or AC groups had a significantly greater proportion (P = 0.006) of purely cystic lesions (88% and 100%, respectively). Calcification detectable on computed tomographic scanning was present in 87% of patients with CR, a significantly greater proportion (P < 0.001) compared to those with RCC (13%) or AC (0%). No significant differences were found between the groups based on computed tomography density, the presence of postcontrast enhancement, or magnetic resonance imaging. Recurrence rate was 62% for CR, 19% for RCC, and 20% for AC. Surgical intervention statistically improved most neurological, ophthalmological, and psychiatric manifestations; in contrast, galactorrhea, menstrual dysfunction, and diabetes insipidus (52% CR; 31% RCC) did not improve or became worse postoperatively. A significantly higher percentage of patients with CR required postoperative hormone replacement. Similarly, there was a biochemical trend suggesting that a smaller proportion of patients with CR improved in at least one pituitary axis after surgery (P = 0.08) compared to those with RCC or AC. There was a positive correlation between cyst size and recurrence rate (r = 0.689; P < 0.01) and between cyst size and time to recurrence (r = 0.582; P = 0.037) for all three groups. We describe the largest clinical, biochemical, radiographic, and histological series of adult patients with cystic disease of the sella turcica. Patients with AC tended to be older at initial diagnosis than CR or RCC patients. Mass effects, such as visual problems and headaches, are common symptoms of all three cystic lesions, but psychiatric deficits favor a diagnosis of CR. Calcification or solid components on neuroimaging characterize CR. Endocrinological deficits, especially diabetes insipidus, had the worst prognosis after surgery. Low recurrence rates can be expected for RCC and AC. These data have direct implications for the management and monitoring of patients with cystic lesions of the sella turcica.


Randomized double-blinded and controlled clinical trial on treatment of HIV/AIDS by Zhongyan-4.
To assess the efficacy and safety of Zhongyan-4 (ZY-4, a Chinese herbal preparation worked out according to the therapeutic principle of supplementing qi, nourishing Yin, clearing heat and detoxication) in treating HIV/AIDS patients in the early or middle stage. Adopted was randomized double-blinded and placebo-parallel-controlled method, with 72 HIV/AIDS patients randomly divided into the ZY-4 group (36 patients) treated with ZY-4 and the control group (36 patients) treated with placebo. The treatment course was six months. The index of CD(4)(+), CD(8)(+) counts, body weight, clinical symptom scoring were estimated at 4 time points (0, 1, 3 and 6 month in the course), and also the viral load before and after treatment. The whole course of observation was completed in 63 patients, 30 in the ZY-4 group and 33 in the control group. CD(4)(+) count in the ZY-4 group got elevated by 7.70 +/- 150.96/mm(3) on average, while that in the control group lowered by 27.33 +/- 85.28/mm(3). Fifteen out of the 30 patients in the ZY-4 group had their CD(4)(+) count increased, which was evidently much higher than that in the control group (8/33, P < 0.05), suggesting that the efficacy of ZY-4 is superior to that of placebo in elevating CD(4)(+) count. Moreover, ZY-4 showed actions in elevating CD(45)RA(+) and CD(8)(+) count, reducing HIV virus load, improving clinical symptom/sign and increasing body weight of patients. No obvious adverse reaction was found in the clinical trial. ZY-4 has an immunity-protective and/or rebuilding function in HIV/AIDS patients in the early and middle stage, and also shows effects in lowering viral load, increasing body weight and improving symptoms and signs to a certain degree.


Evaluation of a phenotypic scheme for identification of the 'butyrate-producing' Peptostreptococcus species.
Gram-positive anaerobic cocci (GPAC) are isolated from approximately one quarter of all infections involving anaerobic bacteria. However, studies of the significance of this group of pathogens have been hindered by an inadequate taxonomy and the lack of a valid identification scheme. In the present study, a phenotypic scheme for the identification of 'butyrate-producing' GPAC based on the analysis of volatile fatty acid profiles by gas-liquid chromatography, biochemical profiles (including the use of the rapid ID 32 A commercial kit) and carbohydrate fermentation reactions, was evaluated. The identity of 68 clinical isolates of GPAC was determined by application of the scheme published by Murdoch. The scheme was found to be easy to apply and only four of the test isolates could not be readily assigned to a species or well-defined group. The species most frequently identified in the test collection were Peptostreptoccoccus vaginalis, P. tetradius and the betaGAL group. A large number of strains was assigned to the heterogeneous 'prevotii/tetradius' group. Some species regarded as being restricted to particular clinical sites were shown to be more widespread than previously thought. The clinical source of the isolates did not show any consistent correlation with species identity.


Lipoprotein concentrations and carotid atherosclerosis by diabetes status: results from the Insulin Resistance Atherosclerosis Study.
Lipoprotein concentrations are associated with the development of atherosclerosis in people with and without diabetes. The relative strength of these associations could differ by diabetes status as a result of diabetes-related lipoprotein modifications. The associations between lipoprotein concentrations and internal and common carotid artery intimal-medial thickness (IMT) assessed by B-mode ultrasonography were examined by diabetes status in a cross-sectional analysis among 1,391 participants in the Insulin Resistance Atherosclerosis Study. Participants included 442 individuals with type 2 diabetes, 308 with impaired glucose tolerance, and 641 with normal glucose tolerance. The differences in internal and common carotid IMT between the highest and lowest tertiles of LDL were 58.1 microm (P = 0.054) and 51.0 microm (P < 0.001), respectively. The differences in internal and common carotid IMT between the lowest and highest tertiles of HDL were 56.2 microm (P = 0.07) and 37.8 microm (P = 0.003), respectively Triglycerides and VLDL were not associated with IMT. These associations did not differ significantly because of diabetes status. These results support the importance of dyslipidemia as a major risk factor for atherosclerosis in people with diabetes. Future research in humans should measure lipoprotein oxidizability, glycation, size, and composition directly in people of differing glucose tolerance status to address the importance of diabetes-related lipoprotein modifications more conclusively.


In Silico Verification of Predicted Potential Promoter Sequences in the Rice (Oryza sativa) Genome.
The exact identification of promoter sequences remains a serious problem in computational biology, as the promoter prediction algorithms under development continue to produce false-positive results. Therefore, to fully assess the validity of predicted sequences, it is necessary to perform a comprehensive test of their properties, such as the presence of downstream transcribed DNA regions behind them, or chromatin accessibility for transcription factor binding. In this paper, we examined the promoter sequences of chromosome 1 of the rice Oryza sativa genome from the Database of Potential Promoter Sequences predicted using a mathematical algorithm based on the derivation and calculation of statistically significant promoter classes. In this paper TATA motifs and cis-regulatory elements were identified in the predicted promoter sequences. We also verified the presence of potential transcription start sites near the predicted promoters by analyzing CAGE-seq data. We searched for unannotated transcripts behind the predicted sequences by de novo assembling transcripts from RNA-seq data. We also examined chromatin accessibility in the region of the predicted promoters by analyzing ATAC-seq data. As a result of this work, we identified the predicted sequences that are most likely to be promoters for further experimental validation in an in vivo or in vitro system.


Early marine migration of European silver eel Anguilla anguilla in northern Norway.
To study the migratory behaviour in wild northern European silver eel Anguilla anguilla during sea entry and early marine migration, 32 individuals were tagged with acoustic transmitters and registered at four automatic listening station arrays from the mouth of the north Norwegian River Alta and throughout the Alta Fjord. The A. anguilla entered the fjord during all parts of the tidal cycle and did not seem to utilize the outgoing tidal currents. They migrated mainly during the night, in both the river mouth and the fjord. On average, they spent 2·7 days travelling from the river mouth to the outermost array, 31 km from the river mouth, corresponding to an average migratory speed of 0·5 km h(-1) . The A. anguilla generally migrated in the central part of the fjord and in the uppermost 10-25% of the water column, but with frequent dives to greater depths. Already 4 km after sea entry, A. anguilla were observed diving deeper than 130 m within 20-30 min periods. Hence, this study demonstrated that A. anguilla may perform an active diving behaviour during the early marine migration. The study took place in a pristine area with a minimum of anthropogenic interventions and by individuals from a population still uninfected by the introduced parasite Anguillicoloides crassus. The results may therefore be used as a baseline for future studies of the A. anguilla early marine migration.


Cuffed versus uncuffed endotracheal tubes for neonates.
Endotracheal intubation is a commonly performed procedure in neonates, the risks of which are well-described. Some endotracheal tubes (ETT) are equipped with a cuff that can be inflated after insertion of the ETT in the airway to limit leak or aspiration. Cuffed ETTs have been shown in larger children and adults to reduce gas leak around the ETT, ETT exchange, accidental extubation, and exposure of healthcare workers to anesthetic gas during surgery. With improved understanding of neonatal airway anatomy and the widespread use of cuffed ETTs by anesthesiologists, the use of cuffed tubes is increasing in neonates. To assess the benefits and harms of cuffed ETTs (inflated or non-inflated) compared to uncuffed ETTs for respiratory support in neonates. We searched CENTRAL, PubMed, and CINAHL on 20 August 2021; we also searched trial registers and checked reference lists to identify additional studies. We included randomized controlled trials (RCTs), quasi-RCTs, and cluster-randomized trials comparing cuffed (inflated and non-inflated) versus uncuffed ETTs in newborns. We sought to compare 1. inflated, cuffed versus uncuffed ETT; 2. non-inflated, cuffed versus uncuffed ETT; and 3. inflated, cuffed versus non-inflated, cuffed ETT. We used the standard methods of Cochrane Neonatal. Two review authors independently assessed studies identified by the search strategy for inclusion, extracted data, and assessed risk of bias. We used the GRADE approach to assess the certainty of evidence. We identified one eligible RCT for inclusion that compared the use of cuffed (inflated if ETT leak greater than 20% with cuff pressure 20 cm H2O or less) versus uncuffed ETT. The author provided a spreadsheet with individual data. Among 76 infants in the original manuscript, 69 met the inclusion and exclusion criteria for this Cochrane Review. We found possible bias due to lack of blinding and other bias. We are very uncertain about frequency of postextubation stridor, because the confidence intervals (CI) of the risk ratio (RR) were very wide (RR 1.36, 95% CI 0.35 to 5.25; risk difference (RD) 0.03, -0.11 to 0.18; 1 study, 69 participants; very low-certainty evidence). No neonate was diagnosed with postextubation subglottic stenosis; however, endoscopy was not available to confirm the clinical diagnosis. We are very uncertain about reintubation for stridor or subglottic stenosis because the CIs of the RR were very wide (RR 0.27, 95% CI 0.01 to 6.49; RD -0.03, 95% CI -0.11 to 0.05; 1 study, 69 participants; very low-certainty evidence). No neonate had surgical intervention (e.g. endoscopic balloon dilation, cricoid split, tracheostomy) for stridor or subglottic stenosis (1 study, 69 participants). Neonates randomized to cuffed ETT may be less likely to have a reintubation for any reason (RR 0.06, 95% CI 0.01 to 0.45; RD -0.39, 95% CI -0.57 to -0.21; number needed to treat for an additional beneficial outcome 3, 95% CI 2 to 5; 1 study, 69 participants; very low-certainty evidence). We are very uncertain about accidental extubation because the CIs of the RR were wide (RR 0.82, 95% CI 0.12 to 5.46; RD -0.01, 95% CI -0.12 to 0.10; 1 study, 69 participants; very low-certainty evidence). We are very uncertain about all-cause mortality during initial hospitalization because the CIs of the RR were extremely wide (RR 2.46, 95% CI 0.10 to 58.39; RD 0.03, 95% CI -0.05 to 0.10; 1 study, 69 participants; very low-certainty evidence). There is one ongoing trial. We classified two studies as awaiting classification because outcome data were not reported separately for newborns and older infants. Evidence for comparing cuffed versus uncuffed ETTs in neonates is limited by a small number of babies in a single RCT with possible bias. There is very low certainty evidence for all outcomes of this review. CIs of the estimate for postextubation stridor were wide. No neonate had clinical evidence for subglottic stenosis; however, endoscopy results were not available to assess the anatomy. Additional RCTs are necessary to evaluate the benefits and harms of cuffed ETTs (inflated and non-inflated) in the neonatal population. These studies must include neonates and be conducted both for short-term use (in the setting of the operating room) and chronic use (in the setting of chronic lung disease) of cuffed ETTs.


[Morphometric analysis of the glomeruli and juxtaglomerular apparatus of rat kidneys during the course of experimental hypokinesia].
In the hypokinetic study a certain correlation between variations in the means of the volume of cortical and juxtamedullary glomerules and the function of the juxtaglomerular apparatus has been established. It is hypothesized that at early hypokinesia renal vascular changes are nonspecific. The phenomenon of renal excretion of fluids and electrolytes is explained in terms of a simultaneous increase in the reninangiotensin activity and 11-hydroxycorticosteroid content in plasma.


CD133, a novel marker for human prostatic epithelial stem cells.
Stem cells are clonogenic cells with self-renewal and differentiation properties, which may represent a major target for genetic damage leading to prostate cancer and benign prostatic hyperplasia. Stem cells remain poorly characterised because of the absence of specific molecular markers that permit us to distinguish them from their progeny, the transit amplifying cells, which have a more restricted proliferative potential. Human CD133 antigen, also known as AC133, was recently identified as a haematopoietic stem cell marker. Here we show that a small population (approximately 1%) of human prostate basal cells express the cell surface marker CD133 and are restricted to the alpha(2)beta(1)(hi) population, previously shown to be a marker of stem cells in prostate epithelia. alpha(2)beta(1)(hi)/CD133(+) cells exhibit two important attributes of epithelial stem cells: they possess a high in vitro proliferative potential and can reconstitute prostatic-like acini in immunocompromised male nude mice.


The Gut Microbiome Alterations and Inflammation-Driven Pathogenesis of Alzheimer's Disease-a Critical Review.
One of the most important scientific discoveries of recent years was the disclosure that the intestinal microflora takes part in bidirectional communication between the gut and the brain. Scientists suggest that human gut microflora may even act as the "second brain" and be responsible for neurodegenerative disorders like Alzheimer's disease (AD). Although human-associated microbial communities are generally stable, they can be altered by common human actions and experiences. Enteric bacteria, commensal, and pathogenic microorganisms, may have a major impact on immune system, brain development, and behavior, as they are able to produce several neurotransmitters and neuromodulators like serotonin, kynurenine, catecholamine, etc., as well as amyloids. However, brain destructive mechanisms, that can lead to dementia and AD, start with the intestinal microbiome dysbiosis, development of local and systemic inflammation, and dysregulation of the gut-brain axis. Increased permeability of the gut epithelial barrier results in invasion of different bacteria, viruses, and their neuroactive products that support neuroinflammatory reactions in the brain. It seems that, inflammatory-infectious hypothesis of AD, with the great role of the gut microbiome, starts to gently push into the shadow the amyloid cascade hypothesis that has dominated for decades. It is strongly postulated that AD may begin in the gut, and is closely related to the imbalance of gut microbiota. This is promising area for therapeutic intervention. Modulation of gut microbiota through personalized diet or beneficial microbiota intervention, alter microbial partners and their products including amyloid protein, will probably become a new treatment for AD.


Predicting cognitive function from clinical measures of physical function and health status in older adults.
Current research suggests that the neuropathology of dementia-including brain changes leading to memory impairment and cognitive decline-is evident years before the onset of this disease. Older adults with cognitive decline have reduced functional independence and quality of life, and are at greater risk for developing dementia. Therefore, identifying biomarkers that can be easily assessed within the clinical setting and predict cognitive decline is important. Early recognition of cognitive decline could promote timely implementation of preventive strategies. We included 89 community-dwelling adults aged 70 years and older in our study, and collected 32 measures of physical function, health status and cognitive function at baseline. We utilized an L1-L2 regularized regression model (elastic net) to identify which of the 32 baseline measures were strongly predictive of cognitive function after one year. We built three linear regression models: 1) based on baseline cognitive function, 2) based on variables consistently selected in every cross-validation loop, and 3) a full model based on all the 32 variables. Each of these models was carefully tested with nested cross-validation. Our model with the six variables consistently selected in every cross-validation loop had a mean squared prediction error of 7.47. This number was smaller than that of the full model (115.33) and the model with baseline cognitive function (7.98). Our model explained 47% of the variance in cognitive function after one year. We built a parsimonious model based on a selected set of six physical function and health status measures strongly predictive of cognitive function after one year. In addition to reducing the complexity of the model without changing the model significantly, our model with the top variables improved the mean prediction error and R-squared. These six physical function and health status measures can be easily implemented in a clinical setting.


The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological treatment of substance use and related disorders. Part 2: Opioid dependence.
To develop evidence-based practice guidelines for the pharmacological treatment of opioid abuse and dependence. An international task force of the World Federation of Societies of Biological Psychiatry (WFSBP) developed these practice guidelines after a systematic review of the available evidence pertaining to the treatment of opioid dependence. On the basis of the evidence, the Task Force reached a consensus on practice recommendations, which are intended to be clinically and scientifically meaningful for physicians who treat adults with opioid dependence. The data used to develop these guidelines were extracted primarily from national treatment guidelines for opioid use disorders, as well as from meta-analyses, reviews, and publications of randomized clinical trials on the efficacy of pharmacological and other biological treatments for these disorders. Publications were identified by searching the MEDLINE database and the Cochrane Library. The literature was evaluated with respect to the strength of evidence for efficacy, which was categorized into one of six levels (A-F). There is an excellent evidence base supporting the efficacy of methadone and buprenorphine or the combination of buprenorphine and naloxone for the treatment of opioid withdrawal, with clonidine and lofexidine as secondary or adjunctive medications. Opioid maintenance with methadone and buprenorphine is the best-studied and most effective treatment for opioid dependence, with heroin and naltrexone as second-line medications. There is enough high quality data to formulate evidence-based guidelines for the treatment of opioid abuse and dependence. This task force report provides evidence for the efficacy of a number of medications to treat opioid abuse and dependence, particularly the opioid agonists methadone or buprenorphine. These medications have great relevance for clinical practice.


Galeterone prevents androgen receptor binding to chromatin and enhances degradation of mutant androgen receptor.
Galeterone inhibits the enzyme CYP17A1 and is currently in phase II clinical trials for castration-resistant prostate cancer (CRPC). Galeterone is also a direct androgen receptor (AR) antagonist and may enhance AR degradation. This study was undertaken to determine the molecular basis for AR effects and their therapeutic potential. Effects of galeterone on AR expression and activities were examined in prostate cancer cell lines. Similar to the AR antagonist enzalutamide, but in contrast to bicalutamide, galeterone did not induce binding of a constitutively active VP16-AR fusion protein to reporter genes and did not induce AR recruitment to endogenous androgen-regulated genes based on chromatin immunoprecipitation. Galeterone at low micromolar concentrations that did not induce cellular stress responses enhanced AR protein degradation in LNCaP and C4-2 cells, which express a T878A mutant AR, but not in prostate cancer cells expressing wild-type AR. Further transfection studies using stable LNCaP and PC3 cell lines ectopically expressing wild-type or T878A-mutant ARs confirmed that galeterone selectively enhances degradation of the T878A-mutant AR. Similar to enzalutamide, galeterone may be effective as a direct AR antagonist in CRPC. It may be particularly effective against prostate cancer cells with the T878A AR mutation but may also enhance degradation of wild-type AR in vivo through a combination of direct and indirect mechanisms. Finally, these findings show that conformational changes in AR can markedly enhance its degradation and thereby support efforts to develop further antagonists that enhance AR degradation.


Amastigotes of Trypanosoma cruzi sustain an infective cycle in mammalian cells.
The two main stages of development of the protozoan parasite Trypanosoma cruzi found in the vertebrate host are the trypomastigote and the amastigote. It has been generally assumed that only trypomastigotes are capable of entering cells and that amastigotes are the intracellular replicative form of the parasite. We show here that after incubation for 4 h with human monocytes in vitro 90% or more of extracellularly derived (24 h) amastigotes of T. cruzi are taken up by the cells. Within 2 h they escape the phagocytic vacuole and enter the cytoplasm, where they divide and after 4-5 d transform into trypomastigotes. Trypomastigotes also invade cultured human monocytes. However, they show a lag of several hours between invasion and the start of DNA duplication, while amastigotes commence replication without an apparent lag. Amastigotes also infect cultured fibroblasts, albeit with lower efficiency. When injected intraperitoneally into mice, amastigotes are as infective as trypomastigotes. Based on these results, and on prior findings that amastigotes are found free in the circulation of mice during the acute stage of the disease (3), it seems likely that the cellular uptake of amastigotes can initiate an alternative subcycle within the life cycle of this parasite in the mammalian host. Also, because trypomastigotes and amastigotes have diverse surface antigens, they may use different strategies to invade host cells.


Expanding PrEP Services for Men Who Have Sex With Men and Transgender Persons Through Health Department Programs: Key Processes and Outcomes From Project PrIDE, 2015-2019.
Pre-exposure prophylaxis (PrEP) Implementation, Data to Care, and Evaluation (PrIDE) was a demonstration project implemented by 12 state and local health departments during 2015-2019 to expand PrEP services for men who have sex with men (MSM) and transgender persons at risk for HIV infection. We describe findings from the cross-jurisdictional evaluation of the project. We analyzed work plans, annual progress reports, and aggregate quantitative program data submitted by funded health departments (n = 12) to identify key activities implemented and summarize key project outcomes. PrIDE jurisdictions implemented multiple health equity-focused activities to expand PrEP services to priority populations, including building program capacity, conducting knowledge and awareness campaigns, providing PrEP support services, and addressing barriers to PrEP use. Overall, PrIDE jurisdictions identified 44 813 persons with PrEP indications. Of these, 74.8% (n = 33 500) were referred and 33.1% (n = 14 821) were linked to PrEP providers, and 25.3% (n = 11 356) were prescribed PrEP. Most persons prescribed PrEP were MSM or transgender persons (87.9%) and persons from racial and ethnic minority groups (65.6%). However, among persons with PrEP indications, non-Hispanic Black/African American persons (14.9% of 18 782) were less likely than non-Hispanic White persons (31.0% of 11 633) to be prescribed PrEP (z = -33.57; P < .001). PrIDE jurisdictions successfully expanded PrEP services for MSM, transgender persons, and racial and ethnic minority groups by implementing health equity-focused activities that addressed barriers to PrEP services. However, PrEP prescription was generally low, with significant disparities by demographic characteristics. Additional targeted interventions are needed to expand PrEP services, achieve equity in PrEP use, and contribute to ending the HIV epidemic in the United States.


Quantitative and qualitative differences in the T cell response to HIV in uninfected Ugandans exposed or unexposed to HIV-infected partners.
HIV-exposed and yet persistently uninfected individuals have been an intriguing, repeated observation in multiple studies, but uncertainty persists on the significance and implications of this in devising protective strategies against HIV. We carried out a cross-sectional analysis of exposed uninfected partners in a Ugandan cohort of heterosexual serodiscordant couples (37.5% antiretroviral therapy naive) comparing their T cell responses to HIV peptides with those of unexposed uninfected individuals. We used an objective definition of exposure and inclusion criteria, blinded ex vivo and cultured gamma interferon (IFN-γ) enzyme-linked immunospot assays, and multiparameter flow cytometry and intracellular cytokine staining to investigate the features of the HIV-specific response in exposed versus unexposed uninfected individuals. A response rate to HIV was detectable in unexposed uninfected (5.7%, 95% confidence interval [CI] = 3.3 to 8.1%) and, at a significantly higher level (12.5%, 95% CI = 9.7 to 15.4%, P = 0.0004), in exposed uninfected individuals. The response rate to Gag was significantly higher in exposed uninfected (10/50 [20.%]) compared to unexposed uninfected (1/35 [2.9%]) individuals (P = 0.0004). The magnitude of responses was also greater in exposed uninfected individuals but not statistically significant. The average number of peptide pools recognized was significantly higher in exposed uninfected subjects than in unexposed uninfected subjects (1.21 versus 0.47; P = 0.0106). The proportion of multifunctional responses was different in the two groups, with a higher proportion of single cytokine responses, mostly IFN-γ, in unexposed uninfected individuals compared to exposed uninfected individuals. Our findings demonstrate both quantitative and qualitative differences in T cell reactivity to HIV between HESN (HIV exposed seronegative) and HUSN (HIV unexposed seronegative) subject groups but do not discriminate as to whether they represent markers of exposure or of protection against HIV infection.


Risk Assessment or Assessment of Risk? Developing an Evidence-Based Approach for Primary Producers of Leafy Vegetables To Assess and Manage Microbial Risks.
Over the last 10 years, some high-profile foodborne illness outbreaks have been linked to the consumption of leafy greens. Growers are required to complete microbiological risk assessments (RAs) for the production of leafy crops supplied either to retail or for further processing. These RAs are based primarily on qualitative judgements of hazard and risks at various stages in the production process but lack many of the steps defined for quantitative microbiological RAs by the Codex Alimentarius Commission. This article is based on the discussions of an industry expert group and proposes a grower RA approach based on a structured qualitative assessment, which requires all decisions to be based on evidence and a framework for describing the decision process that can be challenged and defended within the supply chain. In addition, this article highlights the need for evidence to be more easily available and accessible to primary producers and identifies the need to develop hygiene criteria to aid validation of proposed interventions.


Activation of the phosphatidylinositol 3-kinase Vps34 by a G protein alpha subunit at the endosome.
In the yeast Saccharomyces cerevisiae, the G protein beta gamma subunits are essential for pheromone signaling. The Galpha subunit Gpa1 can also promote signaling, but the effectors in this pathway are not well characterized. To identify candidate Gpa1 effectors, we expressed the constitutively active Gpa1(Q323L) mutant in each of nearly 5000 gene-deletion strains and measured mating-specific responses. Our analysis reveals a requirement for both the catalytic (Vps34) and regulatory (Vps15) subunits of the sole phosphatidylinositol 3-kinase in yeast. We demonstrate that Gpa1 is present at endosomes, where it interacts directly with both Vps34 and Vps15 and stimulates increased production of phosphatidylinositol 3-phosphate. Notably, Vps15 binds to GDP-bound Gpa1 and is predicted to have a seven-WD repeat structure similar to that of known G protein beta subunits. These findings reveal two new components of the pheromone signaling pathway. More remarkably, these proteins appear to comprise a preformed effector-G beta subunit assembly and function at the endosome rather than at the plasma membrane.


Cardiorespiratory Events Following the Second Routine Immunization in Preterm Infants: Risk Assessment and Monitoring Recommendations.
Due to frequent cardiorespiratory events (CREs) in response to the first routine immunization (rIM), current guidelines recommend readmitting and monitoring extremely preterm infants after the second rIM, though evidence on CREs in response to the second rIM is weak. In a prospective observational study, preterm infants with an increase in CREs after the first rIM were monitored for CREs before and after the second rIM. Seventy-one infants with a median gestational age of 26.4 weeks and a median weight of 820 g at birth were investigated at a median postnatal age of 94 days. All but seven infants showed an increase in CREs after the second rIM. The frequency of hypoxemias (p < 0.0001), apneas (p = 0.0003) and cardiorespiratory events requiring tactile stimulation (CRE-ts) (p = 0.0034) increased significantly. The 25 infants (35%) presenting with CRE-ts were significantly more likely to have been continuously hospitalized since birth (p = 0.001) and to receive analeptic therapy at the first rIM (p = 0.002) or some kind of respiratory support at the first (p = 0.005) and second rIM (p < 0.0001). At a postmenstruational age of 43.5 weeks, CRE-ts ceased. Our data support the recommendation to monitor infants who fulfil the above-mentioned criteria during the second rIM up to a postmenstruational age of 44 weeks.


Genomics of invasion: diversity and selection in introduced populations of monkeyflowers (Mimulus guttatus).
Global trade and travel is irreversibly changing the distribution of species around the world. Because introduced species experience drastic demographic events during colonization and often face novel environmental challenges from their native range, introduced populations may undergo rapid evolutionary change. Genomic studies provide the opportunity to investigate the extent to which demographic, historical and selective processes shape the genomic structure of introduced populations by analysing the signature that these processes leave on genomic variation. Here, we use next-generation sequencing to compare genome-wide relationships and patterns of diversity in native and introduced populations of the yellow monkeyflower (Mimulus guttatus). Genome resequencing data from 10 introduced populations from the United Kingdom (UK) and 12 native M. guttatus populations in North America (NA) demonstrated reduced neutral genetic diversity in the introduced range and showed that UK populations are derived from a geographic region around the North Pacific. A selective-sweep analysis revealed site frequency changes consistent with selection on five of 14 chromosomes, with genes in these regions showing reduced silent site diversity. While the target of selection is unknown, genes associated with flowering time and biotic and abiotic stresses were located within the swept regions. The future identification of the specific source of origin of introduced UK populations will help determining whether the observed selective sweeps can be traced to unsampled native populations or occurred since dispersal across the Atlantic. Our study demonstrates the general potential of genome-wide analyses to uncover a range of evolutionary processes affecting invasive populations.


Controlling enantiomeric populations in fluctuating Brownian monolayers of chiral colloids.
An ideal parallelogram platelet, although achiral in 3D, has an identifiable chirality when confined in a 2D monolayer. We lithographically fabricate microscale parallelogram platelets, disperse them in an aqueous surfactant solution, and allow them to settle towards a lower glass wall. To reduce the thermal-gravitational height, we add polystyrene nanospheres as a depletion agent to create a depletion attraction between the parallelograms and the wall. Surprisingly, by increasing the volume fraction of the depletion agent, we show that a nearly enantiopure monolayer can be created. We explain this by developing a model of 2D monolayer formation based on anisotropic facial attractions; one face of a platelet is more strongly attracted to the wall than the other as a consequence of an anisotropy introduced by the lithographic process. We study enantiopure Brownian systems of parallelograms as a function of particle area fraction and show that oblique chiral crystals form at high densities. By mixing parallelogram platelets printed in opposite senses, we also dictate the chiral ratio in the monolayer over the entire possible range. This approach is not limited to parallelograms and provides a means for tuning the chiral ratio in fluctuating 2D monolayers composed of a wide variety of chiral shapes.


Role of the gastroenterologist in managing obesity.
Obesity has become a major public health problem as a consequence of its prevalence, negative impact on morbidity, mortality and quality of life and its associated direct and indirect healthcare costs. The etiology of obesity is multifactorial and reflects complex interactions of genetic, neurohumoral, environmental, behavioral and possibly, microbial factors. Available treatments for obesity include diet and exercise, behavioral modification, medications and surgery. Gastroenterologists are becoming increasingly involved in the care of obese patients. Although much of this care has historically centered on the preoperative and postoperative care of the bariatric patient, gastroenterologists are also evaluating and managing a variety of gastrointestinal symptoms and disorders that occur more commonly among obese individuals and are increasingly involved in the primary treatment of obesity. In this review, the gastrointestinal symptoms and disorders that are associated with obesity will be reviewed, the gastrointestinal contribution to the pathogenesis of obesity will be described and the current treatment options of obesity and where the gastroenterologist typically plays a role in the management will be discussed.