Does television viewing predict dietary intake five years later in high school students and young adults?
Prior research has found that television viewing is associated with poor diet quality, though little is known about its long-term impact on diet, particularly during adolescence. This study examined the associations between television viewing behavior with dietary intake five years later. Survey data, which included television viewing time and food frequency questionnaires, were analyzed for 564 middle school students (younger cohort) and 1366 high school students (older cohort) who had complete data available at Time 1 (1998-1999) and five years later at Time 2 (mean age at Time 2, 17.2 +/- 0.6 and 20.5 +/- 0.8 years, respectively). Regression models examined longitudinal associations between Time 1 television viewing behavior and Time 2 dietary intake adjusting for sociodemographic characteristics, Time 1 dietary intake, and Time 2 total daily energy intake. Respondents were categorized as limited television users (<2 hours/daily), moderately high television viewers (2-5 hours/daily), and heavy television viewers (>/=5 hours/daily). Among the younger cohort, Time 1 heavy television viewers reported lower fruit intake and higher sugar-sweetened beverage consumption than the other two groups. Among the older cohort, watching five or more hours of television per day at Time 1, predicted lower intakes of fruits, vegetables, whole grain and calcium-rich foods, and higher intakes of trans fat, fried foods, fast food menu items, snack products, and sugar-sweetened beverages (products commonly advertised on television) five years later. Television viewing in middle and high school predicted poorer dietary intake five years later. Adolescents are primary targets of advertising for fast food restaurants, snack foods, and sugar-sweetened beverages, which may influence their food choices. Television viewing, especially during high school, may have long-term effects on eating choices and contribute to poor eating habits in young adulthood.


Measuring emergency physicians' work: factoring in clinical hours, patients seen, and relative value units into 1 metric.
Measuring workplace performance is important to emergency department management. If an unreliable model is used, the results will be inaccurate. Use of inaccurate results to make decisions, such as how to distribute the incentive pay, will lead to rewarding the wrong people and will potentially demoralize top performers. This article demonstrates a statistical model to reliably measure the work accomplished, which can then be used as a performance measurement.


Trust as a mediator in the relationship between childhood sexual abuse and IL-6 level in adulthood.
Childhood sexual abuse (CSA) has been shown to predict the coupling of depression and inflammation in adulthood. Trust within intimate relationships, a core element in marital relations, has been shown to predict positive physical and mental health outcomes, but the mediating role of trust in partners in the association between CSA and inflammation in adulthood requires further study. The present study aimed to examine the impact of CSA on inflammatory biomarkers (IL-6 and IL-1β) in adults with depression and the mediating role of trust. A cross-sectional survey data set of adults presenting with mood and sleep disturbance was used in the analysis. CSA demonstrated a significant negative correlation with IL-6 level (r = -0.28, p<0. 01) in adults with clinically significant depression, while trust showed a significant positive correlation with IL-6 level (r = 0.36, p < .01). Sobel test and bootstrapping revealed a significant mediating role for trust between CSA and IL-6 level. CSA and trust in partners were revealed to have significant associations with IL-6 level in adulthood. Counterintuitively, the directions of association were not those expected. Trust played a mediating role between CSA and adulthood levels of IL-6. Plausible explanations for these counterintuitive findings are discussed.


Cells in New Light: Ion Concentration, Voltage, and Pressure Gradients across a Hydrogel Membrane.
The ionic compositions of the intra- and extracellular environments are distinct from one another, with K+ being the main cation in the cytosol and Na+ being the most abundant cation outside of the cell. Specific ions can permeate into and out of the cell at different rates, bringing about uneven distribution of charges and development of negative electric potential inside the cell. Each healthy cell must maintain a specific ion concentration gradient and voltage. To account for these functions, various ionic pumps and channels located within the cell membrane have been invoked. In this work, we use a porous alginate hydrogel as a model gelatinous network representing the plant cell wall or cytoskeleton of the animal cell. We show that the gel barrier is able to maintain a stable separation of ionic solutions of different ionic strengths and chemical compositions without any pumping activity. For the Na+/K+ concentration gradient sustained across the barrier, a negative electric potential develops within the K+-rich side. The situation is reminiscent of that in the cell. Furthermore, also the advective flow of water molecules across the gel barrier is restricted, despite the gel's large pores and the osmotic or hydrostatic pressure gradients across it. This feature has important implications for osmoregulation. We propose a mechanism in which charge separation and electric fields developing across the permselective (gel) membrane prevent ion and bulk fluid flows ordinarily driven by chemical and pressure gradients.


A fish is not a fish: patterns in fatty acid composition of aquatic food may have had implications for hominin evolution.
From c. 2 Ma (millions of years ago) onwards, hominin brain size and cognition increased in an unprecedented fashion. The exploitation of high-quality food resources, notably from aquatic ecosystems, may have been a facilitator or driver of this phenomenon. The aim of this study is to contribute to the ongoing debate on the possible role of aquatic resources in hominin evolution by providing a more detailed nutritional context. So far, the debate has focused on the relative importance of terrestrial versus aquatic resources while no distinction has been made between different types of aquatic resources. Here we show that Indian Ocean reef fish and eastern African lake fish yield on average similarly high amounts of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA). Hence a shift from exploiting tropical marine to freshwater ecosystems (or vice versa) would entail no material difference in dietary long-chain polyunsaturated fatty acid (LC-PUFA) availability. However, a shift to marine ecosystems would likely mean a major increase in access to brain-selective micronutrients such as iodine. Fatty fish from marine temperate/cold waters yield twice as much DHA and four times as much EPA as tropical fish, demonstrating that a latitudinal shift in exploitation of African coastal ecosystems could constitute a significant difference in LC-PUFA availability with possible implications for brain development and functioning. We conclude that exploitation of aquatic food resources could have facilitated the initial moderate hominin brain increase as observed in fossils dated to c. 2 Ma, but not the exceptional brain increase in later stages of hominin evolution. We propose that the significant expansion in hominin brain size and cognition later on may have been aided by strong directional selecting forces such as runaway sexual selection of intelligence, and nutritionally supported by exploitation of high-quality food resources in stable and productive aquatic ecosystems.


Prevalence of impacted third molars among orthodontic patients in different malocclusions.
The aim of this retrospective study was to investigate the prevalence and pattern of third molar impaction and missing third molars in patients over 18 years in different anteroposterior skeletal patterns among central Indian populations. The study reviewed 357 orthopantomograms of patients attending the Government College of Dentistry, Indore, Madhya Pradesh. Patients were evaluated to determine the prevalence of third molar impaction, angulation, and level of eruption in Class I, Class II, and Class III patients using Winter's classification to determine angulation of third molars and Pell and Gregory classification for level of impaction. Out of 357 patients, 187 (52.3%) were present with at least one impacted teeth. The third molar impaction was most commonly present in Class II malocclusion (60.65%). Overall, the most common angulation of impaction in both genders was the mesioangular (39%), and the most common level of impaction in both arches was Level B. In Class I, Class II and Class III malocclusion vertical angulation was the most common finding in the maxillary arch and mesioangular angulation in the mandibular arch. No significant association was observed between different types of malocclusion and third molar impaction (P > 0.4648). This study found that almost half of the adult patients above 18 years had at least one impacted third molar. The anteroposterior relationship does not have any significant role for the third molar impaction.


Native 3D intermediates of membrane fusion in herpes simplex virus 1 entry.
The concerted action of four viral glycoproteins and at least one cellular receptor is required to catalyze herpes simplex virus 1 entry into host cells either by fusion at the plasma membrane or intracellularly after internalization by endocytosis. Here, we applied cryo electron tomography to capture 3D intermediates from Herpes simplex virus 1 fusion at the plasma membrane in their native environment by using two model systems: adherent cells and synaptosomes. The fusion process was delineated as a series of structurally different steps. The incoming capsid separated from the tegument and was closely surrounded by the cortical cytoskeleton. After entry, the viral membrane curvature changed concomitantly with a reorganization of the envelope glycoprotein spikes. Individual glycoprotein complexes in transitional conformations during pore formation and dilation revealed the complex viral fusion mechanism in action. Snapshots of the fusion intermediates provide unprecedented details concerning the overall structural changes occurring during herpesvirus entry. Moreover, our data suggest that there are two functional "poles" of the asymmetric herpesvirion: one related to cell entry, and the other formed during virus assembly.


International union of pharmacology. XLV. Classification of the kinin receptor family: from molecular mechanisms to pathophysiological consequences.
Kinins are proinflammatory peptides that mediate numerous vascular and pain responses to tissue injury. Two pharmacologically distinct kinin receptor subtypes have been identified and characterized for these peptides, which are named B1 and B2 and belong to the rhodopsin family of G protein-coupled receptors. The B2 receptor mediates the action of bradykinin (BK) and lysyl-bradykinin (Lys-BK), the first set of bioactive kinins formed in response to injury from kininogen precursors through the actions of plasma and tissue kallikreins, whereas the B(1) receptor mediates the action of des-Arg9-BK and Lys-des-Arg9-BK, the second set of bioactive kinins formed through the actions of carboxypeptidases on BK and Lys-BK, respectively. The B2 receptor is ubiquitous and constitutively expressed, whereas the B1 receptor is expressed at a very low level in healthy tissues but induced following injury by various proinflammatory cytokines such as interleukin-1beta. Both receptors act through G alpha(q) to stimulate phospholipase C beta followed by phosphoinositide hydrolysis and intracellular free Ca2+ mobilization and through G alpha(i) to inhibit adenylate cyclase and stimulate the mitogen-activated protein kinase pathways. The use of mice lacking each receptor gene and various specific peptidic and nonpeptidic antagonists have implicated both B1 and B2 receptors as potential therapeutic targets in several pathophysiological events related to inflammation such as pain, sepsis, allergic asthma, rhinitis, and edema, as well as diabetes and cancer. This review is a comprehensive presentation of our current understanding of these receptors in terms of molecular and cell biology, physiology, pharmacology, and involvement in human disease and drug development.


Application of the steep ramp test for aerobic fitness testing in children with cancer.
Children with and after cancer are found to have a decreased physical fitness, frequently resulting in decreased physical functioning. The gold standard test for assessing aerobic fitness, a component of physical fitness, is the respiratory gas analyses-based cardiopulmonary exercise test (CPET). However, equipment for gas analysis is often unavailable in local physical therapy centres and non-university hospitals. The steep ramp test (SRT), is a cycle ergometer test with a fast increase in workload, a short duration, and does not require respiratory gas analysis equipment. The aim of this study was to compare the results of the CPET and the SRT, in children with cancer, and to assess whether the SRT can be used for aerobic fitness assessment in clinical practice in this population. This study is a cross-sectional assessment using baseline data of a randomized controlled trial. The study was performed in a hospital setting. Sixty-one children (mean age 12.9 years; 33 boys) with cancer were included in the analysis; 16 children were on non-intensive chemotherapy treatment, 45 were in the first year thereafter. Participants performed both the SRT and the CPET on a cycle ergometer with respiratory gas analysis. Data of the two tests were compared and regression analyses were performed. CPET test results revealed a higher impact on the cardiovascular system, as shown by higher peak ventilation (47.8 versus 52.0 Litres per min) and peak heart rates (173 versus 191 beats per min), compared to the SRT. In addition, the test time was significantly longer (90 s versus 390 s). Yet, the primary outcome of the SRT (peak work rate) was able to reliably estimate the peak oxygen uptake of the CPET. The peak oxygen uptake was comparable between the SRT and the CPET, although the peak work rate was significantly higher during the SRT. This study showed that the SRT is a valid instrument to assess aerobic fitness in children with cancer. The SRT is less time consuming and can be performed without gas analysis in a non-clinical setting, making it less demanding for children.


The Impact of an Enterprise Electronic Medical Record (EEMR) Model vs a Clinical Information System (CIS) Model on Usability, Efficiency, and Adaptability.
This paper describes a methodology that engages the clinical community into the design process of creating Clinical Information Systems (CISs) under a Clinical Team-Led Design (CTLD) approach in the context of using Immediately Adaptable (IA) system development technology. The methodology is contrasted against the Enterprise Electronic Medical Record (EEMR) model for usability, efficiency, and adaptability. The methodology was tested in a Breast Cancer setting where the CIS went through 4 rapid agile stages. Time and motion statistics, training times, system changes, and user feedback data was collected for assessment. The results showed that the Breast CIS increased time efficiency by 30% in the first 3 months of implementation. Users reported high usability and trainability of the system. Over 95% of system design change requests were satisfied with an average turn-around time of 3 days. The results show that systems designed under a CTLD approach, accompanied by Immediately Adaptable system architecture, provide greater efficiency for staff in clinical settings while enabling the workflow processes to be adapted dynamically as part of continuous process improvement.


Scoping review of symptoms in children with rare, progressive, life-threatening disorders.
Q3 conditions are progressive, metabolic, neurological or chromosomal childhood conditions without a cure. Children with these conditions face an unknown lifespan as well as unstable and uncomfortable symptoms. Clinicians and other healthcare professionals are challenged by a lack of evidence for symptom management for these conditions. In this scoping review, we systematically identified and mapped the existing literature on symptom management for children with Q3 conditions. We focused on the most common and distressing symptoms, namely alertness, behavioural problems, bowel incontinence, breathing difficulties, constipation, feeding difficulties, sleep disturbance, temperature regulation, tone and motor problems and urinary incontinence. For children with complex health conditions, good symptom management is pertinent to ensure the highest possible quality of life. Scoping review. Electronic database searches in Ovid MEDLINE, Embase and CINAHL and a comprehensive grey literature search. We included 292 studies in our final synthesis. The most commonly reported conditions in the studies were Rett syndrome (n=69), followed by Cornelia de Lange syndrome (n=25) and tuberous sclerosis (n=16). Tone and motor problems were the most commonly investigated symptom (n=141), followed by behavioural problems (n=82) and sleep disturbance (n=62). The evidence for symptom management in Q3 conditions is concentrated around a few conditions, and these studies may not be applicable to other conditions. The evidence is dispersed in the literature and difficult to access, which further challenges healthcare providers. More research needs to be done in these conditions to provide high-quality evidence for the care of these children.


The epidemiology of substance use disorders in US Veterans: A systematic review and analysis of assessment methods.
Substance use disorders (SUDs), which encompass alcohol and drug use disorders (AUDs, DUDs), constitute a major public health challenge among US veterans. SUDs are among the most common and costly of all health conditions among veterans. This study sought to examine the epidemiology of SUDs among US veterans, compare the prevalence of SUDs in studies using diagnostic and administrative criteria assessment methods, and summarize trends in the prevalence of SUDs reported in studies sampling US veterans over time. Comprehensive electronic database searches were conducted. A total of 3,490 studies were identified. We analyzed studies sampling US veterans and reporting prevalence, distribution, and examining AUDs and DUDs. Of the studies identified, 72 met inclusion criteria. The studies were published between 1995 and 2013. Studies using diagnostic criteria reported higher prevalence of AUDs (32% vs. 10%) and DUDs (20% vs. 5%) than administrative criteria, respectively. Regardless of assessment method, both the lifetime and past year prevalence of AUDs in studies sampling US veterans has declined gradually over time. The prevalence of SUDs reported in studies sampling US veterans are affected by assessment method. Given the significant public health problems of SUDs among US veterans, improved guidelines for clinical screening using validated diagnostic criteria to assess AUDs and DUDs in US veteran populations are needed. These findings may inform VA and other healthcare systems in prevention, diagnosis, and intervention for SUDs among US veterans.


Acid-base balance affects dietary choice in cats.
The effect of acid-base status on self-selection of dietary protein was examined in three groups of adult male cats fed 20% soybean-protein and lactalbumin diets formulated to produce acidic, neutral or alkaline status. In two experiments, cats were offered a choice between the 20% protein diets or (1) the same diet with additional protein as casein (49% total crude protein) or (2) the same diet with added soybean-protein and lactalbumin (43% crude protein). Casein contained 0.63 mmol H+/g and caused all three groups to avoid the high casein diets by day 4. The high soybean-protein-lactalbumin diets did not contain added acid but would produce some extra acid upon catabolism of the sulfur-containing amino acids. Again, all three groups avoided the high protein diets by day 4. In a third choice trial, cats adapted to three low protein diets containing appropriate electrolytes to cause neutrality, acidemia or alkalemia, were offered a choice between: neutral vs. acidic; acidic vs. neutral or basic vs. acidic. The cats chose the neutral, neutral and basic diet respectively, restoring or maintaining acid-base homeostasis for each situation. The diets producing acidosis lowered serum sodium and potassium concentrations. We conclude that cats select appropriate diets in an attempt to maintain acid-base homeostasis.


Brain single-photon emission CT physics principles.
The basic principles of scintigraphy are reviewed and extended to 3D imaging. Single-photon emission computed tomography (SPECT) is a sensitive and specific 3D technique to monitor in vivo functional processes in both clinical and preclinical studies. SPECT/CT systems are becoming increasingly common and can provide accurately registered anatomic information as well. In general, SPECT is affected by low photon-collection efficiency, but in brain imaging, not all of the large FOV of clinical gamma cameras is needed: The use of fan- and cone-beam collimation trades off the unused FOV for increased sensitivity and resolution. The design of dedicated cameras aims at increased angular coverage and resolution by minimizing the distance from the patient. The corrections needed for quantitative imaging are challenging but can take advantage of the relative spatial uniformity of attenuation and scatter. Preclinical systems can provide submillimeter resolution in small animal brain imaging with workable sensitivity.


Effect of an emergency department (ED) managed acute care unit on ED overcrowding and emergency medical services diversion.
To determine the impact of an inpatient, emergency department (ED)-managed acute care unit (ACU) on ED overcrowding and use of ambulance diversion. Descriptive observational study with prospectively collected data from a 14-bed ACU recently opened remote from the main ED. Rates of patients who left without being seen (LWBS) and ambulance diversion frequency and duration were adjusted for ED patient volumes and compared with those for the period immediately before the ACU was opened and with those for a matching time period during the previous year. There were 1,589 patients seen in the ACU during the first ten weeks of operation, representing about 14.5% of the ED volume (10,871). About 33% could be classified as post-ED management, 20% as admission processing, and the rest as primary evaluation. The number of patients who LWBS decreased from 10.1% of the ED census two weeks prior to opening of the ACU, and from 9.4% during the previous year, to 5.0% (range 4.2%-6.2%) during the ensuing ten weeks post opening. Ambulance diversion was a mean of 6.7 hours per 100 patients before the unit opened and 5.6 hours per 100 patients during the same time in the previous year, and decreased to 2.8 hours per 100 patients after the unit opened (p < 0.05, respectively). A six-month pre- and two-month post-examination revealed that the mean monthly hours of ambulance diversion for the ED decreased by 40% (202 hours vs 123 hours) (p < 0.05) in contrast to a mean increase of 44% (186 hours vs 266 hours) (p < 0.05) experienced by four proximate hospitals. An ED-managed ACU can have significant impact on ED overcrowding and ambulance diversion, and it need not be located proximate to the ED.


In vitro immunogenicity of cadaver donor bone marrow cells used for the induction of allograft acceptance in clinical transplantation.
The cascade of immunological effects brought about by donor bone marrow cell (DBMC) infusions to induce allograft acceptance in clinical transplantation is not fully understood. Aside from acting as immune responding and regulatory cells, the infused DBMC also may sensitize the recipient to the donor antigens. To analyze this stimulatory activity of DBMC, in vitro mixed lymphocyte cultures (MLC) and cell-mediated lymphocytotoxicity (CML) culture systems analogous to the transplant model with DBMC infusion were used. When responding peripheral blood lymphocytes (PBL) from normal volunteers were placed in culture with suspensions of Ficoll-purified, T cell-depleted, un-irradiated allogeneic DBMC (NT-DBMC), a reaction was seen in both MLC and CML. However, when compared to allogeneic spleen cells as stimulating cells, the responses to NT-DBMC were of markedly lower magnitude and were not seen when the NT-DBMC was irradiated (3000 R). When responding PBL were stimulated with either NT-DBMC that had been previously cultured with irradiated cells from the responders for 1 week (activated NT-DBMC), NT-DBMC further depleted of CD15+ and glycophorin A-positive cells (NT-LP/DBMC), or purified CD34+ and CD2+ DBMC subsets, stronger lymphoproliferative and cytotoxic responses were observed. Moreover, these responses were not abrogated by irradiation of the stimulating DBMC subpopulations. Depletion of antigen-presenting cells by positive selection of CD3+ cells from the responding PBL abrogated MLC and CML reactivity, even when purified NT-LP/DBMC, the most stimulatory cells, were used. This latter observation was in contrast to the responses seen with cultures containing allogeneic stimulating spleen cell populations. This indicated the requirement for indirect alloantigen presentation, i.e., the failure of these DBMC to stimulate by direct alloantigen presentation. NT-DBMC was able to stimulate responding PBL in secondary MLC and CML responses with an equivalent magnitude, irrespective of whether the stimulators were spleen cells or NT-DBMC. Finally, the MLC and CML responses were inhibited by tacrolimus (FK506), mycophenolic acid (MPA), and cyclosporine (CsA) in a dose dependent manner, in contrast to previously observed refractoriness of DBMC preparations to these agents if DBMC was tested as responder cells or in modulatory assays. These results indicate that DBMC are able to function as effective in vitro stimulators, but only by indirect antigen presentation, and that the immune responses mediated by them can be down-regulated by their own inherent suppressive nature, an effect that can be enhanced by the presence of immunosuppressive drugs.


The influence of fundamental traits on mechanisms controlling appendage regeneration.
One of the most compelling questions in evolutionary biology is why some animals can regenerate injured structures while others cannot. Appendage regeneration appears to be common when viewed across the metazoan phylogeny, yet this ability has been lost in many taxa to varying degrees. Within species, the capacity for regeneration also can vary ontogenetically among individuals. Here we argue that appendage regeneration along the secondary body axis may be constrained by fundamental traits such as body size, aging, life stage, and growth pattern. Studies of the molecular mechanisms affecting regeneration have been conducted primarily with small organisms at early life stages. Such investigations disregard the dramatic shifts in morphology and physiology that organisms undergo as they age, grow, and mature. To help explain interspecific and intraspecific constraints on regeneration, we link particular fundamental traits to specific molecular mechanisms that control regeneration. We present a new synthesis for how these fundamental traits may affect the molecular mechanisms of regeneration at the tissue, cellular, and genomic levels of biological organization. Future studies that explore regeneration in organisms across a broad phylogenetic scale, and within an ontogenetic framework, will help elucidate the proximate mechanisms that modulate regeneration and may reveal new biomedical applications for use in regenerative medicine.


A unified approach for allele frequency estimation, SNP detection and association studies based on pooled sequencing data using EM algorithms.
Genome-wide association studies (GWAS) have identified many common polymorphisms associated with complex traits. However, these associated common variants explain only a small fraction of the phenotypic variances, leaving a substantial portion of genetic heritability unexplained. As a result, searches for "missing" heritability are drawing increasing attention, particularly for rare variant studies that often require a large sample size and, thus, extensive sequencing effort. Although the development of next generation sequencing (NGS) technologies has made it possible to sequence a large number of reads economically and efficiently, it is still often cost prohibitive to sequence thousands of individuals that are generally required for association studies. A more efficient and cost-effective design would involve pooling the genetic materials of multiple individuals together and then sequencing the pools, instead of the individuals. This pooled sequencing approach has improved the plausibility of association studies for rare variants, while, at the same time, posed a great challenge to the pooled sequencing data analysis, essentially because individual sample identity is lost, and NGS sequencing errors could be hard to distinguish from low frequency alleles. A unified approach for estimating minor allele frequency, SNP calling and association studies based on pooled sequencing data using an expectation maximization (EM) algorithm is developed in this paper. This approach makes it possible to study the effects of minor allele frequency, sequencing error rate, number of pools, number of individuals in each pool, and the sequencing depth on the estimation accuracy of minor allele frequencies. We show that the naive method of estimating minor allele frequencies by taking the fraction of observed minor alleles can be significantly biased, especially for rare variants. In contrast, our EM approach can give an unbiased estimate of the minor allele frequency under all scenarios studied in this paper. A SNP calling approach, EM-SNP, for pooled sequencing data based on the EM algorithm is then developed and compared with another recent SNP calling method, SNVer. We show that EM-SNP outperforms SNVer in terms of the fraction of db-SNPs among the called SNPs, as well as transition/transversion (Ti/Tv) ratio. Finally, the EM approach is used to study the association between variants and type I diabetes. The EM-based approach for the analysis of pooled sequencing data can accurately estimate minor allele frequencies, call SNPs, and find associations between variants and complex traits. This approach is especially useful for studies involving rare variants.


Is it now time to promote mixed enteral and parenteral nutrition for the critically ill patient?
Intensive care outcome measured by morbidity and mortality is altered in the severely malnourished ICU patient, and nutritional support of the critically ill is accepted as a standard of care. Current recommendations suggest starting enteral feeding as soon as possible whenever the gastrointestinal tract is functioning. The disadvantage of enteral support is that inadequate energy and protein intake can occur. The present commentary focuses on some recent findings regarding the nutritional support of critically ill patients and proposes to promote mixed nutrition support by enteral nutrition (EN), and by parenteral nutrition (PN) whenever EN is insufficient. An increasing nutrition deficit during a long ICU stay is associated with increased morbidity (increased infection rate or impaired wound healing). Evidence shows that EN can result in underfeeding and that nutrition goals are reached only after 5-7 days. Contrary to former beliefs, recent meta-analyses of studies in the ICU showed that PN is not related to excess mortality but may even be associated with improved survival. Optimising the increased substrate requirement for the critically ill by initiating timely nutrition support and ensuring tight glycaemic control with insulin is now considered central for improved intensive care outcomes. Supplemental PN combined with EN could be an effective alternative to achieve 100% of energy and protein targets at day 4, when EN alone fails to achieve goals greater than 60% by day 3. Whether such combined nutrition support provides additional benefit on overall outcome has to be ascertained in further studies.


Prenatal screening: an ethical agenda for the near future.
Prenatal screening for foetal abnormalities such as Down's syndrome differs from other forms of population screening in that the usual aim of achieving health gains through treatment or prevention does not seem to apply. This type of screening leads to no other options but the choice between continuing or terminating the pregnancy and can only be morally justified if its aim is to provide meaningful options for reproductive choice to pregnant women and their partners. However, this aim should not be understood as maximizing reproductive choice per se. Only if understood as allowing prospective parents to avoid suffering related to living with (a child with) serious disorders and handicaps can prenatal screening be a publicly or collectively funded programme. The alternative of moving prenatal testing outside the healthcare system into the private sector is problematic, as it makes these tests accessible only to those who can afford to pay for it. New developments in prenatal screening will have to be assessed in terms of whether and to what extent they either contribute to or undermine the stated aim of providing meaningful options for reproductive choice. In the light of this criterion, this article discusses the introduction of the new non-invasive prenatal test (NIPT), the tendency to widen the scope of follow-up testing, as well as the possible future scenarios of genome-wide screening and 'prenatal personalised medicine'. The article ends with recommendations for further debate, research and analysis.


Eliminating central line-associated bloodstream infections: a national patient safety imperative.
Several studies demonstrating that central line-associated bloodstream infections (CLABSIs) are preventable prompted a national initiative to reduce the incidence of these infections. We conducted a collaborative cohort study to evaluate the impact of the national "On the CUSP: Stop BSI" program on CLABSI rates among participating adult intensive care units (ICUs). The program goal was to achieve a unit-level mean CLABSI rate of less than 1 case per 1,000 catheter-days using standardized definitions from the National Healthcare Safety Network. Multilevel Poisson regression modeling compared infection rates before, during, and up to 18 months after the intervention was implemented. A total of 1,071 ICUs from 44 states, the District of Columbia, and Puerto Rico, reporting 27,153 ICU-months and 4,454,324 catheter-days of data, were included in the analysis. The overall mean CLABSI rate significantly decreased from 1.96 cases per 1,000 catheter-days at baseline to 1.15 at 16-18 months after implementation. CLABSI rates decreased during all observation periods compared with baseline, with adjusted incidence rate ratios steadily decreasing to 0.57 (95% confidence intervals, 0.50-0.65) at 16-18 months after implementation. Coincident with the implementation of the national "On the CUSP: Stop BSI" program was a significant and sustained decrease in CLABSIs among a large and diverse cohort of ICUs, demonstrating an overall 43% decrease and suggesting the majority of ICUs in the United States can achieve additional reductions in CLABSI rates.


Relationships among capsular structure, phagocytosis, and mouse virulence in Klebsiella pneumoniae.
Klebsiella pneumoniae strains of the K2 capsular serotype are usually highly virulent in mice, which is in contrast to the low virulence of most other serotypes. Here we used a genetic approach to examine the relative contribution of capsule type to the virulence of K. pneumoniae in mice. We used wild-type strains expressing capsular polysaccharide (CPS) serotypes K2 (strain KPA1) and K21a (strains KPB1 and KPC1), which were then used to construct capsule-switched derivatives. The close proximity of the cps gene cluster to selectable his markers made it possible to mobilize the cps genes by conjugation from one serotype (donor) to another (recipient) and to obtain recombinants in which interserotype switching had occurred by reciprocal recombination. Each capsule-switched derivative examined of the KPA and KPC strain backgrounds produced a CPS that was immunologically and structurally identical to that of the donor. Strain background was confirmed by demonstrating restriction fragment length polymorphism patterns identical to those of the respective recipients. The parent strains were then compared with capsule-switched recombinants for phenotypic properties associated with virulence. Clearance from the bloodstreams of mice was rapid in serotype K21a strains of either wild-type or recombinant origin, whereas K2 strains remained viable in the blood during the period examined. These differences appeared to be dependent upon the CPS type but independent of strain background. Binding to macrophages was higher in K21a strains than in those with the K2 capsule and was also independent of the strain background. Both blood clearance and macrophage-binding activities were completely inhibited by yeast mannan, suggesting that they were mediated via the macrophage mannose receptor. The K2 parent strain was highly virulent to mice (50% lethal dose [LD50], 3 x 10(3)), while the K21a parent strains demonstrated low virulence (LD50, > 2 x 10(8)). Interestingly, the virulence of recombinant KPC10(cpsK2), originally of the KPC1(cpsK21a) background, was intermediate (LD50, 4 x 10(5)). In contrast, both cpsK21a recombinants of the originally virulent KPA1 (cpsK2) background became nearly avirulent (LD50, > 2 x 10(8)). Six additional serotypes (K12, K24, K32, K55, K62, and K67) were examined, and all showed a positive correlation between the ability of the Klebsiella serotype to interact with a human mannose receptor, as expressed by Cos I cell recombinants, and the LD50 of the serotype. These results suggest that expression of a capsule which is recognized by the mannose receptor markedly affects the interaction with macrophages and blood clearance.(ABSTRACT TRUNCATED AT 400 WORDS)


Cell analysis using a multiple internal reflection photonic lab-on-a-chip.
Here we present a protocol for analyzing cell cultures using a photonic lab-on-a-chip (PhLoC). By using a broadband light source and a spectrometer, the spectrum of a given cell culture with an arbitrary population is acquired. The PhLoC can work in three different regimes: light scattering (using label-free cells), light scattering plus absorption (using stained cells) and, by subtraction of the two former regimes, absorption (without the scattering band). The acquisition time of the PhLoC is ∼30 ms. Hence, it can be used for rapid cell counting, dead/live ratio estimation or multiparametric measurements through the use of different dyes. The PhLoC, including microlenses, micromirrors and microfluidics, is simply fabricated in a single-mask process (by soft lithographic methods) using low-cost materials. Because of its low cost it can easily be implemented for point-of-care applications. From raw substrates to final results, this protocol can be completed in 29 h.


Viruses and lymphocytes in rheumatoid arthritis. II. Examination of lymphocytes and sera from patients with rheumatoid arthritis for evidence of retrovirus infection.
The possible involvement of retroviruses in the aetiology of rheumatoid arthritis (RA) was investigated. Retrovirus antigens were not expressed on rheumatoid synovial and peripheral blood lymphocytes as judged by membrane immunofluorescence, radioimmunoassay, and complement-mediated cytotoxicity. The specific antiretroviral (anti-RD-144 and anti-SSAV) sera used in this study were produced in rabbits immunised with viral antigens grown in a homologous system (rabbit cells and medium supplemented with normal rabbit serum), avoiding non-specific immunofluorescence previously detected with donated antiretroviral sera. Immune complexes lodged in the rheumatoid synovial membranes did not contain, and other cells within the membranes did not express, retroviral antigens. Antibodies cross-reacting with primate retrovirus antigens were sought in sera from patients with 'autoimmune' diseases by means of solid phase radioimmunoassay. There were no retrovirus antibodies in the 3 groups of patients studied, that is, those with rheumatoid arthritis, systemic lupus erythematosus, and with non-RA conditions. Absorption of rheumatoid factor did not alter this conclusion. These results give little support to the hypothesis that activation of endogenous human retroviruses or an infection with horizontally transmitted retroviruses is associated with the rheumatoid process.


Phylogenetic analyses of the polyprotein coding sequences of serotype O foot-and-mouth disease viruses in East Africa: evidence for interserotypic recombination.
Foot-and-mouth disease (FMD) is endemic in East Africa with the majority of the reported outbreaks attributed to serotype O virus. In this study, phylogenetic analyses of the polyprotein coding region of serotype O FMD viruses from Kenya and Uganda has been undertaken to infer evolutionary relationships and processes responsible for the generation and maintenance of diversity within this serotype. FMD virus RNA was obtained from six samples following virus isolation in cell culture and in one case by direct extraction from an oropharyngeal sample. Following RT-PCR, the single long open reading frame, encoding the polyprotein, was sequenced. Phylogenetic comparisons of the VP1 coding region showed that the recent East African viruses belong to one lineage within the EA-2 topotype while an older Kenyan strain, K/52/1992 is a representative of the topotype EA-1. Evolutionary relationships between the coding regions for the leader protease (L), the capsid region and almost the entire coding region are monophyletic except for the K/52/1992 which is distinct. Furthermore, phylogenetic relationships for the P2 and P3 regions suggest that the K/52/1992 is a probable recombinant between serotypes A and O. A bootscan analysis of K/52/1992 with East African FMD serotype A viruses (A21/KEN/1964 and A23/KEN/1965) and serotype O viral isolate (K/117/1999) revealed that the P2 region is probably derived from a serotype A strain while the P3 region appears to be a mosaic derived from both serotypes A and O. Sequences of the VP1 coding region from recent serotype O FMDVs from Kenya and Uganda are all representatives of a specific East African lineage (topotype EA-2), a probable indication that hardly any FMD introductions of this serotype have occurred from outside the region in the recent past. Furthermore, evidence for interserotypic recombination, within the non-structural protein coding regions, between FMDVs of serotypes A and O has been obtained. In addition to characterization using the VP1 coding region, analyses involving the non-structural protein coding regions should be performed in order to identify evolutionary processes shaping FMD viral populations.


Colloquium paper: are we in the midst of the sixth mass extinction? A view from the world of amphibians.
Many scientists argue that we are either entering or in the midst of the sixth great mass extinction. Intense human pressure, both direct and indirect, is having profound effects on natural environments. The amphibians--frogs, salamanders, and caecilians--may be the only major group currently at risk globally. A detailed worldwide assessment and subsequent updates show that one-third or more of the 6,300 species are threatened with extinction. This trend is likely to accelerate because most amphibians occur in the tropics and have small geographic ranges that make them susceptible to extinction. The increasing pressure from habitat destruction and climate change is likely to have major impacts on narrowly adapted and distributed species. We show that salamanders on tropical mountains are particularly at risk. A new and significant threat to amphibians is a virulent, emerging infectious disease, chytridiomycosis, which appears to be globally distributed, and its effects may be exacerbated by global warming. This disease, which is caused by a fungal pathogen and implicated in serious declines and extinctions of >200 species of amphibians, poses the greatest threat to biodiversity of any known disease. Our data for frogs in the Sierra Nevada of California show that the fungus is having a devastating impact on native species, already weakened by the effects of pollution and introduced predators. A general message from amphibians is that we may have little time to stave off a potential mass extinction.


fMRI Localization of Spinal Cord Processing Underlying Female Sexual Arousal.
Using functional magnetic resonance imaging, the authors aimed to determine the roles of the human spinal cord in mediating sexual responses in women. Functional magnetic resonance imaging of the entire lower thoracic, lumbar, and sacral spinal cord was performed using a sexual stimulation paradigm designed to elicit psychological and physical components of sexual arousal. Responses were measured in 9 healthy adult women during 3 consecutive conditions: (a) erotic audiovisual, (b) manual clitoral, and (c) audiovisual plus manual stimulation. Functional magnetic resonance imaging results in healthy subjects demonstrate that this method is sensitive for mapping sexual function in the spinal cord, and identify several key regions involved in human sexual response, including the intermediolateral cell column, the dorsal commissural nucleus, and the sacral parasympathetic nucleus. Using spinal functional magnetic resonance imaging, this study identified many of the spinal cord regions involved in female sexual responses. Results from audiovisual and manual clitoral stimulation correspond with previous data regarding lumbar and sacral neurologic changes during sexual arousal. This study provides the first characterization of neural activity in the human spinal cord underlying healthy female sexual responses and sets a foundation for future studies aimed at mapping changes that result from sexual dysfunction, spinal cord trauma or disease.


Harnessing Twitter data to survey public attention and attitudes towards COVID-19 vaccines in the UK.
Attitudes to COVID-19 vaccination vary considerably within and between countries. Although the contribution of socio-demographic factors to these attitudes has been studied, the role of social media and how it interacts with news about vaccine development and efficacy is uncertain. We examined around 2 million tweets from 522,893 persons in the UK from November 2020 to January 2021 to evaluate links between Twitter content about vaccines and major scientific news announcements about vaccines. The proportion of tweets with negative vaccine content varied, with reductions of 20-24% on the same day as major news announcement. However, the proportion of negative tweets reverted back to an average of around 40% within a few days. Engagement rates were higher for negative tweets. Public health messaging could consider the dynamics of Twitter-related traffic and the potential contribution of more targeted social media campaigns to address vaccine hesitancy.


Performance of colorectal cancer screening in the European Union Member States: data from the second European screening report.
To present comparative data about the performance of colorectal cancer (CRC) screening programmes in the European Union Member States (EU MSs). Cross-sectional study. We analysed key performance indicators-participation rate, positivity rate (PR), detection rate (DR) and positive predictive value for adenomas and CRC-based on the aggregated quantitative data collected for the second EU screening report. We derived crude and pooled (through a random effects model) estimates to describe and compare trends across different MSs/regions and screening protocols. Participation rate was higher in countries adopting faecal immunochemical test (FIT) (range: 22.8%-71.3%) than in those using guaiac faecal occult blood test (gFOBT) (range 4.5%-66.6%), and it showed a positive correlation (ρ=0.842, p<0.001) with participation in breast cancer screening in the same areas. Screening performance showed a large variability. Compliance with referral for colonoscopy (total colonoscopy (TC)) assessment ranged between 64% and 92%; TC completion rate ranged between 92% and 99%. PR and DR of advanced adenomas and CRC were higher in FIT, as compared with gFOBT programmes, and independent of the protocol among men, older subjects and those performing their first screening. The variability in the results of quality indicators across population-based screening programmes highlights the importance of continuous monitoring, as well as the need to promote quality improvement efforts, as recommended in the EU guidelines. The implementation of monitoring systems, ensuring availability of data for the entire process, together with initiatives aimed to enhance reproducibility of histology and quality of endoscopy, represent a priority in screening programmes management.


Tumor volume as a potential imaging-based risk-stratification factor in trimodality therapy for locally advanced non-small cell lung cancer.
The role of trimodality therapy for locally advanced non-small cell lung cancer (NSCLC) continues to be defined. We hypothesized that imaging parameters on pre- and postradiation positron emission tomography (PET)-computed tomography (CT) imaging are prognostic for outcome after preoperative chemoradiotherapy (CRT)/resection/consolidation chemotherapy and could help risk-stratify patients in clinical trials. We enrolled 13 patients on a prospective clinical trial of trimodality therapy for resectable locally advanced NSCLC. PET-CT was acquired for radiation planning and after 45 Gy. Gross tumor volume (GTV) and standardized uptake value were measured at pre- and post-CRT time points and correlated with nodal pathologic complete response, loco-regional and/or distant progression, and overall survival. In addition, we evaluated the performance of automatic deformable image registration (ADIR) software for volumetric response assessment. All patients responded with average total GTV reductions after 45 Gy of 43% (range: 27-64%). Pre- and post-CRT GTVs were highly correlated (R² = 0.9), and their respective median values divided the patients into the same two groups. ADIR measurements agreed closely with manually segmented post-CRT GTVs. Patients with GTV ≥ median (137 ml pre-CRT and 67 ml post-CRT) had 3-year progression-free survival (PFS) of 14% versus 75% for GTV less than median, a significant difference (p = 0.049). Pre- and post-CRT PET-standardized uptake value did not correlate significantly with pathologic complete response, PFS, or overall survival. Preoperative CRT with carboplatin/docetaxel/45 Gy resulted in excellent response rates. In this exploratory analysis, pre- and post-CRT GTV predicted PFS in trimodality therapy, consistent with our earlier studies in a broader cohort of NSCLC. ADIR seems robust enough for volumetric response assessment in clinical trials.


Ultrasonographical diagnosis of fatty liver: significance of the liver-kidney contrast.
In order to investigate the reliability of ultrasonography in the diagnosis of fatty liver, retrospective evaluation was made of abdominal echograms in 45 patients with various diffuse liver diseases who underwent liver biopsy within 2 weeks after the ultrasound study. Instead of the well-recognized but subjective diagnostic criterion, i.e. the bright liver pattern, liver-kidney contrast is proposed as a new criterion. The liver-kidney contrast is based on the brightness of the liver in comparison to the renal parenchyma where fatty change seldom occurs. Combination of this liver-kidney contrast with two other well-known ultrasonographical findings of fatty liver, vascular blurring and deep attenuation, enables us to grade fatty change semiquantitatively. When fatty change of over 30% in the hepatic lobule was adopted as the definition of fatty liver, the satisfaction of both liver-kidney contrast and vascular blurring presented an ultrasound diagnostic criterion for fatty liver, with sensitivity of 83%, specificity of 100%, and an accuracy of 96%.


Fontan conversion templates: patient-specific hemodynamic performance of the lateral tunnel versus the intraatrial conduit with fenestration.
Intraatrial-conduit Fontan is considered a modification of both extracardiac and lateral-tunnel Fontan. In this study, the patient-specific hemodynamic performance of intraatrial-conduit and lateral-tunnel Fontan with fenestration, considered as conversion templates, was investigated based on the authors' patient cohort. Pulsatile computational fluid dynamics simulations were performed using patient-specific models of intraatrial-conduit and lateral-tunnel Fontan patients. Real-time "simultaneous" inferior and superior vena cava, pulmonary artery, and fenestration flow waveforms were acquired from ultrasound. Multiple hemodynamic performance indices were investigated, with particular focus on evaluation of the pulsatile flow performance. Power loss inside the lateral-tunnel Fontan appeared to be significantly higher than with the intraatrial-conduit Fontan for patient-specific cardiac output and normalized connection size. Inclusion of the 4-mm fenestration at a 0.24 L/min mean flow resulted in a lower cavopulmonary pressure gradient and less time-averaged power loss for both Fontan connections. Flow structures within the intraatrial conduit were notability more uniform than within the lateral tunnel. Hepatic flow majorly favored the left lung in both surgical connections: conversion from lateral-tunnel to intraatrial-conduit Fontan resulted in better hemodynamics with less power loss, a lower pressure gradient, and fewer stagnant flow zones along the conduit. This patient-specific computational case study demonstrated superior hemodynamics of intraatrial-conduit Fontan over those of lateral-tunnel Fontan with or without fenestration and improved performance after conversion of the lateral tunnel to the intraatrial conduit. The geometry-specific effect of the nonuniform hepatic flow distribution may motivate new rationales for the surgical design.


DNA polymerase β gap-filling translesion DNA synthesis.
Although the primary function of DNA polymerase (pol) β is associated with gap-filling DNA synthesis as part of the DNA base excision repair pathway, translesion synthesis activity has also been described. To further understand the potential role of pol β-catalyzed translesion DNA synthesis (TLS) and the structure-function relationships of specific residues in pol β, wild-type and selected mutants of pol β were used in TLS assays with DNA substrates containing bulky polycyclic aromatic hydrocarbon-adducted oligonucleotides. Stereospecific (+) and (-)-anti-trans-(C(10)S and C(10)R) benzo[a]pyrene-7,8-dihydrodiol-9-10-epoxide (BPDE) adducts were covalently attached to both the N(6)-adenine and N(2)-guanine in the major and minor grooves, respectively. For all substrates tested, the presence of the BPDE adducts greatly decreased the efficiency of nucleotide incorporation opposite the lesion, and the stereochemistry of the adducts also further modulated the efficiency of the insertion step, such that lesions which were oriented in the 3' direction relative to the approaching polymerase were considerably more blocking than those oriented in the 5' direction. In the absence of a downstream DNA strand, the extension step beyond the adduct was extremely inefficient, relative to a dinucleotide gap-filling reaction, such that in the presence of the downstream DNA, dinucleotide incorporation was strongly favored. In general, analyses of the TLS activities of four pol β mutants revealed similar overall properties, but wild-type pol β exhibited more than 50-fold greater extension and bypass of the C(10)S-dA adducts as compared to a low fidelity mutant R283K expected to interact with the templating base. Replication bypass investigations were further extended to include analyses of HIV-1 reverse transcriptase, and these studies revealed patterns of inhibition very similar to that observed for pol β.


Donor CD4+ Foxp3+ regulatory T cells are necessary for posttransplantation cyclophosphamide-mediated protection against GVHD in mice.
Posttransplantation cyclophosphamide (PTCy) is an effective prophylaxis against graft-versus-host disease (GVHD). However, it is unknown whether PTCy works singularly by eliminating alloreactive T cells via DNA alkylation or also by restoring the conventional (Tcon)/regulatory (Treg) T-cell balance. We studied the role of Tregs in PTCy-mediated GVHD prophylaxis in murine models of allogeneic blood or marrow transplantation (alloBMT). In 2 distinct MHC-matched alloBMT models, infusing Treg-depleted allografts abrogated the GVHD-prophylactic activity of PTCy. Using allografts in which Foxp3(+) Tregs could be selectively depleted in vivo, either pre- or post-PTCy ablation of donor thymus-derived Tregs (tTregs) abolished PTCy protection against GVHD. PTCy treatment was associated with relative preservation of donor Tregs. Experiments using combinations of Foxp3(-) Tcons and Foxp3(+) Tregs sorted from different Foxp3 reporter mice indicated that donor Treg persistence after PTCy treatment was predominantly caused by survival of functional tTregs that retained Treg-specific demethylation and also induction of peripherally derived Tregs. Finally, adoptive transfer of tTregs retrieved from PTCy-treated chimeras rescued PTCy-treated, Treg-depleted recipients from lethal GVHD. Our findings indicate that PTCy-mediated protection against GVHD is not singularly dependent on depletion of donor alloreactive T cells but also requires rapidly recovering donor Tregs to initiate and maintain alloimmune regulation.


Hostile attributional bias and aggressive behavior in global context.
We tested a model that children's tendency to attribute hostile intent to others in response to provocation is a key psychological process that statistically accounts for individual differences in reactive aggressive behavior and that this mechanism contributes to global group differences in children's chronic aggressive behavior problems. Participants were 1,299 children (mean age at year 1 = 8.3 y; 51% girls) from 12 diverse ecological-context groups in nine countries worldwide, followed across 4 y. In year 3, each child was presented with each of 10 hypothetical vignettes depicting an ambiguous provocation toward the child and was asked to attribute the likely intent of the provocateur (coded as benign or hostile) and to predict his or her own behavioral response (coded as nonaggression or reactive aggression). Mothers and children independently rated the child's chronic aggressive behavior problems in years 2, 3, and 4. In every ecological group, in those situations in which a child attributed hostile intent to a peer, that child was more likely to report that he or she would respond with reactive aggression than in situations when that same child attributed benign intent. Across children, hostile attributional bias scores predicted higher mother- and child-rated chronic aggressive behavior problems, even controlling for prior aggression. Ecological group differences in the tendency for children to attribute hostile intent statistically accounted for a significant portion of group differences in chronic aggressive behavior problems. The findings suggest a psychological mechanism for group differences in aggressive behavior and point to potential interventions to reduce aggressive behavior.


A prospective study of triglyceride level, low-density lipoprotein particle diameter, and risk of myocardial infarction.
To test whether a predominance of small, dense low-density lipoprotein (LDL) particles and elevated triglyceride levels are independent risk factors for myocardial infarction (MI). Nested case-control study with prospectively collected samples. Prospective cohort study. Blood samples were collected at baseline (85% nonfasting samples) from 14916 men aged 40 to 84 years in the Physicians' Health Study. Myocardial infarction diagnosed during 7 years of follow-up. Cases (n=266) had a significantly smaller LDL diameter (mean [SD], 25.6 [0.9] nm) than did controls (n=308) matched on age and smoking (mean [SD], 25.9 [8] nm; P<.001). Cases also had higher median triglyceride levels (1.90 vs 1.49 mmol/L [168 vs 132 mg/dL]; P<.001). The LDL diameter had a high inverse correlation with triglyceride level (r=-0.71), and a high direct correlation with high-density lipoprotein cholesterol (HDL-C) level (r=0.60). We observed a significant multiplicative interaction between triglyceride and total cholesterol (TC) levels (P=.01). After simultaneous adjustment for lipids and a variety of coronary risk factors, LDL particle diameter was no longer a statistically significant risk indicator, with a relative risk (RR) of 1.09 (95% confidence interval [CI], 0.85-1.40) per 0.8-nm decrease. However, triglyceride level remained significant with an RR of 1.40 (95% CI, 1.10-1.77) per 1.13 mmol/L (100-mg/dL) increase. The association between triglyceride level and MI risk appeared linear across the distribution; men in the highest quintile had a risk about 2.5 times that of those in the lowest quintile. The TC level, but not HDL-C level, also remained significant, with an RR of 1.80 (95% CI, 1.44-2.26) per 1.03-mmol/L (40-mg/dL) increase. These findings indicate that nonfasting triglyceride levels appear to be a strong and independent predictor of future risk of MI, particularly when the total cholesterol level is also elevated. In contrast, LDL particle diameter is associated with risk of MI, but not after adjustment for triglyceride level. Increased triglyceride level, small LDL particle diameter, and decreased HDL-C levels appear to reflect underlying metabolic perturbations with adverse consequences for risk of MI; elevated triglyceride levels may help identify high-risk individuals.


Identification of genes involved in the sequestration of iron in mycobacteria: the ferric exochelin biosynthetic and uptake pathways.
Mycobacteria produce two siderophores, mycobactin and exochelin. Mycobacterium smegmatis mutants defective in the production of exochelin were isolated using agar medium containing chrome azural S for the sensitive detection of siderophores. Cosmids of genomic libraries from M. smegmatis and Mycobacterium bovis BCG were screened for complementation of the mutation. Subcloning of the complementing M. smegmatis cosmid identified a 4.3 kb fragment required for restoring exochelin biosynthesis. Sequencing of the DNA revealed four open reading frames whose genes were named fxuA, fxuB, fxuC, and fxbA. FxuA, FxuB, and FxuC share amino acid sequence homology with the iron permeases FepG, FepC, and FepD from Escherichia coli, respectively. Deletion analysis identified fxbA as the gene required to restore exochelin biosynthesis in our mutant. Although fxbA does not share amino acid sequence homology with any of the published sequences for siderophore biosynthetic genes, it does show limited homology with the phosphoribosylglycineamide formyltransferases (GAR enzymes) and methionyl-tRNA formyltransferase over a limited region of the sequence, suggesting that fxbA may code for an enzyme which adds a formyl group in the synthesis of exochelin. A fusion of fxbA with the E. coli lacZ gene demonstrated regulation of gene expression by iron. The ability of M. smegmatis mutants to produce mycobactin in the absence of exochelin supports the hypothesis that exochelin is not a precursor of mycobactin and suggests that the siderophores have independent biosynthetic pathways. In addition, complementation of the M. smegmatis mutant with the BCG cosmid restored the synthesis of the M. smegmatis exochelin, demonstrating the use of M. smegmatis as a surrogate host for analysis of exochelins from slow-growing mycobacteria.


The effects of simulated obstructive apnea and hypopnea on arrhythmic potential in healthy subjects.
Preliminary evidence supports an association between OSA and cardiac dysrhythmias. Negative intrathoracic pressure, as occurring during OSA, may provoke cardiac dysrhythmias. Thus, we aimed to study the acute effects of simulated apnea and hypopnea on arrhythmic potential and measures of cardiac repolarization [QT(C) and T (peak) to T (end) intervals [TpTec]) in humans. In 41 healthy volunteers, ECG was continuously recorded prior, during and after simulated obstructive hypopnea (inspiration through a threshold load), simulated apnea (Mueller maneuver), end-expiratory central apnea and normal breathing in randomized order. The number of subjects with premature beats was significantly higher during inspiration through a threshold load (n = 7), and the Mueller maneuver (n = 7) compared to normal breathing (n = 0) (p = 0.008 for all comparisons), but not during end-expiratory central apnea (n = 3, p = 0.125). Inspiration through a threshold load was associated with a non-significant mean (SD) increase of the QT(C) interval [+5.4 (22.4) ms, 95 %CI -1.7 to +12.4 ms, p = 0.168] and a significant increase of the TpTcc interval [+3.7 (8.9) ms, 95 %CI +0.9 to +6.6 ms, p = 0.010]. The Mueller maneuver induced a significant increase of the QT(C) interval [+8.3 (23.4) ms, 95 %CI 0.9 to +15.6 ms, p = 0.035] and the TpTec interval (+4.2 (8.2) ms, 95 %CI +1.6 to +6.8 ms, p = 0.002). There were no significant changes of the QT(C) and TpTec intervals during central end-expiratory apnea. These data indicate that simulated obstructive apnea and hypopnea are associated with an increase of premature beats and prolongation of QT(C) and TpTec intervals. Therefore, negative intrathoracic pressure changes may be a contributory mechanism for the association between OSA and cardiac dysrhythmias.


Neurology out-patients with symptoms unexplained by disease: illness beliefs and financial benefits predict 1-year outcome.
Patients whose symptoms are 'unexplained by disease' often have a poor symptomatic outcome after specialist consultation, but we know little about which patient factors predict this. We therefore aimed to determine predictors of poor subjective outcome for new neurology out-patients with symptoms unexplained by disease 1 year after the initial consultation. The Scottish Neurological Symptom Study was a 1-year prospective cohort study of patients referred to secondary care National Health Service neurology clinics in Scotland (UK). Patients were included if the neurologist rated their symptoms as 'not at all' or only 'somewhat explained' by organic disease. Patient-rated change in health was rated on a five-point Clinical Global Improvement (CGI) scale ('much better' to 'much worse') 1 year later. The 12-month outcome data were available on 716 of 1144 patients (63%). Poor outcome on the CGI ('unchanged', 'worse' or 'much worse') was reported by 482 (67%) out of 716 patients. The only strong independent baseline predictors were patients' beliefs [expectation of non-recovery (odds ratio [OR] 2.04, 95% confidence interval [CI] 1.40-2.96), non-attribution of symptoms to psychological factors (OR 2.22, 95% CI 1.51-3.26)] and the receipt of illness-related financial benefits (OR 2.30, 95% CI 1.37-3.86). Together, these factors predicted 13% of the variance in outcome. Of the patients, two-thirds had a poor outcome at 1 year. Illness beliefs and financial benefits are more useful in predicting poor outcome than the number of symptoms, disability and distress.


Translational regulation of the DOUBLETIME/CKIδ/ε kinase by LARK contributes to circadian period modulation.
The Drosophila homolog of Casein Kinase I δ/ε, DOUBLETIME (DBT), is required for Wnt, Hedgehog, Fat and Hippo signaling as well as circadian clock function. Extensive studies have established a critical role of DBT in circadian period determination. However, how DBT expression is regulated remains largely unexplored. In this study, we show that translation of dbt transcripts are directly regulated by a rhythmic RNA-binding protein (RBP) called LARK (known as RBM4 in mammals). LARK promotes translation of specific alternative dbt transcripts in clock cells, in particular the dbt-RC transcript. Translation of dbt-RC exhibits circadian changes under free-running conditions, indicative of clock regulation. Translation of a newly identified transcript, dbt-RE, is induced by light in a LARK-dependent manner and oscillates under light/dark conditions. Altered LARK abundance affects circadian period length, and this phenotype can be modified by different dbt alleles. Increased LARK delays nuclear degradation of the PERIOD (PER) clock protein at the beginning of subjective day, consistent with the known role of DBT in PER dynamics. Taken together, these data support the idea that LARK influences circadian period and perhaps responses of the clock to light via the regulated translation of DBT. Our study is the first to investigate translational control of the DBT kinase, revealing its regulation by LARK and a novel role of this RBP in Drosophila circadian period modulation.


Cascade of HIV care and population viral suppression in a high-burden region of Kenya.
Direct measurement of antiretroviral treatment (ART) program indicators essential for evidence-based planning and evaluation - especially HIV incidence, population viral load, and ART eligibility - is rare in sub-Saharan Africa. To measure key indicators in rural western Kenya, an area with high HIV burden, we conducted a population survey in September to November 2012 via multistage cluster sampling, recruiting everyone aged 15-59 years living in 3330 randomly selected households. Consenting individuals were interviewed and tested for HIV at home. Participants testing positive were assessed for CD4 cell count and viral load, and their infections classified as either recent or long term based on Limiting Antigen Avidity assays. HIV-negative participants were tested by nucleic acid amplification to detect acute infections. Of 6833 household members eligible for the study, 6076 (94.7% of all women and 81.0% of men) agreed to participate. HIV prevalence and incidence were 24.1% [95% confidence interval [CI] 23.0-25.2] and 1.9 new cases/100 person-years (95% CI 1.1-2.7), respectively. Among HIV-positive participants, 59.4% (95% CI 56.8-61.9) were previously diagnosed, 53.1% (95% CI 50.5-55.7) were receiving care, and 39.7% (95% CI 37.1-42.4) had viral load less than 1000 copies/ml. Applying 2013 WHO recommendations for ART initiation increased the proportion of ART-eligible people from 60.0% (based on national guidelines in place during the survey; 95% CI 57.3-62.7) to 82.0% (95% CI 79.5-84.5). Among HIV-positive people not receiving ART, viral load increased with decreasing CD4 cell count (500-749 vs. ≥750 cells/μl, adjusted mean difference, 0.40 log10 copies/ml, 95% CI 0.20-0.60, P < 0.01). This study demonstrates how population-level data can help optimize HIV programs. Based on these results, new regional programs are prioritizing diagnosis and expanding ART eligibility, key steps to reach undetectable viral load.


Brugada syndrome.
As a clinical entity the Brugada syndrome has existed since 1992 and has been associated with a high risk of sudden cardiac death predominately in younger males. Patients can present with symptoms (ie syncope, palpitations, aborted sudden cardiac death) and asymptomatically. Its three characteristic electrocardiographic patterns can occur both spontaneously or after provocation with sodium channel-blocking agents. Risk stratification and the need for treatment depend on the patient's symptoms, electrocardiography, family history, and electrophysiological inducibility to discern if treatment by implantable cardioverter defibrillator, the only effective treatment to date, is appropriate. This review focuses on Brugada syndrome and various aspects of the disease including proposed mechanisms, epidemiology, clinical presentations, genetics, diagnosis, risk stratification, and treatment options.


Bovine milk RNases modulate pro-inflammatory responses induced by nucleic acids in cultured immune and epithelial cells.
Activation of innate immune receptors by exogenous substances is crucial for the detection of microbial pathogens and a subsequent inflammatory response. The inflammatory response to microbial lipopolysaccharide via Toll-like receptor 4 (TLR4) is facilitated by soluble accessory proteins, but the role of such proteins in the activation of other pathogen recognition receptors for microbial nucleic acid is not well understood. Here we demonstrate that RNase4 and RNase5 purified from bovine milk bind to Salmonella typhimurium DNA and stimulate pro-inflammatory responses induced by nucleic acid mimetics and S. typhimurium DNA in an established mouse macrophage cell culture model, RAW264.7, as well as in primary bovine mammary epithelial cells. RNase4 and 5 also modulated pro-inflammatory signalling in response to nucleic acids in bovine peripheral blood mononuclear cells, although producing a distinct response. These results support a role for RNase4 and RNase5 in mediating inflammatory signals in both immune and epithelial cells, involving mechanisms that are cell-type specific.


Enhancement of innate immunity in rainbow trout (Oncorhynchus mykiss Walbaum) associated with dietary intake of carotenoids from natural products.
The effects of orally administered carotenoids from natural sources on the non-specific defense mechanisms of rainbow trout were evaluated in a nine-week feeding trial. Fish were fed four diets containing either beta-carotene or astaxanthin at 100 and 200 mg kg-1 from the marine algae Dunaliella salina and red yeast Phaffia rhodozyma, respectively, and a control diet containing no supplemented carotenoids. Specific growth rate and feed:gain ratio were not affected by dietary carotenoid supplementation. Among the humoral factors, serum alternative complement activity increased significantly in all carotenoid supplemented groups when compared to the control. On the other hand, serum lysozyme activity increased in the Dunaliella group but not in the Phaffia group, whereas plasma total immunoglobulin levels were not altered by the feeding treatments. As for the cellular responses, the superoxide anion production from the head kidney remained unchanged while the phagocytic rate and index in all supplemented groups were significantly higher than those of the control. These findings demonstrate that dietary carotenoids from both D. salina and P. rhodozyma can modulate some of the innate defense mechanisms in rainbow trout.


Nutrient removal in hybrid constructed wetlands: spatial-seasonal variation and the effect of vegetation.
Constructed wetlands (CWs) are an aesthetic and sustainable form to treat wastewater, however, their performance can be increased by improving a number of factors. The pilot-scale hybrid constructed wetland (CW) system was the combination of constructed floating treatment wetlands (CFWs) and horizontal subsurface flow constructed wetlands (HSFCWs); operated for a year and covered all seasons. The research was conducted to investigate the performance of the CW system regarding water depth, spatial, and seasonal removal of pollutants. Nine economical plants species were selected and divided into four groups to grow in CW-I to CW-IV, respectively. Removal increased along the bed and most of the total phosphorus (TP) removal occurred in the second bed, whereas total nitrogen (TN) and ammonium (NH4) removal were associated with the plant root system and biomass. Optimum removal of nutrients with respect to water depth was at 35 cm. TN and NH4 removal patterns were similar in different CWs. TN and NH4 removal were higher during summer compared to winter; only CW-IV showed the opposite trend.


Cardiovascular effects of the alpha2-adrenergic receptor agonist medetomidine in clinically normal cats anesthetized with isoflurane.
To assess the cardiovascular effects of the alpha2-adrenergic receptor agonist medetomidine in healthy cats anesthetized with 2% isoflurane. 11 clinically normal cats. Cats were anesthetized with isoflurane, and catheters were inserted for measurement of aortic, left ventricular, and right atrial pressures. For data collection, end-tidal isoflurane concentration was reduced to 2%, and end-tidal CO2 was maintained at 35 to 40 mm of Hg by use of positive-pressure ventilation. After measurement of baseline data, medetomidine (0.01 mg/kg of body weight, i.m.) was administered and data were collected continuously for 75 minutes. At the end of data collection, incisions were closed and cats were allowed to recover from anesthesia. Medetomidine significantly increased mean arterial pressure and systemic vascular resistance. The increase in mean arterial pressure was maximal at 17.8 +/- 7 minutes after medetomidine administration. Medetomidine also increased left ventricular peak systolic pressure, left ventricular end diastolic pressure, and right atrial pressure. Medetomidine significantly decreased heart rate and mean aortic flow. The low dosage of medetomidine (0.01 mg/kg, i.m.) promoted severe vasoconstriction in isoflurane-anesthetized cats, and resulted in sustained increases in left ventricular preload and afterload.


Ultraviolet Irradiation of Skin Alters the Faecal Microbiome Independently of Vitamin D in Mice.
Reduced sunlight exposure has been associated with an increased incidence of Crohn's disease and ulcerative colitis. The effect of ultraviolet radiation (UVR) on the faecal microbiome and susceptibility to colitis has not been explored. C57Bl/6 female mice were fed three different vitamin D-containing diets for 24 days before half of the mice in each group were UV-irradiated (1 kJ/m²) for each of four days, followed by twice-weekly irradiation of shaved dorsal skin for 35 days. Faecal DNA was extracted and high-throughput sequencing of the 16S RNA gene performed. UV irradiation of skin was associated with a significant change in the beta-diversity of faeces compared to nonirradiated mice, independently of vitamin D. Specifically, members of phylum Firmicutes, including Coprococcus, were enriched, whereas members of phylum Bacteroidetes, such as Bacteroidales, were depleted. Expression of colonic CYP27B1 increased by four-fold and IL1β decreased by five-fold, suggesting a UVR-induced anti-inflammatory effect. UV-irradiated mice, however, were not protected against colitis induced by dextran sodium sulfate (DSS), although distinct faecal microbiome differences were documented post-DSS between UV-irradiated and nonirradiated mice. Thus, skin exposure to UVR alters the faecal microbiome, and further investigations to explore the implications of this in health and disease are warranted.


Hepatitis C virus induces CD81 and claudin-1 endocytosis.
Hepatitis C virus (HCV) leads to progressive liver disease and hepatocellular carcinoma. Current treatments are only partially effective, and new therapies targeting viral and host pathways are required. Virus entry into a host cell provides a conserved target for therapeutic intervention. Tetraspanin CD81, scavenger receptor class B member I, and the tight-junction proteins claudin-1 and occludin have been identified as essential entry receptors. Limited information is available on the role of receptor trafficking in HCV entry. We demonstrate here that anti-CD81 antibodies inhibit HCV infection at late times after virus internalization, suggesting a role for intracellular CD81 in HCV infection. Several tetraspanins have been reported to internalize via motifs in their C-terminal cytoplasmic domains; however, CD81 lacks such motifs, leading several laboratories to suggest a limited role for CD81 endocytosis in HCV entry. We demonstrate CD81 internalization via a clathrin- and dynamin-dependent process, independent of its cytoplasmic domain, suggesting a role for associated partner proteins in regulating CD81 trafficking. Live cell imaging demonstrates CD81 and claudin-1 coendocytosis and fusion with Rab5 expressing endosomes, supporting a role for this receptor complex in HCV internalization. Receptor-specific antibodies and HCV particles increase CD81 and claudin-1 endocytosis, supporting a model wherein HCV stimulates receptor trafficking to promote particle internalization.


Selection of maize inbred lines and gene expression for resistance to ear rot.
In recent years, there has been a large incidence of fungi causing "ear rot" in maize in Brazil, the main fungus being Fusarium verticillioides. The most efficient and competitive alternative for control of this disease consists of using maize hybrids resistant to this pathogen. Thus, the aims of this study were to analyze the genetic variability of maize inbred lines in regard to resistance to ear rot to observe if there is a maternal effect to resistance to ear rot, to study genetic control of the traits evaluated in hybrids originating from inbred lines of the maize breeding program at the Agriculture Department of Universidade Federal de Lavras (Lavras, MG, Brazil), and characterize the gene expression pattern related to the plant defense mechanism against F. verticillioides. High genetic availability was observed for resistance to this disease among the inbred lines evaluated. Considering combined diallel analysis, it was observed that the mean square of general combining ability (GCA) was not significant for the characteristic under study. However, specific combining ability (SCA) was significant, which indicates the predominance of non-additive effects involved in control of the characteristic for the population evaluated. A maternal effect was not observed for the characteristic of ear rot resistance in this study. Inbred lines 22, 58, and 91 showed potential for use in breeding programs aiming at resistance to F. verticillioides. Only two genes, LOX8 and Hsp82, had a satisfactory result that was able to be related to a plant defense mechanism when there is ear rot infection, though expression of these genes was observed in only one susceptible genotype. Thus, the genes LOX8 and Hsp82 are potential molecular markers for selection of maize inbred lines resistant to F. verticillioides.


Gender, living arrangements, and social circumstances as determinants of entry into and exit from long-term institutional care at older ages: a 6-year follow-up study of older Finns.
Due to population aging, the need for long-term institutional care is increasing. We study the potentially modifiable sociodemographic factors that affect the rate of entry into and exit from long-term care. A 40% sample from the population registration data of Finns aged 65 and older living in private households at the end of 1997 (n = 280,722) was followed for first entry into (n = 35,926) and subsequent exit -- due to death or return to the community -- from long-term institutional care until the end of 2003. Being female, old, living alone, and of low socioeconomic status increased the risk for entering long-term care. Exit was affected by the same factors, but the associations were weaker and, with the exception of age, in the opposite direction. Women's higher risk for entry was due to older age and greater likelihood of living alone. The effects of living arrangements and socioeconomic factors on entry were stronger among men and were attenuated after adjustment for each other and for health status. The mean duration of care was 1,064 days among women and 686 among men. Gender, age, living arrangements, and socioeconomic status are major determinants of institutional residence. Women and certain other population groups, e.g., those living alone, are likely to spend a longer time in institutional care because of higher rates of entry and lower rates of exit. These results have implications for the financing of long-term care and for targeting of interventions aimed at delaying it.


Human Werner helicase interacting protein 1 (WRNIP1) functions as a novel modulator for DNA polymerase delta.
Human WRNIP1, a Werner DNA helicase interacting protein 1, was expressed in insect cells and E. coli. The purified protein behaved as a homo-oligomeric complex with a native molecular mass indicative of an octamer, and the complex copurified with an ATPase activity that was stimulated by double-stranded DNA ends. As suggested by genetic studies of budding yeast WRNIP1/Mgs1, the purified human WRNIP1 complex interacted physically with human DNA polymerase delta (pol delta), stimulating its DNA synthesis activity more than fivefold in the presence or absence of proliferating cell nuclear antigen. Analysis of reaction products demonstrated the stimulation to be partly due to an increased processivity of pol delta but more importantly to an increase in its initiation frequency. Addition of ATP to reactions partially suppressed stimulation by WRNIP1. Furthermore, a mutant WRNIP1 lacking ATPase activity could stimulate pol delta normally but was insensitive to suppression by ATP. These results indicate that WRNIP1 functions as a modulator for initiation or restart events during pol delta-mediated DNA synthesis and that its ATPase activity is utilized to sense DNA ends and to regulate the extent of stimulation.


Determination of [11C]rifampin pharmacokinetics within Mycobacterium tuberculosis-infected mice by using dynamic positron emission tomography bioimaging.
Information about intralesional pharmacokinetics (PK) and spatial distribution of tuberculosis (TB) drugs is limited and has not been used to optimize dosing recommendations for new or existing drugs. While new techniques can detect drugs and their metabolites within TB granulomas, they are invasive, rely on accurate resection of tissues, and do not capture dynamic drug distribution in the tissues of interest. In this study, we assessed the in situ distribution of (11)C-labeled rifampin in live, Mycobacterium tuberculosis-infected mice that develop necrotic lesions akin to human disease. Dynamic positron emission tomography (PET) imaging was performed over 60 min after injection of [(11)C]rifampin as a microdose, standardized uptake values (SUV) were calculated, and noncompartmental analysis was used to estimate PK parameters in compartments of interest. [(11)C]rifampin was rapidly distributed to all parts of the body and quickly localized to the liver. Areas under the concentration-time curve for the first 60 min (AUC0-60) in infected and uninfected mice were similar for liver, blood, and brain compartments (P > 0.53) and were uniformly low in brain (10 to 20% of blood values). However, lower concentrations were noted in necrotic lung tissues of infected mice than in healthy lungs (P = 0.03). Ex vivo two-dimensional matrix-assisted laser desorption ionization (MALDI) imaging confirmed restricted penetration of rifampin into necrotic lung lesions. Noninvasive bioimaging can be used to assess the distribution of drugs into compartments of interest, with potential applications for TB drug regimen development.


Clinical and genetic factors associated with progression of geographic atrophy lesions in age-related macular degeneration.
Worldwide, age-related macular degeneration (AMD) is a serious threat to vision loss in individuals over 50 years of age with a pooled prevalence of approximately 9%. For 2020, the number of people afflicted with this condition is estimated to reach 200 million. While AMD lesions presenting as geographic atrophy (GA) show high inter-individual variability, only little is known about prognostic factors. Here, we aimed to elucidate the contribution of clinical, demographic and genetic factors on GA progression. Analyzing the currently largest dataset on GA lesion growth (N = 388), our findings suggest a significant and independent contribution of three factors on GA lesion growth including at least two genetic factors (ARMS2_rs10490924 [P < 0.00088] and C3_rs2230199 [P < 0.00015]) as well as one clinical component (presence of GA in the fellow eye [P < 0.00023]). These correlations jointly explain up to 7.2% of the observed inter-individual variance in GA lesion progression and should be considered in strategy planning of interventional clinical trials aimed at evaluating novel treatment options in advanced GA due to AMD.


Safety and efficacy of angiotensin converting enzyme inhibitors and angiotensin receptor blockers in chronic allograft injury.
Angiotensin II plays a crucial role in the development of chronic allograft injury (CAI). Clinical experience with angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blockade (ARBS) in CAI has unfortunately been limited. We carried out a prospective one year single center case controlled study to analyze the effect of ACEI /ARBS on the progression of CAI and in decreasing proteinuria. One hundred patients with CAI were evaluated. Of the 100 patients, 50 were selected to receive ACEI/ ARBS (group 1) and 50 managed without ACEI/ARBS (group 2). Their remaining management was similar in both the groups. Patients with hyperkalemia, history of allergic reactions, ACEI/ARBS intake and pregnancy were excluded. Average time for development of CAI was 19.6 ± 12.7 months in group 1 vs. 20.8 ± 12.8 in group 2. In group 1, mean systolic/diastolic BP was 136/82 mmHg at the time of establishment of CAI and 124/76 mmHg at the end of one year, and in group 2, it was 138/86 mmHg vs. 126/80 mmHg, respectively. Mean glomerular filtration rate (GFR) was 48.78 ± 13.4 in the former vs. 44.23 ± 8.14 in the latter. ACEI/ARBS administration was associated with stabilization of serum creatinine. GFR was maintained up to one year after CAI. Group 1 had a decrease in proteinuria by 1.41 g/day as compared with group 2 with proteinuria of 0.83 g/day. ACEI/ARBS administration is beneficial in CAI for BP control and significant decrease in proteinuria along with the stabilization of graft function.


Pulmonary involvement in rheumatoid arthritis: evaluation by radiography and spirometry.
To determine whether simple diagnostic methods can yield relevant disease information in patients with rheumatoid arthritis (RA). Patients with RA were randomly selected for inclusion in a cross-sectional study involving clinical evaluation of pulmonary function, including pulse oximetry (determination of SpO2, at rest), chest X-ray, and spirometry. A total of 246 RA patients underwent complete assessments. Half of the patients in our sample reported a history of smoking. Spirometry was abnormal in 30% of the patients; the chest X-ray was abnormal in 45%; and the SpO2 was abnormal in 13%. Normal chest X-ray, spirometry, and SpO2 were observed simultaneously in only 41% of the RA patients. A history of smoking was associated with abnormal spirometry findings, including evidence of obstructive or restrictive lung disease, and with abnormal chest X-ray findings, as well as with an interstitial pattern on the chest X-ray. Comparing the patients in whom all test results were normal (n = 101) with those in whom abnormal test results were obtained (n = 145), we found a statistically significant difference between the two groups, in terms of age and smoking status. Notably, there were signs of airway disease in nearly half of the patients with minimal or no history of tobacco smoke exposure. Pulmonary involvement in RA can be identified through the use of a combination of diagnostic methods that are simple, safe, and inexpensive. Our results lead us to suggest that RA patients with signs of lung involvement should be screened for lung abnormalities, even if presenting with no respiratory symptoms.


The role of trust and hope in antipsychotic medication reviews between GPs and service users a realist review.
Increasing number of service users diagnosed with schizophrenia and psychosis are being discharged from specialist secondary care services to primary care, many of whom are prescribed long-term antipsychotics. It is unclear if General Practitioners (GPs) have the confidence and experience to appropriately review and adjust doses of antipsychotic medication without secondary care support. To explore barriers and facilitators of conducting antipsychotic medication reviews in primary care for individuals with no specialist mental health input. Realist review in general practice settings. A realist review has been conducted to synthesise evidence on antipsychotic medication reviews conducted in primary care with service users diagnosed with schizophrenia or psychosis. Following initial scoping searches and discussions with stakeholders, a systematic search and iterative secondary searches were conducted. Articles were systematically screened and analysed to develop a realist programme theory explaining the contexts (C) and mechanisms (M) which facilitate or prevent antipsychotic medication reviews (O) in primary care settings, and the potential outcomes of medication reviews. Meaningful Antipsychotic medication reviews may not occur for individuals with only primary care medical input. Several, often mutually reinforcing, mechanisms have been identified as potential barriers to conducting such reviews, including low expectations of recovery for people with severe mental illness, a perceived lack of capability to understand and participate in medication reviews, linked with a lack of information shared in appointments between GPs and Service Users, perceived risk and uncertainty regarding antipsychotic medication and illness trajectory. The review identified reciprocal and reinforcing stereotypes affecting both GPs and service users. Possible mechanisms to counteract these barriers are discussed, including realistic expectations of medication, and the need for increased information sharing and trust between GPs and service users.


Strong migratory connectivity and seasonally shifting isotopic niches in geographically separated populations of a long-distance migrating songbird.
Whether migratory animals use similar resources during continental-scale movements that characterize their annual cycles is highly relevant to both individual performances and population dynamics. Direct knowledge of the locations and resources used by migrants during non-breeding is generally scarce. Our goal was to estimate migratory connectivity of a small Palaearctic long-distance migrant, the common nightingale Luscinia megarhynchos, and to compare resources used in non-breeding areas with resources used at the breeding grounds. We tracked individuals of three geographically separated populations and characterised their stable isotope niches during breeding and non-breeding over 2 years. Individuals spent the non-breeding period in population-specific clusters from west to central Africa, indicating strong migratory connectivity at the population level. Irrespective of origin, their isotopic niches were surprisingly similar within a particular period, although sites of residence were distant. However, niche characteristics differed markedly between breeding and non-breeding periods, indicating a consistent seasonal isotopic niche shift in the sampled populations. Although nightingales of distinct breeding populations migrated to different non-breeding areas, they chose similar foraging conditions within specific periods. However, nightingales clearly changed resource use between breeding and non-breeding periods, indicating adaptations to changes in food availability.


On the Ca2+-permeability of neurons and glia.
Fractions enriched in pinched-off nerve terminals and astrocytic glial cells were used to analyse the permeability of Ca++ of the two membranes. Three experimental models were used to illustrate a principle difference of the excitatory versus the no-excitatory cell membrane, with respect to Ca-permeability. The effect of an increased [Ca++] on 86Rb+ and 3H-GABA transport was measured in medium containing low and high [K+]. The possibility of GABA stimulation of release of preaccumulated 45Ca+4 with low and high [K+] was compared in neurons and glia. Finally, the effect of depolarizing [K+] on the transmembranal Ca++-gradient was measured by comparing the efficacy of the Ca-ionophore A23187 to depolarize or to inhibit the 3H-GABA uptake at these different [K+]. The data essentially confirms the picture of a potential dependent Ca++-permeability in the neuron, while the permeability of the glial cells seems a "true" constant. It might be relevant to suggest the astrocyte a role as a "Ca-buffer" with possibilities to control extracellular Ca+4 in cases of hyperactivity, this in analogy with what has been suggested for K+.


Evaluation of the role of Shiga and Shiga-like toxins in mediating direct damage to human vascular endothelial cells.
Infection with Shiga toxin- and Shiga-like toxin-producing strains of Shigella dysenteriae and Escherichia coli, respectively, can progress to the hemolytic-uremic syndrome. It has been hypothesized that circulating Shiga toxin, Shiga-like toxins, and endotoxins may contribute to the disease by directly damaging glomerular endothelial cells. The effects of these toxins on HeLa, Vero, and human vascular endothelial cells (EC) were examined. Confluent EC were sensitive to Shiga toxin but were at least 10(6)-fold less sensitive to the toxins than were Vero cells. Shiga toxin was the predominant cytotoxic factor. Lipopolysaccharides were not cytotoxic and did not augment Shiga toxin-mediated toxicity. Lower doses of Shiga toxin caused cytotoxicity when coincubated with tumor necrosis factor. The relative resistance of EC to Shiga toxin and Shiga-like toxins may be due to reduced toxin binding, as low levels of globotriaosylceramide (Gb3), the toxin-specific receptor, were found in EC membranes.