Comparative effectiveness of exercise electrocardiography versus exercise echocardiography in women presenting with suspected coronary artery disease: a randomized study.
There is a paucity of randomized diagnostic studies in women with suspected coronary artery disease (CAD). This study sought to assess the relative value of exercise stress echocardiography (ESE) compared with exercise electrocardiography (Ex-ECG) in women with CAD. Accordingly, 416 women with no prior CAD and intermediate probability of CAD (mean pre-test probability 41%), were randomized to undergo either Ex-ECG or ESE. The primary endpoints were the positive predictive value (PPV) for the detection of significant CAD and downstream resource utilization. The PPV of ESE and Ex-ECG were 33% and 30% (P = 0.87), respectively for the detection of CAD. There were similar clinic visits (36 vs. 29, P = 0.44) and emergency visits with chest pain (28 vs. 25, P = 0.55) in the Ex-ECG and ESE arms, respectively. At 2.9 years, cardiac events were 6 Ex-ECG vs. 3 ESE, P = 0.31. Although initial diagnosis costs were higher for ESE, more women underwent further CAD testing in the Ex-ECG arm compared to the ESE arm (37 vs. 17, P = 0.003). Overall, there was higher downstream resource utilization (hospital attendances and investigations) in the Ex-ECG arm (P = 0.002). Using National Health Service tariffs 2020/21 (British pounds) the cumulative diagnostic costs were 7.4% lower for Ex-ECG compared with ESE, but this finding is sensitive to the cost differential between ESE and Ex-ECG. In intermediate-risk women who are able to exercise, Ex-ECG had similar efficacy to an ESE strategy, with higher resource utilization whilst providing cost savings.


Remote-only monitoring for patients with cardiac implantable electronic devices: a before-and-after pilot study.
Outcomes for patients with cardiac implantable electronic devices are better when follow-up incorporates remote monitoring technology in addition to in-clinic visits. For patients with implantable devices, we sought to determine the feasibility, safety and associated health care utilization of remote-only follow-up, along with its effects on patients' quality of life and costs. This multicentre before-and-after pilot study involved patients with new or existing pacemakers or implantable cardioverter defibrillators. The "before" phase of the study spanned the period October 2015 to February 2017; the "after" phase spanned the period October 2016 to February 2018. The exposure was remote-only follow-up in combination with Remote View, a service that facilitates access to device data, allowing device settings to be viewed remotely to facilitate remote programming. Outcomes at 12 months were feasibility (adherence to remote monitoring), safety (rate of adverse events) and health care utilization (remote and in-clinic appointments). We also assessed quality of life, using 3 validated scales, and costs, taking into account both health care system and patient costs. A total of 176 patients were enrolled. Adherence (defined as at least 1 successful remote transmission during follow-up) was 87% over a mean follow-up of 11.7 (standard deviation 2.2) months. There was a reduction in in-clinic visits at specialized sites among patients with both implantable defibrillators (26 v. 5, p < 0.001, n = 48) and pacemakers (42 v. 10, p < 0.001, n = 51). There was no significant change in visits to community sites for patients with defibrillators (13 v. 17, p = 0.3, n = 48). The composite rate of death, stroke, cardiovascular hospitalization and device-related hospitalization was 7% (n = 164). No adverse events were linked to the intervention. There was no change in quality-of-life scales between baseline and 12 months. Health care costs were reduced by 31% for patients with defibrillators and by 44% for those with pacemakers. This pilot study showed the feasibility of remote-only follow-up, with no increase in adverse clinical outcomes and no effect on quality of life, but with reductions in costs and health care utilization. These results support progression to a larger-scale study of whether superior effectiveness and reduced cost can be achieved, with preservation of safety, through use of remote-only follow-up. ClinicalTrials.gov, no. NCT02585817.


Analgesic drugs and the gut - a reciprocal relationship.
Analgesic drugs, as well as providing pain relief, can cause a range of other symptoms and side effects, most notably on the gastrointestinal system. Conversely, gastrointestinal disease will often require analgesia, and this can be complicated by the fact that the gut is the site of absorption of oral drugs. This paper discusses some of the effects of common oral analgesic drugs on the gastrointestinal tract and their role in managing some of the most common, nonmalignant, chronic gastrointestinal disorders in adults.


Patients who suffer a first atherosclerotic cardiovascular event while taking statins are often far off of lipid targets.
Despite considerable evidence that lipid-lowering therapies (LLTs) afford clinical benefit, the control of low-density lipoprotein cholesterol (LDL-C) is suboptimal, and available LLTs are underused, especially in patients at high and very high cardiovascular (CV) risk. This study assesses the real-world LDL-C target attainment rate in patients on LLT before experiencing a first major acute cardiovascular event (MACE). The HEARTBEAT was a retrospective, multicentre observational study. From March to June 2021 a total of 334 patients on LLT who had a first MACE while being on statins were included in the study. Of these patients, 83.2 % had a high (40.7 %) or very high CV risk (29.0 %) prior to MACE. Overall, 87.5 % and 89.7 % of the patients at high and very high CV risk, respectively, failed to reach the LDL-C target. Regarding LLTs, only 11.8 % and 19.6 % of the patients at high and very high risk had received high-intensity LLTs prior to MACE. It was estimated that if these patients had reached their recommended LDL-C targets, the risk of MACE may have been reduced by a median of 24.5 % and 23.2 % in patients at high and very high risk respectively. Patients who suffer a first MACE while on statin therapy often were at high/very high CV risk. Despite their risk, LDL-levels and being on statins they are undertreated, and too far from lipid targets. A proper use of high-intensity LLTs led to an increase attainment of LDL targets and lower CV events.


Subsequent risk of hospitalization for neuropsychiatric disorders in patients with rheumatic diseases: a nationwide study from Sweden.
To analyze the association between rheumatoid arthritis, systemic lupus erythematosus, and ankylosing spondylitis and hospitalization for psychiatric disorders, as well as the association between hospitalization for dementia or delirium and systemic lupus erythematosus, by using a novel, large-scale approach. Cohort study with follow-up between 1973 and 2004. The entire Swedish population. Affective, psychotic, neurotic, and personality disorders as well as dementia and delirium. Individuals with rheumatic diseases had a higher risk of psychiatric disorders than the general population. Those with systemic lupus erythematosus and ankylosing spondylitis had a higher risk of subsequent psychiatric disorders than did patients with rheumatoid arthritis. The significant standardized incidence ratios for rheumatoid arthritis, systemic lupus erythematosus, and ankylosing spondylitis were 1.45, 2.38, and 1.69, respectively, for men, and 1.36, 2.16, and 1.95, respectively, for women. Differences were also found based on subtypes of the rheumatic disease and the psychiatric disorder, sex, and various follow-up intervals. Systemic lupus erythematosus carried an increased risk of dementia and delirium. Only women with rheumatoid arthritis and systemic lupus erythematosus had an increased risk of psychotic disorders and severe depression. Health care providers who encounter patients with rheumatic diseases should be aware that these patients are more likely to develop neuropsychiatric disorders and that some subgroups seem to be more vulnerable than others.


UPLC-Q-TOF/MS-based urine and plasma metabonomics study on the ameliorative effects of aspirin eugenol ester in hyperlipidemia rats.
The main objective of this study was to investigate the ameliorative effects of aspirin eugenol ester (AEE) in hyperlipidemic rat. After five-week oral administration of AEE in high fat diet (HFD)-induced hyperlipidemic rats, the impact of AEE on plasma and urine metabonomics was investigated to explore the underlying mechanism by UPLC-Q-TOF/MS analysis. Blood lipid levels and histopathological changes of liver, stomach and duodenum were also evaluated after AEE treatment. Without obvious gastrointestinal (GI) side effects, AEE significantly relieved fatty degeneration of liver and reduced triglyceride (TG), low density lipoprotein (LDL) and total cholesterol (TCH) (P<0.01). Clear separations of metabolic profiles were observed among control, model and AEE groups by using principal component analysis (PCA) and orthogonal partial least-squares-discriminate analysis (OPLS-DA). 16 endogenous metabolites in plasma and 18 endogenous metabolites in urine involved in glycerophospholipid metabolism, fatty acid metabolism, fatty acid beta-oxidation, amino acid metabolism, TCA cycle, sphingolipid metabolism, gut microflora and pyrimidine metabolism were considered as potential biomarkers of hyperlipidemia and be regulated by AEE administration. It might be concluded that AEE was a promising drug candidate for hyperlipidemia treatment. These findings could contribute to the understanding of action mechanisms of AEE and provide evidence for further studies.


A Workshop on Writing Letters to the Editor.
This article was migrated. The article was marked as recommended. Background: Writing letters to the editor based on critical appraisal can serve as the first step in scholarly activity. The workshop in this study focused on educating physicians about the best ways to write letters to the editor. Methods: We conducted a 90-minute workshop as a part of scientific conference. Participants were physicians and medical students who chose to join this workshop. We developed the following learning outcomes for participants: 1) to be able to explain falsificationism; 2) to be able to explain how to check author instructions; 3) to be able to explain how to write a letter to the editor. Results: Twenty-eight participants, including three medical students, attended the workshop. Participants' satisfaction with the workshop had a mean of 4.5 points out of 5 (standard deviation: 0.5). Nearly 80% of participants achieved the learning outcomes. Four participants' groups submitted letters within a month after the workshop, and all four were published. These four groups encompassed a total of 13 authors. In addition, none of the first author of each letter had previously written a clinical research paper. Findings and Discussion: This workshop improved not only the participants' knowledge but it also led to the concrete result of four published letters. Japanese physicians would be able to use this framework to write letters to the editor.


Is the economic uncertainty- human health relationship nonlinear? An empirical analysis for the China.
The health costs of economic uncertainty always remain a major concern among policymakers of China. The theoretical and empirical literature on the economic uncertainty-human health nexus is still in its infancy stage. This study is firmly rooted in the economic uncertainty theory advanced by Baker, Bloom, & Davis. In this study, the primary objective of the analysis is to estimate the asymmetric impact of economic uncertainty on human health in China's economy. In order to evaluate the short and long-run estimates of economic uncertainty on human health across various quantiles, we have employed the linear and nonlinear QARDL models. The linear QARDL model shows that the long-run relationship between economic uncertainty and the infant mortality rate is positive and significant at all quantiles, while the long-run relationship between economic uncertainty and the death rate is positive and significant at higher quantiles. The nonlinear QARDL model reveals that, in the long run, the relationship between the positive shock of economic uncertainty and the infant mortality rate is positive and significant at quantiles 0.30 to 0.95, while the long-run relationship between the positive shock of economic uncertainty and the death rate is positive and significant at higher quantiles. The relationship between the negative shock of economic uncertainty and the infant mortality rate is negative and significant at the highest quantiles, while the relationship between the negative shock of economic uncertainty and death rate is negative and significant at higher quantiles in the long run. The findings indicate a positive relationship between economic uncertainty in China and higher rates of infant mortality and death. Thus, adopting suitable policies for controlling economic uncertainty can help in improving human health in China.


Selection of Vaccinia Virus Recombinants Using CRISPR/Cas9.
The engineering of poxvirus genomes is fundamental to primary and applied virology research. Indeed, recombinant poxviruses form the basis for many novel vaccines and virotherapies but producing and purifying these viruses can be arduous. In recent years, CRISPR/Cas9 has become the favoured approach for genome manipulation due to its speed and high success rate. However, recent data suggests poxvirus genomes are not repaired well following Cas9 cleavage. As a result, CRISPR/Cas9 is inefficient as an editing tool, but very effective as a programmable selection agent. Here, we describe protocols for the generation and enrichment of recombinant vaccinia viruses using targeted Cas9 as a selection tool. This novel use of Cas9 is a simple addition to current homologous recombination-based methods that are widespread in the field, facilitating implementation in laboratories already working with poxviruses. This is also the first method that allows for isolation of new vaccinia viruses in less than a fortnight, without the need to incorporate a marker gene or manipulation of large poxvirus genomes in vitro and reactivation with helper viruses. Whilst this protocol describes applications for laboratory strains of vaccinia virus, it should be readily adaptable to other poxviruses. Graphic abstract: Pipeline for Cas9 selection of recombinant poxviruses.


Optimization of allergen standardization.
Preparation of high quality allergen extracts is essential for the diagnosis and immunotherapy of allergic disorders. Standardization of allergen extracts concerns determination of the allergen unit, development of reference material and measurement of the overall IgE binding capacity of an allergen extract. Recently, quantification of individual allergens has been the main focus of allergen standardization because the allergenicity of most allergen extracts is known to be mainly dependent on the content of a small number of allergen molecules. Therefore, characterization of major allergens will facilitate the standardization of allergens. In this article, we review the current state of allergen standardization. In addition, we briefly summarize the components of allergen extracts that should be under control for the optimization of allergen standardization, since its adjuvant-like activities could play an important role in allergic reactions even though the molecule itself does not bind to the IgE antibodies from subjects.


Spectral encoding of the polarization state of light in multiplexed polarization-sensitive lasing structures.
We report the experimental demonstration of spectral encoding of the polarization state of light by use of multiplexed distributed-feedback lasers in a dye-doped organic thin film by exploiting the pump polarization selectivity of the superimposed resonators. Measurement of the Stokes parameters of the pump light without a priori knowledge of the lasing properties of the structure is discussed.


The metal ion-dependent adhesion site motif of the Enterococcus faecalis EbpA pilin mediates pilus function in catheter-associated urinary tract infection.
Though the bacterial opportunist Enterococcus faecalis causes a myriad of hospital-acquired infections (HAIs), including catheter-associated urinary tract infections (CAUTIs), little is known about the virulence mechanisms that it employs. However, the endocarditis- and biofilm-associated pilus (Ebp), a member of the sortase-assembled pilus family, was shown to play a role in a mouse model of E. faecalis ascending UTI. The Ebp pilus comprises the major EbpC shaft subunit and the EbpA and EbpB minor subunits. We investigated the biogenesis and function of Ebp pili in an experimental model of CAUTI using a panel of chromosomal pilin deletion mutants. A nonpiliated pilus knockout mutant (EbpABC(-) strain) was severely attenuated compared to its isogenic parent OG1RF in experimental CAUTI. In contrast, a nonpiliated ebpC deletion mutant (EbpC(-) strain) behaved similarly to OG1RF in vivo because it expressed EbpA and EbpB. Deletion of the minor pilin gene ebpA or ebpB perturbed pilus biogenesis and led to defects in experimental CAUTI. We discovered that the function of Ebp pili in vivo depended on a predicted metal ion-dependent adhesion site (MIDAS) motif in EbpA's von Willebrand factor A domain, a common protein domain among the tip subunits of sortase-assembled pili. Thus, this study identified the Ebp pilus as a virulence factor in E. faecalis CAUTI and also defined the molecular basis of this function, critical knowledge for the rational development of targeted therapeutics. Catheter-associated urinary tract infections (CAUTIs), one of the most common hospital-acquired infections (HAIs), present considerable treatment challenges for physicians. Inherently resistant to several classes of antibiotics and with a propensity to acquire vancomycin resistance, enterococci are particularly worrisome etiologic agents of CAUTI. A detailed understanding of the molecular basis of Enterococcus faecalis pathogenesis in CAUTI is necessary for the development of preventative and therapeutic strategies. Our results elucidated the importance of the E. faecalis Ebp pilus and its subunits for enterococcal virulence in a mouse model of CAUTI. We further showed that the metal ion-dependent adhesion site (MIDAS) motif in EbpA is necessary for Ebp function in vivo. As this motif occurs in other sortase-assembled pili, our results have implications for the molecular basis of virulence not only in E. faecalis CAUTI but also in additional infections caused by enterococci and other Gram-positive pathogens.


A Qualitative Analysis of Low-Income Pregnant and Parenting Caregivers' Experiences With Home Visiting in California During the First 2 Years of the COVID-19 Pandemic.
In-person home visiting programs that provide evidence-based parenting and child development support improve outcomes for low-income children and families. The COVID-19 pandemic led to a shift from primarily in-person to virtual home visiting services, and little is known about clients' experience of home visiting in this context. To describe the experience of clients in the California Work Opportunity and Responsibility to Kids (CalWORKs) Home Visiting Program (HVP) across California during the first 2 years of the pandemic. Three repeated cross-sectional surveys over a 2-year period. Clients' free-text responses to open-ended questions were analyzed using a directed content analysis approach. Forty-one counties in California. Current CalWORKs HVP clients and those who left the program in the 6 months prior to each survey. Clients' experience of the CalWORKs HVP. Five main themes emerged: (1) benefits received from the program; (2) life challenges; (3) COVID-19-related or other program changes; (4) client dissatisfaction and suggestions for improvement; and (5) appreciation for the program. Clients valued the practical, financial, parenting, and interpersonal support provided to themselves and their children. Almost three-quarters commented on life challenges experienced during the program. Significant programmatic changes related to COVID-19 pandemic public health safety and organizational constraints impacted clients both positively and negatively. Very few clients experienced overt dissatisfaction with the program. Many clients expressed appreciation for the program, particularly the individualized and relational support offered by a consistent home visitor. The findings provide insights into the benefits and challenges experienced by clients receiving evidence-based home visiting services. The findings highlight the ongoing life challenges faced by clients who experience poverty, and how those challenges were exacerbated by a global pandemic. The CalWORKs HVP may buffer the substantial personal stresses clients experience related to parenting in the context of poverty and major public health challenges.


Hormonal changes throughout the menstrual cycle and increased anterior cruciate ligament laxity in females.
To determine whether women experience significantly greater anterior cruciate ligament (ACL) laxity in conjunction with estrogen and progesterone surges during a normal 28- to 30-day menstrual cycle. Serial estrogen and progesterone levels were measured via radioimmunoassay procedures to identify the follicular and luteal phases of a subject's menstrual cycle and to determine periods of peak hormonal surges. Concomitant ACL laxity measures were taken using a knee arthrometer. Hormone levels and ACL laxity were assessed on days 1, 10, 11, 12, 13, 20, 21, 22, and 23 of the menstrual cycle. Day 1 corresponds to the menstrual phase, when estrogen and progesterone levels are at their lowest. Days 10 through 13 correspond to peak estrogen surge (follicular phase), and days 20 through 23 correspond to peak progesterone surge (luteal phase). Seven active females between the ages of 21 and 32 years with at least one apparently healthy knee (no known knee anomalies) volunteered for participation in this study. Each subject stated that she experienced a normal (28- to 30-day) menstrual cycle and was not currently taking any type of hormone therapy (eg, birth control medication). Blood was drawn on days 1, 10, 11, 12, 13, 20, 21, 22, and 23 of each subject's menstrual cycle, and ACL laxity measurements were assessed immediately after the blood draws. Estrogen and progesterone levels were determined via radioimmunoassay procedures, and ACL laxity was determined using a knee arthrometer. A within-subjects, repeated-measures analysis of variance was applied to determine the presence or absence of significant differences in ACL laxity values over the course of a subject's menstrual cycle. We found a significant difference in ACL laxity when comparing baseline levels of estrogen with peak levels of estrogen. A significant increase in ACL laxity was also noted when comparing baseline levels of progesterone with peak levels of progesterone. ACL laxity increased significantly throughout the menstrual cycle when comparing baseline with peak levels of estrogen and progesterone.


Carbon-nutrient stoichiometry drives phosphorus immobilization in phototrophic biofilms at the soil-water interface in paddy fields.
Phototrophic biofilms are distributed widely at the sediment/soil-water interfaces (SWI) in paddy fields, where they immobilize phosphorus, thereby reducing its runoff loss. However, how soil carbon, nutrient availability and nutrient ratios drive the phototrophic biofilm community and its contribution to phosphorus cycling is largely unknown. A large scale field investigation in Chinese paddy fields reported here shows that soil organic carbon (SOC) and soil total nitrogen (STN) contents rather than soil total phosphorus (STP) triggered phosphorus immobilization of paddy biofilms, as they changed algal diversity and EPS production. High C: P and N: P ratios favored phosphorus immobilization in biofilm biomass via increasing the abundance of green algae. The C: N ratio on the other hand had only a weak effect on phosphorus immobilization, being counteracted by SOC or STN. Results from this study reveal how the in-situ interception of phosphorus in paddy fields is driven by soil carbon, nutrient availability and nutrient ratios and provide practical information on how to reduce runoff losses of phosphorus by regulating SOC and STN contents.


A potential platform for developing 3D tubular scaffolds for paediatric organ development.
Children suffer from damaged or loss of hollow organs i.e. trachea, oesophagus or arteries from birth defects or diseases. Generally these organs possess an outer matrix consisting of collagen, elastin, and cells such as smooth muscle cells (SMC) and a luminal layer consisting of endothelial or epithelial cells, whilst presenting a barrier to luminal content. Tissue engineering research enables the construction of such organs and this study explores this possibility with a bioabsorbable nanocomposite biomaterial, polyhedral oligomeric silsesquioxane poly(ε-caprolactone) urea urethane (POSS-PCL).Our established methods of tubular graft extrusion were modified using a porogen-incorporated POSS-PCL and a new lamination method was explored. Porogen (40, 60 or 105 µm) were introduced to POSS-PCL, which were fabricated into a bilayered, dual topography matching the exterior and luminal interior of tubular organs. POSS-PCL with different amounts of porogen were tested for their suitability as a SMC layer by measuring optimal interactions with human adipose derived stem cells. Angiogenesis potential was tested with the chorioallantoic membrane assay. Tensile strength and burst pressures of bilayared tubular grafts were determined. Scaffolds made with 40 µm porogen demonstrated optimal adipose derived stem cell integration and the scaffolds were able to accommodate angiogenesis. Mechanical properties of the grafts confirmed their potential to match the relevant physiological and biophysical parameters. This study presents a platform for the development of hollow organs for transplantation based on POSS-PCL. These bilayered-tubular structures can be tailor-made for cellular integration and match physico-mechanical properties of physiological systems of interest. More specific luminal cell integration and sources of SMC for the external layer could be further explored.


GP documentation of obesity: what does it achieve?
Obesity is a major and increasing health problem in the United Kingdom, and, until recently, the government health promotion package for general practice reimbursed general practitioners for documenting obesity. Despite poor evidence for effectiveness of interventions in primary care, documentation of obesity could possibly improve patient awareness and knowledge, or provide public health information. To assess patient perception of obesity and its health risk, and the accuracy of estimating obesity using patient information. Subjects were consecutive attenders to a general practitioner (GP) at a single urban practice in the South and West Region. Outcome measures were 'measured' body mass index (BMI) calculated from measured weight and height, 'estimated' BMI using patient information, and patient perception of obesity and the health risks of obesity. There is good correlation between 'estimated' and 'measured' BMI (intraclass correlation 0.91). Estimated BMI is lower than measured BMI (mean 0.77 lower), and the difference increases with age and level of BMI: for BMIs of < 20, 20-24.99, 25-29.99, and > or = 30 the mean differences (estimated-measured) were -0.06, -0.46, -0.98 and -1.72 respectively. Estimated obesity (BMI > 30) is reasonably sensitive (70%), specific (99%), and predictive (93% positive predictive value) of measured obesity (kappa 0.78). All obese subjects are aware that they are overweight, and most of them (78%, 95% confidence interval 66-88%) are aware that their weight is a health risk. Obese patients attending GPs' surgeries are likely to know if they are overweight, or could easily estimate from their knowledge of height and weight that they were overweight with reasonable accuracy. Obese subjects also know that their weight carries health risks. Thus, measurement of obesity in the general population is not likely to improve risk assessment or patient knowledge significantly. Without evidence for effective intervention or improved decision-making in primary care, reimbursement guidelines linked to the documentation of obesity in the population are probably an inefficient use of resources.


RAG1 co-expression signature identifies ETV6-RUNX1-like B-cell precursor acute lymphoblastic leukemia in children.
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) can be classified into subtypes according to the genetic aberrations they display. For instance, the translocation t(12;21)(p13;q22), representing the ETV6-RUNX1 fusion gene (ER), is present in a quarter of BCP-ALL cases. However, around 10% of the cases lack classifying chromosomal abnormalities (B-other). In pediatric ER BCP-ALL, rearrangement mediated by RAG (recombination-activating genes) has been proposed as the predominant driver of oncogenic rearrangement. Herein we analyzed almost 1600 pediatric BCP-ALL samples to determine which subtypes express RAG. We demonstrate that RAG1 mRNA levels are especially high in the ETV6-RUNX1 (ER) subtype and in a subset of B-other samples. We also define 31 genes that are co-expressed with RAG1 (RAG1-signature) in the ER subtype, a signature that also identifies this subset of B-other samples. Moreover, this subset also shares leukemia and pro-B gene expression signatures as well as high levels of the ETV6 target genes (BIRC7, WBP1L, CLIC5, ANGPTL2) with the ER subtype, indicating that these B-other cases are the recently identified ER-like subtype. We validated our results in a cohort where ER-like has been defined, which confirmed expression of the RAG1-signature in this recently described subtype. Taken together, our results demonstrate that the RAG1-signature identifies the ER-like subtype. As there are no definitive genetic markers to identify this novel subtype, the RAG1-signature represents a means to screen for this leukemia in children.


Toxicity of nanoparticles embedded in paints compared with pristine nanoparticles in mice.
The unique physical and chemical properties of nanomaterials have led to their increased use in many industrial applications, including as a paint additive. For example, titanium dioxide (TiO2) engineered nanoparticles (ENPs) have well-established anti-UV, self-cleaning, and air purification effects. Silver (Ag) ENPs are renowned for their anti-microbial capabilities and silicon dioxide (SiO2) ENPs are used as fire retardants and anti-scratch coatings. In this study, the toxic effects and biodistribution of three pristine ENPs (TiO2, Ag, and SiO2), three aged paints containing ENPs (TiO2, Ag, and SiO2) along with control paints without ENPs were compared. BALB/c mice were oropharyngeally aspirated with ENPs or paint particles (20 μg/aspiration) once a week for 5 weeks and sacrificed either 2 or 28 days post final aspiration treatment. A bronchoalveolar lavage was performed and systemic blood toxicity was evaluated to ascertain cell counts, induction of inflammatory cytokines, and key blood parameters. In addition, the lung, liver, kidney, spleen, and heart were harvested and metal concentrations were determined. Exposure to pristine ENPs caused subtle effects in the lungs and negligible alterations in the blood. The most pronounced toxic effects were observed after Ag ENPs exposure; an increased neutrophil count and a twofold increase in pro-inflammatory cytokine secretion (keratinocyte chemoattractant (KC) and interleukin-1ß (IL-1ß)) were identified. The paint containing TiO2 ENPs did not modify macrophage and neutrophil counts, but mildly induced KC and IL-1ß. The paints containing Ag or SiO2 did not show significant toxicity. Biodistribution experiments showed distribution of Ag and Si outside the lung after aspiration to respectively pristine Ag or SiO2 ENPs. In conclusion, we demonstrated that even though direct exposure to ENPs induced some toxic effects, once they were embedded in a complex paint matrix little to no adverse toxicological effects were identified.


Combined therapy with fluconazole and flucytosine in murine cryptococcal meningitis.
To assess the possible beneficial effects of combined therapy (fluconazole and flucytosine) in the treatment of cryptococcal meningitis in the immunocompromised host, we compared therapy with fluconazole and flucytosine, individually and combined, in the experimental murine model. BALB/c athymic (nu/nu) mice were infected intracerebrally with 150 to 300 CFU of Cryptococcus neoformans. In mortality studies, treatment was initiated 24 h postinfection and continued for 10 to 14 days with either fluconazole (1 to 15 mg/kg of body weight per day), flucytosine (60 to 120 mg/kg/8 h), both drugs, or 0.3% Noble agar (control). Combined therapy delayed mortality significantly when compared with controls and single-drug regimens. This was observed over a broad range of doses. Quantitative determinations of CFU in brain tissue demonstrated a significantly lower burden of C. neoformans in mice receiving combined therapy. The results indicate that combined therapy with fluconazole and flucytosine is superior to single-drug therapy.


Trends in the epidemiology of cutaneous leishmaniasis in a young adult population in Israel: a long-term survey.
The Israel Defense Forces (IDF) medical records offer a unique and valid 28-year view of the striking differences in cutaneous leishmaniasis (CL) seasonality patterns and incidence rates between the military and civilian sectors in Israel. To determine the annual epidemiology and seasonality trends of CL over the long term in the IDF. The database of the Epidemiology Section of the IDF Medical Corps was reviewed for all reported cases of CL (passive surveillance) from 1 January 1978 to 31 December 2006. The diagnosis of reported CL was based on the clinical presentation, relevant epidemiologic data, and, in most cases, microscopic visualization of the parasite. Polymerase chain reaction (PCR) confirmation of the parasite has been more routinely performed since 2003. Rates of CL were generally characterized by peaks every 10 years, until the last 10 years when a second peak occurred in the same decade. The average monthly rates varied from a low of 0.8 cases per 100,000 population in June to a high of 9.83 cases per 100,000 soldiers in December. The results of this study imply that we are currently in the midst of a re-emergence of CL in Israel, in particular among IDF soldiers. This increase warrants a change in the public health approach.


Radiofrequency dielectric properties of animal tissues as a function of time following death.
The dielectric properties of three bovine tissues, liver, kidney and spleen, as a function of time following death, were measured in the frequency range from 20 kHz to 100 MHz using an automatic network analyser and an end-of-the-line sensor. The dielectric constant of kidney and spleen decreases as a function of time following death, particularly at frequencies below 1 MHz. However, all tissues measured show a characteristic increase in the frequency-independent ionic conductivity. This is believed to reflect changes in the conductivity of the extracellular region of tissues after death. The dielectric parameters, i.e. the static dielectric constant, the relaxation time and the coefficient of the relaxation time distribution, obtained by a curve-fitting process, do not change within the first 10 h following death in the case of liver, whereas early changes occur for both kidney and spleen. High initial values of the static dielectric constant for these tissues decrease significantly within a few hours following death. Similarly, the relaxation time which is relatively long for kidney and spleen, as compared with liver, decreases with time. Our data compare favourably with those reported by several investigators for similar tissues in other species (dog, cat, swine and cattle).


Utility and versatility of extracellular recordings from the cockroach for neurophysiological instruction and demonstration.
The principles of neurophysiology continue to be challenging topics to teach in the context of undergraduate neuroscience education. Laboratory classes containing neurophysiological demonstrations and exercises are, therefore, an important and necessary complement for covering those subjects taught in lecture-based courses. We developed a number of simple yet very instructive exercises, described below, which make use of extracellular recordings from different sensory systems of the cockroach (Periplanta americana). The compendium we developed provides students with hands-on demonstrations of several commonly taught topics of neurophysiology including sensory coding by neural activity.


Incidence and causes of urolithiasis in children between 0-2 years.
Urolithiasis (UL) is a common problem in pediatric nephrology practice. About 9-23% of all pediatric UL cases consist of patients under 1 years old. The aim of the present study was to determine etiologic causes, clinical features and short term prognosis of urolithiasis in the first two years of life. Two-hundred children between 0-2 years of age (mean age 10.3±6.1 months) with urolithiasis were included to the study. All children were completely evaluated for urolithiasis etiology. Patients were followed for at least 1 year with 3-month follow-up intervals. The mean follow-up duration was 36.2 months. Family history was positive for urolithiasis in 99 (49.5%) patients. The cause of admission were urinary tract infection and related symptoms in 101 (50.5%), incidentally during imaging for other causes in 40 (20%), stone passage in 21 (10.5%), hematuria in 18 (9%), voiding difficulty in 14 (7%) and antenatal detected urinary anomaly in 6 (3%) patients. Accompanying urinary anomalies (anatomical defects) in 51 (25.5%) patients were detected primarily including vesiculoureteral reflux (VUR) in 32 (62.9%) of them. Development of new stones was determined in 45 (22.5%) patients in the first year, in 15 (22%) patients in the second year and in 8 (36.3%) patients in the third year. In result, among pediatric urinary stone diseases, infantile UL appears to be a seperate clinical entity in terms of both the etiological characteristics and the clinical course of the disease. Furthermore, when an infant is presented with nonspecific symptoms for kidney stone, a renal ultrasonography could be performed for detecting nephrolithiasis.


[Genetic function of the multiploid virions of alphaviruses].
The natural process of infection with multiploid virions of alphaviruses was modeled by inoculation of cells with artificially obtained aggregates. After infection with the aggregates the progeny of attenuated clones of Venezuelan equine encephalomyelitis virus was found to have some new properties. The virus produced larger plaques and had higher reproduction activity. In some cases, changes in the electrophoretic mobility of virion structural proteins was observed, especially a decrease in the molecular weight of the most conservative of them, C-protein. These properties were retained in passages of the virus in cell cultures. The observed phenomenon is associated with genetic interaction between defective virus genomes getting into cells as the aggregate component. Formation of multiploid virions and infection with these particles are considered as the process providing for retention of the biological properties of the virus under conditions of accumulation of DI-particles in the population.


The Messiha and Schiavo cases: third-party ethical and legal [corrected] interventions in futile care disputes.
Relatives may increasingly demand that an incompetent patient's treatment be continued indefinitely, despite clinical advice that it is technically "futile" (offering no reasonable prospect of return to a meaningful quality of life). Third-party interventions may become a more frequent part of attempts to resolve such disputes where there is no formal advance directive. In the Messiha case, the Supreme Court of New South Wales upheld clinical judgement regarding the patient's best interests as most important. In the Schiavo case in the United States, clinicians' decisions on futility of treatment had received unwavering judicial support in more than 20 proceedings. Political differences between the US and Australia make it unlikely clinicians in this country will face Schiavo-type legislative challenges to individual clinical decisions and the judicial rulings upholding them. Consulting a clinical ethics committee in such scenarios is both legally recommended and clinically warranted as an important device for diffusing tensions between relatives and clinicians, as well as clarifying their respective ethical and legal responsibilities. In protracted or apparently irresolvable disputes with relatives, applying for a judicial declaration on futility of treatment has become a practical option for intensivists in Australia and should be a recognised part of their training.


Perspectives of Egyptian research ethics committees regarding their effective functioning.
The recent increase in research in the Middle East has been associated with the establishment of research ethics committees (RECs). Our aim was to obtain perspectives of RECs regarding the challenges that impede their effective functioning. We conducted in-depth interviews using a semi-structured interview guide. We transcribed and analyzed the interviews to uncover major themes and subthemes. We identified the following themes: membership composition; training needs of members; availability of human and capital resources; role of the national government; concerns with the informed consent process; government scrutiny of research; investigator-related issues; and concerns with transfer of biological samples to other countries. Our interview study revealed several barriers that need to be considered by appropriate stakeholders to enhance adequate functioning of RECs.


Clinical Implication of Immunohaematological Tests in ABO haemolytic disease of newborn: Revisiting an old disease.
We aimed to assess the frequency distribution of of ABO haemolytic disease of newborn (ABO-HDN) and to know the predictive value of immunohaematological tests in identifying at risk neonates. ABO incompatibility, although a common cause of haemolytic disease of newborn, has several unaddressed issues related to it. A prospective study over 20 months was carried out in a tertiary care centre in South India. Blood grouping, Direct Antiglobulin test (DAT) and elution studies were performed on neonatal samples, whereas blood grouping, antibody screening and antibody titration were performed on maternal samples. In suspected cases, ABO-HDN was diagnosed after excluding other possible causes for haemolysis. The laboratory results were correlated with the clinical details to assess the predictive value of the tests. Of the total 2856 pregnancies, 34% had ABO incompatibility. On testing with columnagglutination test (CAT), the overall DAT positivity and that among ABO-incompatible cases were 3.8% and 11.2%, respectively,) whereas by conventinal tube technique (CTT) it was 0.6% and 2.4% respectively. CAT was found to have higher sensitivity, and the predictive value was higher for CTT. Maternal IgG titre showed a positive linear relationship with the DAT strength and the rise in indirect bilirubin levels. The positive predictive value of combination of tests such as DAT, elution and titation was 94.12%, which was much higher than that of the individual tests. DAT positivity is a predictor of early rise in serum bilirubin level, and a combination of tests has a better predictive value than individual tests towards development of clinically significant hyperbilirubinemia in ABO-HDN.


IL-13-mediated gender difference in susceptibility to autoimmune encephalomyelitis.
Females tend to have stronger Th1-mediated immune responses and are more prone to develop autoimmune diseases, including multiple sclerosis. Macrophages are major effector cells capable of mediating or modulating immune responses in experimental autoimmune encephalomyelitis (EAE). IL-13 and estrogen have opposing roles on macrophages (the former enhancing and the latter inhibiting) in terms of MHC class II (MHC II) up-regulation and, thus, these factors might influence susceptibility to EAE differently in females vs males. In accordance with this hypothesis, females lacking IL-13 displayed lower incidence and milder EAE disease severity than males after immunization with myelin oligodendrocyte glycoprotein (MOG)-35-55 peptide/CFA/pertussis toxin. Female IL-13 knockout (KO) mice with EAE consistently had reduced infiltration of CD11b(+) macrophages in the CNS along with significantly reduced expression of MHC II on these cells. Impaired MHC II expression was further corroborated upon LPS stimulation of female but not male bone marrow-derived CD11b(+) macrophages from IL-13KO mice, with restored expression after IL-13 pretreatment of female but not male macrophages. APCs from IL-13KO females induced less proliferation by MOG-35-55-reactive T cells, and splenocytes from MOG peptide-immunized females had lower expression of IL-12, IFN-gamma, MIP-2, and IFN-gamma-inducible protein 10 than males. In contrast, these splenocytes had higher expression of anti-inflammatory factors, IL-10, TGF-beta1, and FoxP3, a cytokine pattern typical of regulatory type II monocytes. These data suggest that the difference in EAE susceptibility in females is strongly influenced by gender-specific proinflammatory effects of IL-13, mediated in part through up-regulation of Th1-inducing cytokines and MHC II on CD11b(+) macrophages.


Inhibition of Enterovirus A71 by a Novel 2-Phenyl-Benzimidazole Derivative.
Enterovirus A71 (EV-A71) infection has emerged as a significant public health concern atthe global level. Epidemic events of EV-A71 have been reported worldwide, and this succession of outbreaks has heightened concern that EV-A71 may become a public health threat. In recent years, widespread A71 enterovirus also occurred in European countries. EV-A71 infection causes hand-foot-mouth disease (HFMD), herpangina, and fever. However, it can sometimes induce a variety of neurological complications, including encephalitis, aseptic meningitis, pulmonary edema, and acute flaccid paralysis. We identified new benzimidazole derivatives and described their in vitro cytotoxicity and broad-spectrum anti-enterovirus activity. Among them, derivative 2b resulted in interesting activity against EV-A71, and therefore it was selected for further investigations. Compound 2b proved to be able to protect cell monolayers from EV-A71-induced cytopathogenicity, with an EC50 of 3 µM. Moreover, Vero-76 cells resulted in being significantly protected from necrosis and apoptosis when treated with 2b at 20 and 80 µM. Compound 2b reduced viral adsorption to Vero-76 cells, and when evaluated in a time-of-addition assay, the derivative had the highest effect when added during the infection period. Moreover, derivative 2b reduced viral penetration into host cells. Besides, 2b did not affect intestinal monolayers permeability, showing no toxic effects. A detailed insight into the efficacy of compound 2b against EV-A71 showed a dose-dependent reduction in the viral titer, also at low concentrations. Mechanism of action investigations suggested that our derivative can inhibit viral endocytosis by reducing viral attachment to and penetration into host cells. Pharmacokinetic and toxicity predictions validated compound 2b as a good candidate for further in vivo assays.


Lifestyle factors associated with sex differences in Kaposi sarcoma incidence among adult black South Africans: A case-control study.
Kaposi Sarcoma (KS) is endemic in several countries in Southern and Eastern Africa, relatively rare worldwide but a leading cancer among people living with HIV. KS has always been more common in adult males than females. We assessed the prevalence of known cancer modifying factors (parity, hormonal contraceptive use in females, sex-partners, smoking and alcohol consumption in both sexes), and their relationship to KS, and whether any of these could account for the unequal KS sex ratios. We calculated logistic regression case-control adjusted odds ratios (ORadj), and 95% confidence intervals (95%CI), between KS and each of the modifying factors, using appropriate comparison controls. Controls were cancer types that had no known relationship to exposures of interest (infection or alcohol or smoking or contraceptive use). The majority of the 1275 KS cases were HIV positive (97%), vs. 15.7% in 10,309 controls. The risk of KS among those with HIV was high in males (ORadj=116.70;95%CI=71.35-190.88) and females (ORadj=93.91;95%CI=54.22-162.40). Among controls, the prevalence of smoking and alcohol consumption was five and three times higher in males vs. females. We found a positive association between KS and heavy vs. non-drinking (ORadj=1.31;95%CI=1.03-1.67), and in current heavy vs. never smokers (ORadj=1.82;95%CI=1.07-3.10). These associations remained positive for alcohol consumption (but with wider CIs) after stratification by sex, and restriction to HIV positive participants. We found no evidence of interactions of smoking and alcohol by sex. Smoking and alcohol consumption may provide a possible explanation for the KS sex differences, given both exposures are more common in men, but confounding and bias cannot be fully ruled out. The role smoking and alcohol play in relation to viral loads of HIV/KSHV, differences in immunological responses or other genetic differences between males and females warrant further studies.


Causal relationship of susceptibility genes to ischemic stroke: comparison to ischemic heart disease and biochemical determinants.
Interrelationships between genetic and biochemical factors underlying ischemic stroke and ischemic heart disease are poorly understood. We: 1) undertook the most comprehensive meta-analysis of genetic polymorphisms in ischemic stroke to date; 2) compared genetic determinants of ischemic stroke with those of ischemic heart disease, and 3) compared effect sizes of gene-stroke associations with those predicted from independent biochemical data using a mendelian randomization strategy. Electronic databases were searched up to January 2009. We identified: 1) 187 ischemic stroke studies (37,481 cases; 95,322 controls) interrogating 43 polymorphisms in 29 genes; 2) 13 meta-analyses testing equivalent polymorphisms in ischemic heart disease; and 3) for the top five gene-stroke associations, 146 studies (65,703 subjects) describing equivalent gene-biochemical relationships, and 28 studies (46,928 subjects) describing biochemical-stroke relationships. Meta-analyses demonstrated positive associations with ischemic stroke for factor V Leiden Gln506, ACE I/D, MTHFR C677T, prothrombin G20210A, PAI-1 5G allele and glycoprotein IIIa Leu33Pro polymorphisms (ORs: 1.11 - 1.60). Most genetic associations show congruent levels of risk comparing ischemic stroke with ischemic heart disease, but three genes--glycoprotein IIIa, PAI-1 and angiotensinogen--show significant dissociations. The magnitudes of stroke risk observed for factor V Leiden, ACE, MTHFR and prothrombin, but not PAI-1, polymorphisms, are consistent with risks associated with equivalent changes in activated protein C resistance, ACE activity, homocysteine, prothrombin, and PAI-1 levels, respectively. Our results demonstrate causal relationships for four of the most robust genes associated with stroke while also showing that PAI-1 4G/5G polymorphism influences cardiovascular risk via a mechanism not simply related to plasma levels of PAI-1 (or tPA) alone.


Grain, sugar and biomass accumulation in tropical sorghums. I. Trade-offs and effects of phenological plasticity.
Grain and sweet sorghum (Sorghum bicolor (L.) Moench) differ in their ability to produce either high grain yield or high sugar concentration in the stems. Some cultivars of sorghum may yield both grains and sugar. This paper investigates the trade-offs among biomass, grain and sugar production. Fourteen tropical sorghum genotypes with contrasted sweetness and PP sensitivity were evaluated in the field near Bamako (Mali) at three sowing dates under favourable rainfed conditions. Plant phenology, morphology, dry matter of different organs and stem sugar content were measured at anthesis and grain maturity. A panicle pruning treatment was implemented after anthesis. Late sowing (shorter days) led to a decrease in total leaf number, dry mass and sugar yield even in PP-insensitive genotypes because of an increased phyllochron. Dry matter production and soluble sugar accumulation were strongly correlated with leaf number. Sugar concentration varied little among sowing dates or between anthesis and maturity. This indicates that sugar accumulation happened mainly before anthesis, thus largely escaping from competition with grain filling. This was confirmed by the low impact of panicle pruning on sugar concentration. Changes in sugar concentration from anthesis to maturity were negatively correlated with harvest index but not with grain yield. Physiological trade-offs among sugar, biomass and grain production under favourable rainfall are small in late-maturing and PP-sensitive sweet sorghums cultivated under sudano-sahelian conditions. The results differ from earlier reports that focussed on early maturing, PP-insensitive germplasm. Further research is needed on the interactions of these traits with agricultural practices and drought.


Evidence for lack of a role of cGMP in effect of alpha-hANP on aldosterone inhibition.
To investigate the role of guanosine 3',5'-cyclic monophosphate (cGMP) in the inhibitory effect on aldosterone production of alpha-human atrial natriuretic polypeptide (alpha-hANP) we first compared the effects of the peptide with those of sodium nitroprusside (SNP) on the production of aldosterone and cGMP in dispersed adrenal capsular cells of rats, second, examined the effects of derivatives of cGMP on the production of aldosterone, and, third, studied the influence of potassium on the effects of alpha-hANP on the production of aldosterone and cGMP. alpha-hANP at concentrations of 3 X 10(-8) to 3 X 10(-7) M decreased the production of aldosterone in a dose-dependent manner, while markedly increasing the production of cGMP. On the other hand, although SNP at concentrations of 10(-5) to 10(-3) M increased the production of cGMP in a dose-dependent manner, it caused no significant changes in the production of aldosterone. Neither dibutyryl cGMP nor 8-bromo-cGMP affected the production of aldosterone in the adrenal cells. Although the aldosterone-inhibitory effect of alpha-hANP was lost in the potassium-free medium, the cGMP-stimulatory effect of the peptide was not altered by adding potassium to the incubation medium at concentrations of 0-5 meq/l. These results suggest that cGMP plays a minor role in the inhibitory effect of alpha-hANP on the production of aldosterone and that the production of cGMP stimulated by the peptide is not directly involved in the decrease in aldosterone production in adrenal capsular cells of rats.


Transplantation of a donor liver with haemochromatosis: evidence against an inherited intrahepatic defect.
An iron loaded liver from a 40 year old man with occult haemochromatosis was transplanted into a 19 year old woman with acute liver failure secondary to a paracetamol overdose. Increased parenchymal hepatic iron was found in a liver specimen at biopsy undertaken because of mild rejection 30 days after transplantation. After transplantation the patient had two episodes of liver rejection confirmed by biopsy. The hepatic iron concentration fell from 161 mumol/g on day 30 after transplant to 26.5 mumol/g (normal less than 40) on day 210. Iron absorption, measured 45 days after transplant, was in the normal range at 12.4%. The rapid fall in hepatic iron and the normal iron absorption study result suggest that the genetic defect of haemochromatosis is not exclusively an intrahepatic defect.


[Clinical characteristics and efficacy of oropharyngeal carcinoma with secondary primary tumor].
Objective:To analysis the clinical features and prognosis in oropharyngeal carcinoma with secondary primary tumor. Methods:A retrospective analysis was performed on 468 pathologically confirmed oropharyngeal cancer as the primary tumor patients with p16 status, excluded distant metastasis, and admitted to the Chinese Academy of Medical Sciences from January 2010 to December 2020. The clinical features and prognosis of the secondary primary tumor were analyzed. Results:Among 468 patients with oropharyngeal cancer treated at initial diagnosed, 222 cases were P16-negative. With a median follow-up time of 64.3 months, 66 cases developed second primary cancer, with an incidence of 29.3%, among which 63.6%(42/66) were synchronous and 36.4%(24/66) were heterochronous, esophagus was the most commonly involved site. The 5-year OS of p16-negative oropharyngeal carcinoma with synchronous second primary cancer, without second primary cancer and with heterogeneous second primary cancer were 26.3% and 57.3% and 73.2%(P=0.001); The second primary cancer accounted for 11.2%(12/107) of the deaths in the whole group, among them, the heterochronous second primary accounted for 75.0%(9/12). There were 246 patients with p16 positive, with a median follow-up time of 52.4 months, 20 patients developed second primary cancer(8.1%). Among them, 65.0%(13/20) were synchronous and 35.0%(7/20) were heterochronous. Esophagus was the most commonly involved site. The 4-year OS of p16-positive with synchronous, heterochronous and non-second primary cancer group were 51.9%, 80.7% and 83.3%. Secondary primary cancer accounted for 3.8%(2/52) of all deaths in p16 positvie group. Conclusion:The incidence of second primary cancer of p16 positive and negative oropharyngeal carcinoma were different. The esophagus was the most commonly involved site regardless of p16 status. Regardless of p16 status, the survival of patients with synchronous second primary cancer was worse than those without second primary cancer. For p16-negative oropharyngeal carcinoma, the prognosis was better in patients with heterogeneous second primary cancer, the second primary cancer is one of the main causes of death.


Social communication deficits and restricted repetitive behavior symptoms in Tourette syndrome.
Background: Autism spectrum disorders (ASD) have been found to occur more frequently in individuals with Tourette syndrome (TS) than in the general population. Similarities exist between ASD and TS clinically, which suggests a potential relationship between the two conditions. Purpose: The purpose of this study was to explore the occurrence of autism-related features in ASD and TS, focusing on areas of overlap and difference. Patients and methods: This study examined the nature and extent of autistic traits as measured by the Social Communication Questionnaire (SCQ) in a sample with a diagnosis of TS, a sample diagnosed to have ASD, and a normative general population sample. Results: The TS sample had significantly higher mean SCQ scores than the general population, but generally lower scores than the ASD sample. The group differences in mean SCQ scores between the TS and ASD sample were significant except in the domain of restricted repetitive behaviours (RRB). Conclusion: This suggests that ASD traits occur commonly in the TS population, with a significant overlap in certain clinical features. This was especially the case for complex movements or repetitive behaviours, which may represent either: i) a shared phenotype which is subclinical, ii) a phenocopy where some clinical symptoms mimic each other, or iii) a co-morbidity. Awareness of this association can be useful in identifying these symptoms as part of the comprehensive assessment of TS and addressing these to improve the overall clinical outcomes in these patients.


Down-regulation of CD98 in melphalan-resistant myeloma cells with reduced drug uptake.
Although melphalan has been used as a therapeutic reagent for multiple myeloma, many patients become refractory. To elucidate the mechanism of resistance to melphalan, we generated a melphalan-resistant myeloma cell line, KHM-11(EMS), by treating a parental line, KHM-11, with a mutagen, ethylmethanesulfonate. KHM-11(EMS) is 55 times more resistant to melphalan. gamma-Glutamylcysteine synthetase, P-glycoprotein, multidrug-resistance-associated protein, lung-resistance-related protein and the Bcl-2 family of proteins were not responsible for the drug resistance in KHM-11(EMS). Intracellular incorporation of melphalan to myeloma cells was determined by using [(14)C]-labeled melphalan. Accumulation of melphalan in KHM-11(EMS) was 43% of KHM-11, while the efflux rates were comparable in both cell lines. The uptake of melphalan was inhibited by the addition of L-phenylalanine, indicating that melphalan is incorporated through the L-phenylalanine transporter as reported previously. Expression of CD98, which was recently cloned as an L-phenylalanine transporter, was 6-fold decreased in KHM-11(EMS), suggesting that CD98 may be correlated with the incorporation of melphalan. CD98 expression and incorporation of melphalan were analyzed in fresh purified myeloma cells from 5 patients. All myeloma cells from 4 cases expressed CD98 at a high level and incorporated melphalan. However, tumor cells from 1 case expressed CD98 at low levels and did not incorporate melphalan. Taken together, reduced melphalan uptake could be responsible for the drug resistance in KHM-11(EMS), and down-regulation of CD98 may be related to this phenomenon. Further investigation of the correlation between impaired drug uptake and down-regulation of CD98 in myeloma cells should be important to understand the mechanism of resistance to melphalan.


Cascading walks model for human mobility patterns.
Uncovering the mechanism behind the scaling laws and series of anomalies in human trajectories is of fundamental significance in understanding many spatio-temporal phenomena. Recently, several models, e.g. the explorations-returns model (Song et al., 2010) and the radiation model for intercity travels (Simini et al., 2012), have been proposed to study the origin of these anomalies and the prediction of human movements. However, an agent-based model that could reproduce most of empirical observations without priori is still lacking. In this paper, considering the empirical findings on the correlations of move-lengths and staying time in human trips, we propose a simple model which is mainly based on the cascading processes to capture the human mobility patterns. In this model, each long-range movement activates series of shorter movements that are organized by the law of localized explorations and preferential returns in prescribed region. Based on the numerical simulations and analytical studies, we show more than five statistical characters that are well consistent with the empirical observations, including several types of scaling anomalies and the ultraslow diffusion properties, implying the cascading processes associated with the localized exploration and preferential returns are indeed a key in the understanding of human mobility activities. Moreover, the model shows both of the diverse individual mobility and aggregated scaling displacements, bridging the micro and macro patterns in human mobility. In summary, our model successfully explains most of empirical findings and provides deeper understandings on the emergence of human mobility patterns.


Fatigue in Air Medical Clinicians Undertaking High-acuity Patient Transports.
Abstract Background. Fatigue is likely to be a significant issue for air medical transport clinicians due to the challenging nature of their work, but there is little published evidence for this. Objective. To prospectively assess the levels and patterns of fatigue in air medical transport teams and determine whether specific mission factors influenced clinician fatigue. Methods. Physicians and flight nurses from two intensive care interhospital transport teams routinely completed fatigue report forms before and after patient transport missions over a 4-month period. Data collected included subjective ratings of fatigue (Samn-Perelli and visual analog scale), mission difficulty and performance. Multivariate hierarchical logistic and linear models were used to evaluate the influence of various mission characteristics on post-mission fatigue. Results. Clinicians returned 403 fully complete fatigue report forms at an estimated overall return rate of 73%. Fatigue increased significantly over the course of missions, and on 1 of every 12 fatigue reports returned clinicians reported severe post-mission fatigue (that is, levels of 6 or 7 on the Samn-Perelli scale). Factors that impacted significantly on clinician fatigue were the pre-mission fatigue level of the clinician, night work, mission duration, and mission difficulty. Poorer self-rated performance was significantly associated with higher levels of fatigue (r = -0.4, 95% CI -0.5 to -0.3), and for the 6-month period leading up to the study clinicians reported a total of 22 occasions on which they should have declined a mission due to fatigue. Conclusions. These results suggest that clinicians undertaking interhospital transports of even moderate duration experience high levels of fatigue on a relatively frequent basis. In the unique and challenging environment of air medical transport, prior fatigue, long or difficult missions, and the disadvantageous effect of night work on normal circadian rhythms are a combination where there are minimal safety margins for clinicians' performance capacity. Fatigue prevention or fatigue resistance measures could positively affect air medical clinicians in this context.


Liposomal Encapsulation of Citicoline for Ocular Drug Delivery.
Glaucoma represents a group of neurodegenerative diseases characterized by optic nerve damage and the slowly progressive death of retinal ganglion cells. Glaucoma is considered the second leading cause of irreversible blindness worldwide. Pharmaceutical treatment of glaucoma is critical because of the properties of the ocular barrier that limit the penetration of drugs, resulting in lower systemic bioavailability. This behavior causes the need of frequent drug administration, which leads to deposition of concentrated solutions on the eye, causing toxic effects and cellular damage to the eye. To overcome these drawbacks, novel drug-delivery systems, such as liposomes, can play an important role in improving the therapeutic efficacy of antiglaucomatous drugs. In this work, liposomes were synthesized to improve various aspects, such as ocular barrier penetration, bioavailability, sustained release of the drug, targeting of the tissue, and reduction in intraocular pressure. Citicoline (CDP-choline; cytidine 5'-diphosphocholine) is an important intermediate in the biosynthesis of cell membrane phospholipids, with neuroprotective and neuroenhancement properties, and it was used in the treatment on retinal function and neural conduction in the visual pathways of glaucoma patients. In this study, citicoline was loaded into the 1,2-dioleoyl-sn-glycerol-3-phosphocholine and cholesterol liposomal carrier to enhance its therapeutic effect. The citicoline encapsulation efficiency, drug release, and size analysis of the different liposome systems were investigated using dynamic light scattering, nuclear magnetic resonance, infrared spectroscopy, and ToF-SIMS experiments.


Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology.
Epidemiologic and experimental data suggest that cholesterol may play a role in the pathogenesis of AD. Modulation of cholesterolemia in transgenic animal models of AD strongly alters amyloid pathology. To determine whether a relationship exists between amyloid deposition and total cholesterolemia (TC) in the human brain. The authors reviewed autopsy cases of patients older than 40 years and correlated cholesterolemia and presence or absence of amyloid deposition (amyloid positive vs amyloid negative subjects) and cholesterolemia and amyloid load. Amyloid load in human brains was measured by immunohistochemistry and image analysis. To remove the effect of apoE isoforms on cholesterol levels, cases were genotyped and duplicate analyses were performed on apoE3/3 subjects. Cholesterolemia correlates with presence of amyloid deposition in the youngest subjects (40 to 55 years) with early amyloid deposition (diffuse type of senile plaques) (p = 0.000 for all apoE isoforms; p = 0.009 for apoE3/3 subjects). In this group, increases in cholesterolemia from 181 to 200 almost tripled the odds for developing amyloid, independent of apoE isoform. A logistic regression model showed consistent results (McFadden rho2 = 0.445). The difference in mean TC between subjects with and without amyloid disappeared as the age of the sample increased (>55 years: p = 0.491), possibly reflecting the effect of cardiovascular deaths among other possibilities. TC and amyloid load were not linearly correlated, indicating that there are additional factors involved in amyloid accumulation. Serum hypercholesterolemia may be an early risk factor for the development of AD amyloid pathology.


Overview of PAT process analysers applicable in monitoring of film coating unit operations for manufacturing of solid oral dosage forms.
Over the last two decades, regulatory agencies have demanded better understanding of pharmaceutical products and processes by implementing new technological approaches, such as process analytical technology (PAT). Process analysers present a key PAT tool, which enables effective process monitoring, and thus improved process control of medicinal product manufacturing. Process analysers applicable in pharmaceutical coating unit operations are comprehensibly described in the present article. The review is focused on monitoring of solid oral dosage forms during film coating in two most commonly used coating systems, i.e. pan and fluid bed coaters. Brief theoretical background and critical overview of process analysers used for real-time or near real-time (in-, on-, at- line) monitoring of critical quality attributes of film coated dosage forms are presented. Besides well recognized spectroscopic methods (NIR and Raman spectroscopy), other techniques, which have made a significant breakthrough in recent years, are discussed (terahertz pulsed imaging (TPI), chord length distribution (CLD) analysis, and image analysis). Last part of the review is dedicated to novel techniques with high potential to become valuable PAT tools in the future (optical coherence tomography (OCT), acoustic emission (AE), microwave resonance (MR), and laser induced breakdown spectroscopy (LIBS)).


Evaluation of enzyme linked immunosorbent assay, utilizing native antigen B for serodiagnosis of human hydatidosis.
Hydatidosis is one of the cosmopolitan parasitic zoonoses caused by the larval stage of Echinococcus granulosus. Diagnosis of hydatidosis is still an unresolved problem. Serological tests using crude antigens for diagnosis of E. granulosus are sensitive, however their specificity are not satisfactory. Therefore, WHO recommended specific serological methods using specific antigens, specially native AgB for proper diagnosis. This study was designed to evaluate the ELISA and counter current immunoelectrophresis (CCIEP) method using native antigen B (Ag B) for serodiagnosis of human hydatidosis in Fars Province, Iran, an endemic area for this parasitic disease. Native AgB was purified from sheep hydatid fluid. Serum samples obtained from 40 pathologically confirmed cases of hydatidosis along with samples from patients with fascioliasis, toxocariasis, taeniasis and cancer patients and sera from healthy individuals were tested by ELISA using native antigen B or tested by countercurrent immunoelectrophresis (CCIEP) using crude sheep hydatid cyst fluid. Sensitivity of the ELISA system was determined to be 92.5% and the specificity was found to be 97.3%. Positive and negative predictive values of the system were 92.5% and 97.3%, respectively. For countercurrent immunoelectrophresis the sensitivity of the assay was 97.5% and its specificity was 58.18%. This ELISA system is much more specific in detecting anti hydatid cyst antibody than CCIEP, while CCIEP is more sensitive in detecting anti hydatid cyst antibody. The new ELISA system using native antigen B is a suitable method and preferable to CCIEP for immunodiagnosis of human hydatidosis.


DNA damage in zebrafish larvae induced by exposure to low-dose rate gamma-radiation: detection by the alkaline comet assay.
This study has determined the sensitivity of the alkaline comet assay for the detection of strand breaks in the DNA of cells taken from a whole organism rather than a single cell type as in previously reported studies. The assay has been performed on cells from whole zebrafish larvae irradiated for 1 or 24 h at dose rates of 0.4, 1.2 or 7.2 mGy/h. Zebrafish larvae exposed to only 1.2 mGy/h of gamma-radiation for 1h showed a statistically significant increase in DNA damage compared to controls. This represents a high sensitivity of this animal model for DNA damage and of the comet assay protocol used for detecting such damage. Increasing the exposure time from 1 to 24 h caused significant increases in DNA damage in zebrafish larvae, although the modest size of these increases in damage for the relatively large increases (24 times) in total absorbed dose indicates that dose rate may be the major factor in determining the level of DNA damage observed under the conditions of these experiments.


The Teleost CXCL13-CXCR5 Axis Induces Inflammatory Cytokine Expression through the Akt-NF-κB, p38-AP-1, and p38-NF-κB Pathways.
The ancestors of chemokines originate in the most primitive of vertebrates, which has recently attracted great interest in the immune functions and the underlying mechanisms of fish chemokines. In the current study, we identified an evolutionarily conserved chemokine, CiCXCL13, from a teleost fish, grass carp. CiCXCL13 was characterized by a typical SCY (small cytokine CXC) domain and four cysteine residues (C34, C36, C61, C77), with the first two cysteines separated by a random amino acid residue, although it shared 24.2-54.8% identity with the counterparts from other vertebrates. CiCXCL13 was an inducible chemokine, whose expression was significantly upregulated in the immune tissues of grass carps after grass carp reovirus infection. CiCXCL13 could bind to the membrane of grass carp head kidney leukocytes and promote cell migration, NO release, and the expression of >15 inflammatory cytokines, including IL-1β, TNF-α, IL-10 and TGF-β1, thus regulating the inflammatory response. Mechanistically, CiCXCL13 interacted with its evolutionarily conserved receptor CiCXCR5 and activated the Akt-NF-κB and p38-AP-1 pathways, as well as a previously unrevealed p38-NF-κB pathway, to efficiently induce inflammatory cytokine expression, which was distinct from that reported in mammals. Zebrafish CXCL13 induced inflammatory cytokine expression through Akt, p38, NF-κB, and AP-1 as CiCXCL13. Meanwhile, the CiCXCL13-CiCXCR5 axis-mediated inflammatory activity was negatively shaped by grass carp atypical chemokine receptor 2 (CiACKR2). The present study is, to our knowledge, the first to comprehensively define the immune function of CXCL13 in inflammatory regulation and the underlying mechanism in teleosts, and it provides a valuable perspective on the evolution and biology of fish chemokines.


Formyl peptide receptors are coupled to multiple mitogen-activated protein kinase cascades by distinct signal transduction pathways: role in activation of reduced nicotinamide adenine dinucleotide oxidase.
Formyl peptide receptor activation of three mitogen-activated protein kinase (MAPK) cascades, extracellular signal-regulated kinases (ERKs), N-terminal kinases (JNKs), and p38 MAPK was examined in differentiated HL-60 granulocytes. FMLP stimulated a concentration- and time-dependent increase in ERK, JNK, and p38 MAPK activities, all of which were dependent on a pertussis toxin-sensitive G protein. Pharmacologic inhibitors were used to examine the roles of tyrosine kinases, phosphatidylinositol 3-kinase, protein kinase C, and phospholipase C. FMLP-stimulated ERK activity was dependent on tyrosine kinases, phosphatidylinositol 3-kinase, protein kinase C, and phospholipase C; p38 MAPK activation was dependent on phosphatidylinositol 3-kinase and phospholipase C; while JNK activation was independent of all of these signaling components. The mitogen-activated protein kinase/ERK kinase inhibitor PD098059 reduced ERK activation by 90%, while an inhibitor of p38 MAPK, SB203580, inhibited p38 MAPK activation by 80%. Both PD098059 and SB203580 inhibited FMLP-stimulated superoxide release, as did inhibitors directed against protein kinase C, tyrosine kinases, and phosphatidylinositol 3-kinase. We conclude that formyl peptide receptors are coupled to three MAPK cascades by Gi proteins. ERKs, p38 MAPK, and JNKs are each activated by distinct proximal signal transduction pathways. Activation of p38 MAPK is necessary for FMLP stimulation of respiratory burst activity; however, a second signal that may involve ERK is also required for this activity.


Blockade of 5-HT(2A) receptors by sarpogrelate protects the heart against myocardial infarction in rats.
It has been shown that serotonin (5-hydroxytryptamine, 5-HT) is involved in exacerbating vascular abnormalities; however, its role in mediating changes in cardiac function due to myocardial injury has yet to be established. This study examined the effect of sarpogrelate, a 5-HT(2A) receptor blocker, in preventing cardiac dysfunction due to myocardial infarction (MI). Rats were treated 3 days before surgery with or without 5 mg x kg(-1) x day(-1) sarpogrelate, and the left coronary artery was ligated for 3 weeks to induce MI. Sarpogrelate reduced the mortality from 40% to 30%, infarct size from 35% to 25%, and left ventricular end diastolic pressure from 15 mm Hg to 10 mm Hg in MI rats. Electrocardiographic (ECG) tracings showed a marked deviation in the ST-segment and prolongation of the QTc interval in MI rats during the 3 weeks; these changes were attenuated by sarpogrelate pretreatment. In another set of experiments, MI rats were treated with 5 mg x kg(-1) x day(-1) sarpogrelate 1 hour after the surgery, and the hemodynamic and electrocardiograph changes were assessed at 3 weeks. This posttreatment was also found to reduce infarct size, improve cardiac function, and attenuate ECG changes. Sarpogrelate attenuates cardiac dysfunction, infarct size, and changes in the ECG due to MI. These results also support the view that serotonin and 5-HT(2A) may contribute to the deleterious effects of ischemic injury in the heart.


Central and peripheral fatigue development in the shoulder muscle with obesity during an isometric endurance task.
Fatigue increases the likelihood of developing work-related musculoskeletal disorders and injury. Due to the physiological and neuromuscular changes that accompany obesity, it may alter the fatigue development mechanism and exacerbate injury risk. The upper extremities have the highest incidence rates for work-related musculoskeletal disorders. Therefore, the goals of this study were to investigate the effect of obesity on central vs. peripheral fatigue as well as on the physical signs of fatigue on the middle deltoid muscle. A measure of central activation ratio was used to quantify central fatigue by considering the increment in the torque output by superimposed twitch relative to its corresponding maximum voluntary contraction. For this purpose, electrical stimulation was delivered at the middle deltoid muscles of 22 non-obese (18 < body mass index (BMI) < 25 kg/m2) and 17 obese (30 < BMI < 40 kg/m2) individuals aged 18-32 years old. Participants completed superimposed maximum voluntary isometric contractions of shoulder abduction before and after a sustained isometric fatiguing task at either 30 or 60% of the muscle capacity. Differences in endurance time, torque fluctuation, torque loss, and muscle activity measured by an electromyography sensor were also investigated. A greater reduction of voluntary activation of motor units (p = 0.001) with fatigue was observed for individuals who are obese. Contrary to the effect of obesity on central fatigue, a trend toward reduced peripheral fatigue (p = 0.06) was observed for the obese group compared to the non-obese group. On average, a 14% higher rate of torque loss per second was observed among individuals with obesity in comparison to non-obese participants. The observed greater contribution of central fatigue during the sustained endurance tasks suggests that among young healthy obese individuals, the faster fatigue development with obesity, commonly reported in the literature, is most likely due to the central elements rather than the peripheral factors. This finding has implications for fatigue prevention programs during sustained exertions and can help to develop training, work, and rest schedules considering obesity.


Identification of lineage-specific zygotic transcripts in early Caenorhabditis elegans embryos.
During Caenorhabditis elegans embryogenesis, a maternally supplied transcription factor, SKN-1, is required for the specification of the mesendodermal precursor, EMS, in the 4-cell stage embryo. When EMS divides, it gives rise to a mesoderm-restricted precursor, MS, and an endoderm-restricted precursor, E. To systematically identify genes that function as key regulators of MS and/or E-derived tissues, we identified, by microarray analyses, genes that are newly transcribed within a short developmental window (approximately 30 min) encompassing the generation and fate specification of the MS and E blastomeres. By comparing total cDNAs generated from individual, carefully staged embryos, we identified 275 genes up-regulated in 12-cell embryos compared to 4-cell embryos. Fifty of these 275 genes are down-regulated in 12-cell skn-1 mutant embryos and are designated skn-1-dependent zygotic (sdz) genes. The spatial and temporal expression patterns in C. elegans embryos of 10 randomly selected sdz genes were analyzed by a nuclear GFP reporter driven by the endogenous 5' regulatory sequence of each gene. GFP expression, although absent at the 4-cell stage, was detected at the 12- to 16-cell stage for all 10 genes and was restricted to EMS-derived lineages for 7 of the 10. Among the seven lineage-specific genes, three genes are expressed equally in both MS and E lineages, two are expressed exclusively or predominantly in the MS lineage, and two are expressed exclusively in the E lineage. Depletion of skn-1 by RNAi abolishes the expression of all seven reporter transgenes in vivo, confirming that these genes are indeed skn-1 dependent. These results demonstrate the successful combination of single-staged embryo cDNAs, genetic mutants, and whole transcriptome microarray analysis to identify stage- and lineage-specific transcripts in early C. elegans embryos.


Developmental trajectories for spatial frames of reference in Williams syndrome.
Williams syndrome (WS) is a genetic disorder associated with severe visuocognitive impairment. Individuals with WS also report difficulties with everyday wayfinding. To study the development of body-, environment-, and object-based spatial frames of reference in WS, we tested 45 children and adults with WS on a search task in which the participant and a spatial array are moved with respect to each other. Although individuals with WS showed a marked delay, like young controls they demonstrated independent, additive use of body- and environment-based frames of reference. Crucially, object-based (intrinsic) representations based on local landmarks within the array were only marginally used even by adults with WS, whereas in typical development these emerge at 5 years. Deficits in landmark use are consistent with wayfinding difficulties in WS, and may also contribute to problems with basic localization, since in typical development landmark-based representations supplement those based on the body and on self-motion. Difficulties with inhibition or mental rotation may be further components in the impaired ability to use the correct reference frame in WS.


[Pulmonary alveolar microlithiasis].
Pulmonary alveolar microlithiasis is a rare disease of unknown aetiology, in which calcium phosphate microliths are deposited bilaterally throughout the lung parenchyma. The total number of reported cases is about 400. A case of pulmonary alveolar microlithiasis is presented in a 50-year old man for whom the diagnosis was confirmed by histology via transbronchial biopsy. During a 4-year observation period there was no increase of the disease according to x-ray investigations and with respect to clinical symptoms.


The Impact of Infant Feeding Regimen on Cow's Milk Protein Allergy, Atopic Dermatitis and Growth in High-Risk Infants during the First 6 Months of Life: The Allergy Reduction Trial.
The development of early-onset cow's milk protein allergy and atopic dermatitis during the first months of life is multifactorial, including both genetic and nutritional aspects. This study aims to assess the impact of different feeding patterns on the incidence of cow's milk protein allergy, atopic dermatitis, and growth among infants with a family history of allergy. A total of 551 high-risk infants were randomly recruited from 3 European countries in three feeding regimens: exclusive breastfeeding, partially hydrolyzed formula, or standard formula with intact protein either exclusively or supplementary to breastfeeding. During the first 6 months of intervention, amongst infants with a family history of atopic dermatitis, 6.5% of partially hydrolyzed formula-fed infants and 22.7% of exclusively breastfed infants (p = 0.007) presented with atopic dermatitis respectively. Growth as assessed by weight increase did not differ between the aforementioned groups. Although cow's milk protein allergy was not related to the different milk feeding regimens in the whole cohort, when adjusting for high breast milk intake, the respective incident was significantly lower in the infants consuming partially hydrolyzed formula (p < 0.001). This data indicates that a specific partially hydrolyzed formula could serve as a more appropriate complement to breast milk compared to a standard intact protein formula in high-risk infants, to reduce the incidence of atopic dermatitis.


Synthetic fluorescent probes for studying copper in biological systems.
The potent redox activity of copper is required for sustaining life. Mismanagement of its cellular pools, however, can result in oxidative stress and damage connected to aging, neurodegenerative diseases, and metabolic disorders. Therefore, copper homeostasis is tightly regulated by cells and tissues. Whereas copper and other transition metal ions are commonly thought of as static cofactors buried within protein active sites, emerging data points to the presence of additional loosely bound, labile pools that can participate in dynamic signalling pathways. Against this backdrop, we review advances in sensing labile copper pools and understanding their functions using synthetic fluorescent indicators. Following brief introductions to cellular copper homeostasis and considerations in sensor design, we survey available fluorescent copper probes and evaluate their properties in the context of their utility as effective biological screening tools. We emphasize the need for combined chemical and biological evaluation of these reagents, as well as the value of complementing probe data with other techniques for characterizing the different pools of metal ions in biological systems. This holistic approach will maximize the exciting opportunities for these and related chemical technologies in the study and discovery of novel biology of metals.


Use and outcomes associated with long-acting bronchodilators among patients hospitalized for chronic obstructive pulmonary disease.
Long-acting β-adrenergic agonists and long-acting anticholinergic agents are recommended for the management of patients with stable chronic obstructive pulmonary disease (COPD); however, their role in the acute setting is uncertain. To describe the use and outcomes associated with long-acting bronchodilator therapy (LABD) among patients hospitalized with exacerbations of COPD. We conducted a retrospective cohort study at 421 U.S. hospitals of patients hospitalized with exacerbations of COPD between January 1, 2010, and June 30, 2011. We used propensity score methods to compare the risk of a composite measure of treatment failure, length of stay, and hospital costs in patients who were treated with an LABD to those who did not receive treatment. Of the 77,378 patients included in the analysis, 31,725 (41%) were treated with an LABD on Hospital Day 1 or Day 2, including 15,356 (48.4%) who received a long-acting β-agonist, 6,665 (21%) who received a long-acting anticholinergic, and 9,704 (30.6%) who received both. When compared with patients who were not treated with an LABD, treated patients tended to be younger and had a modestly lower comorbidity burden but were more likely to have had prior admission for COPD and to be treated with inhaled corticosteroids. The incidence of treatment failure was similar among those who were or were not treated with LABDs (13.1 vs. 13.6%, P = 0.06). In propensity-matched analyses we found no difference in the risk of treatment failure associated with exposure to LABDs (relative risk [RR], 1.00; 95% confidence interval [CI], 0.96-1.04), minimal differences in hospital cost (RR, 1.02; 95% CI, 1.01-1.03), and no difference in length of stay (RR, 1.01; 95% CI, 1.00-1.02). Despite a lack of evidence, LABDs are commonly prescribed to patients hospitalized for exacerbations of COPD but are not associated with better clinical or economic outcomes. Clinical trials are needed to determine the optimal use of these medications in the acute care setting.


Considering the patient-partner relationship in cancer care: coping strategies for couples.
A cancer diagnosis, regardless of type or site, raises feelings of fear and loss of control in patients and their partners. Being married is associated with lower mortality from a wide range of illnesses, including cancer.However, the quality of marital interactions is a stronger predictor of health outcomes than marital status alone.When people face great life challenges, they attach importance to their intimate partner's behaviors.Trust, a key component of relationship quality, can lend stability as well as emotional and practical support during treatment.This article will examine the results of research focused on patients with cancer and their partners and discuss the effects of a cancer diagnosis on couples.Recommendations for clinical practice include couple behaviors, communication patterns, and coping strategies.In addition, partners should be included in assessment and interventions to improve the quality of care for patients with cancer.


A review and analysis of accountability in global health funding, research collaborations and training: towards conceptual clarity and better practice.
Accountability is a complex idea to unpack and involves different processes in global health practice. Calls for accountability in global health would be better translated to action through a better understanding of the concept and practice of accountability in global health. We sought to analyse accountability processes in practice in global health funding, research collaborations and training. This study is a literature review that systematically searched PubMed and Scopus for articles on formal accountability processes in global health. We charted information on processes based on accountability lines ('who is accountable to whom') and the outcomes the processes were intended for ('accountability for what'). We visualised the representation of accountability in the articles by mapping the processes according to their intended outcomes and the levels where processes were implemented. We included 53 articles representing a wide range of contexts and identified 19 specific accountability processes for various outcomes in global health funding, research collaborations and training. Target setting and monitoring were the most common accountability processes. Other processes included interinstitutional networks for peer checking, litigation strategies to enforce health-related rights, special bodies that bring actors to account for commitments, self-accountability through internal organisational processes and multipolar accountability involving different types of institutional actors. Our mapping identified gaps at the institutional, interinstitutional and broader system levels where accountability processes could be enhanced. To rebalance power in global health, our review has shown that analysing information on existing accountability processes regarding 'who is accountable to whom' and 'accountability for what' would be useful to characterise existing lines of accountability and create lines where there are gaps. However, we also suggest that institutional and systems processes for accountability must be accompanied by political engagement to mobilise collective action and create conditions where a culture of accountability thrives in global health.


Androgen regulation by the long terminal repeat of mouse mammary tumor virus.
Mouse mammary tumor virus (MMTV) has long been implicated in mouse mammary carcinogenesis, and it is now well established that the long terminal repeat (LTR) contains regulatory sequences responsible for glucocorticoid-mediated induction of viral RNA. However, we have demonstrated previously that androgens as well as glucocorticoids can regulate MMTV RNA in the S115 mouse mammary tumor cell line. To determine if androgens act directly on the LTR in these cells, plasmids were constructed with the MMTV LTR joined to the coding sequences of genes not normally expressed in the cells. Following transfection of these chimeric genes into S115 cells, we show that the expression of the genes is regulated by both androgens and glucocorticoids. Furthermore, hormonal regulation is also conferred by the LTR on the neighboring guanine phosphoribosyltransferase (gpt) gene. Thus, androgens can act on the LTR of MMTV when the appropriate receptors are present in the cells, and this interaction can influence the expression of additional adjacent genes.


Urinary Incontinence and Its Association with Physical and Psycho-Cognitive Factors: A Cross-Sectional Study in Older People Living in Nursing Homes.
Urinary incontinence (UI) is a common geriatric syndrome affecting bladder health and is especially prevalent in nursing homes (NHs). The aim of the study was to determine the prevalence of UI and its associated factors in five Spanish NHs. UI (measured with Minimum Data Set 3.0), sociodemographic, and health-related variables were collected. Chi-square (or Fisher's) or Student's t-test (or Mann Whitney U) for bivariate analysis were used, with Prevalence Ratio (PR) as an association measure. The prevalence of UI was 66.1% (CI:95%, 53.6-77.2) in incontinent (n = 45, mean age 84.04, SD = 7.7) and continent (n = 23, mean age 83.00, SD = 7.7) groups. UI was significantly associated with frailty (PR = 1.84; 95%CI 0.96-3.53), faecal incontinence (PR = 1.65; 95%CI 1.02-2.65), anxiety (PR = 1.64; 95%CI 1.01-2.66), physical performance (PR = 1.77; 95%CI 1.00-3.11), and cognitive state (PR = 1.95; 95%CI 1.05-3.60). Statistically significant differences were found between incontinent and continent NH residents for limitations in activities of daily living (ADL), mobility, quality of life, sedentary behaviour, and handgrip strength. It can be concluded that two out of three of the residents experienced UI, and significant associated factors were mainly physical (sedentary behaviour, frailty, physical performance, ADL limitations, mobility, faecal incontinence, and handgrip strength) followed by psycho-cognitive factors (cognition, anxiety, and quality of life).