Revision and validation of the medication adherence self-efficacy scale (MASES) in hypertensive African Americans.
Study purpose was to revise and examine the validity of the Medication Adherence Self-Efficacy Scale (MASES) in an independent sample of 168 hypertensive African Americans: mean age 54 years (SD = 12.36); 86% female; 76% high school education or greater. Participants provided demographic information; completed the MASES, self-report and electronic measures of medication adherence at baseline and three months. Confirmatory (CFA), exploratory (EFA) factor analyses, and classical test theory (CTT) analyses suggested that MASES is unidimensional and internally reliable. Item response theory (IRT) analyses led to a revised 13-item version of the scale: MASES-R. EFA, CTT, and IRT results provide a foundation of support for MASES-R reliability and validity for African Americans with hypertension. Research examining MASES-R psychometric properties in other ethnic groups will improve generalizability of findings and utility of the scale across groups. The MASES-R is brief, quick to administer, and can capture useful data on adherence self-efficacy.


Self-reported physician-diagnosed asthma among Swedish adolescent, adult and former elite endurance athletes.
Asthma is common among elite endurance athletes. Since the first published Swedish studies in 1993, awareness of "skiers' asthma" has increased. The current prevalence of asthma among Swedish skiers is unknown. This paper aims to present the design of a 5-year prospective annual questionnaire study on asthma among Swedish current and former elite endurance athletes, the first cross-sectional results on prevalence, age of onset, and predictors of self-reported physician-diagnosed asthma in the study population. An annual postal questionnaire is sent to Swedish elite skiers and orienteers during 2011-2015. In 2013, former Swedish Olympic skiers were similarly invited. We present cross-sectional data obtained in 2011 from the adolescents and adults and in 2013 from former skiers. A total of 491 athletes were invited. The results are presented by age, sex and sport. Chi-square test was used for group comparisons. Predictors of asthma were identified using logistic regression. Response rate was 82%. Among athletes aged 15-19, 29% of the skiers (38% of the female skiers), and 17% of the orienteers reported asthma (p = 0.071). Among the athletes aged 20-34, 35% of the skiers and 16% of the orienteers reported asthma (p = 0.029). Among the former skiers aged 40-94, 22% reported asthma. Among the active athletes, the onset of asthma was in early adolescence. Logistic regression found increasing age, female sex, allergy, family history of allergy/asthma and being skier predictors of self-reported physician-diagnosed asthma. The prevalence of physician-diagnosed asthma is high among Swedish endurance athletes, especially female adolescent skiers.


The Rift Valley Fever virus protein NSm and putative cellular protein interactions.
Rift Valley Fever is an infectious viral disease and an emerging problem in many countries of Africa and on the Arabian Peninsula. The causative virus is predominantly transmitted by mosquitoes and high mortality and abortion rates characterize outbreaks in animals while symptoms ranging from mild to life-threatening encephalitis and hemorrhagic fever are noticed among infected humans. For a better prevention and treatment of the infection, an increased knowledge of the infectious process of the virus is required. The focus of this work was to identify protein-protein interactions between the non-structural protein (NSm), encoded by the M-segment of the virus, and host cell proteins. This study was initiated by screening approximately 26 million cDNA clones of a mouse embryonic cDNA library for interactions with the NSm protein using a yeast two-hybrid system. We have identified nine murine proteins that interact with NSm protein of Rift Valley Fever virus, and the putative protein-protein interactions were confirmed by growth selection procedures and β-gal activity measurements. Our results suggest that the cleavage and polyadenylation specificity factor subunit 2 (Cpsf2), the peptidyl-prolyl cis-trans isomerase (cyclophilin)-like 2 protein (Ppil2), and the synaptosome-associated protein of 25 kDa (SNAP-25) are the most promising targets for the NSm protein of the virus during an infection.


Quality of life among patients undergoing bariatric surgery: associations with mental health- A 1 year follow-up study of bariatric surgery patients.
Preoperative mental health seems to have useful predictive value for Health Related Quality of Life (HRQOL) after bariatric surgery. The aim of the present study was to assess pre- and postoperative psychiatric disorders and their associations with pre- and postoperative HRQOL. Data were assessed before (n = 127) and one year after surgery (n = 87). Psychiatric disorders were assessed by Mini International Neuropsychiatric Interview (M.I.N.I.) and Structured Clinical Interview (SCID-II). HRQOL was assessed by the Short Form 36 (SF-36) questionnaire. Significant improvements were found in HRQOL from preoperative assessment to follow-up one year after surgery. For the total study population, the degree of improvement was statistically significant (p values < .001) for seven of the eight SF-36 subscales from preoperative assessment to follow-up one year after surgery. Patients without psychiatric disorders had no impairments in postoperative HRQOL, and patients with psychiatric disorders that resolved after surgery had small impairments on two of the eight SF-36 subscales compared to the population norm (all effect sizes < .5) at follow-up one year after surgery. Patients with psychiatric disorders that persisted after surgery had impaired HRQOL at follow-up one year after surgery compared to the population norm, with effect sizes for the differences from moderate to large (all effect sizes ≥ .6). This study reports the novel finding that patients without postoperative psychiatric disorders achieved a HRQOL comparable to the general population one year after bariatric surgery; while patients with postoperative psychiatric disorders did not reach the HRQOL level of the general population. Our results support monitoring patients with psychiatric disorders persisting after surgery for suboptimal improvements in quality of life after bariatric surgery. The trial is registered at http://www.clinicaltrials.gov prior to patient inclusion (ProtocolID16280).


Cervical and thoracic intervertebral disc hydration increases with recumbency: a study in 101 healthy volunteers.
Variation in the water content and the size of lumbar intervertebral discs (IVDs) is known to occur because of recumbency and has been associated with lumbar IVD herniation risk through the impact of IVD hydration on tissue mechanical properties. It is not clear if similar changes in cervical or thoracic IVDs occur with recumbency. The aim of this study was to determine whether increases in hydration of thoracic and cervical IVDs occur with short-duration recumbency. This study used a test-retest design in a magnetic resonance imaging facility. We examined expansion of all IVDs in the spine in 101 healthy individuals (54 women) aged 25-35 years on sagittal T2-weighted magnetic resonance images after a mean of 26.9 minutes lying in the scanner bore. All scans were performed after midday. To mitigate false positives, p-values were adjusted by the false discovery rate method. At the end of lying, the cervical spine IVD volume increased by a mean (standard deviation) of 2.6 (5.6)% (p<.001) compared with a 1.0 (4.0)% (p=.024) increase in the upper thoracic spine IVD volume and a 2.0 (3.2)% (p<.001) increase at the lower thoracic spine. Lumbar IVD volume increased by 1.2 (2.4)% (p<.001). C2-C3 IVD volume (+4.1 [13.8]%, p=.011) increased the most at the cervical spine, followed by C5-C6 (+3.9 [9.8]%, p<.001) and C3-C4 (+3.8 [13.5]%, p=.014). Lumbar IVDs with higher degeneration grades showed more expansion with lying (p=.0031). We established that cervical and thoracic IVD volumes increase with recumbency. We expect diurnal variation in cervical and thoracic IVD hydration will occur in the general population, with greater cervical and thoracic IVD hydration and size upon rising in the morning.


A survey of post-operative management for patients following first time lumbar discectomy.
This study aimed to identify current NHS physiotherapy practice following first time lumbar discectomy in the United Kingdom (UK) in order to inform future research priorities and design. Descriptive survey methodology was utilised employing a postal questionnaire. A total population sample was identified and questionnaires were posted to 87 NHS physiotherapy departments throughout the UK. Participants were senior physiotherapists working with spinal surgery patients. In the inpatient phase, the majority of patients receive physiotherapy. Management focused on mobility and education to facilitate early discharge with most patients being given exercises. However, there was a wide variation in the actual exercises prescribed. There was more variation in the provision of outpatient physiotherapy treatment. Not all patients have access to physiotherapy treatment post discharge in the UK and when treatment was available the content and amount was variable. There is evidence to support rehabilitation classes to assist early improvements in function and return to work but such classes are only available in around half of the centres involved in this study. Regarding the content of exercise classes and individual treatment sessions, a wide range of clinical practice was evident. This study raises many research questions and highlights the need for future research to optimise patient rehabilitation following first time lumbar discectomy.


Distribution of Xylella fastidiosa in Sycamore Associated with Low Temperature and Host Resistance.
Experiments were conducted in the field and laboratory to determine effects of low temperatures on Xylella fastidiosa populations in American sycamore. Roots and shoots from naturally infected trees at two locations were collected monthly. Sap extracted from the samples was tested by enzyme-linked immunosorbent assay for presence of X. fastidosa and was diluted and plated on periwinkle wilt medium to determine populations of viable bacteria. Cumulative rainfall and hours below temperature thresholds (-5 to 10°C) were recorded at each site. Bacterial populations in shoots were negatively correlated with cumulative hours below -5°C air temperature (r= -0.96). In roots, bacterial populations were only weakly correlated with cumulative hours below soil temperature thresholds (-0.61 < r <-0.25). Bacterial populations were not correlated with monthly rainfall. In the laboratory, resistant and susceptible sycamore trees were inoculated with X. fastidiosa and held in the dark at 5°C or 22°C. After 12 weeks, inoculated stem sections were collected and sap was extracted and tested as described previously. Stems that tested positive for X. fastidiosa were divided into additional samples and tested as described above. Results of the laboratory study indicated no significant effects of low-temperature treatment (5°C) or host resistance on viable bacteria. Bacterial detection frequency and population size were greatest near the inoculation point and the primary direction of early bacterial spread was acropetal.


An Integrative Computational Approach for a Prioritization of Key Transcription Regulators Associated With Nanomaterial-Induced Toxicity.
A rapid increase of new nanomaterial (NM) products poses new challenges for their risk assessment. Current traditional methods for estimating potential adverse health effect of NMs are complex, time consuming, and expensive. In order to develop new prediction tests for nanotoxicity evaluation, a systems biology approach, and data from high-throughput omics experiments can be used. We present a computational approach that combines reverse engineering techniques, network analysis and pathway enrichment analysis for inferring the transcriptional regulation landscape and its functional interpretation. To illustrate this approach, we used published transcriptomic data derived from mice lung tissue exposed to carbon nanotubes (NM-401 and NRCWE-26). Because fibrosis is the most common adverse effect of these NMs, we included in our analysis the data for bleomycin (BLM) treatment, which is a well-known fibrosis inducer. We inferred gene regulatory networks for each NM and BLM to capture functional hierarchical regulatory structures between genes and their regulators. Despite the different nature of the lung injury caused by nanoparticles and BLM, we identified several conserved core regulators for all agents. We reason that these regulators can be considered as early predictors of toxic responses after NMs exposure. This integrative approach, which refines traditional methods of transcriptomic analysis, can be useful for prioritization of potential core regulators and generation of new hypothesis about mechanisms of nanoparticles toxicity.


A new graphical format to communicate treatment effects to patients-A web-based randomized controlled trial.
Patients making treatment decisions require understandable evidence-based information. However, evidence on graphical presentation of benefits and side-effects of medical treatments is not conclusive. The study evaluated a new space-saving format, CLARIFIG (clarifying risk figures), aiming to facilitate accuracy of comprehension. CLARIFIG displays groups of patients with and without treatment benefits as coloured sectors of a proportional bar graph representing in total 100 patients. Supplementary icons indicate the corresponding group's actual condition. The study used an application showing effects of immunotherapy intended to slow disease progression in multiple sclerosis (MS). In a four-arm web-based randomized controlled trial, CLARIFIG was compared to the reference standard, multifigure pictographs (MFP), regarding comprehension (primary outcome) and processing time. Both formats were presented as static and animated versions. People with MS were recruited through the website of the German MS society. Six hundred and eighty-two patients were randomized and analysed for the primary end point. There were no differences in comprehension rates (MFPstatic =46%, CLARIFIGstatic =44%; P=.59; MFPanimated =23%, CLARIFIGanimated =30%; P=.134). Processing time for CLARIFIG was shorter only in the animated version (MFPstatic =162 seconds, CLARIFIGstatic =155 seconds; P=.653; MFPanimated =286 seconds, CLARIFIGanimated =189 seconds; P≤.001). However, both animated versions caused more wrong answers and longer processing time than static presentation (MFPstatic vs animated : P≤.001/.001, CLARIFIGstatic vs animated : P=.027/.017). Comprehension of the new format is comparable to MFP. CLARIFIG has the potential to simplify presentation in more complex contexts such as comparison of several treatment options in patient decision aids, but further studies are needed.


Touching a rubber hand: feeling of body ownership is associated with activity in multisensory brain areas.
In the "rubber-hand illusion," the sight of brushing of a rubber hand at the same time as brushing of the person's own hidden hand is sufficient to produce a feeling of ownership of the fake hand. We shown previously that this illusion is associated with activity in the multisensory areas, most notably the ventral premotor cortex (Ehrsson et al., 2004). However, it remains to be demonstrated that this illusion does not simply reflect the dominant role of vision and that the premotor activity does not reflect a visual representation of an object near the hand. To address these issues, we introduce a somatic rubber-hand illusion. The experimenter moved the blindfolded participant's left index finger so that it touched the fake hand, and simultaneously, he touched the participant's real right hand, synchronizing the touches as perfectly as possible. After approximately 9.7 s, this stimulation elicited an illusion that one was touching one's own hand. We scanned brain activity during this illusion and two control conditions, using functional magnetic resonance imaging. Activity in the ventral premotor cortices, intraparietal cortices, and the cerebellum was associated with the illusion of touching one's own hand. Furthermore, the rated strength of the illusion correlated with the degree of premotor and cerebellar activity. This finding suggests that the activity in these areas reflects the detection of congruent multisensory signals from one's own body, rather than of visual representations. We propose that this could be the mechanism for the feeling of body ownership.


Dyslexia: a deficit in visuo-spatial attention, not in phonological processing.
Developmental dyslexia affects up to 10 per cent of the population and it is important to understand its causes. It is widely assumed that phonological deficits, that is, deficits in how words are sounded out, cause the reading difficulties in dyslexia. However, there is emerging evidence that phonological problems and the reading impairment both arise from poor visual (i.e., orthographic) coding. We argue that attentional mechanisms controlled by the dorsal visual stream help in serial scanning of letters and any deficits in this process will cause a cascade of effects, including impairments in visual processing of graphemes, their translation into phonemes and the development of phonemic awareness. This view of dyslexia localizes the core deficit within the visual system and paves the way for new strategies for early diagnosis and treatment.


Lung consequences in adults born prematurely.
Although survival has improved significantly in recent years, prematurity remains a major cause of infant and childhood mortality and morbidity. Preterm births (<37 weeks of gestation) account for 8% of live births representing >50 000 live births each year in the UK. Preterm birth, irrespective of whether babies require neonatal intensive care, is associated with increased respiratory symptoms, partially reversible airflow obstruction and abnormal thoracic imaging in childhood and in young adulthood compared with those born at term. Having failed to reach their optimal peak lung function in early adulthood, there are as yet unsubstantiated concerns of accelerated lung function decline especially if exposed to noxious substances leading to chronic respiratory illness; even if the rate of decline in lung function is normal, the threshold for respiratory symptoms will be crossed early. Few adult respiratory physicians enquire about the neonatal period in their clinical practice. The management of these subjects in adulthood is largely evidence free. They are often labelled as asthmatic although the underlying mechanisms are likely to be very different. Smoking cessation, maintaining physical fitness, annual influenza immunisation and a general healthy lifestyle should be endorsed irrespective of any symptoms. There are a number of clinical and research priorities to maximise the quality of life and lung health in the longer term not least understanding the underlying mechanisms and optimising treatment, rather than extrapolating from other airway diseases.


Immunoglobulin G Fragment Crystallizable Glycosylation After Hematopoietic Stem Cell Transplantation Is Dissimilar to Donor Profiles.
Immunoglobulin G (IgG) fragment crystallizable (Fc) N-glycosylation has a large influence on the affinity of the antibody for binding to Fcγ-receptors (FcγRs) and C1q protein, thereby influencing immune effector functions. IgG Fc glycosylation is known to be partly regulated by genetics and partly by stimuli in the microenvironment of the B cell. Following allogeneic hematopoietic stem cell transplantation (HSCT), and in the presence of (almost) complete donor chimerism, IgG is expected to be produced by, and glycosylated in, B cells of donor origin. We investigated to what extent IgG glycosylation in patients after transplantation is determined by factors of the donor (genetics) or the recipient (environment). Using an IgG subclass-specific liquid chromatography-mass spectrometry method, we analyzed the plasma/serum IgG Fc glycosylation profiles of 34 pediatric patients pre-HSCT and at 6 and 12 months post-HSCT and compared these to the profiles of their donors and age-matched healthy controls. Patients treated for hematological malignancies as well as for non-malignant hematological diseases showed after transplantation a lower Fc galactosylation than their donors. Especially for the patients treated for leukemia, the post-HSCT Fc glycosylation profiles were more similar to the pre-HSCT recipient profiles than to profiles of the donors. Pre-HSCT, the leukemia patient group showed as distinctive feature a decrease in sialylation and in hybrid-type glycans as compared to healthy controls, which both normalized after transplantation. Our data suggest that IgG Fc glycosylation in children after HSCT does not directly mimic the donor profile, but is rather determined by persisting environmental factors of the host.


Motivating and demotivating factors for community health workers: A qualitative study in urban slums of Delhi, India.
Background Community health workers play an important role in delivering health-care services, especially to underserved populations in low- and middle-income countries. They have been shown to be successful in providing a range of preventive, promotive and curative services. This qualitative study investigated the factors motivating or demotivating community health workers in urban settings in Delhi, India. Methods In this sub-study of the ANCHUL (Ante Natal and Child Healthcare in Urban Slums) implementation research project, four focus-group discussions and nine in-depth interviews were conducted with community health workers and medical officers. Utilizing a reflexive and inductive qualitative methodology, the data set was coded, to allow categories of motivating and demotivating factors to emerge. Results Motivating factors identified were: support from family members for their work, improved self-identity, job satisfaction and a sense of social responsibility, prior experiences of ill health, the opportunity to acquire new skills and knowledge, social recognition and status conferred by the community, and flexible work and timings. Negative experiences in the community and at health centres, constraints in the local health system in response to the demand generated by the community health workers, and poor pay demotivated community health workers in this study, even causing some to quit their jobs. Conclusion Community-health-worker programmes that focus on ensuring the technical capacity of their staff may not give adequate attention to the factors that motivate or discourage these workers. As efforts get under way to ensure universal access to health care, it is important that these issues are recognized and addressed, to ensure that community health worker programmes are effective and sustainable.


Dietary methionine restriction inhibits prostatic intraepithelial neoplasia in TRAMP mice.
Prostate cancer (PCa) is a major aging-related disease for which little progress has been made in developing preventive strategies. Over the past several years, methionine restriction (MR), the feeding of a diet low in methionine (Met), has been identified as an intervention which significantly extends lifespan and reduces the onset of chronic diseases, including cancer, in laboratory animals. We, therefore, hypothesized that MR may be an effective strategy for inhibiting PCa. Control (0.86% Met) or MR (0.12% Met) diets were fed to 5-week old TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice, a well-characterized model for PCa. The mice were sacrificed at 16 weeks of age and prostate and other tissues were harvested for histological and biochemical analyses. As previously reported, MR was associated with a decrease in body weight which was not associated with lowered food intake. MR led to significant reductions in the development of Prostatic Intraepithelial Neoplasia (PIN) lesions, specifically in the anterior and dorsal lobes of the prostate where the incidence of high-grade PIN was reduced by ∼50% (P < 0.02). The reduction in PIN severity was associated with 46-64% reductions in cell proliferation rates (P < 0.02) and plasma IGF-1 levels (P < 0.0001), which might, in part, explain the effects on carcinogenesis. Additionally, no adverse consequences of MR on immune function were observed in the TRAMP mice. Overall, these findings indicate that MR is associated with a reduction in prostate cancer development in the TRAMP model and supports the continued development of MR as a potential PCa prevention strategy.


'It is like a tomato stall where someone can pick what he likes': structure and practices of female sex work in Kampala, Uganda.
Effective interventions among female sex workers require a thorough knowledge of the context of local sex industries. We explore the organisation of female sex work in a low socio-economic setting in Kampala, Uganda. We conducted a qualitative study with 101 participants selected from an epidemiological cohort of 1027 women at high risk of HIV in Kampala. Repeat in-depth life history and work practice interviews were conducted from March 2010 to June 2011. Context specific factors of female sex workers' day-to-day lives were captured. Reported themes were identified and categorised inductively. Of the 101 women, 58 were active self-identified sex workers operating in different locations within the area of study and nine had quit sex work. This paper focuses on these 67 women who gave information about their involvement in sex work. The majority had not gone beyond primary level of education and all had at least one child. Thirty one voluntarily disclosed that they were HIV-positive. Common sex work locations were streets/roadsides, bars and night clubs. Typically sex occurred in lodges near bars/night clubs, dark alleyways or car parking lots. Overall, women experienced sex work-related challenges at their work locations but these were more apparent in outdoor settings. These settings exposed women to violence, visibility to police, a stigmatising public as well as competition for clients, while bars provided some protection from these challenges. Older sex workers tended to prefer bars while the younger ones were mostly based on the streets. Alcohol consumption was a feature in all locations and women said it gave them courage and helped them to withstand the night chill. Condom use was determined by clients' willingness, a woman's level of sobriety or price offered. Sex work operates across a variety of locations in the study area in Kampala, with each presenting different strategies and challenges for those operating there. Risky practices are present in all locations although they are higher on the streets compared to other locations. Location specific interventions are required to address the complex challenges in sex work environments.


Circulating microRNA's as a diagnostic tool for hepatocellular carcinoma in a hyper endemic HIV setting, KwaZulu-Natal, South Africa: a case control study protocol focusing on viral etiology.
A wide range of studies has investigated the diagnostic proficiency of extracellular microRNAs (miRNAs) in hepatocellular cancer (HCC). HCC is expected to increase in Sub-Saharan Africa (SSA), due to endemic levels of viral infection (HBV/HIV), ageing and changing lifestyles. This unique aetiological background provides an opportunity for investigating potentially novel circulating miRNAs as biomarkers for HCC in a prospective study in South Africa. This study will recruit HCC patients from two South African cancer hospitals, situated in Durban and Pietermaritzburg in the province of KwaZulu-Natal. These cases will include both HBV mono-infected and HBV/HIV co-infected HCC cases. The control group will consist of two (2) age and sex-matched healthy population controls per HCC case randomly selected from a Durban based laboratory. The controls will exclude patients if they have any evidence of chronic liver disease. A standardised reporting approach will be adopted to detect, quantify and normalize the level of circulating miRNAs in the blood sera of HCC cases and their controls. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) will be employed to quantity extracellular miRNAs. Differences in concentration of relevant miRNA by case/control status will be assessed using the Wilcoxon rank-sum (Mann-Whitney U) test. Adjustment for multiple testing (Bonferroni correction), receiver operating curves (ROC) and optimal breakpoint analyses will be employed to identify potential thresholds for the differentiation of miRNA levels of HCC cases and their controls. Although there is a growing base of literature regarding the role of circulating miRNAs as biomarkers, this promising field remains a 'work in progress'. The aetiology of HBV infection in HCC is well understood, as well as it's role in miRNA deregulation, however, the mediating role of HIV infection is unknown. HCC incidence in SSA, including South Africa, is expected to increase significantly in the next decade. A combination of factors, therefore, offers a unique opportunity to identify candidate circulating miRNAs as potential biomarkers for HBV/HIV infected HCC.


A case of Kaposi sarcoma in an immunocompetent, heterosexual Irish man: a discussion of etiology and viral transmission.
Four types of Kaposi sarcoma (KS) have been described, all of which are caused by human herpesvirus-8 (HHV-8). The incidence of KS in the United States is highest among HIV-positive homosexual men and elderly men of Eastern European, Jewish, or Mediterranean descent. However, few reports describe KS in HIV-negative, immunocompetent heterosexual men in the United States. HHV-8 is transmitted largely via saliva and close sexual contact, whereas there are only a handful of reports of transmission via blood and blood products. We report a case of an HIV-negative, immunocompetent heterosexual man who acquired KS via blood transfusion. A 77-year-old immunocompetent, monogamously heterosexual, HIV-negative Irish man presented with a biopsy-proven KS lesion on the right thigh. Past surgical history included a coronary artery bypass graft, during which he received a blood transfusion from an unknown donor source. His ecchymotic KS lesions progressed while on doxycycline, intralesional vinblastine, and topical anti-angiogenic medications. The patient eventually achieved stabilization of KS lesions with acitretin. Our case report emphasizes the need to characterize the phenotype and transmission route of HHV-8 in heterosexual, immunocompetent patients in geographic regions with low HHV-8 seroprevalence.


BCR-ABL gene rearrangement and expression of primitive hematopoietic progenitors in chronic myeloid leukemia.
Chronic myeloid leukemia (CML) is characterized by an initial chronic phase of expanded yet orderly clonal hematopoiesis that is distinguished by the BCR-ABL gene rearrangement. We found that although the mature myeloid compartment in patients with CML was expanded and entirely derived from the dominant leukemic clone, the primitive hematopoietic progenitor compartment did not show a corresponding expansion and was substantially enriched for cells without the BCR-ABL gene rearrangement. More importantly, primitive progenitors exhibiting the BCR-ABL gene rearrangement did not express either the BCR-ABL hybrid mRNA or fusion protein (P210). Expression of P210 protein and BCR-ABL mRNA increased with myeloid commitment in vivo as well as with growth factor-induced proliferation and differentiation of the primitive CML progenitors in vitro. This differential expression of BCR-ABL between primitive and mature CML progenitors may explain the expansion of the leukemic clone at the level of mature myeloid progenitors and granulocytes without a concomitant expansion of primitive CML progenitors. Because BCR-ABL mRNA is minimally expressed or may be absent in primitive CML progenitors, these cells may escape detection by reverse transcriptase-polymerase chain reaction and eradication by antisense oligonucleotides targeted against BCR-ABL mRNA.


The nitrogen handling characteristics of white clover (Trifolium repens L.) cultivars and a perennial ryegrass (Lolium perenne L.) cultivar.
Ryegrass (Lolium perenne L.) and white clover (Trifolium repens L.) have contrasting responses to soil mineral N availability and clover has the ability to fix atmospheric N(2) symbiotically. It has been hypothesized that these differences are the key to understanding grass-clover coexistence and vegetative dynamics in pastures. However, the whole plant response of clover and ryegrass to mineral N availability has not been fully characterized and inter-cultivar variability in the N-handling dynamics of clover has not been assessed. A detailed experimental study to address these issues was undertaken. For all clover cultivars and ryegrass, mass specific mineral N uptake rates (of whole plants) were similar saturating functions of mineral N availability. For all clover cultivars total N assimilation rates, whole plant C : N ratios and root : shoot ratios were independent of mineral N availability. Clover growth rates were also independent of mineral N availability except for a slight (<10%) reduction at very low N availability levels. Specific N(2) fixation rate (whole plant) was precisely controlled to ensure fixation balanced the deficit between mineral N uptake and the total N assimilation required to maintain constant whole plant C : N ratio. There was always a deficit between N uptake and the total N assimilation required to maintain C : N ratio. Consequently, some N(2) fixation remained engaged even at high mineral N availability levels. All inter-cultivar variation in N(2) fixation dynamics could be attributed to variations in growth rate. Clover mass specific growth rate declined as plant size increased. Ryegrass specific growth rate, whole plant C : N ratio and root : shoot ratio were dependent on N availability. Increased N availability led to increased growth rate and decreased C : N and root : shoot ratios. Specific growth rate was also dependent on plant size, growth rate declining as plant size increased. It is concluded that clover inter-cultivar variation in field performance is unlikely to be a consequence of variation in N-handling characteristics. Inter-cultivar differences in growth rate are likely to be a much more important source of variation.


Lower Paleolithic bone tools from the 'Spear Horizon' at Schöningen (Germany).
The Lower Paleolithic locality of Schöningen 13 II-4 is famous for the discovery of wooden spears found amongst the butchered remains of numerous horses and other large herbivores. Although the spears have attracted the most interest, other aspects of the associated artifact assemblage have received less attention. Here we describe an extraordinary assemblage of 88 bone tools from the 'Spear Horizon.' This sample includes numerous long-bone shaft fragments (mostly of horse), three ribs used as 'retouchers' to resharpen flint tools, and a complete horse innominate that was used as an anvil in bipolar knapping. Most of the retouchers were prepared by scraping the diaphysis of fresh and dry long-bones. Technological analysis of the associated lithic assemblage demonstrates exhaustive resharpening to maintain functional cutting edges. Whereas the flint tools were brought to the site, curated, and maintained, the retouchers had a shorter use-history and were either discarded after a limited period or broken to extract marrow. Horse and bison metapodials with flaked and rounded epiphyses are interpreted as hammers used to break marrow bones. Several of the 'metapodial hammers' were additionally used as knapping percussors. These constitute the earliest evidence of multi-purpose bone tools in the archeological record. Our results highlight the advanced knowledge in the use of bones as tools during the Lower Paleolithic, with major implications for understanding aspects of non-lithic technology and planning depth in early hominins.


Missed opportunities for the prevention of cardiovascular disease among British hypertensives in primary care.
High-risk strategies for the prevention of cardiovascular disease (CVD) among hypertensive patients require knowledge of the prevalence and interaction of modifiable risk factors to ensure effective targeting of interventions. Comparatively little is known of risk-factor profiles and their modification among hypertensives in primary care. The present study was designed to explore relationships between patients' knowledge of CVD risk factors, their perception of personal risk and health behaviours, and their use of lifestyle interventions. A cross-sectional survey of 2676 men and women with mild to moderate hypertension (diastolic blood pressure 95-115 mmHg), and their general practitioners, recruited from 1044 general practices throughout the UK, was conducted. Levels of modifiable risk factors were high, although there was considerable variation by age and sex; most (98.5%) patients had at least one additional CVD risk factor. A lower standard of living was associated with a higher prevalence of 'unhealthy' behaviours. Out of those with a current lifestyle problem, 85% of obese patients, 59% of smokers, 47% of excess drinkers, 49% of those with dietary risk factors and 32% of inactive patients claimed to have adopted healthier behaviours within the past 3 months. Older subjects and those with a lower standard of living were less likely to acknowledge risks, and those who did were less likely to report improving their lifestyles. While 71% of patients recalled receiving lifestyle advice, the coverage and targeting of specific interventions was generally poor. Overall, 60% of the sample had received advice on weight control, 47% on diet, 38% on exercise, 38% on smoking and 36% on alcohol. Women and older people were less likely to be given relevant counseling, and there was no evidence of targeting with respect to subjects' social class, level of hypertension or duration of diagnosis. Lifestyle interventions are welcomed and are viewed as helpful by patients receiving them. Potential health gains among high-risk hypertensives are being lost because of poor targeting and coverage of those at greatest risk.


Subthreshold dynamics of a single neuron from a Hamiltonian perspective.
We use Hamilton's equations of classical mechanics to investigate the behavior of a cortical neuron on the approach to an action potential. We use a two-component dynamic model of a single neuron, due to Wilson, with added noise inputs. We derive a Lagrangian for the system, from which we construct Hamilton's equations. The conjugate momenta are found to be linear combinations of the noise input to the system. We use this approach to consider theoretically and computationally the most likely manner in which such a modeled neuron approaches a firing event. We find that the firing of a neuron is a result of a drop in inhibition, due to a temporary increase in negative bias of the mean noise input to the inhibitory control equation. Moreover, we demonstrate through theory and simulation that, on average, the bias in the noise increases in an exponential manner on the approach to an action potential. In the Hamiltonian description, an action potential can therefore be considered a result of the exponential growth of the conjugate momenta variables pulling the system away from its equilibrium state, into a nonlinear regime.


Increased Mesenchymal Stem Cell Response and Decreased Staphylococcus aureus Adhesion on Titania Nanotubes without Pharmaceuticals.
Titanium (Ti) implants with enhanced biocompatibility and antibacterial property are highly desirable and characterized by improved success rates. In this study, titania nanotubes (TNTs) with various tube diameters were fabricated on Ti surfaces through electrochemical anodization at 10, 30, and 60 V (denoted as NT10, NT30, and NT60, resp.). Ti was also investigated and used as a control. NT10 with a diameter of 30 nm could promote the adhesion and proliferation of bone marrow mesenchymal stem cells (BMSCs) without noticeable differentiation. NT30 with a diameter of 100 nm could support the adhesion and proliferation of BMSCs and induce osteogenesis. NT60 with a diameter of 200 nm demonstrated the best ability to promote cell spreading and osteogenic differentiation; however, it clearly impaired cell adhesion and proliferation. As the tube diameter increased, bacterial adhesion on the TNTs decreased and reached the lowest value on NT60. Therefore, NT30 without pharmaceuticals could be used to increase mesenchymal stem cell response and decrease Staphylococcus aureus adhesion and thus should be further studied for improving the efficacy of Ti-based orthopedic implants.


Chordoid Meningioma - A Case Report: Clinicopathological Features and Differential Diagnosis of an Uncommon Tumor.
Meningiomas are tumors that originate from the arachnoid cell and the majority are benign and grade I tumors according to World Health Organization. Chordoid meningioma is an uncommon variant of meningioma and corresponds to grade II tumor in the World Health Organization Classification of Tumors of the Nervous System 2007 because of its more aggressive behavior and increased likelihood of recurrence. A 75-year-old female was referred to the neurosurgery department complaining of headache, syncope, and seizure. Radiological examination revealed a mass lesion in the neighbourhood of the frontal lobe that destructed bone and was associated with peritumoral edema. The patient underwent surgery. The tumor was totally excised with the dura beneath. Histopathological examination showed that the tumor was composed of clusters and cords of small polygonal cells with fine chromatin and eosinophilic vacuolated cytoplasm embedded in a myxoid matrix, and also focal whorls of spindle-shaped cells. Two mitoses were seen in 10 high power fields. Vascular proliferation was observed in some tumoral areas. Bone invasion was present. Immunohistochemical analysis of the tumor cells revealed widespread strong membranous and cytoplasmic expression of epithelial membrane antigen. The Ki67 labeling index was 6-8%. All of these findings were consistent with a diagnosis of chordoid meningioma, the neoplasm was identified as grade II based on the World Health Organization Classification, 2007. In this report we present a case of chordoid meningioma without classical radiological findings of meningioma with areas of vascular proliferation that mimicked glial tumors at histopathologic examination.


eMap: A Web Application for Identifying and Visualizing Electron or Hole Hopping Pathways in Proteins.
eMap is a web-based platform for identifying and visualizing electron or hole transfer pathways in proteins based on their crystal structures. The underlying model can be viewed as a coarse-grained version of the Pathways model, where each tunneling step between hopping sites represented by electron transfer active (ETA) moieties is described with one effective decay parameter that describes protein-mediated tunneling. ETA moieties include aromatic amino acid residue side chains and aromatic fragments of cofactors that are automatically detected, and, in addition, electron/hole residing sites that can be specified by the users. The software searches for the shortest paths connecting the user-specified electron/hole source to either all surface-exposed ETA residues or the user-specified target. The identified pathways are ranked according to their effective length. The pathways are visualized in 2D as a graph, in which each node represents an ETA site, and in 3D using available protein visualization tools. Here, we present the capability and user interface of eMap 1.0, which is available at https://emap.bu.edu .


The subthalamic nucleus during decision-making with multiple alternatives.
Several prominent neurocomputational models predict that an increase of choice alternatives is modulated by increased activity in the subthalamic nucleus (STN). In turn, increased STN activity allows prolonged accumulation of information. At the same time, areas in the medial frontal cortex such as the anterior cingulate cortex (ACC) and the pre-SMA are hypothesized to influence the information processing in the STN. This study set out to test concrete predictions of STN activity in multiple-alternative decision-making using a multimodal combination of 7 Tesla structural and functional Magnetic Resonance Imaging, and ancestral graph (AG) modeling. The results are in line with the predictions in that increased STN activity was found with an increasing amount of choice alternatives. In addition, our study shows that activity in the ACC is correlated with activity in the STN without directly modulating it. This result sheds new light on the information processing streams between medial frontal cortex and the basal ganglia.


Aptamer targeted therapy potentiates immune checkpoint blockade in triple-negative breast cancer.
Triple-negative breast cancer (TNBC) is a uniquely aggressive cancer with high rates of relapse due to resistance to chemotherapy. TNBC expresses higher levels of programmed cell death-ligand 1 (PD-L1) compared to other breast cancers, providing the rationale for the recently approved immunotherapy with anti-PD-L1 monoclonal antibodies (mAbs). A huge effort is dedicated to identify actionable biomarkers allowing for combination therapies with immune-checkpoint blockade. Platelet-derived growth factor receptor β (PDGFRβ) is highly expressed in invasive TNBC, both on tumor cells and tumor microenvironment. We recently proved that tumor growth and lung metastases are impaired in mouse models of human TNBC by a high efficacious PDGFRβ aptamer. Hence, we aimed at investigating the effectiveness of a novel combination treatment with the PDGFRβ aptamer and anti-PD-L1 mAbs in TNBC. The targeting ability of the anti-human PDGFRβ aptamer toward the murine receptor was verified by streptavidin-biotin assays and confocal microscopy, and its inhibitory function by transwell migration assays. The anti-proliferative effects of the PDGFRβ aptamer/anti-PD-L1 mAbs combination was assessed in human MDA-MB-231 and murine 4 T1 TNBC cells, both grown as monolayer or co-cultured with lymphocytes. Tumor cell lysis and cytokines secretion by lymphocytes were analyzed by LDH quantification and ELISA, respectively. Orthotopic 4 T1 xenografts in syngeneic mice were used for dissecting the effect of aptamer/mAb combination on tumor growth, metastasis and lymphocytes infiltration. Ex vivo analyses through immunohistochemistry, RT-qPCR and immunoblotting were performed. We show that the PDGFRβ aptamer potentiates the anti-proliferative activity of anti-PD-L1 mAbs on both human and murine TNBC cells, according to its human/mouse cross-reactivity. Further, by binding to activated human and mouse lymphocytes, the aptamer enhances the anti-PD-L1 mAb-induced cytotoxicity of lymphocytes against tumor cells. Importantly, the aptamer heightens the antibody efficacy in inhibiting tumor growth and lung metastases in mice. It acts on both tumor cells, inhibiting Akt and ERK1/2 signaling pathways, and immune populations, increasing intratumoral CD8 + T cells and reducing FOXP3 + Treg cells. Co-treatment of PDGFRβ aptamer with anti-PD-L1 mAbs is a viable strategy, thus providing for the first time an evidence of the efficacy of PDGFRβ/PD-L1 co-targeting combination therapy in TNBC.


Reconstructible phylogenetic networks: do not distinguish the indistinguishable.
Phylogenetic networks represent the evolution of organisms that have undergone reticulate events, such as recombination, hybrid speciation or lateral gene transfer. An important way to interpret a phylogenetic network is in terms of the trees it displays, which represent all the possible histories of the characters carried by the organisms in the network. Interestingly, however, different networks may display exactly the same set of trees, an observation that poses a problem for network reconstruction: from the perspective of many inference methods such networks are "indistinguishable". This is true for all methods that evaluate a phylogenetic network solely on the basis of how well the displayed trees fit the available data, including all methods based on input data consisting of clades, triples, quartets, or trees with any number of taxa, and also sequence-based approaches such as popular formalisations of maximum parsimony and maximum likelihood for networks. This identifiability problem is partially solved by accounting for branch lengths, although this merely reduces the frequency of the problem. Here we propose that network inference methods should only attempt to reconstruct what they can uniquely identify. To this end, we introduce a novel definition of what constitutes a uniquely reconstructible network. For any given set of indistinguishable networks, we define a canonical network that, under mild assumptions, is unique and thus representative of the entire set. Given data that underwent reticulate evolution, only the canonical form of the underlying phylogenetic network can be uniquely reconstructed. While on the methodological side this will imply a drastic reduction of the solution space in network inference, for the study of reticulate evolution this is a fundamental limitation that will require an important change of perspective when interpreting phylogenetic networks.


Impact of body mass index on 30-day outcomes after spinopelvic fixation surgery.
Obesity is one of the most prevalent chronic diseases associated with degenerative spinal disease. There is limited evidence regarding the short-term outcome of patients with elevated BMI following spinopelvic fixation surgery. We used the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database from 2013 to 2014. Inclusion criteria included: adults, aged 18 and older, who underwent all-cause spinopelvic fixation surgery. Primary outcome measures were 30-day readmission, reoperation, and major complication rates. Logistic regression analysis was used to assess the effect of elevated body mass index (BMI) on 30-day outcome. A total of 618 patients met inclusion criteria stratified into levels of BMI: 11.2% were Class 2 obese and 10.3% were Class 3 obese. Significant differences were found between the classes for the incidence of revision surgery, reoperations, and deep wound infections. However, there were no significant increases in readmissions and major complications rates, and only Class 3 obese patients had significantly higher odds of reoperation than those who were not obese. Significant differences between all classes of obesity regarding revision surgery, reoperation, and deep wound infection rates were found. Class 3 obese patients had significantly higher odds of reoperation, most likely attributed to the greater number/severity of preoperative comorbidities.


Virulence difference between the prototypic Schu S4 strain (A1a) and Francisella tularensis A1a, A1b, A2 and type B strains in a murine model of infection.
The use of prototypic strains is common among laboratories studying infectious agents as it promotes consistency for data comparability among and between laboratories. Schu S4 is the prototypic virulent strain of Francisella tularensis and has been used extensively as such over the past six decades. Studies have demonstrated virulence differences among the two clinically relevant subspecies of F. tularensis, tularensis (type A) and holarctica (type B) and more recently between type A subpopulations (A1a, A1b and A2). Schu S4 belongs to the most virulent subspecies of F. tularensis, subspecies tularensis. In this study, we investigated the relative virulence of Schu S4 in comparison to A1a, A1b, A2 and type B strains using a temperature-based murine model of infection. Mice were inoculated intradermally and a hypothermic drop point was used as a surrogate for death. Survival curves and the length of temperature phases were compared for all infections. Bacterial burdens were also compared between the most virulent type A subpopulation, A1b, and Schu S4 at drop point. Survival curve comparisons demonstrate that the Schu S4 strain used in this study resembles the virulence of type B strains, and is significantly less virulent than all other type A (A1a, A1b and A2) strains tested. Additionally, when bacterial burdens were compared between mice infected with Schu S4 or MA00-2987 (A1b) significantly higher burdens were present in the blood and spleen of mice infected with MA00-2987. The knowledge gained from using Schu S4 as a prototypic virulent strain has unquestionably advanced the field of tularemia research. The findings of this study, however, indicate that careful consideration of F. tularensis strain selection must occur when the overall virulence of the strain used could impact the outcome and interpretation of results.


Compatibility of motion information in two aircraft attitude displays for a tracking task.
In a conventional aircraft attitude indicator, the artificial horizon moves in the direction opposite to the pilot's hands and the movement of the aircraft. This horizon-moving format is believed to be response-effect (R-E) incompatible. An alternative format, aircraft-moving, presents movement of the aircraft symbol that is compatible with both the pilot's hand movements and the movement of the aircraft. In the present study, nonpilot participants performed an attitude tracking task with a horizon-moving or aircraft-moving display for 6 training sessions and 1 transfer session in which the display was switched to the other format. The participants performed the task equally well and showed similar rates of improvement with the 2 displays. However, a switch of display format degraded tracking performance, indicating that learned skills did not transfer between formats. The results of a secondary choice reaction task, performed concurrently during tracking, suggested that attention can be divided between visual and auditory modalities better with the horizon-moving display than with the aircraft-moving display. We argue that the horizon-moving format is R-E compatible, as far as the tracking task is concerned, and that the effects of display format on the secondary task may be due to different modes of spatial representation being used to monitor the formats.


Chemotherapy of advanced epithelial cancer--a critical review.
This article is a short version of a report which presents a comprehensive analysis of clinical trials and publications examining the value of cytotoxic chemotherapy in the treatment of advanced epithelial cancer. As a result of the analysis and the comments received from hundreds of oncologists in reply to a request for information, the following facts can be noted. Apart from lung cancer, in particular small-cell lung cancer, there is no direct evidence that chemotherapy prolongs survival in patients with advanced carcinoma. Except for ovarian cancer, available indirect evidence rather supports the absence of a positive effect. In treatment of lung cancer and ovarian cancer, the therapeutical benefit is at best rather small, and a less aggressive treatment seems to be at least as effective as the usual one. It is possible that certain sub-groups of patients benefit from the treatment, yet so far the available results do not allow a sufficiently precise definition of these groups. Many oncologists take it for granted that response to therapy prolongs survival, an opinion which is based on a fallacy and which is not supported by clinical studies. To date, it is unclear whether the treated patients, as a whole, benefit from chemotherapy as to their quality of life. For most cancer sites, urgently required types of studies such as randomized de-escalations of dose or comparisons of immediate versus deferred chemotherapy are still lacking. With few exceptions, there is no good scientific basis for the application of chemotherapy in symptom-free patients with advanced epithelial malignancy.


How many child deaths can we prevent this year?
This is the second of five papers in the child survival series. The first focused on continuing high rates of child mortality (over 10 million each year) from preventable causes: diarrhoea, pneumonia, measles, malaria, HIV/AIDS, the underlying cause of undernutrition, and a small group of causes leading to neonatal deaths. We review child survival interventions feasible for delivery at high coverage in low-income settings, and classify these as level 1 (sufficient evidence of effect), level 2 (limited evidence), or level 3 (inadequate evidence). Our results show that at least one level-1 intervention is available for preventing or treating each main cause of death among children younger than 5 years, apart from birth asphyxia, for which a level-2 intervention is available. There is also limited evidence for several other interventions. However, global coverage for most interventions is below 50%. If level 1 or 2 interventions were universally available, 63% of child deaths could be prevented. These findings show that the interventions needed to achieve the millennium development goal of reducing child mortality by two-thirds by 2015 are available, but that they are not being delivered to the mothers and children who need them.


Oral manifestations of renal tubular acidosis associated with secondary rickets: case report.
This report describes the oral manifestations of renal tubular acidosis (RTA) associated with secondary rickets and discusses the biological plausibility of these findings. The characteristic electrolyte changes during RTA or genetic mutations that trigger RTA may be responsible for impaired amelogenesis, dental malocclusion, impacted teeth, and absent lamina dura. This report reinforces the possibility of an association between RTA and the oral manifestations described.


Induction of stress by the swimbladder nematode Anguillicola crassus in European eels, Anguilla anguilla, after repeated experimental infection.
The purpose of this study was to determine under laboratory conditions over a period of 311 days if infection with the nematode Anguillicola crassus induces stress in European eels (Anguilla anguilla), and stimulates the endocrine stress axis as measured by serum cortisol levels. Eels were experimentally infected with 3rd-stage larvae (L3) in different doses to simulate natural conditions with varying infection pressures. Blood samples were drawn from the caudal vein every 2 weeks and serum cortisol concentrations were determined by radioimmunoassay (RIA). The results showed that the application of L3 resulted in a significant increase in the cortisol levels. The period of time at which elevated cortisol values were observed was consistent with the time of larval development and the appearance of adult A. crassus. Thus, there is a stress response to the larval and young adult stages, but no chronic response to older adults. Therefore, it is likely that infection of eels under natural conditions especially with a high number of larvae may be a considerable stressor, in combination with different environmental factors like water temperature, pH, oxygen concentration, pollution and interindividual relationships.


Using sexually transmitted infection biomarkers to validate reporting of sexual behavior within a randomized, experimental evaluation of interviewing methods.
This paper examines the reporting of sexual and other risk behaviors within a randomized experiment using a computerized versus face-to-face interview mode. Biomarkers for sexually transmitted infection (STI) were used to validate self-reported behavior by interview mode. As part of a parent study evaluating home versus clinic screening and diagnosis for STIs, 818 women aged 18-40 years were recruited in 2004 at or near a primary care clinic in São Paulo, Brazil, and were randomized to a face-to-face interview or audio computer-assisted self-interviewing. Ninety-six percent of participants were tested for chlamydia, gonorrhea, and trichomoniasis. Reporting of STI risk behavior was consistently higher with the computerized mode of interview. Stronger associations between risk behaviors and STI were found with the computerized interview after controlling for sociodemographic factors. These results were obtained by using logistic regression approaches, as well as statistical methods that address potential residual confounding and covariate endogeneity. Furthermore, STI-positive participants were more likely than STI-negative participants to underreport risk behavior in the face-to-face interview. Results strongly suggest that computerized interviewing provides more accurate and reliable behavioral data. The analyses also confirm the benefits of using data on prevalent STIs for externally validating behavioral reporting.


A training program to improve neuromuscular and performance indices in female high school basketball players.
The purpose of this study was to determine if a sports-specific training program could improve neuromuscular and performance indices in female high school basketball players. We combined components from a published anterior cruciate ligament injury prevention program for jump and strength training with other exercises and drills to improve speed, agility, overall strength, and aerobic conditioning. We hypothesized that this sports-specific training program would lead to significant improvements in neuromuscular and performance indices in high school female basketball players. Fifty-seven female athletes aged 14-17 years participated in the supervised 6-week program, 3 d·wk(-1) for approximately 90-120 minutes per session. The program was conducted on the basketball court and in weight room facilities in high schools. The athletes underwent a video drop-jump test, multistage fitness test, vertical jump test, and an 18-m sprint test before and upon completion of the training program. All the subjects attended at least 14 training sessions. After training, a significant increase was found in the mean estimated VO2max (p < 0.001), with 89% of the athletes improving this score. In the drop-jump video test, significant increases were found in the mean absolute knee separation distance (p < 0.0001) and in the mean normalized knee separation distance (p < 0.0001), indicating a more neutral lower limb alignment on landing. A significant improvement was found in the vertical jump test (p < 0.0001); however, the effect size was small (0.09). No improvement was noted in the sprint test. This program significantly improved lower limb alignment on a drop-jump test and estimated maximal aerobic power and may be implemented preseason or off-season in high school female basketball players.


High-resolution FTIR imaging of colon tissues for elucidation of individual cellular and histopathological features.
Novel technologies that could complement current histopathology based cancer diagnostic methods are under examination. In this endeavour mid-infrared spectroscopic imaging is a promising candidate that can provide valuable bio-molecular information from unstained cells and tissues in a rapid and a non-destructive manner. With this imaging technique, the biochemical information obtained from smaller areas of the tissues can be of clinical significance and hence the measured pixel size. Until recently it was difficult to obtain spectral data from pixels below around 5 microns square. High NA objectives have been utilised to reduce the ideal diffraction limit, enabling for the first time elucidation of subcellular features. In this context, the ability of high-resolution imaging, obtained using novel high-magnification optics retro-fitted onto a bench top FTIR imaging system, to characterise histopathological features in colonic tissues has been tested. Formalin fixed paraffin embedded colon tissues from three different pathologies were imaged directly using the conventional and the high-magnification imaging set-ups. To circumvent chemical de-paraffinization protocols, an extended multiplicative signal correction (EMSC) based electronic de-paraffinization was carried out on all the infrared images. Multivariate analysis of the high-magnification infrared imaging data showed a detailed information of the histological features of the colon tissue in comparison to conventional imaging. Furthermore, high-magnification imaging has enabled a label-free characterization of the mucin rich goblet cell features in an unprecedented manner. The current study demonstrates the applicability of high-magnification FTIR imaging to characterise complex tissues on a smaller scale that could be of clinical significance.


Araport11: a complete reannotation of the Arabidopsis thaliana reference genome.
The flowering plant Arabidopsis thaliana is a dicot model organism for research in many aspects of plant biology. A comprehensive annotation of its genome paves the way for understanding the functions and activities of all types of transcripts, including mRNA, the various classes of non-coding RNA, and small RNA. The TAIR10 annotation update had a profound impact on Arabidopsis research but was released more than 5 years ago. Maintaining the accuracy of the annotation continues to be a prerequisite for future progress. Using an integrative annotation pipeline, we assembled tissue-specific RNA-Seq libraries from 113 datasets and constructed 48 359 transcript models of protein-coding genes in eleven tissues. In addition, we annotated various classes of non-coding RNA including microRNA, long intergenic RNA, small nucleolar RNA, natural antisense transcript, small nuclear RNA, and small RNA using published datasets and in-house analytic results. Altogether, we identified 635 novel protein-coding genes, 508 novel transcribed regions, 5178 non-coding RNAs, and 35 846 small RNA loci that were formerly unannotated. Analysis of the splicing events and RNA-Seq based expression profiles revealed the landscapes of gene structures, untranslated regions, and splicing activities to be more intricate than previously appreciated. Furthermore, we present 692 uniformly expressed housekeeping genes, 43% of whose human orthologs are also housekeeping genes. This updated Arabidopsis genome annotation with a substantially increased resolution of gene models will not only further our understanding of the biological processes of this plant model but also of other species.


Hydrogen adsorption in metal-organic frameworks: the role of nuclear quantum effects.
The role of nuclear quantum effects on the adsorption of molecular hydrogen in metal-organic frameworks (MOFs) has been investigated on grounds of Grand-Canonical Quantized Liquid Density-Functional Theory (GC-QLDFT) calculations. For this purpose, we have carefully validated classical H2-host interaction potentials that are obtained by fitting Born-Oppenheimer ab initio reference data. The hydrogen adsorption has first been assessed classically using Liquid Density-Functional Theory and the Grand-Canonical Monte Carlo methods. The results have been compared against the semi-classical treatment of quantum effects by applying the Feynman-Hibbs correction to the Born-Oppenheimer-derived potentials, and by explicit treatment within the GC-QLDFT. The results are compared with experimental data and indicate pronounced quantum and possibly many-particle effects. After validation calculations have been carried out for IRMOF-1 (MOF-5), GC-QLDFT is applied to study the adsorption of H2 in a series of MOFs, including IRMOF-4, -6, -8, -9, -10, -12, -14, -16, -18, and MOF-177. Finally, we discuss the evolution of the H2 quantum fluid with increasing pressure and lowering temperature.


Perceived social status and mental health among young adolescents: Evidence from census data to cellphones.
Adolescents in the United States live amid high levels of concentrated poverty and increasing income inequality. Poverty is robustly linked to adolescents' mental health problems; however, less is known about how perceptions of their social status and exposure to local area income inequality relate to mental health. Participants consisted of a population-representative sample of over 2,100 adolescents (ages 10-16), 395 of whom completed a 14-day ecological momentary assessment (EMA) study. Participants' subjective social status (SSS) was assessed at the start of the EMA, and mental health symptoms were measured both at baseline for the entire sample and daily in the EMA sample. Adolescents' SSS tracked family, school, and neighborhood economic indicators (|r| ranging from .12 to .30), and associations did not differ by age, race, or gender. SSS was independently associated with mental health, with stronger associations among older (ages 14-16) versus younger (ages 10-13) adolescents. Adolescents with lower SSS reported higher psychological distress and inattention problems, as well as more conduct problems, in daily life. Those living in areas with higher income inequality reported significantly lower subjective social status, but this association was explained by family and neighborhood income. Findings illustrate that adolescents' SSS is correlated with both internalizing and externalizing mental health problems, and that by age 14 it becomes a unique predictor of mental health problems. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Pathogenic mitochondrial tRNA point mutations: nine novel mutations affirm their importance as a cause of mitochondrial disease.
Mutations in the mitochondrial genome, and in particular the mt-tRNAs, are an important cause of human disease. Accurate classification of the pathogenicity of novel variants is vital to allow accurate genetic counseling for patients and their families. The use of weighted criteria based on functional studies-outlined in a validated pathogenicity scoring system--is therefore invaluable in determining whether novel or rare mt-tRNA variants are pathogenic. Here, we describe the identification of nine novel mt--tRNA variants in nine families, in which the probands presented with a diverse range of clinical phenotypes including mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes, isolated progressive external ophthalmoplegia, epilepsy, deafness and diabetes. Each of the variants identified (m.4289T>C, MT-TI; m.5541C>T, MT-TW; m.5690A>G, MT-TN; m.7451A>T, MT-TS1; m.7554G>A, MT-TD; m.8304G>A, MT-TK; m.12206C>T, MT-TH; m.12317T>C, MT-TL2; m.16023G>A, MT-TP) was present in a different tRNA, with evidence in support of pathogenicity, and where possible, details of mutation transmission documented. Through the application of the pathogenicity scoring system, we have classified six of these variants as "definitely pathogenic" mutations (m.5541C>T, m.5690A>G, m.7451A>T, m.12206C>T, m.12317T>C, and m.16023G>A), whereas the remaining three currently lack sufficient evidence and are therefore classed as 'possibly pathogenic' (m.4289T>C, m.7554G>A, and m.8304G>A).


Absence of strand breaks in deoxyribonucleic acid treated with metronidazole.
The deoxyribonucleic acid (DNA)-degrading potential of metronidazole was evaluated in vitro by three techniques: determination of melting curve, measurement of viscosity, and centrifugation in neutral or alkaline sucrose gradients. Studies were performed on calf thymus DNA and on (3)H-labeled or unlabeled pneumococcal and T7 phage DNA after treatment with metronidazole alone or metronidazole reduced by sodium dithionite in the presence of DNA. This latter process is known to elicit covalent binding of metronidazole to DNA. Reduced or unreduced metronidazole had no effect on the melting properties, viscosity, or sedimentation velocity of the nucleic acids studied. Sodium dithionite alone, however, caused a 25% decrease in the intrinsic viscosity of pneumococcal DNA, and decreased the sedimentation velocity of pneumococcal and T7 phage DNA in both neutral and alkaline sucrose gradients. These data suggest that degradation of DNA is not important in the interaction of metronidazole with nucleic acids, an interaction assumed relevant to the cytotoxic, radiosensitizing, and mutagenic activities of this compound.


Changes in Zn homeostasis during long term culture of primary endothelial cells and effects of Zn on endothelial cell senescence.
Endothelial cell senescence and Zn nutritional status influence cardiovascular disease. The influence of Zn appears dichotomous, hence it is imperative to understand the relationship with cellular senescence to improve knowledge about the molecular and cellular basis of the disease. Here we aimed to determine: 1) the impact of chronic exposure to a moderately high dose of Zn on senescence of endothelial cells; 2) the changes in Zn homeostasis during the lifespan of primary cultured endothelial cells; and 3) the susceptibility of proliferating and senescent endothelial cells to cell death after short term exposure to increasing doses of Zn and of the Zn chelator TPEN. Chronic exposure to Zn accelerated senescence and untreated cells at later passages, where doubling time had increased, displayed relocation of labile Zn and altered expression of genes involved in the response to Zn toxicity, including SLC30A1, SLC39A6, SLC30A5, SLC30A10 and metallothioneins, indicating that senescent cells have altered zinc homeostasis. Most Zn-dependent genes that were expressed differently between early and late passages were correlated with changes in the expression of anti-apoptotic genes. Short-term treatment with a high dose of Zn leads to cell death, but only in the population of cells at both earlier and later passages that had already entered senescence. In contrast, Zn depletion led to death of cells at earlier but not later passages, which suggests that there are sub-populations of senescent cells that are resistant to Zn depletion. This resistant senescent cell population may accumulate under conditions of Zn deficiency and contribute to vascular pathology.


Development of a triage tool for neurodevelopmental risk in children aged 30 months.
Neurodevelopmental and neuropsychiatric disorders in young children predict educational, health and social problems. Early identification may significantly reduce this burden but relevant tools largely lack validation. We aimed to develop and evaluate the predictive validity of a simple screening tool for neurodevelopmental problems in a community sample of 30 month old children. A sample of children was selected from a community cohort screened at 30 months by health visitors using the Sure Start Language Measure (SSLM) and the Strengths and Difficulties Questionnaire (SDQ) in 2011. Predictive validity was assessed by comparing screening results with detailed psychometric data from the same sample 1-2 years later. Screening performance using different thresholds was explored using Receiver Operating Characteristic (ROC) with ROC area under the curve (AUC) and bootstrapping techniques. The SSLM predicted both language disorder identified by the New Reynell Developmental Language Scales (NRDLS) at follow-up (AUC 0.905) and global developmental delay assessed by the Griffiths Mental Development Scales (AUC 0.983). The SDQ administered at 30 months predicted psychiatric disorders identified by the Development and Wellbeing Assessment (DAWBA) at follow-up (AUC 0.821). Using optimal cut-offs for the SDQ and SSLM at 30 months, both tools together had sensitivity 87%; specificity 64%; positive predictive value 31%; and negative predictive value 97% in the prediction of any kind of neurodevelopmental problem 1-2 years later. The combined measure reported here is not yet sufficient as a stand-alone population screening tool for neurodevelopmental disorders. The SSLM and SDQ did however show promise in identifying preschool children at risk of ongoing language, psychiatric disorders and global developmental delay 1-2 years later but with fairly high false positive rates. Given that current developmental risk prediction in resource-poor settings is little better than random assignment, the SDQ and SSLM may aid clinical judgement when used as interim triage tools for practitioners with no specialist knowledge, in the context of longitudinal follow-up arrangements.


In vivo glycyrrhizin accelerates liver regeneration and rapidly lowers serum transaminase activities in 70% partially hepatectomized rats.
The in vivo effects of glycyrrhizin on restoration of liver mass and recovery of liver function were compared with those of epidermal growth factor (EGF), ibuprofen and dexamethasone in 70% partially hepatectomized rats. Hepatic regenerative activity was assessed based on the ratio of liver weight to 100 g body weight, and 5-bromo-2'-deoxyuridine (BrdU) incorporation into hepatocyte DNA in the remnant liver. Glycyrrhizin (50 mg/kg/day, i.p.)- or EGF (1.0 microg/kg/day, i.p.)-treated rats showed an approx. 1.4-fold increase in liver weight/100 g body weight ratio over saline-treated control rats on days 2 and 3 after 70% partial hepatectomy. BrdU labeling index in the remnant regenerating liver was significantly higher in glycyrrhizin- or EGF-treated rats when compared with saline-treated control rats on days 0.5 and 1. Ibuprofen (100 mg/kg/day, i.p.) and dexamethasone (0.1 mg/kg/day, i.p.) did not significantly increase either liver weight/100 g body weight ratio or BrdU labeling index. Serum activity of liver-related transaminases, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), elevated rapidly on day 1 and decreased to near pre-operative levels on day 5 after 70% partial hepatectomy in saline-treated control rats. Injection of glycyrrhizin or EGF significantly decreased the elevated serum ALT and AST activities on days 2 and 3 after hepatectomy when compared with saline-treated control rats. The transaminase-lowering effects of glycyrrhizin or EGF were smaller than those of ibuprofen and dexamethasone. These results demonstrate that injection of glycyrrhizin or EGF significantly enhances regeneration of liver mass and function, as well as recovery from the liver damage induced by surgical resection.


Projected-wave-function study of the spin-1/2 Heisenberg model on the Kagomé lattice.
We perform a Gutzwiller projected-wave-function study for the spin-1/2 Heisenberg model on the Kagomé lattice to compare energies of several spin-liquid states. The result indicates that a U(1)-Dirac spin-liquid state has the lowest energy. Furthermore, even without variational parameters, the energy turns out to be very close to that found by exact diagonalization. We show that such a U(1)-Dirac state represents a quantum phase whose low-energy physics is governed by four flavors of two-component Dirac fermions coupled to a U(1) gauge field. These results are discussed in the context of recent experiments on ZnCu(3)(OH)(6)Cl(2).


White Matter Damage in the Semantic Variant of Primary Progressive Aphasia.
The semantic variant of primary progressive aphasia (svPPA) is a form of dementia, mainly featuring language impairment, for which the extent of white matter (WM) damage is less described than its associated grey matter (GM) atrophy. Our study aimed to characterise the extent of this damage using a sensitive and unbiased approach. We conducted a between-group study comparing 10 patients with a clinical diagnosis of svPPA, recruited between 2011 and 2014 at a tertiary reference centre, with 9 cognitively healthy, age-matched controls. From diffusion tensor imaging (DTI) data, we extracted fractional anisotropy (FA) values using a tract-based spatial statistics approach. We further obtained GM volumetric data using the Freesurfer automated segmentation tool. We compared both groups using non-parametric Wilcoxon rank-sum tests, correcting for multiple comparisons. Demographic data showed that patients and controls were comparable. As expected, clinical data showed lower results in svPPA than controls on cognitive screening tests. Tractography showed impaired diffusion in svPPA patients, with FA mostly decreased in the longitudinal, uncinate, cingulum and external capsule fasciculi. Volumetric data show significant atrophy in svPPA patients, mostly in the left entorhinal, amygdala, inferior temporal, middle temporal, superior temporal and temporal pole cortices, and bilateral fusiform gyri. This syndrome appears to be associated not only with GM but also significant WM degeneration. Thus, DTI could play a role in the differential diagnosis of atypical dementia by specifying WM damage specific to svPPA.


UPLC-MS/MS Analysis of Urinary Free Oligosaccharides for Lysosomal Storage Diseases: Diagnosis and Potential Treatment Monitoring.
The glycoproteinoses are a subgroup of lysosomal storage diseases (LSDs) resulting from impaired degradation of N-linked oligosaccharide side chains of glycoproteins, which are commonly screened by detecting the accumulated free oligosaccharides (FOSs) in urine via thin layer chromatography (TLC). The traditional TLC method suffers from limited analytical sensitivity and specificity and lacks quantification capability. Therefore, we developed an analytically sensitive and relatively specific assay using ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) for urinary FOS analysis and validated its use for urine screening of glycoproteinoses and other LSDs. Urine volumes equivalent to 30 μg of creatinine were derivatized with butyl-4-aminobenzoate and then purified through a solid-phase extraction cartridge. A 7-min UPLC-MS/MS analysis was performed on a triple quadrupole mass spectrometer using an amide column for separation of derivatized FOS. Urine samples from >100 unaffected controls and 37 patients with various LSDs were studied. Relative quantification was conducted on 7 selected FOSs using a single internal standard, which allowed the identification of patients with 1 of 8 different LSDs: aspartylglucosaminuria, α-fucosidosis, α-mannosidosis, β-mannosidosis, β-galactosidase deficiency, Sandhoff disease, sialidosis, and galactosialidosis. Patients treated with hematopoietic stem cell transplant show decreased FOS responses compared with untreated patients. This UPLC-MS/MS assay offers a valuable tool for screening of glycoproteinoses and other LSDs, with potential use for future treatment monitoring.


Animal drug shortages limit veterinary therapeutic options and introduce artifacts in antimicrobial sales reporting.
Supply chain issues disrupt veterinary care and cause downstream consequences that alter the practice of veterinary medicine. Antimicrobials are just 1 class of pharmaceuticals that have been impacted by supply chain issues over the last couple of years. Since February 2021, 2 sponsors/manufacturers of penicillin products have reported shortages in the active pharmaceutical ingredient. With the release of the 2021 Summary Report on Antimicrobials Sold or Distributed for Use in Food-Producing Animals by the FDA, a key finding was a 19% decrease in penicillin sales and distribution from 2020 to 2021. Herein, we provide our clinicians' professional perspective regarding how drug shortages, specifically that of penicillin, might contribute to misconstrued patterns in antimicrobial use and what can be done by veterinarians and the FDA to minimize the impact of an antimicrobial drug shortage on animal health and well-being.


7-Hydroxylated derivatives of dehydroepiandrosterone in the human ventricular cerebrospinal fluid.
Dehydroepiandrosterone is a long established neuroactive steroid. Some authors documented that 7-oxygenated derivatives of this steroid may be responsive at least by part for its physiological activity. In the ventricular cerebrospinal fluid obtained from 15 patients with hydrocephalus (8 postmenopausal women and 7 men) potentially neuroactive steroid 7-oxygenated derivatives of dehydroepiandrosterone were quantified using gas chromatography/mass spectrometry. Besides free dehydroepiandrosterone 7-oxygenated steroids such as 7alpha- and 7beta-hydroxy-dehydroepiandrosterone, 5-androstene-3beta,7alpha,17beta-triol and 5-androstene-3beta,7beta,17beta-triol in picomolar concentration in serum and cerebrospinal fluid were found. Dehydroepiandrosterone and its 7-oxygenated derivatives are present in ventricular cerebrospinal fluid in concentration 2 -100 times lower than in serum.


Differential effect of auxotrophies on the release of macromolecules by Salmonella enterica vaccine strains.
Attenuated Salmonella enterica strains have been widely used as live carriers for vaccines and therapeutic molecules. Appropriate attenuation has been introduced into such bacteria for safety reasons and the improvement of strain properties. Here, we compared two strains that were rendered auxotroph for diaminopimelic acid or thymidine monophosphate precursors by deletion of the genes asd or thyA, respectively. Upon removal of the complementing compound from bacterial cultures, both strains quickly lose their property to form colonies. However, while the Deltaasd bacteria lysed almost immediately under such conditions, DeltathyA bacteria remained physically intact during the observation period. As a consequence, the Deltaasd bacteria released their intracellular content such as proteins or plasmids into the supernatant. In contrast, no intracellular component, either proteins or plasmids, could be recovered from the supernatants of DeltathyA bacteria upon depletion of thymidine. Thus, the release of macromolecules from the bacterial carrier occurs as a consequence of appropriate lethal attenuation. This might substitute for sophisticated secretion systems.


Trained facilitators' experiences with structured advance care planning conversations in oncology: an international focus group study within the ACTION trial.
In oncology, Health Care Professionals often experience conducting Advance Care Planning (ACP) conversations as difficult and are hesitant to start them. A structured approach could help to overcome this. In the ACTION trial, a Phase III multi-center cluster-randomized clinical trial in six European countries (Belgium, Denmark, Italy, the Netherlands, Slovenia, United Kingdom), patients with advanced lung or colorectal cancer are invited to have one or two structured ACP conversations with a trained facilitator. It is unclear how trained facilitators experience conducting structured ACP conversations. This study aims to understand how facilitators experience delivering the ACTION Respecting Choices (RC) ACP conversation. A qualitative study involving focus groups with RC facilitators. Focus group interviews were recorded, transcribed, anonymized, translated into English, and thematically analysed, supported by NVivo 11. The international research team was involved in data analysis from initial coding and discussion towards final themes. Seven focus groups were conducted, involving 28 of in total 39 trained facilitators, with different professional backgrounds from all participating countries. Alongside some cultural differences, six themes were identified. These reflect that most facilitators welcomed the opportunity to participate in the ACTION trial, seeing it as a means of learning new skills in an important area. The RC script was seen as supportive to ask questions, including those perceived as difficult to ask, but was also experienced as a barrier to a spontaneous conversation. Facilitators noticed that most patients were positive about their ACTION RC ACP conversation, which had prompted them to become aware of their wishes and to share these with others. The facilitators observed that it took patients substantial effort to have these conversations. In response, facilitators took responsibility for enabling patients to experience a conversation from which they could benefit. Facilitators emphasized the need for training, support and advanced communication skills to be able to work with the script. Facilitators experienced benefits and challenges in conducting scripted ACP conversations. They mentioned the importance of being skilled and experienced in carrying out ACP conversations in order to be able to explore the patients' preferences while staying attuned to patients' needs. International Standard Randomised Controlled Trial Number registry 63110516 ( ISRCTN63110516 ) per 10/3/2014.


SW1PerS: Sliding windows and 1-persistence scoring; discovering periodicity in gene expression time series data.
Identifying periodically expressed genes across different processes (e.g. the cell and metabolic cycles, circadian rhythms, etc) is a central problem in computational biology. Biological time series may contain (multiple) unknown signal shapes of systemic relevance, imperfections like noise, damping, and trending, or limited sampling density. While there exist methods for detecting periodicity, their design biases (e.g. toward a specific signal shape) can limit their applicability in one or more of these situations. We present in this paper a novel method, SW1PerS, for quantifying periodicity in time series in a shape-agnostic manner and with resistance to damping. The measurement is performed directly, without presupposing a particular pattern, by evaluating the circularity of a high-dimensional representation of the signal. SW1PerS is compared to other algorithms using synthetic data and performance is quantified under varying noise models, noise levels, sampling densities, and signal shapes. Results on biological data are also analyzed and compared. On the task of periodic/not-periodic classification, using synthetic data, SW1PerS outperforms all other algorithms in the low-noise regime. SW1PerS is shown to be the most shape-agnostic of the evaluated methods, and the only one to consistently classify damped signals as highly periodic. On biological data, and for several experiments, the lists of top 10% genes ranked with SW1PerS recover up to 67% of those generated with other popular algorithms. Moreover, the list of genes from data on the Yeast metabolic cycle which are highly-ranked only by SW1PerS, contains evidently non-cosine patterns (e.g. ECM33, CDC9, SAM1,2 and MSH6) with highly periodic expression profiles. In data from the Yeast cell cycle SW1PerS identifies genes not preferred by other algorithms, hence not previously reported as periodic, but found in other experiments such as the universal growth rate response of Slavov. These genes are BOP3, CDC10, YIL108W, YER034W, MLP1, PAC2 and RTT101. In biological systems with low noise, i.e. where periodic signals with interesting shapes are more likely to occur, SW1PerS can be used as a powerful tool in exploratory analyses. Indeed, by having an initial set of periodic genes with a rich variety of signal types, pattern/shape information can be included in the study of systems and the generation of hypotheses regarding the structure of gene regulatory networks.


[Hydroxychloroquine for autoimmune diseases].
Hydroxychloroquine (HCQ) is by far the most frequently used antimalarial for the management of Systemic Autoimmune Diseases. It has immunomodulatory, hypolipidemic, hypoglycemic and antithrombotic properties and it diminishes the risk of malignancies. The most important mechanisms to explain the immunomodulatory actions are its ability to reduce inflammatory pathways and Toll-like receptors activation. The safety profile is favorable. In spite of its low frequency, retinal toxicity is potentially severe. In systemic lupus erythematous HCQ therapy reduces activity, the accrual of organ damage, risk of infections and thrombosis and improves the cardiometabolic profile. It contributes to induce lupus nephritis remission, spares steroid use and increases survival rates. In rheumatoid arthritis, it improves cardiometabolic risk and has a favorable effect in joint inflammation. In Sjögren's syndrome, an increased lacrimal quality as well as an improvement in objective and subjective inflammatory markers has been demonstrated with HCQ. In Antiphospholipid Syndrome, HCQ is effective in primary and secondary thrombosis prevention. The effectiveness of the drug in other systemic autoimmune diseases is less established. HCQ therapy may improve dermatological manifestations in Dermatomyositis and may have a positive effects in the treatment of Sarcoidosis and Still disease.


Transcriptional regulation of the Bacteroides fragilis ferritin gene (ftnA) by redox stress.
This study shows that the iron-storage protein ferritin is a component of the redox-stress response in the obligate anaerobe Bacteroides fragilis. It is up-regulated at transcriptional level under aerobic conditions but constitutively expressed at low levels under anaerobic conditions. Northern hybridization and primer extension analysis revealed that ftnA is transcribed as a monocistronic mRNA of approximately 600 nt. Under reduced anaerobic conditions, ftnA mRNA levels were not dependent on the iron content of the culture medium. Following oxygen exposure ftnA message increased about 10-fold in iron-replete medium compared to a fourfold increase under low-iron conditions. Addition of the oxidant potassium ferricyanide induced expression of ftnA mRNA anaerobically, suggesting that the oxidation of the medium affected expression of ftnA. Two transcription initiation start sites were identified. Both transcripts were expressed constitutively under anaerobic conditions but one promoter was induced by oxidative stress or the addition of the oxidant potassium ferricyanide. The effect of redox stress on ftnA expression was further investigated by addition of diamide, a thiol-oxidizing agent, which induced ftnA mRNA levels anaerobically, suggesting that an unbalanced cellular redox state also affects ftnA expression. Induction by hydrogen peroxide and oxygen was decreased in an oxyR deletion mutant but some oxygen induction still occurred. This strongly suggests that ftnA is regulated by both the peroxide response transcriptional activator, OxyR, and another unidentified oxygen-dependent regulator. Taken together, these data show that ftnA mRNA levels are controlled by both iron and oxidative stress; this coordinated regulation may be important for survival in an adverse aerobic environment.


Clinical management of psoriatic arthritis.
Psoriatic arthritis, or the broader term psoriatic disease, refers to an inflammatory disorder that affects multiple organs, including the skin and joints, and that also has related extra-articular manifestations and can have comorbidities. Patients with psoriatic disease have a substantial clinical burden. Early identification leading to timely diagnosis and treatment is crucial to prevent long-term structural damage and disability and the associated socioeconomic consequences. The increase in therapeutic options, such as disease-modifying anti-rheumatic drugs, both biological and targeted synthetic, has revolutionised the treatment of skin and joint disease, and has prompted clinicians to use the full clinical picture of an individual patient to make rational treatment decisions. Current research is also focused on treatment strategies, including treat to target, early remission-induction, and tapering.


Intracellular signaling by the unfolded protein response.
The unfolded protein response (UPR) is an intracellular signaling pathway that is activated by the accumulation of unfolded proteins in the endoplasmic reticulum (ER). UPR activation triggers an extensive transcriptional response, which adjusts the ER protein folding capacity according to need. As such, the UPR constitutes a paradigm of an intracellular control mechanism that adjusts organelle abundance in response to environmental or developmental clues. The pathway involves activation of ER unfolded protein sensors that operate in parallel circuitries to transmit information across the ER membrane, activating a set of downstream transcription factors by mechanisms that are unusual yet rudimentarily conserved in all eukaryotes. Recent results shed light on the mechanisms by which unfolded proteins are sensed in the ER and by which the unfolded protein signals are relayed and integrated to reestablish homeostasis in the cell's protein folding capacity or-if this cannot be achieved-commit cells to apoptosis.


Non-interventional study evaluating efficacy and tolerability of rifaximin for treatment of uncomplicated diverticular disease.
Patients with symptomatic uncomplicated diverticular disease represent a spectrum of patients who report recurrent abdominal symptoms, however are lacking substantial colonic inflammation in contrast to patients with acute diverticulitis. This non-interventional study investigated the efficacy and tolerability of rifaximin, a broad-spectrum poorly absorbable antibiotic, in cyclic treatment of these patients. Adult patients with uncomplicated diverticular disease in care of physicians in private practice intended to be treated with rifaximin were included. Patients with acute diverticulitis and symptoms suggestive of more severe intestinal inflammation were excluded. Data of 1,003 patients treated in cycles of 7-10 days per month over a period of 3 months were evaluated. In total, 75 % of patients had more than three episodes of symptoms in the last year before inclusion in the study. However, two-third of patients did not receive any treatment before. Over the 3-month treatment period with rifaximin, all assessed symptoms of diverticular disease, such as abdominal pain, diarrhoea and flatulence, improved significantly. There was an overall good compliance to the scheme of cyclic drug administration of rifaximin. During the study, 24 adverse events in 20 patients were recorded, of which 6 adverse events showed a causal relationship to the use of rifaximin (0.6 %). We conclude that cyclic rifaximin shows good clinical efficacy and tolerability in patients with symptomatic uncomplicated diverticular disease treated in a routine private practice outpatient setting.