Phosphorus remobilization from rice flag leaves during grain filling: an RNA-seq study.
The physiology and molecular regulation of phosphorus (P) remobilization from vegetative tissues to grains during grain filling is poorly understood, despite the pivotal role it plays in the global P cycle. To test the hypothesis that a subset of genes involved in the P starvation response are involved in remobilization of P from flag leaves to developing grains, we conducted an RNA-seq analysis of rice flag leaves during the preremobilization phase (6 DAA) and when the leaves were acting as a P source (15 DAA). Several genes that respond to phosphate starvation, including three purple acid phosphatases (OsPAP3, OsPAP9b and OsPAP10a), were significantly up-regulated at 15 DAA, consistent with a role in remobilization of P from flag leaves during grain filling. A number of genes that have not been implicated in the phosphate starvation response, OsPAP26, SPX-MFS1 (a putative P transporter) and SPX-MFS2, also showed expression profiles consistent with involvement in P remobilization from senescing flag leaves. Metabolic pathway analysis using the KEGG system suggested plastid membrane lipid synthesis is a critical process during the P remobilization phase. In particular, the up-regulation of OsPLDz2 and OsSQD2 at 15 DAA suggested phospholipids were being degraded and replaced by other lipids to enable continued cellular function while liberating P for export to developing grains. Three genes associated with RNA degradation that have not previously been implicated in the P starvation response also showed expression profiles consistent with a role in P mobilization from senescing flag leaves.


Tissue factor expression in human monocytic cell lines.
Tissue factor (TF) is a main initiator of the coagulation protease cascade. Control of the expression of this protein in monocytes is essential, since these cells are the only circulating blood cells responsible for TF expression. In this report we have used two human cell lines, arrested at different stages of monocytic differentiation, to study TF expression. The monoblastic cell line U-937 had a constitutive expression of TF surface protein and low TF mRNA levels detected by immunofluorescence or quantitative reverse transcriptase polymerase chain reaction respectively. The phorbol-12-myristate-13-acetate (PMA) was a potent enhancer of TF expression in U-937. Lipopolysaccharide (LPS) and tumor necrosis factor (TNF) had no effect on TF expression in U-937. The Mono Mac 6 cell line, with phenotypic features similar to that of mature monocytes, expressed lower basal levels of TF mRNA and surface TF antigen. However, in Mono Mac 6 cells TF expression was induced in response to LPS and TNF. These results indicate differences in basal and induced TF expression between U-937 and Mono Mac 6 cell lines.


Calcific aortic valve stenosis: methods, models, and mechanisms.
Calcific aortic valve stenosis (CAVS) is a major health problem facing aging societies. The identification of osteoblast-like and osteoclast-like cells in human tissue has led to a major paradigm shift in the field. CAVS was thought to be a passive, degenerative process, whereas now the progression of calcification in CAVS is considered to be actively regulated. Mechanistic studies examining the contributions of true ectopic osteogenesis, nonosseous calcification, and ectopic osteoblast-like cells (that appear to function differently from skeletal osteoblasts) to valvular dysfunction have been facilitated by the development of mouse models of CAVS. Recent studies also suggest that valvular fibrosis, as well as calcification, may play an important role in restricting cusp movement, and CAVS may be more appropriately viewed as a fibrocalcific disease. High-resolution echocardiography and magnetic resonance imaging have emerged as useful tools for testing the efficacy of pharmacological and genetic interventions in vivo. Key studies in humans and animals are reviewed that have shaped current paradigms in the field of CAVS, and suggest promising future areas for research.


A Work Sampling Assessment of the Nursing Delivery of Palliative Care in Ambulatory Cancer Centers.
Most cancer care occurs within infusion rooms at ambulatory cancer centers, which are staffed by RNs administering chemotherapies and other cancer care medications. Many patients receiving these therapies have basic palliative care needs that could be addressed by the RNs. However, the extent to which these RNs spend their time on basic, or "primary," palliative care is unknown. The aim of this project was to conduct a work sampling assessment of infusion room RNs' work activities and provision of primary palliative care. A single observer conducted direct observation work sampling at three academic cancer center infusion rooms. Nursing tasks were recorded via freehand text and later assigned an appropriate task code. Observed infusion room RNs spent about 1% of their time on direct care palliative care tasks, primarily symptom assessment. The remainder of their time was divided among direct (28%) and indirect (56%) nonpalliative care activities, unit-related activities (7%), and personal time (9%). Infusion room RNs spent less than a third of their time on administering direct patient care and very minimal time on performing palliative care activities.


Classification of lossless first-order optical systems and the linear canonical transformation.
Based on the eigenvalues of the ray transformation matrix, a classification of ABCD systems is proposed and some nuclei (i.e., elementary members) in each class are described. In the one-dimensional case, possible nuclei are the magnifier, the lens, and the fractional Fourier transformer. In the two-dimensional case we have-in addition to the obvious concatenations of one-dimensional nuclei-the four combinations of a magnifier or a lens with a rotator or a shearing operator, where the rotator and the shearer are obviously inherently two-dimensional. Any ABCD system belongs to one of the classes described in this paper and is similar (in the sense of matrix similarity of the ray transformation matrices) to the corresponding nucleus. Knowledge of a nucleus may be helpful in finding eigenfunctions of the corresponding class of first-order optical systems: one only has to find eigenfunctions of the nucleus and to determine how these functions propagate through a first-order optical system.


Quantitative Campylobacter spp., antibiotic resistance genes, and veterinary antibiotics in surface and ground water following manure application: Influence of tile drainage control.
This work investigated chlortetracycline, tylosin, and tetracycline (plus transformation products), and DNA-based quantitative Campylobacter spp. and Campylobacter tetracycline antibiotic resistant genes (tet(O)) in tile drainage, groundwater, and soil before and following a liquid swine manure (LSM) application on clay loam plots under controlled (CD) and free (FD) tile drainage. Chlortetracycline/tetracycline was strongly bound to manure solids while tylosin dominated in the liquid portion of manure. The chlortetracycline transformation product isochlortetracycline was the most persistent analyte in water. Rhodamine WT (RWT) tracer was mixed with manure and monitored in tile and groundwater. RWT and veterinary antibiotic (VA) concentrations were strongly correlated in water which supported the use of RWT as a surrogate tracer. While CD reduced tile discharge and eliminated application-induced VA movement (via tile) to surface water, total VA mass loading to surface water was not affected by CD. At both CD and FD test plots, the biggest 'flush' of VA mass and highest VA concentrations occurred in response to precipitation received 2d after application, which strongly influenced the flow abatement capacity of CD on account of highly elevated water levels in field initiating overflow drainage for CD systems (when water level <0.3m below surface). VA concentrations in tile and groundwater became very low within 10d following application. Both Campylobacter spp. and Campylobacter tet(O) genes were present in groundwater and soil prior to application, and increased thereafter. Unlike the VA compounds, Campylobacter spp. and Campylobacter tet(O) gene loadings in tile drainage were reduced by CD, in relation to FD.


Neuromuscular Physiology, Exercise, and Training During Youth-The Year That Was 2017.
The pressure for children to excel and succeed in sport continues to mount. Although resistance training for youth was in disfavor by many organizations even into the early 21st century, children's training programs are more closely resembling the volume and intensity of adult programs. The physiological maturation of adolescent youth may impact their response to advanced training programs. Furthermore, the pressure to specialize in specific sports rather than engage in a variety of sporting activities may affect not only training responses but also injury incidence. The highlighted articles first illustrate the training-specific responses of prepeak and postpeak height velocity stage youth with more specific training stimuli needed for the postpeak height velocity stage youth. Second, individual sports tend to promote earlier and greater specialization compared with team sports, which tend to result in a higher proportion of overuse injuries. Based on the findings of these 2 studies, the planning and implementation of high-intensity training for youth, such as plyometrics, should take into consideration the physical maturation of the child and that the prevention of overuse injuries would benefit from a more varied participation in sports and activities.


Challenges facing HIV treatment in Guinea-Bissau: the benefits of international research collaborations.
The introduction of antiretroviral therapy (ART) for HIV infection in sub-Saharan Africa has improved the quality of life of millions of people and reduced mortality. However, substantial problems with the infrastructure for ART delivery remain. Clinicians and researchers at an HIV clinic in Guinea-Bissau identified problems with the delivery of ART by establishing a clinical database and by collaborating with international researchers. The Bissau HIV cohort study group was established in 2007 as a collaboration between local HIV physicians and international HIV researchers. Patients were recruited from the HIV clinic at the country's main hospital in the capital Bissau. Between 2005 and 2013, 5514 HIV-positive patients were treated at the clinic. Working together, local health-care workers and international researchers identified the main problems affecting ART delivery: inadequate drug supply; loss of patients to follow-up; and inadequate laboratory services. Solutions to these problems were devised. The collaborations encouraged local physicians to start their own research projects to find possible solutions to problems at the clinic. The HIV clinic in Bissau faced numerous obstacles in delivering ART at a sufficiently high quality and patients' lives were put in jeopardy. The effectiveness of ART could be enhanced by delivering it as part of an international research collaboration since such collaborations can help identify problems, find solutions and increase the capacity of the health-care system.


Pharmacological validation of a new animal model of alcoholism.
A new animal model of alcoholism has been developed. Rats derived from this model show certain characteristics: (i) they have an incentive demand to consume alcohol, (ii) they exhibit relapse-like drinking even after a very long time of abstinence, (iii) they show tolerance to alcohol and have mild signs of physical withdrawal during the onset of abstinence, and (iv) during abstinence they also exhibit a psychological withdrawal syndrome consisting of enhanced anxiety-related behaviour and hyperreactivity to stressful situations. Anti-craving drugs such as acamprosate and naltrexone which proved to be effective in human alcoholics to prevent relapse were also effective in our animal model. Thus, both compounds suppressed the alcohol deprivation effect which is used as a measure for craving and relapse. It is concluded that this pharmacological validation of our model demonstrates the predictive value of our model and enables us to further characterize putative anti-craving drugs and neurobiological mechanisms of addictive behaviour.


Regulatory Genes Controlling Anthocyanin Pigmentation Are Functionally Conserved among Plant Species and Have Distinct Sets of Target Genes.
In this study, we demonstrate that in petunia at least four regulatory genes (anthocyanin-1 [an1], an2, an4, and an11) control transcription of a subset of structural genes from the anthocyanin pathway by using a combination of RNA gel blot analysis, transcription run-on assays, and transient expression assays. an2- and an11- mutants could be transiently complemented by the maize regulatory genes Leaf color (Lc) or Colorless-1 (C1), respectively, whereas an1- mutants only by Lc and C1 together. In addition, the combination of Lc and C1 induces pigment accumulation in young leaves. This indicates that Lc and C1 are both necessary and sufficient to produce pigmentation in leaf cells. Regulatory pigmentation genes in maize and petunia control different sets of structural genes. The maize Lc and C1 genes expressed in petunia differentially activate the promoters of the chalcone synthase genes chsA and chsJ in the same way that the homologous petunia genes do. This suggests that the regulatory proteins in both species are functionally similar and that the choice of target genes is determined by their promoter sequences. We present an evolutionary model that explains the differences in regulation of pigmentation pathways of maize, petunia, and snapdragon.


Active immunisation targeting nerve growth factor attenuates chronic pain behaviour in murine osteoarthritis.
Nerve growth factor (NGF) has emerged as a key driver of pain in osteoarthritis (OA) and antibodies to NGF are potent analgesics in human disease. Here, we validate a novel vaccine strategy to generate anti-NGF antibodies for reversal of pain behaviour in a surgical model of OA. Virus-like particles were derived from the cucumber mosaic virus (CuMV) and coupled to expressed recombinant NGF to create the vaccine. 10-week-old male mice underwent partial meniscectomy to induce OA or sham-surgery. Spontaneous pain behaviour was measured by Linton incapacitance and OA severity was quantified using OARSI histological scoring. Mice (experimental and a sentinel cohort) were inoculated with CuMVttNGF (Vax) or CuMVttctrl (Mock) either before surgery or once pain was established. Efficacy of anti-NGF from the plasma of sentinel vaccinated mice was measured in vitro using a neurite outgrowth assay in PC12 cells. Anti-NGF titres were readily detectable in the vaccinated but not mock vaccinated mice. Regular boosting with fresh vaccine was required to maintain anti-NGF titres as measured in the sentinel cohort. Both prophylactic and therapeutic vaccination demonstrated a reversal of pain behaviour by incapacitance testing, and a meta-analysis of the two studies showing analgesia at peak anti-NGF titres was highly statistically significant. Serum anti-NGF was able to inhibit neurite outgrowth equivalent to around 150 ug/mL of recombinant monoclonal antibody. This study demonstrates therapeutic efficacy of a novel NGF vaccine strategy that reversibly alleviates spontaneous pain behaviour in surgically induced murine OA.


Cannabidiol induced a contrasting pro-apoptotic effect between freshly isolated and precultured human monocytes.
It has been documented that cannabidiol (CBD) induced apoptosis in a variety of transformed cells, including lymphocytic and monocytic leukemias. In contrast, a differential sensitivity between normal lymphocytes and monocytes to CBD-mediated apoptosis has been reported. The present study investigated the pro-apoptotic effect of CBD on human peripheral monocytes that were either freshly isolated or precultured for 72h. CBD markedly enhanced apoptosis of freshly isolated monocytes in a time- and concentration-dependent manner, whereas precultured monocytes were insensitive. By comparison, both cells were sensitive to doxorubicin-induced apoptosis. CBD significantly diminished the cellular thiols and glutathione in freshly isolated monocytes. The apoptosis induced by CBD was abrogated in the presence of N-acetyl-L-cysteine, a precursor of glutathione. In addition, precultured monocytes contained a significantly greater level of glutathione and heme oxygenase-1 (HO-1) compared to the freshly isolated cells. The HO-1 competitive inhibitor zinc protoporphyrin partially but significantly restored the sensitivity of precultured monocytes to CBD-mediated apoptosis. Collectively, our results demonstrated a contrasting pro-apoptotic effect of CBD between precultured and freshly isolated monocytes, which was closely associated with the cellular level of glutathione and the antioxidative capability of the cells.


Fibromyalgia has a high prevalence and impact in cardiac failure patients.
Chronic cardiac failure (CCF) shares several clinical features with fibromyalgia (FM), a syndrome of increased central sensitivity and musculoskeletal pain. FM frequently coexists with other chronic illness. Musculoskeletal pain is reported in patients with CCF; however, the prevalence and impact of FM in patients with CCF is not known. This research aims to assess the prevalence and effects of concurrent FM in patients with CCF and to identify other coexisting central sensitivity syndromes. In a cross-sectional study, demographic, clinical, and functional information was gathered from participants with CCF from public and private clinics. Cardiac failure severity was rated using the New York Heart Association (NYHA) scale. FM diagnosis was determined using 2011 American College of Rheumatology (ACR) criteria. The short-form 36 (SF-36) assessed overall health function. Of the 57 CCF participants (63.2% male, mean age 70.3 years), 22.8% (n=13) met FM diagnostic criteria. CCF patients with FM had poorer outcomes across multiple SF-36 domains (p<0.05), compared to those without, despite having comparable CCF severity. Those with FM were more likely to report other central sensitivity syndromes, especially temporomandibular joint dysfunction (mean Δ=23%, p<0.05), headache (mean Δ=28.8%, p<0.05), and irritable bladder (mean Δ=14%, p<0.05). High prevalence of FM was found in patients with CCF. This was associated with increased likelihood of other comorbid central sensitivity syndromes and with poorer clinical outcomes. The recognition of coexisting FM in patients with CCF provides an important opportunity to improve health outcomes by managing FM-related symptoms, in addition to symptoms that relate specifically to CCF.


Locomotion in alligator mississippiensis: kinematic effects of speed and posture and their relevance to the sprawling-to-erect paradigm
In terms of locomotory posture, amphibians and lizards are considered to be sprawlers, mammals and dinosaurs are considered to be erect, and extant crocodilians are considered to be intermediate because they use the 'high walk', a semi-erect posture where the body is held half-way between the sprawling and erect grades during locomotion. In addition, crocodilians occasionally use a sprawling posture. Extant crocodilians, therefore, provide an interesting model in which to investigate the sprawling-to-erect transition in vertebrate evolution. This study quantifies the sprawl and high walk kinematics of the alligator Alligator mississippiensis moving at different speeds on a treadmill and compares them with kinematic data available for other vertebrates. These data allow us to examine the effects of speed on crocodilian postures and to examine how crocodilian locomotion relates to the sprawling-to-erect paradigm in vertebrate locomotion. Our results show that the crocodilian sprawl is not functionally equivalent to the primitive sprawling behaviors exhibited by salamanders and lizards. In fact, although the high walks and sprawls of alligators exhibit some kinematic differences, they are actually much more similar than expected and, essentially, the crocodilian sprawl is a lower version of a high walk and could be termed a 'low walk'. In terms of the sprawling-to-erect transition, the high walk has knee kinematics intermediate between those of birds and non-archosaurian tetrapods, but alligators increase speed in a way completely different from other terrestrial vertebrates (distal rather than proximal limb elements are used to increase speed). These kinematic data viewed in the light of the fossil and phylogenetic evidence that modern crocodilians evolved from erect ancestors suggest that modern crocodilians have secondarily evolved a variable semi-erect posture and that they are problematic as an intermediate model for the evolutionary transition from sprawling to erect postures in archosaurs.


Quality of Life Analysis and Smoking Correlation in Symptomatic Spine Osteoarthritis: A Nationwide Health Survey Analysis of an Elderly Population with EQ-5D.
To analyze quality of life in people with symptomatic spine osteoarthritis (OA) using the results of a cross-sectional, nationwide survey. This study used data from the Fifth Korean National Health and Nutrition Examination Survey (KNHANES V-5; 2010-2012). After excluding ineligible subjects, the total number of subjects in the study was 8,963, including 4,091 males and 4,872 females. All participants reported disabilities related to spine OA. Plain radiographs of the spine were taken for all participants. Age, sex, smoking, drinking, education, and income level were significantly related to spine OA morbidity (P<0.05). OA morbidity was significantly higher in female ex-smokers (OR; 2.94, P<0.05). Quality of life (EQ-5D: L1~5) was significantly compromised in the group with spine OA compared to the group without spine OA (P<0.05). Overall, LQ 1, 2, 3, 4, and 5 domain scores were significantly higher in the group with spine OA (P<0.05). In the group with spine OA, quality of life was reduced on more than three questions for 34.3% of the group (EQ-5D: grade≥2); on two questions, for 18.5% of the group; and on one question, for 11.1% of the group. Mental stress, melancholy, and suicidal thinking were also more common in the group with spine OA (P<0.05). The group with radiographic spine OA but without symptoms did not have compromised EQ-5D scores, whereas the group with radiographic OA and symptoms showed a significantly reduced quality of life. Quality of life was significantly reduced in the group with symptomatic spine OA in a large cross-sectional analysis. Physicians should consider quality of life in the treatment of patients with spine OA.


Bony impingement affects range of motion after total hip arthroplasty: A subject-specific approach.
Hip range of motion after total hip arthroplasty has been shown to be dependent on prosthetic design and component placement. We hypothesized that bony anatomy would significantly affect range of motion. Computer models of a current generation hip arthroplasty design were virtually implanted in a model of pelvis and femur in various orientations ranging from 35 degrees to 55 degrees cup abduction, 0 degrees to 30 degrees cup anteversion, and 0 degrees to 30 degrees femoral anteversion. Four head sizes ranging from 22.2 to 32 mm and two neck sizes ranging from 10-mm and 12-mm diameter were tested. Range of motion was recorded as maximum flexion-extension, abduction-adduction, and axial rotation of the femur before any contact between prosthetic components or bone was detected. Bony impingement preceded component impingement in about 44% of all conditions tested, ranging from 66% in adduction to 22% in extension. Range of motion increased as head size increased. However, increasing head size also increased the propensity for bony impingement, which tended to reduce the beneficial effect of increased head size on range of motion. Reducing neck diameter had a greater effect on prosthetic impingement (mean, 3.5 degrees increase in range of motion) compared to bone impingement (mean, 1.9 degrees ). This model allowed for a clinically relevant assessment of range of motion after total hip arthroplasty and may also be used with patient-specific geometry [such as that obtained from preoperative computed tomography (CT) scans] for more accurate preoperative planning.


The mechanism of allosteric inhibition of protein tyrosine phosphatase 1B.
As the prototypical member of the PTP family, protein tyrosine phosphatase 1B (PTP1B) is an attractive target for therapeutic interventions in type 2 diabetes. The extremely conserved catalytic site of PTP1B renders the design of selective PTP1B inhibitors intractable. Although discovered allosteric inhibitors containing a benzofuran sulfonamide scaffold offer fascinating opportunities to overcome selectivity issues, the allosteric inhibitory mechanism of PTP1B has remained elusive. Here, molecular dynamics (MD) simulations, coupled with a dynamic weighted community analysis, were performed to unveil the potential allosteric signal propagation pathway from the allosteric site to the catalytic site in PTP1B. This result revealed that the allosteric inhibitor compound-3 induces a conformational rearrangement in helix α7, disrupting the triangular interaction among helix α7, helix α3, and loop11. Helix α7 then produces a force, pulling helix α3 outward, and promotes Ser190 to interact with Tyr176. As a result, the deviation of Tyr176 abrogates the hydrophobic interactions with Trp179 and leads to the downward movement of the WPD loop, which forms an H-bond between Asp181 and Glu115. The formation of this H-bond constrains the WPD loop to its open conformation and thus inactivates PTP1B. The discovery of this allosteric mechanism provides an overall view of the regulation of PTP1B, which is an important insight for the design of potent allosteric PTP1B inhibitors.


Long-Term Effects of Individually Tailored Physical Training and Activity on Physical Function, Well-Being and Cognition in Scandinavian Nursing Home Residents: A Randomized Controlled Trial.
The preservation of physical functions such as muscle strength, balance and mobility is fundamental to maintaining independence in activities of daily living (ADL). The physical activity level of most nursing home residents is very low, which implies that they are often subject to a decline in health, mobility, autonomy and social contacts and are also at risk of suffering a decline in mental well-being. In a previous study, we demonstrated that transfers, balance and physical activity level improved after 3 months of individually tailored intervention in nursing home residents. To evaluate the long-term effects on ADL, balance function, physical activity level, physical performance, falls-related self-efficacy, well-being and cognitive function 3 months after the completion of our intervention in nursing home residents. The study was a multicenter randomized, controlled clinical trial with a parallel-group design. It was conducted in nursing homes in Sweden, Norway and Denmark, with an intervention period lasting 3 months and a follow-up at 6 months. Initially, 322 nursing home residents with a mean age of 85 years were included; 85 from Sweden, 171 from Norway and 66 from Denmark. Of these, 241 [129 intervention group (IG), 112 control group (CG)] were eligible for the 6-month follow-up tests. The level of dependence in ADL, physical activity level, several dimensions of physical function, well-being, falls-related self-efficacy and cognitive function were assessed with reliable and valid instruments at baseline, immediately after 3 months of intervention and 3 months later at the 6-month follow-up. After 3 months of intervention and an additional period of 3 months without intervention, only the following 2 variables demonstrated significant group differences: social and cognitive function, measured by the Functional Independence Measure n-r, where the IG deteriorated while the CG was almost stable. However, regarding transfers, the IG deteriorated significantly less than the CG. Without supervised physical exercise that challenged the individuals' capability, gains in ADL function, balance and transfer ability deteriorated during the 3 months following the intervention period. Thus, continuous, individually adjusted and supported physical activity seems crucial for the maintenance of physical functions in these vulnerable elderly persons.


Age-related changes in visually evoked electrical brain activity.
Whereas much is known about the degenerative effects of aging on cortical tissue, less is known about how aging affects visually evoked electrical activity, and at what latencies. We compared visual processing in elderly and young controls using a visual masking paradigm, which is particularly sensitive to detect temporal processing deficits, while recording EEG. The results show that, on average, elderly have weaker visual evoked potentials than controls, and that elderly show a distinct scalp potential topography (microstate) at around 150 ms after stimulus onset. This microstate occurred irrespective of the visual stimulus presented. Electrical source imaging showed that the changes in the scalp potential resulted from decreased activity in lateral occipital cortex and increases in fronto-parietal areas. We saw, however, no evidence that increased fronto-parietal activity enhanced performance on the discrimination task, and no evidence that it compensated for decreased posterior activity. Our results show qualitatively different patterns of visual evoked potentials (VEPs) in the elderly, and demonstrate that increased fronto-parietal activity arises during visual processing in the elderly already between 150 and 200 ms after stimulus onset. The microstate associated with these changes is a potential diagnostic tool to detect age-related cortical changes.


Expression of mitochondrial cytochrome c oxidase in human colonic cell differentiation, transformation, and risk for colonic cancer.
In a panel of eight cloned complementary DNA sequences whose level of expression characterize colon cells as transformed in vivo and in vitro, one which may also serve as a marker of risk in familial polyposis and familial colon cancer flat mucosa has been identified as mitochondrial cytochrome c oxidase subunit 3. Mean level of expression of cytochrome c oxidase subunit 3 decreases progressively in colon adenomas and carcinomas relative to normal mucosa in vivo, and returns to higher levels present in biopsies of normal mucosa when the HT29 human colonic adenocarcinoma cell line is induced to differentiate with sodium butyrate. Quantitation of cytochrome c oxidase subunit 3 DNA by dot blots indicated that these changes in expression were not associated with alterations in the number of mitochondrial genomes.


NADPH oxidase 4 attenuates cerebral artery changes during the progression of Marfan syndrome.
Marfan syndrome (MFS) is a connective tissue disorder that is often associated with the fibrillin-1 (Fbn1) gene mutation and characterized by cardiovascular alterations, predominantly ascending aortic aneurysms. Although neurovascular complications are uncommon in MFS, the improvement in Marfan patients' life expectancy is revealing other secondary alterations, potentially including neurovascular disorders. However, little is known about small-vessel pathophysiology in MFS. MFS is associated with hyperactivated transforming growth factor (TGF)-β signaling, which among numerous other downstream effectors, induces the NADPH oxidase 4 (Nox4) isoform of NADPH oxidase, a strong enzymatic source of H2O2 We hypothesized that MFS induces middle cerebral artery (MCA) alterations and that Nox4 contributes to them. MCA properties from 3-, 6-, or 9-mo-old Marfan (Fbn1(C1039G/+)) mice were compared with those from age/sex-matched wild-type littermates. At 6 mo, Marfan compared with wild-type mice developed higher MCA wall/lumen (wild-type: 0.081 ± 0.004; Marfan: 0.093 ± 0.002; 60 mmHg; P < 0.05), coupled with increased reactive oxygen species production, TGF-β, and Nox4 expression. However, wall stiffness and myogenic autoregulation did not change. To investigate the influence of Nox4 on cerebrovascular properties, we generated Marfan mice with Nox4 deficiency (Nox4(-/-)). Strikingly, Nox4 deletion in Marfan mice aggravated MCA wall thickening (cross-sectional area; Marfan: 6,660 ± 363 μm(2); Marfan Nox4(-/-): 8,795 ± 824 μm(2); 60 mmHg; P < 0.05), accompanied by decreased TGF-β expression and increased collagen deposition and Nox1 expression. These findings provide the first evidence that Nox4 mitigates cerebral artery structural changes in a murine model of MFS.


Prediction of the varices needing treatment with non-invasive tests in patients with compensated advanced chronic liver disease.
The Baveno VI guidelines proposed criteria including liver stiffness (LS) and platelet count to avoid screening endoscopy in patients with compensated advanced chronic liver disease (cACLD). This study was performed to validate the Baveno IV criteria and to compare its diagnostic accuracy with other non-invasive models. Patients with cACLD who underwent laboratory tests, upper gastrointestinal endoscopy and abdominal ultrasound within 6 months of transient elastography were included. A total of 1218 patients with cACLD were included. VNT occurred in 249 patients (20.4%). With the Baveno VI criteria, the VNT miss rate was 1.9% with a 25.7% saved endoscopy rate. Using two criteria of LS <20 kPa and platelet count >110 × 109 cells/L or LS <25 kPa and platelet count >120 × 109 cells/L, the saved endoscopy rate was 39.1% while maintaining the VNT miss rate <5%. The optimal LS and platelet count-based criteria for predicting VNT differed according to the underlying liver disease. The area under the receiver operating characteristic curve of LS-spleen diameter to platelet score (LSPS) was 0.780 (95% confidence interval: 0.774-0.820), which was significantly higher than other models. The optimal cut-off value of the LSPS for predicting VNT was 1.47. Liver stiffness and platelet count-based criteria are useful for discriminating patients with very low risk of having VNT among patients with cACLD and are partly affected by the type of underlying liver disease. Conversely, the LSPS is a predictor of VNT in patients with cACLD regardless of the type of underlying liver disease.


Serum Transforming Growth Factor-Beta 1 Level in Egyptian Systemic Lupus Erythematosus Patients.
This study aims to assess the role of transforming growth factor-beta 1 (TGF-β1) in systemic lupus erythematosus (SLE). The study included 40 female SLE patients (mean age 25.5±6.2 years; range 15 to 39 years) diagnosed according to the American College of Rheumatology criteria and 30 female healthy controls (mean age 26.2±5.9 years; range 16 to 39 years). Disease activity was assessed using SLE Disease Activity Index. Patients were diagnosed with lupus nephritis if they met the criteria for renal disorder. SLE patients and controls were compared in terms of TGF-β1, low and high density lipoprotein, and triglyceride levels. Mean serum TGF-β1 level of patients with SLE was 1385.7±483.1 pg/mL, with a significant difference compared to control group (2079.6±125.4 pg/mL; p<0.001). TGF-β1 was statistically significantly correlated with SLE disease duration. However, there was no statistically significant correlation between TGF-β1 and erythrocyte sedimentation rate, C-reactive protein, 24-hour urinary protein, complement 3, serum cholesterol, low density lipoprotein, or serum triglyceride. TGF-β1 was statistically significantly correlated with discoid rash. There was a statistically significant correlation between SLE Disease Activity Index and serum cholesterol, and triglyceride. Systemic lupus erythematosus patients had lower levels of TGF-β1, without any significant correlation with SLE Disease Activity Index or lipid profile. TGF-β1 had a significant correlation with discoid lupus.


Orienting Attention across the Vertical Meridian: Evidence from Callosotomy Patients.
This study investigates whether interhemispheric interactions mediated by the corpus callosum play a role in orienting attention across the vertical meridian. Patients with complete or partial section of the corpus callosum participated in a spatial precueing task under conditions that required covert shifts of attention within or between the visual fields. Patients with complete callosal section demonstrated normal costs on invalid trials when the cue and target appeared in the same visual field. However, these patients were impaired on invalid trials in which attention had to be redirected across the vertical meridian. The between-within difference emerged only for patients with complete callosal section; it was not evident for a patient with section restricted to the anterior two-thirds of the callosum. Control experiments demonstrated that the deficit (1) is specific to shifts across the vertical meridian, (2) is not due to shifting between left and right hemispace, and (3) is related to the voluntary allocation of attention in response to the cue. These results suggest that interhemispheric communication, which is normally mediated by the posterior region of the corpus callosum, contributes to the efficient movement of attention between visual fields.


Diminished LcrV secretion attenuates Yersinia pseudotuberculosis virulence.
Many gram-negative bacterial pathogenicity factors that function beyond the outer membrane are secreted via a contact-dependent type III secretion system. Two types of substrates are predestined for this mode of secretion, namely, antihost effectors that are translocated directly into target cells and the translocators required for targeting of the effectors across the host cell membrane. N-terminal secretion signals are important for recognition of the protein cargo by the type III secretion machinery. Even though such signals are known for several effectors, a consensus signal sequence is not obvious. One of the translocators, LcrV, has been attributed other functions in addition to its role in translocation. These functions include regulation, presumably via interaction with LcrG inside bacteria, and immunomodulation via interaction with Toll-like receptor 2. Here we wanted to address the significance of the specific targeting of LcrV to the exterior for its function in regulation, effector targeting, and virulence. The results, highlighting key N-terminal amino acids important for LcrV secretion, allowed us to dissect the role of LcrV in regulation from that in effector targeting/virulence. While only low levels of exported LcrV were required for in vitro effector translocation, as deduced by a cell infection assay, fully functional export of LcrV was found to be a prerequisite for its role in virulence in the systemic murine infection model.


Testosterone and cortisol release among Spanish soccer fans watching the 2010 World Cup final.
This field study investigated the release of testosterone and cortisol of a vicarious winning experience in Spanish fans watching the finals between Spain and the Netherlands in the 2010 FIFA World Cup Soccer. Spanish fans (n = 50) watched the match with friends or family in a public place or at home and also participated in a control condition. Consistent with hypotheses, results revealed that testosterone and cortisol levels were higher when watching the match than on a control day. However, neither testosterone nor cortisol levels increased after the victory of the Spanish team. Moreover, the increase in testosterone secretion was not related to participants' sex, age or soccer fandom, but the increase in total cortisol secretion during the match was higher among men than among women and among fans that were younger. Also, increases in cortisol secretion were greater to the degree that people were a stronger fan of soccer. Level of fandom further appeared to account for the sex effect, but not for the age effect. Generally, the testosterone data from this study are in line with the challenge hypothesis, as testosterone levels of watchers increased to prepare their organism to defend or enhance their social status. The cortisol data from this study are in line with social self-preservation theory, as higher cortisol secretion among young and greater soccer fans suggests that especially they perceived that a negative outcome of the match would threaten their own social esteem.


Myasthenia gravis: An emerging toxicity of immune checkpoint inhibitors.
The advent of immunotherapy has heralded a number of significant advances in the treatment of particular malignancies associated with poor prognosis (melanoma, non-small-cell lung, renal and head/neck cancers). The success witnessed with therapeutic agents targeting cytotoxic T-lymphocyte-associated protein 4, programmed cell death protein 1 and programmed cell death ligand 1 immune checkpoints has inevitably led to an explosion in their clinical application and the subsequent recognition of specific toxicity profiles distinct from those long recognised with chemotherapy. Consequently, as the utility of such therapies broaden, understanding the nature, timing and management of these immune-related adverse events (irAEs) becomes increasingly significant. Although neurological irAEs are considered relatively rare in comparison with hepatitis, colitis, pneumonitis and endocrinopathies, one emerging side-effect is myasthenia gravis (MG). Among the 23 reported cases of immune checkpoint inhibitor-associated MG, 72.7% were de novo presentations, 18.2% were exacerbations of pre-existing MG and 9.1% were exacerbations of subclinical MG. The average onset of symptoms was within 6 weeks (range 2-12 weeks) of treatment initiation. In addition, there was no consistent association with elevated acetylcholine antibody titres and the development of immune checkpoint inhibitor-related MG. Significantly, there was a 30.4% MG-specific-related mortality, which further emphasises the importance of early recognition and robust treatment of this toxicity. In addition to a review of the existing literature, we present a new case of pembrolizumab-induced MG and provide insights into the underlying mechanisms of action of this phenomenon.


A Persian Adaptation of Medication Adherence Self-Efficacy Scale (MASES) in Hypertensive Patients: Psychometric Properties and Factor Structure.
Poor adherence to anti-hypertensive treatment significantly contributes to the failure to achieve well-controlled blood pressure in patients with hypertension. To convert the original English version of Medication Adherence Self-efficacy Scale (MASES) into a Persian version for clinical application in hypertensive patients. The backward-forward translation method was used to produce the Persian version of the questionnaire. Then the internal consistency was assessed using Cronbach's alpha. Exploratory Factor Analysis was applied to extract the components of the questionnaire. Correlation between blood pressures and drug adherence was then determined using the Persian MASES in hypertensive patients. Cronbach's alpha coefficient of the Persian version of MASES was >0.92, suggesting that it can yield consistent results. Exploratory Factor Analysis suggested an uni-dimensionality of the scale. Patients with uncontrolled hypertension showed poor adherence to hypertensive medications, therefore had significant lower self-efficacy scores than those with well-controlled blood pressure by medications. The Persian version of MASES is valid and reliable to assess self-efficacy of antihypertensive medication adherence in hypertensive patient, which is helpful to improve medication compliance in such patients in order to achieve better blood pressure controls.


Atomic snapshots of an RNA packaging motor reveal conformational changes linking ATP hydrolysis to RNA translocation.
Many viruses package their genome into preformed capsids using packaging motors powered by the hydrolysis of ATP. The hexameric ATPase P4 of dsRNA bacteriophage phi12, located at the vertices of the icosahedral capsid, is such a packaging motor. We have captured crystallographic structures of P4 for all the key points along the catalytic pathway, including apo, substrate analog bound, and product bound. Substrate and product binding have been observed as both binary complexes and ternary complexes with divalent cations. These structures reveal large movements of the putative RNA binding loop, which are coupled with nucleotide binding and hydrolysis, indicating how ATP hydrolysis drives RNA translocation through cooperative conformational changes. Two distinct conformations of bound nucleotide triphosphate suggest how hydrolysis is activated by RNA binding. This provides a model for chemomechanical coupling for a prototype of the large family of hexameric helicases and oligonucleotide translocating enzymes.


Coming of Age on a Shoestring Budget: Financial Capability and Financial Behaviors of Lower-Income Millennials.
Lower-income millennials make important financial decisions that may affect their future financial well-being. With limited resources, this population is at risk for acquiring too much debt or being unprepared for a financial emergency that can send them further into poverty and constrain their ability to leverage resources for future economic mobility. A financial capability approach, an intervention that combines financial education with financial inclusion through the use of a savings account, may correlate with millennials' healthy financial behaviors. This study used data from the 2012 National Financial Capability Study to examine the relationship between financial capability and the financial behaviors of lower-income millennials between the ages of 18 and 34 years (N = 2,578). Compared with those lower-income millennials who were financially excluded, those who were financially capable were also 171 percent more likely to afford an unexpected expense, 182 percent more likely to save for emergencies, and 34 percent less likely to carry too much debt, relating to their greater overall financial satisfaction. The findings of this study indicate that interventions that develop lower-income millennials' financial capability may be effective for promoting healthy financial behaviors.


[Behavioral approach and community health.].
According to the behavioural approach, man is the product of his interaction with the environment. Normal as well as pathological behaviours are seen as the result of learning. Even individual subjectivity is perceived as a collection of internal behaviours responding to the same laws as overt behaviour. The therapeutic intervention consists therefore in the restructuring of learning conditions so as to eliminate problem behaviours from the individual's repertoire, and to replace them with more adapted behaviours. The approach does not, however, provide a definition of adaptation. The latter is a value judgement, made by society or the interventive agent, with respect to the individual's behaviour. Serious ethical problems can be posed and the interventive agent must take them into consideration. At the level of intervention in community health the behavioural approach suggests the use of milieu ressources to settle individual problems. Therefore the consultant becomes an educator and a planner in resource-utilization rather than a "therapist" in the traditional sense of the term>> This approach provides very powerful methods of action at the level of primary and tertiary prevention and of evaluation of interventive success.


Inhibiting Polo-like kinase 1 causes growth reduction and apoptosis in pediatric acute lymphoblastic leukemia cells.
This study investigated Polo-like kinase 1, a mitotic regulator often over-expressed in solid tumors and adult hematopoietic malignancies, as a potential new target in the treatment of pediatric acute lymphoblastic leukemia. Polo-like kinase 1 protein and Thr210 phosphorylation levels were higher in pediatric acute lymphoblastic leukemia (n=172) than in normal bone marrow mononuclear cells (n=10) (P<0.0001). High Polo-like kinase 1 protein phosphorylation, but not expression, was associated with a lower probability of event-free survival (P=0.042) and was a borderline significant prognostic factor (P=0.065) in a multivariate analysis including age and initial white blood cell count. Polo-like kinase 1 was necessary for leukemic cell survival, since short hairpin-mediated Polo-like kinase 1 knockdown in acute lymphoblastic leukemia cell lines inhibited cell proliferation by G2/M cell cycle arrest and induced apoptosis through caspase-3 and poly (ADP-ribose) polymerase cleavage. Primary patient cells with a high Polo-like kinase 1 protein expression were sensitive to the Polo-like kinase 1-specific inhibitor NMS-P937 in vitro, whereas cells with a low expression and normal bone marrow cells were resistant. This sensitivity was likely not caused by Polo-like kinase 1 mutations, since only one new mutation (Ser335Arg) was found by 454-sequencing of 38 pediatric acute lymphoblastic leukemia cases. This mutation did not affect Polo-like kinase 1 expression or NMS-P937 sensitivity. Together, these results indicate a pivotal role for Polo-like kinase 1 in pediatric acute lymphoblastic leukemia and show potential for Polo-like kinase 1-inhibiting drugs as an addition to current treatment strategies for cases expressing high Polo-like kinase 1 levels.


Serum oxidant and antioxidant status in adolescents undergoing professional endurance sports training.
This study evaluated the impact of professional training on serum oxidant and antioxidant status in adolescent endurance athletes and compared it with that of untrained individuals. Firstly, serum thiobarbituric-acid-reactive substances (TBARSs), xanthine oxidase (XO), catalase (CAT), reduced glutathione (GSH), superoxide dismutase (SOD), and total antioxidant capacity (T-AOC) were measured in 67 male runners, cyclists, and untrained adolescents. Seven-day dietary intakes were also assessed. Secondly, for age- and Tanner-stage-matched comparison, 36 out of the 67 subjects (12 for each group) were then selected and investigated. In cyclists, XO, GSH, and CAT were higher as compared with runners and controls. The CAT in runners, but not GSH and XO, was also higher than in controls. TBARS, T-AOC, and SOD did not differ among the study populations. Regarding the inter-individual relationships among serum redox statuses and dietary nutrient intakes, significant correlations were noted in CAT versus carbohydrates, protein, magnesium, and manganese; GSH versus carbohydrates, protein, fat, selenium, zinc, iron, and magnesium; XO versus cholesterol; CAT versus GSH. These findings suggest that the resting blood redox balance in the professional adolescent athletes was well maintained partly by the increase of individual antioxidant in adaptation to chronic exercise.


The mechanism of transactivation regulation due to polymorphic short tandem repeats (STRs) using IGF1 promoter as a model.
Functional short tandem repeats (STR) are polymorphic in the population, and the number of repeats regulates the expression of nearby genes (known as expression STR, eSTR). STR in IGF1 promoter has been extensively studied for its association with IGF1 concentration in blood and various clinical traits and represents an important eSTR. We previously used an in-vitro luciferase reporter model to examine the interaction between STRs and SNPs in IGF1 promoter. Here, we further explored the mechanism how the number of repeats of the STR regulates gene transcription. An inverse correlation between the number of repeats and the extent of transactivation was found in a haplotype consisting of three promoter SNPs (C-STR-T-T). We showed that these adjacent SNPs located outside the STR were required for the STR to function as eSTR. The C allele of rs35767 provides a binding site for CCAAT/enhancer-binding-protein δ (C/EBPD), which is essential for the gradational transactivation property of eSTR and FOXA3 may also be involved. Therefore, we propose a mechanism in which the gradational transactivation by the eSTR is caused by the interaction of one or more transcriptional complexes located outside the STR, rather than by direct binding to a repeat motif of the STR.


Microtubule reassembly from nucleating fragments during the regrowth of amputated neurites.
We have proposed that stable microtubule (MT) fragments that resist depolymerization may serve as nucleating elements for the local control of MT dynamics in the axon (Heidemann, S. R., M. A. Hamborg, S. J. Thomas, B. Song, S. Lindley, and D. Chu, 1984, J. Cell Biol., 99:1289-1295). Here we report evidence that supports this proposal in studies on the role of MTs in the regrowth of neurites from the distal segments of amputated chick sensory neurites. Amputated neurites collapse to "beads" of axoplasm that rapidly regrow (Shaw, G., and D. Bray, 1977, Exp. Cell Res., 104:55-62). We examined both unarrested regrowth and regrowth after MT disassembly by either cold (-5 degrees C for 2 h) or nocodazole (0.1 microgram/ml for 15-20 min). In all these cases regrowth occurred at 3.5-4.5 micron/min with no delay times other than the times to reach 37 degrees C or rinse out the nocodazole. Electron micrographs of untreated beads show many MTs of varying lengths, while those of cold- and nocodazole-treated beads show markedly shorter MTs. The robust regrowth of neurites from beads containing only very short MTs argues against unfurling of intact MTs from the bead into the growing neurite. Electron micrographs of cold-treated beads lysed under conditions that cause substantial MT depolymerization in untreated intact neurites show persistent MT fragments similar to those in unlysed cold-treated beads. We interpret this as evidence that the MT fragments in cold-treated beads are somehow distinct from the majority of the MT mass that had depolymerized. Collapsed neurites treated with a higher dose of nocodazole (1.0 microgram/ml for 15-20 min) were completely devoid of MTs and regrew only after a 15-20 min delay in two cases but never regrew in 11 other cases. We found that MTs did not return in beads treated with 1.0 microgram/ml nocodazole even 30 min after removal of the drug. It was unlikely that the inability of these beads to reassemble MTs was due to incomplete removal of nocodazole in that a much higher dose (20 micrograms/ml nocodazole) could be quickly rinsed from intact neurites. Beads treated with 1.0 microgram/ml nocodazole could, however, be stimulated to reassemble MTs and regrow neurites by treatment with taxol. We conclude that the immediate, robust regrowth of neurites from collapsed beads of axoplasm requires MT nucleation sites to support MT reassembly.(ABSTRACT TRUNCATED AT 400 WORDS)


Effect of a kinin antagonist on renal function and haemodynamics during alterations in sodium balance in conscious normotensive rats.
1. To evaluate whether sodium intake can modulate the action of endogenous kinins on renal function and haemodynamics, a receptor antagonist of bradykinin was infused in conscious normotensive rats maintained on either a normal or a low sodium diet. 2. The antagonist inhibited the hypotensive effect of exogenously administered bradykinin. It did not change the vasodepressor effect of acetylcholine, dopamine or prostaglandin E2. 3. The antagonist did not affect mean blood pressure, glomerular filtration rate, renal blood flow or urinary sodium excretion, in rats on sodium restriction. It did not change mean blood pressure, glomerular filtration rate or urinary sodium excretion, but decreased renal blood flow, in rats on a normal sodium intake. 4. The kallikrein-kinin system has a role in the regulation of renal blood flow in rats on a normal sodium diet.


Parental recognition of shunt failure: a prospective single-institution study.
Because there is no gold standard for preoperative diagnosis of shunt failure, understanding the sensitivity, specificity, and predictive values of symptoms, signs, and diagnostic tests enables practitioners to make logical clinical decisions. Parents of children with shunts undergo educational instruction to enable them to recognize shunt failure. The authors prospectively investigated parental ability to recognize shunt failure. Data were prospectively collected on 205 consecutive encounters in 153 children with shunted hydrocephalus presenting to the emergency department or clinic, or as an inpatient consultation, to the Children's Hospital of Alabama between April and October 2010. Regardless of the complaint, all parents were asked if they believed the shunt was in failure. Six children were excluded from analysis because a parental response was lacking. Using the Shunt Design Trial definitions, shunt failure was diagnosed intraoperatively or ruled out if the child did not undergo shunt revision within 1 week of presentation. Sensitivity, specificity, predictive values, and accuracy were calculated using the parental response and shunt failure diagnosis. Secondarily, parents were compared based on their experience with shunt failure in their children; experienced parents were defined as having experienced at least 3 shunt failures. Post hoc analysis evaluated diagnostic test characteristics among hydrocephalus causes and compared parental recognition of shunt failure to head CT and shunt series diagnostic test characteristics. Parents also completed a standardized shunt failure survey regarding their shunt teaching education and symptom tracking. Children enrolled were a mean age of 6.9 years old, 92 (46%) of the encounters were with male patients, and most patients were Caucasian (69%) and had undergone an average of 2.8 previous shunt revisions. Seventy-one children (36%) were diagnosed with shunt failure. Parental response diagnostic test characteristics were: positive predictive value (PPV) of 41%, negative predictive value (NPV) of 79%, sensitivity of 83%, specificity of 34%, and accuracy of 52% for shunt failure. Sixty-three parents were considered experienced and responded with a PPV of 29%, NPV of 92%, sensitivity of 94%, specificity of 23%, and accuracy of 41%. One hundred thirty-six parents were considered inexperienced and responded with a PPV of 48%, NPV of 75%, sensitivity of 80%, specificity of 41%, and accuracy of 57%. When statistically compared, experienced parents had significantly lower PPV (29% vs 48%, respectively; p = 0.035) and accuracy (41% vs 57%, respectively; p = 0.049) than inexperienced parents. On post hoc analysis, parental recognition of shunt failure was inferior to head CT and shunt series diagnostic tests with a lower specificity (20% vs 88%, respectively; p < 0.0005), PPV (44% vs 84%, respectively; p < 0.0005), NPV (61% vs 85%, respectively; p = 0.006), and accuracy (47% vs. 85%, respectively; p < 0.0005). The overall parental response had the greatest value in ruling out shunt failure, reflected in the high NPV, particularly in experienced parents. The head CT and shunt series provide more favorable diagnostic test characteristics than the parental response. Although educational interventions have decreased shunt-related deaths, parents have difficulty differentiating shunt failure from alternative diagnoses.


MTA1 coregulator regulates p53 stability and function.
Although metastasis-associated protein 1 (MTA1) has recently been shown as a DNA damage responsive protein, the underlying mechanism for its role in DNA double-strand break (DSB) repair remains unknown. Here, we show that MTA1 controls p53 stability through inhibiting its ubiquitination by E3 ubiquitin ligases mouse double minute 2 (Mdm2) and constitutive photomorphogenic protein 1 (COP1). The underlying mechanisms involve the ability of MTA1 to compete with COP1 to bind to p53 and/or to destabilize COP1 and Mdm2. Consequently, MTA1 regulates the p53-dependent transcription of p53R2, a direct p53 target gene for supplying nucleotides to repair damaged DNA. Depletion of MTA1 impairs p53-dependent p53R2 transcription and compromises DNA repair. Interestingly, these events could be reversed by MTA1 reintroduction, indicating that MTA1 interjects into the p53-dependent DNA repair. Given the fact that MTA1 is widely up-regulated in human cancers, these findings in conjunction with our earlier finding of a crucial role of MTA1 in DSB repair suggest an inherent role of the MTA1-p53-p53R2 pathway in DNA damage response in cancer cells.


Challenges and Opportunities for Drug Repositioning in Fibrodysplasia Ossificans Progressiva.
Fibrodysplasia ossificans progressiva (FOP) is an ultrarare congenital disease that progresses through intermittent episodes of bone formation at ectopic sites. FOP patients carry heterozygous gene point mutations in activin A receptor type I ACVR1, encoding the bone morphogenetic protein (BMP) type I serine/threonine kinase receptor ALK2, termed activin receptor-like kinase (ALK)2. The mutant ALK2 displays neofunctional responses to activin, a closely related BMP cytokine that normally inhibits regular bone formation. Moreover, the mutant ALK2 becomes hypersensitive to BMPs. Both these activities contribute to enhanced ALK2 signalling and endochondral bone formation in connective tissue. Being a receptor with an extracellular ligand-binding domain and intrinsic intracellular kinase activity, the mutant ALK2 is a druggable target. Although there is no approved cure for FOP yet, a number of clinical trials have been recently initiated, aiming to identify a safe and effective treatment for FOP. Among other targeted approaches, several repurposed drugs have shown promising results. In this review, we describe the molecular mechanisms underlying ALK2 mutation-induced aberrant signalling and ectopic bone formation. In addition, we recapitulate existing in vitro models to screen for novel compounds with a potential application in FOP. We summarize existing therapeutic alternatives and focus on repositioned drugs in FOP, at preclinical and clinical stages.


Evaluation of shark cartilage in patients with advanced cancer: a North Central Cancer Treatment Group trial.
Shark cartilage has been a popular complementary or alternative medicine intervention. The basis for this popularity is the claim that sharks rarely get cancer because of the high proportion of cartilage in the shark's body. However, early studies were equivocal. Therefore, a clinical trial was conducted to look at the impact of shark cartilage in patients with advanced cancer. The primary goal of this trial was to determine whether a shark cartilage product improved overall survival for patients with advanced cancer who were getting standard care. Secondary research goals were to evaluate toxicities, tolerability, and quality of life associated with this shark cartilage product. The study was a two-arm, randomized, placebo-controlled, double-blind, clinical trial. Patients with incurable breast or colorectal carcinoma had to have good performance status and organ function. Patients could be receiving chemotherapy. Patients were all to receive standard care and then to be randomly selected to receive either a shark cartilage product or an identical-appearing and smelling placebo 3 to 4 times each day. Data on a total of 83 evaluable patients were analyzed. There was no difference in overall survival between patients receiving standard care plus a shark cartilage product versus standard care plus placebo. Likewise, there was no suggestion of improvement in quality of life for patients receiving the shark cartilage, compared with those receiving placebo. This trial was unable to demonstrate any suggestion of efficacy for this shark cartilage product in patients with advanced cancer.


Is peer assessment an effective learning tool in an internationally and educationally heterogeneous cohort of students?
Peer assessment is a well-established tool in peer-assisted learning, however there is little work in its use across a multidisciplinary cohort. Twenty-two students of a variety of undergraduate backgrounds from different nationalities attended a 3-week university summer school on the topic of peripheral nerve injuries. Peer assessment of an oral presentation made up an aspect of the formative assessment of the course. Students were surveyed using a Likert score on their impression of peer assessment as a learning and assessment tool. Fourteen (64%) students agreed that the peer assessment process improved the learning process and 5 (23%) strongly agreed. Thirteen (59%) students agreed and nine (41%) strongly agreed that it improved the engagement with their peers' presentation. Seventeen (77%) students either agreed or strongly agreed that it was appropriate to use as a method of formative assessment. Students agreed that peer assessment improved learning and engagement and is an appropriate assessment tool. Whereas peer assessment has been proven to be an effective method for assessment and reflective learning within a homogenous group, this study demonstrates that this remains true in a heterogeneous cohort of international undergraduates where expertise, underlying knowledge base, and learning approaches may vary.


Leptin--a growth factor in normal and malignant breast cells and for normal mammary gland development.
Obesity is a risk factor for breast cancer in postmenopausal women. As body weight and fat mass increase, circulating leptin increases. Leptin is an adipocyte-derived cytokine that acts through the long form of its receptor, termed OB-Rb. To investigate whether leptin is associated with breast cancer, we determined the expression of OB-Rb in human breast epithelial HBL100 cells and human breast carcinoma-derived T-47D cells, determined whether leptin influenced the proliferation of these cells, and evaluated the structure of mammary tissue in genetically obese leptin-deficient Lep(ob)Lep(ob) and leptin receptor-deficient Lepr(db)Lepr(db) mice. Cell numbers and cell colony formation by HBL100 and T-47D cells were determined by anchorage-dependent and anchorage-independent growth assays. OB-Rb expression was examined by reverse transcription-polymerase chain reaction and immunoblot analyses. Expression of leptin signaling pathway components was evaluated with immunoblot and electrophoretic mobility shift assays. Mammary gland development in lean and obese mice was investigated in whole-mount studies. All statistical tests were two-sided. Leptin enhanced anchorage-dependent proliferation by 138% (95% confidence interval [CI] = 108% to 169%) in T-47D cells and 50% (95% CI = 38% to 60%) in HBL100 cells. In both cell lines, OB-Rb was expressed, and leptin increased the expression of phosphorylated signal transducers and activators of transcription 3 (STAT3), phosphorylated extracellular signal-regulated kinase (ERK), and transcript activator protein 1 (AP-1). However, leptin increased anchorage-independent cell growth only in the breast cancer cell line (by 81% [95% CI = 62% to 101%] compared with untreated cells). Obese Lep(ob)Lep(ob) and Lepr(db)Lepr(db) mice had minimal epithelial development in the mature mammary gland compared with their lean counterparts. Leptin appears to be able to control the proliferation of both normal and malignant breast epithelial cells. Consequently, the leptin pathway should be further studied as a target for interventions to treat or prevent breast cancer.


New lessons from random X-chromosome inactivation in the mouse.
X-chromosome inactivation (XCI) ensures dosage compensation in mammals. Random XCI is a process where a single X chromosome is silenced in each cell of the epiblast of mouse female embryos. Operating at the level of an entire chromosome, XCI is a major paradigm for epigenetic processes. Here we review the most recent discoveries concerning the role of long noncoding RNAs, pluripotency factors, and chromosome structure in random XCI.


Locomotion in moles (insectivora, proscalopidae) from the middle tertiary of north america.
The locomotion of proscalopid moles, an extinct group restricted to North America, differed from that of other animals. Analysis of a newly discovered and relatively complete and articulated skeleton shows that the digging technique of proscalopids involved a combination of motions that has not been observed in modern fossorial insectivores. The many anatomical peculiarities of proscalopids are related to their specialized digging technique and justify their assignment to a new family of insectivores, the Proscalopidae.


Energy and nutrient intake in Mexican adolescents: analysis of the Mexican National Health and Nutrition Survey 2006.
To describe energy and nutrient intake and adequacy percentages in Mexican adolescents included in the Mexican National Health and Nutrition Survey 2006 (ENSANUT 2006) as well as the proportion of population at risk of dietary inadequacy. Data were analyzed from 7-day food-frequency questionnaires for 8442 male and female adolescents 12-19 years old. Energy and nutrient adequacies as percentage of the Estimated Average Requirement were calculated and comparisons were done by region, residence area, and socioeconomic status (SES). Energy intake was 1903 kcal [adequacy percentage (AP=75%)] in boys, and 1 571 kcal (AP=79.2%) in girls. Intake of most nutrients (zinc, iron, vitamin C and A) was lower in subjects of low SES, living in the southern region and in rural areas. The rural area, the southern region, and the lower socioeconomic status show the lowest intakes and percentages of nutrient adequacy for both male and female adolescents, in particular vitamin A, folates, heme iron, zinc, and calcium.


Mutations in human O6-alkylguanine-DNA alkyltransferase imparting resistance to O6-benzylguanine.
O6-Benzylguanine is an inactivator of O6-alkylguanine-DNA alkyltransferases (AGT) which is currently entering clinical trials as an agent improving the cancer chemotherapeutic activity of chloroethylnitrosoureas and other alkylating agents. O6-Benzylguanine acts by virtue of its ability to serve as a substrate for the AGT forming S-benzylcysteine at the cysteine acceptor site. The effects of a number of mutations in the human AGT sequence on the reaction with O6-benzylguanine were investigated by two methods: (a) by measuring the loss of the ability of the AGT to repair a methylated DNA substrate after preincubation with O6-benzylguanine; and (b) by measuring the production of guanine from O6-benzylguanine by the AGT proteins. Both assays gave similar results and showed that mutations of the proline residues at positions 138 and 140 and of the glycine residue at position 156 significantly reduced the ability to react with O6-benzylguanine. The combination of these mutations gave even greater resistance. Thus, the 50% effective dose for O6-benzylguanine was increased from 0.25 microM in the control AGT to 29 microM by mutations P138K/P140A, to 60 microM by mutation G156A and to > 300 microM by mutations P140A/G156A. Truncation of the AGT at the carboxyl end, removing either 31 or 23 amino acids did not affect the activity or the ability to react with O6-benzylguanine, but removal of the 36 carboxyl terminal amino acids, which includes a highly conserved glutamic acid residue, led to the loss of all activity. The rate of the reaction between the AGT and O6-benzylguanine was increased when DNA was present. This increase amounted to about 6-fold with the control AGT and the carboxyl-truncated mutants but was reduced to only 2-fold with G156A mutant and increased to 11-18-fold with the mutations of proline residues at 138 and 140. These results indicate that several residues in the AGT sequence affect the access of the active site to O6-benzylguanine and that these residues are located in at least two regions on either side of the active site cysteine, which is located at residue 145. Mutations in these regions may occur during therapy with alkylating agents and O6-benzylguanine. The development of other AGT inactivators which are still able to inactivate the resistant mutants may be necessary to maximize the potential of AGT inhibition for cancer chemotherapy.


Manganese: Its Role in Disease and Health.
Manganese is an essential dietary element that functions primarily as a coenzyme in several biological processes. These processes include, but are not limited to, macronutrient metabolism, bone formation, free radical defense systems, and in the brain, ammonia clearance and neurotransmitter synthesis. It is a critical component in dozens of proteins and enzymes, and is found in all tissues. Concentrated levels of Mn are found in tissues rich in mitochondria and melanin, with both, liver, and pancreas having the highest concentrations under normal conditions. However, overexposure to environmental Mn via industrial occupation or contaminated drinking water can lead to toxic brain Mn accumulation that has been associated with neurological impairment. The objective of this chapter is to address the biological importance of Mn (essentiality), routes of exposure, factors dictating Mn status, a brief discussion of Mn neurotoxicity, and proposed methods for neurotoxicity remediation.


Hydrodynamics of the VanA-type VanS histidine kinase: an extended solution conformation and first evidence for interactions with vancomycin.
VanA-type resistance to glycopeptide antibiotics in clinical enterococci is regulated by the VanSARA two-component signal transduction system. The nature of the molecular ligand that is recognised by the VanSA sensory component has not hitherto been identified. Here we employ purified, intact and active VanSA membrane protein (henceforth referred to as VanS) in analytical ultracentrifugation experiments to study VanS oligomeric state and conformation in the absence and presence of vancomycin. A combination of sedimentation velocity and sedimentation equilibrium in the analytical ultracentrifuge (SEDFIT, SEDFIT-MSTAR and MULTISIG analysis) showed that VanS in the absence of the ligand is almost entirely monomeric (molar mass M = 45.7 kDa) in dilute aqueous solution with a trace amount of high molar mass material (M ~ 200 kDa). The sedimentation coefficient s suggests the monomer adopts an extended conformation in aqueous solution with an equivalent aspect ratio of ~(12 ± 2). In the presence of vancomycin over a 33% increase in the sedimentation coefficient is observed with the appearance of additional higher s components, demonstrating an interaction, an observation consistent with our circular dichroism measurements. The two possible causes of this increase in s - either a ligand induced dimerization and/or compaction of the monomer are considered.


[Inhibiting effects of stroma cell drived factor 1 (SDF-1) on proliferation of human acute myelocytic leukemia cell HL-60].
This study was aimed to investigate the importance of chemokine SDF-1 in maintaining proliferation ability of acute myelocytic leukemia cell line HL-60 when the effects of SDF-1 on HL-60 cell proliferation were inhibited. Marrow stromal cells were cultured and co-cultured with HL-60 cells, and SDF-1 activity was blocked with anti-CXCR4 McAb. HL-60 cell activity was detected by MTT while cell cycle and the expression of CXCR4 on HL-60 cell membrane were observed by flow cytometry meanwhile. The internal calcium ionic concentration in HL-60 cell was detected as well before and after treated with 12G5. The results showed that 12G5 down-regulated the expression of CXCR4 on HL-60 cell membrane; HL-60 cells at G(0)/G(1) phase increased, but decreased at S phase; survive rate of leukemia cells reduced; the intercellular calcium ionic concentration of HL-60 cell decreased after treated with 12G5. It was concluded that brockage of the SDF-1 activity may inhibit proliferation of leukemia cell at certain level.


Clinical and diagnostic findings of an echovirus meningitis outbreak in the north west of England.
An outbreak of echovirus meningitis occurred in the north west of England in 2001. This paper reviewed the clinical features and the role of different diagnostic methods. This was a prospective study of adults admitted to a regional infectious disease unit with a probable diagnosis of meningitis, March to August 2001. Half the 40 cases were male; median age was 28 (range 16-51) years. Fifteen of 38 (39.5%) were smokers, and 20 of 24 (83.3%) had close contact with children. Median (range) duration of symptoms was 1.1 (0.25-7) days. Symptoms included headache (100%), photophobia (87.5%), and nausea (67.5%), and severity ranged from minimal signs to those consistent with a meningoencephalitis. The diagnosis was confirmed virologically in 29 of 40 (72%); echovirus 30 was isolated from six. Cerebrospinal fluid (CSF) enterovirus polymerase chain reaction (PCR) was positive in 26 of 32 (81%), and CSF virus culture in 3 of 16 (19%). Thirty one per cent of CSF samples had a neutrophil predominance, and 3 of 29 (10%) virologically confirmed cases had normal CSF microscopy and biochemistry. CSF microscopy may be normal or suggest bacterial meningitis in a substantial minority of cases of echovirus meningitis. CSF PCR for enterovirus seems to be more sensitive than virus culture of CSF, although PCR does not yield information on circulating virus type. Early and accurate diagnosis could reduce both use of parenteral antibiotics and length of hospital stay with both morbidity and cost implications. Close contact with children may be a risk factor, particularly if good hygiene measures are not practised.


A Cross-Sectional Description of Parental Perceptions and Practices Related to Risky Play and Independent Mobility in Children: The New Zealand State of Play Survey.
The potential for risky play and independent mobility to increase children's physical activity, and enhance cognitive development and emotional wellbeing has been recognised for some time. The aim of this study was to describe the attitudes of New Zealand parents towards such risky play practices and independent mobility, the barriers preventing them from allowing their children to participate, and how often their children engaged in risky play activities. An online survey comprised mostly of validated scales and standardised questions was completed by a nationally representative sample of 2003 parents. We found that parents had neutral feelings about the risk of injury to their child through play, rather they were concerned about road safety and "stranger danger". There was strong agreement that there are multiple benefits to be gained from exposure to risk and challenge, and that health and safety rules are too strict. However, 73% of respondents stated that their 5⁻12 year old child seldom or never engaged in four or more risky activities, and only 14.3% engaged in four or more often or always. While parents agree that their child is likely to benefit from risky play, they do not have the confidence to allow their children to engage in such activities. Future research should address barriers and fears when implementing strategies to facilitate risky play.


Computer-assisted reading intervention for children with sensorineural hearing loss using hearing aids: Effects on auditory event-related potentials and mismatch negativity.
The primary aim was to investigate whether computer-assisted reading intervention somehow can affect event-related potentials (ERP) and mismatch negativity (MMN) in hearing impaired (HI) children with hearing aids (HAs) and normal hearing (NH) children. The study included 15 HI children with sensorineural hearing loss (SNHL) using bilateral HAs and 14 NH children as a reference group; all children between the ages of 5 and 8. A multi-feature MMN-paradigm, Optimum-1, with a standard stimulus alternating with 5 different deviants was used. ERPs were recorded pre and post intervention, i.e. one month of repeatedly computer-assisted training (GraphoGame). MMN was calculated from the average ERP of each deviant minus standard. Data were based on samples within a specific time interval, 80-224 ms, and repeated measures ANOVA was used to analyze possible interactions. There was a significant difference between groups before training, though, the mean obligatory responses or MMN was not statistically significantly different before versus after training, neither among the NH nor the HI children. Further, the HI children did generally achieve lower levels in GraphoGame compared to the NH children. Altogether, our findings indicate differences between the groups and that training may affect the neurophysiological processing in the brain, gaining the HI children. Both MMN and positive mismatch response (pMMR) were seen among both the HA and NH children, irrespective to deviant type. Individually, changes of the MMN and pMMR after training seem unpredictable. There are statistically significant differences in both the obligatory responses in ERP and the MMNs between the NH and HI groups before the computer-assisted training. Though, these differences disappear after the intervention. This suggests possible training effects regarding the central auditory processing among the HI children.


Characterization of the interferon genes in homozygous rainbow trout reveals two novel genes, alternate splicing and differential regulation of duplicated genes.
The genes encoding the type I and type II interferons (IFNs) have previously been identified in rainbow trout and their proteins partially characterized. These previous studies reported a single type II IFN (rtIFN-gamma) and three rainbow trout type I IFN genes that are classified into either group I (rtIFN1, rtIFN2) or group II (rtIFN3). In this present study, we report the identification of a novel IFN-gamma gene (rtIFN-gamma2) and a novel type I group II IFN (rtIFN4) in homozygous rainbow trout and predict that additional IFN genes or pseudogenes exist in the rainbow trout genome. Additionally, we provide evidence that short and long forms of rtIFN1 are actively and differentially transcribed in homozygous trout, and likely arose due to alternate splicing of the first exon. Quantitative reverse transcriptase PCR (qRT-PCR) assays were developed to systematically profile all of the rainbow trout IFN transcripts, with high specificity at an individual gene level, in naïve fish and after stimulation with virus or viral-related molecules. Cloned PCR products were used to ensure the specificity of the qRT-PCR assays and as absolute standards to assess transcript abundance of each gene. All IFN genes were modulated in response to Infectious hematopoietic necrosis virus (IHNV), a DNA vaccine based on the IHNV glycoprotein, and poly I:C. The most inducible of the type I IFN genes, by all stimuli tested, were rtIFN3 and the short transcript form of rtIFN1. Gene expression of rtIFN-gamma1 and rtIFN-gamma2 was highly up-regulated by IHNV infection and DNA vaccination but rtIFN-gamma2 was induced to a greater magnitude. The specificity of the qRT-PCR assays reported here will be useful for future studies aimed at identifying which cells produce IFNs at early time points after infection.


An exploration of the knowledge, attitudes and beliefs of Xhosa men concerning traditional circumcision.
The practice of traditional circumcision is associated with considerable morbidity and mortality, yet there is a paucity of literature that provides an understanding of the cultural values that influence men to choose traditional rather than medical circumcision.The aim of this study was to better understand the culture surrounding traditional circumcision, with a view to addressing morbidity and mortality rates associated with the Xhosa male initiation rituals.We explored Xhosa men's perceptions regarding the need for the risks and the social pressure to undergo traditional circumcision, the impact of non-initiation or failed initiation and the perceived barriers to obtaining medical help for the complications of traditional circumcisions. Individual in-depth interviews were conducted with 10 purposively sampled teenagers and adult men. The interviews were recorded, translated, transcribed and analysed using the framework method. Traditional circumcision was seen as essential to Xhosa culture. Participants rationalised many reasons for participating, including personal growth and development, family and peer pressure, independence and knowledge gained, a connection with ancestors and initiation into manhood. Despite publicity of the dangers of traditional circumcision and the hardships they have to endure, most young men still saw this process as necessary and worthwhile. Traditional initiation and circumcision are here to stay. The majority of boys still trust the elders and supernatural processes to guide them. However, some participants welcomed government initiatives to reduce human error causing unnecessary death and suffering. Current systems to prevent morbidity and mortality are insufficient and should be prioritised.


The genomic dynamics and evolutionary mechanism of the Pi2/9 locus in rice.
The Pi2/9 locus contains at least four resistance specificities to Magnaporthe grisea and belongs to a gene complex comprised of multiple genes that encode highly homologous nucleotide binding site (NBS) and leucine rich repeat (LRR) proteins. To investigate the genetic events involved in the evolution of the Pi2/9 locus, we analyzed the Pi2/9 locus at the inter- and intralocus levels in five rice cultivars. The NBS-LRR genes in the five cultivars belong to the same phylogenetic clade among rice NBS-LRR genes, and all have a phase-2 intron at the N-terminus. However, the paralogs within each haplotype show a significant sequence divergence and their N-terminal intron and 5' regulatory regions are very different. On the contrary, the orthologs from different haplotypes are highly similar, indicating an obvious orthologous relationship has been maintained during the evolution of the Pi2/9 locus. These results suggest that sequence diversification in the 5' regulatory regions and N-terminal introns of the paralogs may have led to suppression of meiotic recombination between the paralogs within each haplotype, facilitating the maintenance of the orthologous relationship among rice cultivars. Our observations provide valuable insight into the genomic dynamics and evolutionary mechanism of an NBS-LRR resistance-gene complex in rice.


Darzens reaction of acyl phosphonates with alpha-bromo ketones: selective synthesis of cis- and trans-epoxyphosphonates.
Acyl phosphonates with alpha-halo ketones in the presence of bases at room temperature afford cis- and trans-epoxyphosphonates in good chemical yields and high selectivities using different bases. The diastereoselectivity of this reaction is easily controlled by changing the base. Changing the base from Cs2CO3 to DBU changed the diastereomeric ratio (trans/cis) from 3/2 to 9/1. Moreover, the treatment of the trans isomer with DBU showed a complete conversion to the corresponding cis isomer.


The Flood-Related Behaviour of River Users in Australia.
Flooding is a common natural disaster affecting 77.8 million people and claiming the lives of 4,731 people globally in 2016. During times of flood, drowning is a leading cause of death. Flooding is a known risk factor for river drowning in Australia. With little known about river usage in Australia, this study aimed to examine the links between person demographics and self-reported participation in two flood-related behaviours, driving through floodwaters and swimming in a flooded river. A self-reported questionnaire was administered to adult river users at four high-risk river drowning locations; Alligator Creek, Townsville, Queensland; Murrumbidgee River, Wagga Wagga, New South Wales; Murray River, Albury, New South Wales; and Hawkesbury River, Windsor, New South Wales. Univariate and chi square analysis was undertaken with a 95% confidence interval (p<0.05). All river users surveyed, were also breathalysed to record an estimate of their blood alcohol content (BAC) on their expired breath. Results: 688 river users responded to the questionnaire; 676 (98.3%) answered the driving question and 674 (98.0%) answered the swimming in floodwaters questions. Of the respondents, 35.7% stated they had driven through floodwater and 18.7% had swum in a flooded river. Males were more likely (p<0.001) to report having undertaken both activities. Australian-born respondents were more likely to report having driven through floodwaters (p=0.006). Those aged 18-24 years old and those residing in outer regional areas were more likely (p<0.001) to have swum in a flooded river. Those who self-reported participating in both driving through floodwaters (p=0.001) and swimming in a flooded river (p<0.001) were significantly more likely to record contributory levels of alcohol (i.e. a BAC ≥0.05%) when breathalysed at the river. Ensuring the safe movement of people during floods is difficult, particularly for those living in regional Australia, due in part to long distances travelled and reduced investment in infrastructure such as bridges. With males and females equally exposed, more effective prevention strategies must target both sexes and may include improved education on when it is safe to drive through (low depth, still water, stable road base) and when it is not (e.g. deep water, moving water and unstable road base). This study identified one in five respondents had swum in a flooded river, most commonly young people aged 18-24 years, with participants signficantly more likely to have recorded contributory levels of alcohol when breathalysed. Further research should examine the reasons behind participation in this behaviour, including the role of alcohol. Preventing drowning in floodwaters is an international challenge, made more difficult by people driving through or swimming in floodwaters. Strategies for driving through floodwaters should educate both males and females on when it is safe to drive through floodwaters and when it is not. Further research is required to improve knowledge of the poorly understood behaviour of swimming in flooded rivers.


Multi-Ancestry Genome-wide Association Study Accounting for Gene-Psychosocial Factor Interactions Identifies Novel Loci for Blood Pressure Traits.
Psychological and social factors are known to influence blood pressure (BP) and risk of hypertension and associated cardiovascular diseases. To identify novel BP loci, we carried out genome-wide association meta-analyses of systolic, diastolic, pulse, and mean arterial BP taking into account the interaction effects of genetic variants with three psychosocial factors: depressive symptoms, anxiety symptoms, and social support. Analyses were performed using a two-stage design in a sample of up to 128,894 adults from 5 ancestry groups. In the combined meta-analyses of Stages 1 and 2, we identified 59 loci (p value <5e-8), including nine novel BP loci. The novel associations were observed mostly with pulse pressure, with fewer observed with mean arterial pressure. Five novel loci were identified in African ancestry, and all but one showed patterns of interaction with at least one psychosocial factor. Functional annotation of the novel loci supports a major role for genes implicated in the immune response (PLCL2), synaptic function and neurotransmission (LIN7A, PFIA2), as well as genes previously implicated in neuropsychiatric or stress-related disorders (FSTL5, CHODL). These findings underscore the importance of considering psychological and social factors in gene discovery for BP, especially in non-European populations.


A five-day inpatient EMDR treatment programme for PTSD: pilot study.
Background: Trauma-focused psychotherapies for posttraumatic stress disorder (PTSD) have been demonstrated to be efficacious, but also have considerable non-response and dropout rates. Intensive treatment may lead to faster symptom reduction, which may contribute to treatment motivation and thereby to reduction of dropout. Objective: The aim of the current study was to investigate the feasibility and preliminary effectiveness of an intensive five-day inpatient treatment with Eye Movement Desensitization and Reprocessing (EMDR) and trauma-informed yoga for patients with PTSD. Method: A non-controlled pilot study with 12 adult patients with PTSD was conducted. At baseline the PTSD diagnosis was assessed with the Clinician-Administered PTSD Scale (CAPS-5) and comorbid disorders with the Mini International Neuropsychiatric Interview (MINI). Primary outcome was self-reported PTSD symptom severity (PTSD Check List for DSM-5; PCL-5) measured at the beginning of day 1 (T1), at the end of day 5 (T2) and at follow-up on day 21 (T3). Reliable change indexes (RCI) and clinically significant changes were calculated. Results: From T1 to T3, PTSD symptoms significantly improved with a large effect size (Cohen's d = 0.91). Nine of the 11 patients who completed treatment showed reliable changes in terms of self-reported PTSD. At T3, two of the patients no longer met criteria for PTSD as measured with the PCL-5. One patient dropped out after the first day. No serious adverse events occurred. Conclusions: The majority of patients in our pilot study experienced symptom reduction consistent with reliable changes in this five-day inpatient treatment with EMDR and yoga. Randomized controlled trials - with longer follow up periods - are needed to properly determine efficacy and efficiency of intensive clinical treatments for PTSD compared to regular treatment. This is one of the first studies to show that intensive EMDR treatment is feasible and is indicative of reliable improvement in PTSD symptoms in a very short time frame.


A research agenda for helminth diseases of humans: the problem of helminthiases.
A disproportionate burden of helminthiases in human populations occurs in marginalised, low-income, and resource-constrained regions of the world, with over 1 billion people in developing areas of sub-Saharan Africa, Asia, and the Americas infected with one or more helminth species. The morbidity caused by such infections imposes a substantial burden of disease, contributing to a vicious circle of infection, poverty, decreased productivity, and inadequate socioeconomic development. Furthermore, helminth infection accentuates the morbidity of malaria and HIV/AIDS, and impairs vaccine efficacy. Polyparasitism is the norm in these populations, and infections tend to be persistent. Hence, there is a great need to reduce morbidity caused by helminth infections. However, major deficiencies exist in diagnostics and interventions, including vector control, drugs, and vaccines. Overcoming these deficiencies is hampered by major gaps in knowledge of helminth biology and transmission dynamics, platforms from which to help develop such tools. The Disease Reference Group on Helminths Infections (DRG4), established in 2009 by the Special Programme for Research and Training in Tropical Diseases (TDR), was given the mandate to review helminthiases research and identify research priorities and gaps. In this review, we provide an overview of the forces driving the persistence of helminthiases as a public health problem despite the many control initiatives that have been put in place; identify the main obstacles that impede progress towards their control and elimination; and discuss recent advances, opportunities, and challenges for the understanding of the biology, epidemiology, and control of these infections. The helminth infections that will be discussed include: onchocerciasis, lymphatic filariasis, soil-transmitted helminthiases, schistosomiasis, food-borne trematodiases, and taeniasis/cysticercosis.


The association between alcohol use and sexual risk behaviors among African American women across three developmental periods: a review.
African American women experience increased rates of sexually transmitted diseases and HIV. The use of alcohol may increase sexual risk behaviors among this population. This paper provides a review and critique of the literature examining the association between alcohol use and sexual risk behaviors among African American females including a: (a) synthesis of research findings from adolescent, college-aged/early adulthood, and adult samples; (b) methodological critique of the literature; and (c) guidance for future research. We reviewed 32 studies examining the association between alcohol use and sexual risk behaviors among African American females across developmental periods. Similar to previous association studies, results suggest that increased use of alcohol is associated with increased sexual risk practices among African American females. Further, even non-abuse levels of drinking among African American females, at all ages, were related to increased sexual risk-taking. Future studies should seek to recruit samples that more fully reflect the diversity of African American women's experiences across the lifespan. Given the association between alcohol use and/or abuse and the prevalence of STI/HIV-associated risk behaviors and adverse biological outcomes (i.e., STIs, including HIV) among African American females across the lifespan, there is a clear need to develop and evaluate prevention research efforts tailored for this subgroup.


[Person centered clinical care: principles and strategies].
The development of person-centered clinical care is inscribed within an international programmatic movement towards a medicine focused on the totality of the person. This movement, with broad historical bases, has been maturing since 2008 through conferences among global health institutions, research projects and academic publications. This paper is aimed at elucidating the conceptual principles of person-centered medicine (PCM) and to delineate strategies for the practical application of such principles in clinical care services. The above objectives have been approached through literature reviews, international consultations, and reflections on the patterns and indications obtained. The principles identified for person-centered medicine are the following: Ethical commitment, holistic framework, cultural awareness and responsiveness, communication and relational focus, individualized clinical care, common ground among clinicians, patient and family for joint diagnostic understanding and shared decision making, person- and community-centered organization of integrated services, and person-centered medical education and research. Additionally, pertinent strategies have been delineated for the implementation of such principles in clinical care. The authors conclude that the presented principles and strategies are consistent with suggestions offered in the literature and may serve as bases for the design of indices and scales. Their continuous refinement is proposed through future international and local studies. to clarify the key concepts of the movement as well as strategies for their practical clinical application.