Clinical trial to assess the effect of physical exercise on endothelial function and insulin resistance in pregnant women

<p>Abstract</p> <p>Background</p> <p>Preeclampsia (PE) is a common maternal disease that complicates 5 to 10% of pregnancies and remains as the major cause of maternal and neonatal mortality. Cost-effective interventions aimed at preventing the development of preeclampsia are urgently needed. However, the pathogenesis of PE is not well known. Multiple mechanisms such as oxidative stress, endothelial dysfunction and insulin resistance may contribute to its development. Regular aerobic exercise recovers endothelial function; improves insulin resistance and decreases oxidative stress. Therefore the purpose of this clinical trial is to determine the effect of regular aerobic exercise on endothelial function, on insulin resistance and on pregnancy outcome.</p> <p>Methods and design</p> <p>64 pregnant women will be included in a blind, randomized clinical trial, and parallel assignment. The exercise group will do regular aerobic physical exercise: walking (10 minutes), aerobic exercise (30 minutes), stretching (10 minutes) and relaxation exercise (10 minutes) in three sessions per week. Control group will do the activities of daily living (bathing, dressing, eating, and walking) without counselling from a physical therapist.</p> <p>Trial registration</p> <p>NCT00741312.</p

Solar-type dynamo behaviour in fully convective stars without a tachocline

In solar-type stars (with radiative cores and convective envelopes), the magnetic field powers star spots, flares and other solar phenomena, as well as chromospheric and coronal emission at ultraviolet to X-ray wavelengths. The dynamo responsible for generating the field depends on the shearing of internal magnetic fields by differential rotation. The shearing has long been thought to take place in a boundary layer known as the tachocline between the radiative core and the convective envelope. Fully convective stars do not have a tachocline and their dynamo mechanism is expected to be very different, although its exact form and physical dependencies are not known. Here we report observations of four fully convective stars whose X-ray emission correlates with their rotation periods in the same way as in Sun-like stars. As the X-ray activity - rotation relationship is a well-established proxy for the behaviour of the magnetic dynamo, these results imply that fully convective stars also operate a solar-type dynamo. The lack of a tachocline in fully convective stars therefore suggests that this is not a critical ingredient in the solar dynamo and supports models in which the dynamo originates throughout the convection zone.Comment: 6 pages, 1 figure. Accepted for publication in Nature (28 July 2016). Author's version, including Method

A metabolite-derived protein modification integrates glycolysis with KEAP1-NRF2 signalling.

Mechanisms that integrate the metabolic state of a cell with regulatory pathways are necessary to maintain cellular homeostasis. Endogenous, intrinsically reactive metabolites can form functional, covalent modifications on proteins without the aid of enzymes1,2, and regulate cellular functions such as metabolism3-5 and transcription6. An important 'sensor' protein that captures specific metabolic information and transforms it into an appropriate response is KEAP1, which contains reactive cysteine residues that collectively act as an electrophile sensor tuned to respond to reactive species resulting from endogenous and xenobiotic molecules. Covalent modification of KEAP1 results in reduced ubiquitination and the accumulation of NRF27,8, which then initiates the transcription of cytoprotective genes at antioxidant-response element loci. Here we identify a small-molecule inhibitor of the glycolytic enzyme PGK1, and reveal a direct link between glycolysis and NRF2 signalling. Inhibition of PGK1 results in accumulation of the reactive metabolite methylglyoxal, which selectively modifies KEAP1 to form a methylimidazole crosslink between proximal cysteine and arginine residues (MICA). This posttranslational modification results in the dimerization of KEAP1, the accumulation of NRF2 and activation of the NRF2 transcriptional program. These results demonstrate the existence of direct inter-pathway communication between glycolysis and the KEAP1-NRF2 transcriptional axis, provide insight into the metabolic regulation of the cellular stress response, and suggest a therapeutic strategy for controlling the cytoprotective antioxidant response in several human diseases

The Anopheles gambiae Oxidation Resistance 1 (OXR1) Gene Regulates Expression of Enzymes That Detoxify Reactive Oxygen Species

OXR1 is an ancient gene, present in all eukaryotes examined so far that confers protection from oxidative stress by an unknown mechanism. The most highly conserved region of the gene is the carboxyl-terminal TLDc domain, which has been shown to be sufficient to prevent oxidative damage.OXR1 has a complex genomic structure in the mosquito A. gambiae, and we confirm that multiple splice forms are expressed in adult females. Our studies revealed that OXR1 regulates the basal levels of catalase (CAT) and glutathione peroxidase (Gpx) expression, two enzymes involved in detoxification of hydrogen peroxide, giving new insight into the mechanism of action of OXR1. Gene silencing experiments indicate that the Jun Kinase (JNK) gene acts upstream of OXR1 and also regulates expression of CAT and GPx. Both OXR1 and JNK genes are required for adult female mosquitoes to survive chronic oxidative stress. OXR1 silencing decreases P. berghei oocyst formation. Unexpectedly, JNK silencing has the opposite effect and enhances Plasmodium infection in the mosquito, suggesting that JNK may also mediate some, yet to be defined, antiparasitic response.The JNK pathway regulates OXR1 expression and OXR1, in turn, regulates expression of enzymes that detoxify reactive oxygen species (ROS) in Anopheles gambiae. OXR1 silencing decreases Plasmodium infection in the mosquito, while JNK silencing has the opposite effect and enhances infection

The epidemiology of hematogenous vertebral osteomyelitis: a cohort study in a tertiary care hospital

<p>Abstract</p> <p>Background</p> <p>Vertebral osteomyelitis is a common manifestation of osteomyelitis in adults and associated with considerable morbidity. Limited data exist regarding hematogenous vertebral osteomyelitis. Our objective was to describe the epidemiology and management of hematogenous vertebral osteomyelitis.</p> <p>Methods</p> <p>We performed a 2-year retrospective cohort study of adult patients with hematogenous vertebral osteomyelitis at a tertiary care hospital.</p> <p>Results</p> <p>Seventy patients with hematogenous vertebral osteomyelitis were identified. The mean age was 59.7 years (±15.0) and 38 (54%) were male. Common comorbidities included diabetes (43%) and renal insufficiency (24%). Predisposing factors in the 30 days prior to admission included bacteremia (19%), skin/soft tissue infection (17%), and having an indwelling catheter (30%). Back pain was the most common symptom (87%). Seven (10%) patients presented with paraplegia. Among the 46 (66%) patients with a microbiological diagnosis, the most common organisms were methicillin-susceptible <it>S. aureus </it>[15 (33%) cases], and methicillin-resistant <it>S. aureus </it>[10 (22%)]. Among the 44 (63%) patients who had a diagnostic biopsy, open biopsy was more likely to result in pathogen recovery [14 (93%) of 15 with open biopsy vs. 14 (48%) of 29 with needle biopsy; p = 0.003]. Sixteen (23%) patients required surgical intervention for therapeutic purposes during admission.</p> <p>Conclusions</p> <p>This is one of the largest series of hematogenous vertebral osteomyelitis. A microbiological diagnosis was made in only approximately two-thirds of cases. <it>S. aureus </it>was the most common causative organism, of which almost half the isolates were methicillin-resistant.</p

Characterising the KMP-11 and HSP-70 recombinant antigens' humoral immune response profile in chagasic patients

11 pages, 6 figures.-- The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-2334/9/186/pre pubBackground: Antigen specificity and IgG subclass could be significant in the natural history of Chagas' disease. The relationship between the different stages of human Chagas' disease and the profiles of total IgG and its subclasses were thus analysed here; they were directed against a crude T. cruzi extract and three recombinant antigens: the T. cruzi kinetoplastid membrane protein-11 (rKMP-11), an internal fragment of the T. cruzi HSP-70 protein192-433, and the entire Trypanosoma rangeli HSP-70 protein. Methods: Seventeen Brazilian acute chagasic patients, 50 Colombian chronic chagasic patients (21 indeterminate and 29 cardiopathic patients) and 30 healthy individuals were included. Total IgG and its subtypes directed against the above-mentioned recombinant antigens were determined by ELISA tests. Results: The T. cruzi KMP-11 and T. rangeli HSP-70 recombinant proteins were able to distinguish both acute from chronic chagasic patients and infected people from healthy individuals. Specific antibodies to T. cruzi crude antigen in acute patients came from IgG3 and IgG4 subclasses whereas IgG1 and IgG3 were the prevalent isotypes in indeterminate and chronic chagasic patients. By contrast, the specific prominent antibodies in all disease stages against T. cruzi KMP-11 and T. rangeli HSP-70 recombinant antigens were the IgG1 subclass.This work was supported by Colciencias Research project No. 1203-333- 18692. IDF was supported by Colciencias and the Universidad Javeriana's Young Researcher 2008 Programme (Bogotá, Colombia). MCT and MCL were supported by P06-CTS-02242 Grant from PAI (Junta de Andalucia) and RICET-RD06/0021-0014, Spain. MS received financial support from the Brazilian agency - CNPq.Peer reviewe

AKR1C enzymes sustain therapy resistance in paediatric T-ALL

BACKGROUND: Despite chemotherapy intensification, a subgroup of high-risk paediatric T-cell acute lymphoblastic leukemia (TALL) patients still experience treatment failure. In this context, we hypothesised that therapy resistance in T-ALL might involve aldo-keto reductase 1C (AKR1C) enzymes as previously reported for solid tumors.METHODS: Expression of NRF2-AKR1C signaling components has been analysed in paediatric T-ALL samples endowed with different treatment outcomes as well as in patient-derived xenografts of T-ALL. The effects of AKR1C enzyme modulation has been investigated in T-ALL cell lines and primary cultures by combining AKR1C inhibition, overexpression, and gene silencing approaches.RESULTS: We show that T-ALL cells overexpress AKR1C1-3 enzymes in therapy-resistant patients. We report that AKR1C1-3 enzymes play a role in the response to vincristine (VCR) treatment, also ex vivo in patient-derived xenografts. Moreover, we demonstrate that the modulation of AKR1C1-3 levels is sufficient to sensitise T-ALL cells to VCR. Finally, we show that T-ALL chemotherapeutics induce overactivation of AKR1C enzymes independent of therapy resistance, thus establishing a potential resistance loop during T-ALL combination treatment.CONCLUSIONS: Here, we demonstrate that expression and activity of AKR1C enzymes correlate with response to chemotherapeutics in T-ALL, posing AKR1C1-3 as potential targets for combination treatments during T-ALL therapy

Pyogenic spondylitis

Pyogenic spondylitis is a neurological and life threatening condition. It encompasses a broad range of clinical entities, including pyogenic spondylodiscitis, septic discitis, vertebral osteomyelitis, and epidural abscess. The incidence though low appears to be on the rise. The diagnosis is based on clinical, radiological, blood and tissue cultures and histopathological findings. Most of the cases can be treated non-operatively. Surgical treatment is required in 10–20% of patients. Anterior decompression, debridement and fusion are generally recommended and instrumentation is acceptable after good surgical debridement with postoperative antibiotic cover

Potential for pancreatic maturation of differentiating human embryonic stem cells is sensitive to the specific pathway of definitive endoderm commitment

This study provides a detailed experimental and mathematical analysis of the impact of the initial pathway of definitive endoderm (DE) induction on later stages of pancreatic maturation. Human embryonic stem cells (hESCs) were induced to insulin-producing cells following a directed-differentiation approach. DE was induced following four alternative pathway modulations. DE derivatives obtained from these alternate pathways were subjected to pancreatic progenitor (PP) induction and maturation and analyzed at each stage. Results indicate that late stage maturation is influenced by the initial pathway of DE commitment. Detailed quantitative analysis revealed WNT3A and FGF2 induced DE cells showed highest expression of insulin, are closely aligned in gene expression patterning and have a closer resemblance to pancreatic organogenesis. Conversely, BMP4 at DE induction gave most divergent differentiation dynamics with lowest insulin upregulation, but highest glucagon upregulation. Additionally, we have concluded that early analysis of PP markers is indicative of its potential for pancreatic maturation. © 2014 Jaramillo et al