Neuromuscular and mobility responses to a vibration session in hypoxia in multiple sclerosis

The aim of this study was to investigate the acute effects of vibration training (WBVT) under hypoxic and normoxic conditions on the voluntary rate of force development (RFD), balance and muscle oxygen saturation (SMO2) in persons with Multiple Sclerosis (MS). 10 participants completed the study (30 % males, 44.4±7.7 years, 164.3±8.9cm, 65.2±11.1kg, 2.5±1.3 Expanded Disability Status Scale, 24.1± 4.0 kg.m− 2 BMI). Maximal force, RFD during isometric knee extension, static balance with eyes open and closed and sit-to-stand test were evaluated before and immediately after one session of WBVT (12 60-s bout of vibration; frequency 35Hz; amplitude 4mm; 1-min rest intervals) under both normoxic and hypoxic conditions. In addition, SMO2 of the gastrocnemius lateralis was assessed during each condition. No changes were found in force, static balance and sit-to-stand test. Time-to-peak RFD increased in the left leg (p = 0.02) and tended to increase in the right leg (p = 0.06) after the hypoxic session. SMO2 resulted in significant increases from the initial to final intervals of the WBVT under both hypoxic and normoxic conditions (p < 0.05). Increases in SMO2 during WBVT demonstrates muscle work that may contribute to the observed muscle adaptations in long-term WBVT programs without inducing decreases in neuromuscular activation, physical function and balance within a session

Phenotypic Characterization of Encephalitis and Immune Response in the Brains of Lambs Experimentally Infected with Spanish Goat Encephalitis Virus

[EN]Spanish goat encephalitis virus (SGEV), a novel subtype of tick-borne flavivirus closely related to louping ill virus, causes a neurological disease in experimentally infected goats and lambs. Here, the distribution of microglia, T and B lymphocytes, and astrocytes was determined in the encephalon and spinal cord of eight Assaf lambs subcutaneously infected with SGEV. Cells were identified based on immunohistochemical staining against Iba1 (microglia), CD3 (T lymphocytes), CD20 (B lymphocytes), and glial fibrillary acidic protein (astrocytes). In glial foci and perivascular cu ng areas, microglia were the most abundant cell type (45.4% of immunostained cells), followed by T lymphocytes (18.6%) and B lymphocytes (4.4%). Thalamus, hypothalamus, corpus callosum, and medulla oblongata contained the largest areas occupied by glial foci. Reactive astrogliosis occurred to a greater extent in the lumbosacral spinal cord than in other regions of the central nervous system. Lesions were more frequent on the side of the animal experimentally infected with the virus. Lesions were more severe in lambs than in goats, suggesting that lambs may be more susceptible to SGEV, which may be due to species di erences or to interindividual di erences in the immune response, rather than to di erences in the relative proportions of immune cells. Larger studies that monitor natural or experimental infections may help clarify local immune responses to this flavivirus subtype in the central nervous system.SIThis work was partially supported by a FEDER co-funded grant from the Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (E-RTA2013-00013-C04-04), Ministerio de Ciencia, Innovación y Universidades (MCIU) and the Agencia Estatal de Investigación (AEI) reference project RTI2018-096010-B-C21 (FEDER co-funded) and by the Principado de Asturias, PCTI 2018–220 (GRUPIN: IDI2018-000237 and FEDER). Ms. Ileana Z. Martínez was supported by a Fundación Carolina PhD scholarship (2017 call)

Fragility Curves for Thin-Walled Cold-Formed Steel Wall Frames Affected by Ground Settlements Due to Land Subsidence

Land subsidence phenomenon due to ground water withdrawal is a current problem in many places around the world, particularly in the shallows of Mexico. This causes ground differential settlements that affect structures, mainly dwellings and buildings based on reinforced concrete and masonry. Eventually, these structural materials do not exhibit an adequate performance beyond a certain level of angular distortion. This work presents the results about a study regarding the performance of thin-walled cold-formed steel wall frames with different sheathing systems affected by angular distortions simulating ground differential settlements due to land subsidence. The wall frames are composed by vertical (studs) and horizontal elements (tracks), with different sheathing systems: polystyrene, OSB, gypsum and calcium silicate. By means of experimental testing of wall frames subjected to monotonic lateral loads, the rotational stiffness was obtained for the wall frames with polystyrene. Likewise the rotational stiffness of the other wall frame systems was calculated based on the data provided by other author’s publications. On the other hand, by means of numerical simulation, all the wall frame systems were modeled in structural analysis software, calibrating them based on the rotational stiffness. Also, the moment-rotation curves were calculated for the studs and tracks based on the direct strength method. A non-linear static pull down analysis was performed producing several degrees of angular distortion simulating ground settlements for all the wall frames sheathing systems. With the data acquired fragility curves were calculated according three levels of damage for the wall frames with different sheathing system

γδ T lymphocytes in the diagnosis of human T cell receptor immunodeficiencies

Supported by grants from MINECO (SAF 2011-24235, BES-2012-055054, SAF2014- 54708-R, and SAF2014-53563-REDT) CAM (S2010/BMD-2316) ISCIII (RD08- 0075-0002 and PI12/02761)Peer Reviewe

Reuse Detector: improving the management of STT-RAM SLLCs

Various constraints of Static Random Access Memory (SRAM) are leading to consider new memory technologies as candidates for building on-chip shared last-level caches (SLLCs). Spin-Transfer Torque RAM (STT-RAM) is currently postulated as the prime contender due to its better energy efficiency, smaller die footprint and higher scalability. However, STT-RAM also exhibits some drawbacks, like slow and energy-hungry write operations that need to be mitigated before it can be used in SLLCs for the next generation of computers. In this work, we address these shortcomings by leveraging a new management mechanism for STT-RAM SLLCs. This approach is based on the previous observation that although the stream of references arriving at the SLLC of a Chip MultiProcessor (CMP) exhibits limited temporal locality, it does exhibit reuse locality, i.e. those blocks referenced several times manifest high probability of forthcoming reuse. As such, conventional STT-RAM SLLC management mechanisms, mainly focused on exploiting temporal locality, result in low efficient behavior. In this paper, we employ a cache management mechanism that selects the contents of the SLLC aimed to exploit reuse locality instead of temporal locality. Specifically, our proposal consists in the inclusion of a Reuse Detector (RD) between private cache levels and the STT-RAM SLLC. Its mission is to detect blocks that do not exhibit reuse, in order to avoid their insertion in the SLLC, hence reducing the number of write operations and the energy consumption in the STT-RAM. Our evaluation, using multiprogrammed workloads in quad-core, eight-core and 16-core systems, reveals that our scheme reports on average, energy reductions in the SLLC in the range of 37–30%, additional energy savings in the main memory in the range of 6–8% and performance improvements of 3% (quad-core), 7% (eight-core) and 14% (16-core) compared with an STT-RAM SLLC baseline where no RD is employed. More importantly, our approach outperforms DASCA, the state-of-the-art STT-RAM SLLC management, reporting—depending on the specific scenario and the kind of applications used—SLLC energy savings in the range of 4–11% higher than those of DASCA, delivering higher performance in the range of 1.5–14% and additional improvements in DRAM energy consumption in the range of 2–9% higher than DASCA.Peer ReviewedPostprint (author's final draft

IFNγ Response to Mycobacterium tuberculosis, Risk of Infection and Disease in Household Contacts of Tuberculosis Patients in Colombia

OBJECTIVES: Household contacts (HHCs) of pulmonary tuberculosis patients are at high risk of Mycobacterium tuberculosis infection and early disease development. Identification of individuals at risk of tuberculosis disease is a desirable goal for tuberculosis control. Interferon-gamma release assays (IGRAs) using specific M. tuberculosis antigens provide an alternative to tuberculin skin testing (TST) for infection detection. Additionally, the levels of IFNgamma produced in response to these antigens may have prognostic value. We estimated the prevalence of M. tuberculosis infection by IGRA and TST in HHCs and their source population (SP), and assessed whether IFNgamma levels in HHCs correlate with tuberculosis development. METHODS: A cohort of 2060 HHCs was followed for 2-3 years after exposure to a tuberculosis case. Besides TST, IFNgamma responses to mycobacterial antigens: CFP, CFP-10, HspX and Ag85A were assessed in 7-days whole blood cultures and compared to 766 individuals from the SP in Medellín, Colombia. Isoniazid prophylaxis was not offered to child contacts because Colombian tuberculosis regulations consider it only in children under 5 years, TST positive without BCG vaccination. RESULTS: Using TST 65.9% of HHCs and 42.7% subjects from the SP were positive (OR 2.60, p<0.0001). IFNgamma response to CFP-10, a biomarker of M. tuberculosis infection, tested positive in 66.3% HHCs and 24.3% from the SP (OR = 6.07, p<0.0001). Tuberculosis incidence rate was 7.0/1000 person years. Children <5 years accounted for 21.6% of incident cases. No significant difference was found between positive and negative IFNgamma responders to CFP-10 (HR 1.82 95% CI 0.79-4.20 p = 0.16). However, a significant trend for tuberculosis development amongst high HHC IFNgamma producers was observed (trend Log rank p = 0.007). DISCUSSION: CFP-10-induced IFNgamma production is useful to establish tuberculosis infection prevalence amongst HHC and identify those at highest risk of disease. The high tuberculosis incidence amongst children supports administration of chemoprophylaxis to child contacts regardless of BCG vaccination

Molecular Pathways Leading to Induction of Cell Death and Anti-Proliferative Properties by Tacrolimus and mTOR Inhibitors in Liver Cancer Cells

Background/Aims: Orthotopic liver transplantation (OLT) is the recommended treatment for patients at early stages of hepatocarcinoma (HCC) with portal hypertension and/or increased bilirubinemia, but without vascular-associated diseases. Tumor recurrence, which is the main drawback for the survival of patients submitted to OLT for HCC, has been related to tumor-related variables and the immunosuppressive therapies. We have previously shown that Tacrolimus (FK506) exerts a more potent pro-apoptotic and anti-proliferative effects than the mammalian target of rapamycin (mTOR) inhibitors (Sirolimus and Everolimus) in liver cancer cells. This study identified the role of the immunosuppressant partners such as FK506-binding proteins (FKBPs) in the induction of cell death and arrest of cell proliferation by immunosuppressants in two representative liver cancer cells. Methods: The regulation of endoplasmic reticulum (ER) stress, apoptosis/autophagy, cell proliferation, and FKBPs expression was determined in Tacrolimus-, Sirolimus- and Everolimus-treated primary human hepatocytes, and hepatoma HepG2 and Huh7 cell lines. The functional repercussion of FKBPs on cell death and proliferation was also addressed using the siRNA technology. The assessed antitumoral properties of the immunosuppressants were associated to microRNAs (miRNAs) pattern. Results: The enhanced pro-apoptotic and anti-proliferative properties of Tacrolimus versus mTOR inhibitors were associated with increased protein kinase RNA-like endoplasmic reticulum kinase (PERK)-related ER stress, Ser15 P-p53/p53 ratio and p21 protein expression that may counterbalance the risk of proliferative upregulation caused by enhanced Thr172 P-Cdk4/ Cdk4 activation in liver cancer cells. The inhibition of the mTOR pathway by Sirolimus and Everolimus was related to an induction of autophagy; and at a high dose, these drugs impaired translation likely at a very early step of the elongation phase. Tacrolimus and mTOR inhibitors increased the protein expression of FKBP12 and FKBP51 that appeared to play pro-survival role. Interestingly, the administration of immunosuppressants yields a specific pattern of miRNAs. Tacrolimus and mTOR inhibitors decreased miR-92a-1-5p, miR-197-3p, miR-483-3p and miR- 720, and increased miR-22-3p, miR-376a-3p, miR-663b, miR-886-5p, miR-1300 and miR-1303 expressions in HepG2 cells. Conclusion: The more potent pro-apoptotic and anti-proliferative properties of Tacrolimus versus mTOR inhibitors were associated with an increased activation of PERK and p53 signaling, and p21 protein expression. FKBP12 and FKBP51 appeared to be the most relevant partners of Tacrolimus and mTOR inhibitors exerting a pro-survival effect in HepG2 cells. The observed effects of immunosuppressants were related to a specific miRNA signature in liver cancer cellsEspaña Ministry of Economy and Competitiveness (MINECO) cofinanced by the ERDF (BFU2016-75352-P AEI/FEDER, EU

Regulation of cell death receptor S-nitrosylation and apoptotic signaling by Sorafenib in hepatoblastoma cells

Nitric oxide (NO) plays a relevant role during cell death regulation in tumor cells. The overexpression of nitric oxide synthase type III (NOS-3) induces oxidative and nitrosative stress, p53 and cell death receptor expression and apoptosis in hepatoblastoma cells. S-nitrosylation of cell death receptor modulates apoptosis. Sorafenib is the unique recommended molecular-targeted drug for the treatment of patients with advanced hepatocellular carcinoma. The present study was addressed to elucidate the potential role of NO during Sorafenib-induced cell death in HepG2 cells. We determined the intra- and extracellular NO concentration, cell death receptor expression and their S-nitrosylation modifications, and apoptotic signaling in Sorafenib-treated HepG2 cells. The effect of NO donors on above parameters has also been determined. Sorafenib induced apoptosis in HepG2 cells. However, low concentration of the drug (10nM) increased cell death receptor expression, as well as caspase-8 and -9 activation, but without activation of downstream apoptotic markers. In contrast, Sorafenib (10 µM) reduced upstream apoptotic parameters but increased caspase-3 activation and DNA fragmentation in HepG2 cells. The shift of cell death signaling pathway was associated with a reduction of S-nitrosylation of cell death receptors in Sorafenib-treated cells. The administration of NO donors increased S-nitrosylation of cell death receptors and overall induction of cell death markers in control and Sorafenib-treated cells. In conclusion, Sorafenib induced alteration of cell death receptor S-nitrosylation status which may have a relevant repercussion on cell death signaling in hepatoblastoma cells.Instituto de Salud Carlos III PI13/00021Ministerio de Economía y Competitividad BFU2012-32056Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía BIO-0216Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía CTS-6264Consejería de Salud, Junta de Andalucía PI13/ 0002

Correlation between HIV viral load and aminotransferases as liver damage markers in HIV infected naive patients: a concordance cross-sectional study

Abnormalities in liver function tests could be produced exclusively by direct inflammation in hepatocytes, caused by the human immunodeficiency virus (HIV). Mechanisms by which HIV causes hepatic damage are still unknown. Our aim was to determine the correlation between HIV viral load, and serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) as markers of hepatic damage in HIV naive infected patients

Relationship between IGF-1 and body weight in inflammatory bowel diseases: Cellular and molecular mechanisms involved

Inflammatory bowel diseases (IBD), represented by ulcerative colitis (UC) and Crohn''s disease (CD), are characterized by chronic inflammation of the gastrointestinal tract, what leads to diarrhea, malnutrition, and weight loss. Depression of the growth hormone-insulin-like growth factor-1 axis (GH-IGF-1 axis) could be responsible of these symptoms. We demonstrate that long-term treatment (54 weeks) of adult CD patients with adalimumab (ADA) results in a decrease in serum IGF-1 without changes in serum IGF-1 binding protein (IGF1BP4). These results prompted us to conduct a preclinical study to test the efficiency of IGF-1 in the medication for experimental colitis. IGF-1 treatment of rats with DSS-induced colitis has a beneficial effect on the following circulating biochemical parameters: glucose, albumin, and total protein levels. In this experimental group we also observed healthy maintenance of colon size, body weight, and lean mass in comparison with the DSS-only group. Histological analysis revealed restoration of the mucosal barrier with the IGF-1 treatment, which was characterized by healthy quantities of mucin production, structural maintenance of adherers junctions (AJs), recuperation of E-cadherin and ß-catenin levels and decrease in infiltrating immune cells and in metalloproteinase-2 levels. The experimentally induced colitis caused activation of apoptosis markers, including cleaved caspase 3, caspase 8, and PARP and decreases cell-cycle checkpoint activators including phosphorylated Rb, cyclin E, and E2F1. The IGF-1 treatment inhibited cyclin E depletion and partially protects PARP levels. The beneficial effects of IGF-1 in experimental colitis could be explained by a re-sensitization of the IGF-1/IRS-1/AKT cascade to exogenous IGF-1. Given these results, we postulate that IGF-1 treatment of IBD patients could prove to be successful in reducing disease pathology. © 2021 The Author