Efficacy of Corticosteroid Therapy for HTLV-1-Associated Myelopathy: A Randomized Controlled Trial (HAMLET-P).
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ABSTRACT:
SUBMITTER: Yamauchi J
PROVIDER: S-EPMC8780460 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe efficacy of intraoperative corticosteroids to improve outcomes following congenital cardiac operations remains controversial.ObjectivesThe purpose of this study was to determine whether intraoperative methylprednisolone improves post-operative recovery in neonates undergoing cardiac surgery.MethodsNeonates undergoing cardiac surgery with cardiopulmonary bypass at 2 centers were enrolled in a double-blind randomized controlled trial of methylprednisolone (30 mg/kg) or placebo after the induction of anesthesia. The primary outcome was a previously validated morbidity-mortality composite that included any of the following events following surgery before discharge: death, mechanical circulatory support, cardiac arrest, hepatic injury, renal injury, or rising lactate level (>5 mmol/l).ResultsOf the 190 subjects enrolled, 176 (n = 81 methylprednisolone, n = 95 placebo) were included in this analysis. A total of 27 (33%) subjects in the methylprednisolone group and 40 (42%) in the placebo group reached the primary study endpoint (odds ratio [OR]: 0.63; 95% confidence interval [CI]: 0.31 to 1.3; p = 0.21). Methylprednisolone was associated with reductions in vasoactive inotropic requirements and in the incidence of the composite endpoint in subjects undergoing palliative operations (OR: 0.38; 95% CI: 0.15 to 0.99; p = 0.048). There was a significant interaction between treatment effect and center. In this analysis, methylprednisolone was protective at 1 center, with an OR: 0.35 (95% CI: 0.15 to 0.84; p = 0.02), and not so at the other center, with OR: 5.13 (95% CI: 0.85 to 30.90; p = 0.07).ConclusionsIntraoperative methylprednisolone failed to show an overall significant benefit on the incidence of the composite primary study endpoint. There was, however, a benefit in patients undergoing palliative procedures and a significant interaction between treatment effect and center, suggesting that there may be center or patient characteristics that make prophylactic methylprednisolone beneficial.
| S-EPMC6684326 | biostudies-literature
Project description:Cervical spondylotic myelopathy (CSM) is the most common cause of spinal cord dysfunction in the world. There are significant practice variation and uncertainty as to the optimal surgical approach for treating CSM.To determine whether ventral surgery is associated with superior Short Form-36 Physical Component Summary outcome at the 1-year follow-up compared with dorsal (laminectomy/fusion or laminoplasty) surgery for the treatment of CSM, to investigate whether postoperative sagittal balance is an independent predictor of overall outcome, and to compare health resource use for ventral and dorsal procedures.The study is a randomized, controlled trial with a nonrandomized arm for patients who are eligible but decline randomization. Two hundred fifty patients (159 randomized) with CSM from 11 sites will be recruited over 18 months. The primary outcome is the Short Form-36 Physical Component Summary score. Secondary outcomes include disease-specific outcomes, overall health-related quality of life (EuroQOL 5-dimension questionnaire), and health resource use.This will be the first randomized, controlled trial to compare directly the health-related quality-of-life outcomes for ventral vs dorsal surgery for treating CSM.A National Institutes of Health-funded (1R13AR065834-01) investigator meeting was held before the initiation of the trial to bring multiple stakeholders together to finalize the study protocol. Study investigators, coordinators, and major stakeholders were able to attend and discuss strengths of, limitations of, and concerns about the study. The final protocol was approved for funding by the Patient-Centered Outcomes Research Institute (CE-1304-6173). The trial began enrollment on April 1, 2014.
| S-EPMC4633023 | biostudies-literature
Project description:Human T cell leukemia virus type 1 (HTLV-1) is a retrovirus with preferential CD4+ T cell tropism that causes a range of conditions spanning from asymptomatic infection to adult T cell leukemia and HTLV-1-associated myelopathy (HAM), an inflammatory disease of the CNS. The mechanisms by which HTLV-1 induces HAM are poorly understood. By directly examining the ex vivo phenotype and function of T cells from asymptomatic carriers and patients with HAM, we show that patients with HAM have a higher frequency of CD4+CD8+ double-positive (DP) T cells, which are infected with HTLV-1 at higher rates than CD4+ T cells. Displaying both helper and cytotoxic phenotypes, these DP T cells are highly proinflammatory and contain high frequencies of HTLV-1-specific cells. Mechanistically, we demonstrate that DP T cells arise by direct HTLV-1 infection of CD4+ and CD8+ T cells. High levels of CD49d and CXCR3 expression suggest that DP T cells possess the ability to migrate to the CNS, and when cocultured with astrocytes, DP T cells induce proinflammatory astrocytes that express high levels of CXCL10, IFN-γ, and IL-6. These results demonstrate the potential of DP T cells to directly contribute to CNS pathology.
| S-EPMC10906466 | biostudies-literature
Project description:BackgroundMasitinib is an oral tyrosine kinase inhibitor that selectively targets mast cell activity and platelet-derived growth factor receptor (PDGFR) signaling, both of which are implicated in various mechanisms of asthma pathogenesis.ObjectiveAssessment of masitinib as an add-on to standard maintenance therapy as compared with placebo in the treatment of oral corticosteroid-dependent severe asthma.MethodsWe conducted a randomized (2:1), placebo-controlled study of masitinib (6 mg/kg/d) in adults with severe asthma uncontrolled by high dose inhaled corticosteroids and long-acting beta-adrenoreceptor agonists plus oral corticosteroids (OCS) (≥7.5 mg/d). No minimum baseline blood eosinophil count was specified. Following a protocol amendment, the primary endpoint was reduction of annualized severe asthma exacerbation rate adjusted for the overall time on treatment (SAER). Subgroup analysis according to yearly cumulative OCS intake was also performed, a higher OCS dose indicating more severe asthma that is harder to control.ResultsFollowing an average exposure of approximately 13 months, masitinib (n = 240) reduced the SAER by 35% relative to placebo (n = 115) (rate ratio (RR) 0.65 (95% CI [0.47-0.90]; P = 0.010)). For patients with eosinophil ≥150 cell/µL, masitinib (n = 181) reduced SAER by 38% relative to placebo (n = 87); RR 0.62 (95% CI [0.42-0.91]; P = 0.016). Benefit of masitinib was shown to increase in the most severely affected patients (OCS intake of >1000 mg/year), with a significant (P < 0.01) reduction in SAER of 50%-70%. Safety was consistent with the known masitinib profile.ConclusionOrally administered masitinib reduces the risk of asthma exacerbations in severe asthma patients, with an acceptable safety profile. Masitinib may potentially provide a new treatment option for oral corticosteroid-dependent severe asthma.
| S-EPMC9188333 | biostudies-literature
Project description:The purpose of this study was to determine whether the provision of corticosteroids improves time to shock reversal and outcomes in patients with post-cardiac arrest shock.We conducted a randomized, double-blind trial of post-cardiac arrest patients in shock, defined as vasopressor support for a minimum of 1 hour. Patients were randomized to intravenous hydrocortisone 100 mg or placebo every 8 hours for 7 days or until shock reversal. The primary endpoint was time to shock reversal.Fifty patients were included with 25 in each group. There was no difference in time to shock reversal between groups (hazard ratio: 0.83 [95% CI: 0.40-1.75], p = 0.63). We found no difference in secondary outcomes including shock reversal (52% vs. 60%, p = 0.57), good neurological outcome (24% vs. 32%, p = 0.53) or survival to discharge (28% vs. 36%, p = 0.54) between the hydrocortisone and placebo groups. Of the patients with a baseline cortisol < 15 ug/dL, 100% (6/6) in the hydrocortisone group achieved shock reversal compared to 33% (1/3) in the placebo group (p = 0.08). All patients in the placebo group died (100%; 3/3) whereas 50% (3/6) died in the hydrocortisone group (p = 0.43).In a population of cardiac arrest patients with vasopressor-dependent shock, treatment with hydrocortisone did not improve time to shock reversal, rate of shock reversal, or clinical outcomes when compared to placebo.Clinicaltrials.gov: NCT00676585, registration date: May 9, 2008.
| S-EPMC4818959 | biostudies-literature
Project description:BackgroundInflammatory reaction can produce several complications after cardiac surgery. Many attempts have been made to reduce these complications; perioperative corticosteroid therapy is one of the simplest methods.ObjectivesWe conducted a randomized study to evaluate the efficacy of single dose methylprednisolone, prescribed after surgery, for reducing the complications. Repair of Tetralogy of Fallot was chosen as a homogenous large group for the study.Patients and methodsOne hundred children who underwent total repair of Tetralogy of Fallot were enrolled in this study. After the surgery, all patients were transferred to pediatric ICU and were randomized (in a double-blind fashion) in 2 groups (A and B); a single dose of methylprednisolone (30 mg/kg of body weight) was injected to participants of group "A" just at the time of ICU entrance. Group "B" received no drug. Then, clinical outcomes and laboratory data were compared between the two groups.ResultsThe only significant differences were lower incidence of bacteremia and higher incidence of hyperglycemia in the group who were used methylprednisolone.ConclusionsUsing a single postsurgical dose of methylprednisolone does not significantly alter the clinical outcome after repairing Tetralogy of Fallot.
| S-EPMC4350157 | biostudies-literature
Project description:BackgroundHuman T lymphotropic virus Type 1 (HTLV-1) causes a chronic inflammatory disease of the central nervous system known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM) which resembles chronic spinal forms of multiple sclerosis (MS). The pathogenesis of HAM remains uncertain. To aid in the differential diagnosis of HAM and to identify pathogenetic mechanisms, we analysed the plasma proteome in asymptomatic HTLV-1 carriers (ACs), patients with HAM, uninfected controls, and patients with MS. We used surface-enhanced laser desorption-ionization (SELDI) mass spectrometry to analyse the plasma proteome in 68 HTLV-1-infected individuals (in two non-overlapping sets, each comprising 17 patients with HAM and 17 ACs), 16 uninfected controls, and 11 patients with secondary progressive MS. Candidate biomarkers were identified by tandem Q-TOF mass spectrometry.ResultsThe concentrations of three plasma proteins--high [β2-microglobulin], high [Calgranulin B], and low [apolipoprotein A2]--were specifically associated with HAM, independently of proviral load. The plasma [β2-microglobulin] was positively correlated with disease severity.ConclusionsThe results indicate that monocytes are activated by contact with activated endothelium in HAM. Using β2-microglobulin and Calgranulin B alone we derive a diagnostic algorithm that correctly classified the disease status (presence or absence of HAM) in 81% of HTLV-1-infected subjects in the cohort.
| S-EPMC3210102 | biostudies-literature
Project description:Since human T-lymphotropic virus type 1 (HTLV-1)-associated diseases are associated with a high HTLV-1 load, reducing this load may treat or prevent disease. However, despite in vitro evidence that certain nucleoside/nucleotide analogue reverse transcriptase inhibitors (NRTIs) are active against HTLV-1, in vivo results have been disappointing. We therefore assayed the sensitivity of HTLV-1 primary isolates to a panel of RT inhibitors. HTLV-1 primary isolates were obtained, pre- and post- NRTI treatment, from patients with HTLV-1-associated myelopathy. Sensitivity to azidothymidine (AZT), lamivudine (3TC), tenofovir (TDF) and three phosphonated carbocyclic 2'-oxa-3'aza nucleosides (PCOANs) was assessed in a RT inhibitor assay. With the exception of 3TC, HTLV RT from primary isolates was less sensitive to all tested inhibitors than HTLV-1 RT from MT-2 cells. HTLV-1 RT from primary isolates and from chronically infected, transformed MT-2 cells was insensitive to 3TC. Sensitivity of primary isolates to RT inhibitors was not reduced following up to 12 months of patient treatment with AZT plus 3TC. The sensitivity of HTLV-1 primary isolates to NRTIs differs from that of cell lines and may vary among patients. Failure of NRTIs to reduce HTLV-1 viral load in vivo was not due to the development of phenotypic NRTI resistance. AZT and the three PCOANs assayed all consistently inhibited primary isolate HTLV-1 RT.
| S-EPMC3185762 | biostudies-literature
Project description:BackgroundHuman T-cell leukemia virus type 1 (HTLV-1) causes HTLV-1-associated myelopathy (HAM), adult T-cell leukemia/lymphoma (ATL), HTLV-1-associated uveitis, and pulmonary diseases. Although both HAM and ATL show proliferation of infected cells, their pathogeneses are quite different. In particular, the pathogenesis of HAM is characterized by hyperimmune responses to HTLV-1-infected cells. Recently, we demonstrated the overexpression of histone methyltransferase EZH2 in ATL cells and the cytotoxic effects of EZH2 inhibitors and EZH1/2 dual inhibitors on these cells. However, these phenomena have never been studied in HAM. Furthermore, what effect these agents have on the hyperimmune response seen in HAM is completely unknown.MethodsIn this study, we investigated histone methyltransferase expression levels in infected cell populations (CD4+ and CD4+CCR4+ cells) from patients with HAM using microarray and RT-qPCR analyses. Next, using an assay system that utilizes the spontaneous proliferation characteristic of peripheral blood mononuclear cells derived from patients with HAM (HAM-PBMCs), we investigated the effects of EZH2 selective inhibitors (GSK126 and tazemetostat) and EZH1/2 dual inhibitors (OR-S1 and valemetostat, also known as DS-3201), particularly on cell proliferation rate, cytokine production, and HTLV-1 proviral load. We also examined the effect of EZH1/2 inhibitors on the proliferation of HTLV-1-infected cell lines (HCT-4 and HCT-5) derived from patients with HAM.ResultsWe found elevated expression of EZH2 in CD4+ and CD4+CCR4+ cells from patients with HAM. EZH2 selective inhibitors and EZH1/2 inhibitors significantly inhibited spontaneous proliferation of HAM-PBMC in a concentration-dependent manner. The effect was greater with EZH1/2 inhibitors. EZH1/2 inhibitors also reduced the frequencies of Ki67+ CD4+ T cells and Ki67+ CD8+ T cells. Furthermore, they reduced HTLV-1 proviral loads and increased IL-10 levels in culture supernatants but did not alter IFN-γ and TNF-α levels. These agents also caused a concentration-dependent inhibition of the proliferation of HTLV-1-infected cell lines derived from patients with HAM and increased annexin-V(+)7-aminoactinomycin D(-) early apoptotic cells.ConclusionThis study showed that EZH1/2 inhibitors suppress HTLV-1-infected cell proliferation through apoptosis and the hyperimmune response in HAM. This indicates that EZH1/2 inhibitors may be effective in treating HAM.
| S-EPMC10291084 | biostudies-literature
Project description:Subacromial corticosteroid injections are frequently performed for pain associated with supraspinatus tendinopathy. Glucose prolotherapy has been used clinically for multiple tendinopathies and is hypothesized to be an alternate injection therapy for supraspinatus tendinopathy.A prospective, randomized, double blinded clinical trial was conducted. Thirty-six patients with supraspinatus tendinopathy were randomized into two groups: 17 received an ultrasound-guided injection of glucose into the tendinopathic parts of the supraspinatus tendon and 19 received an ultrasound-guided injection of corticosteroid into the subacromial bursa. Primary outcome was level of pain with overhead activities at 3 months. Secondary outcome measures included level and frequency of pain and function, shoulder range of motion, impingement tests, strength and tendon changes on ultrasound.Level of pain with overhead activities was significantly reduced at the 3-month follow-up in the prolotherapy group and at the 6-month follow-up for both the prolotherapy and corticosteroid groups. There were no significant differences between the groups at any time point.Both glucose prolotherapy and corticosteroid were generally well tolerated; however, glucose prolotherapy offered no additional benefit over subacromial corticosteroid injection for supraspinatus tendinopathy.
| S-EPMC5960868 | biostudies-other