ABSTRACT
An in vitro model of human meiosis would accelerate research into this important reproductive process and development of therapies for infertility. We have developed a method to induce meiosis starting from male or female human pluripotent stem cells. We demonstrate that DNMT1 inhibition, retinoid signaling activation, and overexpression of regulatory factors (anti-apoptotic BCL2, and pro-meiotic HOXB5, BOLL, or MEIOC) rapidly activates meiosis, with leptonema beginning at 6 days, zygonema at 9 days, and pachynema at 12 days. Immunofluorescence microscopy shows key aspects of meiosis, including chromosome synapsis and sex body formation. The meiotic cells express genes similar to meiotic oogonia in vivo, including all synaptonemal complex components and machinery for meiotic recombination. These findings establish an accessible system for inducing human meiosis in vitro.
ABSTRACT
Treatment with natalizumab has been shown to reduce physical disability in people with multiple sclerosis (MS). However, its effect on neuropsychological dysfunction is not well understood. A single-center, open-label, retrospective study was conducted to evaluate the effect of natalizumab treatment on neuropsychological function in individuals with relapsing-remitting multiple sclerosis (RRMS) who had a measurable neuropsychological deficit prior to natalizumab treatment. A total of 40 MS patients (mean age, 48.5 years; 77.5% female) were evaluated on a neuropsychological battery of nine tests designed for MS patients before and after 6 or more months of treatment with natalizumab. Posttreatment neuropsychological testing results were compared to baseline results. The mean baseline Neuropsychological Impairment Index was 0.49, which improved to 0.41 after treatment (P = .0002) as analyzed using the Wilcoxon signed rank test. The mean Beck Depression Inventory-II (BDI-II) score improved by 2.45 points (P = .001). The mean Expanded Disability Status Scale (EDSS) score improved by 0.30 (P = .02). A total of 52.5% of patients showed neuropsychological improvement, while 30.0% showed no change and 17.5% had worsening. Magnetic resonance imaging showed no changes. The specific prior disease-modifying therapy had no influence on the results for natalizumab effect. The results of this study show that natalizumab can stabilize or improve neuropsychological function in RRMS patients. The improvement was consistent with, but apparently independent of, improvement in depression and physical disability.
ABSTRACT
BACKGROUND: Oxymorphone extended release (ER) is a tablet formulation of the mu-opioid agonist oxymorphone designed to achieve a low peak-to-trough fluctuation in plasma concentrations over a 12-hour dosing period. OBJECTIVE: This study compared the analgesic efficacy, dose response, and tolerability of 3 doses of oxymorphone ER given every 12 hours with those of placebo in patients with pain related to osteoarthritis (OA) of the hip or knee. METHODS: This was a 2-week, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, Phase III trial. Patients with OA of the hip or knee who were receiving an opioid medication for chronic, moderate to severe pain or who were judged by the investigator to have received suboptimal analgesia with nonopioid analgesics entered a 2- to 7-day washout of analgesic medication. When pain in the index joint was >40 mm on a 100-mm visual analog scale (VAS), patients were randomized to receive 1 of 4 regimens: oxymorphone ER 10 mg q12h during weeks 1 and 2; oxymorphone ER 20 mg q12h in week 1 and 40 mg q12h in week 2; oxymorphone ER 20 mg q12h in week 1 and 50 mg q12h in week 2; or placebo q12h during weeks 1 and 2. The primary end point was the change in VAS score for arthritis pain intensity. Other assessments included the Western Ontario and McMaster Universities (WOMAC) OA Index subscales for pain, stiffness, and physical function and the composite index; the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) physical health component summary (PCS) score; the Chronic Pain Sleep Inventory (CPSI) score; vital signs; clinical laboratory parameters; and adverse events (AEs). AEs were recorded at each clinic visit. RESULTS: Three hundred seventy patients were randomized to treatment (95 oxymorphone ER 10 mg, 93 oxymorphone ER 40 mg, 91 oxymorphone ER 50 mg, and 91 placebo), and 198 completed the study. Least squares mean changes from baseline in the VAS arthritis pain intensity score were -21, -28, -29, and -17 mm in the oxymorphone ER 10, 40, and 50 mg and placebo groups, respectively (P = 0.002, modified Tukey linear trend test). Oxymorphone ER 40 and 50 mg produced significant improvements from baseline compared with placebo in the WOMAC subscale scores for pain (least squares mean change: -85.1, -108.0, and -42.5, respectively; P < or = 0.025 for 40 mg, P < or = 0.001 for 50 mg), stiffness (-40.5, -48.1, and -17.0; both, P < or = 0.001), and physical function (-256.8, -310.8, and -116.5; P < or = 0.01 and P < or = 0.001, respectively); the SF-36 PCS score (4.6, 3.6, and -0.1; P < 0.001); and the CPSI score (-21.2, -22.2, and -10.7; P < 0.05). The 10-mg dose also was associated with significant improvements compared with placebo in the WOMAC pain (-83.6; P < or = 0.025) and physical function subscales (-232.9; P < or = 0.025) and the SF-36 PCS score (3.9; P < 0.001). The most frequently reported AEs (> or =5% of patients) in the oxymorphone ER groups were nausea (39.4%), vomiting (23.7%), dizziness (22.6%), constipation (22.2%), somnolence (17.6%), pruritus (16.5%), and headache (15.0%). The majority of AEs with oxymorphone ER were mild or moderate in intensity. Three serious AEs (urinary retention, central nervous system depression, and pancreatitis) were considered possibly or probably related to study medication. CONCLUSION: In these patients with chronic, moderate to severe pain related to OA of the hip or knee, oxymorphone ER administered twice daily for 2 weeks produced dose-related reductions in arthritis pain intensity and improvements in physical function.
