A web-based survey on the occurrence of emotional blunting in patients with major depressive disorder in Japan: Patient perceptions and attitudes.

AIMS: To determine the prevalence and impact of emotional blunting (EB) in patients with major depressive disorder (MDD) in Japan, and identify treatment needs for EB using patients' perceptions and attitudes. METHODS: Eligible patients in Japan (aged 18-59 years) who reported a diagnosis of MDD and antidepressant medication use for >3 months were eligible to complete an online survey. The primary outcome was the prevalence of EB, self-reported using a validated screening question. Secondary outcomes included the correlation between EB symptoms (measured by the Oxford Depression Questionnaire [ODQ]) and scores on the Patient Health Questionnaire 9-item (PHQ-9), Generalized Anxiety Disorder 7-item (GAD-7), Work and Social Adjustment Scale (WSAS), and the EuroQol 5-Dimension 5-Levels questionnaire (EQ-5D-5L). Descriptive questions were used to explore patients' perceptions and attitudes toward EB. RESULTS: In total, 3376 patients were included in the analysis (56% male; 48% aged 50-59 years). Overall, 67.1% of patients self-reported symptoms of EB, with 10% rating these as severe. The mean (SD) ODQ total score was 78.2 (21.5), which increased with worsening EB symptoms. There were correlations between ODQ total scores and the PHQ-9, GAD-7, WSAS, and EQ-5D-5L scores (correlation coefficients: 0.67, 0.55, 0.56, -0.51, respectively; all p < 0.0001). Descriptive analyses showed that one-third of patients reporting EB symptoms did not tell their physician, with two-thirds finding these symptoms distressing and likely to affect recovery. CONCLUSION: EB is an important clinical issue in Japan that needs to be considered alongside functional recovery when managing treatment of patients with MDD.

Safety and effectiveness of rasagiline in patients with Parkinson's disease in Japan: a post-marketing surveillance study.

BACKGROUND: Rasagiline is a monoamine oxidase B inhibitor for the treatment of Parkinson's disease (PD). This study assessed the safety and effectiveness of rasagiline in patients with PD in routine clinical practice in Japan. RESEARCH DESIGN AND METHODS: This multicenter, prospective, observational study (148 sites) enrolled patients (1 November 2018-31 October 2020) with PD. Patients received rasagiline orally 1 mg once daily; maximum observation period was 24 months. The incidence of adverse drug reactions (ADRs) was evaluated; effectiveness was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) Part III total score. RESULTS: The safety analysis set comprised 961 patients (mean age, 72.50 years; 53.80% female; mean duration of PD, 6.82 years). Mean treatment duration was 14.74 months, with 42.25% receiving rasagiline for ≥ 19 months; 189 (19.67%) had ≥ 1 ADR. Common ADRs were dyskinesia (4.06%), orthostatic hypotension (2.29%), hallucination (1.87%), visual hallucination, nausea, fall (1.56% each), dizziness (1.35%), and somnolence (1.25%). Mean (standard deviation) UPDRS Part III total score was 28.5 (14.35) at baseline and 25.5 (14.98) at the final assessment. CONCLUSIONS: No new concerns in safety and effectiveness regarding rasagiline in Japanese patients with PD were raised. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03727139; Japan Pharmaceutical Information Center Clinical Trials Information: JapicCTI-184181.

Video training and certification program improves reliability of postischemic neurologic deficit measurement in the rat.

Scoring systems are used to measure behavioral deficits in stroke research. Video-assisted training is used to standardize stroke-related neurologic deficit scoring in humans. We hypothesized that a video-assisted training and certification program can improve inter-rater reliability in assessing neurologic function after middle cerebral artery occlusion in rats. Three expert raters scored neurologic deficits in post-middle cerebral artery occlusion rats using three published systems having different complexity levels (3, 18, or 48 points). The system having the highest point estimate for the correlation between neurologic score and infarct size was selected to create a video-assisted training and certification program. Eight trainee raters completed the video-assisted training and certification program. Inter-rater agreement ( Κ: score) and agreement with expert consensus scores were measured before and after video-assisted training and certification program completion. The 48-point system correlated best with infarct size. Video-assisted training and certification improved agreement with expert consensus scores (pretraining = 65 ± 10, posttraining = 87 ± 14, 112 possible scores, P < 0.0001), median number of trainee raters with scores within ±2 points of the expert consensus score (pretraining = 4, posttraining = 6.5, P < 0.01), categories with Κ: > 0.4 (pretraining = 4, posttraining = 9), and number of categories with an improvement in the Κ: score from pretraining to posttraining (n = 6). Video-assisted training and certification improved trainee inter-rater reliability and agreement with expert consensus behavioral scores in rats after middle cerebral artery occlusion. Video-assisted training and certification may be useful in multilaboratory preclinical studies.

Sustained functional improvement by hepatocyte growth factor-like small molecule BB3 after focal cerebral ischemia in rats and mice.

Hepatocyte growth factor (HGF), efficacious in preclinical models of acute central nervous system injury, is burdened by administration of full-length proteins. A multiinstitutional consortium investigated the efficacy of BB3, a small molecule with HGF-like activity that crosses the blood-brain barrier in rodent focal ischemic stroke using Stroke Therapy Academic Industry Roundtable (STAIR) and Good Laboratory Practice guidelines. In rats, BB3, begun 6 hours after temporary middle cerebral artery occlusion (tMCAO) reperfusion, or permanent middle cerebral artery occlusion (pMCAO) onset, and continued for 14 days consistently improved long-term neurologic function independent of sex, age, or laboratory. BB3 had little effect on cerebral infarct size and no effect on blood pressure. BB3 increased HGF receptor c-Met phosphorylation and synaptophysin expression in penumbral tissue consistent with a neurorestorative mechanism from HGF-like activity. In mouse tMCAO, BB3 starting 10 minutes after reperfusion and continued for 14 days improved neurologic function that persisted for 8 weeks in some, but not all measures. Study in animals with comorbidities and those exposed to common stroke drugs are the next steps to complete preclinical assessment. These data, generated in independent, masked, and rigorously controlled settings, are the first to suggest that the HGF pathway can potentially be harnessed by BB3 for neurologic benefit after ischemic stroke.

A blinded randomized assessment of laser Doppler flowmetry efficacy in standardizing outcome from intraluminal filament MCAO in the rat.

BACKGROUND: Laser Doppler flowmetry (LDF) is widely used for estimating cerebral blood flow changes during intraluminal middle cerebral artery occlusion (MCAO). No investigation has systematically examined LDF efficacy in standardizing outcome. We examined MCAO histologic and behavioral outcome as a function of LDF measurement. MATERIALS AND METHODS: Rats were subjected to 90min MCAO by 4 surgeons having different levels of MCAO surgical experience. LDF was measured in all rats during ischemia. By random assignment, LDF values were (Assisted) or were not (Blinded) made available to each surgeon during MCAO (n=12-17 per group). Neurologic and histologic outcomes were measured 7 days post-MCAO. A second study examined LDF effects on 1-day post-MCAO outcome. RESULTS: Pooled across surgeons, intra-ischemic %LDF change (P=0.12), neurologic scores (Assisted vs. Blinded=14±6 vs. 13±7, P=0.61, mean±standard deviation) and cerebral infarct volume (162±63mm(3)vs. 143±86mm(3), P=0.24) were not different between groups. Only for one surgeon (novice) did LDF use alter infarct volume (145±28mm(3)vs. 98±61mm(3), P=0.03). LDF use decreased infarct volume coefficient of variation (COV) by 35% (P=0.02), but had no effect on neurologic score COV. COMPARISON WITH EXISTING METHODS: We compared intraluminal MCAO outcome as a function of LDF use. CONCLUSIONS: LDF measurement altered neither neurologic nor histologic MCAO outcome. LDF did not decrease neurologic deficit COV, but did decrease infarct volume COV. LDF may allow use of fewer animals if infarct volume is the primary dependent variable, but is unlikely to impact requisite sample sizes if neurologic function is of primary interest.

Metalloporphyrins as therapeutic catalytic oxidoreductants in central nervous system disorders.

SIGNIFICANCE: Metalloporphyrins, characterized by a redox-active transitional metal (Mn or Fe) coordinated to a cyclic porphyrin core ligand, mitigate oxidative/nitrosative stress in biological systems. Side-chain substitutions tune redox properties of metalloporphyrins to act as potent superoxide dismutase mimics, peroxynitrite decomposition catalysts, and redox regulators of transcription factor function. With oxidative/nitrosative stress central to pathogenesis of CNS injury, metalloporphyrins offer unique pharmacologic activity to improve the course of disease. RECENT ADVANCES: Metalloporphyrins are efficacious in models of amyotrophic lateral sclerosis, Alzheimer's disease, epilepsy, neuropathic pain, opioid tolerance, Parkinson's disease, spinal cord injury, and stroke and have proved to be useful tools in defining roles of superoxide, nitric oxide, and peroxynitrite in disease progression. The most substantive recent advance has been the synthesis of lipophilic metalloporphyrins offering improved blood-brain barrier penetration to allow intravenous, subcutaneous, or oral treatment. CRITICAL ISSUES: Insufficient preclinical data have accumulated to enable clinical development of metalloporphyrins for any single indication. An improved definition of mechanisms of action will facilitate preclinical modeling to define and validate optimal dosing strategies to enable appropriate clinical trial design. Due to previous failures of "antioxidants" in clinical trials, with most having markedly less biologic activity and bioavailability than current-generation metalloporphyrins, a stigma against antioxidants has discouraged the development of metalloporphyrins as CNS therapeutics, despite the consistent definition of efficacy in a wide array of CNS disorders. FUTURE DIRECTIONS: Further definition of the metalloporphyrin mechanism of action, side-by-side comparison with "failed" antioxidants, and intense effort to optimize therapeutic dosing strategies are required to inform and encourage clinical trial design.

[Effect of extended paraaortic lymph node dissection on postoperative pancreatic function in gynecologic procedures].

BACKGROUND: We tested a hypothesis that extended gynecological paraaortic lymph node dissection seriously impairs postoperative pancreatic function. METHODS: We studied 82 patients who underwent gynecologic surgery for malignancy from January, 2002 to October, 2003. After scheduled operation, we assigned them to one of two groups; patients who underwent extended gynecological paraaortic lymph node dissection (n=34) or those who did not (n=48). We measured plasma amylase levels in all patients before operation and 1, 3, 7 days after operation. RESULTS: Preoperative amylase levels were the same in the two groups. Time-dependent increases in plasma amylase level were noted in both groups. From 1 to 3 days after operation, however, plasma amylase levels were significantly higher in patients who had undergone paraaortic lymph node dissection than in those who had not. Furthermore, lethal postoperative pancreatitis developed in one patient who showed marked high levels in plasma amylase level after paraaortic lymph node dissection. CONCLUSIONS: Our results suggest that paraaortic lymph node dissection in gynecologic operations seriously impairs pancreatic function and that one should maintain a high suspicion of postoperative pancreatitis.