Botulinum toxin type A in post-stroke lower limb spasticity: a multicenter, double-blind, placebo-controlled trial

Lower limb spasticity in post-stroke patients can impair ambulation and reduces activities of daily living (ADL) performance of patients. Botulinum toxin type A (BoNTA) has been shown effective for upper limb spasticity. This study assesses the treatment of lower limb spasticity in a large placebo-controlled clinical trial. In this multicenter, randomized, double-blind, parallel-group, placebo-controlled study, we evaluate the efficacy and safety of one-time injections of botulinum toxin type A (BoNTA) in Japanese patients with post-stroke lower limb spasticity. One hundred twenty patients with lower limb spasticity were randomized to a single treatment with BoNTA 300 U or placebo. The tone of the ankle flexor was assessed at baseline and through 12 weeks using the Modified Ashworth Scale (MAS). Gait pattern and speed of gait were also assessed. The primary endpoint was area under the curve (AUC) of the change from baseline in the MAS ankle score. Significant improvement in spasticity with BoNTA 300 U was demonstrated by a mean difference in the AUC of the change from baseline in the MAS ankle score between the BoNTA and placebo groups (−3.428; 95% CIs, −5.841 to −1.016; p = 0.006; t test). A significantly greater decrease from baseline in the MAS ankle score was noted at weeks 4, 6 and 8 in the BoNTA group compared to the placebo group (p < 0.001). Significant improvement in the Clinicians Global Impression was noted by the investigator at weeks 4, 6 and 8 (p = 0.016–0.048, Wilcoxon test), but not by the patient or physical/occupational therapist. Assessments of gait pattern using the Physician’s Rating Scale and speed of gait revealed no significant treatment differences but showed a tendency towards improvement with BoNTA. No marked difference was noted in the frequency of treatment-related adverse events between BoNTA and placebo groups. This was the first large-scale trial to indicate that BoNTA significantly reduced spasticity in lower limb muscles

Exposure to environmental tobacco smoke from husband more strongly impacts on the airway obstruction of nonsmoking women

Background: The impact of airway obstruction of nonsmoking women caused by their husband’s smoking is unclear, despite the association between environmental tobacco smoke (ETS) exposure at home and obstructive pulmonary diseases among nonsmoking women. The aim of this study was to provide evidence that ETS exposure from the husband at home has a more significant influence on the airway obstruction of nonsmoking women than other housemates. Participants and methods: Nonsmoking women aged 40 years or older were recruited from the health checkup during May 2015?December 2016, Japan. They answered structured questionnaires, including ETS exposure from their husbands and other housemates (parents, siblings and dependants), and performed spirometry. We categorized the women with any history of ETS exposure from housemates into three groups (A = husband, B = others and C = both of husband and others) and defined the control group as those with no ETS exposure from housemates. Results: A total of 811 nonsmoking women completed questionnaires and spirometry. The proportion of nonsmoking women who had airway obstruction (forced expiratory volume in 1 second [FEV1]/forced vital capacity [FVC] <70%) among Group A (7.5%) was significantly higher than those in the control group (1.1%, p<0.01) and Group B (0.8%, p<0.01). The proportion of airway obstruction in Group C (6.4%) was also higher than that in the control group (p<0.05) and Group B (p<0.05). ETS exposure from husband (odds ratio [OR], 3.53; 95% confidence interval [CI], 1.48?8.42) remained strongly associated with airway obstruction after multiple logistic regression analysis, adjusting for age, housemate’s smoking habits, family history and ETS exposure in childhood and at work. Conclusion: Nonsmoking women who were exposed to ETS from their husband had the lowest FEV1/FVC, and a higher proportion of them had airway obstruction when compared to nonsmoking women who experienced ETS from housemates other than their husbands. The findings suggest that tobacco control in husbands is the most important measure to prevent airway obstruction of nonsmoking women at home

The anti-tumor effect of trifluridine via induction of aberrant mitosis is unaffected by mutations modulating p53 activity

Abstract The fluorinated thymidine analog trifluridine (FTD) is a chemotherapeutic drug commonly used to treat cancer; however, the mechanism by which FTD induces cytotoxicity is not fully understood. In addition, the effect of gain-of-function (GOF) missense mutations of the TP53 gene (encoding p53), which promote cancer progression and chemotherapeutic drug resistance, on the chemotherapeutic efficacy of FTD is unclear. Here, we revealed the mechanisms by which FTD-induced aberrant mitosis and contributed to cytotoxicity in both p53-null and p53-GOF missense mutant cells. In p53-null mutant cells, FTD-induced DNA double-stranded breaks, single-stranded DNA accumulation, and the associated DNA damage responses during the G2 phase. Nevertheless, FTD-induced DNA damage and the related responses were not sufficient to trigger strict G2/M checkpoint arrest. Thus, these features were carried over into mitosis, resulting in chromosome breaks and bridges, and subsequent cytokinesis failure. Improper mitotic exit eventually led to cell apoptosis, caused by the accumulation of extensive DNA damage and the presence of micronuclei encapsulated in the disrupted nuclear envelope. Upon FTD treatment, the behavior of the p53-GOF-missense mutant, isogenic cell lines, generated by CRISPR/Cas9 genome editing, was similar to that of p53-null mutant cells. Thus, our data suggest that FTD treatment overrode the effect on gene expression induced by p53-GOF mutants and exerted its anti-tumor activity in a manner that was independent of the p53 function