Cerebral Small Vessel Disease Burden for Bleeding Risk during Antithrombotic Therapy: Bleeding with Antithrombotic Therapy 2 Study.

OBJECTIVE: This study was undertaken to determine the excess risk of antithrombotic-related bleeding due to cerebral small vessel disease (SVD) burden. METHODS: In this observational, prospective cohort study, patients with cerebrovascular or cardiovascular diseases taking oral antithrombotic agents were enrolled from 52 hospitals across Japan between 2016 and 2019. Baseline multimodal magnetic resonance imaging acquired under prespecified conditions was assessed by a central diagnostic radiology committee to calculate total SVD score. The primary outcome was major bleeding. Secondary outcomes included bleeding at each site and ischemic events. RESULTS: Of the analyzed 5,250 patients (1,736 women; median age = 73 years, 9,933 patient-years of follow-up), antiplatelets and anticoagulants were administered at baseline in 3,948 and 1,565, respectively. Median SVD score was 2 (interquartile range = 1-3). Incidence rate of major bleeding was 0.39 (per 100 patinet-years) in score 0, 0.56 in score 1, 0.91 in score 2, 1.35 in score 3, and 2.24 in score 4 (adjusted hazard ratio [aHR] for score 4 vs 0 = 5.47, 95% confidence interval [CI] = 2.26-13.23), that of intracranial hemorrhage was 0.11, 0.33, 0.58, 0.99, and 1.06, respectively (aHR = 9.29, 95% CI = 1.99-43.35), and that of ischemic event was 1.82, 2.27, 3.04, 3.91, and 4.07, respectively (aHR = 1.76, 95% CI = 1.08-2.86). In addition, extracranial major bleeding (aHR = 3.43, 95% CI = 1.13-10.38) and gastrointestinal bleeding (aHR = 2.54, 95% CI = 1.02-6.35) significantly increased in SVD score 4 compared to score 0. INTERPRETATION: Total SVD score was predictive for intracranial hemorrhage and probably for extracranial bleeding, suggesting the broader clinical relevance of cerebral SVD as a marker for safe implementation of antithrombotic therapy. ANN NEUROL 2024;95:774-787.

Successful treatment with traditional Japanese medicine (kampo medicine) Yokukansan as a migraine prophylactic drug: A case report.

RATIONALE: The use of anti-CGRP antibody drugs as migraine preventive drugs is increasing worldwide, but there are still a certain number of cases where antibody drugs are ineffective or cannot be used due to high prices. Conventional prophylactic drugs or traditional Japanese medicine (kampo medicine) are still often used in such cases. However, to date, only limited evidence supports the efficacy of kampo medicine for headaches because these treatments have been used primarily empirically and traditionally. However, in recent years studies have begun to be published that describe the efficacy of kampo medicine for various types of headache. Here, we report the case of a patient who achieved a marked reduction in migraine frequency and severity by prophylactic therapy with the kampo drug yokukansan (TSUMURA Yokukansan Extract Granules). PATIENT CONCERNS AND DIAGNOSES: The patient was a 50-year-old woman. She began to experience headaches around high school age and was diagnosed with migraine without aura at 42 years of age. INTERVENTIONS AND OUTCOMES: She started prophylactic therapy with amitriptyline and topiramate and this treatment reduced the frequency of migraines for several years. However, the frequency began to increase again around 47 years, which is when she presented at our hospital. We achieved a temporary reduction in migraine frequency by adjusting the dose of drugs in her prophylactic therapy regimen, but the frequency increased again around age 49. We then tried monotherapy with the kampo medicine yokukansan, and this markedly reduced migraine frequency and severity over the following year. This therapy has remained effective to date. LESSONS: We speculate that, in this case, migraine without aura was improved by prophylactic therapy with yokukansan due to its action on the glutamatergic system or serotonin system through suppression of orexin-A secretion or its anti-inflammatory effects as reported in previous animal studies. Yokukansan could be a usable kampo medicine for migraine prophylaxis in countries all over the world and should be investigated in a large clinical trial as soon as possible.

Dosimetric Comparison Study of Proton Therapy Using Line Scanning versus Passive Scattering and Volumetric Modulated Arc Therapy for Localized Prostate Cancer.

BACKGROUND: The proton irradiation modality has transitioned from passive scattering (PS) to pencil beam scanning. Nevertheless, the documented outcomes predominantly rely on PS. METHODS: Thirty patients diagnosed with prostate cancer were selected to assess treatment planning across line scanning (LS), PS, and volumetric modulated arc therapy (VMAT). Dose constraints encompassed clinical target volume (CTV) D98 ≥ 73.0 Gy (RBE), rectal wall V65 < 17% and V40 < 35%, and bladder wall V65 < 25% and V40 < 50%. The CTV, rectal wall, and bladder wall dose volumes were calculated and evaluated using the Freidman test. RESULTS: The LS technique adhered to all dose limitations. For the rectal and bladder walls, 10 (33.3%) and 21 (70.0%) patients in the PS method and 5 (16.7%) and 1 (3.3%) patients in VMAT, respectively, failed to meet the stipulated requirements. The wide ranges of the rectal and bladder wall volumes (V10-70) were lower with LS than with PS and VMAT. LS outperformed VMAT across all dose-volume rectal and bladder wall indices. CONCLUSION: The LS method demonstrated a reduction in rectal and bladder doses relative to PS and VMAT, thereby suggesting the potential for mitigating toxicities.

Morphological and biochemical characterization of Holstein cow skin at the tail root region susceptible to Chorioptes bovis and texanus parasitism.

Cattle mange causes extreme itchiness, and the associated stress is an animal welfare concern that leads to economic losses due to decreased cattle productivity and deworming costs. This study investigated the reason why Chorioptic mites, C. bovis and C. texanus, preferentially infest the tail root region (rTR) and performed histological and biochemical analysis focusing on the volatile components of host odors that serve as the starting point for infestation of parasitic arthropods. Skin samples were taken from the rTR, lateral abdominal, and central masseteric, with the latter two designated as comparison sites. The two and three-dimensional histological analysis measured each sebaceous and sweat gland percentage per unit volume. The q-PCR analyzed the expression levels of ALDH1A1 and LOC785756, which are genes associated with volatile odoriferous compounds that serve as repellency and attractive messengers for ticks. Immunohistochemistry stained three sites with anti-androgen binding protein beta-like (ABPß-like), encoded by LOC785756, antibody. The three-dimensional analysis showed that sebaceous glands in the rTR tend to be more continuous and existed in larger masses than in other regions. The expression level of LOC785756 was significantly higher in the rTR, and immunohistochemistry revealed the presence of ABPß-like in the sebaceous gland with strong positive signals in the rTR. These results suggest that C. bovis/texanus selectively infests the rTR because that skin has well-developed sebaceous glands, including a large amount of ABPß-like, which acts as a mite attractant.

Effectiveness and safety of MR-guided focused ultrasound thalamotomy in patients with essential tremor and low skull density ratio: a study of 101 cases.

OBJECTIVE: The objective was to investigate the effectiveness and safety of MR-guided focused ultrasound (MRgFUS) treatment in patients with essential tremor, particularly those with low skull density ratio (SDR) and including those with very low SDR, and to identify the factors influencing treatment effectiveness and to provide insights into therapeutic approaches for patients with lower SDR. METHODS: Real-world data from 101 patients who underwent MRgFUS between July 2019 and March 2022 at a single institution were analyzed. Tremor severity was assessed using the Fahn-Tolosa-Marin Clinical Rating Scale for Tremor (CRST). The patients were categorized into quartile groups based on their mean SDR, and the characteristics, treatment effectiveness, treatment parameters, and adverse events were evaluated among these subgroups. RESULTS: Patients were classified into 4 quartiles based on the mean SDR: quartile 1 (Q1) (SDR 0.26-0.37), Q2 (SDR 0.38-0.42), Q3 (SDR 0.43-0.49), and Q4 (SDR 0.50-0.75). MRgFUS significantly improved total CRST and tremor score across all SDR subgroups. Additionally, there were no significant differences in the improvement rates among the 4 subgroups. Analysis of the treatment parameters revealed that lower mean SDR was associated with lower target maximum temperature and smaller coagulation volume after focused ultrasound (FUS). Regarding adverse events, headache and nausea during FUS and facial and head edema on the day after surgery were more frequent in the Q1 subgroup (very low-SDR group). In contrast, numbness was more common in the Q4 subgroup. However, all these adverse events had resolved by the 3-month follow-up except numbness. CONCLUSIONS: This study suggested that MRgFUS is effective and safe for patients with medication-resistant essential tremor, including those with very low mean SDR. However, the very low-SDR group had insufficient temperature elevation at the target site compared with the high-SDR group, suggesting the need for a different strategy. Notably, with careful adjustments and considerations, positive outcomes can still be achieved in patients with very low SDR. Therefore, very low SDR should not be considered an absolute exclusion criterion because it is expected to increase the number of patients who benefit from MRgFUS.

Clinical symptoms, biochemistry, and liver histology during the native liver period of progressive familial intrahepatic cholestasis type 2.

BACKGROUND: Progressive familial intrahepatic cholestasis type 2 (PFIC2) is an ultra-rare disease caused by mutations in the ABCB11 gene. This study aimed to understand the course of PFIC2 during the native liver period. METHODS: From November 2014 to October 2015, a survey to identify PFIC2 patients was conducted in 207 hospitals registered with the Japanese Society of Pediatric Gastroenterology, Hepatology, and Nutrition. Investigators retrospectively collected clinical data at each facility in November 2018 using pre-specified forms. RESULTS: Based on the biallelic pathogenic variants in ABCB11 and/or no hepatic immunohistochemical detection of BSEP, 14 Japanese PFIC2 patients were enrolled at seven facilities. The median follow-up was 63.2 [47.7-123.3] months. The median age of disease onset was 2.5 [1-4] months. Twelve patients underwent living donor liver transplantation (LDLT), with a median age at LDLT of 9 [4-57] months. Two other patients received sodium 4-phenylbutyrate (NaPB) therapy and survived over 60 months with the native liver. No patients received biliary diversion. The cases that resulted in LDLT had gradually deteriorated growth retardation, biochemical tests, and liver histology since the initial visit. In the other two patients, jaundice, growth retardation, and most of the biochemical tests improved after NaPB therapy was started, but pruritus and liver fibrosis did not. CONCLUSIONS: Japanese PFIC2 patients had gradually worsening clinical findings since the initial visit, resulting in LDLT during infancy. NaPB therapy improved jaundice and growth retardation but was insufficient to treat pruritus and liver fibrosis.

Video Motion Analysis as a Quantitative Evaluation Tool for Essential Tremor during Magnetic Resonance-Guided Focused Ultrasound Thalamotomy.

The Clinical Rating Scale for Tremor (CRST) is commonly used to evaluate essential tremor (ET) during focused ultrasound (FUS) thalamotomy. However, it faces challenges such as the ceiling effect and test-retest variability. This study explored the utility of videographic motion analysis as an evaluation index for ET. Forty-three patients with ET performed postural tremor and line-drawing tasks recorded on video, and the data were analyzed using motion analysis software. The test-retest and inter-rater reliability, correlations with the CRST and tremor scores, and pre/post-FUS treatment comparisons were analyzed. The video motion analysis showed excellent test-retest and inter-rater reliability. In the postural tremor tasks, video parameter amplitude significantly correlated with the CRST and tremor scores. Similarly, for the line-drawing task, video parameter amplitude showed significant correlations with CRST and tremor scores, effectively addressing the ceiling effect. Regarding post-FUS treatment improvements, changes in the CRST and tremor scores were significantly associated with changes in video parameter amplitude. In conclusion, quantitative analysis of the video motion of ET enables precise evaluation of kinematic characteristics and effectively resolves the ceiling effect and test-retest variability. The video motion analysis score accurately reflected the tremor severity and treatment effects, demonstrating its high clinical utility.