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Background Naldemedine, a novel peripherally-acting mu-opioid receptor antagonist, has improved opioid-induced constipation in randomized controlled trials. The most frequent adverse event of naldemedine is diarrhea, which can cause abdominal pain and often leads to treatment discontinuation. We aimed to identify risk factors and appropriate management strategies for key adverse events including diarrhea associated with naldemedine, since those have not been extensively studied. Methods We conducted a multi-center retrospective cohort study. Eligible patients had cancer, had undergone palliative care at participating centers, had been prescribed regular opioids, and had taken at least one dose of naldemedine between June 2017 and March 2018. The primary endpoint was the incidence of diarrhea according to baseline characteristics. Secondary endpoints included the duration of naldemedine administration, daily defecation counts before and after starting naldemedine, duration and severity of diarrhea as an adverse event of naldemedine, other adverse events, and the incidence of constipation within 7 days after recovery from diarrhea. We defined patients who started naldemedine within three days of starting a regularly prescribed opioid as the early group, and the remainder as the late group. Results Among 103 patients who received naldemedine, 98 fulfilled the eligibility criteria. The median age was 68 years and 48% of the patients were female. Median performance status was 3, and the median oral intake was 50%. The median duration of naldemedine administration and overall survival were 25 and 64 days, respectively. The incidence of diarrhea in the early group (n = 26) was significantly lower than in the late group (n = 72) (3.9% vs. 22.2%, p = 0.02). Daily defecation counts increased after late (median 0.43 to 0.88, p p = 0.34). Constipation after the diarrhea was resolved was common (53%), especially among patients who stopped naldemedine (78%). The diarrhea was improved within three days in 92% of patients who stopped other laxatives. Conclusions The early administration of naldemedine is beneficial because it reduces adverse events including diarrhea. Diarrhea caused by naldemedine can be effectively managed by stopping other laxatives while continuing naldemedine.

BACKGROUND The pathogenesis and endovascular treatment strategy for spontaneously thrombosed unruptured cerebral aneurysms have not yet been comprehensively described. OBSERVATIONS The authors reported on a 78-year-old woman who had large bilateral unruptured cavernous carotid artery aneurysms that induced chronic disseminated intravascular coagulation and acquired factor XIII deficiency. The right aneurysm was symptomatic and partially thrombosed. Hemorrhagic diathesis and abnormal values of laboratory data improved after administration of recombinant human thrombomodulin followed by endovascular treatment in which three pipeline embolization devices were deployed for the right aneurysm. LESSONS To the best of the authors’ knowledge, this was the first report of an unruptured cerebral aneurysm leading to coagulation disorders with clinical manifestation that was treated successfully by endovascular intervention after intensive perioperative management.

Background Flow diverters (FDs) have marked the beginning of innovations in the endovascular treatment of large unruptured intracranial aneurysms, but no multi-institutional studies have been conducted on these devices from both the clinical and economic perspectives. Objective To compare retreatment rates and healthcare expenditures between FDs and conventional coiling-based treatments in all eligible cases in Japan. Methods We identified patients who had undergone endovascular treatments during the study period (October 2015-March 2018) from a national-level claims database. The outcome measures were retreatment rates and 1-yr total healthcare expenditures, which were compared among patients who had undergone FD, coiling, and stent-assisted coiling (SAC) treatments. The coiling and SAC groups were further categorized according to the number of coils used. Retreatment rates were analyzed using Cox proportional hazards models, and total expenditures were analyzed using multilevel mixed-effects generalized linear models. Results The study sample comprised 512 FD patients, 1499 coiling patients, and 711 SAC patients. The coiling groups with ≥10 coils and ≥9 coils had significantly higher retreatment rates than the FD group with hazard ratios of 2.75 (1.30-5.82) and 2.52 (1.24-5.09), respectively. In addition, the coiling group with ≥10 coils and SAC group with ≥10 coils had significantly higher 1-year expenditures than the FD group with cost ratios (95% CI) of 1.30 (1.13-1.49) and 1.31 (1.15-1.50), respectively. Conclusion In this national-level study, FDs demonstrated significantly lower retreatment rates and total expenditures than conventional coiling with ≥ 9 coils.

The frequency of neurologic complications of cerebral angiography is 0.3%-2.3%, and the frequency of the persistent neurologic deficits that remain over 7-10 days is 0.4%-0.5%. On the other hand, all neurologic complications of balloon test occlusion (BTO) have been reported in 0%-8.3% and especially in 1.6%-1.7% of symptomatic neurologic complications. There are a few reports concerning a seizure related to cerebral angiography and BTO. We report a case of prolonged seizures and left hemiparesis during and after BTO of the right internal carotid artery. The patient showed repeated focal seizures and prolonged left hemiparesis lasting for approximately 2 months. Computed tomography and magnetic resonance imaging demonstrated no abnormal findings. Suspected mechanisms of seizure were a cerebral blood flow change induced by BTO and neurotoxicity of accumulated contrast medium. A combination of prolonged focal seizures and subsequent hemiparesis is a rare complication of BTO, which should be taken into consideration during BTO.

Mouse Gasdermin A3 (Gsdma3) is the causative gene for dominant skin mutations exhibiting alopecia. Mouse has two other Gsdma3-related genes, Gsdma and Gsdma2, whereas human and rat have only one related gene. To date, no skin mutation has been reported for human GSDMA and rat Gsdma as well as mouse Gsdma and Gsdma2. Therefore, it is possible that only Gsdma3 has gain-of-function type mutations to cause dominant skin phenotype. To elucidate functional divergence among the Gsdma-related genes in mice, and to infer the function of the human and rat orthologs, we examined in vivo function of mouse Gsdma by generating Gsdma knockout mice and transgenic mice that overexpress wild-type Gsdma or Gsdma harboring a point mutation (Alanine339Threonine). The Gsdma knockout mice shows no visible phenotype, indicating that Gsdma is not essential for differentiation of epidermal cells and maintenance of the hair cycle, and that Gsdma is expressed specifically both in the inner root sheath of hair follicles and in suprabasal cell layers, whereas Gsdma3 is expressed only in suprabasal layers. By contrast, both types of the transgenic mice exhibited epidermal hyperplasia resembling the Gsdma3 mutations, although the phenotype depended on the genetic background. These results indicate that the mouse Gsdma and Gsdma3 genes share common function to regulate epithelial maintenance and/or homeostasis, and suggest that the function of human GSDMA and rat Gsdma, which are orthologs of mouse Gsdma, is conserved as well.

The only way to prevent venous brain injury is to meticulously preserve the veins. In every surgical approach, there are various bridging veins blocking access to the subarachnoid space. It is necessary to understand venous anatomy, such as frontal bridging veins for the interhemispheric approach, sylvian veins for the pterional approach, and temporal bridging veins for the subtemporal approach. High-quality cerebral angiography is necessary for adequate pre-operative evaluation of venous anatomy. With the advent of new-generation CT scanning, 3D-CT angiograms using 64 slice scanners offer an alternative means of preoperative evaluation of the venous system. Indeed, CT venogram might be superior to conventional cerebral angiography in obtaining 3D anatomical information before surgery. Meticulous microsurgical technique is essential to preserve the venous structure during surgery, as are the appropriate use of high magnification and good illumination, moist operative field, careful dissection and minimized retraction. Vein preservation must be a critical part of surgical strategy, and perhaps the most important point in vein preservation is to keep the importance of those veins in mind at all times. To learn several techniques of vein preservation aids in the surgical strategy, and keeps the skills of the surgeon polished.

Members of the novel gene family Gasdermin (Gsdm) are exclusively expressed in a highly tissue-specific manner in the epithelium of skin and the gastrointestinal tract. Based on their expression patterns and the phenotype of the Gsdma3 spontaneous mutations, it is inferred that the Gsdm family genes are involved in epithelial cell growth and/or differentiations in different tissues. To investigate possible roles of the Gsdm gene family in the development of intestinal tracts, we generated a Gsdmd mutant mouse, which is a solitary member of the Gsdmd subfamily and which is predominantly expressed in the intestinal tract by means of targeted disruption. In the mutant homozygotes, we found no abnormality of intestinal tract morphology. Moreover, in mutant mice, there was normal differentiation of all constituent cell types of the intestinal epithelium. Thus, this study clearly shows that Gsdmd is not essential for development of mouse intestinal tract or epithelial cell differentiation.

GASDERMIN B (GSDMB) belongs to the novel gene family GASDERMIN (GSDM). All GSDM family members are located in amplicons, genomic regions often amplified during cancer development. Given that GSDMB is highly expressed in cancerous cells and the locus resides in an amplicon, GSDMB may be involved in cancer development and/or progression. However, only limited information is available on GSDMB expression in tissues, normal and cancerous, from cancer patients. Furthermore, the molecular mechanisms that regulate GSDMB expression in gastric tissues are poorly understood. We investigated the spatiotemporal expression patterns of GSDMB in gastric cancer patients and the 5' regulatory sequences upstream of GSDMB. GSDMB was not expressed in the majority of normal gastric-tissue samples, and the expression level was very low in the few normal samples with GSDMB expression. Most pre-cancer samples showed moderate GSDMB expression, and most cancerous samples showed augmented GSDMB expression. Analysis of genome sequences revealed that an Alu element resides in the 5' region upstream of GSDMB. Reporter assays using intact, deleted, and mutated Alu elements clearly showed that this Alu element positively regulates GSDMB expression and that a putative IKZF binding motif in this element is crucial to upregulate GSDMB expression.

ObjectThe combination approach of Ommaya reservoir placement and Gamma Knife surgery (GKS) was evaluated for the treatment of large cystic metastatic brain tumors.MethodsThe medical records of 22 patients harboring 28 tumors, who underwent Ommaya reservoir placement followed by GKS for large cystic metastatic brain tumors were retrospectively reviewed. The patients' ages ranged 26 to 77 years (mean 57.1 years). The most common locations of primary malignancy were the breast (11 patients) followed by the lung (seven patients). The mean maximum diameter of the tumor was 40.1 mm before Ommaya reservoir placement and 31.2 mm at GKS (mean reduction of 19.9%). The mean calculated tumor volume at GKS was 13.4 cm3. The mean tumor margin dose was 16 Gy in 17 patients treated by GKS only and 11 Gy in five patients treated using both GKS and external radiotherapy. The mean follow-up period was 11.5 months. Nineteen (67.9%) of the 28 tumors were controlled. The median patient survival time was 7 months. Asymptomatic intracystic hemorrhage associated with Ommaya reservoir placement was seen in two patients with four tumors, but no serious complication occurred.Conclusions Ommaya reservoir placement followed by GKS is relatively effective and safe for large cystic metastatic brain tumors. Gamma Knife surgery should be performed within a few days of Ommaya reservoir placement. Reaccumulation and high viscosity of cystic content must be considered.

Two classical mouse hair coat mutations, Rex (Re) and Rex wavy coat (Rewc), are linked to the type I inner root sheath (IRS) keratin genes of chromosome 11. An N-ethyl-N-nitrosourea-induced mutation, M100573, also maps close to the type I IRS keratin genes. In this study, we demonstrate that Re and M100573 mice bear mutations in the type I IRS gene Krt25; Rewc mice bear an additional mutation in the type I IRS gene Krt27. These three mutations are located in the helix termination motif of the 2B α-helical rod domain of a type I IRS keratin protein. Immunohistological analysis revealed abnormal foam-like immunoreactivity with an antibody raised to type II IRS keratin K71 in the IRS of Re/+ mice. These results suggest that the helix termination motif is essential for the proper assembly of types I and II IRS keratin protein complexes and the formation of keratin intermediate filaments.