No abstract

Parkin (encoded by PRKN) is a ubiquitin ligase that plays an important role in cellular mitochondrial quality control. Mutations in PRKN cause selective dopaminergic cell loss in the substantia nigra and are presumed to induce a decrease in mitochondrial function caused by the defective clearance of mitochondria. Several studies have demonstrated that parkin dysfunction causes mitochondrial injury and astrocytic dysfunction. Using immunohistochemical methods, we analyzed astrocytic changes in human brains from individuals with PRKN mutations. Few glial fibrillary acidic protein- and vimentin-positive astrocytes were observed in the substantia nigra in PRKN-mutated subjects compared with subjects with idiopathic Parkinson’s disease. We also differentiated patient-specific induced pluripotent stem cells into midbrain organoids and confirmed decreased numbers of glial fibrillary acidic protein-positive astrocytes in PRKN-mutated organoids compared with age- and sex-matched controls. Our study reveals PRKN-mutation-induced astrocytic alteration and suggests the possibility of an astrocyte-related non-autonomous cell death mechanism for dopaminergic neurons in brains of PRKN-mutated patients.

IntroductionChronic constipation worsens the quality of life (QOL) of patients with Parkinson’s disease (PD). Elobixibat, an ileal bile acid transporter inhibitor, is a useful laxative, but its effect on chronic constipation in patients with PD remains unclear. Therefore, we designed a placebo-controlled, randomised, double-blind study to investigate the efficacy and safety of elobixibat in patients with PD with chronic constipation.Methods and analysisThe study will consist of 2-week observation and 4-week treatment periods. Patients with clinically established PD will record the status of spontaneous bowel movements and use of rescue medications/concomitant medications in a Bowel Movement Diary from the start of the observation period at visit 1 (week −2). At visit 2 (week 0), patients will be assessed for final registration based on the diary records and physical examinations, and allocated to either the elobixibat or placebo group. Daily intake of the investigational drug will be recorded in the diary. Patients will undergo laboratory tests and answer constipation-related, PD-related and QOL-related questionnaires at visits 2 and 4 (week 4). Subjective symptoms and objective findings will be collected at visits 2, 3 (week 2) and 4. Since patients’ motor function might be improved by treatment of constipation, the use of dopamine preparations will also be monitored. Bowel movement data and other parameters will be compared between groups.Safety information will be collected as adverse events, specifically focusing on those occurring in association with study conduct.Ethics and disseminationThis study will be conducted in accordance with the Helsinki Declaration, the Clinical Trials Act of the Japan Ministry of Health, Labour and Welfare, and related laws and regulations. The study was approved by the Juntendo University Certified Review Board. The results will be disseminated through an online study registry (Japan Registry of Clinical Trials), presented at scientific conferences, and published in medical journals.Trial registration numberJPRN-jRCTs031200172; Pre-results.

Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiological syndrome characterized by headache, confusion, seizures, and cortical visual loss, as well as subcortical edema without infarction on neuroimaging. We report a 56-year-old woman who developed typical manifestations of PRES, 6 days after blood transfusion for severe anemia. Acute volume overloads by transfusion may exceed the capacity of autoregulation of perfusion pressure, possibly resulting in vasogenic edema. We propose that it is clinically important to recognize that rapid correction of anemia by blood transfusion may carry the risk of inducing PRES.

Sera from 60 gastric cancer patients and 20 patients with benign gastric diseases and 8 healthy controls were tested for inhibitory effects on the humoral response to sheep erythrocytes (SRBC) by the plaque forming cell assay (PFC R.I.) using mouse spleen cells and on the phytohemagglutinin (PHA)-induced blastogenesis of normal mouse spleen cells (PHA S.R.). Gastric cancer patient sera showed a significantly lower PFC R.I. than did sera from benign gastric disease patients and from the healthy controls. However, there was no appreciable interstage difference in the degree of depression. The PHA-induced blastogenesis of normal spleen cells was also decreased in the presence of sera from cancer patients, as compared to that in the presence of sera from benign disease patients and from the healthy controls. The depression progressed with advancing stage of cancer. The PHA S.R. showed significant negative correlations with serum levels of IAP, IS, alpha 1-acid glycoprotein and alpha 1-antitrypsin, but there were no such correlations between PFC R.I. and these glycoproteins in serum. There was also no correlation between the values of the PHA S.R. and the PFC R.I. These results suggest that these two assays may depict immunosuppressive activities operating through entirely different mechanisms.