Clinicopathological study of diffuse neurofibrillary tangles with calcification. With special reference to TDP-43 proteinopathy and alpha-synucleinopathy

Diffuse neurofibrillary tangles with calcification (DNTC) is a relatively rare presenile dementia that clinically shows overlapping symptoms of Alzheimer's disease and frontotemporal lobar degeneration (FTLD). DNTC is pathologically characterized by localized temporal or frontotemporal atrophy with massive neurofibrillary tangles, neuropil threads and Fahr's-type calcification without senile plaques. We tried to clarify the molecular basis of DNTC by immunohistochemically examining the appearance and distribution of accumulated alpha-synuclein (aSyn) and TAR DNA-binding protein of 43kDa (TDP-43) in the brains of 10 Japanese autopsy cases. We also investigated the clinically characteristic symptoms from the clinical charts and previous reports, and the correlations with neuropathological findings. The characteristic symptoms were evaluated using the Neuropsychiatric Inventory Questionnaire (NPI-Q). As a result, we confirmed the high frequency of neuronal cytoplasmic accumulation of aSyn (80%) and phosphorylated TDP-43 (90%) in DNTC cases. There was a significant correlation between some selected items of NPI-Q scores and the severity of the limbic TDP-43 pathology. The pathology of DNTC included TDP-43 and aSyn pathology with high frequency. These abnormal accumulations of TDP-43 might be involved in the pathological process of DNTC, having a close relationship to the FTLD-like psychiatric symptoms during the clinical course.     

Studies on the pathogenesis of coagulopathy in patients with arterial thromboembolism and malignancy

Plasma levels of thrombin-antithrombin III complex(TAT), plasmin-₂-plasmin inhibitor complex(PAP), von Willebrand factor antigen (vWF:Ag) plasminogen activator antigen(PA) and plasminogen activator inhibitor-1 antigen(PAI-1), were determined in 110 patients with arterial thromboembolic diseases within 4 weeks after attack (Th; 41 cases with myocardial infarction and 69 with cerebral infarction), 67 patients with various types of carcinoma(Ca; 31 cases without metastasis and 36 with metastasis)and 50 age-matched healthy individuals(Co). The following results were obtained: 1) Mean plasma levels of TAT, PAP, vWF:Ag, PA and PAI-1 were significantly higher in Th than Co. 2) Mean plasma levels of TAT, PA and PAI-1 were significantly higher in Ca than Co regardless of metastasis but those of PAP and vWF:Ag were significantly higher only in Ca with metastasis than Co. 3) Significant relationship was observed between plasma levels of TAT and PAP both in Th and Ca. 4) Significant relationship was also observed between plasma levels of TAT and vWF:Ag, PA or PAI-1 in Th, but not in Ca. It is suggested from these results that the coagulopathies observed in these patients result from the activation of intravascular blood coagulation and fibrinolysis, and that vascular endothelial cell damage may play an important role in the activation in Th.     

Nonlinear mixed effect modeling of the pharmacodynamics of natriuretic peptides in rats

Natriuretic peptides have not only natriuretic/diuretic but also hypotensive activities, and the decreased renal perfusion caused by the excessive hypotension is known to attenuate the diuretic actions. The present study was designed to examine the relationship between the dosing (intravenous constant infusion) rates and the diuretic actions of -rat atrial natriuretic peptide (-rANP) and rat brain natriuretic peptide (rBNP) in rats, and population (nonlinear mixed effect model) analysis was applied to these complicated diuretic actions. The intrinsic diuretic activities of -rANP and rBNP could be analyzed, and the effects of blood pressure, heart rate, and also inhibition of degradation enzyme on the diuresis of natriuretic peptides were estimated simultaneously. The population analysis was useful for analyzing such pharmacodynamic data for which the individual analysis could not be applied easily.     

Advanced paternal age associated with an elevated risk for schizophrenia in offspring in a Japanese population

OBJECTIVE: Advanced paternal age at birth as a risk for schizophrenia in the adult offspring has been reported in previous studies exclusively conducted in Western countries and Israel. The question has arisen whether this finding could be replicated in countries with socially and culturally different attitudes toward marriage, including factors such as age at marriage. To address this question, we conducted a case-control study of a Japanese population. METHODS: The subjects were representative inpatients with a DSM-IV diagnosis of schizophrenia. Unrelated healthy volunteers were recruited as control subjects. This study was conducted as one of a series of the projects by use of "The Mother and Child Health Handbooks (MCHHs)," from which information on parental characteristics around the time of birth, including parental ages at birth, had been extracted and recorded on computer. RESULTS: Ninety-nine subjects with schizophrenia and 381 healthy control subjects enrolled for the study. Advanced paternal, but not maternal, age was associated with an elevated risk for schizophrenia. Reproducibility of the association across different cultures is suggestive of a causal link.     

Cytoskeleton disruption causes apoptotic degeneration of dentate granule cells in hippocampal slice cultures

Colchicine, a potent microtubule-depolymerizing agent, is well known to selectively kill dentate granule cells in the hippocampal formation in vivo. Using organotypic cultures of rat entorhino-hippocampal slices, we confirmed that in vitro exposure to 1 μM and 10 μM of colchicine reproduced a specific degeneration of the granule cells after 24 h. Similar results were obtained with other types of microtubule-disrupting agents, i.e., nocodazole, vinblastine, and Taxol. Interestingly, the actin-depolymerizing agents cytochalasin D and latrunculin A also elicited selective neurotoxicity in the dentate gyrus without affecting survival of hippocampal pyramidal cells. The selective pattern of degeneration was observable 24 h after a brief treatment with the toxins as short as 5 min, but this delayed neuronal death was unlikely to be a result of excitotoxicity because it was virtually unaffected by glutamate receptor antagonists, tetrodotoxin, or extracellular Ca²⁺-free conditions. The damaged tissues contained a large number of TUNEL-positive neurons and exhibited an increased level in caspase-3-like activity, suggesting that cytoskeleton disruption triggers an apoptosis-like process in dentate granule cells. Thus, this study may provide a basis for understanding the distinctive mechanism that supports granule cell survival.     

Dormant chemotherapy by low-dose FP and low-dose UFT-E in recurrent gastric cancer with long-term survival--a case report

We experienced a case of recurrent gastric cancer with a long-term survival. A 64-year-old man was admitted to the hospital for advanced gastric cancer in the upper stomach. Abdominal CT scan revealed para-aortic lymph nodal metastases. The patient underwent total gastrectomy, distal pancreatectomy, splenectomy, left adrenectomy, and left nephrectomy with D4 lymph node dissection, in what was a curability B resection. Conclusive findings were t2 (ss), n4, H0, P0, M0, and stage IVb. One year after the operation, para-aortic lymph node recurrence was evaluated. The patient was treated with low-dose cisplatin-5-FU therapy, and a partial response was observed and continued for over 2 years with an administration of UFT-E (300 mg/day). He died of repeated aggravation of para-aortic lymph node metastases 6 years and 2 months after the operation. We considered that the long-term survival of this patient was attributable to a 3-year tumor dormancy induced by low-dose cisplatin-5-FU therapy and administration of low-dose UFT.     

Histochemical examinations on cortical bone regeneration induced by thermoplastic bioresorbable plates applied to bone defects of rat calvariae

We aimed to histologically elucidate whether bioresorbable plates (DeltaSystem) can induce cortical bone formation, which is essential for long-lasting bone augmentation. Standardized bone defects in rat calvariae were covered with a convexly-shaped DeltaSystem plate, and then processed for histological observations. At 1 week, alkaline phosphatase-positive osteoblasts were seen in the newly-formed bone extending from the cavity's bottom, indicating accelerated osteogenesis. A thick layer of soft connective tissue positive for periostin, a hallmark of periosteum, covered this new bone. At 2 weeks, a spongy bone had filled the cavity up to half its height. The inner layer of the soft tissue facing the spongy bone revealed abundant periostin and osteopontin, and had many tartrate-resistant acid phosphatase-positive osteoclasts. At 4 weeks, this layer had given rise to thin new bony matrices without relation to the spongy bone arising from the cavity. These bone matrices had been thickened by 8 weeks, and turned into a thick cortical bone outlining the regenerated bone at 12 weeks. Thus, our study has provided histological evidences of cortical osteogenesis when DeltaSystem plates are used for bone augmentation procedures.