Determination of ADAMTS13 and Its Clinical Significance for ADAMTS13 Supplementation Therapy to Improve the Survival of Patients with Decompensated Liver Cirrhosis

The liver plays a central role in hemostasis by synthesizing clotting factors, coagulation inhibitors, and fibrinolytic proteins. Liver cirrhosis (LC), therefore, impacts on both primary and secondary hemostatic mechanisms. ADAMTS13 is a metalloproteinase, produced exclusively in hepatic stellate cells, and specifically cleaves unusually large von Willebrand factor multimers (UL-VWFM). Deficiency of ADAMTS13 results in accumulation of UL-VWFM, which induces platelet clumping or thrombi under high shear stress, followed by sinusoidal microcirculatory disturbances and subsequent progression of liver injuries, eventually leading to multiorgan failure. The marked imbalance between decreased ADAMTS13 activity (ADAMTS13 : AC) and increased production of UL-VWFM indicating a high-risk state of platelet microthrombi formation was closely related to functional liver capacity, hepatic encephalopathy, hepatorenal syndrome, and intractable ascites in advanced LC. Some end-stage LC patients with extremely low ADAMTS13 : AC and its IgG inhibitor may reflect conditions similar to thrombotic thrombocytopenic purpura (TTP) or may reflect “subclinical TTP.” Hence, cirrhotic patients with severe to moderate deficiency of ADAMTS13 : AC may be candidates for FFP infusion as a source of ADAMTS13 or for recombinant ADAMTS13 supplementation. Such treatments may improve the survival of patients with decompensated LC

Perampanel Inhibits α‐Synuclein Transmission in Parkinson's Disease Models

パーキンソン病モデルへのペランパネルの有効性を確認 --パーキンソン病の進行抑制治療への期待--. 京都大学プレスリリース. 2021-04-05.[Background]: The intercellular transmission of pathogenic proteins plays a key role in the clinicopathological progression of neurodegenerative diseases. Previous studies have demonstrated that this uptake and release process is regulated by neuronal activity. [Objective]: The objective of this study was to examine the effect of perampanel, an antiepileptic drug, on α‐synuclein transmission in cultured cells and mouse models of Parkinson's disease.Methods: Mouse primary hippocampal neurons were transduced with α‐synuclein preformed fibrils to examine the effect of perampanel on the development of α‐synuclein pathology and its mechanisms of action. An α‐synuclein preformed fibril‐injected mouse model was used to validate the effect of oral administration of perampanel on the α‐synuclein pathology in vivo. [Results]: Perampanel inhibited the development of α‐synuclein pathology in mouse hippocampal neurons transduced with α‐synuclein preformed fibrils. Interestingly, perampanel blocked the neuronal uptake of α‐synuclein preformed fibrils by inhibiting macropinocytosis in a neuronal activity‐dependent manner. We confirmed that oral administration of perampanel ameliorated the development of α‐synuclein pathology in wild‐type mice inoculated with α‐synuclein preformed fibrils.[Conclusion]: Modulation of neuronal activity could be a promising therapeutic target for Parkinson's disease, and perampanel could be a novel disease‐modifying drug for Parkinson's disease

Impact of Gba2 on neuronopathic Gaucher’s disease and α-synuclein accumulation in medaka (Oryzias latipes)

Homozygous mutations in the lysosomal glucocerebrosidase gene, GBA1, cause Gaucher's disease (GD), while heterozygous mutations in GBA1 are a strong risk factor for Parkinson's disease (PD), whose pathological hallmark is intraneuronal α-synuclein (asyn) aggregates. We previously reported that gba1 knockout (KO) medaka exhibited glucosylceramide accumulation and neuronopathic GD phenotypes, including short lifespan, the dopaminergic and noradrenergic neuronal cell loss, microglial activation, and swimming abnormality, with asyn accumulation in the brains. A recent study reported that deletion of GBA2, non-lysosomal glucocerebrosidase, in a non-neuronopathic GD mouse model rescued its phenotypes. In the present study, we generated gba2 KO medaka and examined the effect of Gba2 deletion on the phenotypes of gba1 KO medaka. The Gba2 deletion in gba1 KO medaka resulted in the exacerbation of glucosylceramide accumulation and no improvement in neuronopathic GD pathological changes, asyn accumulation, or swimming abnormalities. Meanwhile, though gba2 KO medaka did not show any apparent phenotypes, biochemical analysis revealed asyn accumulation in the brains. gba2 KO medaka showed a trend towards an increase in sphingolipids in the brains, which is one of the possible causes of asyn accumulation. In conclusion, this study demonstrated that the deletion of Gba2 does not rescue the pathological changes or behavioral abnormalities of gba1 KO medaka, and GBA2 represents a novel factor affecting asyn accumulation in the brains

血漿ADAMTSは肝硬変患者の予後をChild-PughスコアやMELDスコアと同様に生存率を予測できる可能性がある

Aim:  Decreased plasma ADAMTS13 activity (ADAMTS13:AC) results in accumulation of unusually large von Willebrand factor multimers and platelet thrombi formation. Our aim was to evaluate whether ADAMTS13:AC is a prognostic marker in patients with liver cirrhosis. Methods:  Plasma ADAMTS13:AC and its related parameters were examined in 108 cirrhotic patients. Results:  ADAMTS13:AC decreased as the severity of liver disease increased (means: controls 100%, Child A-cirrhotics 79%, Child B-cirrhotics 63%, and Child C-cirrhotics 31%). ADAMTS13:AC markedly decreased in the cirrhotics with hepatorenal syndrome, refractory ascites and hepatic encephalopathy. The cumulative survival time was the shortest (median: 4.5 months) in the cirrhotics with severe to moderate ADAMTS13:AC deficiency (50%). In contrast, based on the Child-Turcotte-Pugh (CTP) score, Child C-cirrhotics had the worst survival, but the survival probabilities did not differ between Child A and B cirrhotics. Based on the Model for End-Stage Liver Disease (MELD) score, the survival was the worst for the cirrhotics in the fourth quartile, but it was not different among cirrhotics in the first three quartiles. Cox proportional-hazards regression analysis showed that ADAMTS13:AC and serum albumin were independent factors affecting the survival. Conclusions:  ADAMTS13:AC concomitantly decreases as the functional liver capacity decreases. This activity may be a useful prognostic marker that is equal or superior to the CTP score and the MELD score to predict not only the short-term prognosis but also the long-term survival of the cirrhotic patients.博士（医学）・甲613号・平成26年3月17

Transient severe hypotension with once-weekly subcutaneous injection of teriparatide in osteoporotic patient : a case report and insight for the drug interaction between hypotensive agents and teriparatide

Teriparatide, a recombinant form of parathyroid hormone, were well recognized as a useful option for the treatment of the osteoporosis. Although some side effects of teriparatide include headache, nausea, dizziness, and limb pain were reported. Here we present a 80-year-old woman of transient asymptomatic hypotension with once-weekly subcutaneous injection of teriparatide for the treatment of osteoporosis with hypertension disease as acute-phase reactions. Systolic blood pressure decreased in both 30 min and 60 min after injection compared with before injection. Heart rate increased with passage of time. Statistically significant were observed among before, 30min, 60min after injection of teriparatide. Slight nausea was seen as subjective symptoms with the first and second injection after 30 min. This case indicates careful attention, at least 1 hr, was recommended with weekly subcutaneous injections of teriparatide in the treatment for osoteoproteic patient with hypertension decreases. This is a first report, to the best of our knowledge, to demonstrate the transient asymptomatic hypotension after once-weekly injection of teriparatide with hypertension disease. Transient hypotension occurred after injection of teriparatide during the treatment period and was asymptomatic except for the first 2 injections