Characteristics and trends of medical malpractice claims in Japan between 2006 and 2021.

Classification and analysis of existing data on medical malpractice lawsuits are useful in identifying the root causes of medical errors and considering measures to prevent recurrence. No study has shown the actual prevalence of all closed malpractice claims in Japan, including the number of cases and their trial results. In this study, we illustrated the recent trends of closed malpractice claims by medical specialty, the effects of the acceptance rates and the settlements and clarified the trends and characteristics. This was a descriptive study of all closed malpractice claims data from the Supreme Court in Japan from 2006-2021. Trends and the characteristics in closed malpractice claims by medical specialty and the outcomes of the claims, including settlements and judgments, were extracted. The total number of closed medical malpractice claims was 13,340 in 16 years, with a high percentage ending in settlement (7,062, 52.9%), and when concluding in judgment (4,734, 35.3%), the medical profession (3,589, 75.8%) was favored. When compared by medical specialty, plastic surgery and obstetrics/gynecology were more likely resolved by settlement. By contrast, psychiatry cases exhibited a lower likelihood of settlement, and the percentage of cases resulting in unfavorable outcomes for patients was notably high. Furthermore, there has been a decline in the number of closed medical malpractice claims in Japan in recent years compared to the figures observed in 2006. In particular, the number of closed medical malpractice claims in obstetrics/gynecology and the number of closed medical malpractice claims per 1,000 physicians decreased significantly compared to other specialties. In conclusion, half of the closed malpractice claims were settled, and a low percentage of patients won their cases. Closed medical malpractice claims in Japan have declined in most medical specialties since 2006. Additionally, obstetrics/gynecology revealed a significant decrease since introducing the Obstetrics/Gynecology Medical Compensation System in 2009.

AIM/CD5L attenuates DAMPs in the injured brain and thereby ameliorates ischemic stroke.

The sterile inflammation caused by damage-associated molecular patterns (DAMPs) worsens the prognosis following primary injury such as ischemic stroke. However, there are no effective treatments to regulate DAMPs. Here, we report that AIM (or CD5L) protein reduces sterile inflammation by attenuating DAMPs and that AIM administration ameliorates the deleterious effects of ischemic stroke. AIM binds to DAMPs via charge-based interactions and disulfide bond formation. This AIM association promotes the phagocytic removal of DAMPs and neutralizes DAMPs by impeding their binding to inflammatory receptors. In experimental stroke, AIM-deficient mice exhibit severe neurological damage and higher mortality with greater levels of DAMPs and associated inflammation in the brain than wild-type mice, in which brain AIM levels increase following stroke onset. Recombinant AIM administration reduces sterile inflammation in the infarcted region, leading to a profound reduction of animal mortality. Our findings provide a basis for the therapies targeting DAMPs to improve ischemic stroke.

TFEB-mediated Enhancement of the Autophagy-lysosomal Pathway Dually Modulates the Process of Amyloid ß-Protein Generation in Neurons.

Abnormalities of the autophagy-lysosomal pathway (ALP) have been implicated in the pathology of Alzheimer's disease (AD). Activation of TFEB (transcription factor EB), a master regulator of the ALP, leads to ALP facilitation. The present study sought to clarify whether TFEB-mediated ALP facilitation influences the process of amyloid ß-protein (Aß) generation in neurons. TFEB was overexpressed in mature rat primary cortical neurons via recombinant adenoviruses, without (basal conditions) or with co-overexpression of wild-type amyloid precursor protein (APP) or its ß-C-terminal fragment (ß-CTF). We confirmed that TFEB overexpression upregulated the lysosomal proteins, cathepsin D and LAMP-1. In TFEB-expressing neurons, protein levels of ADAM10 were profoundly increased, whereas those of APP, BACE1, or γ-secretase complex proteins were unaffected. However, TFEB did not affect ADAM10 mRNA levels. TFEB overexpression had different effects on Aß production depending on the expression level of APP or ß-CTF: TFEB slightly decreased Aß secretion under basal conditions; clearly increased α-CTF levels and marginally increased ß-CTF levels with modest increases in secreted Aß in APP-expressing neurons; and caused a remarkable increase in ß-CTF levels with a significant increase in secreted Aß in ß-CTF-expressing neurons. Inhibition of proteasomes, but not lysosomes, markedly increased ß-CTF levels in ß-CTF-expressing neurons. These results collectively indicate that TFEB modulates Aß production not only by increasing α-secretase processing of APP through ADAM10 upregulation but also by augmenting ß-CTF levels possibly via altered proteasome-mediated catabolism. Thus, TFEB-mediated ALP enhancement appears to have dual, but opposite, effects on Aß production in neurons.

Two new coumarins and a new xanthone from the leaves of Rhizophora mucronata.

Two new coumarins (1, 2) and a new xanthone (3), together with 14 known compounds-eight coumarins (4, 5, 9, 10, 12-15), three xanthones (11, 16, 17), a benzoic acid (6) and two flavonones (7, 8)-were isolated from the leaves of Rhizophora mucronata. The structures of the compounds were elucidated by spectroscopic (IR, MS, and NMR) analyses. The isolated compounds were tested for cytotoxicity against human cancer cell lines HL-60 and HeLa. Among these compounds, only compound 16 inhibited the growth of both HeLa (IC50 = 4.8 µM) and HL-60 (IC50 = 1.0 µM) cells. Compounds 4, 7, 10, and 12 exhibited moderate activity against HeLa cells (IC50 = 3.8-8.3 µM). Compounds 5, 9, 11, and 17 showed moderate activity against HL-60 cells (IC50 = 2.2-6.3 µM). Higher selectivity against HL-60 cell lines was observed for compounds 5, 9, 11, and 16 with SI values (NIH 3T3/HL-60) of 8.6, 19.2, 9.4, and 10.2, respectively.

Inflammatory and anti-inflammatory states of adipose tissue in transgenic mice bearing a single TCR.

Obesity is accompanied by chronic, low-grade inflammation in adipose tissue, which is associated with insulin resistance and consequent multiple metabolic diseases. In addition to M1 macrophage infiltration, multiple involvements of adipose tissue T lymphocytes in the progression of inflammation have been highlighted recently. Here, we isolated a specific Vα5/Vß8.2 TCR-bearing T cell that accumulated in obese adipose tissue of mice, and generated transgenic mice expressing this TCR. Under lean conditions with a normal chow diet, CD4+FoxP3+ Treg cells and M2 macrophages increased in adipose tissue with ageing in wild-type mice, but not in transgenic mice. However, both mice exhibited no obvious adipose tissue inflammation such as the formation of crown-like structures (CLSs) of infiltrating macrophages. When fed a high-fat diet, the proportion of adipose tissue Treg cells was markedly small at a similar level in transgenic and wild-type mice. Both types of mice exhibited comparable inflammatory states in adipose tissue, including vast formation of macrophage CLSs, accompanied by insulin resistance. Together, our findings suggest that the absence of an increase in Treg cells and M2 macrophages is not sufficient to initiate inflammatory macrophage infiltration in lean adipose tissue and also provide a new view about the involvement of T cells in promoting obesity-associated inflammation.

Circulating AIM prevents hepatocellular carcinoma through complement activation.

Hepatocellular carcinoma (HCC) is a widespread fatal disease and the third most common cause of cancer deaths. Here, we show the potent anti-HCC effect of the circulating protein AIM. As in adipocytes, AIM is incorporated into normal hepatocytes, where it interferes with lipid storage. In contrast, AIM accumulates on the HCC cell surface and activates the complement cascade via inactivating multiple regulators of complement activation. This response provokes necrotic cell death specifically in AIM-bound HCC cells. Accordingly, AIM(-/-) mice were highly susceptible to steatosis-associated HCC development, whereas no AIM(+/+) mouse developed the disease despite comparable liver inflammation and fibrosis in response to a long-term high-fat diet. Administration of AIM prevented tumor development in AIM(-/-) mice, and HCC induction by diethylnitrosamine was more prominent in AIM(-/-) than wild-type mice. These findings could be the basis for novel AIM-based therapeutic strategies for HCC.

Aldose reductase inhibitor fidarestat attenuates leukocyte-endothelial interactions in experimental diabetic rat retina in vivo.

PURPOSE: Dysregulation of the polyol pathway has been implicated as a major cause of diabetic retinopathy. The aldose reductase inhibitor fidarestat was recently reported to prevent retinal oxidative stress and overexpression of vascular endothelial growth factor (VEGF) protein in diabetic rats. In this study, we investigated the effect of fidarestat on leukocyte-endothelial cell interactions in an in vivo experimental model for diabetic retina. MATERIALS AND METHODS: Diabetes was induced in six-week-old male Long-Evans rats by intraperitoneal injection of streptozotocin (STZ) (75 mg/kg). The rats were divided into four experimental groups: non-diabetic control rats, untreated diabetic rats, and diabetic rats treated with a low (4 mg/kg/day) or high (16 mg/kg/day) oral dose of fidarestat. After four weeks of treatment, accumulated leukocytes in the retina were counted in vivo by acridine orange digital fluorography. Intercellular adhesion molecule-1 (ICAM-1) and VEGF-164 mRNA levels in the retina were analyzed using the quantitative reverse transcription-polymerase chain reaction. ICAM-1 protein expression in the retina was investigated by immunohistochemistry. RESULTS: Fidarestat treatment significantly decreased concentrations of sorbitol and fructose in the retinas of STZ-induced diabetic rats. Leukocyte accumulation in the retinas of fidarestat-treated rats was significantly less than in the untreated diabetic group (P < 0.01). Fidarestat treatment significantly reduced the expression ICAM-1 mRNA, but not VEGF-164 mRNA, in the retina of diabetic rats. Immunohistochemical study also revealed the suppressive effect of fidarestat on expression of ICAM-1. CONCLUSIONS: Oral administration of fidarestat attenuated leukocyte accumulation in the retina of STZ induced-diabetic rats, suggesting that fidarestat may have a therapeutic role in preventing the progression of diabetic retinopathy.

The death effector domain-containing DEDD forms a complex with Akt and Hsp90, and supports their stability.

Insulin secretion and glucose transport are the major mechanisms to balance glucose homeostasis. Recently, we found that the death effector domain-containing DEDD inhibits cyclin-dependent kinase-1 (Cdk1) function, thereby preventing Cdk1-dependent inhibitory phosphorylation of S6 kinase-1 (S6K1), downstream of phosphatidylinositol 3-kinase (PI3K), which overall results in maintenance of S6K1 activity. Here we newly show that DEDD forms a complex with Akt and heat-shock protein 90 (Hsp90), and supports the stability of both proteins. Hence, in DEDD(-/-) mice, Akt protein levels are diminished in skeletal muscles and adipose tissues, which interferes with the translocation of glucose-transporter 4 (GLUT4) upon insulin stimulation, leading to inefficient incorporation of glucose in these organs. Interestingly, as for the activation of S6K1, suppression of Cdk1 is involved in the stabilization of Akt protein by DEDD, since diminishment of Cdk1 in DEDD(-/-) cells via siRNA expression or treatment with a Cdk1-inhibitor, increases both Akt and Hsp90 protein levels. Such multifaceted involvement of DEDD in glucose homeostasis by supporting both insulin secretion (via maintenance of S6K1 activity) and glucose uptake (via stabilizing Akt protein), may suggest an association of DEDD-deficiency with the pathogenesis of type 2 diabetes mellitus.