Nerve pathology of microangiopathy and thromboinflammation in hereditary transthyretin amyloidosis.

OBJECTIVE: Despite amyloid deposition as a hallmark of hereditary transthyretin amyloidosis (ATTRv) with polyneuropathy, this pathology could not completely account for nerve degeneration. ATTRv patients frequently have vasomotor symptoms, but microangiopathy hypothesis in ATTRv was not systemically clarified. METHODS: This study examined the vascular pathology of sural nerves in ATTRv patients with transthyretin (TTR) mutation of p.Ala117Ser (TTR-A97S), focusing on morphometry and patterns of molecular expression in relation to nerve degeneration. We further applied human microvascular endothelial cell (HMEC-1) culture to examine the direct effect of TTR-A97S protein on endothelial cells. RESULTS: In ATTRv nerves, there was characteristic microangiopathy compared to controls: increased vessel wall thickness and decreased luminal area; both were correlated with the reduction of myelinated fiber density. Among the components of vascular wall, the area of collagen IV in ATTRv nerves was larger than that of controls. This finding was validated in a cell model of HMEC-1 culture in which the expression of collagen IV was upregulated after exposure to TTR-A97S. Apoptosis contributed to the endothelial cell degeneration of microvasculatures in ATTRv endoneurium. ATTRv showed prothrombotic status with intravascular fibrin deposition, which was correlated with (1) increased tissue factor and coagulation factor XIIIA and (2) reduced tissue plasminogen activator. This cascade led to intravascular thrombin deposition, which was colocalized with upregulated p-selectin and thrombomodulin, accompanied by complement deposition and macrophages infiltration, indicating thromboinflammation in ATTRv. INTERPRETATION: Microangiopathy with thromboinflammation is characteristic of advanced-stage ATTRv nerves, which provides an add-on mechanism and therapeutic target for nerve degeneration.

The association between menopause, postmenopausal hormone therapy, and kidney stone disease in Taiwanese women.

PURPOSE: The association between menopause, postmenopausal hormone therapy, and kidney stone disease has long been a topic of discussion and is still unclear. Moreover, most previous research has focused on Caucasians. Therefore, we aimed to explore this issue in an Asian population. METHODS: In this cross-sectional study, we enrolled female participants aged between 30 and 70 years from the Taiwan Biobank. The presence of kidney stone disease (KSD) was defined through a self-reported questionnaire. The participants were divided into two groups according to the presence of menopause; premenopausal and postmenopausal groups. The associations among menopause, postmenopausal hormone therapy, and KSD were examined using binary logistic regression models. RESULTS: A total of 17,460 women with available information were recruited, including 5976 in the premenopausal group and 11,484 in the postmenopausal group. Compared to the premenopausal group, the postmenopausal group had a significantly higher prevalence of KSD (3% vs. 6%). The odds ratio for KSD was higher in the postmenopausal group than in the premenopausal group (odds ratio = 1.50; 95% confidence interval = 1.17-1.92) after adjusting for confounders. We also examined associations between the type of menopause (natural and surgical) and KSD, and found that both types of menopause were associated with KSD in age-adjusted and multivariable models. Compared with those who had never received postmenopausal hormone therapy, those who had received postmenopausal hormone therapy were not associated with a higher risk of KSD. CONCLUSIONS: Our study suggests that natural and surgical menopause were associated with KSD. However, we found no association between the postmenopausal hormone therapy and KSD in the postmenopausal women.

The Safety and Efficacy of Vela Laser En-Bloc Endoscopic Resection versus Conventional Transurethral Resection of Bladder Tumor-A Single Center Experience.

(1) Background: The current gold standard treatment of bladder cancer is conventional transurethral resection of the bladder tumor (CTURBT) using monopolar or bipolar resectoscopes. Laser en-bloc resection of the bladder tumor (LERBT) could achieve a higher quality of the specimen, reduce perioperative complications, and decrease the recurrence rate. Here, we compare the efficacy and safety of en-bloc Vela laser resection versus the conventional monopolar/bipolar resection; (2) Methods: A total of 100 clinically cT1-2 patients with bladder cancer were retrospectively reviewed in this study. Among these patients, 50 patients received LERBT, and 50 patients received CTURBT. The baseline characteristics, operation variables, and clinical outcomes were collected. The primary performance was the presence of muscle layer in the specimen. Perioperative complications and recurrence-free survival (RFS) were also compared. Independent t-test, Chi-square test, Kaplan-Meier curves, and the Cox-regression model were used in the analysis; (3) Results: The median age of the patients in the laser and resectoscope groups was 69.2 and 68.0 years old, respectively. The statistical difference in the presence of the detrusor muscle was 92.0% in the laser group and 70.0% in the CTURBT group (p = 0.005). A lower incidence of bladder perforation (p = 0.041) and major surgical complications (p = 0.046) in the LEBRT group was observed. We found no differences in operation duration, catheterization time, and hospitalization time after adjustment. Additionally, there was no statistical difference in RFS after a median follow-up time of 25 months; (4) Conclusions: Endoscopic laser en-bloc resection of bladder tumor with Vela laser is an effective method with higher muscle inclusion rate and fewer complications.

Electronic brachytherapy for non-melanoma skin cancer in Asians: Experience from a Taiwan medical center.

BACKGROUND/PURPOSE: High-dose-rate (HDR) electronic brachytherapy (EBT) has been shown to be effective for non-melanoma skin cancer (NMSC) in Caucasian patients. However, its efficacy remains unknown in Asian patients. To analyze the clinical outcome of HDR EBT for NMSC in a Taiwanese medical center. METHODS: Medical records over a 5-year period between January 2015 to December 2019 were retrospectively analyzed. RESULTS: Forty-seven patients with 54 NMSC including 42 basal cell carcinomas (BCCs) and 12 squamous cell carcinomas (SCCs) were treated with HDR EBT. The average age was 73.8 years. The mean radiation dose was 45.3 Gy (40-80 Gy). Mean follow-up duration was 33.1 months. Adequate local control was achieved in 50 lesions (92.6%). Grade 1 acute skin toxicity was noted in 63.0% of lesions, while no tumors had Grade 4 acute toxicity. No ulceration was observed six months after completion of treatment. At the last follow-up visit, all lesions were rated to have "fair" to "excellent" cosmetic outcomes. CONCLUSION: HDR EBT provides adequate clinical outcomes and cosmetic results for NMSC in Asian patients. Further investigation of the dosage guidelines is needed for Asian patients with NMSC.

Nonpermissive Skin Environment Impairs Nerve Regeneration in Diabetes via Sec31a.

OBJECTIVE: Although the microenvironment for peripheral nerve regeneration is permissive, such a mechanism is defective in diabetes, and the molecular mediators remain elusive. [Correction added on May 11, 2022, after first online publication: In the preceding sentence, "is ok" was changed to "is defective".] This study aimed to (1) investigate the relationship between skin innervation and collagen pathology in diabetic neuropathy and to (2) clarify the molecular alterations that occur in response to hyperglycemia and their effects on axon regeneration. METHODS: We addressed this issue using two complementary systems: (1) human skin from patients with diabetic neuropathy and to (2) a coculture model of human dermal fibroblasts (HDFs) with rat dorsal root ganglia neurons in the context of intrinsic neuronal factor and extrinsic microenvironmental collagen and its biosynthetic pathways. RESULTS: In diabetic neuropathy, the skin innervation of intraepidermal nerve fiber density (IENFd), a measure of sensory nerve degeneration, was reduced with similar expression of a growth associated protein 43, a marker of nerve regeneration. In contrast, the content and packing of collagen in the diabetic skin became more rigid than the control skin. Sec31a, a protein that regulates the collagen biosynthetic pathway, was upregulated and inversely correlated with IENFd. In the cell model, activated HDFs exposed to high-glucose medium enhanced the expression of Sec31a and collagen I through the activation of transforming growth factor ß, a profibrotic molecule. Sec31a upregulation impaired neurite outgrowth. This effect was reversed by silencing Sec31a expression and neurite outgrowth was resumed. INTERPRETATION: The current study provides evidence that Sec31a plays a key role in inhibiting nerve regeneration in diabetic neuropathy. ANN NEUROL 2022;91:821-833.