A novel age-related venous amyloidosis derived from EGF-containing fibulin-like extracellular matrix protein 1

Most intractable tissue-degenerative disorders share a common pathogenic condition, so-called proteinopathy. Amyloid-related disorders are the most common proteinopathies and are characterized by amyloid fibril deposits in the brain or other organs. Aging is generally associated with the development of these amyloid-related disorders, but we still do not fully understand how functional proteins become pathogenic amyloid deposits during the human aging process. We identified a novel amyloidogenic protein, named epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1), in massive venous amyloid deposits in specimens that we obtained from an autopsied patient who died of gastrointestinal bleeding. Our postmortem analyses of additional patients indicate that EFEMP1 amyloid deposits frequently developed in systemic venous walls of elderly people. EFEMP1 was highly expressed in veins, and aging enhanced venous EFEMP1 expression. In addition, biochemical analyses indicated that these venous amyloid deposits consisted of C-terminal regions of EFEMP1. In vitro studies showed that C-terminal regions formed amyloid fibrils, which inhibited venous tube formation and cell viability. EFEMP1 thus caused a novel age-related venous amyloid-related disorder frequently found in the elderly population. Understanding EFEMP1 amyloid formation provides new insights into amyloid-related disorders occurring during the aging process. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Intratumoral ethanol injection for malignant tracheobronchial lesions: a new bronchofiberscopic procedure

We performed intratumoral ethanol injection via a flexible bronchofiberscope in 13 patients with malignant tracheobronchial lesions in order to evaluate its effects on airway dilatation and hemostasis. The results obtained are described below. Immediately after intratumoral injection of ethanol, bronchofiberscopic findings revealed that the tumor turned faintly white, there was a little regression of tumor, and a promising effect was demonstrated on patients with bleeding from tumors. The injected tumor turned necrotic within several days, and histological examination revealed no viable tumor cells in necrotic tissues. The histological anti-tumor effect of ethanol was also demonstrated in experiments with nude mice. This endoscopic treatment was very effective in polypoid tumor protruding into the tracheobronchial lumen, but ineffective in the case of compressed stenosis or obstruction. In conclusion, intratumoral injection of ethanol is considered to be a promising endoscopic treatment for malignant tracheobronchial lesions.     

Clinical and arthroscopic findings of acute anterior cruciate ligament tears of the knee

Clinical, arthrographic, and arthroscopic findings in 53 patients with acutely torn anterior cruciate ligaments (ACLs) were documented. Arthroscopy and instability tests under anesthesia were performed on all patients within 2 weeks after the initial injury. Twenty-three patients complained of extension blocks, and localized tenderness on the medial side was revealed in 26 patients at the initial examination. Aspiration from joints exhibited hemarthrosis in 52 patients. Arthroscopy revealed ACL ruptures in all patients. Four Segond's fractures, 26 meniscus tears (8 medial and 18 lateral), 1 osteochondral fracture, and 19 medial collateral ligament ruptures were revealed. Arthroscopy detected only 1 of the 5 ruptures of the posteromedial corner of the medial meniscus, which were noted on arthrography. Three ACL stumps were protruding among the femorotibial joint, which seemed to be restricting full extension. Statistical analysis showed that tenderness on the medial side was not revealed more frequently in knees with medial collateral ligament injuries than in the others. The volume of aspirated fluids in knees with no leakage in arthrography significantly increased over those with leakages (p < 0.05). Diagnosis of ACL injuries should be completed by clinical, arthrographic, and arthroscopic examinations.     

Thrombin-antithrombin complex and alpha-plasmin inhibitor-plasmin complex levels in singleton and twin pregnancies

Thrombin-antithrombin complex (TAT) is a sensitive marker for thrombin formation, and alpha2-plasmin inhibitor-plasmin complex (PIC) is a marker for fibrinolysis. Previous studies have shown that blood coagulation and fibrinolysis are activated in normal pregnancies. Thus, the present study examined changes in TAT and PIC levels during the course of singleton and twin pregnancies and compared these markers between the two pregnant groups. The subjects were 148 pregnant women, of whom 84 were women carrying single fetuses and 64 were women with twin fetuses. Their average gestational age at entry was 10, 20, 30 and 38 weeks of gestation in singleton pregnancies and 10, 20, 30 and 35 weeks in twin pregnancies. Peripheral blood was collected, and plasma was separated after centrifugation and then stored at -20 degrees C. The TAT levels increased significantly with the progression of pregnancy in both pregnant groups, whereas the PIC levels increased significantly only in singleton pregnancies between 30 and 38 weeks of gestation. The TAT levels were significantly higher in twin pregnancies than in singleton pregnancies. The PIC levels were significantly lower in twin pregnancies than in singleton pregnancies at 35-38 weeks. Thrombin formation might be enhanced with the progression of pregnancy in both pregnant groups. This enhancement might be more intensified in twin pregnancies. Fibrinolysis might increase only in singleton pregnancies from 30 to 38 weeks of gestation. Fibrinolysis might be less intensified in twin pregnancies than in singleton pregnancies only at 35-38 weeks.     

Analysis of autonomic outcomes in APOLLO,a phase III trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosis

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, debilitating disease often resulting in early-onset, life-impacting autonomic dysfunction. The effect of the RNAi therapeutic, patisiran, on autonomic neuropathy manifestations in patients with hATTR amyloidosis with polyneuropathy in the phase III APOLLO study is reported. Patients received patisiran 0.3 mg/kg intravenously (n = 148) or placebo (n = 77) once every 3 weeks for 18 months. Patisiran halted or reversed polyneuropathy and improved quality of life from baseline in the majority of patients. At baseline, patients in APOLLO had notable autonomic impairment, as demonstrated by the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire autonomic neuropathy domain. At 18 months, patisiran improved autonomic neuropathy symptoms compared with placebo [COMPASS-31, least squares (LS) mean difference, − 7.5; 95% CI: − 11.9, − 3.2; Norfolk QOL-DN autonomic neuropathy domain, LS mean difference, − 1.1; − 1.8, − 0.5], nutritional status (modified body mass index, LS mean difference, 115.7; − 82.4, 149.0), and vasomotor function (postural blood pressure, LS mean difference, − 0.3; − 0.5, − 0.1). Patisiran treatment also led to improvement from baseline at 18 months for COMPASS-31 (LS mean change from baseline, − 5.3; 95% CI: − 7.9, − 2.7) and individual domains, orthostatic intolerance (− 4.6; − 6.3, − 2.9) and gastrointestinal symptoms (− 0.8; − 1.5, − 0.2). Rapid worsening of all study measures was observed with placebo, while patisiran treatment resulted in stable or improved scores compared with baseline. Patisiran demonstrates benefit across a range of burdensome autonomic neuropathy manifestations that deteriorate rapidly without early and continued treatment.

     

Urinary Transthyretin as a Biomarker in ATTRv Val50Met Amyloidosis

Transthyretin (TTR), the precursor protein for amyloidogenic TTR (ATTR) amyloidosis, forms tetramers and escapes glomerular filtration by binding with thyroxine and retinol-binding protein. However, variant TTRs are unstable as tetramers, so monomeric TTR has become the precursor protein of amyloid deposits, via protein misfolding. The aim of the study was to evaluate the utility of urinary TTR in the diagnosis of ATTRv amyloidosis. Urinary samples from healthy volunteers, ATTRv V50M amyloidosis patients, and asymptomatic carriers of the ATTRv V50M gene were analysed using ELISA. To analyse the different forms of TTR secreted to the urine, we performed Western blotting and mass spectrometry. Urinary TTR concentrations were significantly higher in the ATTRv V50M amyloidosis patients than they were in the healthy volunteers and asymptomatic carriers of the gene. Although the TTR concentrations were negligible in the healthy volunteers, they were correlated with disease progression and urinary albumin concentrations in the ATTRv V50M amyloidosis patients. The Western blotting and mass spectrometry revealed the presence of monomeric wild-type and variant TTRs in the urine. Urinary TTR concentrations may become a more sensitive biomarker of ATTRv progression than albumin.     

Miller Fisher Syndrome Following Vaccination against SARS-CoV-2

After BNT162b2 messenger ribonucleic acid (mRNA) coronavirus disease 2019 (COVID-19) vaccination, a 30-year-old man developed bilateral lateral gaze palsy, diplopia, absent tendon reflexes, and ataxic gait. Serum anti-GQ1b and anti-GT1a immunoglobulin G (IgG) antibodies were strongly positive. Based on those findings, he was diagnosed with Miller Fisher syndrome (MFS). Intravenous immunoglobulin therapy was administered, and his symptoms fully recovered within approximately 3 months. To the best of our knowledge, this is the first report to describe the development of MFS after COVID-19 mRNA vaccination.