The effect of truncation on prion-like properties of α-synuclein.

Increasing evidence suggests that α-synuclein (αS) aggregates in brains of individuals with Parkinson's disease and dementia with Lewy bodies can spread in a prion-like manner. Although the initial αS nuclei are pivotal in determining αS fibril polymorphs and resulting phenotypes, it is not clear how the initial fibril seeds are generated. Previous studies have shown that αS truncation might have an important role in αS aggregation. However, little is known about how this truncation influences αS's propagation properties. In the present study, we generated αS fibrils from a series of truncated human αS constructs, characterized their structures and conformational stabilities, and investigated their ability to convert the conformation of full-length αS in vitro, in cultured cells, and in WT mice. We show that both C- and N-terminal truncations of human αS induce fibril polymorphs and exhibit different cross-seeding activities. N-terminally 10- or 30-residue-truncated human αS fibrils induced more abundant αS pathologies than WT fibrils in mice, whereas other truncated fibrils induced less abundant pathologies. Biochemical analyses of these truncated fibrils revealed that N-terminal 10- or 30-residue truncations of human αS change the fibril conformation in a manner that increases their structural compatibility with WT mouse αS fibrils and reduces their stability. C-terminally 20-residue-truncated fibrils displayed enhanced seeding activity in vitro Our findings imply that truncation of αS can influence its prion-like pathogenicity, resulting in phenotypic diversity of α-synucleinopathies.

Cochineal dye-induced immediate allergy: Review of Japanese cases and proposed new diagnostic chart.

BACKGROUND: Cochineal dye is used worldwide as a red coloring in foods, drinks, cosmetics, quasi-drugs, and drugs. The main component of the red color is carminic acid (CA). Carmine is an aluminum- or calcium-chelated product of CA. CA and carmine usually contain contaminating proteins, including a 38-kDa protein thought to be the primary allergen. Severe allergic reactions manifest as anaphylaxis. The aim of this study was to review all Japanese reported cases and propose useful diagnostic chart. METHODS: All reported Japanese cases of cochineal dye-induced immediate allergy were reviewed, and newly registered cases were examined by skin prick test (SPT) with cochineal extract (CE) and measurement of CE and carmine-specific serum IgE test. Two-dimensional (2D) western blotting using patient serum was conducted to identify the antigen. RESULTS: Twenty-two Japanese cases have been reported. SPT and the level of specific IgE test indicated that six cases should be newly registered as cochineal dye allergy. All cases were adult females, and all cases except three involved anaphylaxis; 13 cases involved past history of local symptoms associated with cosmetics use. Japanese strawberry juice and fish-meat sausage, and European processed foods (especially macarons made in France) and drinks were recent major sources of allergen. 2D western blotting showed that patient IgE reacted to the 38-kDa protein and other proteins. Serum from healthy controls also weakly reacted with these proteins. CONCLUSIONS: SPT with CE and determination of the level of CE and carmine-specific IgE test are useful methods for the diagnosis of cochineal dye allergy.

α-Synuclein Fibrils Exhibit Gain of Toxic Function, Promoting Tau Aggregation and Inhibiting Microtubule Assembly.

α-Synuclein is the major component of Lewy bodies and Lewy neurites in Parkinson disease and dementia with Lewy bodies and of glial cytoplasmic inclusions in multiple system atrophy. It has been suggested that α-synuclein fibrils or intermediate protofibrils in the process of fibril formation may have a toxic effect on neuronal cells. In this study, we investigated the ability of soluble monomeric α-synuclein to promote microtubule assembly and the effects of conformational changes of α-synuclein on Tau-promoted microtubule assembly. In marked contrast to previous findings, monomeric α-synuclein had no effect on microtubule polymerization. However, both α-synuclein fibrils and protofibrils inhibited Tau-promoted microtubule assembly. The inhibitory effect of α-synuclein fibrils was greater than that of the protofibrils. Dot blot overlay assay and spin-down techniques revealed that α-synuclein fibrils bind to Tau and inhibit microtubule assembly by depleting the Tau available for microtubule polymerization. Using various deletion mutants of α-synuclein and Tau, the acidic C-terminal region of α-synuclein and the basic central region of Tau were identified as regions involved in the binding. Furthermore, introduction of α-synuclein fibrils into cultured cells overexpressing Tau protein induced Tau aggregation. These results raise the possibility that α-synuclein fibrils interact with Tau, inhibit its function to stabilize microtubules, and also promote Tau aggregation, leading to dysfunction of neuronal cells.

A Case of Bilateral Retinal Vasculitis in Atypical Cogan Syndrome.

Cogan syndrome (CS) is a rare chronic inflammatory disease characterized by ocular and inner ear inflammation. Well-known ocular manifestations include non-syphilitic interstitial keratitis (IK); however, some cases are not associated with IK. Inner ear symptoms include sensorineural hearing loss, rotatory vertigo, and tinnitus, which can become irreversible without timely treatment. Therefore, early and appropriate diagnosis and therapeutic intervention are important. However, due to its rarity, few physicians have encountered CS and early diagnosis is difficult. In this report, we present the details of the diagnosis and treatment of an atypical CS. The patient was a 44-year-old Japanese woman who was admitted to the Department of Immunology and Allergy at Itami City Hospital (Itami City, Hyogo, Japan) due to a persistent fever of approximately 40°C for nine days. Multiple erythematous lesions appeared on both lower legs, and she experienced decreased vision in her left eye. Uveitis with retinal vasculitis was observed in both eyes and the optic nerve head showed remarkable swelling in the left eye. Hearing tests revealed impaired hearing in both ears. Based on these findings, we diagnosed atypical CS and initiated systemic and topical steroid therapy. Approximately two weeks later, visual acuity and hearing levels improved. Fluorescein angiography (FA) revealed a non-perfusion area in both eyes, and retinal photocoagulation was performed using a pattern-scanning laser. Eighteen months after the laser irradiation, retinal neovascularization (RNV) was observed in the area where the laser was applied to the left eye; therefore, an additional laser was applied. Combination therapy with steroids and immunosuppressive drugs was continued until the patient's last visit three years later and she did not experience any recurrence of uveitis or hearing loss. In this case, a pattern-scanning laser was used for retinal photocoagulation to prevent RNV; however, RNV occurred within the area of the laser spots. In such cases of retinal capillary occlusion due to vasculitis, it may be better to close the spacing or use a conventional laser system. In the presence of retinal vasculitis with systemic inflammation, CS should be suspected, and a hearing test should be performed, even in the absence of subjective symptoms. Early treatment and prevention of irreversible hearing loss should be necessary. Careful follow-up in collaboration with other departments is important for CS cases.

Tracheoarterial fistula in a patient with amyotrophic lateral sclerosis successfully managed by overinflation of the tracheostomy tube cuff alone: a case report.

BACKGROUND: Tracheoarterial fistula is the most devastating complication after tracheostomy, and its mortality, without definitive treatment, approaches 100%. In general, the combination of bedside emergency management, that is, overinflation of the tracheostomy tube cuff, and definitive treatment such as surgical or endovascular intervention is necessary to prevent the poor outcome. Patients with neuromuscular diseases such as amyotrophic lateral sclerosis are susceptible to tracheoarterial fistula because of long-term mechanical ventilation and muscle weakness. CASE PRESENTATION: We describe a case of tracheoarterial fistula in a Japanese 39-year-old patient with amyotrophic lateral sclerosis with long-term ventilator management. The patient was clinically diagnosed with a tracheoarterial fistula because of massive bleeding following sentinel hemorrhage. The massive hemorrhage was controlled by overinflation of the tracheostomy tube cuff alone, without definitive treatment. CONCLUSIONS: This case suggests overinflation of the tracheostomy tube cuff alone plays an important role, semi-permanently, in the management of tracheoarterial fistula, especially in cases where surgical or endovascular intervention is not indicated. Clinicians taking care of patients with tracheostomy undergoing long-term mechanical ventilation should be aware that tracheoarterial fistula might occur following tracheostomy.

Autoimmune pancreatitis associated with myelodysplastic syndrome.

A 65-year-old man with myelodysplastic syndrome (MDS) was admitted for progressive jaundice. Diffuse pancreatic swelling and stricture of the main pancreatic duct were observed with elevated serum levels of direct bilirubin, aspartate transaminase, alanine transaminase, alkaline phosphatase, gammaGTP and amylase, and impaired glucose tolerance. Serum IgG and IgG4 levels were highly elevated, and both the direct antiglobulin test and platelet-associated IgG were positive. He was diagnosed with autoimmune pancreatitis associated with MDS, and biliary drainage followed by immunosuppressive therapy ameliorated the jaundice and laboratory findings. In addition to diffuse pancreatic FDG accumulation, fine incorporations of FDG to the lachrymal and submandibular glands were demonstrated, suggesting the recently proposed IgG4+ multiorgan lymphoproliferative syndrome (MOLPS). The etiology of IgG4+ MOLPS is still unknown; however, autoantibodies to blood cells in this case suggested that the autoimmune mechanism, which is caused by abnormal immune functions in MDS patients, might be involved in the pathogenesis of IgG4+ MOLPS.

Mizoribine protects against bleomycin-induced lung injury.

Bleomycin (BLM)-induced lung injury has become a model for studies of interstitial pneumonitis and pulmonary fibrosis. BLM induces lung injury in two phases: early inflammation characterized by infiltration of inflammatory cells into the lungs, followed by a late phase of fibrosis characterized by deposition of collagen. In this study, we examined the role of mizoribine (MZB) in the regulation of inflammatory tissue injury caused by BLM. We examined the role of MZB using a mouse model of BLM-induced lung injury. We demonstrated that mice subjected to instillation of BLM into the lungs had a significantly increased number of macrophages and lymphocytes in bronchoalveolar lavage fluid (BALF), but that those treated with MZB in the early phase showed a significant reduction in the total number of BALF macrophages and lymphocytes. However, MZB was unable to inhibit fibrosis in the late phase of BLM injury. Our findings suggest that MZB inhibits the proliferation of both lymphocytes and macrophages in the early phase of the BLM-induced acute inflammatory response, as well as its development and amplification, but does not inhibit fibrotic change in the late phase.