Tumor Necrosis Factor Alpha-Induced Recruitment of Inflammatory Mononuclear Cells Leads to Inflammation and Altered Brain Development in Murine Cytomegalovirus-Infected Newborn Mice

Congenital human cytomegalovirus (HCMV) infection is a significant cause of abnormal neurodevelopment and long-term neurological sequelae in infants and children. Resident cell populations of the developing brain have been suggested to be more susceptible to virus-induced cytopathology, a pathway thought to contribute to the clinical outcomes following intrauterine HCMV infection. However, recent findings in a newborn mouse model of the infection in the developing brain have indicated that elevated levels of proinflammatory mediators leading to mononuclear cell activation and recruitment could underlie the abnormal neurodevelopment. In this study, we demonstrate that treatment with tumor necrosis factor alpha (TNF-α)-neutralizing antibodies decreased the frequency of CD45+ Ly6Chi CD11b+ CCR2+ activated myeloid mononuclear cells (MMCs) and the levels of proinflammatory cytokines in the blood and the brains of murine CMV-infected mice. This treatment also normalized neurodevelopment in infected mice without significantly impacting the level of virus replication. These results indicate that TNF-α is a major component of the inflammatory response associated with altered neurodevelopment that follows murine CMV infection of the developing brain and that a subset of peripheral blood myeloid mononuclear cells represent a key effector cell population in this model of virus-induced inflammatory disease of the developing brain

Molecular changes in the heart of a severe case of arrhythmogenic right ventricular cardiomyopathy caused by a desmoglein-2 null allele.

INTRODUCTION: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder caused by mutations in desmosomal genes. It is often associated with life-threatening arrhythmias. Some affected individuals develop progressive heart failure and may require cardiac transplantation. METHODS: The explanted heart of a young adult with end-stage heart failure due to a null allele in desmoglein-2 was studied at macroscopic, microscopic, and molecular level. Myocardial samples were probed for junctional localization of desmosomal components and the gap junction protein connexin43 by immunohistochemical staining. In addition, the protein content of desmosomal and adherens junction markers as well as connexin43 was assessed by Western blotting. RESULTS: Histological analysis confirmed ARVC. Despite the loss of specific immunoreactive signal for desmosomal components at the cardiac intercalated disks (shown for plakoglobin, desmoplakin, and plakophilin-2), these proteins could be detected by Western blotting. Only for desmoglein-2, desmocollin-2, and plakoglobin were reduced protein levels observed. Adherens junction proteins were not affected. Lower phosphorylation levels were observed for connexin43; however, localization of the gap junction protein displayed regional differences. At the molecular level, disease progression was more severe in the right ventricle compared to the left ventricle. CONCLUSION: Our data suggest that, in the ARVC heart, plakoglobin is mainly redistributed from the junctions to other cellular pools and that protein degradation only plays a secondary role. Homogenous changes in the phosphorylation status of connexin43 were observed in multiple ARVC samples, suggesting that this might be a general feature of the disease

Účinnost a bezpečnost abobotulinumtoxinu A v tekuté formě u cervikální dystonie: randomizovaná, kontrolovaná studie.

Approved botulinum toxin A products require reconstitution. AbobotulinumtoxinA solution for injection is a ready-to-use liquid formulation of abobotulinumtoxinA. The objective of this study was to demonstrate the superior efficacy of abobotulinumtoxinA solution for injection to placebo and to test the noninferior efficacy of abobotulinumtoxinA solution for injection versus abobotulinumtoxinA (dry formulation) in cervical dystonia. At week 4, both products were superior to placebo (Toronto Western Spasmodic Torticollis Rating Scale total score least square mean decrease from baseline, abobotulinumtoxinA solution for injection 500 U -12.5, abobotulinumtoxinA 500 U -14.0, placebo -3.9; P < .0001 vs placebo). The noninferiority limit of 3 points in the Toronto Western Spasmodic Torticollis Rating Scale total score at week 4 was not met for abobotulinumtoxinA solution for injection versus abobotulinumtoxinA. Toronto Western Spasmodic Torticollis Rating Scale total score reductions were maintained for up to 4 cycles of abobotulinumtoxinA solution for injection open-label follow-up treatment. Safety profiles of abobotulinumtoxinA solution for injection and abobotulinumtoxinA were similar, with dysphagia and injection-site pain the most frequent drug-related adverse events. Although the predefined noninferiority criterion was not met, abobotulinumtoxinA solution for injection was similarly effective to freeze-dried abobotulinumtoxinA in reducing Toronto Western Spasmodic Torticollis Rating Scale total scores with a similar safety profile. AbobotulinumtoxinA solution for injection efficacy was maintained with chronic open-label treatment, and this novel formulation may add convenience as well as dosing accuracy to treatment with abobotulinumtoxinA.Pozadí: Již schválené produkty botulotoxinu A vyžadují rekonstituci. Tekutý abobotulotoxin A je již připraven k přímému použití. Cíle: Cílem této studie byl průkaz vyšší efektivity tekuté formy abobotulotoxinu A proti placebu a non-inferioritní účinnost abobotulotoxinu A v tekuté formě proti abobotulotoxinu A dodávaného v práškové formě u cervikální dystonie. Metody: Jednalo se o fázi 3, multicentrickou, prospektivní, dvojitě zaslepenou, randomizovanou, aktivní a placebem kontrolovanou studii (N=369). Pacient s cervikální dystonií byli randomizováni (3:3:1) pro abobotulinumtoxin A v tekuté formě 500 U, pro abobotulinumtoxin A 500 U dodávaný v práškové formě a pro placebo. Následně po dvojitě zaslepené fázi pak nemocní dostávali tekutý abobotulinumtoxin A v otevřené fázi studie a to po dobu 4 cyklů. Primární cílem byla změna v týdnu 4 hodnocena pomocí TWSTRS (Toronto Western Spasmodic Torticollis Rating Scale) skóre. Sekundární cíle byly – změny proti bazální návštěvě či základně návštěvě cyklu (TWSTRS). Výsledky: V týdnu 4 byly oba hodnocené produkty superiorní proti placebu. Snížení TWSTRS skóre proti placebu - pro tekutou formu -12.5, pro klasickou -14.0 a pro placebo -3.9. Limit noninferiority (3 body dle TWSTRS) nebyl v týdnu 4 dosažen pro tekutou formu, ale byl dosažen ve všech cyklech extenční fáze. Bezpečnostní profil byl stejný u obou hodnocených preparátů – dysfágie a bolesti v místě aplikace. Závěr: I když nebylo dosaženo kritériu non-inferiority, je tekutá preparát podobně účinný jako klasický preparát, kdy se vytváří aplikační forma rozpuštěním suché práškové formy. Nově zkoušený tekutý preparát je určen pro chronickou léčbu a vyznačuje se zlepšenými – vyhovujícími podmínkami při přípravě preparátu k aplikaci