Efficacy and Safety of the Bruton's Tyrosine Kinase Inhibitor Evobrutinib in Systemic Lupus Erythematosus: Results of a Phase II, Randomized, Double-Blind, Placebo-Controlled Dose-Ranging Trial.

Objective: Evobrutinib is a highly selective, orally administered Bruton's tyrosine kinase (BTK) inhibitor. The objective of this phase II, multicenter, randomized, double-blind, placebo-controlled trial was to evaluate the efficacy and safety of evobrutinib in patients with active autoantibody-positive systemic lupus erythematosus (SLE).

Methods: Patients were diagnosed with SLE by either the Systemic Lupus International Collaborating Clinics criteria or at least four American College of Rheumatology criteria 6 months or more prior to screening, had an SLE Disease Activity Index-2000 score of 6 or more, were autoantibody-positive and on standard-of-care therapy.

A Comprehensive Update on Kawasaki Disease Vasculitis and Myocarditis.

Purpose Of The Review: Kawasaki disease (KD) is a childhood systemic vasculitis of unknown etiology that causes coronary artery aneurysms (CAA), and if left undiagnosed can result in long-term cardiovascular complications and adult cardiac disease. Up to 20% of KD children fail to respond to IVIG, the mainstay of therapy, highlighting the need for novel therapeutic strategies. Here we review the latest findings in the field regarding specific etiology, genetic associations, and advancements in treatment strategies to prevent coronary aneurysms.

The recovery index: A novel approach to measuring recovery and predicting remission in major depressive disorder.

Background: Clinicians view "recovery" as the reduction in severity of symptoms over time, whereas patients view it as the restoration of premorbid functioning level and quality of life (QOL). The main purpose of this study is to incorporate patient-reported measures of functioning and QOL into the assessment of patient outcomes in MDD and to use this data to define recovery.

Method: Using the STAR*D study of patients diagnosed with MDD, this present analysis grades patients' MDD severity, functioning level, and QOL at exit from each level of the study, as well as at follow-up.

Patient-reported outcomes of quality of life, functioning, and depressive symptom severity in major depressive disorder comorbid with panic disorder before and after SSRI treatment in the star*d trial.

Background: Panic disorder (PD) is highly comorbid with major depressive disorder (MDD) with potential impact on patient-reported outcomes of quality of life (QOL), functioning, and depressive symptom severity.

Methods: Using data from the sequenced treatment alternatives to relieve depression (STAR*D) trial, we compared entry and post-SSRI-treatment QOL, functioning, and depressive symptom severity scores in MDD patients with comorbid PD (MDD+PD) to MDD patients without PD (MDDnoPD). We also compared pre- and posttreatment proportions of patients with severe impairments in quality of life and functioning.

Burnout in medical students: a systematic review.

Background: Burnout is a state of mental and physical exhaustion related to work or care-giving activities. Distress during medical school can lead to burnout, with significant consequences, particularly if burnout continues into residency and beyond. The authors reviewed literature pertaining to medical student burnout, its prevalence, and its relationship to personal, environmental, demographic and psychiatric factors.

Development and validation of the Individual Burden of Illness Index for Major Depressive Disorder (IBI-D).

This study aims at developing a single numerical measure that represents a depressed patient's individual burden of illness. An exploratory study examined depressed outpatients (n = 317) followed by a hypothesis confirmatory study using the NIMH STAR*D trial (n = 2,967). Eigenvalues/eigenvectors were obtained from the Principal Component Analyses of patient-reported measures of symptom severity, functioning, and quality of life.

Emerging role of IL-17 in atherosclerosis.

The IL-23-IL-17 axis is emerging as a critical regulatory system that bridges the innate and adaptive arms of the immune system. Th17 cells have been linked to the pathogenesis of several chronic inflammatory and autoimmune diseases. However, the role of Th17 cells and IL-17 in various stages of atherogenesis remains poorly understood and is only beginning to be elucidated.

The role of dopaminergic agents in improving quality of life in major depressive disorder.

Quality of life (QOL) is greatly diminished in patients with major depressive disorder (MDD) before treatment. This deficit persists even when patients are in remission; thus, interventions are needed to improve QOL. This article reviews QOL impairment in MDD and the cost of impairment, then summarizes the empiric literature on the effects of dopaminergic agents on QOL in patients with MDD.

Familialism, social support, and stress: positive implications for pregnant Latinas.

This study examined the association of familialism, a cultural value that emphasizes close family relationships, with social support, stress, pregnancy anxiety, and infant birth weight. Foreign-born Latina (n = 31), U.S.

Preshock phase singularity and the outcome of ventricular defibrillation.

Background: Phase singularity (PS) is a topological defect that serves as a source of ventricular fibrillation (VF). Whether or not the quantity of preshock PS determines defibrillation outcome is unclear.

Objective: The purpose of this study was to test the hypothesis that the number of PSs at the time of shock is an important factor that determines the shock outcome.

Active and passive immunization for atherosclerosis.

This review summarizes experimental findings that highlight the role of immune mechanisms in atherosclerosis and the potential atheroprotective effects of active or passive immunization strategies. Inmmunomodulation therapy appears to be feasible and effective, suggesting that a vaccine for atherosclerosis can be developed for clinical testing. Given the increasing number of patients with atherosclerotic disease on current therapy, a new therapy is needed and an immunization strategy could provide such a possibility.

Extra-renal 25-hydroxyvitamin D3-1alpha-hydroxylase in human health and disease.

Although ectopic expression of 25-hydroxyvitamin D(3)-1alpha-hydroxylase (1alpha-OHase) has been recognized for many years, the precise function of this enzyme outside the kidney remains open to debate. Three specific aspects of extra-renal 1alpha-OHase have attracted most attention: (i) expression and regulation in non-classical tissues during normal physiology; (ii) effects on the immune system and inflammatory disease; (iii) expression and function in tumors. The most well-recognized manifestation of extra-renal 1alpha-OHase activity remains that found in some patients with granulomatous diseases where locally synthesized 1alpha,25(OH)(2)D(3) has the potential to spill-over into the general circulation.

Review article: the burden of hepatic encephalopathy.

Hepatic encephalopathy, a challenging complication of advanced liver disease, occurs in approximately 30-45% of patients with cirrhosis and 10-50% of patients with transjugular intrahepatic portosystemic shunt, while minimal hepatic encephalopathy affects approximately 20-60% of patients with liver disease. Although the total direct and indirect costs of hepatic encephalopathy have not been formally quantified, data from the Healthcare Cost and Utilization Project suggest that hepatic encephalopathy-related hospitalizations are associated with substantial costs. In 2003, there were over 40 000 patients hospitalized in the United States for a primary diagnosis of hepatic encephalopathy, resulting in total charges of approximately $932 million.

Ubiquitination and de-ubiquitination: role in regulation of signaling by Toll-like receptors.

Signaling by Toll-like receptors (TLRs) has attracted accelerating attention over the past decade because of the central role of TLR signaling in both innate and adaptive immunity. In addition, TLR signaling is now increasingly implicated in a remarkably wide range of diseases that are either caused, or accompanied, by dysregulated inflammation. Much has been learned about the basic signaling framework and participants, as well as how signaling is turned off and fine-tuned.

Bone marrow transplantation shows superior atheroprotective effects of gene therapy with apolipoprotein A-I Milano compared with wild-type apolipoprotein A-I in hyperlipidemic mice.

Objectives: We tested the hypothesis that gene therapy using apolipoprotein A-I Milano (apoA-IMilano) is more effective than that using wild-type apolipoprotein A-I (apoA-I) in reducing atherosclerosis.

Background: Apolipoprotein A-I Milano is a naturally occurring mutant with established antiatherogenic activity; however, its relative antiatherogenic efficacy compared with that of wild-type apoA-I remains unclear.

Methods: We performed bone marrow transplantation in female double-knockout mice lacking both the apoE and apoA-I genes using male donor mice-derived bone marrow that had been transduced with a retroviral vector alone or retroviral vector expressing wild-type apoA-I or apoA-IMilano gene under the control of macrophage-specific scavenger receptor A promoter.

Passive immunization with monoclonal IgM antibodies against phosphorylcholine reduces accelerated vein graft atherosclerosis in apolipoprotein E-null mice.

Phosphorylcholine (PC) headgroup is one of the neoantigens exposed by LDL oxidation that can elicit an immune response. Active immunization with Streptococcus pneumoniae, which bears PC on its cell wall, reduced atherosclerosis in hypercholesterolemic mice and this effect was attributed to an immune response to PC. In this study we tested the hypothesis that passive immunization with a monoclonal anti-PC IgM antibody can be athero-protective in a murine model of native aortic and vein graft atherosclerosis.

Immunization using an Apo B-100 related epitope reduces atherosclerosis and plaque inflammation in hypercholesterolemic apo E (-/-) mice.

Immune system modulates atherosclerosis and immunization using homologous LDL reduces atherosclerosis in hyperlipidemic animals. The nature of athero-protective antigenic epitopes in LDL remains unclear. We have recently identified nearly a 100 antigenic epitopes in human apo B-100 and in this study we evaluated the effects of immunization with two such epitopes on atherosclerosis in hypercholesterolemic apo E (-/-) mice.

Phenotype of non-syndromic deafness associated with the mitochondrial A1555G mutation is modulated by mitochondrial RNA modifying enzymes MTO1 and GTPBP3.

Phenotypic expression of the deafness-associated mitochondrial A1555G mutation in the 12S rRNA gene is influenced by aminoglycosides and complex inheritance of nuclear-encoded modifier genes. The position of a major nuclear modifier gene has been localized to chromosome 8p23.1, but the identification of this gene has remained elusive.

Differential effects of apolipoprotein A-I-mimetic peptide on evolving and established atherosclerosis in apolipoprotein E-null mice.

Background: Apolipoprotein (apo) A-I and apoA-I-mimetic peptides showed promise to prevent atherosclerosis development. Using a bypassed vein graft model in apoE-null mice, we evaluated the effects of oral or intraperitoneal administration of an apoA-I-mimetic peptide on evolving atherosclerotic lesions in the vein graft and compared such effects on the established atherosclerotic lesions in aortic sinus in the same mice.

Methods And Results: We used apoE-null mice in which a segment of inferior vena cava was grafted into the right carotid artery at 16 weeks of age.

Watershed infarcts in the fetal and neonatal brainstem. An aetiology of central hypoventilation, dysphagia, Möibius syndrome and micrognathia.

Watershed zone infarcts of the human cerebral cortex at the overlapping junctions of the anterior and middle cerebral arterial territories are well known. Another watershed zone exists in the brainstem tegmentum, between the terminal perfusion zones of the paramedian penetrating and long circumferential arteries, which are paired segmental vessels arising from the basilar artery. The vertebrobasilar circulation achieves its mature configuration and caudorostral flow by 9 weeks gestation.

Intracoronary beta-irradiation enhances balloon-injury-induced tissue factor expression in the porcine injury model.

Intracoronary brachytherapy (ICBT) effectively reduces restenosis but is associated with late thrombosis. Since tissue factor (TF) is an important mediator of arterial thrombosis, we tested the hypothesis that ICBT results in persistently augmented TF expression. Coronary arteries from 12 pigs were randomized to: control (C; no injury), oversized balloon injury (BI), or BI followed by ICBT.