A Concise Panel of Biomarkers Identifies Neurocognitive Functioning Changes in HIV-Infected Individuals

Neurocognitive (NC) impairment (NCI) occurs commonly in people living with HIV. Despite substantial effort, no biomarkers have been sufficiently validated for diagnosis and prognosis of NCI in the clinic. The goal of this project was to identify diagnostic or prognostic biomarkers for NCI in a comprehensively characterized HIV cohort. Multidisciplinary case review selected 98 HIV-infected individuals and categorized them into four NC groups using normative data: stably normal (SN), stably impaired (SI), worsening (Wo), or improving (Im). All subjects underwent comprehensive NC testing, phlebotomy, and lumbar puncture at two timepoints separated by a median of 6.2 months. Eight biomarkers were measured in CSF and blood by immunoassay. Results were analyzed using mixed model linear regression and staged recursive partitioning. At the first visit, subjects were mostly middle-aged (median 45) white (58 %) men (84 %) who had AIDS (70 %). Of the 73 % who took antiretroviral therapy (ART), 54 % had HIV RNA levels below 50 c/mL in plasma. Mixed model linear regression identified that only MCP-1 in CSF was associated with neurocognitive change group. Recursive partitioning models aimed at diagnosis (i.e., correctly classifying neurocognitive status at the first visit) were complex and required most biomarkers to achieve misclassification limits. In contrast, prognostic models were more efficient. A combination of three biomarkers (sCD14, MCP-1, SDF-1α) correctly classified 82 % of Wo and SN subjects, including 88 % of SN subjects. A combination of two biomarkers (MCP-1, TNF-α) correctly classified 81 % of Im and SI subjects, including 100 % of SI subjects. This analysis of well-characterized individuals identified concise panels of biomarkers associated with NC change. Across all analyses, the two most frequently identified biomarkers were sCD14 and MCP-1, indicators of monocyte/macrophage activation. While the panels differed depending on the outcome and on the degree of misclassification, nearly all stable patients were correctly classified.     

Novel Therapies and Treatment Strategies for Patients with Inflammatory Bowel Disease

Purpose of review

This article reviews current treatment options and strategies and provides an update on the status of drug development programs of new therapeutic agents for inflammatory bowel diseases (IBD).

Recent findings

In the past two decades, tumor necrosis factor antagonist therapy has given clinicians better treatment options. However, not all patients respond to induction therapy with these agents, and of those initially responding, up to 40% ultimately lose response due to suboptimal drug exposure (e.g., caused by immunogenicity), side effects, or other poorly characterized mechanisms. Recently, additional therapies, such as vedolizumab, an integrin blocker that prevents T cell trafficking to the gut, and ustekinumab, an antibody blocking the common p40 subunit of interleukin (IL)-12 and 23, were introduced to the market. In addition, other agents including novel anti-trafficking therapies (e.g., anti-β7 and sphingosine-1-phosphate receptor modulators), antibodies against p19 (unique to IL-23), and small molecules including Janus kinase inhibitors are under investigation in phase II and III trials.Furthermore, the management of IBD has evolved from targeting control of symptoms to suppression of mucosal inflammation. This shift in thinking has been accompanied by the early use of highly effective therapy in poor prognosis patients, accelerated treatment escalation and utilization of a treat to target paradigm approach, and adoption of therapeutic drug monitoring.

Summary

The treatment landscape for IBD is rapidly evolving with the recent approval of novel biologics as well as several other agents in late phase of clinical development. Moreover, we have started to use agents more intelligently with a focus on risk stratification and early use of highly effective therapy in high-risk patients, treat to target using patient-reported outcomes (PROs), biomarkers, endoscopy, and therapeutic drug monitoring.

     

Methyldopa hepatitis: A report of six cases and review of the literature

Six cases of methyldopa hepatitis, including two in which the patients died are reported; and 77 cases from the literature are reviewed. Patients in whom severe hepatotoxic reactions to methyldopa develop usually complain of prodromal symptoms typical of hepatitis, often with fever, one to four weeks after therapy is initiated. Jaundice, when it occurs, is usually manifest within three months.

Asymptomatic, transient elevations of serum transaminase levels may occur in patients receiving methyldopa. However, since the clinical and histologic features of hepatic injury from methyldopa are indistinguishable from viral hepatitis, it is suggested that the incidence of this iatrogenic disease is higher than generally appreciated.

Serum transaminase levels should be determined at the initiation of therapy with methyldopa and four weeks later. Moreover, any patient who has unexplained fever or the prodromal symptoms of hepatitis should undergo liver chemistry studies immediately.     

Antineutrophil cytoplasmic autoantibody-negative antiproteinase 3 syndrome presenting as vasculitis,endocarditis, polyneuropathy and Dupuytren's contracture

Antiproteinase 3 antibodies (antiPR3) are assumed to be subtypes of antineutrophil cytoplasmic autoantibodies (ANCA), with a high specificity for active Wegener's granulomatosis and microscopic polyangiitis. Thus, antiPR3 positivity in ELISA, together with negativity in indirect immunofluorescence (IIF) is a rare finding. A 56-year-old man with Dupuytren's contracture and polyneuropathy was admitted for leukocytoclastic vasculitis. Echocardiography, performed because of fever and dyspnea, detected aortic valve endocarditis. Because of severe aortic insufficiency the valve was replaced. Blood cultures and bacteriologic investigations of the explanted valve were negative. AntiPR3 were elevated (123-163 U/ml; normal <6 U/ml), together with negativity in IIF. This case shows that antiPR3 elevation with negative ANCA may be associated with vasculitis, endocarditis, polyneuropathy and Dupuytren's contracture. A causal relationship between the clinical presentation and antiPR3 elevation is likely. In order not to miss such cases of vasculitis, combined screening by IIF and ELISA is recommended in selected cases.     

Abdominal Pain Severity Is Mainly Associated with Bloating Severity in Patients with Functional Bowel Disorders and Functional Abdominal Pain

Digestive Diseases and Sciences - Abdominal pain is a cardinal sign of functional bowel disorders (FBD), in favor of irritable bowel syndrome (IBS). However, the determinants of abdominal pain...     

Impact of the sleep apnea management group clinic on positive airway pressure adherence

Sleep and Breathing - Positive airway pressure (PAP) adherence is critical for managing obstructive sleep apnea (OSA). We postulate that&nbsp;group-based Sleep Apnea Management (SAM) clinic,...     

The risk of cholecystectomy for acute cholecystitis in diabetic patients.

In order to evaluate the risk of acute cholecystitis in diabetic patients, we analyzed 2,700 consecutive cholecystectomies, 566 of which were performed in the presence of acute cholecystitis. Of these patients 123 had diabetes mellitus (DM) and 433 had no diabetes (ND). The aim of this study was to establish the comparative risks in the two groups. We found that diabetics are more likely to be operated on in the acute stage of their disease (22% vs. 12%). The DM group had a higher rate of septic bile, gangrenous changes and perforations of the gallbladder wall. The morbidity rate was higher in the DM group (21% vs. 9%), and mortality was slightly higher in the DM group. The degree of additional operative risk does not in our view justify recommending cholecystectomy in diabetic patients with asymptomatic gallstones. Early surgery however, is highly recommended in diabetics with symptomatic gallstones and acute cholecystitis.