Characteristics and survival for HIV-associated multicentric Castleman disease in Malawi

Introduction

Clinical reports of multicentric Castleman disease (MCD) from sub-Saharan Africa (SSA) are scarce despite high prevalence of HIV and Kaposi sarcoma-associated herpesvirus (KSHV). Our objective is to describe characteristics and survival for HIV-associated MCD patients in Malawi. To our knowledge, this is the first HIV-associated MCD case series from the region.

Methods

We describe HIV-positive patients with MCD in Lilongwe, and compare them to HIV-associated lymph node Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL) patients treated at our centre. All patients were enrolled into a prospective longitudinal cohort study at a national teaching hospital and cancer referral centre serving half of Malawi''s 16 million people. We included adult patients≥18 years of age with HIV-associated MCD (n=6), lymph node KS (n=5) or NHL (n=31) enrolled between 1 June 2013 and 31 January 2015.

Results and discussion

MCD patients had a median age of 42.4 years (range 37.2–51.8). All had diffuse lymphadenopathy and five had hepatosplenomegaly. Concurrent KS was present for one MCD patient, and four had performance status ≥3. MCD patients had lower median haemoglobin (6.4 g/dL, range 3.6–9.3) than KS (11.0 g/dL, range 9.1–12.0, p=0.011) or NHL (11.2 g/dL, range 4.5–15.1, p=0.0007). Median serum albumin was also lower for MCD (2.1 g/dL, range 1.7–3.2) than KS (3.7 g/dL, range 3.2–3.9, p=0.013) or NHL (3.4 g/dL, range 1.8–4.8, p=0.003). All six MCD patients were on antiretroviral therapy (ART) with median CD4 count 208 cells/µL (range 108–1146), and all with HIV RNA <400 copies/mL. Most KS and NHL patients were also on ART, although ART duration was longer for MCD (56.4 months, range 18.2–105.3) than KS (14.2 months, range 6.8–21.9, p=0.039) or NHL (13.8 months, range 0.2–98.8, p=0.017). Survival was poorer for MCD patients than lymph node KS or NHL.

Conclusions

HIV-associated MCD occurs in Malawi, is diagnosed late and is associated with high mortality. Improvements in awareness, diagnostic facilities, treatment and supportive care are needed to address this likely under-recognized public health problem in SSA.     

Pharmacokinetics and Pharmacodynamics of Clofazimine in a Mouse Model of Tuberculosis

The antileprosy drug clofazimine has shown potential for shortening tuberculosis treatment; however, the current dosing of the drug is not evidence based, and the optimal dosing is unknown. Our objective was to conduct a preclinical evaluation of the pharmacokinetics and pharmacodynamics of clofazimine in the mouse model of tuberculosis, with the goal of providing useful information on dosing for future studies. Pharmacokinetic parameters were evaluated in infected and uninfected BALB/c mice. Pharmacodynamic parameters were evaluated in Mycobacterium tuberculosis-infected mice that were treated for 12 weeks with one of six different clofazimine dosing regimens, i.e., doses of 6.25, 12.5, and 25 mg/kg of body weight/day and 3 regimens with loading doses. Clofazimine progressively accumulated in the lungs, livers, and spleens of the mice, reaching levels of greater than 50 μg/g in all tissues by 4 weeks of administration, while serum drug levels remained low at 1 to 2 μg/ml. Elimination of clofazimine was extremely slow, and the half-life was dependent on the duration of drug administration. Clofazimine exhibited dose-dependent tissue and serum concentrations. At any dose, clofazimine did not have bactericidal activity during the first 2 weeks of administration but subsequently demonstrated potent, dose-independent bactericidal activity. The antituberculosis activity of clofazimine was dependent on neither the dose administered nor the drug concentrations in the tissues, suggesting that much lower doses could be effectively used for tuberculosis treatment.     

Metformin and heart failure–related outcomes in patients with or without diabetes: a systematic review of randomized controlled trials

Heart Failure Reviews - Metformin is considered a safe anti-hyperglycemic drug for patients with type 2 diabetes (T2D); however, information on its impact on heart failure–related outcomes...     

Pancreatic β-cell dysfunction in type 2 diabetes: Implications of inflammation and oxidative stress

Insulin resistance and pancreatic β-cell dysfunction are major pathological mechanisms implicated in the development and progression of type 2 diabetes(T2D). Beyond the detrimental effects of insulin resistance, inflammation and oxidative stress have emerged as critical features of T2D that define β-cell dysfunction. Predominant markers of inflammation such as C-reactive protein, tumor necrosis factor alpha, and interleukin-1β are consistently associated with β-cell failure in preclinical models...     

A hybrid form of cardiac resynchronisation therapy in patients with failing systemic right ventricles

INTRODUCTION: Late systemic right ventricular (RV) dysfunction after atrial redirection surgery is common. Patients may require cardiac transplantation in early adulthood. METHODS: We undertook cardiac resynchronisation (CRT)/defibrillator therapy in two patients as a bridge to transplantation. RESULTS: Two males (aged 24, 110 kg and 26 years, 106 kg); having undergone a Mustard procedure for dextro-transposition of the great arteries at 7 and 6 months of age respectively, presented with impaired systemic RV function and New York Heart Association III symptoms. Both patients had dual chamber pacemakers in-situ for sinus bradycardia. Upgrade to CRT was performed by conserving the existing endocardial leads and placement of epicardial electrodes. One demonstrated sustained improvement over a 24 month follow-up period. CONCLUSION: A hybrid CRT strategy is feasible in patients with failing systemic RVs and pre-existent endocardial dual chamber pacemakers. Appropriate patient selection criteria and optimum lead placement, however, still needs further evaluation in this population.     

A modern approach to tuberculous pericarditis

The human immunodeficiency virus (HIV) epidemic has been associated with an increase in all forms of extrapulmonary tuberculosis including tuberculous pericarditis. Tuberculosis is responsible for approximately 70% of cases of large pericardial effusion and most cases of constrictive pericarditis in developing countries, where most of the world's population live. However, in industrialized countries, tuberculosis accounts for only 4% of cases of pericardial effusion and an even smaller proportion of instances of constrictive pericarditis. Tuberculous pericarditis is a dangerous disease with a mortality of 17% to 40%; constriction occurs in a similar proportion of cases after tuberculous pericardial effusion. Early diagnosis and institution of appropriate therapy are critical to prevent mortality. A definite or proven diagnosis is based on demonstration of tubercle bacilli in pericardial fluid or on histologic section of the pericardium. A probable or presumed diagnosis is based on proof of tuberculosis elsewhere in a patient with otherwise unexplained pericarditis, a lymphocytic pericardial exudate with elevated biomarkers of tuberculous infection, and/or appropriate response to a trial of antituberculosis chemotherapy. Treatment consists of 4-drug therapy (isoniazid, rifampicin, pyrazinamide, and ethambutol) for 2 months followed by 2 drugs (isoniazid and rifampicin) for 4 months regardless of HIV status. It is uncertain whether adjunctive corticosteroids are effective in reducing mortality or pericardial constriction, and their safety in HIV-infected patients has not been established conclusively. Surgical resection of the pericardium is indicated for those with calcific constrictive pericarditis or with persistent signs of constriction after a 6 to 8 week trial of antituberculosis treatment in patients with noncalcific constrictive pericarditis.     

Design of a Randomized Placebo-Controlled Trial to Assess Dabigatran and Omeprazole in Patients with Myocardial Injury after Noncardiac Surgery (MANAGE)

Background

Worldwide approximately 200 million adults undergo major surgery annually, of whom 8 million are estimated to suffer a myocardial injury after noncardiac surgery (MINS). There is currently no trial data informing the management of MINS. Antithrombotic agents such as direct oral anticoagulants might prevent major vascular complications in patients with MINS.

Echocardiographic Screening for Subclinical Rheumatic Heart Disease Remains a Research Tool Pending Studies of Impact on Prognosis

Paravalvular regurgitation (PVR) is a symptomatic or asymptomatic complication after surgical valve replacement. It may be related to calcification, infection or tissue friability and occurs in 5 % to 17 % of surgical implanted heart valves. Reoperation is associated with a higher morbidity and mortality than the index procedure. Percutaneous closure of PVR can be an effective and lower risk alternative to reoperation. However, feasibility for percutaneous closure has to be assessed by defining the shape, size and location of the defect. Echocardiography with three-dimensional defect reconstruction is a cornerstone for guiding percutaneous PVR closure. Access for aortic PVR is usually retrograde via the femoral artery and access to mitral PVR either retrograde from the aorta, transvenous-transseptal or transapical. Meticulous planning and prudent procedural execution by experienced operators ensuring no impingement of the prosthetic leaflets leads to a high success rate of percutaneous PVR repair.