The effect of oral clarithromycin on bronchial airway inflammation in moderate-to-severe stable COPD: a randomized controlled trial.

INTRODUCTION: COPD is characterized by bronchial neutrophilic inflammation. Clarithromycin is a macrolide antibiotic that has antibacterial and anti-inflammatory properties. Macrolide antibiotics have been shown to improve airway inflammation in diffuse pan-bronchiolitis but their role in COPD is undetermined. The aim of the study was to determine if 3 months of therapy with modified-release oral clarithromycin (Klaricid XL) 500 mg/day reduced bronchial airway inflammation in patients with moderate-to-severe stable COPD compared with placebo. METHODS: A prospective, double-blind controlled trial randomized patients with moderate-to-severe stable COPD to 3 months' therapy with oral modified-release clarithromycin 500 mg/day or placebo. Patients underwent saline sputum induction before and after treatment with clarithromycin. The effects of clarithromycin on sputum total cell and neutrophil counts, supernatant interleukin-8 (IL-8), leukotriene B(4) (LTB(4)), tumor necrosis factor (TNF)-alpha, neutrophil elastase (NE), and neutrophil chemotaxis were assessed in comparison with placebo. RESULTS: Of a total of 67 patients included in the trial, 31 were treated with clarithromycin and 36 with placebo. The groups were similar in age, body mass index, history of smoking, and spirometry. Of 60 evaluable patients, 26 and 34 completed 3 months' therapy with clarithromycin and placebo, respectively. Clarithromycin had no significant effect on sputum total cell count, neutrophil count, IL-8, LTB(4), TNFalpha levels or neutrophil elastase. However, clarithromycin did cause a small reduction in the neutrophil differential (p = 0.04 relative to placebo) and neutrophil chemotaxis (p = 0.058 relative to placebo). CONCLUSIONS: Oral clarithromycin 500 mg/day administered for 3 months had no significant effect on sputum neutrophil numbers or cytokine levels in patients with moderate-to-severe stable COPD. However, clarithromycin did cause a small reduction in the neutrophil differential and neutrophil chemotaxis. Further studies may be warranted to determine the clinical significance of these findings.

Ventricular-arterial coupling in obstructive sleep apnea.

Arterial elastance (Ea) and systolic elastance are important parameters determining effective functional interaction of heart and vessels. The aims of this study were to (1) compare arterial (arterial elastance index [EaI]) and ventricular (end-systolic elastance [Ees] and end-diastolic elastance [Eed]) elastance in subjects with obstructive sleep apnea (OSA) and patients with treated 'high-risk' hypertension (HHT) and (2) test whether these parameters in OSA patients can be improved by continuous positive airway pressure (CPAP) therapy. Echocardiographic parameters of cardiac and vascular stiffness (EaI, Ees, and Eed) were quantified in 28 patients with OSA (mean [standard deviation], age 51 [11] years; 79% male) and 28 treated subjects with HHT (mean [standard deviation], age 48 [12] years; 61% male). Twenty-three OSA patients were treated with CPAP for median of 26 weeks. Ea was calculated from stroke volume and systolic BP and adjusted by body area (EaI). Both study groups had preserved and comparable left ventricle contractility. There was no significant differences in EaI (P = .94), Ees (P = .5), Eed (P = .63), and arterial-ventricular interaction (P = .62) between OSA and HHT groups. After CPAP therapy, there was a significant reduction in EaI (paired t test, P = .013) and arterial-ventricular interaction (paired t test, P = .004). Ees (P = .17) and Eed (P = .66) parameters did not change significantly. OSA and HHT patients have similar parameters of elastance and ventricular-arterial coupling. CPAP treatment in OSA patients significantly improved ventricular-arterial coupling.

Left ventricular systolic and diastolic function in obstructive sleep apnea: impact of continuous positive airway pressure therapy.

BACKGROUND: Previous studies in obstructive sleep apnea (OSA) were limited by study cohorts with comorbidities that confound assessment of left ventricular (LV) systolic and diastolic function. We comprehensively evaluated LV function using 2-dimensional echocardiography (2DE), tissue Doppler imaging (TDI), and 3-dimensional echocardiography (3DE) in subjects moderate-severe OSA, who were compared with disease (patients with hypertension, no OSA) and healthy control subjects. METHODS AND RESULTS: A total of 120 subjects (n=40 each of matched OSA, hypertension and healthy cohorts) underwent echocardiographic examination for the assessment of septal and posterior wall thickness, LV mass index, LV volumes and ejection fraction, mitral valve inflow indices (E, A), mitral annular velocity (S, E'), and left atrial volume index (LAVI). OSA subjects were treated with continuous positive airway pressure (mean duration of 26 weeks), after which the echocardiographic parameters were reassessed. Posterior wall thickness and LV mass index were significantly higher in OSA and hypertensive groups compared with healthy. Systolic S velocity was reduced in OSA and hypertensive compared with healthy control subjects (P<0.05). Diastolic function (E/A, IVRT, and E/E') was impaired in both OSA and hypertensive groups. On 3DE, mean LAVI was significantly greater in OSA and hypertensive compared with healthy. In OSA patients, continuous positive airway pressure therapy resulted in reduction of the posterior wall thickness (P=0.02) and improvement in LV ejection fraction (P<0.05), systolic S velocity (P<0.05), and diastolic LV impairment parameters. CONCLUSIONS: Moderate to severe OSA causes structural and functional changes in V function and are comparable to that seen in hypertension. These abnormalities significantly improve after CPAP therapy.

Refractory multisystem sarcoidosis responding to infliximab therapy.

Chronic progressive multisystem granulomatous disease is seen in 10-30% of patients with sarcoidosis and can result in end organ damage. Corticosteroids are the mainstay of treatment with the addition of cytotoxic agents in severe cases. Some patients are refractory to such treatment and, therefore, management is a challenge. There is currently limited evidence for biological agents such as infliximab, a monoclonal anti-tumor necrosis factor-α antibody in the treatment of multisystem sarcoidosis. We report outcomes of three patients with extensive multisystem sarcoidosis refractory to conventional treatment and treated at our center. Clinical assessment and radiographic imaging were used to assess the response to infliximab treatment. Infliximab therapy induced clinical remission in all three patients, and this clinical response correlated with radiographic evidence of the resolution of granulomatous disease. Serum ACE level was reduced in all cases, and daily steroid dosage was reduced. We propose that infliximab can be an effective treatment in patients with multisystem complex sarcoidosis refractory to conventional drug therapy and can result in sustained clinical remission. Our experience supports the urgent need for randomized controlled clinical trials of anti-TNF therapy in refractory systemic sarcoidosis.

Hypospadias in Sudan, clinical and surgical review.

BACKGROUND: Hypospadias is one of the commonest penile abnormalities in new born males, and occurs as a result of a birth defect resulting in a urethral opening anywhere from the glans penis along the ventral aspect of the shaft of the penis up to the scrotum or the perineum in extreme cases. The condition has a huge impact on the patient's psychological, emotional and sexual well being. This study aimed to evaluate the current trend in the treatment of hypospadias in Sudan. MATERIALS AND METHODS: The was a retrospective study done in Elribat university hospital, department of Paediatrics surgery, for patients who underwent hypospadias surgical repair in the period January 2006 to June 2007. RESULTS: There were 50 patients in this study. Regional distribution of the patients showed that 52% of the patients live in Khartoum state, the capital, while 48% were from the peripheries; 12% of patients had family history of similar condition (Hypospadias) and 54% were of low socioeconomic status. Anterior hypospadias was the commonest type (46%), and associated chordee occurred in most of the patients (88%). The most common associated anomalies found were undescended testicles (20%) and inguinal hernia only in 2%. The most common type of repair was MAGPI (meatal advancement and glanuloplasty) with 42% of cases, anterior hypospadias commonest type with 46% of cases, 12% of cases had a family history of the condition and an overall complication rate of 26%. Chordee was the most prevalent association in 88% of cases. CONCLUSION: There is a high familial tendency for hypospadias in Sudan. Associated chordee and other anomalies are in keeping with other reports. Corrective surgery for hypospadias is associated with high complication rate in our setting. Collaboration between surgical specialties such as plastic surgeons, paediatrics urologist and general surgeons may improve the present complication scenario.

Myocardial perfusion by myocardial contrast echocardiography and endothelial dysfunction in obstructive sleep apnea.

Obstructive sleep apnea is associated with increased cardiovascular morbidity and mortality. We investigated myocardial perfusion using real-time quantitative myocardial contrast echocardiography with concurrent assessment of macrovascular and microvascular endothelial dysfunction in normotensive subjects with moderate-to-severe obstructive sleep apnea, who were compared with hypertensive and healthy subjects, as well as the impact of continuous positive airway pressure treatment on obstructive sleep apnea subjects. We measured flow (hyperemia)-mediated dilation and response to glyceryl trinitrate of brachial artery (ultrasound), cutaneous perfusion responses to acetylcholine and sodium nitroprusside (laser Doppler), pulse wave velocity, and circulating endothelial and endothelial progenitor cells in a total of 108 subjects (n=36 each of matched obstructive sleep apnea, hypertension, and healthy cohorts). Subjects with obstructive sleep apnea and hypertension demonstrated abnormal myocardial perfusion (P<0.001 for both comparisons), attenuated brachial artery reactivity (P<0.001), and cutaneous perfusion responses (P<0.001) compared with healthy individuals. Both hypertensive and obstructive sleep apnea patients showed significant improvements in myocardial perfusion (P<0.01), brachial artery reactivity (P<0.001), and cutaneous perfusion responses (P<0.001) after 26 weeks of continuous positive airway pressure therapy. There were no significant differences in pulse wave velocity and endothelial cells across the 3 groups. Concomitant endothelial dysfunction and impaired myocardial perfusion are present in otherwise normal subjects with moderate-to-severe obstructive sleep apnea, and effective continuous positive airway pressure treatment reverses many of these macrovascular/microvascular abnormalities.

Obstructive sleep apnea and cardiovascular disease.

Obstructive sleep apnea (OSA) is a common yet an under-diagnosed sleep related breathing disorder affecting predominantly middle-aged men. OSA is associated with many adverse health outcomes, including cardiovascular disease. Common OSA associated/induced cardiovascular disorders include coronary artery disease, heart failure, hypertension, cardiac arrhythmias and stroke, which further increase morbidity and mortality in the OSA population. Endothelial dysfunction, coagulopathy, impaired sympathetic drive, oxidative and inflammatory stress are the pathophysiological pathways suggested for the development of cardiovascular disease in OSA. The evidence would suggest that OSA should be considered as a cardiovascular risk factor, and is a treatable condition. Multiple studies using Continuous Positive Airway Pressure (CPAP) have shown improvements in the clinical state as well as retardation of disease progression. Therefore, patients with cardiovascular disease should be proactively screened for OSA and vice versa.

Endothelial dysfunction: methods of assessment & implications for cardiovascular diseases.

The endothelium is a thin monocellular layer lining the entire human vascular system, separating blood from interstitium. It plays a core role in the vascular tone by releasing a variety of vasoactive substances, such as nitric oxide (NO) and endothelin. In addition to regulating vasomotion, the healthy endothelium also has anti-thrombotic (through prostacyclins), anti-inflammatory (through developmental endothelial locus-1{Del-1}) and anti-proliferative (through NO and prostaglandin I2) properties. All such mechanisms are regulated by a strict balance amongst several agonist and antagonist biochemical substances secreted by the endothelium. Endothelial dysfunction (ED) is a systemic process in which the endothelium loses the ability/capacity to maintain vascular equilibrium. ED is strongly associated with cardiovascular risk factors/diseases and can be assessed by a number of invasive and non invasive methods. Strict physiological and/or pharmacological management of cardiovascular risk factors improves the functional status of the endothelium and reduces the risk of future cardiac events. This review will provide an overview of the modern perception of endothelial biology, the methods of its assessment and interaction of the endothelium with cardiovascular risk factors and prognosis.