Infective endocarditis: a five-year experience at a tertiary care hospital in Pakistan.

OBJECTIVES: Infective endocarditis is common and data regarding its pattern and outcome from developing countries is sparse. We therefore examined the spectrum, demographics and clinical features of infective endocarditis and sought to determine the factors affecting its clinical outcome. PATIENTS AND METHODS: Over a five-year period at our university hospital in Karachi, Pakistan, we identified 66 patients with infective endocarditis and compared their clinicoepidemiologic features and outcomes to subjects in the West. RESULTS: The male:female ratio was 2:1; overall median age was 24 years (35.5 years for men and 13.5 years for women) (p < 0.001). Median duration of symptoms before presentation was 20.5 days. Major predisposing cardiac abnormalities included congenital (50%) and rheumatic (23%) lesions, and a history of heart surgery (17%). Causative organisms and valvular sites of infection were similar to those seen in developed countries. Blood culture-negative infective endocarditis was found in 48% of cases. Renal failure was more frequent among culture-positive patients (p = 0.055). Risk factors for mortality included neurologic (p = 0.003) and embolic (p = 0.02) complications, renal (p = 0.03) and left ventricular failure (p = 0.002), and a history of cardiac surgery (p = 0.026). Overall mortality was 27%. CONCLUSIONS: Patients with infective endocarditis in Pakistan exhibit significant differences compared to their counterparts in the West, including younger age at presentation, incidence of predisposing cardiac conditions, and gender differences reflecting sociocultural bias. Neurologic and embolic complications, renal failure and heart failure predict a worse outcome.     

Trends in heart failure outcomes and pharmacotherapy: 1992 to 2000

PURPOSE: To review trends in drug therapy and concomitant outcomes of elderly heart failure patients in Ontario, Canada. METHODS: Utilization of drug therapies, mortality, and rehospitalization rates from April 1992 to March 2000 were determined in 77,421 elderly (aged >/=65 years), community-based heart failure patients using linked administrative databases. Treatment effects were identified from published meta-analyses and randomized trials. The effect of drug trends on mortality and morbidity were assessed based on their absolute treatment effects. RESULTS: From 1992 to 2000, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use increased from 58% to 62% (P = 0.001) while beta-blocker use increased from 6% to 22% (P <0.001). There was a decrease in the use of treatments for which no survival advantage had been demonstrated in randomized trials, such as digitalis (49% to 35%, P <0.001), Vaughan-Williams class I antiarrhythmic agents (3.5% to 1.4%, P <0.001), and first-generation calcium antagonists (21.3% to 9.6%, P <0.001). The trends in drug therapy were associated with a 2.8% reduction in age-, sex-, and comorbidity-adjusted 1-year mortality and a 4.1% reduction in 1-year hospitalization rates. The observed trends in therapy over time explained 37% of the decrease in mortality and 30% of the decrease in rehospitalization rates. The treatment effect from beta-blockers was most pronounced, explaining 30% of the decrease in mortality and 10% of the decrease in rehospitalization rates. CONCLUSION: During 1992 to 2000, mortality and morbidity improved among elderly patients with heart failure, with increased utilization of beta-blockers contributing most to the beneficial trends in outcomes.     

GABAergic synapses suppress intestinal innate immunity via insulin signaling in Caenorhabditis elegans

GABAergic neurotransmission constitutes a major inhibitory signaling mechanism that plays crucial roles in central nervous system physiology and immune cell immunomodulation. However, its roles in innate immunity remain unclear. Here, we report that deficiency in the GABAergic neuromuscular junctions (NMJs) of Caenorhabditis elegans results in enhanced resistance to pathogens, whereas pathogen infection enhances the strength of GABAergic transmission. GABAergic synapses control innate immunity in a manner dependent on the FOXO/DAF-16 but not the p38/PMK-1 pathway. Our data reveal that the insulin-like peptide INS-31 level was dramatically decreased in the GABAergic NMJ GABA_AR-deficient unc-49 mutant compared with wild-type animals. C. elegans with ins-31 knockdown or loss of function exhibited enhanced resistance to Pseudomonas aeruginosa PA14 exposure. INS-31 may act downstream of GABAergic NMJs and in body wall muscle to control intestinal innate immunity in a cell-nonautonomous manner. Our results reveal a signaling axis of synapse–muscular insulin–intestinal innate immunity in vivo.

Innate immunity, an evolutionally conserved behavior, constitutes the first defense line of multiple organisms to prevent microbial infections (1). The nematode Caenorhabditis elegans has been used as a model host for human opportunistic pathogen Pseudomonas aeruginosa infection (2) to identify evolutionarily conserved mechanisms of innate immunity. Typically, p38/PMK-1 mitogen-activated protein kinases (MAPKs) (3) and insulin/insulin-like signaling (IIS)/DAF-2 signaling cascades are recognized as two key components of the C. elegans intestinal innate immune response upon P. aeruginosa strain PA14 infection (4), as they are in mammals (3, 4). Moreover, increasing evidence has revealed several neural mechanisms as also being involved in the regulation of innate immunity. For example, G protein–coupled receptor (GPCR) NPR-1– and soluble guanylate cyclase GCY-35–expressing sensory neurons actively suppress the immune response of nonneuronal tissues (5). Additionally, a putative octopamine GPCR, OCTR-1, which is expressed and functions in the C. elegans sensory neurons ASH and ASI (6), down-regulates the unfolded protein response genes pqn/abu to further suppress the immune response of nonneuronal tissues (5, 6).Recent studies demonstrate that dopaminergic signaling inhibits innate immunity (7) whereas neuronal acetylcholine stimulates muscarinic signaling in the epithelium and activates the epithelial canonical Wnt pathway to promote the ability to defend against bacterial infection (8). Moreover, insulin-like peptide INS-7 secreted by the nervous system functions in a cell-nonautonomous manner to activate the IIS/DAF-2 pathway and modulate the intestinal innate immunity of C. elegans (9).GABAergic signaling constitutes a major inhibitory neurotransmission system that plays crucial roles in the central nervous system, especially for maintaining the balance between excitation and inhibition of neuronal networks (10). Disruption of this balance is not only linked to several neuropsychiatric disorders including schizophrenia, autism, and epilepsy (11) but also implicated in autoimmune disease (12). Up to date, multiple lines of evidence have shown that GABAergic signaling cell-autonomously modulates the immune response in immune cells (13–15). However, the roles of GABAergic synapses in innate immunity remain unknown.Here, we found that the nematode C. elegans harboring a deficiency in GABAergic neuromuscular junctions (NMJs) exhibits enhanced resistance to pathogens. P. aeruginosa PA14 infection increases synaptic expression of GABAergic synaptic components at the nerve cord of worms and enhances the strength of GABAergic transmission. Moreover, we identified an insulin-like peptide, INS-31, acting downstream of GABAergic NMJs and in body wall muscle (BWM) to control intestinal innate immunity in a cell-nonautonomous manner. This work reveals a signaling axis of synapse–muscular insulin–intestinal innate immunity in vivo.     

Is rectal intussusception a cause of idiopathic incontinence?

PURPOSE: The cause of rectal intussusception in patients primarily dominated by symptoms of anal incontinence has not been fully elucidated, especially for patients with idiopathic incontinence. METHODS: Between 1991 and 1996, 51 patients referred with a diagnosis of idiopathic incontinence were prospectively evaluated by standard questionnaire, clinical examination, defecography, and anal manometry. Fourteen female patients were identified with rectal intussusception and were treated by transabdominal rectopexy. Postoperatively, clinical assessment and anal manometry were performed at regular intervals. RESULTS: Continence was improved after rectopexy (P<0.01). The postoperative increases in the anal resting pressure, maximum squeeze pressure, and maximum tolerated volume were not statistically significant. CONCLUSIONS: Rectopexy improved anal incontinence in patients with rectal intussusception. The cause of rectal intussusception in anal incontinence could not be explained by functional improvement of the internal anal sphincter tone or an increase in the maximum tolerated volume. Rectal intussusception may be a cause of idiopathic incontinence in patients; however, larger prospective studies are required to support this concept.     

An Endoscopic Transluminal Approach,Compared With Minimally Invasive Surgery,Reduces Complications and Costs for Patients With Necrotizing Pancreatitis

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Induction of angiogenesis in tissue-engineered scaffolds designed for bone repair: a combined gene therapy-cell transplantation approach

One of the fundamental principles underlying tissue engineering approaches is that newly formed tissue must maintain sufficient vascularization to support its growth. Efforts to induce vascular growth into tissue-engineered scaffolds have recently been dedicated to developing novel strategies to deliver specific biological factors that direct the recruitment of endothelial cell (EC) progenitors and their differentiation. The challenge, however, lies in orchestration of the cells, appropriate biological factors, and optimal factor doses. This study reports an approach as a step forward to resolving this dilemma by combining an ex vivo gene transfer strategy and EC transplantation. The utility of this approach was evaluated by using 3D poly(lactide-co-glycolide) (PLAGA) sintered microsphere scaffolds for bone tissue engineering applications. Our goal was achieved by isolation and transfection of adipose-derived stromal cells (ADSCs) with adenovirus encoding the cDNA of VEGF. We demonstrated that the combination of VEGF releasing ADSCs and ECs results in marked vascular growth within PLAGA scaffolds. We thereby delineate the potential of ADSCs to promote vascular growth into biomaterials.     

Risk factors associated with diabetic foot ulcer-free survival in patients with diabetes

Aims

This study was done to assess the risk factors associated with diabetic foot ulcer-free survival in patients with diabetes.

Network Tomography for Understanding Phenotypic Presentations in Aortic Stenosis

Objectives

This study sought to build a patient?patient similarity network using multiple features of left ventricular (LV) structure and function in patients with aortic stenosis (AS). The study further validated the observations in an experimental murine model of AS.