Distinct Strategies Employed by Dendritic Cells and Macrophages in Restricting Mycobacterium tuberculosis Infection: Different Philosophies but Same Desire

Dendritic cells (DCs) and macrophages (M?s) are professional antigen-presenting cells (APCs) that can efficiently phagocytose Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB). It is quite interesting to mention here that DCs and M?s use distinct strategies to combat and eliminate Mtb. Similarly, Mtb employs different mechanisms to counteract the action of DCs and M?s. M?s are evolved with specialized, innate, defensive machinery to restrict growth of Mtb at the initial phase of infection. However, DCs are more endowed toward initiating adaptive immunity by activating naïve T cells. During encounter with Mtb, DCs and M?s deliver discrete functions via triggering through different pattern recognition receptors (PRRs) expressed by these APCs. Mtb-infected DCs and M?s show differential expression of genes encoding cytokines, chemokines, costimulatory molecules, and adhesion molecules. Interestingly, Mtb impairs the immune defensive machinery by exploiting various PRRs. Remarkably, selective signaling through PRRs by Mtb abrogates the bactericidal activity of M?s, but subverts differentiation of monocytes to DCs. In this article, we highlight the role of PRRs in inducing distinct immune response by DCs and M?s against Mtb. Concurrently, we also discuss smart strategies exploited by Mtb to impair the function of host DCs and M?s.     

ACE Overexpression in Myelomonocytic Cells: Effect on a Mouse Model of Alzheimer’s Disease

The angiotensin AT2-receptor mediates tissue protective actions. Its regenerative potential has been tested in multiple disease models including models of myocardial infarction. These studies used different experimental approaches in order to detect AT2-receptor-related effects such as AT2-receptor deficiency or overexpression, treatment with an AT1-receptor blocker leading to indirect stimulation of the unopposed AT2-receptor, or studies using AT2-receptor agonists. It is a common finding in these studies that the AT2-receptor improves cardiac function in the early phase post-MI, and that this effect is preserved over periods of up to four months. Depending on the experimental protocol, the AT2R also attenuates post-MI left ventricular remodeling or protects the heart from early left ventricular thinning and rupture. In combination with AT1-receptor blockade or deficiency, post-MI cardiac hypertrophy is reduced. This article reviews studies on the role of the AT2-receptor in myocardial infarction with an emphasis on the most recent data obtained in studies using AT2-receptor agonists.     

Factors Associated with Intern Fatigue

BACKGROUND  Prior data suggest that fatigue adversely affects patient safety and resident well-being. ACGME duty hour limitations were intended, in part, to reduce resident fatigue, but the factors that affect intern fatigue are unknown. OBJECTIVE  To identify factors associated with intern fatigue following implementation of duty hour limitations. DESIGN  Cross-sectional confidential survey of validated questions related to fatigue, sleep, and stress, as well as author-developed teamwork questions. SUBJECTS  Interns in cognitive specialties at the University of California, San Francisco. MEASUREMENTS  Univariate statistics characterized the distribution of responses. Pearson correlations elucidated bivariate relationships between fatigue and other variables. Multivariate linear regression models identified factors independently associated with fatigue, sleep, and stress. RESULTS  Of 111 eligible interns, 66 responded (59%). In a regression analysis including gender, hours worked in the previous week, sleep quality, perceived stress, and teamwork, only poorer quality of sleep and greater perceived stress were significantly associated with fatigue (p < 0.001 and p = 0.02, respectively). To identify factors that may affect sleep, specifically duty hours and stress, a secondary model was constructed. Only greater perceived stress was significantly associated with diminished sleep quality (p = 0.04), and only poorer teamwork was significantly associated with perceived stress (p < 0.001). Working >80 h was not significantly associated with perceived stress, quality of sleep, or fatigue. CONCLUSIONS  Simply decreasing the number of duty hours may be insufficient to reduce intern fatigue. Residency programs may need to incorporate programmatic changes to reduce stress, improve sleep quality, and foster teamwork in order to decrease intern fatigue and its deleterious consequences.     

Safety of therapeutic beta-blockade in patients with coexisting bronchospastic airway disease and coronary artery disease

Atherosclerotic coronary artery disease and bronchospastic airway disease frequently coexist in older patients. There are substantial data suggesting reduced mortality with the use of beta-adrenergic blocking drugs in patients with symptomatic coronary artery disease, especially patients who have postmyocardial infarction and/or severe coronary artery disease associated with left ventricular dysfunction. Conversely, the use of beta-adrenergic blocking drugs (even selective beta(1)-adrenergic blocking drugs) has the potential of exacerbating bronchospasm. This prospective registry evaluates the safety of use of selective beta(1)-adrenergic blocking drugs in patients with symptomatic coronary artery disease and bronchospastic airway disease. A total of 835 consecutive patients with symptomatic coronary artery disease were prospectively evaluated for coexisting coronary and bronchospastic airway disease. Of these, 30 patients (mean age: 61 +/- 14 years) met the qualifying inclusion criteria. All these study patients except 1 (29/30 [96%]) reached therapeutic beta-blockade (resting heart rate <70 beats per minute). The 1 patient who discontinued use of beta-adrenergic blocking drugs as a result of lifestyle-limiting bronchospasm had no serious adverse outcome. No hospitalizations were required because of worsening bronchospasm. Ten percent of patients reported increased requirement of inhaled beta(2)-agonist use. The patients were followed for 15 +/- 9 months. One patient died of stroke at 22 weeks of follow-up. In conclusion, use of selective beta(1)-adrenergic blocking drugs at a therapeutic dose is safe (as long as careful clinical follow-up is available) and should be considered in all patients with coexisting symptomatic coronary artery disease and bronchospastic airway disease.     

Acute and long-term results after intra-arterial thrombolysis of occluded lower extremity bypass grafts using recombinant tissue plasminogen activator for acute limb-threatening ischemia

Occlusion of lower extremity vascular bypass grafts results in acute limb-threatening ischemia. The underlying cause of graft failure generally is distal anastomosis stenosis, and relief of culprit stenosis is a required to maintain long-term patency. Of the three thrombolytic agents used for prolonged infusion to accomplish fibrinolysis, streptokinase was the first to be used and is limited owing to the antigenicity that precludes repeated use. Urokinase had been the mainstay of thrombolytic therapy until it was withdrawn by the U.S. Food and Drug Administration in 1999 because of the potential of transmission of infectious agents during its manufacturing process. Recombinant tissue plasminogen activator (rt-PA) has not been studied adequately to assess safety and efficacy, and there are no standardized dosing guidelines. We report our experience with six patients presenting with acute limb-threatening ischemia attributable to thrombosis of synthetic lower extremity bypass grafts. After thrombolysis using rt-PA (mean bolus dose, 12.2 +/- 3.6 mg; range, 6-15 mg administered over 5 minutes followed by infusion at 2 mg/h for 15.6 +/- 6.4 hours; total dose, 51 +/- 16 mg), successful thrombolysis was achieved in 84% of the patients. The primary patency rate was 75% and the secondary patency rate 100% at 16 weeks. One patient underwent amputation owing to unsuccessful thrombolysis. No major bleeding or vascular complications occurred. We conclude that intra-arterial thrombolysis using rt-PA is a safe and effective therapy for patients with thrombotic occlusion of synthetic lower extremity bypass grafts presenting with acute limb-threatening ischemia and allows a high rate of secondary patency, avoiding amputation.     

Computational intelligence in early diabetes diagnosis: a review

The development of an effective diabetes diagnosis system by taking advantage of computational intelligence is regarded as a primary goal nowadays. Many approaches based on artificial network and machine learning algorithms have been developed and tested against diabetes datasets, which were mostly related to individuals of Pima Indian origin. Yet, despite high accuracies of up to 99% in predicting the correct diabetes diagnosis, none of these approaches have reached clinical application so far. One reason for this failure may be that diabetologists or clinical investigators are sparsely informed about, or trained in the use of, computational diagnosis tools. Therefore, this article aims at sketching out an outline of the wide range of options, recent developments, and potentials in machine learning algorithms as diabetes diagnosis tools. One focus is on supervised and unsupervised methods, which have made significant impacts in the detection and diagnosis of diabetes at primary and advanced stages. Particular attention is paid to algorithms that show promise in improving diabetes diagnosis. A key advance has been the development of a more in-depth understanding and theoretical analysis of critical issues related to algorithmic construction and learning theory. These include trade-offs for maximizing generalization performance, use of physically realistic constraints, and incorporation of prior knowledge and uncertainty. The review presents and explains the most accurate algorithms, and discusses advantages and pitfalls of methodologies. This should provide a good resource for researchers from all backgrounds interested in computational intelligence-based diabetes diagnosis methods, and allows them to extend their knowledge into this kind of research.     

Comparative analysis of different DNA-binding drugs for leishmaniasis cure: a pharmacoinformatics approach

Several experiments have been performed to test DNA-binding drugs to cure Leishmania infection. However, there are no details of pharmacoinformatics study. Herein, we have selected a good number of compounds from experimentally verified studies and performed a comparative analysis based on pharmacoinformatics techniques. In silico docking study was performed to observe the molecular level interactions of these known ligands with the DNA receptor by automated computational docking using Glide. A comparison between the calculated interaction energies and in silico ADME/T study was made. In agreement with drug likeness rules, our study suggests that seco-hydroxy-aza-CBI-TMI (compound 4b; GScore, -12.058) is a potential molecule for targeting the DNA to cure leishmaniasis.     

Long noncoding RNAs could be potential key players in the pathophysiology of Sjögren's syndrome

Long noncoding RNAs (lncRNAs) are a recently discovered class of noncoding functional RNAs encoded by metazoan genomes. Recent studies suggest a larger regulatory role for lncRNAs in critical biological and disease processes. Mounting evidence on the role of lncRNAs in regulating key processes of the immune system prompted us to hypothesize the role of lncRNAs as key regulators of the pathophysiology of Sjögren's syndrome (SS). We used two similar approaches based on reanalysis of microarray expression datasets and curation of lncRNA‐protein coding gene interactions from literature to derive support for our hypothesis. We also discuss potential caveats to our approach and suggest approaches to validate the hypothesis. Our analysis suggests the potential larger and hitherto unknown role of lncRNA regulatory networks in modulating the expression of key genes involved in the pathogenesis of SS and thereby modulating the pathophysiology of SS.