Clopidogrel: How good is it and how does it work?

Until recently, long-term antiplatelet therapy for the treatment and prevention of the complications of atherothrombotic disease was limited to aspirin. Although an incredibly costeffective therapy, in placebo-controlled clinical trials approximately 75% of patients at risk continue to experience thrombotic events despite chronic aspirin therapy. The availability of the thienopyridines, in particular clopidogrel, represents an important addition to the physician’s armamentarium. A number of clinical trials have confirmed the efficacy of the combination of clopidogrel and aspirin therapy compared with aspirin alone, with multiple other important largescale clinical trials currently ongoing. The exact mechanism of this benefit is still being elucidated but is clearly related to the inhibition of the many consequences of platelet activation—vascular inflammation, endothelial dysfunction, and localized angiogenesis/mitogenesis—and not just aggregation.     

Pacing for hypertrophic obstructive cardiomyopathy does it work?

Sixty-nine years old lady presented with sudden cardiac arrest, she was found to have hypertrophic obstructive cardiomyopathy, she refused septal myomectomy and had a dual chamber ICD implanted, she was put on right ventricular apical pacing with short AV interval, after pacing her max pressure gradient across left ventricular out flow tract (LVOT) dropped from 117 mmHg to 21 mmHg and her symptoms much improved over a follow up period of 1 year.     

Screening for lung cancer: it works, but does it really work?

After the publication of the NLST (National Lung Screening Trial) results, physicians will be faced with whether to begin ordering low-dose computed tomography (LDCT) of the chest to screen for lung cancer in patients with a history of tobacco use. Despite the encouraging reduction in deaths observed by using LDCT in the NLST study population, recommending adoption of lung cancer screening in general practice is premature. Lessons learned from prostate and breast cancer screening should remind us that the reductions in deaths expected with screening are unfortunately not as readily achievable as initially believed. Furthermore, the potential harms of false-positive findings on chest computed tomography are very real. The morbidity and even mortality associated with invasive diagnostic testing and surgical resection due to false- and true-positive findings on computed tomography are likely to increase when the approach taken in the NLST is applied in non-specialty care settings and among the population at highest risk, namely, those with smoking-related comorbid conditions. Although the NLST results are perhaps encouraging, they do not tell us enough that we can be sure that patients who undergo LDCT in an attempt to find early-stage lung cancer will have more benefit than harm.     

Pneumococcal vaccination in adults: does it really work?

The universal burden of pneumococcal disease is high. As pneumococcal capsular antigens induce serotype specific antibodies, both the available vaccines (polysaccharide and polysaccharide conjugated) are able to produce serological response. However, there is reasonable skepticism about the effectiveness and efficacy of the 23-valent polysaccharide vaccine, especially in the elderly and in immunocompromised adults. Results from numerous studies are conflicting but the more recent data suggest that polysaccharide vaccine raises inadequate protection against non-bacteremic pneumonia, while the benefit against invasive pneumococcal disease in high-risk population is uncertain. On the contrary, conjugate vaccine, -originally indicated only for infants and young children- appears to be highly effective but it does not cover the tremendous diversity of pneumococcal serotypes being able to cause disease in adults. Despite this, there is growing evidence that conjugate vaccines, due to their superior immunogenicity, could also be offered for adult vaccination, but still there are certain issues that warrant further investigation.     

Graded activity for workers with low back pain: who benefits most and how does it work?

OBJECTIVE: To identify subgroups of workers absent from work due to low back pain who are more or less likely to return to work earlier as a result of a graded activity intervention, and to investigate whether this intervention is effective in reducing pain-related fears and if so, whether these reductions in pain-related fears mediate return to work. METHODS: A subgroup analysis was conducted on data from a previous randomized controlled trial of 134 Dutch airline workers, which found that a behaviorally-oriented graded activity intervention was more effective than usual care in stimulating return to work. The subgroup analyses added interaction terms to a Cox regression model that described the relationship between treatment allocation and return to work over 12 months of followup. Furthermore, we studied the effects of graded activity on pain-related fears and added variables indicating a reduction in pain-related fears to the model in order to investigate their influence on return to work. RESULTS: Statistically significant interactions were found for disability, fear-avoidance beliefs about physical activity, and fear-avoidance beliefs about work. No indication was found that the reduction in pain-related fears in the graded activity group mediated more favorable return-to-work results in this group. CONCLUSION: Workers who perceive their disability to be moderate and workers with moderate scores for fear-avoidance beliefs return to work more rapidly as a result of the graded activity intervention than workers with higher scores. The return to work of workers receiving the graded activity intervention is possibly independent from the reductions in pain-related fears caused by this intervention.     

Endogenous cardioprotective mechanisms - what is it about and how does it work?

Reperfusion therapy is the primary treatment for acute myocardial infarction. Its infarct-limiting effectiveness is, however, limited by so called reperfusion-induced myocardial injury likely related to reperfusion-mediated opening of the mitochondrial permeability transition pore (mPTP). While pharmacologic cardioprotection has proved to effectively reduce infarct size in the experimental models its clinical usefulness is problematic. In this context, a clinical exploitation of endogenous cardioprotective mechanisms, known as ischaemic preconditioning and ischaemic postconditioning, emerges as an attractive therapeutic alternative. This is particularly so because ischaemic pre- and post-conditionig seem to afford cardioprotection by preventing reperfusion-induced deleterious opening of mPTP.     

No antibiotics in acute uncomplicated diverticulitis: does it work?

Abstract

Background. The first randomized multicenter study evaluating the need for antibiotic treatment in patients with acute uncomplicated diverticulitis (AUD) could not demonstrate any benefit gained from antibiotic use. The aim of this study was to review the application of the no antibiotic policy and its consequences in regard to complications and recurrence. Methods. This retrospective population-based cohort study included all patients diagnosed with all types of colonic diverticulitis during the year 2011 at Västmanland Hospital Västerås, Sweden. All medical records were carefully reviewed. Primary outcomes were the types of treatment adopted for diverticulitis, complications and recurrence. Results. In total, 246 patients with computer tomography-verified diverticulitis were identified, 195 with primary AUD and 51 with acute complicated diverticulitis. Age, sex, and temperature at admission were similar between the groups but there was a significant difference in white blood cell count, C-reactive protein, and length of hospital stay. In the AUD group, 178 (91.3%) patients were not treated with antibiotics. In this group, there were six (3.4%) readmissions but only two developed an abscess. Of the remaining 17 patients (8.7%) who were treated with antibiotics in the AUD group, one developed an abscess. Twenty-five (12.8%) patients in the AUD group presented with a recurrence within 1 year. Conclusion. The no-antibiotic policy for AUD is safe and applicable in clinical practice. The previous results of a low complication and recurrence rate in AUD are confirmed. There is no need for antibiotic treatment for AUD.

What does this paper add to the literature? Despite published papers with excellent results, there are still doubts about patient safety against the policy to not use antibiotics in acute uncomplicated diverticulitis. This is the first paper, in actual clinical practice, to confirm that the no antibiotic policy for acute uncomplicated diverticulitis is applicable and safe.     

Health status: what does it mean for payers and patients?

Disturbances to health can be divided broadly into limitations of basic activities of daily living (washing, dressing, etc.) that are common to all patients and other limitations that depend on individual circumstances. A distinction should be drawn between health status and health-related quality of life. Health status questionnaires are standardized for "typical patients," and this should be borne in mind when interpreting such scores from studies that give an average result using population-based measurements. Such studies give a good indication to payers of the average effects of a treatment, but provide no indication other than probability of benefit to individuals. This applies even more with health improvements that manifest uniquely in each patient. Two widely used disease-specific questionnaires in chronic obstructive pulmonary disease-the Chronic Respiratory Questionnaire and the St. George's Respiratory Questionnaire-are health status, rather than quality of life, instruments. Health status scores from questionnaires provide measures of the effects of disease, not measures of the disease itself. The relationship between high health status score and increased risk of dying is due to the fact that both reflect underlying disease activity. In therapeutic studies, health status improves because the underlying disease activity has been moderated by therapy. Improved health does not improve mortality or morbidity per se. It is also important to appreciate that the impact of any measured change in health may also be determined by the patient's baseline state.     

BCR-ABL in chronic myelogenous leukemia--how does it work?

The discovery of the BCR-ABL fusion gene on the Philadelphia (Ph) chromosome in 1985 was the start of a new era in understanding the molecular basis of hematologic malignancies. It provided the rationale for producing first imatinib and then a series of small molecules designed to inhibit the tyrosine kinase activity of the Bcr-Abl oncoprotein, all of which can induce complete cytogenetic remissions in the majority of patients with chronic myelogenous leukemia (CML) in the chronic phase. However, we still do not know for sure whether the BCR-ABL fusion gene is really the initiating lesion for the chronic phase of CML and we have an incomplete understanding of the so-called genomic instability that underlies the production of the fusion gene and predisposes the Ph-positive clone to acquire further genetic events that lead to advanced-phase disease. Moreover, it is clear that though some of the mutant Ph-positive subclones that develop in patients taking tyrosine kinase inhibitors (TKIs) are the direct cause of the resistance observed, in other cases, its cause is unclear. It is likely that in the next few years we will see (1) improved methods for predicting responses to TKIs, (2) the use of TKIs in combination with other effective molecules such as farnesyl transferase inhibitors, and (3) a gradual reduction in the proportion of chronic-phase patients resistant to therapy.     

NO and the vasculature: where does it come from and what does it do?

Nitric oxide (NO) is involved in a large number of cellular processes and dysfunctions in NO production have been implicated in many different disease states. In the vasculature NO is released by endothelial cells where it modulates the underlying smooth muscle to regulate vascular tone. Due to the unique chemistry of NO, such as its reactive and free radical nature, it can interact with many different cellular constituents such as thiols and transition metal ions, which determine its cellular actions. In this review we also discuss many of the useful pharmacological tools that have been developed and used extensively to establish the involvement of NO in endothelium-derived relaxations. In addition, the recent literature identifying a potential source of NO in endothelial cells, which is not directly derived from endothelial nitric oxide synthase is examined. Finally, the photorelaxation phenomena, which mediates the release of NO from a vascular smooth muscle NO store, is discussed.     

Nongenomic, ER-mediated activation of endothelial nitric oxide synthase: how does it work? What does it mean?

The administration of estrogens in animals tends to inhibit the development of atherosclerosis. [Therefore], attempts are being made in human males to prevent further progress of the disease in cases of angina or previous coronary thrombosis by long-range estrogen therapy. This work is in its infancy. It is hoped that, with further research, compounds might be found that eliminate the undesirable action of such hormones and yet retain its beneficial effects on arteries (Samuel A. Levine, 1958).