BMC Medicine - Latest Articles

Special considerations in prognostic research in cancer involving genetic polymorphisms

Sevtap Savas — 2013-06-17T00:00:00Z

Analysis of genetic polymorphisms may help identify putative prognostic markers and determine the biological basis of variable prognosis in patients. However, in contrast to other variables commonly used in the prognostic studies, there are special considerations when studying genetic polymorphisms. For example, variable inheritance patterns (recessive, dominant, codominant, and additive genetic models) need to be explored to identify the specific genotypes associated with the outcome. In addition, several characteristics of genetic polymorphisms, such as their minor allele frequency and linkage disequilibrium among multiple polymorphisms, and the population substructure of the cohort investigated need to be accounted for in the analyses. In addition, in cancer research due to the genomic differences between the tumor and non-tumor DNA, differences in the genetic information obtained using these tissues need to be carefully assessed in prognostic studies. In this article, we review these and other considerations specific to genetic polymorphism by focusing on genetic prognostic studies in cancer.

When to Start Antiretroviral Therapy: The Need for an Evidence Base During Early HIV Infection

Jens Lundgren — 2013-06-14T00:00:00Z

Background: Strategies for use of antiretroviral therapy (ART) have traditionally focused on providing treatment to persons who stand to benefit immediately from initiating the therapy. There is global consensus that any HIV+ person with CD4 counts less than 350 cells/μl should initiate ART. However, it remains controversial whether ART is indicated in asymptomatic HIV-infected persons with CD4 counts above 350 cells/μl, or whether it is more advisable to defer initiation until the CD4 count has dropped to 350 cells/μl. The question of when the best time is to initiate ART during early HIV infection has always been vigorously debated. The lack of an evidence base from randomized trials, in conjunction with varying degrees of therapeutic aggressiveness and optimism tempered by the risks of drug resistance and side effects, has resulted in divided expert opinion and inconsistencies among treatment guidelines.DiscussionOn the basis of recent data showing that early ART initiation reduces heterosexual HIV transmission, some countries are considering adopting a strategy of universal treatment of all HIV+ persons irrespective of their CD4 count and whether ART is of benefit to the individual or not, in order to reduce onward HIV transmission. Since ART has been found to be associated with both short-term and long-term toxicity, defining the benefit:risk ratio is the critical missing link in the discussion on earlier use of ART. For early ART initiation to be justified, this ratio must favor benefit over risk. An unfavorable ratio would argue against using early ART.SummaryThere is currently no evidence from randomized controlled trials to suggest that a strategy of initiating ART when the CD4 count is above 350 cells/μl (versus deferring initiation to around 350 cells/μl) results in benefit to the HIV+ person and data from observational studies are inconsistent. Large, clinical endpoint-driven randomized studies to determine the individual health benefits versus risks of earlier ART initiation are sorely needed.The counter-argument to this debate topic can be freely accessed here: http://www.biomedcentral.com/1741-7015/11/147.

When to Start Antiretroviral Therapy: As Soon As Possible

Ricardo Franco — 2013-06-14T00:00:00Z

Background: The debate regarding ‘When to Start’ antiretroviral therapy has raged since the introduction of zidovudine in 1987. Based on the entry criteria for the original Burroughs Wellcome 002 study, the field has been anchored to CD4 cell counts as the prime metric to indicate treatment initiation for asymptomatic individuals infected with Human Immunodeficiency Virus. The pendulum has swung back and forth based mostly on the relative efficacy, toxicity and convenience of available regimens.DiscussionIn today’s world, several factors have converged that compel us to initiate therapy as soon as possible: 1) The biology of viral replication (1 to 10 billion viruses per day) strongly suggests that we should be starting early. 2) Resultant inflammation from unchecked replication is associated with earlier onset of multiple co-morbid conditions. 3) The medications available today are more efficacious and less toxic than years past. 4) Clinical trials have demonstrated benefits for all but the highest CD4 strata (>500 cells/μl). 5) Some cohort studies have demonstrated the clear benefit of antiretroviral therapy at any CD4 count and no cohort studies have demonstrated that early therapy is more detrimental than late therapy at the population level. 6) In addition to the demonstrated and inferred benefits to the individual patient, we now have evidence of a Public Health benefit from earlier intervention: treatment is prevention.SummaryFrom a practical, common sense perspective we are talking about life-long therapy. Whether we start at a CD4 count of 732 cells/μl or 493 cells/μl, the patient will be on therapy for over 40 to 50 years. There does not seem to be much benefit in waiting and there likely is significant long-term harm. Do not wait. Treat early.The counter-argument to this debate topic can be freely accessed here: http://www.biomedcentral.com/1741-7015/11/148.

Phenotype, donor age and gender affect function of human bone marrow-derived mesenchymal stromal cells

Georg Siegel — 2013-06-11T00:00:00Z

Background: Mesenchymal stromal cells (MSCs) are attractive for cell-based therapies ranging from regenerative medicine and tissue engineering to immunomodulation. However, clinical efficacy is variable and it is unclear how the phenotypes defining bone marrow (BM)-derived MSCs as well as donor characteristics affect their functional properties. Methods: BM-MSCs were isolated from 53 (25 female, 28 male; age: 13 to 80 years) donors and analyzed by: (1) phenotype using flow cytometry and cell size measurement; (2) in vitro growth kinetics using population doubling time; (3) colony formation capacity and telomerase activity; and (4) function by in vitro differentiation capacity, suppression of T cell proliferation, cytokines and trophic factors secretion, and hormone and growth factor receptor expression. Additionally, expression of Oct4, Nanog, Prdm14 and SOX2 mRNA was compared to pluripotent stem cells. Results: BM-MSCs from younger donors showed increased expression of MCAM, VCAM-1, ALCAM, PDGFRbeta, PDL-1, Thy1 and CD71, and led to lower IL-6 production when co-cultured with activated T cells. Female BM-MSCs showed increased expression of IFN-gammaR1 and IL-6beta, and were more potent in T cell proliferation suppression. High-clonogenic BM-MSCs were smaller, divided more rapidly and were more frequent in BM-MSC preparations from younger female donors. CD10, beta1integrin, HCAM, CD71, VCAM-1, IFN-gammaR1, MCAM, ALCAM, LNGFR and HLA ABC were correlated to BM-MSC preparations with high clonogenic potential and expression of IFN-gammaR1, MCAM and HLA ABC was associated with rapid growth of BM-MSCs. The mesodermal differentiation capacity of BM-MSCs was unaffected by donor age or gender but was affected by phenotype (CD10, IFN-gammaR1, GD2). BM-MSCs from female and male donors expressed androgen receptor and FGFR3, and secreted VEGF-A, HGF, LIF, Angiopoietin-1, basic fibroblast growth factor (bFGF) and NGFB. HGF secretion correlated negatively to the expression of CD71, CD140b and Galectin 1. The expression of Oct4, Nanog and Prdm14 mRNA in BM-MSCs was much lower compared to pluripotent stem cells and was not related to donor age or gender. Prdm14 mRNA expression correlated positively to the clonogenic potential of BM-MSCs. Conclusions: By identifying donor-related effects and assigning phenotypes of BM-MSC preparations to functional properties, we provide useful tools for assay development and production for clinical applications of BM-MSC preparations.

Origins of increased airway smooth muscle mass in asthma

Rachid Berair — 2013-06-06T00:00:00Z

Asthma is characterized by both chronic inflammation and airway remodeling. Remodeling - the structural changes seen in asthmatic airways - is pivotal in the pathogenesis of the disease. Although significant advances have been made recently in understanding the different aspects of airway remodeling, the exact biology governing these changes remains poorly understood. There is broad agreement that, in asthma, increased airway smooth muscle mass, in part due to smooth muscle hyperplasia, is a very significant component of airway remodeling. However, significant debate persists on the origins of these airway smooth muscle cells. In this review article we will explore the natural history of airway remodeling in asthma and we will discuss the possible contribution of progenitors, stem cells and epithelial cells in mesenchymal cell changes, namely airway smooth muscle hyperplasia seen in the asthmatic airways.

Ipsilateral lower extremity joint involvement increases the risk of poor pain and function outcomes after hip or knee arthroplasty

Jasvinder Singh — 2013-06-05T00:00:00Z

Background: Poor pain and function outcomes are undesirable after an elective surgery such as total hip or knee arthroplasty (THA/TKA). Recent studies have indicated that the presence of contralateral joint influences outcomes of THA/TKA, however the impact of ipsilateral knee/hip involvement on THA/TKA outcomes has not been explored. The objective of this study was to assess the association of ipsilateral knee/hip joint involvement on short-term and medium-term pain and function outcomes after THA/TKA. Methods: In this retrospective study of prospectively collected data, we used the data from the Mayo Clinic Total Joint Registry to assess the association of ipsilateral knee or hip joint involvement with moderate to severe pain and moderate to severe activity limitation at 2-year and 5-year follow-up after primary and revision THA and TKA using multivariable-adjusted logistic regression analyses. Results: At 2 years, 3,823 primary THA, 4,701 primary TKA, 1,218 revision THA and 725 revision TKA procedures were studied. After adjusting for multiple covariates, ipsilateral knee pain was significantly associated with outcomes after primary THA (all P values <0.01): (1) moderate to severe pain: at 2 years, odds ratio (OR), 2.3 (95% confidence interval (CI) 1.5 to 3.6); at 5 years, OR 1.8 (95% CI 1.1 to 2.7); (2) moderate to severe activity limitation: at 2 years, OR 3.1 (95% CI 2.3 to 4.3); at 5 years, OR 3.6 (95% CI 2.6 to 5.0). Ipsilateral hip pain was significantly associated with outcomes after primary TKA (all P values <0.01): (1) moderate to severe pain: at 2 years, OR 3.3 (95% CI 2.3 to 4.7); at 5 years, OR 1.8 (95% CI 1.1 to 2.7); (2) moderate to severe activity limitation: at 2 years, OR 3.6 (95% CI 2.6 to 4.9); at 5 years, OR 2.2 (95% CI 1.6 to 3.2). Similar associations were noted for revision THA and TKA patients. Conclusions: To the best of our knowledge, this is the first study showing that the presence of ipsilateral joint involvement after THA or TKA is strongly associated with poor pain and function outcomes. A potential way to improve outcomes is to address ipsilateral lower extremity joint involvement.

The collateral circulation of the heart

Pascal Meier — 2013-06-04T00:00:00Z

The coronary arteries have been regarded as end arteries for decades. However, there are functionally relevant anastomotic vessels, known as collateral arteries, which interconnect epicardial coronary arteries. These vessels provide an alternative source of blood supply to the myocardium in cases of occlusive coronary artery disease. The relevance of these collateral arteries is a matter of ongoing debate, but increasing evidence indicates a relevant protective role in patients with coronary artery disease. The collateral circulation can be assessed by different methods; the gold standard involves intracoronary pressure measurements. While the first clinical trials to therapeutically induce growth of collateral arteries have been unavailing, recent pilot studies using external counterpulsation or growth factors such as granulocyte colony stimulating factor (G-CSF) have shown promising results.

Venous hemodynamics in neurological disorders: an analytical review with hydrodynamic analysis

Clive Beggs — 2013-05-31T00:00:00Z

Venous abnormalities contribute to the pathophysiology of several neurological conditions. This paper reviews the literature regarding venous abnormalities in multiple sclerosis (MS), leukoaraiosis, and normal-pressure hydrocephalus (NPH). The review is supplemented with hydrodynamic analysis to assess the effects on cerebrospinal fluid (CSF) dynamics and cerebral blood flow (CBF) of venous hypertension in general, and chronic cerebrospinal venous insufficiency (CCSVI) in particular.CCSVI-like venous anomalies seem unlikely to account for reduced CBF in patients with MS, thus other mechanisms must be at work, which increase the hydraulic resistance of the cerebral vascular bed in MS. Similarly, hydrodynamic changes appear to be responsible for reduced CBF in leukoaraiosis. The hydrodynamic properties of the periventricular veins make these vessels particularly vulnerable to ischemia and plaque formation.Venous hypertension in the dural sinuses can alter intracranial compliance. Consequently, venous hypertension may change the CSF dynamics, affecting the intracranial windkessel mechanism. MS and NPH appear to share some similar characteristics, with both conditions exhibiting increased CSF pulsatility in the aqueduct of Sylvius.CCSVI appears to be a real phenomenon associated with MS, which causes venous hypertension in the dural sinuses. However, the role of CCSVI in the pathophysiology of MS remains unclear.

Why do hypertensive patients of African ancestry respond better to calcium blockers and diuretics than to ACE inhibitors and β-adrenergic blockers? A systematic review

Lizzy Brewster — 2013-05-30T00:00:00Z

Background: Clinicians are encouraged to take an individualized approach when treating hypertension in patients of African ancestry, but little is known about why the individual patient may respond well to calcium blockers and diuretics, but generally has an attenuated response to drugs inhibiting the renin-angiotensin system and to β-adrenergic blockers. Therefore, we systematically reviewed the factors associated with the differential drug response of patients of African ancestry to antihypertensive drug therapy. Methods: Using the methodology of the systematic reviews narrative synthesis approach, we sought for published or unpublished studies that could explain the differential clinical efficacy of antihypertensive drugs in patients of African ancestry. PUBMED, EMBASE, LILACS, African Index Medicus and the Food and Drug Administration and European Medicines Agency databases were searched without language restriction from their inception through June 2012. Results: We retrieved 3,763 papers, and included 72 reports that mainly considered the 4 major classes of antihypertensive drugs, calcium blockers, diuretics, drugs that interfere with the renin-angiotensin system and β-adrenergic blockers. Pharmacokinetics, plasma renin and genetic polymorphisms did not well predict the response of patients of African ancestry to antihypertensive drugs. An emerging view that low nitric oxide and high creatine kinase may explain individual responses to antihypertensive drugs unites previous observations, but currently clinical data are very limited. Conclusion: Available data are inconclusive regarding why patients of African ancestry display the typical response to antihypertensive drugs. In lieu of biochemical or pharmacogenomic parameters, self-defined African ancestry seems the best available predictor of individual responses to antihypertensive drugs.

Is a combination of varenicline and nicotine patch more effective in helping smokers quit than varenicline alone? A randomised controlled trial

Peter Hajek — 2013-05-29T00:00:00Z

Background: Nicotine replacement therapy (NRT) and varenicline are both effective in helping smokers quit. There is growing interest in combining the two treatments to improve treatment outcomes, but no experimental data exist on whether this is efficacious. This double-blind randomized controlled trial was designed to evaluate whether adding nicotine patches to varenicline improves withdrawal relief and short-term abstinence rates. Methods: In total, 117 participants seeking help to stop smoking were randomly allocated to varenicline plus placebo patch or to varenicline plus nicotine patch (15 mg/16 hours). Varenicline use commenced 1 week before the target quit date (TQD), and patch use started on the TQD. Ratings of urges to smoke and cigarette withdrawal symptoms were collected weekly over the 4 weeks post-TQD. Medication use and smoking status were determined at 1, 4, and 12 weeks. Participants lost to follow-up were considered to be continuing smokers. Results: Over 95% of the participants used both medications during the first week after the TQD. The combination treatment generated no increase in nausea or other adverse events. It had no overall effect on urges to smoke or on other withdrawal symptoms. The combination treatment did not improve biochemically validated abstinence rates at 1 and 4 weeks post-TQD in the nicotine patch and placebo patch arm respectively (69% versus 59%, P = 0.28 and 60% versus 59%, P = 0.91), or self-reported abstinence rates at 12 weeks (36% versus. 29%, P = 0.39). Conclusion: The efficacy of varenicline was not enhanced by the addition of nicotine patches.Trial registration: Clinicaltrials.gov; Registration Number: NCT01184664