Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes

Context  Both bone mineral density (BMD) and fracture risk have a strong genetic component. Estrogen receptor (ESR1) is a candidate gene for osteoporosis, but previous studies of ESR1 polymorphisms in this field were hampered by small sample size, lack of standardization, and inconclusive results. Objective  To generate large-scale evidence on whether 3 common ESR1 polymorphisms (intron 1 polymorphisms XbaI [dbSNP: rs9340799] and PvuII [dbSNP: rs2234693] and promoter TA repeats microsatellite) and haplotypes thereof are associated with BMD and fractures. Design and Setting  Meta-analysis of individual-level data involving standardized genotyping of 18 917 individuals in 8 European centers. Main Outcome Measures  BMD of femoral neck and lumbar spine; all fractures and vertebral fractures by genotype. Results  No between-center heterogeneity was observed for any outcome in any genetic contrast. None of the 3 polymorphisms or haplotypes had any statistically significant effect on BMD in adjusted or unadjusted analyses, and estimated differences between genetic contrasts were 0.01 g/cm² or less. Conversely, we found significant reductions in fracture risk. In women homozygous for the absence of an XbaI recognition site, the adjusted odds of all fractures were reduced by 19% (odds ratio, 0.81 [95% CI, 0.71-0.93]; P = .002) and vertebral fractures by 35% (odds ratio, 0.65 [95% CI, 0.49-0.87]; P = .003). Effects on fractures were independent of BMD and unaltered in adjusted analyses. No significant effects on fracture risk were seen for PvuII and TA repeats. Conclusions  ESR1 is a susceptibility gene for fractures, and XbaI determines fracture risk by mechanisms independent of BMD. Our study demonstrates the value of adequately powered studies with standardized genotyping and clinical outcomes in defining effects of common genetic variants on complex diseases.      

Is an early invasive approach superior to a conservative strategy in patients with acute coronary syndrome?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether an early invasive approach (involving early coronary angiography followed by revascularisation if suitable) is superior to a conservative approach (with revascularisation only in patients with failed medical therapy) in patients with acute coronary syndrome. Altogether 282 papers were found using the reported search, of which seven presented the best evidence to answer the clinical question. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses of these papers are tabulated. We conclude that in patients diagnosed with acute coronary syndrome, an early invasive approach is clearly superior to a conservative approach.     

What is the optimal anticoagulation management of patients post-cardiac surgery who go into atrial fibrillation?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether anticoagulation is indicated for patients in atrial fibrillation (AF) following coronary artery bypass grafting. Altogether 166 papers were found using the reported search, of which 10 presented the best evidence to answer the clinical question. In addition the American Heart Association guidelines for management of atrial fibrillation were reviewed. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses of these papers are tabulated. We conclude that patients post-cardiac surgery require warfarinisation while in atrial fibrillation with an INR of 2-3, and full anticoagulation should be commenced within 48 h of the onset of AF as their risk of stroke is doubled by the onset of AF.     

Does ultrasound-guided central line insertion reduce complications and time to placement in elective patients undergoing cardiac surgery

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether ultrasound probe central line placement reduced complications and time to placement in patients undergoing coronary artery bypass grafting surgery. Altogether, 193 papers were found from Medline using the reported search of which 6 papers presented the best evidence to answer the clinical question. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses and comments were tabulated. We conclude that in patients with a potentially difficult central line insertion, the ultrasound technique reduces complications and time to insertion. However, in those patients where no difficulty is predicted, there is no evidence that the ultrasound technique confers any advantage.     

Is transmyocardial revascularisation of benefit in addition to coronary artery bypass grafting for patients with diffuse coronary disease?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether the use of transmyocardial revascularisation (TMR) in addition to coronary artery bypass grafting (CABG) is of benefit in patients with ischaemic heart disease with areas of ungraftable myocardium. Altogether 233 papers were found using the reported search, of which 9 represented the best evidence to answer the clinical question. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses were tabulated. We conclude that while the society of thoracic surgeons now recommend TMR+CABG, and the available studies indicate that mortality is not increased by this additional procedure, it is currently not clear whether TMR reduces symptoms of angina in addition to CABG alone.     

Long-term follow-up with stress echocardiograms of patients with Kawasaki's disease

Patients with a history of Kawasaki's disease (KD), particularly those not treated with intravenous gamma-globulin, are at risk of coronary artery aneurysms and later obstruction. Twenty-eight patients with a history of KD (4 had coronary artery aneurysms) were examined with stress echocardiograms. Fourteen patients received gamma-globulin < or =10 days of the onset, 8 patients received gamma-globulin >10 days and 6 received no gamma-globulin. The mean age at diagnosis was 7.2 +/- 4.1 years; the median follow-up was 8.0 +/- 7.4 years. All tests were negative. Using a binomial model, a power of 0.80, a sensitivity of each test of 80% and assuming uniform risk, the individual rate of failure to detect was <7%. At least 640 patients in each group would be needed to detect a difference of 3.5% vs. 7.0% and 184 in each group would be needed to detect a difference of 1.5% vs. 7.5%. We conclude that the probability of an abnormal stress echo in asymptomatic patients with a history of KD is at most 7% and that a more precise determination of the risk of an abnormal stress echo in KD requires a much larger study.     

Double aortic arch masquerading as asthma for thirty years

A case of a 30-year-old woman with a double-barrelled aorta misdiagnosed as asthma is presented. The patient was significantly improved after surgical treatment but a degree of airway symptoms persisted. She was further investigated and diagnosed with tracheomalacia. The paediatric experience with managing tracheomalacia is briefly reviewed and recommendations for the treatment of the rare adult cases are made. Our report emphasises the importance of early diagnosis and treatment of aortic arch abnormalities.     

Activation of peripheral excitatory amino acid receptors decreases the duration of local anesthesia

BACKGROUND: Postsurgical wound infiltration with the -methyl-d-aspartate receptor antagonist ketamine and bupivacaine can significantly prolong the duration of local anesthesia. One possible mechanism for this effect is that increased glutamate concentrations, caused by tissue damage, sensitize nociceptive primary afferent fibers through activation of peripheral excitatory amino acid receptors. METHODS: The effect of intramuscular injection of hyper-tonic glutamate (1,000 mm), dextrose (1,400 mm), glutamate (1,000 mm) with the broad spectrum excitatory amino acid receptor antagonist kynurenate (100 mm), or isotonic saline (155 mm) on the duration of masseter muscle afferent fiber blockade after lidocaine (37 mm [1%], 10 microl) infiltration, on muscle edema formation and on muscle blood flow was examined. RESULTS: Injection of either glutamate or dextrose significantly shortened the duration of lidocaine blocks compared with isotonic saline; however, block duration was significantly shorter after glutamate than after dextrose. Injection of glutamate, but not isotonic saline, dextrose, or glutamate with kynurenate, significantly decreased the mechanical threshold of muscle afferent fibers. Injection of glutamate, dextrose, or glutamate with kynurenate produced equivalent large, long-lasting (> 60 min) edemas with high initial peak extracellular water content. Peak extracellular water decreased more rapidly when kynurenate was coinjected with glutamate. Both glutamate and dextrose significantly increased muscle blood flow for 30 min after injection. Glutamate-induced increases in blood flow were attenuated by kynurenate. CONCLUSIONS: These results suggest that shortened lidocaine block durations observed after glutamate injection into the masseter muscle result from sensitization of afferent fibers as well as increases of peak extracellular water content and blood flow in masseter muscle. These effects of glutamate are mediated in part through activation of peripheral excitatory amino acid receptors.     

Towards evidence-based medicine in cardiothoracic surgery: best BETS

Cardiothoracic surgeons are faced with the dilemma that many clinical questions in their daily practice to do not have universally agreed answers, but patients increasingly demand the 'best practice' from their doctors. In addition time pressures mean that clinicians are unable to keep up with the full spectrum of published research and current resources that collate evidence for clinicians have few if any resources for cardiothoracic surgeons. We have adopted an approach pioneered in emergency medicine, namely the Best Evidence Topic or BestBET. Clinicians select a clinical scenario from their daily practice that highlighted an area of controversy. From this, a three-part question is generated and this is used to search Medline for relevant papers. Once the relevant papers are found, these papers are critically appraised using validated checklists and the results are summarized. A clinical bottom line is reached after this process. To add confidence to the quality of the search a second author and then an Evidence Based Journal Club checks the BET to ensure that no relevant evidence is missed. These BETs will then be posted on the ICVTS website prior to publication for widespread commentary. The resulting BETs, written by practising cardiothoracic surgeons, will then provide robust evidence-based answers to important clinical questions asked during our daily practice.