Atrial fibrillation in the elderly: anticoagulation strategies and indications in the very elderly

With increasing life expectancy and the older mean age of the general population, the prevalence of atrial fibrillation is likely to increase, making this arrhythmia an even more important public health problem, especially in the elderly. While atrial fibrillation is increasingly common in the elderly, paradoxically, the data on intervention trials in atrial fibrillation among the elderly are limited. When considering anticoagulation in the elderly patient with atrial fibrillation, the following five questions should be addressed. 1) Is there a definite indication (for example, atrial fibrillation plus risk factor[s])? 2) Is there a high risk of bleeding or strong contraindication against anticoagulation? 3) Will concurrent medication or disease states significantly increase bleeding risk or interfere with anticoagulation control? 4) Is drug compliance and attendance at anticoagulant clinic for monitoring likely to be a problem? 5) Will there be regular review of the patient, especially with regard to risks and benefits of anticoagulation? Careful and continuing evaluation of the elderly patient with atrial fibrillation is necessary to ensure that the risks of bleeding do not outweigh the benefits from anticoagulation.     

Neuroprotection with glatiramer acetate: evidence from the PreCISe trial

The phase III, multicenter, randomized, placebo-controlled PreCISe trial assessed glatiramer acetate (GA) effects in patients with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS). To assess the neuroprotective effect of GA in a subset of patients in the PreCISe trial, we used proton magnetic resonance spectroscopy (MRS) to measure N-acetylaspartate (NAA), a marker of neuronal integrity, in a large central volume of brain. Thirty-four CIS patients randomized to GA 20 mg/day (n = 19) SC or placebo (n = 15) were included. Patients who relapsed (developed clinically definite MS [CDMS]) were removed from the substudy. NAA/creatine (NAA/Cr) ratios were compared between GA-treated and placebo-treated patients. Twenty patients with CIS had not converted to CDMS and were still in the double-blind phase of the trial at 12 months of follow-up. Paired changes in NAA/Cr differed significantly in patients treated with GA (+0.14, n = 11) compared with patients receiving placebo (?0.33, n = 9, p = 0.03) at 12 months, consistent with a neuroprotective effect of GA in vivo. Patients with CIS who received GA showed improvement in brain neuroaxonal integrity, as indicated by increased NAA/Cr, relative to comparable patients treated with placebo, who showed a decline in NAA/Cr consistent with findings from natural history studies.     

Magnetization transfer can predict clinical evolution in patients with multiple sclerosis

The clinical course of multiple sclerosis (MS) is highly variable ranging from benign to aggressive, and is difficult to predict. Since magnetization transfer (MT) imaging can detect focal abnormalities in normal-appearing white matter (NAWM) before the appearance of lesions on conventional MRI, we hypothesized that changes in MT might be able to predict the clinical evolution of MS. We assessed MR data from MS patients who were subsequently followed clinically for 5 years. We computed the mean MT ratio (MTr) in gray matter, in lesions identified on T2-weighted MRI, and in NAWM, as well as in a thick central brain slice for each patient. Patients were divided into stable and worsening groups according to their change in Expanded Disability Status Scale (EDSS) scores over 5 years. We calculated the sensitivity, specificity, predictive value, and odds ratio of the baseline MTr measures in order to assess their prognostic utility. We found significant differences in baseline MTr values in NAWM (p = 0.005) and brain slice (p = 0.03) between clinically stable and worsening MS patients. When these MTr values were compared with changes in EDSS over 5 years, a strong correlation was found between the EDSS changes and MTr values in both NAWM (SRCC = −0.76, p < 0.001) and in the brain slice (SRCC = 0.59, p = 0.01). Baseline NAWM MTr correctly predicted clinical evolution in 15/18 patients (1 false positive and 2 false negatives), yielding a positive predictive value of 77.78 %, a negative predictive value of 88.89 %, and an odds ratio of 28. The relationship between 5-year changes in EDSS and MTr values in T2 weighted MRI lesions was weaker (SRCC = −0.43, p = 0.07). Our data support the notion that the quantification of MTr in the NAWM can predict the clinical evolution of MS. Lower MTr values predict poorer long-term clinical outcome. Abnormalities of MTr values in the NAWM are more relevant to the development of future patient disability than those in the T2-weighted MRI lesions. Received: 3 May 2001, Received in revised form: 11 October 2001, Accepted: 22 October 2001     

The relationship between diffuse axonal damage and fatigue in multiple sclerosis

BACKGROUND: Fatigue is a common and distressing symptom for patients with multiple sclerosis (MS). There is growing evidence that fatigue in MS has a central nervous system component. We hypothesized that diffuse cerebral axonal damage could be associated with fatigue and used proton magnetic resonance spectroscopy to noninvasively measure axonal damage or loss in the brains of patients with MS. OBJECTIVE: To assess the strength of the relationship between central brain N-acetylaspartate and fatigue. DESIGN: Data from 73 patients who had undergone proton magnetic resonance spectroscopy imaging and completed the Fatigue Severity Scale questionnaire were analyzed. RESULTS: The N-acetylaspartate-creatine ratio (NAA/Cr) was significantly lower in the high-fatigue group than the low-fatigue group (mean +/- SD, 2.69 +/- 0.29 and 2.99 +/- 0.33, respectively. P =.003). Independent of the Kurtzke Expanded Disability Status Scale, T2 lesion volume, age, and disease duration, NAA/Cr was significantly lower in the high-fatigue group as compared with the low-fatigue group. There was a statistically significant linear correlation between the Fatigue Severity Scale scores and NAA/Cr (Spearman rank rho = -0.361, P =.02). CONCLUSIONS: The results of this study, combined with those of others, suggest that widespread axonal dysfunction is associated with fatigue in MS. Increased recruitment of cortical areas and pathways in response to brain injury may be responsible for the patient's sense that the effort required to perform actions is disproportionately high.     

ROLE OF SELECTIVE INTRA‐OPERATIVE CHOLANGIOGRAPHY DURING CHOLECYSTECTOMY

Background : The use of routine intra‐operative cholangiography (IOC) remains controversial. This prospective study was carried out to determine whether to perform selective or routine IOC in patients undergoing cholecystectomy for gallstones. Methods : All consecutive patients undergoing open cholecystectomy over a 16‐month period were included in the present study. They were divided into two groups based on the absence (n = 79) or presence (n = 55) of indicators of choledocholithiasis. All patients were subjected to cholangiography. Each indicator, subsets of indicators and all indicators combined were evaluated for their ability to predict choledocholithiasis. Results : There would be only two missed stones (1.5%) if selective cholangiography was to be practised. Intra‐operative cholangiography had a positive predictive value of 100%. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of all the indicators combined were 93.5%, 84.6%, 74.5%, 97.5% and 88.0%, respectively. The best indicators in each subset were jaundice, common bile duct diameter as assessed by ultrasonography, and a palpable stone during surgery with NPV of 82.7%, 91.1% and 96.8%, respectively. Conclusion : Routine IOC during cholecystectomy is not essential for the prevention of retained stones. A combination of the various indicators of choledocholithiasis can be used to select patients for cholangiography.     

Effect of tamoxifen on the enzymatic activity of human cytochrome CYP2B6

Tamoxifen is primarily used in the treatment of breast cancer. It has been approved as a chemopreventive agent for individuals at high risk for this disease. Tamoxifen is metabolized to a number of different products by cytochrome P450 enzymes. The effect of tamoxifen on the enzymatic activity of bacterially expressed human cytochrome CYP2B6 in a reconstituted system has been investigated. The 7-ethoxy-4-(trifluoromethyl)coumarin O-deethylation activity of purified CYP2B6 was inactivated by tamoxifen in a time- and concentration-dependent manner. Enzymatic activity was lost only in samples that were incubated with both tamoxifen and NADPH. The inactivation was characterized by a K(I) of 0.9 microM, a k(inact) of 0.02 min(-1), and a t(1/2) of 34 min. The loss in the 7-ethoxy-4-(trifluoromethyl)coumarin O-deethylation activity did not result in a similar percentage loss in the reduced carbon monoxide spectrum, suggesting that the heme moiety was not the major site of modification. The activity of CYP2B6 was not recovered after removal of free tamoxifen using spin column gel filtration. The loss in activity seemed to be due to a modification of the CYP2B6 and not reductase because adding fresh reductase back to the inactivated samples did not restore enzymatic activity. A reconstituted system containing purified CYP2B6, NADPH-reductase, and NADPH-generating system was found to catalyze tamoxifen metabolism to 4-OH-tamoxifen, 4'-OH-tamoxifen, and N-desmethyl-tamoxifen as analyzed by high-performance liquid chromatography analysis. Preliminary studies showed that tamoxifen had no effect on the activities of CYP1B1 and CYP3A4, whereas CYP2D6 and CYP2C9 exhibited a 25% loss in enzymatic activity.     

Identification of amino acid residues involved in the inactivation of cytochrome P450 2B1 by two acetylenic compounds: the role of three residues in nonsubstrate recognition Sites

The homologous rat cytochrome P450s 2B1 and 2B2 differ by 13 amino acids. A chimeric construct of P450 2B1/2B2 was used in conjunction with several site-directed mutants to identify key residues involved in the inactivation of P450 2B1 by two acetylenic compounds, 17alpha-ethynylestradiol (17EE) and tert-butyl 1-methyl-2-propynyl ether (tBMP). 17EE is a mechanism-based inactivator of P450 2B1 but not of P450 2B2. We show here that tBMP is also a mechanism-based inactivator of P450 2B1 and not P450 2B2. Minimal loss in 7-ethoxy-4-(trifluoromethyl)coumarin (7-EFC) activity was observed when P450 2B1 G478A was incubated with either inactivator, suggesting that this residue plays a role in the inactivation. However, P450 2B2 A478G behaved like wild-type P450 2B2, indicating that this residue alone is not sufficient for inactivation. A chimeric construct of P450 2B1/2B2 that is essentially P450 2B1 with five residues of P450 2B2 (including residue 478), was not inactivated by either tBMP or 17EE, suggesting that these five residues are important for inactivation. Sequential mutagenesis of the chimeric construct to quadruple (S407T-N417D-A419T-G478A) and triple (S407T-N417D-A419T) mutants of P450 2B1 did not result in inactivation by either inactivator. However, the triple mutant with mutations only in non-substrate recognition site (SRS) regions still exhibits wild-type P450 2B1 7-EFC O-deethylation activity with a K(m) value of 25 microM and V(max) of 8 nmol/min/nmol P450. These results demonstrate that substitution of three non-SRS residues in P450 2B1 leads to protection against inactivation of 2B enzymes by these two acetylenic compounds.     

Reproducibility of quantitative magnetization‐transfer imaging parameters from repeated measurements

Quantitative magnetization‐transfer imaging methods provide in vivo estimates of parameters of the two‐pool model for magnetization‐transfer in tissue. The goal of this study was to evaluate the reproducibility of quantitative magnetization‐transfer imaging parameter estimates in healthy subjects. Magnetization‐transfer–weighted and T₁ relaxometry data were acquired in five healthy subjects at multiple time points, and the variability of the resulting fitted magnetization‐transfer parameters was evaluated. The impact of subsampling the magnetization‐transfer data and correcting field inhomogeneities was also evaluated. The key parameters measured in this study had an average variability, across time points, of 4.7% for the relative size of the restricted pool (F), 7.3% for the forward exchange constant (k_f), 1.9% for the free pool spin‐lattice relaxation constant (R_1f), 4.5% for the T₂ of the free pool (T_2f), and 2.3% for the T₂ of the restricted pool (T_2r). Our findings show that serial quantitative magnetization‐transfer imaging experiments can be performed reliably, with good reproducibility of the model parameter estimates, and demonstrate the reproducibility of acquisition schemes with fewer magnetization‐transfer contrasts. This establishes the feasibility of this technique for monitoring patients affected by degenerative white matter diseases while providing critical data to estimate the statistical power of such studies. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.     

Cerebellar Granule Cell Death Induced by Aluminum

Using flow cytometry of acutely isolated cerebellar granule cell neurons, we have determined the effects of Al (III) on viability, membrane potential, intracellular calcium concentration and generation of reactive oxygen species (ROS). Al (III) killed granule cells in a time- and concentration-dependent fashion when monitored by use of the DNA-binding dye, propidium iodide. The threshold concentration was about 50 micromolar, and cell death at 100 micromolar was apparent after 30 min exposure and increased over time. Cell death was accompanied by cell swelling and a decrease in membrane potential, and was not dependent on external calcium concentration. While exposure to Al (III) was accompanied by an increase in ROS and an elevation of intracellular calcium concentration, calcium chelators and ROS scavengers did not reduce cell death. The action of Al (III) was not accompanied by activation of caspase-3 or an increase in annexin-V binding, both indicators of apoptosis. In the presence of intracellular O,O'-bis(2-aminophenyl)ethyleneglycol-N,N,N',N'-tetraacetic acid (BAPTA) and absence of extracellular calcium there was still a fluo-3 signal, which likely reflects an accumulation of intracellular Al (III). These observations suggest that the cell death is subsequent to intracellular accumulation of Al (III) and subsequent perturbation of cellular metabolism.