A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate

OBJECTIVE: To assess the efficacy and safety of 100 mg daily anakinra (Kineret), a recombinant form of the naturally occurring interleukin 1 receptor antagonist, plus methotrexate (MTX) in reducing the signs and symptoms of rheumatoid arthritis (RA). METHODS: Patients with active RA (n = 506) despite current treatment with MTX were enrolled in this multicentre, double blind, randomised, placebo controlled study. Patients received subcutaneous injections of anakinra 100 mg/day or placebo. They were assessed monthly for 6 months for improvement in signs and symptoms of RA and for adverse events. The primary efficacy measure was the percentage of patients attaining ACR20 response at week 24. RESULTS: Significantly greater proportions of patients treated with anakinra compared with placebo achieved ACR20 (38% v 22%; p<0.001), ACR50 (17% v 8%; p<0.01), and ACR70 (6% v 2%; p<0.05) responses. The response to anakinra was rapid; the proportion of patients with an ACR20 response at the first study assessment (4 weeks) was twice as high with anakinra as with placebo (p<0.005). Clinically meaningful and statistically significant responses were also seen in individual components of the ACR response (for example, Health Assessment Questionnaire, pain, C reactive protein levels, and erythrocyte sedimentation rate). Anakinra was well tolerated, with a safety profile, similar to that of placebo with one exception: mild to moderate injection site reactions were more common with anakinra than with placebo (65% v 24%). CONCLUSIONS: This study confirms previous observations from a dose-ranging study showing that anakinra, in combination with MTX, is an effective and safe treatment for patients with RA who have inadequate responses to MTX alone.     

Vitamin C,cancer and aging

Oxidative damage to DNA, proteins and lipids appears to be a major contributing factor in aging and the degenerative processes that accompany it, including cancer, heart disease, cataracts, and cognitive dysfunction. Numerous epidemiologic studies have found that persons with lower intake of antioxidant nutrients or the fruits and vegetables that provide them have a higher risk of almost every type of cancer. In many studies, those with low intake had twice the risk of those with high intake. A large-scale follow-up study found that persons with a low vitamin C intake had a statistically significantly higher risk of heart disease mortality and total mortality over the subsequent 10 years. In addition, several studies have found that persons with low intake of antioxidant nutrients such as vitamin C and carotene had significantly increased risk of developing age-related eye diseases such as cataracts. Although many older people consume more antioxidants than younger people, very substantial proportions of older persons have very low intakes and blood levels. Among white men 65–74 in the U.S., 15% have blood ascorbate levels below 0.4 mg/dl, the lower boundary of “normal.” Among black men of that age, 25% have levels below 0.4 mg/dl. Persons with high intakes of dietary vitamin C or citrus fruit have repeatedly been found to have a lower risk of developing cancer. In addition, recent research indicates an important role in heart disease and other disabilities of aging. This paper will summarize the epidemiologic literature briefly, and provide data on intake of this vitamin in the United States. Vitamin C has numerous biologic functions, including collagen, hormone and neurotransmitter synthesis. Its role as an antioxidant and free radical scavenger may be of primary importance in many of its roles in disease prevention. Oxidative and free radical damage to DNA and cell membranes is an important factor in cancer initiation, and it is clear that ascorbic acid can help prevent such damage.     

Echophonocardiography in patients undergoing percutaneous mitral balloon valvotomy (PMV): the learning curve of PMV

Percutaneous mitral balloon valvotomy (PMV) was performed in 10 female patients with mitral stenosis; their mean age was 31 +/- 1 years. All patients underwent echophonocardiography (Echophono) before and less than 24 hours after PMV1. Cardiac catheterization and Echophono were repeated 10 and 22 months after PMV1. Eight patients with suboptimal results (defined as a post-PMV mitral valve area [MVA]/less than 1.0 cm2 and mean gradient greater than/10 mm Hg) underwent repeat PMV (PMV2) 10 months after PMV1. The Echophono data are correlated with clinical and hemodynamic changes produced by PMV1 and PMV2. MVA increased from 0.6 +/- 0.1 to 1.1 +/- 0.01 cm2 (p = 0.0009) when PMV1 was performed with a mean effective balloon dilating area (EBDA) of 5 +/- 0.19 cm2. MVA increased from 1.0 +/- 0.1 to 1.7 +/- 0.2 cm2 (p = 0.0002) when PMV2 was performed with larger EBDA (6.4 +/- 0.34 cm2). Two factors related to the learning curve account for the superior result of PMV2: (1) use of larger EBDA and (2) optimal position of the balloons parallel to the long axis of the left ventricle. PMV1 resulted in Echophono changes consistent with decreased severity of mitral stenosis: shortening of Q-S1 from 93 +/- 4 to 82 +/- 4 msec (p less than 0.05) and (Q-S1)-(S2-OS) from 1.8 +/- 0.8 to -0.9 +/- 0.6 (p less than 0.01); prolongation of S2-OS from 75 +/- 5 to 91 +/- 5 msec (p less than 0.05) and increase of EF slope from 7 +/- 1 to 17 +/- 4 mm/sec (p less than 0.05). Compared with PMV1, post PMV2 Echophono showed a further decrease in the severity of mitral stenosis: Q-S1 decreased to 78 +/- 3 msec and (Q-S1)-(S2-OS) decreased to -0.5 +/- 0.3 msec. S2-OS increased to 86 +/- 5 msec and EF slope increased to 22 +/- 4 mm/sec. The hemodynamic and Echophono changes produced by PMV1 and PMV2 persisted at the corresponding follow-up studies. There was no evidence of restenosis. Thus Echophono is a simple, low cost method helpful in the evaluation and follow-up of patients undergoing PMV.     

Relation of percutaneous coronary intervention of complex lesions to clinical outcomes (from the NHLBI Dynamic Registry)

Advances in percutaneous coronary intervention (PCI) have reduced complications but expanded indications. We used the National Heart, Lung, and Blood Insitute Dynamic Registry to determine clinical outcomes up to 1 year after PCI in 2,839 patients with at least 1 treated complex lesion (defined as a lesion showing evidence of thrombus, calcification, bifurcation or ostial location, or chronic occlusion) and 1,790 patients with only simple lesions treated. Complex lesion interventions were associated (p <0.05) with more sustained major dissections, distal embolization, side branch occlusion, and persistent flow reduction. Patients with treated complex lesions had a lower procedural success rate (93.8% vs 97.3%, p <0.001) and increased in-hospital rates (p <0.001) of death (2.0% vs 0.6%), death/myocardial infarction [MI] (5.2% vs 2.4%), or death/MI/coronary artery bypass graft [CABG] surgery (6.5% vs 2.9%). After adjustment for potential confounders, patients treated for multiple complex lesions were more likely to experience the in-hospital combined end points of death/MI (odds ratio 3.22, 95% confidence interval 2.10 to 4.92), or death/MI/CABG (odds ratio 2.55, 95% confidence interval 1.71 to 3.80). At 1 year, patients with treated complex lesions were more likely (p <0.001) to die (6.2% vs 3.7%), suffer death/MI (11.7% vs 7.5%), or death/MI/CABG/repeat PCI (27.2% vs 23.4%). Patients treated for multiple complex lesions were approximately 50% more likely to die or to have major adverse events than with patients only treated for simple lesions. An increased in-hospital adverse clinical event rate was independently noted for thrombotic, bifurcation, and calcified lesions, and bifurcation lesions had worse long-term event rates.     

Phosphorylation of the rodent negative acute-phase protein alpha 1-inhibitor-III by the insulin receptor tyrosine kinase.

alpha 1-Inhibitor-III (alpha 1I3), a broad range proteinase inhibitor, member of the alpha-macroglobulin family, is abundant in normal rat plasma. Insulin-dependent tyrosine phosphorylation of a monomeric 195K glycoprotein (pp195) was observed in wheatgerm agglutinin (WGA)-Sepharose-purified insulin receptor preparations from rat liver and muscle. Phosphorylation of pp195 in vitro required a basic poly-amino acid, i.e. poly-L-lysine. We present evidence identifying pp195 as alpha 1I3. In situ perfusion with saline essentially removed pp195 from rat livers. Addition of normal rat plasma to liver homogenates or to WGA eluates restored insulin-stimulated phosphorylation of pp195; plasma from streptozotocin-diabetic rats was much less effective. Liver-derived pp195 copurified with an abundant plasma protein, with the characteristics of alpha 1I3, on size exclusion and ion-exchange chromatography. An approximately 195K protein, comigrating with alpha 1I3, was markedly diminished in plasma from diabetic rats, and alpha 1I3 concentration was decreased by approximately 70% upon immunoblot analysis. Highly purified alpha 1I3 was phosphorylated by muscle- or liver-derived insulin receptors in the presence of 1 microM poly-L-lysine and comigrated with pp195 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. alpha 1I3 phosphorylation was half-maximal at approximately 70 nM and was stimulated by insulin 7-fold. Hindlimb perfusion removed more than 90% plasma albumin but only approximately 20% pp195 from muscles. alpha 1I3 messenger RNA was identified in liver but not in muscle. A specific antibody against alpha 1I3 immunoprecipitated phosphorylated pp195 in WGA-purified insulin receptor preparations from nonperfused liver and from saline perfused and nonperfused muscle. alpha 1I3 is bound and internalized by alpha-macroglobulin receptors; whether it is phosphorylated in vivo is unknown. Hepatic alpha 1I3 synthesis may diminish in diabetic rats.     

Efficacy of automatic multimodal device therapy for ventricular tachyarrhythmias as delivered by a new implantable pacing cardioverter-defibrillator. Results of a European multicenter study of 102 implants.

BACKGROUND. Third-generation implantable cardioverter-defibrillators are devices designed to treat ventricular tachycardia (VT) and ventricular fibrillation (VF) by means of overdrive pacing, cardioversion, or defibrillation. So far, the efficacy of tiered therapy has been documented only in small series. Therefore, a European multicenter clinical evaluation study of a new tachyarrhythmia control device, the Medtronic PCD pacer-cardioverter-defibrillator with epicardial patch-lead configuration, was undertaken. METHODS AND RESULTS. We report on 102 patients (mean age, 55 +/- 13 years) from 11 European centers. PCD devices implanted between May 1989 and February 1991 were included. The patients suffered from hemodynamically significant ventricular tachyarrhythmias not suppressed by antiarrhythmic drug therapy and unrelated to acute myocardial infarction; one patient had nonsustained VT and severely depressed left ventricular function. Seventy patients had coronary artery disease with old myocardial infarctions, 23 had cardiomyopathies of various etiologies, and nine patients had no detectable heart disease. Mean ejection fraction was 36 +/- 14% (range, 10-76%). Mean intraoperative defibrillation threshold (51 patients) was 10.6 +/- 5.1 J (range, 2-18 J). The documented follow-up ranged from 1 to 21 months (mean, 9.4 +/- 5.8 months), or 79.9 cumulative patient-years. Perioperative mortality was 3.9%. The actuarial survival rate at 12 months was 91%. One sudden arrhythmic death occurred. Sixty patients (58%) received device therapy. Seventeen patients had therapies only for "VF" episodes, 16 patients only for VT, and 28 patients for VT and "VF" episodes. Based on device memory data, 1,235 spontaneous VT episodes were detected and treated in 43 patients. Twelve hundred four of these VT episodes received painless initial antitachycardia pacing therapy, restoring sinus rhythm in 91%. The 108 ongoing episodes received 209 multiple therapeutic attempts. Eighty-five additional overdrive pacing therapies restored sinus rhythm in 30%. Initial ineffective antitachycardia pacing therapies received 51 cardioversion pulses. The success rate was 61%. Seventy-three additional cardioversion pulses were delivered to backup ineffective pacing therapy as well as ineffective secondary cardioversion pulses. Their success rate was only 40%. Two hundred eighty-six spontaneous episodes were detected in 44 patients as "VF." Overall defibrillation efficacy was 97.6%. CONCLUSIONS. The implanted device nearly eliminates sudden arrhythmic death in patients with documented, potentially fatal ventricular tachyarrhythmias. Automatic tiered therapy is highly effective to restore sinus rhythm, provided that an integrated two-zone tachycardia detection algorithm is used, assigning lower tachycardia rates to overdrive pacing and/or cardioversion and higher tachycardia rates to defibrillation. In general, spontaneous VTs can be terminated by automatic overdrive pacing, and painful or disturbing countershock therapies are not required to terminate the majority of spontaneous VT episodes.     

Clinical outcomes three years after PLAATO implantation.

BACKGROUND: The percutaneous left atrial appendage transcatheter occlusion system (PLAATO) is an alternative to coumadin in patients with atrial fibrillation (AF) and contraindications to anticoagulation. It appears to be protective against stroke in intermediate follow-up studies. Hypothesis: The PLAATO system is protective against stroke and is safe in long-term follow-up. METHODS: Eleven patients (age 72 +/- 9 years) enrolled in the PLAATO feasibility and safety trial at our institution were followed (36 +/- 1.4) months. All patients had contraindications to anticoagulation and had at least one risk factor for stroke. The predicted stroke risk for this cohort was 8.6% per year as calculated using the CHADS2 score (A validated scoring system assigning 1 point for CHF, hypertension, diabetes, and age >75 years, and 2 points for history of stroke). The primary end-point was the incidence of stroke, and secondary end points were complications related to PLAATO device and systemic embolic events. RESULTS: There was one stroke during follow-up; the stroke risk in our population was 3% per year. Interestingly, the observed stroke risk in these patients after occluding the left atrial appendage is comparable to what would have been observed with warfarin. No systemic embolic events were noted in our cohort and no long term complications related to PLAATO were seen. CONCLUSION: The PLAATO device decreases the risk of stroke in a high-risk cohort of AF patients. Furthermore, the safety of this device is confirmed during this long-term follow-up study. A larger trial is needed to validate these findings.     

Nonpharmacological therapy for malignant ventricular arrhythmias: Implantable defibrillator trials

Implantable cardioverter-defibrillators (ICDs) are an important nonpharmacological option in the treatment of malignant ventricular arrhythmias. Technological advances in current devices permit nonthoracotomy implantation with transvenous lead systems using biphasic shocks. Decreasing device size has resulted in pectoral implantation. Battery longevity is still short in comparison with that of pacemakers. Lead failure rates as well as pacing thresholds are significantly higher than those for cardiac pacing lead systems. Other complications of ICD systems include infection, perforation, and thrombosis. The long-term performance of nonthoracotomy lead systems for ICD devices has now been extensively studied. Sudden death recurrence rates for these systems are less than 2% in 3 years and less than 5% at 5 years. Clinical trials with both monophasic and biphasic systems show a high degree of prevention of sudden death. Comparison of ICD outcome with that of drug therapy in three large retrospective studies and two small prospective randomized trials favors improved survival and sudden death prevention with device therapy. However, these studies need corroboration from large prospective trials. Two large prospective trials, CIDS and the AVID study, are now in progress to address this issue.     

Human splanchnic metabolism during diabetic ketoacidosis.

Splanchnic exchange rates of glucose, acetoacetate, beta-hydroxybutyrate, lactate, pyruvate, glycerol, alanine, glutamine, glutamate, free fatty acids, and triglycerides were measured in eight patients during moderate to severe diabetic ketoacidosis. Their arterial glucose concentration was 20.68 (9.80-52.79) mumole/liter and tic glucose release was 0.77 (0.09-2.44) mmole/min. Gluconeogenesis accounted for about one-half of net splanchnic glucose release, assuming quantitative conversion of net splanchnic extracted lactate, pyruvate, glycerol, alanine, and alpha-ketoglutarate equivalents to glucose. Net splanchnic free fatty acid extraction was 0.24 (0.09-0.52) mmole/min. There was a positive correlation between free fatty acid uptake and ketone-body release. Net splanchnic acetoacetate release was 0.50 (0.05-0.92) mmole/min and beta-hydroxybutyrate release was 0.35 (-0.16 to 0.84) mmole/min. Total ketone-body release was 0.84 (0.37-1.61) mmole/min. The wide ranges of net splanchnic glucose and ketone-body production rates show the heterogeneous characteristics of the diabetic patient in ketoacidosis. It is concluded that the hyperglycemia and hyperketonemia of diabetic ketoacidosis is due to the lack of reciprocity among rates of hepatic glycogenlysis, gluconeogenesis, and ketogenesis resulting in inappropriate net splanchnic release of glucose and ketone bodies.