Driving performance of long-term users of sedating antidepressants and benzodiazepines.

OBJECTIVE: Using benzodiazepines and certain antidepressants is associated with an increased risk of motor vehicle crashes due to impaired driving skills. Hence, several countries prohibit people who use these drugs from driving. Traffic regulations for driving under the influence of these drugs are, however, largely based on single-dose studies with healthy participants. The effects of drugs on chronic users may be different because of potential development of tolerance or by adapting behavior. In this study, we test the effects of anti-depressants, hypnotics, or anxiolytics use on driving performance in patients who use these drugs for different durations and compare the effects to healthy controls' performance. METHODS: Sixty-six healthy controls and 82 medication users were recruited to perform four drives in a driving simulator. Patients were divided into groups that used anti-depressants, hypnotics, or anxiolytics, for shorter or longer than 3 years (i.e. LT3- or LT3+, respectively). The minimum term of use was 6 months. Driving behavior was measured in terms of longitudinal and lateral control (speed variability and Standard Deviation of Lateral Position: SDLP), brake reaction time, and time headway. Impaired driving performance was defined as performing similar to driving with a Blood Alcohol Concentration of 0.5‰ or higher, determined by means of non-inferiority analyses. RESULTS: Reaction time analyses revealed inconclusive findings in all groups. No significant performance differences between matched healthy controls, LT3- (n = 2), and LT3+ (n = 8) anxiolytics users were found. LT3+ antidepressants users (n = 12) did not perform inferior to their matched controls in terms of SDLP. LT3- hypnotics users (n = 6) showed more speed variability than their matched healthy controls, while this effect was not found for the LT3+ group (n = 14): the latter did not perform inferior to the healthy controls. Regarding Time Headway, no conclusions about the LT3- hypnotics group could be drawn, while the LT3+ group did not perform inferior compared to the control group. CONCLUSIONS: The small number of anxiolytics users prohibits drawing conclusions about clinical relevance. Although many outcomes were inconclusive, there is evidence that some elements of complex driving performance may not be impaired (anymore) after using antidepressants or hypnotics longer than 3 years.

Alcohol metabolism in hangover sensitive versus hangover resistant social drinkers.

BACKGROUND: Previous research demonstrated that urinary ethanol concentrations were significantly lower in hangover resistant individuals compared to drinkers who reported having a hangover. This finding suggests that the rate of ethanol metabolism is faster in drinkers who do not experience an alcohol hangover. This study aimed to directly compare alcohol metabolism after administering a low dose of ethanol to hangover sensitive drinkers and hangover resistant drinkers. METHODS: Social drinkers who previously participated in hangover trials at Utrecht University were invited to participate. It was aimed to include 12 hangover resistant drinkers and 12 hangover sensitive drinkers. Participants consumed alcohol to reach a breath alcohol concentration (BrAC) of 0.05%. Every 5 min BrAC was determined, until BrAC reached zero. Every 15 min, the Karolinska Sleeping Scale (KSS) was administered to assess subjective sleepiness, and subjective intoxication was measured. RESULTS: Data of N = 23 participants with a mean age of 22.4 (±1.9) years was included in the analyses. No significant difference in BrAC over time was found between the hangover resistant group and the hangover sensitive group. In line, subjective sleepiness scores and subjective intoxication ratings did not significantly differ between the groups at any point in time after alcohol consumption. CONCLUSION: Hangover resistant individuals and hangover sensitive drinkers did not significantly differ on BrAC, subjective sleepiness, and subjective intoxication after consuming a moderate amount of alcohol. These findings suggest that drinkers who usually experience hangovers after a heavy drinking occasion do not experience alcohol intoxication differently than hangover resistant drinkers.

Urine methanol concentration and alcohol hangover severity.

BACKGROUND: Congeners are substances, other than ethanol, that are produced during fermentation. Previous research found that the consumption of congener-rich drinks contributes to the severity of alcohol hangover. Methanol is such a congener that has been related to alcohol hangover. Therefore, the aim of this study was to examine the relationship between urine methanol concentration and alcohol hangover severity. METHODS: N = 36 healthy social drinkers (22 females, 14 males), aged 18-30 years old, participated in a naturalistic study, comprising a hangover day and a control day (no alcohol consumed the previous day). N = 18 of them had regular hangovers (the hangover group), while the other N = 18 claimed to be hangover-immune (hangover-immune group). Overall hangover severity was assessed, and that of 23 individual hangover symptoms. Urine methanol concentrations on the hangover and control days were compared, and correlated to hangover (symptom) severity. RESULTS: Urine methanol concentration was significantly higher on hangover days compared to control days (p = 0.0001). No significant differences in urine methanol concentration were found between the hangover group and hangover-immune group. However, urine methanol concentration did not significantly correlate with overall hangover severity (r = -0.011, p = 0.948), nor with any of the individual hangover symptoms. These findings were observed also when analyzing the data separately for the hangover-immune group. In the hangover group, a significant correlation with urine methanol concentration was found only with vomiting (r = 0.489, p = 0.037). CONCLUSION: No significant correlation was observed between urine methanol concentration and hangover severity, nor with individual core hangover symptoms.

Trait anxiety affects decision-making differently in healthy men and women: towards gender-specific endophenotypes of anxiety.

Excessive levels of trait anxiety are a risk factor for psychiatric conditions, including anxiety disorders and substance abuse. High trait anxiety has been associated with altered cognitive functioning, in particular with an attentional bias towards aversive stimuli. Decision-making is a crucial aspect of cognitive functioning that relies on the correct processing and control of emotional stimuli. Interestingly, anxiety and decision-making share underlying neural substrates, involving cortico-limbic pathways, including the amygdala, striatum and medial and dorsolateral prefrontal cortices. In the present study, we investigated the relationship between trait anxiety, measured by the State-Trait Anxiety Inventory, and complex decision-making, measured by the Iowa Gambling Task, in healthy male and female volunteers. The main focus of this study was the inclusion of gender as a discriminative factor. Indeed, we found distinct gender-specific effects of trait anxiety: in men, both low and high anxiety groups showed impaired decision-making compared to medium anxiety individuals, whereas in women only high anxiety individuals performed poorly. Furthermore, anxiety affected decision-making in men early in the task, i.e. the exploration phase, as opposed to an effect on performance in women during the second part of the test, i.e. the exploitation phase. These findings were related to different profiles of trait anxiety in men and women, and were independent of performance in the Wisconsin Card Sorting Test and cortisol levels. Our data show gender-specific effects of trait anxiety on emotional decision-making. We suggest gender-specific endophenotypes of anxiety to exist, that differentially affect cognitive functioning.

Depression and panic disorder after heart transplantation--treatment with sertraline.

This report focuses on a case of major depression and panic disorder after heart transplantation. Due to these disorders, the male patient's compliance with cardiological treatment became increasingly insufficient. There are no controlled studies on psychopharmacological opportunities in cases such as this one. The patient was treated with sertraline and the outcome was healthy, without cardiovascular adverse effects or drug-drug interactions.

Left ventricular reduction for idiopathic dilated cardiomyopathy as alternative to transplant--truth or dare?

BACKGROUND: Although the concept of reducing wall tension a treatment for advanced heart failure is convincing, clinical data from the Batista operation are conflicting. Despite a number of publications, it is not clear whether left ventricular reduction surgery truly benefits patients with idiopathic, dilated cardiomyopathy (DCM). Surgery may reduce wall tension, but the reason for dilation and contractile dysfunction remains. Thus, the potential benefit of the operation may be overshadowed by the natural course of the underlying disease. CASES: We report a series of five cases where left ventricular reduction was performed and physiological geometry was restored in patients with DCM by a modification of Dor's endoventricular patch plasty. All patients demonstrated an improvement in cardiac function immediately after the operation. This improvement was sustained in one of the patients after 18 months of follow-up. Another patient developed severe heart failure due to therapy-resistant ventricular arrhythmia (Lown IV b), and underwent successful transplantation 4 months after ventricular reduction surgery. Left ventricular dilation reoccurred in two patients 9 and 12 months after reduction surgery, and they were listed for transplant. One patient died after 9 weeks due to sepsis and respiratory dysfunction. CONCLUSIONS: Although the endoventricular patch plasty, as used in this study, is well tolerated by most patients with dilated cardiomyopathy, and results in immediate improvement of contractile function, the long-term benefits of this technique for DCM are uncertain. Thus, the technique is currently not an alternative for heart transplantation. However, the procedure may be an option in patients with contraindications for transplantation.

[Endoventricular patch plasty in patients with idiopathic dilated cardiomyopathy: an alternative to heart transplantation?]. / Endoventrikuläre Patchplastik bei Patienten mit idiopathischer, dilatativer Kardiomyopathie--eine Alternative zur Herztransplantation?

BACKGROUND: Although the concept of reducing wall tension as a treatment for advanced heart failure is convincing, clinical data from the Batista operation are conflicting. Despite a number of publications, it is not clear whether left ventricular reduction surgery is truly of benefit for patients with idiopathic, dilated cardiomyopathy (DCM). Surgery may reduce wall tension but the reason for dilation and contractile dysfunction remains. Thus, the potential benefit of the operation may be overshadowed by the natural course of the underlying disease. CASES: We report a series of five cases where left ventricular reduction was performed and physiological geometry was restored in patients with DCM by a modification of Dor's endoventricular patch plasty. All patients demonstrated an improvement in cardiac function immediately after the operation. This improvement was sustained in one of the patients at 18 months follow-up. Another patient developed severe heart failure due to therapy resistant ventricular arrhythmia (Lown IVb), and underwent successful transplantation 4 months after ventricular reduction surgery. Left ventricular dilation reoccurred in two patients 9 and 12 months after reduction surgery, and they were listed for transplant. One patient died after 9 weeks due to sepsis and respiratory dysfunction. CONCLUSIONS: Although the endoventricular patch plasty as used in this study is well tolerated by most patients with dilated cardiomyopathy and results in immediate improvement of contractile function, the long-term benefits of this technique for DCM are uncertain. Thus, the technique is currently not an alternative for heart transplantation. However, the procedure may be an option in patients with contraindications for transplantation.

Recombinant hirudin (lepirudin) as anticoagulant in intensive care patients treated with continuous hemodialysis.

BACKGROUND: Recombinant hirudin (lepirudin) is a potent direct thrombin inhibitor, which has been approved for the treatment of heparin-induced thrombocytopenia type II (HIT). Because the drug is mainly eliminated by the kidneys, a single loading dose of hirudin may induce therapeutic anticoagulation for up to one week in patients with renal insufficiency. Thus, the use of hirudin in critically ill patients with renal failure could markedly increase their bleeding risk. In this study, hirudin was used in critically ill patients with suspected HIT while on continuous venovenous hemodialysis (CVVHD). METHODS: Hirudin anticoagulation was performed in seven critically ill patients with suspected HIT. Four patients were initially anuric. Three patients had residual renal function. In all 64 CVVHD treatments (mean duration 12 hr), a polysulfone high-flux hemodialyzer (0.75 m2) with a dialysate flow rate of 1.5 liter/hr and an ultrafiltration rate of up to 200 ml/hr was used. Hirudin was given either as continuous intravenous infusion or as repetitive intravenous boli. Monitoring of anticoagulation was performed by measurements of the systemic activated partial thromboplastin time (aPTT). RESULTS: Hirudin dosage had to be individualized according to the risk of bleeding or clotting. During CVVHD, a continuous intravenous infusion (0.006 to 0.025 mg/kg body wt/hr, N = 2) or repetitive intravenous boli (0.007 to 0.04 mg/kg, N = 5) were given. Two patients required blood transfusions prior to and during hirudin treatment. In five patients without a high bleeding risk, the hirudin dose was adjusted to achieve the target aPTT (1.5 to 2.0 x baseline) in order to prevent thrombotic complications or frequent clotting in the extracorporal circuit. Hirudin dose requirements depended on residual renal function and extracorporal clearance. CONCLUSIONS: We conclude from these first clinical data that anticoagulation with hirudin in critically ill patients on continuous hemodialysis can be performed without excessive bleeding risk by combining close clinical and laboratory monitoring. The hirudin dose has to be reduced because of renal failure, and may require adjustment for residual or recovering renal function and extracorporal elimination.

Increased vulnerability of postarthritic cartilage to a second arthritic insult: accelerated MMP activity in a flare up of arthritis.

OBJECTIVE: Murine antigen induced arthritis (AIA) is a chronic, smouldering inflammation. Flares of arthritis can be induced by antigen rechallenge or exposure to inflammatory mediators like interleukin 1 (IL1). These flares are characterised by a fast and marked proteoglycan (PG) depletion if compared with the initial arthritis. This study investigated the involvement of metalloproteinases in both the initial and the flare phase of arthritis. METHODS: Murine AIA was induced and a flare up of arthritis was induced by injection of 10 ng of IL1beta. Messenger RNA levels of MMP-1 and -3 were studied by RT-PCR. MMP activity in cartilage, during both primary AIA as well as the flare up of arthritis, was studied by immunodetection of MMP specific neoepitopes in aggrecan (VDIPEN). Cartilage just before flare induction was analysed for presence of MMPs at the mRNA level as well as at the protein level by zymography. RESULTS: At the onset of AIA, a fast upregulation of mRNA for stromelysin and collagenase was noted. However, no VDIPEN epitopes were detected during this early phase of arthritis. They appeared when PG depletion was severe at day 7 of arthritis and disappeared when cartilage was repaired. IL1 injection into a knee joint at week 4 of AIA caused a flare up of arthritis, coinciding with a fast and marked PG degradation. This degradation was characterised by accelerated expression of VDIPEN epitopes if compared with the expression in primary AIA. Analysis of cartilage at week 4 of AIA showed still increased mRNA levels of MMP-1 and -3. Moreover, increased levels of latent MMPs were present as well, as APMA activation induced profound VDIPEN epitope. In vitro exposure to IL1 did show increased PG breakdown but no VDIPEN expression, suggesting that factors in addition to IL1 are needed to cause the in vivo VDIPEN expression. CONCLUSIONS: The fast and marked PG depletion seen in a flare up of AIA coincides with accelarated expression of MMP induced neoepitopes compared with expression during primary AIA. This accelerated expression is probably linked to increased levels of latent enzyme, which were found to be present in the cartilage before induction of a flare up.

Enhancement of platelet inhibition of ticlopidine plus aspirin vs aspirin alone given prior to elective PTCA.

BACKGROUND: In many patients today, elective percutaneous transluminal coronary angioplasty is followed by implantation of coronary stents to achieve optimal results. The current medical strategy to prevent early reocclusion is the inhibition of platelet aggregation by administration of ticlopidine, in addition to aspirin, immediately after the procedure. In order to inhibit platelet aggregation as early as possible, many centres begin to treat patients with additional ticlopidine the day before elective coronary intervention. The aim of this study was to determine the effect of this strategy on platelet aggregation before angioplasty. METHOD: Fifty-two consecutive patients admitted to hospital for elective balloon angioplasty were prospectively randomized to receive either standard oral aspirin 100 mg per day or standard therapy plus 250 mg ticlopidine at the time of admission and the morning before angioplasty. Adenosine diphosphate-, collagen- and epinephrine-induced platelet aggregation was measured immediately before the procedure by an investigator who was blinded concerning the arm of therapy. RESULTS: The two groups of patients were comparable in terms of age, sex, body mass index, anginal state, time interval between application of study drug and coronary intervention. Patients on aspirin and ticlopidine had a mean maximal platelet aggregation of 36 +/- 12% with adenosine diphosphate as agonist. For the control group, 54 +/- 12% was measured (P < 0.001). Myocardial infarction or emergency coronary bypass grafting did not occur in either group. Local haemorrhagic complications at the arterial access site occurred in five (aspirin) and six (aspirin and ticlopidine) patients (P = ns) none of them requiring blood transfusion. CONCLUSION: The additional application of ticlopidine to chronic aspirin therapy the day before elective coronary balloon angioplasty leads to a significantly higher inhibition of platelet aggregation at the time of the intervention. It seems to be safe compared to the standard procedure.

MEDOS HIA-VAD biventricular assist device for bridge to recovery in fulminant myocarditis.

Successful weaning from biventricular mechanical support with full recovery of the myocardial function is extremely rare in fulminant myocarditis. We report on our experience with the MEDOS HIA-VAD ventricular assist device. The device worked for 17 days and provided adequate hemodynamics. Despite anticoagulation therapy, we had to change both ventricles because of clot formation on the surface of the outflow tract. After 17 days the myocardial function had recovered and we could remove the assist system.

[Successful treatment of fulminant myocarditis with the biventricular MEDOS Assist System (MEDOS HIA-VAD)]. / Erfolgreiche Behandlung einer fulminanten Myokarditis mit dem biventrikulären MEDOS Assist-System (MEDOS HIA-VAD).

BACKGROUND: Successful weaning from biventricular mechanical support with full recovery of the myocardial function is extremely rare in fulminant myocarditis. We report on our experience with the new MEDOS HIA ventricular assist device. METHODS AND RESULTS: We used the MEDOS assist system to support a 30-year-old woman with profound circulatory impairment caused by acute myocarditis. The device provided adequate hemodynamics and recovery of myocardial function. Despite anticoagulation therapy we had to change either the left or right ventricular pump chamber because of clot formation on the surface of the outflow tract. On the 14th postoperative day a surgical reintervention was necessary for bleeding from the cannulation site of the pulmonary artery. After 17 days the myocardial function had recovered and we could remove the assist system. The following parameters were measured before implantation of the MEDOS assist system and after weaning from circulatory support: ejection fraction 15 vs. 45%, cardiac index 0.7 vs. 2.6 L/min/m2, arterial pressure (systolic/diastolic/mean) 81/55/66 vs. 113/66/82 mm Hg, pulmonary artery pressure 33/25/29 vs. 34/20/28 mm Hg, pulmonary capillary wedge pressure 24 vs. 19 mm Hg. CONCLUSIONS: Despite severe cardiac failure in fulminant myocarditis requiring biventricular mechanical support full recovery of the myocardium is possible.

[Batista partial left ventricular resection in terminal heart failure]. / Partielle linksventrikuläre Resektion nach Batista bei terminaler Herzinsuffizienz.

Congestive heart failure is a clinical condition with a high mortality. Medical therapy has improved the clinical course of these patients considerably in recent years. Numerous surgical interventions such as high risk coronary bypass surgery, resection of left ventricular aneurysms, heart valve replacement and cardiac transplantation became accepted therapeutical options. More recently, transmyocardial laser revascularization, implantation of mechanical assist devices, implantable cardioverters/defibrillators and dynamic cardiomyoplasty were introduced into clinical practice and are still under evaluation. For most patients suffering from congestive heart failure cardiac transplantation is the only therapeutical option. However, age of the patients, decreasing number of donors, mortality on the waiting list, high morbidity under immunosuppressive therapy and graft vasculopathy characterize the problems of this therapeutical strategy. The brasilian cardiac surgeon Randas Batista therefore has introduced a new organ preserving surgical technique. First reports on "partial left ventricular resection" for patients with end-stage cardiac failure and dilated ventricles are promising. The possible importance of this new surgical technique implies that precise clinical and scientific evaluation are imperatively needed. In this review we present the surgical procedure, published data on clinical outcome and hemodynamic changes and possible indications for this new technique. The few data which have been published so far might indicate that there is an acceptable perioperative mortality associated with a symptomatic improvement. However, intermediate and long-term follow-up data are not available, and refinements in the surgical technique are necessary.

Amiodarone Therapy After Previous Sotalol-induced Torsade de Pointes: Analysis of AT Dispersion to Predict Proarrhythmia.

BACKGROUND: Polymorphic ventricular tachycardia of the torsade de pointes type represents, potentially, the most dangerous side effect of antiarrhythmic drugs that prolong ventricular repolarization. Much effort has been devoted to the identification of the degree of drug-associated QT prolongation that might predict the occurrence of torsade de pointes. However, there is still no general agreement as to which level of QT prolongation might be the harbinger of torsade and which may simply represent the manifestation of the class III antiarrhythmic effect of a given compound. METHODS AND RESULTS: A 70-year-old woman who had survived an episode of cardiac arrest outside of a hospital was treated with dl-sotalol (320 mg/d). After 8 days of therapy, she developed two episodes of hemodynamically unstable torsade de pointes. Sotalol was withdrawn and after extensive diagnostic work, therapy with amiodarone therapy was comparable to that observed during sotalol exposure, the patient tolerated amiodarone and is now free of recurrent ventricular tachyarrhythmias over a follow-up period of 1 year. Analysis of QT dispersion in the surface electrocardiograph revealed a marked increase during sotalol therapy but not during amiodarone administration (77 vs 47 ms). During drug-free control, QT dispersion was 43 ms. CONCLUSIONS: These findings emphasize the potential usefulness of determination of QT dispersion from the surface ECG to assess disparity in ventricular recovery, which is known to favor the occurrence of torsade de pointes. These observations need to be corroborated in large prospective trials. Finally, this case report further emphasizes the low arrhythmogenic potential of amiodarone-an unexplained paradox, the understanding of which might provide insights for the development of newer antifibrillatory compounds.

Efficacy and proarrhythmic hazards of pharmacologic cardioversion of atrial fibrillation: prospective comparison of sotalol versus quinidine.

OBJECTIVES: This study compared the efficacy and safety of sotalol and quinidine for conversion and prevention of recurrent atrial fibrillation. BACKGROUND: Atrial fibrillation is the most common arrhythmia. Pharmacologic therapy has been advocated for both immediate restoration of sinus rhythm and prevention of recurrent atrial fibrillation. Quinidine is the therapeutic mainstay for both purposes, but its safety has recently been questioned. Although sotalol has been used successfully to maintain sinus rhythm after direct current cardioversion, its efficacy in pharmacologically reverting atrial fibrillation has not been examined. METHODS: Fifty consecutive patients with persistent atrial fibrillation were randomized to receive quinidine or sotalol for up to 7 days to restore sinus rhythm. Patients were followed up for 6 months. RESULTS: Quinidine was more effective than sotalol in terminating atrial fibrillation (60% vs. 20%, p = 0.009). When nonresponders to drug therapy underwent subsequent direct current cardioversion, total conversion rates in the quinidine and sotalol groups were comparable (88% vs. 68%, p = 0.17), as was the efficacy of the two drugs in preventing recurrent atrial fibrillation. Side effects necessitating drug discontinuation were more often observed with quinidine. No patient receiving sotalol but four patients receiving quinidine had drug-associated arrhythmia (torsade de pointes in three patients, sustained ventricular tachycardia in one patient). Precordial QT dispersion determined on the surface electrocardiogram (ECG) increased with quinidine (mean +/- SD 34 +/- 9 vs. 44 +/- 16 ms, p = 0.02), indicating enhanced inhomogeneity in ventricular repolarization. There was no change in QT dispersion in patients receiving sotalol (36 +/- 18 vs. 40 +/- 17 ms, p = 0.44). CONCLUSIONS: Quinidine is more effective than sotalol in terminating atrial fibrillation but is associated with more side effects. The proarrhythmic risk may be related to quinidine's propensity to increase disparity in ventricular repolarization. This risk warrants careful ECG monitoring during the 1st 4 to 7 days of therapy. Because most proarrhythmic effects occurred shortly after restoration of sinus rhythm, observation should continue > or = 2 to 3 days after sinus rhythm is reestablished.

Role of interleukin 1 in antigen-induced exacerbations of murine arthritis.

The mechanism underlying the chronic and intermittent course of rheumatoid arthritis is not elucidated. In the present study, the role of interleukin 1 (IL-1) was investigated in exacerbations of antigen-induced arthritis in mice. A flare-up of smoldering inflammation (weeks 3 to 4 of antigen-induced arthritis) was inducible by injection of a small amount of methylated bovine serum albumin into the hypersensitive knee joint. Immunohistochemistry showed IL-1 expression in the synovial lining layer and in focal areas of the inflamed synovium during the flare-up. IL-1 was also measured in 1-hour culture supernatant of synovial tissue taken during the flare-up by a bioassay. The expression of both immunoreactive and bioactive IL-1 in the hypersensitive joint peaked around 6 hours after antigen (2 micrograms of methylated bovine serum albumin) injection and declined thereafter. Antigen rechallenge induced an acute joint swelling of the arthritic joint but not in the naive joint of the sensitized mouse, yet synovia of both joints produced IL-1 after antigen injection. Remarkably, a single intravenous injection of rabbit anti-IL-1 alpha and -beta antibodies 1 hour before antigen rechallenge neutralized IL-1 in the joint. Anti-IL-1 treatment significantly reduced the antigen-induced joint swelling (30 to 40%) but did not affect the profound influx of polymorphonuclear cells in the onset of the exacerbation. However, a profound relief of the inflammation (synovitis) was obtained by IL-1 blockade on day 4 of the exacerbation. Chondrocyte proteoglycan synthesis was markedly suppressed in the antigen-challenged naive knee joints suggesting that this was a direct IL-1 effect as the inflammation was insignificant. Anti-IL-1 treatment was able to maintain chondrocyte proteoglycan synthesis in the antigen-rechallenged joint, which was highly suppressed in the control group. Furthermore, the enhanced proteoglycan breakdown in the antigen-rechallenged joints was significantly decreased in the anti-IL-1 group. We concluded that IL-1 is an important mediator in exacerbations of murine arthritis, and amelioration of cartilage pathology was obtained with anti-IL-1 antibody treatment.

Variability of QT dispersion measurements in the surface electrocardiogram in patients with acute myocardial infarction and in normal subjects.

QT dispersion (defined as maximal QT interval minus minimal QT interval) as assessed on the surface electrocardiogram has been demonstrated to reflect regional inhomogeneity of ventricular repolarization. However, the variability of repeated QT dispersion measurements has not been validated in a prospective study. Thus, the present study is based on the analysis of standard 12-lead surface electrocardiographic (ECG) tracings obtained in 127 persons including 50 subjects without structural heart disease and 77 patients presenting with acute myocardial infarction. RR and QT intervals were measured by means of a digitizer tablet and QT/QTc dispersion was subsequently calculated automatically by PC-based analysis software. Measurements were obtained on 2 separate occasions by the same observer to assess the intraobserver variability. In addition, all tracings were evaluated by a second investigator to determine the interobserver variability. QT dispersion in persons without heart disease averaged 30 +/- 10 ms compared with 56 +/- 24 ms in patients with acute myocardial infarction (p < 0.0001). Patients with infarction who developed ventricular fibrillation within the first 24 hours after admission (11 of 77) had an even larger QT dispersion of 88 +/- 30 ms (p < 0.0001). Repeated measurements of QT dispersion in all 127 subjects revealed a correlation coefficient of 0.91 for both intra- and interobserver variability. Similar results were obtained for repeated determination of QTc dispersion (r = 0.93 and r = 0.90, respectively). When only patients with infarction were considered, correlation coefficients between 0.84 and 0.88 were obtained.(ABSTRACT TRUNCATED AT 250 WORDS)

[Amiodarone therapy after sotalol-induced torsade de pointes: prolonged QT interval and QT dispersion in differentiation of pro-arrhythmic effects]. / Amiodarontherapie nach Sotalol-induzierter Torsade de pointes: QT-Verlängerung und QT-Dispersion zur Differenzierung proarrhythmischer Effekte.

In a 70-year-old patient with sotalol-induced torsade de pointes, QT-dispersion in the 12-lead surface ECG was determined in an attempt to evaluate the role of this method in determining risk factors for the development of proarrhythmic effects. After recovery from torsade, the patient was successfully treated with amiodarone over a 3-month follow-up period. Whereas the degree of QT prolongation was comparable during amiodarone therapy to that observed with sotalol, QT dispersion was markedly less (47 ms) than during previous treatment with sotalol (77 ms). During drug-free control, QT dispersion was 43 ms. This case-report indicates that determination of QT dispersion can provide information with respect to identification of patients prone to class III antiarrhythmic drug-induced proarrhythmic effects.

Proteoglycan loss and subsequent replenishment in articular cartilage after a mild arthritic insult by IL-1 in mice: impaired proteoglycan turnover in the recovery phase.

The reparative responses of articular cartilage after an arthritic insult have not been studied extensively to this day. In the present study, we injected interleukin-1 (IL-1) into knee joints of mice to provoke a mild and transient arthritic insult, and characterized both the catabolic and the subsequent recovery phase. In the catabolic phase, which lasted 2 days after IL-1 injection, proteoglycan (PG) breakdown was profoundly accelerated and PG synthesis was markedly inhibited. Sulfation and polysaccharide synthesis were not affected, yet the number of chondroitin sulfate chains was decreased. The general chondrocyte protein synthesis was not inhibited by IL-1. IL-1 injected every other day for a total of three injections prolonged this catabolic phase and resulted in frank loss of articular cartilage proteoglycans. In the recovery phase, started 3 days after IL-1, PG synthesis was enhanced (1.7 times the normal) and proteoglycans had normal hydrodynamic properties. Remarkably, PG degradation was significantly decreased (approximately 50% of the normal). Zymographic analysis demonstrated enhanced expression of gelatinolytic activities in the extracts of the articular tissues shortly after IL-1 exposure and decreased levels in the recovery phase. We found that the overshoot of PG synthesis and impaired degradation act together to facilitate full cartilage repair 7 days after the last of the three IL-1 injections.

Torsade de pointes complicating drug treatment of low-malignant forms of arrhythmia: four cases reports.

In patients with malignant ventricular arrhythmias, antiarrhythmic therapy is known to carry a substantial risk of proarrhythmia. This risk is usually considered to be low when supraventricular arrhythmias or benign ventricular arrhythmias are considered. We were able to collect data on four patients without a history of life-threatening arrhythmias, in whom antiarrhythmic therapy was used and resulted in documented ventricular fibrillation or torsade de pointes. In Cases No. 1 and 2, atrial fibrillation was treated with either quinidine or quinidine and sotalol in combination. In both patients Holter monitoring, 4-12 h after conversion to sinus rhythm, documented the spontaneous occurrence of torsade de pointes degenerating into ventricular fibrillation and requiring DC shock for termination. In Case No. 3, atrial fibrillation was treated with sotalol and amiodarone for 2 months when incessant episodes of torsade de pointes were documented. In Case No. 4, frequent but unsustained ventricular arrhythmias were treated with amiodarone in a patient suffering dilative cardiomyopathy. After 6 days of treatment at a heart rate of 54 beats/min, a marked QT increase was associated with the occurrence of repetitive episodes of polymorphic ventricular tachycardia degenerating into ventricular fibrillation. None of the patients presented significant electrolyte abnormalities in the laboratory. A pathologic increase of the QTc-time was documented in Cases No. 1, 3, and 4. In all patients antiarrhythmic therapy was withdrawn after the proarrhythmic event and the patient became free of malignant tachyarrhythmias. Antiarrhythmic therapy also carries a considerable risk of proarrhythmia when "benign" cardiac arrhythmias are treated. The risk seems to be lower than in patients with malignant arrhythmias, however it includes the occurrence of lethal tachyarrhythmias. Special attention should be paid to the selection of antiarrhythmic agents when used in combination.