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Background: Health-related quality of life (HRQL) is increasingly accepted as an outcome measure when considering the effectiveness of therapeutic interventions. Little is known about the HRQL of patients with different clinical circumstances before and after pacemaker implantation (PMI). The purpose of this study was to investigate the influence of clinical symptoms and ECG diagnoses as predictors of improved HRQL in patients referred for PMI., Methods: Sixty eight patients with different indications for PMI completed the MacNew Heart Disease Health-related Quality of Life Questionnaire (MacNew) and the Short Form-36 Health Survey (SF-36) before and one, three and six months after PMI. Symptoms, ECG indications and pacing mode were collected using the European Pacemaker Patient Identification Card codes., Results: Within the first month after PMI overall Mac-New but not SF-36 scores improved significantly and was maintained during the entire 6 month follow up period. Improvement in HRQL as measured with the MacNew was rather related to baseline symptoms and ECG diagnosis than to the pacing mode., Conclusion: The important finding of this study is that improved HRQL seen after PMI appears to be largely driven by baseline symptoms and the ECG diagnoses rather than the pacing mode of the device.

Background: Frequent and unnecessary right ventricular apical pacing increases the risk of atrial fibrillation or congestive heart failure. We evaluated a new pacing algorithm, managed ventricular pacing (MVP) which automatically changes modes between AAI/R and DDD/R in patients receiving pacemakers for symptomatic bradycardia., Methods: Patients were randomized to the MVP mode or DDD/R mode for 1 month and then crossed over to the alternate pacing modality for an additional month. On completion of the crossover phase, the pacing mode selected was individualized and patients were followed for an additional 4 months., Results: Of the 129 patients who successfully completed the crossover study, the cumulative percent ventricular pacing was significantly reduced in the MVP mode (median 1.4%) compared to the DDD/R mode (median 89.6%, 94.0% relative reduction; 95% CI 89.3-98.8%, P < 0.001). Patients with sinus node disease (SND, n = 51) when compared to patients with AV block (AVB) (n = 68) experienced a greater reduction in ventricular pacing with the MVP mode compared to the DDD/R mode (median relative reduction 99.1%; 95% CI 97.5-99.9% vs median relative reduction 60.1%; 95% CI 16.7-93.9% P < 0.001). The reduced percent ventricular pacing during MVP was sustained over longer term follow-up., Conclusions: The majority of patients with a bradycardia indication for cardiac pacing do not require ventricular pacing most of the time. The MVP mode significantly reduces unnecessary right ventricular pacing. This mode benefits even patients with intermittent AVB and is sustained over longer term follow-up.

Little is known about the HRQL of pacemaker patients due to the limited availability of disease-specific instruments. The aim of the Pacemaker Patients Quality of Life (PAPQoL) study was to determine the psychometric properties for the MacNew Heart Disease Health-related Quality of Life Questionnaire (MacNew) in patients before and after pacemaker implantation. Patients with a given indication for pacemaker therapy (N = 68) completed two self-administered HRQL instruments, the SF-36, a well-known and psychometrically sound health survey, and the MacNew, a reliable and valid heart-disease-specific HRQL instrument, before and one, three and six months after pacemaker implantation. We assessed disease severity with the New York Heart Association (NYHA) classification. Test-retest reliability, intra-class correlation, Cronbach's alpha, validity coefficients, sensitivity analyses (effect sizes) and confirmatory factor analysis were carried out. The MacNew demonstrated adequate reliability (Cronbach's alpha and ICCs > 0.80 on all scales), validity (correlations between similar SF-36 and MacNew subscales > 0.80), and responsiveness (all effect sizes > or = 0.67) in pacemaker patients. The MacNew demonstrates adequate psychometric properties for evaluating HRQL in patients before and after pacemaker implantation.

Objectives: In this single-center study we reviewed our experience with a significant number of cardiac myxoma cases occurring over the past two decades., Patients and Methods: Cardiac myxomas represented 86% of all surgically treated cardiac tumors at our center. Specifically, there were 49 consecutive patients, each with at least one myxoma. A detailed clinical, immunological, and echocardiographic long-term examination of 37 patients revealed one recurrent myxoma., Results: Most myxomas originated from the left atrium (87.7%), but also much less frequently from the mitral valve (6.1%), from the right atrium (4.1%), and from the left and right atria (2.0%). The myxomas produced a prolapse into the left ventricle in 40.8% of the patients, mitral stenosis in 10.2%, and threatened left ventricular outflow tract obstruction in 2.0%. Multiple myxomas were found in 20.4% of the patients. Cardiac signs appeared in 93.9% of the patients. Preoperative embolic events had occurred in 26.5%. Immunologic alterations were present in 87.5%. For resection, a bilateral atriotomy was used. An additional aortotomy was needed to expose one mitral valve myxoma. Postoperatively, 81.1% of the patients remained without cardiac symptoms. The early mortality rate was 2.0% and the late mortality rate was 6.1%. Long-term prognosis was excellent with an actuarial survival rate of 0.74. Specific immunologic alterations were found in 71.4% of the patients. The actuarial freedom from reoperation of the myxoma was 0.96. The rate of reoperations was low with 2.0% after 24 years., Conclusions: Myxomas were usually detected and operated on in symptomatic patients. A high index of suspicion seems important for early diagnosis. Immunologic findings may play an additional role in confirming the diagnosis and the recurrence of a myxoma. Immediate surgical treatment was indicated because of the high risk of embolization or of sudden cardiac death. Also, a familial genesis must be excluded in myxoma patients.

A pilot survey of 1025 patients receiving homeopathic treatment in six European countries is reported. An initial questionnaire included demographic information and questions from health-related Quality of Life (QoL) scales. A follow-up questionnaire collected data on changes in QoL. The demographic characteristics of respondents were similar to previous studies. 82.8% of respondents had previously tried conventional treatments. Satisfaction with consultations was high. The changes of QoL status are positive but weak. 2.7% of patients experienced side-effects which they attribute to homeopathic treatment. 7.8% of patients reported significant aggravation at the beginning of the homeopathic treatment, 25.4% slight aggravation of symptoms. A new survey should be performed with a better motivation of doctors and patients. Further description of treatment would be helpful.

Pacing threshold is not a stable value during the pacemaker's life. It is affected by many physiological, pharmacological and pathophysiological factors. A pacing system able to confirm capture and automatically adjust its output to the actual pacing threshold is highly desirable for a prolonged battery life and maximal patient safety. The Autocapture(TM) of St. Jude Medical and the Capture Management(TM) of Medtronic are currently available on the market. The key feature is the measurement of the evoked response (ER) signal by the pacemaker for capture confirmation. In case of loss of capture, the Autocapture(TM) System delivers a back up safety pulse of 4.5 Volt and 0.49 ms and starts a new threshold search. The pacemaker adapts its output to 0.3V/0.25V above the newly measured threshold. This system needs bipolar leads with low polarization for the first generation in Microny® and Regency® pacemakers; in the second generation with Affinity® and Integrity® pacemakers various bipolar leads are suitable. The Capture Management(TM) System of Medtronic, available in the Kappa® DR 700 series, performs a two point automatic threshold search once every day during rest. The output is determined by the programmed safety margin (nominal 1.5×voltage threshold). A backup pulse is only delivered during the threshold search. No special electrodes are necessary.    These functions were shown to work safely and efficaciously in multicenter trials to decrease the current consumption with a prolongation of battery life up to 142%. The patients safety was increased by identifying changes of the capture threshold over time and adjusting the pacing stimulus. The conventional safety margins of 100% might not be safe for all patients. We also learned much about lead maturation and lead instability by the possibility of continuous follow-up of threshold changes in a larger group of leads in order to identify the risk group of about 10% of patients with late threshold increase and lead instability.

Objectives: Left ventricular hypertrophy in patients with critical aortic stenosis (AS) is an adaptive process that compensates for high intracavitary pressure and reduces systolic wall stress followed by an increase in myocardial masses. In the present prospective clinical trial, we investigated long-term compensatory changes in left ventricular geometry and function after aortic valve replacement using mechanical bileaflet prostheses with the main emphasis on the small-sized aortic annulus and valve prosthesis-patient mismatch., Methods: A total of 58 patients with critical AS were assigned to the following groups according to the predictive value of prosthetic valve area index (VAI): group EXMIS: 29 patients (VAI < or =0.99), expected mismatch; group NOMIS: 29 patients (VAI < or =0.99), no mismatch. At controls T(0) (before operation/operation (OP), T(1) and T(2) (4 and 20 months after OP) the left ventricular geometry was recorded by means of Imatron electron beam tomography and the transprosthetic velocities were measured by echocardiography., Results: Statistical analysis showed a consistent reduction in the absolute (P=0.04) and indexed (P=0.04) left ventricular myocardial mass for both cohorts; furthermore, there was a significant difference between EXMIS and NOMIS patients concerning the factors, time and mass reduction (P=0.005), because of distinct baselines. A logistic regression report revealed preoperative cardiac output, absolute left ventricular myocardial mass, perfusion, body surface area and the native valve orifice area as predicting coefficients and factors for a minimum mass reduction of 25%. We explain a mathematical formula that turned out to be the most sensitive for correctly classified factors., Conclusions: The left ventricular geometry and transprosthetic velocities resulted in the same postoperative recovery for both EXMIS and NOMIS patients. The presented data showed that valve prosthesis-patient mismatch had no influence in several stepwise logistic regression models. We conclude that modern mechanical bileaflet prostheses allow both acceptable hemodynamics and recovery of left ventricular hypertrophy, even in small aortic annuli.

The grounds for liability with robotic surgery include damage to patients, causality, illegality and guilt. The patient must receive very comprehensive information on the treatment under consideration, his/her risk and what will be done in the case of technical failure. The surgeon operating the robotic device is obliged to provide normal conscientious care and state-of-the-art treatment. In addition, there is possible neglect of supervisory duties vis-à-vis other hospital personnel to be considered. A special problem is posed by a forensic physician who lacks experience in robotic surgery. There should be a surgeon at the operating table who is at least equally skilled as the surgeon operating the monitor. Robotic surgery must ultimately be at least as effective as conventional surgery, if not better. It must, however, be borne in mind that in cases involving this new technology, it is that patient who is the pioneer.

A life-threatening left ventricular outflow tract obstruction developed in a 26-year-old man because of a very uncommon myxoma emerging from the ventricular side of the mitral valve. Immediate surgical treatment was indicated because of high-risk factors reported herein. After transaortic resection of a single myxoma, the progress of this patient has been excellent, especially as a familial myxoma could be excluded.

From 1990 to 1999, 2,853 ventricular and 1,084 atrial bipolar leads of various manufacturers (Medtronic, Biotronik, Vitatron, Ela, Pacesetter and Stöckert) were implanted during first implantations of pacemakers at the University of Graz, Dept. of Cardiac Surgery. Surgical complications with the need of reintervention were analyzed during a follow up period of up to 10 years. The overall lead-related complication rate for ventricular bipolar leads was 6.5% (187 of 2,853) and 5.3% (58 of 1,084) for atrial bipolar leads. Early complications within the first month were higher in the atrium (5.3% versus 2.2% in the ventricle), primarily due to dislocation, late complications were higher in the ventricle (4.3% versus 2% in the atrium) due to insulation problems and lead fracture. Insulation material had a marked influence with a higher failure rate in some leads with polyurethane insulation compared with silicone. Therefore we recommend a close follow-up of bipolar polyurethane leads by measurement of chronic impedance in order to assess insulation problems as early as possible.

Background: Risk evaluation comparing the minimally invasive and standard aortic valve operations has not been studied., Methods: Four surgeons were randomly assigned to perform the minimally invasive (L-shaped sternotomy) (group 1) or the conventional (group 2) operation in 120 patients exclusively., Results: In both groups (n = 60) a CarboMedics prothesis was implanted in 90% of patients. There was no significant difference in the cross-clamping period (group 1, 60 minutes; range, 35 to 116 minutes), in the duration of extracorporal circulation (group 1, 84 minutes; range, 51 to 179 minutes) or in the time from skin-to-skin (group 1, 195 minutes; range, 145 to 466 minutes). Patients in group 1 were extubated earlier (p<0.001), the postoperative blood loss was less (p<0.001), and the need for analgesics was reduced (p<0.05). In 5 patients in group 1 a redo operation was required for bleeding (p>0.05), 3 patients in group 1 required a redo operation because of paravalvular leakage or endocarditis (p>0.05), the 30-day mortality rate was 1.6%. Overall the survival rate was 95% in group 1 and 97% in group 2 (mean follow-up, 294 days; range, 30 to 745 days)., Conclusion: The advantages of minimally invasive aortic valve operation include reduced trauma from incision and duration of ventilation, decreased blood loss and postoperative pain, the avoidance of groin cannulation, and a cosmetically attractive result. Simple equipment is used with a high degree of effectiveness and with no sacrifice of safety. Our study demonstrated the practicability and reliability of this new method.

After twenty-five years of therapy with different unifocal pacemaking systems, an 84-year old male patient developed a nonseptic pacemaker decubitus. A rare incidental finding of invasive ductal carcinoma of the right mammary gland was surgically treated by a generous excision of the tumor and by consecutive modified radical mastectomy. According to published literature, the association of invasive ductal carcinoma arising from a pacemaker pocket decubitus and followed by curative treatment has not been previously reported. We do conclude that pacemaker generators in close relationship to the mammary gland should be considered with suspicion.

The neuropharmacological effects of repeated oral doses of dexfenfluramine (DF; 1.25-10 mg/kg, twice daily for 21 days) were examined in rats and related to the drug brain levels. Results were compared with fluoxetine (FL) given at similar doses relative to its anorectic ED50. Both drugs dose-dependently slowed body weight gain and reduced brain serotonin (5-HT). However, at 1.25 mg/kg DF caused only a slight and transient decrease in cortical 5-HT. Comparable doses of FL (6.25-12.5 mg/kg) lowered 5-HT more than DF, besides slightly reducing striatal dopamine. At higher doses DF markedly reduced 5-HT in all regions, and to a lesser extent noradrenaline in hippocampus. There was a negative relationship between 5-HT and log total active drug levels and the indole was approximately halved at drug levels about 50 times lower with DF than FL. However, the ratio between drug levels causing marked 5-HT reductions and those considered anorectic was similar for DF and FL because brain levels at the anorectic ED50 were higher with FL than DF. Long-lasting reductions of 5-HT were also observed but recovery was only consistently slow beginning from 5 mg/ kg DF. Comparable doses of FL could not be used because its general toxicity leads to the death of rats after only 2-4 multiples of its anorectic ED50.

Atrial electrical activities during hypothermic, K(+)-induced cardioplegic arrest correlate with an increased incidence of postoperative supraventricular dysrhythmias in coronary artery bypass graft patients. Surface electrocardiogram (ECG) (S-ECG) may be insufficiently sensitive to detect such activity intraoperatively, and invasive methods are impractical and traumatic. From induction of anesthesia until the end of surgery, esophageal ECG signals were detected with a new bipolar esophageal probe and a new high-resolution preamplifier (frequency range 0.01-2000 Hz). The S-ECG and the esophageal ECG (E-ECG) were evaluated independently in 18 patients. Eight of 18 patients presented during cardioplegic arrest a mean of 483 +/- 119 high-amplitude, biphasic P components (mean amplitude 0.7 +/- 0.1 mV, range 0.35-1.15 mV) per patient (mean 36 +/- 6 [5-59] potentials/min) similar to those coinciding with the surface ECG P-waves during sinus rhythm. Six of these eight patients presented a mean of 29 +/- 11 low atrial activities (mean amplitude 0.14 +/- 0.023 mV; range 0.1-0.25 mV) per patient (mean 8.4 +/- 5.6 [2.3-48] potentials/min) in the E-ECG. In the S-ECG, one patient of these eight presented 26 P waves during cardioplegic arrest simultaneously with activities in the E-ECG. During the first 5 days, seven of eight (88%) patients with atrial activities in the E-ECG versus 3 of 10 (30%) patients without atrial activities developed supraventricular tachyarrhythmias postoperatively (P < 0.05). This new high-resolution E-ECG device detected in a beat-to-beat technique more atrial activity during cardioplegic arrest than a S-ECG and offered the advantages of artifact exclusion and better prediction of postoperative supraventricular dysrhythmias.

Background and Aims of the Study: Aortic valve replacement (AVR) in the small aortic root (SAR) has always been a severe challenge with an uncertain surgical outcome. The purpose of this study was to assess the surgical and clinical performance of 19 mm and 21 mm CarboMedics valves (CPHV) based on a review of valve-related morbidity and mortality over a period of six years., Methods: A total of 361 patients undergoing aortic valve replacement (AVR) with the CPHV between January 1989 and August 1995 was subdivided and studied. (i) Group A patients (n = 137) received 19 mm or 21 mm prostheses; subgroup AI (n = 85) underwent isolated AVR and subgroup AII (n = 52) underwent AVR with associated cardiac procedures. (ii) Group B patients (n = 224) were given 23 mm or larger prostheses; subgroup BI (n = 147) underwent isolated AVR and subgroup BII (n = 77) underwent AVR with concomitant cardiac procedures., Results: Hospital mortality was group A 7.3% versus group B 4.9%. Cumulative survival after six years was 83.7% in AI and 76.9% in AII versus 72.1% in BI and 77.4% in BII. There were no significant statistical differences between the subgroups concerning cardiac mortality. Thromboembolic events occurred with a linearized rate of 1.41%/pty in group A versus 1.03%/pty in group B, the incidence of anticoagulant-related major hemorrhage was 1.41%/pty in group A versus 1.20%/pty in group B and that of periprosthetic leakage 1.69%/pty in group A versus 1.89%/pty in group B., Conclusion: Our results demonstrate that this bileaflet prosthesis is highly efficient in patients with small aortic roots undergoing AVR with or without associated procedures.

Flunarizine (35 mg/kg), but not haloperidol and trifluperazine, counteracted the initial indole depletion induced by D-fenfluramine (dF) in vivo (5 mg/kg), without affecting ex vivo [3H]-serotonin (5-HT) uptake by synaptosomes or changing the brain concentrations of the parent drug and its main active metabolite, D-norfenfluramine (dNF). The long-term indole depletion induced by repeated doses of dF (5 mg/kg, b.i.d. for 4 days) was also reversed by flunarizine pretreatment. Flunarizine, methiothepin, and trifluperazine, but not haloperidol, reduced in vitro the Ca(2+)-dependent [3H]5-HT release stimulated by 0.5 microM dF and dNF from superfused synaptosomes. At the concentrations used in release experiments the drugs were not active on [3H]5-HT uptake nor on the calcium-calmodulin protein kinase activity, thus excluding an effect on the uptake carrier or on phosphorylation of synaptic proteins involved in exocytosis, respectively. The drugs did not consistently affect [3H]5-HT release induced by depolarization, or dNF-induced [3H]dopamine release in vitro. The fact that flunarizine, as methiothepin and 5-HT uptake inhibitors, counteract dF-induced indole depletion in vivo suggests a relation between the reduction of the Ca(2+)-dependent release of [3H]5-HT induced by dF in vitro and the protective effect on the short- and long-lasting depletion of indoles induced in vivo by high doses of dF.

The effects of pretreatment with inducers of hepatic cytochrome P450 isoenzymes (phenobarbital, dexamethasone and beta-naphthoflavone) on the metabolism of d-fenfluramine (d-F) and its acute and long-lasting indole-depleting effects were studied in rats, in an effort to obtain further information on the importance of hepatic drug metabolism in relation to its neurochemical actions. Twenty-four hours after the last dose of each inducer, rats were injected with d-F hydrochloride (5 mg/kg, IP) and killed at various times thereafter for parallel determination of indoles and drug concentrations in plasma and brain. Additional rats were treated as above and killed 1 week after d-F hydrochloride (5 and 10 mg/kg) to study the recovery of indole in the cortex, a particularly sensitive brain area. Phenobarbital and beta-naphthoflavone and, to a lesser degree, dexamethasone, stimulated the metabolism of d-F, as evidenced by a decrease in plasma and brain areas under the curve (AUC) compared to vehicle-treated rats. This indicated that multiple isoenzymes are capable of mediating the drug's metabolism, primarily by N-dealkylation to d-norfenfluramine (d-NF). None of the inducers raised plasma and brain AUC of the nor-derivative, and in fact phenobarbital and particularly beta-naphthoflavone reduced it. These different effects were even apparent in rats given d-NF (2.5 mg/kg), indicating that both phenobarbital and beta-naphthoflavone also stimulate the sequential metabolism of the nor-metabolite (by N-deamintaion) which, however, is apparently enhanced most actively by beta-naphthoflavone-inducible forms of P-450.(ABSTRACT TRUNCATED AT 250 WORDS)

The original Fontan operation was employed for patients with tricuspid atresia, but its application has been extended to a broad spectrum of congenital cardiac defects with a functional or anatomical single ventricle. From 1989 to 1995, 35 patients (23 males, 12 females) underwent a modified Fontan procedure; their age ranged from 14 months to 15 years (mean 5.1 a). Indications for operation were the following: D(S)ILV = 16, TA = 9, MA = 3, TGA with straddling AV-valve = 2, DORV = 4 and criss-cross heart = 1. The same surgical technique was utilized in all patients with redirection of the systemic venous return by means of a bidirectional cavopulmonary anastomosis and an intraatrial baffle, adaptable to all the various forms of underlying anatomy. Associated anomalies such as dextrocardia, coarctation, anomalous systemic or pulmonary venous return, subaortic stenosis and situs anomalies were present in 26%, 9%, 26%, 9%, and 20%, respectively. 12 patients were presumed to be at high risk and underwent a two-stage procedure (n = 7 bidirectional Glenn preceding the definitive repair and n = 5 a fenestration of the intraatrial baffle). Risk factors in our group of patients were: age under 2 years, abnormal systemic venous drainage, stenotic pulmonary arteries, PVR over 2 Wood units, mPAP over 15 mmHg, AV-valve incompetence, subaortic obstruction and ventricular dysfunction. Two patients had failure of the total cavo-pulmonary connection necessitating the take-down to a bidirectional Glenn anastomosis in the early postoperative period, with one death. Hospital mortality was 24% (n = 8). One child did not survive complications following the fenestration closure 4 months postoperatively.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Troponin-T is one of the contractile proteins of the myocardium. Its release into the circulation indicates various degrees of myocardial cell damage. Troponin-T may be measured in serum with a recently developed enzyme immunoassay. This immunoassay was used to evaluate the preoperative myocardial cell damage in patients with stable and unstable angina undergoing elective coronary artery bypass graft surgery, and it was compared with conventional assays of creatine kinase (CK) MB isoenzyme activity and mass., Methods: Twenty-one patients with unstable angina and 31 with stable angina were studied. Troponin-T, CK-MB activity, and CK-MB mass were measured 24 h before anesthesia and surgery, immediately before induction of anesthesia, before and after cardiopulmonary bypass, at the end of surgery, and 24 h afterward., Results: In 90% (19 of 21) of the patients with unstable angina, troponin-T was increased 24 h before anesthesia (median 0.33 microgram/l, range 0.15-5.2 micrograms/l), whereas only 3% (1 of 31) of the patients with stable angina had increased values (median 0.0 microgram/l, range 0.0-0.53 microgram/l). The difference was statistically significant (P < 0.001). The same profile was found in patients with and without unstable angina immediately before induction of anesthesia (86% [18 of 21] and 0%, respectively) and before cardiopulmonary bypass (62% [13 of 21] and 0%, respectively). In contrast to troponin-T, CK-MB activity was increased in only 0-14% of patients with unstable angina, and CK-MB mass was increased in only 9-24%. After bypass troponin-T increased in both groups (P < 0.01), but there was no longer a statistically significant difference between the groups. Twelve percent (4 of 31) of the patients in the stable angina group and 28% (6 of 21) in the unstable group had major cardiac events (P not significant)., Conclusions: The study data suggest that many patients with unstable angina undergoing elective coronary artery bypass graft surgery have already increased troponin-T levels preoperatively, although conventional biochemical markers such as CK-MB activity and mass are at a normal range. Increased troponin-T and normal CK-MB concentrations may reflect some degree of ischemic myocardial cell damage. Because of the small number of patients in the study, the influence of preoperative myocardial injury on perioperative outcome could not be clarified.

1. The effects of acute and repeated equiactive anorectic doses (ED50) of recently marketed 5-hydroxytryptamine (5-HT) uptake inhibitors on the content of brain indoles were compared in rats in relation to the brain regional concentrations of unchanged drug and its known active metabolite. 2. Single intraperitoneal (i.p.) doses of the anorectic ED50 of fluoxetine (35 mumol kg-1), fluvoxamine (60 mumol kg-1), paroxetine (20 mumol kg-1) and sertraline (49 mumol kg-1) slightly reduced brain 5-hydroxyindoleacetic acid (5-HIAA), with regional differences, this being compatible with 5-HT uptake blockade. Only fluvoxamine and sertraline significantly enhanced the content of 5-HT in the cortex. 3. The regional sensitivity to the acute effect of a given drug was not related to any preferential drug distribution, as these compounds distributed almost uniformly in the brain areas considered (cortex, striatum and hippocampus). 4. Repeating the same doses twice daily, i.p. for 14 days, however gave a different picture, fluvoxamine having little or no effect on the content of indoles and fluoxetine, paroxetine and sertraline lowering both 5-HT and 5-HIAA in all the brain regions compared to pair-fed control animals, 1 h after the last dose. 5. One week later only fluoxetine-treated animals still had reduced brain 5-HT, this probably being related to the accumulation of its main metabolite norfluoxetine in rat brain after chronic dosing. 6. Further studies on the relationship between the long-term neurochemical changes and anorectic activity are required but it appears from these results that anorectic drugs with similar acute effects on 5-HT uptake may differ in their long-term effects on 5-HT mechanisms.

1. The effect of the CCKA receptor antagonist, devazepide (100 mg kg-1) on meal parameters during the initial phase of the dark period was studied in free-feeding rats by use of a procedure for continuously monitoring feeding patterns. 2. In a second experiment, the effect of devazepide on the reduction in meal parameters induced by the 5-hydroxytryptamine (5-HT) releaser and uptake inhibitor, (+)-fenfluramine (1.5 mg kg-1) in 4 h food-deprived rats was examined. 3. The hypophagic effect of an intraperitoneal injection of cholecystokinin (CCK-8, 4 micrograms kg-1) was studied in rats treated with the 5-HT receptor antagonist, metergoline (1 and 2 mg kg-1). 4. Devazepide increased the size of the first meal in free-feeding, but not in 4 h food-deprived rats and partially antagonized the effect of (+)-fenfluramine on the size and duration of the first meal. The reduction in eating rate induced by (+)-fenfluramine was not modified by devazepide. No changes in (+)-fenfluramine or (+)-norfenfluramine levels were found in the brain of rats treated with devazepide. 5. The effect of CCK-8 on meal size was completely antagonized by 2 mg kg-1 metergoline. A significant interaction was also found between 2 mg kg-1 metergoline and CCK-8 as regards their effect on the inter-meal interval. 6. The results suggest a reciprocal interaction between 5-HT and CCK-8 in enhancing the satiating effect of food in rats.

The importance of d-norfenfluramine in regard to the indole-depleting action of d-fenfluramine has not been well studied in sensitive animal species. The present study therefore examined the intensity and time course of the neurochemical effects of i.p. injected d-fenfluramine (2.5 and 5 mg/kg) and d-norfenfluramine (2.5 mg/kg) in vehicle- and SKF-525A-pretreated rats, relating the effects to the brain concentration-time profiles of the drug and its active metabolite. At the lower dose d-fenfluramine caused only a small, short-lasting decrease in brain serotonin (5-HT) without affecting the 5-hydroxyindoleacetic acid (5-HIAA). Higher doses affected both 5-HT and 5-HIAA (50-60 and 30-40% reductions, respectively), the effect being maximal for at least 8 h. d-Norfenfluramine reduced the brain content of 5-HT and 5-HIAA less (by about 30%) than 5 mg/kg d-fenfluramine did. Brain concentrations of d-norfenfluramine at the time of the maximal depletion of indoles were close to those of the metabolite after 5 mg/kg d-fenfluramine, indicating that the acute indole-depleting effects did not depend solely on the brain concentrations of its nor-metabolite. SKF-525A changed the metabolite-to-parent drug ratios in brain without appreciably influencing the action of d-fenfluramine. However, the maximum decrease in indole content caused by 2.5 mg/kg d-fenfluramine in SKF-525A-pretreated rats was only 12% of the control level, although the brain concentration of unchanged drug was comparable to that after 5 mg/kg d-fenfluramine in vehicle-pretreated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study investigated the anorectic activity of d-fenfluramine (d-F) and the relationship with brain levels of unchanged drug and its metabolite d-norfenfluramine (d-NF) in marmosets, relating them to neurochemical effects on the serotoninergic system. d-F and d-NF were equally active in reducing food intake (ED50 about 3 mg/kg, p.o.). However, the brain concentrations of the metabolite required to reduce food intake after synthetic d-NF were more than twice those after d-F, indicating that d-NF contributes to but does not completely explain the anorectic effect of d-F. At this dose d-F did not appreciably modify the serotonin (5-HT) and 5-hydroxyindoleacetic (5-HIAA) contents of the brain regions examined, except for a slight enhancement of 5-HIAA in hippocampus. In vitro in brain cortical synaptosomes d-F inhibited [3H]5-HT uptake more potently than d-NF, as in other species. d-F and d-NF showed similar potency in stimulating [3H]5-HT release, in a Ca++ dependent manner. The tritium released by d-F and d-NF appeared to be mainly unmetabolized [3H]5-HT. Like in other species the marmoset too has saturable and specific [3H]d-F binding sites, for which d-NF has lower affinity. d-F and d-NF have low affinities for 5-HT receptor subtypes, except that d-NF has appreciable affinity for 5-HT1C and 5-HT1D receptors. Unlike in rodents but similarly to primates in the striatum the pharmacology of 5-HT receptors seems to correspond to the 5-HT1D subtype.(ABSTRACT TRUNCATED AT 250 WORDS)

Six years after the first aortic valve replacement with the Starr-Edwards Silastic ball prosthesis at Oregon Health Sciences University, the model 1260 was implanted in a 44-year-old patient at our department. During 24 years no signs of dysfunction, thromboembolism, thrombosis, periprosthetic leaks or hemolysis were observed. Material test showed no signs of fatigue. The dimension of the Silastic poppet was found to be one millimeter less than the original specifications of these poppets and there were some lipid infiltrations. Functionally the poppet was found to be nonvariant. Histologic findings detected focal hyalinization and giant cells without signs of acute inflammation or ulceration. With regard to its reliability and durability, the Starr-Edwards valve prosthesis should not be viewed with disfavor.

beta-Blockers are known to protect a vulnerable aorta from acute dissection, as well as reducing the risk of recurrent dissection. This case presentation reports the history of a 60-year-old male suffering from acute aortic dissection following discontinuation of beta-blocker therapy. The patient has shown arterial hypertension for about 20 years treated solely by beta-blockers. Two days after stopping the use of metoprolol, a nonselective beta 1-blocker without ISA, the patient developed severe chest pain during exercise. Diagnosis of type I-aortic dissection according to DeBakey was achieved by transthoracal echocardiography and computed tomography. Successful surgery by replacement of the ascending aorta was performed about 1 h following admission to the intensive care unit. During the procedure, tamponade of the left ventricle occurred followed by cardiogenic shock. Postoperative management was complicated by prolonged respiratory therapy and acute gastrointestinal bleeding; 1-year follow-up showed no evidence of disease. Thus, in this case acute dissection may be the consequence of discontinuing the use of metoprolol, possibly due to uncontrolled hypertension or specific response to the beta-blocker.

The neurochemical effects of a large dose challenge (5 mg/kg, i.p.) of d-fenfluramine (d-F) in rats, given saline or gradually escalating doses of d-F (0.1-2.5 mg/kg, i.p.), were examined with regard to regional sensitivity and the time-course of recovery. The indole-depleting effect after the large dose of d-F to saline-pretreated animals appeared to differ, depending on the areas of brain considered (cortex greater than hippocampus greater than striatum), despite the fact that the drug and its main metabolite, d-norfenfluramine (d-NF) distributed almost uniformly in the regions of brain examined. The depletion in all these regions of the brain was reversible within 6 weeks, serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) being back to control levels in the hippocampus and striatum but not 5-HT in the cortex. However, when rats were exposed to gradually escalating doses of d-F the recovery of indoles in the brain, after injection of the large dose challenge, appeared to be faster. Indoles were markedly less reduced 1 week later in the cortex, hippocampus and striatum, with content of indole in the striatum showing complete recovery and the long-term depletion of 5-HT and 5-HIAA, by the subsequent large dose challenge was almost completely reversed in all regions. Analysis of the concentrations of d-F and its main metabolite d-fenfluramine (d-NF) in brain excluded any pharmacokinetic tolerance. These results suggest that during therapeutic treatment with d-F, the use of escalating doses may attenuate the potential for the long-lasting decrease of 5-HT in brain.

The present study aimed to establish the role of the metabolite norfluoxetine in the anorectic activity of fluoxetine, and to relate the anorectic doses (ED50) to the brain concentrations of the parent drug and its metabolite. Fluoxetine showed anorectic activity at increasing intraperitoneal doses (ED50 = 39.1, 34.7 and 21.7 mumol kg-1 in mouse, rat and guinea-pig, respectively) and norfluoxetine was slightly more active (24.3, 22.9 and 19.1 mumol kg-1, respectively) in all three species. In terms of maximum concentration (Cmax) and area under the curve (AUC) within the experimental period (0-90 min), brain concentrations varied widely and were poorly related to the dose; guinea-pig appeared to be much more sensitive to fluoxetine than was mouse or rat. Administered norfluoxetine was present in the brain of the three species in approximately the same order as fluoxetine, i.e. lower in guinea-pig than in mouse or rat. The Cmax and AUC of norfluoxetine after fluoxetine administration was 50-60% of the values after an equiactive dose of norfluoxetine in mouse and guinea-pig, and more than 80% in rat.

1. High parenteral doses of a twice-daily schedule of d,l-fenfluramine (d,l-F) may cause long-lasting decrease of functional indices of brain serotoninergic neurones in rats. The single- and multiple-dose (b.i.d. x 4 days) kinetics of low (1.25 mg/kg) and high (12.5 mg/kg) subcutaneous (s.c.) doses of d-F, which accounts of the anorectic effects of the racemate, and its deethylated metabolite d-norfenfluramine (d-NF), were therefore examined and compared with those of pharmacologically effective oral doses (0.3-1.25 mg/kg) in rats. 2. There were dose-dependent alterations of kinetic parameters after s.c. and oral dosing, indicating that hepatic clearance of d-F in the rat can be saturated either by increasing the size of the single dose or during repeated dosing. Nonlinearity was also observed for d-NF. Consequently at high doses exposure of rat to the drug, as measured by the sum of area under the plasma concentration-time curve (AUC) of d-F and d-NF considerably exceeded that expected from simple dosage considerations, particularly with repeated administration of d-F. 3. Total exposure at the high doses considerably exceeded that at pharmacological doses, however, indicating an ample margin in favour of anorectic activity. The possibility that the long-term depletion of brain 5-HT by d-F and/or its metabolite d-NF may have relevance at the usual therapeutic dose, is discussed.

997 strains isolated from clinical specimens arrived at the "Pio Albergo Trivulzio" microbiology laboratory were tested using disks of cefpodoxime, amoxicillin + clavulanic acid, cefaclor, cefuroxime, ofloxacin, cotrimoxazole, ceftriaxone and cefalexin. Gram-positive strains were tested also with erythromycin, while gram-negative bacteria were tested against aztreonam. Cefpodoxime overall activity was well above the effectiveness of the other oral cephalosporins and on the same order as ceftriaxone and ofloxacin. Cefpodoxime proved to be also more active than the combination amoxicillin-clavulanic acid.

A clinical trial, involving 16 male subjects affected by a relapse of chronic bronchitis, was performed in order to evaluate the possible interference of roxithromycin (RU 28965) with theophylline plasma levels. Theophylline was administered to patients as a controlled release formulation. Results did not show any clinically relevant change in theophylline blood levels, implying the conclusion that the new macrolide roxithromycin can be administered simultaneously with a controlled release theophylline.

Data regarding 11,541 cases of school accidents (from kindergarten to senior high school) that required hospital attention for treatment were examined. The information was obtained from the records of the "School Medicine Service of the City of Milan", and covered five school years (from 1980-81 to 1984-85). The surveyed population included over 160,000 subjects for each year. After computer processing, data regarding type of school, year, age of the victim, place of the accident and type of lesions were obtained. The frequency of accidents was highest (about 2%) among kindergarten pupils, while in senior high school the lowest frequency (less than 1%) was accompanied by the greatest percentage of hospitalizations (about 6%). From our results it appears that most accidents occur in school gyms (around 50%), and that the percentage of sprains and fractures is also highest in this area. School gyms can therefore be considered as a primary target for any prevention activity.