Reproducible model of post-infarction left ventricular dysfunction: haemodynamic characterization by conductance catheter.

OBJECTIVE: The understanding of pathophysiology and cellular mechanisms of chronic heart failure requires the creation of appropriate and accurately characterized animal models, thus enabling meaningful evaluation of evolving medical and surgical therapies. METHODS: The left anterior descending and its diagonal branch were ligated in 12 sheep to induce left ventricular dysfunction. RESULTS: Study of left ventricular pressure-volume loops 3 months post-operatively showed a significant deterioration of both systolic and diastolic indexes of left ventricular function. The left ventricular end-diastolic pressure increased from 3+/-1 to 7+/-1 mmHg (P<0.001) along with a substantial increase in end-diastolic volume from 78+/-8 to 121+/-6 ml (P=0.002) and a significant decrease in cardiac output from 2+/-0.2 to 1.5+/-0.2 l/min (P=0.001). The left ventricular end-systolic pressure-volume relationship deteriorated from 2.7+/-0.37 to 0.7+/-0.16 mmHg/ml (P=0.0002) along with a significant reduction in the pre-load recruitable stroke work (P=0.001). The ejection fraction decreased from 34+/-2% to 16+/-4% (P<0.001) with a significant decrease in +dp/dt and -dp/dt (P=0.009). The mean systemic blood pressure, however, was maintained due to a substantial increase in the systemic vascular resistance (P=0.007). CONCLUSION: This study describes a reproducible large animal model of left ventricular dysfunction. This model is potentially useful to study the pathogenesis of remodelling, surgical management of heart failure and development of novel treatment strategies.     

Pharmacodynamic effects of S-(+)-ketamine on EEG, evoked potentials and respiration. A study in the awake dog]

Until recently, only the racemic mixture of ketamine has been used in anaesthesia. Little is known of the central nervous effects of the pharmacologically more potent S(+)-isomer. Information in regard to the putative receptor site involved in the mediation of its anaesthetic/analgesic effect is particularly sparse. METHODS. In order to evaluate the anaesthetic and antinociceptive properties of S(+)-ketamine, a dose-response relationship of the compound on the EEG, somatosensory-evoked potentials (SEP), and respiration was established. Increasing doses (2, 5, 10, 20 mg/kg) were given to trained and awake dogs (n = 10) at 10-min intervals. In order to detect a possible opioid receptor-related interaction, an antagonist of the methoxymorphinane series (cyprodime 80 g/kg i.v.) with higher selectivity than naloxone for the mu-receptor was given at the end. RESULTS. Compared to controls, S(+)-ketamine induced a dose-related increase in output in the theta-(3-8 Hz) band and an increase in output in the alpha-domain (8-13 Hz) following 20 mg/kg. Both effects were reversed completely by the opioid antagonist. At low doses (2-5 mg/kg) there was an increase in output (P less than 0.05) in the beta-(13-30 Hz) and a concomitant decrease in output (P less than 0.05) in the delta-(0.5-3 Hz) band. These effects were reversed with increasing doses (5-10 mg/kg). After 20 mg/kg, however, output in the delta-domain increased while power in the beta band decreased significantly (P less than 0.005) when compared to controls. Both effects were reversed by the opioid antagonist. Compared to controls, the reversal resulted in a 12% increase in output in the beta- and a 49% decrease in output in the delta-domain. In SEP, S(+)-ketamine induced a dose-related increase in peak latency and depression of amplitude of more than 50% when compared to controls. While latency changes were completely reversed, amplitude height was only partly restored by the antagonist. Respiration was depressed in a dose-related fashion (PaO2 decreased, PaCO2 increased). Hypoxaemia was fully reversed by the antagonist; hypercapnia was only partly reversed. CONCLUSION. The results support the presumption that the S(+)-isomer of ketamine induces opioid mu-receptor-mediated central effects. Hypersynchronisation of the EEG suggests a deep plane of anaesthesia after S(+)-ketamine. The pronounced blockade of impulses in the sensory nervous pathways suggests an efficient analgesic effect that is partly mediated by the opioid-receptor. The respiratory depression may be of importance when S(+)-ketamine is used in high dosages in man.     

Subtyping of Mycoplasma pneumoniae isolates based on extended genome sequencing and on expression profiles

Mycoplasma pneumoniae isolates from patients, collected over a period of 12 years in Germany, were characterized by various methods (parameters) including multilocus sequence typing, restriction fragment length polymorphisms, Western blotting with mono-specific antibodies directed against selected proteins or with polyspecific antibodies directed against the Triton X-114-soluble protein fraction, and two-dimensional gel electrophoresis. The results for 91 isolates from Germany, which were complemented with 14 isolates from the USA and 10 isolates from France, clearly showed that M. pneumoniae is a highly uniform species and that most of the isolates could be assigned to one of the two subtypes 1 and 2. The members of one subtype differ from the other with respect to the sequence of the P1 gene, the ORF6 gene, the P65 gene, and by a typical DNA restriction fragment pattern. We observed four isolates (variants), which seemed identical by the above mentioned criteria, but did not belong to either one of the two subtypes. They showed most of the subtype 2-specific features, but differed in the sequence of the P1 gene and showed a variation in the restriction fragment pattern. The appearance of subtype 1 or 2 over the last 12 years in Germany showed a dominance of subtype 1 between 1989 and 1996 and a dominance of subtype 2 between 1997 and 1998. The variant (neither subtype 1 nor subtype 2) was only detected in 1991 and 1995 but it had no epidemiological consequences.     

Cardiac sympathetic denervation does not change the load dependence of the left ventricular end-systolic pressure/volume relationship in dogs

It has been shown that in the intact canine heart the left-ventricular end-systolic pressure/volume relation (ESPVR) depends on loading conditions: an increase in arterial vascular resistance causes a leftwards shift and a steeper slope of the ESPVR, suggesting an increased inotropic state. Our purpose was to investigate the possible contribution of the sympathetic nervous system to this load sensitivity of the ESPVR, using intact, but denervated, hearts with normal coronary perfusion and afterload. We used two types of loading intervention: venous volume infusion and gradual occlusion of the descending aorta. ESPVRs were obtained in six anaesthetized open-chest dogs, both before and after bilateral ablation of the stellate ganglia. To exclude the influence of heart rate changes, bilateral vagotomy was performed and the heart was paced. The absence of (unpaced) heart rate changes in response to pressure alterations was used to confirm total denervation. Left ventricular pressure was measured with a micromanometer and volume with a conductance catheter. ESPVRs were essentially linear and characterized by their slope (E _es) and volume intercept at 12 kPa (V ₁₂). We found that E _es (P<0.0001) and V₁₂ (P<0.05) were both significantly different during pressure and volume interventions (0.67±0.29 and 0.41±0.18 kPa/ml for E _es and 16.2±8.2 and 18.2±8.4ml for V₁₂ respectively). Denervation did not significantly affect the parameters of the ESPVR obtained by either volume infusion or aortic occlusion. Two-way analysis of variance revealed no significant interactive effect between denervation and intervention, indicating that the sympathetic nervous system does not influence the load dependency of the ESPVR. The dP/dt _max: EDV relationship behaved similarly. These results suggest that load dependency is an intrinsic property of the myocardium.     

Molecular Approaches to Diagnosis of Pulmonary Diseases Due to Mycoplasma pneumoniae

In this prospective study, the use of a culture-enhanced PCR assay for the detection of Mycoplasma pneumoniae, followed by hybridization with a specific probe (MP-HPCR) or without hybridization (MP-PCR), and the use of a nested PCR (MP-NPCR) were evaluated. Clinical samples (190 specimens) from 190 patients with respiratory complaints were incubated in culture broth overnight and then subjected to PCR. The results of the PCR were compared to those obtained by culture, the direct antigen test, and serologic testing by microparticle agglutination and by immunoblotting in unclear cases. The sensitivities were 19 CFU for MP-PCR, 1.9 CFU for MP-HPCR, and 0.019 CFU for MP-NPCR. PCR amplification of the β-globin gene was possible in 98% of cases: after dilution of the β-globin-negative samples, all samples were reactive. Correlation between negative MP-NPCR results and negative serology results was found in 89% of cases; a positive correlation was found with 10% of the patients. Samples from three immunocompromised patients were MP-NPCR positive but serologically negative. High respiratory colonization by M. pneumoniae (>10⁵ CFU/ml) in patients with acute respiratory disease could be detected by culture, MP-PCR, and MP-NPCR. These results indicate that MP-PCR and MP-NPCR are reliable methods for the detection of M. pneumoniae in respiratory tract samples of patients with respiratory complaints.     

14-methoxymetopon, a potent opioid, induces no respiratory depression, less sedation, and less bradycardia than sufentanil in the dog

Opioids of the mu-receptor type depress respiration and induce addiction. At 10-min intervals 14-methoxymetopon (HS-198), which is 20,000 times more potent than morphine in the acethylcholine-writhing test, was given in graded IV doses (3, 6, and 12 microg/kg) to awake, trained canines (n = 7). The following variables were derived: PaO(2), PaCO(2), heart rate (lead II of the electrocardiogram), mean arterial blood pressure, relative changes in the delta domain and the beta domain of the electroencephalogram, the somatosensory evoked potential, and the skin-twitch reflex to electrical stimuli. Thereafter, 20 microg/kg naltrexone was given for reversal. After a washout period, the same animals were exposed to similar doses of sufentanil (SUF) followed by naltrexone. Both opioids induced a dose-related bradycardia and hypotension. The maximal bradycardic effect was 19% after HS-198 and 42% after SUF (P < 0.005). The maximal hypotension was 6% after HS-198 and 20% after SUF (P < 0.01). In the electroencephalogram, power in the delta band increased by 288% after HS-198 and by 439% after SUF (P < 0.01); simultaneously, power in the beta band decreased by 71% and by 95.7%, respectively (P < 0.01). PaO(2) decreased by 41% after SUF and by 4% after HS-198, and PaCO(2) increased by 56.8% and 6.6% in SUF and HS-198, respectively (P < 0.001). Both opioids induced a dose-related depression in the somatosensory evoked potential and increased tolerance to skin-twitch. The maximal effect was 92.7% after SUF and 81.3% after HS-198 was not significant. Naltrexone reversed all changes back to control. Compared with SUF, HS-198 does not induce hypoxia and hypercarbia, induces less hypotension and bradycardia, and induces less sedative effects. Implications: Compared with sufentanil, 14-methoxymetopone does not induce hypoxia and hypercarbia, induces less hypotension and bradycardia, and induces less sedative effects (electroencephalogram). Antinociception is similar to sufentanil (skin-twitch method, amplitude depression in the evoked potential). All effects are reversed by naltrexone. Interaction of kappa-receptor is suggested.