EVIDENCE FOR MEDETOMIDINE AS A SELECTIVE AND POTENT AGONIST α2-ADRENORECEPTORS

• 1 The activity on α-adrenoreceptors of medetomidine (±)-4-(α,2,3-trimethylbenzyl)imidazole), an α-methyl derivative of detomidine, has been characterized in vivo and in vitro using detomidine, MPV 207, MPV 295, azepexole, clonidine and xylazine for reference purposes.
• 2 Medetomidine (1–100 μg/kg i.v.) was a hypotensive and bradycardic compound in anaesthetized rats. Furthermore, it induced vasopressor (PD₅₀ 1.7 μg/kg) and sympatho-inhibitory (ID₅₀ 1.6 μg/kg) actions in pithed rats, the effects being antagonized by idazoxan (0.3 mg/kg i.v.) but not by prazosin (0.1 mg/kg i.v.). Medetomidine (30–300 μg/kg i.m.) had an α₂-adrenoreceptor mediated sedative effect on chicks.
• 3 Medetomidine was, overall, more potent than detomidine, MPV 207, clonidine, xylazine, MPV 295 or azepexole in central (sedation in the chick) and peripheral (cardiac presynaptic in the pithed rat) actions on α₂-adrenoreceptors. Clonidine had, however, about an equal potency to medetomidine in the vascular smooth muscle of the pithed rat.
• 4 Like detomidine and MPV 295, medetomidine had no agonistic activity in the rat aortic ring, but high concentrations antagonized methoxamine-induced contractions, giving a pA₂ value of 5.68 for α₁-adrenoreceptor antagonism.
• 5 The overall lipophilicity (log P') of medetomidine in the octanol/buffer (pH 7.4, 24–26°C, HPLC technique) was 2.80.
• 6 In summary, the experimental data suggest that medetomidine is a lipophilic compound with selective α₂-adrenoreceptor-stimulating properties and high potency. It may, therefore, prove to be a suitable pharmacologic tool for interventions in α₂-adrenoreceptor mediated effects in the autonomic nervous system.

     

Microvolt T-Wave Alternans During Exercise and Pacing in Patients with Acute Myocardial Infarction

Cardiac Arrhythmias and Risk Stratification after Myocardial infarction (CARISMA) is a prospective multicenter trial designed to document the incidence of cardiac arrhythmias after acute myocardial infarction (AMI), and to assess the predictive accuracy of various arrhythmic risk markers. In this substudy of the CARISMA trial, microvolt T-wave alternans (TWA) was assessed with specific equipment 6 weeks after AMI during bicycle exercise, atrial (A) pacing, and simultaneous ventricular and atrial (V + A) pacing in 80 patients with left ventricular ejection fraction (LVEF) <40%. The agreement between the acute test results was determined by overall proportion of concordance and the kappa statistic. Sustained TWA was observed in 24, 45, and 50% of the patients during the exercise test, A pacing, and V + A pacing, respectively. The number of indeterminate TWA was significantly lower during V + A pacing (n = 7) than exercise test (n = 34). The TWA concordance rate was 71% between exercise and V + A pacing (κ= 0.53, P = 0.001), 79% between exercise and A pacing (κ= 0.54, P < 0.001), and 95% between the two pacing modes (κ= 0.89, P < 0.001). Patients with positive TWA in all tests had lower LVEF (28 ± 7% vs 35 ± 9%, P < 0.01) and wider QT dispersion (99 ± 44 ms vs 67 ± 38 ms, P < 0.01) than those with inconsistent test result. The low number of indeterminate tests and high concordance between the test results indicate that V + A pacing may provide a valuable means to assess TWA in patients who cannot complete the exercise test.     

Detection of virulence genes of Clostridium difficile by multiplex PCR

Antikainen J, Pasanen T, Mero S, Tarkka E, Kirveskari J, Kotila S, Mentula S, Könönen E, Virolainen‐Julkunen A‐R, Vaara M, Tissari P. Detection of virulence genes of Clostridium difficile by multiplex PCR. APMIS 2009; 117: 607–13. Clostridium difficile strains belonging to the PCR ribotype 027, pulse‐field gel electrophoresis (PFGE) type NAP1, toxinotype III and restriction endonuclease analysis group BI harbouring mutations in the tcdC gene and possessing binary toxin components A and B have been described to cause epidemics with increased morbidity and mortality. In the present study we developed a conventional multiplex PCR designed to detect selected virulence associated markers of the hypervirulent C. difficile PCR ribotype 027. The multiplex PCR assay detected the major toxins A and B, binary toxin components A and B as well as a possible deletion in the tcdC gene: a characteristic pattern of amplification products for the PCR ribotype 027 strains was detected. This rather simple method was specific for the screening of this hypervirulent C. difficile strain. The correlation between the multiplex PCR and PCR ribotyping methods was excellent. The sensitivity and specificity were 100% in our epidemiological situation. In conclusion, this multiplex PCR was found useful in the preliminary screening for the hypervirulent C. difficile PCR ribotype 027.     

The Feasibility of Fully Automated Pacemaker Advise in Treating Atrial Tachyarrhythmias

Background: Modern pacemakers continuously store significant cardiac‐related events. Interpreting these data and reprogramming the pacemaker can be time‐consuming and demands expert knowledge. A software‐based expert system, the therapy advisor (TA), was developed, which analyzes stored data and provides reprogramming recommendations. This study addresses whether pacemaker experts consider the messages that are automatically generated appropriate in the management of atrial tachyarrhythmias/atrial fibrillation (AT/AF). Methods: This observational, international, multicenter study follows 150 patients with suspected or documented atrial arrhythmias who received a dual‐chamber pacemaker (model Vitatron T‐70, Medtronic Inc., Minneapolis, MN, USA) incorporating the TA. The TA summarizes technical and clinical data stored in the pacemaker into key messages and may suggest programming changes. Twenty‐five cardiologists examined their patients per normal practice during two follow‐up visits. They reported the therapy changes they deemed necessary without initially reviewing the TA messages. Next, they rated their satisfaction with and the clinical relevance of the TA messages and recorded the final therapy changes. Results: The TA generated (mostly AT/AF‐related) main observations in 49% and programming advice in 33% of the patients. The experts rated 95% of the TA messages as satisfactory and deemed therapy changes necessary in roughly half the patients. Pacemaker changes in AT/AF therapy or general settings were prompted primarily by the diagnostic information stored in the device. Medication changes were mostly led by the symptoms reported by the patient. Conclusion: This study demonstrates that experienced cardiologists agree with 95% of the observations and programming suggestions that the TA automatically generates. (PACE 2010; 605–614)     

Biochemical characterization of variants of the Ehlers-Danlos syndrome type VI

Three variants of the Ehlers-Danlos syndrome type VI are described: a severe form with skeletal, dermal and ocular manifestations associated with a lack of hydroxylysine in skin and little lysyl hydroxylase activity in cultured fibroblasts; a similarly affected form with a nearly normal hydroxylsine content in skin, but with only little enzyme activity in cultured fibroblasts; and a predominantly ocular form with no biochemical abnormality in skin or cultured skin fibroblasts. The activities of prolyl 4-hydroxylase and the two hydroxylysyl glycosyltransferases were normal in all cases, and the failure to find lysyl hydroxylase activity was not due to altered solubility characteristics of the enzyme or to the presence of an enzyme inhibitor. The collagen produced in cell culture, however, was hydroxylated to a markedly higher extent than that found in skin. In both the mutant and control cells hydroxylation of lysyl residues was less sensitive to ascorbate deficiency than that of prolyl residues.     

Gonial angles and condylar and ramus height of the mandible in complete denture wearers—a panoramic radiograph study

summary It has been accepted that the shape of the mandibular base, and especially the gonial angle of the mandible, correlates with the function of the jaw closing muscles. The gonial angles of the mandible and condylar and ramus heights of 30 complete denture wearers (18 women, 12 men, mean age 61 years, range 42–74 years) coming for renewal of their dentures were measured using panoramic radiographs. The mean period of edentulousness was 26 years (range 10–53 years). No statistically significant difference was observed between the sexes in the the sizes of gonial angles and condylar and ramus heights. The right gonial angle was statistically significantly smaller than the left one and correlated negatively with the ramus height in both sides but positively with the increased EMG activity in the right masseter muscle. The size of the gonial angle and the condylar and ramus heights did not correlate with the age of the patients, edentulous period or alveolar ridge resorption.     

Collagen metabolism in normal and complicated pregnancy: changes in the aminoterminal propeptide of type III procollagen in serum

The turnover of type III collagen, a major constituent of the myometrium and the uterine cervix, during pregnancy was evaluated by monitoring serum antigens related to the aminoterminal propeptide of type III procollagen. Their concentration increased markedly towards term in most uncomplicated pregnancies, while their size distribution throughout the pregnancy resembled that seen in the sera of normal healthy persons. In some patients, however, the level remained low, indicating interindividual variation in the release into serum and metabolism of the propeptide. There were no distinct changes during or immediately after vaginal delivery. Values exceeding the reference range for uncomplicated pregnancies were found during weeks 28-37 in patients with pre-eclampsia, essential hypertension, intrahepatic cholestasis of pregnancy or twin pregnancy. Thus, pregnancy should be taken into account when evaluating results of the serum assay for the aminopropeptide and the use of this assay as an indicator of pregnancy complications warrants further study.     

Thallium Scintigraphy in Prediction of Occlusion of Bypass Grafts in Asymptomatic and Symptomatic Patients

ABSTRACT To evaluate thallium scintigraphy in predicting coronary artery bypass graft patency, exercise thallium scintigraphy and selective graft and native vessel angiograms were performed in 22 asymptomatic and 29 symptomatic consecutive patients three months after coronary artery bypass grafting (CABG). Twelve out of 22 asymptomatic patients (55%) had reversible thallium defects on postoperative images; in 10 patients the postoperative scans were normal. The graft patency was significantly lower in asymptomatic patients with abnormal thallium perfusion compared to those with normal perfusion after CABG (68% vs. 91%. p<0.05). The rate of graft patency in symptomatic patients was 66/87 (76%). Thallium scintigraphy was 77% sensitive and 78% specific in detecting one or more stenosed or occluded bypass grafts in patients without angina (accuracy 77%). When data from exercise electrocardiography were combined with scintigraphy, all but one patient with incomplete revascularization could be detected (positive predictive accuracy 92%). In symptomatic patients, thallium scintigraphy accurately predicted the presence or absence of graft occlusion in 24/29 (83%) cases. Thus, abnormal myocardial perfusion due to stenosis or occlusion of bypass grafts is common in both asymptomatic and symptomatic patients after CABG. Thallium scintigraphy together with exercise electrocardiography appear to be useful non-invasive methods in detecting painless myocardial ischemia and in predicting bypass graft occlusion after CABG.     

Electrophysiological evidence for cross-modal plasticity in humans with early- and late-onset blindness

It is commonly believed that sensory deprivation can lead to cross-modal reorganization in an immature hut not in a mature brain. The results of the present study suggest, however, that plasticity between sensory modalities is possible even in adults: activity indicating involvement of parietal or occipital brain areas in pitch-change discrimination was found in individuals blinded after childhood. Event-related brain potentials of early blinded (before the age of 2 years). late-blinded (12–28 years of age), and sighted adults were recorded to stimulus sequences consisting of standard tones occasionally replaced by deviant tones. Even when participants were not attending to auditory stimuli, the deviant tones elicited the mismatch negativity (MMN) in each group. There were no significant MMN front-back scalp distribution differences among the groups. However, when participants were detecting deviant stimuli, these stimuli elicited N2 and P3 waves that were posterior in distribution in both groups of blind participants relative to those of the sighted participants. These results suggest that cross-modal reorganization may occur even in the mature human brain.