Biomedical subjects
Publications and source records attributed to P Urban.
Isolated cortical vein thrombosis is only rarely diagnosed, although it presents with typical signs on imaging, presented in the paper. We report on five patients with this diagnosis, who all presented with focal sensomotoric seizures. Imaging with CT and MRI was the leading method. All patients were treated with oral anticoagulation and showed full recovery.
From 1997 to 2005, 19461 patients admitted for acute coronary syndrome in 68 hospitals in Switzerland were included in the AMIS Plus registry, of whom 11 543 showed ST segment elevation or left bundle branch block on the ECG at admission. During this period, there was an important increase in the proportion of patients treated by primary percutaneous coronary intervention (8% to 74%), and a marked reduction in the use of thrombolysis (47% to 6%) and also in the proportion of patients who did not receive any reperfusion treatment (45% to 20%). Furthermore, there was a decrease in hospital mortality (12% to 7%). Main predictors of hospital mortality were withholding PCI and thrombolysis, advanced age and the presence of cardiogenic shock. Moreover, primary PCI was associated with lower hospital mortality when compared to thrombolysis.
OBJECTIVE: To document the trends in reperfusion therapy for ST segment elevation myocardial infarction (STEMI) in Switzerland. DESIGN: National prospective multicentre registry, AMIS Plus (acute myocardial infarction and unstable angina in Switzerland), of patients admitted with acute coronary syndromes. SETTING: 54 hospitals of varying size and capability in Switzerland. PATIENTS: 7098 of 11 845 AMIS Plus patients who presented with ST segment elevation or left bundle branch block on the ECG at admission. MAIN OUTCOME MEASURES: In-hospital mortality and its predictors at admission by multivariate analysis. RESULTS: The proportion of patients treated by primary percutaneous coronary intervention (PCI) progressively increased from 1997 to 2002, while the proportion with thrombolysis or no reperfusion decreased (from 8.0% to 43.1%, from 47.2% to 25.6%, and from 44.8% to 31.4%, respectively). Overall in-hospital mortality decreased over the study period from 12.2% to 6.7% (p < 0.001). Main in-hospital mortality predictors by multivariate analysis were primary PCI (odds ratio (OR) 0.52, 95% confidence interval (CI) 0.33 to 0.81), thrombolysis (OR 0.63, 95% CI 0.47 to 0.83), and Killip class III (OR 3.61, 95% CI 2.49 to 5.24) and class IV (OR 5.97, 95% CI 3.51 to 10.17) at admission. When adjusted for the year, multivariate analysis did not show PCI to be significantly superior to thrombolysis for in-hospital mortality (OR 1.2 for PCI better, 95% CI 0.8 to 1.9, p = 0.42). CONCLUSION: Primary PCI has become the preferred mode of reperfusion for STEMI since 2002 in Switzerland, whereas use of intravenous thrombolysis has decreased from 1997 to 2002. Furthermore, there was a major reduction of in-hospital mortality over the same period.
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Cytochromes P450 constitute a superfamily of haem-thiolate mono-oxygenases that are involved in the oxidative metabolism of lipophilic subtrates. These enzymes require association with cytochrome P450 reductase (CPR) to achieve optimal activities. We have expressed human cytochrome P450 CYP1A1 under the POX2 promoter (pPOX2-CYP1A1) in Y. lipolytica, with or without overproduction of Y. lipolytica CPR expressed under the ICL promoter (pICL-CPR) or the POX2 promoter (pPOX2-CPR). Activity of cytochrome CYP1A1 was analysed by conversion of hydroxyresorufin to resorufin. Strain JMY330 and JMY330-CPR present no activity, the monocopy cytochrome CYP1A1 integrant JMY331 and JMY331-CPR derivatives present an average activity of 32.0 pM/min/dw and 48.3 and 64.6 pM/min/dw for pICL-CPR and pPOX2-CPR, respectively. Increase of CPR expression resulted in about two-fold higher activity. The multicopy 1A1 integrant JMY339 and JMY339-CPR derivatives present an activity of 129 pM/min/dw and 815-1845 pM/min/dw, respectively. Increase of CPR expression resulted in 6.3-12.8-fold higher activity, depending on the CPR transformant. We observed a 50-fold increase of activity between the monocopy integrant JMY331 as compared to the multicopies integrant JMY339-CPR in which CPR was overexpressed.
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PURPOSE: To assess, by a European registry trial, the clinical event rate in patients with discrete stenotic lesions of coronary arteries (de novo or restenotic) in single or multiple vessels (native or bypass grafts) treated with beta-radiation. MATERIALS AND METHODS: Between April 1999 and September 2000, 1098 consecutive patients treated in 46 centers in Europe and the Middle East with the Novoste Beta-Cath System were included in Registry Novoste (RENO). RESULTS: Six-month follow-up data were obtained for 1085 patients. Of 1174 target lesions, 94.1% were located in native vessels and 5.9% in a bypass graft; 17.7% were de novo lesions, 4.1% were restenotic, and 77.7% were in-stent restenotic lesions. Intravascular brachytherapy was technically successful in 95.9% of lesions. Multisegmental irradiation, using a manual pullback stepping maneuver to treat longer lesions, was used in 16.3% of the procedures. The in-hospital rate of major adverse cardiac events was 1.8%. At 6 months, the rate was 18.7%. Angiographic follow-up was available for 70.4% of the patients. Nonocclusive restenosis was seen in 18.8% and total occlusion in 5.7% of patients. A combined end point for late (30-180 days) definitive or suspected target vessel closure was reached in 5.4%, but with only 2% of clinical events. Multivariate analysis was performed for major adverse cardiac events and late thrombosis. CONCLUSIONS: Data obtained from the multicenter RENO registry study, derived from a large cohort of unselected consecutive patients, suggest that the good results of recent randomized controlled clinical trials can be replicated in routine clinical practice.
AIMS: To assess the feasibility, safety and effectiveness of intravascular brachytherapy (VBT) in routine clinical practice. METHODS AND RESULTS: Between April 1999 and September 2000, 1098 consecutive patients treated in 46 European centres by intraluminal irradiation using a Sr/Y(90)source train (BetaCath, Novoste, GA) were included in a registry, and follow-up data were obtained for 98.8% of them after 6.3+/-2.4 months. Eight hundred and forty (76.5%) patients were males, and mean age was 62.0+/-10.2 years. Two hundred and seventy-one (26.9%) had unstable angina, and 256 (23.5%) were diabetics. Nine hundred and thirteen lesions (77.7%) were the result of in-stent restenosis, 208 (17.7%) were de novo lesions and 48 (4.1%) non-stented restenotic lesions. Mean estimated reference diameter was 3.2+/-0.5mm and mean estimated lesion length was 19.0+/-11.8mm. The prescribed radiation dose was 18.8+/-3.2Gy. Multivessel irradiation was done in 6.2% of cases, and a new stent was implanted in 29.6% of cases. Most patients received 6 or 12 months of combined aspirin and thienopyridin treatment after the procedure. Technical success was obtained in 95.9% of treated lesions, and the in-hospital major adverse cardiac event (MACE) rate was 1.8%. At follow-up, the MACE rate was 18.7% (1.9% deaths from any cause, 2.6% AMI, 13.3% TVR by PCI and 3.3% TVR by CABG). CONCLUSION: The major current application of VBT is the treatment of in-stent restenosis. The good results of VBT observed in recent randomized controlled trials can be reproduced in clinical practice.
OBJECTIVE: To assess clinically and angiographically the feasibility, safety, and effectiveness of vascular brachytherapy (VBT) in saphenous vein bypass grafts (SVG). PATIENTS AND METHODS: 67 of 1098 (6.1%) consecutive patients of the European registry of intraluminal coronary beta brachytherapy underwent treatment for 68 SVG lesions by VBT using a Sr/Y(90) source train (BetaCath). Clinical follow up data were obtained for all of them after a mean (SD) of 6.3 (2.4) months and angiographic follow up was performed in 61 patients (91.0%) after 6.9 (2.0) months. RESULTS: 58 (86.6%) patients were men, their mean (SD) age was 66 (10) years, 28 (41.8%) had unstable angina, and 21 (31.3%) had diabetes. Fifty three (77.9%) lesions were in-stent restenosis, 13 (19.1%) de novo lesions, and 2 (3.0%) non-stented restenotic lesions. Mean (SD) reference diameter before the intervention was 4.19 (0.52) mm, mean (SD) lesion length was 23.56 (20.38) mm, and mean (SD) minimum lumen diameter measured 0.73 (0.62) mm. Mean (SD) acute gain was 3.02 (0.88) mm. The prescribed radiation dose was 20.1 (3.2) Gy. Pullback manoeuvres were performed in 17 (25.0%) of cases. Most patients received combined aspirin and thienopyridin treatment for 6 or 12 months after the procedure. Technical success was obtained in 62 (91.2%) treated lesions and in-hospital major adverse cardiac events occurred in 4.5%. At follow up, mean (SD) reference diameter was 4.20 (0.53) mm, minimum lumen diameter 2.94 (1.50) mm, and late loss 0.86 (1.25) mm. The overall major adverse cardiac events rate was 26.7%. CONCLUSION: VBT of SVG is feasible and safe. At follow up the reintervention rate and cardiac morbidity and mortality seem to be favourable, considering that interventions in SVG usually are associated with the highest risks.
Exhaled breath condensate (EBC) pH is low in several lung diseases and it normalises with therapy. The current study examined factors relevant to EBC pH monitoring. Intraday and intraweek variability were studied in 76 subjects. The pH of EBC collected orally and from isolated lower airways was compared in an additional 32 subjects. Effects of ventilatory pattern (hyperventilation/hypoventilation), airway obstruction after methacholine, temperature (-44 to +13 degrees C) and duration of collection (2-7 min), and duration of sample storage (up to 2 yrs) were examined. All samples were collected with a disposable condensing device, and de-aerated with argon until pH measurement stabilised. Mean EBC pH (n=76 subjects, total samples=741) was 7.7+/-0.49 (mean+/-SD). Mean intraweek and intraday coefficients of variation were 4.5% and 3.5%. Control of EBC pH appears to be at the level of the lower airway. Temperature of collection, duration of collection and storage, acute airway obstruction, subject age, saliva pH, and profound hyperventilation and hypoventilation had no effect on EBC pH. The current authors conclude that in health, exhaled breath condensate pH is slightly alkaline, held in a narrow range, and is controlled by lower airway source fluid. Measurement of exhaled breath condensate pH is a simple, robust, reproducible and relevant marker of disease.
OBJECTIVE: A one-year follow-up was performed of a 21-year-old man with a 16-year history of diabetes mellitus type I, who had been using ointment containing 10% mercuric ammonium chloride (hydrargyrum amidochloratum; HgNH(2)Cl) for eczema for approximately 3 weeks. Tiredness, fasciculations on the extremities and poor control of diabetes appeared after the end of the ointment treatment. Nephrotic syndrome and hypertension were diagnosed 1 month later. Two months after the ointment application the patient was very weak with tremors of the hands, almost unable to walk, and had lost 20 kg of body weight. He had severe neurasthenic symptoms and his behaviour suggested acute psychosis. METHODS: Internal, neurological and neuropsychological examinations were performed. Mercury in urine was determined by flameless atomic absorption spectrometry. RESULTS: The urine mercury level on admission was 252.0 microg/l. He was treated with Dimaval, sodium (2,3)-dimercaptopropane(-1)-sulphonate capsules for 12 days (total dose 6.3 g). The highest urine mercury excretion during antidote treatment was 2336.0 microg/24 h. The patient had proteinuria of up to 11.10 g/24 h, and renal biopsy revealed diffuse membranous glomerulonephritis of the 1st stage without apparent diabetic nephropathy. Similarly, neuropathy did not have typical signs of diabetic neuropathy. His clinical condition started to improve during the first 2 weeks. Further follow-up has shown slow normalisation of renal functions. After 1 year, proteinuria decreased to 0.62 g/24 h and body weight normalised. Neuropsychological and electromyographic findings became almost normal. CONCLUSION: Severe intoxication developed after a short period of ointment application. Most signs of damage disappeared in the course of 1 year, except mild proteinuria and neuropathy. The evolution was favourable and confirmed the primary role of mercury intoxication in the severe deterioration of the clinical status of the patient.
OBJECTIVE: More than 35 years ago, during 1965-1968, in the former Czechoslovakia, approximately 80 persons became ill due to occupational exposure to 2,3,7,8-tetrachlordibenzo- p-dioxin (2,3,7,8-TCDD). The objective of this study was to investigate the incidence of disorders related to occupational exposure to 2,3,7,8-TCDD. METHODS: Most subjects in the group of 12 former 2,3,7,8-TCDD workers (mean age 56.8 years, exposure 10 days to 23 months) still suffer from disturbances of lipid metabolism, psychic disorders, chloracne, and/or nervous system lesions. All workers were given internal, neuropsychological and ophthalmological examinations. Blood cholesterol and triglycerides were measured, and the common carotid artery was examined by ultrasound (B-mode), with the intima-media thickness (IMT) also being measured. Findings were compared with the 2,3,7,8-TCDD level in 1996. RESULTS: Nine of the 12 previously exposed workers had elevated plasma lipids, and hyperlipidaemia was statistically more frequent in patients with higher 2,3,7,8-TCDD levels ( P=0.03). Subject 1, with the highest 2,3,7,8-TCDD plasma level, had 80% stenosis of the diameter of the carotid artery, which needed acute surgery. Besides him, seven persons had atherosclerotic plaques in the carotid arteries. The mean IMT in the group was 0.85 mm (SD+/-0.19); the normal value is 0.62 mm. Eight subjects had degenerative changes of the ocular fundus. Chloracne was still present in two persons. Neuropsychological findings were assessed as normal only in three persons with lower 2,3,7,8-TCDD plasma levels in 1996. Mean 2,3,7,8-TCDD plasma level in 1996 was 256 pg g(-1) fat (range 14-760). CONCLUSION: Hyperlipidaemia, atherosclerotic plaques, increased IMT, ischaemic heart disease and neuropsychological disturbances were frequent in this group of former 2,3,7,8-TCDD workers. Hyperlipidaemia might have played an important role in most of these disorders. The level of 2,3,7,8-TCDD correlated with the highest level of triglycerides ( P=0.02) and cholesterol ( P=0.01) that was found during the 35-year follow-up. This group belongs to the most heavily 2,3,7,8-TCDD-exposed groups of workers, because the mean estimated concentration at the time of intoxication was approximately 5000 pg g(-1) plasma fat.
AIMS: The BRIE trial is a registry evaluating the safety and performance of (90)Sr delivered locally (Beta-Cath TM system of Novoste) to de-novo and restenotic lesions in patients with up to two discrete lesions in different vessels. METHODS AND RESULTS: In total, 149 patients (175 lesions) were enrolled; 62 treated with balloons and 113 with stents. The restenosis rate, the minimal luminal diameter and the late loss were determined in three regions of interest: (a) in a subsegment of 5mm containing the original minimal luminal diameter pre-intervention termed target segment; (b) the irradiated segment, 28 mm in length, and (c) the entire analysed segment, 42 mm in length, termed the vessel segment. Binary restenosis was 9.9% for the target segment, 28.9% for the irradiated segment, and 33.6% for the vessel segment. These angiographic results include 5.3% total occlusions. Excluding total occlusions binary restenosis was 4.9%, 25% and 29.9%, respectively. At 1 year the incidence of major adverse cardiac events placed in a hierarchical ranking were: death 2%, myocardial infarction 10.1%, CABG 2%, and target vessel revascularization 20.1%. The event-free survival rate was 65.8%. Non-appropriate coverage of the injured segment by the radioactive source termed geographical miss affected 67.9% of the vessels, and increased edge restenosis significantly (16.3% vs 4.3%, P=0.004). It accounted for 40% of the treatment failures. CONCLUSION: The results of this registry reflect the learning process of the practitioner. The full therapeutic potential of this new technology is reflected by the restenosis rate at the site of the target segment. It can only be unravelled once the incidence of late vessel occlusion and geographical miss has been eliminated by the prolonged use of thienopyridine, the appropriate training of the operator applying this new treatment for restenosis prevention, and the use of longer sources.
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PATIENT: A 63-year-old female with bilateral recurrent corneal ulcerations for 10 years, suffered from vascularisation of the cornea and absence of corneal sensitivity. Other symptoms were multifocal hypoaesthesia with hypalgesia of hands and legs, generalised lack of deep tendon reflexes, absence of somato-sensory evoked potentials (SSEP) and of sensory nerve action potentials (SNAP) in these regions. A sural biopsy demonstrated extreme lack of myelinated fibres. Acquired causes for polyneuropathy were excluded. THERAPY: Subsequent to local ocular treatment we carried out a perforating corneal transplantation of the left eye because of corneal scars. This had to be repeated 2 years later because of vascularisation of the transplant. The visual function of the left eye could be stabilised at values between 0.2 and 1/50. CONCLUSION: Anamnesis and clinical symptoms of the patient are compatible with the diagnosis of hereditary sensory neuropathy type II (HSN II) affecting the trigeminal nerves. In patients with neuropathy and impaired corneal sensitivity, a favourable prognosis may be achieved by a corneal transplant.
Cytochrome P450 (CYP) enzymes represent a large superfamily that displays extraordinarily diverse substrate specificities. After a concise review about CYPs of the CYP1A subfamily, which plays a crucial role in procarcinogen activation, this paper presents segment-directed mutagenesis. This approach generates a library of random combinatorial mutants limited to a precise region of human CYP1A1, namely amino acids 204-214 in which nine positions differ between CYP1A1 and CYP1A2. The resulting mutants present all combinations possible among these nine positions shifting mutated residues to their CYP1A2 counterpart. The mutants were cloned and expressed in an engineered Saccharomyces cerevisiae strain that has a microsomal oxido-reduction environment optimized for CYPs. This procedure resulted in yeast transformants that express a library of mutant CYP1A1. A subset of transformants were chosen at random, assayed for a typical CYP1A1 activity and the plasmidic DNA of functional clones was rescued and sequenced. In this approach, no preconceived idea is made as to which combination of amino acid residues controls substrate selectivity. The functional mutants were analysed further for alteration of substrate specificity with a series of heterocyclic and polycyclic aromatic hydrocarbons. Some of the implications of these analyses are discussed for the role of this region in substrate specificity, since it corresponds to a putative loop and is not part of one of the CYP substrate-recognition sites.
The purpose of this study was to identify clinical predictors and anatomical structures involved in patients with pain after dorsolateral medullary infarction. Eight out of 12 patients (67%) developed poststroke pain within 12 days to 24 months after infarction. The pain occurred in the ipsilateral face (6 patients) and/or the contralateral limbs and trunk (5 patients, 3 of whom also had facial pain). Ipsilateral facial pain was significantly correlated with lower medullary lesions, including those of the spinal trigeminal tract and/or nucleus, as documented by magnetic resonance imaging. The R2 blink reflex component was abnormal only in patients with facial pain. Likewise, pain and temperature sensation in the ipsilateral face was decreased in all patients with facial pain but not in patients without pain. Ipsilateral touch sensation in the face was also decreased in all patients with facial pain, but the lesions revealed on magnetic resonance imaging did not involve the principal sensory nucleus of the fifth cranial nerve, and the R1 blink reflex latencies were normal. Although facial pain was correlated with lesions of the spinal trigeminal tract and/or nucleus, none of the lesions involved the subnucleus caudalis, which contains most nociceptive neurons. These findings suggest that facial pain after medullary infarction is due to lesions of the lower spinal trigeminal tract (axons of primary afferent neurons), leading to deafferentation of spinal trigeminal nucleus neurons.