Newly produced T and B lymphocytes and T-cell receptor repertoire diversity are reduced in peripheral blood of fingolimod-treated multiple sclerosis patients.

BACKGROUND: Fingolimod inhibits lymphocyte egress from lymphoid tissues, thus altering the composition of the peripheral lymphocyte pool of multiple sclerosis patients. OBJECTIVE: The objective of this paper is to evaluate whether fingolimod determines a decrease of newly produced T- and B-lymphocytes in the blood and a reduction in the T-cell receptor repertoire diversity that may affect immune surveillance. METHODS: Blood samples were obtained from multiple sclerosis patients before fingolimod therapy initiation and then after six and 12 months. Newly produced T and B lymphocytes were measured by quantifying T-cell receptor excision circles and K-deleting recombination excision circles by real-time PCR, while recent thymic emigrants, naive CD8(+) lymphocytes, immature and naive B cells were determined by immune phenotyping. T-cell receptor repertoire was analyzed by complementarity determining region 3 spectratyping. RESULTS: Newly produced T and B lymphocytes were significantly reduced in peripheral blood of fingolimod-treated patients. The decrease was particularly evident in the T-cell compartment. T-cell repertoire restrictions, already present before therapy, significantly increased after 12 months of treatment. CONCLUSIONS: These results do not have direct clinical implications but they may be useful for further understanding the mode of action of this immunotherapy for multiple sclerosis patients.

Frequency and clinical correlates of bipolar features in acute coronary syndrome patients.

BACKGROUND: Depression and acute coronary syndrome (ACS) are both extremely prevalent diseases. Studies aimed at evaluating whether depression is an independent risk factor for cardiac events provided no definitive results. In most of these studies, depression has been broadly defined with no differentiation between unipolar (MDD) versus bipolar forms (BD). The aim of this study was to evaluate the frequency of DSM-IV BD (bipolar I and bipolar II subtypes, cyclothymia), as well as temperamental or isolated bipolar features in a sample of 171 patients hospitalized for ACS. We also explored whether these psychopathological conditions were associated with some clinical characteristics of ACS. METHODS: Patients with ACS admitted to three neighboring Cardiac Intensive Care Units (CICUs) in a 12-month continuative period of time were eligible for inclusion if they met the criteria for either acute myocardial infarct with or without ST-segment elevation or unstable angina, verified by standard ACS criteria. All patients underwent standardized cardiological and psychopathological evaluations. RESULTS: Of the 171 ACS patients enrolled, 37 patients (21.7%) were found to have a DSM-IV mood disorder. Of these, 20 (11.7%) had bipolar type I or type II or cyclothymia, while 17 (10%) were the cases of MDD. Rapid mood switches ranged from 11% of ACS patients with no mood disorders, to 47% of those with MDD to 55% of those with BD. Linear regression analysis showed that a diagnosis of BD (p=.023), but not that of MDD (p=.721), was associated with a significant younger age at the index episode of ACS. A history of previous coronary events was more frequent in ACS patients with BD than in those with MDD. CONCLUSIONS: Our data indicate that bipolar features and diagnosis are frequent in ACS patients. Bipolar disorder has a negative impact on cardiac symptomatology. Further research in this area is warranted.

Complicated pericardial cyst: atypical anatomy and clinical course.

Pericardial cysts are usually detected by chance are are clinically silent in most cases. Nevertheless, symptoms and serious complications may occur. We describe a case of pericardial cyst diagnosed in an 8-year-old boy who was admitted with chest pain. Echocardiography revealed a mild to moderate pericardial effusion and a 7.5 x 5.5 cm intrapericardial echo-free lesion consistent with a pericardial cyst. Surgery was carried out 3 days afterward because of the patient's worsening condition, the progressive increase of pericardial effusion, and the onset of initial signs of cardiac tamponade. The cyst showed a long and easily movable vascular pedicle and inflammatory areas involving the pericardial surface. Like the pericardial effusion, the contents of the mass appeared as serosanguineous fluid on aspiration. Histologic examination confirmed the diagnosis of pericardial cyst and showed findings according to ischemia-related lesions of the cyst. The coexistence of pericardial cyst and cardiac tamponade is very unusual. The atypical anatomy and clinical course suggest a distinct and so far undescribed pathogenetic mechanism for this association: the torsion of a vascular pedicle and the subsequent development of ischemia-related lesions of the cyst.

Normal echocardiographic characteristics of the Sorin Bicarbon bileaflet prosthetic heart valve in the mitral and aortic positions.

Doppler echocardiographic characteristics of normally functioning Sorin Bicarbon prostheses were prospectively assessed in 226 consecutive patients (135 male and 91 female patients, mean age 61 +/- 10 years) with 233 valves in the mitral (n = 67) and aortic (n = 166) positions whose function was considered normal by clinical and echocardiographic evaluation. Patterns of "normal" transprosthetic leakage were assessed with transthoracic echocardiography in all valves and with transesophageal echocardiography in six selected mitral valve prostheses. For the mitral valve prostheses, we found that peak and mean gradient, as well as pressure half-time, were not significantly different in either the 25 or the 31 mm valves (median values from 15 to 10 mm Hg, from 4 to 4 mm Hg, and from 70 to 83 ms; p = Not significant for all). On transthoracic study, 12 patients (17%) with a Sorin Bicarbon valve in the mitral position showed minimal transprosthetic leakage. On transesophageal study, all patients showed a transprosthetic leakage whose spatial distribution had a complex pattern: in planes orthogonal to the leaflet axis, two to four jets arising from the hinge points and converging toward the center of the valve plane could be visualized; in planes parallel to the leaflet axis, there were three jets, the two lateral ones diverging and the central one perpendicular to the valve plane. For the aortic valve prostheses, there was a significant decrease in transprosthetic gradients and an increase in effective orifice areas as prosthesis size increased. Peak and mean gradients decreased from a median value of 25 and 13 mm Hg in the 19 mm valves to 9 and 5 mm Hg in the 29 mm valves, respectively. Effective prosthetic valve area calculated with the continuity equation increased from a median value of 0.97 cm2 for the 19 mm size valves to 3.45 cm2 for the 29 mm size. With analysis of variance, effective prosthetic aortic valve area differentiated various valve sizes (F = 40.9, p < 0.0001) better than peak (F = 10.3, p < 0.0001) or mean (F = 8.04, p < 0.0001) gradients alone did. Furthermore, effective prosthetic aortic valve area correlated better than peak and mean gradients with prosthetic size (r = 0.76, r = -0.45, and r = -0.39, respectively). On transthoracic study, 109 patients (66%) showed minimal transprosthetic leakage. These normal values, obtained in a large number of patients with normofunctioning mitral and aortic Sorin Bicarbon valves, may help to identify Sorin Bicarbon prosthesis dysfunction.

Changes in effective aortic valve area during ejection in adults with aortic stenosis.

Measurements of valve orifice area in aortic stenosis are based on the assumption that orifice area remains constant throughout ejection and is independent of transvalvular gradients and flow. Recent studies, however, have suggested that the calculated valve area of calcific aortic stenosis may change in different flow conditions. Therefore, we tested the hypothesis that in vivo effective orifice area of a stenotic aortic valve changes continuously during ejection, which would make a single area measurement a potentially inadequate indicator of the severity of the stenosis. Doppler measurements of flow velocity in the ascending aorta and in the left ventricular outflow tract at peak velocity, at half-peak velocity during acceleration (midacceleration), and at half-peak velocity during deceleration (mid-deceleration) were obtained in 26 patients with aortic stenosis (mean gradient 50 +/- 19 mm Hg and effective aortic orifice are 0.7 +/- 0.3 dcm2) and in 14 normal subjects of similar age and gender, to calculate instantaneous effective aortic orifice area at midacceleration, at peak velocity and at mid-deceleration. In the 26 patients with aortic stenosis, aortic valve area at midacceleration was 84 +/- 15% of valve area at peak velocity (p < 0.0001), and valve area at mid-deceleration was 113 +/- 17% of that measured at peak velocity (p < 0.01). Conversely, in normal subjects, aortic valve area remained constant during ejection and was 97 +/- 5% and 99 +/- 6% of valve area at peak velocity, respectively, at midacceleration and mid-deceleration (p > 0.05). In addition, in patients with aortic stenosis the percentage of change in effective aortic valve area from midacceleration to mid-deceleration varied widely, from -17% to +49% (mean change +26 +/- 14%). There was no relation between percentage of change in effective valve area and mean transaortic gradient (r = 0.05; p = 0.30) or effective valve area at peak velocity (r = -0.11; p = 0.14). Our results indicate that effective aortic valve area continues to change during ejection in patients with aortic stenosis, and that the magnitude of this change is independent of the usual indexes of severity of the stenosis. Conversely, effective aortic valve area remains constant during ejection in normal subjects.

[The methods of using the echocardiogram in outpatients. The role of the cardiologist for more appropriate use of the procedure. The Ligurian Group of the Italian Society of Cardiovascular Echocardiography]. / Modalità di utilizzazione dell'ecocardiogramma in pazienti ambulatoriali. Ruolo del cardiologo per l'appropriatezza della prescrizione. Gruppo Ligure della Società Italiana di Ecografia Cardiovascolare.

Concerns about the increasing medical care costs are causing the medical community to focus its attention on the appropriate of diagnostic tests such as echocardiography. Prerequisite to a better utilization of the limited economic resources assigned to our health care system is an analysis of how, why, and with which results diagnostic tests with a widespread use and relevant cost, like echocardiography, are requested. During the last 2 weeks of September 1994, a transversal, observational study was carried out at 13 hospital echocardiographic laboratories. Ordering physician characteristics, reasons for ordering the test, cardiological diagnostic tests previously performed and their relationship with the test results, were evaluated with a questionnaire completed by the physician who performed the test, in all the out-patients undergoing echocardiogram in that fortnight. Five hundred and sixteen consecutive questionnaires were successfully completed. Fourty-five percent of the echocardiograms were ordered by cardiologists, 35% by general practitioners, 10% by internists, and 10% by other specialists. Hypertension (16.4%) and ischemic heart disease (14.8%) were the most common indications for the test, followed by palpitations or arrhythmias (7.5%), mitral valve prolapse or mitral valve disease (7.3%), chest pain or angina pectoris (6.3%), cardiac murmur (5.5%), dyspnea or heart failure (5.2%), aortic valve disease (5%), prosthetic heart valve evaluation (4.6%), others (27%). Before undergoing the echocardiogram, 433 (84%) patients underwent an electrocardiogram, 242 (47%) a cardiological clinical evaluation, 196 (38%) a chest X-ray, and 191 (37%) had had a previous echocardiogram. The most common echocardiographic diagnosis was normal (29.2%) followed by hypertensive heart disease (16.2%), mitral valve disease (12.3%), aortic valve disease (10.5%), ischemic heart disease (9.3%), cardiomyopathy (4.9%) normal prosthetic heart valve function (4.5%), pericardial effusion (3.8%), others (11.3%). Among the echocardiograms ordered by cardiologists, 21.8% were normal in comparison with 35.4% of those ordered by general practitioners (p < 0.004), 35.3% of those ordered by internists (p = 0.04), 35.3% of those ordered by other specialists (p = 0.04). Among the 284 patients whose echocardiograms were not requested by a cardiologist, only 215 (76%) had undergone an electrocardiogram and only 68 (24%) a clinical evaluation by a cardiologist. In these patients, the frequency of normal echocardiograms was not influenced by having undergone a previous electrocardiogram or a chest X-ray. Conversely, patients in whom the echocardiogram was ordered after a cardiology consult showed a significant lower frequency of normal results compared to patients not evaluated by a cardiologist (23% vs 39%; p < 0.05). More than 50% of the echocardiograms performed in out-patients are ordered by physicians who are not cardiologists. Among these echocardiograms, about 1 out of 3 results normal. This finding suggests an improper use of echocardiogram as a screening tool by non-cardiologists in out-patients. A preceding clinical evaluation by a cardiologist, but not an electrocardiogram or a chest X-ray alone, may determine a more appropriate use of the test being associated with a reduced frequency of normal results.

[The resolution of a mitral valve prosthesis thrombosis with low-dose plasminogen tissue activator and the role of Doppler echocardiographic monitoring]. / Risoluzione di trombosi di protesi valvolare mitralica con basso dosaggio di attivatore tissutale del plasminogeno e ruolo del monitoraggio ecocardiografico Doppler.

The case of a 63-year-old woman with a Bjork-Shiley mitral valve prosthesis who developed acute thrombosis of mitral prosthesis and acute pulmonary edema is described. Full clinical success was achieved with medical therapy with tissue-type plasminogen activator. The dosage of drug was titrated by serial echo-Doppler examinations of prosthetic structures and functional area. A low-dose (60 mg over 1 hour) of tissue-type plasminogen activator was sufficient to obtain thrombus resolution. Embolic or hemorrhagic complications were absent. This is the first report of successful use of Doppler echocardiography titrated low-dose of tissue-type plasminogen activator for acute thrombosis of mitral prosthetic valve.

Doppler haemodynamic assessment of clinically and echocardiographically normal mitral and aortic Allcarbon valve prostheses. Valve Prostheses Ligurian Cooperative Doppler Study.

Doppler echocardiographic characteristics of normally functioning Allcarbon prostheses were studied in 149 consecutive patients with 157 valves in the mitral (n = 73) and aortic (n = 84) positions whose function was considered normal by clinical and echocardiographic evaluation. In the mitral position, the mean gradient and the effective mitral orifice area were not significantly different in either the 25-mm or the 31-mm size valves (from 5 +/- 1 to 4 +/- 1 mmHg and from 2.2 +/- 0.6 to 2.8 +/- 0.9 cm2, respectively; P = ns for both). Conversely, peak gradient was significantly and inversely correlated to actual orifice area (r = -0.70; P < 0.0006), decreasing from 15 +/- 3 mmHg in the 25-mm size valve to 9 +/- 1 mmHg in the 31-mm size. In the aortic position, the mean gradient was 29 +/- 8 mmHg in the 19-mm size valve; it decreased to 8 +/- 2 mmHg in the 29-mm size. Effective prosthetic aortic valve area, calculated using the continuity equation, ranged between 0.9 +/- 0.1 cm2 for the 19-mm size valve to 4.1 +/- 0.7 cm2 for the 29-mm size. By analysis of variance, effective prosthetic aortic valve area differentiated various valve sizes (F = 25.3; P < 0.0001) better than peak (F = 5.34; P = 0.012) or mean (F = 4.34; P = 0.0052) gradients alone, and it correlated better with actual orifice area (r = 0.89, r = -0.70 and r = -0.65, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Thallium-201: what do we gain from new clinical protocols and acquisition procedures? The Italian Study on Thallium Reinjection/SIRT).

Nine medical centers, equipped with the same gamma camera and computer software, participated in this multicenter study on thallium-201 reinjection imaging. Preliminary findings for the first 143 patients with ischemic heart disease and perfusion defects at stress imaging are reported. Eighty-eight patients were reinjected at rest after conventional stress-redistribution imaging. Another 55 patients were reinjected at rest on a separate day. After segmental comparison of conventional redistribution versus stress imaging, differences > 1 in the segmental scores on a reduced 3 point scale identified 58 patients with irreversible or mainly irreversible defects (dominant scar pattern) and 85 patients with reversible or mainly reversible defects (dominant ischemic pattern). When reinjection was compared to stress images, 24 patients out of 58 with a dominant scar pattern at the conventional analysis were then assigned to the group with a dominant ischemic pattern. No clinical variables or exercise stress data were found to be significantly different in this patient subgroup. Only 4 out of 85 patients with a dominant ischemic pattern were reassigned to a dominant scar pattern after reinjection scoring. These preliminary results of the SIRT study confirm the consistent problem of scar overestimation by conventional stress-redistribution imaging and the clinical value of the thallium-201 reinjection procedure for differentiating viable from necrotic myocardium.

Evaluation of pulmonary vascular pressures in cardiac patients: the role of the chest roentgenogram.

In 77 patients (34 with left heart valvulopathy, 17 with dilated cardiomyopathy, and 26 with chronic coronary artery disease) pulmonary vascular pressures were estimated from the chest film by means of a new scoring system. Standard chest x-ray films taken immediately before diagnostic right and left cardiac catheterization were analyzed independently by three readers without knowledge of the hemodynamic findings. The radiographic signs were subdivided into three groups as follows, and to each one a score derived from a retrospective statistical analysis was attributed: (A) signs of interstitial edema, (B) patterns of pulmonary blood flow distribution, and (C) alterations in the pulmonary arteries. The sum of the scores of groups A and B x-ray findings correlated well with pulmonary wedge pressure, and the sum of the scores of groups A, B, and C correlated more strongly with the mean pulmonary artery pressure. These results confirm that it is possible, in patients with chronic heart disease, to assess accurately the pulmonary artery and wedge pressures by means of the noninvasive and easily performed chest roentgenogram.

Carcinogenicity study of doxefazepam administered in the diet to Sprague-Dawley rats.

Groups of 50 male and 50 female Sprague-Dawley rats were given food containing sufficient doxefazepam, a benzodiazepine derivative, to ensure intakes of 0, 3, 10, or 30 mg/kg/day. These dosages respectively correspond to 2, 20, and 60 times the mean daily hypnotic dose level of an adult man. Rats were treated for 104 weeks and then euthanized. An extensive autopsy was performed on those animals that died intercurrently and on euthanized animals. The chronic administration of doxefazepam did not influence the survival of the rats. No treatment-related changes in clinical signs and body weight gains occurred and malignant tumor rates were similar in controls and treated animals. A significant linear trend in the incidence of hepatocellular neoplasms, primarily benign, was observed in the female treated groups. This higher incidence was not associated to a higher occurrence of focal hyperplasia or other preneoplastic lesions in treated rats. The brain, a target organ for the pharmacological activity of doxefazepam, was carefully examined to search for microscopic foci of proliferative cells. A total of 12 and 6 malignant gliomas were observed in male and female rats, respectively; only two were noticed at autopsy. These tumors were mainly of the oligodendroglioma type commonly found in aged rats. Their incidence was slightly higher in treated rats, but results were not of statistical significance. The overall evaluation of the present study indicates that doxefazepam is noncarcinogenic in rats. However, the increase in liver adenomas found here as well as in previous bioassays with similar drugs and the lack of reliable historical data on the incidence of brain tumors in benzodiazepine-treated rodents suggest that additional experimental and epidemiological studies should be undertaken to exhaustively assess the toxic potential of this widely used class of drugs.

Morphological and biochemical effects of intrahepatic alcohol injection in the rabbit.

The local and systemic effects, as well as the repair mechanisms, of sterile absolute ethyl alcohol injection were evaluated at a range of doses (0.1-2.0 mL/kg body weight) in rabbit liver in order to confirm the feasibility and safety of local treatment of tumours in man. Saline injection was used in the control animals. The animals were killed at varying intervals (range: 1-30 days after injection), and the liver was studied by gross and microscopic examination. The ethyl alcohol injection was well tolerated and did not induce significant systemic side-effects. All doses could induce necrosis and none proved to be lethal. The alcohol injection produced an area of coagulation necrosis, the size of which appeared to be dose-related, and which was surrounded by granulation tissue, gradually repairing the necrotic lesion; the adjacent tissue was intact, or had signs of mild steatosis. However, at higher doses (1.0 and 2.0 mL/kg bodyweight), necrotic lesions were observed in the liver both near and remote from the site of injection. Fine needle percutaneous alcohol injection is effective in producing necrotic lesions which appear to be dose-related; at higher doses, however, an unpredictable intrahepatic diffusion may occur.

Toxicological evaluations of the benzodiazepine doxefazepam.

1-(2-Hydroxyethyl)-3-hydroxyl-7-chloro-1,3-dihydro-5-(O-fluorophenyl)-2H - 1,4-benzodiazepin-2-one (doxefazepam, SAS 643, Doxans) was investigated in a series of toxicological studies. Oral LD50 values were greater than 2000 mg/kg in mice, rats and dogs, while endoperitoneal LD50 values were 746 and 544 mg/kg in the mice and rats, respectively, and greater than 1000 mg/kg in the dogs. Subacute and chronic studies in rats and dogs evidenced a transient ataxia after administration of the test compound, which was dose-dependent in the subacute experiment, and occurred only at the highest dose in the chronic studies. No pathological findings were registered at necropsy or in microscopic observations, except an increase of liver weight at the highest dosage in the chronic study in the rat. Doxefazepam did not exert any teratogenic effects in rats and rabbits. Moreover in rats it did not alter the reproductive performance. The mutagenic studies did not reveal any mutagenic potential. In the cancerogenicity study in rats doxefazepam did not show positive carcinogenic potential.

Transcutaneous absorption of a topical rifamycin preparation: rifaximin (L/105).

The transcutaneous absorption of a new rifamycin preparation "Rifaximin", in comparison with that of rifampicin, was evaluated in the rat. Contrary to what was observed for rifampicin, Rifaximin was practically not absorbed.

General pharmacological properties of a low molecular weight heparin in rodents.

The effects on central nervous system of a new low molecular weight heparin (OP/LMWH) were studied in mice and rats. The effect of OP/LMWH on respiration, blood pressure and heart rate was studied in guinea-pigs and rats. In these studies unfractionated heparin was used for comparison. OP/LMWH, up to 10 mg/kg/s.c., did not show any effect on central nervous system and did not increase the blood pressure, heart rate and respiration rate up to 10 mg/kg i.v. At the same dosages, heparin presented effects similar to those shown by OP/LMWH.