Biomedical subjects
R Ricci
Publications and source records attributed to R Ricci.
beta-galactosidase gene mutations affecting the lysosomal enzyme and the elastin-binding protein in GM1-gangliosidosis patients with cardiac involvement.
GM1-gangliosidosis is a lysosomal storage disorder caused by deficiency of acid beta-galactosidase (GLB1). We report five new beta-galactosidase gene mutations in nine Italian patients and one fetus, segregating in seven unrelated families. Six of the eight patients with the infantile, severe form of the disease presented cardiac involvement, a feature rarely associated with GM1-gangliosidosis. Molecular analysis of the patients' RNA and DNA identified two new RNA splicing defects, three new and three previously described amino acid substitutions. Interestingly, all patients with cardiac involvement were homozygous for one of these mutations: R59H, Y591C, Y591N, or IVS14-2A>G. In contrast, all other patients were compound heterozygous for one of the following mutations: R201H, R482H, G579D, IVS8+2T>C. Although we could not directly correlate the presence of cardiac abnormalities with specific genetic lesions, the mutations identified in patients with cardiomyopathy fell in the GLB1 cDNA region common to the lysosomal enzyme and the Hbeta-Gal-related protein, also known as the elastin binding protein (EBP). Consequently, both molecules are affected by the mutations, and they may contribute differently to the occurrence of specific clinical manifestations.
Solid-phase synthesis of MEN 11270, a new cyclic peptide kinin B2 receptor antagonist.
An efficient synthesis of the cyclic decapeptide MEN 11270 [H-DArg1-Arg2 Pro3-Hyp4-Gly5-Thi6-Dab7-DTic8-Oic9-Arg10 c(7gamma - 10alpha)] was developed. Two three-dimensional orthogonal strategies were applied and compared: Fmoc/Tos/Boc (procedure A) and Fmoc/Pmc/Dde (procedure B). Both resulted in a 23-step strategy comprising the stepwise solid-phase chain assembly of the linear protected peptide, partial deprotection, solution-phase cyclization and final full deprotection. The stepwise assembly of the linear peptide was optimized by double coupling and acylation time prolongation for critical residues (Tic, Dab, Thi, Pro). O-(7-azabenzotriazol-1-yl)-N,N,N',N' tetramethyluronium (HATU) was preferred as coupling reagent for Dab. In the cyclization step, the partial racemization of Arg10 (31% using 1-ethyl-3-(3'-dimethyl-aminopropyl) carbodiimide/1-hydroxybenzotriazole (EDC/HOBt) as activation system) was reduced to 3% with HATU. The final deprotection was performed in the presence of dimethylsulfide (procedure A) and thiocresol (procedure B) as scavengers, to avoid the sulfation of Hyp side chain. The final compound and the main by-products were characterized by mass spectroscopy (MS), nuclear magnetic resonance (NMR) and racemization test. Procedure B produced operationally simpler and more efficient results than A (28% overall yield versus 4%).
Orientation bias in unilateral neglect: representational contributions.
Left-neglect patients bisect horizontal lines to the right of true center. Longer lines are bisected further to the right than shorter lines. This line-length effect might be explained by an increase in the rightward bias of attention because longer lines extend further ipsilesionally. Alternatively, neglect patients might be limited in their abilities to internally represent horizontal magnitudes. Patients might orient further rightward with longer lines because these lines have longer representations. If the line-length effect occurs on lines of identical objective length but they are represented differently, then central mechanisms must contribute to the orientation bias. We constructed two types of lines that were perceived by normal subjects as having different lengths, but were of identical extents. Three neglect patients bisected lines perceived as longer, further to the right than lines perceived as shorter. These results demonstrate that relative magnitudes of internal representations contribute to the degree of bias in neglect patients.
Weighing the evidence for cross over in neglect.
When patients with left-sided neglect are asked to bisect horizontal lines, they tend to place their marks to the right of the line's objective mid-point. However, when asked to bisect short lines they are either more accurate or paradoxically cross over and place their marks to the left of the objective mid-point. Previous explanations of the cross over phenomenon have considered specific aberrations of spatial attention. However, these explanations make no predictions about judgments of non-spatial stimuli. Two patients with right brain damage were asked to judge weights placed on both hands simultaneously. They were biased in reporting weights on the right as being heavier than those on the left. This rightward bias changed with lighter pairs of weights presented in the context of equal reference weights. In one patient the directional bias was eliminated and in the other the bias was reversed so that she was more likely to report the left weight as heavier than the right. These data suggest that a phenomenon analogous to cross over in line bisections also occurs with judgments of non-spatial stimuli. Representations of stimuli appear to be influenced by features of the stimuli encountered on-line and by memory traces of similar stimuli encountered previously. With an attentional deficit, memory traces influence the magnitude of the representation derived on-line disproportionately.
Ala scan analogues of HOE 140. Synthesis and biological activities.
The role of the amino acids contained in the sequence of HOE 140 (H-DArg(1)-Arg(2)-Pro(3)-Hyp(4)-Gly(5)-Thi(6)-Ser(7)-DTic(8)-Oic(9 )-Arg(10)-OH), a potent and selective bradykinin B(2) receptor peptide antagonist, has been investigated by the replacement of each original residue (one by one) with Ala. The resulting set of decapeptides has been tested for the B(2) antagonist activity as well as for competition with the binding of [3H]BK to plasma membranes of the human umbilical vein (hUV). Positive correlations have been established between data obtained with the bioassay and with the binding in the hUV (same species, same tissue) and also between the two bioassays, the guinea-pig ileum (GPI) and the hUV (different species, different tissue). The structure-activity study has shown that the replacement of any of the residues that constitute HOE 140 with Ala is accompanied by a decrease of potency of at least 1 log unit. The analogues can be divided into three groups, with Ala(1) and Ala(7) showing affinities lower than HOE 140 by a factor of 10, Ala(4) and Ala(10) by a factor of 100 and Ala(2), Ala(5), Ala(6), Ala(8) and Ala(9) by a factor higher than 100 (100-1000). To verify the effect of chirality, the DAla(5) and DSer(7) analogues were synthesized and it was found that the substitution with a D-residue in position 5 is not tolerated while that in position 7 is favourable. The DSer(7) derivative is the most potent analogue found in this study: it shows potency as high as that of HOE 140 in the bioassays.
Combining antiarrhythmic drugs and implantable devices therapy: benefits and outcome.
At least 50% of patients who received an ICD have been treated with antiarrhythmic drugs (AAD). The potential indications for combining antiarrhythmic drugs and ICD are generally the following: reduction of the number of episodes of ventricular tachycardia or ventricular fibrillation and therefore of the number of shocks, improving patient's quality of life and extending the battery life of the ICD, prevention of supraventricular arrhythmias and/or control of their rate, lengthening of the tachycardia cycle length to allow ventricular tachycardia conversion by antitachycardia pacing and reduction of the number of episodes of syncope. Although previous papers reported conflicting results about pharmacologic therapy in reducing the frequency of iCD shocks, some recent randomized prospective studies showed the efficacy of pharmacologic therapy in reducing the frequency of ICD shocks. The use of antiarrhythmic drugs can have also adverse effect: an increase in the defibrillation threshold, an increase in the pacing threshold and an increase in the VT cycle length leading to detection failure. We have also to consider that some advantages derived from antiarrhythmic drugs can be reached by the new devices with atrial sensing and pacing and/or the possibility of atrial defibrillation or by using catheter ablation as adjunctive therapy to ICD. For these reasons, the concomitant use of antiarrhythmic drugs and ICD should be evaluated in each patient in relation to specific clinical and electrophysiologic features including: the frequency, the rate and the clinical presentation of the ventricular arrhythmia, the effect of the selected drug on the defibrillation threshold, the defibrillation threshold at the implant, the effect of the selected drug on the ventricular function and the likelihood of proarrhythmic events.
Idarubicin intensified BUCY2 regimen in allogeneic unmanipulated transplant for high-risk hematological malignancies.
Twenty-nine consecutive patients with high-risk hematological malignancy aged from 3 to 58 years underwent an unmanipulated graft from an HLA-identical sibling after an irradiation-free preparative regimen consisting of idarubicin (IDA), 21 mg/m2/day administered by continuous infusion on days -12 and -11, followed by busulphan (BU), 4 mg/kg/day orally from day -7 to -4, and cyclophosphamide (CY), 60 mg/kg/day intravenously on days -3 and -2 (IDA-BUCY2). Most clinically relevant extra-hematological regimen-related toxicities consisted of stomatitis observed in all subjects and hemorrhagic cystitis occurred in five cases (17%) within 100 days after transplant. Six patients (21%) developed a grade 2 acute graft-versus-host disease (GVHD) and three (10%) a grade 3 or 4; extensive chronic GVHD was assessed in nine of 22 (41%) evaluable patients. So far, 12 patients have died and 17 are alive, 16 of whom disease-free, 5-41 months after transplant (median, 15 months). The causes of death were related to GVHD in three patients, to sepsis in one and to disease recurrence in the remaining eight. At present, only one of nine relapsed patients is alive. For all patients the actuarial probability of survival (OS) at 1 and 2 years +/- standard error (s.e.) was 63 +/- 9% and 52 +/- 10%, respectively. The actuarial probabilities of disease-free survival (DFS), relapse and transplant-related mortality (TRM) at both 1 and 2 years +/- s.e. were 53 +/- 9%, 35 +/- 9% and 16 +/- 7%, respectively. These results are encouraging but not substantially different from those obtained in 28 patients with malignancy in advanced phase transplanted after the standard BUCY2 regimen, who had an actuarial probability of OS, DFS, relapse and TRM projected at 10 years +/- s.e. of 54 +/- 10%, 57 +/- 9%, 36 +/- 9% and 11 +/- 6%, respectively. Although the retrospective comparison between the two groups does not seem to show any advantage in the use of the IDA intensified regimen, only a prospective randomized trial could answer this question.
Urinary excretion of glycosaminoglycans in patients with isolated nocturnal enuresis or combined with diurnal incontinence.
OBJECTIVE: To determine variations in the amount of glycosaminoglycans (GAGs) excreted by patients with nocturnal enuresis and/or diurnal incontinence. PATIENTS, SUBJECTS AND METHODS: The study included 27 patients (aged 5-15 years) with nocturnal enuresis and/or diurnal incontinence, and 27 healthy age-matched children. Their urinary GAG excretion was assessed over 24 h using the sodium tetraborate-carbazole method. RESULTS: Patients with nocturnal enuresis and/or diurnal incontinence had higher mean values of urinary GAG excretion than age-matched controls. There were significant differences in GAG excretion between those with nocturnal enuresis and diurnal incontinence and those with nocturnal enuresis alone. CONCLUSIONS: GAG excretion in patients with nocturnal enuresis and/or diurnal incontinence was significantly higher than in normal children, suggesting that measuring urinary GAGs may be useful in evaluating physiopathological conditions of the bladder wall, and hence in monitoring potential damage in the bladder mucosa.
[New indications for permanent cardiac pacing].
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Bax mutations are an infrequent event in indolent lymphomas and in mantle cell lymphoma.
BACKGROUND AND OBJECTIVES: The Bax gene is one of the most important genes involved in apoptosis regulation. Recently, it has been proposed that inactivating mutations of this death agonist may contribute to the pathogenesis of human tumors. This study was aimed at defining the status of the Bax gene in indolent lymphomas. DESIGN AND METHODS: Fifty paraffin-embedded biopsies from indolent lymphomas (10 small lymphocytic lymphomas, 5 immunocytomas, 20 follicular lymphomas and 15 marginal zone lymphomas) and 10 mantle cell lymphomas ( MCL ) were studied. All six exons of the Bax gene, together with their flanking sequences, underwent mutational analysis by PCR-SSCP followed by direct sequencing of positive cases. Moreover, Bax protein expression was investigated in all samples by immunohistochemical analysis. RESULTS: All analyzed cases showed wild type Bax gene alleles and variable levels of Bax protein expression. INTERPRETATION AND CONCLUSIONS: This study indicates that deregulation of apoptotic control in indolent lymphomas and MCL is not caused by Bax mutations and that other molecular mechanisms must, therefore, be involved.
High-performance liquid chromatographic analysis of physiological amino acids in human brain tumors by pre-column derivatization with phenylisothiocyanate.
A reversed-phase high-performance liquid chromatographic technique for the determination of free amino acids in five biopsies of human brain tumors (two meningiomas, one glioblastoma and two oligodendrogliomas) is described. The frozen tissues were homogenized, deproteinized with perchloric acid and neutralized with potassium hydroxide. Aliquots of the supernatant containing the physiological amino acids are used for pre-column derivatization with phenylisothiocyanate. The derivatized PTC-amino acids (phenylthiocarbamyl derivatives) are stable for a five day period if stored as a powder at -20 degrees C in an inert atmosphere and they can be analyzed on a reversed-phase column (PicoTag) using a gradient of two eluents with absorption detection at a wavelength of 254 nm. Good resolution of several amino acids (>30) is achieved within ca. 60 min. For most amino acids this method is suitable for an accurate measurement over a wide range of physiological concentrations (50-400 pmol) starting from a very small amount of sample.
Quantitative comparison of technetium-99m tetrofosmin and thallium-201 images of the thyroid and abnormal parathyroid glands.
The aim of the study was to quantitatively compare the scintigraphic images of the thyroid and abnormal parathyroid glands obtained with technetium-99m tetrofosmin and thallium-201 in patients with hyperparathyroidism. Forty-six patients with hyperparathyroidism underwent (201)Tl (74 MBq), (99m)Tc-pertechnetate (74 MBq) and (99m)Tc-tetrofosmin (555-740 MBq) scintigraphy in a single session. Image analysis included the computation of the thyroid/background ratio in the whole study population and the parathyroid/background ratio, parathyroid/thyroid ratio and diagnostic sensitivity in 17 patients who underwent parathyroid surgery. The pertechnetate subtraction technique was used. (201)Tl and (99m)Tc-tetrofosmin showed a similar thyroid/background ratio (1.79+/-0.41 and 1.81+/-0. 47, respectively, P=NS); however, (99m)Tc-tetrofosmin showed a higher parathyroid/background ratio than (201)Tl (2.06+/-0.54 vs 1. 79+/- 0.50, P=0.007). Despite the superior quality of (99m)Tc-tetrofosmin images, both tracers showed identical sensitivity in detecting enlarged parathyroid glands in patients with primary hyperparathyroidism (89%) and in those with secondary hyperparathyroidism (50%).
Quantitative analysis of cancellation tasks in neglect.
Patients with spatial neglect do not explore contralateral space effectively. Although cancellation tasks are used widely to assess this visual search deficit, their methods of analysis are not well established. We introduce logistic regression analyses for cancellation tasks in 7 patients with left neglect. We investigated the influences of spatial location, stimuli number, and target discriminability on the probability of canceling a target. As a group, neglect patients showed left and near neglect. They also explored and canceled targets further into contralateral space on arrays with fewer visual stimuli. Individual analyses revealed exceptions to these group patterns, such as two patients with far rather than near neglect. Only patients with relatively mild neglect canceled more targets when they were more easily discriminated from distracters. Logistic regression models accounted for 0.68 the variance in cancellation performances of the entire group. Shifting the unit of analysis from the proportion of targets canceled to the probability of detecting individual targets offers a powerful parametric method to analyze group and individual performances on cancellation tasks and can reveal functional dissociations in neglect.
Hypermnesia in unilateral neglect.
Thirteen right brain-damaged patients who were found to neglect pictures presented on the left of a display were presented the same stimuli, intermixed with foils, in a yes-no recognition test. Fifty per cent of patients claimed to have already seen one or more of the previously neglected pictures. This demonstrates that visual information that fails to access consciousness in neglect patients does retain the ability to surface as explicit memory at a later stage.
Two-dimensional distortion of space representation in unilateral neglect: perceptual and response-related factors.
The paper reports the results of an experiment in which left-neglect patients were required to point at the location they judged vertically to correspond (within the frame of the visual stimulus display they were given) with a cue that was variably located along a left-right axis lying proximally or distally with respect to the left-right axis over which they had to give their response. Patients were found to make rightward errors as in a similar, single-case study. The significant positive correlation between those errors and the degree of response bias on a manual-response version of the Milner Landmark Task suggests that rightward pointing errors made by left-neglect patients in conditions such as those set in the present experiment are due to a dysfunction selectively affecting an output-related component of space representation.
Coronary flow reserve of normal left anterior descending artery in patients with ischemic heart disease: A transesophageal Doppler study.
The aim of this study was to investigate the flow reserve of a normal left anterior descending coronary artery (LAD) in patients with coronary artery disease (CAD) of other epicardial vessels by Doppler transesophageal echocardiography (TEE). Thirty-one consecutive patients (age 59 +/- 8 years; 23 men) referred for TEE were considered. Eighteen patients had CAD and a 70% or greater LAD stenosis (group 1); 13 patients had right and/or circumflex CAD (>/=70% stenosis) and normal or minimally diseased LAD (group 2). Ten patients (age 54 +/- 11 years) with normal coronary arteries constituted group 3. Baseline and adenosine (0.160 microg/kg per minute intravenously over 60 minutes) flow velocities in the LAD were measured by pulsed Doppler examination during TEE. Peak and mean systolic and diastolic flow velocities were calculated. Adenosine/baseline peak and mean velocity ratios were used for evaluating blood flow reserve in the LAD. Heart rate and arterial pressure values were similar in the 3 groups at baseline and during adenosine infusion. Baseline and adenosine-related flow velocities were comparable in the 3 groups. Peak and mean diastolic velocity ratios were lower in groups 1 and 2 compared with group 3 (peak velocity ratio 1.68 +/- 0.81 and 1.93 +/- 0.35 vs 2.62 +/- 0.32, P <. 05; mean velocity ratio 1.71 +/- 0.86 and 2.01 +/- 0.41 vs 2.84 +/- 0.74, P <.05), whereas no differences were found between groups 1 and 2. No significant differences were found in systolic flow velocity ratios among the 3 groups. Patients with ischemic heart disease have a reduced diastolic flow velocity reserve in the LAD independent from the presence of significant LAD stenosis. Thus the adenosine TEE-Doppler study should be considered a screening test for CAD rather than for LAD disease.
Antiarrhythmic benefits of dual chamber stimulation with rate-response in patients with paroxysmal atrial fibrillation and chronotropic incompetence: a prospective, multicentre study.
BACKGROUND: While the haemodynamic benefits of DDDR pacing compared with DDD pacing in patients with brady-tachy syndrome and chronotropic incompetence (CI) are well demonstrated, the antiarrhythmic advantage is controversial and so far not clearly demonstrated. AIM: We have performed a prospective, randomized, multicentre study to evaluate the efficacy of DDDR and DDD pacing modes in preventing paroxysmal atrial fibrillation (PAF) episodes in patients with brady-tachy syndrome and CI. METHODS AND RESULTS: Seventy-eight patients were included in the study. All patients had a dual chamber pacemaker implanted and were randomly programmed to DDD or DDDR with a cross over (DDD --> DDDR or vice versa) at 3 months. The final evaluation was performed at 6 months by means of two self-administered symptom questionnaires to evaluate activity. Symptoms of palpitations were analysed and scored. The patients were less symptomatic with the DDDR mode. The number of mode-switch activations compared with symptomatic episodes of PAF confirmed the high rate of asymptomatic PAF episodes in patients with brady-tachy syndrome. We conclude that in a small but well defined population of patients affected by sick sinus syndrome with CI and severely symptomatic PAF, DDDR pacing compared with DDD pacing may offer an additional antiarrhythmic benefit and should be considered the primary mode of pacing.