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Biomedical subjects

N Sacchi

Publications and source records attributed to N Sacchi.

At least 37 records · Page 2Linked to original sources
PubMed1999

[Genetic analysis of Italian hematologic patients candidates for bone marrow transplantation from unrelated donors].

Frequencies of HLA-A, -B and -DR antigens and haplotypes were determined in 1945 Italian patients suffering from hematologic diseases and requiring bone marrow transplantation from unrelated donors. These frequencies were compared with those obtained from the Italian bone marrow donor population. No significant differences were found when considering the number of comparisons made, suggesting that the genetic structure of the Italian patients is not different from that of the Italian donor population.

Bone Marrow Transplantation↗
PubMed1999

Influence of cigarette smoking on the electrocardiographic diagnosis of left ventricular hypertrophy in arterial hypertension.

Electrocardiography (ECG) has a lower sensitivity for the diagnosis of left ventricular (LV) hypertrophy in smokers than in non-smokers, but the explanation for this finding is not known. In the setting of the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) study, all subjects smoking > or = 15 cigarettes/day (n = 121, 89 men, age 48 +/- 11 years) were selected from 1443 untreated hypertensive subjects undergoing ECG and M-mode echocardiography, and matched with 484 hypertensive non-smokers by gender (same sex), age (+/- 5 years), and systolic and diastolic blood pressure (both +/- 5 mmHg) in a case-to-control design with a 1:4 matching ratio. Smokers and non-smokers did not differ by age, gender, body mass index, and blood pressure. The voltage of SV1 + RV5 or V6 and RI (p < 0.05), but not of SV3 + RaVL, was lower in smokers. Sensitivity of ECG was lower in smokers when using peripheral or left precordial voltage criteria (e.g. 11 vs 26% for Sokolow-Lyon voltage). When using definitions based on different criteria (voltage of S wave in V3, LV axis, LV strain), sensitivity was not dissimilar in smokers and non-smokers (e.g. 19 vs 18% for Romhilt-Estes score, 40 vs 34% for Perugia criterion). Thus, in hypertensive smokers, sensitivity of ECG is lower than in non-smokers when using peripheral or left precordial voltage criteria, probably due to increased chest size in smokers resulting from increased lung compliance. For LV hypertrophy detection, Sokolow-Lyon voltage should be avoided in hypertensive smokers and replaced by other criteria (Cornell voltage, Romhilt-Estes score, Perugia criterion), which are not influenced by cigarette smoking.

Adult↗
PubMed1998

Development of an interphase fluorescent in situ hybridization (FISH) test to detect t(8;21) in AML patients.

The translocation (8;21) is a chromosome abnormality associated with acute myeloid leukemia (AML). As a consequence of the translocation the AML1 (CBFA2) gene in the 21q22 region is fused to the ETO(CDR,MTG8) gene in the 8q22 region, resulting in one transcriptionally active gene on the 8q- derivative chromosome. In this report we demonstrate the use of a highly specific dual-colour FISH method for the detection of t(8;21) on interphase cells. Genomic probes able to detect the chimeric AML1/ETO gene on the 8q- derivative chromosome were assayed on both normal and leukemic bone marrow and peripheral blood samples. Cut-off values were established by independent analysis of 15 bone marrow specimens negative for the translocation. The cut-off value of positive nuclei was determined to be 2% and the cut-off value for both positive nuclei and nuclei of uncertain classification, 4%. Persistence of cells above these cut-off values was interpreted as persistence of the mutated clone. A total of 36 samples at different disease stages were tested. Interphase cytogenetics detected the translocation at the onset and relapse in the BM or the PB of 14 AML patients with t(8;21). The technique appears to be an alternative tool to both conventional cytogenetics and reverse transcription polymerase chain reaction (RT-PCR) for the monitoring of disease during patients' follow-up. By enabling the analysis of individual cells, interphase FISH is ideal for clonality studies both for clinical and experimental applications.

Acute Disease↗
PubMed1998

Subcellular localization of the oncoprotein MTG8 (CDR/ETO) in neural cells.

The t(8;21) translocation associated with acute myeloid leukemia (AML) disrupts two genes, the AML1 gene also known as the core binding factor A2 (CBFA2) on chromosome 21, and a gene on chromosome 8, hereafter referred to as MTG8, but also known as CDR and ETO. Extensive information is available on AML1, a member of the CBF family of transcription factors, containing a highly conserved domain, the runt box, of the Drosophila segmentation gene runt. This gene is essential for the hematopoietic development and is found disrupted in several leukemias. In contrast, the function of the MTG8 gene is poorly understood. The predicted protein sequence shows two unusual, putative zinc-fingers, three proline-rich regions, a PEST domain and several phosphorylation sites. In addition, we found a region encompassing aa 443-514 predicted to have a significant propensity to form coiled coil structures. MTG8 displays a high degree of similarity with nervy, a homeotic target gene of Drosophila, expressed in the nervous system. Human and mouse wild-type MTG8 are also highly expressed in brain relative to other tissues. For these reasons, we set out to investigate the expression and subcellular localization of the MTG8 protein in neural cells. Immunohistochemical experiments in a 12.5-day-old mouse embryo clearly showed that the protein was expressed in the neural cells of the developing brain and the spinal cord. In primary cultures of hippocampal neurons of 2-3 day-old mice, MTG8 was found in the nucleus, in the cytoplasm and as fine granules in the neurites. Cytoplasmic localization of the protein was observed in Purkinje cells of both human and mouse cerebellum. The molecular mass of MTG8 in total human and mouse brain was analysed by immunoblotting and determined to be between 70 and 90 kDa. Isoforms with the same molecular mass were demonstrated in synaptosomes isolated from mouse forebrain. The evidence of MTG8 in the nucleus and cytoplasm of neural cells suggests a specific mechanism regulating the subcellular localization of the protein.

Animals↗
PubMed1998

HLA polymorphisms in Italian bone marrow donors: a regional analysis.

The aim of this study was to analyse the genetic structure of the Italian bone marrow donor population on the basis of HLA polymorphisms. Maximum likelihood estimates of gene and haplotype frequencies, goodness of fit to Hardy-Weinberg predictions and heterozygosity were calculated for 18 Italian administrative regions. Moreover, the phenotypic peculiarity of the regional populations was assessed by analysing the number of "typical phenotypes" found in each region. Multivariate analyses carried out on HLA-A and HLA-B gene frequencies gave a genetic pattern of the donor pools that reflects the structure of the Italian population determined in previous population genetic studies. Sardinia shows a very large genetic difference with respect to the other regions; of these, the central-southern regions are well-differentiated from the central-northern. Southern regions present higher genetic heterogeneity and a higher probability of providing donors with phenotypes not already present in the Italian bone marrow registry. The large sample size of the bone marrow donor registry allowed us to estimate gene and haplotype frequencies with greater accuracy than in previous studies. Our results may be of use in determining strategies for donor recruitment and selecting unrelated donors for patients requiring bone marrow grafting, as well as for anthropological, epidemiological and population genetics studies.

Alleles↗
PubMed1997

Bone marrow transplantation for chronic myeloid leukemia (CML) from unrelated and sibling donors: single center experience.

This is a report on 60 consecutive patients with chronic myeloid leukemia (CML) who received an allogeneic bone marrow transplant (BMT) in this Unit. Donors were HLA-identical siblings (SIB) (n = 36) or unrelated donors (MUD) (n = 24) matched by serology for HLA A and B and by molecular biology for HLA DR. All patients were prepared with cyclophosphamide 120 mg/kg and fractionated total body irradiation 10-12 Gy. GVHD prophylaxis consisted of cyclosporin A (CsA) starting on day -7 and short-course methotrexate. Bone marrow was unmanipulated in all cases. Cytomegalovirus prophylaxis consisted of acyclovir for SIBs and foscarnet for MUDs. When compared to SIB transplants, MUD patients were younger (29 vs 36 years; P = 0.002), had younger donors (31 vs 39; P = 0.001), had a longer interval between diagnosis and BMT (1459 vs 263 days; P < 0.001) and received a smaller number of nucleated cells at transplant (3.3 vs 4.4 x 10(8)/kg; P = 0.003). More MUDs had advanced disease (50 vs 17%, P = 0.005). The median day to 0.5 x 10(9)/l neutrophils was similar in both groups (18 days for SIBs vs 17 days for MUDs; P = 0.06); the median platelet count on days +30, +50, +100 was significantly (P < 0.01) higher in SIB than in MUD patients (122 vs 38, 113 vs 50 and 97 vs 45 x 10(9)/l, respectively). Acute GVHD was scored as absent-mild, moderate, or severe, in 36, 58 and 6% of SIBs vs 25, 42 and 33% in MUD patients (P = 0.01). Chronic GVHD was comparable (P = 0.1). The actuarial risk of CMV antigenemia at 1 year was 60% in both groups. There were six deaths in SIB patients (two leukemia, two infections, one GVHD, one pneumonitis) and four deaths in MUD patients (three acute GVHD and one infection). Fifty patients survive with a median follow-up of 656 days for SIBs and 485 for MUDs. The actuarial 3-year transplant-related mortality is 12% in SIBs and 17% in MUDs (P = 0.5); the actuarial relapse is 18% in SIBs vs 6% in MUDs (P = 0.4) and 3-year survival 78% in SIBs vs 82% in MUDs (P = 0.7). This study suggests that survival of CML patients after marrow transplantation from unrelated or sibling donors is currently similar, provided the former are well matched. The increased incidence of GVHD in MUD patients is possibly compensated by a lower risk of relapse.

Acyclovir↗
PubMed1997

Clonality analysis of hematopoietic cell lineages in acute myeloid leukemia and translocation (8;21): only myeloid cells are part of the malignant clone.

Bone marrow from six patients with acute myeloid leukemia (AML) and t(8;21) (q22;q22) or a variant t(8;13;21) was studied by simultaneous analysis of cell morphology and karyotype. Combination of May-Grünwald-Giemsa (MGG) and fluorescence in situ hybridization (FISH) using probes specific for the breakpoint regions of chromosome 8 and 21 allowed us to establish the extent of cell-lineage involvement of the translocation. The translocation was found in all myeloid blasts and in high percentages of the more mature neutrophilic cells. In one patient we could demonstrate the translocation in the eosinophils as well. Erythroblasts and lymphocytes did not show the t(8;21) abnormality. These results indicate that the t(8;21) in AML is restricted to the myeloid (granulocytic) lineage.

Adolescent↗
PubMed1996

Detection and subcellular localization of an AML1 chimeric protein in the t(8;21) positive acute myeloid leukemia.

AML1, a gene encoding a protein of the PEBP2/CBF family of transcription factors is disrupted by translocations associated with human leukemia. In the t(8;21) acute myelogenous leukemia (AML), AML1 was found fused to a gene on chromosome 8 that we designated CDR (also known as ETO and MTG8). Immunoprecipitation experiments followed by immunoblotting using a combination of antibodies against different epitopes of one of the predicted chimeric proteins encoded by a fully characterized fusion transcript enabled us to visualize a chimeric protein in the t(8;21) Kasumi-1 cell line. The estimated size of this protein is 64 kDa. Immunoblotting of leukemic blasts containing the t(8;21) detected a protein of the same size. Immunofluorescence experiments indicate that the chimeric protein is localized in the nucleus. A normal AML1 protein of 27 kDa was also detected in t(8;21) Kasumi-1 cells. It remains to be established by which mechanism the mutant AML1 isoform may contribute to the leukemogenesis process of t(8;21)-positive acute myeloid leukemia.

Amino Acid Sequence↗
PubMed1996

Predictors of diurnal blood pressure changes in 2042 subjects with essential hypertension.

OBJECTIVE: To determine the independent predictors of day-night blood pressure changes in a large population of subjects with essential hypertension. METHODS: We studied 2042 white untreated subjects with essential hypertension (mean age 52 years, range 17-93, 1052 men) who underwent 24 h ambulatory blood pressure monitoring on an outpatient basis. Night-time workers were excluded from analysis. RESULTS: For both sexes, the changes in systolic and diastolic blood pressures from day to night decreased progressively with age and increased with the reported duration of sleep. The 1207 employed subjects who underwent ambulatory blood pressure monitoring during a usual working day had greater day-night blood pressure differences than did those who did not work (16.2 versus 14.0%). By using multiple regression analysis we assessed the independent association of several variables with the diurnal blood pressure changes. Age and diabetes for both sexes, and clinic blood pressure in men, were inversely associated with the nocturnal fall in blood pressure. The duration of sleep and the occurrence of blood pressure monitoring during a normal work day predicted a greater day-night blood pressure difference for both sexes; smoking predicted a greater nocturnal fall in blood pressure for women. CONCLUSIONS: Age is associated with an important and progressive attenuation of the day-night blood pressure difference in untreated and unrestricted subjects with essential hypertension. Other factors influencing diurnal blood pressure variations include clinic blood pressure, diabetes, the reported duration of sleep, smoking habits and working activity during blood pressure monitoring. These factors should be treated as potential confounders in the analysis of the relationship between diurnal blood pressure changes and target organ damage or prognosis.

Adolescent↗
PubMed1996

A stable marker chromosome with a cryptic centromere: evidence for centromeric sequences associated with an inverted duplication.

Centromere activation, an important mechanism in karyotype evolution, is occasionally observed in some human chromosome rearrangements. We report a possible occurrence of centromere activation in a marker chromosome containing an atypical centromere associated with an inverted duplication of the region 14q32 --> qter. The marker chromosome's reduced centromere lacks both the alpha and beta satellite sequences usually found at normal centromeres. In an attempt to identify the centromeric sequences, the marker chromosome was flow-sorted and amplified by a degenerate oligonucleotide primer polymerase chain reaction. Reverse chromosome painting experiments showed that the marker chromosome contains sequences that are unique to the distal region of chromosome 14, as well as a low copy number of (centromeric) sequences that are also highly represented in the centromeres of chromosomes 18 and 19. These data suggest the activation of a novel centromere in the 14q32 --> qter region, very likely consequent to the duplication of the region itself.

Adult↗
PubMed1996

Association between persistent pressure overload and ventricular arrhythmias in essential hypertension.

Hypertension is a risk factor for sudden cardiac death, and some data indicate that frequent and complex ventricular arrhythmias may be additional risk markers in hypertensive individuals. We investigated the relation between ventricular arrhythmias and the persistence of increased blood pressure levels over 24 hours in subjects with essential hypertension. We studied 126 never-treated subjects with essential hypertension (83 men) who underwent 24-hour electrocardiographic monitoring, 24-hour ambulatory blood pressure monitoring, and echocardiography. Premature ventricular beats were detected in 71% of the subjects. Compared with subjects in Lown class 0-1, subjects with frequent or complex ventricular arrhythmias (Lown class > or = 2) were older (54 versus 45 years) and had a longer duration of hypertension (5.4 versus 2.8 years), a greater left ventricular mass (147 versus 127 g.m-2), and a blunted nocturnal reduction in ambulatory blood pressure (7%/12% versus 12%/16%). The number of premature ventricular beats over 24 hours was associated with age (r = .25), left ventricular mass (r = .24), and pulse pressure (r = .18) and inversely associated with the present reduction in blood pressure from day to night (r = -.29 for systolic and -.25 for diastolic pressures). In a multiple logistic regression analysis, frequent or complex ventricular arrhythmias (Lown class > or = 2) were predicted by an age > or = 60 years (odds ratio, 10.4 95% confidence interval, 2.4-44.8), left ventricular hypertrophy at echocardiography (odds ratio, 4.2; 95% confidence interval, 1.5-11.6), and a < 10% reduction in blood pressure from day to night ("nondipping" pattern; odds ratio, 2.9;95% confidence interval, 1.2-7.0). We conclude that in addition to the strong effect of age and left ventricular hypertrophy at echocardiography, the persistence of high blood pressure levels over the 24 hours ("nondipping" pattern) is an independent predictor of the frequency and complexity of ventricular arrhythmias in never treated subjects with essential hypertension.

Blood Pressure↗
PubMed1996

Prognostic significance of blood pressure variability in essential hypertension.

BACKGROUND: Blood pressure variability is a determinant of target organ damage in essential hypertension, but its independent prognostic significance has not yet been assessed in prospective studies of cardiovascular morbidity and mortality. OBJECTIVE: To assess the relationship between blood pressure variability, assessed non-invasively using 24 h ambulatory blood pressure monitoring and subsequent incidence of cardiovascular morbid events in persons with essential hypertension. DESIGN: Prospective observational study. PATIENTS AND METHODS: We followed for up to 8.6 years (mean 2.92) 1372 individuals with essential hypertension whose initial off-therapy diagnostic work-up included 24 h non-invasive ambulatory blood pressure monitoring. Those with a standard deviation of daytime or night-time blood pressure below or above the group mean were classified as having low or high blood pressure variability, respectively. One hundred and eighty-two participants underwent repeated ambulatory blood pressure monitoring and echocardiography during follow-up, 2.7 years later. RESULTS: Target organ damage score was greater in the participants with high variability of daytime (P = 0.004) and night-time (P = 0.011) systolic blood pressure than in those with low blood pressure variability. In those who underwent repeated echocardiography, for every quartile of baseline ambulatory blood pressure, left ventricular mass at follow-up was greater (all P < 0.05) in those with high baseline blood pressure variability than in those with low baseline variability. During follow-up there were 106 major cardiovascular morbid events. Event rate was 1.99 and 3.26 events per 100 patient-years, respectively, in participants with low and high variability of daytime systolic pressure and 1.98 and 3.38 events per 100 patient-years, respectively, in those with low and high variability of night-time systolic pressure (log-rank test: both P < 0.05). However, in a Cox multivariate analysis, the variability score for daytime and night-time systolic pressure failed to enter the model (age, diabetes mellitus, previous cardiovascular events and average night-time systolic pressure were independently associated with cardiovascular events). CONCLUSION: Increased blood pressure variability, assessed with non-invasive monitoring, is associated with a higher incidence of cardiovascular morbid complications of hypertension, but also with a higher blood pressure, older age and a higher prevalence of diabetes mellitus. Because of the relevant predictive effect of these associated factors, the adverse prognostic significance of increased blood pressure variability is no longer detectable in multivariate analysis.

Journal Article↗
PubMed1996

Identification of subjects with white-coat hypertension and persistently normal ambulatory blood pressure.

OBJECTIVE: To assess the spontaneous changes in clinic blood pressure, ambulatory blood pressure (ABP) and left ventricular structure in untreated subjects with white-coat hypertension (WCH). DESIGN: A prospective observational study. PATIENTS AND METHODS: In 83 untreated subjects with WCH, 24 h non-invasive ABP monitoring and echocardiographic studies of the left ventricle were repeated after 0.5-6.5 years (mean 2.5) in the absence of antihypertensive drug treatment. WCH was defined by an average daytime ABP < 131/86 mmHg in women and < 136/87 mmHg in men. Ambulatory hypertension was defined by higher ABP values. RESULTS: In the whole population, the clinic blood pressure, ABP and left ventricular mass did not change from baseline to the follow-up visit, whereas the peak A: peak E ratio (where A is the velocity of transmitral blood flow after atrial contraction and E is the velocity during passive left ventricle filling) increased from 0.86 to 0.93. Sixty-three per cent of subjects remained in the WCH category at follow-up study; the remaining 37% shifted to the ambulatory hypertension category. The former group showed no changes in clinic blood pressure, ABP, left ventricular mass and peak A: peak E ratio. The clinic blood pressure of those who developed ambulatory hypertension did not change, whereas their ABP and peak A: peak E ratio increased and their left ventricular mass increased slightly but not significantly. The left ventricular mass increased from baseline to follow-up study by 6.2% in those who developed ambulatory hypertension and decreased by 1.6% in those who remained in the WCH category. The changes in left ventricular mass were associated with the changes in average 24 h systolic blood pressure, but not with the changes in clinic blood pressure. In a stepwise logistic regression analysis, average daytime diastolic blood pressure was the sole variable to enter the model and the probability of ambulatory hypertension at follow-up study was 20.0%percnt; in those with basal daytime ABP <130/80 mmHg, versus 81% in those with higher basal daytime blood pressure levels. CONCLUSION: After 0.5-6.5 years, WCH spontaneously evolved into ambulatory hypertension in 37% of subjects, with an accompanying rise in left ventricular mass. The probability of ambulatory hypertension increased with the baseline values of ABP, rather than with those of clinic blood pressure. WCH might be a prehypertensive state (particularly in subjects with higher baseline ABP levels) and should be defined by low levels of daytime ABP, possibly lower than 130/80 mmHg.

Journal Article↗
PubMed1996

DNA-binding domain of AML1, expressed in t(8;21) and t(3;21) myeloid leukemias, inhibits PEBP2/CBF DNA-binding but is not sufficient to transform 32D cl3 myeloid cells.

Truncated AML1 proteins are predicted to be expressed from out-of-frame AML1 transcripts present in myeloid leukemia cells harboring t(8;21) and t(3;21). To test whether these proteins, consisting of almost exclusively an N-terminal AML1 DNA-binding domain, interfere with myeloid differentiation we expressed a similar truncated AML1 protein in 32D cl3 myeloid cells. In all clones examined, the ectopically expressed truncated AML1 protein prevented binding of endogenous PEBP2/CBFs to DNA, possibly by interacting with all available CBF beta subunits. However, compared to control clones, the 32D cl3 clones expressing truncated AML1 remained IL-3 dependent for survival, proliferated similarly in low and high concentrations of IL-3, and differentiated similarly upon transfer to G-CSF. Thus, truncated AML1 proteins may contribute to myeloid leukemogeneis by inhibiting PEBP2/CBF activities, although contributions from other oncoproteins are likely required as well.

Animals↗
PubMed1996

Unrelated donor marrow transplantation: initial experience of the Italian bone marrow transplant group (GITMO).

From 1 September 1988 to 30 September 1993, a search for an unrelated donor (URD) was started for 633 Italian patients. Eighty-five of them (13%) were transplanted. Despite the introduction of more strict criteria for the selection of compatible donors, the percentage of patients who reached transplant increased significantly after December 1992. For patients who started a search before and after January 1993, respectively the probability of transplant by 8 and 16 months from search activation was 4 and 10%, compared to 22 and 37% (P = 0.0001). The average intervals between search activation and graft were 15 and 8 months respectively, for the first and second group (P = 0.0001). Data of 75 consecutive transplants performed up to March 1994 were analyzed. Actuarial 2-year survival was 15% for patients grafted before 1992 and 40% for those grafted after January 1992. In this latter period, survival of patients with malignant and non-malignant disorders was 32 and 67%, respectively. In univariate analysis, patients younger than 16 years (P = 0.01), patients grafted after 1992 (P = 0.01) and patients receiving the marrow from a 6-antigen matched donor (P = 0.01) showed a higher survival probability. Multivariate analysis did not show any difference, probably due to the low number of patients and to short follow-up. The adoption of stricter and more accurate HLA-matching criteria and the consequent reduction of deaths related to acute GVHD were the main reasons for the improvement of survival observed in patients grafted after 1992.

Adolescent↗