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Biomedical subjects

E Zanelli

Publications and source records attributed to E Zanelli.

At least 19 recordsLinked to original sources

Precipitating factors and decision-making processes of short-term worsening heart failure despite "optimal" treatment (from the IN-CHF Registry).

This study sought to prospectively assess which factors were related to short-term worsening heart failure (HF) leading to or not to hospital admission, in long-term outpatients followed by cardiologists. The subsequent decision-making process was also analyzed. The study population consisted of 2,701 outpatients enrolled in the registry of the Italian Network on Congestive Heart Failure (IN-CHF) and followed by 133 cardiology centers (19% of all existing Italian cardiology centers). Clinical and follow-up data were collected by local trained clinicians; 215 patients (8%) had short-term decompensation (on average 2 months after the index outpatient visit). Multivariate analysis showed that previous hospitalization, long duration of symptoms, ischemic etiology, atrial fibrillation, higher functional class (New York Heart Association classification III to IV), higher heart rate, and low systolic blood pressure were independently associated with HF destabilization. Poor compliance (21%) and infection (12%) were the most frequent precipitating factors, but a precipitating factor was not identified in 40% of the patients. Poor compliance was more common in women, but no other clinical characteristics emerged as being related with a specific precipitating factor. Fifty-seven percent of the patients with a short-term recurrence of worsening HF required hospital admission; infusion treatment with inotropes and/or vasodilators was necessary in 19% of them. Long-term therapy was changed in 48% of the patients. Thus, in ambulatory HF patients, short-term worsening HF can be predicted according to the clinical characteristics on an outpatient basis. Nearly 1/3 of precipitating factors can be prevented. Patient education and avoidance of inappropriate treatment may reduce the number of relapses.

Aged↗

Rheumatoid arthritis in southern Spain: toward elucidation of a unifying role of the HLA class II region in disease predisposition.

OBJECTIVE: To evaluate the contributions of HLA-DQ and -DR polymorphisms to susceptibility to rheumatoid arthritis (RA) in a population in southern Spain, and to compare the value of the shared epitope (SE) and RA protection (RAP) models in accounting for the HLA class II region's contribution to RA predisposition. METHODS: One hundred sixty RA patients and 153 healthy controls were typed for HLA-DRB1 and -DQB1 using high-resolution DNA techniques. Distributions of predisposing DRB1 alleles in patients and control subjects according to the SE model were compared with distributions of predisposing DQ and protective DERAA-positive DRBI alleles according to the RAP model. RESULTS: DQ3 (DQBI*03 and *04 combined with DQA1*03) and DQ5 (DQB1*0501/DQA1*0101) alleles predisposed individuals to RA independently of SE-positive DRB1 alleles. DQ3/3-homozygous individuals had the strongest risk of developing RA. DQ3 molecules predisposed to RA more than did DQ5 molecules. The weaker predisposition mediated by DQ5 included the DRB1*1001-carrying haplotype; no DRB1*1001-homozygous patients were observed. DRBI*0401 played a unique role in the contribution of DQ3-DR4 haplotypes to RA, in spite of its low frequency in southern Spain. CONCLUSION: The low prevalences of RA and of mild disease observed in Spain, and in southern Europe in general, can be explained in great part by the low frequency of DQ3-DR4 haplotypes, especially those carrying DRB1*0401. However, the overall distribution of HLA-DQ and -DR alleles in RA patients compared with control subjects is similar to that in other European and North American populations. A model involving both DQ and DR can best account for the contribution of HLA to RA.

Alleles↗

Distribution of HERV-LTR elements in the 5'-flanking region of HLA-DQB1 and association with autoimmunity.

We established the detailed polymorphism of the 5'-flanking region and the first exon of the human leukocyte antigen (HLA)-DQB1 alleles. One hundred and forty-five Spanish rheumatoid arthritis (RA) patients and 200 healthy voluntary blood donors from southern Spain along with 42 B-cell lines were analyzed for the presence of the retrovirus-derived long terminal repeats (LTRs) LTR3, LTR5, and LTR13. LTR3 positivity was always associated with certain DQB1 alleles, i.e., *0302, *0402, *0601, *0202, and *0305. Sequencing analysis of the 5'-flanking region of DQB1*0301, *0303 and *0502 alleles in homozygous B-cell lines showed the absence of LTR3 and a massive deletion of 5635 base pairs. The undetected deletion in the flanking region of some DQB1 alleles and a lack of stratification for HLA typing explain previously reported associations of the LTR3 element with RA and type I diabetes (IDDM). LTR5 showed identical distribution to LTR3, consistent with a previously suggested LTR3-LTR5 tandem arrangement. LTR13 positivity was associated with DQB1*0302, *0303, and *0402 alleles. Distributions of the LTR elements in all B-cell lines, RA patients, and controls could be explained entirely by linkage disequilibrium with DQB1 alleles, independently of the haplotypes carrying them. LTR elements are known to regulate gene expression. Therefore, a possible involvement of LTR13 in the association of DQB1*0302, *0303, and *0402 with IDDM requires further investigation. The sequencing results of the DQB1 first exon demonstrated that DQB1*0601 was generated by a recombination event between a DR53 and a non-DR53 haplotype. Our results shed new light on the phylogeny of the HLA region and the possible contribution of DQB1 to susceptibility to autoimmunity.

Alleles↗

The telomeric part of the HLA region predisposes to rheumatoid arthritis independently of the class II loci.

We have evaluated the possible contribution of genes besides DQ and DR to the association of HLA with rheumatoid arthritis (RA). To this end, we have looked at the allele distributions of six microsatellites, D6S1014, D6S2673, TNFalpha, MIB, C1-2-5, and C1-3-2 among 132 RA patients and 254 controls. We have defined 19 microsatellite clusters corresponding to previously described ancestral haplotypes. One of them was D6S1014*143-D6S273*139-TNFalpha*99-MIB*350-C1-2-5*196-C1-3-2*354, often found associated with DQB1*0201-DRB1*0301. As part of this microsatellite cluster, the allele MIB*350 was found to be a RA-predisposing factor, independent of DRB1*0301 and RA-predisposing haplotypes DQB1*03-DRB1*04 and DQB1*0501-DRB1*01. We conclude that the telomeric part of the HLA region contains a locus conferring predisposition to RA independently of HLA class II.

Arthritis, Rheumatoid↗

Protection against severe disease is conferred by DERAA-bearing HLA-DRB1 alleles among HLA-DQ3 and HLA-DQ5 positive rheumatoid arthritis patients.

Experimental studies in transgenic mice have suggested that HLA-DQ predisposes to rheumatoid arthritis (RA), but could also modulate disease severity by presenting peptides derived from self-DR molecules. In particular, a short amino acid sequence, (70)DERAA(74), in the third hypervariable region of HLA-DRB1 confers protection for the disease, while particular HLA-DQ [DQB1*0501/DQA1*01 (DQ5) and DQB1*03/DQA1*03 (DQ3)] molecules predispose to the disease. We have therefore analyzed the allelic distribution of HLA-DRB1, DQA1, and DQB1 and the presence of rheumatoid factor and nodules among 199 German RA patients and 196 healthy controls. Our results show that HLA-DQB1*03/DQA1*03 (or DRB1*04) predisposes to RA more than HLA-DQB1*0501/DQA1*01 (i.e., DRB1*01 and DRB1*10). Homozygosity for DQ3 confers the strongest genetic risk for RA (OR = 19.79 compared to OR = 10.05 for two doses of shared epitope (SE) positive HLA-DRB1 alleles). Furthermore, patients carrying both predisposing DQ and (70)DERAA(74)-positive HLA-DRB1 alleles are more often rheumatoid factor (RF) negative than patients carrying predisposing DQ alleles alone. Only one out of 14 patients (7%) with a protective combination (DQ3/(70)DERAA(74) and DQ5/(70)DERAA(74)) had rheumatoid nodules compared to 67 out of 144 patients (46.5%) with predisposing DQ alleles alone (OR = 0.12, 95% CI: 0.02-0.72, p = 0.004). These results demonstrate a protective role of (70)DERAA(74)-positive DRB1 alleles against disease severity among RA patients.

Alleles↗

Evidence for a protective role of the human leukocyte antigen class II region in early rheumatoid arthritis.

OBJECTIVE: To analyse the distribution of predisposing DQ3 (DQB1*03(*04)/DQA1*03) and DQ5 (DQB1*0501/DQA1*01), shared epitope encoding and protective DRB1 alleles in patients with early rheumatoid arthritis (RA) and undifferentiated arthritis (UA). METHODS: Consecutive patients enrolled in an early arthritis clinic were DNA-typed for HLA-DQ and DR. RA patients (n=195), UA patients (n=160) and controls from the same region (n=306) were sorted according to their DQ-DR phenotypes: DQ3 vs DQ5 and the presence or absence of a protective DERAA-positive DRB1 molecule. The three groups were also sorted according to the shared epitope (SE) hypothesis. RESULTS: We observed the association of both DQ3 and DQ5 with RA. DQ3/3 homozygous individuals had the highest risk of developing disease [odds ratio (OR)=20.00]. Conversely DQ5, but not DQ3, was associated with undifferentiated arthritis (OR=2.15 vs 1.25). Consistent with these differences, DQ3-positive individuals had significantly more active disease at the first visit at the outpatient clinic than DQ5-positive patients. DRB1 alleles encoding a DERAA motif in their third hypervariable region provided a strong dominant protection against RA among DQ5-positive individuals and decreased arthritis activity among DQ3-positive patients. Individuals with SE-positive DR1, DR4 and DR10 alleles were also predisposed to RA, DR4/4 homozygous individuals having the highest risk of developing RA (OR=11.00). CONCLUSION: The DQ3-DR4/9 haplotypes are associated with RA. The DQ5-DR1/10 haplotypes are associated with less active disease, i.e. UA, and DERAA encoding DRB1 alleles modulate either predisposition to or the severity of RA. We propose that HLA polymorphism influences not only the initiation or perpetuation of RA but also protection against the disease.

Arthritis, Rheumatoid↗

TNF-308A and HLA-DR3 alleles contribute independently to susceptibility to systemic lupus erythematosus.

OBJECTIVE: To evaluate the respective contributions of tumor necrosis factor (TNF) promoter polymorphisms and HLA-DR alleles to susceptibility to systemic lupus erythematosus (SLE). METHODS: TNF-238G/A and 308G/A promoter polymorphisms and HLA-DRB1 alleles were determined in 99 consecutive Caucasian SLE patients and 177 Caucasian controls. Standard and Mantel-Haenszel odds ratios were calculated to assess the magnitude of the susceptibility factors. The presence or absence of the SLE classification criteria was determined and correlated with the TNF promoter and HLA-DRB1 genotypes. RESULTS: The frequency of the TNF-308A/A and 308G/A genotypes was significantly higher in SLE patients (odds ratio 5.0). Conversely, TNF-238G/A and 238A/A genotypes were equally prevalent in SLE patients and controls. The HLA-DR3 specificity (DRBI*0301 allele) was significantly more prevalent in the SLE population (odds ratio 4.4). Stratification to correct for interdependence of the 2 loci confirmed the association of both TNF-308A and HLA-DR3 with SLE (Mantel-Haenszel odds ratio 3.2 and 2.4, respectively). No correlation was found between TNF promoter and HLA-DRB1 genotypes and any SLE classification criterion or disease manifestation. CONCLUSION: TNF-308A and HLA-DR3 alleles are independent susceptibility factors for SLE.

Adult↗

HLA class II association with rheumatoid arthritis: facts and interpretations.

We have reviewed the literature on the association of HLA class II with rheumatoid arthritis (RA). Strong linkage disequilibrium among DQB1, DQA1 and DRB1 alleles makes it difficult to evaluate the individual contribution of each locus. Nonetheless, there is a strong case for the role of DQB1*03 and *04 combined with DQA1*03 in susceptibility to severe RA while DQB1*0501 combined with DQA1*0101 and *0104 weakly predisposes to a mild form of RA. However, it is also clear that DRB1*0401 has a particular role in predisposition to the most severe form of the disease while other DRB1 alleles might provide protection. We would like to propose that in RA, as in type I diabetes, both DQ and DR loci contribute to predisposition to the disease.

Alleles↗

HLA association with autoimmune disease: a failure to protect?

That certain HLA specificities are associated with predisposition to autoimmune disease does not necessarily imply that self-reactive T cells restricted to particular HLA alleles are eliciting the disease. In the present essay, we argue that HLA can be a major genetic factor in the development of autoimmune diseases without T cells being primarily involved in its initiation or perpetuation. There is now ample evidence that self-reactive, regulatory T cells can protect against pernicious autoimmunity. Hereafter, we propose that extended HLA haplotypes, such as DQ3-DR4, DQ3-DR9, DQ5-DR1 and DQ5-DR10 in the case of rheumatoid arthritis, predispose to impaired T-cell-mediated immune regulation. The haplotypes associated with impaired regulation are the combination of certain class II alleles and a yet unknown 'amplifier'. In this model, products of the HLA class II region are not involved in the presentation of particular organ-specific autoantigens. Therefore, HLA does not predispose to autoimmune disease per se, but rather fails to provide efficient protection.

Animals↗

[Appropriateness of referral to the emergency department through a telecardiology service. "Boario Home-Care" researchers].

BACKGROUND: The use of telemedicine appears particularly promising in cardiovascular diseases; it may reduce the decisional time during an acute myocardial infarction, which is the greater part of the so-called "avoidable delay" and the inappropriate admission to the Emergency Department with the possibility of ruling out an acute pathology. The aim of our study was to show the diagnostic accuracy of a telecardiology service in the daily activity of general practitioners. METHODS: From February 1998 to February 1999, 150 general practitioners received a portable electrocardiographer (Card-Guard 7100) transferring, by a mobile or fixed telephone, a 12-lead ECG to a receiving station, where a cardiologist was available for the reporting and interactive teleconsultation. RESULTS: During 1 year 3456 calls took place. At the time of the ECG recording 44% of patients were symptomatic. Chest pain was present in 669 patients (44%), dyspnea in 21%, palpitation in 18%, dizziness in 7%, and asthenia in 13%. ECG and teleconsultation solved all the problems for 2452 patients (71%) and further diagnostic tests were requested in 862 patients (25%); 142 patients (4%) were sent to the Emergency Department. Cardiological diagnosis was confirmed in 95 patients (73%), while anxiety or gastritis were presumed in 35 patients (27%). In the group of patients (n = 3314) for whom the cardiologist solved the problem without admission to the Emergency Department, there were 5 patients who were admitted to the Emergency Department for myocardial ischemia in the following 48 hours after the teleconsultation. Telecardiology service showed versus Emergency Department admission a sensitivity of 95%, a specificity of 97.5%, and a diagnostic accuracy of 92.5%. CONCLUSIONS: These data confirm a good diagnostic value to the service and a useful support to the general practitioners' activity.

Electrocardiography↗

HLA-DQ-associated predisposition to and dominant HLA-DR-associated protection against rheumatoid arthritis.

We have recently proposed a new hypothesis to explain the association of Human Leukocyte Antigen (HLA) with rheumatoid arthritis (RA) predisposition. In this model, which challenges the Shared Epitope (SE) hypothesis, HLA-DQ predisposes while HLA-DR protects. In the present study, we have compared these two models in an Early Arthritis Clinic started in 1993 in the Department of Rheumatology at the Leiden University Medical Centre. Out of 524 patients who enrolled this programme in the period 1993-1998 and completed the one year follow-up, 155 have been classified as RA. These patients along with 306 consecutive cadaveric renal organ donors have been typed for HLA-DR and -DQ. The distributions of predisposing DR alleles according to SE, and predisposing DQ and protective DR according to our model were analysed. We found that two doses of predisposing DQ alleles strongly predisposed to RA, even in individuals with a single dose of SE while DRB1 alleles carrying the motif DERAA confered a dominant protection in DQ5-positive individuals. We conclude that the present findings are consistent with our previously described model of HLA and RA association. Using this new model, we have been able to characterise two novel groups of individuals on the basis of their HLA typing: one strongly predisposed to RA and one protected. Knowing the mechanism of HLA-related dominant natural protection may help in designing novel treatment modalities for RA.

Alleles↗

Association of the TNF +489 polymorphism with susceptibility and radiographic damage in rheumatoid arthritis.

Multiple genetic factors contribute to susceptibility to rheumatoid arthritis (RA). The extent of variability in disease presentation in RA may be related to genetic heterogeneity. In this study we investigated the association of the TNF gene polymorphism at position +489 with susceptibility to and severity of RA. Analysis of the frequency of the +489 A and G alleles in a group of 293 consecutive RA patients and 138 healthy controls revealed a significant decrease of the A allele. The +489 GA patients had a 3.9 times decreased chance of having erosive disease than +489 GG patients. These results were confirmed in a prospective study using a cohort of 112 patients who were followed for 12 years. The progression rate of the erosion score over 12 years expressed as Sharp score for X-rays of hands and feet was 3.4 per year for the GA-genotyped patients and 12.1 for the GG-genotyped patients. These associations were independent of rheumatoid factor and HLA-shared epitope positivity. In conclusion, these data suggest that the intron TNF +489 polymorphism is associated with susceptibility to and disease severity of RA independently of HLA-shared epitope-positive alleles.

Adult↗

Effects of oxygen on autonomic nervous system dysfunction in patients with chronic obstructive pulmonary disease.

Chronic hypoxaemia can play a pathological role in abnormalities of the autonomic nervous system (ANS). In patients with chronic obstructive pulmonary disease (COPD), chronic hypoxaemia is associated with increased mortality and only long-term oxygen therapy is able to improve their survival. Normoxaemic COPD patients have been shown to suffer from abnormalities in ANS function. The aims of this study were to evaluate ANS function in COPD patients with chronic hypercapnic respiratory insufficiency and to test whether oxygen supplementation could reverse any ANS dysfunction. Eleven stable COPD patients with chronic hypercapnic respiratory insufficiency underwent evaluation of ANS by analysis of variability in cardiac frequency at rest and during both vagal (controlled breathing) and sympathetic (tilting) stimuli breathing with and without oxygen supplementation. Thirteen male, healthy, nonsmoking volunteers served as controls. Evaluation of ANS in COPD patients during hypoxic conditions showed alterations both at rest and in response to vagal and sympathetic stimuli. Oxygen supply reversed hypoxaemia without significant changes in arterial carbon dioxide tension and, therefore, ANS alterations were corrected during sympathetic stimulus only. Breathing room air and oxygen, the resting low-frequency (LF) powers were 45+/-15 and 148+/-55 ms2 x Hz(-1), respectively, and controlled breathing LF were 107+/-41 and 141+/-113 ms2 x Hz(-1), respectively. In stable patients with chronic obstructive pulmonary disease with chronic respiratory insufficiency, hypoxaemia is associated with derangements in the autonomic nervous system which may be partially reversed by oxygen administration.

Aged↗

Telecardiology community: a new approach to take care of cardiac patients. "Boario Home-Care" Investigators.

BACKGROUND: Cardiovascular diseases are the leading cause of morbidity and mortality in Western countries and represent, in terms of diagnostic and treatment measures, a large amount of health care expenses. A telecardiology service may offer to general practitioners, in real time, a useful diagnostic tool and the possibility of an accurate screening of patients with suspected ischemic heart disease. METHODS: From February to July 1998, in the provinces of Bergamo and Brescia (Italy), 178 general practitioners received a portable Card Guard 7100 electrocardiographer transferring, by a mobile or fixed telephone, a 12 lead ECG to a receiving station, where a cardiologist was available for the reporting and interactive teleconsultation. RESULTS: During the first 6 months a total 2800 calls took place. Due to incompleteness of requested data only 2254 traces, corresponding to 2254 subjects (mean age 63 +/- 18 years) were entered in the study. In 27% of patients (n = 609) there was a history of systemic hypertension, in 12.5% (n = 283) there was a history of coronary artery disease, and in 38% (n = 834) there was no history of cardiovascular diseases. At the time of ECG recording, 42% of patients (n = 949) were symptomatic: more common symptoms were chest pain (39%), dyspnea (23%), palpitation (19%), dizziness or faint (10%), and asthenia (9%). No action was suggested by cardiologists in 74% of cases. Of the remaining patients, 16% (n = 92) were referred to the Emergency Department, 27% (n = 158) were offered further diagnostic tests as an out patient, and 56% (n = 328) were started on medication or had their treatment changed. CONCLUSIONS: A telecardiology system provides a useful support to general practitioners in the management, in real time, of patients with cardiovascular conditions, and possibly contributes to optimization of health care costs in terms of appropriateness of hospital admissions and diagnostic tests.

Aged↗

Is heart rate variability a reliable method to assess autonomic modulation in left ventricular dysfunction and heart failure? Assessment of autonomic modulation with heart rate variability.

Autonomic dysfunction seems to be involved in the progression and prognosis of congestive heart failure. Measurement of heart rate variability (HRV) provides a noninvasive method to obtain reliable and reproducible information on autonomic modulation of heart rate, but there is a difficulty in using HRV as a quantitative estimate of autonomic dysfunction in heart failure. This study was aimed at testing the hypothesis that abnormal modulation of heart rate assessed by power spectrum analysis may be present also in asymptomatic patients with left ventricular dysfunction and progress in patients with overt symptoms of congestive heart failure. HRV was measured in three groups of subjects: Group 1: 30 patients with chronic heart failure; Group 2: 21 patients with asymptomatic left ventricular dysfunction; and Group 3: 25 healthy volunteers as control group. HRV was evaluated by autoregressive spectral analysis with 600-beat ECG samples, while subjects were quietly recumbent (BSI), in conditions of controlled breathing (15 acts/min) (RSC) and passive orthostatism after tilting (80 degrees) (TLT). Patients in group 1 showed a reduction in the standard deviation of the R-R intervals (SDRR) (p<0.0003) and in the low frequency component (LF) (p<0.0001) compared to normal subjects. Low frequency component was not detectable in 11 patients of group I (p<0.0008). On RSC and TLT, group 1 failed to show any modification in the low frequency and high frequency components (HF) under any stimulation. Group 2 showed no modification at baseline evaluation, no increase in the high frequency component on RSC and in LF during TLT compared to controls (p<0.01 and p<0.0001 respectively). At baseline, group 1 had a lower SDRR (p<0.03) and LF (p<0.0001) vs. group 2, whereas during stimulation the two groups exhibited the same behaviour. In conclusion, reduced heart rate variability is specific for both asymptomatic and symptomatic post-ischemic left ventricular dysfunction. Our results suggest that frequency domain analysis of heart rate variability during a stimulation test allows a more accurate definition of the degree of autonomic control of heart rate.

Autonomic Nervous System↗

Identification of HLA class II-restricted determinants of Mycobacterium tuberculosis-derived proteins by using HLA-transgenic, class II-deficient mice.

T helper 1 cells play a major role in protective immunity against mycobacterial pathogens. Since the antigen (Ag) specificity of CD4(+) human T cells is strongly controlled by HLA class II polymorphism, the immunogenic potential of candidate Ags needs to be defined in the context of HLA polymorphism. We have taken advantage of class II-deficient (Ab0) mice, transgenic for either HLA-DRA/B1*0301 (DR3) or HLA-DQB1*0302/DQA*0301 (DQ8) alleles. In these animals, all CD4(+) T cells are restricted by the HLA molecule. We reported previously that human DR3-restricted T cells frequently recognize heat shock protein (hsp)65 of Mycobacterium tuberculosis, and only a single hsp65 epitope, p1-20. DR3.Ab0 mice, immunized with bacillus Calmette-Guérin or hsp65, developed T cell responses to M. tuberculosis, and recognized the same hsp65 epitope, p1-20. Hsp65-immunized DQ8.Ab0 mice mounted a strong response to bacillus Calmette-Guérin but not to p1-20. Instead, we identified three new DQ8-restricted T cell epitopes in the regions 171-200, 311-340, and 411-440. DR3.Ab0 mice immunized with a second major M. tuberculosis protein, Ag85 (composed of 85A, 85B, and 85C), also developed T cell responses against only one determinant, 85B p51-70, that was identified in this study. Importantly, subsequent analysis of human T cell responses revealed that HLA-DR3+, Ag85-reactive individuals recognize exactly the same peptide epitope as DR3.Ab0 mice. Strikingly, both DR3-restricted T cell epitopes represent the best DR3-binding sequences in hsp65 and 85B, revealing a strong association between peptide-immunodominance and HLA binding affinity. Immunization of DR3.Ab0 with the immunodominant peptides p1-20 and p51-70 induced T cell reactivity to M. tuberculosis. Thus, for two different Ags, T cells from DR3.Ab0 mice and HLA-DR3+ humans recognize the same immunodominant determinants. Our data support the use of HLA-transgenic mice in identifying human T cell determinants for the design of new vaccines.

Amino Acid Sequence↗