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A Doria

Publications and source records attributed to A Doria.

At least 73 records · Page 4Linked to original sources
PubMed1998

Genetic markers of increased susceptibility to diabetic nephropathy.

The effect of exposure to diabetes on the kidney appears to be modulated by genetic factors determining a variable degree of susceptibility to diabetic nephropathy. Multiple loci are probably involved. Some of them might be found among the genes coding for components of the renin angiotensin system (renin, angiotensinogen, angiotensin I-converting enzyme, angiotensin receptors), some may regulate the way in which cells manage hyperglycemia (e.g. aldose reductase). Various genes have been examined to date, mainly by means of association studies. Positive results have been found for some of them (e.g. ACE, AGTR1, aldose reductase), but have not been confirmed in other populations. Thus, no genetic marker of increased susceptibility to diabetic nephropathy having clinical utility is currently available. New insights are expected from the systematic scanning of the genome for linkage with diabetic nephropathy.

Diabetic Nephropathies↗
PubMed1998

An association between NIDDM and a GAA trinucleotide repeat polymorphism in the X25/frataxin (Friedreich's ataxia) gene.

Friedreich's ataxia is the most common hereditary ataxia and is frequently associated with disturbances of glucose metabolism. This autosomal recessive disease is caused by the decreased expression of a mitochondrial protein, frataxin, encoded by the X25 gene. Homozygous expansion of a GAA repeat in the first intron of X25 inhibits frataxin expression and is associated with clinical disease. We evaluated whether heterozygous expansions of the triplet repeat in the frataxin gene X25 may be associated with NIDDM in two genetically distinct populations--one in Germany (n = 358) and the other in the U.S. (n = 292)--using a polymerase chain reaction-based assay. Intermediate expansions (10-36 repeats), which are longer than normal but not sufficient for the appearance of the ataxia phenotype, were found in 24.7 and 27.3% of these two NIDDM cohorts compared with 7.6 and 6.3% of the matched control subjects (both P < 0.001). The odds ratios were 3.36 (95% CI 1.72-6.55) for the German group and 4.01 (2.08-7.74) for the U.S. group. Therefore, we conclude that the X25/frataxin GAA repeat polymorphism is associated with NIDDM in a frequency higher than any other mutation heretofore described. Further studies are needed to elucidate the possible role of frataxin in the pathogenesis of NIDDM.

Aged↗
PubMed1997

Synergistic effect of angiotensin II type 1 receptor genotype and poor glycaemic control on risk of nephropathy in IDDM.

We investigated the contribution of polymorphisms in the angiotensin II type 1 receptor gene (AGTR1) to renal complications in an inception cohort of 152 insulin-dependent diabetic (IDDM) patients examined 15-21 years after diabetes onset. This nested case-control study included 79 normoalbuminuric control subjects and 73 cases with evidence of nephropathy ranging from microalbuminuria to overt proteinuria. Subjects were genotyped for two AGTR1 polymorphisms (T573-->C and A1166-->C), and an adjacent CA repeat microsatellite. Allele C1166 and the 140 bp allele of the microsatellite were more frequent among nephropathy cases than normoalbuminuric control subjects (0.322 vs 0.247, and 0.618 vs 0.521, respectively), but these differences were not statistically significant. Although not significant by themselves, the AGTR1 polymorphisms contributed significantly to the risk of diabetic nephropathy when accompanied by poor glycaemic control. Among patients with frequent severe hyperglycaemia during the first decade of diabetes, the relative risk of nephropathy among allele C1166 carriers was 12.1 (95% CI: 3.7-39.8), whereas it was only 1.4 (95% CI: 0.6-3.5) among allele A1166 homozygotes. The difference between relative risks was highly significant (chi(2) = 8.25, p = 0.004 with 1 df). A similar pattern of higher risk of microalbuminuria, specifically among those carriers of allele C1166 who had poor glycaemic control was also found in an independent study of a cross-sectional sample of 551 IDDM individuals, although the effect was smaller in magnitude. We conclude that DNA sequence differences in the AGTR1 gene may modify the noxious effects of hyperglycaemia on the kidney. Allele C1166 carriers might especially benefit from nephropathy prevention programmes.

Adult↗
PubMed1997

Esophageal motor function in primary Sjögren's syndrome: correlation with dysphagia and xerostomia.

The incidence of dysphagia in patients with primary Sjogren's syndrome (pSS) has been underestimated and all too often ascribed to xerostomia, without considering the possible presence of esophageal motor abnormalities affecting other nonscleroderma connective tissue diseases. Esophageal and salivary functions were prospectively evaluated in 27 females who met the four criteria proposed by Fox for the diagnosis of pSS, using esophageal manometry after wet swallows and Saxon's test, respectively. Dysphagia was graded using a standard symptoms questionnaire and results were compared with those obtained in a group of 21 healthy controls. Seven patients with pSS (26%) had no swallowing discomfort, 2 (7.4%) had mild dysphagia, 7 (26%) had moderate dysphagia, and 11 (40.6%) had severe dysphagia. Saxon's test revealed an overall decrease in the salivary flow rate compared to controls, with no difference between patients with or without dysphagia. Esophageal manometry demonstrated the absence of any lower or upper esophageal sphincter function abnormalities in all patients. In the patients with pSS as a whole, manometric study of the esophageal body showed a motor pattern comparable with that of controls, with no difference between patients with and without dysphagia. Defective peristalsis, ie, the presence of simultaneous contractions in more than 30% of wet swallows was detected, however, in the distal tract of the esophagus of six patients (22.2%) and in the proximal tract of three (11.1%). All these patients had severe dysphagia and the modified Saxon's test revealed a salivary secretion comparable with that of patients with a normal peristalsis. Dysphagia is a very common complaint in patients with pSS and does not seem to correlate with xerostomia, which is a constant and typical finding of the disease. About one third of patients with pSS have an abnormal esophageal peristalsis that is responsible for severe dysphagia, whereas decreased salivary outflow exacerbates the swallowing discomfort. This has to be taken into account and justifies the routine use of esophageal manometry in patients with pSS. The cause of dysphagia in pSS patients without peristaltic disorders of the esophagus has to be investigated.

Adult↗
PubMed1997

'Autoantibody dominance' pattern following idiotypic manipulation of naive mice by immunization with anti-U1RNP antibodies.

OBJECTIVE: To study the immune response and clinical findings in mice immunized with different epitope-specific anti-U1RNP antibodies purified from the sera of mixed connective tissue disease (MCTD) patients with various clinical manifestations. METHODS: BALB/c mice were immunized with anti-U1RNP-IgG preparations from 3 patients with MCTD. Group 1 was immunized with U1 70 kD A-positive IgG, group 2 with U1 70 kD-negative, U1A, U1C, B-B'-positive IgG and group 3 with U1 70 kD, U1A, U1C-positive IgG. The induced autoantibody response in the mice was studied by ELISA and immunoblots and the clinical findings of MCTD in humans were assessed. RESULTS: Immunoblot assays showed that mice immunized with different human anti-U1RNP antibodies developed predominantly autoantibodies directed against U1 68-70 kD epitope. This 'autoantibody dominance' pattern was not associated with clinical findings. CONCLUSIONS: The restricted murine autoimmune response may provide clues to the diversified autoantibody production in autoimmune diseases and explain in part the changing patterns of clinical findings in individuals with MCTD.

Animals↗
PubMed1996

Molecular cloning of the human rad gene: gene structure and complete nucleotide sequence.

We have isolated and sequenced human genomic DNA clones encoding the Ras-related GTP-binding protein, Rad. The gene spans 3.75 kb and consists of five exons and four introns. Translation initiates from the first of two in-frame methionine residues in the second exon. Several potential transcription cis-elements were revealed throughout the 1.7 kb 5'-flanking region, including 'E box' and CArG binding sites for regulators of transcription in muscle.

Amino Acid Sequence↗
PubMed1996

Diabetes susceptibility at IDDM2 cannot be positively mapped to the VNTR locus of the insulin gene.

An inconsistency has come to light between the conclusion of Lucassen et al. that IDDM2 (11p15.5) must lie within a 4.1 kilobase (kb) segment at the insulin (INS) locus and their own data showing statistically significant associations between insulin-dependent diabetes mellitus (IDDM) and markers beyond the boundaries of that segment. We present data from an independent study of 201 IDDM patients and 107 non-diabetic control subjects that also show significant association with a marker 5' of the INS locus. Patients and control subjects were genotyped at INS/+ 1140 A/C (a surrogate for the variable number tandem repeat (VNTR) polymorphism in the regulatory part of the INS gene) and a marker 5' of the tyrosine hydroxylase (TH) gene, TH/pINS500-RsaI, making it 10 kb 5' of the VNTR. Homozygotes for INS/ + 1140 allele '+' were significantly more frequent among IDDM patients than among control subjects (73 vs 45%, p < 0.001) giving an odds ratio of 3.3 (95% confidence interval (CI): 2.0-5.3). A very similar association was found for homozygotes for the TH/RsaI allele '+' (53 vs 31%, p < 0.001) giving an odds ratio of 2.6 (95%CI 1.6-4.2). By multilocus analysis, the TH/RsaI allele '+' identified a subset of INS/ + 1140 alleles '+' haplotypes that are more specifically associated with IDDM (odds ratio = 5.4, 95%CI 2.9-10.4) than allele + 1140 '+' as a whole. In conclusion, the segment of chromosome 11 that is associated with IDDM spans, at least, the INS and TH loci. No legitimate claim can be made that IDDM2 corresponds to the VNTR polymorphism at the INS locus until the correct boundaries for IDDM2 have been defined and other loci within them have been excluded as determinants of IDDM.

Adult↗
PubMed1996

Blotting patterns of IgG anti-(U1)RNP antibodies in mixed connective tissue disease.

Serum reactivities towards individual U1 snRNP proteins were determined by immunoblotting in 32 patients with mixed connective tissue disease (MCTD). Time persistence of immunoblot profiles and clinical significance of anti-(U1)RNP antibody specificities were also investigated. IgG anti-(U1)RNP antibodies were found in the sera of 29 out of 32 patients (90.6%): 21 (65.6%) reacted with the 70-kD protein, 25 (78.1%) with A, 23 (71.9%) with C and 20 (62.5%) with B/B' proteins. None were reactive with the Sm-D peptide. Seventy kilodalton antibody specificity was strongly associated with a higher antinuclear antibody titre (> 160) and slightly associated with disease activity; anti-B/B' specificity was associated with lymphadenopathy. Anti-A, -C and -B/B' antibodies were negatively associated with systemic lupus erythematosus (SLE) skin rashes. Two types of anti-(U1)RNP blotting patterns were selected: "full spectrum" (53.1% of cases) and a "partially/no reactive" one (46.9%). Such patterns were unchanged over time in 14 out of 16 cases prospectively examined (87.5%), while the pattern shifted from "full spectrum" to "partially/no reactive" in 2 cases (12.5%): in 1 after a prolonged clinical remission (> or = 4 years) and in the other following immunosuppressive therapy. The anti-(U1)RNP antibody immunoblot profile in MCTD patients consisted of various reactivities and remained unchanged over time in most cases. Antibody reactivity against the 70-kD protein represented the major U1 snRNP specificity. The various anti-(U1)RNP specific reactivities demonstrated poor clinical significance within MCTD. Thus, MCTD seems to be characterized by a longstanding serological heterogeneity whose reactivities do not apparently correspond to distinct features within the broad clinical spectrum of MCTD.

Adult↗
PubMed1996

Arthroscopic synovectomy in rheumatoid and psoriatic knee joint synovitis: long-term outcome.

A long-term prospective study was performed to evaluate the safety and long-term outcome of surgical arthroscopy (AS) for persistent rheumatoid (RA) and psoriatic (PsA) knee joint synovitis (KJS). Local signs of joint inflammation (tenderness, swelling, "ballottement') and range of motion (ROM) were scored and the sum, taken as a global outcome measure, was recorded in 17 RA and 18 PsA knees, both before and at follow-up periods of 2, 6, 12, 24 and 36 months after surgical AS (knee joint synovectomy; meniscal curettage, cartilage shaving or chondrectomy, according to the degree of cartilage damage). A survival analysis (Kaplan-Meier) of the long-term outcome of surgical AS treatment and of the predictive value of clinical parameters of knee joint involvement was also performed. No intra- or post-operative morbidity, pain worsening or loss of joint motion was observed and all patients were discharged within 48 h. Comparison of the parameters of knee joint evaluation showed a significant reduction of the signs of joint inflammation and a significant increase in the ROM in all follow-up periods. At 36 months, the survival curves showed a 61.2% cumulative probability of clinical remission and 72.8% of definite improvement. No significant differences in the prognostic importance of RA, compared to PsA diagnosis, were observed, although higher percentages of PsA compared to RA knees (86.3% and 45.7% respectively) reached the end point of clinical remission at 36 months. KJS duration, radiographic severity and cartilage damage were not predictors of poor long-term outcome of AS synovectomy. Surgical AS treatment for PsA knees with more advanced cartilage damage gave a better long-term outcome. A total of 50.7% of operated knees reached the end point of a KJS relapse at 36 months, the majority (82%) within the initial 18 months of follow-up. Our study indicates that AS synovectomy is a safe procedure requiring short hospitalization which, in combination with second-line medical treatment, can reduce local inflammation in RA and PsA KJS, and preserve knee joint ROM for up to 3 yr.

Adult↗
PubMed1996

Genetics of non-insulin-dependent (type-II) diabetes mellitus.

Both genetic and environmental factors contribute to the etiology of non-insulin-dependent diabetes. The genetic component is heterogeneous and in some patients is probably complex, involving multiple genes. Specific genetic defects have been identified for rate monogenic forms of NIDDM: maturity-onset diabetes of the young, or MODY (which is due to glucokinase mutations in about 40% of families), syndromes of extreme insulin resistance (which often involve the insulin receptor), and diabetes-deafness syndromes (with defects in mitochondrial genes). In contrast, the genes involved in common forms of NIDDM are still uncertain. Mutations have been extensively searched in genes regulating insulin signaling and secretion. Some evidence of involvement has been produced for insulin-receptor substrate-1, glycogen synthase, the glucagon receptor, a ras-related protein (Rad), histocompatibility antigens, PC-1, and fatty acid binding protein, but the contributions of these genes to NIDDM is probably small. Other candidate genes (e.g. insulin, insulin receptor, glucose transporters) have been excluded as major diabetogenes. New insights are expected in the near future from the systematic scanning of the genome for linkage with NIDDM.

DNA, Mitochondrial↗
PubMed1996

Angiotensinogen polymorphism M235T, hypertension, and nephropathy in insulin-dependent diabetes.

The allele 235T (a threonine in place of a methionine at position 235) of angiotensinogen has been found to be associated with a predisposition to essential hypertension. We investigated whether this allele also confers increased susceptibility to nephropathy in patients with insulin-dependent diabetes mellitus (IDDM). A group of 380 patients who had had IDDM for 15 to 20 years were genotyped at the angiotensinogen 235 locus. Included were 75 patients with normoalbuminuria (albumin excretion rate < 30 micrograms/min), two series of patients with microalbuminuria (n = 30 and n = 136), and two series with overt proteinuria (n = 41 and n = 98). Allele 235T frequency was higher among cases with microalbuminuria (0.41 in the two series combined) or overt proteinuria (0.40) than in the normoalbuminuria group (0.36). However, this difference was not statistically significant with this sample size (chi 2 = 1.2, P = NS with 2 df). Under a recessive model, allele 235T homozygotes had a 1.6-fold risk of developing nephropathy relative to carriers of other genotypes, but this value was not significantly different from 1(95% CI = 0.8 to 3.5). The strength of the association did not improve after stratification by degree of glycemic control. With respect to the hypertension in these IDDM patients, no association with allele 235T was found. Allele 235T frequencies in normotensive and hypertensive individuals were 0.363 and 0.353, respectively, among normoalbuminuric IDDM individuals (chi 2 = 0.01, P = NS) and 0.411 and 0.414 among microalbuminuric IDDM subjects (chi 2 = 0.0, P = NS). We conclude that the angiotensinogen polymorphism M235T might influence susceptibility to nephropathy in insulin-dependent diabetes, but its effect, if any, is rather small and independent of hypertension.

Adult↗
PubMed1996

Photosensitivity in systemic lupus erythematosus: laboratory testing of ARA/ACR definition.

OBJECTIVE: The aim of our study was to evaluate the prevalence of photosensitivity in SLE as defined by either clinical or laboratory assessment, the concordance of findings obtained by two methods, and the relationship between photosensitivity and clinical and immunological parameters. METHODS: Forty-four SLE patients and 31 healthy subjects were included. Patients and controls underwent a standard questionnaire testing and the minimal erythemal dose (MED) measurement performed by Dermalight-Blue Point. The standard questionnaire was designed in order to meet, as near as possible, the definition of photosensitivity included in the ARA/ACR criteria for classification of SLE. RESULTS: The prevalence of photosensitivity was (patients vs controls): 57% vs 45% according to questionnaire; 79.5% vs 51.6% (P = 0.02) according to MED. The agreement between questionnaire and phototest was absent in SLE (kappa 0.01) and poor in controls (kappa 0.36). Discoid rash was significantly associated with questionnaire positive (P = 0.01) and renal involvement with questionnaire negative results (P = 0.02), serositis with MED abnormality (P = 0.03), malar rash and anti-Sm antibody with MED normal values (P = 0.03 and P = 0.01), respectively). Moreover, by multivariate analysis, malar rash and anti-Sm antibody significantly predicted MED-defined photosensitivity, with probability ranging from 42% (presence of both) to 92% (lack of both). CONCLUSIONS: Photosensitivity is frequently observed in SLE patients as well as in healthy subjects. Its prevalence is significantly higher in SLE than in controls only when it is detected using the laboratory method. However, due to the difficulty in objectively defining such manifestation, the disagreement between questionnaire and MED results was high and its clinical meaning appears ambiguous. Thus, the use of photosensitivity as a classification criterion for SLE remains questionable, at least when it is assessed according to the ARA/ACR definition.

Adolescent↗
PubMed1996

Codon 972 polymorphism in the insulin receptor substrate-1 gene, obesity, and risk of noninsulin-dependent diabetes mellitus.

Because of the role of insulin receptor substrate-1 in insulin action, the insulin receptor substrate-1 gene is a candidate gene for noninsulin-dependent diabetes mellitus (NIDDM). Modest associations between NIDDM and a GGG-->AGG single base substitution (corresponding to a glycine-->arginine amino acid substitution) in codon 972 of the gene have been found, but none reached statistical significance. To examine further how large a proportion of NIDDM cases could be caused by the mutation, we performed a stratified analysis combining the results from the 6 earlier studies and those from our panel of 192 unrelated NIDDM subjects and 104 healthy controls. In addition, we looked for a possibility that the codon 972 mutation plays a role only in the presence of certain conditions. Genomic DNA samples obtained from NIDDM cases and healthy controls were genotyped using a PCR-restriction fragment length polymorphism protocol modified for genomic DNA. The GGG-->AGG substitution was found in 5.7% of the diabetic subjects (11 of 192) and 6.9% of the controls (7 of 104). The difference between groups was not statistically significant, and it was not different from the results of other studies. The Mantel-Haenszel summary odds ratio across all studies was 1.49 (P < 0.05; 95% confidence intervals, 1.01-2.2). This summary odds ratio is consistent with a small proportion of NIDDM cases (approximately 3%) being caused by the mutation. Exploratory subgroup analyses on our panel suggested a clustering of NIDDM, the codon 972 mutation, and overweight, raising the hypothesis that the mutation may predispose to NIDDM only in the presence of excess body weight.

Adult↗
PubMed1995

Fibrinolysis and coagulation abnormalities in systemic lupus erythematosus. Relationship with Raynaud's phenomenon, disease activity, inflammatory indices, anticardiolipin antibodies and corticosteroid therapy.

Endothelial cell damage in systemic lupus erythematosus (SLE) was evaluated by measuring fibrinolytic activity and von Willebrand factor levels. Tissue-type plasminogen activator (t-PA) antigen, plasminogen activator inhibitor (PAI) activity, and von Willebrand factor antigen (vWF:Ag) and activity (vWF:RCof) were measured in 21 SLE patients (12 of whom were therapy free) and 22 controls. In addition, the relationship between such parameters and Raynaud's phenomenon, disease activity [according to personal criteria, Systemic Lupus Activity Measure (SLAM) and European Consensus Lupus Activity Measurement (ECLAM) scores] inflammatory indices [ESR, C-reactive protein (CRP), alpha 2-globulin], anticardiolipin antibodies and corticosteroid therapy was investigated. Lower levels of t-PA antigen (P = 0.003) and higher levels of vWF:Ag (P = 0.001) were found in SLE patients in comparison with controls. Moreover, t-PA antigen was lower (P = 0.02) in steroid-free patients in comparison with those taking steroids. No relationship was found between fibrinolysis and coagulation abnormalities and Raynaud's phenomenon, disease activity, inflammatory indices and anticardiolipin antibodies. Endothelial cell damage is probably a common feature in SLE patients; nevertheless, we were unable to clarify the nature of such abnormality. It is worth noting that low doses of steroids seem to be effective in improving endothelial cell function in SLE patients.

Adolescent↗
PubMed1995

Activity and expression of the Na+/H+ exchanger in human endothelial cells cultured in high glucose.

Establishing whether high ambient glucose affects the plasma membrane Na+/H+ exchanger is relevant to understanding the adverse effects of high glucose on cell replication and the mechanisms of the increased exchanger activity encountered in diabetic patients with nephropathy. In 8 primary and 15 first-passage isolates of human endothelial cells cultured in 30 mmol/l glucose for 8.7 +/- 2.3 and 15.8 +/- 2.3 days, respectively, we determined Na+/H+ exchanger activity and mRNA levels. Activity was determined by measuring 22Na+ influx in the presence or absence of dimethylamiloride (DMA) after intracellular acidification. We also measured fibronectin mRNA because fibronectin provides signals for cell replication through the Na+/H+ antiporter. Control cells grown in 5 mmol/l glucose showed at morphologic confluency a total Na+ influx (in nmol.mg protein-1.min-1) of 10.1 +/- 3.2 in primary and 11.7 +/- 2.2 in first subculture, which was reduced to 5.3 +/- 0.3 in the presence of DMA. Paired cultures exposed to 30 mmol/l glucose and exhibiting pHi and cell densities identical to controls showed in both primary and first subculture a reduction in total Na+ influx (delta = -0.98 +/- 0.93 nmol.mg protein-1.min-1 p < 0.005) whereas DMA-resistant Na+ influx was identical to that of control. Neither chronic hypertonicity nor acute exposure to high glucose mimicked the effects of chronic high glucose. The level of the Na+/H+ exchanger isoform 1 (NHE-1) mRNA was unchanged by high glucose whereas fibronectin mRNA levels were increased 1.5-fold.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiloride↗
PubMed1995

Trinucleotide repeats at the rad locus. Allele distributions in NIDDM and mapping to a 3-cM region on chromosome 16q.

A 10-allele polymorphism was identified in rad (ras associated with diabetes), a gene that is overexpressed in non-insulin-dependent diabetes mellitus (NIDDM) muscle. The polymorphism, designated RAD1, consists of a variable number of trinucleotide repeats (GTT and ATT) located in the poly(A) region of an intronic Alu sequence. Based on the number of GTT and ATT repetitions, the alleles can be grouped into four classes (I-IV). RAD1 allele frequencies were determined in 210 NIDDM patients and 133 nondiabetic control subjects, all Caucasians. One allele (number 8, class III) accounted for > 80% of the chromosomes in both groups. However, an excess of minor alleles, all belonging to class I, II, or IV, was observed among NIDDM chromosomes (P < 0.025), suggesting a possible association between RAD1 and NIDDM predisposition. To promote further studies to test the hypothesis that genetic variability at the rad locus contributes to NIDDM, we mapped rad on the human genome. Using the fluorescence in situ chromosomal hybridization technique, rad was unequivocally assigned to chromosomal band 16q22. In families that were informative for RAD1, the rad locus was mapped within a 3-cM region defined by the markers D16S265, D16S186, and D16S397 (logarithm of odds scores = 10.08, 10.9, and 10.84 at recombination fractions of 0.024, 0.001, and 0.03, respectively). The high degree of heterozygosity of these markers will allow large-scale family studies to be performed to test the presence of linkage between rad and NIDDM.

Alleles↗