Partial remission in Brazilian children and adolescents with type 1 diabetes. Association with a haplotype of class II human leukocyte antigen and synthesis of autoantibodies.

OBJECTIVE: Characterization of partial remission using the insulin dose-adjusted HbA1c (IDAA1c) ≤ 9 definition in a multiethnic Brazilian population of children and adolescents with type 1 diabetes (T1D), in addition with the determination of both Class II HLA genotype and autoantibodies. METHODS: We analyzed the prevalence of partial remission in 51 new-onset T1D patients with a median time follow-up of 13 months from diagnosis. For this study, anti-GAD65, anti-IA2 and HLA class II genotyping were considered. RESULTS: Partial remission occurred in 41.2% of T1D patients until 3 months after diagnosis, mainly in those aged 5-15 years. We have demonstrated a significant increase in the haplotypes of class II HLA DRB1*0301-DQB1*0201 in children and adolescents with a partial remission phase of the disease (42.9% vs 21.7% in non-remitters, P = .0291). This haplotype was also associated with the reduction of anti-IA2 antibodies production. Homozygote DRB1*03-DQB1*0201/DRB1*03-DQB1*0201 children had the lowest prevalence of IA-2A antibodies (P = .0402). However, this association does not correlate with the time of the remission phase. CONCLUSION: Although the number of patients studied was reduced, our data suggested that the association between genetics and decrease in antibody production to certain islet auto-antigen may contribute, at least in part, to the remission phase of T1D.

Linkage disequilibrium with HLA-DRB1-DQB1 haplotypes explains the association of TNF-308G>A variant with type 1 diabetes in a Brazilian cohort.

BACKGROUND: A functional variant in the promoter region of the gene encoding tumor necrosis factor (TNF; rs1800629, -308G>A) showed to confer susceptibility to T1D. However, TNF rs1800629 was found, in several populations, to be in linkage disequilibrium with HLA susceptibility haplotypes to T1D. We evaluated the association of TNF rs1800629 with T1D in a cohort of Brazilian subjects, and assessed the impact of HLA susceptibility haplotypes in this association. METHODS: 659 subjects with T1D and 539 control subjects were genotyped for TNF-308G>A variant. HLA-DRB1 and HLA-DQB1 genes were genotyped in a subset of 313 subjects with T1D and 139 control subjects. RESULTS: Associations with T1D were observed for the A-allele of rs1800629 (OR 1.69, 95% CI 1.33-2.15, p<0.0001, in a codominant model) and for 3 HLA haplotypes: DRB1*03:01-DQB1*02:01 (OR 5.37, 95% CI 3.23-8.59, p<0.0001), DRB1*04:01-DQB1*03:02 (OR 2.95, 95% CI 1.21-7.21, p=0.01) and DRB1*04:02-DQB1*03:02 (OR 2.14, 95% CI 1.02-4.50, p=0.04). Linkage disequilibrium was observed between TNF rs1800629 and HLA-DRB1 and HLA-DQB1 alleles. In a stepwise regression analysis HLA haplotypes, but not TNF rs1800629, remained independently associated with T1D. CONCLUSION: Our results do not support an independent effect of allelic variations of TNF in the genetic susceptibility to T1D.

Thyroid imaging reporting and data system score combined with Bethesda system for malignancy risk stratification in thyroid nodules with indeterminate results on cytology.

CONTEXT: The thyroid imaging reporting and data system (TI-RADS) was designed to better select patients who had undergone fine-needle aspiration biopsies (FNABs) with high sensitivity and accuracy. However, the combination of TI-RADS scores and Bethesda system categories in indeterminate thyroid nodules has not been examined extensively. OBJECTIVE: This study aimed to stratify indeterminate thyroid nodules (Bethesda categories III, IV and V) according to risk of malignancy as determined by combining TI-RADS score with Bethesda system classification. DESIGN: Retrospective study. Histopathological, cytological and ultrasound (US) data were available for 242 cases after surgery, including 136 indeterminate nodules. METHODS: All thyroid cytopathological slides and US reports were reviewed and classified according to Bethesda system and TI-RADS categories. The malignancy rate was determined for each Bethesda category, TI-RADS score and both methods combined of indeterminate nodules. RESULTS: The malignancy rates were 8·7%, 51·3% and 67·5% for Bethesda categories III, IV and V, respectively. Based on histopathological comparison, the accuracy was 66·7% for TI-RADS greyscale. TI-RADS 3 and 4A scores were observed in 80% of Bethesda III cases, which led to 80% sensitivity and 90% of negative predictive value (NPV). In contrast, for nodules scored as TI-RADS 4B and 5, the combined cytological results of Bethesda IV and V resulted in a higher risk of malignancy (75% and 76·9%, respectively, P < 0·001). CONCLUSIONS: In view of the high NPV of TI-RADS 3/4A only in Bethesda III category, a surgical approach could be considered for lesions defined as Bethesda III, IV and V when TI-RADS 4B and 5 were concomitant.

Catalase activity, allelic variations in the catalase gene and risk of kidney complications in patients with type 1 diabetes.

AIMS/HYPOTHESIS: Oxidative stress is involved in the pathogenesis of diabetic nephropathy. The antioxidant enzyme catalase plays a key role in redox regulation in the kidney. We investigated associations of catalase gene (CAT) polymorphisms and plasma catalase activity with diabetic nephropathy in type 1 diabetic patients. METHODS: We genotyped nine single nucleotide polymorphisms (SNPs) in the CAT region in participants from the Survival Genetic Nephropathy (SURGENE) (340 French participants, 10 year follow-up) and the Génétique de la Néphropathie Diabétique (GENEDIAB) (444 Belgian and French participants, 8 year follow-up) study cohorts. Replication was performed in a Brazilian cross-sectional cohort (n = 451). Baseline plasma catalase activity was measured in SURGENE (n = 120) and GENEDIAB (n = 391) participants. RESULTS: The A allele of rs7947841 was associated with the prevalence of incipient (OR 2.79, 95% CI 1.21, 6.24, p = 0.01) and established or advanced nephropathy (OR 5.72, 95% CI 1.62, 22.03, p = 0.007), and with the incidence of renal events, which were defined as new cases of microalbuminuria or progression to a more severe stage of nephropathy during follow-up (HR 1.82, 95% CI 1.13, 2.81, p = 0.01) in SURGENE participants. The same risk allele was associated with incipient nephropathy (OR 3.13, 95% CI 1.42, 7.24, p = 0.004) and with the incidence of end-stage renal disease (ESRD) (HR 2.11, 95% CI 1.23, 3.60, p = 0.008) in GENEDIAB participants. In both cohorts, the risk allele was associated with lower catalase activity. Associations with incipient and established or advanced nephropathy were confirmed in the replication cohort. CONCLUSIONS/INTERPRETATION: CAT variants were associated with the prevalence and incidence of diabetic nephropathy and ESRD in type 1 diabetic patients. Our results confirm the protective role of catalase against oxidative stress in the kidney.

Association of genetic variants in the promoter region of genes encoding p22phox (CYBA) and glutamate cysteine ligase catalytic subunit (GCLC) and renal disease in patients with type 1 diabetes mellitus.

BACKGROUND: Oxidative stress is recognized as a major pathogenic factor of cellular damage caused by hyperglycemia. NOX/NADPH oxidases generate reactive oxygen species and NOX1, NOX2 and NOX4 isoforms are expressed in kidney and require association with subunit p22phox (encoded by the CYBA gene). Increased expression of p22phox was described in animal models of diabetic nephropathy. In the opposite direction, glutathione is one of the main endogenous antioxidants whose plasmatic concentrations were reported to be reduced in diabetes patients. The aim of the present investigation was to test whether functional single nucleotide polymorphisms (SNPs) in genes involved in the generation of NADPH-dependent O2•⁻ (-675 T → A in CYBA, unregistered) and in glutathione metabolism (-129 C → T in GCLC [rs17883901] and -65 T → C in GPX3 [rs8177412]) confer susceptibility to renal disease in type 1 diabetes patients. METHODS: 401 patients were sorted into two groups according to the presence (n = 104) or absence (n = 196) of overt diabetic nephropathy or according to glomerular filtration rate (GFR) estimated by Modification of Diet in Renal Disease (MDRD) equation: ≥ 60 mL (n = 265) or < 60 mL/min/1.73 m² (n = 136) and were genotyped. RESULTS: No differences were found in the frequency of genotypes between diabetic and non-diabetic subjects. The frequency of GFR < 60 mL/min was significantly lower in the group of patients carrying CYBA genotypes T/A+A/A (18.7%) than in the group carrying the T/T genotype (35.3%) (P = 0.0143) and the frequency of GFR < 60 mL/min was significantly higher in the group of patients carrying GCLC genotypes C/T+T/T (47.1%) than in the group carrying the C/C genotype (31.1%) (p = 0.0082). Logistic regression analysis identified the presence of at least one A allele of the CYBA SNP as an independent protection factor against decreased GFR (OR = 0.38, CI95% 0.14-0.88, p = 0.0354) and the presence of at least one T allele of the GCLC rs17883901 SNP as an independent risk factor for decreased GFR (OR = 2.40, CI95% 1.27-4.56, p = 0.0068). CONCLUSIONS: The functional SNPs CYBA -675 T → A and GCLC rs17883901, probably associated with cellular redox imbalances, modulate the risk for renal disease in the studied population of type 1 diabetes patients and require validation in additional cohorts.

Value of ultrasound and cytological classification system to predict the malignancy of thyroid nodules with indeterminate cytology.

Although fine-needle aspiration cytology is considered the gold standard for evaluating thyroid nodules, in about 10-30% of the cases, cytology is indeterminate. This study aimed to determine the value of cytological classification system and ultrasound (US) to predict malignancy in indeterminate thyroid nodule. This retrospective analysis enrolled 80 patients surgically treated at a single center, 75% (60) with benign vs. 25% (20) with malignant lesions at final histology. The clinical, scintigraphic, sonographic, and cytological classification (Bethesda) variables were analyzed in these selected cases of indeterminate cytology, and a prediction model was designed after the multivariate analysis. There was a 25% prevalence of malignancy (20/80). There were no differences in gender, serum thyroid-stimulating hormone and FT4 levels, thyroid auto-antibodies, thyroid dysfunction, and scintigraphic results between benign and malignant nodule groups. The border irregularity in sonographic study was at increased risk for malignancy. The cytological analysis based on Bethesda System (category IV) was an independent predictor for malignancy in indeterminate thyroid nodules. After the multivariate analysis, the model obtained showed border irregularity and Bethesda System category IV as predictive factors of malignancy in indeterminate thyroid nodules, featuring 76.9% of accuracy. This study confirmed a significant increase of risk for malignancy in thyroid nodules with indeterminate cytology showing Bethesda System category IV and suspicious features at US. These findings enhance our current limited predictive armamentarium and can be used to guide surgical decision making.

Value of repeat ultrasound-guided fine-needle aspiration in thyroid nodule with a first benign cytologic result: impact of ultrasound to predict malignancy.

This study aimed to investigate the value of repeat ultrasound-guided fine-needle aspiration (FNAC-US) in benign thyroid nodules and determine the ultrasound (US) predictors of malignancy in this group of nodules. The authors studied 35 of 143 nodules with initially benign cytological result who underwent serial re-biopsy (FNAC-US). By means of surgery, malignancy histology results were confirmed in 10 (28.5%) cases (G1) versus 25 (71.5%) benign nodules (G2). The clinical, lab, scintigraphyc, and US features were compared between the two groups to predict malignancy in thyroid nodules with initially benign cytological result. The cytological finding of 28/35 nodules were change to indeterminate cytology (Bethesda system category III or IV) at second and/or ≥third cytological study. In this group of 28 cases, 23 (82.1%) was identified until the third procedure. The interval between first and third re-biopsy was 13 months (median). There were no differences in age, gender, thyrotropin (TSH) levels, thyroid auto-antibodies, or thyroid dysfunctions. The scintigraphy showed cold nodule in 80% of G1 versus 78.9% of G2 (NS). Sonographic studies showed malignant suspected US features in G1: microcalcifications, central flow, hypoechogenicity, and border irregularity. This study suggests repeating FNAC-US in nodules with first benign cytologic result and suspicious US features of malignancy for at least two times (until the third FNAC) in about 13 months horizon.

Role of ultrasound, clinical and scintigraphyc parameters to predict malignancy in thyroid nodule.

BACKGROUND: This study aimed to evaluate clinical, laboratory, ultrasound (US) and scintigraphyc parameters in thyroid nodule and to develop an auxiliary model for clinical application in the diagnosis of malignancy. METHODS: We assessed 143 patients who were surgically treated at a single center, 65% (93) benign vs. 35% (50) malignant lesions at final histology (1998-2008). The clinical, laboratory, scintigraphyc and US features were compared and a prediction model was designed after the multivariate analysis. RESULTS: There were no differences in gender, serum TSH and FT4 levels, thyroid auto-antibodies (TAb), thyroid dysfunction and scintigraphyc results (P=0.33) between benign and malignant nodule groups. The sonographic study showed differences when the presence of suspected characteristics was found in the nodules of the malignant lesions group, such as: microcalcifications, central flow, border irregularity and hypoechogenicity. After the multivariate analysis the model obtained showed age (>39 years), border irregularity, microcalcifications and nodule size over 2 cm as predictive factors of malignancy, featuring 81.7% of accuracy. CONCLUSIONS: This study confirmed a significant increase of risk for malignancy in patients of over 39 years and with suspicious features at US.

Comparison of three systems of classification in predicting the outcome of diabetic foot ulcers in a Brazilian population.

OBJECTIVE: The aim was to compare three ulcer classification systems as predictors of the outcome of diabetic foot ulcers: the Wagner, the University of Texas (UT) and the size (area, depth), sepsis, arteriopathy, denervation system (S(AD)SAD) systems in a specialist clinic in Brazil. METHODS: Ulcer area, depth, appearance, infection and associated ischaemia and neuropathy were recorded in a consecutive series of 94 subjects. A novel score, the S(AD)SAD score, was derived from the sum of individual items of the S(AD)SAD system, and was evaluated. Follow-up was for at least 6 months. The primary outcome measure was the incidence of healing. RESULTS: Mean age was 57.6 years; 57 (60.6%) were male. Forty-eight ulcers (51.1%) healed without surgery; 11 (12.2%) subjects underwent minor amputation. Significant differences in terms of healing were observed for depth (P=0.002), infection (P=0.006) and denervation (P=0.002) using the S(AD)SAD system, for UT grade (P=0.002) and stage (P=0.032) and for Wagner grades (P=0.002). Ulcers with an S(AD)SAD score of or=10 (P<0.001). CONCLUSIONS: All three systems predicted ulcer outcome. The S(AD)SAD score of ulcer severity could represent a useful addition to routine clinical practice. The association between outcome and ulcer depth confirms earlier reports. The association with infection was stronger than that reported from the centres in Europe or North America. The very strong association with neuropathy has only previously been observed in Tanzania. Studies designed to compare the outcome in different countries should adopt systems of classification, which are valid for the populations studied.