Idiopathic Hypocomplementaemic Tubulointerstitial Nephritis

Background: Tubulointerstitial nephritis (TIN) is a common cause of kidney injury typically seen in association with drug exposure, infection or autoimmune diseases. However, TIN with interstitial immune complex deposition, without glomerular injury, is rarely observed. Case: We report a case of a 64-yearold Indian woman admitted for dialysis-requiring renal failure, without involvement of other organs. Urinalysis showed blood 3+ and 24h proteinuria of 1.5 g. Renal ultrasound revealed normal sized kidneys with loss of parenchymal-sinus differentiation. Laboratory tests disclosed low C3, positive ANA but negative anti-dsDNA, SSA and SSB. Serum protein electrophoresis was normal. The renal biopsy showed tubulointerstitial nephritis with positive immunoglobulin staining involving the interstitium and tubular basement membrane with glomerular sparing. The patient started prednisolone (1mg/kg/day) without recovery of the renal function. Conclusion: Idiopathic hypocomplementaemic tubulointerstitial nephritis is a rare disease with few cases described in the literature. To our knowledge this is the first case reported in Portugal.

Novel FGFR1 Mutations in Kallmann Syndrome and Normosmic Idiopathic Hypogonadotropic Hypogonadism: Evidence for the Involvement of an Alternatively Spliced Isoform

OBJECTIVE: To determine the prevalence of fibroblast growth factor receptor 1 (FGFR1) mutations and their predicted functional consequences in patients with idiopathic hypogonadotropic hypogonadism (IHH). DESIGN: Cross-sectional study. SETTING: Multicentric. PATIENT(S): Fifty unrelated patients with IHH (21 with Kallmann syndrome and 29 with normosmic IHH). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Patients were screened for mutations in FGFR1. The functional consequences of mutations were predicted by in silico structural and conservation analysis. RESULT(S): Heterozygous FGFR1 mutations were identified in six (12%) kindreds. These consisted of frameshift mutations (p.Pro33-Alafs*17 and p.Tyr654*) and missense mutations in the signal peptide (p.Trp4Cys), in the D1 extracellular domain (p.Ser96Cys) and in the cytoplasmic tyrosine kinase domain (p.Met719Val). A missense mutation was identified in the alternatively spliced exon 8A (p.Ala353Thr) that exclusively affects the D3 extracellular domain of FGFR1 isoform IIIb. Structure-based and sequence-based prediction methods and the absence of these variants in 200 normal controls were all consistent with a critical role for the mutations in the activity of the receptor. Oligogenic inheritance (FGFR1/CHD7/PROKR2) was found in one patient. CONCLUSION(S): Two FGFR1 isoforms, IIIb and IIIc, result from alternative splicing of exons 8A and 8B, respectively. Loss-of-function of isoform IIIc is a cause of IHH, whereas isoform IIIb is thought to be redundant. Ours is the first report of normosmic IHH associated with a mutation in the alternatively spliced exon 8A and suggests that this disorder can be caused by defects in either of the two alternatively spliced FGFR1 isoforms.

Reinfections with strains of Trypanosoma cruzi, of different biodemes as a factor of aggravation of myocarditis and myositis in mice

Reinfections with Trypanosoma cruzi in patients from endemic areas have been claimed to be an aggravation factor of cardiac manifestations in Chagas' disease. In the present study, the influence of triple infections with strains of different biodemes, on cardiac and skeletal muscle lesions was experimentally tested. Fifty eight mice chronically infected with the Colombian strain (Biodeme Type III) were successively reinfected as follows: 1st group - reinfected with 21 SF strain (Type II) followed by Y strain (Type I ); 2nd - group reinfections with Y strain followed by 21SF strain. Isoenzyme analysis of parasites from hemocultures obtained from triple infected mice, revealed the patterns of three distinct zymodemes in the same animal. Each Trypanosoma cruzi strain was reisolated after four passages in mice on either the 7th, 14th or 30th day after inoculation with the blood of triple infected mice. Histopathology results demonstrated a significant exacerbation of cardiac and skeletal muscle inflammatory lesions, confirmed by morphometric evaluation, in mice with triple infection. No aggravation of parasitism was detected. The possibility of an enhancement of cellular response in the triple infected mice is suggested.

Dental and facial characteristics of patients with juvenile idiopathic arthritis

OBJECTIVE: It has been shown that the temporomandibular joint is frequently affected by juvenile idiopathic arthritis, and this degenerative disease, which may occur during facial growth, results in severe mandibular dysfunction. However, there are no studies that correlate oral health (tooth decay and gingival diseases) and temporomandibular joint dysfunction in patients with juvenile idiopathic arthritis. The aim of this study is to evaluate the oral and facial characteristics of the patients with juvenile idiopathic arthritis treated in a large teaching hospital. METHOD: Thirty-six patients with juvenile idiopathic arthritis (26 female and 10 male) underwent a systematic clinical evaluation of their dental, oral, and facial structures (DMFT index, plaque and gingival bleeding index, dental relationship, facial profile, and Helkimo's index). The control group was composed of 13 healthy children. RESULTS: The mean age of the patients with juvenile idiopathic arthritis was 10.8 years; convex facial profile was present in 12 juvenile idiopathic arthritis patients, and class II molar relation was present in 12 (P = .032). The indexes of plaque and gingival bleeding were significant in juvenile idiopathic arthritis patients with a higher number of superior limbs joints involved (P = .055). Anterior open bite (5) and temporomandibular joint noise (8) were present in the juvenile idiopathic arthritis group. Of the group in this sample, 94% (P = .017) had temporomandibular joint dysfunction, 80% had decreased mandibular opening (P = 0.0002), and mandibular mobility was severely impaired in 33% (P = .015). CONCLUSION: This study confirms that patients with juvenile idiopathic arthritis a) have a high incidence of mandibular dysfunction that can be attributed to the direct effect of the disease in the temporomandibular joint and b) have a higher incidence of gingival disease that can be considered a secondary effect of juvenile idiopathic arthritis on oral health.

Susceptibility and prognostic factors in portuguese patients with juvenile idiopathic arthritis

ABSTRACT: Objectives: This study aimed to confirm whether 15 single nucleotide polymorphisms (SNPs) of selected genes are also associated with susceptibility for Juvenile idiopathic Arthritis (JIA) in thePortuguese population. Methods: Our study was conducted on Reuma.pt, the Rheumatic Diseases Portuguese Register, which includes patients with JIA receiving biological therapies and synthetic Disease Modifying Anti Rheumatic Drugs (DMARDs) since June 2001. Fifteen SNPs were investigated using Taqman® SNP genotyping assays in 291 Portuguese patients with JIA and 300 ethnically matched healthy controls. Results: Prior to Bonferroni correction for multiple testing, significant genotype association between one SNP and overall group of JIA was observed (PTPN22 rs2476601). In subgroup analysis, associations between six SNPs and the subgroup of patients with rheumatoid factor (RF)-positive Polyarticular (PTPN2 rs7234029), Extended oligoarticular (PTPN22 rs2476601), Systemic (PTPRC rs10919563, ANGPT1 rs7151781 and TNF rs361525) and Psoriatic JIA (IL2RA/CD25 rs2104286) were found. After Bonferroni correction for multiple testing, 3 genotype associations remained significant in the subgroup of patients with RF-positive polyarticular JIA (PTPN2 rs7234029 [corrected P 0.026]), extended oligoarticular (PTPN22 rs2476601 [corrected P 0.026]) and systemic JIA (ANGPT1 rs7151781 [corrected P 0.039]). Conclusion: Our results provide additional evidence for an association between polymorphisms in genes PTPN2, PTPN22 and ANGPT1 and the risk of RF-positive polyarticular, extended oligoarticular and systemic JIA, respectively, in a Portuguese population.

Influence of nephrotic state on the infectious profile in childhood idiopathic nephrotic syndrome

Patients with idiopathic nephrotic syndrome present alterations in their cellular and humoral immune reactions that predispose them to the development of infectious processes. PURPOSE: To characterize the infectious processes in patients with idiopathic nephrotic syndrome. PATIENTS AND METHODS: Ninety-two children and adolescents with idiopathic nephrotic syndrome were assessed retrospectively. The types of infection were grouped as follows: upper respiratory tract infections; pneumonia; skin infections; peritonitis; diarrhea; urinary tract infection ; herpes virus; and others. The patients were divided into 2 groups: Group I (steroid-responsive) n = 75, with 4 subgroups-IA (single episode) n = 10, IB (infrequent relapsers) n = 5, IC (frequent relapsers) n = 14, and ID (steroid-dependent) n = 46; and Group II (steroid-resistant) n = 17. The incidence-density of infection among the patients was assessed throughout the follow-up period. Comparisons for each group and subgroup were done during the periods of negative and nephrotic proteinuria. RESULTS: The analysis revealed a greater incidence-density of infections during the period of nephrotic proteinuria in all the groups and subgroups, with the exception of subgroup IA. During the period of nephrotic proteinuria, subgroups IC, ID, and Group II presented a greater incidence-density of infections as compared to subgroup IA. For the period of negative proteinuria, there was no difference in the incidence-density of infections between the groups and subgroups. Upper respiratory tract infections were the most frequent infectious processes. CONCLUSION: The nephrotic condition, whether as part of a course of frequent relapses, steroid dependence, or steroid resistance, conferred greater susceptibility to infection among the patients with idiopathic nephrotic syndrome. The results of this study suggest that the best preventive action against infection in this disease is to control the nephrotic state.

Thiamin, selenium, and copper levels in patients with idiopathic dilated cardiomyopathy taking diuretics

OBJECTIVE: To analyze the association of thiamin, selenium, and copper serum levels with cardiac function in patients with idiopathic dilated cardiomyopathy using diuretics, and also to compare them with levels in control patients with no evidence of disease. METHODS: The study comprised 30 patients with heart disease and 30 healthy control individuals. Thiamin was analyzed by measuring the activity of erythrocytic transketolase and the effect of thiamin pyrophosphate. Selenium and copper serum levels were measured by hydride generation and flame atomic absorption spectrophotometry, respectively. RESULTS: Thiamin deficiency was observed in 10% of the control individuals and in 33% of the patients with heart disease (p=0.02). The mean selenium and copper serum levels in control individuals and patients with heart disease were, respectively, 73.2±9.9 µg/L (56.5 to 94.5 µg/L) and 72.3±14.3 µg/L (35.5 to 94 µg/L) (p=0.77); 1.1±0.4mg/L (0.6 to 1.8mg/L) and 1.2± 0.4mg/L (0.6 to 2.2mg/L) (p=0.27). No association between the levels of these nutrients and cardiac function was observed. CONCLUSION: Thiamin deficiency was significantly more frequent in patients with heart disease. No significant difference was observed between the mean selenium and copper serum levels in control individuals and in patients with heart disease. The results suggest possible benefits with thiamin replacement in patients taking diuretics.

Autologous Transplantation of Bone Marrow Adult Stem Cells for the Treatment of Idiopathic Dilated Cardiomyopathy

Background:Morbimortality in patients with dilated idiopathic cardiomyopathy is high, even under optimal medical treatment. Autologous infusion of bone marrow adult stem cells has shown promising preliminary results in these patients.Objective:Determine the effectiveness of autologous transplantation of bone marrow adult stem cells on systolic and diastolic left ventricular function, and on the degree of mitral regurgitation in patients with dilated idiopathic cardiomyopathy in functional classes NYHA II and III.Methods:We administered 4,54 x 108 ± 0,89 x 108 bone marrow adult stem cells into the coronary arteries of 24 patients with dilated idiopathic cardiomyopathy in functional classes NYHA II and III. Changes in functional class, systolic and diastolic left ventricular function and degree of mitral regurgitation were assessed after 3 months, 6 months and 1 year.Results:During follow-up, six patients (25%) improved functional class and eight (33.3%) kept stable. Left ventricular ejection fraction improved 8.9%, 9.7% e 13.6%, after 3, 6 and 12 months (p = 0.024; 0.017 and 0.018), respectively. There were no significant changes neither in diastolic left ventricular function nor in mitral regurgitation degree. A combined cardiac resynchronization and implantable cardioversion defibrillation was implanted in two patients (8.3%). Four patients (16.6%) had sudden death and four patients died due to terminal cardiac failure. Average survival of these eight patients was 2.6 years.Conclusion:Intracoronary infusion of bone marrow adult stem cells was associated with an improvement or stabilization of functional class and an improvement in left ventricular ejection fraction, suggesting the efficacy of this intervention. There were no significant changes neither in left ventricular diastolic function nor in the degree of mitral regurgitation.

Functional Class in Children with Idiopathic Dilated Cardiomyopathy. A pilot Study

Abstract Background: Idiopathic dilated cardiomyopathy (IDCM), most common cardiac cause of pediatric deaths, mortality descriptor: a low left ventricular ejection fraction (LVEF) and low functional capacity (FC). FC is never self reported by children. Objective: The aims of this study were (i) To evaluate whether functional classifications according to the children, parents and medical staff were associated. (iv) To evaluate whether there was correlation between VO2 max and Weber's classification. Method: Prepubertal children with IDCM and HF (by previous IDCM and preserved LVEF) were selected, evaluated and compared. All children were assessed by testing, CPET and functional class classification. Results: Chi-square test showed association between a CFm and CFp (1, n = 31) = 20.6; p = 0.002. There was no significant association between CFp and CFc (1, n = 31) = 6.7; p = 0.4. CFm and CFc were not associated as well (1, n = 31) = 1.7; p = 0.8. Weber's classification was associated to CFm (1, n = 19) = 11.8; p = 0.003, to CFp (1, n = 19) = 20.4; p = 0.0001and CFc (1, n = 19) = 6.4; p = 0.04). Conclusion: Drawing were helpful for children's self NYHA classification, which were associated to Weber's stratification.

Pneumopathies interstitielles diffuses idiopathiques [Idiopathic interstitial pneumonias].

Idiopathic interstitial pneumonias represent approximately 30% of all interstitial lung diseases. The new classification of idiopathic interstitial pneumonias published in 2013 distinguishes 6 major entities, including chronic fibrosing forms (idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia), acute/subacute forms (cryptogenic organizing pneumonia and acute interstitial pneumonia) and smoking-related disorders (respiratory bronchiolitis interstitial lung disease and desquamative interstitial pneumonia). Pleuroparenchymal fibroelastosis is individualized as a new rare clinco-pathologic entity. For cases not fitting any specific clinic- pathological category, a pragmatic classification based on disease behavior is proposed.

Morphological aspects of the myocarditis and myositis in Calomys callosus experimentally infected with Trypanosoma cruzi: fibrogenesis and spontaneous regression of fibrosis

Calomys callosus a wild rodent, is a natural host of Trypanosoma cruzi. Twelve C. callosus were infected with 10(5) trypomastigotes of the F strain (a myotropic strain) of T. cruzi. Parasitemia decreased on the 21 st day becoming negative around the 40th day of infection. All animals survived but had positive parasitological tests, until the end of the experiment. The infected animals developed severe inflammation in the myocardium and skeletal muscle. This process was pronounced from the 26 th to the 30th day and gradually subsided from the 50 th day becoming absent or residual on the 64 th day after infection. Collagen was identified by the picro Sirius red method. Fibrogenesis developed early, but regression of fibrosis occurred between the 50th and 64th day. Ultrastructural study disclosed a predominance of macrophages and fibroblasts in the inflammatory infiltrates, with small numbers of lymphocytes. Macrophages had active phagocytosis and showed points of contact with altered muscle cells. Different degrees of matrix expansion were present, with granular and fibrilar deposits and collagen bundles. These alterations subsided by the 64th days. Macrophages seem to be the main immune effector cell in the C. callosus model of infection with T. cruzi. The mechanisms involved in the rapid fibrogenesis and its regression deserve further investigation.

Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism.

Neuronal development is the result of a multitude of neural migrations, which require extensive cell-cell communication. These processes are modulated by extracellular matrix components, such as heparan sulfate (HS) polysaccharides. HS is molecularly complex as a result of nonrandom modifications of the sugar moieties, including sulfations in specific positions. We report here mutations in HS 6-O-sulfotransferase 1 (HS6ST1) in families with idiopathic hypogonadotropic hypogonadism (IHH). IHH manifests as incomplete or absent puberty and infertility as a result of defects in gonadotropin-releasing hormone neuron development or function. IHH-associated HS6ST1 mutations display reduced activity in vitro and in vivo, suggesting that HS6ST1 and the complex modifications of extracellular sugars are critical for normal development in humans. Genetic experiments in Caenorhabditis elegans reveal that HS cell-specifically regulates neural branching in vivo in concert with other IHH-associated genes, including kal-1, the FGF receptor, and FGF. These findings are consistent with a model in which KAL1 can act as a modulatory coligand with FGF to activate the FGF receptor in an HS-dependent manner.