Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome

Nephrotic syndrome (NS) represents the association of proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Steroid-resistant NS (SRNS) is defined by primary resistance to standard steroid therapy. It remains one of the most intractable causes of ESRD in the first two decades of life. Mutations in the NPHS2 gene represent a frequent cause of SRNS, occurring in approximately 20 to 30% of sporadic cases of SRNS. On the basis of a very small number of patients, it was suspected that children with homozygous or compound heterozygous mutations in NPHS2 might exhibit primary steroid resistance and a decreased risk of FSGS recurrence after kidney transplantation. To test this hypothesis, NPHS2 mutational analysis was performed with direct sequencing for 190 patients with SRNS from 165 different families and, as a control sample, 124 patients with steroid-sensitive NS from 120 families. Homozygous or compound heterozygous mutations in NPHS2 were detected for 43 of 165 SRNS families (26%). Conversely, no homozygous or compound heterozygous mutations in NPHS2 were observed for the 120 steroid-sensitive NS families. Recurrence of FSGS in a renal transplant was noted for seven of 20 patients with SRNS (35%) without NPHS2 mutations, whereas it occurred for only two of 24 patients with SRNS (8%) with homozygous or compound heterozygous mutations in NPHS2. None of 29 patients with homozygous or compound heterozygous mutations in NPHS2 who were treated with cyclosporine A or cyclophosphamide demonstrated complete remission of NS. It was concluded that patients with SRNS with homozygous or compound heterozygous mutations in NPHS2 do not respond to standard steroid treatment and have a reduced risk for recurrence of FSGS in a renal transplant. Because these findings might affect the treatment plan for childhood SRNS, it might be advisable to perform mutational analysis of NPHS2, if the patient consents, in parallel with the start of the first course of standard steroid therapy.     

Conversion and somatization disorders; dissociative symptoms and other characteristics

OBJECTIVE: There is a difference in classification of conversion disorder in ICD-10 and DSM-IV. Conversion disorder is included in dissociative disorders in ICD-10. In view of this, we aimed to clarify this discrepancy in the classification of this diagnosis. METHODS: We assessed 87 patients with conversion disorder and 71 patients with somatization disorder for sociodemographic characteristics, suicide ideation, psychiatric symptoms and dissociative symptoms using the Patient Information Form, the Dissociative Experience Scale (DES), the Symptom Check List (SCL-90-R) and the Suicide Ideation Scale. RESULTS: The number of the high school graduates, singles and students with conversion disorders was higher than the number of patients with the same characteristics who have somatization disorder. In conversion disorder, the SCL-90-R total score and the score in paranoid ideation, psychoticism subgroups were higher than the scores in somatization disorders. There were no statistical differences in suicide ideation and the total score of dissociative symptoms between the two disorders. The number of patients whose total DES score of 30 and above was higher in conversion disorders. DISCUSSION: As a result of this present study, we concluded that to enlighten the concepts of conversion, further somatization and dissociation studies are necessary.     

Tunnel enlargement after arthroscopic anterior cruciate ligament reconstruction: Comparison of bone-patellar tendon-bone and hamstring autografts

Bone tunnel enlargement associated with anterior cruciate ligament (ACL) reconstruction has recently become a topic of interest in the literature. This association was examined, along with the effect of femoral and tibial tunnel enlargement on the clinical results of ACL reconstruction performed with either bone-patellar tendon-bone (BPTB) or hamstring (HST) autografts. Forty-six patients underwent arthroscopic ACL reconstruction (23 receiving BPTB autograft and 23 HST) between March 1999 and July 2001. Thirty patients (13 receiving BPTB autograft and 17 HST) completed the last clinical and radiologic evaluations and were included in the study. The mean age of patients in the HST group was 29.8 years (range 18–39) and that in the BPTB group was 27.6 years (range 20–37). The mean follow-up period was 24.6 months (range 12–36) in HST group and 18.5 months (range 12–40) in BPTB group. The effect of tunnel enlargement on the clinical results was evaluated by comparing preoperative and postoperative Lysholm, Tegner, and International Knee Documentation Committee scores and ligament laxity measurements between and within the groups. Postoperative femoral and tibial tunnel diameters in both groups were significantly larger than their corresponding preoperative tunnel diameters. In an intergroup evaluation, the enlargement of the tibial tunnel was similar in both groups (P=.556), but the femoral tunnel diameter was significantly larger in the HST group than in the BPTB group (P>.001). Preoperative laxity of the knees significantly improved after the operations in both groups, but no difference between the groups was evident at the final follow-up visit. No correlation between tunnel widening and the clinical results of the BPTB and HST procedures was observed.     

Risk factors in community-acquired urinary tract infections caused by ESBL-producing bacteria in children

In this study, risk factors were investigated in children with community-acquired urinary tract infections (UTI) caused by extended-spectrum beta-lactamases (ESBL)-producing E. coli or Klebsiella spp. One hundred and fifty-five patients were diagnosed with ESBL-positive UTI (case group) in the outpatient clinics of Hacettepe University Children’s Hospital between 1 January 2004 and 31 December 2006. A control group, 155 out of 4,105 children, was matched by age and sex among children with ESBL-negative UTI. A total of 310 patients’ files were evaluated retrospectively. As regards the symptoms of UTI, no statistical differences were seen between the two groups. Although the most frequently isolated microorganism was E. coli in both groups, Klebsiella spp. was found to be more frequent in those diagnosed with ESBL(+) UTI (p?<?0.001). Having an underlying disease and hospitalization, infections, and use of antibiotics within the last 3 months were found to be potential risk factors (p?<?0.001). With conditional logistic regression analysis, having an underlying disease and hospitalization within the last 3 months were identified as independent risk factors for ESBL(+) UTI. In conclusion, the recognition of risk factors for UTI, caused by ESBL(+) bacteria in children, may aid in the identification of high-risk cases and may enable proper management of these patients.     

The use of low-dose cyclophosphamide followed by AZA/MMF treatment in childhood lupus nephritis

Cyclophosphamide (CYC) has been the landmark in the treatment of lupus nephritis. However, long-term treatment with CYC is associated with significant side effects. We aimed to evaluate the efficacy of short-term intravenous (IV) CYC treatment as a remission induction treatment followed by azathioprine (AZA) or mycophenolate mofetil (MMF) as a maintenance treatment. Twenty patients (18 girls) with biopsy-proven class III (5) and IV (15) lupus nephritis were included in to the study. Detailed clinical and laboratory data and patient outcomes were evaluated. All patients received three methylprednisolone (MP) IV pulses, followed by oral prednisone 0.5−1 mg/kg per day and one IV pulse of CYC per month for 6 months. Azathioprine was started as a remission-maintaining treatment. In ten of 20 patients, treatment was switched to MMF. The mean age at the time of diagnosis was 16.11 ± 3.49 years, and the mean duration of follow-up was 49.6 ± 27 months. Fourteen patients (70%) had complete remission, three (15%) had partial remission, one (5%) continued to have active disease, and two (10%) progressed to end-stage renal disease. Nine of the patients (45%) with complete remission had received AZA, and switching to MMF increased complete remission rate (additional five patients; 25%). In conclusion, short-term (6-month) IV bolus CYC treatment followed by AZA is a safe and effective treatment in children with severe lupus nephritis, and using MMF increases remission rate in resistant cases.     

Assessment of alveolar epithelial permeability with Tc-99m DTPA aerosol scintigraphy in patients with Sjogren syndrome

Sjögren’s syndrome (SjS) is a systemic autoimmune disease that mainly affects the exocrine glands and usually presents as persistent dryness of the mouth and eyes. Lung disease in SjS has been reported to occur early following clinical presentation of the disease. In this study, technetium-99m diethylene triamine penta-acetic acid (Tc-99m DTPA) aerosol inhalation scintigraphy was used to assess the pulmonary membrane permeability in patients with primary SjS. A total of 18 patients with primary SjS and 13 healthy controls were investigated. Clinical evaluation, chest X-ray examination, pulmonary function tests, Tc-99m DTPA aerosol scintigraphy were performed in all the cases. The presence of respiratory symptoms (dyspnea and cough), duration of sicca symptoms were recorded. The clearance half time of Tc-99m DTPA radioaerosols in patients with SjS (20.49 ± 2.56 min) was faster when compared to normal controls (42.32 ± 13.28 min) (P = 0.000) which means that there is a significant increase in lung permeability in patients with SjS compared to the controls. There is also a significant difference between PI of patients with SjS (0.34 ± 0.09) and that of controls (0.42 ± 0.07) (P = 0.012). According to the results of our preliminary study, one can detect pulmonary involvement by Tc-99m DTPA aerosol inhalation scintigraphy in patients with primary SjS.     

Functional analysis of <Emphasis Type="Italic">BMP4</Emphasis> mutations identified in pediatric CAKUT patients

Human congenital anomalies of the kidney and urinary tract (CAKUT) represent the major causes of chronic renal failure (CRF) in children. This set of disorders comprises renal agenesis, hypoplasia, dysplastic or double kidneys, and/or malformations of the ureter. It has recently been shown that mutations in several genes, among them BMP4, are associated with hereditary renal developmental diseases. In BMP4, we formerly identified three missense mutations (S91C, T116S, N150K) in five pediatric CAKUT patients. These BMP4 mutations were subsequently studied in a cellular expression system, and here we present functional data demonstrating a lower level of messenger RNA (mRNA) abundance in Bmp4 mutants that indicates a possible negative feedback of the mutants on their own mRNA expression and/or stability. Furthermore, we describe the formation of alternative protein complexes induced by the S91C-BMP4 mutation, which results in perinuclear endoplasmic reticulum (ER) accumulation and enhanced lysosomal degradation of Bmp4. This work further supports the role of mutations in BMP4 for abnormalities of human kidney development.     

SIX2 and BMP4 mutations associate with anomalous kidney development

Renal hypodysplasia (RHD) is characterized by reduced kidney size and/or maldevelopment of the renal tissue following abnormal organogenesis. Mutations in renal developmental genes have been identified in a subset of affected individuals. Here, we report the first mutations in BMP4 and SIX2 identified in patients with RHD. We detected 3 BMP4 mutations in 5 RHD patients, and 3 SIX2 mutations in 5 different RHD patients. Overexpression assays in zebrafish demonstrated that these mutations affect the function of Bmp4 and Six2 in vivo. Overexpression of zebrafish six2.1 and bmp4 resulted in dorsalization and ventralization, respectively, suggesting opposing roles in mesendoderm formation. When mutant constructs containing the identified human mutations were overexpressed instead, these effects were attenuated. Morpholino knockdown of bmp4 and six2.1 affected glomerulogenesis, suggesting specific roles for these genes in the formation of the pronephros. In summary, these studies implicate conserved roles for Six2 and Bmp4 in the development of the renal system. Defects in these proteins could affect kidney development at multiple stages, leading to the congenital anomalies observed in patients with RHD.