Tumor necrosis factor alpha gene polymorphism affects the pattern of idiopathic nephrotic syndrome in Kuwaiti Arab children.

OBJECTIVES: TNF-α is a pro-inflammatory cytokine that has been implicated in many inflammatory diseases, but its association with idiopathic nephrotic syndrome (INS) is poorly understood. This study looked for an association of TNF-α gene polymorphisms with INS, as well as its effect on steroid responsiveness among Kuwaiti Arab children. METHODS: Genotypes of the TNF-a gene polymorphisms were analyzed using polymerase chain reaction-restriction fragment length polymorphism in 151 INS Kuwaiti Arab patients and 64 age and sex-matched controls. Clinical data of all subjects were reviewed. RESULTS: The heterozygous AG genotype was detected in 8.6% of INS patients compared 23.4% of the controls (p < 0.01). Comparing steroid responsiveness, AA genotype was significantly more common in steroid-sensitive nephrotic syndrome (SSNS) cases than steroid-resistant nephrotic syndrome (SRNS) patients (p = 0.001). However, AG genotype was significantly more common in SRNS patients compared to the SSNS cases (p = 0.001). No difference was found between these two subgroups in the GG genotype frequency. CONCLUSION: AG genotype of TNF-a gene polymorphisms may be considered a suitable marker for INS disease among Kuwaiti children. Both AA and AG genotypes may be useful in predicting steroid responsiveness among these cases of Arab ethnicity. The findings might open the era for the use of genetic markers in the early treatment of NS.

Autosomal dominant cases of chronic mucocutaneous candidiasis segregates with mutations of signal transducer and activator of transcription 1, but not of Toll-like receptor 3.

We report a family with autosomal dominant chronic mucocutaneous candidiasis as well as recurrent viral infections that segregate with a novel signal transducer and activator of transcription 1 (STAT1) mutation. Prophylactic treatment with fluconazole and immunoglobulin replacement has been initiated, with good clinical response.

Children with Delayed-Type Cow's Milk Protein Allergy May Be at a Significant Risk of Developing Immediate Allergic Reactions Upon Re-introduction.

Background: Cow's Milk Protein Allergy (CMPA) is the most common food allergy in children. The reaction is classified into IgE-mediated immediate reaction and delayed-onset, according to the underlying immune mechanism, and hence, the timing of the symptoms. Case reports suggest that children, with delayed CMPA reactions on elimination diet, may develop severe immediate reactions on reintroduction. Aim: The objective of this study was to evaluate the incidence and the risk factors of developing immediate reactions to milk and dairy products in children with CMPA whose initial presentations were of delayed type. Methods: A retrospective chart review of children, aged 0-12 years, presented with delayed type CMPA reactions to the allergy-clinical immunology clinics, was performed. The diagnosis was made clinically, and with appropriate allergy tests when indicated. Results: Sixty children were included. Males:female ratio was 1.7:1. Family history of atopy was in 72%, and 57% had personal history of atopy. Sixty percent were not breast fed. The most common concomitant food allergy was egg. The most common initial presentation was diarrhea without protein loss or bleeding followed by exacerbation of atopic dermatitis upon exposure to dairy products. Immediate reactions developed in 21.6% upon re-exposure. There were significant associations with concomitant food allergy (OR 56.6 (3.15-1016.1) P<0.0001), especially eggs (OR 12.85 (3.09-53.5) P<0.01). Conclusion: Children with CMPA, who present with delayed-type allergic reactions, may be at a significant risk of developing immediate reactions upon reintroduction. Evaluation of possible IgE-mediated allergic reactions before reintroduction may be advisable.

Association of interleukin-4, interleukin-13 gene polymorphisms, HLA-DQ and DR genotypes with genetic susceptibility of type-1 Diabetes Mellitus in Kuwaiti children.

Background: Type-1 diabetes mellitus (T1DM) is a complex multifactorial disease with an autoimmune etiology and is thought to result from an interaction between genetic and non-genetic factors. Cytokines play a crucial role in the pathogenesis of autoimmune diseases due to their effector and regulatory functions in immune responses. Interleukin-4 (IL4) and Interleukin-13 (IL13) are anti-inflammatory cytokines and are considered as important mediators in pathology of the autoimmune diseases. Methods: We have determined the genotype frequency of IL4 gene promoter polymorphism (-590C/T, rs2243250), IL13 gene polymorphism p.(Arg130Glu, rs20541) and human leukocyte antigen, HLA-DQ and DR genotypes in Kuwaiti children with T1DM to investigate their role in genetic susceptibility. This study included 261 Kuwaiti children with T1DM and 214 healthy controls. The genotypes for IL4 (-590C/T) and IL13 p.(Arg130Glu) gene polymorphisms were detected by PCR-RFLP methods. HLA-DQ and DR genotypes were determined by sequence-specific PCR methods. Results: The CC genotype of IL4 gene polymorphism (-590C/T) was significantly related to the risk for T1DM in Kuwaiti patients (OR 1.64). The homozygous AA (QQ) and heterozygous AG (RQ) genotypes of IL13 gene polymorphism p.(Arg130Glu), also manifested a statistically significant association with T1DM (OR 2.92 and 4.79). In 55% T1DM patients, the HLA genotype was either DQ2/DQ2 or in combination with a DQ8 allele. Collectively, 91% Kuwaiti T1DM patients had either DQ2 or DQ8 alleles in different combinations highlighting them as the high risk-genotypes in comparison to the controls. In the case of HLA-DR, the genotypes DR3/DRB5, DR3/DR4, DR3/DR7 and DR4/DR4 showed highest frequency amongst the Kuwaiti T1DM patients and thus can be considered as high-risk genotypes when compared to the controls. A high degree of co-inheritance (>80%) was detected between IL4 and IL13 gene polymorphism genotypes (CC and QQ) and the high-risk HLA-DQ and DR genotypes amongst the Kuwaiti T1DM patients. Conclusions: We have identified the association of IL4 and IL13 gene polymorphisms with susceptibility to T1DM in Kuwaiti children and the co-inheritance of these polymorphisms with high-risk HLA genotypes. The findings may contribute to early identification of childhood diabetes.

Protein-Activated Kinase 3 (PAK3)-Related Intellectual Disability Associated with Combined Immunodeficiency: A Case Report.

BACKGROUND X-linked intellectual disabilities constitute a group of clinically and genetically heterogeneous disorders that are divided into syndromic and nonsyndromic forms. PAK3 mutations are associated with X-linked nonsyndromic forms of intellectual disability, with the most common clinical features being cognitive deficit, large ears, oral motor hypotonia, and neurobehavioral abnormalities. These mutations have been reported to be associated with either loss of the PAK3 protein or loss of its kinase activity. We report a case with the novel PAK3 variant c.685C>T p.(Pro229Ser), which has not been previously described. CASE REPORT We report the first case of a PAK3 mutation to present with the common clinical features along with immunodeficiency resembling common variable immune deficiency. Our patient was a 10-year-old girl who had experienced septic shock with a rapidly deteriorating course when she was 5-years-old. The initial immune work-up showed lymphopenia affecting all cell lines, but preferentially the B-cell compartment. Further work-up of this patient revealed low levels of immunoglobulin (Ig) G, undetectable IgA, reduced IgG1 and IgG2 subclasses, and poor response to the diphtheria/tetanus vaccine. Lymphocyte function, tested as the response to the mitogen phytohemagglutinin, was low and fluctuated between 9% and 22% compared with control samples. The patient experienced recurrent respiratory tract infections, and she responded well to regular intravenous Ig treatment and antibiotic prophylaxis. CONCLUSIONS The current case might provide a new insight into PAK3 gene function. Although further evidence is needed, it is worth considering that immunological abnormalities may be associated with PAK3 gene mutations.

Factors predicting students' performance in the final pediatrics OSCE.

BACKGROUND: Objective Structured Clinical Examinations (OSCEs) have been used to assess the clinical competence of medical students for decades. Limited data are available on the factors that predict students' performance on the OSCEs. The aim of our study was to evaluate the factors predicting performance on the pediatrics final OSCE, including the timing of students' clerkship and their performance on the in-training OSCE and written examinations. METHODS: Grades in pediatrics for 3 consecutive academic years (2013-2016) were included. The average scores of the in-training OSCEs, written and final OSCEs and written exams were compared among the three years using the analysis of variance (ANOVA) test. The correlations between performance on the final OSCEs and the in-training OSCEs, in-training written exams and final written exams were studied using Spearman's Rho correlation test. The effect of the timing of the clerkship on the final OSCE performance was evaluated. RESULTS: A total of 286 students' records were included. There were 115 male students and 171 female students (M:F 1:1.5). There were strong positive correlations between students' performance on the in-training examinations (OSCE and written) and the final OSCE (correlation coefficients of 0.508 and 0.473, respectively). The final written exam scores were positively correlated with the final OSCEs (r = 0.448). There was no significant effect of the timing of the clerkship. CONCLUSIONS: Students' performance on in-training examinations might predict their final OSCE scores. Thus, it is important to provide students with the necessary intervention at an early stage to reduce failure rates. The final OSCE performance does not seem to be affected by the timing of the clerkship.

Interleukin-4 and Interleukin-13 Gene Polymorphisms in Children With Idiopathic Nephrotic Syndrome.

Background: Idiopathic Nephrotic syndrome (INS) is an immune-mediated disease in which a number of cytokines, including IL-4 and IL-13, have been implicated in the pathogenesis. Cytokine gene polymorphisms might affect their levels and activity. Therefore, may affect INS susceptibility and response to treatment. The aim of the study was to determine the association of IL-4 and IL-13 gene polymorphisms and INS susceptibility and their effects on steroid responsiveness in children. Methods: The polymorphisms in IL-4 and IL-13 genes were detected by PCR-RFLP in 155 INS patients and 64 controls. Results: A total of 132 steroid-sensitive (SS) and 23 steroid resistance (SR) INS patients; mean age 7.3 ± 4.0 years, were included. Male: Female ratio was 2:1. No significant statistical differences were detected in the frequency of CC, CT, and TT genotypes of IL-4 gene compared to controls (P = 0.57, 0.61, and 1.00, respectively). There was no significant difference in the T and C-allele frequencies, in SS and SR subgroups. Analysis of IL-13 gene polymorphism also did not show significant statistical differences in the frequency of QQ, RQ, and RR genotypes compared to controls (P = 0.74, 1.00, and 0.68, respectively). No significant difference was found in the Q and R-allele frequency. However, the heterozygous RQ genotype of the IL13 gene was significantly higher in SS INS patients compared to the SR INS cases (P = 0.04). Conclusion: Our findings did not show an association between IL-4 and IL-13 gene polymorphisms and INS susceptibility. However, IL-13 RQ genotype was expressed more in children with INS who are steroid sensitive.

Serum and Urine Interleukin-6 and Interleukin-8 Levels Do Not Differentiate Acute Pyelonephritis from Lower Urinary Tract Infections in Children.

BACKGROUND: Urinary tract infection (UTI) is common in pediatrics. Infection of the upper urinary tract may cause renal scarring, and subsequently renal failure and hypertension. Permanent renal damage has been suggested to be caused by the host inflammatory response. Therefore, it is crucial to understand the host defense mechanisms against such infection in order to make timely diagnosis. The aim of this study was to evaluate interleukin-6 (IL-6) and IL-8 as potential biomarkers in differentiating acute pyelonephritis (AP) from cystitis (Cys) in children. METHODS: Forty-three children (21 with AP and 22 with Cys) were included. Serum and urinary IL-6 and IL-8 were measured during the acute phase (within 12 hours of presentation) and the convalescent phase (8 weeks post-infection). Thirty-eight healthy children were included as controls. RESULTS: During the acute phase, the mean urinary IL-6 level in the Cys group was significantly higher than that in the controls (17.8 pg/mL vs 14.8 pg/mL, P=0.03), while the serum levels were significantly higher in both the Cys and AP groups than in the controls (19.5 pg/mL, 19.4 pg/mL, 15 pg/mL, P=0.005 and 0.02, respectively). During the convalescent phase, serum and urinary IL-6 levels were higher in patients than in controls. Urinary IL-8 levels were significantly higher in both the AP and Cys groups compared to controls (206.5 pg/mL, 291.8 pg/mL, 89.4 pg/mL, P=0.05 and 0.02, respectively) during the acute phase. Serum IL-8 was not significantly different between the 3 groups. Nonetheless, no significant differences were found between the AP and Cys groups, in urinary or serum levels of IL-6 or IL-8, during both phases. CONCLUSION: IL-6 and IL-8 levels are elevated in patients with UTI. However, the levels did not differentiate between AP and cystitis. Further studies are warranted to evaluate their roles as indicators of the site of UTIs.

Urinary excretion of IL-1ß, IL-6 and IL-8 cytokines during relapse and remission of idiopathic nephrotic syndrome.

BACKGROUND/AIM: The role of pro-inflammatory cytokines in the immunopathogenesis of idiopathic nephrotic syndrome had been widely postulated. Reports on the release of cytokines, during idiopathic nephrotic syndrome (INS) activation, were conflicting in defining a specific interleukin pattern during relapse and remission of the disease. The aim of this study was to explore the role of IL-1ß, IL-6 and IL-8 in the pathophysiology of INS during relapse and remission. PATIENTS AND METHODS: A total of 37 INS patients were included. Their demographic and biochemical data were reviewed. Levels of IL-1ß, IL-6 and IL-8 were measured in the urine of patients during relapse and remission of the disease. Urine samples from 30 age- and sex-matched controls were checked for the same 3 cytokines. RESULTS: Mean age of patients at study was 6.4 ± 3.2 years (range: 14 months-12 years). Male:female ratio was 24:13. Mean serum creatinine was 47 ± 13 µmol/L, and mean serum albumin was 21 ± 7 g/L. Mean urinary IL-1ß, IL6 and IL8 levels, corrected to urinary creatinine, in patients during relapse were 132.94 ± 654.97, 217.82 ± 1124.31 and 150.227 ± 523.97 pg/µmol compared to 9.11 ± 40.75, 0.146 ± 0.652, and 6.455 ± 24.53 pg/µmol in controls, respectively (P = 0.02, 0.03 and 0.014, respectively). No significant difference was reported in the mean level of the 3 cytokines compared to controls during remission (P = 0.94, 0.092 and 0.076). CONCLUSION: Our results support the role of T-cell activation and the subsequent release of IL-1ß, IL6 and IL8 in the pathogenesis of relapses in INS. The use of steroid-sparing cytokine blockers in managing relapses of INS remains a tempting challenge.