Genomic Testing Identifies Monogenic Causes in Patients with Very Early-Onset Inflammatory Bowel Disease: A Multi-center Survey in an Iranian Cohort.

Patients with very early-onset inflammatory bowel disease (VEO-IBD) may present because of underlying monogenic inborn errors of immunity (IEI). Strong differences have been observed in the causes of monogenic IBD among ethnic populations. This multi-center study was carried out on 16 Iranian patients with VEO-IBD. We reviewed clinical and basic immunologic evaluation including flow cytometry and immunoglobulin levels. All patients underwent clinical whole exome sequencing (WES). Sixteen patients (8 females and 8 males) with a median age of 43.5 months were enrolled. The median age at the onset of symptoms was 4 months. Most patients (12, 75%) had consanguineous parents. Chronic non-bloody diarrhea (13, 81.3%) and perianal diseases including perianal abscess (6, 37.5%), anal fissure (6, 37.5%), or anal fistula (2, 12.5%) were the most common manifestations. WES identified a spectrum of genetic variants in 13 patients (81.3%): IL10RB (6, 37.5%), MVK (3, 18.8%), and CASP8, SLC35C1, G6PC3, and IKBKB in one patient, respectively. In 3 patients (18.7%) no variant was identified. Flow cytometry identified a spectrum of abnormalities that helped to assess the evidence of genetic diagnosis. At the end of the survey, 3 (18.8%) patients were deceased. This high rate of monogenic defects with a broad spectrum of genes reiterates the importance of investigating IEI in patients with infantile-onset IBD.

Is CKD Screening Program Necessary in Developing Countries?

INTRODUCTION: The prevalence of congenital anomaly of kidney and urinary tract (CAKUT) and related chronic kidney disease (CKD) may be increased in countries with higher rate of consanguineous marriage. Therefore, we evaluated the prevalence of CKD by biochemical and kidney ultrasound measurements in the firstgrade pupils. METHODS: This cross -sectional study was carried on children aged 6 to 7 years. Urine analysis, serum creatinine, urine microalbumin to creatinine ratio and kidney ultrasound have been evaluated for participants. RESULTS: 653 children were recruited to the study. Stage 1 and stage 2 systolic hypertension have been found in 6.5 and 1%, respectively. The percentage of stage 1 and stage 2 diastolic hypertension were 1.3 and 0.3%, respectively. Both weight Z-score and waist Z-score had positive correlation with systolic and diastolic blood pressure. Microalbuminuria (in 2.5%) did not have any correlation with the following factors: hypertension, body mass index, microscopic hematuria, glomerular filtration rate, kidney sonographic abnormalities or kidney parenchymal thickness and family history of kidney transplantation. GFR less than 90 mL/ min /1.73 m2 has been detected in 1.8% of the students. Only 1.7% had urine RBC more than 5 in each high-power field (hpf). Approximately 1.5% had anatomical abnormality of kidney and urinary tract (hydronephrosis or hydroureter). CONCLUSION: Considering the higher prevalence of elevated blood pressure and microalbuminuria in Iranian children, a CKD screening program based on evaluating microalbuminuria and blood pressure measurement is needed. However, irrespective of high prevalence of consanguineous marriage in Iran, using kidney ultrasound as a screening tool has not been recommended.  DOI: 10.52547/ijkd.7306.

The Assessment of Neonatal Anthropometric Indices Association with Umbilical Cord Blood Zinc and Magnesium Levels.

Background: The present research aims to find the association between neonatal anthropometric parameters and zinc and magnesium concentration in cord blood. Materials and Methods: The current cross-sectional report is a sub-study from the "PERSIAN Birth Cohort Study" conducted on 112 pairs of mother-neonate referring to the index hospitals for giving birth to their children during 2018-19. Umbilical cord blood was collected at delivery for the measurement of zinc and magnesium. Anthropometric indices were measured in standard protocols. Validated questionnaires were used for maternal diet in different trimesters. Dietary patterns were acquired based on exploratory factor analysis. Results: The birth weight was reversely correlated with zinc concentration (r = -0.249, P-value = 0.008); however, the other anthropometric parameters did not show any association with zinc levels (P-value > 0.05). Similar evaluations for magnesium revealed no association between any of the anthropometric indices and this micronutrient agent (P-value > 0.05). Further evaluations represented insignificant differences in both zinc (P-value = 0.51) and magnesium levels (P-value = 0.49) between those with normal versus low birth weight. There was a negative association between the Western dietary pattern in the first trimester of pregnancy and cord blood zinc concentration (ß (SE) = -0.21 (0.10); P = 0.026); while healthy and traditional dietary patterns in second and third trimesters were positively related to cord zinc concentration (all P < 0.05). Conclusion: This research did not document a positive statistical association of cord blood zinc and magnesium with birth weight. The association of maternal Western dietary patterns with lower cord blood zinc levels highlights the importance of healthy nutritional habits in pregnancy.

The Effectiveness of Synbiotic on the Improvement of Clinical Symptoms in Children with Eosinophilic Esophagitis.

Background: Eosinophilic esophagitis (EoE) is an allergic inflammatory disorder of the esophagus. Today, probiotics are included as adjuvant therapy in the treatment of allergic diseases. The aim of this study was to assess the effect of synbiotic on clinical symptom improvement in EoE patients. Methods: This study is designed by a double-blind, placebo-controlled clinical trial with two parallel groups, which was performed on 30 children with eosinophilic esophagitis. All participants were children aged 6 months to 15 years. Both groups received the same treatment (elimination diet, topical steroid, and proton pump inhibitor). A synbiotic (KidiLact) was added to the medication regimen of 15 patients (case), while the next 15 patients received a placebo (control). Severity and frequency of symptoms were assessed with a checklist derived from a validated scoring tool in both groups before and after 8 weeks of treatment. Results: There was a significant reduction in the severity score of chest pain and poor appetite (P value < 0.05) in the case group taking probiotics, while nausea and poor appetite were the only symptoms with a significant reduction in the frequency score after intervention in this group. Conclusion: Probiotics can be used as adjuvant treatment for patients with EoE. Improvement in the severity of chest pain and poor appetite and reduction in the frequency of nausea and poor appetite in these patients can be seen.

Overexpression of protein kinase Mζ in the hippocampal dentate gyrus rescues amyloid-ß-induced synaptic dysfunction within entorhinal-hippocampal circuit.

Entorhinal cortex (EC) is one of the first cerebral regions affected in the early phase of Alzheimer's disease (AD). Soluble forms of amyloid beta (Aß) impair synaptic transmission in experimental AD models. Protein kinase Mζ (PKMζ) is an atypical persistently active protein kinase C, known to maintain long term synaptic plasticity and memory, but its role in AD has not yet been described. We examined effect of PKMζ overexpression on the late long-term potentiation (L-LTP) in the dentate gyrus (DG) following EC amyloidopathy. Oligomeric Aß 1-42 (oAß) or vehicle was bilaterally microinjected into the EC of the male Wistar rats. After 1 week, 2 µL of lentiviral vector (~108 TU/mL) encoding PKMζ genome was injected into the DG. One week later, synaptic responses and the LTP persistence were assessed in DG of freely moving animals during 90 minutes to 7 days period. Novel object recognition, passive avoidance and spatial memories were also tested. In rats with EC amyloidopathy, LTP was induced with less amplitude compared to the control group, and extinguished after 24 h. PKMζ overexpression in DG augmented synaptic responses (PS-LTP amplitudes) and maintained LTP over 1 week. PKMζ ameliorated recognition and memory deficits in rats with EC amyloidopathy. Microinjection of PKMζ inhibitor, zeta inhibitory peptide, into the DG abolished the boosting effect of PKMζ on synaptic activity and memory performance. PKMζ-dependent pathway could be a potential therapeutic target to combat synaptic failure and memory deficit in the early phase of AD.

Overexpression of protein kinase Mζ in the hippocampus mitigates Alzheimer's disease-related cognitive deficit in rats.

Accumulation of amyloid beta (Aß) soluble forms in the cerebral parenchyma is the mainstream concept underlying memory deficit in the early phase of Alzheimer's disease (AD). PKMζ plays a critical role in the maintenance of long-term memory. Yet, the role of this brain-specific enzyme has not been addressed in AD. We examined the impact of hippocampal PKMζ overexpression on AD-related memory impairment in rats. Oligomeric form of Aß (oAß) or vehicle was bilaterally microinjected into the dorsal hippocampus of male Wistar rats under stereotaxic surgery. One week later, 2 µl of lentiviral vector (108 T.U. / ml.) encoding PKMζ genome was microinjected into the dorsal hippocampus. Seven days later, behavioral performance was assessed using shuttle box and Morris water maze. The expression levels of GluA1, GluA2 and KCC2 were determined in the hippocampus using western blot technique. Our data showed that oAß impairs both passive avoidance and spatial learning and memory. However, overexpression of PKMζ in the dorsal hippocampus restored the behavioral performance. This improving effect was blocked by microinjection of ZIP, a PKMζ inhibitor, into the hippocampus. oAß or PKMζ did not significantly change GluA1 level in the hippocampus. Furthermore, PKMζ failed to restore elevated KCC2 level induced by oAß. However, oAß decreased GluA2 level, and overexpression of PKMζ restored its expression toward the control level. In conclusion, hippocampal overexpression of PKMζ restored memory dysfunction induced by amyloidopathy in part, through preserving hippocampal GluA2 containing AMPA receptors. PKMζ's signaling pathway could be considered as a therapeutic target to battle memory deficits in the early phase of AD.