Upregulation of MTOR,RPS6KB1, and EIF4EBP1 in the whole blood samples of Iranian patients with multiple sclerosis compared to healthy controls

Metabolic Brain Disease - Various genetic and epigenetic mechanisms have been suggested to play roles as the underlying pathophysiology of Multiple Sclerosis (MS). Changes in different parts of the...     

Identification of a Mutation in SPG11 in an Iranian Patient with Spastic Paraplegia and Ears of the Lynx Sign

Hereditary spastic paraplegia (HSP) includes a number of inherited disorders which are characterized by stiffness in the lower extremities and progressive gait disturbance. Mutations in terms of spastic gait genes (SPGs) are responsible for occurrence of different types of HPS with autosomal recessive, X-linked recessive, and autosomal dominant modes of inheritance. In the current case report, we identified a mutation in SPG11 gene in a female patient with progressive stiffness of lower extremities and atrophy of corpus callosum and the “lynx ear” sign in brain MRI. Whole exome sequencing (WES) revealed a homozygote frameshift deletion variant in SPG11 gene (NM001160227: exon 28: c.4746delT, p.N1583Tfs*23). This variant is a null variant classified as a pathogenic variant (PVS1) according to ACMG standards and guidelines. The frequency of this variant in 1000G, ExAC, and Iranome databases was 0. This study shows the role of WES in the identification of disease-causing mutations in a disease such as HSP which can be caused by diverse mutations in several genes.     

Polymorphisms in the renin-angiotensin system and endothelium-dependent vasodilation in normotensive subjects.

BACKGROUND: Our aim was to test the hypothesis that genes encoding components in the renin-angiotensin system influence endothelial vasodilatory function. METHODS: In 59 apparently healthy, normotensive individuals, endothelium-dependent vasodilation (EDV) and endothelial-independent vasodilation (EIDV) was evaluated by infusing metacholine and sodium nitroprusside into the brachial artery. Forearm blood flow was measured by venous occlusion plethysmography. The ACE insertion (I)/deletion (D) polymorphism, the T174M and M235T angiotensinogen restriction fragments length polymorphisms, the angiotensin II receptor type 1 (AT1R) A1166C, and the aldosterone synthase gene (CYP11B2) C-344T polymorphisms were analysed. RESULTS: When analysing the ACE, the two angiotensinogen and the aldosterone synthase CYP11B2 genotypes independently, no significant association with endothelial vasodilatory function was found. However, a significant reduction in endothelium-dependent vasodilation was observed in the subjects (n=9) with the ACE D allele and the angiotensinogen T174M genotype (P<0.05). Subjects with the AT1R genotype AC showed a reduction in both EDV (P=0.05) and EIDV (P=0.04) when compared with those with the AA genotype. CONCLUSIONS: The subjects with the ACE D allele in combination with the angiotensinogen T174M genotype are associated with a reduced EDV. This together with the observation that the AC AT1R genotype is associated with a reduction in both EDV and EIDV, supports the hypothesis that endothelial vasodilatory function is influenced by genes in the renin-angiotensinogen system.     

A critical role for the programmed death ligand 1 in fetomaternal tolerance

Fetal survival during gestation implies that tolerance mechanisms suppress the maternal immune response to paternally inherited alloantigens. Here we show that the inhibitory T cell costimulatory molecule, programmed death ligand 1 (PDL1), has an important role in conferring fetomaternal tolerance in an allogeneic pregnancy model. Blockade of PDL1 signaling during murine pregnancy resulted in increased rejection rates of allogeneic concepti but not syngeneic concepti. Fetal rejection was T cell- but not B cell-dependent because PDL1-specific antibody treatment caused fetal rejection in B cell-deficient but not in RAG-1-deficient females. Blockade of PDL1 also resulted in a significant increase in the frequency of IFN-gamma-producing lymphocytes in response to alloantigen in an ELISPOT assay and higher IFN-gamma levels in placental homogenates by ELISA. Finally, PDL1-deficient females exhibited decreased allogeneic fetal survival rates as compared with littermate and heterozygote controls and showed evidence of expansion of T helper type 1 immune responses in vivo. These results provide the first evidence that PDL1 is involved in fetomaternal tolerance.     

The Role of IL-6 for Predicting Neonatal Sepsis: A Systematic Review and Meta-Analysis

Objective

Neonatal sepsis (NS) is a common and life-threatening disorder in infants. Previous studies showed that interleukin-6 (IL-6) may be a valid non-invasive and rapid method for diagnosis of NS. We conducted this review to assess the validity of IL-6 for predicting NS.

Methods

This was a systematic review with meta-analysis. Embase, Medline and Web of Science databases were searched between January 1990 and December 2009. The search terms used were “cytokine”, “neonate”, “sepsis” and “interleukin-6". We used standard methods recommended for meta analyses of diagnostic test evaluations. The analysis was based on a summary ROC (SROC) curve. Meta-regression analysis was used to assess the effects of some confounding factors on the results of meta-analysis. Potential presence of publication bias was tested using funnel plots and the Egger test.

Findings

Meta-analysis was performed on 13 publications including 353 infants with sepsis and 691 control infants. The pooled sensitivity and specificity of IL-6 was 0.79 and 0.84, respectively. The maximum joint sensitivity and specificity (i.e., the Q value) in SROC curve was 0.82 and the area under curve (AUC) was 0.89 (95% CI: 0.84-0.94). Meta-regression analysis showed that the diagnostic accuracy of IL-6 was not affected by confounding variables. The evaluation of publication bias showed that the Egger test was not significant (P=0.07).

Conclusion

IL-6 seems to be a valid marker for predicting NS. It may be considered for early diagnosis of sepsis in neonatal care units.