Association of IRS1 gene Pro512Ala polymorphism with nonalcoholic fatty liver disease.

Objective: This study was designed to investigate the possible effect of the insulin receptor substrate 1 (IRS1) gene rs1801276 polymorphism on the risk of nonalcoholic fatty liver disease (NAFLD). Subjects and methods: The rs1801276 polymorphism was investigated in 127 controls and 123 biopsy-proven NAFLD patients using PCR-RFLP. Results: No deviation from Hardy-Weinberg equilibrium was discovered for the rs1801276 variant of IRS1 in either NAFLD patients or controls (P>0.05). The distribution of different rs1801276 genotypes and alleles showed significant variations between controls and NAFLD patients. In comparison to rs1801276 'CC' genotype, the "GG+GC" genotype occurred less frequently in NAFLD patients than in controls, which also persisted after adjustment for confounding factors (P = 0.041, OR = 0.60, 95% CI = 0.45-0.93). In comparison with the IRS1 rs1801276 "C" allele, the "G" allele was significantly less prevalent in NAFLD patients than in controls (P = 0.045, OR = 0.69, 95% CI = 0.58-0.91). Conclusions: For the first time, we reported a significant association between the IRS1 rs1801276 polymorphism and biopsy-proven NAFLD. More studies are required to further elucidate the contribution of the IRS1 gene to NAFLD susceptibility.

Diagnosis and Treatment of Lacrimal Gland Prolapse: A Narrative Review.

BACKGROUND: Lacrimal gland prolapse (LGP) is considered to be one of the causes for upper eyelid contour abnormality that should be recognized and treated properly to yield satisfactory outcomes in blepharoplasty. To describe current findings about the prevalence, pre- and intraoperative diagnosis of LGP and its treatment options. METHODS: PubMed and Google Scholar were thoroughly searched for articles published describing the diagnosis and treatment of LGP. RESULTS: The reported prevalence of LGP by various authors varies between 10 and 60% based on their preoperative or intraoperative reports. Techniques such as dacryoadenopexy, modified dacryoadenopexy, and dacryoplasty have been described to secure the prolapsed lacrimal gland back into its original position. Additionally, creating a Whitnall's barrier has also been suggested as a method to reposition the gland. While all these surgical procedures have shown promising immediate results, there is a lack of published data on their long-term outcomes. CONCLUSION: Diagnosis and proper treatment of LGP could enhance the cosmetic results of upper eyelid blepharoplasty. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Superior Oblique Muscle Extramedullary Plasmacytoma in a Patient with Multiple Myeloma and a Review of Literature.

Introduction: Multiple myeloma (MM), a plasma cell malignancy, is a systemic disease affecting various body organs. Plasmacytoma of bone and extramedullary disease (EMD) are presentations of MM. EMD is usually the sign of a more aggressive form of the disease. Herein, we report a patient with refractory MM presenting with extramedullary plasmacytoma in the superior oblique (SO) muscle. Case Presentation: A 51-year-old female presented complaining of gradual protrusion of the left eye and ocular pain from 20 days prior. She received bone marrow transplantation 1 year prior and was on a chemotherapy regimen for MM for the past 1 year. Ocular examination revealed proptosis of the left eye and mild limitations of adduction and elevation. Orbital magnetic resonance imaging demonstrated remarkable enlargement of the left SO muscle with focal contrast enhancement. The patient underwent a biopsy and mass debulking. The histopathologic exam revealed fibromuscular tissue containing a neoplasm composed of sheets of plasmacytoid cells in a varying degree of differentiation with intervening scantly vascularized stromal components. The plasmacytoid cells were diffusely positive for a cluster of differentiation 138 (CD138), leading to a diagnosis of EMD involving the EOM and soft tissue of the orbit. The patient underwent palliative radiotherapy and a systemic workup. The PET-CT scan revealed involvement of the pelvic bone and left calf. Accordingly, the chemotherapy regimen was upgraded to reflect the aggressive nature of the disease. In the last follow-up, there was no sign of tumor reactivation in the orbital soft tissues. Unfortunately, the patient succumbed to her illness 7 months following her most recent presentation. Conclusion: Early recognition of disease recurrence is lifesaving in MM patients; ophthalmic manifestations should be seriously considered as a sign of MM activity.

Dietary Antioxidant Capacity Indices are Negatively Correlated to LDL-Oxidation in Adults.

Introduction: Former research studies have demonstrated controversial associations between dietary indices and oxidative stress biomarkers including oxidized low-density lipoprotein (ox-LDL) and malondialdehyde (MDA). So, in this cross-sectional study, we aimed to assess the association of dietary total antioxidant capacity (DTAC), oxidative balance score, and phytochemical index (PI) with ox-LDL/MDA in a healthy adult population of Shiraz, Iran. Methods: 236 individuals participated in this cross-sectional study. DTAC, OBS, and PI were calculated using a 168-item food frequency questionnaire (FFQ), which was previously validated in Iran. We measured ox-LDL and MDA in blood samples of the participants using commercially existing kits. Crude and adjusted models of linear regression were used to evaluate the relation of dietary indices with ox-LDL and MDA. Results: There was a significant association between ox-LDL and DTAC in both crude (ß = -1.55; 95% CI: -2.53, -0.58; P-trend = 0.002) and adjusted (ß = -1.65 95% CI: -2.66, -0.64; P-trend = 0.001) models. Also, a negative association was observed between ox-LDL and PI in the crude (ß = -1.26 95% CI: -2.33, -0.29; P-trend = 0.01) and adjusted (ß = -1.36 95% CI: -2.38, -0.34; P-trend = 0.01) models. Conclusion: Results of this study showed that DTAC and PI were inversely associated with ox-LDL as markers of lipid peroxidation. But no correlations were seen between MDA and dietary antioxidant indices.

Facial and Abducens Nerve Palsies Following COVID-19 Vaccination: Report of Two Cases.

A broad spectrum of neurological side effects has been reported after immunisation for COVID-19, including functional neurological disorders, cerebral vascular events, cerebral venous thrombosis, intracerebral haemorrhage, neuroleptic malignant syndrome, cranial nerve palsies, and otologic manifestations. Multiple cranial neuropathies have also been reported following vaccination in which involvement of VII nerve is the most prevalent, followed by the VI, III, and IV nerves. We describe two male patients, one with with facial nerve palsy and the other with abducens nerve palsy following COVID-19 vaccination. The patient with facial nerve palsy received the AstraZeneca vaccine 2 days before the symptoms began. In contrast, the patient with the abducens palsy had received his first dose of the Sinopharm vaccine 7 days previously. Both patients demonstrated a gradual recovery within the next 2 months. Further studies are required to investigate the proper relationship between cranial nerve palsies and vaccinations.

Identification of three novel homozygous variants in COL9A3 causing autosomal recessive Stickler syndrome.

BACKGROUND: Stickler syndrome (STL) is a rare, clinically and molecularly heterogeneous connective tissue disorder. Pathogenic variants occurring in a variety of genes cause STL, mainly inherited in an autosomal dominant fashion. Autosomal recessive STL is ultra-rare with only four families with biallelic COL9A3 variants reported to date. RESULTS: Here, we report three unrelated families clinically diagnosed with STL carrying different novel biallelic loss of function variants in COL9A3. Further, we have collected COL9A3 genotype-phenotype associations from the literature. CONCLUSION: Our report substantially expands the molecular genetics and clinical basis of autosomal recessive STL and provides an overview about allelic COL9A3 disorders.

A 57 kB Genomic Deletion Causing CTNS Loss of Function Contributes to the CTNS Mutational Spectrum in the Middle East.

Background: Nephropathic Cystinosis, the most common cause of renal Fanconi syndrome, is a lysosomal transport disorder with an autosomal recessive inheritance pattern. A large number of mutations in CTNS have been identified as causative to date. A 57 kb deletion encompassing parts of CTNS is most commonly identified in Caucasians but this allele has not been identified in individuals of Eastern Mediterranean, Middle Eastern, Persian, or Arab origin to date. Methods and Results: Implementing whole exome sequencing (WES) in a consanguineous Iranian family, we identified this large deletion affecting CTNS in a patient initially presenting with hypokalemic metabolic alkalosis symptoms and considerable proteinuria. Conclusion: We show WES is a cost and time efficient genetic diagnostics modality to identify the underlying molecular pathology in Cystinosis individuals and provide a summary of all previously reported CTNS alleles in the Middle east population. Our work also highlights the importance to consider the 57-kb deletion as underlying genetic cause in non-European populations, including the Middle East. Limited diagnostic modalities for Cystinosis in developing countries could account for the lack of previously reported cases in these populations carrying this allele. Further, our findings emphasize the utility of WES to define genetic causes in clinically poorly defined phenotypes and demonstrate the requirement of Copy number variation (CNV) analysis of WES data.

Mimicry and well known genetic friends: molecular diagnosis in an Iranian cohort of suspected Bartter syndrome and proposition of an algorithm for clinical differential diagnosis.

BACKGROUND: Bartter Syndrome is a rare, genetically heterogeneous, mainly autosomal recessively inherited condition characterized by hypochloremic hypokalemic metabolic alkalosis. Mutations in several genes encoding for ion channels localizing to the renal tubules including SLC12A1, KCNJ1, BSND, CLCNKA, CLCNKB, MAGED2 and CASR have been identified as underlying molecular cause. No genetically defined cases have been described in the Iranian population to date. Like for other rare genetic disorders, implementation of Next Generation Sequencing (NGS) technologies has greatly facilitated genetic diagnostics and counseling over the last years. In this study, we describe the clinical, biochemical and genetic characteristics of patients from 15 Iranian families with a clinical diagnosis of Bartter Syndrome. RESULTS: Age range of patients included in this study was 3 months to 6 years and all patients showed hypokalemic metabolic alkalosis. 3 patients additionally displayed hypercalciuria, with evidence of nephrocalcinosis in one case. Screening by Whole Exome Sequencing (WES) and long range PCR revealed that 12/17 patients (70%) had a deletion of the entire CLCNKB gene that was previously identified as the most common cause of Bartter Syndrome in other populations. 4/17 individuals (approximately 25% of cases) were found to suffer in fact from pseudo-Bartter syndrome resulting from congenital chloride diarrhea due to a novel homozygous mutation in the SLC26A3 gene, Pendred syndrome due to a known homozygous mutation in SLC26A4, Cystic Fibrosis (CF) due to a novel mutation in CFTR and apparent mineralocorticoid excess syndrome due to a novel homozygous loss of function mutation in HSD11B2 gene. 1 case (5%) remained unsolved. CONCLUSIONS: Our findings demonstrate deletion of CLCNKB is the most common cause of Bartter syndrome in Iranian patients and we show that age of onset of clinical symptoms as well as clinical features amongst those patients are variable. Further, using WES we were able to prove that nearly 1/4 patients in fact suffered from Pseudo-Bartter Syndrome, reversing the initial clinical diagnosis with important impact on the subsequent treatment and clinical follow up pathway. Finally, we propose an algorithm for clinical differential diagnosis of Bartter Syndrome.

Expanding the clinical phenotype of IARS2-related mitochondrial disease.

BACKGROUND: IARS2 encodes a mitochondrial isoleucyl-tRNA synthetase, a highly conserved nuclear-encoded enzyme required for the charging of tRNAs with their cognate amino acid for translation. Recently, pathogenic IARS2 variants have been identified in a number of patients presenting broad clinical phenotypes with autosomal recessive inheritance. These phenotypes range from Leigh and West syndrome to a new syndrome abbreviated CAGSSS that is characterised by cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, as well as cataract with no additional anomalies. METHODS: Genomic DNA from Iranian probands from two families with consanguineous parental background and overlapping CAGSSS features were subjected to exome sequencing and bioinformatics analysis. RESULTS: Exome sequencing and data analysis revealed a novel homozygous missense variant (c.2625C > T, p.Pro909Ser, NM_018060.3) within a 14.3 Mb run of homozygosity in proband 1 and a novel homozygous missense variant (c.2282A > G, p.His761Arg) residing in an ~ 8 Mb region of homozygosity in a proband of the second family. Patient-derived fibroblasts from proband 1 showed normal respiratory chain enzyme activity, as well as unchanged oxidative phosphorylation protein subunits and IARS2 levels. Homology modelling of the known and novel amino acid residue substitutions in IARS2 provided insight into the possible consequence of these variants on function and structure of the protein. CONCLUSIONS: This study further expands the phenotypic spectrum of IARS2 pathogenic variants to include two patients (patients 2 and 3) with cataract and skeletal dysplasia and no other features of CAGSSS to the possible presentation of the defects in IARS2. Additionally, this study suggests that adult patients with CAGSSS may manifest central adrenal insufficiency and type II esophageal achalasia and proposes that a variable sensorineural hearing loss onset, proportionate short stature, polyneuropathy, and mild dysmorphic features are possible, as seen in patient 1. Our findings support that even though biallelic IARS2 pathogenic variants can result in a distinctive, clinically recognisable phenotype in humans, it can also show a wide range of clinical presentation from severe pediatric neurological disorders of Leigh and West syndrome to both non-syndromic cataract and cataract accompanied by skeletal dysplasia.

Expression of Pluripotency Markers, SOX2 and OCT4, in Pterygium Development.

Pterygium is a common ocular surface disease characterized by the abnormal epithelial proliferation, matrix remodeling, vascularization and the migration of the lesion. Although the etiology of pterygium is elusive, recent studies have focused on the role of limbal stem cells (LSCs) damage and effects of UVB. This study aimed to determine the expression levels of pluripotent markers of SOX2 and OCT4 in primary pterygium and normal conjunctiva. Using real time polymerase chain reaction (PCR), the SOX2 and OCT4 expressions were compared in primary pterygium and normal conjunctiva. This study assessed the correlation between SOX2 mRNA expression and OCT4 mRNA expression, as well as the association between the clinicopathological indices and both gene expression levels. The relative mRNA expression levels of OCT4 genes in primary pterygium were significantly reduced compared to the normal conjunctiva tissues. The association between OCT4 gene expression and the clinicopathological indices reported significant laterality (P = .004) and marginal growth activity indices (P = .063). The univariate correlation between the SOX2 and OCT4 expressions was statistically significant (P = .001). The present study emphasized the downregulation of pluripotent marker OCT4 genes in the pterygium. It is speculated that these results may predict a new avenue for exploring the role of stem cell deficiency in the development of pterygium.

Crosstalk between SHH and stemness state signaling pathways in esophageal squamous cell carcinoma.

The expression of GLI1 as a downstream gene of sonic hedgehog (Hh) pathway, studied in a variety of cancers including esophageal squamous cell carcinoma (ESCC). However, the interaction of Hh with other developmental pathways needs to be elucidated. In this study, we aimed to investigate the correlation of GLI1 expression with transcription factors (TFs) of stem cell signaling pathways, and their association with clinico-pathological data of ESCC. Using real-time PCR, we assessed the expression of GLI1 mRNA in 49 ESCC patients, and analyzed the correlation between GLI1 and selected TFs. The results showed overexpression of GLI1 in ESCC tissues in significant correlation with lymph node metastasis. The GLI1 up-regulation was also correlated to the SOX2 and SIZN1 (Smad-interacting zinc finger protein) expression. These correlations may confirmed the role of GLI1 in crosstalk among different cell signaling pathways in ESCC. To our knowledge, this is the first study to demonstrate the correlation of GLI1 expression with stemness marker and BMP signaling in ESCC.

Contribution of LATS1 and LATS2 promoter methylation in OSCC development.

The aberrant DNA methylation of the tumor suppressor genes involved in DNA Damage Response (DDR) signaling and cell cycle regulation may lead to the tumorigenesis. Our purpose here is to analyze the promoter methylation and mRNA expression levels of LATS1 and LATS2 (LATS1/2) genes in OSCC. Promoter methylation status of LATS1/2 genes was evaluated in 70 OSCC paraffin-embedded tissues and 70 normal oral samples, using Methylation Specific PCR (MSP). LATS1/2 mRNA expression profiles were also investigated in 14 OSCC patients and 14 normal samples, using real-time PCR. In both candidate genes, promoter methylation assessment revealed significant relationship between cases and controls (OR = 2.24, 95 % CI = 1.40-3.54, P = 0.001; LATS1 and OR = 15.5, 95%CI = 3.64-64.76, P < 0.001; LATS2). As well as, the evaluation of mRNA expression levels showed decreased expression in OSCC tissues in compare to control tissues. (Mean ± SD 1.74 ± 0.14 in OSCC versus 2.10 ± 0.24 in controls, P < 0.001; LATS1 and Mean ± SD 1.36 ± 0.077 in OSCC versus 1.96 ± 0.096 in controls, P < 0.001; LATS2). To the best our knowledge, this is the first report regarding the down-regulation of LATS1/2 through promoter methylation in OSCC. It is suggested to explore the down-stream transcription factors of both genes for finding the molecular mechanism of this deregulation in OSCC.

SOX1 is correlated to stemness state regulator SALL4 through progression and invasiveness of esophageal squamous cell carcinoma.

SOX1, as a tumor suppressor, play anti-tumorigenecity role in different cells and its expression is inhibited in a variety of cancers. The aim of this study was to evaluate SOX1 expression and its correlation with cancer stem cell (CSC) markers in ESCC. Using real time PCR, the relative comparative expression of SOX1 in 40 ESCC samples was assessed compared to related margin normal tissues, and its correlation with CSC markers including SALL4, SOX2, and MEIS1 was analyzed statistically. The results revealed significant under-expression of SOX1 in ESCC in significant correlation with different indices of poor prognosis including depth of tumor invasion (P=0.02), Stage of tumor cell progression (P=0.05), and number of involved lymph node metastasis (P=0.05). Furthermore, the under-expression of SOX1 was associated significantly with SALL4 overexpression. This study was the first to evaluate SOX1 underexpression and its association with poor prognosis in ESCC. Since correlation of SOX1 and SALL4 was detected in advanced stages of ESCC progression, as well as high invasive and aggressive tumor tissues, it may be extrapolated that SOX1 expression may have critical role in inhibition of ESCC invasiveness and aggressiveness especially in advanced stages of the disease.