A comprehensive study of mutation and phenotypic heterogeneity of childhood mitochondrial leukodystrophies.

OBJECTIVE: Mitochondrial leukodystrophies (MLs) are mainly caused by impairments of the mitochondrial respiratory chains. This study reports the mutation and phenotypic spectrum of a cohort of 41 pediatric patients from 39 distinct families with MLs among 320 patients with a molecular diagnosis of leukodystrophies. METHODS: This study summarizes the clinical, imaging, and molecular data of these patients for five years. RESULTS: The three most common symptoms were neurologic regression (58.5%), pyramidal signs (58.5%), and extrapyramidal signs (43.9%). Because nuclear DNA mutations are responsible for a high percentage of pediatric MLs, whole exome sequencing was performed on all patients. In total, 39 homozygous variants were detected. Additionally, two previously reported mtDNA variants were identified with different levels of heteroplasmy in two patients. Among 41 mutant alleles, 33 (80.4%) were missense, 4 (9.8%) were frameshift (including 3 deletions and one duplication), and 4 (9.8%) were splicing mutations. Oxidative phosphorylation in 27 cases (65.8%) and mtDNA maintenance pathways in 8 patients (19.5%) were the most commonly affected mitochondrial pathways. In total, 5 novel variants in PDSS1, NDUFB9, FXBL4, SURF1, and NDUSF1 were also detected. In silico analyses showed how each novel variant may contribute to ML pathogenesis. CONCLUSIONS: The findings of this study suggest whole-exome sequencing as a strong diagnostic genetic tool to identify the causative variants in pediatric MLs. In comparison between oxidative phosphorylation (OXPHOS) and mtDNA maintenance groups, brain stem and periaqueductal gray matter (PAGM) involvement were more commonly seen in OXPHOS group (P value of 0.002 and 0.009, respectively), and thinning of corpus callosum was observed more frequently in mtDNA maintenance group (P value of 0.042).

Erector Spinae Plane Block for the Treatment of Intractable Pain in a Patient with Pancoast Tumor: A Case Report.

Introduction: The erector spinae plane (ESP) block is a regional anesthetic technique that involves injecting a local anesthetic below the erector spinae muscle in an interfascial plane. Case Presentation: We report a case of a 66-year-old man with cervicothoracic junction pain caused by an advanced Pancoast tumor. The administration of ESP block at the T2-T3 level led to pain relief of more than 50% in this patient after two sessions. Conclusions: Therefore, the application of this method of regional analgesia is both convenient and safe and reduces opioid consumption. Further studies are needed to evaluate the safety and effectiveness of continuous blocks in outpatient settings.

Refractory Complex Regional Pain Syndrome: A Case Report and Review of Literature.

Introduction: Complex regional pain syndrome (CRPS) is characterized by extreme pain in a limb disproportional to the clinical history or physical findings accompanied by the signs of autonomic dysfunction. The pathophysiology of CRPS is obscure, making it challenging to treat. Treatment options include medications, physical therapy, and psychological support. In some cases, surgery or other minimally-invasive procedures such as nerve blocks may be recommended, while several novel treatments, such as ozone therapy, lack sufficient clinical evidence. Case Presentation: A 40-year-old man with CRPS was referred to our clinic with pain in his right arm and left lower leg. The patient had a history of trauma to the ulnar nerve and had undergone a sural to ulnar nerve autograft surgery. After the surgery, the patient's symptoms began, primarily in the right arm. Despite receiving conventional drugs, multiple nerve blocks, and lidocaine patches, the patient's symptoms persisted. In addition, we tried medical ozone for 14 sessions along with ketamine infusion, but these treatments were also ineffective. Conclusions: We emphasize the importance of studying and developing more effective treatments for CRPS and suggest that further randomized clinical trials are needed to determine whether ozone therapy is effective for patients with severe, intractable CRPS symptoms.

Prevalence of human papilloma virus (HPV) genotypes between outpatients males and females referred to seven laboratories in Tehran, Iran.

BACKGROUND: Human papilloma virus (HPV) causes the most common sexually-transmitted infection especially among sexually-active individuals. The aim of study was to characterize the molecular characterization of HPV genotypes between 5176 female and male patients. METHODS: HPV DNA was extracted from genital swabs of the study participants and amplified by Real Time Polymerase Chain Reaction (PCR). Genotyping was performed for 2525 cases using REALQUALITY RQ-Multi HPV Detection Kit for the identification of 14 high risk (HR) and 2 low risk (LR) HPV genotypes. Demographic figures were analyzed in correlation with virological data statistically. RESULTS: Out of 5176 cases from 7 laboratories, 2727 (53%) were positive for HPV, of which. 2372(87%) women and 355 (13%) men were HPV positive. However, in an intra-gender analysis, positive rate was higher in men (355/637, 55.7%) than in women (2372/4539, 52%; P value 0.007). HPV positive patients were younger than negative individuals. Positive rate was higher among age categories 20-40. Genotyping was performed for 2525 cases. Out of 1219 (48%) patients who contained single genotypes, 566 (22%) and 653 (26%) harboured HR and LR genotypes, respectively. In females and males, 1189 (54%) and 117 (37%) contained multiple genotypes. No substantial associations were found between different age categories and HR/LR and multiple genotypes distribution. CONCLUSION: The prevalence of HPV infection in both genders was high. However, men had a higher rate of infection. These observations highlighted the necessity for a plan for targeted education to younger population in the society as well as application of infection control measures against HPV infection, especially in terms of general population mass HPV vaccination.

Recommendation agents and information sharing through social media for coronavirus outbreak.

The novel outbreak of coronavirus disease (COVID-19) was an unexpected event for tourism in the world as well as tourism in the Netherlands. In this situation, the travelers' decision-making for tourism destinations was heavily affected by this global event. Social media usage has played an essential role in travelers' decision-making and increased the awareness of travel-related risks from the COVID-19 outbreak. Online consumer media for the outbreak of COVID-19 has been a crucial source of information for travelers. In the current situation, tourists are using electronic word of mouth (eWOM) more and more for travel planning. Opinions provided by peer travelers for the outbreak of COVID-19 tend to reduce the possibility of poor decisions. Nevertheless, the increasing number of reviews per experience makes reading all feedback hard to make an informed decision. Accordingly, recommendation agents developed by machine learning techniques can be effective in the analysis of such social big data for the identification of useful patterns from the data, knowledge discovery, and real-time service recommendations. The current research aims to adopt a framework for the recommendation agents through topic modeling to uncover the most important dimensions of COVID-19 reviews in the Netherland forums in TripAdvisor. This study demonstrates how social networking websites and online reviews can be effective in unexpected events for travelers' decision making. We conclude with the implications of our study for future research and practice.

Identical twins with progressive kyphoscoliosis and ophthalmoplegia.

The possible differential diagnoses for children presenting with kyphoscoliosis, skeletal deformities and ophthalmoplegia are diverse. We present 11-year-old identical twins with these symptoms, with interesting etiological concern for those practicing in the fields of neurology, pediatrics, spine surgery and related specialties. A new presentation for a rare genetic condition was the final diagnosis for our patients. In this movement disorder round we describe our approach to this clinical constellation and discuss clinical significance of this genetic condition.

The Association between TNF-alpha Gene Polymorphisms and Endometriosis in An Iranian Population.

BACKGROUND: Tumor necrosis factor-alpha (TNF-α) is an important cytokine in acute inflammatory response to infective factors. Based on investigation in different populations, it is thought that this response increases in patients with endometriosis due to the presence of cytokines such as TNF-α. This study aimed to examine the association of four TNF-α polymorphisms, namely -238G/A, -308G/A, -857C/T and -863C/A, with susceptibility to endometriosis in an Iranian population. MATERIALS AND METHODS: We recruited 150 women with endometriosis and 150 women without endometriosis in this case-control study and collected 4 ml of blood from all subjects. After DNA extraction, the polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The allele frequency of TNF-α -863C/A in the case and control groups showed a significant difference [odds ratios (OR)=0.64, 95% confidence interval (CI)=0.41-0.99, P=0.047] but the result is not significant when Adjusting for multiple testing (P=0.188). No significant difference in the allele frequencies of -238G/A (OR=1.07, 95% CI=0.51-2.25, P=0.862), -308G/A (OR=0.79, 95% CI=0.43-1.45, P=0.438) and -857C/T (OR=1.03, 95% CI=0.66- 1.61, P=0.887) was observed. We adjusted all four polymorphism genotypes by age and body mass index (BMI), however, no significant difference was detected. There was an association between the case and control and BMI when adjusting by age (OR=1.082, 95% CI=1.009-1.162, P=0.028). CONCLUSION: For the first time the association of the four polymorphisms in the promoter region of the TNF-α gene with endometriosis has been conducted in women of Iranian origin. The present research reveals the -863 A allele may play a role in incidence of endometriosis among Iranian women. Development of endometriosis among those people with -863 A allele seems low. According to the results, the current study indicates that there might be a correlation between BMI and progression of endometriosis.

A soft computing approach for diabetes disease classification.

As a chronic disease, diabetes mellitus has emerged as a worldwide epidemic. The aim of this study is to classify diabetes disease by developing an intelligence system using machine learning techniques. Our method is developed through clustering, noise removal and classification approaches. Accordingly, we use expectation maximization, principal component analysis and support vector machine for clustering, noise removal and classification tasks, respectively. We also develop the proposed method for incremental situation by applying the incremental principal component analysis and incremental support vector machine for incremental learning of data. Experimental results on Pima Indian Diabetes dataset show that proposed method remarkably improves the accuracy of prediction and reduces computation time in relation to the non-incremental approaches. The hybrid intelligent system can assist medical practitioners in the healthcare practice as a decision support system.

Genetic Screening of Iranian Patients with 46,XY Disorders of Sex Development.

BACKGROUND: Disorders of sex development (DSDs) belong to uncommon pathologies and result from abnormalities during gonadal determination and differentiation. Various gene mutations involved in gonadal determination and differentiation have been associated with gonadal dysgenesis. Despite advances in exploration of genes and mechanisms involved in sex disorders, most children with severe 46,XY DSDs have no definitive etiological diagnoses; therefore, the possibility that other genes or loci might play important roles in these disorders needs to be explored. METHODS: Patients (37) clinically suspicious for 46,XY gonadal dysgenesis (46,XY GD) of unknown etiology were studied. SRY, encoding the sex-determining region Y protein, NR5A1, encoding a transcription factor called steroidogenic factor 1, and DHH, encoding the desert hedgehog protein, were directly sequenced. Multiplex ligation-dependent probe amplification (MLPA) was used to detect deletions in NR0B1, encoding the DAX1 protein, and WNT4, encoding the WNT4 protein, and real-time PCR (qPCR) confirmed the MLPA data. Other potential loci have been investigated in the complete genome using Array-Comparative Genomic Hybridization, (Array CGH). RESULTS: The SRY deletion was found in five patients. One each of previously described NR5A1, DHH, and AR (androgen receptor) allelic variants were identified. A pathogenic c.2522G>A AR mutation was found in two affected brothers. A heterozygous partial deletion was found in NR5A1 and heterozygous partial duplications were found in WNT4. These deletions and duplications (del/dup) were confirmed by qPCR. The Array CGH result demonstrated one partial deletion in SOX2-OT, which encodes a member of the SOX family of transcription factors, and the exact region of the rearrangements. CONCLUSION: According to our study, del/dup mutations could be checked prior to point mutations, SOX2-OT has a potential role in gonadal dysgenesis, and Array CGH has a prominent role in gonadal dysgenesis diagnosis.

Accuracy Improvement for Predicting Parkinson's Disease Progression.

Parkinson's disease (PD) is a member of a larger group of neuromotor diseases marked by the progressive death of dopamineproducing cells in the brain. Providing computational tools for Parkinson disease using a set of data that contains medical information is very desirable for alleviating the symptoms that can help the amount of people who want to discover the risk of disease at an early stage. This paper proposes a new hybrid intelligent system for the prediction of PD progression using noise removal, clustering and prediction methods. Principal Component Analysis (PCA) and Expectation Maximization (EM) are respectively employed to address the multi-collinearity problems in the experimental datasets and clustering the data. We then apply Adaptive Neuro-Fuzzy Inference System (ANFIS) and Support Vector Regression (SVR) for prediction of PD progression. Experimental results on public Parkinson's datasets show that the proposed method remarkably improves the accuracy of prediction of PD progression. The hybrid intelligent system can assist medical practitioners in the healthcare practice for early detection of Parkinson disease.

An ABCD1 Mutation (c.253dupC) Caused Diverse Phenotypes of Adrenoleukodystrophy in an Iranian Consanguineous Pedigree.

OBJECTIVES: Current study was the first to report a consanguineous Iranian pedigree with ABCD1 mutation. METHODS: Targeted molecular analysis was initially performed in three affected individuals in one family suspected to have X-ALD due to chronic progressive spasticity. Upon confirmation of genetic diagnosis, further neurologic and genetic evaluation of all family members was done. RESULTS: A mutation in ABCD1 was identified in 35 affected individuals (out 96 pedigree members). The c. 253dup, in exon 1, leads to a frame shift and a premature stop codon at amino acid position 194 (p.Arg85Profs*110). Surprisingly, affected individuals in our cohort show some variability in phenotype, including childhood cerebral ALD, adrenomyeloneuropathy, and addison-only disease phenotypes, expanding the phenotype of X-ALD with p.Arg85Profs*110. CONCLUSION: This report characterizes the clinical spectrum of an expanded Iranian pedigree with X-ALD due to an ABCD1 mutation. Given a high frequency of carriers in this region, we expect the prevalence of X-ALD to be higher, underscoring the importance of genetic counseling through reliable identification of heterozygous as well as homozygote females in consanguineous communities.

Association study of the common polymorphisms in the folate-methionine pathway with retinoblastoma.

BACKGROUND: Folate and methionine metabolism enzymes could affect DNA synthesis and repair, and their methylation and polymorphisms have been associated with some forms of cancer. This study was carried out to investigate whether the MTHFR C677T (rs1801133), MTHFR A1298C (rs1801131) and TYMS 2R/3R (rs34743033) polymorphisms are associated with susceptibility to retinoblastoma in an Iranian population. METHODS: A case-control study was conducted involving 96 patients with retinoblastoma and 204 healthy controls. Genotyping of the MTHFR C677T, MTHFR A1298C, and TYMS 2R/3R polymorphism were assessed by PCR-RFLP, high resolution melting curve (HRM), and PCR methods, respectively. RESULTS: The frequencies of MTHFR 677CT and 677TT genotypes were significantly lower in cases than controls (p values, 0.012 and 0.034, respectively). The MTHFR 677T allele was significantly lower in patients than in the control group (p = 0.003). In contrast, no association was observed with respect to the MTHFR A1298C and TYMS 2R/3R polymorphisms. CONCLUSIONS: The MTHFR C677T polymorphism was associated with the risk of retinoblastoma in this Iranian population and the T allele had a protective effect on the susceptibility to retinoblastoma.

Methionine synthase A2756G variation is associated with the risk of retinoblastoma in Iranian children.

Association of epigenetic modifications with cancer has been widely studied. Gene-specific hypermethylation and global DNA hypomethylation are the most frequently observed patterns in great number of tumors. The methionine synthase (MTR) gene plays key role in maintaining adequate intracellular folate, methionine and normal homocysteine concentrations and, its polymorphism have been associated with the risk of retinoblastoma and other neoplasms. We evaluated the association of MTR A2756G polymorphism with the risk of retinoblastoma in an Iranian population. Totally, 150 retinoblastoma patients and 300 individuals with no family history of cancer as control were included in this study. Genotyping of the A2756G polymorphism was performed by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) using the restriction enzymes HaeIII. Our results showed that the "G" was the minor allele with a frequency of 31.7% and 20.3% in both retinoblastoma and control groups, respectively. The frequency of the 2756GG genotype (P=0.023) and 2756G allele (P=0.0001) were significantly higher in the patients than control group, respectively. Individual with the 2756GG genotype had a 2.99 fold increased risk for retinoblastoma. According to our results, the MTR A2756G polymorphism was associated with the risk of retinoblastoma in Iranian patients.

Comparative evaluation of differentiation potential of menstrual blood- versus bone marrow-derived stem cells into hepatocyte-like cells.

Menstrual blood has been introduced as an easily accessible and refreshing stem cell source with no ethical consideration. Although recent works have shown that menstrual blood stem cells (MenSCs) possess multi lineage differentiation capacity, their efficiency of hepatic differentiation in comparison to other stem cell resources has not been addressed so far. The aim of this study was to investigate hepatic differentiation capacity of MenSCs compared to bone marrow-derived stem cells (BMSCs) under protocols developed by different concentrations of hepatocyte growth factor (HGF) and oncostatin M (OSM) in combination with other components in serum supplemented or serum-free culture media. Such comparison was made after assessment of immunophenotye, trans-differentiation potential, immunogenicity and tumorigeicity of these cell types. The differential expression of mature hepatocyte markers such as albumin (ALB), cytokeratin 18 (CK-18), tyrosine aminotransferase and cholesterol 7 alpha-hydroxylase activities (CYP7A1) at both mRNA and protein levels in differentiating MenSCs was significantly higher in upper concentration of HGF and OSM (P1) compared to lower concentration of these factors (P2). Moreover, omission of serum during differentiation process (P3) caused typical improvement in functions assigned to hepatocytes in differentiated MenSCs. While up-regulation level of ALB and CYP7A1 was higher in differentiated MenSCs compared to driven BMSCs, expression level of CK-18, detected level of produced ALB and glycogen accumulation were lower or not significantly different. Therefore, based on the overall comparable hepatic differentiation ability of MenSCs with BMSCs, and also accessibility, refreshing nature and lack of ethical issues of MenSCs, these cells could be suggested as an apt and safe alternative to BMSCs for future stem cell therapy of chronic liver diseases.

Mutation Analysis of SLC20A2 and SPP2 as Candidate Genes for Familial Idiopathic Basal Ganglia Calcification.

BACKGROUND: Familial Idiopathic Basal Ganglia Calcification (IBGC) is a rare neurodegenerative disorder which is usually transmitted as an autosomal dominant trait. IBGC is genetically heterogeneous and SLC20A2, on chromosome 8p21.1-8q11.23, is the first gene found in IBGC-affected patients with varied ancestry. On the other hand, several candidate genes for IBGC on chromosome 2q37, including the SPP2 gene, may play a role in inhibiting calcification. METHODS: Totally, 22 members of a three generational Iranian family affected by IBGC, with an autosomal dominant pattern of inheritance were included in this study. DNA was extracted from the whole blood using standard salting out method. To find a mutation responsible for IBGC, we sequenced the coding region of SLC20A2 as well as promoter and coding region of SPP2 in the index subject of IBGC-affected family. RESULTS: Pathogenic mutation was found neither in SLC20A2 nor in SPP2. CONCLUSION: Our results strengthen genetic heterogeneity of this condition. Additional mutation studies are necessary to find a gene or genes responsible for IBGC in this affected family.

Recurrent Hepatitis in Two Iranian Children: A Novel (Q166R) Mutation in EIF2AK3 Leading to Wolcott-Rallison Syndrome.

Early-onset diabetes, liver dysfunction, growth retardation, spondyloepiphyseal dysplasia, and tendency to skeletal fractures due to osteopenia are characteristics of Wolcott-Rallison syndrome (WRS). Eukaryotic translation initiation factor 2α kinase (EIF2AK3) is the only known gene, which is responsible for this rare autosomal recessive disorder. Here, we report two siblings a girl and a boy with diabetes mellitus (DM) who presented in one and two months of age respectively. Recurrent self-limiting hepatitis developed later, and severe hepatic failure resulted in death of the first child. The second child visited was a 7.75 year old boy who had spondyloepiphyseal dysplasia and subclinical hypothyroidism besides DM and recurrent hepatitis. We suggested WRS for this patient, and it was confirmed by identification of a novel homozygous missense mutation (Q166R) in exon 3 of the EIF2AK3 gene. The aim of this report is to remind the possibility of WRS in isolated neonatal diabetes; while, the other clinical manifestations of this syndrome including its major symptom of recurrent hepatitis may appear later.

Screening for large rearrangements of the RB1 gene in Iranian patients with retinoblastoma using multiplex ligation-dependent probe amplification.

PURPOSE: To screen deletions/duplications of the RB1 gene in a large cohort of Iranian patients using the multiplex ligation-dependent probe amplification (MLPA) technique. METHODS: A total of 121 patients with retinoblastoma, involving 55 unilateral and 66 bilateral or familial retinoblastomas, were included in this study. Among these patients, 121 blood and 43 tissue samples were available. DNA was extracted from the blood and tissue samples and analyzed with an RB1-specific MLPA probe set. The mutation findings were validated with SYBR Green Real-Time PCR. RESULTS: Twenty-two mutations were found in 21 patients; of these, ten mutations were detected in patients with isolated unilateral retinoblastoma. CONCLUSIONS: Our results suggested that MLPA is a fast, reliable, and powerful method for detecting deletions/duplications in patients with retinoblastoma.

Genotyping of Polymorphic Microsatellite Markers Linked to RB1 Locus in Iranian Population.

BACKGROUND: Retinoblastoma is the most common intraocular tumor in childhood and mutation in the RB1 gene will trigger the tumorigenesis. So far, a wide range of the mutations along the length of RB1 gene have been reported. However, some could not be detected by common detection methods. In such condition, linkage analysis using microsatellite markers is suggested to trace unknown RB1 mutations in the affected family. The aim of the present study was to evaluate the heterozygosity rates and genotyping of three microsatellite markers near or inside of the RB1 gene. METHODS: Totally, 120 unrelated healthy people from Fardis, Karaj, Iran were recruited and from each participant genomic DNA was extracted from 5 ml of peripheral blood. Three microsatellite markers D13S153, D13S156 and D13S128 located within or adjacent to the RB1 gene were selected for linkage analysis. The reliability of microsatellite markers and linkage analysis were investigated in 10 members of 2 families with familial retinoblastoma. RESULTS: Our results showed that heterozygosity rates for the three markers D13S153, D13S156 and D13S128 were 74, 70 and 78%, respectively. On the other hand, 2 and 36 out of 120 people were homozygote and heterozygous for all loci, respectively. CONCLUSION: Given the heterozygosity rates, it may be concluded that all microsatellite markers D13S153, D13S156 and D13S128 are informative and have a high rate of heterozygosity and sensitivity. Therefore, tracing the unknown RB1 mutated alleles using linkage analysis in Iranian family with familial retinoblastoma could be recommended by means of these three microsatellite markers.