Predictors of forniceal rupture in patients with obstructing ureteral calculi: Analysis of multicenter data.

Background: Renal forniceal rupture (FR) is a unique complication of obstructive uropathy. This study aimed to identify the predictors of FR among patients presenting with renal colic due to obstructing ureteral calculi. Materials and Methods: After obtaining ethics approval, electronic records of patients from three National Guard hospitals in Saudi Arabia were reviewed between 2016 and 2020 to identify patients who presented with renal colic and were diagnosed with FR due to obstructive ureteric stones (FR group). An equivalent number of consecutive patients presenting with renal colic due to obstructing ureteric stones without FR was selected as a control group (non-FR group). Patients were grouped according to age group (<30, 30-40, 41-50, and >50 years), body mass index (BMI) class, gender, comorbidities, grade of hydronephrosis, location of the stone in the ureter, size of the stone (<3 mm, 3-7 mm, and >7 mm), and stone former status. Baseline patients' and stone characteristics were compared, and a regression analysis was performed to identify predictors of FR. Results: A total of 50 patients with FR were identified, and a control group of 50 patients without FR were selected. The baseline patients' and stone demographic characteristics in terms of age (P = 0.42), gender (P = 0.275), BMI (P = 0.672), comorbidity, grade of hydronephrosis (P = 0.201), and stone location (P = 0.639) were comparable between the FR group and the non-FR group. However, the stone size was statistically significant between both groups (P = 0.014). On multivariable analysis, it was found that the stone size was associated with a significantly higher increase in the incidence of FR (odds ratio [OR]: 6.5 [1.235-34.434]; P = 0.027). Furthermore, the age group between 30 and 40 years was potentially at a lower risk for FR (OR: 0.262 [0.069-0.999]; P = 0.049). Conclusion: This multicenter study showed that the stone size 3-7 mm had a six-fold increase in the chance of FR, and the age group between 30 and 40 years is potentially at a lower risk for FR.

Smartphone and new tools for atrial fibrillation diagnosis: evidence for clinical applicability.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in adults. AF increases the risk of heart failure, cardiac ischemic disease, dementia and Alzheimer's disease. Either clinical and subclinical AF increase the risk of stroke and worsen the patients' clinical outcome. The early diagnosis of AF episodes, even if asymptomatic or clinically silent, is of pivotal importance to ensure prompt and adequate thromboembolic risk prevention therapies. The development of technology is allowing new systematic mass screening possibilities, especially in patients with higher stroke risk. The mobile health devices available for AF detection are: smartphones, wrist-worn, earlobe sensors and handheld ECG. These devices showed a high accuracy in AF detection especially when a combined approach with single-lead ECG and photoplethysmography algorithms is used. The use of wearable devices for AF screening is a feasible method but more head-to-head comparisons between mHealth and medical devices are needed to establish their comparative effectiveness across different study populations.

Athletes' knowledge and attitude concerning the meniscus, meniscal injury, and management.

Introduction: Knee injuries largely vary including cartilaginous, ligamentous, bony, and tendinous injuries. Greatest of the reported knee injuries associated with in a non-contact method includes mainly the anterior cruciate ligament (ACL). Additionally, medial and lateral menisci act as shock absorbers with an additional role in stabilizing the joint which can be or partially or totally torn. The current study aimed to assess athletes' knowledge and attitude concerning the meniscus, meniscal injury, and management. Methodology: A descriptive cross-sectional study was conducted to achieve the objectives. A pre-structured electronic questionnaire was used to collect the data, covered participants socio-demographic data, personal and family history of meniscus injury and surgery, physical activity during past year, and also knowledge regarding the meniscal injury and management. Results: A total of 448 athletes fulfilling the inclusion criteria completed the study questionnaire. Participants 'age ranged from 18 to 60 years with mean age of 26.7 ± 7.7 years old. A total of 256 (57.1%) participants were males. Exact of 21 participants had meniscus surgery. As for family history, 75 (16.7%) had family history of meniscus injury. Exact of 95 (21.2%) athletes had good knowledge level, while vast majority (78.8%; 353) had poor knowledge level. Conclusions: In conclusion, the study showed that the estimated rate of meniscus injury and surgery was not high (within the international range). The participants' knowledge regarding meniscus injury and meniscus surgery with its related management was unsatisfactory, where 1 out of each 5 was knowledgeable.

Homozygous mutation in ABCA4 associated with cone rod dystrophy in a patient with Turner syndrome.

PURPOSE: We report a special case of a patient who presented with two rare genetic diseases, Turner syndrome and cone-rod dystrophy (CRD), caused by mutation in the ABCA4 gene. METHODS: We present a case of a 12-year-old female with a progressive visual loss, poor night vision and short stature. We performed a clinical, karyotype of peripheral blood and molecular genetic study. DNA sample from the index patient was subjected to whole exome sequencing. Variants localized in homozygous regions were validated by Sanger sequencing. RESULTS: Fundus examination presented CRD phenotype and the general examination revealed short stature, aortic coarctation and infantile uterus, without visible ovaries on pelvic ultrasound. The karyotype of peripheral blood showed monosomy 45,X. We identified a known homozygous deletion c.[885delC];[885delC] in ABCA4, resulting in a frameshift at the position p.[L296Cfs*4];[ L296Cfs*4] . In addition, mutations in RPGR and ORF15 were excluded. CONCLUSIONS: Several ocular disorders are known to be associated with Turner syndrome, however, in this case, we hypothesize that CRD is not related to Turner syndrome but may be a manifestation of the lack of a normal X chromosome with ABCA4 mutation.

Genetic spectrum of retinal dystrophies in Tunisia.

We report the molecular basis of the largest Tunisian cohort with inherited retinal dystrophies (IRD) reported to date, identify disease-causing pathogenic variants and describe genotype-phenotype correlations. A subset of 26 families from a cohort of 73 families with clinical diagnosis of autosomal recessive IRD (AR-IRD) excluding Usher syndrome was analyzed by whole exome sequencing and autozygosity mapping. Causative pathogenic variants were identified in 50 families (68.4%), 42% of which were novel. The most prevalent pathogenic variants were observed in ABCA4 (14%) and RPE65, CRB1 and CERKL (8% each). 26 variants (8 novel and 18 known) in 19 genes were identified in 26 families (14 missense substitutions, 5 deletions, 4 nonsense pathogenic variants and 3 splice site variants), with further allelic heterogeneity arising from different pathogenic variants in the same gene. The most common phenotype in our cohort is retinitis pigmentosa (23%) and cone rod dystrophy (23%) followed by Leber congenital amaurosis (19.2%). We report the association of new disease phenotypes. This research was carried out in Tunisian patients with IRD in order to delineate the genetic population architecture.

Correction: Habibi I. et al. "Clinical and Genetic Findings of Autosomal Recessive Bestrophinopathy (ARB)" Genes, 2019, 10, 953.

The authors wish to make a correction to the published version of their paper [...].

Clinical and Genetic Findings of Autosomal Recessive Bestrophinopathy (ARB).

Mutations in BEST1 cause several phenotypes including autosomal dominant (AD) Best vitelliform macular dystrophy type 2 (BVMD), AD vitreo-retino-choroidopathy (ADVIRC), and retinitis pigmentosa-50 (RP50). A rare subtype of Bestrophinopathy exists with biallelic mutations in BEST1. Its frequency is estimated to be 1/1,000,000 individuals. Here we report 6 families and searched for a genotype-phenotype correlation. All patients were referred due to reduced best-corrected visual acuity (BCVA), ranging from 0.1/10 to 3/10. They all showed vitelliform lesions located at the macula, sometimes extending into the midperiphery, along the vessels and the optic disc. Onset of the disease varied from the age of 3 to 25 years. Electrooculogram (EOG) revealed reduction in the EOG light rise in all patients. Molecular analysis revealed previously reported mutations p.(E35K);(E35K), p.(L31M);(L31M), p.(R141H);(A195V), p.(R202W);(R202W), and p.(Q220*);(Q220*) in five families. One family showed a novel mutation: p.(E167G);(E167G). All mutations were heterozygous in the parents. In one family, heterozygous children showed various reductions in the EOG light rise and autofluorescent deposits. Autosomal recessive Bestrophinopathy (ARB), although rare, can be recognized by its phenotype and should be validated by molecular analysis. Genotype-phenotype correlations are difficult to establish and will require the analysis of additional cases.

Phenotypic Progression of Stargardt Disease in a Large Consanguineous Tunisian Family Harboring New ABCA4 Mutations.

To assess the progression of Stargardt (STGD) disease over nine years in two branches of a large consanguineous Tunisian family. Initially, different phenotypes were observed with clinical intra- and interfamilial variations. At presentation, four different retinal phenotypes were observed. In phenotype 1, bull's eye maculopathy and slight alteration of photopic responses in full-field electroretinography were observed in the youngest child. In phenotype 2, macular atrophy and yellow white were observed in two brothers. In phenotype 3, diffuse macular, peripapillary, and peripheral RPE atrophy and hyperfluorescent dots were observed in two sisters. In phenotype 4, Stargardt disease-fundus flavimaculatus phenotype was observed in two cousins with later age of onset. After a progression of 9 years, all seven patients displayed the same phenotype 3 with advanced stage STGD and diffuse atrophy. WES and MLPA identified two ABCA4 mutations M1: c.[(?_4635)_(5714+?)dup; (?_6148)_(6479_+?) del] and M2: c.[2041C>T], p.[R681∗]. In one branch, the three affected patients had M1/M1 causal mutations and in the other branch the two affected patients had M1/M2 causal mutations. After 9-year follow-up, all patients showed the same phenotypic evolution, confirming the progressive nature of the disease. Genetic variations in the two branches made no difference to similar end-stage disease.

Defining the pattern of initiation of monomorphic ventricular tachycardia using the beat-to-beat intervals recorded on implantable cardioverter defibrillators from the RAFT study: A computer-based algorithm.

Arrhythmia onset pattern may have important implications on morbidity, recurrent implantable cardioverter defibrillator (ICD) shocks, and mortality, given the proposed correlation between initiation pattern and arrhythmia mechanism. Therefore, we developed and tested a computer-based algorithm to differentiate the pattern of initiation based on the beat-to-beat intervals of the ventricular tachycardia (VT) episodes in ICD recordings from the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT). Intervals on intracardiac electrograms from ICDs were analyzed backwards starting from the marker of VT detection, comparing each interval with the average tachycardia cycle length. If the morphology of the beat initiating the VT was similar to the morphology of the VT itself, the episode was considered sudden. If the morphology of the beat initiating the VT was not similar to the morphology of the VT itself, the episode was considered non-sudden. The capability of the algorithm to classify the pattern of initiation based only on the beat-to-beat intervals allows for the classification and analysis of large datasets to further investigate the clinical importance of classifying VT initiation. If analysis of the VT initiation proves to be of clinical value, this algorithm could potentially be integrated into ICD software, which would make it easily accessible and potentially helpful in clinical decision-making.

Clinical Assessment of the Congenital Absence of Palmaris Longus and Flexor Digitorum Superficialis Muscles in Young Saudi Population.

Introduction. Congenital Palmaris Longus (PL) absence was found in 15%-20.25% of population globally. This condition and Flexor Digitorum Superficialis (FDS) tendon absence in little finger are not known in Saudi Arabia. We studied prevalence of PL and FDS agenesis in Saudi Arabian population. Methods. A random cross-sectional study was carried out after an ethical approval in the Riyadh universities. Schaeffer's test was used to examine PL absence. The Modified test was used to examine FDS absence. Data was analyzed using Microsoft Excel and the SPSS Software version 22. Results. The volunteers, 331, males 164 (49.5%) and females 167 (50.5%), mean age of 23 (SD ± 5.3), showed right hand dominance in 294 (88.8%) and bilateral absence of PL and FDS in 15.1% and 14.8%, respectively. The hand dominance showed no significant relation between PL and FDS absence, p value = 0.788, 0.835, respectively. Generally, we found a weak correlation between absence of the PL and FDS, p value ≥ 0.595. Conclusion. The bilateral absence of PL and FDS was found as 15.1% and 14.8%, respectively. Variation of the FDS tendon absence was an independent entity for the PL absence. The dominance of hands was not related to the tested variables found in PL and FDS agenesis.

Ameliorative properties of Iranian Trigonella foenum-graecum L. seeds and Punica granatum L. peel extracts in streptozotocin-induced experimental diabetic guinea pigs

Objective To assess the ameliorative properties of Iranian Trigonella foenum-graecum L. (T. foenum-graecum) seeds and Punica granatum L. (P. granatum) peel extracts against streptozotocin-induced diabetes in male guinea pigs. Methods Sixty guinea pigs were divided into six groups (10 guinea pigs per group). Group 1 consisted of normal animals. Groups 2 and 3 were treated with Iranian T. foenum-graecum seeds and P. granatum peel extract alone, respectively. Group 4 was treated with streptozotocin only; whereas Groups 5 and 6 receiving streptozotocin were treated with Iranian T. foenum-graecum seeds and P. granatum peel extract, respectively. All animals were treated for 30 days, and the body weight, blood and liver biochemical parameters were measured. Results Guinea pigs exposed to streptozotocin showed an alteration in body weight gain, fasting glucose level, kidney function parameters (blood urea nitrogen and creatinine) as well as decreased serum and hepatic total protein level. In addition, it increased the cholesterol and triglyceride level, while decreasing the hepatic glucose-6 phosphate dehydrogenase activity, glycogen, glutathione content and hepatic catalase activity. Oral treatment with T. foenum-graecum seeds and P. granatum peel extracts revealed significant protective properties with respect to body weight gain and other biochemical parameters studied. Conclusions The Iranian T. foenum-graecum seeds and P. granatum peel extracts are significantly potent in ameliorating diabetic condition induced by streptozotocin and improving various biochemical parameters in serum and liver of guinea pigs.

[Clinical characterization of the Stargardt disease and molecular exploration of the c.2041C>T mutation (ABCA4 gene) in Tunisian patients]. / Caractérisation clinique de la maladie de Stargardt et exploration moléculaire de la c.2041C>T (gène ABCA4) chez des patients tunisiens.

In order to charaterize the Stargardt disease, the molecular exploration of the c.2041C>T mutation (ABCA4 gene) and genotype phenotype correlation in Tunisian patients, seven unrelated propositi underwent a complete ophthalmological examination. The search for the mutation was performed by a direct sequencing after a specific amplification of exon 14 of the ABCA4 gene. Baseline, the average age of propositi was 20.7 ± 15 years and the sex-ratio was 1.3. The age of the visual impairment perception was 8.1 ± 3.2 years. In all patients, the loss of visual acuity was bilateral and ranged from "counting fingers" to 3.2/10. Fundus and retinal fluorescein angiography examination showed advanced stages of the disease. The allele frequency of the c.2041C>T was 28.5% (4/14). We have reported this mutation in two patients. Their average age at onset was 5 and a half years and the disease progression was rapid with a severe visual loss after 1 and 5 years. All patients had a juvenile macular dystrophy with flavimaculatus flecks. To our knowledge, we reported for the first time the homozygous state of the c.2041C>T mutation. Among homozygous patients, the age at onset was early, the loss of visual acuity was important and the prognosis was severe. Due to the severity of the phenotype and the high rate of inbreeding, genetic counseling for healthy heterozygotes is essential.

Defective regulation of microRNA target genes in myoblasts from facioscapulohumeral dystrophy patients.

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant hereditary neuromuscular disorder linked to the deletion of an integral number of 3.3-kb-long macrosatellite repeats (D4Z4) within the subtelomeric region of chromosome 4q. Most genes identified in this region are overexpressed in FSHD myoblasts, including the double homeobox genes DUX4 and DUX4c. We have carried out a simultaneous miRNome/transcriptome analysis of FSHD and control primary myoblasts. Of 365 microRNAs (miRNAs) analyzed in this study, 29 were found to be differentially expressed between FSHD and normal myoblasts. Twenty-one microRNAs (miR-1, miR-7, miR-15a, miR-22, miR-30e, miR-32, miR-107, miR-133a, miR-133b, miR-139, miR-152, miR-206, miR-223, miR-302b, miR-331, miR-362, miR-365, miR-382, miR-496, miR-532, miR-654, and miR-660) were up-regulated, and eight were down-regulated (miR-15b, miR-20b, miR-21, miR-25, miR-100, miR-155, miR-345, and miR-594). Twelve of the miRNAs up-regulated in FHSD were also up-regulated in the cells ectopically expressing DUX4c, suggesting that this gene could regulate miRNA gene transcription. The myogenic miRNAs miR-1, miR-133a, miR-133b, and miR-206 were highly expressed in FSHD myoblasts, which nonetheless did not prematurely enter myogenic differentiation. This could be accounted for by the fact that in FSHD myoblasts, functionally important target genes, including cell cycle, DNA damage, and ubiquitination-related genes, escape myogenic microRNA-induced repression.

Standard precautions and infection control, medical students' knowledge and behavior at a Saudi university: the need for change.

BACKGROUND: No previous studies have reported the knowledge of Saudi medical students about Standard Precautions (SPs) and infection control. OBJECTIVES: The objectives of this study were to assess medical students' knowledge in clinical years at King Faisal University, Saudi Arabia about SPs' and to explore their attitudes toward the current curricular/training in providing them with effective knowledge and necessary skills with regard to SPs. SUBJECTS AND METHODS: This cross sectional study targeted students in clinical stage at College of Medicine, King Faisal University, Saudi Arabia. A pre-tested anonymous self administered data collection form was used. Inquires about students' characteristics, general concepts of infection control/SPs, hand hygiene, personal protective equipment, sharp injuries and disposal, and care of health providers were included. The main source of information for each domain was also inquired. The second part dedicated to explore the attitudes toward the curricular and teaching relevant to SPs. RESULTS: A total of 251 students were included. Knowledge scores in all domains were considerably low, 67 (26.7%) students scored ? 24 (out of 41points) which was considered as an acceptable level of knowledge, 22.2% in 4th year, 20.5% in 5th year and 36.8% in 6th year. Sharp injuries, personal protective equipment and health care of the providers showed the least knowledge scores. The main sources of knowledge were self learning, and informal bed side practices The majority of students' believed that the current teaching and training are insufficient in providing them with the necessary knowledge and skills regarding SPs. CONCLUSION: The overall knowledge scores for SPs were low especially in the domains of hand hygiene, sharp management, and personal protective equipment reflecting insufficient and ineffective instructions received by medical students through the current curriculum posing them vulnerable to health facilities related infections. Proper curricular reform and training are required to protect students and their patients.

Prevalence and factors associated with the use of illicit substances among male university students in Kuwait.

OBJECTIVES: To estimate the prevalence of illicit use of substances and identify the factors associated with illicit drug use among male students in the state-run Kuwait University and private universities in Kuwait. SUBJECTS AND METHODS: The study was a cross-sectional survey with a sample of 1,587 male students from both private universities (n = 869) and the public (n = 718) Kuwait University in Kuwait. A self-administered questionnaire was used to collect data. Overall lifetime prevalence of substance use was computed with 95% confidence interval. Logistic regression was used to identify the factors influencing substance use, which was adjusted for potential confounders. RESULTS: The total lifetime prevalence of illicit drug use was 14.4% and the most frequently used illicit substance was marijuana (11%). The substance use in general varied significantly (p ≤ 0.001) between private (18%) and public (10%) universities. Multivariate logistic regression model revealed that drug use was positively associated with age, poor academic performance, high family income, being an only child, divorced parents, and graduation from a private high school. CONCLUSION: Drug use among male university students in Kuwait was high and requires attention and appropriate intervention. The factors identified with drug use in this study could be utilized to develop appropriate public health policies and preventive measures that may improve the health status of the student population.

Simultaneous miRNA and mRNA transcriptome profiling of human myoblasts reveals a novel set of myogenic differentiation-associated miRNAs and their target genes.

BACKGROUND: miRNA profiling performed in myogenic cells and biopsies from skeletal muscles has previously identified miRNAs involved in myogenesis. RESULTS: Here, we have performed miRNA transcriptome profiling in human affinity-purified CD56+ myoblasts induced to differentiate in vitro. In total, we have identified 60 miRNAs differentially expressed during myogenic differentiation. Many were not known for being differentially expressed during myogenic differentiation. Of these, 14 (miR-23b, miR-28, miR-98, miR-103, miR-107, miR-193a, miR-210, miR-324-5p, miR-324-3p, miR-331, miR-374, miR-432, miR-502, and miR-660) were upregulated and 6 (miR-31, miR-451, miR-452, miR-565, miR-594 and miR-659) were downregulated. mRNA transcriptome profiling performed in parallel resulted in identification of 6,616 genes differentially expressed during myogenic differentiation. CONCLUSIONS: This simultaneous miRNA/mRNA transcriptome profiling allowed us to predict with high accuracy target genes of myogenesis-related microRNAs and to deduce their functions.

Glutathione peroxidase 3, a new retinoid target gene, is crucial for human skeletal muscle precursor cell survival.

Protection of satellite cells from cytotoxic damages is crucial to ensure efficient adult skeletal muscle regeneration and to improve therapeutic efficacy of cell transplantation in degenerative skeletal muscle diseases. It is therefore important to identify and characterize molecules and their target genes that control the viability of muscle stem cells. Recently, we demonstrated that high aldehyde dehydrogenase activity is associated with increased viability of human myoblasts. In addition to its detoxifying activity, aldehyde dehydrogenase can also catalyze the irreversible oxidation of vitamin A to retinoic acid; therefore, we examined whether retinoic acid is important for myoblast viability. We showed that when exposed to oxidative stress induced by hydrogen peroxide, adherent human myoblasts entered apoptosis and lost their capacity for adhesion. Pre-treatment with retinoic acid reduced the cytotoxic damage ex vivo and enhanced myoblast survival in transplantation assays. The effects of retinoic acid were maintained in dystrophic myoblasts derived from facioscapulohumeral patients. RT-qPCR analysis of antioxidant gene expression revealed glutathione peroxidase 3 (Gpx3), a gene encoding an antioxidant enzyme, as a potential retinoic acid target gene in human myoblasts. Knockdown of Gpx3 using short interfering RNA induced elevation in reactive oxygen species and cell death. The anti-cytotoxic effects of retinoic acid were impaired in GPx3-inactivated myoblasts, which indicates that GPx3 regulates the antioxidative effects of retinoic acid. Therefore, retinoid status and GPx3 levels may have important implications for the viability of human muscle stem cells.

Functional muscle impairment in facioscapulohumeral muscular dystrophy is correlated with oxidative stress and mitochondrial dysfunction.

Facioscapulohumeral muscular dystrophy (FSHD), the most frequent muscular dystrophy, is an autosomal dominant disease. In most individuals with FSHD, symptoms are restricted to muscles of the face, arms, legs, and trunk. FSHD is genetically linked to contractions of the D4Z4 repeat array causing activation of several genes. One of these maps in the repeat itself and expresses the DUX4 (the double homeobox 4) transcription factor causing a gene deregulation cascade. In addition, analyses of the RNA or protein expression profiles in muscle have indicated deregulations in the oxidative stress response. Since oxidative stress affects peripheral muscle function, we investigated mitochondrial function and oxidative stress in skeletal muscle biopsies and blood samples from patients with FSHD and age-matched healthy controls, and evaluated their association with physical performances. We show that specifically, oxidative stress (lipid peroxidation and protein carbonylation), oxidative damage (lipofuscin accumulation), and antioxidant enzymes (catalase, copper-zinc-dependent superoxide dismutase, and glutathione reductase) were higher in FSHD than in control muscles. FSHD muscles also presented abnormal mitochondrial function (decreased cytochrome c oxidase activity and reduced ATP synthesis). In addition, the ratio between reduced (GSH) and oxidized glutathione (GSSG) was strongly decreased in all FSHD blood samples as a consequence of GSSG accumulation. Patients with FSHD also had reduced systemic antioxidative response molecules, such as low levels of zinc (a SOD cofactor), selenium (a GPx cofactor involved in the elimination of lipid peroxides), and vitamin C. Half of them had a low ratio of gamma/alpha tocopherol and higher ferritin concentrations. Both systemic oxidative stress and mitochondrial dysfunction were correlated with functional muscle impairment. Mitochondrial ATP production was significantly correlated with both quadriceps endurance (T(LimQ)) and maximal voluntary contraction (MVC(Q)) values (rho=0.79, P=0.003; rho=0.62, P=0.05, respectively). The plasma concentration of oxidized glutathione was negatively correlated with the T(LimQ), MVC(Q) values, and the 2-min walk distance (MWT) values (rho=-0.60, P=0.03; rho=-0.56, P=0.04; rho=-0.93, P<0.0001, respectively). Our data characterized oxidative stress in patients with FSHD and demonstrated a correlation with their peripheral skeletal muscle dysfunction. They suggest that antioxidants that might modulate or delay oxidative insult may be useful in maintaining FSHD muscle functions.

The Krüppel-like factor 15 as a molecular link between myogenic factors and a chromosome 4q transcriptional enhancer implicated in facioscapulohumeral dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD), a dominant hereditary disease with a prevalence of 7 per 100,000 individuals, is associated with a partial deletion in the subtelomeric D4Z4 repeat array on chromosome 4q. The D4Z4 repeat contains a strong transcriptional enhancer that activates promoters of several FSHD-related genes. We report here that the enhancer within the D4Z4 repeat binds the Krüppel-like factor KLF15. KLF15 was found to be up-regulated during myogenic differentiation induced by serum starvation or by overexpression of the myogenic differentiation factor MYOD. When overexpressed, KLF15 activated the D4Z4 enhancer and led to overexpression of DUX4c (Double homeobox 4, centromeric) and FRG2 (FSHD region gene 2) genes, whereas its silencing caused inactivation of the D4Z4 enhancer. In immortalized human myoblasts, the D4Z4 enhancer was activated by the myogenic factor MYOD, an effect that was abolished upon KLF15 silencing or when the KLF15-binding sites within the D4Z4 enhancer were mutated, indicating that the myogenesis-related activation of the D4Z4 enhancer was mediated by KLF15. KLF15 and several myogenesis-related factors were found to be expressed at higher levels in myoblasts, myotubes, and muscle biopsies from FSHD patients than in healthy controls. We propose that KLF15 serves as a molecular link between myogenic factors and the activity of the D4Z4 enhancer, and it thus contributes to the overexpression of the DUX4c and FRG2 genes during normal myogenic differentiation and in FSHD.