Analysis of disease characteristics of a large patient cohort with congenital generalized lipodystrophy from the Middle East and North Africa.

BACKGROUND: Congenital generalized lipodystrophy (CGL) is a rare inherited disease characterized by a near-total absence of adipose tissue and is associated with organ system abnormalities and severe metabolic complications. Here, we have analyzed the disease characteristics of the largest CGL cohort from the Middle East and North Africa (MENA) who have not received lipodystrophy-specific treatment. METHODS: CGL was diagnosed clinically by treating physicians through physical assessment and supported by genetic analysis, fat loss patterns, family history, and the presence of parental consanguinity. Data were obtained at the time of patient diagnosis and during leptin-replacement naïve follow-up visits as permitted by available medical records. RESULTS: Data from 43 patients with CGL (37 females, 86%) were collected from centers located in eight countries. The mean (median, range) age at diagnosis was 5.1 (1.0, at birth-37) years. Genetic analysis of the overall cohort showed that CGL1 (n = 14, 33%) and CGL2 (n = 18, 42%) were the predominant CGL subtypes followed by CGL4 (n = 10, 23%); a genetic diagnosis was unavailable for one patient (2%). There was a high prevalence of parental consanguinity (93%) and family history (67%) of lipodystrophy, with 64% (n = 25/39) and 51% (n = 20/39) of patients presenting with acromegaloid features and acanthosis nigricans, respectively. Eighty-one percent (n = 35/43) of patients had at least one organ abnormality; the most frequently affected organs were the liver (70%, n = 30/43), the cardiovascular system (37%, n = 16/43) and the spleen (33%, n = 14/43). Thirteen out of 28 (46%) patients had HbA1c > 5.7% and 20/33 (61%) had triglyceride levels > 2.26 mmol/L (200 mg/dl). Generally, patients diagnosed in adolescence or later had a greater severity of metabolic disease versus those diagnosed during childhood; however, metabolic and organ system abnormalities were observed in a subset of patients diagnosed before or at 1 year of age. CONCLUSIONS: This analysis suggests that in addition to the early onset of fat loss, family history and high consanguinity enable the identification of young patients with CGL in the MENA region. In patients with CGL who have not received lipodystrophy-specific treatment, severe metabolic disease and organ abnormalities can develop by late childhood and worsen with age.

Glycan Modifications as Regulators of Stem Cell Fate.

Glycosylation is a process where proteins or lipids are modified with glycans. The presence of glycans determines the structure, stability, and localization of glycoproteins, thereby impacting various biological processes, including embryogenesis, intercellular communication, and disease progression. Glycans can influence stem cell behavior by modulating signaling molecules that govern the critical aspects of self-renewal and differentiation. Furthermore, being located at the cell surface, glycans are utilized as markers for stem cell pluripotency and differentiation state determination. This review aims to provide a comprehensive overview of the current literature, focusing on the effect of glycans on stem cells with a reflection on the application of synthetic glycans in directing stem cell differentiation. Additionally, this review will serve as a primer for researchers seeking a deeper understanding of how synthetic glycans can be used to control stem cell differentiation, which may help establish new approaches to guide stem cell differentiation into specific lineages. Ultimately, this knowledge can facilitate the identification of efficient strategies for advancing stem cell-based therapeutic interventions.

Gene transfer therapy in children with spinal muscular atrophy: A single-center experience with a cohort of 25 children.

INTRODUCTION/AIMS: New therapeutic strategies to increase survival motor neuron protein levels in spinal muscular atrophy (SMA) have focused on replacing the SMN1 gene. Onasemnogene abeparvovec was approved by the US Food and Drug Administration in 2019 for treatment of children with SMA less than 2 years of age. Postmarketing studies are limited, especially outside of Europe and the United States. Herein we describe a single-center experience with onasemnogene abeparvovec from the Middle East. METHODS: Between November 17, 2020 and January 31, 2022, 25 children with SMA received onasemnogene abeparvovec at our center in the United Arab Emirates. Data were collected on patients' demographics, age at diagnosis, SMA type, genetic information, relevant medical history, laboratory investigations, and Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) functional assessment scores at baseline and 1 and 3 months after gene therapy. RESULTS: Onasemnogene abeparvovec was well tolerated. Significant improvements in CHOP-INTEND scores were observed after the therapy. Elevation of liver enzymes and thrombocytopenia were the most common adverse events, but were transient and managed with high-dose corticosteroids. There were no life-threatening adverse events or deaths reported during the 3-month follow-up period. DISCUSSION: The study findings concurred with those of previously published studies. Side effects of gene transfer therapy are well tolerated, although serious complications can arise. In such cases, persistent transaminitis for example, steroid dose escalation is warranted with close observation of the patient's clinical status and lab values. Combination therapy should be explored as an alternative to gene transfer therapy only.

Influencing Factors of Future Specialty Choice for Undergraduate Medical Students: An Updated Experience from the UAE.

Background Medical students' career choices determine the prospects of the future medical workforce, thus influencing the delivery of medical care. This study aims to identify and provide information about factors affecting the selection of future specialties among medical students. Methods A cross-sectional study was conducted on students in both preclerkship and clerkship phases at a single institution in the United Arab Emirates. A self-administered questionnaire included questions about demographic data, most preferred specialties, and influential factors. The influential factors were measured using a Likert scale. Results Surgery and internal medicine were the most desired specialties, respectively. Gender has a significant role in influencing career choice. There was no association between preclerkship and clerkship students' career choices. The most influential factors were seeing good treatment outcomes and having abilities for the specialty. Conclusions Surgery and internal medicine were the most preferred specialties, even though significant gender differences existed in specialty choices among these students.

The genomic landscape of rare disorders in the Middle East.

BACKGROUND: Rare diseases collectively impose a significant burden on healthcare systems, especially in underserved regions, like the Middle East, which lack access to genomic diagnostic services and the associated personalized management plans. METHODS: We established a clinical genomics and genetic counseling facility, within a multidisciplinary tertiary pediatric center, in the United Arab Emirates to locally diagnose and manage patients with rare diseases. Clinical genomic investigations included exome-based sequencing, chromosomal microarrays, and/or targeted testing. We assessed the diagnostic yield and implications for clinical management among this population. Variables were compared using the Fisher exact test. Tests were 2-tailed, and P < .05 was considered statistically significant. RESULTS: We present data on 1000 patients with rare diseases (46.2% females; average age, 4.6 years) representing 47 countries primarily from the Arabian Peninsula, the Levant, Africa, and Asia. The cumulative diagnostic yield was 32.5% (95% CI, 29.7-35.5%) and was higher for genomic sequencing-based testing than chromosomal microarrays (37.9% versus 17.2%, P = 0.0001) across all indications, consistent with the higher burden of single gene disorders. Of the 221 Mendelian disorders identified in this cohort, the majority (N = 184) were encountered only once, and those with recessive inheritance accounted for ~ 62% of sequencing diagnoses. Of patients with positive genetic findings (N = 325), 67.7% were less than 5 years of age, and 60% were offered modified management and/or intervention plans. Interestingly, 24% of patients with positive genetic findings received delayed diagnoses (average age, 12.4 years; range 7-37 years), most likely due to a lack of access to genomic investigations in this region. One such genetic finding ended a 15-year-long diagnostic odyssey, leading to a life-threatening diagnosis in one patient, who was then successfully treated using an experimental allogenic bone marrow transplant. Finally, we present cases with candidate genes within regions of homozygosity, likely underlying novel recessive disorders. CONCLUSIONS: Early access to genomic diagnostics for patients with suspected rare disorders in the Middle East is likely to improve clinical outcomes while driving gene discovery in this genetically underrepresented population.

Biomaterials as a Vital Frontier for Stem Cell-Based Tissue Regeneration.

Biomaterials and tissue regeneration represent two fields of intense research and rapid advancement. Their combination allowed the utilization of the different characteristics of biomaterials to enhance the expansion of stem cells or their differentiation into various lineages. Furthermore, the use of biomaterials in tissue regeneration would help in the creation of larger tissue constructs that can allow for significant clinical application. Several studies investigated the role of one or more biomaterial on stem cell characteristics or their differentiation potential into a certain target. In order to achieve real advancement in the field of stem cell-based tissue regeneration, a careful analysis of the currently published information is critically needed. This review describes the fundamental description of biomaterials as well as their classification according to their source, bioactivity and different biological effects. The effect of different biomaterials on stem cell expansion and differentiation into the primarily studied lineages was further discussed. In conclusion, biomaterials should be considered as an essential component of stem cell differentiation strategies. An intense investigation is still required. Establishing a consortium of stem cell biologists and biomaterial developers would help in a systematic development of this field.

Case Report: Expanding the Phenotypic Spectrum of Timothy Syndrome Type 1: A Sporadic Case With a de novo CACNA1C Pathogenic Variant and Segmental Ileal Dilatation.

Background: Long QT syndactyly syndrome (long QT syndrome type 8), also known as Timothy Syndrome (TS) was first described in 1994 with still <50 case reported in the literature. The full spectrum of the syndrome is not yet known. Results: Here we report a girl who presented with new onset refractory seizures and an undiagnosed cause of intermittent abdominal distention. She also had syndactyly of her fingers and toes and was found to have prolonged QT. Upon further investigations she was found to have a de novo pathogenic variant in CACNA1C, along with Segmental Ileal Dilatation (SID), and subsequently diagnosed with Timothy syndrome. Conclusion: To our knowledge, the association of Timothy Syndrome with Segmental Ileal Dilatation, was not described before.

Analgesia and sedation modalities used with botulinum toxin injections in children with cerebral palsy: a literature review.

Cerebral palsy (CP) is a non-progressive motor dysfunction leading to multiple morbidities, including spasticity, which can be managed with botulinum toxin injection (BTI). This literature review aims to examine published studies on the efficacy and safety of different interventions used to reduce pain and anxiety associated with BTI in children with CP. A literature review of all published evidence in English language, or with an English translation between 1999 and 2019, using PubMed, EBSCO host, and Medline databases was carried out. All identified papers were screened for inclusion criteria. Data from included papers were entered and analyzed on an Excel database. Twenty-one studies conducted in multiple clinical settings identified 10 different analgesia and sedation modalities including intravenous ketamine, midazolam, inhaled nitrous oxide, general anesthesia, and Eutectic Mixture of Local Anesthetics (EMLA®) cream. Most of the studies were descriptive with the exception of two clinical trials and one qualitative study. All interventions had some adverse effects, but they were generally mild and no long-term sequelae were reported. The combination of inhaled nitrous oxide with EMLA® cream showed promising primary results. However, ketamine and midazolam combination could be a safe alternative. Currently, there is no sufficient data to draw on the superiority of any modality. Further high-quality studies are warranted.

Potential role for microRNA-16 (miR-16) and microRNA-93 (miR-93) in diagnosis and prediction of disease progression in mycosis fungoides in Egyptian patients.

Mycosis Fungoides (MF) is the most common type of cutaneous T-cell lymphomas. Early stage patients are treated with topical therapies and have normal life expectancy whereas patients with advanced disease encounter frequent relapses and have a five-year survival rate that does not exceed 15%. The aim of the present study was to characterize the expression of microRNA-16 (miR-16) and microRNA-93 (miR-93) in early and advanced cases of MF in relation to the clinicopathological parameters. Ten skin biopsies of early and advanced MF were investigated for the expression of miR-16 and miR-93 using RT-PCR. Immunohistochemical expression of apoptosis markers (BCL-2 and Survivin) were also investigated in the studied cases compared to normal skin and eczema biopsies. In the present study, BCL-2 and Survivin showed strong positive expression on neoplastic lymphocytes in all cases of MF regardless of their stage. We have also shown that miR-16 was significantly upregulated in advanced cases of MF compared to cases with early disease (p-value was less than 0.05). However, expression of miR-16 did not show any statistically significant correlation with age, gender, or expression of apoptotic markers. On the other hand, the expression of miR-93 showed significant downregulation in all lymphoma cases irrespective of their stage, compared to normal and eczema cases. Our results suggest that upregulation of miR-16 could be used to predict an aggressive course of the disease. We also suggest that miR-93 downregulation could serve as possible tool for establishing early diagnosis in early challenging cases. Our findings also provide consistent evidence that the anti-apoptotic molecules may play an important role in the pathogenesis of this type of cutaneous lymphomas and promote the idea that their inhibition could be an interesting novel therapeutic strategy in the treatment of MF.

Perinatal risk factors for development of retinopathy of prematurity in a tertiary neonatal intensive care unit.

OBJECTIVE: Retinopathy of prematurity (ROP) is a vasoproliferative disorder that is one of the main preventable causes of blindness among preterm neonates. This study aimed to determine the incidence of ROP and investigate the relationship between perinatal risk factors and ROP development. METHODS: This retrospective, non-interventional, non-comparative, hospital-based study was conducted at a tertiary-level neonatal intensive care unit. A total of 163 consecutive patients who met the inclusion criteria were recruited in this study. RESULTS: ROP prevalence was 0.01. During the study period, 44 patients developed ROP (27%), and 119 (73%) did not. Stage I ROP was detected in 8 patients (4.9%); stage II ROP without plus-disease in 26 patients (16%); stage II disease with comorbidities in 1 patient (0.6%); and stage III disease in 9 patients (5.5%). None of the patients showed stage IV and V disease. The mean gestational age was 27.7 ± 2.08 weeks in babies who had ROP and 29.59 ± 1.80 weeks in the other group. Neonates with ROP required more frequent blood transfusion (average, 4.89 ± 3.164 transfusions) compared to their counterparts who received an average of 1.19 ± 1.733 transfusions. Intracranial haemorrhage was identified in 55 (33.7%) patients, of whom 14.1% had ROP. Moreover, neonatal seizures occurred in 23 (14.11%) babies and were more common among babies who had ROP (n = 14). CONCLUSION: This study identified key factors associated with ROP, such as intracranial haemorrhage with or without neonatal seizures and a high frequency of blood transfusions.

Kawasaki shock syndrome in an Arab female: case report of a rare manifestation and review of literature.

BACKGROUND: Kawasaki disease shock syndrome is a relatively new and rare complication of Kawasaki disease first described in 2009. CASE PRESENTATION: This report describes a two-year-old Arab descent female presenting with a history of high-grade fever of 2 days duration with non-specific signs of viral illness and erythematous rash. The patients' condition deteriorated rapidly requiring admission to intensive care unit. In the intensive care unit, she developed a right upper quadrant mass that was diagnosed as hydrops of the gallbladder by ultrasonography. After one dose of intravenous immunoglobulin, the patient started to recover and was transferred out of intensive care after 2 days. CONCLUSION: Among the complications of Kawasaki disease, shock syndrome is rare and usually will have deleterious results if not diagnosed and managed promptly.

Two faces of the coin: Minireview for dissecting the role of reactive oxygen species in stem cell potency and lineage commitment.

Reactive oxygen species (ROS) are produced as by-products of several intracellular metabolic pathways and are reduced to more stable molecules by several protective pathways. The presence of high levels of ROS can be associated with disturbance of cell function and could lead to apoptosis. The presence of ROS within the physiological range has many effects on several signalling pathways. In stem cells, this role can range between keeping the potency of the naive stem cells to differentiation towards a certain lineage. In addition, the level of certain ROS would change according to the differentiation stage. For example, the presence of ROS can be associated with increasing the proliferation of mesenchymal stem cells, decreasing the potency of embryonic stem cells and adding to the genomic stability of induced pluripotent stem cells. ROS can enhance the differentiation of stem cells into cardiomyocytes, adipocytes, endothelial cells, keratinocytes and neurons. In the meantime, ROS inhibits osteogenesis and enhances the differentiation of cartilage to the hypertrophic stage, which is associated with chondrocyte death. Thus, ROS may form a link between naïve stem cells in the body and the environment. In addition, monitoring of ROS levels in vitro may help in tissue regeneration studies.