Abstract Background Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare and genetically heterogeneous cerebral white matter disease. Clinically, it is characterized by ...macrocephaly, developmental delay, and seizures. We explore the clinical spectrum, neuroimaging characteristics, and gene involvement in the first patients with megalencephalic leukoencephalopathy with subcortical cysts described from Egypt. Patients Six patients were enrolled from three unrelated families. Patient inclusion criteria were macrocephaly, developmental delay, normal urinary organic acids, and brain imaging of diffuse cerebral white matter involvement. Direct sequencing of the MLC1 gene in patients' families and GliaCAM in one questionable case was performed using BigDye Terminator cycle sequencing. Results Clinical heterogeneity, both intra- and interfamilial, was clearly evident. Developmental delays ranged from globally severe or moderate to mild delay in achieving walking or speech. Head circumference above the ninety-seventh percentile was a constant feature. Neuroimaging featured variability in white matter involvement and subcortical cysts. However, findings of posterior fossa changes and brain stem atrophy were frequently (66.6%) identified in these Egyptian patients. Discrepancy between severe brain involvement and normal mental functions was evident, particularly in patients from the third family. MLC1 mutations were confirmed in all patients. Deletion/insertion mutation in exon 11 (c.908-918delinsGCA, p.Val303 Gly fsX96) was recurrent in two families, whereas a missense mutation in exon 10 (c.880 C > T, p.Pro294Ser) was identified in the third family. Conclusions This report extends our knowledge of the clinical and neuroimaging features of megalencephalic leukoencephalopathy with subcortical cysts. It confirms the apparent lack of selective disadvantage of MLC1 mutations on gamete conception and transmission as supported by the presence of multiple affected siblings in Egyptian families.
Objective
To describe the spectrum, relative prevalence and molecular background of lysosomal storage disorders in Egypt.
Methods
The authors evaluated the selective screening program for the ...diagnosis of lysosomal storage disorders in Egyptian children presenting to the inherited metabolic disease unit at Cairo University Children’s Hospital, the largest tertiary care pediatric hospital in Egypt, over a six-year period (April 2008 through April 2014). During this period, 1,065 suspected children were assessed clinically, biochemically and some genetically.
Results
Two hundred and eleven children (aged 44 ± 32 mo; 56 % boys, 82 % with consanguineous parents) were confirmed with 21 different lysosomal disorders. The diagnostic gap ranged between 2 mo and 14 y (average 25 mo). Mucopolysaccharidoses were the most common group of diseases diagnosed (44.5 %), while Maroteaux-Lamy, Gaucher and nephropathic cystinosis were the most commonly detected syndromes (17.1, 14.7 and 13.7 %, respectively). Eighty mutant alleles and 17 pathogenic mutations were detected in 48 genetically assessed confirmed patients (30 Gaucher, 16 cystinosis and two Niemann-Pick type C patients).
Conclusions
This report is the first to describe relative frequency and spectrum of clinical and molecular data in a large cohort of Egyptian lysosomal patients. The crude estimate denotes that over 80 % of Egyptian lysosomal patients do not have access to optimal diagnosis. Upgrading diagnostic and genetic services for lysosomal storage disorders in Egypt is absolutely necessary.
Abstract Background and objectives Total thyroidectomy is indicated in most cases with postcricoid carcinoma, circumferential hypopharyngeal carcinoma and in advanced laryngeal carcinoma. Persistent ...hypoparathyroidism is a frequent complication after total thyroidectomy which is difficult to manage unlike hypothyroidism. This study was to assess the feasibility of parathyroid gland autotranplantation after total thyroidectomy in advanced carcinomas and their effectiveness in preventing persistent hypoparathyroidism. Methods This study included 26 patients with hypopharyngeal and laryngeal carcinoma presented to National Cancer Institute, Cairo University. Total thyroidectomy and total parathyroid gland excision were performed as a part of adequate oncologic surgical procedure. The parathyroid glands were identified, resected and stored in iced saline. Histological confirmation was necessary before implantation into separated muscle pockets in the anterior forearm muscles. Regular samples were drawn to assess serum parathormone and calcium levels. Results All patients experienced hypocalcaemia within 1–5 days after operation. Only one patient experienced parathyroid graft failure while the remaining patients were normocalcemic during follow up after surgery, indicating functioning parathyroid grafts. Conclusions Parathyroid gland autotranplantation is a simple safe technique with high success rate in preventing persistent hypoparathyroidism after total thyroidectomy in surgical management of advanced hypopharyngeal and laryngeal carcinomas.
Hereditary spastic paraplegias (HSPs) are neurodegenerative motor neuron diseases characterized by progressive age-dependent loss of corticospinal motor tract function. Although the genetic basis is ...partly understood, only a fraction of cases can receive a genetic diagnosis, and a global view of HSP is lacking. By using whole-exome sequencing in combination with network analysis, we identified 18 previously unknown putative HSP genes and validated nearly all of these genes functionally or genetically. The pathways highlighted by these mutations link HSP to cellular transport, nucleotide metabolism, and synapse and axon development. Network analysis revealed a host of further candidate genes, of which three were mutated in our cohort. Our analysis links HSP to other neurodegenerative disorders and can facilitate gene discovery and mechanistic understanding of disease.
Umbelliferone (UMB) is a natural coumarin that has diverse biological activities. However, its potential to protect against liver fibrosis has not been reported yet. This study aimed to investigate ...the protective effect of UMB against carbon tetrachloride (CCl
4
)-induced liver fibrosis in rats. Rats received CCl
4
and UMB for 8 weeks and samples were collected for analyses. CCl
4
induced a significant increase in serum levels of liver function markers and pro-inflammatory cytokines. Treatment with UMB significantly ameliorated liver function markers and pro-inflammatory cytokines and prevented CCl
4
-induced histological alterations. CCl
4
promoted significant upregulation of α-smooth muscle actin (SMA), collagen I, collagen III, NF-κB p65, TGF-β1, and p-Smad3. Masson’s trichrome staining revealed a significant fibrogenesis in CCl
4
-induced rats. Treatment with UMB suppressed TGF-β1/Smad3 signaling and downregulated α-SMA, collagen I, collagen III, and NF-κB p65. In addition, UMB diminished malondialdehyde and nitric oxide levels, boosted reduced glutathione and antioxidant enzymes, and upregulated the expression of PPARγ. In conclusion, our results demonstrated that UMB prevented CCl
4
-induced liver fibrosis by attenuating oxidative stress, inflammation, and TGF-β1/Smad3 signaling, and upregulating PPARγ. Therefore, UMB may be a promising candidate for preventing hepatic fibrogenesis, given that further research is needed to delineate the exact molecular mechanisms underlying its antifibrotic efficacy.
Mesenchymal stem cells (MSCs) therapy show different levels of effectiveness in the context of different types of liver damage, suggesting that the microenvironment of the injured liver is a key ...determinant for effective stem cell therapy. The objective was to assess the modulatory effect of hepatic stem cell niche components on the transplanted MSCs during liver injury induced by carbon tetrachloride (CCl
). Superparamagnetic iron oxide (SPIO)-labeled human MSCs were injected intravenously into mice treated with CCl
and subjected to hepatic macrophage-depletion. Liver tissues were collected at different intervals post transplantation for subsequent histopathological, morphometric, immunohistochemical, gene expression and ultrastructural studies. The homing of the transplanted MSCs was evidenced by tracing them within the niche by iron staining and immunohistochemical studies. MSCs differentiated into hepatocyte-like cells and intimal smooth muscle cells as evidenced by their expression of human albumin and α-smooth muscle actin with a concomitant increase in the level of mouse hepatocyte growth factor. A post transplantation reduction in the liver fibro-inflammatory reaction was found and was promoted by liver macrophages depletion. Thus, it could be concluded from the present study that prior manipulation of the microenvironment is required to improve the outcome of the transplanted cells.
Background Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. Thyroid dysfunction and oxidative stress can be associated with POAG. Purpose The aim of this study was to ...determine whether thyroid dysfunction (hypothyroidism or hyperthyroidism) is associated with glaucoma in Egyptian patients and to evaluate the level of oxidative stress (OS) markers in the serum of POAG patients. It also aimed to investigate the relationship between the OS markers and thyroid hormones in those patients. Patients and methods The study included 60 patients with POAG who were compared with 20 normal controls. Serum samples from the POAG patients and controls were examined for thyroid hormones triiodothyronine (T3), thyroxine (T4), and thyroid stimulating hormone (TSH) using the ELISA technique. The OS markers hydrogen peroxide (H2O2), nitric oxide (NO), malondialdehyde (MDA), and reduced glutathione (GSH) were also determined using colorimetric methods. Results There were no significant differences in the levels of T4 and TSH in the patients (3.14±2.25 ng/dl and 2.43±1.37 u/l, respectively) compared with the controls (3.35±1.88 ng/dl and 1.76±0.99 u/l, respectively) (P=0.245 and 0.064, respectively). However, there was a significant decrease in the T3 level in the POAG patients (2.88±0.54 pg/ml) compared with the controls (3.35±0.6 pg/ml) (P=0.029). In addition, there was a significant increase in the levels of H2O2 (2.83±1.66 mM/l), NO (54.64±29.21 umol/l), and MDA (164.12±96.5 nmol/ml) in the patients compared with the controls (0.83±0.55 mMol/l, 22.49±6.37 umol/l, and 44.36±12.59 nmol/ml, respectively) (P<0.001). There was also a significant decrease in the level of GSH in patients (54.32±32.1 mg/dl) compared with controls (103.99±45.52 mg/dl), (P<0.001). A significant negative correlation was detected between TSH and T4 (r=−0.41, P= 0.001), TSH and MDA (r=−0.27, P=0.04), T3 and H2O2 (r=−0.05, P=0.05), and T4 and NO (r=−0.35, P=0.01). Conclusion There was no association between POAG and thyroid dysfunction. However, the POAG patients are susceptible to OS and damage, as they had elevated serum levels of H2O2, NO, and MDA and reduced levels of GSH. Since the thyroid hormone level was associated with the OS markers, antioxidant therapy may be beneficial and may help to regulate the intraocular pressure and protect the trabecular meshwork cells from OS in those patients.
Protein corona (PC) deposition on nanoparticles (NPs) in biological systems contributes to a great extent to NPs' fates; their targeting potential, the interaction with different biological systems ...and the subsequent functions. PC - when properly tuned - can serve as a potential avenue for optimization of NPs' use in cancer therapy.
Poly-lactic co-glycolic acid (PLGA)-based NPs exhibiting different physicochemical properties were fabricated and characterized. The PC makeup of these NPs were qualitatively and quantitatively analyzed by Western blot and Bradford assay, respectively. The effect of PC on the release of NPs' cargos and the intracellular uptake into B16F10 melanoma cells has been studied.
The composition of NPs (polymeric PLGA NPs vs lipid-polymer hybrid NPs) and the conjugation of an active targeting ligand (cRGDyk peptide) represented the major determinants of the PC makeup of NPs. The in vitro release of the loaded cargos from the NPs depended on the PC and the presence of serum proteins in the release medium. Higher cumulative release has been recorded in the presence of proteins in the case of peptide conjugated NPs, cNPs, while the unconjugated formulations, uNPs, showed an opposite pattern. NPs intracellular uptake studies revealed important roles of distinct serum and cellular proteins on the extent of NPs' accumulation in melanoma cells. For example, the abundance of vitronectin (VN) protein from serum has been positively related to the intracellular accumulation of the NPs.
Careful engineering of nanocarriers can modulate the recruitment of some proteins suggesting a potential use for achieving endogenous targeting to overcome the current limitations of targeted delivery of chemotherapeutic agents.
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