Therapeutic Applications of Stem Cell-Derived Exosomes.

Exosomes are extracellular vesicles of endosomal origin, ranging from 30 to 150 nm in diameter, that mediate intercellular transfer of various biomolecules, such as proteins, lipids, nucleic acids, and metabolites. They modulate the functions of recipient cells and participate in diverse physiological and pathological processes, such as immune responses, cell-cell communication, carcinogenesis, and viral infection. Stem cells (SCs) are pluripotent or multipotent cells that can differentiate into various cell types. SCs can also secrete exosomes, which exhibit remarkable therapeutic potential for various diseases, especially in the field of regenerative medicine. For example, exosomes derived from mesenchymal stem cells (MSCs) contain proteins, lipids, and miRNAs that can ameliorate endocrine disorders, such as diabetes and cancer. Exosomes from SCs (sc-exos) may offer similar advantages as SCs, but with reduced risks and challenges. Sc-exos have lower tumorigenicity, immunogenicity, and infectivity. They can also deliver drugs more efficiently and penetrate deeper into tissues. In this review, we provide an overview of the recent advances in sc-exos and their therapeutic applications in various diseases, such as diabetes and cancer. We also elucidate how the biological effects of sc-exos depend on their molecular composition. We also address the current challenges and future directions of using sc-exos.

Dementia in Diabetes: The Role of Hypoglycemia.

Hypoglycemia, a common consequence of diabetes treatment, is associated with severe morbidity and mortality and has become a major barrier to intensifying antidiabetic therapy. Severe hypoglycemia, defined as abnormally low blood glucose requiring the assistance of another person, is associated with seizures and comas, but even mild hypoglycemia can cause troubling symptoms such as anxiety, palpitations, and confusion. Dementia generally refers to the loss of memory, language, problem-solving, and other cognitive functions, which can interfere with daily life, and there is growing evidence that diabetes is associated with an increased risk of both vascular and non-vascular dementia. Neuroglycopenia resulting from a hypoglycemic episode in diabetic patients can lead to the degeneration of brain cells, with a resultant cognitive decline, leading to dementia. In light of new evidence, a deeper understating of the relationship between hypoglycemia and dementia can help to inform and guide preventative strategies. In this review, we discuss the epidemiology of dementia among patients with diabetes, and the emerging mechanisms thought to underlie the association between hypoglycemia and dementia. Furthermore, we discuss the risks of various pharmacological therapies, emerging therapies to combat hypoglycemia-induced dementia, as well as risk minimization strategies.

Galantamine beyond Alzheimer's disease-a fact or artefact?

Galantamine is US-Food and Drug Administration FDA-approved for mild-to-moderate Alzheimer's disease. However, its unique pharmacological portfolio speaks to the idea of a pluripotent agent with a broad therapeutic potential. Here, authors briefly discuss these off-label clinical indications synthesizing the extant evidence.

Exploring the Advantages of a Hydrolyzed Rice Formula in the Dietary Management of Infants with Cow's Milk Allergy in the Middle East, North Africa, and Pakistan Region.

Cow's milk allergy (CMA) is the most common food allergy in early childhood, and its prevalence continues to rise. Exclusive breastfeeding is recommended for infants in the first 6 months of life, but this recommendation is poorly adhered to in many parts of the world, including the Middle East, North Africa, and Pakistan (MENAP) region. If the infant is affected by CMA, current guidelines recommend extensively hydrolyzed formulas (eHFs) or amino acid-based formulas (AAFs) in the case of severe symptoms, and hydrolyzed rice formulas (HRFs) where available. In recent years, HRFs have been proposed as a plant-based alternative to cow's milk protein-based eHFs, and updates to current guidelines have been recommended. In 2014, a consensus statement and guidelines were published for the Middle East region on the prevention, diagnosis, and management of CMA. As new advances have been made in the extensively hydrolyzed hypoallergenic infant formula space, along with updated scientific evidence, a workshop of experts from the MENAP region focused on HRF was convened in 2021. This publication summarizes the insights from this meeting. During the consensus part of the meeting, a new approach was discussed and approved by all participants, and agreement was reached that HRF can be recommended as a first-line alternative to cow's milk-based eHF in the dietary management of CMA.

Probing hole spin transport of disorder quantum dots via Pauli spin-blockade in standard silicon transistors.

Single hole transport and spin detection is achievable in standard p-type silicon transistors owing to the strong orbital quantization of disorder based quantum dots. Through the use of the well acting as a pseudo-gate, we discover the formation of a double-quantum dot system exhibiting Pauli spin-blockade and investigate the magnetic field dependence of the leakage current. This enables attributes that are key to hole spin state control to be determined, where we calculate a tunnel couplingtcof 57µeV and a short spin-orbit lengthlSOof 250 nm. The demonstrated strong spin-orbit interaction at the interface when using disorder based quantum dots supports electric-field mediated control. These results provide further motivation that a readily scalable platform such as industry standard silicon technology can be used to investigate interactions which are useful for quantum information processing.

Early childhood obesity: a survey of knowledge and practices of physicians from the Middle East and North Africa.

BACKGROUND: Childhood obesity is one of the most serious public health issues of the twenty-first century affecting even low- and middle-income countries. Overweight and obese children are more likely to stay obese into adulthood. Due to the paucity of data on local practices, our study aimed to assess the knowledge and practices of physicians from the Middle East and North Africa region with respect to early-onset obesity. METHODS: A specific questionnaire investigating the perception and knowledge on early-onset obesity was circulated to healthcare providers (general physicians, pediatricians, pediatric gastroenterologist, neonatologists) practicing in 17 Middle East and North African countries. RESULTS: A total of 999/1051 completed forms (95% response) were evaluated. Of all respondents, 28.9% did not consistently use growth charts to monitor growth during every visit and only 25.2% and 46.6% of respondents were aware of the correct cut-off criterion for overweight and obesity, respectively. Of those surveyed, 22.3, 14.0, 36.1, 48.2, and 49.1% of respondents did not consider hypertension, type 2 diabetes, coronary heart disease, fatty liver disease, and decreased life span, respectively, to be a long-term complication of early childhood obesity. Furthermore, only 0.7% of respondents correctly answered all survey questions pertaining to knowledge of early childhood overweight and obesity. CONCLUSION: The survey highlights the low use of growth charts in the evaluation of early childhood growth in Middle East and North Africa region, and demonstrated poor knowledge of healthcare providers on the short- and long-term complications of early-onset obesity. This suggests a need for both continued professional education and development, and implementation of guidelines for the prevention and management of early childhood overweight and obesity.

Mediastinal ganglioneuroblastoma-secreting vasoactive intestinal peptide causing secretory diarrhoea.

In this case report we describe a case of mediastinal ganglioneuroblastoma-secreting vasoactive intestinal peptide (VIP), causing secretory diarrhoea in an 18-month-old child. An 18-month-old girl presented with a 2-month history of diarrhoea, abdominal distension and weight loss. Investigations revealed secretory diarrhoea with hypokalaemia, hyponatraemia and hypochloraemia and metabolic acidosis. Her stool output was 2.5-3.lday(-1) with increased stool sodium. VIP levels were strikingly high with normal glucagon and gastrin levels. X-ray of the chest revealed a well-defined mass in the right upper zone with tracheal shift, which was confirmed with computed tomography (CT) of the chest. The mass was resected and the patient became asymptomatic. This case shows that secretory diarrhoea caused by VIP and produced by ganglioneuroblastoma indicates a favourable prognosis, provided it is resectable.

Pegylated interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C genotype 4 in adolescents.

BACKGROUND: Hepatitis C is endemic in the Middle East where genotype 4 accounts for most cases. Data regarding the safety and efficacy of peginterferon plus ribavirin for the treatment of chronic hepatitis C in children and adolescents, particularly those infected with genotype 4 is limited. Aim. To evaluate the efficacy and tolerability of peginterferon alfa-2b in combination with ribavirin in adolescents chronically infected with HCV genotype 4. PATIENTS AND METHODS: In an open-labeled, uncontrolled pilot study, 12 adolescents (range14-17 years) were treated with subcutaneous peginterferon alfa-2b at a dose of 1.5 mg/kg body weight once per week plus oral ribavirin (15 mg/kg/day) for 48 weeks. Patients were followed for 24 weeks post-treatment. All patients had biopsy proven hepatitis without cirrhosis. RESULTS: One patient withdrew from the study due to developing insulin dependent diabetes mellitus 4 months into treatment. The remaining patients received at least 80% of the prescribed dose of pegylated interferon and ribavirin. Sustained viral response was observed in 9 patients (75%). The most frequent side effect was flu like illness which was reported in all patients. Sixty seven percent had leucopenia, but only one individual required adjuvant therapy with hematologic growth factor. Four patients had anemia requiring ribavirin dose reduction. One patient developed hypothyroidism. CONCLUSION: Combination treatment of peginterferon alfa-2b with ribavirin appears to be efficacious and relatively safe in adolescents with chronic hepatitis C genotype 4.B.

Desquamative enteropathy and pyloric atresia without skin disease caused by a novel intracellular beta4 integrin mutation.

BACKGROUND: Mutations in alpha6 or beta4 integrins (ITGA6, ITGB4) are known to cause junctional epidermolysis bullosa with pyloric atresia (JEB-PA), often lethal in infancy through skin desquamation. There is 1 report of pyloric atresia associated with a desquamatory enteropathy but without skin disease, of unknown molecular basis. PATIENTS AND METHODS: We report 2 Kuwaiti siblings with pyloric atresia and life-threatening intestinal desquamation without significant skin abnormality. The older sibling died of intractable diarrhoea, and the younger sibling suffered episodes of massive protein-losing enteropathy, triggered by viral infections, in addition to obstructive uropathy. Mutation analysis was performed for ITGA6 and ITGB4 and expression of ITGA6 and ITGB4 protein was examined in skin and intestinal biopsies. Her serum also was incubated with normal intestine. RESULTS: We identified a novel mutation in ITGB4, with homozygous deletion of a single residue (isoleucine 1314) within the intracellular plectin-binding domain. Expression of ITGA6 and ITGB4 within skin, duodenal, and colonic epithelium was normal or minimally reduced, in contrast to previous reports. Biopsies taken during relapse showed accumulation of immunoglobulin G and C1q within intestinal basement membrane, whereas immunoglobulin G from her serum bound to basement membrane of normal small intestine. Immunomodulatory therapy induced significant improvement following relapses. CONCLUSIONS: ITGB4 mutation may induce a desquamative enteropathy in infancy without significant skin disease. A history of pyloric atresia is important in infants with severe chronic diarrhoeal disease and should prompt investigation for JEB-PA associated mutations. Acquired immune responses may exacerbate primary genetic disorders of epithelial adhesion and immunomodulatory therapy may be beneficial.

Association of Schatzki ring with eosinophilic esophagitis in children.

OBJECTIVE: To describe the clinicopathologic characteristics of children with Schatzki ring and to determine if Schatzki ring is associated with eosinophilic esophagitis. METHODS: The authors report 18 adolescents with radiographically diagnosed Schatzki ring (SR). Their clinical and histologic characteristics were reviewed in a blinded fashion. RESULTS: The mean age of the patients was 15.8 +/- 0.8 years and mean duration of symptoms was 2.6 +/- 0.4 years. By histologic criteria, two groups of patients were defined. Eight had clinical and histologic criteria of eosinophilic esophagitis (EE) and 10 of peptic esophagitis. There were no differences in the symptoms or radiographic findings in the two groups. The SR was not identified by endoscopy in any EE patient and was identified in 70% of peptic esophagitis patients. Grossly apparent mucosal features associated with EE were significantly more common in those with EE. Those with peptic esophagitis had a significantly higher acid exposure than did those with EE (12.6 +/- 2.9 v 2.0 +/- 1.1%; P < 0.01) by esophageal pH probe. Patients with peptic esophagitis responded to proton pump inhibitors and/or dilatation, whereas those with EE did not have good response and required specific therapy for EE. CONCLUSIONS: EE may play a role in the pathogenesis of some patients with SR.