Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). The most common mutation, DeltaF508, results in the production of a misfolded CFTR protein that is retained in the endoplasmic reticulum and targeted for degradation. Curcumin is a nontoxic Ca-adenosine triphosphatase pump inhibitor that can be administered to humans safely. Oral administration of curcumin to homozygous DeltaF508 CFTR mice in doses comparable, on a weight-per-weight basis, to those well tolerated by humans corrected these animals' characteristic nasal potential difference defect. These effects were not observed in mice homozygous for a complete knockout of the CFTR gene. Curcumin also induced the functional appearance of DeltaF508 CFTR protein in the plasma membranes of transfected baby hamster kidney cells. Thus, curcumin treatment may be able to correct defects associated with the homozygous expression of DeltaF508 CFTR.

Several studies have demonstrated that bone marrow (BM)-derived cells give rise to rare epithelial cells in the gastrointestinal (GI) and respiratory tracts after BM transplantation into myeloablated recipients. We investigate whether, after transplantation of cystic fibrosis transmembrane conductance regulator (CFTR)-positive BM-derived cells, BM-derived GI and airway epithelial cells can provide CFTR activity in the GI tract and nasal epithelium of recipient cystic fibrosis mice. CFTR؊͞؊ mice were transplanted with wild-type BM after receiving different doses of irradiation, and CFTR activity was assessed in vivo in individual mice over time by using rectal and nasal potential difference analyses and in vitro by Ussing chamber analysis. The data suggest that rare BM-derived epithelial cells in the GI and nasal epithelium detected in CFTR؊͞؊ transplanted mice provide a modest level of CFTR-dependent chloride secretion. Detection of CFTR mRNA and protein in tissues of transplanted CFTR؊͞؊ mice supports these data.bone marrow stem cells ͉ chloride channel ͉ epithelial cells

Bone marrow-derived cells (BMDCs) can engraft as epithelial cells throughout the body, including in the lung, liver, and gastrointestinal (GI) tract following transplantation into lethally irradiated adult recipients. Except for rare disease models in which marrow-derived epithelial cells have a survival advantage over endogenous cells, the currently attained levels of epithelial engraftment of BMDCs are too low to be of therapeutic benefit. Here we tested whether the degree of bone marrow to epithelial engraftment would be higher if bone marrow transplantation (BMT) were performed on 1-day-old mice, when tissues are undergoing rapid growth and remodeling. BMT into newborn mice after multiple different regimens allowed for robust hematopoietic engraftment, as well as the development of rare donor-derived epithelial cells in the GI tract and lung but not in the liver. The highest epithelial engraftment (0.02%) was obtained in mice that received a preparative regimen of two doses of busulfan in utero. When BMDCs were transplanted into myelosuppressed newborn mice that lacked expression of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, the chloride channel that is not functional in patients with cystic fibrosis, the engrafted mice showed partial restoration of CFTR channel activity, suggesting that marrow-derived epithelial cells in the GI tract were functional. However, BMT into newborn mice, regardless of the myeloablative regimen used, did not increase the number of bone marrow-derived epithelial cells over that which occurs after BMT into lethally irradiated adult mice.

BackgroundMutations in GLIS3 cause a rare syndrome characterized by neonatal diabetes mellitus (NDM), congenital hypothyroidism, congenital glaucoma and cystic kidneys. To date, 14 mutations in GLIS3 have been reported, inherited in an autosomal recessive manner. GLIS3 is a key transcription factor involved in β-cell development, insulin expression, and development of the thyroid, eyes, liver and kidneys.CasesWe describe non-identical twins born to consanguineous parents presenting with NDM, congenital hypothyroidism, congenital glaucoma, hepatic cholestasis, cystic kidney and delayed psychomotor development. Sequence analysis of GLIS3 identified a novel homozygous nonsense mutation, c.2392C>T, p.Gln798Ter (p.Q798*), which results in an early stop codon. The diabetes was treated with a continuous subcutaneous insulin infusion pump and continuous glucose monitoring. Fluctuating blood glucose and intermittent hypoglycemia were observed on follow-up.ConclusionsThis report highlights the importance of early molecular diagnosis for appropriate management of NDM. We describe a novel nonsense mutation of GLIS3 causing NDM, extend the phenotype, and discuss the challenges in clinical management. Our findings provide new areas for further investigation into the roles of GLIS3 in the pathophysiology of diabetes mellitus.

Cystic fibrosis (CF) is an autosomal recessive disease that results from mutations in the CF transmembrane conductance regulator (CFTR) gene. The effect of interventions aimed at correcting the CF electrophysiologic phenotype has been primarily measured using in vitro methods in gastrointestinal and respiratory epithelia. A reliable in vivo assay of CFTR function would be of great value in the investigation of pharmacologic interventions for CF mouse models. We performed the in vivo rectal potential difference (RPD) assay on three different mouse models. We then compared the in vivo data with the results obtained using the in vitro Ussing chamber method. The results from the in vitro method correlated closely with the results acquired using the in vivo method and were reproducible. The data suggest that the in vivo RPD assay is a reliable assay of functional CFTR expression in CF mouse models. (Pediatr Res 63: 73-78, 2008)

Introduction: Maternal thyroid disease is considered as a risk factor for abnormal thyroid function at birth as well as for long-term morbidity in offspring. The potential harmful effects on the neonate had led to the clinical practice of thyroid function assessment in infants born to mothers with thyroid disease during pregnancy. We evaluated the usefulness of routine thyroid function tests for every newborn of a mother with thyroid dysfunction. Methods: Data were collected retrospectively from the medical files of mothers diagnosed with thyroid disease and their infants (496 mother–neonate pairs). All mothers with diagnosed thyroid disease who gave birth in the years 2016–2019 at our medical center were included. Results: Hypothyroidism was the most common maternal diagnosis (91.4%), among which 48.7% had Hashimoto's thyroiditis. Hyperthyroidism was diagnosed in 8.6% of the cohort; 71.6% of them with Graves' disease. None of the newborns was diagnosed with congenital hypothyroidism in the screening program. Thyroid-stimulating hormone was >10 mIU/l in 14.6% and >20 mUI/l in 2.2%; all had free thyroxine within normal range. Serum thyroid function test identified four infants with thyroid disease: two had congenital hypothyroidism not related to maternal thyroid disease, one had transient familial congenital hypothyroidism and one had neonatal Graves' disease. Conclusions: Thyroid function testing for all newborns of mothers with thyroid dysfunction seems redundant. However, in cases of congenital hypothyroidism in siblings, thyroid function test, in addition to newborn thyroid screening, is recommended and more careful follow-up is indicated. In maternal Graves' disease, thyroid function test on day 2–3 of life is recommended.

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