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Carbon Monoxide Rapidly Impairs Alveolar Fluid Clearance by Inhibiting Epithelial Sodium Channels
(2009)
Carbon monoxide (CO) is currently being evaluated as a therapeutic modality in the treatment of patients with acute lung injury and acute respiratory distress syndrome. No study has assessed the effects of CO on transepithelial ion transport and alveolar fluid reabsorption, two key aspects of alveolocapillary barrier function that are perturbed in acute lung injury/acute respiratory distress syndrome. Both CO gas (250 ppm) and CO donated by the CO donor, CO-releasing molecule (CORM)-3 (100 mu M in epithelial lining fluid), applied to healthy, isolated, ventilated, and perfused rabbit lungs, significantly blocked Na-22(+) clearance from the alveolar compartment, and blocked alveolar fluid reabsorption after fluid challenge. Apical application of two CO donors, CORM-3 or CORM-A1 (100 mu M), irreversibly inhibited amiloride-sensitive short-circuit currents in H441 human bronchiolar epithelial cells and primary rat alveolar type II cells by up to 40%. Using a nystatin permabilization approach, the CO effect was localized to amiloride-sensitive channels on the apical surface. This effect was abolished by hemoglobin, a scavenger of CO, and was not observed when inactive forms of CO donors were employed. The effects of CO were not blocked by 8-bromoguanosine-3',5'-cyclic guanosine monophosphate, soluble guanylate cyclase inhibitors (methylene blue and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), or inhibitors of trafficking events (phalloidin oleate, MG-132, and brefeldin A), but the amiloride affinity of H441 cells was reduced after CO exposure. These data indicate that CO rapidly inhibits sodium absorption across the airway epithelium by cyclic guanosine monophosphate-and trafficking-independent mechanisms, which may rely on critical histidine residues in amiloride-sensitive channels or associated regulatory proteins on the apical surface of lung epithelial cells.
The nutrient element calcium
(2009)
Physiology and behavior have historically been treated as separate subjects in the study of Drosophila. The latter is mentioned mainly in the context of neurobiology, while the former has been considered to take in studies of metabolism, cell biology and anatomy, among others. Of late, the line distinguishing physiology and behavior has become thinner, and this is exceptionally apparent in recent studies of nutrient signaling and of the regulation of feeding. This review represents a brief examination of the nexus between these intersecting fields of research in Drosophila. Other recently published reviews serve as complements to this one.
Dihydropyrimidine dehydrogenase (DPD) deficiency is an infrequently described autosomal recessive disorder of the pyrimidine degradation pathway and can lead to mental and motor retardation and convulsions. DPD deficiency is also known to cause a potentially lethal toxicity following administration of the antineoplastic agent 5-fluorouracil. In an ongoing study of 72 DPD deficient patients, we analysed the molecular background of 5 patients in more detail in whom initial sequence analysis did not reveal pathogenic mutations. In three patients, a 13.8 kb deletion of exon 12 was found and in one patient a 122 kb deletion of exon 14–16 of DPYD. In the fifth patient, a c.299_302delTCAT mutation in exon 4 was found and also loss of heterozygosity of the entire DPD gene. Further analysis demonstrated a de novo deletion of approximately 14 Mb of chromosome 1p13.3–1p21.3, which includes DPYD. Haploinsufficiency of NTNG1, LPPR4, GPSM2, COL11A1 and VAV3 might have contributed to the severe psychomotor retardation and unusual craniofacial features in this patient. Our study showed for the first time the presence of genomic deletions affecting DPYD in 7% (5/72) of all DPD deficient patients. Therefore, screening of DPD deficient patients for genomic deletions should be considered.
Mitochondrial neurogastrointestinal encephalomyopathy is an autosomal recessive disorder in which a nuclear mutation of the thymidine phosphorylase gene leads to mitochondrial genomic dysfunction. Herein, we report a 29-year-old Iranian man with abdominal pain, diarrhea, hearing loss, ophthalmoplegia, sensorimotor axonal neuropathy, and elevated muscle enzymes. Magnetic resonance imaging showed leukoencephalopathic changes. Metabolite analysis revealed a very high thymidine concentration in the patient's urine consistent with the diagnosis of mitochondrial neurogastrointestinal encephalomyopathy.