Decreased mRNA and protein stability of W1282X limits response to modulator therapy.

BACKGROUND: Cell-based studies have shown that W1282X generates a truncated protein that can be functionally augmented by modulators. However, modulator treatment of primary cells from individuals who carry two copies of W1282X generates no functional CFTR. To understand the lack of response to modulators, we investigated the effect of W1282X on CFTR RNA transcript levels. METHODS: qRT-PCR and RNA-seq were performed on primary nasal epithelial (NE) cells of a previously studied individual who is homozygous for W1282X, her carrier parents and control individuals without nonsense variants in CFTR. RESULTS: CFTR RNA bearing W1282X in NE cells shows a steady-state level of 4.2 ±â€¯0.9% of wild-type (WT) CFTR RNA in the mother and 12.4 ±â€¯1.3% in the father. NMDI14, an inhibitor of nonsense-mediated mRNA decay (NMD), restored W1282X mRNA to almost 50% of WT levels in the parental NE cells. RNA-seq of the NE cells homozygous for W1282X showed that CFTR transcript level was reduced to 1.7% of WT (p-value: 4.6e-3). Negligible truncated CFTR protein was generated by Flp-In 293 cells stably expressing the W1282X EMG even though CFTR transcript was well above levels observed in the parents and proband. Finally, we demonstrated that NMD inhibition improved the stability and response to correctors of W1282X-CFTR protein expressed in the Flp-In-293 cells. CONCLUSION: These results show that W1282X can cause substantial degradation of CFTR mRNA that has to be addressed before efforts aimed at augmenting CFTR protein function can be effective.

Role of nitric oxide in hypoxia-induced changes in newborn rats.

In order to investigate the role of nitric oxide (NO) in hypoxic tissue damage in newborns, we studied the effects of systemic administration of an inhibitor of NO synthase, N(G)-nitro-L-arginine (L-NNA), and the precursor for the synthesis of NO, L-arginine (L-ARG), on the biochemical and histological changes in brain, heart, lung, liver, kidney, intestine, and skeletal muscle tissues. Four groups of 1-day-old Wistar rat pups were used: control, hypoxic, L-ARG, and L-NNA groups. L-ARG 100 mg/kg or L-NNA 2 mg/kg was administered as a bolus intraperitoneally 1.5 h before hypoxia. Hypoxia increased lipid peroxidation in all tissues except muscle; this increase was prevented by L-NNA and L-ARG in brain, heart, lung, kidney, and liver tissues. L-NNA in intestine and L-ARG in muscle tissue increased lipid peroxidation. The tissue-associated myeloperoxidase activity was decreased in the liver by L-NNA and L-ARG. Histopathological changes in intestines were villous epithelial separation and hyperemia in hypoxic and L-NNA groups which were not observed in control and L-ARG groups. In lungs, pulmonary hemorrhage was observed only in the hypoxic group. These data suggest that NO acts both as a destructive and a protective agent in the pathogenesis of hypoxia-reoxygenation injuries.

Paraurethral cysts in newborn: a case report and review of literature.

Paraurethral cysts are uncommonly reported in the newborn. Twenty-eight cases have been reported in the English literature until now. These lesions generally resolve spontaneously. For this reason, a conservative approach is recommended, especially in paraurethral cysts of newborn without complications and symptoms. In this paper, we describe a female neonate who had a paraurethral cyst that spontaneously resolved one month after birth and review the literature.

Camptodactyly, myopia, and fibrosis of the medial rectus of the eye in two sibs born to consanguineous parents: autosomal recessive entity?

Unaffected but consanguineous parents suggest autosomal recessive inheritance of a previously apparently undescribed syndrome of camptodactyly, fibrosis of the medial rectus muscle of the eye, severe myopia, facial anomalies, joint contractures, and mild scoliosis in a 13-year-old Turkish girl and her 11-year-old brother. The girl also had ptosis.

Holoprosencephaly anomaly with nasal and premaxillar agenesis (possibly autosomal recessive type).

A one-day-old male infant with cleft lip and palate, microcephaly, hypotelorism, microphthalmia and absence of the nose is presented. The intermaxillar segment and nasal bone structure were not seen on radiological examination of the skull. Chromosome examination showed a 46, XY karyotype. On postmortem examination, the cerebrum was seen to be a single lobe. Olfactory nerves, corpus callosum and nasal formation, besides the septum were absent. The first and second ventricles were formed as a single ventricle. These findings were compatible with alobar holoprosencephaly.

[Distribution and typing in salmonellosis in children 1978-1983]. / 1978-1983 yillari arasinda cocuklarda görülen salmonellozislerin dagilimi ve tiplendirilmesi.

329 infants with salmonellosis were evaluated in Pediatric and Microbiology Department of Anadolu University Teaching and Training Hospital. It was established 127 (38.6%) S. typhimurium, 42 (12.8%) S. typhosa and 6 (1.8%) S. paratyphi A and B in our series. Besides these serotypes, 154 (46.8%) patients could not be typed. S. typhimurium was importantly noticed than other types (p less than 0.001) and this feature makes the distribution of typing of salmonellosis in children as characteristic. This infection was encountered especially between December (8.5%), it made peak in January (20.3%) and April (9.73%) period. Then, between April-December, this infections was established quite lower (p less than 0.001). This distribution is specific for Eskisehir district, and it was gradually decreased year by year (p less than 0.05).

[Investigations of Listeria monocytogenes in infections of the newborn]. / Yenidogan infeksiyonlarinda listeria monocytogenes arastirilmasi.

In order to isolate Listeria monocytogenes from 42 high-risk infants and infection-suspected neonates, blood, external ear canal, throat and urine cultures were made. But, no Listeria monocytogenes could be isolated. Other cultured microorganisms are discussed.