No abstract

Increasing evidence suggests heterogeneity in the molecular pathogenesis of cystic fibrosis (CF). Mutations such as deletion of phenylalanine at position 508 (AF508) within the cystic fibrosis transmembrane conductance regulator (CFTR), for example, appear to cause disease by abrogating normal biosynthetic processing, a mechanism which results in retention and degradation of the mutant protein within the endoplasmic reticulum. Other mutations, such as the relatively common glycine -, aspartic acid replacement at CFTR position 551 (G551D) appear to be normally processed, and therefore must cause disease through some other mechanism. Because AF508 and G551D both occur within a predicted nucleotide binding domain (NBD) of the CFTR, we tested the influence of these mutations on nucleotide binding by the protein. We found that G551D and the corresponding mutation in the CFTR second nucleotide binding domain, G1349D, led to decreased nucleotide binding by CFTR NBDs, while the AF508 mutation did not alter nucleotide binding. These results implicate defective ATP binding as contributing to the pathogenic mechanism of a relatively common mutation leading to CF, and suggest that structural integrity of a highly conserved region present in over 30 prokaryotic and eukaryotic nucleotide binding domains may be critical for normal nucleotide binding. (J. Clin. Invest. 1994. 94:228-236.)

No abstract

Although lightning-strike injury is uncommon, it is the cause of death in more people in the United States annually than any other natural disaster. Consequently, the emergency medicine specialist and intensivist should be familiar with the special problems of a lightning-strike victim. Lightning is a massive electrical discharge that results from a complex sequence of atmospheric events. When this massive electrical discharge strikes a human being, it causes predictable cardiac and neurological injuries. Synchronous myocardial contraction occurs at the moment of impact and is followed by a variable period of asystole. Prolonged asystole may cause ischemia and ventricular fibrillation. Alternatively, ventricular fibrillation may occur primarily if the electrical discharge strikes during the vulnerable period of the cardiac cycle. Unconsciousness, depression of respiratory efforts, and seizures are also immediate consequences of lightning strike. Respiratory arrest is presumed to be a consequence of inhibition of the medullary respiratory center. Retrograde and antegrade amnesia, confusion, disorientation, and vasomotor instability with transient paralysis of usually the lower extremities are commonly seen in lightning-strike victims. Other complications occur more variably, but should be carefully sought by the responsible clinician. These include burns at the exit and entrance sites of the lightning strike, eye injuries (e.g., cataracts, corneal lesions, intraocular bleeding), and rupture of the tympanic membrane. Besides describing the pathophysiology of these and other consequences of lightning strike, a comprehensive approach to the initial and long-term management of the lightning-strike victim is discussed.