Howard W. Robinson

HEAT STROKE: CLINICAL AND CHEMICAL OBSERVATIONS ON 44 CASES

The problem of heat diseases has long been an important one in the tropics, in certain industries and occupations requiring exposure of individuals to high temperatures, and during periods of excessively hot weather in the cities of the United States. In spite of the voluminous literature on the subject, there is no unanimity of opinion regarding the predisposing and precipitating factors which bring about such reactions. Three fairly distinct clinical syndromes may occur as the result of an excessively high environmental temperature. These are heat cramps, heat exhaustion, and heat stroke. The syndrome of heat cramps has long been known among workers in hot environments. In addition to severe muscular cramps, these patients sweat profusely and have a normal temperature. The work of Edsall (1), Moss (2), Haldane (3), Glover (4), Talbott and his coworkers (5, 6), and others (7) suggests that this syndrome results primarily from an excessive loss of electrolytes, namely sodium chloride, in the sweat. The symptoms can be relieved or prevented by the administration of sodium chloride, and the mortality is negligible. The syndrome of heat exhaustion is characterized by profuse perspiration, pallor of the skin and low blood pressure-manifestations of peripheral circulatory collapse. The temperature may be subnormal, normal, or slightly elevated. The symptoms are of a syncopal nature, namely, weakness, dizziness, and sometimes fainting. Nausea and vomiting may occur. As a rule, heat exhaustion is not a serious condition. Recovery is rapid and the mortality low. Heat stroke, on the other hand, is a most serious condition, having a mor-

Crystal Structure of Haemophilus influenzae NadR Protein A BIFUNCTIONAL ENZYME ENDOWED WITH NMN ADENYLYLTRANSFERASE AND RIBOSYLNICOTINAMIDE KINASE ACTIVITIES

Haemophilus influenzae NadR protein (hiNadR) has been shown to be a bifunctional enzyme possessing both NMN adenylytransferase (NMNAT; EC 2.7.7.1) and ribosylnicotinamide kinase (RNK; EC 2.7.1.22) activities. Its function is essential for the growth and survival of H. influenzae and thus may present a new highly specific anti-infectious drug target. We have solved the crystal structure ofhiNadR complexed with NAD using the selenomethionine MAD phasing method. The structure reveals the presence of two distinct domains. The N-terminal domain that hosts the NMNAT activity is closely related to archaeal NMNAT, whereas the C-terminal domain, which has been experimentally demonstrated to possess ribosylnicotinamide kinase activity, is structurally similar to yeast thymidylate kinase and several other P-loop-containing kinases. There appears to be no cross-talk between the two active sites. The bound NAD at the active site of the NMNAT domain reveals several critical interactions between NAD and the protein. There is also a second non-active-site NAD molecule associated with the C-terminal RNK domain that adopts a highly folded conformation with the nicotinamide ring stacking over the adenine base. Whereas the RNK domain of the hiNadR structure presented here is the first structural characterization of a ribosylnicotinamide kinase from any organism, the NMNAT domain ofhiNadR defines yet another member of the pyridine nucleotide adenylyltransferase family.