Characterization of the human homologue of the mouse Tg737 candidate polycystic kidney disease gene.

We previously identified a gene from the mutant locus in a new mouse mutation that causes recessive polycystic kidney disease. Here we describe the cloning, characterization and mapping of the homologous human gene. The human and mouse genes are 95% identical at the predicted amino acid sequence level, and both genes encode a putative protein that contains a tetratricopeptide repeat motif. The human gene, called hTg737, is expressed with a broad tissue distribution that includes the the kidney and liver, and gives rise to a 2.9 kb mRNA. The gene contains 26 exons and spans a genomic region greater than 100 kb. Chromosome mapping experiments revealed that the hTg737 gene maps near the centromere on the long arm of human chromosome 13, at position 13q12.1. While this gene does not map to the primary locus that has been identified for ARPKD in humans, it may represent a candidate gene for other recessive renal disorders that have yet to be mapped.

Candidate gene associated with a mutation causing recessive polycystic kidney disease in mice.

A line of transgenic mice was generated that contains an insertional mutation causing a phenotype similar to human autosomal recessive polycystic kidney disease. Homozygotes displayed a complex phenotype that included bilateral polycystic kidneys and an unusual liver lesion. The mutant locus was cloned and characterized through use of the transgene as a molecular marker. Additionally, a candidate polycystic kidney disease (PKD) gene was identified whose structure and expression are directly associated with the mutant locus. A complementary DNA derived from this gene predicted a peptide containing a motif that was originally identified in several genes involved in cell cycle control.

Vasopressor agents in shock.

PIP: Critical hemodynamic changes that are observed with the reduction of blood pressure in shock and the use of vasopressor agents as a temporary measure for maintaining arterial pressure so that irreparable tissue damage can be prevented are considered in this review of the use and efficacy of vasopressor agents in shock. Indications for adrenergic stimulators include severe hypotensive episodes, in which case an alpha-beta stimulator such as metaraminol or norepinephrine is the therapy of choice; hemorrhagic shock, in which administration of an alpha-beta stimulator will help maintain essential cerebral and cardiac function by shunting blood to these areas while volume is being replaced; cardiogenic shock, in which vasodilators may reduce cardiac work by reducing diastolic blood pressure but coronary blood flow will also be reduced, counteracting the effects of decreasing the cardiac load; and endotoxic shock, in which the circulating blood volume decreases and venous return and cardiac output also decrease. Prolonged use of these agents in any of these shock situations is ultimately deleterious. Vasopressor drugs are best used to treat acute hypotension that occurs in myocardial infarction; in such cses, vasopressors are used to keep the blood pressure within normal range, but only as adjunctive therapy. In hemorrhagic shock, though norepinephrine administration may increase blood pressure, the only lasting treatment is to replace the blood as rapidly as possible.^ieng

Vasopressors for treating shock.

PIP: Shock must be treated by correcting the cause, for any treatment of hypotension or shock, as such, is only an adjunctive measure; but the hemodynamic manifestations also need treatment. Vasopressors are helpful and effective under the right circumstances. Unless the blood volume is normal, the use of drugs that block the sympathetic nervous system (e.g., phenoxybenxamine) can be extremely hazardous and hasten death. However, the effect of adrenergic blocking drugs in endotoxic shock and other types of toxic shock is still to be determined; use of such drugs should be considered experimental until the results have been studied more extensively. Clinically, the most common forms of vascular shock are associated with blood loss, myocardial infarction, and endotoxemia. Characteristic hemodynamics of each situation are presented tabularly, and the physicians need to understand the differences is emphasized. The pharmacology of vasopressors, relating primarily to hemodynamic considerations and the response to vasopressors when severe reduction in blood pressure is associated with the shock syndrome is discussed. Drugs that stimulate the adrenergic receptors in the heart and blood vessels, with the exception of isoproteronol, are commonly referred to as vasopressors. The adrenergic stimulators may be classified into 3 groups: alpha (phenylephrine hydrochloride), beta (epinephrine), and alpha-beta (l-norepinephrine). Because alpha stimulators do not usually increase cardiac output, alpha-beta and beta-adrenergic stimulators are generally the most useful for treating shock. Routine use of adrenergic stimulators with the exclusion of other therapies, however, is generally unwarranted.^ieng