Metabolic defects of primary hyperuricemia and gout

Gout is a syndrome of multiple pathogeneses rather than a single disease entity. Reviewed here are the metabolic defects of primary gout, with major emphasis upon two well characterized, although uncommon, variants due to specific enzyme abnormalities: (1) structural mutants of phosphoribosylpyrophosphate (PP-ribose-P) synthetase with increased activities, resulting in increased rates of synthesis of PP-ribose-P, a key substrate of purine biosynthesis, and (2) structural mutants of hypoxanthineguanine phosphoribosyltransferase (HGPRT) with reduced activities, resulting in reduced consumption of PP-ribose-P and therefore a surplus in the amount available for purine biosynthesis de novo. The present state of our limited knowledge of control of purine biosynthesis is also reviewed briefly, and the potential mechanisms of excessive uric acid production in idiopathic gout are discussed in terms of possible excesses of substrates (PP-ribose-P or L-glutamine) of the first specific reaction of purine biosynthesis, possible defects of control of the enzyme catalyzing this reaction, or defects in maintenance of optimal concentrations of nucleotide regulators of this reaction. It is likely that the rate of production of uric acid in man is influenced by availability of substrates, cofactors and regulatory compounds, and activities of enzymes at many reaction sites other than the first specific reaction of the purine sequence, but their influences upon the rate of purine production can be conveniently analyzed in terms of their indirect effects upon this reaction. Examples cited include glucose-6-phosphatase deficiency glycogen storage disease, in which marked hyperuricemia and purine overproduction are present, and elevated activities of hepatic xanthine oxidase in gouty patients with increased uricaciduria, perhaps occurring secondary to other factors but nevertheless contributing to the excessive purine production. The basic lesions of the more than 95 per cent of patients with primary gout who do not have abnormalities of either PP-ribose-P synthetase or HGPRT remain to be defined, but will almost certainly turn out to be multiple, complex and, in many cases, subtle deviations of metabolic control.     

The physiology of renin secretion in essential hypertension. Estimation of renin secretion rate and renal plasma flow from peripheral and renal vein renin levels

From renin measurements made in blood collected simultaneously from renal veins, aorta and vena cava, an equation was developed for estimating renin secretion rates in patients with three renin subtypes of essential hypertension. From these data a second equation was derived for estimating differential renal plasma flow in patients with unequal kidney perfusion. The latter equation achieves maximum precision when there is no renin secretion from one side.Plasma renin activity was identical in blood collected from the aorta or the vena cava. It was also similar, but higher, in blood collected from either right or left renal veins. The ratio of renin from the two renal veins, an expression of the variability in renal vein renin measurements in essential hypertension, was 1.5 or less in 87 per cent of patients and less than 1.63 in 95 per cent.Renal vein renin content remained proportional to arterial renin over the range of peripheral renin levels found in essential hypertension, so that renal vein renin concentration from each kidney was consistently 124 per cent of arterial renin. The constancy of this relationship complements previous observations indicating that the metabolic clearance rate of renin is proportional to arterial renin levels. The observed equality of renin values between renal veins suggests that differential renal plasma flow is fairly equal and constant in patients with essential hypertension. Moreover, since renal plasma flow from each kidney is inversely related to the increment in renal vein renin concentration relative to arterial renin input [(V-A)/A], differential changes in (V-A)/A can be used to identify differential changes in renal plasma flow.These derived interrelationships are relevant to an analysis of renovascular hypertension since, with this approach, reductions in renal plasma flow can be estimated using only renal vein and arterial renin measurements and adequacy of sampling can be assessed from the sum of (V-A)/A from each kidney.There was no measurable difference in plasma renin substrate in the three renin subgroups of patients with essential hypertension so that observed differences in plasma renin activity levels appear entirely due to differences in renal renin secretion. Under conditions of this study renal renin secretion per minute was 144 times the arterial renin level.     

Comparison of endemic and epidemic nosocomial infections

Epidemics account for a small proportion of preventable infections acquired in hospitals, but they have been important in defining sources, modes of spread, and methods for prevention and control of nosocomial infections. To characterize hospital-based epidemics, 265 consecutive outbreaks investigated by the Center for Disease Control between 1956 and 1979 were reviewed.Pseudoepidemics were found in 11 percent of the investigations, most often resulting from errors in processing microbiologic specimens or from surveillance artifacts. In 223 actual epidemics, the pathogens most commonly involved were Staphylococcus aureus (19 percent), tribe Klebsielleae (14 percent), Salmonella (13 percent), hepatitis B virus (8 percent), enteropathogenic Escherichia coli (5 percent), Pseudomonas (4 percent) and group A streptococci (4 percent). Sites of epidemic infection were closely linked to the responsible pathogens. Gastroenteritis (21 percent), skin infection (18 percent), bacteremia (12 percent), meningitis (11 percent) and hepatitis (10 percent), infrequent causes of endemic nosocomial infections, were frequently involved in epidemics. Over the 25-year period reviewed, staphylococcal epidemics and outbreaks of gastroenteritis due to Salmonella and Esch. coli declined in frequency and those due to gram-negative bacilli and hepatitis B virus increased. Since 1970, clusters of primary bacteremia were the most frequently investigated type of epidemic. Many epidemic strains of staphylococci obtained since 1975 or Enterobacteriaceae obtained since 1970 exhibited unusual drug resistance. Specific site-pathogen combinations were closely associated with characteristic reservoirs and modes of spread.     

The reflex sympathetic dystrophy syndrome. II. Roentgenographic and scintigraphic evidence of bilaterality and of periarticular accentuation.

Patchy osteoporosis is the primary roentgenologic manifestation of the reflex sympathetic dystrophy syndrome (RSDS). As recent clinical and histologic data suggested articular changes in RSDS, fine-detail roentgenograms were obtained in eight consecutive patients. Juxta-articular and soft-tissue swelling, osteoporosis and erosions of the subchondral bone were found. 99mTcO4 and 99mTc-EHDP scintigraphy showed localization of nuclide predominantly in the juxta-articular tissues. Serial roentgenographic, scintigraphic and quantitative bone densitometric measurements showed changes that reflected the clinical course of the disease.     

Searching out low renin patients: limitations of some commonly used methods

This study was designed to determine optimum conditions for measuring plasma renin activity in low renin samples. Optimum conditions were found to be an 18 hour incubation at pH 5.7 and 37 °C in the presence of ethylenediaminetetracetic acid (EDTA), diisopropyl fluorophosphate (DFP) and neomycin. Alkaline pH was disadvantageous because of lower rates of generation of angiotensin I, inability to maintain constant pH without addition of buffer and because the incubation time cannot be prolonged beyond 3 hours. An 18 hour incubation increases sensitivity and eliminates the need for blank subtractions. Dilution prior to incubation is detrimental since the reaction rate is slowed due to dilution of both enzyme and substrate with an inability to correct for the effect of substrate dilution. It was also found, in both acid and alkaline incubations, that dimercaprol (BAL) and 8-hydroxyquinoline are considerably less effective in protecting against angiotensinase than DFP.Commercial kits provide conveniently packaged reagents for renin radioimmunoassay. However, incubation steps currently recommended are inadequate for physiologic studies. Renin measurements were consistently lower using the kits and the amounts of angiotensin generated in low renin samples were only 1 to 4 per cent of those generated using our method. Thus, most low renin samples are undetectable by kit radioimmunoassays and therefore often cannot be discriminated with confidence from many normal renin samples. Moreover, incomplete angiotensinase inhibition and the necessity of subtracting a blank from each value lead to considerable loss of accuracy in both the low and normal renin samples when measured with commercial kits.     

The biochemistry of the renin-angiotensin system and its role in hypertension.

The renin-angiotensin system has an important role in maintaining elevated blood pressure levels in certain forms of experimental and human hypertension. Renin, an enzyme produced by the juxtaglomerular cells of the kidney, acts on a protein substrate found in the alpha 2-globulin fraction of the plasma to produce a decapeptide, angiotensin I. This decapeptide is not directly pressor, but on passage through the pulmonary circulation is converted to an octapeptide, angiotensin II, a very potent pressor substance which acts by causing constriction of arteriolar smooth muscle. In addition to its direct action which increases blood pressure, angiotensin II acts on the adrenal cortex to cause the release of the sodium-retaining hormone aldosterone. Recent evidence suggests that this action may be mediated by the heptapeptide, angiotensin III. Both renin and its protein substrate exist in multiple forms and renin may also exist as a high molecular-weight "pro-hormone," although the physiologic significance of these forms is not clear. The elucidation of the biochemistry of the renin-angiotensin system has provided us with inhibitors which allow the system to be blocked effectively in vivo. Thus, angiotensin antagonists such as Sar 1, IIe 8-angiotensin II and converting enzyme inhibitors such as BPP 9a (SQ 20881) have proved useful in the study of experimental and human hypertension.     

The essential action of propranolol in hypertension.

The unique action of propranolol and other beta blockers in lowering raised arterial pressure is discussed. Although the onset of the antihypertensive effect is not immediate, many trials have confirmed the efficacy of these drugs. Animal experiments have thrown little light on the mechanism of action of beta blockers in hypertension: this may be because in animals, especially the rat, peripheral beta adrenoceptor vasodilatation is relatively more important than in man. Five principal theories have been advanced to explain the antihypertensive effect. None of these, the renin, central nervous system, cardiac, baroceptor or metabolite theory, is totally satisfactory. A new theory is proposed suggesting that the essential action is to diminish sympathetic nerve output by damping sensory input to the central nervous system from a heart whose capacity to respond to exercise and stress is blunted by beta adrenoceptor blockade.     

Multisystem involvement in chronic liver disease. Studies on the incidence and pathogenesis

Sjögren's syndrome occurred in 37 per cent, renal tubular acidosis in 32 per cent, pulmonary diffusion defects in 26 per cent and peripheral neuropathy in 10 per cent of patients with active chronic hepatitis, primary biliary cirrhosis or cryptogenic cirrhosis. The incidence of certain other conditions determined from clinical features alone was lower; these included arthropathy in 14 per cent, thyroid disorders in 10 per cent, skin lesions in 17 per cent and colitis in 5 per cent. In the complete series of 218 patients, 125 (57 per cent) had involvement of at least one organ other than the liver, such involvement being significantly more common in those with active chronic hepatitis (63 per cent of cases) and primary biliary cirrhosis (68 per cent) than in those with cryptogenic cirrhosis (38 per cent). In a number of patients, prednisone therapy was followed by both subjective and objective improvement in the features of the multisystem involvement.No correlation could be found between multisystem involvement and the presence of mitochondrial, smooth muscle or antinuclear antibodies in the serum or with the serum levels of immunoglobulins A (IgA), M (IgM) and G (IgG). Histologie examination of the various organs disclosed dense infiltration with small lymphocytes, suggesting that delayed hypersensitivity reactions were involved in the production of tissue damage. In support of this was the demonstration of cell-mediated reactivity in vitro to salivary or renal antigens in 42 per cent of the patients with Sjögren's syndrome and in 62 per cent of those with renal tubular acidosis, respectively.These findings, together with the frequency and similar pattern of multisystem involvement in the three conditions, suggest a common pathogenetic mechanism, and disordered cellular immune reactions directed primarily against the liver could affect other organs as a result of cross antigenicity.     

Blood in the lymph (hemochylia) and intestinal lymphangiectasia associated with Lutembacher's syndrome

A 31 year old man presenting with Lutembacher's syndrome and protein-losing enteropathy is described. Reversal of the protein-losing enteropathy 7 months after cardiac surgery suggested that it was secondary to the cardiac disorder. Spontaneous rupture of a congenital aneurysm of the splenic artery created a spleno-portal arteriovenous fistula which caused a massive sequestration of blood into the dilated abdominal lymphatic system, severe hypovolemic shock and death.The pathogenesis and relation of two rare disorders of the lymphatic system, contamination of the lymph with blood (hemochylia) and intestinal lymphangiectasia are discussed.     

Total occlusion of the left main coronary artery. A clinical, hemodynamic and angiographic profile

Although left main coronary artery stenosis has been extensively revicwed, total occlusion of the left main coronary artery has received scant attention. Six patients were diagnosed at cardiac catheterization as having total occlusion of the left main coronary artery over a period of seven years at two institutions. They ranged in age from 32 to 72 years, and all had symptoms ranging from NYHA Class 1-IV at initial presentation. One patient died three days after coronary artery bypass graft surgery. Of the remaining five, two treated medically are alive four and 40 months after catheterization, and three treated with coronary artery bypass graft surgery are alive three, 66 and 68 months after catheterization. Electrocardiogram showed prior myocardial infarction in three patients, stress tests were positive in three of four patients, and hyperlipidemia was present in the five tested. In the three patients without prior myocardial infarction, left ventricular function was preserved (ejection fractions = 0.52, 0.55 and 0.64; left ventricular end-diastolic pressures = 6, 9 and 14 mm Hg). Injection of the right coronary artery in this group revealed extensive collaterals filling the left coronary artery. The three patients with prior myocardial infarction had impaired left ventricular function (ejection fractions = 0.18, 0.30 and 0.33; left ventricular end diastolic pressures = 26, 35 and 35 mm Hg) and sparse intercoronary collaterals. Patients with total occlusion of the left main coronary artery have a varying clinical presentation and may have prolonged survival. In patients with good collaterals, left ventricular function may be preserved.     

Immunoglobulin E (IgE) multiple myeloma: A case report and review of the literature

A case of immunoglobulin E (IgE) myeloma with clinical features of “classic” myeloma is presented. Skeletal roentgenograms showed osteoporosis and compression fractures of the vertebrae but no osteosclerosis. Protein analyses revealed an M component of the IgE kappa type with a concentration of 3.1 g/dl. Although morphologic examination revealed that the plasma cells were not so differentiated, well-developed Golgi apparatus and abundant rough-surfaced endoplasmic reticulum were observed. An indirect immunofluorescence technique showed characteristic apple green fluorescence. The E myeloma protein of our patient had no antibody activity. Treatment with melphalan or cyclophosphamide resulted in a decrease in the serum IgE level and in the level of Bence Jones protein in the urine. The clinical and laboratory features of IgE myeloma were summarized and compared with those of other classes of myeloma.