College of American Pathologists
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  Clinical Abstracts





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February 2002

  • Circulating endostatin levels in patients with systemic sclerosis
  • Hematocrit and bleeding time in very low birth weight infants
  • Molecular variation in sodium balance in hypertension in blacks vs. whites
  • Defining hypercalciuria in children
  • Light chain gammopathy-associated adult Fanconi syndrome
  • A new candidate marker for mortality in chronic heart failure
  • Association of Lewis-negative blood group phenotype and atherosclerosis

    Circulating endostatin levels in patients with systemic sclerosis Systemic sclerosis is a connective tissue disease characterized by vascular injury and collagen accumulation in the skin and internal organs. Endothelial cell lesions and activation of endothelial cells are important factors in the morphology of the vascular injury, and some experimental data suggest a reduction in angiogenesis in systemic sclerosis. The pathogenesis of vascular injury in systemic sclerosis is controversial, and the relationship between such injury and collagen accumulation is unclear. Endostatin is an angiogenesis inhibitor molecule that is endogenously produced. It is a peptide 20-kd proteolytic fragment of type XVIII collagen. Type XVIII collagen is a basement membrane heparan sulfate proteoglycan that is found along blood vessels in the skin and lungs, which are tissues that are frequently involved in systemic sclerosis. Type XVIII collagen is released by fibroblasts and hepatocytes, and its proteolytic fragment, endostatin, can be easily detected in the circulation. The authors assessed the relationship between the circulating levels of endostatin and the tissue extension of systemic sclerosis and the presence of cutaneous scars or ulcers in 50 patients with systemic sclerosis and 30 healthy subjects. They graded the extension of sclerosis according to the Barnett classification system: 33 patients had grade one systemic sclerosis and 17 patients had grade two or three. Pulmonary function tests were abnormal in 31 of 50 of the patients, eight of whom also had abnormalities on chest radiograms. Cutaneous scars or ulcers were found in 22 of the 50 patients. In all cases, endostatin concentrations were determined using a competitive enzyme immunoassay method. The mean circulating endostatin concentration was 53.2±22.4 ng/mL in the systemic sclerosis group versus 9.9±9.7 ng/mL in healthy subjects. Patients with grade two or three systemic sclerosis had even higher levels: 63.2±20.2 ng/mL versus 45.1±15.6 ng/mL. Patients with abnormal findings on chest radiograms had higher levels than patients with normal findings on chest radiograms, and patients with cutaneous scars or ulcers had higher levels than patients without these manifestations. The authors concluded that circulating endostatin concentrations are significantly increased in systemic sclerosis and may represent a marker for that condition.

    Hebbar M, Peyrat J-P, Hornez L, et al. Increased concentrations of the circulating angiogenesis inhibitor endostatin in patients with systemic sclerosis. Arthritis Rheum. 2000;43:889-893.

    Reprints: Dr. Mohamed Hebbar, Service de Médicine Interne, Hôpital Claude Huriez, CHRU, 1 Place de Verdun, 59037 Lille, France

    Hematocrit and bleeding time in very low birth weight infants
    Very low birth weight infants (<1,500 g) frequently develop anemia during their first week of life. The risk for intraventricular bleeding is also greatest during this time. The authors examined the neonatal template bleeding time in 20 very low birth weight infants before and after red blood cell transfusion during their first week of life. All infants weighed less than 1,500 g at birth, were no more than seven days old, and were scheduled to receive an RBC transfusion (15 mL/kg). Infants were ineligible if they had a platelet count of less than 100 x 103/µL or had a disorder that would predispose them to abnormal bleeding—for example, DIC or liver failure. A template bleeding time (Surgicutt newborn device, International Technidyne Corp., Edison, NJ) was performed during the six hours before and the six hours after an RBC transfusion. Hematocrits for the 20 infants ranged from 0.22 to 0.34 before the transfusions and 0.31 to 0.44 after. The hematocrit, over the entire range of hematocrits observed, did not correlate with bleeding time. However, a threshold effect appeared at a hematocrit of about 0.28. Patients with a pretransfusion hematocrit of 0.28 or less (n=10) had a reduction of 164±25 seconds in bleeding time following transfusion (P<0.0001). Patients with a pretransfusion hematocrit of more than 0.28 (n=10) had an insignificant reduction in bleeding time following transfusion (28±24 seconds; P<0.0001) versus those with a pretranfusion hematocrit of less than 0.28. The authors concluded that during the first week of life of very low birth weight infants, a low hematocrit is associated with a significantly prolonged bleeding time. In very low birth weight neonates with pretransfusion hematocrits of 0.28 or less, bleeding times decreased after transfusions by an average of more than two minutes. The effect of RBC transfusion on bleeding time was minimal in neonates with a pretransfusion hematocrit of more than 0.28.

    Sola MC, del Vecchio A, Edwards TJ, et al. The relationship between hematocrit and bleeding time in very low birth weight infants during the first week of life.
    J Perinatol. 2001;21:368-371.

    Correspondence: Dr. Martha C. Sola, Div. of Neonatology, Dept. of Pediatrics, University of Florida, Gainesville, FL 32610-0296

    Molecular variation in sodium balance in hypertension in blacks vs. whites
    The risk of developing hypertension increases when sodium reabsorption increases beyond what is necessary for normal regulation of blood pressure. A number of mechanisms potentially are involved in elevations of blood pressure secondary to greater retention of sodium. The authors explored the component of sodium reabsorption that is linked to calcium handling by the kidney. A calcium-induced natriuretic effect may implement the lowering of blood pressure that can follow increased calcium intake. The authors hypothesized that a difference in the calcium-related mechanism for sodium handling may be related to the ethno-physiological differences in hypertension between blacks and whites. The effects of extracellular calcium on the kidney are mediated in part by the calcium-sensing receptor (CaSR). Several molecular variants in the CaSR molecule resulting from single nucleotide polymorphisms are known. The authors studied three molecular variants in the CaSR molecule. Two—A986S and G990R—were shown to be more frequent in white subjects, and the third—Q1011E—was more frequent in blacks. The authors studied two cohorts of subjects: normal, healthy schoolchildren in whom the renin-aldosterone axis and blood pressure were measured, and normotensive and hypertensive adults. Studies of association were done separately in whites and blacks. No association of any of the variants with sodium balance, as estimated from renin-aldosterone levels, was observed. The Q1011E variant in the black schoolchildren showed only a marginal association with higher blood pressure that was not statistically significant. Similarly, no significant association was noted between the variants and presence or absence of hypertension. The authors concluded that there is no evidence that molecular variations in the CaSR molecule influence sodium or blood pressure.

    Pratt JH, Ambrosius WT, Wagner MA, et al. Molecular variations in the calcium-sensing receptor in relation to sodium balance and presence of hypertension in blacks and whites. Am J Hypertens. 2000;13:654-658.

    Reprints: Dr. J. Howard Pratt, 541 Clinical Drive, Indianapolis, IN 46202-5111;

    Defining hypercalciuria in children
    Hypercalciuria can be symptomatic or asymptomatic and can cause numerous urinary symptoms; defining it in children can be difficult. A number of factors, including age, race, gender, and diet, influence the urinary excretion of calcium. Previous definitions of pediatric hypercalciuria have been defined by values ranging from more than 2 mg/kg of body weight per day to more than 8 mg/kg of body weight per day. Twenty-four-hour urine collections are difficult in children and are especially difficult without bladder catheterization in very young children. The use of random calcium/creatinine ratios to initially assess hypercalciuria in adults has been proposed. More recently, a strong linear correlation has been found between 24-hour urinary calcium excretion and the random urine calcium/creatinine ratio of first morning urine samples in children. The authors undertook a study to determine reference values for random urine calcium/creatinine ratios in children in southern Thailand and to compare urinalysis and urinary sodium and potassium levels in children with normal random urine calcium/creatinine ratios with those having high random urine calcium/creatinine ratios. The authors collected nonfasting, random urine samples from 488 healthy children (282 males, 206 females) who ranged in age from 17 days to 15 years. They divided the samples into six groups based on age. Those subjects whose calcium levels exceeded the 95th percentile within each age group were classified as having hypercalciuria. The presence or absence of pyuria, hematuria, and proteinuria, as well as the urinary sodium and potassium levels in the urine samples of children with normal random urine calcium/creatinine levels were compared with those from children with high calcium/creatinine levels. Pyuria, hematuria, and proteinuria were no more prevalent in the 22 children with hypercalciuria than in the children with normal urinary calcium levels. Urinary sodium/creatinine ratios and urinary sodium/potassium ratios were correlated closely with the urine calcium/creatinine ratio. Urinary potassium/creatinine ratios, however, were not. Children with high calcium/creatinine ratios also had higher urinary sodium creatinine and urinary sodium potassium. The authors concluded that urinalysis is not a good indicator of hypercalciuria, and they established reference ranges for random, nonfasting urinary creatinine ratios for children. The 95th percentiles for this parameter by age were: less than six months, 0.75; six to 12 months, 0.64; 12 months to two years, 0.40; two to five years, 0.38; five to 10 years, 0.29; and 10 to 15 years, 0.26.

    Vachvanichsanong P, Lebel L, Moore ES. Urinary calcium/excretion in healthy Thai children. Pediatr Nephrol. 2000;14:847-850

    Reprints: P. Vachvanichsanong, Dept. of Pediatrics, Faculty of Medicine, Prince of Songkla University, Hat-Yai, Songkla, 90112 Thailand;

    Light chain gammopathy-associated adult Fanconi syndrome
    Adult Fanconi syndrome is a metabolic disorder of proximal renal tubule transport function. It involves abnormally increased urinary concentrations of phosphate, amino acids, glucose, uric acid, and various ions. In contrast to the childhood form of the disease, which may be related to inborn metabolic error, and to the FS associated with drugs and heavy metal toxicity, most adult cases are related to light chain proteinuria. The fewer than 60 cases of light-chain-associated FS in the literature have shown crystal formation in proximal tubule cells without the presence of distal tubular myeloma casts. The authors, having observed cases at variance with this, examined a series of 11 cases of light-chain-associated FS. Seven of these patients presented with low-mass myeloma or monoclonal gammopathy of undetermined significance, which corresponded with the typical clinical and pathologic features of FS. Three patients, however, showed myeloma cast nephropathy and high-mass myeloma; and one of those patients had numerous crystals in proximal tubule cells. The remaining patient had FS with MGUS and no crystals. In contrast, analysis of the light chains in all cases showed them to be of the kappa type, with eight of nine belonging to the VkI variability subgroup. These sequences likely originated from only two germlike genes—LC02/012 and LC08/018. A number of these showed an unusual hydrophobic residue at position 30, possibly accounting for their resistance to cathespin B proteolysis. This resistance to proteolysis may explain the accumulation of the light chain in proximal tubule cells in FS.

    Messiaen T, Deret S, Mougenot B, et al. Adult Fanconi syndrome secondary to light chain gammopathy. Medicine. 2000;79: 135-154.

    Reprints: Dr. Pierre Ronco, INSERM U489, Hôpital Tenon, 4 rue de la Chine, 75020 Paris, France;

    A new candidate marker for mortality in chronic heart failure
    Semicarbazide-sensitive amine oxidase (SSAO) is a group of widely distributed enzymes that is especially prevalent in the vasculature and that circulates in plasma. The enzyme can convert various exogenous and endogenous amines into the corresponding aldehydes, generating hydrogen peroxide and ammonia. Recent attention has focused on the endogenous compounds methylamine and aminoacetone, which are readily converted by SSAO into formaldehyde and methylglyoxal, respectively. The aldehydes, as well as hydrogen peroxide and ammonia, can damage endothelial cells directly and indirectly through the formation of protein-aldehyde reaction products and the formation of reactive oxygen species. Plasma SSAO activity is elevated in type 1 and type 2 diabetes and increases even more when there are a greater number of diabetic complications. The enzyme is also increased in chronic heart failure, in which endothelial function is disturbed. Elevated SSAO activity, therefore, is believed to be involved in vascular damage, endothelial dysfunction, and the process of atherosclerosis. It recently was determined that VAP-1 (vascular adhesion protein-1), which plays a role in the extravasation of leukocytes in some chronic inflammatory conditions, appears to be similar to SSAO. The authors investigated whether plasma SSAO activities in patients with chronic heart failure correlate with prognosis. Plasma SSAO activity was measured at baseline in patients with varying degrees of chronic heart failure who participated in a large European study (PRIME-II). Three hundred and seventy-two patients participated in a substudy in the Netherlands, and a survival followup (mean, 3.4 years) was carried out. One hundred and ninety-five patients died within the followup period. Plasma SSAO activity was higher at baseline in those who died than in the survivors (653±258 versus 540±242 mU/L; P<0.001). SSAO levels were found to be a prognostic parameter for survival by univariate and multivariate analysis. Patients with SSAO levels greater than 550 mU/L had a 50 percent increased risk of death. The authors concluded that plasma SSAO levels appear to be an independent prognostic marker for mortality in chronic heart failure.

    Boomsma F, DeKam PJ, Tjeerdsma G, et al. Plasma semicarbazide-sensitive amine oxidase (SSAO) is an independent prognostic marker for mortality in chronic heart failure. Eur Heart J. 2000;21:1859-1863.

    Reprints: Dr. F. Boomsma, Dept. of Internal Medicine I, University Hospital Dijkzigt, Dr. Molewaterplein 40, 3015 GD Rotterdam, Netherlands

    Association of Lewis-negative blood group phenotype and atherosclerosis
    Recent epidemiologic studies suggest that the Lewis blood group phenotype Lewis (a-b-) may be an independent risk factor for coronary artery disease. The Lewis a and b antigens are fucosylated oligosaccharides on glycosphingolipids that are synthesized by exocrine epithelial cells, transported on high-density and low-density lipoproteins, and adsorbed into erythrocyte bilayers. The antigens appear to participate in embryogenesis, tissue differentiation, tumor cell metastasis, inflammation, and bacterial adhesion. Inflammation and chronic infections may contribute to atherosclerosis. The Lewis (a-b-) phenotype occurs in about 10 percent of Caucasians and doubles the risk of coronary artery disease in this group. The authors examined the prevalence of four Lewis mutations—T59G, T1067A, T202C, and C314T—among Lewis-negative and Lewis-positive phenotypes and related this to coronary heart disease and inflammation. They used a population-based cross-sectional study of samples and data from the National Heart Lung and Blood Institute Family Heart Study. The study involved 136 Lewis-negative and 136 Lewis-positive patients. The study found that 90 to 95 percent of Caucasian Lewis (a-b-) individuals can be identified by screening for the four mutations. All of the mutations, except T59G, were positively associated with coronary heart disease.

    Salomaa V, Pankow J, Heiss G, et al. Genetic background of Lewis negative blood group phenotype and its association with atherosclerotic disease in the NHLBI Family Heart Study. J Intern Med. 2000;247:689-698.

    Reprints: Dr. Veikko Salomaa, National Public Health Institute, Dept. of Epidemiology & Health Promotion, Mannerheiminitie 166, FIN-00320 Helsinki, Finland;