Urinary Sulfate Excretion Research Articles

Alteration of Sulfate and Hydrogen Metabolism in the Human Colon by Changing Intestinal Transit Rate

Changes in intestinal transit rate are also implicated in the etiology of many colonic diseases and strongly influence many metabolic processes in the colon. We set out to investigate whether intestinal transit time could influence the activity of the hydrogen-consuming bacterial flora and sulfate metabolism. Normal volunteers underwent four interventions while taking a low-sulfate diet: placebo, sulfate supplements, or sulfate supplements with either senna or loperamide. Stools were cultured and analyzed for sulfate, sulfide, methionine, sulfate reduction rates, methionine reduction rates, acetic acid production rates, methane production rates, short-chain fatty acids, and bile acids. Urine was analyzed for sulfate. The addition of sulfate alone increased fecal and urinary excretion of sulfate, fecal sulfide, sulfate reduction rates, and acetic acid production rates; it reduced fecal methanogenic bacterial concentrations. Faster intestinal transit increased fecal sulfate, sulfide, bile acids, the reduction rates of sulfate, and methionine and the production rates of acetic acid. Reduction in fecal methanogens and methane production was seen. The reverse effects were seen with loperamide. Both sulfate supplements and changes in intestinal transit rate markedly alter the activity of the colonic bacterial flora with respect to sulfate metabolism and hydrogen disposal. Dietary influences on intestinal transit and sulfate consumption may influence disease processes. While a variety of processes govern sulfate metabolism and hydrogen disposal, our knowledge is far from complete. How far the observed changes in sulfate metabolism seen in certain diseases are relevant to the pathogenesis of the disease or secondary to the disease itself is unclear.

Differences in 24-Hour Urine Composition between Black and White Women

Black women are less likely to develop kidney stones and have greater bone mass than white women. However, little is known about racial differences in urine composition. Urine pH, volume, and 24-h urinary excretion of calcium, citrate, oxalate, uric acid, sodium, potassium, magnesium, phosphate, sulfate, and creatinine of 146 black women were compared with 330 white women in the Nurses' Health Study. All participants were postmenopausal non-stone formers. ANOVA was used to compare mean urinary values. Linear regression models were adjusted for age, body mass index, dietary intake, and urinary factors. On average, black women excreted 65 mg less urinary calcium (P < 0.001), 4 mg more oxalate (P < 0.001), 9 mEq less potassium (P < 0.001), 11 mg less magnesium (P = 0.003), 120 mg less phosphate (P < 0.001), and 3 mmol less sulfate (P < 0.001) per day than did white women. The urine pH of black women was 0.11 units higher (P = 0.03) and urine volume was 0.24 L less (P = 0.001). The urinary relative supersaturations of calcium oxalate (P = 0.03) and brushite (P = 0.002) were lower in black women. No other significant differences were observed. Differences in urinary calcium and pH persisted after multivariate adjustment and after exclusion of participants who were taking thiazide diuretics or those with diabetes. In conclusion, black women excrete less urinary calcium and have a higher urinary pH than do white women. These differences are not explained by differences in age, body mass index, or diet and may account for the lower incidence of both nephrolithiasis and osteoporosis in black women.

A Case of Estrogen-secreting Adrenocortical Carcinoma with Subclinical Cushing's Syndrome

A 25-year-old man was found to have a large right adrenal mass detected by abdominal echography and computed tomography, and presented with a mild gynecomastia. Endocrine study showed increased serum concentrations and urinary excretion of estrogens and dehydroepiandorosterone sulfate (DHEA-S). The patient had no Cushingoid features but autonomous cortisol secretion, compatible with the diagnosis of subclinical Cushing's syndrome. Surgical removal of the adrenal tumor led to normalization of serum and urinary excretion of estrogens and DHEA-S. Histopathological examination revealed a high-grade adrenocortical carcinoma (ACC). The disorganized expression of all the steroidogenic enzymes in individual tumor cells was demonstrated by immunohistochemical analysis, and the abundant expression of both aromatase mRNA and insulin-like growth factor (IGF)-II mRNA was shown by RT-PCR. These data suggest the excessive secretion of estrogen as well as the ineffective steroidogenesis by the adrenal tumor. This is a very rare case of estrogen-secreting ACC associated with subclinical Cushing's syndrome.

Contribution of dietary protein and inorganic sulfur to urinary sulfate: toward a biomarker of inorganic sulfur intake

Sulfiting agents are widely used as food additives. Limits are set on their use in foods because they may adversely affect health. Sulfiting agents are excreted in urine as sulfate, which is indistinguishable from sulfate derived from sulfur amino acids. The objective was to assess the contribution of inorganic sulfur to urinary sulfate excretion and of dietary protein to urinary sulfate and nitrogen excretion with the aim of developing a urinary biomarker of inorganic sulfur intake. Nine healthy men were fed a sequence of 3 diets for 15 d (n = 7), 5 diets for 10 d (n = 6), or both. The diets contained 51-212 g protein/d (0.43-1.71 g S/d) and 0.17-0.27 g inorganic S/d; p-aminobenzoic acid-validated 24-h urine samples (n = 47) were analyzed for sulfate and nitrogen. Dietary inorganic sulfur was efficiently excreted as sulfate in urine. Urinary sulfate derived from protein correlated strongly (r(2) = 0.86) with urinary nitrogen. Urinary recovery of protein sulfur and nitrogen decreased from 84% at average protein intakes (72 g/d) to 70% at high protein intakes (212 g/d). The nitrogen:sulfur ratio (in g) of the protein in the study diets was 18.9, which was maintained in urine (18.4 +/- 0.1) after dietary inorganic sulfur intake was subtracted from urinary sulfate. Therefore, inorganic sulfur intake (g/d) = urinary sulfur (g/d) - 0.054 x urinary nitrogen (g/d). For typical UK intakes of inorganic sulfur (0.25 g/d), this biomarker should produce mean (+/- SD) values of 0.24 +/- 0.10 g S/d. Twenty-four-hour urinary nitrogen and sulfate values can be used to predict inorganic sulfur intake.

Critical role of vitamin D in sulfate homeostasis: regulation of the sodium-sulfate cotransporter by 1,25-dihydroxyvitamin D3.

As the fourth most abundant anion in the body, sulfate plays an essential role in numerous physiological processes. One key protein involved in transcellular transport of sulfate is the sodium-sulfate cotransporter NaSi-1, and previous studies suggest that vitamin D modulates sulfate homeostasis by regulating NaSi-1 expression. In the present study, we found that, in mice lacking the vitamin D receptor (VDR), NaSi-1 expression in the kidney was reduced by 72% but intestinal NaSi-1 levels remained unchanged. In connection with these findings, urinary sulfate excretion was increased by 42% whereas serum sulfate concentration was reduced by 50% in VDR knockout mice. Moreover, levels of hepatic glutathione and skeletal sulfated proteoglycans were also reduced by 18 and 45%, respectively, in the mutant mice. Similar results were observed in VDR knockout mice after their blood ionized calcium levels and rachitic bone phenotype were normalized by dietary means, indicating that vitamin D regulation of NaSi-1 expression and sulfate metabolism is independent of its role in calcium metabolism. Treatment of wild-type mice with 1,25-dihydroxyvitamin D3 or vitamin D analog markedly stimulated renal NaSi-1 mRNA expression. These data provide strong in vivo evidence that vitamin D plays a critical role in sulfate homeostasis. However, the observation that serum sulfate and skeletal proteoglycan levels in normocalcemic VDR knockout mice remained low in the absence of rickets and osteomalacia suggests that the contribution of sulfate deficiency to development of rickets and osteomalacia is minimal.

Behavioural abnormalities of the hyposulphataemic Nas1 knock-out mouse

We recently generated a sodium sulphate cotransporter knock-out mouse ( Nas1−/−) which has increased urinary sulphate excretion and hyposulphataemia. To examine the consequences of disturbed sulphate homeostasis in the modulation of mouse behavioural characteristics, Nas1−/− mice were compared with Nas1+/− and Nas1+/+ littermates in a series of behavioural tests. The Nas1−/− mice displayed significantly ( P<0.001) decreased marble burying behaviour (4.33±0.82 buried) when compared to Nas1+/+ (7.86±0.44) and Nas1+/− (8.40±0.37) animals, suggesting that Nas1−/− mice may have decreased object-induced anxiety. The Nas1−/− mice also displayed decreased locomotor activity by moving less distance (1.53±0.27 m, P<0.05) in an open-field test when compared to Nas1+/+ (2.31±0.24 m) and Nas1+/− (2.15±0.19 m) mice. The three genotypes displayed similar spatiotemporal and ethological behaviours in the elevated-plus maze and open-field test, with the exception of a decreased defecation frequency by the Nas1−/− mice (40% reduction, P<0.01). There were no significant differences between Nas1−/− and Nas1+/+ mice in a rotarod performance test of motor coordination and in the forced swim test assessing (anti-)depressant-like behaviours. This is the first study to demonstrate behavioural abnormalities in the hyposulphataemic Nas1−/− mice.

Transport, enzymatic activity, and stability of mutant sulfamidase (SGSH) identified in patients with mucopolysaccharidosis type III A.

Mucopolysaccharidosis type IIIA (MPSIIIA) is an autosomal recessive lysosomal storage disease caused by mutations in the N-sulfoglucosamine sulfohydrolase gene (SGSH; encoding sulfamidase, also sulphamidase) leading to the lysosomal accumulation and urinary excretion of heparan sulfate. Considerable variation in the onset and severity of the clinical phenotype is observed. We report here on expression studies of four novel mutations: c.318C>A (p.Ser106Arg), c.488T>C (p.Leu163Pro), c.571G>A (p.Gly191Arg), and c.1207_1209delTAC (p.Tyr403del), and five previously known mutations: c.220C>T (p.Arg74Cys), c.697C>T (p.Arg233X), c.1297C>T (p.Arg433Trp), c.1026dupC (p.Leu343fsX158), and c.1135delG (p.Val379fsX33) identified in MPSIIIA patients. Transient expression of mutant sulfamidases in BHK or CHO cells revealed that all the mutants were enzymatically inactive with the exception of c.318C>A (p.Ser106Arg), which showed 3.3% activity of the expressed wild-type enzyme. Western blot analysis demonstrated that the amounts of expressed mutant sulfamidases were significantly reduced compared with cells expressing wild type. No polypeptides were immunodetectable in extracts of cells transfected with the cDNA carrying the c.697C>T (p.Arg233X) nonsense mutation. In vitro translation and pulse-chase experiments showed that rapid degradation rather than a decrease in synthesis is responsible for the low, steady-state level of the mutant proteins in cells. The amounts of secreted mutant precursor forms, the cellular stability, the proteolytic processing, and data from double-label immunofluorescence microscopy suggest that the degradation of the majority of newly synthesized c.220C>T (p.Arg74Cys), c.571G>A (p.Gly191Arg), c.1297C>T (p.Arg433Trp), c.1026dupC (p.Leu343fsX158), and c.1135delG (p.Val379fsX33) mutant proteins probably occurs in the ER, whereas c.488T>C (p.Leu163Pro) mutant protein showed instability in the lysosomes.

Hyposulfatemia, growth retardation, reduced fertility, and seizures in mice lacking a functional NaSi-1 gene.

Inorganic sulfate is required for numerous functions in mammalian physiology, and its circulating levels are proposed to be maintained by the Na+-SO42- cotransporter, (NaSi-1). To determine the role of NaSi-1 in sulfate homeostasis and the physiological consequences in its absence, we have generated a mouse lacking a functional NaSi-1 gene, Nas1. Serum sulfate concentration was reduced by >75% in Nas1-/- mice when compared with Nas1+/+ mice. Nas1-/- mice exhibit increased urinary sulfate excretion, reduced renal and intestinal Na+-SO42- cotransport, and a general growth retardation. Nas1-/- mouse body weight was reduced by >20% when compared with Nas1+/+ and Nas1+/- littermates at 2 weeks of age and remained so throughout adulthood. Nas1-/- females had a lowered fertility, with a 60% reduction in litter size. Spontaneous clonic seizures were observed in Nas1-/- mice from 8 months of age. These data demonstrate NaSi-1 is essential for maintaining sulfate homeostasis, and its expression is necessary for a wide range of physiological functions.

Interactions of human organic anion as well as cation transporters with indoxyl sulfate

Various uremic toxicants including indoxyl sulfate exert a number of biological effects on uremic patients. In order to elucidate the molecular mechanisms for the pharmacokinetics of indoxyl sulfate in human, we examined the interactions of human organic anion transporters (human-OATs) and human organic cation transporters (human-OCTs) with indoxyl sulfate using stable transfectants. Indoxyl sulfate inhibited human-OAT1, human-OAT3 and human-OAT4, but not human-OAT2, human-OCT1 and human-OCT2. Kinetic analysis revealed that the K i values for human-OAT1, human-OAT3 and human-OAT4 were 22.7, 168.7 and 181.3 μM, respectively. Human-OAT1 and human-OAT3 mediated the uptake of indoxyl sulfate and human-OAT4 mediated not only the uptake but also the efflux of indoxyl sulfate. In conclusion, by comparing the K i values with the plasma concentration of unbound indoxyl sulfate, it was predicted that human-OAT1 and human-OAT3 mediate the transport of indoxyl sulfate in vivo. In addition, it was suggested that human-OAT1 and human-OAT3 are involved in the urinary excretion of indoxyl sulfate, the exacerbation of renal dysfunction and the induction of uremic encephalopathy by indoxyl sulfate.

Association of hyperhomocysteinemia with plasma sulfate and urine sulfate excretion in patients with progressive renal disease

Background: Plasma total homocysteine (tHcy) level is increased in patients with renal disease, parallel to serum creatinine concentration. In renal failure, the final product of sulfated amino acid metabolism, sulfate, also accumulates as renal function declines. We hypothesized that the elevation in sulfate level could cause hyperhomocysteinemia and tested the relation between tHcy level and both urinary excretion and plasma levels of sulfate. Methods: Forty patients with renal disease were divided into three groups: patients without renal failure (nRF; creatinine clearance [CCr] ≥ 80 mL/min/1.73 m2 [≥1.33 mL/s/1.73 m2]), patients with mild renal failure (mRF; 80 > CCr ≥ 25 mL/min/1.73 m2 [1.33 > CCr ≥ 0.42 mL/s/1.73 m2]), and patients with severe renal failure (sRF; CCr < 25 mL/min/1.73 m2 [<0.42 mL/s/1.73 m2]). Daily urinary excretion and plasma levels of tHcy, total cysteine (tCys), and sulfate were measured. A healthy control (HC) group also was tested. Serum methionine, taurine, vitamin B12, and folate levels also were determined in patients with renal disease. Results: Plasma tHcy and sulfate concentrations in the groups with mRF and sRF were greater than in the HC group. Plasma tCys concentrations in the mRF and sRF groups were greater than in the nRF group. Daily urinary Hcy and Cys excretion did not differ among the four groups. Daily urine sulfate and urea nitrogen excretion in the sRF group were significantly less than in the HC and nRF groups. Multiple regression analyses showed that plasma creatinine (β = 0.40) and sulfate (β = 0.43) levels were independently associated with plasma Hcy level; among urine parameters, only daily urine sulfate excretion (β = −0.52) was independently associated with plasma Hcy level. Conclusion: The elevated plasma sulfate level, in accordance with renal function, is associated with plasma tHcy level. Decreased sulfate excretion, which might parallel the intake of sulfated amino acid or protein, may increase tHcy levels. Am J Kidney Dis 40:909-915. © 2002 by the National Kidney Foundation, Inc.

Effect of protein restriction on sulfur amino acid catabolism in insulin-dependent diabetes mellitus.

Persons with conventionally treated insulin-dependent diabetes mellitus (IDDM) appear to be impaired in their ability to reduce fed-state urea production appropriately in response to dietary protein restriction (Hoffer LJ, Taveroff A, and Schiffrin A. Am J Physiol 272: E59-E67, 1997). To determine whether these conclusions apply to whole body sulfur amino acid (SAA) catabolism, we used samples from this protocol to measure daily urinary sulfate excretion and fed-state sulfate production after a high-protein test meal before and after dietary protein restriction. Eight normal subjects and six IDDM subjects treated with twice-daily intermediate- and short-acting insulin consumed a mixed test meal containing 0.50 g protein/kg after adaptation to 4 days of high protein intake (1.28 g protein/kg body wt) and again after 5 days of dietary protein restriction (0.044 g/kg). Adaptation to protein restriction decreased daily urinary sulfate and urea-N excretion by approximately 80%. Over the first 24 h of protein restriction, urinary sulfate excretion decreased more than urea-N excretion for both the normal and IDDM subjects. Under conditions of a high prior protein intake, fed-state sulfate production was normal for the IDDM subjects; protein restriction reduced fed-state sulfate production by 51% (normal subjects) and 59% (IDDM subjects; not significant). We conclude that whole body SAA metabolism is normal in conventionally treated IDDM before and after dietary protein restriction. SAA catabolism, as measured by fed-state sulfate production, may be a convenient and useful method to determine the extent of whole body protein dysregulation in IDDM.

Identification of a Mutation Causing Mucopolysaccharidosis Type IIIA in New Zealand Huntaway Dogs

Mucopolysaccharidosis type IIIA (MPS IIIA) is an autosomal recessive disease that occurs due to a deficiency of heparan sulfate sulfamidase (SGSH). The deficiency of SGSH results in the lysosomal accumulation and urinary excretion of the glycosaminoglycan heparan sulfate. The clinical severity of MPS IIIA is predominantly characterized by severe central nervous system degeneration. Naturally occurring MPS IIIA has recently been described in New Zealand Huntaway dogs, with similar disease progression and biochemical characteristics observed in severely affected MPS IIIA patients. Here, we identify the disease-causing mutation in the MPS IIIA Huntaway dog as 708-709insC. The frequency of the 708-709insC mutation in a sample group of 203 New Zealand Huntaway dogs was determined to be 3.8%. The identification of the 708-709insC mutation will permit the identification of heterozygous carriers as an initial step toward establishing a breeding colony of MPS IIIA dogs for the study of various therapeutic strategies targeted to the central nervous system.

White matter changes mimicking a leukodystrophy in a patient with Mucopolysaccharidosis: characterization by MRI

Mucopolysaccharidosis (MPS) type I (α-iduronidase deficiency) is characterized by storage and massive urinary excretion of dermatan sulfate and heparan sulfate; it may be distinguished into three different subtypes based on age at onset and severity of the clinical symptoms. We report on progressive white matter involvement documented by serial MR imaging in a patient with the MPS type I, severe skeletal involvement and preserved mental capabilities (intermediate phenotype or Hurler/Scheie syndrome). The natural history of white matter abnormalities in patients with MPS is still unclear; based on the present study, it appears that degenerative changes of the white matter mimicking a leukodystrophy may mark the course of MPS type I. We also suggest that the degree of MR changes in patients with MPS does not always reflect their neurological impairment.

Serial magnetic resonance imaging findings in mucopolysaccharidosis IIIB (Sanfilippo's syndrome B)

Sanfillippo B syndrome (mucopolysaccharidosis (MPS) III, type B) is characterized by mild expression of the characteristic ‘Hurler’ phenotype and a severe central nervous system involvement. We report three patients with Sanfilippo B syndrome, referred to our clinic because of peculiar facies, delay in language development and behavioral problems, at the ages of 4, 3 and 5 years, respectively. At presentation they manifested clinical features of MPS, severe developmental retardation, radiological features of dysostosis mutiplex, as well as neurophysiological findings suggestive of carpal tunnel syndrome and sensorineural hearing impairment. Due to marked urinary excretion of heparan sulfate, as well as deficiency of α- N-acetylglucosaminidase in leukocytes, the diagnosis of Sanfilippo B syndrome was made. Serial brain magnetic resonance imaging (MRI) at different ages demonstrated white matter abnormalities, cortical atrophy and ventricular enlargement in all three patients, while other findings included thickening of the diploe in two patients and callosal atrophy, basal ganglia involvement, cerebellar changes and dilatation of venous sinuses in one patient. Although the combination of the above MRI findings is highly suggestive of a MPS, they carry a little predictive value in the different clinical stages of MPS IIIB.

The effect of aminoguanidine on urinary heparan sulphate levels in experimental diabetes.

In the present study, we investigated whether the ameliorating effect of aminoguanidine on diabetes-related proteinuria and nephropathy is associated with glomerular basement membrane heparan sulphate contents. STZ-induced diabetic rats developed proteinuria (at the tenth week: diabetic rats, 713 +/- 418 mg protein per millimole creatinine; control rats, <30) and increased urinary heparan sulphate excretion (diabetic rats, 1,400 +/- 83 microg/mmol creatinine; control rats, 41 +/- 13; p < 0.001), suggesting loss of glomerular basement membrane charge. Aminoguanidine treatment of diabetic rats diminished urinary heparan sulphate levels (196 +/- 52), suggesting high incorporation of heparan sulphate-associated charge into glomerular basement membrane. Aminoguanidine administration to diabetic rats also relatively improved proteinuria (456 +/- 255). It is concluded that aminoguanidine treatment has a relative beneficial effect by restoring the diabetes-induced change in renal basement membrane heparan sulphate levels.

Increased excretion of urinary glycosaminoglycans in meningococcal septicemia and their relationship to proteinuria

Meningococcal septic shock is a devastating illness associated with an increase in vascular permeability leading to hypovolemia and accumulation of plasma proteins and fluid in tissues. The capillary leak syndrome is often associated with widespread thrombosis in the skin, limbs, and digits. We postulated that the increase in vascular permeability and the intravascular thrombosis might be caused by an inflammation-induced loss of endothelial and basement membrane glycosaminoglycans (GAGs), which play a role in the permeability and thromboresistant properties of the microvasculature. Prospective, single-center observational study. University-affiliated meningococcal research unit and pediatric intensive care unit. Eighteen children requiring intensive care for meningococcal sepsis, 18 children with steroid-responsive nephrotic syndrome, and 18 healthy control children. None. Serum concentrations and urine excretion of glycosaminoglycans were measured and related to changes in glomerular permeability to plasma proteins. The size-distribution and nature of glycosaminoglycans were defined by Polyacrylamide Gel Electrophoresis and specific enzyme digestion. Urinary excretion of heparan sulfate, chondroitin-4-sulfate, and chondroitin-6-sulfate were significantly increased in meningococcal disease (MD) relative to healthy controls and children with steroid-responsive nephrotic syndrome. The urinary GAGs in MD were of similar size to those in controls when analyzed after pronase digestion. However, analysis of proteoglycan size before proteolytic digestion showed the urinary GAGs in MD were of lower molecular weight and unattached to proteins. The fractional excretion of albumin and immunoglobulin G in MD increased with severity of disease. Patients with severe or fatal MD had albumin clearances overlapping those seen in steroid-responsive nephrotic syndrome. There was a significant correlation between proteinuria in MD and urinary excretion of heparan sulfate (r2 = 0.611, p < .0001), chondroitin-4-sulfate (r2 = 0.721, p < .0001), and chondroitin-6-sulfate (r2 = 0.395, p < .0001). The capillary leak in meningococcal disease is associated with increased plasma and urine concentrations of GAGs, which may be proteolytically cleaved from endothelial and basement membrane sites. The correlation between the severity of protein leakage and the urine excretion of GAGs suggests that loss of GAGs may be causally related to the increase in permeability to proteins.

Impact of body weight on urinary electrolytes in urinary stone formers

Objectives. Obesity increases the risk of developing chronic medical conditions such as diabetes mellitus, hypertension, and coronary artery disease. We performed a retrospective review of a large data base on urinary stones to determine if differences are found in urine and serum chemistries among obese and nonobese stone-forming patients. The effect of body weight on stone recurrence among urinary stone formers was also determined. Methods. A national data base containing serum biochemical profiles, 24-hour urine specimens, and standardized questionnaires was retrospectively evaluated from 5942 consecutive patients with urinary stone disease. Stone-forming patients were classified by body weight: nonobese men, less than 100 kg and nonobese women, less than 85 kg; intermediate men, 100 to 120 kg and intermediate women, 85 to 100 kg; and obese men, more than 120 kg and obese women, more than 100 kg. Results. Obese stone formers comprised 6.8% (n = 404) of the patient population. The mean weight in the nonobese and obese groups was 81 kg versus 134 kg, respectively, for men and 64 kg versus 112 kg, respectively, for women. Obese patients represented 3.8% of the male and 12.6% of the female population. Obese patients had increased urinary excretion of sodium, calcium, magnesium, citrate, sulfate, phosphate, oxalate, uric acid, and cystine; obesity was associated with increased urinary volumes and urine osmolality compared with the nonobese patients. Obese men had increased concentration of urinary sodium, oxalate, uric acid, sulfate, and phosphate when corrected for urinary volume. Obese women had increased concentrations of sodium, uric acid, sulfate, phosphate, and cystine. The mean number of stone episodes in nonobese versus obese men was similar (3.55 and 3.56), whereas mean stone episodes were 2.93 and 3.38 ( P = 0.045) for nonobese versus obese women. Conclusions. Among known stone formers, obesity is associated with unique changes in both serum and urinary chemistries. These changes are associated with an increased incidence of urinary stone episodes in obese women but not in obese men.

Dietary cyanide from insufficiently processed cassava and growth retardation in children in the Democratic Republic of Congo (formerly Zaire).

Dietary cyanide exposure from cyanogenic glucosides in insufficiently processed cassava has been advanced as a contributing factor in child growth retardation. Whether cyanide exposure aggravates children's growth retardation was studied by comparing two populations of children from the northern and the southern zones of the Bandundu region, Democratic Republic of Congo (former Zaire), using dietary interviews, anthropometry and urine analyses. Both populations consumed cassava as their staple diet, but whereas in the north the cassava was well processed, in the south it was inadequately processed. The mean urinary thiocyanate was much higher in the south, whereas mean urinary sulphate excretion was equally low in the two areas. However, the mean urinary SCN/SO4 molar ratio was higher in the south (0.20), indicating that 10-20% of sulphur amino-acids were used for cyanide detoxication. No significant differences were found between the two populations in weight-for-height and weight-for-age indices but the height-for-age index was significantly lower in children from the south, indicating more severe growth retardation in children exposed to dietary cyanide. Because of the preferential use of sulphur amino-acids for cyanide detoxification in the human body, dietary cyanide exposure from cassava may be a factor aggravating growth retardation in Bandundu.

Massive loss of sulfur in HIV infection.

Skeletal muscle tissue from SIV-infected macaques was previously found to contain abnormally high sulfate and low glutathione levels indicative of an excessive cysteine catabolism. We now confirm the peripheral tissue as a site of massive cysteine catabolism in HIV infection and have determined the urinary loss of sulfur per time unit. The comparison of the sulfate concentrations of the arterial and venous blood from the lower extremities of 16 symptomatic HIV+ patients and 18 HIV- control subjects (study 1) revealed (1) that the peripheral tissue of HIV+ patients with or without highly active antiretroviral therapy (HAART) releases large amounts of sulfate and (2) that plasma sulfate, thioredoxin, and interleukin-6 levels are elevated in these patients. A complementary investigation of 64 asymptomatic HIV+ patients and 65 HIV- subjects (study 2) revealed increased plasma sulfate levels in the asymptomatic patients. The analysis of the daily urinary excretion of sulfate and urea of another group of 19 HIV+ patients and 22 healthy HIV- subjects (study 3) confirmed (1) that HIV+ patients experience a massive loss of sulfur and (2) that this loss is not ameliorated by HAART. The sulfur loss of asymptomatic patients was equivalent to a mean loss of about 10 g of cysteine per day. If extrapolated, this would correspond to an alarming negative balance of approximately 2 kg of cysteine per year under the assumption that the normal sulfate excretion equivalent to approximately 3 g of cysteine per day is balanced by a standard Western diet. The abnormally high sulfate/urea ratio suggests that this process drains largely the glutathione pool.

Proteoglycan and collagen biochemical variations during fluoroquinolone-induced chondrotoxicity in mice.

Although fluoroquinolone antibacterials have a broad therapeutic use, with a relatively low incidence of severe side effects, they have been reported to induce lesions in the cartilage of growing animals by a mechanism that remains unclear. This study was undertaken to determine the potentially deleterious effect of a high dose of pefloxacin (400 mg/kg of body weight) on two main constituents of cartilage in mice, i.e., proteoglycans and collagen. Variations in levels of proteoglycan anabolism measured by in vivo [(35)S]sulfate incorporation into cartilage and oxidative modifications of collagen assessed by detection of carbonyl derivatives were monitored after administration of pefloxacin. Treatment of mice with 1 day of pefloxacin treatment significantly decreased the rate of biosynthesis of proteoglycan for the first 24 h. However, no difference was observed after 48 h. The decrease in proteoglycan synthesis was accompanied by a marked drop in serum sulfate concentration and a concomitant increase in urinary sulfate excretion. The decrease in proteoglycan synthesis, also observed ex vivo, may suggest a direct effect of pefloxacin on this process, rather than it being a consequence of a low concentration of sulfate. On the other hand, treatment with pefloxacin for 10 days induced oxidative damage to collagen. In conclusion, this study demonstrates, for the first time, that pefloxacin administration to mice leads to modifications in the metabolism and integrity of extracellular proteins, such as collagen and proteoglycans, which may account for the side effects observed. These results offer new insights to explain quinolone-induced disorders in growing articular cartilage.