Long term ‘marine diet’ in Eskimos is not associated with altered urinary excretion of total tetranor prostaglandin metabolites

The total urinary excretion of tetranor prostaglandin metabolites, measured as tetranorprostanedioic acid (TPD), was quantified in traditionally living Greenland Eskimos (E) and compared with that in Caucasian Danes (D). TPD excretion (μg/24h) was not significantly different between both groups, neither for males (331 ± 62.4 (E) vs. 331 ± 25.7 (D), mean ± SEM, n = 9 and 10) nor for females (190 ± 31.7 (E) vs. 264 ± 27.4 (D), n = 11 and 10, P₂ > 0.05). Since urinary prostaglandin metabolites are thought to reflect the total prostaglandin turnover in vivo, these results suggest that a long-term intake of relatively large amounts of polyunsaturated fatty acids of the (n-3) family does not alter total prostaglandin turnover in vivo. This is in contrast to stimulated prostanoid formation in vitro, and thus suggests a different regulatory role of dietary and tissue fatty acids for ‘stimulated’ and ‘basal’ prostaglandin production.     

Estradiol-induced attenuation of pulmonary hypertension is not associated with altered eNOS expression

Female rats develop less severe pulmonary hypertension (PH) in response to chronic hypoxia compared with males, thus implicating a potential role for ovarian hormones in mediating this gender difference. Considering that estrogen upregulates endothelial nitric oxide (NO) synthase (eNOS) in systemic vascular tissue, we hypothesized that estrogen inhibits hypoxic PH by increasing eNOS expression and activity. To test this hypothesis, we examined responses to the endothelium-derived NO-dependent dilator ionomycin and the NO donors S-nitroso-N-acetylpenicillamine and spermine NONOate in U-46619-constricted, isolated, saline-perfused lungs from the following groups: 1) normoxic rats with intact ovaries, 2) chronic hypoxic (CH) rats with intact ovaries, 3) CH ovariectomized rats given 17 beta-estradiol (E(2)beta), and 4) CH ovariectomized rats given vehicle. Additional experiments assessed pulmonary eNOS levels in each group by Western blotting. Our findings indicate that E(2)beta attenuated chronic hypoxia-induced right ventricular hypertrophy, pulmonary arterial remodeling, and polycythemia. Furthermore, although CH augmented vasodilatory responsiveness to ionomycin and increased pulmonary eNOS expression, these responses were not potentiated by E(2)beta. Finally, responses to S-nitroso-N-acetylpenicillamine and spermine NONOate were similarly attenuated in all CH groups compared with normoxic control groups. We conclude that the inhibitory influence of E(2)beta on chronic hypoxia-induced PH is not associated with increased eNOS expression or activity.     

Long term urinary platinum, palladium, and gold excretion of patients after insertion of noble metal dental alloys

The aim of this study was to investigate to which extent noble-metal dental alloys contribute to the total platinum (Pt), palladium (Pd), and gold (Au) body burden of the general population. The urinary Pt, Pd, and Au excretion was determined in three non-occupationally exposed volunteers before and up to 3 months after insertion of a highgold dentalalloy. The in-vitro release of Pt, Pd, and Au from four different types of dental alloys into either artificial saliva or 1% lactic acid solution was additionally investigated. The Pt, Pd, and Au concentrations were determined by sector field inductively coupled plasma mass spectrometry (SF-ICP-MS). Before insertion of the high-gold dental alloy, the Pt excretion of the patients ranged between 1.0 and 7.4 ng l-1 (0.6-3.3 ng g-1 creatinine). In the immediate post-insertion phase the Pt excretion rose to 10.5-59.6 ng l-1 (14.5-33.2 ng g-1 creatinine). This is a mean increase by a factor of 12 compared with the average Pt excretion before insertion. Three months after insertion, the Pt excretion was still elevated by a factor of 7. Contrary to Pt, the Au and Pd excretion in urine was not significantly increased after insertion of this type of high-gold dental alloy. Our in-vitro investigations confirm the assumption that Pt, Pd, and Au are released from noble metal containing dental alloys by corrosion. Under the applied conditions, the release was in the lower ng cm-2 range. It can be concluded that the Pt release from dental alloys can predominantly contribute to the Pt exposure of non-occupationally exposed persons. It can exceed the exposure from all other environmental sources including the Pt release from automobile exhaust catalysts.     

Increased urinary protein excretion in the "normal" range is associated with increased renin-angiotensin system activity

Increased levels of albuminuria and proteinuria, both linked to augmented renin-angiotensin system (RAS) activity, are associated with adverse kidney and cardiovascular events. However, the relationship between variations in urinary albumin excretion (UAE) and total protein excretion (UTPE) in the normal range and RAS activity is unclear. We examined the association between UAE and UTPE and the hemodynamic response to angiotensin II (ANG II) challenge, a well-accepted indirect measure of RAS activity, in healthy individuals with normal UAE and UTPE. Forty subjects (15 men, 25 women; age 38 ± 2 yr; UAE, 3.32 ± 0.55 mg/day; UTPE, 56.8 ± 3.6 mg/day) were studied in high-salt balance. Blood pressure (BP), arterial stiffness determined by applanation tonometry, and circulating RAS components were measured at baseline and in response to graded ANG II infusion. The primary outcome was the BP response to ANG II challenge at 30 and 60 min. UAE was associated with a blunted diastolic BP response to ANG II infusion (30 min, P = 0.005; 60 min, P = 0.17), a relationship which remained even after adjustment (30 min, P < 0.001; 60 min, P = 0.035). Similar results were observed with UTPE (30 min, P = 0.031; 60 min, P = 0.001), even after multivariate analysis (30 min, P = 0.008; 60 min, P = 0.001). Neither UAE nor UTPE was associated with systolic BP, circulating RAS components, or arterial stiffness responses to ANG II challenge. Among healthy individuals with UAE and UTPE in the normal range, increased levels of these measures were independently associated with a blunted diastolic BP response to ANG II, indicating increased vascular RAS activity, which is known to be deleterious to both renal and cardiac function.     

Concentration compared with total urinary excretion of 11,17-DOA in cynomolgus monkey urine

Strees sensitive molecules exhibit great variation in concentration in the circulation and it may often be advantageous to quantify these in urine or feces rather than in serum or plasma. We advocate that all urine-or feces-should be collected, and that excretion of stress sensitive molecules should be expressed as amounts excreted per time unit per kg body-weight, rather than being expressed as concentrations in samples. Urine and feces excretion varies significantly within and between animals over time, which may render simple concentration measures of molecules of little biological relevance.     

Increased renin excretion is associated with augmented urinary angiotensin II levels in chronic angiotensin II-infused hypertensive rats

Renin expression in principal cells of collecting ducts (CD) is upregulated in angiotensin II (ANG II)-dependent hypertensive rats; however, it remains unclear whether increased CD-derived renin undergoes tubular secretion. Accordingly, urinary levels of renin (uRen), angiotensinogen (uAGT), and ANG II (uANG II) were measured in chronic ANG II-infused Sprague-Dawley rats (80 ng/min for 14 days, n = 10) and sham-operated rats (n = 10). Systolic blood pressure increased in the ANG II rats by day 5 and continued to increase throughout the study (day 13; ANG II: 175 ± 10 vs. sham: 116 ± 2 mmHg; P < 0.05). ANG II infusion increased renal cortical and medullary ANG II levels (cortical ANG II: 606 ± 72 vs. 247 ± 43 fmol/g; P < 0.05; medullary ANG II: 2,066 ± 116 vs. 646 ± 36 fmol/g; P < 0.05). Although plasma renin activity (PRA) was suppressed in the ANG II-infused rats (0.3 ± 0.2 vs. 5.5 ± 1.8 ng ANG I·ml(-1)·h(-1); P < 0.05), renin content in renal medulla was increased (12,605 ± 1,343 vs. 7,956 ± 765 ng ANG I·h(-1)·mg(-1); P < 0.05). Excretion of uAGT and uANG II increased in the ANG II rats [uAGT: 1,107 ± 106 vs. 60 ± 26 ng/day; P < 0.0001; uANG II: 3,813 ± 431 vs. 2,080 ± 361 fmol/day; P < 0.05]. By day 13, despite suppression of PRA, urinary prorenin content increased in ANG II rats [15.7 ± 3 vs. 2.6 ± 1 × 10(-3) enzyme units excreted (EUE)/day, P < 0.01] as was the excretion rate of renin (8.6 ± 2 × 10(-6) EUE/day) compared with sham (2.8 ± 1 × 10(-6) EUE/day; P < 0.05). Urinary renin and prorenin protein levels examined by Western blot were augmented ～10-fold in the ANG II-infused rats. Concomitant AT(1) receptor blockade with candesartan prevented the increase. Thus, in ANG II-dependent hypertensive rats with marked PRA suppression, increased urinary levels of renin and prorenin reflect their augmented secretion by CD cells into the luminal fluid. The greater availability of renin and AGT in the urine reflects the capability for intratubular ANG II formation which stimulates sodium reabsorption in distal nephron segments.     

Bradykinin B2 receptor gene polymorphism is associated with altered urinary albumin/creatinine values in diabetic patients

Diabetic nephropathy (DN) is an important microvascular complication of both insulin-dependent and non-insulin-dependent diabetes mellitus. Considerable evidence exists that genetic predisposition is a major determinant in the development of DN. Progress in the understanding of the kinin receptor gene expression indicates their relevance in nephrology and renal pathology. In order to investigate whether clinically relevant polymorphisms of the kinin receptor genes contribute to the genetic predetermination of the renal complication of diabetes, we have initiated a retrospective study with a mixed population of 49 type 1 and 112 type 2 diabetic patients who have been followed for several years by an endocrinologist and (or) nephrologist with periodical functional tests relevant to DN (microalbuminuria, serum and urinary creatinine). The allelic frequencies of four kinin receptor polymorphisms, including three B2R polymorphisms (the C/T-58 promoter polymorphism, the exon 2 and exon 1 polymorphisms, all of them with assumed clinical significance) and the putative nephroprotective (G/C-699) B1R promoter polymorphism, were analyzed in all recruited diabetic patients. Our results indicate a significant association of the B2R exon 1 (+/-) genotype with increased urinary albumin/creatinine values (P = 0.026) and serum creatinine levels (P = 0.028). More importantly, the (+) allele of B2R exon 1 polymorphism was associated very significantly with lower albumin/creatinine values in these patients (P = 0.0087). Thus, the B2R exon 1 polymorphism may represent a susceptibility marker for nephropathy progression in diabetic patients.     

Effect of acetylsalicylic acid on urinary excretion of prostaglandin E in stroke patients

In 12 of 76 stroke patients complicated by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), a significant increase in urinary prostaglandin E (PGE) (p less than 0.005), and a significant positive relationship between the plasma arginine vasopressin (AVR) level and urinary PGE excretion were observed (r = 0.72, p less than 0.05). The experimental results are consistent with the view that renal PGE acts as a modulator of ADH. Nowadays acetylsalicylic acid (ASA), an inhibitor of prostaglandin biosynthesis, is widely used in ischemic stroke, it was felt necessary to study the effect of this drug on urinary PGE excretion. Therefore various daily doses of ASA were given orally for 3 days to patients with ischemic stroke. PGE values in 24-hour urine samples were measured every day for 3 days before administration of the drug and for 3 days during ASA administration. In 10 patients who took 75 mg of ASA, the decrease in urinary PGE excretion was not statistically significant. On the other hand when ASA was administered 300 mg once in 19 patients or 300 mg 4 times in 11 cases, urinary PGE excretion decreased significantly (p less than 0.05 and p less than 0.05 respectively). In another group of 8 patients who were observed before, during and after the ASA administration, a daily oral dose of 300 mg for 3 days caused a significant decrease in urinary PGE excretion during these 3 days (p less than 0.05). The urinary PGE excretion returned to the control level within 3 days after cessation of the ASA administration.     

Influence of spironolactone on urinary prostaglandin E2 and kinin excretion in rats

Spironolactone was administered to spontaneously hypertensive rats (SHRs) in order to examine the urinary excretions of prostaglandin E2 (PGE2) and kinin. Thirteen SHRs were divided into 2 groups: 0.1 ml of sesame oil was administered to one group (the spironolactone-lactone-untreated group, n = 6) and 20 mg of spironolactone in 0.1 ml of sesame oil was administered to the other group (the spironolactone-treated group, n = 7) by the subcutaneous route for 10 days in succession. Determinations were then made of the body weight, blood pressure, urine volume, and excretion levels of Na, K, kinin and PGE2 in the 24-hour urine. After the animals had been killed by decapitation, blood samples were drawn for determination of the plasma renin activity (PRA). The results obtained indicated decreased blood pressure and increased urinary Na excretion in the spironolactone-treated group. On the other hand, the PGE2 excretion level in the 24-hour urine decreased markedly immediately after administration of spironolactone (p less than 0.05) and was maintained at lower levels up to the end of the experiment. However, the 24-hour urinary kinin levels showed similar changes in both the spironolactone-treated group and the untreated group with no significant difference between them. These findings suggest that spironolactone has a suppressive effect on urinary PGE2 excretion, the activity of which is not mediated by kinin production in the kidneys but is the result of a direct action of spironolactone itself.     

Diclofenac toxicity in Gyps vulture is associated with decreased uric acid excretion and not renal portal vasoconstriction

Diclofenac (DF), a non-steroidal anti-inflammatory drug (NSAID), is largely regarded as one of the most devastating environmental toxicant in recent times, after accidental exposure via their food-chain lead to massive mortalities in three vulture species on the Asian subcontinent. Although the use of diclofenac was recently banned on the Indian subcontinent, following the favourable safety profile of meloxicam, its mechanism of toxicity remains unknown. In an attempt to establish this mechanism, we test three hypotheses using models established from either the domestic chicken (Gallus domesticus) or the African White-backed vulture (Gyps africanus). We demonstrate that both DF and meloxicam are toxic to renal tubular epithelial (RTE) cells following 12 h of exposure, due to an increase in production of reactive oxygen species (ROS), which could be temporarily ameliorated by pre-incubation with uric acid (UA). When cultures were incubated with either drug for only 2 h, meloxicam showed no toxicity in contrast to diclofenac. In both cases no increase in ROS production was evident. In addition, diclofenac decreased the transport of uric acid, by interfering with the p-amino-hippuric acid (PAH) channel. We conclude that vulture susceptibility to diclofenac results from a combination of an increased ROS, interference with UA transport and the duration of exposure.     

Effect of isradipine on urinary excretion of catecholamines and their metabolites in patients with pheochromocytoma]

An effect of calcium antagonist-isradipine-on catecholamines and their metabolites excretion with the urine in 4 patients with pheochromocytoma has been analysed. It was found that the excretion of OFFnoradrenaline and vanilaminomandelic acid is reduced. It may indicate inhibitory effect of calcium antagonists on catecholamines secretion in patients with pheochromocytoma.     

Effect of furosemide on urinary excretion of prostaglandin E in normal volunteers and pateints with essential hypertension

Urinary excretion of prostaglandin E was measured radioimmunologically in 19 healthy persons ( 15 men and 4 women ) and in 16 patients ( 10 men and 6 women ) with essential hypertension before and after the administration of furosemide. The excretion rates were increased from 26.3±3.0 to 64.5±11.3 ng/hr in the former and from 11.9±2.7 to 26.9±85 ng/hr in the latter. There was a significant difference between them, healthy subjects showing a greater increase than patients with essential hypertension.There was an obvious sexual difference in urinary excretion of prostaglandin. In men, greater increase in the excretion rates was found than in the women. Greater increases were also obtained in healthy men than in hypertensive men and in healthy women than in hypertensive women. The present results suggest that furosemide enhances urinary excretion of prostaglandin E by mechanisms which entails either an increase in prostaglandin synthesis or a decrease in renal metabolism.     

Long time to diagnosis of medulloblastoma in children is not associated with decreased survival or with worse neurological outcome

Background

The long time to diagnosis of medulloblastoma, one of the most frequent brain tumors in children, is the source of painful remorse and sometimes lawsuits. We analyzed its consequences for tumor stage, survival, and sequelae.

Patients and Methods

This retrospective population-based cohort study included all cases of pediatric medulloblastoma from a region of France between 1990 and 2005. We collected the demographic, clinical, and tumor data and analyzed the relations between the interval from symptom onset until diagnosis, initial disease stage, survival, and neuropsychological and neurological outcome.

Results

The median interval from symptom onset until diagnosis for the 166 cases was 65 days (interquartile range 31–121, range 3–457). A long interval (defined as longer than the median) was associated with a lower frequency of metastasis in the univariate and multivariate analyses and with a larger tumor volume, desmoplastic histology, and longer survival in the univariate analysis, but not after adjustment for confounding factors. The time to diagnosis was significantly associated with IQ score among survivors. No significant relation was found between the time to diagnosis and neurological disability. In the 62 patients with metastases, a long prediagnosis interval was associated with a higher T stage, infiltration of the fourth ventricle floor, and incomplete surgical resection; it nonetheless did not influence survival significantly in this subgroup.

Conclusions

We found complex and often inverse relations between time to diagnosis of medulloblastoma in children and initial severity factors, survival, and neuropsychological and neurological outcome. This interval appears due more to the nature of the tumor and its progression than to parental or medical factors. These conclusions should be taken into account in the information provided to parents and in expert assessments produced for malpractice claims.