Tamm-Horsfall protein in recurrent calcium kidney stone formers with positive family history: abnormalities in urinary excretion, molecular structure and function

Tamm-Horsfall protein (THP) powerfully inhibits calcium oxalate crystal aggregation, but structurally abnormal THPs from recurrent calcium stone formers may promote crystal aggregation. Therefore, increased urinary excretion of abnormal THP might be of relevance in nephrolithiasis. We studied 44 recurrent idiopathic calcium stone formers with a positive family history of stone disease (RCSFfam) and 34 age- and sex-matched healthy controls (C). Twenty-four-hour urinary THP excretion was measured by enzyme linked immunosorbent assay. Structural properties of individually purified THPs were obtained from analysis of elution patterns from a Sepharose 4B column. Sialic acid (SA) contents of native whole 24-h urines, crude salt precipitates of native urines and individually purified THPs were measured. THP function was studied by measuring inhibition of CaOx crystal aggregation in vitro (pH 5.7, 200mM sodium chloride). Twenty-four-hour urine excretion of THP was higher in RCSFfam (44.0±4.0mg/day) than in C (30.9±2.2mg/day, P=0.015). Upon salt precipitation and lyophilization, elution from a Sepharose 4B column revealed one major peak (peak A, cross-reacting with polyclonal anti-THP antibody) and a second minor peak (peak B, not cross-reacting). THPs from RCSFfam eluted later than those from C (P=0.021), and maximum width of THP peaks was higher in RCSFfam than in C (P=0.024). SA content was higher in specimens from RCSFfam than from C, in native 24-h urines (207.5±20.4mg vs. 135.2±16.1mg, P=0.013) as well as in crude salt precipitates of 24-h urines (10.4±0.5mg vs. 7.4±0.9mg, P=0.002) and in purified THPs (75.3±9.3μg/mg vs. 48.8±9.8μg/mg THP, P=0.043). Finally, inhibition of calcium oxalate monohydrate crystal aggregation by 40mg/L of THP was lower in RCSFfam (6.1±5.5%, range −62.0 to +84.2%) than in C (24.9±6.0%, range −39.8 to +82.7%), P=0.022, and only 25 out of 44 (57%) THPs from RCSFfam were inhibitory (positive inhibition value) vs. 25 out of 34 (74%) THPs from C, P<0.05. In conclusion, severely recurrent calcium stone formers with a positive family history excrete more THP than healthy controls, and their THP molecules elute later from an analytical column and contain more SA. Such increasingly aggregated THP molecules predispose to exaggerated calcium oxalate crystal aggregation, an important prerequisite for urinary stone formatio

Prevalence and densitometric characteristics of incomplete distal renal tubular acidosis in men with recurrent calcium nephrolithiasis

The aim of this study was to assess the prevalence of incomplete distal renal tubular acidosis (idRTA) in men with recurrent calcium nephrolithiasis and its potential impact on bone mineral density. We conducted a retrospective analysis of 150 consecutive, male idiopathic recurrent calcium stone formers (RCSFs), which had originally been referred to the tertiary care stone center of the University Hospital of Berne for further metabolic evaluation. All RCSFs had been maintained on a free-choice diet while collecting two 24-h urine samples and delivered second morning urine samples after 12h fasting. Among 12 RCSFs with a fasting urine pH >5.8, a modified 3-day ammonium chloride loading test identified idRTA in 10 patients (urine pH >5.32, idRTA group). We matched to each idRTA subject 5 control subjects from the 150 RCSFs, primary by BMI and then by age, i.e., 50 patients, without any acidification defect (non-RTA group) for comparative biochemistry and dual energy X-ray absorptiometry (DEXA) analyses. The prevalence of primary idRTA among RCSFs was 6.7% (10/150). Patients with idRTA had significantly higher 2-h fasting and 24-h urine pH (2-h urine pH: 6.6±0.4 vs. 5.2±0.1, p=0.001; 24-h urine pH: 6.1±0.2 vs. 5.3±0.3, p=0.001), 24-h urinary calcium excretion (7.70±1.75 vs. 5.69±1.73mmol/d, p=0.02), but significantly lower 24-h urinary urea excretion (323±53 vs. 399±114mmol/d, p=0.01), urinary citrate levels (2.32±0.82 vs. 3.01±0.72mmol/d, p=0.04) and renal phosphate threshold normalized for the glomerular filtration rate (TmPO4/GFR: 0.66±0.17 vs. 0.82±0.21, p=0.03) compared to non-RTA patients. No significant difference in bone mineral density (BMD) was found between idRTA and non-RTA patients for the lumbar spine (LS BMD (g/cm2): 1.046±0.245 SD vs. 1.005±0.119 SD, p=0.42) or femoral neck (FN BMD (g/cm2): 0.830±0.135 SD vs. 0.852±0.127 SD). Thus, idRTA occurs in 1 in 15 male RCSFs and should be sought in all recurrent calcium nephrolithiasis patients. Bone mineral density, however, does not appear to be significantly affected by idRT

Structural and metamorphic evolution of the Camughera - Moncucco, Antrona and Monte Rosa units southwest of the Simplon line,Western Alps

Abstract.: This structural and petrological study examines relationships between Alpine deformation and metamorphism in the Camughera-Moncucco, Antrona and northeastern Monte Rosa units, and it correlates major late stage deformation structures, such as the Vanzone antiform and Simplon normal fault. D1/D2 deformation and related top-N or top-NW thrusting started under high-pressure conditions (12.5-16kbar) at relatively high temperatures (c. 620-700°C). Petrological and structural data, together with published radiometric data, suggest that top-SE shearing within the structural top of the high-pressure units in the upper Penninic Alps is coeval with top-N or top-NW thrusting at their structural base. This suggests differential ascent of high-pressure units relative to the surrounding units during nappe stacking and associated crustal shortening. Barrovian metamorphism in the upper Penninic Alps is related to a first phase of backfolding, active between c. 35Ma and c. 29-26Ma ago (D3). D3 involves dextral shearing, combined with top-WSW shearing and orogen-parallel extension. Unroofing by orogen-parallel extension delays cooling during decompression and leads to isothermal decompression after the high-pressure stage. Towards deeper structural levels in the east, D3 deformation becomes progressively younger and prevailed at increasingly higher temperatures. Hence, compared to the higher structural levels further west, the brittle-ductile transition occurs later in the Ossola valley. Masera synform and Brevettola antiform form an open fold pair and represent the eastern continuation of the major Vanzone antiform (D4). Normal faulting across the Simplon line overlaps in time with the formation of these major D4 backfolds. Displacement along the Simplon normal fault decreases to insignificant values towards the southeast. Contemporaneous dextral shearing, however, occurs within the southern limbs of the Vanzone and Brevettola antiform

Coronary collateral perfusion in patients with coronary artery disease: effect of metoprolol

Background The use of ultrathin Doppler angioplasty guidewires has made it possible to measure collateral flow quantitatively. Pharmacologic interventions have been shown to influence collateral flow and, thus, to affect myocardial ischaemia. Methods Twenty-five patients with coronary artery disease undergoing PTCA were included in the present analysis. Coronary flow velocities were measured in the ipsilateral (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} $n=25$ \end{document}) and contralateral (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} $n=6$ \end{document}; two Doppler wires) vessels during PTCA with and without i.v. adenosine (140 μg/kg.min) before and 3 min after 5 mg metoprolol i.v., respectively. The ipsilateral Doppler wire was positioned distal to the stenosis, whereas the distal end of the contralateral wire was in an angiographically normal vessel. The flow signals of the ipsilateral wire were used to calculate the collateral flow index (CFI). CFI was defined as the ratio of flow velocity during balloon inflation divided by resting flow. Results Heart rate and mean aortic pressure decreased slightly (ns) after i.v. metoprolol. The collateral flow index was 0.25±0.12 (one fourth of the resting coronary flow) during the first PTCA and 0.27±0.14 (ns versus first PTCA) during the second PTCA, but decreased with metoprolol to 0.16±0.08 (\batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} $p{<}0.0001$ \end{document} vs. baseline) during the third PTCA. Conclusions Coronary collateral flow increased slightly but not significantly during maximal vasodilatation with adenosine but decreased in 23 of 25 patients after i.v. metoprolol. Thus, there is a reduction in coronary collateral flow with metoprolol, probably due to an increase in coronary collateral resistance or a reduction in oxygen deman

Incremental prognostic value of troponin I and echocardiography in patients with acute pulmonary embolism

Background To test the hypothesis that troponin I and echocardiography have an incremental prognostic value in patients with pulmonary embolism (PE). Methods and results In 91 patients with acute PE, echocardiography was performed within 4h of admission. Troponin I levels were obtained on admission and 12h thereafter. The 0.06μg/l troponin I cut-off level was identified as the most useful, high-sensitivity cut-off level for the prediction of adverse outcome by receiver operating characteristic analysis with a sensitivity and specificity of 86%, respectively. Twenty-eight (31%) patients had elevated troponin I levels (4.9±3.8μg/l). Twenty-one (23%) patients had adverse clinical outcomes including in-hospital death in five, cardiopulmonary resuscitation in four, mechanical ventilation in six, pressors in 14, thrombolysis in 14, catheter fragmentation in three, and surgical embolectomy in three. The area under the receiver operating characteristic curve from multivariate regression models for predicting adverse outcome without troponin I and echocardiography (0.765), with troponin I (0.890) or echocardiography alone (0.858), and the combination of both tests (0.900) was incremental. Three-month survival rate was highest in patients with both a normal troponin I level and a normal echocardiogram (98%). Positive predictive value for adverse clinical outcomes of the combination of echocardiography and troponin I was higher (75% (95%CI 55-88%)) compared with each test alone (echocardiography: 41%, 95% CI 28-56%; troponin I: 64%, 95% CI 46-79%). Conclusions While troponin I measurements added most of the prognostic information for identifying high-risk patients, a normal echocardiogram combined with a negative troponin I level was most useful to identify patients at lowest risk for early deat

Low Calcium Diet in Hypercalciuric Calcium Nephrolithiasis: First Do No Harm

Many studies indicate that up-regulated production of 1,25(OH)2-vitamin D3 (calcitriol) with increased intestinal absorption of calcium is the primary event causing idiopathic hypercalciuria. Thus, a low calcium diet appears to be a straightforward strategy in calcium stone formers with hypercalciuria (HCSF). However, the efficacy of such a regimen has never been established, and lowering calcium intake from 1000 to 400 mg/day further enhances calcitriol production. On a diet chronically restricted in calcium, many stone formers increase their intake of animal flesh protein. The latter is known to increase renal mass, and calcitriol levels indeed are positively correlated with renal mass in animals as well as in HCSF. Thus, low calcium and high animal flesh protein consumption are independent stimuli for further up-regulation of calcitriol production. The rise in calcitriol suppresses parathyroid hormone synthesis thereby diminishing renal tubular calcium reabsorption, and increasing urinary calcium losses. Since calcitriol up-regulation also increases bone resorption, the combination of low calcium and high protein intake is particularly likely to induce negative calcium balance and thus osteopenia. Finally, low calcium intake carries the risk of insufficient intestinal binding of oxalate with subsequent increases in intestinal absorption and urinary excretion of oxalate. Indeed, most recent studies suggest that high amounts of calcium, when ingested simultaneously with oxalate-containing meals, are able to prevent hyperoxaluria during severe oral oxalate loading

Stent thrombosis following bare-metal stent implantation: success of emergency percutaneous coronary intervention and predictors of adverse outcome

Aims To investigate the efficacy and outcome of emergency percutaneous coronary interventions (PCI) in patients with stent thrombosis. Methods and results Between 1995 and 2003, 6058 patients underwent bare-metal stent implantation, of which 95 (1.6%) patients suffered from stent thrombosis. The timing of stent thrombosis was acute in 10 (11%), subacute in 61 (64%), and late in 24 (25%) patients. Procedural and clinical outcomes of emergency PCI for treatment of stent thrombosis were investigated. Emergency PCI was successful in 86 (91%), complicated by death in 2 (2%), and coronary artery bypass grafting in 2 (2%) patients. Myocardial infarction occurred in 77 (81%) patients with a peak creatine kinase level of 1466±1570 U/L. Left ventricular ejection fraction declined from 0.54±0.19 prior to 0.48±0.16 (P<0.05) at the time of stent thrombosis after emergency PCI. A 6 month major adverse clinical events comprised death (11%), reinfarction (16%), and recurrent stent thrombosis (12%) after emergency PCI. Multivariable logistic regression analysis identified the achievement of TIMI 3 flow (OR=0.1, CI 95% 0.01-0.54, P<0.001) and diameter stenosis <50% (OR=0.06, CI 95% 0.01-0.32, P<0.001) during emergency PCI to be independently associated with a reduced risk of cardiac death. Recurrent stent thrombosis was independently predicted by the omission of abciximab (OR=4.3, CI 95% 1.1-17.5). Conclusion Emergency PCI for treatment of stent thrombosis effectively restores vessel patency and flow. Patients presenting with stent thrombosis are at risk for recurrent myocardial infarction and recurrent stent thrombosi

The Tale of Parathyroid Function in Idiopathic Hypercalciuria

At the origin, idiopathic hypercalciuria has been described as a syndrome consisting of normocalcemia, low plasma phosphate levels and abnormally high urinary calcium excretion. The cause of this syndrome was subject to many investigations throughout the years. Two main pathophysiologic hypotheses have been proposed: a) primary intestinal hyperabsorption of calcium, leading to depression of parathyroid hormone (PTH) secretion ( absorptive hypercalciuria); and b) primary renal tubular leak of calcium which stimulates PTH secretion (secondary hyperparathyroidism). Most of the published studies indicate that intestinal hyperabsorption of calcium with subsequent relative hypoparathyroidism is the primary event causing idiopathic hypercalciuria, and that this occurs as a consequence of increased production of 1,25(OH)2-vitamin D3 (calcitriol). Fasting hypercalciuria, originally taken as evidence for a renal leak of calcium, appears to be, at least in part, the consequence of relative hypoparathyroidism

Does the β-Blocker Nebivolol Increase Coronary Flow Reserve?

Introduction: Nebivolol, a highly selective β1-adrenergic receptor-blocker, increases basal and stimulated endothelial nitric oxide (NO)-release. It is unknown, whether coronary perfusion is improved by the increase in NO availability. Therefore, we sought to evaluate the effect of nebivolol on coronary flow reserve (CFR) and collateral flow. Methods: Doppler-flow wire derived coronary flow velocity measurements were obtained in ten controls and eight patients with coronary artery disease (CAD) at rest and after intracoronary nebivolol. CFR was defined as maximal flow during adenosine-induced hyperemia divided by resting flow. In the CAD group, collateral flow was determined after dilatation of a flow-limiting coronary stenosis. Collateral flow index (CFI) was defined as the ratio of flow velocity during balloon inflation divided by resting flow. Results: CFR at rest was 3.0 ± 0.6 in controls and 2.1 ± 0.4 in CAD patients. After intracoronary doses of 0.1, 0.25, and 0.5mg nebivolol, CFR increased to 3.4 ± 0.7, 3.9 ± 0.9, and 4.0 ± 0.1 (p < 0.01) in controls, and to 2.3 ± 0.7, 2.6 ± 0.9, and 2.6 ± 0.5 (p < 0.05) in CAD patients. CFI decreased significantly with intracoronary nebivolol and correlated to changes in heart rate (r = 0.75, p < 0.001) and rate-pressure product (r = 0.59, p = 0.001). Discussion: Intracoronary nebivolol is associated with a significant increase in CFR due to reduction in resting flow (controls), or due to an increase in maximal coronary flow (CAD patients). CFI decreased with nebivolol parallel to the reduction in myocardial oxygen consumptio