Reduced bone formation and relatively increased bone resorption in absorptive hypercalciuria.

Absorptive hypercalciuria (AH), a common stone-forming condition characterized biochemically by intestinal hyperabsorption of calcium and hypercalciuria may be associated with bone loss. In AH type I (AH-1), hypercalciuria persists despite restriction in dietary calcium intake. We therefore hypothesized that the skeleton may contribute to the hypercalciuria in this subgroup of patients. Histomorphometric analysis of iliac crest biopsies were performed on nine stone-formers with AH-1 and on nine matched normal subjects. After stabilization on a stone-prevention diet, calcium homeostasis in the stone formers was then evaluated on inpatient constant metabolic diet before and after short-term blockade of bone resorption by alendronate (10 mg daily, 17 days total). Compared with controls, the stone-formers had lower indices of bone formation (osteoblast surface/bone surface 1.8+/-2.1 vs 3.0+/-1.5%, P=0.04; wall thickness 35.8+/-6.9 vs 47.2+/-7.6%, P=0.001) and relatively higher bone resorption (osteoclast surface/bone surface 0.4+/-0.2 vs 0.2+/-0.2%, P=0.05). In the stone-formers, a short-term course of alendronate treatment corrected fasting urinary calcium (0.14+/-0.06 to 0.06+/-0.04 mg Ca/mg Cr, P=0.001) and marginally reduced 24-h urinary calcium by 48 mg/day (P=0.06). Increased intestinal calcium absorption and hypercalciuria persisted, but estimated calcium balance improved (P=0.007). Our results suggest that the hypercalciuria of AH-1 originates primarily from intestinal hyperabsorption of calcium, but bone resorption in excess of bone formation may contribute.

Adverse cardiac events after surgery: assessing risk in a veteran population.

OBJECTIVE: To establish rates of and risk factors for cardiac complications after noncardiac surgery in veterans. DESIGN: Prospective cohort study. SETTING: A large urban veterans affairs hospital. PARTICIPANTS: One thousand patients with known or suspected cardiac problems undergoing 1,121 noncardiac procedures. MEASUREMENTS: Patients were assessed preoperatively for important clinical variables. Postoperative evaluation was done by an assessor blinded to preoperative status with a daily physical examination, electrocardiogram, and creatine kinase with MB fraction until postoperative day 6, day of discharge, death, or reoperation (whichever occurred earliest). Serial electrocardiograms, enzymes, and chest radiographs were obtained as indicated. Severe cardiac complications included cardiac death, cardiac arrest, myocardial infarction, ventricular tachycardia, and fibrillation and pulmonary edema. Serious cardiac complications included the above, heart failure, and unstable angina. MAIN RESULTS: Severe and serious complications were seen in 24% and 32% of aortic, 8.3% and 10% of carotid, 11.8% and 14.7% of peripheral vascular, 9.0% and 13.1% of intraabdominal/intrathoracic, 2.9% and 3.3% of intermediate-risk (head and neck and major orthopedic procedures), and 0.27% and 1.1% of low-risk procedures respectively. The five associated patient-specific risk factors identified by logistic regression are: myocardial infarction < 6 months (odds ratio [OR], 4.5; 95% confidence interval [CI], 1.9 to 12.9), emergency surgery (OR, 2.6; 95% CI, 1.2 to 5.6), myocardial infarction > 6 months (OR, 2.2; 95% CI, 1.4 to 3.5), heart failure ever (OR, 1.9; 95% CI, 1.2 to 3.0), and rhythm other than sinus (OR, 1.7; 95% CI, 0.9 to 3.2). Inclusion of the planned operative procedure significantly improves the predictive ability of our risk model. CONCLUSIONS: Five patient-specific risk factors are associated with high risk for cardiac complications in the perioperative period of noncardiac surgery in veterans. Inclusion of the operative procedure significantly improves the predictive ability of the risk model. Overall cardiac complication rates (pretest probabilities) are established for these patients. A simple nomogram is presented for calculation of post-test probabilities by incorporating the operative procedure.

Pharmacokinetic and pharmacodynamic comparison of two calcium supplements in postmenopausal women.

This randomized crossover study compared the single-dose bioavailability and effects on parathyroid function of two commercially formulated calcium supplements containing 500 mg of elemental calcium. Twenty-five postmenopausal women underwent three phases of study wherein they each took a single dose of calcium citrate with a standard breakfast (as Citracal 250 mg + D), calcium carbonate (as Os-Cal 500 mg + D), or placebo at 8 a.m. Blood samples were drawn at baseline and hourly for 4 or 6 hours after each dose. Fasting and postload urine samples were also collected. Compared with calcium carbonate, calcium citrate provided a 46% greater peak-basal variation and 94% higher change in area under the curve for serum calcium and a 41% greater increment in urinary calcium. Moreover, the decrement in serum parathyroid hormone concentration from baseline was greater after calcium citrate. In conclusion, calcium citrate is more bioavailable than calcium carbonate when given with a meal.

Pharmacokinetics of calcium absorption from two commercial calcium supplements.

This study was conducted to compare pharmacokinetic indices of calcium absorption after a single oral (500 mg calcium) load of Citracal (calcium citrate) and Os-Cal (calcium carbonate). In 18 postmenopausal normal women, venous blood samples were obtained for the measurement of calcium before and hourly for 6 hours after an oral ingestion of Citracal, Os-Cal, or placebo with a breakfast meal. The change in area under the curve (delta AUC) in serum calcium from preload was 2.5-fold greater for Citracal than Os-Cal, and the peak-basal variation in serum calcium was 76% higher for Citracal than Os-Cal. The increment in serum calcium from preload after Citracal administration was significantly higher than that obtained after placebo load during most time periods and significantly higher than that of Os-Cal at 1, 4, and 5 hours after load. In contrast, delta AUC and peak basal variation of Os-Cal did not differ significantly from placebo and increment in serum calcium was significantly increased from placebo only at 6 hours. In conclusion, Citracal is much more bioavailable than Os-Cal.

Mapping a gene defect in absorptive hypercalciuria to chromosome 1q23.3-q24.

Absorptive hypercalciuria (AH), a common cause of kidney stones, is due to intestinal hyperabsorption of calcium. The presence of a family history of nephrolithiasis, in about half of the affected individuals studied indicates that an inherited genetic defect is one likely cause of AH. Although it is known that intestinal calcium absorption is regulated by a number of factors, the molecular biological basis for the increased calcium absorption in AH is unknown. This study was designed to determine the chromosomal locus of the gene defect linked to the AH phenotype in three families with a severe form of AH. Three kindreds were evaluated in a systematic autosomal genome-wide linkage analysis study. The AH phenotype, characterized by hyperabsorption of calcium and hypercalciuria, was linked to only one chromosomal locus, 1q23.3-q24. A 2-point logarithm of odds score of 3.3 was obtained with markers D1S318 and D1S196 at a recombination frequency of theta = 0. Nonparametric multipoint linkage analysis yielded a peak nonparametric linkage Z(all)-score of 12.7, P = 6 x 10(-6) Analysis of key recombinants within the families studied localized the gene to a 4.3-megabase region between markers D1S2681 (centromere) and D1S2815. A trait associated with intestinal hyperabsorption of calcium in a severe form of absorptive hypercalciuria has been mapped to chromosome 1q23.3-q24.

The role of calcium in the prevention of kidney stones.

Nephrolithiasis is a common and important condition. Several lines of evidence suggest that increased urinary calcium increases the risk of kidney stones. Since dietary calcium raises urinary calcium, it has been common practice to reduce calcium intake in stone-formers who hyperabsorb calcium from the intestine, although no trial has yet been designed to directly demonstrate the effectiveness of calcium restriction. In contrast, some have suggested that calcium restriction may be harmful due to resultant hyperoxaluria and risk of bone loss. In fact, two powerful prospective observational studies have suggested that increased dietary calcium reduces the risk of the first kidney stone. However, calcium was not the only variable, since those with the highest quintile of calcium intake also ingested more fluid, potassium, magnesium and phosphate. Moreover, the otherwise thorough analysis was not adjusted for alkali intake, which may prevent stones, or oxalate intake, which may increase stone risk. Due to limitations in available data, future prospective studies should be designed to probe the effect of specific interventions with calcium, both dietary and supplemental, on urinary parameters and stone formation, particularly in hypercalciuric stone-formers, who may respond conversely. For now, dietary calcium should be gradually increased in stone-formers as guided by the urinary calcium, and hypocalciuric agents should be added as necessary.

Normal vitamin D receptor concentration and responsiveness to 1, 25-dihydroxyvitamin D3 in skin fibroblasts from patients with absorptive hypercalciuria.

To evaluate whether there is an increase in vitamin D receptor (VDR) concentration which could raise intestinal calcium absorption in absorptive hypercalciuric (AH) patients and promote hypercalciuria, we measured VDR concentration and VDR mRNA levels in skin fibroblasts from 16 patients with AH and 17 age-matched normal subjects before and following a 16-hour incubation in the presence of 10(-8) M 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. There were no significant differences in VDR concentration between normal subjects and AH patients in the basal state (30 +/- 11 vs. 30 +/- 15 ng/mg protein, respectively) or following 1,25(OH)2D3-mediated upregulation (43 +/- 18 vs. 42 +/- 16 ng/mg protein) as measured by immunoblot methodology. Analysis of VDR mRNA/beta-actin mRNA ratios demonstrated no significant differences between normal subjects and AH patients prior to (2.1 +/- 1.7 vs. 1.8 +/- 2.4) or following (2.7 +/- 2.8 vs. 1.9 +/- 1.8) 1,25(OH)2D3 exposure. As a measure of VDR bioactivity, we quantitated 1,25(OH)2D3-mediated induction of 25-hydroxyvitamin D3-24-hydroxylase. Again, no significant differences were observed between normal subjects and all patients (2.1 +/- 1.6 vs. 1.9 +/- 1.6 pmol/mg/30 min, respectively). These findings indicate that there is neither an increase in VDR concentration in skin fibroblasts, a recognized vitamin D responsive cell, nor increased sensitivity to upregulation of VDR numbers by 1, 25(OH)2D3 in patients with AH. This suggests an alternative cause of intestinal hyperabsorption of calcium in AH other than alteration of the VDR number.

Physiological effects of slow release potassium phosphate for absorptive hypercalciuria: a randomized double-blind trial.

PURPOSE: We examined the physiological effects and tolerance of UroPhos-K, a slow release neutral form of potassium phosphate (155 mg. phosphate and 8 mEq. potassium per tablet) in patients with absorptive hypercalciuria. MATERIALS AND METHODS: A total of 31 patients with absorptive hypercalciuria were studied at baseline and after 3 months of treatment with 4 tablets twice daily of UroPhos-K or placebo (identical in appearance) in a prospective randomized, placebo controlled, double-blind trial during a 4-day inpatient study with a daily constant metabolic diet containing 400 mg. calcium, 100 mEq. sodium and 800 mg. phosphate. RESULTS: Treatment with UroPhos-K did not cause significant gastrointestinal side effects, increase fasting serum potassium or phosphorus, or reduce hemoglobin or creatinine clearance. It reduced urinary calcium excretion from 277 +/- 72 to 166 +/- 43 mg. per day (p < 0.001), associated with a reduction in serum 1,25-dihydroxyvitamin D concentration from 50 +/- 11 to 42 +/- 9 pg./ml. (p < 0.001). Indexes of intestinal calcium absorption and markers of bone turnover also decreased modestly. None of these changes was seen in the placebo group. CONCLUSIONS: In patients with absorptive hypercalciuria UroPhos-K seems to correct hypercalciuria by a combination of reduced intestinal absorption, bone resorption and improved renal calcium reabsorption. The drug is well tolerated compared to placebo.

Sustained reduction in urinary calcium during long-term treatment with slow release neutral potassium phosphate in absorptive hypercalciuria.

PURPOSE: We tested whether UroPhos-K, a new slow release neutral form of potassium phosphate (155 mg. phosphate, 8 mEq. potassium per tablet) in a dose of 4 tablets twice daily would produce a sustained hypocalciuric response and maintain bone mass in patients with absorptive hypercalciuria, a major cause of nephrolithiasis characterized by excessive intestinal calcium absorption accompanied in some patients by excessive bone loss. MATERIALS AND METHODS: A total of 25 patients with absorptive hypercalciuria were studied in a 4-year, prospective, open trial with UroPhos-K at yearly intervals during a 4-day inpatient physiological study with a constant metabolic diet containing 400 mg. calcium, 100 mEq. sodium and 800 mg. phosphate daily. RESULTS: Treatment with UroPhos-K caused a sustained, marked reduction in urinary calcium (264 to 181 mg. daily). Fractional 47calcium absorption decreased modestly (74.0 to 64.6%) commensurate with a reduction in serum 1,25-dihydroxyvitamin D (42 to 34 pg./ml.). Intact parathyroid hormone increased within the normal range (30 to 42 pg./ml.). Bone mineral density was stable at the lumbar spine, femoral neck and distal third of the radius. CONCLUSIONS: UroPhos-K may provide a long-term alternative for hypercalciuric patients in whom thiazide therapy fails.

Comparison of the effects of medium-chain triacylglycerols, palm oil, and high oleic acid sunflower oil on plasma triacylglycerol fatty acids and lipid and lipoprotein concentrations in humans.

Although medium-chain triacylglycerols (MCTs, composed of medium-chain fatty acids 8:0 and 10:0) have long been described as having neutral effects on serum cholesterol concentrations, experimental evidence supporting this claim is limited. In a randomized, crossover, metabolic-ward study, we compared the lipid effects of a natural food diet supplemented with either MCTs, palm oil, or high oleic acid sunflower oil in nine middle-aged men with mild hypercholesterolemia. Rather than having a neutral effect, MCT oil produced total cholesterol concentrations that were not significantly different from those produced by palm oil (MCT oil: 5.87 +/- 0.75 mmol/L; palm oil: 5.79 +/- 0.72 mmol/L) but significantly higher than that produced by high oleic acid sunflower oil (5.22 +/- 0.52 mmol/L). Low-density-lipoprotein (LDL)-cholesterol concentrations paralleled those of total cholesterol. MCT oil tended to result in higher triacylglycerol concentrations than either palm oil or high oleic acid sunflower oil, but this difference was not significant. There were no differences in high-density-lipoprotein cholesterol concentrations. The palmitic acid and total saturated fatty acid content of plasma triacylglycerols in the MCT-oil diet was not significantly different from that in the palm oil diet. On the basis of percentage of energy, this study suggests that medium-chain fatty acids have one-half the potency that palmitic acid has at raising total and LDL-cholesterol concentrations.

Evidence for normal vitamin D receptor messenger ribonucleic acid and genotype in absorptive hypercalciuria.

Absorptive hypercalciuria (a stone-forming condition) is characterized by gut hyperabsorption of calcium, hypercalciuria, and reduced bone density. Inasmuch as these features implicate enhanced calcitriol action in gut and bone, we analyzed the vitamin D receptor (VDR) gene to ascertain whether an abnormality of this gene marks patients with intestinal hyperabsorption of calcium. We have compared the frequency of a restriction fragment length polymorphism (Bsm I) associated with different alleles of the VDR gene in a group of 33 well characterized absorptive hypercalciuric patients and a group of 36 normal race- and age-matched control subjects. There was no difference between the distribution of the VDR alleles in the patient population when compared with the normal population. The coding region of VDR messenger RNA was also normal, as determined by both DNA sequence analysis and chemical mismatch cleavage analysis of copy DNA from 11 index absorptive hypercalciuric patients. On the basis of these results, we propose that the enhanced intestinal calcium absorption invariably seen in absorptive hypercalciuria and attendant symptoms of this disorder are not attributable to mutations of the VDR and are not linked to a common VDR genotype.

Angiographic ablation of mediastinal parathyroid adenomas: local experience and review of the literature.

PURPOSE: To evaluate local experience with a modified technique for angiographic ablation of mediastinal parathyroid adenomas. PATIENTS AND METHODS: Three patients with likely mediastinal parathyroid adenomas that had single feeding arteries underwent attempted arteriographic ablation with a slow continuous infusion of contrast medium. Patients were closely monitored for symptoms and calcium dynamics immediately postprocedure and then on a long-term outpatient basis. RESULTS: All three patients were cured (follow-up 22 to 68 months) with no long-term complications. CONCLUSION: Percutaneous angiographic ablation with contrast medium is a reasonable alternative for patients with hyperparathyroidism due to a mediastinal adenoma who can be treated in centers with well-trained interventional radiologists.

Bereitschaftspotential in patients with unilateral lesions of the supplementary motor area.

In the present study, an attempt was made to examine the sensitivity of the Bereitschaftspotential (BP) preceding simple finger movement in revealing pathophysiological patterns of premovement cortical activity in patients with chronic unilateral lesions of the supplementary motor area (SMA). Usually, in healthy subjects, BP has a clear maximum in Cz with larger amplitudes than in Ccon (located over the motor cortex, contralateral to the performing hand). In the patients, amplitudes did not differ between Cz and Ccon. This effect of the lesion on BP topography, was found in movements of either side. However, intraindividual comparisons revealed that the reduction of the BP in Cz (relative to Ccon) was larger for movements contralateral to the SMA lesion than for those ipsilateral of it.

[Imaging of the internal structures of the knee by MR tomography]. / Die Darstellung der Kniegelenksbinnenstrukturen durch die MR-Tomographie.

With magnetic resonance imaging it is possible to demonstrate the cruciate ligaments of the knee reproducibly without the need for invasive measures. Prerequisites for this are high-resolution coil systems and a stratum thickness of 5 mm or less. Examination of 29 patients and volunteers showed that normal cruciate ligaments can be delineated as homogeneous zones of low signal intensity and high contrast from the surrounding fatty tissue, while in cases of injury to the cruciate ligaments an interruption of the ligament structure, inability to detect them in anatomic position, or an intermediate signal is observed. In 13 cases operated on, with 12 injuries of the cruciate ligaments, the MR findings corresponded to findings at surgery. In 6 patients who had previously had cruciate ligament plasties there correlation with clinical findings was only partial.

[MR tomography of gynecologic diseases of the minor pelvis]. / Die MR-Tomographie bei gynäkologischen Erkrankungen im kleinen Becken.

The results of MR examinations of 31 women with gynaecological diseases are described; all had CT and histological confirmation at operation. The extent and relationship of the lesions were well demonstrated by the three-dimensional sections of MR, in some cases better than on CT. Variations in the signals allowed better differentiation of myomas and ovarian carcinomas from normal tissue. Like CT, MR tomography was not reliable in showing the extent of infiltration into neighbouring structures.

[The aortic aneurysm in the magnetic resonance tomogram]. / Das Aortenaneurysma im MR-Tomogramm.

Aortic aneurysms can be visualised in the transverse, sagittal and coronary planes using magnetic resonance (MR) thereby enabling their cranio-caudal distension as well as their breadth and depth to be accurately determined. The important question concerning the vessel exits of the main branches of the aorta and their involvement in the aneurysm can be reliably answered. In the case of dissecting aortic aneurysms, the two lumina as well as the dissected vessel wall can be seen in the image. By choosing suitable recording parameters it is possible to differentiate between flowing blood and a thrombus attached to the vessel wall. The thrombus is recognisable from the decrease it causes in the signal intensity of the T2-selected image, whereas flowing blood emits a stronger signal in the T2-selected image than in the T1-selected image. An indication of the flow behaviour and flow rate of blood can be obtained from the differences in the signal intensity distribution in the vessel lumen.

MR in the diagnosis of bone tumours.

Forty-two patients with benign as well as malignant bone tumours or with tumour-like lesions of bone were evaluated using MR tomography. The appropriate choice of examination parameters is an essential prerequisite for the adequate visualisation and the definitive verification of the presence of a tumour. By means of its multi-planar display, MR provides definite advantages in the determination of tumour localisation and extension as well as in differentiating intra-tumoural haemorrhage from surrounding, non-involved tissue. In addition, the clear delineation of neighbouring structures such as muscular compartments and blood vessels achieved in MR can be useful in the planning of an eventual surgical approach. This new technique has proved itself superior to other available imaging modalities in the differentiation of residual or recurrent tumour from post-operative changes. A characterisation of the nature or histology of a suspicious lesion on the basis of relaxation-times or signal intensities, however, is not yet possible.