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Efficient calcium absorption is essential for skeletal health. Patients with impaired gastric acidification display low bone mass and increased fracture risk because calcium absorption is dependent on gastric pH. We investigated fracture healing and post-traumatic bone turnover in mice deficient in Cckbr, encoding a gastrin receptor that affects acid secretion by parietal cells. Cckbr-/- mice display hypochlorhydria, calcium malabsorption, and osteopenia. Cckbr-/- and wildtype (WT) mice received a femur osteotomy and were fed either a standard or calcium-enriched diet. Healed and intact bones were assessed by biomechanical testing, histomorphometry, micro-computed tomography, and quantitative backscattering. Parathyroid hormone (PTH) serum levels were determined by enzyme-linked immunosorbent assay. Fracture healing was unaffected in Cckbr-/- mice. However, Cckbr-/- mice displayed increased calcium mobilization from the intact skeleton during bone healing, confirmed by significantly elevated PTH levels and osteoclast numbers compared to WT mice. Calcium supplementation significantly reduced secondary hyperparathyroidism and bone resorption in the intact skeleton in both genotypes, but more efficiently in WT mice. Furthermore, calcium administration improved bone healing in WT mice, indicated by significantly increased mechanical properties and bone mineral density of the fracture callus, whereas it had no significant effect in Cckbr-/- mice. Therefore, under conditions of hypochlorhydria-induced calcium malabsorption, calcium, which is essential for callus mineralization, appears to be increasingly mobilized from the intact skeleton in favor of fracture healing. Calcium supplementation during fracture healing prevented systemic calcium mobilization, thereby maintaining bone mass and improving fracture healing in healthy individuals whereas the effect was limited by gastric hypochlorhydria. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1914-1921, 2016., (© 2016 The Authors. Journal of Orthopaedic Research Published by by Wiley Periodicals, Inc.)

Disorders of calcium and magnesium balance are physiologically interesting and clinically challenging. In this review, we attempt to bridge the gap between physiology and practice by providing a physiology-based approach to understanding hypocalcemia, hypercalcemia and hypomagnesemia. Calcium and, to a lesser extent, magnesium balance is achieved through a complex interplay between the parathyroid gland, bone, the intestine and the kidney. Our understanding of the molecular physiology of calcium and magnesium balance has grown considerably following the discovery of the calcium-sensing receptor (CaSR) and the main intestinal and renal transporters for calcium and magnesium, namely, the transient receptor potential channels TRPV5, TRPV6 and TRPM6. The regulation of parathyroid hormone (PTH) secretion by CaSR and the subsequent effects of PTH and vitamin D on TRPV5 constitute an increasingly characterized regulatory loop. In contrast, no truly magnesiotropic hormones have been identified, although the recently established interactions between the epidermal growth factor and TRPM6 suggest a possible candidate. Overall, the aim of this review is to illustrate the clinical disorders of calcium and magnesium balance from the perspective of their integrated physiology.

Many disorders can injure the spinal cord resulting in long-term chronic myelopathy. Spinal cord dysfunction influences the homeostasis of multiple organ systems ranging from the heart or lung to the integument, thus presenting a wide variety of challenges for medical management. Although most of our knowledge about the consequences of myelopathies derives from the study of traumatic spinal cord injuries, similar complications occur in myelopathies of all etiologies. The authors survey some of the important clinical issues that the general neurologist needs to consider in caring for patients with chronic spinal cord disease.

Hemichorea and generalized chorea are well-recognized syndromes associated with nonketotic hyperglycemia. This condition usually occurs in older age, affects females more than men, and often heralds a new diagnosis of diabetes, usually type 2. It may resolve over days with treatment of the underlying hyperglycemia or persist for years. Magnetic resonance imaging is very characteristic, and shows T1 hyperdensity in the striatum. The underlying pathophysiology is not clear, but recent evidence suggests that the imaging may represent zinc, as opposed to calcium. Tetrabenazine has worked well when symptomatic treatment is required. Other rare causes of metabolic choreas include hypoparathyroid abnormalities, hypoglycemia, and hypernatremia., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The genetic contribution to calcium metabolism is well recognized. Many of the proteins that contribute to calcium homeostasis through intestinal absorption, bone deposition and resorption, renal reabsorption and the molecules regulating these processes have been identified. Mutations in many of the genes coding for these proteins have been identified and often have clear clinical phenotypes. These mutations are generally rare with large effect sizes and a high degree of penetrance. As monogenetic diseases, they have a mendelian inheritance pattern and have been identified with traditional family-based linkage studies. A great deal of progress has been made in the understanding of the physiology of calcium metabolism; however, it remains an evolving field. The identification of the monogenetic etiology of disease has contributed greatly to our understanding of calcium handling and homeostasis. Transgenic animal models of these diseases continue to offer new insights into the mechanisms of calcium metabolism and its regulation. The purpose of this review is to briefly outline calcium metabolism focusing on the mechanisms of intestinal absorption and renal reabsorption as a framework to review the monogenic causes of dysregulated calcium metabolism., (Copyright © 2010 S. Karger AG, Basel.)

Background: Inherited arrhythmias can be caused by mutations in the cardiac ryanodine receptor (RyR2). The cellular source of these arrhythmias is unknown. Isolated RyR2(R4496C) mouse ventricular myocytes display arrhythmogenic activity related to spontaneous Ca(2+) release during diastole. On the other hand, recent whole-heart epicardial and endocardial optical mapping data demonstrate that ventricular arrhythmias in the RyR2(R4496C) mouse model of catecholaminergic polymorphic ventricular tachycardia (CPVT) originate in the His-Purkinje system, suggesting that Purkinje cells, and not ventricular myocytes, may be the cellular source of arrhythmogenic activity. The relative effect of the RyR2(R4496C) mutation on calcium homeostasis in ventricular myocytes versus Purkinje cells is unknown., Objective: This study sought to determine which cardiac cell type is more severely affected, in terms of calcium handling, by expression of the RyR2(R4496C) mutant channel: the ventricular myocytes or the Purkinje cells., Methods and Results: To discriminate Purkinje cells from ventricular myocytes, we crossed the RyR2(R4496C) mouse model of CPVT with the Cx40(EGFP/+) transgenic mouse. This genetic cross yields Purkinje cells that express eGFP, and therefore fluoresce green when excited by the appropriate wavelength; ventricular myocytes, which do not express connexin 40, are not green. Intracellular calcium was measured in each cell type using calcium-sensitive probes. Purkinje cells of the RyR2(R4496C) mouse model of CPVT show an approximately 2x greater rate (P < .05) and approximately 2x to 3x greater amplitude (P < .000001) of spontaneous calcium release events than ventricular myocytes isolated from the same heart., Conclusion: These results demonstrate that focally activated arrhythmias originate in the specialized electrical conducting cells of the His-Purkinje system in the RyR2(R4496C) mouse model of CPVT., (Copyright 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Alternans in action potential voltage (APV-ALT) at heart rates <110 bpm is a novel index to predict ventricular arrhythmias. However, the rate dependency of APV-ALT and its mechanisms in failing versus nonfailing human myocardium are poorly understood. It is hypothesized that APV-ALT in human heart failure (HF) reflects abnormal calcium handling., Objective: Using a modeling and clinical approach, our objectives were to (1) determine how APV-ALT varies with pacing rate and (2) ascertain whether abnormalities in calcium handling explain the rate dependence of APV-ALT in HF., Methods: APV-ALT was analyzed at several cycle lengths (CLs) using a dynamic pacing protocol applied to a human left ventricle wedge model with various alterations in calcium handling. Modeled APV-ALT was used to predict APV-ALT in left ventricle monophasic action potentials recorded from HF (n = 3) and control (n = 2) patients with the same pacing protocol., Results: Reducing the sarcoplasmic reticulum calcium uptake current < or =25%, the release current < or =11%, or the sarcolemmal L-type calcium channel current < or =43% of control predicted APV-ALT to arise at CL > or =600 ms and then increase in magnitude by >400% for CL <400 ms. In HF patients, APV-ALT arose at CL = 600 ms and then increased in magnitude by >500% at CL <350 ms. For all other model alterations and for control patients, APV-ALT occurred only at CL <500 ms., Conclusions: APV-ALT shows differing rate dependence in HF versus control patients, arising at slower rates in HF and predicted by models with abnormal calcium handling. Future studies should investigate whether APV-ALT at slow rates identifies patients with deranged calcium handing, including HF patients before decompensation or at risk for arrhythmias., (Copyright 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

This paper aims to study the correlation between biochemical risk factors of the stone former and the type of oxalate stone formed, namely calcium oxalate monohydrate (COM) and calcium oxalate dehydrate (COD). A retrospective study of 487 patients who had been attending the urinary stone clinic, Trivandrum during 1998-2007 was conducted. The stones retrieved from them were subjected to chemical analysis and FTIR spectrographic analysis. They were categorized into COM, COD, mixed COM+COD and others. Of 142 pure calcium oxalate stone patients, 87 were predominantly COM stone formers and 55 COD stone formers. Their metabolic status of 24 h urine and serum was assessed. The values of urine calcium, phosphorus, uric acid, magnesium, creatinine, oxalate, citric acid, sodium and potassium, serum values of calcium, phosphorus, uric acid, magnesium and creatinine and calculated values of creatinine clearance, tubular reabsorption of phosphate, calcium magnesium ratio and calcium oxalate ratio were recorded. Comparison was made between the COM stone group and the COD stone group. Patients forming COM stones had significantly higher mean values for urine calcium (P < 0.05), oxalate (P < 0.01) and magnesium (P < 0.05) levels and significantly lower level of urine calcium-oxalate ratio (P < 0.01) and urine calcium-magnesium ratio (P < 0.01) compared to COD stone forming patients. All other values failed to show significant difference. Patients, with higher urine oxalate, formed COM stones. Those with low magnesium (which is an inhibitor) formed more of COD stones. Urine calcium was high in both groups without showing significant variation from the mean. In patients with high calcium-oxalate and calcium-magnesium ratios, there is higher chance of forming a COD stone than COM. Identification of the crystallization pattern of the calcium stone will help in selecting treatment modalities.

Importance of the Field: The socioeconomic burden of an aging population has accelerated the urgency of novel therapeutic strategies for neurodegenerative disease. One possible approach is to target mitochondrial dysfunction, which has been implicated in the pathogenesis of numerous neurodegenerative disorders., Areas Covered in This Review: This review examines the role of mitochondrial defects in aging and neurodegenerative disease, ranging from common diseases such as Alzheimer's and Parkinson's disease to rare familial disorders such as the spinocerebellar ataxias. The review is provided in two parts; in this first part, we discuss the mitochondrial defects that have been most extensively researched: oxidative stress; bioenergetic dysfunction and calcium deregulation., What the Reader Will Gain: This review provides a comprehensive examination of mitochondrial defects observed in numerous neurodegenerative disorders, discussing therapies that have reached clinical trials and considering potential novel therapeutic strategies to target mitochondrial dysfunction., Take Home Message: This is an important area of clinical research, with several novel therapeutics already in clinical trials and many more in preclinical stages. In part II of this review we will focus on possible novel approaches, looking at mitochondrial defects which have more recently been linked to neurodegeneration.

Widespread vascular calcification is a ubiquitous feature of aging and is prevalent in association with a number of common pathologies including atherosclerosis, renal failure, and diabetes. Once thought of as innocuous, emerging evidence suggests that calcification is causal in precipitating vascular events and mediating chronic cardiovascular damage, independent of disease context. Importantly, a large body of data has shed light on the factors that favor the formation of calcification in vivo, as well as on the complex mechanisms that initiate and promote it. This has identified some novel targets and allowed for the possibility that calcification can potentially be blocked and ultimately regressed. Targets include local and circulating inhibitors of calcification as well as factors that may ameliorate vascular smooth muscle cell (VSMC) apoptosis. Despite this, the vasculature remains a difficult tissue to target and currently there are no effective treatments in general use. More crucially, any potential treatments will need to be carefully evaluated as they may impinge on bone metabolism. Our best hope for the near future is to normalize factors associated with accelerated calcification in pathologies such as renal failure where, aberrant mineral metabolism, as well as treatment regimes, may contribute to the initiation and progression of calcification.

The extracellular calcium ion (Ca(2+)(e))-sensing receptor (CaR) enables key tissues that maintain Ca(2+)(e) homeostasis to sense changes in the Ca(2+)(e) concentration. These tissues respond to changes in Ca(2+)(e) with functional alterations that will help restore Ca(2+)(e) to normal. For instance, decreases in Ca(2+)(e) act via the CaR to stimulate secretion of parathyroid hormone-a Ca(2+)(e)-elevating hormone-and to increase renal tubular calcium reabsorption; each response helps promote normalization of Ca(2+)(e) levels. Further work is needed to determine whether the CaR regulates other parameters of renal function (e.g. 1,25-dihydroxyvitamin D(3) synthesis, intestinal absorption of mineral ions, and/or bone turnover). Identification of the CaR has also elucidated the pathogenesis and pathophysiology of inherited disorders of mineral and electrolyte metabolism; moreover, acquired abnormalities of Ca(2+)(e)-sensing can result from autoimmunity to the CaR, and reduced CaR expression in the parathyroid may contribute to the abnormal parathyroid secretory control that is observed in primary and secondary hyperparathyroidism. Finally, calcimimetics-allosteric activators of the CaR-treat secondary hyperparathyroidism effectively in end-stage renal failure.

Coronary heart disease and osteoporosis are common diseases in aging populations. Traditionally, these diseases have been considered as distinct and unrelated. However, nowadays there has been increasing evidence indicating a pathological link between these two disorders. Both diseases share etiological factors as hyperlipidemia, hypertension, diabetes, oxidative stress, inflammation, hyperhomocysteinemia. Statins, hypolipidemic drugs, not only reduce atherogenesis but also stimulate bone formation. Bisphosphonates, drugs used in osteoporosis treatment, have been shown to influence serum cholesterol levels and inhibit atherosclerotic plaque formation.

Purpose: In a subgroup of children with enuresis an increase in nighttime water and solute excretion has been documented. To investigate if modifications in renal function are involved in nocturnal enuresis, we assessed circadian variation in natriuresis and tubular sodium handling in polyuric hypercalciuric children., Materials and Methods: A total of 10 children with proved hypercalciuria and nocturnal polyuria and 10 age matched controls were included in the study. A 24-hour urine collection was performed in 8 sampling periods for measurement of urinary sodium excretion. Segmental tubular sodium transport was investigated during a daytime oral water load test and calculated according to standardized clearance methodology., Results: The children with enuresis showed a marked increase in the fractional excretion of sodium during the night (0.93% +/- 0.36%), while daytime sodium excretion was decreased (0.84% +/- 0.23%). Analysis of segmental tubular sodium transport revealed decreased delivery of sodium to distal tubule (C(H2O) + C(Na) = 10.7 ml/100 ml glomerular filtration rate), indicating increased proximal tubular sodium reabsorption but also stimulation of distal sodium reabsorption as demonstrated by increased fractional distal sodium reabsorption (92.9% +/- 2.2%, controls 90.5% +/- 2.9%). Increased distal reabsorption was associated with increased fractional potassium excretion (17.5% +/- 2.7%, controls 13.6% +/- 6.4%), indicating increased distal tubular sodium/potassium exchange., Conclusions: No intrinsic defect in renal tubular sodium transport was found, but during the day increased sodium reabsorption in proximal and distal tubules was observed, suggesting extrarenal factors to be involved in altered circadian variation in solute and water excretion by the kidney.

Disturbances in calcium and phosphorus metabolism are almost invariable consequences of chronic kidney disease (CKD). Because the capacity to regulate calcium and phosphorus metabolism becomes compromised progressively as kidney function declines, calcium and phosphorus homeostasis is disrupted and serum calcium or phosphorus levels are perturbed in many patients with CKD. The level of interest in, and concerns about, abnormalities in calcium and phosphorus metabolism among patients with CKD has increased substantially in recent years. Strategies for clinical management are being revised, and recent recommendations differ substantially from those used previously with a renewed emphasis on safety.

Hypercalciuria is an important, identifiable, and reversible risk factor in stone formation. The foremost and most fundamental step in dissecting the genetics of hypercalciuria is understanding its pathophysiology. Hypercalciuria is a complex trait. This article outlines the various factors that compromise the attempt to dissect the genetics of hypercalciuria, summarizes the clinical and experimental monogenic causes of hypercalciuria, and outlines the initial results from attempts in studying polygenic hypercalciuria. Finally, the problem is set in perspective of the current database, technologic advances and limitations are highlighted, and prospects of further advances in the field are speculated upon.

Primary hypercalciuria (PH) is very often accompanied by some degree of bone demineralization. The most frequent clinical condition in which this association has been observed is calcium nephrolithiasis. In patients affected by this disorder, bone density is very frequently low, and increased susceptibility to fragility fractures is reported. The very poor definition of this bone disease from a histomorphometric point of view is a crucial aspect. At present, the most common finding seems to be a low bone turnover condition. Many factors are involved in the complex relationships between bone loss and PH. Since bone loss was mainly reported in patients with fasting hypercalciuria, a primary alteration in bone metabolism was proposed as a cause of both hypercalciuria and bone demineralization. This hypothesis was strengthened by the observation that some bone resorbing-cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor nechrosis factor-alpha (TNF-alpha), are high in hypercalciuric patients. An excessive response to the acid load induced by dietary protein intake seems to be an additional factor explaining a primitive alteration of bone. The intestine plays a major role in the clinical course of bone disease in PH. Patients with absorptive hypercalciuria less frequently show bone disease, and a reduction in dietary calcium greatly increases the probability of bone loss in PH subjects. It has recently been reported that greater bone loss is associated with a larger increase in intestinal calcium absorption in PH patients. Considering the absence of parathyroid hormone (PTH) alterations, it was proposed that this is not a compensatory phenomenon, but probably the marker of disturbed cell calcium transport, involving both intestinal and bone tissues. While renal hypercalciuria is rather uncommon, the kidney still seems to play a role in the pathogenesis of bone loss in PH patients, possibly via the effect of mild-to-moderate urinary phosphate loss with secondary hypophosphatemia. In conclusion, bone loss is very common in PH patients. Even if most of the factors involved in this process have been identified, many aspects of this intriguing clinical condition remain to be elucidated.

The changes in cardiac function caused by calcium overload are reviewed. Intracellular Ca(2+) may increase in different structures [e.g. sarcoplasmic reticulum (SR), cytoplasm and mitochondria] to an excessive level which induces electrical and mechanical abnormalities in cardiac tissues. The electrical manifestations of Ca(2+) overload include arrhythmias caused by oscillatory (V(os)) and non-oscillatory (V(ex)) potentials. The mechanical manifestations include a decrease in force of contraction, contracture and aftercontractions. The underlying mechanisms involve a role of Na(+) in electrical abnormalities as a charge carrier in the Na(+)-Ca(2+) exchange and a role of Ca(2+) in mechanical toxicity. Ca(2+) overload may be induced by an increase in [Na(+)](i) through the inhibition of the Na(+)-K(+) pump (e.g. toxic concentrations of digitalis) or by an increase in Ca(2+) load (e.g. catecholamines). The Ca(2+) overload is enhanced by fast rates. Purkinje fibers are more susceptible to Ca(2+) overload than myocardial fibers, possibly because of their greater Na(+) load. If the SR is predominantly Ca(2+) overloaded, V(os) and fast discharge are induced through an oscillatory release of Ca(2+) in diastole from the SR; if the cytoplasm is Ca(2+) overloaded, the non-oscillatory V(ex) tail is induced at negative potentials. The decrease in contractile force by Ca(2+) overload appears to be associated with a decrease in high energy phosphates, since it is enhanced by metabolic inhibitors and reduced by metabolic substrates. The ionic currents I(os) and I(ex) underlie V(os) and V(ex), respectively, both being due to an electrogenic extrusion of Ca(2+) through the Na(+)-Ca(2+) exchange. I(os) is an oscillatory current due to an oscillatory release of Ca(2+) in early diastole from the Ca(2+)-overloaded SR, and I(ex) is a non-oscillatory current due to the extrusion of Ca(2+) from the Ca(2+)-overloaded cytoplasm. I(os) and I(ex) can be present singly or simultaneously. An increase in [Ca(2+)](i) appears to be involved in the short- and long-term compensatory mechanisms that tend to maintain cardiac output in physiological and pathological conditions. Eventually, [Ca(2+)](i) may increase to overload levels and contribute to cardiac failure. Experimental evidence suggests that clinical concentrations of digitalis increase force in Ca(2+)-overloaded cardiac cells by decreasing the inhibition of the Na(+)-K(+) pump by Ca(2+), thereby leading to a reduction in Ca(2+) overload and to an increase in force of contraction.

There is a significant amount of knowledge that has been gained in recent years in the study of endocrine disorders in the newborn. The explosion of genetic data shedding light on the origins of endocrine disease has expanded the level of diagnostic evaluation and management of these infants. This article provides a general review of endocrine disorders as they present in a newborn.

In order to probe the relationship between calcium content and its status in fetal tissue and minor's calcium deficiency, the calcium content of seven tissues of fetus aged 4 to 10 month was measured and analyzed. Results showed that the calcium content in fetal tissues was an unstable variable, and it was a function of spatio-temporal factors. Calcium content in fetal tissues reduced with the increase of age and weight of tissue, making a continuous decrease of the calcium content in per gram tissue. This characteristic could last to about the age of 20 years old of children. The physiological character that calcium content in tissues of fetus and minor decreases with the development can make people to be more aware to calcium deficiency, laying the physiological basis of calcium deficiency of the people in low age, providing the physiological information for adjusting and controlling the calcium nutrition of the fetus, minor and pregnant woman.

Background: Congenital "Swiss-cheese" platelets are a rare disorder of platelet function due to impaired calcium mobilization. Management of pregnancy in patients with this disorder had not been reported previously., Case: Successful pregnancy occurred in a woman with congenital Swiss-cheese platelets. Neither the mother nor neonate experienced any hemorrhagic complications., Conclusion: Successful pregnancy is possible in women with congenital Swiss-cheese platelets. The lack of hemorrhagic complications may be due to the increase in platelet intracellular free calcium concentration during pregnancy.

Objective: To study the capacity of renal acidification in a group of children diagnosed of idiopathic hypercalciuria., Patient and Methods: 36 children were studied, to those that were determined the pCO2 (UpCO2) maximum urinary with two different stimuli, acetazolamide and sodium bicarbonate (NaHCO3). At 33 of them, was performed an acidification test with frusemide stimulus. We studied a control group of 13 healthy children so much for the first one as the second tests and other 14 healthy children for the acidification test with frusemide., Results: In the tests performed with NaHCO3 and acetazolamide stimulus, they were not proven differences in the values of UpCO2 neither in the urinary concentration of HCO3- (UHCO3-) than control children. Nevertheless, the UpCO2 and the concentration of UHCO3- in the patients were significantly lower with acetazolamide with regard to the NaHCO3 stimulus. In the acidification test with frusemide, significantly lower values of titratable acid and ammonium were obtained than control children., Conclusions: In children with idiopathic hypercalciuria, the capacity of secretion of H+ is normal, what is evidenced, especially, when studying the maximum UpCO2 after stimulus with NaHCO3. When diuretics are used as stimuli, exists more negative results that can be due to a certain partial resistance to the action of the same ones or to that are less potent to induce the secretion of H+.

Differently from other metabolic conditions, most of calcium metabolism disorders are diagnosed through simple detection of both serum and urinary excretion (24-h urine collection), levels of calcium, total and ionized form, and phosphate, and of calciotropic hormone serum levels, such as calcitonin, PTH and vitamin D metabolites. For the diagnosis and clinical monitoring of some metabolic bone diseases, such as osteoporosis and Paget's disease, the assessment of bone turnover is offering a useful tool for the evaluation of the therapeutic response in affected individuals. Markers of bone formation are represented by bone alkaline phosphatase and osteocalcin, while principal bone resorption markers are represented by pyridinoline, deoxypyridinoline and crosslinks of collagen N-telopeptide, both in the 24-h and fasting second morning urine collection. Only in selected conditions, here briefly reviewed, dynamic tests can offer an interpretation on the pathogenetic events causing a disorder of calcium metabolism.

Epidemiological, clinical and experimental evidence suggests that fatty acids may have an effect (due to their chemical structure) on calcium metabolism in animals and man. Fatty acid deficiency in animals can lead to a loss of bone calcium and matrix, resulting in marked bone demineralization, and treatment with a mixture of omega-3 and omega-6 polyunsaturated fatty acids can induce significant reduction in some biochemical markers of bone reabsorption. A relationship, between phospholipid fatty acid content, calcium-regulating hormones and intestinal, renal, and bone calcium metabolism alterations, has been reported in patients with renal stones and hypercalciuria. Recent studies have shown specific effects of fatty acids on the gene expression of some bone cytokines. Fatty acids might be involved in calcium metabolism influencing cellular calcium ion transport directly, as second messengers, or generating, through the cyclooxygenase pathway, potential biological mediators which have complex effects on bone remodeling. Experimental and clinical documentation of the specific and indirect effects of fatty acids on calcium and bone metabolism could open up new and interesting clinical prospects.

Unlabelled: The Aral Sea region is a natural area seriously polluted by human activities. In addition to the increased prevalence of diverse chronic diseases in children, the risk of developing urolithiasis is reported to be high in this region. This study was undertaken to clarify the prevalence of hypercalciuria in children of the Aral Sea region. A group of 205 children living in Kazalinsk, close to the Aral Sea, and a group of 187 children living in Zhanakorgan, far from the Aral Sea, were screened for hypercalciuria. Urinary sodium excretion (sodium per creatinine, uNa/Cr) in addition to calcium excretion (calcium per creatinine, uCa/Cr) was also calculated for each subject. Mean uCa/Cr (mmol/mmol) and uNa/Cr (mmol/mmol) excretions were significantly higher in Kazalinsk than in Zhanakorgan (uCa/Cr: 0.75 +/- 0.74 and 0.33 +/- 0.30; uNa/Cr: 3.54 +/- 2.27 and 2.89 +/- 1.69, respectively, mean +/- SD, p < 0.01). Hypercalciuria regarded as an uCa/Cr of more than 0.703 was observed in 79 out of 205 Kazalinsk children (38.6%) while this was seen in only 24 out of 187 Zhanakorgan children (12.8%). Linear regression analysis revealed a direct positive correlation between urinary calcium and sodium excretion (p < 0.01) in Kazalinsk children., Conclusion: The prevalence of hypercalciuria in children around the Aral Sea region is extremely high. This may be associated with excessive intake of calcium and sodium, or due to impaired renal tubular function caused by toxic chemicals. Therefore, hypercalciuria that may lead to urolithiasis should be taken into account when considering the health problems of this area.

Increased QT dispersion (QT(d)) has been associated with increased risk for ventricular arrhythmias. Pathologic extracellular electrolyte concentrations may result in ventricular arrhythmias. The aim of this study was to evaluate the effect of electrolyte abnormalities on QT(d). Ten consecutive patients with isolated electrolyte abnormalities were selected for each of the following groups: hypokalemia, hyperkalemia, hypercalcemia, hypocalcemia, hypomagnesemia, and normal controls. Standard 12-lead electrocardiography was performed for each patient and average QT, JT, and RR intervals were calculated for each lead. Dispersion of QT, JT (JT(d)), and QTc (QTc(d)) intervals were calculated as the range between the longest and shortest measurements. Compared with controls, only patients with hypokalemia had a greater QT(d) (115 +/- 31 vs. 49 +/- 15 ms), JT(d) (116 +/- 34 vs. 52 +/- 12 ms), and QTc(d) (141 +/- 40 vs. 58 +/- 1 ms), (P < 0.05). In an experimental substudy, seven rats were maintained on K(+) and seven on Mg(2+)-free diet followed by normal diet. Experimental hypokalemia significantly increased QT(d) (10 +/- 4 to 37 +/- 7 ms), and QTc(d) (32 +/- 6 to 79 +/- 27 ms) (P < 0.05), whereas hypomagnesemia did not. Restoration of serum potassium resulted in normalization of dispersion (QT(d), 14 +/- 2; QTc(d), 34 +/- 6 ms). Hypokalemia increases the dispersion of ventricular repolarization that may be responsible for arrhythmias. Even though hyperkalemia, hypocalcemia, and hypercalcemia are known to affect ventricular repolarization, our study shows that they are not associated with increased dispersion.

Disruption of intracellular calcium homeostasis is thought to play a role in neurodegenerative disorders such as Huntington's disease (HD). To study different aspects of putative pathogenic mechanisms in HD, we aimed to establish an in vitro model of calcium-induced toxicity in striatal neurons. The calcium ionophore A23187 induced a concentration- and time-dependent cell death in cultures of embryonic striatal neurons, causing both apoptosis and necrosis. Cell death was significantly reduced by the cell-permeant antioxidant manganese(III)tetrakis(4-benzoic acid) porphyrin (MnTBAP). Cyclosporin A and its analogue N-MeVal-4-cyclosporin also reduced the incidence of cell death, suggesting the participation of mitochondrial permeability transition in this process. Furthermore, addition of either of two types of caspase inhibitors, Ac-YVAD-CHO (acetyl-Tyr-Val-Ala-Asp-aldehyde) and Ac-DEVD-CHO (acetyl-Asp-Glu-Val-Asp-aldehyde), to the striatal cells blocked A23187-induced striatal cell death in a concentration-dependent manner. These results suggest that oxidative stress, opening of the mitochondrial permeability transition pore and activation of caspases are important steps in A23187-induced cell death.

Many important aspects of our life are regulated by the free cytosolic Ca2+ concentration. The intracellular Ca2+ signal is regulated both in space, frequency and amplitude. Each cell chooses a unique set of Ca2+ signals to control its function. Ca2+ signal transduction is based on rises in free cytosolic Ca2+ concentration. Ca2+ can come from the extracellular space or be released from intracellular stores. Extracellular Ca2+ enters the cell through various types of plasma-membrane Ca2+ channels and leaves the cell using Ca2+ pumps and Na+/Ca(2+)-exchangers. Ca2+ is accumulated in intracellular stores by means of Ca2+ pumps and is released via inositol 1,4,5-trisphosphate (IP3) and ryanodine receptors. Mutations or abnormalities in one of the above mentioned Ca(2+)-transporting proteins can lead to disease. Skeletal-muscle pathology can be caused by abnormal ryanodine receptors (malignant hyperthermia, porcine stress syndrome, central core disease), plasma-membrane Ca2+ channels (hypokalemic periodic paralysis, muscular dysgenesis mice, paraneoplastic Lambert-Eaton myasthenia syndrome) or Ca2+ pumps (Brody disease). Neurologic disorders can be related to altered function of plasma-membrane Ca2+ channels (episodic ataxia type 2, spinocerebellar ataxia type 6, familial hemiplegic migraine, glutamate excitotoxicity, tottering, leaner, lethargic and stargazer mice), IP3 receptors (Lowe's oculocerebrorenal syndrome, manic depression, Alzheimer's disease, opisthotonos mice) and Ca2+ pumps (deafwaddler mouse and wriggle mouse sagami). Two skin diseases are caused by Ca(2+)-pump mutations (Darier disease and Hailey-Hailey disease). Incomplete X-linked congenital stationary night blindness is caused by a mutation in the plasma-membrane Ca2+ channels in rods and cones.

The role of estrogen in the regulation of calcium balance is still poorly understood. A calcium balance study was performed to examine the effects of estrogen status in relation to fecal calcium loss as a component of bone loss after oophorectomy (OOX) in the mature rat. The components of the classic calcium balance were compared with calcium balance estimates obtained from whole body bone density. Six month or older Sprague Dawley rats were allocated to either a sham-operated or OOX group and fed a 0.1% calcium diet. The bone mineral density (BMD) and bone mineral content (BMC) were measured at baseline, 6 weeks, and 9 weeks. A calcium balance was done for 6 days before and 6 weeks post OOX. The fall in BMD from baseline to 9 weeks in the OOX group was significantly greater than in the sham-operated group. The calcium balance was more negative at baseline than at 6 weeks in both groups of animals because they had not adapted to the low calcium diet. However, the increase in calcium balance was significantly less in the OOX animals than in the sham-operated animals. The greater the rise in calcium balance from the baseline to the 6 weeks balance the less the fall in the calcium content of the whole body (Spearman correlation: r = 0.604 P = 0.008). The fall in fecal calcium, but not urine calcium or calcium consumed, was negatively correlated with the change in whole body BMC (Spearman correlation: fecal calcium r = -0.763 P = 0.001). Thus, the primary effect of estrogen deficiency on calcium balance in the mature rat appears to be calcium flux in the bowel, rather than renal calcium handling.

Nearly 50 years after its initial description by Dr. F. Albright, the term idiopathic hypercalciuria (IH) is still in use. The exact mechanism of hypercalciuria is still unknown despite extensive pathophysiologic investigations; recent advances represent the focus of this review. A precise definition of true IH is proposed, taking into account the various nutritional conditions influencing calcium excretion. The potential pathogenic mechanisms are discussed, and the limits of the classical Pak's pathophysiological classification are recalled. The evidence supporting the role of an increased intestinal calcium absorption, a defect in renal tubular calcium reabsorption, or an increased bone loss as a primary mechanism in IH are successively examined. Since overall available human data indicates that all three mechanisms may be found in IH, the hypothesis that a broader disorder encompassing all these various abnormalities may be involved in IH is discussed. Three global hypotheses to account for IH physiopathology are examined: a diffuse defect in fatty acid content of cell membranes, an increased expression of the vitamin D receptor of the 25(OH) vitamin D 1 alpha-hydroxylase, or of the calcium sensor receptor and a monocyte disease. Finally, the available clinical data justifying the therapeutic approaches are reviewed, and guidelines for dietary recommendations regarding calcium and also animal protein, sodium chloride, alcohol, carbohydrate, phosphate, and potassium intakes are proposed, and drug therapy indications are discussed.

Idiopathic calcium nephrolithiasis (ICN) is a frequent disease in Western countries. The physicochemical theory of lithogenesis, which explains stone formation by the precipitation, growth, and crystalline aggregation of lithogenic salts in the urine, has contributed greatly to the understanding of the pathogenesis of calcium urolithiasis. However, several aspects are still unexplained; the co-existence of familial occurrence, primary tubular dysfunctions with ICN, and anomalies in the systemic handling of oxalate and calcium led to the development of a cellular hypothesis of ICN. A number of cellular defects in the handling of ions has been reported that involves both anion and cation transport. These anomalies are probably the expression of a still unknown cellular defect in idiopathic calcium stone formers. We suggested that an anomaly in the cell membrane composition might be responsible for the complex array of cell ion flux abnormalities observed in ICN. Recently, a disorder in the n-6 polyunsaturated fatty acid series has been described; it is characterized by a lower linoleic acid content and a higher arachidonic acid concentration in both plasma and erythrocyte membrane phospholipids of renal calcium stone patients. This anomaly could cause an increased activity of ion carriers; furthermore, it may lead to increased prostaglandin synthesis and to secondary phenomena at the kidney, skeletal, and intestinal level. As a consequence, critical conditions for lithogenesis in the kidney may ensue. The data suggest a common pathogenesis for hypercalciuria and hyperoxaluria. The systemic defect in the phospholipid arachidonic acid level may be both of dietary or genetic origin; experimental data suggest that the increase in delta-6 desaturase activity, the limiting enzyme in the metabolic pathway of polyunsaturated fatty acids, might be relevant to the pathogenesis of lipid abnormalities observed in nephrolithiasis and to the pathogenesis of ICN and its related problems (at the kidney, intestinal, and bone level).

Purpose: A decreased concentration of magnesium in the urine is a risk factor for renal calcium stone disease that may be caused by decreased enteral absorption of magnesium. We analyze the possible reciprocal influences of enteral absorption of calcium and magnesium in patients with renal stone disease., Materials and Methods: We measured the fractional enteral absorption of 47calcium and 28magnesium in 11 patients with renal calcium stone disease, including 8 with and 3 without hypercalciuria. Two tests were performed using calcium and magnesium, respectively, followed by another test in which the enteral absorption of calcium and magnesium was measured after both cations were administered together., Results: We noted no clear influence of either cation on the absorption of the other in the 3 patients without hypercalciuria. However, in the 8 hypercalciuric patients enteral calcium absorption decreased after the concurrent administration of magnesium and enteral magnesium absorption increased after the concurrent administration of calcium. Each effect was proportional to the other., Conclusions: The results of this study indicate that the oral supplementation of magnesium in patients with hyperabsorptive hypercalciuria and renal calcium stone disease is favorable because it decreases calcium absorption and increases magnesium absorption. Both factors may reduce risk factors for renal calcium stone formation.

A decrease in bone density of the spine has been reported in individuals with hypercalciuria and the finding of the latter in osteoporosis patients is not uncommon. We studied 21 men and 8 women (mean age 47 +/- 13) with idiopathic hypercalciuria (IHCU) defined by an urinary calcium of more than 7.5 mmol/24 h in men and 6.25 mmol/24 h in women. The duration of IHCU was 10 (+/-) 8 years. Among the 29 patients, 24 had one or more renal calculi. Twenty one had been treated, by low calcium diet only (and diuresis), combined with a thiazide diuretic, or sodium phytate, or phosphorus. Bone mineral content (BMC) was measured in the lumbar spine and the upper end of the femur using an ORIS ODC 200 densitometer and compared with 29 control subjects paired for age and sex. No difference was found between the two groups concerning BMC values in either the spine or the 3 femoral sites (neck, Ward, trochanter). BMC was not correlated with urinary calcium. Thus individuals with IHCU showed no decrease in their bone mass, among this group seen in a department of nephrology. The influence of the treatment of IHCU remains to be defined.

The primary hereditary cardiomyopathy of the Syrian hamster is a particularly interesting model of experimental cardiomyopathy 1) because of its slow progression to cardiac failure unlike acute experimental volume and pressure overloading; 2) because of the reproducibility and predictable nature of the mechanical, biochemical and electrophysiological abnormalities observed at each stage of the disease; 3) because of involvement of other muscle groups, and particularly, skeletal muscle. The physiopathology is not fully understood but a disturbance of intracellular calcium homeostasis appears to play a major role. From the therapeutic point of view, a number of calcium antagonists have been shown to be effective in restoring myocardial function, but they have no effect on skeletal muscular lesions. Recently, early prophylactic intervention with therapeutic doses of perindopril has been shown to prevent the decrease of certain parameters of myocardial contractility in vitro in the dilated group, before the appearance of any signs of cardiac failure. This study also showed that angiotensin converting enzyme inhibitors had no intrinsic negative inotropic effects.

Osteomalacia is characterized by large osteoid seams and a preserved volume of bone trabeculae. The mineralization of newly formed bone requires adequate concentrations of calcium and phosphate: the Ca.P product has been regarded as a useful, empirical diagnostic test of osteomalacia. It decreases in patients with osteomalacia mainly because they have very low plasma phosphate levels. At present total body bone mineral and total body bone density can be directly measured by whole body absorptiometry, which indicates the lowest total mineral content of the skeleton which can increase quickly after adequate treatment. The main symptoms of osteomalacia are: bone pain; muscular weakness (commonly as pelvic girdle myopathy); Looser-Milkman pseudofractures or more often a pattern of generalized demineralization at X-ray. The main biochemical parameters in osteomalacia include: defective calcium absorption with hypocalcemia and hypocalciuria; defective intestinal phosphate absorption with hypophosphatemia; there is often increased renal phosphate clearance due to hypocalcemia and secondary hyperparathyroidism; elevated alkaline phosphatase and osteocalcin levels; high bone turnover confirmed by kinetic studies carried out with radiocalcium or 99mTc-MDP. An etiological classification of the osteomalacias includes: 1) nutritional osteomalacia: a) inadequate exposure to sunlight and/or insufficient vitamin D intake; b) defective intestinal absorption of vitamin D because of malabsorption syndromes (e.g. jejuno-ileal bypass for obesity).(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium and phosphorus are, respectively, the fifth and sixth most abundant elements in the body; both play vital roles in a multitude of physiologic systems. Because the great bulk of these elements is found in the skeleton, a large part of the discussion of calcium and phosphorus metabolism focuses on skeletal disorders, the impact of which falls heavily on young children. This article reviews the physiology of calcium and phosphorus, the skeletal and systemic consequences of disorders of vitamin D nutrition and metabolism, and the metabolic bone disease of prematurity.

The occurrence of calcareous renal stones in 12 members of a family was consistent with an autosomal dominant mode of inheritance. All 6 members with stones who were evaluated were shown to have absorptive hypercalciuria. The mother of 2 members with stones did not suffer stones but had biochemical evidence of absorptive hypercalciuria (increased intestinal calcium absorption, hypercalciuria and normal parathyroid function). Nephrolithiasis was encountered only in the progeny of members who had stones of biochemical absorptive hypercalciuria. The results suggest that physiological feature(s) of absorptive hypercalciuria may be an expression of the genetic trait.

In normal individuals, 1,25-dihydroxyvitamin D (1,25-D) levels regulate calcium (Ca) absorption according to Ca intake; its synthesis is stimulated by low Ca intake, probably via increased parathyroid hormone (PTH) secretion, to increase Ca absorption, and suppressed during high intake to reduce Ca absorption. The body also adapts Ca absorption in response to renal Ca excretion, and phosphate absorption in response to phosphate intake. These adaptations may fail or be impaired in certain diseases. In disorders of overadaptation, the intestinal tract absorbs excessive amounts of Ca due to overproduction of 1,25-D, as in absorptive hypercalciuria, sarcoidosis, primary hyperparathyroidism, and tumoral calcinosis. Intestinal hyperabsorption and hypercalciuria may occur on both low- and high-Ca diets. Primary hyperparathyroidism and hypoparathyroidism are bihormonal, related to over- and underproduction, respectively, of both 1,25-D and PTH. Underadaptation disorders are typically related to low 1,25-D synthesis or resistance to this metabolite; examples include postmenopausal osteoporosis, chronic renal failure, and osteomalacia. Many of these adaptational disorders can be relieved or improved by manipulating Ca, phosphate, sodium, or protein intake or by administering exogenous 1,25-D. Overabsorption of Ca and other substances, such as oxalate, may be responsible for Ca nephrolithiasis. Hypocitraturia (which may be a complication of certain diseases or the result of unbalanced diet or excessive exercise), diets high in readily metabolizable sugars and purine-rich proteins (meat, poultry, and fish), and low fluid intake can all contribute to stone formation. Various regimens may reduce the risk of Ca nephrolithiasis.

Male Wistar rats that were experimentally hypokinetic were fed 24,25(OH)2D3 or 1,25(OH)2D3 separately or in combination to determine the effect on bone growth and on bone formation and resorption. It was shown that these parameters of bone metabolism are influenced by these metabolites of vitamin D3 by their effect on bone sensitivity to their activity and perhaps in the regulation of bone histogenesis.

Fifty patients with absorptive hypercalciuria (AH), 25 normal subjects (NS), and 25 nonhypercalciuric patients with stone disease (NHSF) were studied using an oral calcium tolerance test and 24-h urine collections on both a restricted and an unrestricted calcium intake. Mean (+/- SD) fasting fractional calcium excretion was increased in the patients with AH (2.7 +/- 1.1% vs. 1.4 +/- 0.6% in the NS; P less than 0.001) and was negatively correlated with fasting nephrogenous cAMP, suggesting that this renal calcium leak was secondary to parathyroid suppression. Plasma 1,25-dihydroxyvitamin D [1,25-(OH)2D] was elevated in 80% of patients with AH and was high normal in the remaining 20%. Ten patients, selected on the basis of results for 1,25-(OH)2D greater than 4 SD from the normal mean, displayed a particularly severe pattern of abnormalities, including mild hypercalcemia in two patients. Pooled data from the NS and patients with AH revealed a significant negative correlation between the plasma concentration of 1,25-(OH)2D and the renal phosphate threshold (r = -0.40; P less than 0.001), but this correlation lost significance when the NHSF were substituted for the NS as a control group (r = -0.07; P = NS). These findings 1) provide a pathophysiological basis for the increase in fasting calcium excretion commonly observed in hypercalciuric patients, and 2) stress the importance of circulating 1,25-(OH)2D in the pathogenesis of the syndrome, but 3) fail to support the phosphate leak theory of pathogenesis.