Increased Calcium Load Research Articles

CaV3.3 Channelopathies.

CaV3.3 is the third member of the low-voltage-activated calcium channel family and the last to be recognized as disease gene. Previously, CACNA1I, the gene encoding CaV3.3, had been described as schizophrenia risk gene. More recently, de novo missense mutations in CACNA1I were identified in patients with variable degrees of neurodevelopmental disease with and without epilepsy. Their functional characterization indicated gain-of-function effects resulting in increased calcium load and hyperexcitability of neurons expressing CaV3.3. The amino acids mutated in the CaV3.3 disease variants are located in the vicinity of the channel's activation gate and thus are classified as gate-modifying channelopathy mutations. A persistent calcium leak during rest and prolonged calcium spikes due to increased voltage sensitivity of activation and slowed kinetics of channel inactivation, respectively, may be causal for the neurodevelopmental defects. The prominent expression of CaV3.3 in thalamic reticular nucleus neurons and its essential role in generating the rhythmic thalamocortical network activity are consistent with a role of the mutated channels in the etiology of epileptic seizures and thus suggest T-type channel blockers as a viable treatment option.

SARCOIDOSIS AND HYPERCALCIURIA: A STONE COLD INDICATION FOR TREATMENT

TOPIC: Diffuse Lung Disease TYPE: Fellow Case Reports INTRODUCTION: Sarcoidosis may cause renal disease by several different mechanisms. Symptomatic nephrolithiasis is a rare occurrence as the initial manifestation of sarcoidosis. Hypercalciuria may occur commonly in sarcoidosis and warrants treatment. There is lack of data supporting screening for hypercalciuria. Herein we present a patient with asymptomatic sarcoidosis until she developed nephrolithiasis with a normal serum calcium but an elevated urine calcium. CASE PRESENTATION: 62 year old woman with a history of diabetes mellitus II and obesity was followed in the pulmonology clinic for abnormal chest imaging. She had previously presented to the emergency department for chest pain that lead to a chest radiograph and Chest CT scan. CT scan showed mediastinal adenopathy and pulmonary nodules. Bronchoscopy was performed with biopsies which revealed non necrotizing granulomas consistent with sarcoidosis. Patient had a normal spirogram, and no other extrapulmonary manifestations that would warrant treatment for sarcoidosis. Serum calcium and albumin were normal. 25 hydroxy vitamin D levels were 23 ng/ml. She did take over the counter Vitamin D supplements. Later she developed nephrolithiasis. Analysis of the stone revealed 65% calcium oxalate monohydrate and 15% calcium oxalate dihydrate. A 24 hour urine calcium showed 328 mg of calcium per volume of urine. Patient had a history of diabetes mellitus so treatment with steroids was avoided and she was started on 10 mg of methotrexate. Follow up urine calcium levels are pending. DISCUSSION: While there are guideline recommendations to screen for hypercalcemia with a serum calcium level and for measuring vitamin D levels for replacement, there is scant literature on screening for hypercalciuria in the setting of normal calcium levels, despite hyercalciuria being the most common renal manifestation of renal sarcoidosis. The incidence of renal disease in sarcoidosis varies from 1.1% to 9.7% with hypercalciuria occurring in up to 50% while hypercalcemia may occur in only 10-20% of cases, making hypercalciuria the most common renal manifestation of sarcoidosis. Hypercalciuria is the result of increasing calcium load filtered at glomerulus as a result of decreased PTH secretion secondary to elevated circulating calcitriol levels leading to a diminished tubular reabsorption of calcium. Hypercalciuria predisposes to calcium oxalate nephrolithiasis. Approximately 10 % of patients with sarcoidosis have 1 symptomatic stone. For 1 % of these patients it may be the initial presentation. Approximately 2.7% of sarcoidosis patients have asymptomatic stones. CONCLUSIONS: Hyercalciuria is the most common renal manifestation of sarcoidosis, yet it is not commonly screened for in asymptomatic sarcoidosis patients. Timely treatment may attenuate renal impairment secondary to sarcoidosis. It is suggested that hypercalciuria in the setting of sarcoidosis always be treated. REFERENCE #1: Adam R. Berliner, Mark Haas, Michael J. Choi, Sarcoidosis: The Nephrologist's Perspective, American Journal of Kidney Diseases, Volume 48, Issue 5,2006, Pages 856-870, ISSN 0272-6386, https://doi.org/10.1053/j.ajkd.2006.07.022. REFERENCE #2: Thomas KW, Hunninghake GW. Sarcoidosis. JAMA. 2003 Jun 25;289(24):3300-3. doi: 10.1001/jama.289.24.3300. PMID: 12824213 DISCLOSURES: No relevant relationships by Jonathan gwizdala, source=Web Response Grant for research relationship with Sanofi Please note: January 2021 Added 04/20/2021 by Daniel Ouellette, source=Web Response, value=Grant/Research No relevant relationships by Rajaninder Sharma, source=Web Response

Synthesis and characterization of nanostructured calcium oxides supported onto biochar and their application as catalysts for biodiesel production

Abstract Nanostructured calcium oxides supported onto biochar obtained by pyrolysis of avocado seeds were prepared, characterized and successfully used as catalysts to produce biodiesel from waste oils. The effect of increasing calcium load (5, 10 and 20 wt%) was investigated. Elemental analysis, FTIR, XRD, SEM, BET, acid and basic sites were used to characterize the resulting carbon-based calcium oxides. Supported systems efficiently promoted the transesterification of oil with methanol, but differently from calcium oxide, they were easily recoverable and reusable for three cycles without any loss of activity. Kinetic data were better fitted by a pseudo-second order model with an activation energy of 39.9 kJ mol−1. Thermodynamic parameters of activation energy were also determined for the transesterification reaction ( Δ ‡ G: 98.68-106.08 kJ mol−1, Δ ‡ H: 37.05 kJ mol−1 and Δ ‡ S: 0.185 kJ mol−1 K). Finally, reaction conditions were optimized using the desirability function applied on the response surface methodology analysis of a Box–Behnken factorial design of experiments. By carrying out the reaction at 99.5 °C for 5 h with 7.3 wt% of catalyst and a molar ratio of methanol to oil of 15.6, a FAME content over 96% was achieved. Even starting from waste cooking oil, final biodiesel was conform to the main EN14214 specifications.

Biocompatibility Studies of Nanoengineered Polycaprolactone and Nanohydroxyapatite Scaffold for Craniomaxillofacial Bone Regeneration.

Currently there is an increased demand for synthetic bone substitute materials (SBSMs) due to avoidance of donor-site surgery and morbidity. Attempts are done to create SBSM mimicking the bone microarchitecture for enhanced healing. In this study, the authors nanoengineered polycaprolactone (PCL) and nanohydroxyapatite (nHAp) composite scaffold by electrospinning. The nHAp is synthesized via hydrothermal process followed by microwave irradiation. In vitro biocompatibility evaluation with MG63 osteoblastic cell line showed enhanced cell proliferation in the PCL-nHAp scaffold than plain PCL by MTT assay and fluorescence microscopy. Increased osteogenesis in the PCL-nHAp scaffold was shown by the increased calcium load, alkaline phosphatase activity, and expression of osteogenic biomarkers namely osteocalcin, osteonectin, and osteopontin. In vivo studies conducted in rabbit femur bone defects showed increased bone regeneration in PCL-nHAp implanted defects. The results show that PCL-nHAp electrospun scaffold is biomimetic and highly osteogenic and thus a potential SBSM for critical size craniomaxillofacial bone defect applications.

Cost-Effectiveness Analysis for the Treatment of Hyperphosphatemia in Predialysis Patients: Calcium-Based versus Noncalcium-Based Phosphate Binders.

Background Hyperphosphatemia in chronic kidney disease (CKD) patients is often treated with calcium carbonate (CaCO3) despite the fact that CaCO3 is associated with increased calcium load and potentially increased cardiovascular risk. Alternative treatments with noncalcium-based phosphate binders do not increase the calcium load but are more costly. This study analyzes the cost-effectiveness of sevelamer versus CaCO3 for the treatment of hyperphosphatemia in stage III-V predialysis CKD patients in Malaysia. Methods A Markov decision model was adapted to simulate a hypothetical cohort of CKD patients requiring treatment for hyperphosphatemia. Survival was estimated by using efficacy data from the INDEPENDENT-CKD clinical trial. Cost data was obtained from Malaysian studies while health state utilities were derived from literature. Analysis was performed over lifetime duration from the perspective of the Ministry of Health Malaysia with 2013 as reference year. Results In the base case analysis, sevelamer treatment gained 6.37 life years (5.27 QALY) compared to 4.25 life years (3.54 QALY) with CaCO3. At 3% discount, lifetime costs were RM159,901 ($48,750) and RM77,139 ($23,518) on sevelamer and CaCO3, respectively. Incremental cost-effectiveness (ICER) of sevelamer versus CaCO3 was RM47,679 ($14,536) per QALY, which is less than the WHO threshold of three times GDP per capita (RM99,395) per QALY. Sensitivity analyses, both using scenario sensitivity analysis and probabilistic sensitivity analysis, showed the result to be robust. Conclusions Our study finds that sevelamer is potentially cost-effective compared to CaCO3, for the treatment of hyperphosphatemia in predialysis CKD III-V. We propose that sevelamer should be an option in the treatment of Malaysian predialysis patients with hyperphosphatemia, particularly those with high calcium load.

Probabilistic encoding of stimulus strength in astrocyte global calcium signals.

Astrocyte calcium signals can range in size from subcellular microdomains to waves that spread through the whole cell (and into connected cells). The differential roles of such local or global calcium signaling are under intense investigation, but the mechanisms by which local signals evolve into global signals in astrocytes are not well understood, nor are the computational rules by which physiological stimuli are transduced into a global signal. To investigate these questions, we transiently applied receptor agonists linked to calcium signaling to primary cultures of cerebellar astrocytes. Astrocytes repetitively tested with the same stimulus responded with global signals intermittently, indicating that each stimulus had a defined probability for triggering a response. The response probability varied between agonists, increased with agonist concentration, and could be positively and negatively modulated by crosstalk with other signaling pathways. To better understand the processes determining the evolution of a global signal, we recorded subcellular calcium "puffs" throughout the whole cell during stimulation. The key requirement for puffs to trigger a global calcium wave following receptor activation appeared to be the synchronous release of calcium from three or more sites, rather than an increasing calcium load accumulating in the cytosol due to increased puff size, amplitude, or frequency. These results suggest that the concentration of transient stimuli will be encoded into a probability of generating a global calcium response, determined by the likelihood of synchronous release from multiple subcellular sites.

Calcium supplements controversy in osteoporosis: a physiological mechanism supporting cardiovascular adverse effects.

Recently, administration of calcium supplements for the prevention and treatment of osteoporosis has become a highly controversial issue. The findings of epidemiological studies are not necessarily supportive of the practice and are also open to different interpretations. In this article, we attempt to broaden the discussion and provide evidence that calcium supplementation may fail to compensate for renal calcium loss, and also that the resultant increased calcium load in the circulation could lead to extraskeletal deposition, including in the coronary arteries.

Importance of abnormal bone metabolism in the acceleration of atherosclerosis in hemodialysis patients.

Increases in serum calcium and phosphate are known as main risk factors for cardiovascular mortality in hemodialysis patients. However, increased phosphate, a definite mortality risk in the general population, should be more remarkable in hemodialysis patients, as their renal capacity to excrete phosphate into urine is negligible. Phosphate acts directly and indirectly to cause vascular injury by stimulating the apoptosis of vascular endothelial cells and the vascular calcification of vascular smooth muscle cells. Bone releases not only phosphate but also calcium during bone resorption. An increased calcium load reduces bone turnover by suppressing parathyroid function, resulting in the formation of adynamic bone disease. Adynamic bone disease is a major risk factor for ectopic calcification in areas including the vascular wall by diminishing the capacity of bone to absorb surplus calcium and phosphate in the circulation. Therefore, it is recognized that the maintenance of bone turnover within a normal range might be the most important strategy to protect against the development of vascular calcification and to attenuate the load of phosphate and calcium, particularly in hemodialysis patients.

G.P.125: Manganese enhanced muscle MRI as a sensitive outcome measure of dystrophin restoration in the mdx mouse

A central component of dystrophic pathology in DMD patients as well as mdx mice is a persistent increase in steady-state calcium levels in muscle. Increased calcium load leads to loss of muscle strength, activation of calcium-dependent proteases and may increase muscle cell necrosis. As a key primary event in dystrophic pathology, measurement of calcium levels may offer a sensitive marker of the efficacy of therapeutic agents. Manganese is a divalent cation with very similar chemical properties to calcium and is thought to be taken up by cardiac and skeletal muscle by the same receptors as calcium ions. It is also a contrast agent in T1 weighted MRI, enabling calcium levels in muscle to be measured non-invasively. We have previously shown that manganese-enhanced MRI (MEMRI) contrast is elevated in cardiac pathology in mdx and can track the dynamics of calcium channel blockade in dystrophic models. Here, we have extended this analysis by infusing manganese intravenously and observing the uptake by skeletal muscle using MRI, showing that the mdx mouse has an increased steady-state level of MEMRI contrast in both chest wall and triceps. Furthermore, we treated a cohort ( n = 6) of 12-week old mdx mice with an increasing dosage (64 mg/kg or 133 mg/kg) of phosphorothioate Morpholino oligonucleotides (PMOs) to induce exon skipping. Animals were treated with a series of three i.v. injections spaced two weeks apart, scanned after a further two weeks, and muscle (heart, chest wall and triceps) harvested for dystrophin quantification by IF and Western blotting, as well as for histology. We show that inducing exon skipping, even at very low levels, can be detected by changes in the MEMRI signal in both cardiac and skeletal muscle, even in the absence of discernable changes in histology. These data suggest that muscle MEMRI may be a valuable tool for longitudinal studies on dystrophin restoration in mdx and may have increased sensitivity when compared to more established methods.

Tachycardia-Induced Diastolic Dysfunction and Resting Tone in Myocardium From Patients With a Normal Ejection Fraction

The purpose of this study is to evaluate tachycardia-induced relaxation abnormalities in myocardium from patients with a normal ejection fraction. Diastolic dysfunction and left ventricular (LV) hypertrophy are closely linked. Tachycardia can induce heart failure symptoms in otherwise asymptomatic patients. To study the effects of tachycardia on myocardial contractility and relaxation, we evaluated the effects of increasing pacing rates in myocardial biopsy samples obtained from patients with a normal ejection fraction. LV biopsy samples were obtained during coronary bypass surgery. Myocardial strip preparations were electrically paced at rates from 60 to 180 beats/min. Diastolic resting tone was assessed by cross-bridge deactivation. Calcium transporting systems were functionally examined, and myofilament calcium sensitivity was studied. Incomplete relaxation developed in 7 preparations, with increased diastolic tension development at increasing pacing rates. This was absent in the remaining 7 preparations. Incomplete relaxation was found to be associated with increased LV mass and left atrial volume. Cross-bridge deactivation showed that these preparations also had a significant resting tone. Additional functional analyses suggest that incomplete relaxation is associated with disproportionately elevated cellular calcium loads due to a reduced sarcolemmal calcium extrusion reserve. Tachycardia-induced incomplete relaxation was associated with increased LV mass and left atrial volumes. We also found a disproportionately increased calcium load at high rates and a substantial resting tone due to diastolic cross-bridge cycling. These observations may play a role in reduced exercise tolerance and tachycardia-induced diastolic dysfunction.

Parathyroid hormone improves contractile performance of adult rat ventricular cardiomyocytes at low concentrations in a non-acute way

In patients with congestive heart failure, plasma parathyroid hormone (PTH) levels are positively associated with cardiac function. PTH, used to mobilize stem cells from the bone marrow after myocardial infarction, causes an increased left ventricular ejection fraction. The aim of this study was to investigate whether low but plasma-relevant concentrations of PTH directly influence the contractile properties of cardiomyocytes. Isolated adult rat ventricular cardiomyocytes were exposed to PTH(1-34) or full-length PTH at picomolar concentrations for 24 h. Cell shortening was measured at 2 Hz as a cellular correlate of inotropic responsiveness. Intracellular calcium was measured in Fura-AM-loaded cells. PTH(1-3) (20-200 pM) and full-length PTH (200 pM) increased cell shortening within 24 h. PTH had no effect on cell size, but resting and peak systolic calcium concentrations were elevated. The beneficial effect of PTH was mediated via its cAMP/protein kinase A-activating domain and attenuated by addition of a protein kinase A inhibitor. In contrast, PTH peptides representing a protein kinase C-activating domain but not a cAMP/protein kinase A-activating domain or peptides that represent none of these domains had no effect on cell shortening. The effect of PTH on cell shortening was strong at low concentrations of extracellular calcium but declined at higher calcium concentrations. PTH downregulated the expression of the calcium sensing receptor, a receptor known to antagonize the action of PTH on calcium transport. Furthermore, PTH antagonized the angiotensin II-induced loss of cell function. Low concentrations of PTH improve cell shortening by increasing calcium load at rest. By this mechanism cardiomyocytes compensate reduced extracellular calcium levels as they occur in patients with heart failure.

Essential role of diastolic oscillatory potentials in adrenergic control of guinea pig sino-atrial node discharge

BackgroundThe diastolic oscillatory after-potential Vos and pre-potential ThVos play an essential role in the pacemaker mechanism of sino-atrial node (SAN). The aim of this study was to investigate whether these oscillatory potentials are also involved in adrenergic control of SAN discharge.MethodsVos and ThVos were visualized by superfusing guinea pig SAN in high [K+]o. The actions of adrenergic agonists on oscillatory potentials were studied by means of a microelectrode technique. Statistical significance was determined by means of Student's paired t-test.ResultsIn non-spontaneous SAN, norepinephrine (NE) decreased the resting potential into a voltage range ("oscillatory zone") where increasingly larger ThVos appeared and initiated spontaneous discharge. In slowly discharging SAN, NE gradually increased the rate by increasing the amplitude and slope of earlier-occurring ThVos and of Vos until these oscillations fused with initial diastolic depolarization (DD1). In the presence of NE, sudden fast rhythms were initiated by large Vos that entered a more negative oscillatory zone and initiated a large ThVos. Recovery from NE exposure involved the converse changes. The β-adrenergic agonist isoproterenol had similar actions. Increasing calcium load by decreasing high [K+]o, by fast drive or by recovery in Tyrode solution led to growth of Vos and ThVos which abruptly fused when a fast sudden rhythm was induced. Low [Ca2+]o antagonized the adrenergic actions. Cesium (a blocker of If) induced spontaneous discharge in quiescent SAN through ThVos. In spontaneous SAN, Cs+increased Vos and ThVos, thereby increasing the rate. Cs+ did not hinder the positive chronotropic action of NE. Barium increased the rate, as Cs+ did.ConclusionAdrenergic agonists: (i) initiate SAN discharge by decreasing the resting potential and inducing ThVos; (ii) gradually accelerate SAN rate by predominantly increasing size and slope of earlier and more negative ThVos; (iii) can induce sudden fast rhythms through the abrupt fusion of large Vos with large ThVos; (iv) increase Vos and ThVosby increasing cellular calcium; and (v) do not modify the oscillatory potentials by means of the hyperpolarization-activated current If. The results provide evidence for novel mechanisms by which the SAN dominant pacemaker activity is initiated and enhanced by adrenergic agonists.

Calcium load during administration of calcium carbonate or sevelamer in individuals with normal renal function

Under steady-state conditions urinary calcium (Ca) excretion corresponds to the Ca load in healthy subjects. However, in chronic haemodialysis patients reliable data on Ca load are not available. In these patients Ca-containing phosphate binders are suspected to play a role in the progression of arteriosclerosis via increased but not quantified Ca load. The present study evaluated the effect of calcium carbonate (CC) and sevelamer hydrochloride (SEV), a calcium-free phosphate binder, on serum Ca and urinary Ca excretion in healthy individuals. Twelve healthy male individuals were included in a monocentre, randomized, single-blind, placebo-controlled, three-way crossover phase I study. Concurrently with their meals, participants received 4 x 2 tablets of SEV (800 mg), CC (500 mg) or placebo for 6 days with 1-week washout between the treatment periods. During the study, weekly blood samples were taken and 24-h urine was collected each day for measurement of calcium, magnesium, phosphorus, chloride and iPTH. Mean daily urinary phosphorus excretion was significantly lower in subjects undergoing SEV treatment compared to those taking placebo (P < 0.001). Mean daily total urinary excretion of calcium was significantly higher in CC-treated participants compared to those receiving placebo (P < 0.001). Mean 24-h calcium excretion during the 6 treatment days was 6.60 +/- 2.62 mmol [265 +/- 105 mg] (CC) versus 5.15 +/- 2.16 mmol [206 +/- 87 mg] (SEV) versus 4.95 +/- 1.63 mmol [198 +/- 65 mg] (Placebo). Taking into account nutritional calcium intake estimated from dietary records fractional calcium absorption was 8.7% (CC), 13.3% (placebo) and 14.8% (sevelamer). Intake of calcium carbonate compared to placebo in contrast to sevelamer in healthy individuals was associated with increased total urinary calcium excretion indicating an increased calcium load due to increased intestinal calcium absorption.

Effect of Chronic Stress and Mifepristone Treatment on Voltage‐Dependent Ca2+ Currents in Rat Hippocampal Dentate Gyrus

Chronic unpredictable stress affects many properties in rat brain. In the dentate gyrus, among other things, increased mRNA expression of the Ca2+ channel alpha1C subunit has been found after 21 days of unpredictable stress in combination with acute corticosterone application (100 nM). In the present study, we examined: (i) whether these changes in expression are accompanied by altered Ca2+ currents in rat dentate granule cells recorded on day 22 and (ii) whether treatment with the glucocorticoid receptor antagonist mifepristone during the last 4 days of the stress protocol normalises the putative stress-induced effects. Three weeks of unpredictable stress did not affect Ca2+ current amplitude in dentate granule cells under basal conditions (i.e. after incubation with vehicle solution). However, the sustained Ca2+ current component (which largely depends on the alpha1C subunit) was significantly increased in amplitude after chronic stress when slices had been treated with corticosterone 1-4 h before recording. These findings suggest that dentate granule cells are exposed to an increased calcium load after exposure to an acute stressor when they have a history of chronic stress, potentially leading to increased vulnerability of the cells. The present results are in line with the molecular data on Ca2+ channel alpha1C subunit expression. A significant three-way interaction between chronic stress, corticosterone application and mifepristone treatment was found, indicating that the combined effect of stress and corticosterone depends on mifepristone cotreatment. Interestingly, current density (defined as total current divided by capacitance) did not differ between the groups. This indicates that the observed changes in Ca2+ current amplitude could be attributable to changes in cell size.

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Vascular calcifications as a footprint of increased calcium load and chronic inflammation in uremic patients: a need for a neutral calcium balance during hemodialysis?

Cardiovascular complications caused by an accelerated atherosclerotic disease represent the largest single cause of mortality in chronic renal failure patients. The rapidly developing atherosclerosis of the uremic syndrome appears to be caused by a synergism of different mechanisms, such as malnutrition, oxidative stress and genetic factors. Recent studies provide evidence that chronic inflammation plays an important role in the pathogenesis of cardiovascular diseases. Hyperphosphatemia and an increased calcium-phosphate ion product have also been associated with an increased risk of death. Cardiovascular calcifications secondary to increases in phosphate and calcium load in dialysis patients might exert an important contribution to the excess cardiovascular mortality and morbidity in dialysis patients. Elevated serum levels of plasma C-reactive protein (CRP) are associated with the extent and severity of the atherosclerotic processes as well as with an increased risk of experiencing myocardial infarction and sudden cardiac death in apparently healthy subjects. In patients affected by pre-dialytic renal failure increased levels of CRP and IL-6 were recorded in 25% of our population; CRP and IL-6 were inversely related with renal function. These data suggest the activation--even in the predialytic phase of renal failure--of mechanisms known to contribute to the enhanced cardiovascular morbidity and mortality of the uremic syndrome. In recent years we have investigated the hypothesis that the chronic inflammatory state of the uremic patient could be at least in part due to the dialytic technique. We have shown that the increase of CRP in stable dialysis patients may be due to the stimulation of monocyte/macrophage by backfiltration of dialysate contaminants. During conventional dialysis, a positive calcium balance and a concomitant inflammatory state may act as cofactors in the development of cardiovascular calcifications. We suggest that this hypothesis should be verified by clinical studies. A reevaluation of the ideal calcium levels in the dialysate is warranted: a neutral intradialytic calcium balance is probably more appropriate, although not easily attainable.

Calcium: the Darth Vader of ALS

Motor neuron dysfunction and loss in amyotrophic lateral sclerosis (ALS) have been attributed to several different mechanisms, including increased intracellular calcium, glutamate excitotoxicity, oxidative stress and free radical damage, mitochondrial dysfunction, and neurofilament aggregation and dysfunction of transport mechanisms. These alterations are not mutually exclusive, and increased calcium could be a common denominator. Furthermore, the selective vulnerability of spinal motor neurons and the relative sparing of eye motor neurons represent striking features of both sporadic and familial ALS. Here we review the evidence that calcium homeostasis is altered in ALS, and that low levels of the calcium binding proteins parvalbumin and calbindin-D28K contribute to selective vulnerability by decreasing the ability of motor neurons to handle an increased calcium load, with cell injury and death as the consequence.

Impact of target lesion calcification on coronary stent expansion after rotational atherectomy

Background Calcified lesions carry the risk of suboptimal stent expansion. The purpose of this study was to investigate the impact of target lesion calcification on intracoronary ultrasound (ICUS) guided stent expansion after rotational atherectomy. Methods Stent expansion was assessed by ICUS in 39 patients with the aid of the proximal stent/proximal reference lumen, the minimal stent/mean reference lumen, and the minimal stent/minor reference lumen ratios as well as the symmetry index. Thirty-nine stent implantations in uncalcified lesions served for comparison. Results Relative stent expansion ranged between 76.3% ± 6.7% and 98.4% ± 16.4%. Categorization according to an ICUS-derived arc of superficial lesion calcium of <180 degrees (average 102 ± 74 degrees) or >180 degrees (average 248 ± 71 degrees) revealed decreased stent symmetry in calcified lesions >180 degrees compared with the control group ( P < .05). Despite a trend toward less expansion with increasing calcium load, no significant differences of the lumen area ratios between the study groups was present. Conclusion Rotational atherectomy before ICUS-guided stent implantation enables adequate stent expansion even in significant superficial target lesion calcification. (Am Heart J 1999;137:93-9.)

3-Nitropropionic acid exacerbates N-methyl- d-aspartate toxicity in striatal culture by multiple mechanisms

We examined the effects of 3-nitropropionic acid-induced succinate dehydrogenase inhibition on neuronal ATP content, N-methyl- d-aspartate-induced neuronal death, resting membrane potential, and N-methyl- d-aspartate-induced changes in cytosolic calcium concentration ([Ca 2+] c) in cultured rat striatal neurons. Exposure of cultures to 3 mM 3-nitropropionic acid for 3 h did not cause overt toxicity, but reduced ATP content by 35%. Treatment with 3-nitropropionic, or removal of Mg 2+ from the medium, enhanced subsequent N-methyl- d-aspartate toxicity, reducing the LC 50 from 250 μM to 12 μM or 30 μM, respectively. Even after Mg 2+ removal, enhancement of N-methyl- d-aspartate toxicity by 3-nitropropionic acid remained pronounced, with the LC 50 further decreasing to 3 μM. The mean resting membrane potential of neurons treated with 3-nitropropionic acid was −37 mV, while that in control neurons was −61 mV. Treatment with 3-nitropropionic did not affect baseline [Ca 2+] c as determined by fura-2 microfluorimetry. N-methyl- d-aspartate (30 μM) caused a rapid rise in [Ca 2+] c, the initial magnitude of which was not affected by 3-nitropropionic acid. However, after a 1-h treatment, [Ca 2+] c was dramatically higher in 3-nitropropionic acid-treated neurons. This increased calcium load was washed out slowly and only partially, although calcium in control neurons washed out rapidly and almost completely. These results suggest that in striatal neurons, the enhancement of N-methyl- d-aspartate toxicity caused by succinate dehydrogenase inhibition may be due to synergism between partial relief of the Mg 2+ blockade of the N-methyl- d-aspartate receptor and other mechanisms, including disruption of neuronal calcium regulation. This synergism may be relevant to the neuronal death observed in neurodegenerative disorders.

Increased propensity of the aged myocardium to develop calcium-related electrophysiological alterations

The electrico-mechanical effects of calcium overload have been studied in cardiac papillary muscles of young adult and senescent Wistar rats driven at different rates. Action potential duration and contraction duration were found to be more prolonged in senescent than in younger animals during control conditions. Oscillatory afterpotentials and aftercontractions were more frequent in senescent than in younger rats during high calcium perfusion. Triggered activity was induced in senescent fibers but not in younger ones. Resting tension increased more in senescent fibers whereas the peak tension was not different in the two groups. It is concluded that aging is associated with a reduced capacity of the cardiac cells to handle an increased calcium load.