UMLS:C0020437 - FACTA Search

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Query: UMLS:C0020437 (hypercalcemia)
10,293 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The myopathy associated with vitamin D deficiency has not been well characterized, and it is not known if weakness is a result of a specific effect of vitamin D deficiency on skeletal muscle. Chicks were raised from hatching on a vitamin D-deficient diet, and by 3 wk of age were hypocalcemic and appeared weak. Tension generated by triceps surae during repetitive stimulation of posterior tibial nerve was significantly less than that developed by chicks given vitamin D(3) supplements (309 g tension/g wet weight of triceps surae, SD 60, for vitamin D-deficient chicks; 470, SD 77, for vitamin D(3)-treated chicks, P < 0.01). Histochemical and electron microscopic examination of skeletal muscles of these chicks showed no abnormalities, and there were no electrophysiologic evidences of motor nerve or neuromuscular junction dysfunction. The concentration of ATP in skeletal muscle of the vitamin D-deficient chicks (5.75 mumol/g wet weight, SD 0.17) was not significantly different from that in vitamin D-treated chicks (5.60, SD 0.50). There was no correlation between strength and serum calcium, serum inorganic phosphate, or skeletal muscle inorganic phosphate. Relaxation of tension after tetanic stimulation was slowed in the vitamin D-deficient chicks (20.6 ms, SD 1.7, vs. 15.4, SD 1.3, in vitamin D-treated chicks and 15.3, SD 1.0, in normal control chicks), and in vitro (45)Ca(++) transport by sarcoplasmic reticulum from the vitamin D-deficient chicks was reduced. Calcium content of mitochondria prepared from leg muscles of vitamin D-deficient chicks (24 nmol/mg mitochondrial protein, SD 6) was considerably lower than that of mitochondria from normal control chicks (45, SD 8) or from chicks treated with vitamin D for 2 wk or more (66-100, depending upon level and duration of therapy). Treatment of the vitamin D-deficient chicks from hatching with sufficient dietary calcium to produce hypercalcemia did not significantly raise skeletal muscle mitochondrial calcium content (31 nmol/mg mitochondrial protein, SD 7) and did not prevent weakness. These studies demonstrate objective weakness as a result of myopathy in vitamin D-deficient chicks, and provide evidence that vitamin D deficiency has effects on skeletal muscle calcium metabolism not secondary to altered plasma concentrations of calcium and phosphate.
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PMID:Skeletal muscle calcium metabolism and contractile force in vitamin D-deficient chicks. 22 25

In the lymphocytes infected in vitro with BLV (bovine leukemia virus) the contents of Ca2+ and Mg2+ were determined using roentgen microanalyser JXA-5 A Joel-form (Japan). In the smears prepared from these cells the activity of enzyme markers of cell membranes i.e. alkaline phosphatase (AP - EC 3.1.3.1), 5'-nucleotidase (5'-NT - EC 3.1.3.5) and adenosine-triphosphatases - Ca2+ and Mg2+ dependent (ATP-ase - EC 3.6.1.3) was determined. The decrease in AP and ATP-assess activity and increase in 5'-NT in the membranes of leukemic lymphocytes were observed. During these changes the increase in Ca2+ and decrease in Mg2+ ions occurred. These processes lead to clear disturbances in the metabolism of cells transformed by the neoplasm. The effect of this phenomenon is probably the opening of calcium canals with the following cytoplasmatic hypercalcemia. It's very destructive for the change in permeability of the membrane of lymphocytes.
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PMID:[The content of Ca2+ and Mg2+ ions and membrane enzyme activity (AP, 5'-NT, ATPases) in the lymphocytes infected in vitro with bovine leukemia virus]. 166 9

A possible involvement of cyclic nucleotides (cAMP and cGMP) in the regulation of cardiac contractility and glycolysis during hypoxia was examined in spontaneously beating rat atria. A reduction of the high oxygen saturation (HiOxSa) of the incubation medium from 95-100% to half produced a rapid decline of the amplitude. The deterioration of 50% was seen after 30 sec. of hypoxia. The decline was partly antagonized by noradrenaline (NA, 1 X 10(-6) M) or hypercalcaemia (5.7 X 10(-3) M instead of 1.9 X 10(-3) M). The cAMP level remained unchanged during the first 12 min. of hypoxia, but the cGMP content increased gradually and reached a significantly increased level in 4-8 min. Paradoxically, the production of lactate decreased, after 30 sec. of hypoxia, but accelerated then 2-4 min. after the onset of hypoxia. The depletion of creatine phosphate and ATP stores was initiated after 2 min. of hypoxia. The arterial content of the active forms of phosphofructokinase and lactate dehydrogenase gradually rose during hypoxia. Sodium nitroprusside (SNP, 1 X 10(-4) M) and NA produced increases in cGMP and cAMP levels, respectively, both in HiOxSa and hypoxia. SNP induced a slight and NA a marked increase in the amplitude in HiOxSa. Verapamil (1 X 10(-6) M) decreased the contractility, but did not affect the levels of cAMP and cGMP. Both SNP and verapamil decreased the lactate production, but they could not resist the NA-induced increase in the atrial lactate level. Hypercalcaemia increased the amplitude but slightly reduced the lactate production in HiOxSa. 45Ca-uptake was reduced to about 35 per cent of control as measured between 5 and 10 min. of hypoxia. It is concluded that the lack of oxygen could have direct and parallel effects on the sarcolemma and on the mitochondria. The former could result in the deterioration of contractility and the latter in the termination of aerobic energy production. Cyclic nucleotides are not involved in either of these phenomena. However, at the low rate of anaerobic glycolysis, e.g. in HiOxSa or at the very early stage of hypoxia, cGMP could inhibit and cAMP accelerate the lactate production.
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PMID:On the role of cyclic nucleotides in the regulation of cardiac contractility and glycolysis during hypoxia. 627 32

It has been suggested that cyclic nucleotides (cAMP and cGMP) participate in the regulation of cardiac contractility and glycolysis. In the present study, this possible involvement was examined in spontaneously beating rat atria during hypoxia (50% oxygen saturation). Thirty seconds after reduction of high oxygen saturation (HiOxSa) in the incubation medium, the contraction amplitude declined to 50% of the initial level. The decline was partly antagonized by norepinephrine (NE) or hypercalcemia. The cAMP level remained unchanged during hypoxia, but the cGMP content gradually increased. Paradoxically, the production of lactate decreased after 30 sec of hypoxia but had increased by 2 min, when depletion of creatine phosphate and ATP stores was also initiated. Sodium nitroprusside (nitroprusside) and NE elevated the cGMP and cAMP, respectively, in both HiOxSa and hypoxia. Nitroprusside and NE also showed a positive inotropic effect in HiOxSa. Verapamil decreased contractility without changing the levels of cAMP or cGMP. In HiOxSa, both nitroprusside and verapamil decreased lactate production but were not able to resist the increase in atrial lactate level brought about by NE. In hypercalcemia the amplitude increased, but lactate production was slightly reduced in HiOxSa. Between 5 and 10 min of hypoxia, 45Ca uptake was reduced to about one-third of that in the control. It is suggested that lack of oxygen has direct and parallel effects on the sarcolemma and the mitochondria. The former induces deterioration of contractility, the latter termination of aerobic energy production. Cyclic nucleotides are not involved in either of these phenomena. However, at a low rate of anaerobic glycolysis, e.g., in HiOxSa or at the very early stage of hypoxia, cGMP could inhibit and cAMP accelerate lactate production.
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PMID:Regulation of cardiac contractility and glycolysis by cyclic nucleotides during hypoxia. 685 62

Parathyroid hormone-related protein (PTHrP) was discovered as a hypercalcemia-inducing product of malignant cells and has since been demonstrated to be a product of many tissues. Although it is robustly expressed in fetal lung, PTHrP expression has not been assigned to alveolar epithelial cells in adult lung. We have shown that PTHrP is expressed in the adult rat lung and by cultured rat alveolar type II epithelial cells with sensitive and specific immunoassays and immunohistochemical techniques. Immunoassay of cell extracts demonstrated that freshly isolated type II cells contained PTHrP (136 pg/10(7) cells), whereas freshly isolated alveolar macrophages and cultured macrophages did not express PTHrP. Cultured type II cells secreted PTHrP into medium, 202 +/- 11 fg PTHrP/micrograms cell protein in 24 h. Basal secretion remained stable up to 7 days in culture. Treatment with phorbol myristate acetate or 1-oleoyl-2-acetyl-sn-glycerol produced a dose-related, 2- to 4-fold increase in PTHrP secretion. However, forskolin, ionomycin, ATP, phenylephrine, capsaicin, and bradykinin had no effect. Thus, PTHrP secretion appeared to be regulated by a protein kinase C-dependent pathway. PTHrP could also be demonstrated in pulmonary lavage fluid. Although the function of PTHrP in the adult lung is unknown, it could involve control of cell growth and differentiation or control of surfactant lipid secretion. Further studies are necessary to elucidate the function of PTHrP in the lung.
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PMID:Alveolar epithelial cells express and secrete parathyroid hormone-related protein. 794 99

Williams syndrome (WS) is a multisystem developmental disorder caused by the deletion of contiguous genes at 7q11.23. Hemizygosity of the elastin (ELN) gene can account for the vascular and connective tissue abnormalities observed in WS patients, but the genes that contribute to features such as infantile hypercalcemia, dysmorphic facies, and mental retardation remain to be identified. In addition, the size of the genomic interval commonly deleted in WS patients has not been established. In this study we report the characterization of a 500-kb region that was determined to be deleted in our collection of WS patients. A detailed physical map consisting of cosmid, P1 artificial chromosomes, and yeast artificial chromosomes was constructed and used for gene isolation experiments. Using the techniques of direct cDNA selection and genomic DNA sequencing, three known genes (ELN, LIMK1, and RFC2), a novel gene (WSCR1) with homology to RNA-binding proteins, a gene with homology to restin, and four other putative transcription units were identified. LIMK1 is a protein kinase with two repeats of the LIM/double zinc finger motif, and it is highly expressed in brain. RFC2 is the 40-kDa ATP-binding subunit of replication factor C, which is known to play a role in the elongation of DNA catalyzed by DNA polymerase delta and epsilon. LIMK1 and WSCR1 may be particularly relevant when explaining cognitive defects observed in WS patients.
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PMID:Identification of genes from a 500-kb region at 7q11.23 that is commonly deleted in Williams syndrome patients. 881 60

Parathyroid hormone-related protein (PTHrP) is an important causal factor of hypercalcemia associated with malignancy. PTHrP also modulates cell growth and differentiation of normal cells through mechanisms that include binding to cell surface-specific receptors as well as by possible intracellular routes. To understand the regulation of intracellular PTHrP expression, post-translational processing of PTHrP was investigated. Using cell-free translations it was shown that PTHrP can be ligated efficiently to multiple ubiquitin moieties. Both conjugation to ubiquitin and degradation of prepro-PTHrP synthesized in vitro were ATP-dependent. Translation in vitro in the presence of the proteasome inhibitor MG-132 abolished the degradation of PTHrP. Treatment of cells, cotransfected with hemagglutinin-tagged ubiquitin and histidine-tagged prepro-PTHrP, with MG-132, led to the accumulation of ubiquitinated prepro-PTHrP. Deletion mutagenesis experiments indicated that both the prepro secretory domain and a PEST (amino acid residues Pro (P), Glu (E), and/or Asp (D), Ser (S), and Thr (T)) motif in the COOH-terminal region of the protein were not required as cis-acting determinants for ubiquitination. This is the first report of a wild-type secretory polypeptide serving as a substrate of the ubiquitin proteolytic pathway. These results suggest that the ubiquitin-dependent proteolytic pathway is involved in regulating the metabolic stability of intracellular PTHrP, and this regulation may be an important mechanism for modulating its effects on cell growth and differentiation.
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PMID:Preproparathyroid hormone-related protein, a secreted peptide, is a substrate for the ubiquitin proteolytic system. 904 3

The response of adult T-cell leukemia (ATL) to chemotherapy is poor, and a major obstacle to successful treatment is intrinsic or acquired drug resistance. To determine the clinical significance of multidrug resistance protein (MRP) 1 in ATL, we studied MRP1 expression and its association with clinical outcome. The expression of MRP1 mRNA in leukemia cells from 48 ATL patients was studied by slot blot analysis. The expression level of MRP1 mRNA in chronic-type ATL was significantly higher than that in lymphoma-type ATL (P = 0.033). There was no correlation between MRP1 expression and age, gender, WBC count, LDH, hypercalcemia, blood urea nitrogen, or performance status. However, the expression of MRP1 mRNA correlated only with peripheral blood abnormal lymphocyte counts (P = 0.008). The transporting activity of MRP1 was assessed using membrane vesicles. Membrane vesicles prepared from ATL cells with high expression of MRP1 mRNA showed a higher ATP-dependent leukotriene C(4) uptake than did those with low expression of MRP1 mRNA. This uptake was almost completely inhibited by LTD(4) antagonists ONO-1078 and MK571. In acute- and lymphoma-type ATL, high expression of MRP1 mRNA at diagnosis correlated with shorter survival, and Cox regression analysis revealed that MRP1 expression was an independent prognostic factor. These findings suggest that functionally active MRP1 is expressed in some ATL cells and that it is involved in drug resistance and has a possible causal relationship with poor prognosis in ATL. Multidrug resistance-reversing agents, such as ONO-1078 and MK571, that directly interact and inhibit the transporting activity of MRP1 may be useful for treating ATL patients.
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PMID:Prognostic significance of multidrug resistance protein in adult T-cell leukemia. 1159 4

The skeleton is the most common site of metastatic disease in breast cancer and the most common site of first distant relapse. Bone metastases in breast cancer are the source of considerable morbidity, including severe pain, pathological fractures, need for radiotherapy or surgery, and hypercalcemia. Bisphosphonates are potent inhibitors of osteoclast-mediated bone resorption, and it is well known that breast cancer cells in bone can stimulate osteoclast formation and activity leading to the release of growth factors and cytokines, which will further stimulate cancer cell growth and their secretion of osteolytic factors. We are thus typically dealing with a vicious cycle, as the bone resorption-induced release of growth factors from the bone matrix will stimulate breast cancer cell growth (probably mainly by IGFs) and the production of the osteolytic factor PTHrP (probably mainly by TGF-beta but also by extracellular calcium). Clodronate, but not the aminobisphosphonates, can be metabolized to an ATP analog that is toxic for osteoclasts. Nitrogen-containing bisphosphonates, such as pamidronate, ibandronate, and zoledronate, interfere with the mevalonate pathway that is crucial to maintain cell membrane integrity. The net result, regardless of the mechanism, is osteoclast apoptosis, notably through the induction of caspase-3. Bisphosphonates are now the standard treatment for cancer hypercalcemia. Repeated bisphosphonate infusions also exert clinically relevant analgesic effects in at least one half of the patients with metastatic bone pain. Most importantly, prolonged administration of bisphosphonates (for at least 1 year) reduces the frequency of morbid skeletal events by 30-40% in breast cancer metastatic to bone and in up to 50% in patients with multiple myeloma. Newer bisphosphonates, such as ibandronate and zoledronate, will simplify the current therapeutic schemes and improve the cost-effectiveness ratio, and they have the potential to improve the therapeutic efficacy, at least in patients with aggressive osteolytic disease or in the adjuvant setting.
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PMID:Bisphosphonates in the treatment of metastatic breast cancer. 1201 36

Soft tissue tumors arising in association with genetic or malformation syndromes have been increasingly reported. Malignant rhabdoid tumor (MRT) is a highly aggressive neoplasm of infancy and young childhood, characterized by typical morphology and biallelic inactivation of the SMARCB1 (INI1/hSNF5/BAF47) gene on chromosome 22q.2 which encodes a subunit of the SWI/SNF ATP-dependent chromatin remodeling complex. Congenital infantile disseminated MRT represents a unique clinicopathologic presentation of this tumor. We report a case occurring in a female neonate who presented at birth a voluminous left thigh mass. Surgical biopsy performed at day 9 showed morphology and immunoprofile of MRT. Staging evaluation identified hypercalcemia and distant nodules. The mass showed rapid growth. Despite chemotherapy, the tumor progressed with exteriorization through the biopsy scar. Chemotherapy was discontinued and treatment limited to palliative care and the child died on day 51. The tumor was homozygous for the SMARCB1 deletion with apparent de novo heterozygous germ line deletion in the infant, not identified in the parents.
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PMID:Congenital Disseminated Extrarenal Malignant Rhabdoid Tumor. 2575 58

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