[Changes to calcium-phosphate metabolism associated with chronic nephropathies]. / Zmeny kalcium-fosfátového metabolizmu pri chronických nefropatiích.

The paper discusses bone mineral and bone disorders associated with chronic nephropathies that are a logical consequence of reduced renal function. These are principally driven by changes in parathormone production and vitamin D synthesis. Bones are usually affected by renal osteopathy - osteodystrophy with abnormities of bone turnover, mineralization and volume, and with growth retardation in children. Extra-skeletal calcifications may occur, of which vascular wall localization is the most serious. A collection of pathologies develops, now termed chronic kidney disease - mineral and bone disorder (CKD-MBD).

[Current and future options for treatment of osteoporosis]. / Aktuální a budoucí moznosti lécby osteoporózy.

The author describes actual and perspective treatment ofosteoporosis. Basic treatment consists in calcium, vitamin D, physical activity, restriction of risk factors and prevention of falls. Actual treatment includes antiresorptive drugs (calcitonin, bisphosphonates, estrogens and SERM) and denosumab. Perspective emerging drugs are also mentioned.

Regulation of group II metabotropic glutamate receptors by G protein-coupled receptor kinases: mGlu2 receptors are resistant to homologous desensitization.

We examined the regulation of mGlu2 and mGlu3 metabotropic glutamate receptor signaling prompted by the emerging role of these receptor subtypes as therapeutic targets for psychiatric disorders, such as anxiety and schizophrenia. In transfected human embryonic kidney 293 cells, G-protein-coupled receptor kinase (GRK) 2 and GRK3 fully desensitized the agonist-dependent inhibition of cAMP formation mediated by mGlu3 receptors. In contrast, GRK2 or other GRKs did not desensitize the cAMP response to mGlu2 receptor activation. Desensitization of mGlu3 receptors by GRK2 required an intact kinase activity, as shown by the use of the kinase-dead mutant GRK2-K220R or the recombinant GRK2 C-terminal domain. Overexpression of beta-arrestin1 also desensitized mGlu3 receptors and did not affect the cAMP signaling mediated by mGlu2 receptors. The difference in the regulation of mGlu2 and mGlu3 receptors was signal-dependent because GRK2 desensitized the activation of the mitogen-activated protein kinase pathway mediated by both mGlu2 and mGlu3 receptors. In vivo studies confirmed the resistance of mGlu2 receptor-mediated cAMP signaling to homologous desensitization. Wild-type, mGlu2(-/-), or mGlu3(-/-) mice were treated intraperitoneally with saline or the mixed mGlu2/3 receptor agonist (-)-2-oxa-4-aminobicyclo[3.1.0]-exhane-4,6-dicarboxylic acid (LY379268; 1 mg/kg) once daily for 7 days. Inhibition of forskolin-stimulated cAMP formation by LY379268 was measured in cortical slices prepared 24 h after the last injection. Agonist pretreatment fully desensitized the cAMP response in wild-type and mGlu2(-/-) mice but had no effect in mGlu3(-/-) mice, in which LY379268 could only activate the mGlu2 receptor. We predict the lack of tolerance when mixed mGlu2/3 receptor agonists or selective mGlu2 enhancers are used continually in patients.

[Coffee, its legend, history, and influence on human health]. / Káva, její legenda, historie a vliv na lidské zdraví.

In the introductory part of this article the history/legend of coffee as well as its spread to different parts of the world including Europe is discussed. Data sofar available in literature do not give any convincing evidence regarding clear relationship between coffee and the etiopathogenesis of several diseases including diabetes mellitus type 2, cardiovascular diseases, gout, osteoporosis, neurologic disorders and colorectal cancer. Favorable (protective) effects of coffee consumption against hepatocellular cancer have been repeatedly described. The autors discuss on todate findings about relationship between blood cholesterol and uric acid in literature and remind their own experience with different population groups in Harar, Ethiopia, where consumption of coffee is habitual in daily life of the inhabitants.

Endocrine disruptors of the bisphenol and paraben families and bone metabolism.

After menopause, when estrogen levels decrease, there is room for the activity of anthropogenic substances with estrogenic properties - endocrine disruptors (EDs) - that can interfere with bone remodeling and changes in calcium-phosphate metabolism. Selected unconjugated EDs of the bisphenol group - BPA, BPS, BPF, BPAF, and the paraben family - methyl-, ethyl-, propyl-, butyl-, and benzyl-parabens - were measured by high performance liquid chromatography-tandem mass spectrometry in the plasma of 24 postmenopausal women. Parameters of calcium-phosphate metabolism and bone mineral density were assessed. Osteoporosis was classified in 14 women, and 10 women were put into the control group. The impact of EDs on calcium-phosphate metabolism was evaluated by multiple linear regressions. In women with osteoporosis, concentrations of BPA ranged from the lower limit of quantification (LLOQ) - 104 pg/ml and methyl paraben (MP) from LLOQ - 1120 pg/ml. The alternative bisphenols BPS, BPF and BPAF were all under the LLOQ. Except for MP, no further parabens were detected in the majority of samples. The multiple linear regression model found a positive association of BPA (beta=0.07, p<0.05) on calcium (Ca) concentrations. Furthermore, MP (beta=-0.232, p<0.05) was negatively associated with C-terminal telopeptide. These preliminary results suggest that these EDs may have effects on calcium-phosphate metabolism.

New molecules modulating bone metabolism - new perspectives in the treatment of osteoporosis.

In this review the authors outline traditional antiresorptive pharmaceuticals, such as bisphosphonates, monoclonal antibodies against RANKL, SERMs, as well as a drug with an anabolic effect on the skeleton, parathormone. However, there is also a focus on non-traditional strategies used in therapy for osteolytic diseases. The newest antiosteoporotic pharmaceuticals increase osteoblast differentiation via BMP signaling (harmine), or stimulate osteogenic differentiation of mesenchymal stem cells through Wnt/beta-catenin (icarrin, isoflavonoid caviunin, or sulfasalazine). A certain promise in the treatment of osteoporosis is shown by molecules targeting non-coding microRNAs (which are critical for osteoclastogenesis) or those stimulating osteoblast activity via epigenetic mechanisms. Vitamin D metabolites have specific antiosteoporotic potencies, modulating the skeleton not only via mineralization, but markedly also through the direct effects on the bone microstructure.

Trace elements have beneficial, as well as detrimental effects on bone homeostasis.

The protective role of nutrition factors such as calcium, vitamin D and vitamin K for the integrity of the skeleton is well understood. In addition, integrity of the skeleton is positively influenced by certain trace elements (e.g. zinc, copper, manganese, magnesium, iron, selenium, boron and fluoride) and negatively by others (lead, cadmium, cobalt). Deficiency or excess of these elements influence bone mass and bone quality in adulthood as well as in childhood and adolescence. However, some protective elements may become toxic under certain conditions, depending on dosage (serum concentration), duration of treatment and interactions among individual elements. We review the beneficial and toxic effects of key elements on bone homeostasis.

A developmental change in NMDA receptor-associated proteins at hippocampal synapses.

The membrane-associated guanylate kinases [Chapsyn-110/postsynaptic density-93 (PSD-93), synapse-associated protein-90 (SAP-90)/PSD-95, and SAP-102] are believed to cluster and anchor NMDA receptors at the synapse and to play a role in signal transduction. We have investigated the developmental changes in expression of these proteins in rat hippocampus using biochemical analyses and quantitative immunogold electron microscopy. At postnatal day 2 (P2), SAP-102 was highly expressed, whereas PSD-93 and PSD-95 were low. SAP-102 expression increased during the first week, stayed stable through P35, and showed a reduced expression at 6 months. From P2 through 6 months, PSD-93 and PSD-95 increased. For PSD-95, the percent of labeled synapses increased almost threefold with age, whereas the number of gold particles per labeled synapse did not change significantly, suggesting that the increase in PSD-95 is attributable primarily to an increase in the number of synapses containing PSD-95. In contrast, for SAP-102, both percent labeled synapses and the number of gold particles per labeled synapse decreased during this time. From Western blots of hippocampus and immunogold analysis of CA1 synapses, the high expression of NR2B at P2 coincides with the high level of SAP-102 at synapses, whereas the later expression of NR2A coincides with that of PSD-93 and PSD-95. To determine whether the changes in PSD-93/95 and SAP-102 reflect preferred associations with NR2A and NR2B, respectively, we measured co-immunoprecipitation in the adult hippocampus. These studies suggest that there is a preference for complexes of NR2A/PSD-93/95 and NR2B/SAP-102. These results indicate that individual receptor-associated proteins may have specific functions that are critical to synapse development.

C-terminal interaction is essential for surface trafficking but not for heteromeric assembly of GABA(b) receptors.

Assembly of fully functional GABA(B) receptors requires heteromerization of the GABA(B(1)) and GABA(B(2)) subunits. It is thought that GABA(B(1)) and GABA(B(2)) undergo coiled-coil dimerization in their cytoplasmic C termini and that assembly is necessary to overcome GABA(B(1)) retention in the endoplasmatic reticulum (ER). We investigated the mechanism underlying GABA(B(1)) trafficking to the cell surface. We identified a signal, RSRR, proximal to the coiled-coil domain of GABA(B(1)) that when deleted or mutagenized allows for surface delivery in the absence of GABA(B(2)). A similar motif, RXR, was recently shown to function as an ER retention/retrieval (ERR/R) signal in K(ATP) channels, demonstrating that G-protein-coupled receptors (GPCRs) and ion channels use common mechanisms to control surface trafficking. A C-terminal fragment of GABA(B(2)) is able to mask the RSRR signal and to direct the GABA(B(1)) monomer to the cell surface, where it is functionally inert. This indicates that in the heteromer, GABA(B(2)) participates in coupling to the G-protein. Mutagenesis of the C-terminal coiled-coil domains in GABA(B(1)) and GABA(B(2)) supports the possibility that their interaction is involved in shielding the ERR/R signal. However, assembly of heteromeric GABA(B) receptors is possible in the absence of the C-terminal domains, indicating that coiled-coil interaction is not necessary for function. Rather than guaranteeing heterodimerization, as previously assumed, the coiled-coil structure appears to be important for export of the receptor complex from the secretory apparatus.

The heteromeric GABA-B receptor recognizes G-protein alpha subunit C-termini.

The recently cloned GABA-B receptors are related to the metabotropic glutamate receptors (mGlu receptors), the Ca2+-sensing receptor and one group of vomeronasal receptors. The GABA-B receptors likely function in a heterodimeric form, constituted of GABA-BR1 and GABA-BR2. This novel feature in the G-protein coupled receptors (GPCRs) structure raises questions as to the mechanism of recognition of G-proteins by such receptors. In the present study we show that the GABA-BR1 and BR2 subunits form a functional receptor that recognizes the extreme C-termini of the G alpha i and G alpha o proteins when expressed in HEK293 cells. Indeed, heteromeric GABA-BR1/BR2 receptors do not activate PLC when co-expressed with G alpha q, but do so when co-expressed with the chimeric G alpha qi5 or G alpha qo5 subunits, the G alpha q subunit in which the 5 C-terminal residues are those of G alpha i or G alpha o, respectively. Interestingly, the heteromeric GABA-B receptor did not activate the chimeric G alpha qz5 subunit that contains the 5 C-terminal residues of G alpha z. Among the three residues that are distinct between G alpha qo5 and G alpha qz5 (at position -5, -4 and -1), the amino acid residue at position -4 of G alpha o proteins is critical for specifying the coupling selectivity with the receptor and residue -5 influences the coupling efficacy. Interestingly, these findings correspond to data obtained with the mGluR2 receptor, a distant relative of GABA-B proteins. This shows that the same molecular determinants of the G-protein alpha-subunits are involved in the specific recognition of both the heteromeric GABA-B receptors and the other GPCRs.

Effects of low calcium and low phosphorus diets on the duodenal absorption of calcium in betamethasone-treated chicks.

The effect of oral administration of betamethasone (25 microgram kg-1 day-1) on the duodenal absorption of calcium has been studied in chicks using the ligated loop technique in vivo. The chicks were fed normal calcium, normal phosphorus (NCaNP), low calcium, normal phosphorus (LCaNP) or normal calcium, low phosphorus (NCaLP) diets. Daily oral administration of betamethasone for 2-3 weeks markedly reduced the absorption of calcium in chicks fed the NCaNP diet, but did not significantly affect the adaptation in absorption when the NCaLP or LCaNP diets were fed for the same period of time. In one group of chicks, betamethasone was administered daily for 10 days before the birds were transferred to the NCaLP or LCaNP diets. Adaptation was again unaffected by betamethasone treatment. Administration of betamethasone caused a marked retardation in growth-rate, hypercalcaemia and an increased percentage of ash in the tibiae.

Comparison of microsurgical suture with fibrin glue connection of the sciatic nerve in rabbits.

The regeneration of the sciatic nerve after microsuture was compared with the connection of transected nerve with a coagulum of autologous blood plasma in 20 rabbits. The epineuroperineural suture was performed in 10 rabbits (group A). The severed nerve was approximated with fibrin glue of autologous blood plasma in 10 rabbits (group B). Their skin sensation margin during a 3-month-period of regeneration was examined, 90 days after surgery the connection was inspected and the nerve conduction velocity was measured across the site of the anastomosis. The microsuture was found to be firm in all 10 animals of group A. On the other hand, in 2 animals of group B, the glue failed to keep the nerve stumps approximated (dehiscence occurred in 20% of the animals). There were no significant differences found on clinical and electrophysiological testing of regenerated nerves of both groups. The method of autologous fibrin glue in the repair of peripheral nerve transection does not provide a sufficiently firm connection. This procedure with the preparation of the centrifuged plasma is a more time-consuming method in comparison with the microsuture. Epineuroperineural microsuture with maximal effort to adapt the corresponding nerve fibres remains the method of choice for peripheral nerve reconstruction.

[The role of aluminum-induced inhibition of the intestinal absorption of calcium in the pathogenesis of aluminum osteopathy]. / Le rôle de l'inhibition de l'absorption intestinale du calcium par l'aluminium dans la pathogénèse de l'ostéopathie aluminique.

The aim of the study was to investigate the effect of aluminium on duodenal calcium absorption, the impairment of which can represent a pathogenic factor in the development of aluminium bone lesions. The authors investigated in the chick the effect of Al(OH)3 administered orally and of AlCl3 administered subcutaneously on the duodenal absorption of 47Ca, on serum concentration of calcium, phosphorous, aluminium and 1,25-dihydroxycholecalciferol and on bone morphology. Oral administration of Al(OH)3 for 8, 15, and 22 days was without any significant change. Subcutaneous administration of Al/Cl/3 for 8 day was associated with a significant increase in serum aluminium and 1,25-dihydroxycholecalciferol levels and with a significant decrease of the duodenal absorption of 47Ca. Decreased intestinal absorption of calcium may play a pathogenic role in the development of aluminium osteopathy. Increased serum 1,25-dihydroxycholecalciferol reflects presumably a compensatory mechanism of the lowered calcium absorption.

[Life style risk factors in the etiopathogenesis of osteoporosis and possibilities of prevention]. / Civilizacní rizikové faktory v etiopatogenezi osteoporózy a moznosti prevence.

The prevalence of osteoporosis and its complications, in particular fractures of the femur, are rising and at present special attention is devoted to osteoporosis from the scientific, health and socio-economic aspect. The authors deal with factors of civilization which are involved in the aetiopathogenesis of osteoporosis and its complications and which can be influenced by preventive provisions. These factors which are part of the modern lifestyle comprise physical load, nutritional influences, the influence of toxic substances and drugs. As to nutritional factors the authors pay attention to an adequate calcium intake. They deal in detail also with aluminium intoxications. Attention is also drawn to the possible pathogenetic importance of stress and the authors contemplate on the inclusion of osteoporosis among diseases of civilization.

[The effect of aluminum on the structure and metabolism of collagen]. / Ovlivnení struktury a metabolismu kolagenu hliníkem.

BACKGROUND: Aluminium is considered to be the etiopathogenetic factor in various pathological conditions. It was demonstrated already previously that metals even under conditions in vivo link with collagen structures and influence the protein metabolism. Therefore the authors investigated the effect of aluminium (Al) on collagen and its metabolism. METHODS AND RESULTS: In the described trial aluminium was used as potassium alum, oxalate alum or aluminium chloride. The effect of aluminium was investigated in rats, chick embryos or fibroblast cultures. Using electron microscopy of collagen from the tail tendons, the development of transverse striation following 15 weeks of i.m. Al administration was revealed. At the same time also an increase of temperature of contraction of this collagen by 1.5 to 3.7 degrees C occurred, depending on the Al compound used. On fibroblast cultures an inhibitory effect of Al on their proliferation was found. In chick embryos Al caused a decline of the radioactive hydroxyproline concentration and thus also a reduced collagen synthesis practically in all investigated tissues. Similarly the negative effect of Al was manifested in the incorporation of radioactive glucosamine into proteoglycans of granulation tissue of rats. In cartilaginous collagen enhanced proline hydroxylation caused by Al was observed. CONCLUSIONS: Although it is not possible, with regard to Al chemistry, to make an unequivocal statement on the nature of the compound which causes a particular reaction in biological systems, it may be said, based on the achieved results, that Al has an effect on biological systems due to its bond with collagen structures and by influencing their metabolism.

[Postmenopausal osteoporosis. Treatment with calcitonin and a diet rich in collagen proteins]. / Postmenopauzální osteoporóza. Lécba kalcitoninem pri diete bohaté na kolagenní bílkoviny.

BACKGROUND: Calcitonin has an important role in the treatment of post-menopausal osteoporosis. The authors investigated the effect of calcitonin administration or calcitonin administration supplement with a diet rich in collagen proteins on markers of bone metabolism. METHODS AND RESULTS: A group of 108 patients with postmenopausal osteoporosis (BMD lower than 80% of the BMD in premenopausal women) was treated with Calsynar (Rhoune Poulenc-Rorer), 100 u., i.m. twice a week for 24 weeks. Forty-nine of these women took an oral collagen hydrolysate, 10 g per day, for the same period of time. Before and after termination of treatment clinical and laboratory tests were made, X-ray examination of the LS spine and the right forearm, single-photon osteometry of the right forearm and urinary excretion of pyridinoline (UPD), deoxypyridinoline (UDPD) and hydroxyproline (Uhyp) was assessed. As a result of treatment the BMD values increased only insignificantly (by 1.8%) the UPD values declined (to 62.51%) and those of UDPD (to 70.4%), as compared with basal values. The statistical significance is at the 1% level. When collagen proteins were administered concurrently, the decline was more marked (to 56.22% and 56.1% resp.), and as compared with the calcitonin treated group (to 67.73% and 82.30% resp.); the difference is significant at the 5% level. The decline of UPD and UDPD values persisted also three months after discontinued treatment; in patients on the diet with collagen hydrolysate practically no rise of these indicators occurred (54.02% and 56.66% resp.). CONCLUSIONS: a) administration of 100 u. calcitonin twice a week for 24 weeks led to a decline of excretion indicators of bone collagen breakdown products, b) the effect of treatment must be monitored using these indicators, c) oral administration of collagen proteins enhanced and prolonged the effect of calcitonin.

[Economic aspects of osteoporosis]. / Ekonomické aspekty osteoporózy.

BACKGROUND: The objective of this study was to evaluate expenditures and efficacy of osteoporosis treatment in the Czech Republic (CZ) (1.38 million women and 0.99 million men > 55 years of age). METHODS AND RESULTS: Demographic data, incidence of hip fractures and prevalence of osteoporosis and osteopenia in Czech women and men, cost burden to healthcare agencies due to hip fractures and costs of diagnostic procedures, preventive measures and therapies of osteoporosis were obtained from published data and from database of the main health insurance agency (VZP) and the State Institute for Drug Control. The direct costs for treatment of hip fractures in the CZ in 1997 averaged Kc (Czech Crown) 2.5 billion, diagnosis of osteoporosis, Kc 150 million, prevention of osteoporosis using hormone replacement therapy, Kc 66 million, and treatments of osteoporosis which has been applied to less than 5% of osteoporosis patients, 482 million. However, despite the continuously increasing expenditures for treatments of osteoporosis, the incidence of hip fractures doubled in the last 10 years. This is mainly due to increased life expectancy in Czech women and men. CONCLUSIONS: The results of this first economic evaluation of diagnosis, treatment and consequences of osteoporosis in the CZ indicate a need for conceptual decisions in both treatment and prevention of osteoporosis.

[New views on the pathogenesis of osteoporosis]. / Nové poznatky o patogenezi osteoporózy.

The author points out new aspects on pathogenetic factors of osteoporosis and its complications. the character of these factors shows that osteoporosis may be considered as a "civilization disease". The incidence of osteoporosis in all civilized countries is increasing and there is a striking resemblance of factors involved in the pathogenesis of osteoporosis to factors involved in the pathogenesis of other "typical civilization diseases" as are cardiovascular diseases or cancer. In more detail are mentioned the roles of physical exercise, nutrition, drugs and various toxic factors.

[Hypocalcemic states]. / Hypokalcemické stavy.

The authors review contemporary knowledge of acute and chronic hypocalcaemia. They mention in more detail the most typical symptom of acute hypocalcaemia, tetany, and emphasize some chronic symptoms of chronic hypocalcaemia. Diagnostic difficulties may arise in particular in epileptic states, hypocalcaemic organic psychosyndrome and cataract. Diagnosis of their hypocalcaemic cause is important from the therapeutic and preventive aspect. The authors mention also states which may cause hypocalcaemia and finally they give an account of therapeutic possibilities in acute and chronic hypocalcaemia. Data from the literature are supplemented by the authors' data on the prevalence, pathogenesis and treatment of hypocalcaemia.