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In this paper, the molecular dynamics, H-bonding pattern and wettability of the primary and secondary monohydroxyalcohols, 2-ethyl-1-hexanol (2E1H), 2-ethyl-1-butanol (2E1B) and 5-methyl-3-heptanol (5M3H) infiltrated into native and functionalized silica and alumina pores having pore diameters, d = 4 nm and d = 10 nm, have been studied with the use of Broadband Dielectric (BDS) and Fourier Transform InfraRed (FTIR) spectroscopies, as well as contact angle measurements. We found significant differences in the behavior of alcohols forming chain- (2E1H, 2E1B) or micelle-like (5M3H) supramolecular structures despite of their similarities in the wettability and interfacial energy. It turned out that nanoassociates as well as H-bonds are more or less affected by the confinement dependently on the chemical structure and alcohol order. Moreover, a peculiar behavior of the self-assemblies at the interface was noted in the latter material (5M3H). Finally, it was found that irrespectively to the sample, type of pores, functionalization, the temperature evolution of Debye relaxation times, τ D , of the confined systems deviates from the bulk behavior always at similar τ D due to vitrification of the interfacial layer. This finding is a clear indication that unexpectedly dynamics (mobility) of the supramolecular structures close to the hydrophilic and hydrophobic surfaces is similar in each system. [ABSTRACT FROM AUTHOR]

Abstract Background Advanced melanoma is characterized by a pronounced resistance to therapy leading to a limited patient survival of ~6 - 9 months. Here, we report on a novel bifunctional therapeutic fusion protein, designated anti-MCSP:TRAIL, that is comprised of a melanoma-associated chondroitin sulfate proteoglycan (MCSP)-specific antibody fragment (scFv) fused to soluble human TRAIL. MCSP is a well-established target for melanoma immunotherapy and has recently been shown to provide important tumorigenic signals to melanoma cells. TRAIL is a highly promising tumoricidal cytokine with no or minimal toxicity towards normal cells. Anti-MCSP:TRAIL was designed to 1. selectively accrete at the cell surface of MCSP-positive melanoma cells and inhibit MCSP tumorigenic signaling and 2. activate apoptotic TRAIL-signaling. Results Treatment of a panel of MCSP-positive melanoma cell lines with anti-MCSP:TRAIL induced TRAIL-mediated apoptotic cell death within 16 h. Of note, treatment with anti-MCSP:sTRAIL was also characterized by a rapid dephosphorylation of key proteins, such as FAK, implicated in MCSP-mediated malignant behavior. Importantly, anti-MCSP:TRAIL treatment already inhibited anchorage-independent growth by 50% at low picomolar concentrations, whereas > 100 fold higher concentrations of non-targeted TRAIL failed to reduce colony formation. Daily i.v. treatment with a low dose of anti-MCSP:TRAIL (0.14 mg/kg) resulted in a significant growth retardation of established A375 M xenografts. Anti-MCSP:TRAIL activity was further synergized by co-treatment with rimcazole, a σ-ligand currently in clinical trials for the treatment of various cancers. Conclusions Anti-MCSP:TRAIL has promising pre-clinical anti-melanoma activity that appears to result from combined inhibition of tumorigenic MCSP-signaling and concordant activation of TRAIL-apoptotic signaling. Anti-MCSP:TRAIL alone, or in combination with rimcazole, may be of potential value for the treatment of malignant melanoma.

Background A number of compounds, including ascorbic acid, catecholamines, flavonoids, p -diphenols and hydrazine derivatives have been reported to interfere with peroxidase-based medical diagnostic tests (Trinder reaction) but the mechanisms of these effects have not been fully elucidated. Methods Reactions of bovine myeloperoxidase with o -dianisidine, bovine lactoperoxidase with ABTS and horseradish peroxidase with 4-aminoantipyrine/phenol in the presence of carbidopa, an anti-Parkinsonian drug, and other catechols, including l -dopa, were monitored spectrophotometrically and by measuring hydrogen peroxide consumption. Results Chromophore formation in all three enzyme/substrate systems was blocked in the presence of carbidopa and other catechols. However, the rates of hydrogen peroxide consumption were not much affected. Irreversible enzyme inhibition was also insignificant. Conclusions Tested compounds reduced the oxidation products or intermediates of model substrates thus preventing chromophore formation. This interference may affect interpretation of results of diagnostic tests in samples from patients with Parkinson's disease treated with carbidopa and l -dopa. General significance This mechanism allows prediction of interference in peroxidase-based diagnostic tests for other compounds, including drugs and natural products. [ABSTRACT FROM AUTHOR]

[Display omitted] • A comprehensive study on self-aggregation of monohydroxy alcohols (MAs). • Impact of phenyl and cyclohexyl ring on the aggregation of MAs. • Aromaticity affects the self-assembling of MAs. • Phenyl ring introduces more heterogeneity in the organization of molecules than the cyclic one. In this paper, the steric hindrance effect related to the presence of either a cyclic or aromatic ring on the self-association process in the series of monohydroxy alcohols (MAs), from cyclohexanemethanol to 4-cyclohexyl-1-butanol and from benzyl alcohol to 4-phenyl-1-butanol, was studied using X-Ray Diffraction (XRD), Differential Scanning Calorimetry (DSC), Fourier Transform Infrared (FTIR) spectroscopy, Broadband Dielectric Spectroscopy (BDS) and the Pendant Drop (PD) methods. Based on FTIR results, it was shown that phenyl alcohol (PhA) and cyclohexyl alcohol (CA) derivatives reveal substantial differences in the association degree, the activation energy of dissociation, and the homogeneity of supramolecular nanoassociates suggesting that the phenyl ring exerts a stronger steric impact on the self-assembling of molecules than cyclohexyl one. Additionally, XRD data revealed that phenyl moiety introduces more heterogeneity in the organization of molecules compared to the cyclic one. The changes in the self-association process of alcohols were also reflected in differences in the molecular dynamics of the H-bonded aggregates, as well as in the Kirkwood factor, defining the long-range correlation between dipoles, which were slightly higher for CAs with respect to those determined for PhAs. Unexpectedly it was also found that the surface layers of PhAs were more organized than those formed by CAs. Thus, these findings provided insight into the impact of aromaticity on the self–assembly process, H-bonding pattern, supramolecular structure, and intermolecular dynamics of the studied alcohols. [ABSTRACT FROM AUTHOR]

Abstract: A series of 3-[(4,5-dihydroimidazolidin-2-yl)imino]indazoles has been synthesized as positional analogues of marsanidine, a highly selective α2-adrenoceptor ligand. Parent compound 4a and its 4-chloro (4c) and 4-methyl (4d) derivatives display α2-adrenoceptor affinity at nanomolar concentrations (K i =39.4, 15.9 and 22.6nM, respectively) and relatively high α2/I1 selectivity ratios of 82, 115 and 690, respectively. Evidence was obtained that these compounds act as partial agonists at α2A-adrenoceptors. Compound 4d with intrinsic activity comparable with that of marsanidine, but lower than that of clonidine, elicited pronounced cardiovascular effects in anesthetized rats at doses as low as 0.01mg/kg iv [ABSTRACT FROM AUTHOR]

Poly(1-vinyl-2-pyrrolidone) (Povidone, PVP) is one of the most interesting and versatile synthetic polymers utilised in the pharmaceutical and cosmetic industries. Its large-scale commercial production offers an assortment of products in a wide range of molecular weights but poorly-controlled (macro)structural parameters (i.e., dispersity, functionality) limiting the efficiency of PVP-based drug delivery systems (DDS). In this work, synthesised linear and star-shaped PVPs with a strictly defined structure and functionality were compared with the linear, commercially-supplied product and explored as potential vehicles for physical entrapment of metronidazole (MTZ). Here, a question is addressed how differences in their macromolecular properties affect the amorphisation of MTZ, drug encapsulation, the stability of drug-loaded micellar structures and their in vitro release from the carrier. The X-ray diffraction studies and calorimetric measurements revealed that MTZ crystallises in all investigated herein systems reducing the glass transition temperature of the binary mixture significantly. Transmission electron microscopy and dynamic light scattering analysis revealed that MTZ-loaded DDS are able to form ultrasmall regular nanocarriers with an increasing effect of regularity and sphericity from star-shaped DDS to linear-based ones. We founded that synthesised linear-based DDS is the most effective for MTZ entrapment (PVP:MTZ = 1:1 weight ratio) due to their smallest hydrodynamic radius d h = 14.7 nm, the highest stability of micellar structures −2.37 mV, and the highest values of loaded drug 76.5%. Moreover, all applied PVP-based DDS revealed an initial burst release effect of MTZ (pH = 7.4) reaching up to 60% of drug released within the first 5 h (the first-order release model fits). The marked efficiency of MTZ-loaded DDS of strictly defined structural parameters indicates the great importance of polymer preparation strategy in the targeted therapy. [Display omitted] • Metronidazole-polyvinylpyrrolidone (MTZ-PVP) drug delivery systems were obtained using polymers of various topology. • Commercial linear pvp has been compared with synthesised linear and star ones in terms of ability to form stable micelles and solubilize MTZ. • MTZ-loaded DDS are able to form ultrasmall regular nanocarriers with an increasing effect of regularity and sphericity from star-shaped DDS to linear-based ones. • MTZ crystallises in all investigated herein systems reducing the glass transition temperature of the binary mixture significantly. • Synthesised linear-based DDS is the most effective for MTZ entrapment. [ABSTRACT FROM AUTHOR]

The present study was designed to identify the biological activity of three ecdysones, i.e., 20-hydroxyecdysone (20-HE), ajugasterone C, and polypodine B isolated from Serratula coronata. The main objective was to investigate the molecular mechanism of the biological activity of those compounds and to assess their impact on breast cancer cell survival and cell cycle. Cell lines were selected according to their hormone receptor status since this factor is perceived as a crucial one in the cancer prognosis as well as cancer cell response to therapy. Consequently, MCF7 (ER/PR+, HER2-), T-47D (ER/PR+, HER2−/+), and MDA-MB-231 (ER/PR-, HER2-) were enrolled in the study. Additionally, a non-tumorigenic, MCF10A cells were selected to verify any potential specificity to cancer cells. Interestingly, none of the studied compounds affected the viability of MCF10A cells while cancer cells were altered, albeit in different ways. Polypodine B did not affect the viability or cell cycle distribution of studied breast cancer cells. By contrast, 20-HE and ajugasterone C significantly inhibited the viability of triple-negative cell line, MDA-MB-231. Interestingly, 20-HE revealed proapoptotic activity in MDA-MB-231 and T-47D cells that was manifested by alterations in PARP, Bax, and Bcl-2 levels as well as caspase-3 activation. Moreover, 20-HE induced autophagy that was mediated by modification of autophagy-associated proteins, i.e., LC3, p62, and mTOR, but only in MDA-MB-231 cells. This study is the first to report diverse biological activity of phytoecdysones in different breast cancer cells, that suggests association with molecular characteristics including receptor status but also other biological properties and genetic markers. • This study report the biological activity of phytoecdysones in breast cancer cells. • None of the studied compounds affected the viability of MCF10A breast cell line. • Polypodine B did not affect the viability or cell cycle of studied cancer cells. • 20-HE and ajugasterone C significantly inhibited the MDA-MB-231 cells. [ABSTRACT FROM AUTHOR]

The properties of liquids under geometrical confinement are affected by a subtle counterbalance between the genuine confinement effect and surface conditions. Therefore, depending on the interactions of the guest molecules with the solid surface, the effect caused by increasing geometrical constraints might be diversified. In this work, using Dielectric Spectroscopy (DS) and Differential Scanning Calorimetry (DSC), we aim to examine the effect of surface modification on the glassy dynamics and crystallization tendency of van der Waals liquid - dimethyl phthalate - embedded within cylindrical nanopores. The inner surface of the pore walls was modified by Atomic Layer Deposition (ALD) using two oxide coatings of much different hydrophilicity, namely, alumina oxide (Al 2 O 3) and hafnium oxide (HfO 2). The analysis of experimental data revealed that the changes in the surface conditions produced by both types of ALD coatings do not affect significantly the average time of the α-relaxation and the values of the glass transition temperatures for the interfacial and core layers as compared to native nanopores. However, the distribution of the α-relaxation time clearly broadens in the presence of more hydrophobic HfO 2 coating. Finally, we also show that the changes in the hydrophilic-hydrophobic nature of the pores can be used to control the crystallization tendency of the nano-confined liquid. We found that with increasing the hydrophobic character of the surface crystallization rates increase while the values of the Avrami parameter decrease. Unlabelled Image • ALD coatings change the hydrophobic nature of the internal pore walls. • Changes in the hydrophobicity of pores affect the distribution of a-relaxation time. • The hydrophobicity of the pores influences the crystallization tendency. [ABSTRACT FROM AUTHOR]

Understanding the properties of thin films remains an unresolved issue even after decades of scientific research. In this article, we investigate the role of surface roughness, one of the various factors that affect the dynamics of polymer films. The tested sample is poly-(4-chlorostyrene) coated onto silicon substrates treated with plasma for different amounts of time. By using dielectric spectroscopy, we provide experimental evidence that as substrate roughness increases (i) the segmental mobility slows down, and (ii) the distribution of the α-relaxation time becomes narrower. Ultimately, the confinement effect vanishes, and the polymer film recovers its bulk-like behavior for sufficiently rough surfaces. Further studies that employ AFM, ellipsometry, and contact angle measurements allowed us to conclude that the deviation in segmental dynamics as a function of surface roughness is due to the changes in interfacial energy that affects the number of chains irreversibly absorbed to the substrate which in turn improve packing density near the substrate. Therefore, the surface roughness is an inevitable factor to consider when designing numerous devices which rely on supported polymer films. Image 1 • Nanometric surface roughness can influence the segmental dynamics of confined polymer films. • Segmental mobility of polymer thin films slow down with the increase in surface roughness of substrate. • Bulk recovery of segmental dynamics in polymer thin films with increasing surface roughness. • Confinement effect vanishes by changing the surface properties of supported polymer thin films. • Surface roughness aids the increased adsorption of polymer chain on the substrate. [ABSTRACT FROM AUTHOR]

N-[(Imidazolin-2-yl)amino]indolines and N-[(imidazolin-2-yl)amino]-1,2,3,4-tetrahydroquinolines, previously described in patent literature as hypertensive agents, were synthesized and tested in viny for their affinities to α1- and α2-adrenoceptors as well as imidazoline I, and I2 receptors. The compounds most potent at either α1- or α2-adrenoceptors were administered intravenously to normotensive Wistar rats to determine their effects on mean arterial blood pressure and heart rate. Upon intravenous administration at dose of 0.1 mg/kg to normotensive male Wistar rats, the initial transient pressor effect was followed by long-lasting hypotension and bradycardia. In view of the above results the 1-[(imidazolin-2-yl)amino]indolines and [(imidazolin-2-yl)amino]-1,2,3,4-tetrahydroquinolines are now found to possess circulatory profile characteristic of the centrally acting clonidine-like hypotensive imidazolines.

A series of 2-[(arylmethoxy)imino]imidazolidines was synthesized by reacting 2-chloro-4,5-dihydroimidazole with corresponding O-arylmethylhydroxylamines and evaluated for their alpha-, alpha2-adrenergic and imidazoline I1, I2 receptor binding affinities. The most potent 2-[(naphthalen-1-ylmethoxy)imino]imidazolidine showed a high selectivity and good affinity for the [3H]prazosin-labeled alpha1-adrenoceptors (K(i) = 107 nM). Representative compounds of this series were also tested in vivo for possible circulatory effects in rats after intravenous administration.

Aim: To assess selected angiogenic markers; microvascular density and the expression of VEGF and Flk-1 in relation to clinical features and morphologic types of neuroblastoma., Patients and Methods: Eighty-two children with neuroblastoma were studied. Morphological assessment was performed in paraffin embedded tissues of the primary tumours. Microvessels within tumour tissue were counted on immunohistochemically stained sections using anti CD34 antibody. The expression of VEGF and Flk-1 was estimated semiquantitively in immunohistochemically stained sections with adequate antibodies. The results of angiogenic studies were referred to the clinical data: age, clinical stage, localization and site of the primary tumour, serum LDH and ferritin at diagnosis. The correlation between angiogenic markers and morphological type of neuroblastoma was also evaluated., Results: Microvascular density varies in a wide range (32-325/mm(2)). There was no significant statistical difference between previously untreated and tumours assessed after chemotherapy. Analyzing the correlations between the angiogenic markers and clinical features we found a converse relation between the age and microvascular density. The highest expression of VEGF was found in adrenal tumours in comparison to other localizations. Undifferentiated and poorly differentiated tumours presented a higher expression of VEGF and higher vascular density. Non significant higher expression of VEGF and higher vascular density was noticed in smaller <5 cm tumours., Conclusions: Correlations were found between the microvascular density and the age, diameter and the localisation of the primary tumour. Expression of VEGF depends on the localisation of the tumour. Neuroblastoma tumours arising in small children and poorly differentiated types of neuroblastoma indicate higher angiogenic activity.

Calcimimetics administered orally cause "pharmacological parathyroidectomy" confirmed by a decrease in parathyroid hormone secretion (PTH) and in plasma Ca(2+) concentration. Parathyroids are also the source of parathyroid hypertensive factor (PHF). The aim of this study was to determine the dose-dependent effect of an intravenously (iv) applied calcimimetic, NPS R-568, on plasma Ca(2+) concentration, urinary phosphate excretion and mean arterial blood pressure (MAP) in rats. Clearance experiments were performed on male Wistar rats anesthetized with thiopental and infused iv with saline supplemented with (3)H inulin for glomerular filtration rate (GFR) determination. NPS R-568 was administered iv as a bolus at the doses: 0.5, 1.0, 2.5 and 5.0 mg/kg. Control group of rats received vehicle only. MAP was monitored continuously in the carotid artery. Urine was collected from cannulated urinary bladder. NPS R-568 applied iv dose-dependently decreased plasma Ca(2+) and fractional phosphate excretion (FE(Pi)). In the control group, no significant changes in plasma Ca(2+) and FE(Pi) were observed. The most efficient hypotensive effect vs. control group was induced by the NPS R-568 of a dose of 1.0 mg/kg. Our results indicate that the dose of 1 mg/kg of the calcimimetic NPS R-568 administered iv is sufficient to induce the decrease in plasma Ca(2+) and urinary phosphate excretion accompanied with hypotensive effect in Wistar rats.

Unlabelled: Malignant vascular tumours represent a rare group of neoplasms, usually treated according to protocols for soft tissue sarcomas., The Aim of the Study: To assess the clinical characteristics, disease course and outcome in Polish children with malignant vascular neoplasms., Material and Methods: The Polish Paediatric Rare Tumours Study retrospectively analysed multicentre data on 32 children with vascular tumours, registered between 1992 and 2002. On the basis of the histological type of the neoplasm these patients have been divided into three groups: group I -- 10 patients with angiosarcoma (ASA), group II -- 7 children with haemangioendothelioma (HE) and group III- 15 patients with haemangiopericytoma (HP), of both infantile (7 children) and adult-types (8 patients)., Results: Group I: 5 patients presented with local, 3 with systemic and 2 with regional disease. Primary complete resection (PRC) was performed in 7 patients, not resulting in local control in any of them. Radiotherapy (RTX) was administered in 5 patients, chemotherapy (CHT) in all. 7 patients relapsed, 3 never entered clinical remission. 9 of the 10 patients of group I, died of disease progression. Group II: PRC was performed in 5 patients and led to local control in 2. Adjuvant RTX was used in 2 and CHT in 4 patients. 2 children relapsed and died of the disease. Infantile HP: PRC was performed in 3 children, remaining 4 patients received adjuvant CHT All children entered complete remission and are disease-free. Adult-type HP: PRC was performed in 5 patients, resulting in local control in 4. Five children were given adjuvant RTX and six CHT Three patients relapsed and died of disease progression., Conclusions: The effectiveness of primary complete resection in all groups was doubtful. The high rate of metastatic relapses suggests that the currently given systemic therapy is not satisfactory. The only tumour with excellent prognosis was infantile type HP (all patients are alive and free of disease). Adequate treatment for children with angiosarcoma remains still unknown -- 9 of 10 patients died of disease progression. Prognosis in patients with haemangioendothelioma is intermediate, however the role of immunotherapy should be further investigated.

Clear statement that pediatric neoplasms are really rare is not easy. Thus the incidence of rare tumours in children has not been defined so far. The paper efforts to assess the topic of rare tumours of childhood in the Polish population. Following two categories are proposed: tumours typical for adults, but possible in children (neoplasms of epithelial origin--mainly carcinomas, melanomas, carcinoids) and paediatric tumours consisting less than 10% of cases in corresponding clinical groups according to the ICCC classification. Data on 317 patients aged 0-18 years treated in centres associated in the Polish Paediatric Group for Solid Tumours (PPGST) were analysed. Classical adult malignancies were registered in 130 patients: carcinomas in 90 (mean age 12.6 +/- 4.5 years), melanomas in 25 (mean age 9.4 +/- 4.9) and carcinoids in 9 (mean age 14.5 +/- 1.2 years). Non epithelial neoplasms were registered in 187 patients (mean age 10.4 +/- 5.5). That group included rare tumours of soft tissue, CNS, bones and other organs. Treatments of certain groups were specified by separate therapeutic protocols within PPGST. Rare malignancies of adult-type among children under 18 years of age in Poland comprised 1.5% of all pediatric neoplasms. The incidence of adult-type neoplasms increased with age until 14 years. In patients over 15 years of age the number of registered cases decreased. It may suggest a first peak of incidence in early adolescence or an underestimation of number of patients with carcinoma aged over 15 years. In the analyzed group, the mean age of patients with carcinomas and other epithelial and unspecified tumours significantly exceeded the age of children with rare neoplasms of non-epithelial origin (12.1 +/- 4.7 vs 10.4 +/- 5.5 years; p<0.05). A very young age at diagnosis of malignant melanomas (mean 9.4 years) and numerous cases of carcinomas affecting the digestive tract (n=24; 27% of all carcinomas), especially those located in colorectal region (n=10), seem surprising. The preliminary analysis of the collected data on rare neoplasms in Poland encourage to undertake a prospective study, meant to link the epidemiology and characteristics of rare epithelial tumours in childhood with diagnostic and therapeutic suggestions for these types that are not coordinated within Polish Paediatric Group of Solid Tumours.

Treatment of excessive secretion of parathyroid hormone (PTH) in primary hyperparathyroidism (I degree HPT) as well as in secondary hyperparathyroidism (II degree HPT) in chronic renal insufficiency is symptomatic, short-term acting and far from expectations. Recognition of properties of calcium receptor (CaR) expressed on parathyroid principal cell membranes created possibilities to explore new compounds that could alter directly PTH secretion and provide a novel therapy for direct correction of increased secretion of the hormone in these disorders. Ligands that activate this receptor and inhibit PTH secretion are called calcimimetics. Recently clinical trials with NPS R-568, a calcimimetic of the Ist generation, and AMG 073, a representative of calcimimetics of IInd generation, were completed. Calcimimetics, taken orally, effectively lower increased secretion of PTH and hypercalcemia in I degree HPT, by "pharmacologic parathyroidectomy". Such compounds are also safe and effective in dialysed patients with II degree HPT in chronic renal insufficiency: they decrease PTH plasma level and prevent parathyroid cell hyperplasia. The other compounds, called calcilytics and represented by NPS 2143, inhibit CaR resulting therefore in increase of PTH secretion. Administration of calcilytics would provide a valuable alternative to inhibit progression of osteoporosis. Subcutaneous, pulsative low doses of recombinant PTH (ALX1-11) administration induces increase of bone formation. Such an effect to some extent was obtained by transient increase of endogenous PTH secretion induced by oral administration of calcilytic NPS 2143 to osteopenic ovariectomized rats, especially if it was accompanied by supplementation of estrogens.

Studies in respiratory alkalotic or short-term phosphate deprived rats raised the possibility that in straight portion of proximal tubules (PST) cAMP might be not a mediator of PTH in inhibition of phosphate reabsorption. The present experiments directly compared the sensitivity of Na-dependent phosphate [32P] (Na-Pi) uptake to PTH or cAMP by PCT or PST cells freshly prepared from outer cortex and outer stripe of outer medulla of rat kidney. The purity of the cells was examined by activity of enzymes specific for PST i.e. glutamine synthetase, gamma-glutamyl transpeptidase and creatine kinase, a marker enzyme for medullary thick ascending limb (MTAL) and distal convoluted tubule. Similar inhibition of Na-Pi uptake by 1-34 bPTH by PST and PCT cells was observed: -33.0 and -30.0% (ns), respectively. In contrast, dibutyryl cAMP decreased Na-Pi uptake only by PCT but not by PST cells: -31.0 and -3.6% (p<0.02), respectively. The 3-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor, resulted in slight stimulation of Na-Pi uptake by PST but strong inhibition by PCT cells: 7.8 vs -26.0% (p<0.001). In contrast to PCT in PST cells cAMP seems to play a minor role as a mediator of inhibition of Na-Pi uptake by PTH.

In recent years the receptor sensing calcium (CaR) has been discovered on the surface of parathyroid cells and some other organs cells which revised our understanding of mechanisms involved in regulation of body calcium balance. It was shown that stimulation of CaR induced by an increase of extracellular ionized calcium concentration resulted in an increase of intracellular calcium and subsequent decrease of parathyroid hormone (PTH) secretion from parathyroid cells. Calcium receptor was also discovered in nephron segments reabsorbing calcium which allowed to understand the mechanisms underlying some inherited disturbances of calcium balance regulation i.e. in familial hypocalciuric hypercalcemia or hypercalciuric hypocalcemia. Investigations on CaR structure revealed the mutations in those inherited syndromes leading to increase or decrease of parathyroid and nephron cells receptor sensitivity to calcium. The description of the receptor properties resulted in development of a new group of compounds called calcimimetics which are more efficient than calcium itself in stimulation of CaR and subsequent decrease of PTH secretion. Calcimimetics in perspective might have a therapeutic application. Under investigation is synthesis of calcilytics, compounds which through an interaction with CaR result in increase of PTH secretion potentially leading to a clinical application.

2-Oxoglutarate metabolism in the isolated rat kidney cortex tubules was inhibited by lithium at 5 mM concentration, and at pH increased from 7.1 to 7.6. The metabolism of pyruvate and acetylcarnitine to citrate and 2-oxoglutarate was enhanced by lithium and the increased pH value. The content of 2-oxoglutarate in the renal tubular cells was lowered by lithium but increased at elevated pH values. Both the intracellular pH value and bicarbonate ion concentrations in renal tubular cells were increased by lithium in the medium containing 2-oxoglutarate. The results obtained indicate that lithium disturbs renal metabolism by intracellular alkalization, with a simultaneous inhibition of the inflow of dicarboxylic substrates to the renal tubular cells.

Prophylactic gynecologic examinations were carried out in 218 women-workers of a cement plant. The most frequent diseases were: retroflexion of the uterus (55.5%), inflammation of the ovary (50.45%), erosion of the vaginal part of the uterus (41.8%), prolapse of the vaginal walls (39.45%), incontinence (35.32%) and Trichomonas vaginalis (18.7%). The extensive prevalence of the diseases imposes a need to carry on preventive examinations of women employed in cement industry. The authors indicate that certain diseases are obviously due to deficient hygiene.

Respiratory alkalosis results in a resistance to the phosphaturic effect of parathyroid hormone (PTH) and dibutyryl adenosine 3',5'-cyclic monophosphate (cAMP). The present studies evaluated the role of the beta-adrenergic system in that resistance phenomenon. In clearance experiments on acutely thyroparathyroidectomized male Wistar rats, respiratory alkalosis blunted the PTH-mediated increase in absolute and fractional excretion of phosphate (FEPi). Propranolol infusion restored the phosphaturic response to PTH:FEPi, 0.8 +/- 0.3 vs. 8.1 +/- 2.5% (P less than 0.005). Similarly, the increase of FEPi during cAMP infusion was also diminished by respiratory alkalosis: FEPi, 15.5 +/- 2.2 vs. 5.5 +/- 1.1% (P less than 0.005). This hypophosphaturic effect of respiratory alkalosis in the presence of cAMP was not observed in rats infused with propranolol compared with the period of normal ventilation: FEPi, 21.1 +/- 1.7 vs. 15.3 +/- 1.6 (P less than 0.02). Also, during the infusion of the highly selective beta 2-adrenoceptor antagonist, ICI 118,551, cAMP was phosphaturic in respiratory alkalosis compared with FEPi in the absence of the antagonist: FEPi, 13.0 +/- 2.5 vs. 5.5 +/- 1.1% (P less than 0.02). Finally, the infusion of the beta 2-agonist, fenoterol, to the normally ventilated rats significantly decreased FEPi in cAMP-infused rats in comparison to the absence of the agonist: FEPi, 4.0 +/- 0.7 vs. 22.1 +/- 2.6% (P less than 0.001). We conclude that the resistance to the phosphaturic effect of PTH and cAMP in respiratory alkalosis is mediated by beta-adrenoceptors.

Acute lithium administration (5 mmol/kg b.w.) to parathyroidectomized (PTX) rats induces extracellular acidosis, lower plasma phosphate concentration and increased phosphate reabsorption. The present studies evaluate the effect of lithium administration on tissue phosphate distribution, metabolites content in the kidneys and renal phosphate, 2-oxoglutarate and citrate transport in the presence and absence of db-cyclic AMP. Lithium decreased plasma and renal phosphate concentrations and increased phosphate concentration in the skeletal muscle, db-cyclic AMP was not phosphaturic in lithium-treated PTX rats. In PTX rats infused with 20 mM phosphate lithium depressed fractional phosphate excretion induced by db-cyclic AMP from 20 +/- 0.3% to 3.2 +/- 1.0%. However, metabolic or respiratory acidosis restored the responsiveness to db-cyclic AMP. Citraturia and ketoaciduria induced by lithium were depressed in db-cyclic AMP-treated rats. Kidney citrate and 2-oxoglutarate concentrations increased drastically, ATP level fell significantly whereas cAMP content did not change after lithium. We conclude that lithium administration increases phosphate uptake by the muscle which largely accounts for hypophosphatemia. The kidney responds with increased phosphate reabsorption independent of plasma and kidney phosphate concentrations, and with refractoriness to the phosphaturic effects of db-cyclic AMP. Acute lithium administration to rats induces extracellular acidosis and, probably, renal intracellular alkalosis as reflected by citraturia and ketoaciduria as well as the renal metabolite profile. The phosphaturic responsiveness to db-cyclic AMP is dependent, at least in part, on intracellular pH.