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Biomedical subjects

A Pavlova

Publications and source records attributed to A Pavlova.

At least 19 recordsLinked to original sources
PubMed2006

Radiation protection and safety in medical use of ionising radiation in Republic of Bulgaria--harmonization of the national legislation with Euratom directives.

From February 2002 to November 2003 the National Centre of Radiobiology and Radiation Protection conducted a PHARE twinning project 'Radiation Protection and Safety at Medical Use of Ionising Radiation'. The main purposes of the project were the harmonization of Bulgarian legislation in the field of radiation protection with EC Directives 96/29 and 97/43 Euratom, and the establishment of appropriate institutional infrastructure and administrative framework for their implementation. This paper presents the main results of the project: elaboration of Ordinance for Protection of Individuals from Medical Exposure; performance of a national survey of distribution of patient doses in diagnostic radiology and of administered activities in nuclear medicine and establishment of national reference levels for the most common diagnostic procedures.

Bulgaria↗
PubMed2006

Inhibition of mammalian cathepsins by Plesiomonas shigelloides.

To study molecular mechanisms underlying self-defense of the bacterial pathogen Plesiomonas shigelloides against host inflammatory and immune responses, we evaluated its interactions with mammalian papain-like cathepsins that are essential for host immunity. When grown under anaerobic, but not aerobic, conditions, P. shigelloides was shown to bind and inhibit papain, a model representative of the papain family of cysteine proteinases. This points to mammalian cathepsins as likely physiological targets of a novel cysteine-proteinase inhibitor expressed on bacterial cell surface. Both papain and mammalian cathepsins L and B were inhibited by periplasmic extracts of aerobically and anaerobically grown bacteria, the inhibitory activity being higher in the latter. Inhibition by both intact cells and periplasmic samples was rapid and efficient. The results suggest a possible defensive role of bacterial inhibitors of cathepsins during invasion of a mammalian host. The bacteria thus may modulate host protective responses through inhibiting cathepsins involved in antigen processing and presentation.

Animals↗
PubMed2006

Genetic risk factors for inhibitors to factors VIII and IX.

The formation of alloantibodies against factor VIII (FVIII) or factor IX (FIX) is the most severe complication of replacement therapy in patients with haemophilia. In the last decade, genetic factors have been shown to constitute a decisive risk determinant for the development of inhibitors. In severe haemophilia A and B, mutations that result in an absent or truncated FVIII/FIX protein are associated with a 20-80% risk of inhibitor formation. In mild to moderate haemophilia, missense mutations represent the main mutation type, with an inhibitor prevalence of 5%. These patients synthesize some endogenous, although non-functional protein that is sufficient to induce immune tolerance. However, in patients with missense mutations clustered in the A2 and C2 domains (C1/C2 junction), the risk of inhibitor formation is fourfold greater than in patients with mutations outside this region, indicating that inhibitor prevalence in missense mutations is also dependent on localization of the mutation. Recently, a significant association between inhibitor formation and polymorphisms in genes coding for cytokines (IL-10) and other immunoregulatory factors (TNF-alpha) has been shown. These genetic factors constitute the individual genetic risk profile of a haemophilic patient. This risk is imprinted and fixed; however, environmental factors such as treatment schedule may increase or decrease the inhibitor risk in an individual patient. Improved understanding of these complex interactions may lead to the development of preventive measures to minimize inhibitor formation.

Blood Coagulation Factor Inhibitors↗
PubMed2003

Determination of petroleum hydrocarbons and polycyclic aromatic hydrocarbons in sludge from wastewater treatment basins.

Screening by gas chromatography with flame ionization detection and gas chromatography-mass spectrometry has been carried out on sludge extracts of wastewater treatment basins. Soxhlet extraction with trichlorotrifluoroethane was applied. The yields for petroleum hydrocarbons and PAH recovery were high, usually in excess of 90%. The proposed investigations permit a quick assessment of petroleum pollutants in the environment.

Environmental Monitoring↗
PubMed2001

Comparison of Pkd1-targeted mutants reveals that loss of polycystin-1 causes cystogenesis and bone defects.

A high level of polycystin-1 expression is detected in kidneys of all patients with autosomal dominant polycystic kidney disease (ADPKD). Mice that overexpress polycystin-1 also develop renal cysts. Whether overexpression of polycystin-1 is necessary for cyst formation is still unclear. Here, we report the generation of a targeted mouse mutant with a null mutation in Pkd1 and its phenotypic characterization in comparison with the del34 mutants that carry a 'truncation mutation' in Pkd1. We show that null homozygotes develop the same, but more aggressive, renal and pancreatic cystic disease as del34/del34. Moreover, we report that both homozygous mutants develop polyhydramnios, hydrops fetalis, spina bifida occulta and osteochondrodysplasia. Heterozygotes also develop adult-onset pancreatic disease. We show further that del34 homozygotes continue to produce mutant polycystin-1, thereby providing a possible explanation for increased immunoreactive polycystin-1 in ADPKD cyst epithelia in the context of the two-hit model. Our data demonstrate for the first time that loss of polycystin-1 leads to cyst formation and defective skeletogenesis, and indicate that polycystin-1 is critical in both epithelium and chondrocyte development.

Animals↗
PubMed2001

Biostimulation-based bioremediation of diesel fuel: field demonstration.

Ex-situ bioremediation of leached cynamonic forest soil at initial diesel oil contamination of 6,000 mg kg(-1), 4,000 mg kg(-1) and 2,000 mg kg(-1) was investigated after biostimulation with inorganic fertilizers. It was found that the added nutrients had no effect on the decontamination of polluted soils. A precise and reliable approach for evaluation of the biodegradation process is proposed. It comprises application of sensitive and easily accessible diagnostic parameters and relations, calculated on the basis of n-alkanes and isoprenoids--pristane (2.6.10.14-tetramethylpentadecane, i-C19H40) and phytane (2.6.10.14-tetramethylhexadecane, i-C20H42) distribution.

Alkanes↗
PubMed2001

EEG1, a putative transporter expressed during epithelial organogenesis: comparison with embryonic transporter expression during nephrogenesis.

A screen for genes differentially regulated in a model of kidney development identified the novel gene embryonic epithelia gene 1 (EEG1). EEG1 exists as two transcripts of 2.4 and 3.5 kb that are most highly expressed at embryonic day 7 and later in the fetal liver, lung, placenta, and kidney. The EEG1 gene is composed of 14 exons spanning a 20-kb region at human chromosome 11p12 and the syntenic region of mouse chromosome 2. Six EEG1 exons have previously been assigned to a longer isoform of eosinophil major basic protein termed proteoglycan 2. Another gene distantly related to EEG1, POV1/PB39, is located 88 kb upstream from the EEG1 gene on chromosome 11. Temporal expression of 65 members of the solute carrier (SLC)-class of transport proteins was followed during kidney development using DNA arrays. POV-1 and EEG1, like glucose transporters, displayed very early maximal gene expression. In contrast, other SLC genes, such as organic anion and cation transporters, amino acid permeases, and nucleoside transporters, had maximal expression later in development. Thus, although the bulk of transporters are expressed late in kidney development, a fraction are expressed near the onset of nephrogenesis. The data raise the possibility that EEG1 and POV1 may define a new family of transport proteins involved in the transport of nutrients or metabolites in rapidly growing and/or developing tissues.

Amino Acid Transport System y+L↗
PubMed2000

Cystatin inhibition of cathepsin B requires dislocation of the proteinase occluding loop. Demonstration By release of loop anchoring through mutation of his110.

Cystatins A and C were both shown to inhibit cathepsin B by a two-step mechanism, involving an initial weak interaction followed by a conformational change. Disruption of the major salt bridge anchoring the occluding loop of cathepsin B to the main body of the enzyme by mutation of His110 to Ala converted the binding to an apparent one-step reaction. The second step of cystatin binding to cathepsin B must therefore be due to the inhibitor having to alter the conformation of the enzyme by displacing the occluding loop to allow a tight complex to be formed. Cystatin A was appreciably less effective in displacing the loop than cystatin C, resulting in a considerably lower overall inhibition rate constant.

Alanine↗
PubMed2000

A role for Timeless in epithelial morphogenesis during kidney development.

Central to the process of epithelial organogenesis is branching morphogenesis into tubules and ducts. In the kidney, this can be modeled by a very simple system consisting of isolated ureteric bud (UB) cells, which undergo branching morphogenesis in response to soluble factors present in the conditioned medium of a metanephric mesenchyme cell line. By employing a targeted screen to identify transcription factors involved early in the morphogenetic program leading to UB branching, we identified the mammalian ortholog of Timeless (mTim) as a potential immediate early gene (IEG) important in this process. In the embryo, mTim was found to be expressed in patterns very suggestive of a role in epithelial organogenesis with high levels of expression in the developing lung, liver, and kidney, as well as neuroepithelium. In the embryonic kidney, the expression of mTim was maximal in regions of active UB branching, and a shift from the large isoform of mTim to a smaller isoform occurred as the kidney developed. Selective down-regulation of mTim resulted in profound inhibition of embryonic kidney growth and UB morphogenesis in organ culture. A direct effect on the branching UB was supported by the observation that down-regulation of mTim in the isolated UB (cultured in the absence of mesenchyme) resulted in marked inhibition of morphogenesis, suggesting a key role for Tim in the epithelial cell morphogenetic pathway leading to the formation of branching tubules.

Animals↗
PubMed2000

Traceability from weathered oil spills in the marine environment to the original contamination source. A case study.

An algorithm for stepwise approximation to the most reliable source of contamination is proposed. The concept of the algorithm is based on discrimination rather than on similarity. Gradually, by means of more complicated and higher distinguishing power approaches, the differences between the spilled sample and the suspected source are checked. Capillary gas chromatography with flame-ionization and mass spectrometric detection was applied to gather the necessary data. Fingerprint, diagnostic parameter approaches and pattern recognition methods were used for reliably distinguishing the analytical results. If the compared samples are not discriminated by any means, they are considered as identical.

Algorithms↗
PubMed2000

Developmentally regulated expression of organic ion transporters NKT (OAT1), OCT1, NLT (OAT2), and Roct.

Several xenobiotic (organic cation and anion) transporters have recently been identified, although their endogenous substrates, if such exist, remain unknown. When we initially identified NKT, also known as OAT1, the first member of the organic anion transporter (OAT) family (Lopez-Nieto CE, You G, Bush KT, Barros EJ, Beier DR, and Nigam SK. J Biol Chem 272: 6471-6478, 1997), we noted its expression in the embryonic kidney. We have now demonstrated its transporter function and more fully examined the spatiotemporal expression patterns of representative organic ion transporters, [NKT (OAT1), Roct, OCT1, and NLT, also known as OAT2] during murine development. In the kidney, NKT (OAT1), OCT1, and Roct transcripts appeared at midgestation, coinciding with proximal tubule differentiation, and gradually increased during nephron maturation. A similar pattern was observed for NLT (OAT2) in the liver and kidney, although, in the kidney, NLT (OAT2) transcription did not increase as dramatically. The roughly cotemporal expression of these related transporters in the developing proximal tubule may indicate common transcriptional regulation. Expression during embryogenesis in extrarenal sites could suggest a role in the formation and maintenance of nonrenal tissues. Importantly, all four genes were expressed in unexpected places during nonrenal organogenesis: Roct in the fetal liver (temporally coinciding with the onset of hematopoiesis) and neural tissue; NKT (OAT1) in the fetal brain; OCT1 in the ascending aorta and atrium; and NLT (OAT2) in the fetal lung, intestine, skin, and developing bone. Because these gene products mediate the transport of a broad range of metabolites and toxins, it seems likely that, apart from their known functions, these transporters play a role in transport of organic molecules, perhaps including those with morphogenetic activity. These genes could also play important developmental roles independent of transport function.

Aging↗
PubMed1999

The contribution of N-terminal region residues of cystatin A (stefin A) to the affinity and kinetics of inhibition of papain, cathepsin B, and cathepsin L.

The affinity and kinetics of binding of three N-terminally truncated variants of the cysteine proteinase inhibitor cystatin A to cysteine proteinases were characterized. Deletion of Met-1 only minimally altered the inhibitory properties of the protein. However, deletion also of Ile-2 resulted in reduced affinities of 900-, >/=3-, and 200-fold for papain and cathepsins L and B, respectively. Further truncation of Pro-3 substantially increased the inhibition constants to approximately 0.5 microM for papain and cathepsin L and to 60 microM for cathepsin B, reflecting additionally 2 x 10(3)-, 2 x 10(4)-, and 400-fold decreased affinities, respectively. The reductions in affinity shown by the latter mutant indicate that the N-terminal region contributes about 40% of the total free energy of binding of cystatin A to cysteine proteinases. Moreover, Pro-3 and to a lesser extent Ile-2 are the residues responsible for this binding energy. The reduced affinities for papain and cathepsin L were due only to higher dissociation rate constants, whereas both lower association and higher dissociation rate constants contributed to the decreased affinity for cathepsin B. These differential effects indicate that the N-terminal portion of cystatin A primarily functions by stabilizing the complexes with enzymes having easily accessible active-site clefts, e.g., papain and cathepsin L. In contrast, the N-terminal region is required also for an initial binding of cystatin A to cathepsin B, presumably by promoting the displacement of the occluding loop and allowing facile interaction of the rest of the inhibiting wedge with the active-site cleft of the enzyme.

Animals↗
PubMed1999

Evolution of gene expression patterns in a model of branching morphogenesis.

Branching morphogenesis of the ureteric bud in response to unknown signals from the metanephric mesenchyme gives rise to the urinary collecting system and, via inductive signals from the ureteric bud, to recruitment of nephrons from undifferentiated mesenchyme. An established cell culture model for this process employs cells of ureteric bud origin (UB) cultured in extracellular matrix and stimulated with conditioned media (BSN-CM) from a metanephric mesenchymal cell line (H. Sakurai, E. J. Barros, T. Tsukamoto, J. Barasch, and S. K. Nigam. Proc. Natl. Acad. Sci. USA 94: 6279-6284, 1997.). In the presence of BSN-CM, the UB cells form branching tubular structures reminiscent of the branching ureteric bud. The pattern of gene regulation in this model of branching morphogenesis of the kidney collecting system was investigated using high-density cDNA arrays. Software and analytical methods were developed for the quantification and clustering of genes. With the use of a computational method termed "vector analysis," genes were clustered according to the direction and magnitude of differential expression in n-dimensional log-space. Changes in gene expression in response to the BSN-CM consisted primarily of differential expression of transcription factors with previously described roles in morphogenesis, downregulation of pro-apoptotic genes accompanied by upregulation of anti-apoptotic genes, and upregulation of a small group of secreted products including growth factors, cytokines, and extracellular proteinases. Changes in expression are discussed in the context of a general model for epithelial branching morphogenesis. In addition, the cDNA arrays were used to survey expression of epithelial markers and secreted factors in UB and BSN cells, confirming the largely epithelial character of the former and largely mesenchymal character of the later. Specific morphologies (cellular processes, branching multicellular cords, etc.) were shown to correlate with the expression of different, but overlapping, genomic subsets, suggesting differences in morphogenetic mechanisms at these various steps in the evolution of branching tubules.

Animals↗
PubMed1998

Differential expression patterns of Wnt genes in the murine female reproductive tract during development and the estrous cycle.

The murine female reproductive tract differentiates during postnatal development. This process of cytodifferentiation and morphogenesis is dependent upon specific mesenchymal-epithelial interactions as well as circulating steroid hormones (Cunha, G.R., 1976. Int. Rev. Cytol. 47, 137-194; Pavlova, A. et al., 1994. Development 120, 335-346). Members of the Wnt family of signaling molecules have been recently identified in this system (Pavlova, A. et al., 1994. Development 120, 335-346; Bui, T.D. et al., 1997. Br. J. Cancer 75, 1131-1136; Miller, C., Sassoon, D.A., 1998. Development, in press). We describe the expression patterns of Wnt genes in the developing and adult female reproductive tract. Additionally, we note that changes in the levels of expression occur during the estrous cycle. Wnt gene expression patterns are regulated by the presence of epithelium in tissue graft experiments, suggesting that Wnt genes may indeed play roles in the mesenchymal-epithelial interactions critical for female reproductive tract development and function.

Animals↗
PubMed1998

Tubular localization and tissue distribution of peptide transporters in rat kidney.

PURPOSE: To define the tubular localization and tissue distribution of PEPT1 (low-affinity, high-capacity transporter) and PEPT2 (high-affinity, low-capacity transporter) in rat kidney. METHODS: mRNA expression of PEPT1 and PEPT2 was assessed with reverse transcription-polymerase chain reaction (RT-PCR) methods using cDNA prepared from microdissected nephron segments in rat. Tissue localization of rat renal PEPT1 and PEPT2 mRNA was further assessed by in situ hybridization with radiolabeled probes. RESULTS: RT-PCR analysis of microdissected segments from rat nephron showed that both PEPT1 and PEPT2 are confined to a proximal tubule. While PEPT1 is specific for early regions of the proximal tubule (pars convoluta), PEPT2 is overwhelmingly but not exclusively expressed in latter regions of the proximal tubule (pars recta). All other segments along the nephron were negative for PEPT1 or PEPT2 mRNA transcripts. These finding were supported by in situ hybridization results in which PEPT1 was selectively expressed in kidney cortex and PEPT2 in the outer stripe of outer medulla. CONCLUSIONS: Contrary to current opinion, the data suggest that peptides are handles in a sequential manner in proximal regions of the nephron, first by the low-affinity, high-capacity transport system and second by the high-affinity, low-capacity transport system.

Animals↗
PubMed1997

Perinatal lethality with kidney and pancreas defects in mice with a targetted Pkd1 mutation.

PKD1 is the most common site for mutations in human autosomal dominant polycystic kidney disease (ADPKD). ADPKD is characterized by progressive replacement of kidney tissue by epithelial cysts and eventual renal failure. Hepatic and pancreatic cysts are also common. The PKD1 protein, polycystin, is a cell-surface protein of unknown function that is widely expressed in epithelia and in vascular smooth muscle and myocardium. None of the genetic forms of murine polycystic disease map to the murine Pkd1 locus. We introduced into mice by homologous recombination a Pkd1 truncation mutation, Pkd1-, that mimics a mutation found in ADPKD. Pkd1- heterozygotes have no discernible phenotype, whereas homozygotes die during the perinatal period with massively enlarged cystic kidneys, pancreatic ductal cysts and pulmonary hypoplasia. Renal cyst formation begins at embryonic day 15.5 (E15.5) in proximal tubules and progresses rapidly to replace the entire renal parenchyma. The timing of cyst formation indicates that full-length polycystin is required for normal morphogenesis during elongation and maturation of tubular structures in the kidney and pancreas.

Abnormalities, Multiple↗
PubMed1997

Distribution and developmentally regulated expression of murine polycystin.

PKD1, the gene that is mutated in approximately 85% of autosomal dominant polycystic kidney disease (ADPKD) cases in humans, has recently been identified (Eur. PKD Consortium. Cell 77: 881-894, 1994; also, erratum in Cell 78: 1994). The longest open-reading frame of PKD1 encodes polycystin, a novel approximately 460-kDa protein that contains a series of NH2-terminal adhesive domains (J. Hughes, C. J. Ward, B. Peral, R. Aspinwall, K. Clark, J. San Millan, V. Gamble, and P. C. Harris. Nat. Genet. 10: 151-160, 1995; and Int. PKD Consortium. Cell 81: 289-298, 1995) and several putative transmembrane segments. To extend studies of polycystin to an experimentally accessible animal, we have isolated a cDNA clone encoding the 3' end of Pkd1, the mouse homologue of PKD1, and raised a specific antibody to recombinant murine polycystin. This antibody was used to determine the subcellular localization and tissue distribution of the protein by Western analysis and immunocytochemistry. In the mouse, polycystin is an approximately 400-kDa molecule that is predominantly found in membrane fractions of tissue and cell extracts. It is expressed in many tissues including kidney, liver, pancreas, heart, intestine, lung, and brain. Renal expression, which is confined to tubular epithelia, is highest in late fetal and early neonatal life and drops 20-fold by the third postnatal week, maintaining this level into adulthood. Thus the temporal profile of polycystin expression coincides with kidney tubule differentiation and maturation.

Aging↗