Biomedical subjects

A Nagy

Publications and source records attributed to A Nagy.

At least 19 recordsLinked to original sources

PubMed2007

Improved embryonic stem cell technologies.

Murine embryonic stem (ES) cells have become an indispensable tool for investigating genetic function both in vitro and, importantly, in vivo. Recent advances, including tetraploid aggregation, new site-specific recombinases and RNAi, have enabled more sophisticated manipulation of the ES cell genome. For instance, it is now possible to control gene expression in both a temporally and spatially restricted manner. Such new technologies are answering complex questions surrounding the function and interaction of an increasing number of genes. This chapter will review both the history and recent technological progress that has been made in mouse ES cell derivation, genetic manipulation and the generation of ES cell-derived chimaeric animals.

Animals↗

PubMed2006

Spherically and system-averaged pair density functional theory.

In a couple of recent papers Gori-Giorgi and Savin [Phys. Rev. A 71, 032513 (2005)] proposed a theory that provides simple radial equations to generate the spherically and system averaged pair density. In a recent density matrix functional theory [A. Nagy, Phys. Rev. A 66, 022505 (2002)] it was shown that the problem of an arbitrary system can be reduced to a two-particle problem. Based on this theory, via a double adiabatic connection, it is rigorously derived that the square root of the ground-state spherically and system averaged pair density is the solution of a simple radial equation, that is, contrary to the theory of Gori-Giorgi and Savin only a single equation has to be considered.

Journal Article↗

PubMed2006

Mechanical manipulation of Alzheimer's amyloid beta1-42 fibrils.

The 39- to 42-residue-long amyloid beta-peptide (Abeta-peptide) forms filamentous structures in the neuritic plaques found in the neuropil of Alzheimer's disease patients. The assembly and deposition of Abeta-fibrils is one of the most important factors in the pathogenesis of this neurodegenerative disease. Although the structural analysis of amyloid fibrils is difficult, single-molecule methods may provide unique insights into their characteristics. In the present work, we explored the nanomechanical properties of amyloid fibrils formed from the full-length, most neurotoxic Abeta1-42 peptide, by manipulating individual fibrils with an atomic force microscope. We show that Abeta-subunit sheets can be mechanically unzipped from the fibril surface with constant forces in a reversible transition. The fundamental unzipping force (approximately 23 pN) was significantly lower than that observed earlier for fibrils formed from the Abeta1-40 peptide (approximately 33 pN), suggesting that the presence of the two extra residues (Ile and Ala) at the peptide's C-terminus result in a mechanical destabilization of the fibril. Deviations from the constant force transition may arise as a result of geometrical constraints within the fibril caused by its left-handed helical structure. The nanomechanical fingerprint of the Abeta1-42 is further influenced by the structural dynamics of intrafibrillar interactions.

Alzheimer Disease↗

PubMed2006

Lipopolysaccharide exposure makes allergic airway inflammation and hyper-responsiveness less responsive to dexamethasone and inhibition of iNOS.

Allergic airway disease can be refractory to anti-inflammatory treatment, whose cause is unclarified. Therefore, in the present experiment, we have tested the hypothesis that co-exposure to lipopolysacharide (Lps) and allergen results in glucocorticoid-resistant eosinophil airway inflammation and hyper-responsiveness (AHR). Ovalbumin (Ova)-sensitized BALB/c mice were primed with 10 microg intranasal Lps 24 h before the start of Ova challenges (20 min on 3 consecutive days). Dexamethasone (5 mg/kg/day) was given on the last 2 days of Ova challenges. AHR, cellular build-up, cytokine and nitrite concentrations of bronchoalveolar lavage fluid (BALF) and lung histology were examined. To assess the role of iNOS-derived NO in airway responsiveness, mice were treated with a selective inhibitor of this enzyme (1400W) 2 h before AHR measurements. More severe eosinophil inflammation and higher nitrite formation were found in Lps-primed than in non-primed allergized mice. After Lps priming, AHR and concentrations of T-helper type 2 cytokines in BALF were decreased, but still remained significantly higher than in controls. Eosinophil inflammation was partially, while nitrite production and AHR were observed to be largely dexamethasone resistant in Lps-primed allergized animals. 1400W effectively and rapidly diminished the AHR in Ova-sensitized and challenged mice, but failed to affect it after Lps priming plus allergization. In conclusion, Lps inhalation may exaggerate eosinophil inflammation and reduce responsiveness to anti-inflammatory treatment in allergic airway disease.

Animals↗

PubMed2006

Trendelenburg positioning does not prevent a decrease in cardiac output after induction of anaesthesia with propofol in children.

BACKGROUND AND OBJECTIVE: Induction of anaesthesia may cause decreased cardiac output and blood pressure. Head-down tilt is often the first clinical step to treat hypotension. The objective of this randomized single centre study was to determine, with the use of impedance cardiography (ICG), whether Trendelenburg positioning modifies the haemodynamic response to propofol/fentanyl induction of anaesthesia in ASA I children. METHODS: Thirty ASA I children aged between 7 and 16 years scheduled for elective minor orthopaedic surgery were included. After intravenous induction with propofol and fentanyl in the head-down group (HDG, n = 15), 5 min of 20 degrees head-down tilt was applied. In the supine group (SG, n = 15), no change in the supine position was made. Heart rate (HR), mean arterial blood pressure (MABP), end-tidal carbon dioxide (ETCO(2)), stroke volume index (SVI), cardiac index (CI), systemic vascular resistance index (SVRI) and Heather index (HI) were recorded before (B), at 3 (A(3)), 5 (A(5)) and 8 (A(8)) minutes after induction in each group. RESULTS: After induction, a significant decrease in CI, MABP, HR and HI was recorded in both groups. In the study group, significantly lower values of HR (66 vs. 78 beat/min) and higher values of SVI (42.9 vs. 40.6 ml/min/m(2)) were measured at A(3) compared with the control group. After induction, no difference in CI and SVRI was found between the two groups. CONCLUSION: The present study shows that cardiac performance is not improved by Trendelenburg positioning after propofol/fentanyl induction of anaesthesia in children.

Adolescent↗

PubMed2006

Nuclear transfer reprogramming does not improve the low developmental potency of embryonic stem cells induced by long-term culture.

Epigenetic states of embryonic stem (ES) cells are easily altered by long-term cultivation and lose their developmental potential. To rescue this reduced developmental capacity, nuclear transfer (NT) of ES cells was carried out, and original ES and ES cells from cloned blastocysts (ntES) cells established after NT were compared with in vitro differentiation ability and developmental potential by embryoid body formation and tetraploid aggregation respectively. In the establishment of ntES cell lines, the oocytes fused with the ES cell were activated, and further cultured to cloned blastocysts. When in vitro differentiation ability was examined between original and ntES cell lines derived from ES cells with extensive passages (ES-ep), the day of appearance of simple embryoid body, cystic embryoid body, and spontaneous beating was almost similar. The developmental rates of ES-ep cells, that aggregated with tetraploid embryos to term, ranged from 3 to 6%. Moreover, the majority of live pups died soon after birth. In the ntES cell lines derived from ES-ep cells, developmental rates ranged from 0 to 5%. Those pups also died soon after birth, similar to the ES-ep-derived pups. These results suggest that profound epigenetic modifications of ES cells were retained in the re-established cell lines by NT.

Animals↗

PubMed2005

Spatial and temporal visual properties of single neurons in the suprageniculate nucleus of the thalamus.

The spatial and temporal visual sensitivity to drifting sinusoidal gratings was studied in 105 neurons of the suprageniculate nucleus of the feline thalamus. Extracellular single-unit recordings were performed in halothane-anesthetized, immobilized, artificially ventilated cats. Most suprageniculate nucleus cells were strongly sensitive to the direction of drifting gratings. The suprageniculate nucleus units had a clear preference for very low spatial frequencies with a mean of 0.05 cycle/deg. The spatial resolution was also very low with a mean of 0.16 cycle/deg. Most of the cells displayed low-pass spatial tuning characteristics, while the remainder of the units were band-pass tuned. The suprageniculate nucleus units were extremely narrowly tuned, to spatial frequencies with a mean spatial bandwidth of 1.07 octaves. A majority of the units responded optimally to high temporal frequencies, with a mean of 8.53 Hz. The temporal frequency tuning functions predominantly revealed a band-pass character, with a mean temporal bandwidth of 1.66 octaves. These results demonstrate that the neurons in the suprageniculate nucleus display particular spatial and temporal characteristics. The spatial and temporal tuning properties of the suprageniculate nucleus neurons are very similar to those of the superior colliculus and the anterior ectosylvian cortex, structures that provide the main visual afferentation toward the suprageniculate nucleus. This suggests their common function in motion perception, and especially in the recording of movements of the visual environment relative to the body, and the related behavioral action.

Animals↗

PubMed2005

Two successful pregnancies following eight miscarriages in a patient with antithrombin deficiency.

Inherited thrombophilias are associated with an increased risk of maternal thromboembolism and certain adverse pregnancy outcomes, including second- and third-trimester fetal loss, placental abruption, severe intrauterine growth restriction, and early-onset, severe preeclampsia. Pregnant patients with severe thrombophilias, especially antithrombinopathies are at very high risk for both thromboembolism and adverse pregnancy outcomes. A case of a patient with antithrombin deficiency is reported, who had two successful pregnancies after eight miscarriages. Our case shows that a combined treatment with antithrombin substitution and a prophylactic, body-weight-adjusted dose of low-molecular-weight heparin may be successful in preventing pregnancy loss and thromboembolism in antithrombin deficiency during pregnancy, although other complications, such as preeclampsia and intrauterine growth restriction cannot always be prevented.

Abortion, Habitual↗

PubMed2005

Density scaling and exchange-correlation energy.

The exchange-correlation energy is studied using the density scaling proposed by Chan and Handy [G. K.-L. Chan and N. C. Handy, Phys. Rev. A 59, 2670 (1999)]. It is shown that there exists a value of the scaling factor for which the correlation energy disappears. The optimized potential method and the Krieger-Li-Iafrate approach are generalized to incorporate correlation.

Journal Article↗

PubMed2005

Hierarchical extensibility in the PEVK domain of skeletal-muscle titin.

Titin is the main determinant of passive muscle force. Physiological extension of titin derives largely from its PEVK (Pro-Glu-Val-Lys) domain, which has a different length in different muscle types. Here we characterized the elasticity of the full-length, human soleus PEVK domain by mechanically manipulating its contiguous, recombinant subdomain segments: an N-terminal (PEVKI), a middle (PEVKII), and a C-terminal (PEVKIII) one third. Measurement of the apparent persistence lengths revealed a hierarchical arrangement according to local flexibility: the N-terminal PEVKI is the most rigid and the C-terminal PEVKIII is the most flexible segment within the domain. Immunoelectron microscopy supported the hierarchical extensibility within the PEVK domain. The effective persistence lengths decreased as a function of ionic strength, as predicted by the Odijk-Skolnick-Fixman model of polyelectrolyte chains. The ionic strength dependence of persistence length was similar in all segments, indicating that the residual differences in the elasticity of the segments derive from nonelectrostatic mechanisms.

Amino Acid Motifs↗

PubMed2005

Generalized density functional theory for degenerate states.

An extension of density functional theory is proposed for degenerate states. There are suitably selected basic variables beyond the subspace density. Generalized Kohn-Sham equations are derived. A direct method is proposed to ensure the fixed value of ensemble quantities. Then the Kohn-Sham equations are similar to the conventional Kohn-Sham equations. But the Kohn-Sham potential is different for different ensembles. A simple local expression is proposed for the correlation energy.

Journal Article↗

PubMed2005

Visual receptive field properties of excitatory neurons in the substantia nigra.

The substantia nigra has been widely regarded as a structure involved in visuomotor co-ordination, but little is known about the sensory background of its function. Here we give a detailed description of the visual receptive field properties of excitatory substantia nigra neurons. The visual responses of 59 excitatory neurons were recorded in both the substantia nigra pars reticularis and the pars compacta of halothane-anesthetized, immobilized, artificially respirated cats. The substantia nigra neurons were not responsive or exhibited very low sensitivity to stationary visual stimulation. The units responded optimally to small stimuli moving at intermediate or high velocities in their extremely large receptive field. We observed no signs of retinotopical organization within the substantia nigra. A majority of the units exhibited narrow direction tuning and high direction selectivity, while a smaller proportion of them were broadly tuned and not direction-sensitive. Our results suggest that the visual properties of the excitatory substantia nigra units are quite similar to those of the superior colliculus and other extrastriatal structures that receive tectal afferents. This supports the notion that the substantia nigra processes dynamic visual information and that its excitatory visual neurons are modulated by the extrageniculate tectal visual system of the mammalian brain.

Action Potentials↗

PubMed2005

Targeting cytotoxic conjugates of somatostatin, luteinizing hormone-releasing hormone and bombesin to cancers expressing their receptors: a "smarter" chemotherapy.

Chemotherapy is one of the main modalities in the therapy of cancer. However, an improvement in the efficacy and a reduction in the toxicity of chemotherapeutic agents remains a great challenge to oncologists. A specific delivery of cytotoxic drugs to cancerous cells may help improving both aspects. Peptide hormones, for which receptors have been found in various human cancers, can serve as carriers for a local delivery of cytotoxic agents or radiopharmaceuticals to the tumors, as demonstrated by the successful clinical use of radiolabeled somatostatin analog Octreoscan for the detection and treatment of some somatostatin receptor-positive tumors. Thus, in recent years we developed a series of cytotoxic peptide hormone conjugates based on derivatives of hypothalamic hormones such as somatostatin and luteinizing hormone-releasing hormone (LHRH), and the brain-gut hormone bombesin. To create targeted conjugates with high cytotoxic activity, a derivative of doxorubicin (DOX), 2-pyrrolino-DOX (AN-201), which is 500-1, 000 times more active than its parent compound, was developed. This agent was coupled to somatostatin octapeptide RC-121 to form cytotoxic conjugate AN-238, and to [D-Lys6]LHRH carrier to produce analog AN-207. Cytotoxic bombesin hybrid AN-215 also contains AN-201. DOX was likewise linked to [D-Lys6]LHRH to form AN-152. A comprehensive testing of these cytotoxic conjugates in experimental models of various human and rodent cancers led to their selection as candidates for clinical trials.

Animals↗

PubMed2004

Effective potential in density matrix functional theory.

In the previous paper it was shown that in the ground state the diagonal of the spin independent second-order density matrix n can be determined by solving a single auxiliary equation of a two-particle problem. Thus the problem of an arbitrary system with even electrons can be reduced to a two-particle problem. The effective potential of the two-particle equation contains a term v(p) of completely kinetic origin. Virial theorem and hierarchy of equations are derived for v(p) and simple approximations are proposed. A relationship between the effective potential u(p) of the shape function equation and the potential v(p) is established.

Journal Article↗

PubMed2004

New approaches to therapy of cancers of the stomach, colon and pancreas based on peptide analogs.

Cancers of the stomach, colon and exocrine pancreas are major international health problems and result in more than a million deaths worldwide each year. The therapies for these malignancies must be improved. The effects of gastrointestinal (GI) hormonal peptides and endogenous growth factors on these cancers were reviewed. Some GI peptides, including gastrin and gastrin-releasing peptide (GRP) (mammalian bombesin), appear to be involved in the growth of neoplasms of the GI tract. Certain growth factors such as insulin-like growth factor (IGF)-I, IGF-II and epidermal growth factor and their receptors that regulate cell proliferation are also implicated in the development and progression of GI cancers. Experimental investigations on gastric, colorectal and pancreatic cancers with analogs of somatostatin, antagonists of bombesin/GRP, antagonists of growth hormone-releasing hormone as well as cytotoxic peptides that can be targeted to peptide receptors on tumors were summarized. Clinical trials on peptide analogs in patients with gastric, colorectal and pancreatic cancers were reviewed and analyzed. It may be possible to develop new approaches to hormonal therapy of GI malignancies based on various peptide analogs.

Animals↗

PubMed2004

[Parastomal hernia repair and prevention with PHSL type mesh after abdomino-perineal rectum extirpation].

The parastomal hernia is a continuing challenge, because of the disappointing results of the different procedures available to repair it. The mesh implantation seems to be the best, but not optimal method with 8-22 % recurrence rate and about 15-20% other complications. The PHSL (Polypropylene hernia system large; Ethicon inc. Johnson and Johnson, USA) device proved to be an acceptable solution in correction the medium and large parastomal hernia with low recurrence and complication rate. The device enforces the abdominal wall with double mesh layer connected with a tube. The sigmoid colostomy is lifted trough the tube to the abdominal surface. The device was implanted with preventive intent in 14 cases, without any parastomal hernia formation in the first postoperative year. The preventive PHSL mesh implantation at the Miles operation seems to be an useful method for prevention of parastomal hernias.

Colostomy↗

PubMed2004

Microsatellite allelotyping differentiates chromophobe renal cell carcinomas from renal oncocytomas and identifies new genetic changes.

AIMS: The diagnosis of renal oncocytomas (ROs) and chromophobe renal cell carcinomas (RCCs) based on histological features is often uncertain. To assess the value of genetic analysis in their differential diagnosis we analysed 27 ROs and 21 chromophobe RCCs by microsatellite allelotyping. METHODS AND RESULTS: Markers at the short and long arms of chromosomes specifically involved in the genetic changes of the four main types of renal cancers were selected. Allelic changes were identified by automated sequencing. Allelic changes at chromosome 1p occurred in 8/26 (31%) and at chromosome 14q in 4/27 (15%) ROs. Loss of heterozygosity (LOH) at chromosomes 1, 2, 6, 10, 13, 17 and 21 were seen in 90%, 90%, 96%, 86%, 85%, 90% and 72% of the chromophobe RCCs, respectively. Alterations of at least three of these chromosomal sites were detected in each chromophobe RCC. In addition, we found recurrent LOH at chromosomes 9p23 (43%), 18q22 (30%), 5q22 (28%) and 8p (28%) in chromophobe RCCs. CONCLUSIONS: Chromophobe RCCs can be differentiated from ROs by analysing specific chromosomal regions with microsatellites.

Adenoma, Oxyphilic↗

PubMed2003

Targeted deletion of histidine decarboxylase gene in mice increases bone formation and protects against ovariectomy-induced bone loss.

Targeted disruption of the histidine decarboxylase gene (HDC(-/-)), the only histamine-synthesizing enzyme, led to a histamine-deficient mice characterized by undetectable tissue histamine levels, impaired gastric acid secretion, impaired passive cutaneous anaphylaxis, and decreased mast cell degranulation. We used this model to study the role of histamine in bone physiology. Compared with WT mice, HDC(-/-) mice receiving a histamine-free diet had increased bone mineral density, increased cortical bone thickness, higher rate of bone formation, and a marked decrease in osteoclasts. After ovariectomy, cortical and trabecular bone loss was reduced by 50% in HDC(-/-) mice compared with WT. Histamine deficiency protected the skeleton from osteoporosis directly, by inhibiting osteoclastogenesis, and indirectly, by increasing calcitriol synthesis. Quantitative RT-PCR showed elevated 25-hydroxyvitamin D-1alpha-hydroxylase and markedly decreased 25-hydroxyvitamin D-24-hydroxylase mRNA levels. Serum parameters confirming this indirect effect included elevated calcitriol, phosphorus, alkaline phosphatase, and receptor activator of NF-kappaB ligand concentrations, and suppressed parathyroid hormone concentrations in HDC(-/-) mice compared with WT mice. After ovariectomy, histamine-deficient mice were protected from bone loss by the combination of increased bone formation and reduced bone resorption.

Animals↗