Biomedical subjects

P Szabo

Publications and source records attributed to P Szabo.

At least 19 recordsLinked to original sources

PubMed2004

Assessment of jaundice in preterm neonates: comparison between clinical assessment, two transcutaneous bilirubinometers and serum bilirubin values.

AIM: 1) To compare the clinical assessment of craniocaudal progression of jaundice and two transcutaneous bilirubinometers with serum bilirubin values in preterm neonates; 2) to identify factors affecting the difference between non-invasive bilirubin estimation and serum bilirubin. METHODS: Serum bilirubin was clinically estimated in healthy preterm newborn infants (34 to 36.9 gestational weeks) independently by a primary investigator and by nurses, and subsequently compared with separate measures of two transcutaneous bilirubinometers. RESULTS: A total of 107 measurements were performed on 69 infants. Minolta JM-102 showed the best performance, with ROC area under the curve of 0.96, followed by BiliCheck over the sternum (0.89) and over the forehead (0.88), clinical assessment by nurses (0.73) and by a physician (0.70). Serum bilirubin >190 micromol/l can be detected with 95% sensitivity with Minolta JM-102 > or =19 units, with BiliCheck > or =145 micromol/l over the sternum and > or =165 micromol/l over the forehead and with jaundice progression to the trunk or further (Kramer zone > or =2). Gestational age affects all non-invasive methods in the estimation of serum bilirubin, whereas skin colour affects both BiliCheck and clinical assessment. Ambient light affects only clinical assessment. CONCLUSION: Minolta JM-102 showed the best performance, closely followed by BiliCheck, with clinical assessment performing far worse than either transcutaneous method. None of the three methods are recommended as complete substitutes for serum bilirubin values in jaundiced preterm infants.

Bilirubin↗

PubMed2002

Anomalous magnetic field dependence of the thermodynamic transition line in the isotropic superconductor (K,Ba)BiO3.

Thermodynamic (specific heat, reversible magnetization, tunneling spectroscopy) and transport measurements have been performed on high quality (K,Ba)BiO3 single crystals. The temperature dependence of the magnetic field H(C(p)) corresponding to the onset of the specific heat anomaly presents a clear positive curvature. H(C(p)) is significantly smaller than the field H(Delta) for which the superconducting gap vanishes but is closely related to the irreversibility line deduced from transport data. Moreover, the temperature dependence of the reversible magnetization presents a strong deviation from the Ginzburg-Landau theory emphasizing the peculiar nature of the superconducting transition in this material.

Journal Article↗

PubMed2002

Iron deficiency in outdoor pig production.

It has been claimed that outdoor-reared suckling piglets do not need iron supplementation. According to practical experience, outdoor-reared and non-iron-supplemented piglets show a lower performance in comparison with their iron-supplemented counterparts. The purpose of the present study was to determine the effect of iron supplementation on outdoor-reared suckling piglets. In a large Hungarian outdoor pig production unit, 4691 piglets were assigned to one of two treatment groups. Piglets in group 1 (n = 2344): received no iron supplementation, whereas piglets in group 2 (n = 2347) were intramuscularly injected in the neck on day 3 post-partum with 1.5 ml of Ferriphor 10% solution (TAD Pharmaceutical GmbH, Bremerhaven, Germany). Animal weights, morbidity, haemoglobin concentration and mortality were recorded and analysed. At weaning the iron-injected piglets were significantly (P < 0.05) heavier. The iron-supplemented piglets also revealed significantly (P < 0.01) less pre-weaning morbidity and mortality and higher (P < 0.01) blood haemoglobin concentration compared with the non-injected ones. This study suggests that in order to prevent pre-weaning losses and support piglet health and weight performance, iron supplementation should be administered to piglets in outdoor pig production units.

Anemia, Iron-Deficiency↗

PubMed2001

Impaired regeneration of the peripheral B cell repertoire from bone marrow following lymphopenia in old mice.

Aging is associated with a decreased production of B cells by the bone marrow and an increased life-span of peripheral B cells. To determine whether the decreased bone marrow B cell production is linked to the increased life-span of B cells in old mice, B cell regeneration following lymphopenia was studied in young and old mice. The rate of bone marrow pre-B cell and of splenic B cell regeneration is slower in irradiated, old compared to irradiated, young recipients of young, congeneic bone marrow. This finding reflects an age-associated defect in the bone marrow microenvironment. As the bone marrow is the only source of a diverse population of B cells, we measured the diversity of the splenic B cell repertoire regenerated following drug-induced lymphopenia in old and young mice. The heterogeneity of mRNA size from IgH complementarity determining region 3 (CDR3) was more restricted in splenic B cells from old compared to young mice providing additional evidence for an age-associated impairment in B cell production by the bone marrow.

Aging↗

PubMed2001

Glucose-induced inhibition of in vitro bone mineralization.

Patients with diabetes tend to have an increased incidence of osteopenia that may be related to hyperglycemia. However, little is known about how glucose may alter bone formation and osteoblast maturation. To determine whether glucose affects osteoblastic calcium deposition, MC3T3-E1 cells were incubated in media containing either a normal (5.5 mmol/L) or high glucose concentration (15 mmol/L) or mannitol (15 mmol/L), and bone nodule formation was examined. Net calcium flux was measured thrice weekly and cumulative calcium uptake was determined. Compared with control incubations, glucose significantly inhibited daily and cumulative calcium uptake into the nodules. At the time of matrix maturation, cultures undergo a rapid phase of increased calcium deposition; this was significantly inhibited by the presence of glucose. Total calcium uptake, determined by acid digestion, was also significantly inhibited by glucose. Area and number of nodules were quantitated at the end of the incubation period (day 30) by staining with Alizarin Red S calcium stain. Compared with both control and mannitol-treated cultures, the number of nodules was increased by incubation with glucose. Furthermore, both the average total nodular area and calcified nodular area of large nodules were increased by glucose. Cellular proliferation as well as the release of markers of osteoblast activity (osteocalcin and alkaline phosphatase) were determined at the end of the experimental period (day 30). Cellular proliferation and alkaline phosphatase activity was significantly increased in the presence of glucose, however, the release of osteocalcin into culture media was similar in all three groups. In conclusion, the present study shows that elevated glucose concentration present throughout the development of murine osteoblasts stimulates cellular proliferation while inhibiting calcium uptake. The result of glucose inhibition of calcium uptake suggests that bone could be structurally altered in diabetes.

Alkaline Phosphatase↗

PubMed2001

[A French tool for evaluation of home palliative care: adaptation of the Support Team Assessment Schedule].

The authors describe the utilisation of a quality assessment tool for palliative care administered at home. The questionnaire entitled Support Team Assessment Schedule (STAS) was translated from English for this study. It was then utilised comparatively with different quality of life evaluation instruments. Only the results of the STAS are described here. The approach allows for the unresolved problems in the care to come to the surface week after week. The STAS comprises nine items pertaining to the patient and his/her family, and seven items concerning the services provided. The study exhibits the results of 107 evaluations completed from 50 patients stricken with cancer or AIDS in an advanced phase. The availability of this auto clinical audit tool, employable at home or in a hospital, constitutes an essential initial step in the field of French-speaking clinical evaluation of palliative care.

Acquired Immunodeficiency Syndrome↗

PubMed2000

Age-related dysregulation in CD8 T cell homeostasis: kinetics of a diversity loss.

Relative diversity and representation of peripheral T cells bearing different TCR Vbeta families are remarkably tightly regulated between birth and advanced adulthood. By contrast, individual elderly humans and C3H.SW and B10.BR aged mice display drastic disruption in such regulation. It was suggested that the alterations in the murine aged T cell compartment were due to age-related clonal T cell expansions (TCE). Here, we studied the kinetics of homeostatic dysregulation of T cell populations in aged C57BL/6 (B6) mice. Using mAb staining, we show that the percentages of alphabeta+CD8+ or CD4+ T cells bearing different TCRVbeta elements remain virtually constant in mice up to 12 mo of age. In 22-mo-old mice, however, there is a dramatic disturbance of this pattern owing to the emergence of CD8+ TCE. Expanded T cells did not show any obvious bias in Vbeta usage and were derived in all cases examined thus far from a single clone. TCE appeared later in life, compared with B cell clonal expansions. However, and in contrast to those detected in humans, TCE were frequently unstable disappearing within 2-4 mo, with other TCE appearing within the same time frame. Additional studies carried on thymic T cells, thymectomized mice, and young T transferred cells into Rag1-/- mice suggest that the clonal expansions occur in the periphery and that their onset is accelerated by decreased thymic output and/or function(s).

Aging↗

PubMed2000

The effect of age on the B-cell repertoire.

The antibody repertoire changes with age. This change reflects, in part, the age-associated impairment in the production of a diverse population of naive B cells in the bone marrow and, in part, by the decreased diversification of B cells in the germinal center where affinity maturation and isotype switching takes place. B cell number is strictly regulated and despite the decreased output of B cells by the bone marrow does not decline during aging. Self-renewal of peripheral B cells is sufficient to assure the stability of peripheral B cell number. However, when B cell production is stressed as, for example, following drug-induced lymphopenia, the rate of recovery of B cell number as well as of B cell diversity is compromised in old compared to young mice. Finally, aging is associated with the appearance of B cell clonal expansions which not only limit the diversity of the B cell repertoire but very likely give rise to monoclonal serum immunoglobulins and B cell neoplasms.

Adjuvants, Immunologic↗

PubMed2000

Spatial evolutionary prisoner's dilemma game with three strategies and external constraints

The emergency of mutual cooperation is studied in a spatially extended evolutionary prisoner's dilemma game in which the players are located on the sites of cubic lattices for dimensions d=1, 2, and 3. Each player can choose one of the three following strategies: cooperation (C), defection (D) or "tit for tat" (T). During the evolutionary process the randomly chosen players adopt one of their neighboring strategies if the chosen neighbor has a higher payoff. Moreover, an external constraint imposes that the players always cooperate with probability p. The stationary state phase diagram is computed by both using generalized mean-field approximations and Monte Carlo simulations. Nonequilibrium second-order phase transitions associated with the extinction of one of the possible strategies are found and the corresponding critical exponents belong to the directed percolation universality class. It is shown that externally forcing the collaboration does not always produce the desired result.

Journal Article↗

PubMed1999

Molecular mechanism of the short-term cardiotoxicity caused by 2',3'-dideoxycytidine (ddC): modulation of reactive oxygen species levels and ADP-ribosylation reactions.

The short-term cardiac side effects of 2',3'-dideoxycytidine (ddC, zalcitabine) were studied in rats in order to understand the biochemical events contributing to the development of ddC-induced cardiomyopathy. In developing animals, ddC treatment provoked a surprisingly rapid appearance of cardiac malfunctions characterized by prolonged RR, PR, and QT intervals and J point depression. The energy metabolism in the heart was compromised, characterized by a decreased creatine phosphate/creatine ratio (from 2.05 normal value to 0.75) and a decreased free ATP/ADP ratio (from 332 normal value to 121). The activity of respiratory complexes (NADH: cytochrome c oxidoreductase and cytochrome oxidase) also decreased significantly. Southern blot and polymerase chain reaction analysis did not show deletions or a decrease in the quantity of mitochondrial DNA (mtDNA) deriving from ddC-treated rat hearts, indicating that under our experimental conditions, ddC-induced heart abnormalities were not the direct consequence of mtDNA-related damage. The ddC treatment of rats significantly increased the formation of reactive oxygen species (ROS) in heart and skeletal muscle as determined by the oxidation of non-fluorescent dihydrorhodamine123 to fluorescent rhodamine123 and the oxidation of cellular proteins determined from protein carbonyl content. An activation of the nuclear poly-(ADP-ribose) polymerase (EC 2.4.2.30) and an increase in the mono-ADP-ribosylation of glucose-regulated protein and desmin were observed in the cardiac tissue from ddC-treated animals. A decrease in the quantity of heat shock protein (HSP)70s was also detected, while the level of HSP25 and HSP60 remained unchanged. Surprisingly, ddC treatment induced a skeletal muscle-specific decrease in the quantity of three proteins, one of which was identified by N-terminal sequencing as myoglobin, and another by tandem mass spectrometer sequencing as triosephosphate isomerase (EC 5.3.1.1). These data show that the short term cardiotoxicity of ddC is partially based on ROS-mediated signalling through poly- and mono-ADP-ribosylation reactions and depression of HSP70 levels, whose processes represent a new mtDNA independent mechanism for ddC-induced cell damage.

Adenosine Diphosphate Ribose↗

PubMed1999

Adeno-associated virus (AAV) site-specific integration: formation of AAV-AAVS1 junctions in an in vitro system.

An in vitro system to study the mechanism of site-specific integration of adeno-associated virus (AAV) was developed. This system is based on two substrates, a linear or circular AAV donor and a circular acceptor containing the preintegration locus AAVS1. In the presence of HeLa extract and the His-Tag-purified Rep68 protein, specific covalent junctions between AAV and AAVS1 were formed and detected by PCR. The majority of the junctions were located within the Rep binding site of both the AAV and the AAVS1 substrates, underlining the involvement of the Rep protein. A limited amount of replication and the presence of nuclear factors promoted the efficiency of the reaction. The process was ATP-dependent, indicating that the helicase activity of Rep may be important in the formation of the junctions. According to current models of integration, the formation of the junctions would represent a first step in the process of AAV integration. This step could be crucial for the site specificity of the recombination event that leads to the integration of AAV into human chromosome 19 in vivo.

Base Sequence↗

PubMed1999

Cellular basis of B cell clonal populations in old mice.

Previous studies from this laboratory have shown that >85% of old mice have stable B cell clonal populations detectable by Ig heavy chain complementary-determining region 3 mRNA size analysis and confirmed by sequence analysis. B cells from the same clone are frequently detected in several lymphoid compartments of the same mouse. We now report the phenotype of all ten stable B cell clonal populations detected in five 20-month-old C57BL/6 mice. These clonal B cells appear to develop in the periphery and nine of the ten B cell clonal populations expressed the CD5 cell surface marker. Stable B cell expansions may be dominated by cells at two stages of differentiation. Some B cell populations were detected with DNA as well as RNA and represent large clonal populations of B cells, detectable in several lymphoid compartments. These populations are found predominantly in B cell populations expressing CD45R/B220 and the mRNA coding for the membrane-bound form of the mu Ig heavy chain, which suggests a predominance of B lymphocytes in these populations. In other cases, smaller clonal populations were detected only in splenic RNA samples. These clonal populations were found predominantly among CD45R/B220- B cells and did not express the membrane-bound form of the micro Ig heavy chain. We offer the hypothesis that the B cell clonal populations present in old mice may be precursors of the two types of B cell neoplasms which are dominated by CD5+ B cells (B cell chronic lymphocytic leukemia) or plasma cells (multiple myeloma).

Aging↗

PubMed1999

Age-associated defects in B lymphocyte development.

The steady-state level of both RAG-1 and RAG-2 mRNA, the number of Pre-B cells, and the number of Pre-B cells expressing RAG-2 protein decrease in the bone marrow of old mice. These differences appear to be due, at least in part, to increased apoptosis of bone marrow Pre-B cells. To determine whether the age-associated increase in apoptosis reflects the impaired expression of the Pre-B cell receptor required for the survival of Pre-B cells, we examined the recombination of D to J and V to DJ in bone marrow from young and old mice. Both D to J recombination, which occurs early in the Pro-B cell stage of development, and V to DJ, which occurs just prior to the transition to the Pre-B cell stage, are diminished with age. These findings support the view that immunoglobulin recombination may impair the expression of the Pre-B cell receptor and may contribute to the increased rate of apoptosis of Pre-B cells in the bone marrow of old mice.

Aging↗

PubMed1998

Heteroclitic immunization induces tumor immunity.

In tumor transplantation models in mice, cytotoxic T lymphocytes (CTLs) are typically the primary effector cells. CTLs recognize major histocompatibility complex (MHC) class I-associated peptides expressed by tumors, leading to tumor rejection. Peptides presented by cancer cells can originate from viral proteins, normal self-proteins regulated during differentiation, or altered proteins derived from genetic alterations. However, many tumor peptides recognized by CTLs are poor immunogens, unable to induce activation and differentiation of effector CTLs. We used MHC binding motifs and the knowledge of class I:peptide:TCR structure to design heteroclitic CTL vaccines that exploit the expression of poorly immunogenic tumor peptides. The in vivo potency of this approach was demonstrated using viral and self-(differentiation) antigens as models. First, a synthetic variant of a viral antigen was expressed as a tumor antigen, and heteroclitic immunization with peptides and DNA was used to protect against tumor challenge and elicit regression of 3-d tumors. Second, a peptide from a relevant self-antigen of the tyrosinase family expressed by melanoma cells was used to design a heteroclitic peptide vaccine that successfully induced tumor protection. These results establish the in vivo applicability of heteroclitic immunization against tumors, including immunity to poorly immunogenic self-proteins.

Amino Acid Sequence↗

PubMed1998

Maturation of B cell precursors is impaired in thymic-deprived nude and old mice.

We have previously reported that bone marrow B cell precursors from thymic-deprived nude and old mice express less recombination-activating gene-1 (RAG-1) mRNA than they do in young euthymic mice. We now report that both nude and old mice have decreased bone marrow pre-B cells and that fewer pre-B cells express RAG protein. This combination of events appears to be the basis for the lower level of bone marrow RAG mRNA in thymic-deprived mice. A link between thymic function and B cell development was suggested by the similar kinetics of thymic involution and of declining bone marrow RAG-1 gene expression during aging. Support for this hypothesis was obtained by demonstrating that injection of supernatant medium from activated CD8+ but not CD4+ young T cells from mice increases RAG mRNA, RAG protein, and the number of bone marrow pre-B cells in nude and old mice. Furthermore, in vivo CD8+ T cells also regulate bone marrow RAG gene expression. Thus, mice deficient in CD8+ T cells expressed levels of RAG-1 mRNA in their bone marrow that were only 10% of those observed in normal or CD4+ T cell-deficient mice. IL-16 was detected in the supernatant medium from activated T cell cultures, and injection of nanogram quantities of recombinant IL-16 (rIL-16) into nude or old mice increased the levels of RAG mRNA in bone marrow B cell precursors and the number of bone marrow pre-B cells. We conclude that the impaired development of B cells within the bone marrow of thymic-deprived nude and old mice can be reversed, at least in part, by the administration of rIL-16.

Aging↗

PubMed1998

Increased VH 11 and VH Q52 gene use by splenic B cells in old mice associated with oligoclonal expansions of CD5 + B cells.

A significant increase in the utilization of the VH gene families VH11 and Q52 was observed in LPS-stimulated splenic B lymphocytes from aged mice compared to young mice. VH gene usage was assayed by in situ DNA/RNA hybridization using VH family-specific and kappa chain probes. The observed age-dependent differences appear to reflect the preferential use of VH11 and Q52 VH gene use by the CD5 + B lymphocyte subset whose numbers in the spleen increase with age. The increased use of VH11 by splenic cells from old mice is associated with clonal expansions of splenic CD5 + B lymphocytes.

Aging↗

PubMed1998

Antiretroviral effects of deoxyhypusyl hydroxylase inhibitors: a hypusine-dependent host cell mechanism for replication of human immunodeficiency virus type 1 (HIV-1).

The HIV-1 protein Rev, critical for translation of incompletely spliced retroviral mRNAs encoding capsid elements, requires a host cell protein termed "eukaryotic initiation factor 5A" (eIF-5A). This is the only protein containing hypusine, a lysine-derived hydroxylated residue that determines its proposed bioactivity, the translation of a subset of cellular mRNAs controlling G1-to-S transit of the cell cycle. We postulated that inhibiting the hypusine-forming deoxyhypusyl hydroxylase (DOHH) should, by depleting eukaryotic initiation factor 5A, compromise Rev function and thus reduce HIV-1 multiplication. We now report that the alpha-hydroxypyridones, specifically mimosine, a natural product, and deferiprone, an experimental drug, inhibited deoxyhypusyl hydroxylase in T-lymphocytic and promonocytic cell lines and, in a concentration-dependent manner, suppressed replication of HIV-1. However, the alpha-hydroxypyridones did not affect the formation of unspliced or multiply spliced HIV-1 transcripts. Rather, these agents caused Rev-dependent incompletely spliced HIV-1 mRNA such as gag, but not cellular "housekeeping" mRNAs, to disappear from polysomes. Consequently, alpha-hydroxypyridone-mediated depletion of eIF-5A decreased biosynthesis of structural HIV-1 protein encoded by gag, measured as p24, whereas the induced formation of cellular protein like tumor necrosis factor alpha remained unaffected. By interfering with the translation of incompletely spliced retroviral mRNAs, these compounds restrict HIV-1 to the early, nongenerative phase of its reproductive cycle. In the inducibly HIV-1 expressing T-cell line ACH-2, the deoxyhypusyl hydroxylase inhibitors triggered extensive apoptosis, particularly of cells that actively produce HIV-1. Selective suppression of retroviral protein biosynthesis and preferential apoptosis of retrovirally infected cells by alpha-hydroxypyridones point to a novel mode of antiretroviral action.

Anti-HIV Agents↗

PubMed1998

Cross-linked high amylose starch for controlled release of drugs: recent advances.

Cross-linked high amylose starches have been developed as excipients for the formulation of controlled-release solid dosage forms for the oral delivery of drugs. Advantages of this new class of excipients include cost-effectiveness, readily accessible industrial manufacturing technology, high active ingredient core loading and the possibility of achieving a quasi zero-order release for most drugs. In addition to the latter, other features distinguish cross-linked high amylose starches from other excipients used to prepare hydrophilic matrices. Among these are the absence of erosion, the limited swelling and the fact that increasing cross-linking degrees results in increased water uptake rate, drug release rate and equilibrium swelling. Thus the goal of the present study was to gain some insights into the mechanism of drug release control by matrices of cross-linked high amylose starch. Water transport kinetics and dimensional changes were studied in matrices placed in water at 37 degrees C by an image analysis technique. The results show that in the first 5 min, a gel layer is formed at the surface of the tablet, after which the gel front seems to halt its progression toward the center of the tablet. Water continues to diffuse through the front and to invade the core. As a consequence, this latter swells, with a predominance for radial swelling. Equilibrium swelling is reached over 3 days, when the water concentration in the tablet becomes homogeneous and the whole tablet gelifies. Solid-state 13C-NMR were acquired on cross-linked high amylose starch powders, tablets and hydrated tablets with varying cross-linking degrees. They show a predominance of the V-type single helix arrangement of amylose in the dry state irrespective of the cross-linking degree. Upon hydration, the homologues with a low cross-linking degrees show a transition from the V to the B-type double helix arrangement. It is therefore hypothesized that the capacity of amylose to undergo the V to B transition is an important factor in controlling water transport and drug release rate. Finally applications to different drugs are reviewed briefly. They illustrate the versatility of this technology as generic versions of zero order OROS drug (Efidac) and Fickian release conventional matrices (Voltaren SR) were developed and successfully tested in pilot clinical studies to be bioequivalent to the references. These studies further showed that cross-linked high amylose starch matrices have the lowest inter-subject variability among the systems tested and show a total absence of food effect.

Administration, Oral↗