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Biomedical subjects

P Hermann

Publications and source records attributed to P Hermann.

At least 19 recordsLinked to original sources
PubMed2005

Incidence of oropharyngeal candidosis in stem cell transplant (SCT) patients.

Eighty persons with haematological malignancies receiving stem cell transplantation (SCT) were examined over a 24 months period. Hyposalivation, a common complaint in patients treated by intensive chemotherapy and radiotherapy can predispose to oral candidal colonisation as well. This study was focused on correlation between the fungal colonisation of the oral cavity and the total unstimulated saliva flow rate of 80 patients with haematological malignancies before and after stem cell transplantation and in addition, on their oral health state. Despite the fact that prior to being involved in the transplantation programme, the patients were subjected to dental examination and decayed teeth were found in 20 out of 80 patients (25%). From the 2233 different oropharyngeal specimens fungi were isolated before conditioning from 16 patients (20%), and during aplasia from 19 patients (23.7%). Objective xerostomia (unstimulated total saliva flow rate < or = 0.1 ml/min) was detected in 28 patients (35%). Stem cell transplant patients with pretransplant mouth dryness had higher incidence of Candida albicans and other fungal colonisation than those with normal saliva secretion.

Adolescent↗
PubMed2003

Effects of alkali metal ions on some virulence traits of Candida albicans.

The effects of the alkali metal ions (Li+, Na+ and K+) on the growth and on certain virulence factors (adhesion, cell-surface hydrophobicity and germinating ability) of Candida albicans were determined. High concentrations of these ions displayed an inhibitory effect on the growth of the Candida cells; preincubation in their presence showed a negative effect on all virulence factors studied. The changes induced during the preincubation remained there even when high concentration of the ions was removed from the cell suspension. In contrast, a considerable growth was found at high Na+ and K+ concentrations. Although alkali metal ions significantly decreased certain virulence traits of the fungus they did not totally inhibit adhesion and germ-tube formation. This suggests that C. albicans may represent a health hazard even at a high salt concentration.

Candida albicans↗
PubMed2001

[Clinical, microbiological and therapeutic aspects of oral candidiasis (candidosis)].

Exogenic, prosthetical and endogenic factors that may influence and facilitate fungal infections of the oral cavity are summarized. The clinical classification of the oral candidiasis is based on the criteria accepted in the international literature. The main points for the classification are the clinical appearances, the histopathological alterations and the possible manifestation of an underlying disease. In the last part of the review a brief summary is given on the antifungal agents such as polyenes, azole-derivatives and DNA analogs available for candidiasis.

Antifungal Agents↗
PubMed2001

[Molecular pathogenesis of oral candidiasis (candidosis)].

Candida species are the most important pathogenic fungi in the oral cavity with the predominance of Candida albicans. In this review the authors summarise the most important cell-surface bound pathogenical factors such as fibrinogen, fibronectin, thrombin, collagen, laminin and vitronectin-binding proteins and extracellular virulence enzymes of Candida albicans and some microbiological aspects of oral candidiasis (candidosis). Adherence to both artificial and mucosal surfaces is mediated by hydrophobic interactions and by ligand-receptor attachment. Surface bound proteins on Candida cells bind to mucosal surface proteins. Broad spectrum antibacterial treatment liberates binding sites for Candida colonisation by means of reducing the number of bacterial normal flora in the oral cavity. Non immune humoral factors such as iron, lysosyme, hystidine-rich-polypeptides, lactoferrin, lactoperoxidase and immune globulins such as s-IgA, moreover, elements of cellular immunity, especially polymorphonuclear leucocytes contribute to preventing the establishment of Candida infection. A disbalance in these constituents may result in colonisation and biofilm production of Candida. The biofilm consist of serum proteins mainly fibrin, desquamated epithelial cells, dead leukocytes, living and multiplying candida cells, pseudohyphae and extracellular matrix excreted by candida cells. Living candida cells are deeply embedded in the biofilm, thus protected from defence mechanisms of the host. Continuous destruction of mucosal surfaces beneath the biofilm may create a portal of entry for systematic candidal infections.

Candidiasis, Oral↗
PubMed2001

Pathogenesis, microbiological and clinical aspects of oral candidiasis (candidosis).

The clinical significance of the oral candidiasis (either as independent disorder, or as a part of another disease) is increasing with time. The diagnosis and local treatment of the oral candidiasis may not be satisfactory, this disorder cannot be eliminated without the correct diagnosis and management of the underlying disease. At the same time, some disorders, such as Candida induced leukoplakia, may significantly enhance tumor development. Fungal infection of the mouth is often the initial sign of several immunodeficiency diseases. It is, therefore, very important to clarify the background of a fungal infection, since this may be critical regarding the prognosis.

Antifungal Agents↗
PubMed2001

Risk group assessment of oral precancer attached to X-ray lung-screening examinations.

The mortality rate of oral tumours in Hungary, as in some other countries, is increasing. In order to assess risk groups for oral cancer and precancer, oral examinations were carried out as part of the X-ray screenings for lung cancer in the 3rd district of Budapest, Hungary. There were 5,034 adults who participated voluntarily in these investigations. After completing a questionnaire with 23 questions, a short oral examination was performed. Males comprised 57.7% of the group, and the age-distribution among men and women was similar. Oral precancerous lesions were found in 3.7% of the whole group, in 3.3% of those with leukoplakia, and in 0.4% of those with oral lichen planus. The prevalence of leukoplakia in men was 5.8%, and in women 1.5%, with significantly higher prevalences in men and women over 40. Among the examined persons there were 31% who were smokers, and 6% reported that they were regular consumers of alcohol. Fifty-four percent of those examined reported that they did not visit the dentist regularly. Oral complaints came mostly from those with lichen planus. The described model, where the oral screening examinations are done in conjunction with other examinations, in a so-called multiphasic screening system, seems to be a worthwhile approach for early diagnosis of oral cancer and precancer.

Adolescent↗
PubMed2000

Identification of CRAM, a novel unc-33 gene family protein that associates with CRMP3 and protein-tyrosine kinase(s) in the developing rat brain.

Four members of collapsin response mediator proteins (CRMPs) are thought to be involved in the semaphorin-induced growth cone collapse during neural development. Here we report the identification of a novel CRMP3-associated protein, designated CRAM for CRMP3-associated molecule, that belongs to the unc-33 gene family. The deduced amino acid sequence reveals that the CRAM gene encodes a protein of 563 amino acids, shows 57% identity with dihydropyrimidinase, and shows 50-51% identity with CRMPs. CRAM appears to form a large complex composed of CRMP3 and other unidentified proteins in vivo. Indeed, CRAM physically associates with CRMP3 when co-expressed in COS-7 cells. The expression of CRAM is brain-specific, is high in fetal and neonatal rat brain, and decreases to very low levels in adult brain. Moreover, CRAM expression is up-regulated during neuronal differentiation of embryonal carcinoma P19 and PC12 cells. Finally, immunoprecipitation analysis of rat brain extracts shows that CRAM is co-immunoprecipitated with proteins that contain protein-tyrosine kinase activity. Taken together, our results suggest that CRAM, which interacts with CRMP3 and protein-tyrosine kinase(s), is a new member of an emerging family of molecules that potentially mediate signals involved in the guidance and outgrowth of axons.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Purification of a 72-kDa protein-tyrosine kinase from rat liver and its identification as Syk: involvement of Syk in signaling events of hepatocytes.

Syk protein-tyrosine kinase (PTK) has been implicated in a variety of hematopoietic cell responses including immunoreceptor signaling. However, so far, there has been no evidence of the expression of Syk or Syk-related PTK in non-hematopoietic tissues. In this study, we have purified from blood cell-depleted rat liver a 72-kDa cytoplasmic PTK which shows cross-reactivity with anti-Syk antibody. Partial amino acid sequence analysis revealed that this 72-kDa PTK is identical to Syk. Immunohistochemical and RT-PCR analyses demonstrated that Syk is expressed in human hepatocytes and two rat liver-derived cell lines, JTC-27 and RLC-16. Furthermore, Syk is significantly tyrosine-phosphorylated in response to angiotensin II in JTC-27 cells, and angiotensin II-induced MAP kinase activation is blocked by the treatment of cells with a Syk-selective inhibitor, piceatannol. These results suggest that Syk plays an important role in signaling events of hepatocytes, such as signaling steps leading to MAP kinase activation by G-protein-coupled receptors. This is the first report of the expression of Syk in non-hematopoietic tissue.

Amino Acid Sequence↗
PubMed2000

Distinctive functions of Syk N-terminal and C-terminal SH2 domains in the signaling cascade elicited by oxidative stress in B cells.

Syk plays a crucial role in the transduction of oxidative stress signaling. In this paper, we investigated the roles of Src homology 2 (SH2) domains of Syk in oxidative stress signaling, using Syk-negative DT40 cells expressing the N- or C-terminal SH2 domain mutant [mSH2(N) or mSH2(C)] of Syk. Tyrosine phosphorylation of Syk in cells expressing mSH2(N) Syk after H(2)O(2) treatment was higher than that in cells expressing wild-type Syk or mSH2(C) Syk. The tyrosine phosphorylation of wild-type Syk and mSH2(C) Syk, but not that of mSH2(N), was sensitive to PP2, a specific inhibitor of Src-family protein-tyrosine kinase. In oxidative stress, the C-terminal SH2 domain of Syk was demonstrated to be required for induction of tyrosine phosphorylation of cellular proteins, phospholipase C (PLC)-gamma2 phosphorylation, inositol 1,4, 5-triphosphate (IP(3)) generation, Ca(2)(+) release from intracellular stores, and c-Jun N-terminal kinase activation. In contrast, in mSH2(N) Syk-expressing cells, tyrosine phosphorylation of intracellular proteins including PLC-gamma2 was markedly induced in oxidative stress. The enhanced phosphorylation of mSH2(N) Syk and PLC-gamma2, however, did not link to Ca(2)(+) mobilization from intracellular pools and IP(3) generation. Thus, the N- and C-terminal SH2 domains of Syk possess distinctive functions in oxidative stress signaling.

Animals↗
PubMed1999

CD47 ligation selectively downregulates human interleukin 12 production.

Interleukin (IL)-12 plays a key role not only in protective innate and adaptive T helper cell type 1 (Th1) responses but also in chronic inflammatory diseases. We report here that engagement of CD47 by either monoclonal antibody, its natural ligand thrombospondin (TSP), or 4N1K (a peptide of the COOH-terminal domain of TSP selectively binding CD47) inhibits IL-12 release by monocytes. The suppression occurred after T cell-dependent or -independent stimulation of monocytes and was selective for IL-12 inasmuch as the production of tumor necrosis factor (TNF)-alpha, IL-1, IL-6, and granulocyte/macrophage colony-stimulating factor was not inhibited. CD47 ligation did not alter transforming growth factor (TGF)-beta and IL-10 production, and the suppressive effect on IL-12 was not due to autocrine secretion of TGF-beta or IL-10. The IL-12 inhibition was not mediated by Fcgamma receptor ligation, did not require extracellular Ca(2+) influx, but was reversed by two phosphoinositide 3-kinase inhibitors (wortmannin and Ly294002). Thus, engagement of CD47 on monocytes by TSP, which transiently accumulates at the inflammatory site, is a novel and unexplored pathway to selectively downregulate IL-12 response. The pathway may be relevant in limiting the duration and intensity of the inflammatory response, and in developing novel therapeutic strategies for Th1-mediated diseases.

Androstadienes↗
PubMed1999

The vitronectin receptor and its associated CD47 molecule mediates proinflammatory cytokine synthesis in human monocytes by interaction with soluble CD23.

The vitronectin receptor, alphavbeta3 integrin, plays an important role in tumor cell invasion, angiogenesis, and phagocytosis of apoptotic cells. CD47, a member of the multispan transmembrane receptor family, physically and functionally associates with vitronectin receptor (VnR). Although vitronectin (Vn) is not a ligand of CD47, anti-CD47 and beta3 mAbs suppress Vn, but not fibronectin (Fn) binding and function. Here, we show that anti-CD47, anti-beta3 mAb and Vn, but not Fn, inhibit sCD23-mediated proinflammatory function (TNF-alpha, IL-12, and IFN-gamma release). Surprisingly, anti-CD47 and beta3 mAbs do not block sCD23 binding to alphav+beta3+ T cell lines, whereas Vn and an alphav mAb (clone AMF7) do inhibit sCD23 binding, suggesting the VnR complex may be a functional receptor for sCD23. sCD23 directly binds alphav+beta3+/CD47(-) cell lines, but coexpression of CD47 increases binding. Moreover, sCD23 binds purified alphav protein and a single human alphav chain CHO transfectant. We conclude that the VnR and its associated CD47 molecule may function as a novel receptor for sCD23 to mediate its proinflammatory activity and, as such, may be involved in the inflammatory process of the immune response.

Animals↗
PubMed1998

OX40 costimulation enhances interleukin-4 (IL-4) expression at priming and promotes the differentiation of naive human CD4(+) T cells into high IL-4-producing effectors.

Th2 cell development is critically dependent on the presence of interleukin-4 (IL-4) at priming. The cellular origin and the mechanisms regulating this early production of IL-4 at the site of naive T-cell priming are extensively investigated. We previously reported that anti-CD3-activated and CD28-costimulated naive human CD4(+) T cells themselves release very low but sufficient levels of IL-4 to support their development into high IL-4-producing cells. We show here that ligation of OX40 Ag, a member of the tumor necrosis factor receptor (TNF-R) family, on activated umbilical cord blood CD4(+) T cells upregulates IL-4 production at priming and thereby promotes their development into effector cells producing high levels of the type 2 cytokines IL-4, IL-5, and IL-13. OX40 ligation increases four times the expression of IL-4 mRNA after 48 hours of anti-CD3/B7.1 activation and significantly augments the release of IL-4 and IL-13 in primary cultures. The effects of OX40 costimulation on Th cell differentiation are observed in the presence of optimal and suboptimal CD28 stimulation. Because OX40 ligand is expressed on dendritic cells, the OX40 costimulation pathway may be involved in the physiological regulation of Th cell development by augmenting the differentiation of IL-4-producing cells.

CD28 Antigens↗
PubMed1998

IFN-alpha priming of human monocytes differentially regulates gram-positive and gram-negative bacteria-induced IL-10 release and selectively enhances IL-12p70, CD80, and MHC class I expression.

Administration of IFN-gamma and IFN-alpha may protect or induce autoimmune diseases. Although the in vitro regulation of monokine secretion by IFN-gamma have been extensively studied, the regulatory function of IFN-alpha has not yet been elucidated. We compared IFN-alpha and IFN-gamma, added alone or simultaneously before bacterial stimulation, for the control of monokine release and the expression of costimulatory molecules by human monocytes. Our data show that: 1) IFN-alpha primes monocytes for increased production of IL-10 in response to Staphylococcus aureus Cowan I strain (SAC) but not to LPS, leading to a lack of IFN-alpha priming for TNF-alpha secretion; 2) pretreatment of monocytes with IFN-alpha inhibits LPS- or SAC-induced IL-12p40 production but unexpectedly enhances the release of the biologically active form of IL-12 (IL-12p70); 3) IFN-alpha and IFN-gamma exert an antagonistic effect on LPS- and SAC-induced IL-10 as well as IL-12p40 release, whereas they further enhance IL-12p70 production when added simultaneously; 4) in contrast to IFN-alpha, IFN-gamma primes monocytes to enhance LPS- or SAC-induced TNF-alpha and IL-12 production, but surprisingly, it increases IL-10 production by monocytes following LPS but not SAC stimulation; and finally, 5) IFN-alpha pretreatment selectively up-regulates CD80 and MHC class I expression on monocytes. It is proposed that the outcome of the immune response at the site of inflammation may depend on both the type of bacterial injury (gram-positive or -negative) and of locally produced IFNs, and that the differential and opposite effects of type I and type II IFNs on monocytes may account for the beneficial or detrimental effects of IFN-alpha therapy.

Adjuvants, Immunologic↗
PubMed1998

Enterohepatic recirculation of the new antihypertensive drug UP 269-6 in humans. A possible model to account for multiple plasma peaks.

Following a single dose of a new antihypertensive drug, UP 269-6 (5-methyl-7-propyl-8-[(2'-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl]-1,2,4-triazolo[1,5-c]pyrimidin-2(3H)-one, CAS 148504-51-2), to 12 healthy volunteers, the plasma levels showed at least two secondary peaks. To explain this observation, the data were fitted to a new compartmental model of enterohepatic recirculation, without using a numerical method. Most subjects exhibited two cycles of recirculation. The amount of drug involved in each recirculation was calculated and the AUCs compared. The drug showed high biliary excretion and reabsorption.

Adult↗
PubMed1998

Blood and cerebral concentrations of the new potential analgesic UP 26-91 measured in vivo by microdialysis after toxic doses.

The concept of proportionality between the pharmacological effects of drugs and their dosage has been questioned since the discovery of saturable phenomenon for some drug dispositions, either during their absorption or their elimination. Such saturation may also occur during the distribution phase in the tissues. This phenomenon, however, is often difficult to demonstrate and microdialysis is a powerful technique to assess precise changes in drug concentrations in tissue. This technique has been used to compare brain and blood concentrations of a potential analgesic, UP 26-91 (3-¿[2-[4-(2,4-difluorophenyl)piperazin-1-yl]ethyl]thio¿ -1,2,4-triazolo[4,3-a]pyrioline, citrate salt, CAS 115762-17-9 for the base), at different intravenous doses. Microdialysis probes were surgically implanted in the cerebral cortex and the jugular vein of male Sprague-Dawley rats (about 350 g). A single dose of radiolabelled 14(C) UP 26-91 mixed with unlabelled drug was injected into the animal's tail vein. Three doses of drug (2.5, 12.5 and 22.5 mg.kg-1) were tested, with three rats for each dose. All the doses consisted of the same amount of radiolabelled product, used as a tracer, supplemented by the amount of non-radiolabelled UP 26-91 necessary to reach the desired concentration. The rats were conscious, freely moving and had free access to food and water. Microdialysis samples were collected at the rate of 1 microliter.min-1, and sampled every 15 min for 16-17 h. The two highest doses were in the range of those used for toxicological studies. Blood UP 26-91 radioactivity concentrations were superimposable independent of the dose. Thus, it can be concluded that there was a linear relationship between blood concentrations and administered doses. By contrast, the brain concentration for the highest administered dose was statistically higher than the two others (p < 0.05), which demonstrated that UP 26-91 exhibited a non-linear pharmacokinetics in the brain. It is therefore likely that a saturable transport mechanism occurs across the blood-brain barrier. This study demonstrates that blood toxicokinetics may not correctly reflect tissue exposure to a drug.

Analgesics, Non-Narcotic↗
PubMed1995

CD40 ligand-positive CD8+ T cell clones allow B cell growth and differentiation.

A fraction of activated CD8+ T cells expresses CD40 ligand (CD40L), a molecule that plays a key role in T cell-dependent B cell stimulation. CD8+ T cell clones were examined for CD40L expression and for their capacity to allow the growth and differentiation of B cells, upon activation with immobilized anti-CD3. According to CD40L expression, CD8+ clones could be grouped into three subsets. CD8+ T cell clones expressing high levels of CD40L (> or = 80% CD40L+ cells) were equivalent to CD4+ T cell clones with regard to induction of tonsil B cell proliferation and immunoglobulin (Ig) production, provided the combination of interleukin (IL)-2 and IL-10 was added to cultures. CD8+ T cell clones, with intermediate levels of CD40L expression (10 to 30% CD40L+ cells), also stimulated B cell proliferation and Ig secretion with IL-2 and IL-10. B cell responses induced by these CD8+ T cell clones were neutralized by blocking monoclonal antibodies specific for either CD40L or CD40. By contrast, CD40L- T cell clones (< or = 5% CD40L+ cells), only induced marginal B cell responses even with IL-2 and IL-10. All three clone types were able to activate B cells as shown by up-regulation of CD25, CD80 and CD86 expression. A neutralizing anti-CD40L antibody indicated that T cell-dependent B cell activation was only partly dependent on CD40-CD40L interaction. These CD40L- clones had no inhibitory effects on B cell proliferation induced by CD40L-expressing CD8+ T cell clones. Taken together, these results indicate that CD8+ T cells can induce B cell growth and differentiation in a CD40L-CD40-dependent fashion.

Animals↗