Biomedical subjects

M Kubin

Publications and source records attributed to M Kubin.

At least 19 recordsLinked to original sources

PubMed2006

Which patients should receive aspirin for primary prevention of cardiovascular disease? An economic evaluation.

Low-dose aspirin is a standard care for secondary prevention of cardiovascular disease (CVD). Its use in primary prevention is less widely accepted, however, despite recent meta-analyses and US and European guidelines supporting its use in individuals at increased CVD risk. The aim of this study was to define which patients should receive aspirin for primary prevention of CVD using data from four European countries. Based on the clinical data from two meta-analyses, a state-transition model was developed to compare the costs and effects of no treatment and low-dose aspirin as primary prevention for CVD over 10 years. The model was applied to patients at different 10-year risks (2-5%) of fatal CVD according to the SCORE equation. Direct costs from the perspective of the healthcare payer were used (base year 2003). Country-specific discounting was applied. Treating patients with a 10-year risk of fatal CVD of 2% or higher with low-dose aspirin resulted in lower total costs and more quality-adjusted life-years gained in the UK, Germany and Spain. In Italy, savings started at a 10-year fatal CVD risk of 3%. This difference was due to the higher cost of gastrointestinal bleeding in Italy. Monte Carlo analysis showed that aspirin was dominant in more than 90% of patients at a 10-year risk of 4% and 5% in the four countries. In conclusion, low-dose aspirin treatment becomes cost-saving at a very low 10-year risk of fatal CVD. The cost of gastrointestinal bleeding defines the level at which low-dose aspirin becomes cost-saving.

Aspirin↗

PubMed2004

Early conceptual and linguistic development of a patient and partner treatment satisfaction scale (TSS) for erectile dysfunction.

OBJECTIVE: To describe the early development of a pluri-language self-report questionnaire to assess male patients and their female partners' satisfaction with drug treatment for erectile dysfunction (ED). METHODS: This first development phase proceeded in several parts. Item generation followed literature review, hypothesized characteristics of the drug and in-depth interviews with patients and their partners. Perceptions and feelings related to ED and patients' expectations of treatment were explored. Items were generated simultaneously in 5 languages (American English, Canadian French, English, French and German). Content and face validity were empirically assessed by interviews with a few patients and partners in each country. Conceptual equivalence between languages was ascertained. RESULTS: The final content domains included satisfaction with: sexual spontaneity, quality of erection, quality of ejaculation, sexual pleasure, orgasm, confidence, reliability of treatment, side effects, convenience, overall satisfaction, conformity to treatment expectations and intent to continue use of drug. Cognitive debriefing with patients and partners found few issues with comprehension, however some words were considered problematic. The simultaneous development for the different languages allowed adaptation of the content at this stage and ensured consistency of all language versions. The final questionnaire consisted of 4 modules: unmedicated patient, medicated patient, unmedicated partner, and medicated partner modules. The questionnaire was then linguistically validated into 15 additional languages for further psychometric validation. CONCLUSIONS: The Treatment Satisfaction Scale (TSS) is a multi-facetted measure of patients' and partners' satisfaction with their sexual life relating to erectile dysfunction and intended for prospective use. Its simultaneous development for a variety of countries and languages has fostered true item equivalence across language versions. However, further work is needed to validate the TSS psychometrically, including identification of domains, test responsiveness and determination of appropriate scoring prior to its clinical use.

Erectile Dysfunction↗

PubMed2003

Epidemiology of erectile dysfunction.

This review of the current epidemiological literature on erectile dysfunction (ED) suggests that approximately 5-20% of men have moderate-to-severe ED. Different definitions of ED, age distributions and concomitant medical conditions, as well as methodological differences, may explain much of the variance in reported prevalence rates. Various chronic disorders are associated with elevated rates of ED including depression, diabetes, and cardiovascular and neurological diseases. Such disorders are more common in the elderly, which may partially explain the elevated prevalence of ED in men over 60 y of age. Currently, up to 70% of men with ED are not treated. However, so many men experience considerable distress from their condition, that the increasing awareness of ED as well as the availability of noninvasive treatments may result in a greater proportion of patients seeking treatment, and eventually regaining satisfaction with their sex life.

Adolescent↗

PubMed2002

Intravenous and oral antibiotics in respiratory tract infection: an international observational study of hospital practice.

BACKGROUND: Hospitalised patients with respiratory tract infections (RTI) frequently receive intravenous (i.v.) antibiotics followed by a short course of oral treatment. OBJECTIVES: To observe antibiotic use in hospitals in Germany, Spain, France, Italy and the UK and the reasons for choosing the i.v. route and switching to oral treatment. METHODS: Research pharmacists sought the opinions of physicians and senior nurses in the completion of a semi-structured questionnaire on the treatment of RTI with i.v. antibiotics. Questions focussed on antimicrobials of choice, reasons for choosing i.v., reasons for changing to oral administration, and duration of treatment. RESULTS: This study recruited 796 patients with RTI, usually pneumonia. Prescribing patterns varied widely between the five hospitals. Accepted clinical criteria were only commonly cited in Germany, Spain and the UK as reasons for choosing the i.v. route at the beginning of the study. These were more commonly cited at the time of switch, although other criteria such as improved condition, were other significant reasons. The mean duration of i.v. treatment ranged from 4 days in the UK to 10 days in Italy, where most patients received the full course of treatment by the i.v. route. Unlike the other hospitals studied, the few patients in Italy who were switched to another form of treatment were as likely to receive intramuscular as oral administration (13% and 11%, respectively). CONCLUSIONS: The practice of and reasons for prescribing i.v. antibiotics varied in the hospitals studied. Objective clinical criteria were inconsistently cited as reasons for administering i.v. antibiotics and in general these reasons were unrelated to those given for the switch from i.v. to oral administration. In order for guidelines for switching from i.v. to oral antimicrobials to be routinely employed, explicit physiological criteria need to be recorded in a routine fashion. Closer co-operation between pharmacists and physicians may help in developing and implementing guidelines at a local level.

Administration, Oral↗

PubMed2001

ULBP1, 2, 3: novel MHC class I-related molecules that bind to human cytomegalovirus glycoprotein UL16, activate NK cells.

New members of the extended MHC class I-like family were identified based on their ability to bind human cytomegalovirus glycoprotein UL16 and/or their mutual homology. Soluble UL16 binding proteins (ULBP) competed with each other for binding to NK cells. Treatment of human and mouse NK cells with ULBP led to increased production of cytokines/chemokines, proliferation, cytotoxic activity and up-regulation of activation-associated surface molecules. The presence of ULBP during the stimulation phase of the CTL assay caused increased cytotoxic activity. Addition of soluble recombinant UL16 protein inhibited the biological activities mediated by ULBP, suggesting the existence of a novel mechanism utilized by CMV to evade elimination by the host immune system.

Animals↗

PubMed2001

ULBPs, novel MHC class I-related molecules, bind to CMV glycoprotein UL16 and stimulate NK cytotoxicity through the NKG2D receptor.

The human cytomegalovirus glycoprotein, UL16, binds to two members of a novel family of molecules, the ULBPs, and to the MHC class I homolog, MICB. The ULBPs are GPI-linked glycoproteins belonging to the extended MHC class I family but are only distantly related to MICB. The ULBP and MICB molecules are ligands for the activating receptor, NKG2D/DAP10, and this interaction is blocked by a soluble form of UL16. The ULBPs stimulate cytokine and chemokine production from NK cells, and expression of ULBPs in NK cell-resistant target cells confers susceptibility to NK cell cytotoxicity. Masking of NK cell recognition of ULBP or MIC antigens by UL16 provides a potential mechanism by which human cytomegalovirus-infected cells might evade attack by the immune system.

Amino Acid Sequence↗

PubMed2001

Prevention of coronary heart disease through treatment of infection with Chlamydia pneumoniae? Estimation of possible effectiveness and costs.

Evidence has been accumulating for a link between Chlamydia pneumoniae and coronary heart disease (CHD). A spreadsheet model was used to estimate the impact of different strategies for screening and treating C. pneumoniae on the incidence of myocardial infarction and cardiac mortality over a 1-year post-intervention period. It was found that screening would potentially be most cost-effective in men aged over 35 with a history of myocardial infarction (around ł2,000 per life-year saved). Cost-effectiveness would be inferior in those with established heart disease but no history of myocardial infarction (MI), and poor for people at elevated risk of CHD. If causality of the association were proven, the cost-effectiveness of treating C. pneumoniae in post-MI patients would compare favourably with, for example, statins for treating hypercholesterolaemia.

Adult↗

PubMed2001

Family outbreaks of tuberculosis in South Moravia, a low incidence area of the Czech Republic.

OBJECTIVES: To identify suspected family outbreaks of tuberculosis in South Moravia, an area with the lowest notification rates in the Czech Republic. METHOD: The insertion sequence IS6110-based RFLP analysis of Mycobacterium tuberculosis was applied in isolates collected from 17 indigenous excretors giving the same family name and/or domicile. The fingerprints were matched with a database of 184 RFLP profiles of Czech M. tuberculosis isolates originating from remote localities. RESULTS: The RFLP analysis revealed uniform fingerprints in each of six indigenous outbreaks consisting of two to six family members or relatives. In three of them no matching case has been found in the Czech fingerprint database. The remaining three clusters showed identical patterns with RFLP profiles of 13 Czech M. tuberculosis strains originating from remote areas: five were from patients living in the immediate vicinity and eight were from distant regions. CONCLUSION: Different clustered genotypes of M. tuberculosis were identified in epidemiologically linked family outbreaks of tuberculosis, half of them indigenous and half matching fingerprints of strains from remote areas. It seems that family outbreaks may contribute to the continued occurrence of tuberculosis in South Moravia, which reports the lowest notification values in the Czech Republic.

Adolescent↗

PubMed2000

Four new members expand the interleukin-1 superfamily.

We report here the cloning and characterization of four new members of the interleukin-1 (IL-1) family (FIL1delta, FIL1epsilon, FIL1zeta, and FIL1eta, with FIL1 standing for "Family of IL-1"). The novel genes demonstrate significant sequence similarity to IL-1alpha, IL-1beta, IL-1ra, and IL-18, and in addition maintain a conserved exon-intron arrangement that is shared with the previously known members of the family. Protein structure modeling also suggests that the FIL1 genes are related to IL-1beta and IL-1ra. The novel genes form a cluster with the IL-1s on the long arm of human chromosome 2.

Amino Acid Sequence↗

PubMed1999

Interleukin-1 protects transformed keratinocytes from tumor necrosis factor-related apoptosis-inducing ligand- and CD95-induced apoptosis but not from ultraviolet radiation-induced apoptosis.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a new member of the tumor necrosis factor (TNF) family, induces apoptosis primarily of transformed cells. Interleukin-1 was previously found to protect the keratinocyte cell line KB from TRAIL-induced apoptosis, thus we studied whether interleukin-1 also protects from other apoptotic stimuli (ultraviolet radiation (UV), CD95-ligand). Interleukin-1 rescued KB cells from TRAIL- and CD95-induced apoptosis, which was critically dependent on nuclear factor kappaB, because cells transfected with a super-repressor form of the nuclear factor kappaB inhibitor IkappaB were less protected. In contrast, UV-mediated apoptosis was not only not prevented by interleukin-1 but even enhanced. This opposite effect of interleukin-1 was also observed for the expression of the inhibitor of apoptosis proteins (IAP). Whereas TRAIL- and CD95-mediated suppression of IAP expression was partially reversed by interleukin-1, UV-mediated down-regulation of IAPs was not reversed but even further enhanced. Increased apoptosis induced by interleukin-1 plus UV was accompanied by excessive TNFalpha release, implying that enhanced cytotoxicity is due to the additive effect of these two apoptotic stimuli. Accordingly, enhanced apoptosis was reduced by blocking the TNF receptor-1. The opposite effects of interleukin-1 indicate that different mechanisms are involved in UV-induced apoptosis compared with CD95- and TRAIL-mediated apoptosis. Furthermore, the data suggest that whether a signal acts in an antiapoptotic way or not does not only depend on the signal itself but also on the stimulus causing apoptosis.

Apoptosis↗

PubMed1999

Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo.

To evaluate the utility of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as a cancer therapeutic, we created leucine zipper (LZ) forms of human (hu) and murine (mu) TRAIL to promote and stabilize the formation of trimers. Both were biologically active, inducing apoptosis of both human and murine target cells in vitro with similar specific activities. In contrast to the fulminant hepatotoxicity of LZ-huCD95L in vivo, administration of either LZ-huTRAIL or LZ-muTRAIL did not seem toxic to normal tissues of mice. Finally, repeated treatments with LZ-huTRAIL actively suppressed growth of the TRAIL-sensitive human mammary adenocarcinoma cell line MDA-231 in CB.17 (SCID) mice, and histologic examination of tumors from SCID mice treated with LZ-huTRAIL demonstrated clear areas of apoptotic necrosis within 9-12 hours of injection.

Animals↗

PubMed1999

Retinoids synergize with interleukin-2 to augment IFN-gamma and interleukin-12 production by human peripheral blood mononuclear cells.

We have demonstrated previously that cells from both the skin and peripheral blood from patients with cutaneous T cell lymphoma (CTCL) have elevated levels of protein and mRNA for Th2 cytokines, interleukin-4 (IL-4) and IL-5, and depressed levels of Thl cytokines, IL-2 and interferon-gamma (IFN-gamma). Furthermore, IL-12 in vitro can restore IFN-gamma production by these patients' cells to near normal levels. Because retinoids exert therapeutic activity in CTCL and are potent modulators of growth and differentiation of hematopoietic cells, we investigated the role of retinoids in modulating Thl cytokine production. Peripheral blood mononuclear cells (PBMC) from normal donors and patients with CTCL were cultured with medium, IL-2, 13-cis-retinoic acid, all-trans-retinoic acid, acetretin or etretinate alone, or IL-2 plus the retinoids for 24 h, and levels of IFN-gamma were determined using ELISA. IL-2 or retinoids alone could induce low but significant levels of IFN-gamma. However, when IL-2 was cultured with each retinoid, a synergistic augmentation of IFN-gamma levels (4-fold to 90-fold) was observed except in the case of etretinate. All-trans-retinoic acid (ATRA) was the most potent IFN-y inducer. Similar studies performed using PBMC from CTCL patients indicated the IFN-gamma augmentation occurred but in a blunted manner. The IFN-y-inducing effect of ATRA and 13-cis-retinoic acid could be abrogated by addition of anti-IL-12 antibodies, suggesting that IL-12 plays a role in the synergistic upregulation of IFN-gamma. Using an IL-12 p40-specific radioimmunoassay (RIA), we confirmed the presence of IL-12 in IL-2 plus retinoid-treated culture supernatants. Purified monocytes cultured with IL-2 plus ATRA did not secrete IL-12. Only when monocytes were cocultured with lymphocytes was there an increase in IL-12 production, suggesting the involvement of a paracrine feedback loop requiring both monocytes and lymphocytes. These data suggest that retinoids can induce Th1 cytokines from normal and CTCL PBMC and that this induction may be mediated through IL-12 production.

Antigen-Antibody Reactions↗

PubMed1998

Interleukin-1 protects transformed keratinocytes from tumor necrosis factor-related apoptosis-inducing ligand.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family. It induces apoptosis primarily of transformed but not of normal cells and may therefore be a promising anti-cancer drug. Studying the role of TRAIL in apoptosis of keratinocytes, we detected TRAIL transcripts and protein in both normal human keratinocytes and transformed keratinocyte cell lines HaCaT and KB. Although normal keratinocytes were resistant to TRAIL, HaCaT and KB cells underwent apoptosis following TRAIL exposure. When HaCaT and KB cells were pretreated with the pro-inflammatory cytokine interleukin-1 (IL-1), cells became resistant to TRAIL-induced apoptosis. IL-1 significantly induced activation of the transcription factor NFkappaB in transformed keratinocytes. Moreover, the proteasome inhibitor MG132, which inhibits IL-1-induced NFkappaB activation, completely prevented the protective effect of IL-1. Thus, IL-1 appears to protect transformed keratinocytes from the cytotoxic effect of TRAIL via activation of NFkappaB. These data suggest that NFkappaB activation may protect cells from TRAIL-induced apoptosis and indicate a TRAIL receptor-independent pathway, which allows cells to escape the cytotoxic effect of TRAIL. Because IL-1 is secreted by a variety of tumor cells and is also released by inflammatory cells participating in the tumor-host immune response, tumors under these conditions could become resistant to TRAIL.

Apoptosis↗

PubMed1998

Decreased production of interleukin-12 and other Th1-type cytokines in patients with recent-onset systemic lupus erythematosus.

OBJECTIVE: To determine the profile of Th1-type and Th2-type cytokines produced by mononuclear cells from patients with recent-onset systemic lupus erythematosus (SLE), prior to the initiation of treatment with corticosteroids. METHODS: Using sensitive radioimmunoassays, interleukin-4 (IL-4), IL-10, IL-12 p40, tumor necrosis factor alpha (TNF alpha), interferon-gamma (IFN gamma), and granulocyte-macrophage colony-stimulating factor (GM-CSF) released into the culture supernatants of various unstimulated and stimulated blood mononuclear cell populations from 10 SLE patients was assessed in comparison with 10 matched healthy controls studied in parallel. RESULTS: In early SLE, monocyte-enriched cells constitutively produced increased amounts of IL-10 and decreased amounts of IL-12 following stimulation. Lymphocyte-enriched cells in SLE produced decreased amounts of IFN gamma and TNF alpha following stimulation. In "rested" cells, these defects were accentuated and a defect in IL-12 production was suggested. Depletion studies suggested that CD8+ cells were a major source of TNF alpha and IFN gamma in controls, but not in SLE patients. Increased IL-4 production or abnormalities in GM-CSF production were not observed. CONCLUSION: This study suggests that even early in the course of SLE, monocyte production of IL-10 is increased and that of IL-12 is decreased. Decreased production of Th1-type cytokines in SLE may be secondary to this imbalance between IL-10 and IL-12. A contributory role of dysfunctional CD8+ cells is suggested.

Adult↗

PubMed1997

A family of human lymphoid and myeloid Ig-like receptors, some of which bind to MHC class I molecules.

Leukocyte Ig-like receptors (LIRs) are a newly discovered family of immunoreceptors expressed on monocytes and B cells and at lower levels on dendritic cells and NK cells. The amino acid sequences in the extracellular regions of eight of these receptors show between 63 and 84% identity to the prototypic LIR-1 sequence. LIRs contain either two or four Ig domains and fall into three classes: those with cytoplasmic domains containing two, three, or four immunoreceptor tyrosine-based inhibitory motif-like motifs; those with a short cytoplasmic domain and no immunoreceptor tyrosine-based inhibitory motif-like motifs; and those with no transmembrane domain represented by a single LIR molecule that is presumably secreted. The LIRs are structurally related to the human Fc(alpha)R and the killer inhibitory receptors and map to the same region of chromosome 19 as these genes. Like killer inhibitory receptors, at least two LIRs bind to MHC class I Ags, but their different cellular distribution suggests a distinct role in immune system modulation.

Amino Acid Sequence↗

PubMed1997

A novel immunoglobulin superfamily receptor for cellular and viral MHC class I molecules.

The human cytomegalovirus UL18 gene product is a homolog of cellular major histocompatibility (MHC) class I antigens. UL18 has been proposed to protect virus-infected cells against natural killer (NK) cell cytotoxicity by engaging NK cell killer inhibitory receptors (KIR) for MHC class I. UL18 binds to a novel immunoglobulin superfamily glycoprotein, designated Leukocyte Immunoglobulin-like Receptor (LIR-1). This protein is distinct from, but related to, known KIRs and binds cellular MHC class I antigens. The cytoplasmic domain of LIR-1 contains four putative immunoreceptor tyrosine-based inhibitory motifs. Upon tyrosine phosphorylation, LIR-1 associates with the tyrosine phosphatase SHP-1. In contrast to KIRs, LIR-1 is expressed predominantly on monocytic and B lymphoid cell types, suggesting a distinct biological function.

Amino Acid Sequence↗

PubMed1997

Calcitonin gene-related peptide inhibits proliferation and antigen presentation by human peripheral blood mononuclear cells: effects on B7, interleukin 10, and interleukin 12.

CGRP is a neuropeptide that has previously been described to possess immunosuppressive activities. CGRP is released from peripheral nerves that, in the skin, are in close physical association with dendritic APC. We sought to investigate the mechanisms by which CGRP can inhibit immune responses by studying its effects on human peripheral blood mononuclear cells (PBMC). Using allogeneic monocytes as stimulator cells, CGRP could inhibit the proliferation of PBMC by 47% when CGRP was present for the duration of culture. Interestingly, when the stimulator monocytes were incubated with CGRP for 2 h prior to irradiation then washed, the observed inhibition increased to 85%, suggesting that CGRP was exerting a direct effect on the monocyte stimulator population. Finally, the recall response to tetanus toxoid (TT) by PBMC from individuals vaccinated with TT 14 d prior was inhibited by 25-50% in the presence of CGRP. Also, CGRP decreased the levels of B7.2 but not B7.1 on treated monocytes, and this inhibition could be abrogated by the addition of anti-IL-10 antibody, suggesting that the inhibition was mediated by an increase in IL-10 production. Moreover, increased IL-10 production was confirmed by ELISA. Both IL-12 p40 and IFN-gamma levels in CGRP-treated cultures were found to be decreased by approximately 30%. The decrease in IL-12 p40 levels could be reversed by addition of anti-IL-10. These data suggest that CGRP inhibits PBMC proliferation, in part, through the release of IL-10, which in turn can downregulate important co-stimulatory molecules and the cytokines IL-12 and IFN-gamma.

Antigen Presentation↗

PubMed1997

Differential stimulation of interleukin-12 (IL-12) and IL-10 by live and killed Helicobacter pylori in vitro and association of IL-12 production with gamma interferon-producing T cells in the human gastric mucosa.

The objective of these experiments was to examine the ability of Helicobacter pylori to stimulate interleukin-10 (IL-10) or IL-12 and select for either Th1 or Th2 cells. Gastric biopsy specimens were collected from patients who were categorized with respect to the presence of H. pylori and gastric disease as well as their age, gender, medications, and other factors. As Th1 and Th2 cells are selected by IL-12 and IL-10, respectively, biopsy specimens were screened for mRNA and protein for these cytokines. Although mRNA for IL-12 and IL-10 was detected in biopsy specimens obtained from both infected and uninfected patients, IL-12 protein predominated. Levels of IL-10 and IL-12 in gastric tissue did not change in response to infection. Moreover, gamma interferon (IFN-gamma)-producing T cells were found in both the infected and the uninfected gastric mucosa. Stimulation of peripheral blood leukocytes from either infected or uninfected donors with various concentrations of live or killed H. pylori induced immunoreactive IL-12 and IL-10. After stimulation with live H. pylori, IL-12 levels increased more than 30-fold, whereas IL-10 levels increased only 2- to 5-fold, compared to cells stimulated with medium alone. Interestingly, killed H. pylori induced significantly more IL-10 (P < 0.05) than live H. pylori, while recombinant urease only induced IL-10. These results demonstrate that live H. pylori selectively stimulates the induction of IL-12 and Th1 cells that produce IFN-gamma, whereas preparations used in oral vaccines induce more IL-10 and may favor Th2 cell responses.

Adult↗