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Biomedical subjects

M Laan

Publications and source records attributed to M Laan.

At least 19 recordsLinked to original sources
PubMed2007

Haplotype structure of FSHB, the beta-subunit gene for fertility-associated follicle-stimulating hormone: possible influence of balancing selection.

Follicle-stimulating hormone (FSH) is essential for human reproduction. The unique functions of this hormone are provided by the FSH receptor-binding beta-subunit encoded by the FSHB gene. Resequencing and genotyping of FSHB in three European, two Asian and one African population, as well as in the great apes (chimpanzee, gorilla, orangutan), revealed low diversity and significant excess of polymorphisms with intermediate frequency alleles. Statistical tests for FSHB showed deviations from neutrality in all populations suggesting a possible effect of balancing selection. Two core haplotypes were identified (carried by 76-96.6% of each population's sample), the sequences of which are clearly separated from each other. As fertility most directly affects an organism's fitness, the carriers of these haplotypes have apparently had more success in human history to contribute to the next generation. There is a preliminary observation suggesting that the second most frequent FSHB haplotype may be associated with rapid conception success in females. Interestingly, the same haplotype is related to an ancestral FSHB variant shared with the ancestor of the great apes. The determination of the functional consequence of the two core FSHB variants may have implications for understanding and regulating human fertility, as well as in assisting infertility treatments.

Animals↗
PubMed2005

Neutrophils, interleukin-17A and lung disease.

It is now established that an excessive and sustained mobilisation of neutrophils is a hallmark of several chronic inflammatory lung disorders, including severe obstructive lung disease. This article reviews evidence that the cytokine interleukin (IL)-17A is a major orchestrator of sustained neutrophilic mobilisation. Current evidence suggests that IL-17A is produced by T-lymphocytes, and that it exerts an orchestrating effect on the accumulation and associated activity of neutrophils in the bronchoalveolar space indirectly, through an induced release of specific cytokines and colony-stimulating factors in resident lung cells. Although the involvement of IL-17A in inflammatory lung disorders is supported by several recent studies, its causative role is still uncertain. However, the unique position of interleukin-17A at the interface between acquired and innate immunity puts this cytokine forward as an important signal for the reinforcement of host defence; it also implies that interleukin-17A may constitute a useful target for pharmacotherapeutic intervention.

Biomarkers↗
PubMed2004

What does measure the scaling exponent of the correlation sum in the case of human heart rate?

It is shown that in the case of human heart rate, the scaling behavior of the correlation sum (calculated by the Grassberger-Procaccia algorithm) is a result of the interplay of various factors: finite resolution of the apparatus (finite-size effects), a wide dynamic range of mean heart rate, the amplitude of short-time variability being a decreasing function of the mean heart rate. This is done via constructing a simple model of heart rhythm: a signal with functionally modulated Gaussian noise. This model reproduces the scaling behavior of the correlation sum of real medical data. The value of the scaling exponent depends on all the above-mentioned factors, and is a certain measure of short-time variability of the signal.

Algorithms↗
PubMed2004

Impact of tobacco smoke on interleukin-16 protein in human airways, lymphoid tissue and T lymphocytes.

CD4(+) and CD8(+) lymphocytes are mobilized in severe chronic obstructive pulmonary disease (COPD) and the CD8(+) cytokine interleukin (IL)-16 is believed to be important in regulating the recruitment and activity of CD4(+) lymphocytes. In the current study, we examined whether tobacco smoke exerts an impact not only on IL-16 in the lower airways but also in CD4(+) or CD8(+) lymphocytes or in lymphoid tissue. The concentration of IL-16 protein was measured by enzyme-linked immunosorbent assay (ELISA) in concentrated bronchoalveolar lavage fluid (BALF) collected from 33 smokers with chronic bronchitis (CB), eight asymptomatic smokers (AS) and seven healthy never-smokers (NS). The concentrations of IL-16 and soluble IL-2 receptor alpha (sIL-2Ralpha) protein were also measured in conditioned medium from human blood CD4(+) and CD8(+) lymphocytes stimulated with tobacco smoke extract (TSE) in vitro. IL-16 mRNA was assessed in vitro as well, using reverse transcription-polymerase chain reaction (RT-PCR). Finally, the intracellular immunoreactivity for IL-16 protein (IL-16IR) was assessed in six matched pairs of palatine tonsils from smokers and non-smokers. BALF IL-16 was higher in CB and AS than in NS. TSE substantially increased the concentration of IL-16 but not sIL-2Ralpha in conditioned medium from CD4(+) and CD8(+) lymphocytes. There was no corresponding effect on IL-16 mRNA. IL-16IR in tonsils was lower in smokers than in non-smokers. The current findings demonstrate that tobacco smoke exerts a wide impact on the CD8(+) cytokine IL-16, in the airway lumen, in blood CD4(+) and CD8(+) lymphocytes and in lymphoid tissue. The effect on IL-16 release may be selective for preformed IL-16 in CD4(+) lymphocytes. New clinical studies are required to evaluate whether tobacco smoke mobilizes T lymphocytes via IL-16 in the lower airways and whether this mechanism can be targeted in COPD.

Adult↗
PubMed2003

IL-16 in the airways of lung allograft recipients with acute rejection or obliterative bronchiolitis.

Acute rejection (AR) is the principal risk factor for obliterative bronchiolitis (OB), the major complication of lung transplantation. It is known that activated CD4+ T lymphocytes are involved in the development of AR and that interleukin (IL)-16 can inhibit the activity of CD4+ T lymphocytes. In this study, we evaluated whether the concentration of IL-16 in the airways is altered in AR or OB and, if so, how this IL-16 concentration relates to the number or activity of airway lymphocytes. The concentration of IL-16 protein was measured in bronchoalveolar lavage (BAL) fluid at three time-points in lung allograft recipients with either AR or OB and in matched controls using ELISA. The concentration of soluble IL-2 receptor (R) protein was measured in BAL fluid using ELISA as well, as an indicator of lymphocyte activity. The percentage of airway lymphocytes was evaluated by performing BAL differential cell counts. Lung allograft recipients with AR displayed lower IL-16 concentrations compared with matched control patients and this IL-16 concentration correlated negatively with the sIL-2R concentration, but it did not correlate with the percentage of lymphocytes in BAL fluid. In contrast, in BAL fluid from lung allograft recipients with OB, the IL-16 concentration was not altered compared with matched control patients and it did not correlate with the percentage of lymphocytes or with the sIL-2R concentration. These data are compatible with an increase in IL-16 playing a protective role against AR but not against OB and, hypothetically, this type of protective effect could be exerted via a down-regulation of the activity of T lymphocytes.

Acute Disease↗
PubMed2003

A role of GM-CSF in the accumulation of neutrophils in the airways caused by IL-17 and TNF-alpha.

The T-cell cytokine interleukin (IL)-17 selectively accumulates neutrophils in murine airways in vivo and may thus constitute a link between activation of T-lymphocytes and accumulation of neutrophils. In this study, the authors evaluated the role of granulocyte macrophage-colony stimulating factor (GM-CSF) in accumulation of neutrophils in the airways caused by IL-17 and tumour necrosis factor (TNF)-alpha. In vitro, human (h) IL-17 concentration-dependently stimulated the release of GM-CSF protein (enzyme-linked immunosorbent assay) in human bronchial epithelial cells (16HBE). IL-17 also time-dependently stimulated the release of GM-CSF protein in venous endothelial (human umbilical vein endothelial cells) cells in vitro. Co-stimulation with IL-17 plus the pro-inflammatory cytokine TNF-alpha potentiated the release of GM-CSF protein in 16HBE cells. hIL-17 also enhanced the expression of GM-CSF messenger ribonucleic acid in 16HBE cells (reverse transcriptase polymerase chain reaction), with a similar order of magnitude as TNF-alpha. Conditioned cell medium from bronchial epithelial cells co-stimulated with hIL-17 plus TNF-alpha prolonged survival (trypan blue exclusion) of human neutrophils in vitro and this effect was blocked by an anti-GM-CSF antibody. In vivo, local co-stimulation with mouse IL-17 plus TNF-alpha caused an additive potentiation of the accumulation of neutrophils in bronchoalveolar lavage fluid from mouse airways and this effect was blocked by an anti-GM-CSF antibody given systemically. In conclusion, granulocyte macrophage-colony stimulating factor is involved in the accumulation of neutrophils in the airways caused by interleukin-17 and tumour necrosis factor-alpha, probably via effects on both recruitment and survival of neutrophils.

Animals↗
PubMed2002

Free, soluble interleukin-17 protein during severe inflammation in human airways.

Studies in rodents indicate that the cytokine, interleukin (IL)-17, links the activation of T-lymphocytes to neutrophilic inflammation. The aim of the current study was to determine whether free, soluble IL-17 protein can be released during severe inflammation in human airways. Fifteen healthy subjects were exposed to a swine confinement in order to induce severe inflammation characterized by high neutrophil numbers in the airways. Bronchoalveolar lavage (BAL) fluid was harvested 2 weeks prior to and 24 h after this exposure and the concentration of IL-17 protein was measured using an enzyme-linked immunosorbent assay. Total and cell differential counts were also performed in BAL fluid. Prior to exposure to the swine confinement, the concentration of IL-17 in BAL fluid was low (<7.8 pg x mL(-1)) in 14 out of 15 subjects. However, exposure to the swine confinement caused an increase in IL-17 in 13 out of 15 subjects (median IL-17 concentration of 26.9 pg x mL(-1)). This exposure also caused a 51-fold increase in the concentration of neutrophils in BAL fluid. To conclude, free, soluble interleukin-17 protein can be released during severe inflammation characterized by high neutrophil numbers in human airways. The significance of interleukin-17 in inflammatory airway diseases therefore deserves further evaluation.

Adult↗
PubMed2001

Pituitary adenylate cyclase-activating peptide inhibits neutrophil chemotaxis.

Pituitary adenylate cyclase-activating peptide 38 (PACAP 38) is a neuropeptide that displays several biological effects of interest in the context of airway diseases such as asthma and chronic obstructive pulmonary disease. These effects include inhibition of airway and vascular smooth muscle tone as well as modulation of inflammatory cell activity. However, little is known about the effect of PACAP on granulocytes. The present study was designed to investigate if PACAP and the closely related peptide vasoactive intestinal peptide (VIP) could affect neutrophil migration. A standard 48 well chemotaxis chamber was used to assess the effects of PACAP on N-Formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP)-induced neutrophil chemotaxis and spontaneous random migration. PACAP 38 and VIP inhibited fMLP-induced human neutrophil chemotaxis. Furthermore, both peptides also exhibited a dose-related trend toward inhibiting the spontaneous, unstimulated migration of neutrophils. Since enhanced cell migration in cell chamber systems is reported to correlate with increased invasive properties in vivo, the presented inhibitory effects of PACAP 38 on neutrophil chemotaxis, supports the idea of an anti-inflammatory role for PACAP. This together with the well documented bronchodilatory capacity of PACAP might indicate a role for PACAP-agonists in future treatment of asthma and other inflammatory airway diseases.

Chemotaxis, Leukocyte↗
PubMed2001

IL-17-induced cytokine release in human bronchial epithelial cells in vitro: role of mitogen-activated protein (MAP) kinases.

1. Recent data indicate that interleukin (IL)-17 may contribute to neutrophilic airway inflammation by inducing the release of neutrophil-mobilizing cytokines from airway cells. The aim of this study was to evaluate the role of mitogen activated protein kinases in IL-17 induced release of IL-8 and IL-6 in bronchial epithelial cells. 2. Transformed human bronchial epithelial cells (16HBE) were stimulated with either IL-17 or vehicle. Both groups were treated either with SB202190 (inhibitor of p38 MAP kinase), PD98059 (inhibitor of extracellular-signal-regulated kinase [ERK] pathway), Ro-31-7549 (protein kinase C [PKC] inhibitor), LY 294002 (a phosphatidylinositol 3-kinase [PI 3-kinase] inhibitor) or vehicle. IL-6 and IL-8 levels were measured in conditioned media by ELISA. 3. The IL-17-induced release of IL-6 and IL-8 was concentration-dependently inhibited by SB202190 and by PD98059 in bronchial epithelial cells without affecting cell proliferation or survival. 4. Ro-31-7549 and LY294002 had no significant effect on IL-17-induced IL-6 or IL-8 release in bronchial epithelial cells. 4. Taken together, these data indicate a role for p38 and ERK kinase pathways in IL-17-induced release of neutrophil-mobilizing cytokines in human bronchial epithelial cells. These mechanisms constitute potential pharmacotherapeutical targets for inhibition of the IL-17-mediated airway neutrophilia.

Bronchi↗
PubMed2000

Increased elastase and myeloperoxidase activity associated with neutrophil recruitment by IL-17 in airways in vivo.

BACKGROUND: A recent study demonstrated that intratracheal administration of the T-lymphocyte cytokine IL-17 recruits neutrophils into airways in vivo by C-X-C chemokine release. It is not known whether IL-17 may also activate airway neutrophils. OBJECTIVE: Our purpose was to evaluate whether IL-17 activates neutrophils in airways in vivo and, if so, whether the proinflammatory cytokine IL-1beta modulates this action of IL-17. METHODS: Intratracheal administration of human (h) IL-17 or rat (r) IL-1beta or hIL-17 plus rIL-1beta in anesthetized, spontaneously breathing rats was followed by bronchoalveolar lavage (BAL) 6 hours later. The BAL fluid was characterized in terms of neutrophil count, of the activity for myeloperoxidase (MPO), and in some cases of the activity for elastase (ELA). Isolated rat neutrophils were stimulated with hIL-17 in vitro, followed by characterization of MPO activity in the cell medium. RESULTS: hIL-17 (1 microg) increased the ELA and the MPO activity, as well as the neutrophil count in BAL fluid, whereas the proinflammatory cytokine rIL-1beta (2.5 ng) did not. Pretreatment with rIL-1beta enhanced IL-17induced ELA and MPO activity, without increasing the neutrophil count. The BAL ELA activity was inhibited by a specific inhibitor of neutrophil serine proteases. Stimulation with hIL-17 in vitro did not increase MPO activity in isolated neutrophils. CONCLUSION: IL-17 can activate neutrophils in association with their recruitment into the airways in vivo and this effect is probably achieved through induced release of mediators from other airway cells.

Animals↗
PubMed2000

Airway neutrophils and interleukin-17.

It is well known that exacerbations of obstructive airways disease such as asthma and chronic obstructive pulmonary disease are associated with an increased number of neutrophils in the airways. However, the mechanisms behind this phenomenon are poorly understood. There is in vivo experimental evidence that the number of airway neutrophils is controlled by certain T-lymphocytes, but the mediators responsible for this lymphocyte-related neutrophilia have not yet been identified. In this review, novel evidence that the T-lymphocyte-related cytokine interleukin (IL)-17 can link the activation of certain T-lymphocytes to the recruitment and activation of airway neutrophils is described. The IL-17-induced neutrophil recruitment is mediated via induced CXC chemokine release through steroid-sensitive mechanisms and is modulated by release of endogenous tachykinins. These effects of IL-17 are potentiated by other pro-inflammatory cytokines such as (IL-1beta) and tumour necrosis factor-alpha. Clinical studies are needed to evaluate whether or not targeting these mechanisms can provide a useful pharmacotherapeutical approach against exaggerated mobilization of neutrophils in obstructive airways disease.

Cytokines↗
PubMed2000

Linkage disequilibrium in isolated populations: Finland and a young sub-population of Kuusamo.

Linkage disequilibrium (LD), non-random association of alleles at closely linked chromosomal loci, has been used as a tool in the identification of disease alleles, and this has led to an improved understanding of pathology in many monogenic Mendelian human diseases. We are currently moving from the mapping and identification of monogenic disease loci to attempts at identifying loci involved in predisposition to multifactorial diseases. In the selection of ascertainment strategies in the studies of these complex diseases, the extent of background LD in different populations is an important consideration. Here, we compare the extent of LD among the alleles of linked loci in a randomly ascertained sample of individuals from the Finnish population and a set of individuals ascertained from the region of Kuusamo, a small sub-population, founded some 13 generations ago, which has experienced very little subsequent immigration. Thirty-three microsatellite loci were genotyped in chromosomal regions on 13q, 19q, 21q, Xq, and Xp. The genetic diversity of these loci was determined separately in the general Finnish sample and in the Kuusamo sample. The X-chromosomal loci are characterised by higher levels of LD in the samples from Kuusamo than in the much larger (and older) general population of Finland, whereas in alleles of autosomal loci very little LD was seen in either of these two samples.

Alleles↗
PubMed1999

Neutrophil recruitment by human IL-17 via C-X-C chemokine release in the airways.

IL-17 is a recently discovered cytokine that can be released from activated human CD4+ T lymphocytes. This study assessed the proinflammatory effects of human (h) IL-17 in the airways. In vitro, hIL-17 increased the release of IL-8 in human bronchial epithelial and venous endothelial cells, in a time- and concentration-dependent fashion. This effect of hIL-17 was inhibited by cotreatment with an anti-hIL-17 Ab and was potentiated by hTNF-alpha. In addition, hIL-17 increased the expression of hIL-8 mRNA in bronchial epithelial cells. Conditioned medium from hIL-17-treated bronchial epithelial cells increased human neutrophil migration in vitro. This effect was blocked by an anti-hIL-8 Ab. In vivo, intratracheal instillation of hIL-17 selectively recruited neutrophils into rat airways. This recruitment of neutrophils into the airways was inhibited by an anti-hIL-17 Ab and accompanied by increased levels of rat macrophage inflammatory protein-2 (rMIP-2) in bronchoalveolar lavage (BAL) fluid. The BAL neutrophilia was also blocked by an anti-rMIP-2 Ab. The effect of hIL-17 on the release of hIL-8 and rMIP-2 was also inhibited by glucocorticoids, in vitro and in vivo, respectively. These data demonstrate that hIL-17 can specifically and selectively recruit neutrophils into the airways via the release of C-X-C chemokines from bronchial epithelial cells and suggest a novel mechanism linking the activation of T-lymphocytes to recruitment of neutrophils into the airways.

Adult↗
PubMed1999

Increased levels of interleukin-16 in the airways of tobacco smokers: relationship with peripheral blood T lymphocytes.

BACKGROUND: The mechanisms behind the development of systemic immunomodulation among tobacco smokers are not fully understood, but several studies have indicated a role for CD8+ and/or CD4+ T cells. Interleukin (IL)-16, a cytokine released from inflammatory cells as well as bronchial epithelial cells, can recruit and activate CD4+ T cells. A study was undertaken to establish whether the IL-16 level is increased in the airways of tobacco smokers and to determine whether airway levels of IL-16 are related to the number and function of systemic T lymphocytes. METHODS: Bronchoalveolar lavage (BAL) fluid was collected from eight never smokers and 18 tobacco smokers without clinical airway symptoms, and from 16 tobacco smokers with clinical airway symptoms. Interleukin-16 protein levels in BAL fluid were determined using enzyme-linked immunosorbent assay (ELISA). Peripheral blood was collected for determination of CD4+ T cell content using flow cytometry. The responsiveness of systemic lymphocytes in smokers was assessed by measuring the proliferative response of peripheral blood lymphocytes to the superantigen staphylococcus enterotoxin A (SEA). RESULTS: The IL-16 protein level in the BAL fluid was significantly higher in tobacco smokers than in non-smokers. However, among tobacco smokers the IL-16 level was similar in asymptomatic smokers and in those with airway symptoms. The level of IL-16 in the BAL fluid of smokers correlated negatively with the percentage of CD4+ T cells and positively with superantigen stimulated lymphocyte proliferation in peripheral blood. CONCLUSIONS: In tobacco smokers the airway IL-16 level is increased and it is possible that this increase in IL-16 influences systemic immunomodulation by altering the number and responsiveness of systemic T lymphocytes.

Adult↗
PubMed1998

A novel snoRNA (U73) is encoded within the introns of the human and mouse ribosomal protein S3a genes.

The mouse ribosomal protein S3a-encoding gene (mRPS3a) was cloned and sequenced in this study. mRPS3a shares identical exon/intron structure with its human counterpart. Both genes are split to six exons and exhibit remarkable conservation of the promoter region (68.8% identity in the 250 bp upstream of cap site) and coding region (the proteins differ in two amino acids). mRPS3a displays many features common to other r-protein genes, including the CpG-island at 5'-end of the gene, cap site within an oligopyrimidine tract and no consensus TATA or CAAT boxes. However, mRPS3a represents a rare subclass of r-protein genes that possess a long coding sequence in the first exon. Comparison of human and mouse S3a genes revealed sequence fragments with striking similarity within introns 3 and 4. Here we demonstrate that these sequences encode for a novel small nucleolar RNA (snoRNA) designated U73. U73 contains C, D and D' boxes and a 12-nucleotide antisense complementarity to the 28S ribosomal RNA. These features place U73 into the family of intron-encoded antisense snoRNAs that guide site-specific 2'-O-ribose methylation of pre-rRNA. We propose that U73 is involved in methylation of the G1739 residue of the human 28S rRNA. In addition, we present the mapping of human ribosomal protein S3a gene (hRPS3a) and internally nested U73 gene to the human chromosome 4q31.2-3.

Amino Acid Sequence↗
PubMed1997

The visual assignment of genes by fiber-fish: BTF3 protein homologue gene (BTF3) and a novel pseudogene of human RNA helicase A (DDX9P) on 13q22.

Chromosome 13 is one of the poorly mapped human chromosomes. As an example, only two cloned genes have been assigned to bands 13q22-q31. Our characterization of the critical region for the variant form of late infantile neuronal ceroid lipofuscinosis (vLINCL, locus definition CLN5) disease region on 13q22 resulted in the identification of the sequences encoding the BTF3 protein homologue gene (HGMW-approved symbol BTF3) and a novel pseudogene for RNA Helicase A (HGMW-approved symbol DDX9P). Precise visual assignment to the physical clones covering this region and the positional relationships of these genes were achieved by the use of tyramine enhancement of Fiber-FISH hybridization signals, demonstrating the power of this technique in efficient positioning of coding regions on the physical maps.

Chromosomes, Human, Pair 13↗
PubMed1997

Demographic history and linkage disequilibrium in human populations.

In the human genome, linkage disequilibrium (LD)--the non-random association of alleles at chromosomal loci--has been studied mainly in regions surrounding disease genes on affected chromosomes. Consequently, little information is available on the distribution of LD across anonymous genomic regions in the general population. However, demographic history is expected to influence the extent of overall LD across the genome, so a population that has been of constant size will display higher levels of LD than a population that has expanded. In support of this, the extent of LD between anonymous loci on chromosome 4 in chimpanzees (as a model of a population of constant size) has been compared to that in Finns (as a model of an expanded population; refs 8,9) and found to exhibit more LD than in the latter population. In Europe, studies of mitochondrial (mt) DNA sequences have suggested that most populations have experienced expansion, whereas the Saami in northern Fenno-Scandinavia have been of constant size (Table 1). Thus, in northern Europe, populations with radically different demographic histories live in close geographic proximity to each other. We studied the allelic associations between anonymous microsatellite loci on the X chromosome in the Saami and neighbouring populations and found dramatically higher levels of LD in the Saami than in other populations in the region. This indicates that whereas recently expanded populations, such as the Finns, are well suited to map single disease genes affected by recent mutations, populations that have been of constant size, such as the Saami, may be much better suited to map genes for complex traits that are caused by older mutations.

Alleles↗