Histamine receptor 4 (H₄R) in pathogenesis of Sjögren’s syndrome

Vasili Stegajev

Research output: ThesisDoctoral ThesisCollection of Articles

Abstract

Sjögren's syndrome (SS) is a chronic autoimmune disease with yet unknown etiology and partly unclear pathogenesis that affects exocrine glands. Cardinal symptoms of the disease are dry mouth and eyes. Fas-apoptosis is considered as a key event in breach of autoimmune tolerance in SS. Increased levels of histamine in serum and tissue fluids characterize many autoimmune diseases, including SS. However, trials have showed ineffectiveness of H1 and H2 histamine receptor antagonists in the treatment of autoimmune diseases. More recently, it has been reported that many cells throughout the human body synthesize histamine in small nanomolar quantities in a non-professional manner. Unlike professional histamine-synthesizing, -storing and stimulus-mediated burst-like -releasing cells, such as mast cells, basophils and ECL-cells, many other cells, including dendritic- and T cells can synthesize histamine at 100-1000-fold lower rate and release it continuously into the extracellular milieu. In the beginning this discovery drew little attention until a new H4 receptor (H4R) was discovered in immune cells in 1994. H4R has about 10000-fold higher affinity to histamine than conventional H1R and H2R. This discovery shortly became a hot topic and started a new era for studies of immunomodulatory histamine/H4R-mediated effects. Today clinical trials of H4R antagonist as treatment for inflammatory diseases are ongoing. It was hypothesized that H4R is involved in SS pathogenesis. To test this hypothesis the following objectives were studied: (1) expression of H4R in salivary glands of healthy and SS individuals; (2) H4R internalization and functionality upon specific agonist stimulation; (3) transport of histamine in HSG cells and expression of histamine metabolizing enzymes in salivary glands of healthy and SS individuals; (4) mechanisms of anti-apoptotic activity of H4R; (5) mRNA levels of moH4R in orchidectomized and intact male mice. Briefly, this study was performed on snap-frozen and/or paraffin-embedded biopsies of minor salivary glands from SS patients, which were routinely taken as a part of the diagnostic procedure. Samples were considered as healthy if diagnostic criteria were not fulfilled. In vitro experiments were performed on two cell lines: human salivary gland (HSG) line, which is phenotypically a ductal epithelial line, and normal salivary Simian virus 40-immortalized acinar cell (NS-SV-AC) line. Additionally, we were gifted by snap-frozen murine salivary glands from BALB/c, NOD, orhydectomized and intact HDC+/HDC+ lines. Protein expression levels of histamine receptors, transporters and metabolizing enzymes in tissue samples and cell lines were tested by immunohistochemistry and immunofluorescence staining, mRNA were quantified by qRT-PCR technique (including TaqMan technology). Two specific H4R agonists ST-1006 and HST-10 were used for in vitro functional (HSG), internalization and apoptosis (NS-SV-AC) cell line experiments. Levels of IL-8 and VEGF produced by HSG cells ± ST-1006 were analyzed by xMAP and ELISA assays. [3H]histamine transport in HSG cells ± OCT3 inhibitor MMP was analyzed by liquid scintillation technique. hrTNFα/IMD0354-induced apoptosis of NS-SV-AC cells ± HST-10 was analyzed with following techniques: Western blot to study late apoptosis marker cPARP, anti- and pro-apoptotic proteins BAX and Bcl-XL and phosphorylation of JNK and ERK MAPKs; flow cytometry to study Annexin-V and PI labeling of apoptotic and necrotic cells; phase-contrast microscopy to study morphological changes of apoptotic cells; additionally, BAX and Bcl-XL mRNA levels were studied by qRT-PCR. H4R was found in the acinar and ductal epithelium in healthy salivary glands on both mRNA and protein levels. Immunohistochemical staining showed relatively low H4R expression in samples from SS patients as compared to those from healthy controls. Healthy ductal salivary epithelium is fully equipped with a histamine synthesizing, transporting and intracellular degrading machinery. SS salivary glands were characterized by drastically diminished expression of major histamine transporter OCT3 at both protein and mRNA levels. In vitro experiments showed time dependent up-regulated production of IL-8 and VEGF by HSG cell upon high-dose stimulation of H4R with ST-1006 agonist. NS-SV-AC cells express H4R, which internalization was delayed by clathrin inhibitor methyl-β-dextrin. qRT-PCR and [3H]histamine transport experiments proposed OCT3 as the major histamine transporter in HSG cells. hrTNFα/IMD0354-induced apoptosis of NS-SV-AC cells was successfully inhibited by HST-10-induced activation of H4R in a dose-dependent manner via inhibition of JNK MAPK pathways and up-regulation of Bcl-XL anti-apoptotic protein. mRNA levels of salivary moH4R relatively low in orhydectomized HDC+/HDC+ as compared to intact control. Salivary ductal epithelial cells are equipped with a HDC/OCT3/HNMT-machinery therefore considering them as non-professional histamine-producing cells. H4R-mediated locally produced low nanomolar levels of histamine maintain homeostasis of the salivary epithelium. H4R activation favors cell survival. Altered histamine transport together with decreased expression of H4R in salivary epithelium can contribute to SS pathogenesis by predisposing epithelial cells to an apoptotic pre-condition. Mast-cell-derived high concentrations of histamine in SS salivary glands may excessively stimulate H4R, leading to an up-regulated production of pro-inflammatory IL-8 and VEGF, followed by a down-regulation of H4R. Diminished expression of H4R in salivary epithelium in SS patients may also be aggravated by local/systemic androgen levels. In future, local use of low molecular weight H4R agonists may become an alternative for costly biologicals in the treatment of autoimmune diseases, including Sjögren´s syndrome.
Original languageEnglish
Place of PublicationHelsinki
Publisher
Print ISBNs978-951-51-2360-2
Electronic ISBNs978-951-51-2361-9
Publication statusPublished - 2016
MoE publication typeG5 Doctoral dissertation (article)

Fields of Science

  • 3111 Biomedicine

Cite this

Stegajev, V. (2016). Histamine receptor 4 (H₄R) in pathogenesis of Sjögren’s syndrome. Helsinki : University of Helsinki.
Stegajev, Vasili. / Histamine receptor 4 (H₄R) in pathogenesis of Sjögren’s syndrome. Helsinki : University of Helsinki, 2016. 99 p.
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title = "Histamine receptor 4 (H₄R) in pathogenesis of Sj{\"o}gren’s syndrome",
abstract = "Sj{\"o}gren's syndrome (SS) is a chronic autoimmune disease with yet unknown etiology and partly unclear pathogenesis that affects exocrine glands. Cardinal symptoms of the disease are dry mouth and eyes. Fas-apoptosis is considered as a key event in breach of autoimmune tolerance in SS. Increased levels of histamine in serum and tissue fluids characterize many autoimmune diseases, including SS. However, trials have showed ineffectiveness of H1 and H2 histamine receptor antagonists in the treatment of autoimmune diseases. More recently, it has been reported that many cells throughout the human body synthesize histamine in small nanomolar quantities in a non-professional manner. Unlike professional histamine-synthesizing, -storing and stimulus-mediated burst-like -releasing cells, such as mast cells, basophils and ECL-cells, many other cells, including dendritic- and T cells can synthesize histamine at 100-1000-fold lower rate and release it continuously into the extracellular milieu. In the beginning this discovery drew little attention until a new H4 receptor (H4R) was discovered in immune cells in 1994. H4R has about 10000-fold higher affinity to histamine than conventional H1R and H2R. This discovery shortly became a hot topic and started a new era for studies of immunomodulatory histamine/H4R-mediated effects. Today clinical trials of H4R antagonist as treatment for inflammatory diseases are ongoing. It was hypothesized that H4R is involved in SS pathogenesis. To test this hypothesis the following objectives were studied: (1) expression of H4R in salivary glands of healthy and SS individuals; (2) H4R internalization and functionality upon specific agonist stimulation; (3) transport of histamine in HSG cells and expression of histamine metabolizing enzymes in salivary glands of healthy and SS individuals; (4) mechanisms of anti-apoptotic activity of H4R; (5) mRNA levels of moH4R in orchidectomized and intact male mice. Briefly, this study was performed on snap-frozen and/or paraffin-embedded biopsies of minor salivary glands from SS patients, which were routinely taken as a part of the diagnostic procedure. Samples were considered as healthy if diagnostic criteria were not fulfilled. In vitro experiments were performed on two cell lines: human salivary gland (HSG) line, which is phenotypically a ductal epithelial line, and normal salivary Simian virus 40-immortalized acinar cell (NS-SV-AC) line. Additionally, we were gifted by snap-frozen murine salivary glands from BALB/c, NOD, orhydectomized and intact HDC+/HDC+ lines. Protein expression levels of histamine receptors, transporters and metabolizing enzymes in tissue samples and cell lines were tested by immunohistochemistry and immunofluorescence staining, mRNA were quantified by qRT-PCR technique (including TaqMan technology). Two specific H4R agonists ST-1006 and HST-10 were used for in vitro functional (HSG), internalization and apoptosis (NS-SV-AC) cell line experiments. Levels of IL-8 and VEGF produced by HSG cells ± ST-1006 were analyzed by xMAP and ELISA assays. [3H]histamine transport in HSG cells ± OCT3 inhibitor MMP was analyzed by liquid scintillation technique. hrTNFα/IMD0354-induced apoptosis of NS-SV-AC cells ± HST-10 was analyzed with following techniques: Western blot to study late apoptosis marker cPARP, anti- and pro-apoptotic proteins BAX and Bcl-XL and phosphorylation of JNK and ERK MAPKs; flow cytometry to study Annexin-V and PI labeling of apoptotic and necrotic cells; phase-contrast microscopy to study morphological changes of apoptotic cells; additionally, BAX and Bcl-XL mRNA levels were studied by qRT-PCR. H4R was found in the acinar and ductal epithelium in healthy salivary glands on both mRNA and protein levels. Immunohistochemical staining showed relatively low H4R expression in samples from SS patients as compared to those from healthy controls. Healthy ductal salivary epithelium is fully equipped with a histamine synthesizing, transporting and intracellular degrading machinery. SS salivary glands were characterized by drastically diminished expression of major histamine transporter OCT3 at both protein and mRNA levels. In vitro experiments showed time dependent up-regulated production of IL-8 and VEGF by HSG cell upon high-dose stimulation of H4R with ST-1006 agonist. NS-SV-AC cells express H4R, which internalization was delayed by clathrin inhibitor methyl-β-dextrin. qRT-PCR and [3H]histamine transport experiments proposed OCT3 as the major histamine transporter in HSG cells. hrTNFα/IMD0354-induced apoptosis of NS-SV-AC cells was successfully inhibited by HST-10-induced activation of H4R in a dose-dependent manner via inhibition of JNK MAPK pathways and up-regulation of Bcl-XL anti-apoptotic protein. mRNA levels of salivary moH4R relatively low in orhydectomized HDC+/HDC+ as compared to intact control. Salivary ductal epithelial cells are equipped with a HDC/OCT3/HNMT-machinery therefore considering them as non-professional histamine-producing cells. H4R-mediated locally produced low nanomolar levels of histamine maintain homeostasis of the salivary epithelium. H4R activation favors cell survival. Altered histamine transport together with decreased expression of H4R in salivary epithelium can contribute to SS pathogenesis by predisposing epithelial cells to an apoptotic pre-condition. Mast-cell-derived high concentrations of histamine in SS salivary glands may excessively stimulate H4R, leading to an up-regulated production of pro-inflammatory IL-8 and VEGF, followed by a down-regulation of H4R. Diminished expression of H4R in salivary epithelium in SS patients may also be aggravated by local/systemic androgen levels. In future, local use of low molecular weight H4R agonists may become an alternative for costly biologicals in the treatment of autoimmune diseases, including Sj{\"o}gren´s syndrome.",
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author = "Vasili Stegajev",
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year = "2016",
language = "English",
isbn = "978-951-51-2360-2",
series = "Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis",
publisher = "University of Helsinki",
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}

Histamine receptor 4 (H₄R) in pathogenesis of Sjögren’s syndrome. / Stegajev, Vasili.

Helsinki : University of Helsinki, 2016. 99 p.

Research output: ThesisDoctoral ThesisCollection of Articles

TY - THES

T1 - Histamine receptor 4 (H₄R) in pathogenesis of Sjögren’s syndrome

AU - Stegajev, Vasili

N1 - M1 - 99 s. + liitteet Helsingin yliopisto Volume: Proceeding volume:

PY - 2016

Y1 - 2016

N2 - Sjögren's syndrome (SS) is a chronic autoimmune disease with yet unknown etiology and partly unclear pathogenesis that affects exocrine glands. Cardinal symptoms of the disease are dry mouth and eyes. Fas-apoptosis is considered as a key event in breach of autoimmune tolerance in SS. Increased levels of histamine in serum and tissue fluids characterize many autoimmune diseases, including SS. However, trials have showed ineffectiveness of H1 and H2 histamine receptor antagonists in the treatment of autoimmune diseases. More recently, it has been reported that many cells throughout the human body synthesize histamine in small nanomolar quantities in a non-professional manner. Unlike professional histamine-synthesizing, -storing and stimulus-mediated burst-like -releasing cells, such as mast cells, basophils and ECL-cells, many other cells, including dendritic- and T cells can synthesize histamine at 100-1000-fold lower rate and release it continuously into the extracellular milieu. In the beginning this discovery drew little attention until a new H4 receptor (H4R) was discovered in immune cells in 1994. H4R has about 10000-fold higher affinity to histamine than conventional H1R and H2R. This discovery shortly became a hot topic and started a new era for studies of immunomodulatory histamine/H4R-mediated effects. Today clinical trials of H4R antagonist as treatment for inflammatory diseases are ongoing. It was hypothesized that H4R is involved in SS pathogenesis. To test this hypothesis the following objectives were studied: (1) expression of H4R in salivary glands of healthy and SS individuals; (2) H4R internalization and functionality upon specific agonist stimulation; (3) transport of histamine in HSG cells and expression of histamine metabolizing enzymes in salivary glands of healthy and SS individuals; (4) mechanisms of anti-apoptotic activity of H4R; (5) mRNA levels of moH4R in orchidectomized and intact male mice. Briefly, this study was performed on snap-frozen and/or paraffin-embedded biopsies of minor salivary glands from SS patients, which were routinely taken as a part of the diagnostic procedure. Samples were considered as healthy if diagnostic criteria were not fulfilled. In vitro experiments were performed on two cell lines: human salivary gland (HSG) line, which is phenotypically a ductal epithelial line, and normal salivary Simian virus 40-immortalized acinar cell (NS-SV-AC) line. Additionally, we were gifted by snap-frozen murine salivary glands from BALB/c, NOD, orhydectomized and intact HDC+/HDC+ lines. Protein expression levels of histamine receptors, transporters and metabolizing enzymes in tissue samples and cell lines were tested by immunohistochemistry and immunofluorescence staining, mRNA were quantified by qRT-PCR technique (including TaqMan technology). Two specific H4R agonists ST-1006 and HST-10 were used for in vitro functional (HSG), internalization and apoptosis (NS-SV-AC) cell line experiments. Levels of IL-8 and VEGF produced by HSG cells ± ST-1006 were analyzed by xMAP and ELISA assays. [3H]histamine transport in HSG cells ± OCT3 inhibitor MMP was analyzed by liquid scintillation technique. hrTNFα/IMD0354-induced apoptosis of NS-SV-AC cells ± HST-10 was analyzed with following techniques: Western blot to study late apoptosis marker cPARP, anti- and pro-apoptotic proteins BAX and Bcl-XL and phosphorylation of JNK and ERK MAPKs; flow cytometry to study Annexin-V and PI labeling of apoptotic and necrotic cells; phase-contrast microscopy to study morphological changes of apoptotic cells; additionally, BAX and Bcl-XL mRNA levels were studied by qRT-PCR. H4R was found in the acinar and ductal epithelium in healthy salivary glands on both mRNA and protein levels. Immunohistochemical staining showed relatively low H4R expression in samples from SS patients as compared to those from healthy controls. Healthy ductal salivary epithelium is fully equipped with a histamine synthesizing, transporting and intracellular degrading machinery. SS salivary glands were characterized by drastically diminished expression of major histamine transporter OCT3 at both protein and mRNA levels. In vitro experiments showed time dependent up-regulated production of IL-8 and VEGF by HSG cell upon high-dose stimulation of H4R with ST-1006 agonist. NS-SV-AC cells express H4R, which internalization was delayed by clathrin inhibitor methyl-β-dextrin. qRT-PCR and [3H]histamine transport experiments proposed OCT3 as the major histamine transporter in HSG cells. hrTNFα/IMD0354-induced apoptosis of NS-SV-AC cells was successfully inhibited by HST-10-induced activation of H4R in a dose-dependent manner via inhibition of JNK MAPK pathways and up-regulation of Bcl-XL anti-apoptotic protein. mRNA levels of salivary moH4R relatively low in orhydectomized HDC+/HDC+ as compared to intact control. Salivary ductal epithelial cells are equipped with a HDC/OCT3/HNMT-machinery therefore considering them as non-professional histamine-producing cells. H4R-mediated locally produced low nanomolar levels of histamine maintain homeostasis of the salivary epithelium. H4R activation favors cell survival. Altered histamine transport together with decreased expression of H4R in salivary epithelium can contribute to SS pathogenesis by predisposing epithelial cells to an apoptotic pre-condition. Mast-cell-derived high concentrations of histamine in SS salivary glands may excessively stimulate H4R, leading to an up-regulated production of pro-inflammatory IL-8 and VEGF, followed by a down-regulation of H4R. Diminished expression of H4R in salivary epithelium in SS patients may also be aggravated by local/systemic androgen levels. In future, local use of low molecular weight H4R agonists may become an alternative for costly biologicals in the treatment of autoimmune diseases, including Sjögren´s syndrome.

AB - Sjögren's syndrome (SS) is a chronic autoimmune disease with yet unknown etiology and partly unclear pathogenesis that affects exocrine glands. Cardinal symptoms of the disease are dry mouth and eyes. Fas-apoptosis is considered as a key event in breach of autoimmune tolerance in SS. Increased levels of histamine in serum and tissue fluids characterize many autoimmune diseases, including SS. However, trials have showed ineffectiveness of H1 and H2 histamine receptor antagonists in the treatment of autoimmune diseases. More recently, it has been reported that many cells throughout the human body synthesize histamine in small nanomolar quantities in a non-professional manner. Unlike professional histamine-synthesizing, -storing and stimulus-mediated burst-like -releasing cells, such as mast cells, basophils and ECL-cells, many other cells, including dendritic- and T cells can synthesize histamine at 100-1000-fold lower rate and release it continuously into the extracellular milieu. In the beginning this discovery drew little attention until a new H4 receptor (H4R) was discovered in immune cells in 1994. H4R has about 10000-fold higher affinity to histamine than conventional H1R and H2R. This discovery shortly became a hot topic and started a new era for studies of immunomodulatory histamine/H4R-mediated effects. Today clinical trials of H4R antagonist as treatment for inflammatory diseases are ongoing. It was hypothesized that H4R is involved in SS pathogenesis. To test this hypothesis the following objectives were studied: (1) expression of H4R in salivary glands of healthy and SS individuals; (2) H4R internalization and functionality upon specific agonist stimulation; (3) transport of histamine in HSG cells and expression of histamine metabolizing enzymes in salivary glands of healthy and SS individuals; (4) mechanisms of anti-apoptotic activity of H4R; (5) mRNA levels of moH4R in orchidectomized and intact male mice. Briefly, this study was performed on snap-frozen and/or paraffin-embedded biopsies of minor salivary glands from SS patients, which were routinely taken as a part of the diagnostic procedure. Samples were considered as healthy if diagnostic criteria were not fulfilled. In vitro experiments were performed on two cell lines: human salivary gland (HSG) line, which is phenotypically a ductal epithelial line, and normal salivary Simian virus 40-immortalized acinar cell (NS-SV-AC) line. Additionally, we were gifted by snap-frozen murine salivary glands from BALB/c, NOD, orhydectomized and intact HDC+/HDC+ lines. Protein expression levels of histamine receptors, transporters and metabolizing enzymes in tissue samples and cell lines were tested by immunohistochemistry and immunofluorescence staining, mRNA were quantified by qRT-PCR technique (including TaqMan technology). Two specific H4R agonists ST-1006 and HST-10 were used for in vitro functional (HSG), internalization and apoptosis (NS-SV-AC) cell line experiments. Levels of IL-8 and VEGF produced by HSG cells ± ST-1006 were analyzed by xMAP and ELISA assays. [3H]histamine transport in HSG cells ± OCT3 inhibitor MMP was analyzed by liquid scintillation technique. hrTNFα/IMD0354-induced apoptosis of NS-SV-AC cells ± HST-10 was analyzed with following techniques: Western blot to study late apoptosis marker cPARP, anti- and pro-apoptotic proteins BAX and Bcl-XL and phosphorylation of JNK and ERK MAPKs; flow cytometry to study Annexin-V and PI labeling of apoptotic and necrotic cells; phase-contrast microscopy to study morphological changes of apoptotic cells; additionally, BAX and Bcl-XL mRNA levels were studied by qRT-PCR. H4R was found in the acinar and ductal epithelium in healthy salivary glands on both mRNA and protein levels. Immunohistochemical staining showed relatively low H4R expression in samples from SS patients as compared to those from healthy controls. Healthy ductal salivary epithelium is fully equipped with a histamine synthesizing, transporting and intracellular degrading machinery. SS salivary glands were characterized by drastically diminished expression of major histamine transporter OCT3 at both protein and mRNA levels. In vitro experiments showed time dependent up-regulated production of IL-8 and VEGF by HSG cell upon high-dose stimulation of H4R with ST-1006 agonist. NS-SV-AC cells express H4R, which internalization was delayed by clathrin inhibitor methyl-β-dextrin. qRT-PCR and [3H]histamine transport experiments proposed OCT3 as the major histamine transporter in HSG cells. hrTNFα/IMD0354-induced apoptosis of NS-SV-AC cells was successfully inhibited by HST-10-induced activation of H4R in a dose-dependent manner via inhibition of JNK MAPK pathways and up-regulation of Bcl-XL anti-apoptotic protein. mRNA levels of salivary moH4R relatively low in orhydectomized HDC+/HDC+ as compared to intact control. Salivary ductal epithelial cells are equipped with a HDC/OCT3/HNMT-machinery therefore considering them as non-professional histamine-producing cells. H4R-mediated locally produced low nanomolar levels of histamine maintain homeostasis of the salivary epithelium. H4R activation favors cell survival. Altered histamine transport together with decreased expression of H4R in salivary epithelium can contribute to SS pathogenesis by predisposing epithelial cells to an apoptotic pre-condition. Mast-cell-derived high concentrations of histamine in SS salivary glands may excessively stimulate H4R, leading to an up-regulated production of pro-inflammatory IL-8 and VEGF, followed by a down-regulation of H4R. Diminished expression of H4R in salivary epithelium in SS patients may also be aggravated by local/systemic androgen levels. In future, local use of low molecular weight H4R agonists may become an alternative for costly biologicals in the treatment of autoimmune diseases, including Sjögren´s syndrome.

KW - Acinar Cells

KW - Apoptosis

KW - +drug effects

KW - Apoptosis Regulatory Proteins

KW - Benzamides

KW - +pharmacology

KW - Biological Transport

KW - +physiology

KW - Epithelial Cells

KW - +metabolism

KW - Histamine

KW - Histamine N-Methyltransferase

KW - Histidine Decarboxylase

KW - NF-kappa B

KW - +antagonists & inhibitors

KW - Organic Cation Transport Proteins

KW - Receptors, G-Protein-Coupled

KW - Receptors, Histamine

KW - Salivary Glands

KW - Sialadenitis

KW - +etiology

KW - Signal Transduction

KW - Sjogren’s Syndrome

KW - +complications

KW - +physiopathology

KW - Submandibular Gland

KW - Tumor Necrosis Factor-alpha

KW - Vascular Endothelial Growth Factor A

KW - 3111 Biomedicine

M3 - Doctoral Thesis

SN - 978-951-51-2360-2

T3 - Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis

PB - University of Helsinki

CY - Helsinki

ER -

Stegajev V. Histamine receptor 4 (H₄R) in pathogenesis of Sjögren’s syndrome. Helsinki : University of Helsinki, 2016. 99 p. (Dissertationes Scholae Doctoralis Ad Sanitatem Investigandam Universitatis Helsinkiensis; 53/2016).