Browsing by Author "Dambergs, Kristaps"

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    Characterisation of Acquired Human Cholesteatoma in Ontogenetic Aspect. Summary of the Doctoral Thesis
    (Rīga Stradiņš University, 2024) Dambergs, Kristaps; Segliņa, Gunta; Pilmane, Māra
    Cholesteatoma is a benign, but locally aggressive formation in the middle ear. Human cholesteatoma may be congenital or acquired. Acquired cholesteatoma occurs when skin epithelium migrates into the middle ear where it transforms into cholesteatoma tissue. Cholesteatoma tissue is hyperproliferative and erodes surrounding tissue in the middle ear. The most common patient complaints are impaired hearing and frequent otorrhoea. However, a cholesteatoma can cause complications such as meningitis, brain abscess, facial nerve palsy and sigmoid sinus thrombosis. The morphopatogenesis of cholesteatoma is a complex process characterised by proliferation, the presence of inflammation and remodelling of surrounding tissue. The aim of the study was to determine and describe the relative amount of tissue factors that characterise the morphopatogenetic processes of acquired cholesteatoma and their interaction with each other in the ontogenetic aspect. The study included cholesteatoma tissue from 50 patients. The patients were divided into two groups according to their age, a group of children and a group of adults. Each group consisted of 25 patients. The control group consisted of unaltered skin of seven different deceased people taken from the outer ear meatus. The immunohistochemical method was used to assess the relative amount of matrix metalloproteinase 2 (MMP-2), matrix metalloproteinase 9 (MMP-9), tissue inhibitor of matrix metalloproteinase 2 (TIMP-2), tissue inhibitor of matrix metalloproteinase 4 (TIMP-4), proliferation marker Ki-67, nuclear factor kappa beta (NF-κβ), interleukin 1 alpha (IL-1 α), interleukin 10 (IL-10), human beta defensin 2 (HβD-2), human beta defensin 4 (HβD-4), vascular endothelial growth factor (VEGF) and Sonic hedgehog (SHH) gene protein in both cholesteatoma and control tissues. Healthy tissues were characterised by a stable relative balance of remodelling factors (MMP/TIMP) and pro- and anti-inflammatory cytokine complexes (IL-1 α/IL-10), required for normal skin function. In cholesteatoma tissue, an increased expression of Ki-67 was observed, which characterises the hyperproliferation of cells in this formation. Increased expression of NF-κβ also shows the involvement of this factor in cell proliferation and inflammatory processes by enhancing their activity. The overexpression of HβD-2 indicates an intensification of local tissue protection. And the increased number of SHH-positive cells in the perimatrix of the cholesteatoma indicates the intensification of this gene protein in tumour growth. The variable expression of remodelling factors in cholesteatoma tissue indicates an imbalance between remodelling factors. The increase in the number of IL-1α positive structures and the decrease in the number of IL-10 positive cells in cholesteatoma tissue indicate a change in the balance between pro-inflammatory and anti-inflammatory cytokines. Changes in the levels of all these factors are not age-related.
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    Cilvēka iegūtas holesteatomas audu pārmaiņu ontoģenētiskais raksturojums. Promocijas darba kopsavilkums
    (Rīgas Stradiņa universitāte, 2024) Dambergs, Kristaps; Segliņa, Gunta; Pilmane, Māra
    Holesteatoma ir labdabīgs, bet lokāli agresīvs veidojums vidusausī. Cilvēka holesteatoma var būt iedzimta vai iegūta. Cilvēka iegūta holesteatoma rodas, ādas epitēlijam iemigrējot vidusausī, kur tas pārveidojas par holesteatomas audiem. Holesteatomas audi ir hiperproliferatīvi, un tie erodē apkārtējos audus vidusausī. Biežākās pacienta sūdzības ir pasliktināta dzirde un strutaini izdalījumi no auss, kas bieži atkārtojas. Tomēr holesteatoma var radīt tādas komplikācijas kā meningīts, smadzeņu abscess, sejas nerva paralīze un S veida sinusa tromboze. Holesteatomas morfopatoģenēze ir komplekss process un tiek raksturots ar proliferāciju, iekaisuma klātbūtni un apkārtējo audu remodelāciju. Pētījuma mērķis bija noteikt un aprakstīt holesteatomas morfopatoģenētisko procesu raksturojošo audu faktoru relatīvo daudzumu un to savstarpējo mijiedarbību cilvēka iegūtas holesteatomas audos ontoģenētiskā aspektā. Pētījumā tika iekļauti 50 pacientu holesteatomas audi. Pacienti tika sadalīti divās grupās atkarībā no vecuma – bērnu un pieaugušo grupas. Katrā pacientu grupā bija 25 pacienti. Kontroles grupu veidoja septiņu dažādu mirušu cilvēku neizmainīta āda, kas tika iegūta no ārējās auss ejas. Ar imūnhistoķīmijas metodi tika izvērtēts matrices metaloproteināzes 2 (MMP-2), matrices metaloproteināzes 9 (MMP-9), matrices metaloproteināzes audu inhibitora 2 (TIMP- 2), matrices metaloproteināzes audu inhibitora 4 (TIMP-4), proliferācijas marķiera Ki- 67, nukleārā faktora kapa beta (NF-κβ), interleikīna 1 alfa (IL-1α), interleikīna 10 (IL-10), cilvēka beta defensīna 2 (HβD-2), cilvēka beta defensīna 4 (HβD-4), vaskulārā endoteliālā augšanas faktora (VEGF) un Sonic hedgehog (SHH) gēna proteīna imūnpozitīvo struktūru relatīvais daudzums gan holesteatomas, gan kontroles audos. Veselos audus raksturoja remodelācijas faktoru (MMP/TIMP) un iekaisuma veicinošo un nomācošo citokīnu (IL-1α/IL-10) kompleksu stabils relatīvais līdzsvars, kas nepieciešams normālas ādas funkcijai. Holesteatomas audos tika novērota palielināta Ki-67 ekspresija, kas raksturo šī veidojuma šūnu hiperproliferāciju. Arī palielinātā NF-κβ ekspresija raksturo šī faktora iesaisti šūnu proliferācijas un iekaisuma procesos, pastiprinot šo procesu aktivitāti. Savukārt palielinātais HβD-2 daudzums norāda uz lokālu audu aizsardzības intensifikāciju. Palielinātais SHH relatīvais daudzums holesteatomas perimatriksā atklāj šī gēna proteīna intensifikāciju audzēja augšanā. Variablā remodelācijas faktoru ekspresija holesteatomas audos norāda uz šo faktoru disbalansu, savukārt IL-1α pozitīvo struktūru skaita palielināšanās un IL-10 pozitīvo šūnu skaita samazināšanās tendence holesteatomas audos – uz iekaisuma veicinošo un nomācošo citokīnu savstarpējā līdzsvara izmaiņām. Visu šo faktoru daudzuma izmaiņas ir ar vecumu nesaistītas.
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    Cilvēka iegūtas holesteatomas audu pārmaiņu ontoģenētiskais raksturojums. Promocijas darbs
    (Rīgas Stradiņa universitāte, 2024) Dambergs, Kristaps; Segliņa, Gunta; Pilmane, Māra
    Holesteatoma ir labdabīgs, bet lokāli agresīvs veidojums vidusausī. Cilvēka holesteatoma var būt iedzimta vai iegūta. Cilvēka iegūta holesteatoma rodas, ādas epitēlijam iemigrējot vidusausī, kur tas pārveidojas par holesteatomas audiem. Holesteatomas audi ir hiperproliferatīvi, un tie erodē apkārtējos audus vidusausī. Biežākās pacienta sūdzības ir pasliktināta dzirde un strutaini izdalījumi no auss, kas bieži atkārtojas. Tomēr holesteatoma var radīt tādas komplikācijas kā meningīts, smadzeņu abscess, sejas nerva paralīze un S veida sinusa tromboze. Holesteatomas morfopatoģenēze ir komplekss process un tiek raksturots ar proliferāciju, iekaisuma klātbūtni un apkārtējo audu remodelāciju. Pētījuma mērķis bija noteikt un aprakstīt holesteatomas morfopatoģenētisko procesu raksturojošo audu faktoru relatīvo daudzumu un to savstarpējo mijiedarbību cilvēka iegūtas holesteatomas audos ontoģenētiskā aspektā. Pētījumā tika iekļauti 50 pacientu holesteatomas audi. Pacienti tika sadalīti divās grupās atkarībā no vecuma – bērnu un pieaugušo grupas. Katrā pacientu grupā bija 25 pacienti. Kontroles grupu veidoja septiņu dažādu mirušu cilvēku neizmainīta āda, kas tika iegūta no ārējās auss ejas. Ar imūnhistoķīmijas metodi tika izvērtēts matrices metaloproteināzes 2 (MMP-2), matrices metaloproteināzes 9 (MMP-9), matrices metaloproteināzes audu inhibitora 2 (TIMP- 2), matrices metaloproteināzes audu inhibitora 4 (TIMP-4), proliferācijas marķiera Ki- 67, nukleārā faktora kapa beta (NF-κβ), interleikīna 1 alfa (IL-1α), interleikīna 10 (IL-10), cilvēka beta defensīna 2 (HβD-2), cilvēka beta defensīna 4 (HβD-4), vaskulārā endoteliālā augšanas faktora (VEGF) un Sonic hedgehog (SHH) gēna proteīna imūnpozitīvo struktūru relatīvais daudzums gan holesteatomas, gan kontroles audos. Veselos audus raksturoja remodelācijas faktoru (MMP/TIMP) un iekaisuma veicinošo un nomācošo citokīnu (IL-1α/IL-10) kompleksu stabils relatīvais līdzsvars, kas nepieciešams normālas ādas funkcijai. Holesteatomas audos tika novērota palielināta Ki-67 ekspresija, kas raksturo šī veidojuma šūnu hiperproliferāciju. Arī palielinātā NF-κβ ekspresija raksturo šī faktora iesaisti šūnu proliferācijas un iekaisuma procesos, pastiprinot šo procesu aktivitāti. Savukārt palielinātais HβD-2 daudzums norāda uz lokālu audu aizsardzības intensifikāciju. Palielinātais SHH relatīvais daudzums holesteatomas perimatriksā atklāj šī gēna proteīna intensifikāciju audzēja augšanā. Variablā remodelācijas faktoru ekspresija holesteatomas audos norāda uz šo faktoru disbalansu, savukārt IL-1α pozitīvo struktūru skaita palielināšanās un IL-10 pozitīvo šūnu skaita samazināšanās tendence holesteatomas audos – uz iekaisuma veicinošo un nomācošo citokīnu savstarpējā līdzsvara izmaiņām. Visu šo faktoru daudzuma izmaiņas ir ar vecumu nesaistītas.
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    Comparison of tissue factors in the ontogenetic aspects of human cholesteatoma
    (2024-03-21) Dambergs, Kristaps; Sumeraga, Gunta; Pilmane, Māra; Department of Otorhinolaryngology; Department of Morphology; Institute of Anatomy and Anthropology
    Background: An acquired cholesteatoma is a benign but locally aggressive lesion in the middle ear. It is characterized by chronic inflammation and the destruction of surrounding bone. Therefore, the aim of this study was to compare defensins HβD-2 and HβD-4; pro- and anti-inflammatory cytokines IL-1α and IL-10; proliferation marker Ki-67; transcription factor NF-κβ; angiogenetic factor VEGF; Sonic hedgehog gene protein SHH; and remodeling factors MMP-2, MMP9, TIMP-2, and TIMP-4 in adult and pediatric cholesteatoma tissue, and to compare these groups with control skin tissue. Methods: The study included 25 cholesteatoma tissue material samples from children, 25 from adults, and 7 deep external ear canal skin samples from cadavers. The tissues were stained immunohistochemically and evaluated using semi-quantitative methods. Nonparametric tests, such as the Kruskal–Wallis test and Spearman rank correlation, were used. Results: There were no statistically discernible differences between the adult and children groups when comparing the relative numbers of factor-positive cells. Conclusions: There are no histopathological differences between adult and children cholesteatoma tissues.
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    Complex Evaluation of Tissue Factors in Pediatric Cholesteatoma
    (2021-10-16) Dambergs, Kristaps; Sumeraga, Gunta; Pilmane, Māra; Department of Otorhinolaryngology; Department of Morphology; Institute of Anatomy and Anthropology
    The aim of this study was to describe the appearance and distribution of tissue remodeling markers (MMP-2, MMP-9, TIMP-2, TIMP-4), Sonic hedgehog gene protein (Shh), pro- and anti-inflammatory cytokines (IL–1, IL–10), transcription factor (NF-κβ), proliferation marker (Ki–67), angiogenetic factor (VEGF), tissue defensins (HβD–2, HβD–4) of the pediatric cholesteatoma. Sixteen cholesteatoma samples were obtained from children, eleven skin controls from cadavers. Tissues were stained for MMP-2, MMP-9, TIMP-2, TIMP-4, Shh, IL–1, IL–10, NF-κβ, Ki–67, VEGF, HβD–2, HβD–4. Non-parametric statistic, Mann–Whitney, and Spearman’s coefficient was used. A statistically significant difference was seen between Shh and HβD–2 in perimatrix and control connective tissue, between NF-κβ in cholesteatoma and control skin, and between HβD–4 in matrix and skin epithelium. Complex intercorrelations between MMPs, NF-κβ and VEGF cause the intensification of angiogenesis in cholesteatoma. The persistent increase in Shh gene protein expression in cholesteatoma perimatrix suggests the stimulation of the cholesteatoma growth in children. Similar expression of IL-1 and IL-10 and their intercorrelation, proves there is a balance between pro- and anti-inflammatory cytokines. NF-κβ, and not Ki-67, seems to be the main inducer of cellular proliferation. The main antimicrobial protection is provided by HβD-2.
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    Remodeling Factors, Transcription Factors and Angiogenetic Factors in Cholesteatoma in Ontogenetic Aspect
    (2022-03) Dambergs, Kristaps; Sumeraga, Gunta; Pilmane, Māra; Department of Otorhinolaryngology; Institute of Anatomy and Anthropology
    Introduction: The main goal of our study was to describe the transcription factor (NF-κβ), angiogenetic factor (VEGF), and remodeling markers (MMP-9 and TIMP-4) of the cholesteatoma tissue compared to control skin tissue. There are still uncertainties how transcription, angiogenetic and remodeling factors affect the cholesteatoma course. Materials and Methods: Eight cholesteatoma tissue specimens were retrieved from children, seven – from adults, seven skin controls – from cadavers. Obtained material immunohistochemically were stained for NF-κβ, MMP-9, TIMP-4, VEGF. Non-parametric statistic methods were used. Results: A statistically significant higher numbers of NF-κβ and TIMP-4 immunoreactive cells in the cholesteatoma compared to control group. A very strong positive correlation between MMP-9 and TIMP-4 was seen in the patient group. A strong positive correlation - between MMP-9 in matrix and MMP-9, VEGF in perimatrix, between TIMP-4 in matrix and TIMP-4 in perimatrix, NF-κβ in the matrix and VEGF; between TIMP-4 in perimatrix and NF-κβ in the matrix. Conclusions: Correlation between MMP-9 and TIMP-4 suggests that TIMP-4 in cholesteatoma tissue intercorrelates to MMP9. TIMP-4 likely regulates the development of cholesteatoma. Disbalance between MMPs and TIMPs affects NFκβ and causes uncontrolled cell proliferation and immune response in this tumor. There is a lack of VEGF strong expression in cholesteatoma perimatrix.