Alcohol and its associated oxidative stress is one of the widespread contributors to the brain damage. Matrix metalloproteinases, which are extensively analyzed in brain pathology studies, are not sufficiently investigated in chronic alcohol consumption. This study evaluated regional brain damage caused by oxidative stress. Contribution of metalloproteinase-9 to this affection was evidenced in alcoholic subjects and correlated with ultrastructural changes. The authors found correlation between neuronal expression patterns of superoxide dismutase-1 and metalloproteinase-9 in nigral (r = 0.532, p < 0.001), striatal (r = 0.327, p < 0.001), and cortical (r = 0.306, p < 0.001) regions, and a significant decrease of nigral superoxide dismutase-1 median values accompanied by severe myelin damage.

The relationship among inflammation, pain, and cognitive decline in osteoarthritis (OA) patients is complex and has not been sufficiently explored; therefore, we undertook this research to evaluate how OA-related inflammation and pain affect cognitive functions, as well as to examine the potential of urinary markers as indicators of these conditions. This study examined fifty OA patients through clinical and cognitive assessments, morphological analyses, urinary biomarkers, and bioinformatics. Morphologically, 24% of patients had moderate to high synovial inflammation, which was significantly correlated with depressive symptoms, pain intensity, and self-reported anxiety. The Montreal Cognitive Assessment indicated minimal decline in most patients but showed negative correlations with age and inflammation severity. Urinary TNF-α and TGF-β1 levels positively correlated with body mass index and pain and synovitis score and immune cell infiltration, respectively. In contrast, cartilage oligomeric matrix protein and C-telopeptides of type II collagen showed inverse correlations with pain duration and cognitive function, respectively. Distinct patient clusters with higher inflammation were identified and were associated with reported pain and depressive symptoms. Urinary TNF-α and TGF-β1 can serve as biomarkers reflecting inflammation and disease severity in OA. This study suggests that synovial inflammation may be linked to mental and cognitive health in some patient cohorts.

A direct association between joint inflammation and the progression of osteoarthritis (OA) has been proposed, and synovitis is considered a powerful driver of the disease. Among infections implicated in the development of joint disease, human herpesvirus 7 (HHV-7) infection remains poorly characterized. Therefore, we assessed synovitis in OA patients; determined the occurrence and distribution of the HHV-7 antigen within the synovial membrane of OA-affected subjects; and correlated plasma levels of the pro-inflammatory cytokines tumor necrosis factor (TNF), interleukin-6 (IL-6), and TNF expressed locally within lesioned synovial tissues with HHV-7 observations, suggesting differences in persistent latent and active infection. Synovial HHV-7, CD4, CD68, and TNF antigens were detected immunohistochemically. The plasma levels of TNF and IL-6 were measured by an enzyme-linked immunosorbent assay. Our findings confirm the presence of persistent HHV-7 infection in 81.5% and reactivation in 20.5% of patients. In 35.2% of patients, virus-specific DNA was extracted from synovial membrane tissue samples. We evidenced the absence of histopathologically detectable synovitis and low-grade changes in the majority of OA patients enrolled in the study, in both HHV-7 PCR+ and HHV-7 PCR‒ groups. The number of synovial CD4-positive cells in the HHV-7 polymerase chain reaction (PCR)+ group was significantly higher than that in the HHV-7 PCR‒ group. CD4- and CD68-positive cells were differently distributed in both HHV-7 PCR+ and HHV-7 PCR‒ groups, as well as in latent and active HHV-7 infection. The number of TNF+ and HHV-7+ lymphocytes, as well as HHV-7+ vascular endothelial cells, was strongly correlated. Vascular endothelial cells, especially in the case of infection reactivation, appeared vulnerable. The balance between virus latency and reactivation is a long-term relationship between the host and infectious agent, and the immune system appears to be involved in displaying overreaction when a shift in the established equilibrium develops.

The role of inflammation in the development of osteoarthritic joint degeneration is not completely understood. Recent data suggest that processes that cause and orchestrate inflamed synovial lesions may be implicated in the development of the disease. The morphological changes of the synovium in patients with osteoarthritis (OA), as well as the level of synovial inflammation cautiously graded, in association to the presence of human parvovirus B19 (B19V) infection markers, were evaluated. Qualitative and quantitative detection of B19V genomic sequence was performed in OA and rheumatoid arthritis (RA) groups. The expression of CD68, S100 (Ca ²⁺ binding proteins soluble in 100% ammonium sulfate) and B19 VP1/VP2 capsid proteins found in the synovium were investigated by single and double immunolabeling, whereas fine features of synoviocytes — by electron microscopy. One-third of OA and RA patients demonstrated synovial expression of B19V antigen, which was confirmed in both types of synoviocytes. The overall expression of B19V in OA patients was weaker than that found in RA subjects. Positive correlation between B19V-positive vascular endothelial cells, sublining infiltrating lymphocytes, macrophages, and B19V-positive synoviocytes was established. No correlation between synovitis score indices as well as the expression of S100 and expression of B19V was found. The results suggest that the synovial membrane maintains local joint homeostasis, and that virus mediated synovitis is implicated in the development of OA.

Osteoarthritis (OA) remains the most prevalent joint disorder worldwide, particularly affecting individuals over the age of 50. Although numerous pathogenetic mechanisms contribute to the initiation and progression of articular cartilage degeneration, synovial inflammation plays a significant role in the disease process. While the degree of inflammation in OA is less pronounced and not systemic as seen in inflammatory arthritides, its involvement constitutes a critical element in the pathogenesis, progression, and persistence of the disease. The effects of synovial inflammation extend beyond the stimulation of catabolic processes, encompassing the acceleration of cellular senescence and potential contributions to neuropsychiatric disturbances, including mood and cognitive alterations. While inflammation in OA has been previously investigated, the complex and multifactorial nature of its triggers, such as latent viral infections, requires further study. Moreover, the potential associations between synovial inflammation and depressive symptoms or cognitive decline remain insufficiently understood and warrant comprehensive investigation. In this study, two independent cohorts of 54 and 50 individuals undergoing joint replacement surgery were analysed. In the first cohort, a focused investigation on the persistence of parvovirus B19 (B19V) and human herpesvirus 7 (HHV-7) in the synovial membrane and their potential impact on inflammation was conducted using the Krenn synovitis histological scoring system. Immunohistochemical analyses were performed to evaluate the expression of tumour necrosis factor alpha (TNF-α) and transforming growth factor-beta (TGF-β) in synovial tissue and to investigate their association with viral presence. Nonetheless, HHV-7-positive samples showed a significant correlation between CD4+ lymphocyte infiltration and TNF-α expression, suggesting immune cell-specific responses to latent viral presence. Additionally, the role of S100 protein expression in the inflammatory process was assessed, showing a positive correlation. This integrative approach aimed to elucidate the contribution of chronic viral persistence and local immune responses to the synovial pathology observed in OA. The second cohort was evaluated for synovial inflammation and its correlation with urinary biomarkers, using ELISA method: C-telopeptide of type II collagen (CTX-II), cartilage oligomeric matrix protein (COMP), TNF-α, TGF-β1 and neuropsychological assessments, including Montreal Cognitive Assessment (MoCA), Patient Health Questionnaire-9 (PHQ-9), and Generalised Anxiety Disorder-7 (GAD-7) tests. In the second cohort, histologically confirmed synovitis scores varied widely and correlated with urinary TGF-β1 levels. Cognitive (MoCA) and affective (PHQ-9, GAD-7) scores showed significant associations with synovial inflammation, particularly in patients with moderate-to-high inflammatory grades. Cluster analysis revealed distinct inflammatory phenotypes with gender-linked variations in symptom severity and cognitive and affective symptom outcomes. The Doctoral Thesis was developed at RSU AAI Joint Laboratory of Electron Microscopy and the RSU Department of Internal Diseases, Latvia. Defence of the Doctoral Thesis will take place at the public session of the Promotion Council of Clinical Medicine on 18 December 2025 at 14.00 in the Hippocrates Lecture Theatre, 16 Dzirciema Street, Rīgas Stradiņš University and remotely via online platform Zoom. This Doctoral Thesis was developed with the support of the Fundamental and Applied Research grant No lzp-2018/1-0149 “Interdisciplinary study on the effects of inflammatory joint diseases on neurocognitive function” and support of European grant “Reducing networking gaps between Rīga Stradiņš University (RSU) and internationally-leading counterparts in viral infection-induced autoimmunity research” (VirA)”. 3.2. Clinical Medicine; Sub-Sector – Internal Medicine. Keywords: Synovial inflammation; HHV-7; Parvo-B19; cognitive decline; depression; anxiety.

Osteoartrīts (OA) ir izplatītākā locītavu slimība visā pasaulē, biežāk skarot cilvēkus virs 50 gadiem. Lai arī dažādi patoģenētiskie mehānismi veicina gan locītavu skrimšļu deģenerācijas aizsākumu, gan deģenerācijas tālāku norisi, sinoviālajam iekaisumam ir būtiska loma šīs slimības norisē. Kaut gan iekaisuma pakāpe OA gadījumā ir mazāk izteikta un nav sistēmiska, kā tas ir iekaisuma artrīta gadījumā, tas ir nozīmīgs komponents slimības patoģenēzē, progresēšanā un noturībā. Sinoviālā iekaisuma ietekme neaprobežojas tikai ar katabolisko procesu stimulēšanu – tā ietver arī šūnu novecošanās procesu paātrināšanu un sekmē neiropsihiatrisku traucējumu attīstību, tostarp ietekmējot garastāvokli un kognitīvo funkciju. Neņemot vērā, ka OA iekaisuma procesi ir pētīti jau iepriekš, to veicinošo faktoru sarežģītā un daudzfaktoriālā daba, tostarp latento vīrusu infekciju iesaiste, joprojām prasa padziļinātu izpēti. Turklāt iespējamās saistības starp OA pacientu sinoviālo iekaisumu un depresīviem simptomiem, kā arī kognitīvās funkcijas traucējumiem vēl nav pietiekami izprastas un ir nepieciešami turpmāki pētījumi šo sakarību izzināšanai. Šajā pētījumā tika analizētas divas neatkarīgas OA pacientu kohortas – attiecīgi 54 un 50 indivīdi, kuriem tika veiktas locītavas endoprotezēšanas operācijas. Pirmajā kohortā tika veikta parvovīrusa B19 (parvo-B19V) un cilvēka herpesvīrusa 7 (HHV-7) proteīnu izpēte sinoviālajā membrānā, kā arī vīrusu infekciju saistības ar iekaisumu novērtēšana pēc Krena skalas. Sinoviālajos audos novērtēta tumora nekrozes faktora alfa (TNF-α) un transformējošā augšanas faktora beta (TGF-β) imūnekspresija, kā arī tās saistība ar vīrusu proteīnu klātbūtni. HHV-7 pozitīvajos audu paraugos tika konstatēta statistiski nozīmīga korelācija starp CD4+ limfocītu infiltrāciju un TNF-α ekspresiju, kas liecina par imūnšūnām raksturīgu atbildes reakciju uz latento vīrusu infekciju. Papildus tika vērtēta arī S100 proteīna ekspresijas saistība ar iekaisuma procesa smaguma pakāpi, kas uzrādīja pozitīvu korelāciju. Šī integratīvā pieeja padziļina izpratni par hroniskas vīrusu persistences un lokālu imūno reakciju nozīmi sinoviālajā patoloģijā, kas novērojama OA gadījumā. Otrā OA pacientu kohorta tika pētīta attiecībā uz sinoviālo iekaisumu un tā korelāciju ar urīna biomarķieriem, izmantojot ELISA metodi II tipa kolagēna C-telopeptīda (CTX-II), skrimšļa oligomeriskā matriksa proteīna (COMP), TNF-α un TGF-β1 noteikšanai. Papildus tika analizēta šo rādītāju saistība ar neiropsiholoģiskiem traucējumiem, izmantojot sekojošus testus: Monreālas kognitīvo funkciju izvērtēšanas skalu (MoCA), depresijas pašnovērtējuma instrumentu – pacientu veselības aptauju 9 (PHQ-9) – un trauksmes pašnovērtējuma instrumentu – ģeneralizētas trauksmes aptauju 7 (GAD-7). Šajā grupā izmantoto marķieru imūnekspresija savstarpēji ievērojami atšķīrās un TGF-β1 audos korelēja ar urīnā noteikto TGF-β1 līmeni. Kognitīvās funkcijas (MoCA) un afektīvo traucējumu (PHQ-9, GAD-7) testu rezultāti parādīja statistiski nozīmīgas asociācijas ar sinoviālā iekaisuma smagumu, īpaši pacientiem ar vidēju līdz augstu iekaisuma pakāpi sinovijā. Klasteranalīze atklāja atšķirīgus iekaisuma fenotipus ar dzimumam raksturīgām atšķirībām simptomu smagumā un kognitīvi afektīvajās izpausmēs. Promocijas darbs izstrādāts RSU AAI Starpkatedru elektronmikroskopijas laboratorijā un RSU Iekšķīgo slimību katedrā, Latvijā. Aizstāvēšana: Klīniskās medicīnas promocijas padomes atklātā sēdē 2025. gada 18. decembrī plkst. 14:00 Hipokrāta auditorijā, Dzirciema ielā 16, Rīgas Stradiņa universitātē un attālināti, tiešsaistes platformā Zoom. Promocijas darbs izstrādāts ar fundamentālo un lietišķo pētījumu granta Nr. lzp-2018/1-0149 “Starpdisciplinārs pētījums par iekaisuma izraisītu locītavu slimību ietekmi uz neirokognitīvo funkciju” un Eiropas projekta “Tīklošanas nepilnību samazināšana starp Rīgas Stradiņa universitāti (RSU) un starptautiski vadošajiem partneriem vīrusu infekciju izraisītu autoimūnu slimību pētniecībā (VirA)” atbalstu. 3.2. Klīniskā medicīna; Apakšnozare – Internā medicīna. Atslēgvārdi: sinoviāls...