Browsing by Author "Isajevs, Sergejs"
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Item Addressing the importance of melanoma tumor-infiltrating lymphocytes in disease progression and clinicopathological characteristics(2021-12) Zablocka, Tatjana; Nikolajeva, Anna; Kreismane, Madara; Pjanova, Dace; Isajevs, SergejsTumor-infiltrating lymphocytes (TILs) in primary cutaneous melanoma are considered to represent the host's antitumor immunological response; however, whether there are associations between TIL grade and histopathological characteristics and disease survival remains controversial. BRAF mutational status has been established as a routine screening method in advanced malignant melanoma, and worse prognosis rates have been demonstrated in patients harboring BRAF mutations. However, the general impact of BRAF mutational status on survival and histopathological characteristics is still debated. The aim of the present study was to compare the value of the assessment of TIL grade in stages I-II nodular and superficial spreading melanoma and BRAF mutational status, and its influence on clinicopathological characteristics. Altogether, 85 patients at stage IA-IIC who underwent melanoma surgical treatment at the Riga East University Hospital between 2012 and 2017 were retrospectively enrolled in the study. The histopathological characteristics were assessed according to the current World Health Organization and The American Joint Committee on Cancer 8th edition guidelines. The current study showed that patients with melanoma with high TIL grade had significantly better progression-free survival than patients with low TIL grade (hazard ratio, 4.9; 95% CI, 2.3-11.2; P<0.0001). BRAF mutations were observed in 52 patients (61.2%). BRAF mutational status in melanoma was associated with Clark invasion level (P=0.045), patient age (P=0.02) and TIL (P=0.04). The assessment of TIL grade in stage I-II melanoma demonstrated prognostic significance value and may help improve risk assessment in the future.Item Assessment of Serum Pepsinogens with and without Co-Testing with Gastrin-17 in Gastric Cancer Risk Assessment—Results from the GISTAR Pilot Study(2022-07) Robles, Claudia; Rudzite, Dace; Polaka, Inese; Sjomina, Olga; Tzivian, Lilian; Kikuste, Ilze; Tolmanis, Ivars; Vanags, Aigars; Isajevs, Sergejs; Liepniece-Karele, Inta; Razuka-Ebela, Danute; Parshutin, Sergej; Murillo, Raul; Herrero, Rolando; Young Park, Jin; Leja, MarcisIntroduction––Serum pepsinogen tests for gastric cancer screening have been debated for decades. We assessed the performance of two pepsinogen assays with or without gastrin-17 for the detection of different precancerous lesions alone or as a composite endpoint in a Latvian cohort. Methods––Within the intervention arm of the GISTAR population-based study, participants with abnormal pepsinogen values by ELISA or latex-agglutination tests, or abnormal gastrin-17 by ELISA and a subset of subjects with all normal biomarker values were referred for upper endoscopy with biopsies. Performance of biomarkers, corrected by verification bias, to detect five composite outcomes based on atrophy, intestinal metaplasia, dysplasia or cancer was explored. Results––Data from 1045 subjects were analysed, of those 273 with normal biomarker results. Both pepsinogen assays showed high specificity (>93%) but poor sensitivity (range: 18.4–31.1%) that slightly improved when lesions were restricted to corpus location (40.5%) but decreased when dysplasia and prevalent cancer cases were included (23.8%). Adding gastrin-17 detection, sensitivity reached 33–45% while specificity decreased (range: 61.1–62%) and referral rate for upper endoscopy increased to 38.6%. Conclusions––Low sensitivity of pepsinogen assays is a limiting factor for their use in population-based primary gastric cancer screening, however their high specificity could be useful for triage.Item CD63 and Dna Mismatch Repair Protein Expression in Prostate Cancer(2021-06-01) Folkmanis, Kristofs; Eglītis, Jānis; Jakubovskis, Māris; Lietuvietis, Vilnis; Folkmane, Inese; Isajevs, Sergejs; Rīga Stradiņš UniversityProtein expression levels in immunohistochemistry and molecular biomarkers have been reported for their ability to predict recurrence, progression, development of metastases, and patient survival. The molecular features in low- and high-grade prostate cancer can differ and influence treatment decision and prognosis. The objective of the current study was to compare the expression of exosomal biomarkers CD63 and mismatch repair proteins (MSH2, MSH6, MLH1, and PMS2) by immunohistochemistry (IHC) in tissue of patients with prostate cancer and benign hyperplasia. Altogether, 62 patients with prostate acinar adenocarcinoma and 20 patients with prostate benign hyperplasia were enrolled in this retrospective study. CD63, MSH2, MSH6, MLH1, and PMS2 expression was analysed by immunohistochemistry. The obtained results showed that CD63 expression was significantly higher in patients with Grade III-V prostate cancer compared to Grade I-II, respectively; 2.23 (1-3) vs 0.92 (0-2) score, p = 0.001. In addition, a significant positive correlation between CD63 expression and grade groups was revealed (Rho = +0.54; p < 0.0001). Furthermore, progression-free survival was significantly higher in patients with low CD63 expression, compared to high CD63 expression (p = 0.0007). MMR expression was absent in 14 patients (four patients with Grade I-II cancer and 10 patients with Grade III-cancer). MMR was present in all cases of benign prostate hyperplasia (mild to moderate staining). The conclusion was that high grade prostate cancer (Grade groups III-V) was characterised by increased CD63 expression, which correlated with progression-free survival.Item Clinicopathological Significance of Exosomal Proteins CD9 and CD63 and DNA Mismatch Repair Proteins in Prostate Adenocarcinoma and Benign Hyperplasia(2022-02) Folkmanis, Kristofs; Junk, Elizabete; Merdane, Evelina; Folkmane, Inese; Folkmanis, Valdis; Ivanovs, Igors; Eglitis, Janis; Jakubovskis, Maris; Laabs, Sven; Isajevs, Sergejs; Lietuvietis, Vilnis; Faculty of MedicineIntroduction. Recently, it has been shown that exosomal biomarkers and DNA mismatch repair proteins (MMR) could play an important role in cancer risk stratification and prognosis assessment. The gold standard for prostate carcinoma (PCa) diagnosis is biopsy and histopathological examination. Thus, the complex evaluation of exosomal and MMR proteins could be beneficial for prostate cancer risk stratification and diagnostics. The aim of the current study was to evaluate and compare the expression of exosomal proteins CD9 and CD63 and MMR proteins in the tissue of patients with prostate benign hyperplasia (BPH) and PCa. Methods. The study was retrospective. Altogether, 92 patients with PCa and 20 patients with BPH (control group) were enrolled in the study. Exosomal and MMR protein expression was analyzed by immunohistochemistry (IHC). The follow-up for each PCa patient in our study lasted till disease progression and/or a maximum of 5 years. Results. Low-grade PCa was observed in 56 patients and high-grade PCa in 36 patients. CD63 expression was significantly higher in patients with high-grade PCa compared to those with low-grade PCa. CD9 expression was significantly downregulated in PCa patients compared to the control group. MMR protein expression deficiency was observed in 10 PCa patients. MMR proteins were maintained in all cases of BPH. The study found a negative correlation between MMR protein loss and PCa ISUP grade groups. Progression-free survival (PFS) in patients with MMR deficiency was significantly shorter than in patients with maintained MMR expression. Conclusions. CD9 protein expression was downregulated in PCa, compared to BPH, while CD63 protein expression was upregulated in high-grade PCa but downregulated in low-grade PCa. CD63 protein upregulation, CD9 downregulation, and loss of MMR protein characterized the shorter PFS of high-grade PCa patients. CD9, CD63, and MMR could be the routine immunohistochemical biomarkers for the diagnosis and risk stratification of PCa.Item The diagnostic value of anti-parietal cell and intrinsic factor antibodies, pepsinogens, and gastrin-17 in corpus-restricted atrophic gastritis(2022-11) Kriķe, Petra; Shums, Zakera; Polaka, Inese; Kikuste, Ilze; Vanags, Aigars; Tolmanis, Ivars; Isajevs, Sergejs; Liepniece-Karele, Inta; Santare, Daiga; Tzivian, Lilian; Rudzite, Dace; Song, Minkyo; Camargo, Maria Constanza; Norman, Gary; Leja, Mārcis; Department of PathologyItem Effects of BRAF V600E and NRAS mutational status on the progression-free survival and clinicopathological characteristics of patients with melanoma(2023-01) Zablocka, Tatjana; Kreismane, Madara; Pjanova, Dace; Isajevs, SergejsHotspot mutations of the BRAF and NRAS genes are the most common genetic alterations in invasive cutaneous melanoma; however, the prognostic significance of BRAF and NRAS co-mutations remains controversial. The present study aimed to determine the association between NRAS and BRAF mutation status and the clinicopathological characteristics of patients with stage IA-IIC melanoma. A total of 118 patients who underwent surgical treatment for stage IA-IIC melanoma at the Riga East University Hospital between 2012 and 2018 were retrospectively enrolled in the present study. BRAF and NRAS mutation status was assessed by digital droplet PCR using the BRAFV600, NRAS Q61 and NRAS G12/G13 Screening Assays. The association between mutation status and clinicopathological features and progression-free survival (PFS) was then analyzed. The BRAF V600 mutation was detected in 67 out of 118 patients (56.8%). The PFS did not differ between patients with BRAF wild-type and BRAF-mutant melanoma. NRAS mutations were detected in 35 out of 118 patients (29.6%). The NRAS mutational status was associated with Breslow thickness (P=0.035), tumor type (P=0.020; χ2=0.20), mitotic rate (P=0.025) and lymphovascular invasion (P=0.02; χ2=0.20). Patients with NRAS-mutant melanoma had significantly worse PFS compared with NRAS wild-type melanoma (HR=12.30; 95% CI=5.78-26.21, P<0.0001). Furthermore, BRAF and NRAS co-mutant melanoma was associated with a significantly worse PFS compared with BRAF-mutant melanoma (HR=6.30; 95% CI=3.10-12.70, P<0.0001). In conclusion, NRAS-mutant and NRAS/BRAF co-mutant stage IA-IIC melanoma was associated with worse PFS compared with NRAS wild-type and BRAF-mutant melanoma. The assessment of NRAS mutation status in melanoma in routine clinical practice may be beneficial for the risk stratification of disease progression for primary non-metastatic malignant melanoma.Item Expression of p63, p53 and Ki-67 in patients with cervical intraepithelial neoplasia(2017) Mitildzans, Androniks; Arechvo, Anastasija; Rezeberga, Dace; Isajevs, Sergejs; Department of Obstetrics and GynaecologyObjective: Cervical intraepithelial neoplasia (CIN) is a dysplastic process in cervical squamous epithelium and carries a risk of progression to cervical cancer. The aim of this study was to compare expression of three biomarkers named p53, p63 and Ki-67 in patients with various grades of cervical intraepithelial neoplasia and in a control group. Material and Method: 58 patients were enrolled in the study. Each patient underwent a colposcopy-guided biopsy of the cervix. Immunostaining for markers (p53, p63 and Ki-67) was performed on tissue samples of normal cases (n=10), CIN I (n=20), CIN II (n=14), and CIN III (n=14). Results: Our study showed a significant increase of the expression of the analyzed biomarkers in most patients with CIN III compared to CIN II and CIN I. Furthermore, p53 and p63 were significantly increased in CIN I compared to the control group. Conclusion: The expression of Ki-67, p63 and p53 differed between CIN I, CIN II and CIN III. p63 and p53 were reliable biomarkers to distinguish reactive changes from CIN I, while all three biomarkers (Ki-67, p53 and p63) had a high degree of sensitivity and specificity to distinguish between CIN III, CIN II and CIN I.Item H1-antihistamines suppress wheal-and-flare reaction and skin blood perfusion measured by laser dopppler flowmetry : Randomized, double-blind, placebo-controlled, crossover design study(2010-01) Bukovskis, Māris; Tirzīte, Madara; Strazda, Gunta; Jurka, Normunds; Ligere, Renāte; Isajevs, Sergejs; Taivans, ImmanuelsThe aim of our study was to compare the influence of pre-treatment with H1-antihistamines (levocetirizine, desloratadine, clemastine, quifenadine, and sequifenadine) and a placebo on the histamine-induced weal and flare reaction, increase of skin blood perfusion and sedation. Thirty healthy volunteers were enrolled in the study. The study design was a prospective, randomised, double-blind, placebo-controlled, crossover, balanced clinical trial. Volunteers in randomised and double-blind order were treated with oral levocetirizine 5 mg, desloratadine 5 mg, clemastine 1 mg, quifenadine 50 mg, sequifenadine 50 mg or a placebo. Two hours after intake of medication, the histamine skin prick test was performed and skin blood perfusion was registered with further evaluation of sedative effect. We conclude that levocetirizine induced a significant and pronounced decrease of weal and flare reaction and skin blood perfusion compared to the placebo and the other H1-antihistamines. The effect of quifenadine and sequifenadine on weal reaction area was similar to desloratadine and clemastine. Regarding the sedative effect, we can conclude that second generation antihistamines appear to be not non-sedative but the least impairing, and the first generation antihistamines appear to be the most impairing on central nervous system function. There is a necessity to consider the sedating potential of antihistamines, along with other factors such as efficacy, when prescribing antihistamines to patients.Item Lack of Association between Rs2067474 Polymorphism in the Histamine Receptor H2 Gene and Gastric Cancer in Latvian Population(2018-12-01) Moisejevs, Georgijs; Gailite, Linda; Isajevs, Sergejs; Nikitina-Zaķe, Liene; Kempa, Inga; Jančiauskas, Dainius; Kikuste, Ilze; Siviņš, Armands; Ancans, Guntis; Leja, Marcis; Scientific Laboratory of Molecular GeneticsHistamine has an important role in the process of the gastric mucosa inflammation acting via histamine receptor H2 (encoded by the gene HRH2). Single nucleotide polymorphism of the enhancer element of HRH2 gene promoter rs2067474 (1018G>A)may be associated with changes of expression of the receptor. We attempted to clarify the association of this polymorphism with gastric cancer and/or atrophic gastritis in the Latvian (Caucasian) population. The study group consisted of 121 gastric cancer patients and 650 patients with no evidence of gastric neoplasia on upper gastrointestinal endoscopy. Genotyping for rs2067474 was performed with the TaqMan probe-based system using a commercially available probe for RT-PCR. The frequency of the A allele in the gastric cancer group was 0.41% and in the control group - 1.54% (p = 0.231). No significant differences were found comparing genotypes between gastric cancer versus control patients (OR = 0.236, CI95% = 0.030-1.896), patients with (n = 165) versus without (n = 485) gastric metaplastic lesions (OR = 0.854, CI95% = 0.288-2.540) and patients with (n = 297) and without (n = 353) gastric atrophic lesions (OR = 1.145, CI95% = 0.451-2.906). Our findings suggest that the HRH2 -1018G>A polymorphism (rs2067474) is neither associated with gastric cancer nor the grade of atrophic gastritis in the Latvian (Caucasian) population.Item Long-term treatment with the oncolytic ECHO-7 virus Rigvir of a melanoma stage IV M1c patient, a small cell lung cancer stage IIIA patient, and a histiocytic sarcoma stage IV patient-three case reports(2016-10-01) Alberts, Pēteris; Olmane, Evija; Brokāne, Linda; Krastiņa, Zanda; Romanovska, Māra; Kupčs, Kārlis; Isajevs, Sergejs; Proboka, Guna; Erdmanis, Romualds; Nazarovs, Jurijs; Venskus, Dite; Department of RadiologyOncolytic virotherapy is a recent addition to cancer treatment. Here, we describe positive treatment outcomes in three patients using Rigvir virotherapy. One of the patients is diagnosed with melanoma stage IV M1c, one with small cell lung cancer stage IIIA, and one with histiocytic sarcoma stage IV. The diagnoses of all patients are verified by histology or cytology. All patients started Rigvir treatment within a few months after being diagnosed and are currently continuing Rigvir treatment. The degree of regression of the disease has been determined by computed tomography. Safety assessment of adverse events graded according to NCI CTCAE did not show any value above grade 1 during Rigvir® treatment. Using current standard treatments, the survival of patients with the present diagnoses is low. In contrast, the patients described here were diagnosed 3.5, 7.0, and 6.6 years ago, and their condition has improved and been stabile for over 1.5, 6.5, and 4 years, respectively. These observations suggest that virotherapy using Rigvir can successfully be used in long-term treatment of patients with melanoma stage IV M1c, small cell lung cancer stage IIIA, and histiocytic sarcoma stage IV and therefore could be included in prospective clinical studies.Item Management of a primary malignant melanoma of uterine cervix stage IVA patient with radical surgery and adjuvant oncolytic virus Rigvir(R) therapy: A case report.(2020-05-22) Pumpure, Elizabete; Dručka, Eva; Kigitoviča, Dana; Meškauskas, Raimundas; Isajevs, Sergejs; Nemiro, Ineta; Rasa, Agnija; Olmane, Evija; Zablocka, Tatjana; Alberts, Pēteris; Doniņa, SimonaPrimary malignant melanoma of the uterine cervix is a rare disease with poor prognosis and high recurrence rate. We used Rigvir® as adjuvant therapy for a stage IVA patient. Tolerability, overall and progression-free survival are good.Item Mildronate and its Neuroregulatory Mechanisms : Targeting the Mitochondria, Neuroinflammation, and Protein Expression(2013-08-04) Beitnere, Ulrika; Pupure, Jolanta; Isajevs, Sergejs; Rumaks, Juris; Svirskis, Simons; Dzirkale, Zane; Kalvinsh, IvarsThis review for the first time summarizes the data obtained in the neuropharmacological studies of mildronate, a drug previously known as a cardioprotective agent. In different animal models of neurotoxicity and neurodegenerative diseases, we demonstrated its neuroprotecting activity. By the use of immunohistochemical methods and Western blot analysis, as well as some selected behavioral tests, the new mechanisms of mildronate have been demonstrated: a regulatory effect on mitochondrial processes and on the expression of nerve cell proteins, which are involved in cell survival, functioning, and inflammation processes. Particular attention is paid to the capability of mildronate to stimulate learning and memory and to the expression of neuronal proteins involved in synaptic plasticity and adult neurogenesis. These properties can be useful in neurological practice to protect and treat neurological disorders, particularly those associated with neurodegeneration and a decline in cognitive functions.Item Mildronate's protective effects in the peripheral nervous system : Stavudine-induced neuropathy and formalin-induced inflammation(2010-01-01) Pupure, Jolanta; Rumaks, Juris; Isajevs, Sergejs; Korzakova, Olga; Puncule, Jelena; Svirskis, Simons; Kalviņš, Ivars; Kluša, VijaMildronate, previously known as a cardioprotective drug, recently was found to normalise mitochondrial processes by preventing the dysfunction of complex I in rat liver mitochondria. Previously we have shown also the ability of mildronate to prevent pathologies in the central nervous system by normalizing the expression of different signalling molecules in brain tissue. This allowed us to suggest that mildronate may possess a beneficial role also in peripheral nervous system pathologies. The present study was designed to assess the peripheral tissue damage caused by anti-HIV drug stavudine, as well as pain and inflammation caused by formalin. For this demonstration, we investigated the influence of mildronate: (1) on decreased myelin expression and increased neuron degeneration in rat sciatic nerve tissue caused by stavudine; and (2) on formalin-induced inflammation in mice. We found that mildronate protected the stavudine-induced degeneration of neurons in rat peripheral sciatic nerve without a significant influence on demyelination. In a formalin test, mildronate showed anti-inflammatory action comparable to that of indomethacin, a reference drug. The present results show that mildronate is capable of regulating peripheral nerve damage and peripheral inflammatory responses. We suggest that the multifunctional effects of mildronate can be attributed to its ability to regulate mitochondrial processes. The obtained data indicate protective effects of mildronate in different peripheral neurological pathologies.Item Neuroprotective properties of mildronate, a small molecule, in a rat model of parkinson's disease(2010-11) Klusa, Vija Z.; Isajevs, Sergejs; Svirina, Darja; Pupure, Jolanta; Beitnere, Ulrika; Rumaks, Juris; Svirskis, Simons; Jansone, Baiba; Dzirkale, Zane; Muceniece, Ruta; Kalvinsh, Ivars; Vinters, Harry V.Previously, we have found that mildronate [3-(2,2,2-trimethylhydrazinium) propionate dihydrate], a small molecule with charged nitrogen and oxygen atoms, protects mitochondrial metabolism that is altered by inhibitors of complex I and has neuroprotective effects in an azidothymidine-neurotoxicity mouse model. In the present study, we investigated the effects of mildronate in a rat model of Parkinson's disease (PD) that was generated via a unilateral intrastriatal injection of the neurotoxin 6-hydroxydopamine (6-OHDA). We assessed the expression of cell biomarkers that are involved in signaling cascades and provide neural and glial integration: the neuronal marker TH (tyrosine hydroxylase); ubiquitin (a regulatory peptide involved in the ubiquitin-proteasome degradation system); Notch-3 (a marker of progenitor cells); IBA-1 (a marker of microglial cells); glial fibrillary acidic protein, GFAP (a marker of astrocytes); and inducible nitric oxide synthase, iNOS (a marker of inflammation). The data show that in the 6-OHDA-lesioned striatum, mildronate completely prevented the loss of TH, stimulated Notch-3 expression and decreased the expression of ubiquitin, GFAP and iNOS. These results provide evidence for the ability of mildronate to control the expression of an array of cellular proteins and, thus, impart multi-faceted homeostaticmechanisms in neurons and glial cells in a rat model of PD. We suggest that the use of mildronate provides a protective effect during the early stages of PD that can delay or halt the progression of this neurodegenerative disease.Item Non-invasive diagnosis of gastroesophageal reflux disease using gastrin- and pepsinogen-based tests(2018) Moisejevs, Georgijs; Daugule, Ilva; Isajevs, Sergejs; Rudzite, Dace; Janciauskas, Dainius; Tolmanis, Ivars; Leja, Marcis; Scientific Laboratory of Molecular Genetics; Department of Internal DiseasesGastrin-17 (G-17), pepsinogen-1 (Pg1) and pepsinogen-2 (Pg2) reflect the functional state of gas-tric mucosa and are used for non-invasive diagnosis and screening of atrophic gastritis. The aimof the study was to clarify if erosive reflux disease (ERD) or non-ERD (NERD) can be distin-guished from other dyspeptic conditions in patients, in a non-invasive manner using specificbiomarkers. Levels of G-17, Pg1, and Pg2 were measured in 141 ERD patients (median age 48years, males — 68), 122 NERD patients (median age 45 years, males — 32) and 410 control pa-tients (median age 50 years, males — 97). Levels of biomarkers in ERD and NERD groups werecompared to controls. Median levels of G-17 (1.94 vs 2.92 pmol/L, p = 0.036) and Pg2 (6.70 vs7.79 μg/l,p= 0.046) were lower in the ERD group compared to control patients; no differencewith respect to the control was found for the NERD group. After exclusion of the patients havingat least one potential condition that might modify the levels of the biomarkers (gastric mucosa at-rophy, Helicobacter pylori colonisation), no difference in levels of biomarkers was observed withrespect to the control for both the ERD and NERD groups. G-17, Pg1, and Pg2 based tests can-not be used to distinguish ERD or NERD from other dyspeptic conditions in patients.Item Rare liver tumour - epithelioid haemangioendothelioma: a case report(2022-12-01) Laivacuma, Sniedze; Zeltiņa, Indra; Derovs, Aleksejs; Norko, Andris; Isajevs, Sergejs; Makejeva, Karīna; PH Drenth, Joost; Department of Infectology; Department of Internal DiseasesEpithelioid haemangioendothelioma (EHE) is a rare vascular soft tissue malignant tumour with unknown etiology; the estimated prevalence of EHE is less than one in 1 million. A 56-year-old man was admitted in our department due to pain in the right side of the abdomen lasting for two years and weight loss up to 10 kg. Since 2012, the patient underwent lung and abdominal CT scanning as well as biopsy, however the diagnosis was challenging. In 2015, repeated abdominal CT scanning and a liver core biopsy was performed. The epithelioid haemangioendothelioma was diagnosed based by histopathological examination with subsequent radiological and clinical correlation. Therefore, accurate histopathological examination with radiological and clinical correlation is essential in the diagnosis of epithelioid haemangioendothelioma.Item Search for stroke-protecting agents in endothelin-1-induced ischemic stroke model in rats(2012) Rumaks, Juris; Pupure, Jolanta; Svirskis, Simons; Isajevs, Sergejs; Duburs, Gunars; Kalvinsh, Ivars; Klusa, VijaBackground and Objective. Ischemic stroke may initiate a reperfusion injury leadingto brain damage cascades where inflammatory mechanisms play a major role. Therefore, thenecessity for the novel stroke-protecting agents whose the mechanism of action is focused on their anti-inflammatory potency is still on the agenda for drug designers. Our previous studies demonstrated that cerebrocrast (a 1,4-dihydropyridine derivative) and mildronate (a representative of the aza-butyrobetaine class) possessed considerable anti-inflammatory and neuroprotective properties in different in vitro and in vivo model systems.The present study investigated their stroke-protecting ability in an endothelin-1 (ET-1)-induced ischemic stroke model in rats. Material and Methods. Male Wistar rats were pretreated (for 7 days, per os) with cerebrocrast (0.1 mg/kg), mildronate (100 mg/kg), or their combination, followed by the intracerebral injection of ET-1. Functional and behavioral tests were carried out up to 14 days after the ET-1 injection. Ex vivo, the number of degenerated neurons and the infarction size in the cerebral cortical tissue were assessed histologically. Results. Cerebrocrast and mildronate effectively normalized ET-1-induced disturbances in neurological status, improved the muscle tone, and decreased the number of degenerated cortical cells. Both drugs also reduced the infarction size, and cerebrocrast showed at least a 2-fold higher activity than mildronate. The combination of both drugs did not cause a more pronounced effect in comparison with the action of drugsadministered separately. Conclusions. The 1,4-dihydropyridine and aza-butyrobetaine structures may serve for the design of novel stroke-protecting agents to prevent severe neurological poststroke consequences.Item Severe Clostridium difficile infection with extremely high leucocytosis complicated by a concomitant bloodstream infection caused by Klebsiella pneumoniae after osteomyelitis surgery: A case report(2021-01-01) Golubovska, Iveta; Vigante, Dace; Malzubris, Martins; Raga, Luize; Isajevs, Sergejs; Miscuks, AleksejsIntroduction: Clostridium difficile is one of the most common healthcare-associated infections. Pseudomembranous colitis is a serious complication of Clostridium difficile infection (CDI) after septic surgery and antibacterial therapy. A sudden white blood cell (WBC) count increase and extremely high leucocytosis may be a predictor of a poor outcome. Presentation of case: A 77 years old male was hospitalised because of lower leg osteomyelitis and was operated. He received antibacterial treatment with Cefazolin for three days and then developed a high WBC count. The course of the disease was fulminant, with a rapid increase in the WBC count up to 132,000/mm3 and a septic shock, and required cardiovascular and ventilatory support. The patient was started on intravenous Metronidazole (500 mg every eight hours) and oral Vancomycin (500 mg every six hours). The patient's condition gradually improved over a period of six days. Then a hyperthermia above 39 degrees Celsius, hypotension and painful abdominal bloating developed, and the WBC count peaked to 186,000/mm3. The blood cultures were positive for Klebsiella pneumoniae. The patient died. Discussion: In our case, we describe a community-onset, healthcare-facility-associated, severe CDI complicated by a blood stream infection. The administration of oral Vancomycin, which is highly active against the intestinal flora, could have been responsible for the persistence and overgrowth of Klebsiella pneumoniae. Conclusions: Severe CDIs after orthopaedic surgery and antibacterial treatment complicated by the development of nosocomial infection significantly worsen the prognosis of the disease. Careful consideration of antibacterial therapy and early symptom recognition may help prevent catastrophic events.Item Stage IIA Skin Melanoma Treatment With ECHO-7 Oncolytic Virus Rigvir(2022-09-14) Čēma, Ingrīda; Kleina, Regīna; Doniņa, Simona; Isajevs, Sergejs; Zablocka, Tatjana; Rasa, Agnija; Alberts, Pēteris; Rīga Stradiņš University; Faculty of Medicine; Institute of Microbiology and VirologyMelanoma is a global problem due to the rising numbers of skin melanoma cases. Current treatment guidelines for patients with stage IIA melanoma recommend only observation after surgery. In this report, the authors describe a patient with stage IIA skin melanoma treated with surgery and Rigvir virotherapy. Two years after the patient discovered a brown spot on the right cheek, surgery was indicated because the mass had started to ulcerate. Rigvir virotherapy was applied both before and after surgery. Observations made more than 7 years after surgery indicated no signs of disease progression. This case report illustrates an early treatment approach. Neoadjuvant treatment for early-stage melanoma is gaining more interest in both scientific and medical communities; therefore, the authors believe it is relevant to share their observations.Item Upregulation of FOXP3+Regulatory T Lymphocytes and CD8+Lymphocytes in Patients with High-Grade Squamous Intraepithelial Lesions Correlated with HPV Infection(2022-04) Mitiļdžans, Androniks; Zablocka, Tatjana; Isajevs, Sergejs; Gordjušina, Valentina; Rezeberga, Dace; Department of Obstetrics and GynaecologyModern therapeutic strategies for precancerous cervical intraepithelial neoplasia (CIN) focus on immune-modulatory and cancer vaccination. The local cervical immune status in cervical cancer and CIN could influence HPV infection persistence, progression and carcinogenesis. We analysed the role of FOXP3+ regulatory T lymphocytes, CD4+ and CD8+ T lymphocytes in CIN I, CIN II and CIN III patients with and without HPV infection. Sixty-two patients were enrolled in the study. Each patient underwent a colposcopy-guided cervical biopsy. FOXP3+ lymphocytes and CD4+,CD8+ lymphocytes were detected by immunostaining in tissue samples obtained from a control group (n = 10), patients with CIN I (n = 20), CIN II (n = 14) and CIN III (n = 18) lesions. HPV was assayed by Aptima. The results showed that the numbers of CD4+ T lymphocytes did not differ between patients with CIN I, CIN II, and CIN III. However, patients with CIN II and CIN III had significantly upregulated CD8+T lymphocytes compared to patients with CIN I. In addition, patients with CIN II and CIN III had increased FOXP3 + T lymphocytes compared with patients with CIN I, which was associated with HPV status. Upregulation of FOXP3+ regulatory T lymphocytes and CD8-positive lymphocytes in patients with CIN II and CIN III suggested a pivotal role of T regulatory lymphocytes and CD8+ lymphocytes for counteracting the host immune response in the progression from CIN I to CIN II and CIN III.