[Clinical and psychopathological characteristics of patients with late-onset schizophrenia and schizophrenia-like psychoses in clusters identified by biological parameters]. / Kliniko-psikhopatologicheskie kharakteristiki bol'nykh s pozdno manifestiruyushchimi shizofreniei i shizofrenopodobnymi psikhozami v klasterakh, vydelennykh po biologicheskim parametram.

OBJECTIVE: To assess clinical and psychopathological characteristics of late-aged female patients with late-onset psychoses in clusters formed on the basis of biochemical and immunological blood parameters. MATERIAL AND METHODS: We examined 59 women with schizophrenia and schizophrenia-like psychoses with onset after 40 years (ICD-10 F20, F22.8, F25, F23, F06.2), including 34 women with late-onset (40-60 years) and 25 with very late onset psychoses (after 60 years). At the time of hospitalization, a clinical/ psychopathological study was carried out using CGI-S, PANSS, CDSS, and HAMD-17, as well as the activities of glutathione reductase (GR) and glutathione-S-transferase (GT) have been determined in erythrocyte hemolysates, and the activities of leukocyte elastase (LE) and α1-proteinase inhibitor (α1-PI) have been assessed in blood plasma. Biochemical and immunological parameters have been also determined in 34 age-matched mentally healthy women. RESULTS: Clustering by signs such as GR, GT, LE and α1-PI has yielded two clusters of objects (patients) significantly different in GT (p<0.0001), LE (p<0.0001), and α1-PI (p<0.001) activities. Relatively to the controls, in the cluster 1 patients, the activities of GST and α1-PI are increased, the activity of LE is decreased, whereas, in the cluster 2 patients, the activity of GR is decreased, and the activities of LE and α1-PI are increased. Cluster 1 patients differ from cluster 2 patients in greater severity of the condition (CGI-S, p=0.04) and higher total scores on PANSS subscales' items. Cluster 1 includes 76% of patients with very late onset. Different correlations between clinical and biological signs are found in two clusters. CONCLUSION: The identified clusters have different clinical and psychopathological characteristics. Dividing patients into subgroups according to biochemical and immunological parameters is promising for the search for differentiated therapeutic approaches.

Correlations between different protein species of oral rinse MMP-8 and patient-related factors.

OBJECTIVES: The aim of this study is to examine correlations between different oral rinse matrix metalloproteinase (MMP)-8 protein species in western blot (WB) analysis, quantitative MMP-8 measurements, and patient-related factors. Elevated activated MMP-8 (aMMP-8) associate with periodontitis and a diagnostic point-of-care technology has been developed based on aMMP-8. In WB, different MMP-8 protein species can be analyzed. Relative abundancy of fragmented 20-25 kDa forms in WB has been associated with and reflects MMP-8 activation and related fragmentation and elevated quantitative aMMP-8 measurements. MATERIAL AND METHODS: A random sample of 192 participants from a periodontal disease screening study was used for this study. Oral rinse samples for biomarker analyses were collected before clinical periodontal examinations. aMMP-8 immunofluorometric (IFMA) and WB analysis (utilizing the same monoclonal antibody, 8708), polymorphonuclear leukocyte (PMN) elastase activity test and tissue inhibitor of metalloproteinases (TIMP)-1 ELISA levels were performed from the oral rinse samples. Distinct MMP-8 protein species were differentiated in the WB analysis. Principal component (PC) analysis was conducted to explore correlation patterns between the different species. Adjusted correlation analysis between the extracted PCs of WB and aMMP-8 IFMA levels and multilevel regression analysis were conducted to explore if the other periodontal disease-related biomarkers and clinical surrogate measures and patient-related factors are co-variating with the extracted components. RESULTS: Distinct correlation patterns between the MMP-8 protein species were observed. The first four PCs explained 89% of the whole variance in PC analysis. Statistically significant correlation (p < 0.05) were observed as follows: PC1 positively with 21 kDa (r = .69) and 25 kDa fragments (r = .55) and negatively with 150 kDa complexes (r = -.46). PC2 correlated with 45 (r = .70) and 55 kDa (r = .65) activated forms, PC3 with 70-80 kDa latent proforms (r = .63) and 90-100 kDa complexes (r = .67), and PC4 with 35 kDa fragments (r = .81). There were significant correlations between quantitative (IFMA) aMMP-8 measurements and PC1 (p < 0.001), PC2 (<0.05) and PC3 (<0.05) but not with PC4. In multilevel regression models age, PMN elastase activity, TIMP-1 levels, and a number of 4-5 mm periodontal pockets were associated with PC1, nonsmoking with PC2, age and PMN elastase activity with PC3, and age and smoking with PC4. CONCLUSIONS: Relative abundancy of fragmented 21-25 kDa protein species was correlated with the quantitative aMMP-8 (IFMA) measurements, which is in line with previous results. Different patient-related factors (smoking, age, proteolytic activity) may modify the formation of different MMP-8 protein species in oral rinse samples and may cause variability in quantitative aMMP-8 measurement.

Causal Role for Neutrophil Elastase in Thoracic Aortic Dissection in Mice.

BACKGROUND: Thoracic aortic dissection (TAD) is a life-threatening aortic disease without effective medical treatment. Increasing evidence has suggested a role for NE (neutrophil elastase) in vascular diseases. In this study, we aimed at investigating a causal role for NE in TAD and exploring the molecular mechanisms involved. METHODS: ß-aminopropionitrile monofumarate was administrated in mice to induce TAD. NE deficiency mice, pharmacological inhibitor GW311616A, and adeno-associated virus-2-mediated in vivo gene transfer were applied to explore a causal role for NE and associated target gene in TAD formation. Multiple functional assays and biochemical analyses were conducted to unravel the underlying cellular and molecular mechanisms of NE in TAD. RESULTS: NE aortic gene expression and plasma activity was significantly increased during ß-aminopropionitrile monofumarate-induced TAD and in patients with acute TAD. NE deficiency prevents ß-aminopropionitrile monofumarate-induced TAD onset/development, and GW311616A administration ameliorated TAD formation/progression. Decreased levels of neutrophil extracellular traps, inflammatory cells, and MMP (matrix metalloproteinase)-2/9 were observed in NE-deficient mice. TBL1x (F-box-like/WD repeat-containing protein TBL1x) has been identified as a novel substrate and functional downstream target of NE in TAD. Loss-of-function studies revealed that NE mediated inflammatory cell transendothelial migration by modulating TBL1x-LTA4H (leukotriene A4 hydrolase) signaling and that NE regulated smooth muscle cell phenotype modulation under TAD pathological condition by regulating TBL1x-MECP2 (methyl CpG-binding protein 2) signal axis. Further mechanistic studies showed that TBL1x inhibition decreased the binding of TBL1x and HDAC3 (histone deacetylase 3) to MECP2 and LTA4H gene promoters, respectively. Finally, adeno-associated virus-2-mediated Tbl1x gene knockdown in aortic smooth muscle cells confirmed a regulatory role for TBL1x in NE-mediated TAD formation. CONCLUSIONS: We unravel a critical role of NE and its target TBL1x in regulating inflammatory cell migration and smooth muscle cell phenotype modulation in the context of TAD. Our findings suggest that the NE-TBL1x signal axis represents a valuable therapeutic for treating high-risk TAD patients.

Clinical-Immunological Correlates in Post-COVID-19 Endogenous Psychoses.

Objectives. To carry out a clinical and immunological study of the potential impact of coronavirus infection on the course of endogenous psychoses. Materials and methods. A total of 33 female patients aged 16-48 years with depressive-delusional states (F20.01, F21, F31) developing after coronavirus infections took part; group 1 consisted of 15 people who developed depressive-delusional states 1-2 months after COVID-19; group 2 consisted of 18 people with similar psychoses developing at later time points (2-6 months). The severity of psychopathological symptoms was assessed using the PANSS and HDRS-21 scales. The activity of inflammatory markers leukocyte elastase (LE) and α1-proteinase inhibitor (α1-PI) was determined in patients' blood. Absolute neutrophil and lymphocyte contents and their ratio (the neutrophil:lymphocyte index) were also evaluated. Standard values for indicators from healthy donors corresponding to patients in terms of age and sex were used as control values. Results. Endogenous psychosis developing at longer intervals after coronavirus infection (group 2) was found to be associated with "typical" inflammatory reactions, with increases in the activity of acute-phase proteins (α1-PI: 43.0 (35.6-49.7) IU/ml, p = 0.001) and neutrophil degranulation activity (LE - 254.8 (238.0-271.0) nmol/min·ml, p < 0.001), which was associated with the development of depressive-delusional states with dominance of manifestations of positive affectivity (anxiety, melancholy) and the extended nature of delusional disorders, which were mostly incongruent to affect. Conversely, development of endogenous psychosis during the first two months after COVID-19 (group 1) was characterized by a spectrum of inflammatory biomarkers with a decrease in neutrophil count ((2.6 ± 0.9)·109/liter, p < 0.05) and low LE activity (196 (172-209.4) nmol/min·ml, p < 0.001). This immunological profile was associated with predominance of manifestations of negative affectivity (apathy, asthenia, adynamia) in the structure of depressive-delusional states and the relatively undeveloped nature of delusional disorders, which were predominantly congruent to affect. Conclusions. The clinical and biological correlates found here presumptively indicate that experience of COVID-19 infection has a modulatory effect on neuroinflammation and the structure of endogenous psychosis.

[Inflammatory markers in organic nonpsychotic disorders]. / Vospalitel'nye markery pri organicheskikh nepsikhoticheskikh rasstroistvakh.

OBJECTIVE: To determine the indicators of systemic inflammation in peripheral blood samples of patients with organic non-psychotic disorders. MATERIAL AND METHODS: The study included 60 patients, aged 56.9±7.7 years, with a disease duration of 7.3±5.55 years, with a verified ICD-10 diagnosis «Organic emotionally labile (asthenic) disorder¼ (F06.6) and «Organic Anxiety Disorder¼ (F06.4). Patients with organic asthenic disorder were divided into two groups according to the prevailing symptoms: 36 patients with asthenic-cephalgic syndrome (AC); 10 patients with astheno-dysthymic syndrome (AD); the third group (n=14) included patients with organic anxiety disorder (AND). The control group consisted of 65 people matched for age and sex with patients. The activity of leukocyte elastase (LE) and α1-proteinase inhibitor (α1-PI) was determined by the spectrophotometric method, the levels of aAB to S100b and MBP were determined by ELISA. The protease-inhibitory index (PII), i.e., the ratio of LE activity to α1-PI, was calculated. RESULTS: A significant increase in LE (235.4 [216.4; 258.1] nmol/min*ml, p<0.001), the functional activity of α1-PI (43.1 [38.7; 47.6] u/ml, p<0.001), the level of aAB to S100b (0.78 [0.70; 0.89] opt.units, p<0.05) and a decrease in PII (6.19 [5.32; 6.9], p<0.05) in the group of patients with organic non-mental disorders compared with controls were shown. Deviations from the normal values of immune markers of inflammation in blood samples were also found in various syndromes. Clustering of the total group of patients by LE activity made it possible to identify 2 immunotypes with a balanced and unbalanced inflammatory process, confirming the clinical diversity of the disease: 60% of patients with AC syndrome belong to the 1st cluster, in which the ratio of immune markers characterizes a balanced inflammatory process aimed at restoration of homeostasis; 80% of patients with organic AND belong to the second cluster, which characterizes low proteolytic activity and imbalance of inflammation, which is an unfavorable prognostic factor in terms of the further course of the disease and therapy. CONCLUSION: The results confirm the importance of the inflammatory link in the neuroprogression of organic non-psychotic disorders. The identified features of the immune response can serve as an additional paraclinical criterion for differential diagnosis and evaluation of the prognosis of the further development of the disease.

[Clinical and immunological effects of choline alfoscerate in the treatment of amnestic type Mild Cognitive Impairment]. / Kliniko-immunologicheskie effekty kholina al'fostserata pri lechenii sindroma myagkogo kognitivnogo snizheniya amnesticheskogo tipa.

OBJECTIVE: To evaluate the change of a number of clinical and immunological parameters of patients with amnestic type Mild Cognitive Impairment (aMCI) in the course of therapy with Choline alfoscerate (α-GPC) in order to develop a monitoring and predicting system of its effectiveness in people at risk for Alzheimer's disease. MATERIAL AND METHODS: Thirty patients with aMCI, aged 56 to 82 years (mean age 68.8±9.4 years), received course therapy with α-GPC in capsules of 400 mg 3 times a day (1200 mg per day) for 3 months. Therapeutic efficacy evaluation according to psychometric tests and scales was carried out three times (0, 45 and 90 days), immunological parameters of leukocyte elastase (LE) and α1-protease inhibitor (α1-PI) were evaluated twice on days 0 and 90 of therapy. RESULTS: A good therapeutic effect over the course treatment with α-GPC, both in terms of cognitive functioning and a number of immunological parameters in patients with aMCI was shown. Significant clinical and immunological correlations included both an improvement in cognitive functions (according to MMSE and the Boston Naming Test) and an increase in LE activity level after the completion of a course of α-GPC therapy, which suggest that an increase in LE functional activity can be considered as a potential marker of a positive therapeutic response to α-GPC treatment in aMCI patients. CONCLUSION: This study shows high significance of further research in assessing the role of immune mechanisms of α-GPC therapeutic efficacy in aMCI patients and the possibility of using immunological parameters as prognostic markers of its therapeutic effect.

Herbal Arsenal against Skin Ailments: A Review Supported by In Silico Molecular Docking Studies.

Maintaining healthy skin is important for a healthy body. At present, skin diseases are numerous, representing a major health problem affecting all ages from neonates to the elderly worldwide. Many people may develop diseases that affect the skin, including cancer, herpes, and cellulitis. Long-term conventional treatment creates complicated disorders in vital organs of the body. It also imposes socioeconomic burdens on patients. Natural treatment is cheap and claimed to be safe. The use of plants is as old as mankind. Many medicinal plants and their parts are frequently used to treat these diseases, and they are also suitable raw materials for the production of new synthetic agents. A review of some plant families, viz., Fabaceae, Asteraceae, Lamiaceae, etc., used in the treatment of skin diseases is provided with their most common compounds and in silico studies that summarize the recent data that have been collected in this area.

[Clinical and immunological correlates in endogenous psychoses developed after COVID-19]. / Kliniko-immunologicheskie korrelyaty pri endogennykh psikhozakh, razvivshikhsya posle perenesennogo COVID-19.

OBJECTIVE: The clinical and immunological study of the potential impact of coronavirus infection on the course of endogenous psychosis. MATERIAL AND METHODS: Thirty-three female patients, aged 16 to 48 years, with depressive-delusional conditions (ICD-10 F20.01, F21, F31) developed after coronavirus infection, of whom 15 people (group 1) had depressive-delusional states 1-2 months after COVID-19 and 18 people (group 2), who developed similar psychoses in later periods (2-6 months). The severity of the psychopathologic symptoms was evaluated with PANSS and HDRS-21 scales. The activity of inflammatory markers - leukocyte elastase (LE) and α1-proteinase inhibitor (α1-PI) in the blood was determined. The absolute neutrophil count, the absolute lymphocyte count and the neutrophil/lymphocyte ratio were calculated. As a control, we used standard values of indicators of age - and sex-matched healthy donors. RESULTS: The endogenous psychosis that developed later after a coronavirus infection (group 2) is associated with a "typical" inflammatory reaction with an increase in the activity of acute phase proteins (according to α1-PI) and degranulation activity of neutrophils (according to LE), which is associated with the development of depressive-delusional states in patients with the dominance of manifestations of positive affectivity (anxiety, melancholy) and the extended nature of delusional disorders, which were predominantly incongruent to affect. On the contrary, the development of endogenous psychosis during the first two months after COVID-19 (group 1) is characterized by a spectrum of inflammatory biomarkers with a decrease in the number of neutrophils and low activity of LE. This immunological profile is associated with the predominance of manifestations of negative affectivity (apathy, asthenia, adynamia) in the structure of depressive-delusional states and the relatively undeveloped nature of delusional disorders, which were predominantly congruent to affect. CONCLUSION: The clinical and biological correlates presumably indicate the modulating effect of the coronavirus infection (COVID-19) on neuroinflammation and the structure of endogenous psychosis.

Endogenous Retroviral Elements Generate Pathologic Neutrophils in Pulmonary Arterial Hypertension.

Rationale: The role of neutrophils and their extracellular vesicles (EVs) in the pathogenesis of pulmonary arterial hypertension is unclear. Objectives: To relate functional abnormalities in pulmonary arterial hypertension neutrophils and their EVs to mechanisms uncovered by proteomic and transcriptomic profiling. Methods: Production of elastase, release of extracellular traps, adhesion, and migration were assessed in neutrophils from patients with pulmonary arterial hypertension and control subjects. Proteomic analyses were applied to explain functional perturbations, and transcriptomic data were used to find underlying mechanisms. CD66b-specific neutrophil EVs were isolated from plasma of patients with pulmonary arterial hypertension, and we determined whether they produce pulmonary hypertension in mice. Measurements and Main Results: Neutrophils from patients with pulmonary arterial hypertension produce and release increased neutrophil elastase, associated with enhanced extracellular traps. They exhibit reduced migration and increased adhesion attributed to elevated ß1-integrin and vinculin identified by proteomic analysis and previously linked to an antiviral response. This was substantiated by a transcriptomic IFN signature that we related to an increase in human endogenous retrovirus K envelope protein. Transfection of human endogenous retrovirus K envelope in a neutrophil cell line (HL-60) increases neutrophil elastase and IFN genes, whereas vinculin is increased by human endogenous retrovirus K deoxyuridine triphosphate diphosphatase that is elevated in patient plasma. Neutrophil EVs from patient plasma contain increased neutrophil elastase and human endogenous retrovirus K envelope and induce pulmonary hypertension in mice, mitigated by elafin, an elastase inhibitor. Conclusions: Elevated human endogenous retroviral elements and elastase link a neutrophil innate immune response to pulmonary arterial hypertension.

The neutrophil elastase-upregulated placenta growth factor promotes the pathogenesis and progression of periodontal disease.

BACKGROUND: Periodontal disease is a chronic inflammatory disease. Given its high prevalence, especially in aging population, the detailed mechanisms about pathogenesis of periodontal disease are important issues for study. Neutrophil firstly infiltrates to periodontal disease-associated pathogen loci and amplifies the inflammatory response for host defense. However, excessive neutrophil-secreted neutrophil elastase (NE) damages the affected gingival. In lung and esophageal epithelium, NE had been proved to upregulate several growth factors including placenta growth factor (PGF). PGF is an angiogenic factor with proinflammatory properties, which mediates the progression of inflammatory disease. Therefore, we hypothesize excessive NE upregulates PGF and participates in the pathogenesis and progression of periodontal disease. METHODS: In gingival epithelial cells (GEC), growth factors array demonstrated NE-increased growth factors and further be corroborated by Western blot assay and ELISA. The GEC inflammation was evaluated by ELISA. In mice, the immunohistochemistry results demonstrated ligature implantation-induced neutrophil infiltration and growth factor upregulation. By multiplex assay, the ligature-induced proinflammatory cytokines level in gingival crevicular fluid (GCF) were evaluated. Finally, alveolar bone absorption was analyzed by micro-CT images and H & E staining. RESULTS: NE upregulated PGF expression and secretion in GEC. PGF promoted GEC to secret IL-1ß, IL-6, and TNF-α in GCF In periodontal disease animal model, ligature implantation triggered NE infiltration and PGF expression. Blockade of PGF attenuated the ligature implantation-induced IL-1ß, IL-6, TNF-α and MIP-2 secretion and ameliorated the alveolar bone loss in mice. CONCLUSION: In conclusion, the NE-induced PGF triggers gingival epithelium inflammation and promotes the pathogenesis and progression of periodontal disease.

Efficacy of minocycline hydrochloride ointment combined with metronidazole film in the treatment of periodontitis and their effects on C-reactive protein and elastase levels in gingival crevicular fluid / 中国基层医药

Objective:To investigate the efficacy of minocycline hydrochloride ointment combined with metronidazole film in the treatment of periodontitis and their effects on C-reactive protein and elastase levels in the gingival crevicular fluid.Methods:76 patients with periodontitis who received treatment in Jiaxing Hospital of Traditional Chinese Medicine from May 2019 to January 2020 were included in this study. They were randomly allocated to undergo treatment with metronidazole film (control group, n = 38) or minocycline hydrochloride ointment plus metronidazole film (observation group, n = 38) for 4 weeks. We compared clinical efficacy, periodontal system examination indexes (gingival index, periodontal probing pocket depth, gingival bleeding index, plaque index, loss of attachment), gingival crevicular fluid biochemical markers (C-reactive protein, elastase in the pellet, elastase in the supernatant) measured before and after treatment, the incidence of adverse reactions, and the recurrence rate within half a year after treatment between the two groups. Results:The total response rate was significantly higher in the observation group than in the control group [97.37% (37/38) vs. 78.95% (30/38), χ2 = 6.17 , P < 0.05]. Gingival index, periodontal probing pocket depth, gingival bleeding index, plaque index, and loss of attachment measured after treatment were significantly lower in the observation group than in the control group (all P < 0.001). C-reactive protein, elastase in the pellet, and elastase in the supernatant measured after treatment were (5.31 ± 1.19) μg/L, (0.70 ± 0.20) Abs/mL, (0.48 ± 0.19) Abs/mL respectively in the observation group, which were significantly lower than those in the control group [(7.92 ± 1.27) μg/L, (1.15 ± 0.52) Abs/mL, (1.12 ± 0.31) Abs/mL, t = 9.24, 4.97, 10.85, all P < 0.001]. The recurrence rate within half a year in the observation group was significantly lower than that in the control group [2.63% (1/38) vs. 20% (6/38), χ2 = 3.93, P < 0.05]. There was no significant difference in the incidence of adverse reactions between the two groups ( P > 0.05). Conclusion:Minocycline hydrochloride ointment combined with metronidazole film is safe and effective in the treatment of periodontitis. The combined therapy help downregulate the levels of C-reactive protein, elastase in the pellet, elastase in the supernatant of the gingival crevicular fluid, alleviate inflammation, improve the periodontal status, and reduce the recurrence rate.

Associations of Genetic Polymorphisms and Neuroimmune Markers With Some Parameters of Frontal Lobe Dysfunction in Schizophrenia.

We investigated the associations of DRD3 rs6280, HTR1A rs6295, BDNF rs6265, SCL6A4 rs16965628, and 5HT2A rs7322347 with schizophrenia in a case-control study, and associations of these genetic variants with several clinical features. We also investigated markers of inflammatory response (C-reactive protein, IL-2, IL-6, IL-10), the activity of leukocytic elastase (LE) and α1-proteinase inhibitor (a1-PI), antibodies to S100B and myelin basic protein (MBP) in schizophrenia. Clinical symptoms were assessed on three scales: Positive and Negative Syndrome Scale, The Bush - Francis Catatonia Rating Scale and Frontal Assessment Battery. All SNPs were typed using predesigned TaqMan SNP genotyping assays. The biomarkers related to the immune system were routinely tested using ELISA kits. The association with schizophrenia was found for DRD3 rs6280 (p = 0.05) and HTR2A rs7322347 (p = 0.0013). We found differences between groups by parameters of LE and a1-PI and LE/a1-PI (p < 0.001). And IL-6 was evaluated in the schizophrenia group (p < 0.001). We showed that patients with the TT allele (BDNF rs6265) had more severe impairments in frontal lobe function. a1-PI can serve as a marker for assessing the severity of frontal lobe damage in patients with frontal dementia. We found some biological parameters reflecting the severity of frontal dysfunction in schizophrenia.

[Specific features of immunological reactions in elderly and young patients with exacerbation of schizophrenia]. / Osobennosti immunologicheskikh reaktsii u patsientov pozhilogo i molodogo vozrasta s obostreniem shizofrenii.

OBJECTIVE: To identify levels of inflammation markers (the enzymatic activity of leukocyte elastase (LE), the functional activity of the α1-proteinase inhibitor (α1-PI), autoantibodies to neurotrophin S100b and myelin basic protein (MBP)) in blood plasma of old- and young-aged patients with schizophrenia in comparison with features of the clinical course of schizophrenia. MATERIAL AND METHODS: Two age groups of patients with schizophrenia were examined. The 1st group consisted of 19 female patients, aged 60 to 78 years (mean age 67.3±5.4 years), with disease duration from 0.5 months to 29 years (9.7±7.6). The 2nd group comprised 24 female patients, aged 19 to 42 years (mean age 26.8±6.3 years), with disease duration from 0.15 to 6.6 years (3.3±2.4). Nineteen age-matched healthy women were included in two control groups. Inflammatory and autoimmune markers were measured in blood plasma using «Neuro-immuno-test technology¼. RESULTS: In the 1st group, a relative smoothness and rigidity of the productive symptoms profile, a reduction of disease progression and a tendency to the development of negative symptoms were established. The 2nd group was characterized by polymorphism, severity and dynamism of productive disorders, as well as the progression and lability of the schizophrenic process. The most significant differences in the spectrum of the analysed immune markers relate to the ratio of the activity of LE and its inhibitor α1-PI, i.e. proteinase-inhibitory index (PII). CONCLUSIONS: The identified multidirectional changes of PII in elderly patients compared to the controls may reflect the imbalance of the inflammatory response and the role of this imbalance in shaping the characteristics of psychopathological symptoms in these patients.

A Proteinase 3 Contribution to Juvenile Idiopathic Arthritis-Associated Cartilage Damage.

A full understanding of the molecular mechanisms implicated in the etiopathogenesis of juvenile idiopathic arthritis (JIA) is lacking. A critical role for leukocyte proteolytic activity (e.g., elastase and cathepsin G) has been proposed. While leukocyte elastase's (HLE) role has been documented, the potential contribution of proteinase 3 (PR3), a serine protease present in abundance in neutrophils, has not been evaluated. In this study we investigated: (1) PR3 concentrations in the synovial fluid of JIA patients using ELISA and (2) the cartilage degradation potential of PR3 by measuring the hydrolysis of fluorescently labeled collagen II in vitro. In parallel, concentrations and collagen II hydrolysis by HLE were assessed. Additionally, the levels of the co-secreted primary granule protein myeloperoxidase (MPO) were assessed in synovial fluid of patients diagnosed with JIA. We report the following levels of analytes in JIA synovial fluid: PR3-114 ± 100 ng/mL (mean ± SD), HLE-1272 ± 1219 ng/mL, and MPO-1129 ± 1659 ng/mL, with a very strong correlation between the PR3 and HLE concentrations (rs = 0.898, p < 1 × 10-6). Importantly, PR3 hydrolyzed fluorescently labeled collagen II as efficiently as HLE. Taken together, these novel findings suggest that PR3 (in addition to HLE) contributes to JIA-associated joint damage.

[Therapy optimization of asthenic disorders in remissions in patients with paroxysmal-progressive schizophrenia (a clinical and immunological analysis)]. / Optimizatsiya terapii astenicheskikh rasstroistv v remissii u bol'nykh pristupoobrazno-progredientnoi shizofreniei (kliniko-immunologicheskii analiz).

OBJECTIVE: To study the efficacy of the immunomodulatory drug γ-D-glutamyl-L-tryptophan in complex therapy of asthenic disorders in remissions in patients with schizophrenia and to analyze clinical and immunological indicators. MATERIALS AND METHODS: Sixty-three male patients (aged 41.9±9.46 years) with paroxysmal-progressive schizophrenia in remission (ICD-10 F20.x1; F20.x2), including 24 patients with affective-asthenic and 39 with negative-asthenic types, were studied. The assessment of the patients' condition was carried out using PANSS, SANS, CDSS, MFI-20. The activity of inflammatory markers: leukocyte elastase (LE) and α1-proteinase inhibitor (a1-PI) was determined in blood serum. The clinical and immunological assessment was performed before, after therapy (in 5 days) and at the remote stage (in a month). RESULTS: Augmentation of standard therapy with γ-D-glutamyl-L-tryptophan facilitated positive reduction in the main clinical manifestations of endogenous asthenia of both types in comparison with placebo (p<0.02). The features of the protease inhibitor system revealed in the patients confirm their clinical heterogeneity and also determine varying efficacy of augmentation by the immunotropic medicine. For patients with the low level of protease activity, which is characteristic of endogenous asthenia with prevalence of negative disorders in clinical picture, the augmentation by γ-D-glutamyl-L-tryptophan was more effective: the decrease in severity of asthenic symptoms was followed by the significant increase in the relatively reduced LE activity (p<0.01), which presumably, relates to the insufficiency of functional activity of neutrophils. CONCLUSION: Augmentation of complex therapy of asthenic disorders in schizophrenia by γ-D-glutamyl-L-tryptophan can be recommended.

[Some inflammation factors and immunophenotypes of depression in elderly patients]. / Nekotorye faktory vospaleniia i immunofenotipy pri depressii u pozhilykh bol'nykh.

AIM: To search for the immunological features of depressions in elderly patients, select certain immunophenotypes and analyze their possible connection with clinical and psychopathological features of depression of old age. MATERIAL AND METHODS: The study included 55 inpatients of old age (median 68 years) with a depressive episode of mild or moderate severity. The control group consisted of 41 elderly people (median 67 years) without depressive disorders. Clinical, psychometric, immunological and statistical methods were used. The rating scales were HAMD-17 and MMSE. The activity of inflammatory and autoimmune markers, including enzymatic activity of leukocyte elastase (LE), α1-proteinase inhibitor (α1-PI), level of autoantibodies to neurospecific antigens S-100B and myelin basic protein, in the serum of patients and control subjects was determined. RESULTS AND CONCLUSION: The scatter in the immunological parameters both in the direction of exceeding the average values and their decrease was shown in the group of depressed elderly patients compared to the controls. Cluster analysis revealed two immunophenotypes of elderly patients with depression. Immunophenotype A is a group of patients with increased PE activity and immunophenotype B is a group of patients with decreased LE activity (p<0.0000). Immunophenotype A includes patients with complex depressions, comorbid with anxiety and senesto-hypochondriac disorders. In immunophenotype B, patients with prolonged apatic/adynamic depressions (p<0.05), with an earlier onset and longer duration of the disease, with incomplete remissions and more burdened with cardiovascular diseases were more common (p<0.05).

Elastase-Positive Neutrophils Are Associated With Refractoriness of Chronic Rhinosinusitis With Nasal Polyps in an Asian Population.

PURPOSE: Various immune cells, including eosinophils and neutrophils, are known to contribute to the development of chronic rhinosinusitis with nasal polyps (CRSwNP). However, the current understanding of the role of neutrophils in the development of CRSwNP still remains unclear. Therefore, we investigated risk factors for refractoriness of CRSwNP in an Asian population. METHODS: Protein levels of 17 neutrophil-related mediators in nasal polyps (NPs) were determined by multiplex immunoassay, and exploratory factor analysis using principal component analysis was performed. Immunofluorescence analysis was conducted to detect human neutrophil elastase (HNE) or myeloperoxidase (MPO)-positive cells. Tissue eosinophilic nasal polyp (ENP) and tissue neutrophilia (Neuhigh) were defined as greater than 70 eosinophils and 20 HNE-positive cells, otherwise was classified into non-eosinophilic nasal polyp (NENP) and absence of tissue neutrophilia (Neulow). RESULTS: In terms of disease control status, NENP-Neulow patients showed the higher rate of disease control than NENP-Neuhigh and ENP-Neuhigh patients. Linear by linear association demonstrated the trend in refractoriness from NENP-Neulow to NENP-Neuhigh or ENP-Neulow to ENP-Neuhigh. When multiple logistic regression was performed, tissue neutrophilia (hazard ratio, 4.38; 95% confidence interval, 1.76-10.85) was found as the strongest risk factor for CRSwNP refractoriness. Additionally, exploratory factor analysis revealed that interleukin (IL)-18, interferon-γ, IL-1Ra, tumor necrosis factor-α, oncostatin M, and MPO were associated with good disease control status, whereas IL-36α and IL-1α were associated with refractory disease control status. In subgroup analysis, HNE-positive cells and IL-36α were significantly upregulated in the refractory group (P = 0.0132 and P = 0.0395, respectively), whereas MPO and IL-18 showed higher expression in the controlled group (P = 0.0002 and P = 0.0009, respectively). Moreover, immunofluorescence analysis revealed that IL-36R⁺HNE⁺-double positive cells were significantly increased in the refractory group compared to the control group. We also found that the ratio of HNE-positive cells to α1 anti-trypsin was increased in the refractory group. CONCLUSIONS: Tissue neutrophilia had an influence on treatment outcomes in the Asian CRSwNP patients. HNE-positive cells and IL-36α may be biomarkers for predicting refractoriness in Asians with CRSwNP. Additionally, imbalances in HNE and α1 anti-trypsin may be associated with pathophysiology of neutrophilic chronic rhinosinusitis.

Elastase-Positive Neutrophils Are Associated With Refractoriness of Chronic Rhinosinusitis With Nasal Polyps in an Asian Population

PURPOSE: Various immune cells, including eosinophils and neutrophils, are known to contribute to the development of chronic rhinosinusitis with nasal polyps (CRSwNP). However, the current understanding of the role of neutrophils in the development of CRSwNP still remains unclear. Therefore, we investigated risk factors for refractoriness of CRSwNP in an Asian population. METHODS: Protein levels of 17 neutrophil-related mediators in nasal polyps (NPs) were determined by multiplex immunoassay, and exploratory factor analysis using principal component analysis was performed. Immunofluorescence analysis was conducted to detect human neutrophil elastase (HNE) or myeloperoxidase (MPO)-positive cells. Tissue eosinophilic nasal polyp (ENP) and tissue neutrophilia (Neu(high)) were defined as greater than 70 eosinophils and 20 HNE-positive cells, otherwise was classified into non-eosinophilic nasal polyp (NENP) and absence of tissue neutrophilia (Neu(low)). RESULTS: In terms of disease control status, NENP-Neu(low) patients showed the higher rate of disease control than NENP-Neu(high) and ENP-Neu(high) patients. Linear by linear association demonstrated the trend in refractoriness from NENP-Neu(low) to NENP-Neu(high) or ENP-Neu(low) to ENP-Neu(high). When multiple logistic regression was performed, tissue neutrophilia (hazard ratio, 4.38; 95% confidence interval, 1.76-10.85) was found as the strongest risk factor for CRSwNP refractoriness. Additionally, exploratory factor analysis revealed that interleukin (IL)-18, interferon-γ, IL-1Ra, tumor necrosis factor-α, oncostatin M, and MPO were associated with good disease control status, whereas IL-36α and IL-1α were associated with refractory disease control status. In subgroup analysis, HNE-positive cells and IL-36α were significantly upregulated in the refractory group (P = 0.0132 and P = 0.0395, respectively), whereas MPO and IL-18 showed higher expression in the controlled group (P = 0.0002 and P = 0.0009, respectively). Moreover, immunofluorescence analysis revealed that IL-36R⁺HNE⁺-double positive cells were significantly increased in the refractory group compared to the control group. We also found that the ratio of HNE-positive cells to α1 anti-trypsin was increased in the refractory group. CONCLUSIONS: Tissue neutrophilia had an influence on treatment outcomes in the Asian CRSwNP patients. HNE-positive cells and IL-36α may be biomarkers for predicting refractoriness in Asians with CRSwNP. Additionally, imbalances in HNE and α1 anti-trypsin may be associated with pathophysiology of neutrophilic chronic rhinosinusitis.

[Immunological predictors of acute post-stroke period]. / Immunologicheskie prediktory techeniia ostrogo perioda insul'ta.

INTRODUCTION: At the present time, there is an increased interest in the search for biological predictors of the course and outcome of ischemic stroke (IS). Numerous studies have shown the relationship between neuroinflammation (in the brain) and systemic inflammatory response (in the blood). AIM: To study the relationship of inflammatory and autoimmune markers in blood serum of patients with acute ischemic stroke (on the 1st day) with the dynamics of the severity of neurological deficit (on the 1st and 10th day) and to assess the predictive ability of these indicators. MATERIAL AND METHODS: Twenty-two patients in the acute period of IS (mean age 60±15.5 years) were examined. The severity of neurological deficit was assessed by ESS and NIHSS. The enzymatic activity of leukocyte elastase (LE), α1-proteinase inhibitor (α1-PI), level of autoantibodies to S-100B and MBP in serum was determined. The control group consisted of 33 healthy subjects. Blood samples were carried out on the 1st day of the post-stroke period, the clinical examination was performed on the 1st and 10th day of observation. RESULTS: Depending on the dynamics of neurological symptoms by the 10th day of observation, two subgroups of patients were identified. The1st subgroup was characterized by the normalization of neurological deficit (n=10). In the 2nd group, the negative dynamics of neurological deficit/lack of any positive changes was observed (n=12). Both subgroups demonstrated the increase in the LE and α1-PI activity as compared to the control (p=0.0019, p=0.00079; p=0.038, p=0.00041, respectively). The highest LE activity was detected in the 1st subgroup (p=0.035). The high level of autoantibodies to MBP was also observed in the 1st subgroup as compared to the control and the 2nd group (p=0.047, p=0.03, respectively). The 2nd subgroup was characterized by a higher functional activity of acute phase protein α1-PI (p=0.04). Using regression analysis, a model for predicting the course of the early post-stroke period depending on the determined immunological parameters was developed. CONCLUSION: The results suggest that the studied inflammatory and autoimmune markers may be possible predictors of the course of the early post-stroke period.