Prognostic significance of lymphocytic foci composition in minor salivary gland biopsies for severe disease flare and severity in Sjögren's syndrome: a 3-year follow-up cohort study.

Introduction: This was an ambispective cohort study evaluating the prognostic significance of lymphocytic foci and its lymphoid composition in minor salivary gland biopsy (MSGB) for short-term disease flare and severity in Sjögren's syndrome (SS). Methods: The inclusion criteria comprised individuals meeting the ACR/EULAR 2016 criteria who underwent MSGB with an infiltration of more than 50 lymphocytes and received clinical diagnosis between September 2017 and December 2018. Patients with inadequate biopsy samples were excluded. The number of lymphocytic foci and their lymphoid composition in MSGB were assessed using immunofluorescence staining. Major organ damage and improvements in the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) were measured. Statistical analyses, including Cox and linear regressions, were conducted. Results: A total of 78 patients with at least one lymphocytic focus were included in the study. The presence of higher T-cell counts in lymphocytic foci in MSGB was associated with severe disease flare, and a logarithmic transformation of T-cell count indicated increased risk (HR 1.96, 95% CI 0.91-4.21). Improvements in the ESSDAI were associated with higher total lymphocyte count and T- and B-cell numbers in the lymphoid composition of the lymphocytic foci. Seropositive patients exhibited higher T CD4+ cell numbers. Correlation analysis showed negative associations between age and lymphocytic foci and the T-cell count. Positive correlations were observed between antinuclear antibody (ANA) titers and total lymphocyte numbers. Discussion: Patients with a higher number of T cells in the lymphocytic infiltrates of lymphocytic foci may have a two-fold risk of severe disease flare. The number of B cells and T CD4+ cells in the lymphocytic infiltrates of lymphocytic foci showed a weak but positive relation with the ESSDAI improvement during follow-up. Age and seropositivity appeared to influence the lymphoid composition of the lymphocytic foci.

Impact of IL6R genetic variants on treatment efficacy and toxicity response to sarilumab in rheumatoid arthritis.

BACKGROUND: Sarilumab, an IL-6 receptor antagonist, is a first-line biologic disease-modifying anti-rheumatic drug for rheumatoid arthritis. The identification of genetic biomarkers as predictors of response to sarilumab could allow for a personalized treatment strategy to improve clinical outcomes. METHODS: We conducted a retrospective cohort study of 62 patients treated with sarilumab to determine whether single-nucleotide polymorphisms (SNP) in the IL6R gene could predict efficacy and toxicity responses. Six SNPs previously described in the IL6R gene (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625) were genotyped in DNA samples obtained from these patients. Using parametric tests, we evaluated the association between these polymorphisms and clinicopathological features. Treatment response was assessed six months after treatment initiation. Satisfactory response was based on EULAR criteria. Low disease activity was determined according to DAS28 and CDAI and quantitative improvements in DAS28 and CDAI scores. RESULTS: Three SNPs (rs4845625, rs4329505 and rs11265618) were significantly associated with response outcomes. All of the SNPs, except for rs12083537, had at least one significant association with dyslipidemia or hepatotoxicity. CONCLUSIONS: These findings support the potential clinical value of SNPs, particularly rs4845625, as potentially useful biomarkers to predict response to sarilumab in patients with RA.

Recommendations by the Spanish Society of Rheumatology on risk management of biological treatment and JAK inhibitors in patients with rheumatoid arthritis.

OBJECTIVE: To present recommendations based on the available evidence and the consensus of experts, for risk management of biological treatment and JAK inhibitors in patients with rheumatoid arthritis. METHODS: Clinical research questions relevant to the purpose of the document were identified. These questions were reformulated in PICO format (patient, intervention, comparison, outcome or outcome) by a panel of experts, selected based on their experience in the area. A systematic review of the evidence was carried out, grading according to the GRADE criteria (Grading of Recommendations Assessment, Development, and Evaluation). Specific recommendations were then formulated. RESULTS: 6 PICO questions were proposed by the panel of experts based on their clinical relevance and the existence of recent information regarding the risk of occurrence of serious infections, the risk of reactivation of the hepatitis B virus, the risk of reactivation of the virus varicella-zoster, the risk of appearance of skin (melanoma and non-melanoma) or haematological cancer, the risk of appearance of thromboembolic disease and the risk of progression of the human papilloma virus. A total of 28 recommendations were formulated, structured by question, based on the evidence found and the consensus of the experts. CONCLUSIONS: The SER recommendations on risk management of treatment with biologic therapies and JAK inhibitors in rheumatoid arthritis are presented.

Role of IL6R Genetic Variants in Predicting Response to Tocilizumab in Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a prevalent autoimmune disease characterized by chronic arthritis that may lead to irreversible joint damage and significant disability. Patients with RA are commonly treated with Tocilizumab (TCZ), an IL-6 receptor (IL-6R) antagonist, but many patients refractorily respond to this therapy. Identifying genetic biomarkers as predictors of TCZ response could be a key to providing a personalized medicine strategy. We aimed to evaluate whether functional single nucleotide polymorphisms (SNPs) in the IL6R gene could predict TCZ response in patients with RA. We retrospectively included 88 RA patients treated with TCZ. Six SNPs previously described in the IL6R gene (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625) were genotyped in DNA samples from these patients. Using parametric tests, we evaluated the association between these polymorphisms and clinicopathological features. Responses to treatments were assessed at six months using three variables: a quantitative improvement in Disease activity score including 28 joints (DAS28), a satisfactory European League Against Rheumatism (EULAR) response, and low disease activity (LDA) achievement. The three response variables studied were associated with genetic variant rs4845625, and no association was found with the other five SNPs. Our findings support the potential clinical value of SNPs in the IL6R gene as predictive biomarkers for TCZ response.

Characteristics associated with the perception of high-impact disease (PsAID ≥4) in patients with recent-onset psoriatic arthritis. Machine learning-based model.

OBJECTIVES: To evaluate which patient and disease characteristics are associated with the perception of high-impact disease (PsAID ≥4) in recent-onset psoriatic arthritis. METHODS: We performed a multicenter observational prospective study (2-year follow-up, regular annual visits). The study population comprised patients aged ≥18 years who fulfilled the CASPAR criteria and less than 2 years since the onset of symptoms. The dataset was generated using data for each patient at the 3 visits (baseline, first year, and second year of follow-up) matched with the PsAID values at each of the 3 visits. PsAID was categorized into two groups (<4 and ≥4). We trained a logistic regression model and random forest-type and XGBoost machine learning algorithms to analyze the association between the outcome measure and the variables selected in the bivariate analysis. A k-fold cross-validation with k = 5 was performed. RESULTS: The sample comprised 158 patients. Of the patients who attended the clinic, 45.8% scored PsAID ≥4 at baseline; 27.1%, at the first follow-up visit, and in 23.0%, at the second follow-up visit. The variables associated with PsAID ≥4 were, in decreasing order of importance: HAQ, pain, educational level, and physical activity. Higher HAQ (logistic regression coefficient 10.394; IC95% 7.777,13.011), higher pain (5.668; 4.016, 7.320), lower educational level (-2.064; -3.515, -0.613) and high level of physical activity (1.221; 0.158, 2.283) were associated with a higher frequency of PsAID ≥4. The mean values of the measures of validity of the algorithms were all ≥85%. CONCLUSIONS: Despite the higher weight given to pain when scoring PsAID, we observed a greater influence of physical function on disease impact.

Physical exercise ameliorates memory impairment in offspring of old mice.

For humans, maternal old age means the age of 35 or older at the time of childbirth. Maternal metabolism not only affects the cognitive function of the offspring, but also affects their physical and neurological development. This study aims to elucidate the effects of exercise training on spatial learning memory, neurogenesis, and apoptosis in the off-spring of old mice. Using mice, the offspring of old mothers showed impaired spatial learning memory, decreased brain-derived neurotrophic factor and postsynaptic density protein 95 levels, suppressed neurogenesis, and increased hippocampal apoptotic cell death. In contrast, the offspring of the old mothers had improved spatial learning memory, increased brain-derived neurotrophic factor and postsynaptic density protein 95 levels, increased neurogenesis, and decreased hippocampal apoptotic cell death when they received exercise training. The present results indicate that there is apparent spatial learning memory impairment among the offspring of old mothers, but by contrast, exercise can ameliorate spatial learning memory impairment. Exercise can be an effective countermeasure against memory decline in the offspring of old mothers.

Minimal disease activity (MDA) in patients with recent-onset psoriatic arthritis: predictive model based on machine learning.

BACKGROUND: Very few data are available on predictors of minimal disease activity (MDA) in patients with recent-onset psoriatic arthritis (PsA). Such data are crucial, since the therapeutic measures used to change the adverse course of PsA are more likely to succeed if we intervene early. In the present study, we used predictive models based on machine learning to detect variables associated with achieving MDA in patients with recent-onset PsA. METHODS: We performed a multicenter observational prospective study (2-year follow-up, regular annual visits). The study population comprised patients aged ≥18 years who fulfilled the CASPAR criteria and less than 2 years since the onset of symptoms. The dataset contained data for the independent variables from the baseline visit and from follow-up visit number 1. These were matched with the outcome measures from follow-up visits 1 and 2, respectively. We trained a random forest-type machine learning algorithm to analyze the association between the outcome measure and the variables selected in the bivariate analysis. In order to understand how the model uses the variables to make its predictions, we applied the SHAP technique. We used a confusion matrix to visualize the performance of the model. RESULTS: The sample comprised 158 patients. 55.5% and 58.3% of the patients had MDA at the first and second follow-up visit, respectively. In our model, the variables with the greatest predictive ability were global pain, impact of the disease (PsAID), patient global assessment of disease, and physical function (HAQ-Disability Index). The percentage of hits in the confusion matrix was 85.94%. CONCLUSIONS: A key objective in the management of PsA should be control of pain, which is not always associated with inflammatory burden, and the establishment of measures to better control the various domains of PsA.

Severe Disease in Patients With Recent-Onset Psoriatic Arthritis. Prediction Model Based on Machine Learning.

Objectives: To identify patient- and disease-related characteristics that make it possible to predict higher disease severity in recent-onset PsA. Methods: We performed a multicenter observational prospective study (2-year follow-up, regular annual visits). The study population comprised patients aged ≥ 18 years who fulfilled the CASPAR criteria and less than 2 years since the onset of symptoms. Severe disease was defined at each visit as fulfillment of at least 1 of the following criteria: need for systemic treatment, Health Assessment Questionnaire (HAQ) > 0.5, polyarthritis. The dataset contained data for the independent variables from the baseline visit and follow-up visit number 1. These were matched with the outcome measures from follow-up visits 1 and 2, respectively. We trained a logistic regression model and random forest-type and XGBoost machine learning algorithms to analyze the association between the outcome measure and the variables selected in the bivariate analysis. Results: The sample comprised 158 patients. At the first follow-up visit, 78.2% of the patients who attended the clinic had severe disease. This percentage decreased to 76.4% at the second visit. The variables predicting severe disease were patient global pain, treatment with synthetic DMARDs, clinical form at diagnosis, high CRP, arterial hypertension, and psoriasis affecting the gluteal cleft and/or perianal area. The mean values of the measures of validity of the machine learning algorithms were all ≥ 80%. Conclusion: Our prediction model of severe disease advocates rigorous control of pain and inflammation, also addressing cardiometabolic comorbidities, in addition to actively searching for hidden psoriasis.

Effects of Exercise Training during Advanced Maternal Age on the Cognitive Function of Offspring.

Advanced maternal age (AMA) denotes an age of ≥35 years during the time of delivery. Maternal metabolism affects the offspring's physical and neurological development as well as their cognitive function. This study aimed to elucidate the effects of exercise training among old female animals on the cognitive function, hippocampal neuroplasticity, mitochondrial function, and apoptosis in the offspring. We found that the offspring of mothers with AMA without exercise training had decreased spatial learning and memory, brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD-95) protein levels, neurogenesis, and mitochondrial function, as well as hippocampal cell death. Contrastingly, offspring of mothers with AMA with exercise training showed improved spatial learning, memory, hippocampal neuroplasticity, and mitochondrial function. These findings indicate that despite the AMA, increasing fitness through exercise significantly contributes to a positive prenatal environment for fetuses. The maternal exercises augmented the hippocampal levels of BDNF, which prevents decreased cognitive function in the offspring of mothers with AMA.

Prevalence and Risk for Bundle Branch Block, Atrioventricular Block and Pacemaker Implantation in Spondyloarthritis. A Systematic Review of the Literature.

Objective: To evaluate the evidence regarding the prevalence and risk of bundle branch block (BBB), atrioventricular block (AVB) and pacemaker implantation (PMI) in patients with spondyloarthritis compared to a control group without spondyloarthritis. Methods: A systematic review of the literature was performed using Pubmed (Medline), EMBASE (Elsevier) and Cochrane Library (Wiley) databases until December 2021. The prevalence and risk for AVB, BBB and PMI were analyzed. Cohort, case control and cross-sectional studies in patients ≥18 years meeting the classification criteria for spondyloarthritis were included. The Odds ratio (OR), risk ratio (RR), or Hazard ratio (HR) and prevalence difference were considered as outcomes. Data was synthesized in a previously defined extraction form which included a risk of bias assessment using the Newcastle-Ottawa Scale. Results: In total, eight out of 374 studies were included. None of the studies provided results regarding the risk of low grade AVB and BBB in SpA patients. Only indirect results comparing prevalences from low to medium quality studies were found. According to population based registries, the sex and age adjusted HR of AVB was 2.3 (95% CI 1.6-3.3) in ankylosing spondylitis, 2.9 (95% CI 1.8-4.7) in undifferentiated spondyloarthritis and 1.5 (95% CI 1.1 a 1.9) in psoriatic arthritis. The absolute risk for AVB was 0.4% (moderate to high; 95% CI 0.34%-0.69%) for AS, 0.33% (moderate to high; 95% CI 0.21%-0.53%) for uSpA and 0.34% (moderate to high; 95% CI 0.26%-0.45%) for PsA.The RR for PMI in AS patients was 1.3 (95% CI 1.16-1.46) for groups aged between 65 and 69 years, 1.33 (95% CI 1.22-1.44) for 70-75 years, 1.24 (95% CI 1.55-1.33) for 75-79 years and 1.11 (95% CI 1.06-1.17) for groups older than 80 years. The absolute risk for PMI in AS patients was 0.7% (moderate to high risk; 95% CI 0.6-0.8%) for groups aged between 65-69, 1.44% (high risk; 95% CI 1.33-1.6%) for 70-75 years, 2.09% (high risk; 95% CI 2.0-2.2%) for 75-79 years and 4.15% (high risk; 95% CI 4.0-4.3%) for groups older than 80 years. Conclusions: Very few cases of low grade AVB and BBB were observed in observational studies. No study evaluated association measures for low grade AVB and BBB but the differences of prevalence were similar in SpA and control groups even though studies lacked the power to detect statistical differences. According to population based registries there was an approximately two fold-increased risk of high grade AVB in SpA patients. RR for PMI was higher in younger age groups.

Flow-induced endothelial mitochondrial remodeling mitigates mitochondrial reactive oxygen species production and promotes mitochondrial DNA integrity in a p53-dependent manner.

Tumor suppressor p53 plays a pivotal role in orchestrating mitochondrial remodeling by regulating their content, fusion/fission processes, and intracellular signaling molecules that are associated with mitophagy and apoptosis pathways. In order to determine a molecular mechanism underlying flow-mediated mitochondrial remodeling in endothelial cells, we examined, herein, the role of p53 on mitochondrial adaptations to physiological flow and its relevance to vascular function using endothelial cell-specific p53 deficient mice. We observed no changes in aerobic capacity, basal blood pressure, or endothelial mitochondrial phenotypes in the endothelial p53 mull animals. However, after 7 weeks of voluntary wheel running exercise, blood pressure reduction and endothelial mitochondrial remodeling (biogenesis, elongation, and mtDNA replication) were substantially blunted in endothelial p53 null animals compared to the wild-type, subjected to angiotensin II-induced hypertension. In addition, endothelial mtDNA lesions were significantly reduced following voluntary running exercise in wild-type mice, but not in the endothelial p53 null mice. Moreover, in vitro studies demonstrated that unidirectional laminar flow exposure significantly increased key putative regulators for mitochondrial remodeling and reduced mitochondrial reactive oxygen species generation and mtDNA damage in a p53-dependent manner. Mechanistically, unidirectional laminar flow instigated translocalization of p53 into the mitochondrial matrix where it binds to mitochondrial transcription factor A, TFAM, resulting in improving mtDNA integrity. Taken together, our findings suggest that p53 plays an integral role in mitochondrial remodeling under physiological flow condition and the flow-induced p53-TFAM axis may be a novel molecular intersection for enhancing mitochondrial homeostasis in endothelial cells.

Combined effects of aerobic exercise and 40-Hz light flicker exposure on early cognitive impairments in Alzheimer's disease of 3×Tg mice.

Alzheimer's disease (AD) is a progressive degenerative brain disease and the primary cause of dementia. At an early stage, AD is generally characterized by short-term memory impairment, owing to dysfunctions of the cortex and hippocampus. We previously reported that a combination of exercise and 40-Hz light flickering can protect against AD-related neuroinflammation, gamma oscillations, reduction in Aß, and cognitive decline. Therefore, we sought to extend our previous findings to the 5-mo-old 3×Tg-AD mouse model to examine whether the same favorable effects occur in earlier stages of cognitive dysfunction. We investigated the effects of 12 wk of exercise combined with 40-Hz light flickering on cognitive function by analyzing neuroinflammation, mitochondrial function, and neuroplasticity in the hippocampus in a 3×Tg-AD mouse model. Five-month-old 3×Tg-AD mice performed 12 wk of exercise with 40-Hz light flickering administered independently and in combination. Spatial learning and memory, long-term memory, hippocampal Aß, tau, neuroinflammation, proinflammatory cytokine expression, mitochondrial function, and neuroplasticity were analyzed. Aß and tau proteins levels were significantly reduced in the early stage of AD, resulting in protection against cognitive decline by reducing neuroinflammation and proinflammatory cytokines. Furthermore, mitochondrial function improved, apoptosis was reduced, and synapse-related protein expression increased. Overall, exercise with 40-Hz light flickering was significantly more effective than exercise or 40-Hz light flickering alone, and the improvement was comparable to the levels in the nontransgenic aged-match control group. Our results indicate a synergistic effect of exercise and 40-Hz light flickering on pathological improvements in the hippocampus during early AD-associated cognitive impairment.NEW & NOTEWORTHY Exercising in a 40-Hz light flicker environment was more effective than exercise or 40-Hz light flicker alone. This synergistic effect may prevent cognitive dysfunction by inhibiting Aß, tau pathway, and neuroinflammation and enhancing neuroplasticity and mitochondrial functions in the hippocampus during early Alzheimer's disease.

Effectiveness and safety of anakinra in gouty arthritis: A case series and review of the literature.

Background: Gout is the most common type of inflammatory arthritis. Nonsteroidal anti-inflammatory drugs, corticosteroids, and colchicine are the first-line agents, although they are contraindicated in many patients. Blockade of IL-1 with anakinra can be an alternative. Objective: To present a case series of 10 difficult-to-treat gout patients treated with anakinra and perform a scoping review of the effectiveness and safety of anakinra in gout patients. Methods: A total of 1,519 citations were screened. The reviewers ran a two-stage screening process by title/abstract and full-text reading. Thirty-eight articles finally met the selection criteria and were included for data extraction and synthesis. Experience in difficult-to treat and complex clinical scenarios, such as active infection, hemodialysis, and transplantation, were specifically described. Results: The study sample comprised 551 patients, from whom 648 flares were finally analyzed. The mean age was 57.9 years, and 82.9% were men. The clinical presentation was polyarticular in 47.5% and tophaceous in 66.9%. Sixty-five patients with an active infection, 41 transplanted patients and 14 in haemodyalisis treated with anakinra are described. More than half of the patients had >1 associated comorbidity. Anakinra was effective both for flares (94%) and for long-term treatment (91%) and well tolerated. In the case of flares, 34 (6.7%) adverse effects were registered. Adverse events were more prevalent in long-term treatment. Conclusion: Anakinra was effective and safe for management of gout flares in difficult-to-treat patients. It has been used in multiple complex scenarios, such as active infections, dialysis, transplantation, chronic kidney disease, and polyarticular gout. Anakinra has also proven effective as long-term treatment, although there are more concerns about its safety.

Clinical Value of IL6R Gene Variants as Predictive Biomarkers for Toxicity to Tocilizumab in Patients with Rheumatoid Arthritis.

Tocilizumab is a first-line biologic disease-modifying anti-rheumatic drug (bDMARD) that inhibits the interleukin-6 (IL-6) pathway by antagonizing the IL-6 receptor (IL-6R). Tocilizumab is widely used to treat rheumatoid arthritis (RA), a prevalent autoimmune disease that can cause irreversible joint damage and disability. Although many bDMARDs have been developed for RA, there is a lack of validated biomarkers which could guide personalized medicine strategies. To evaluate whether single-nucleotide polymorphisms (SNPs) in the IL6R gene could predict tocilizumab toxicity in patients with RA, we conducted a retrospective cohort study of 88 patients treated with tocilizumab. Six SNPs previously described in the IL6R gene were genotyped (rs12083537, rs11265618, rs4329505, rs2228145, rs4537545, and rs4845625). Using parametric tests, we studied the association between the SNPs and hepatotoxicity, infection, hypersensitivity, gastrointestinal, hematological, and dyslipidemia adverse events (AEs). We found associations between dyslipidemia and rs4845625 and between hematological AEs and rs11265618 and rs4329505. No further associations were found for the remaining SNPs and other AEs. Our findings support the potential clinical value of SNPs in the IL6R gene as predictive biomarkers for toxicity to tocilizumab in patients with RA.

Valve Abnormalities, Risk Factors for Heart Valve Disease and Valve Replacement Surgery in Spondyloarthritis. A Systematic Review of the Literature.

Objective: Evaluate the evidence on the abnormalities of the aortic root and heart valves, risk and prognostic factors for heart valve disease and valve replacement surgery in spondyloarthritis. Methods: A systematic literature review was performed using Medline, EMBASE and Cochrane databases until July 2021. Prevalence, incidence, risk and prognostic factors for heart valve disease; dimension, morphology, and pathological abnormalities of the valves were analyzed. Patient characteristics (younger age, history of cardiac disease or longer disease duration) and period of realization were considered for the analysis. The SIGN Approach was used for rating the quality of the evidence of the studies. Results: In total, 37 out of 555 studies were included. Overall, the level of evidence was low. The incidence of aortic insufficiency was 2.5-3.9‰. Hazard Ratio for aortic insufficiency was 1.8-2.0. Relative risk for aortic valve replacement surgery in ankylosing spondylitis patients was 1.22-1.46. Odds ratio for aortic insufficiency was 1.07 for age and 1.05 for disease duration. Mitral valve abnormalities described were mitral valve prolapse, calcification, and thickening. Aortic valve abnormalities described were calcification, thickening and an echocardiographic "subaortic bump." Abnormalities of the aorta described were thickening of the wall and aortic root dilatation. The most common microscopic findings were scarring of the adventitia, lymphocytic infiltration, and intimal proliferation. Conclusions: A higher prevalence and risk of aortic valve disease is observed in patients with ankylosing spondylitis. Studies were heterogeneous and analysis was not adjusted by potential confounders. Most studies did not define accurate outcomes and may have detected small effects as being statistically significant.

Treadmill exercise ameliorates social isolation-induced memory impairment by enhancing silent information regulator-1 expression in rats.

The effect of treadmill exercise on the social isolation-induced memory impairment in relation with the silent information regulator-1 (SIRT-1) was investigated. The rats in the control groups lived four in the stan-dard cages for 8 weeks. The rats in the social isolation groups lived alone in the small cages for 8 weeks. The rats in the treadmill exercise groups were subjected to run on a treadmill for 30 min once a day for 8 weeks. We used step-through avoidance test for short-term memory and Morris water maze task for spatial working memory. Immunohisto-chemistry for SIRT-1 and western blot analysis for Bax, Bcl-2, cleaved caspase-3, brain-derived neurotrophic factor (BDNF), and tropomyosin receptor kinase B (TrkB) were performed. The rats in the social isolation group showed a decrease in short-term memory and spatial working memory. Treadmill exercise alleviated short-term memory and spatial working memory in the social isolation rats. SIRT-1 expression in the hippocampus was decreased in the rats of social isolation group. Treadmill exercise increased SIRT-1 expression in the social isolation rats. Bax expression was increased, Bcl-2 expression was decreased, and cleaved caspase-3 expression in the hippocampus was increased in the rats of social isolation group. Treadmill exercise decreased Bax expression, increased Bcl-2 expression, and decreased cleaved caspase-3 expression in the social isolation rats. Hippocampal BDNF and TrkB expression was decreased in the rats of social isolation group. Treadmill exercise increased BDNF and TrkB expression in the social isolation rats.

Effects of swimming exercise on social isolation-induced memory impairment and apoptosis in old rats.

Effect of swimming exercise on serotonin (5-hydroxytryptamine, 5-HT) expression and apoptosis in social isolation rats during old age was investigated. Rats in the old social isolation groups were housed alone per cage for 4 weeks. Rats in the swimming exercise groups were allowed to swim for 30 min once daily for 4 weeks. Morris water maze task determined spatial working memory and elevated plus maze test determined anxiety. Immunohistochemistry for tryptophan hydroxylase (TPH) and 5-HT in the dorsal raphe and for doublecortin (DCX) in the hippocampal dentate gyrus was conducted. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining in the hippocampal dentate gyrus was performed. Western blot analysis for Bax, Bcl-2, and cytochrome c in the hippocampus was conducted. Social isolation in rats of old age reduced spatial working memory and increased anxiety level. Swimming exercise enhanced spatial working memory and suppressed anxiety level. Social isolation in rats of old age inhibited TPH and 5-HT expression in dorsal rape. Swimming exercise increased TPH and 5-HT expression. Social isolation in rats of old age inhibited DCX-positive cells in the hippocampal dente gyrus. Swimming exercise increased DCX-positive cells. Social isolation in rats of old age increased TUNEL-positive cells, Bax and cytochrome c expression, and decreased Bcl-2 expression, which promoted apoptosis. Swimming exercise suppressed TUNEL-positive cells, Bax and cytochrome c expression, and increased Bcl-2 expression, which inhibited apoptosis. Swimming exercise improved 5-HT expression and suppressed apoptosis to alleviate anxiety and memory impairment during old age.

Effects of treadmill exercise on activity, short-term memory, vascular dysfunction in maternal separation rats.

Maternal separation during early life causes psychiatric and neurologi-cal disorders such as anxiety and depression. Depression or anxiety is closely associated with memory impairment. The purpose of this study was to investigate the effect of treadmill exercise on activity, short-term memory, vascular dysfunction using maternal separation-induced de-pression model. Maternal separation started on 15-day-old rats. The rats in the maternal separation and fluoxetine injection group received intraperitoneal injection of 5 mg/kg of fluoxetine one time daily for 15 days from 21 to 35 days. The rats performed treadmill exercise once a day during 15 days from 21 to 35 days. There was low activity and short-term memory was decreased in the maternal separation rats. Treadmill exercise and fluoxetine injection increased activity and ameliorated memory impairment. The number of rat endothelial cells antigen-1 (RECA-1) of microvessels was decreased in the maternal separation rats. The number of RECA-1was increased by treadmill exercise and fluoxetine injection. Expression of matrix metalloproteinase-9 (MMP-9) was increased and expressions of zonula occludens-2 (ZO-2) and oc-cludin were decreased in the maternal separation rats. Treadmill exer-cise and fluoxetine injection suppressed MMP-9 expression and en-hanced ZO-2 and occludin expressions in the maternal separation rats. The present study shows treadmill exercise and antidepressant treat-ment ameliorates depressive symptom and short-term memory impair-ment by protecting from blood-brain barrier damage.

Swimming exercise ameliorates mood disorder and memory impairment by enhancing neurogenesis, serotonin expression, and inhibiting apoptosis in social isolation rats during adolescence.

Social isolation during adolescence is associated with anxiety, depres-sion, and memory impairment. Exercise has been reported as a positive effect on brain function, especially hippocampus. The present study ex-amined the effect of swimming exercise on apoptosis, cell proliferation, and serotonin expression in social isolation rats during adolescence stage. Social isolation started at postnatal day 21 and continued for 6 weeks. The rats in the swimming group were forced to swim for 60 min once daily during 6 days per week for 6 consecutive weeks. The rats in the social isolation during adolescence showed anxiety, depression, short-term memory impairment. Social isolation facilitated apoptosis and inhibited cell proliferation and differentiation. Social isolation sup-pressed expression of serotonin, brain-derived neurotrophic factor, and tyrosine kinase B. Swimming exercise alleviated anxiety, depression, short-term impairment. Swimming exercise suppressed apoptosis, en-hanced neurogenesis, and increased serotonin expression. In our study, swimming exercise ameliorates mood disorder and memory impairment by enhancing neurogenesis and serotonin expression and inhibiting apoptosis in social isolation.