Exploring the role of mitochondrial-associated and peripheral neuropathy genes in the pathogenesis of diabetic peripheral neuropathy.

BACKGROUND: Diabetic peripheral neuropathy (DPN) is a prevalent and serious complication of diabetes mellitus, impacting the nerves in the limbs and leading to symptoms like pain, numbness, and diminished function. While the exact molecular and immune mechanisms underlying DPN remain incompletely understood, recent findings indicate that mitochondrial dysfunction may play a role in the advancement of this diabetic condition. METHODS: Two RNA transcriptome datasets (codes: GSE185011 and GSE95849), comprising samples from diabetic peripheral neuropathy (DPN) patients and healthy controls (HC), were retrieved from the Gene Expression Omnibus (GEO) database hosted by the National Center for Biotechnology Information (NCBI). Subsequently, differential expression analysis and gene set enrichment analysis were performed. Protein-protein interaction (PPI) networks were constructed to pinpoint key hub genes associated with DPN, with a specific emphasis on genes related to mitochondria and peripheral neuropathy disease (PND) that displayed differential expression. Additionally, the study estimated the levels of immune cell infiltration in both the HC and DPN samples. To validate the findings, quantitative polymerase chain reaction (qPCR) was employed to confirm the differential expression of selected genes in the DPN samples. RESULTS: This research identifies four hub genes associated mitochondria or PN. Furthermore, the analysis revealed increased immune cell infiltration in DPN tissues, particularly notable for macrophages and T cells. Additionally, our investigation identified potential drug candidates capable of regulating the expression of the four hub genes. These findings were corroborated by qPCR results, reinforcing the credibility of our bioinformatics analysis. CONCLUSIONS: This study provides a comprehensive overview of the molecular and immunological characteristics of DPN, based on both bioinformatics and experimental methods.

Role of microglia in HIV-1 infection.

The usage of antiretroviral treatment (ART) has considerably decreased the morbidity and mortality related to HIV-1 (human immunodeficiency virus type 1) infection. However, ART is ineffective in eradicating the virus from the persistent cell reservoirs (e.g., microglia), noticeably hindering the cure for HIV-1. Microglia participate in the progression of neuroinflammation, brain aging, and HIV-1-associated neurocognitive disorder (HAND). Some methods have currently been studied as fundamental strategies targeting microglia. The purpose of this study was to comprehend microglia biology and its functions in HIV-1 infection, as well as to look into potential therapeutic approaches targeting microglia.

Factors associated with human immunodeficiency virus-1 low-level viremia and its impact on virological and immunological outcomes: A retrospective cohort study in Beijing, China.

OBJECTIVES: We evaluated the impact of low-level viremia (LLV) on virological failure and immune reconstitution among people living with human immunodeficiency virus type 1 (HIV-1) treated with different antiretroviral regimens in Beijing, China. METHODS: Human immunodeficiency virus type 1-positive adults who were registered at an infectious disease hospital in Beijing between January 1, 2005 and January 1, 2020 were administered antiretroviral therapy (ART) and whose viral load and CD4 counts were monitored were included in this retrospective cohort study. Univariate and multivariate logistic regression analyses were performed to identify risk factors associated with LLV in patients on different ART regimens. Cox proportional hazard model was employed to analyze the virological suppression and immune reconstitution cumulative probability in patients with LLV during follow-up. RESULTS: A total of 10 124 HIV-1-infected participants was included. LLV occurred in 723 (8.2%), 204 (10.9%), 133 (8.6%), and 53 (14.4%) patients on first-line ART, second-line ART, third-line ART, and simplified regimens, respectively. Virological failure occurred in 514 (5.8%), 289 (15.5%), 86 (5.5%), and 34 (9.2%) patients on first-line ART, second-line ART, third-line ART, and simplified regimens, respectively. Earlier enrollment, lower baseline CD4 count, and higher baseline viral load were risk factors associated with LLV. LLV was related to increased hazards of virological failure compared to viral suppression of ≤50 copies/ml for those on first-line ART. CONCLUSIONS: The risk of virological failure and poor immune reconstitution increases when LLV occurs. Targeted viral load and CD4 count monitoring are recommended for people living with HIV-1 with LLV to improve health-related outcomes.

Effects of different integrase strand transfer inhibitors on body weight in patients with HIV/AIDS: a network meta-analysis.

BACKGROUND: Global antiretroviral therapy has entered a new era. Integrase strand transfer inhibitor (INSTI) has become the first choice in acquired immunodeficiency syndrome (AIDS) treatment. Because INSTI has high antiviral efficacy, rapid virus inhibition, and good tolerance. However, INSTIs may increase the risk of obesity. Each INSTI has its unique impact on weight gain in patients with human immunodeficiency virus (HIV)/AIDS. This study systematically assessed different INSTIs in causing significant weight gain in HIV/AIDS patients by integrating data from relevant literature. METHODS: PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), China Science and Technology Journal Database (VIP), and Wanfang databases were searched to find studies on the influence of different INSTIs in weight gain. Data on weight change were extracted, and a network meta-analysis was performed. RESULTS: Eight studies reported weight changes in HIV/AIDS patients were included. Results of the network meta-analysis showed that the weight gain of HIV/AIDS patients treated with Dolutegravir (DTG) was significantly higher than that of Elvitegravir (EVG) [MD = 1.13, (0.18-2.07)]. The consistency test results showed no overall and local inconsistency, and no significant difference in the results of the direct and indirect comparison was detected (p > 0.05). The rank order of probability was DTG (79.2%) > Bictegravir (BIC) (77.9%) > Raltegravir (RAL) (33.2%) > EVG (9.7%), suggesting that DTG may be the INSTI drug that causes the most significant weight gain in HIV/AIDS patients. CONCLUSION: According to the data analysis, among the existing INSTIs, DTG may be the drug that causes the most significant weight gain in HIV/AIDS patients, followed by BIC.

Volume-based predictive biomarkers of sequential FDG-PET/CT for sunitinib in cancer of unknown primary: identification of the best benefited patients.

PURPOSE: To test the performance of sequential 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in predicting survival after sunitinib therapies in patients with cancer of unknown primary (CUP). METHODS: CUP patients were enrolled for sequential PET/CT scanning for sunitinib and a control group. Univariate and multivariate analysis were applied to test the efficacy of sunitinib therapy in CUP patients. Next, sequential analyses involving PET/CT parameters were performed to identify and validate sensitive PET/CT biomarkers for sunitinib therapy. Finally, time-dependent receiver operating characteristic (TDROC) analyses were performed to compare the predictive accuracy. RESULTS: Multivariate analysis proved that sunitinib group had significantly improved survival (p < 0.01) as compared to control group. After cycle 2 of therapy, multivariate analysis identified volume-based PET/CT parameters as sensitive biomarkers for sunitinib (p < 0.01). TDROC curves demonstrated whole-body total lesion glycolysis reduction (Δ WTLG) and follow-up WTLG to have good accuracy for efficacy prediction. This evidence was validated after cycle 4 of therapy with the same method. CONCLUSION: Sunitinib therapy proved effective in treatment of CUP. PET/CT volume-based parameters may help predict outcome of sunitinib therapy, in which Δ WTLG and follow-up WTLG seem to be sensitive biomarkers for sunitinib efficacy. Patients with greater reduction and lower WTLG at follow-up seem to have better survival outcome.

Flow Cytometric Characterization of T Cell Subsets and Microglia After Repetitive Mild Traumatic Brain Injury in Rats.

Although, there is growing awareness in the progressive neurodegeneration of chronic traumatic encephalopathy, changes of immune reactions remain equivocal at best. Thus, in a clinically relevant rat repetitive mild traumatic brain injury (rmTBI) model, some immunologic cells (T cell subsets, microglia) in the injured brain and peripheral blood were analyzed by flow cytometry and immunofluorescence. In the injured brain, CD3+ T cells showed a bimodal increase during 42 days post-injury (dpi). CD3+CD4+ T cells firstly increased and then decreased, while CD3+CD8+ T cells had reversed tendency. CD86+/CD11b+ M1-like microglia increased at 42 dpi and CD206+/CD11b+ M2-like microglia peaked at 7 dpi. In addition, peripheral immune suppression was implicated in the chronic phase after rmTBI. Taken together, the study provided useful information on long-term dynamic changes of some immune cells after rmTBI in rats.

Long-Term Kinetics of Immunologic Components and Neurological Deficits in Rats Following Repetitive Mild Traumatic Brain Injury.

BACKGROUND Despite growing awareness of repetitive mild traumatic brain injury (rmTBI), understanding of the involvement of long-term kinetics of immunologic components in the central and peripheral immune system took part remains incomplete. The present study aimed to provide a quantitative assay for certain immune system parameters in rmTBI rats. MATERIAL AND METHODS Neurological functions were assessed by modified Neurological Severity Score (mNSS) and Morris Water Maze (MWM), immunologic components from brain and peripheral blood were analyzed by flow cytometry (FCM), and concentrations of inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 were measure by enzyme-linked immunosorbent assay (ELISA). RESULTS Neurological functions of rmTBI rats were seriously impaired. In the brain, T cells were up-regulated and peaked at week 1. The percentage of CD4+ T cells decreased from week 1 to week 4, while CD8+ T cells notably decreased at week 1, then increased until week 4. The infiltration proportion of Treg cells was reduced at week 1 and peaked at week 2. CD86+/CD11b+ M1 peaked at week 4 and CD206+/CD11b+ M2 rose at week 1. IL-6/IL-10 showed a similar pattern, whose rise corresponded to the decrease in TNF-α at week 2 after rmTBI. FCM demonstrated peripheral immune dysfunction after rmTBI. CONCLUSIONS mNSS and MWM demonstrated neuronal deficits in rmTBI rats, and central and peripheral immune systems were implicated in the pathophysiological processes of rmTBI. Long-term immune response may play dual roles in injury and repair of rmTBI.

Blood-brain barrier disruption following brain injury: Implications for clinical practice.

The blood-brain barrier (BBB) plays a critical role in regulating the exchange of substances between peripheral blood and the central nervous system and in maintaining the stability of the neurovascular unit in neurological diseases. To guide clinical treatment and basic research on BBB protection following brain injury, this manuscript reviews how BBB disruption develops and influences neural recovery after stroke and traumatic brain injury (TBI). By summarizing the pathological mechanisms of BBB damage, we underscore the critical role of promoting BBB repair in managing brain injury. We also emphasize the potential for personalized and precise therapeutic strategies and the need for continued research and innovation. From this, broadening insights into the mechanisms of BBB disruption and repair could pave the way for breakthroughs in the treatment of brain injury-related diseases.

Interactions and Implications of Klebsiella pneumoniae with Human Immune Responses and Metabolic Pathways: A Comprehensive Review.

Klebsiella pneumoniae (K. pneumoniae), a significant contributor to the global challenge of antibiotic resistance, is not only a ubiquitous component of the human microbiome but also a potent pathogen capable of causing a spectrum of diseases. This review provides a thorough analysis of the intricate interactions between K. pneumoniae and the human immune system, elucidating its substantial impact on metabolic processes. We explore the mechanisms employed by K. pneumoniae to evade and manipulate immune responses, including molecular mimicry, immune modulation, and biofilm formation. The review further investigates the bacterium's influence on metabolic pathways, particularly glycolysis, highlighting how these interactions exacerbate disease severity. The emergence of multidrug-resistant and extremely drug-resistant strains within the Enterobacteriaceae family has heightened the public health crisis, underscoring the urgency for comprehensive research. We investigate the roles of the host's complement system, autophagy, cell death mechanisms, and various cytokines in combating K. pneumoniae infections, shedding light on areas that warrant further academic investigation. Additionally, the review discusses the challenges posed by K1- and K2-capsule polysaccharides in vaccine development due to their complex molecular structures and adhesive properties. Acknowledging the limited availability of effective antimicrobials, this review advocates for exploring alternative approaches such as immunotherapeutics, vaccinations, and phage therapy. We consolidate current knowledge on K. pneumoniae, covering classical and non-classical subtypes, antimicrobial resistance-mediated genes, virulence factors, and epidemiological trends in isolation and antibiotic resistance rates. This comprehensive review not only advances our understanding of K. pneumoniae but also underscores the imperative for ongoing research and collaborative efforts to develop new prevention and treatment strategies against this formidable pathogen.

Selective sodium-glucose cotransporter-2 inhibitors in the improvement of hemoglobin and hematocrit in patients with type 2 diabetes mellitus: a network meta-analysis.

Objective: To compare the effects of different selective sodium-glucose cotransporter-2 inhibitors (SGLT2i) on hemoglobin and hematocrit in patients with type 2 diabetes mellitus (T2DM) with a network meta-analysis (NMA). Methods: Randomized controlled trials (RCTs) on SGLT2i for patients with T2DM were searched in PubMed, Embase, Cochrane Library, and Web of Science from inception of these databases to July 1, 2023. The risk of bias (RoB) tool was used to evaluate the quality of the included studies, and R software was adopted for data analysis. Results: Twenty-two articles were included, involving a total of 14,001 T2DM patients. SGLT2i included empagliflozin, dapagliflozin, and canagliflozin. The NMA results showed that compared with placebo, canagliflozin 100mg, canagliflozin 300mg, dapagliflozin 10mg, dapagliflozin 2mg, dapagliflozin 50mg, dapagliflozin 5mg, empagliflozin 25mg, and dapagliflozin 20mg increased hematocrit in patients with T2DM, while canagliflozin 100mg, canagliflozin 200mg, canagliflozin 300mg increased hemoglobin in patients with T2DM. In addition, the NMA results indicated that canagliflozin 100mg had the best effect on the improvement of hematocrit, and canagliflozin 200mg had the best effect on the improvement of hemoglobin. Conclusion: Based on the existing studies, we concluded that SGLT2i could increase hematocrit and hemoglobin levels in patients with T2DM, and canagliflozin 100mg had the best effect on the improvement of hematocrit, while canagliflozin 200mg had the best effect on the improvement of hemoglobin. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/#loginpage, identifier PROSPERO (CRD42023477103).

Role of Proviral HIV-1 DNA Genotyping for People Living with HIV (PLWH) Who Had Low-Level Viremia While Receiving Antiretroviral Therapy.

Objective: To analyze the antiretroviral resistance in people living with HIV (PLWH) who developed low-level viremia (LLV) during antiretroviral therapy (ART) via sequencing of their HIV-1 proviral DNA and RNA and comparisons of their proviral DNA genotyping data with their past and synchronous RNA genotyping data. Patients and Methods: PLWH with LLV while receiving ART for 6 months or longer from January 2020 to September 2021 were included. HIV-1 proviral DNA and RNA were extracted from white-blood cells and concentrated plasma by ultracentrifugation, respectively, and HIV-1 pol gene fragments were amplified and sequenced. The concordance in the detection of resistance-associated mutations (RAMs) were examined between proviral DNA vs past RNA genotyping and proviral DNA vs synchronous RNA genotyping. Results: Of the 150 PLWH with LLV, 117 proviral DNA pol sequences detected in 105 PLWH were successfully amplified and RAMs were present in 27.6% and the rate of RAMs conferring low-level or greater resistance to antiretrovirals examined was 17.1%. Fifty-six and 57 PLWH had results of past and synchronous RNA genotyping, respectively, for comparisons with those of proviral DNA genotyping; and the concordance rates were 76.8% and 75.4%, respectively. However, proviral DNA genotyping lost than gained partial information on antiretroviral resistance compared with past or synchronous RNA genotyping. Conclusion: We found that the concordance between proviral DNA and past and synchronous RNA genotyping was moderate. Proviral DNA genotyping lost than gained more information on antiretroviral resistance compared with past or synchronous RNA genotyping. To optimize ART in PLWH with LLV, antiretroviral resistance profile should be interpreted in combination with proviral DNA and RNA genotyping and a comprehensive review of previous treatment history.

Low-level Viremia in Treated HIV-1 Infected Patients: Advances and Challenges.

Antiretroviral therapy (ART) can effectively suppress HIV-1 replication, improving quality of life and restoring the lifespan of persons living with HIV (PLWH) to near-normal levels. However, after standardized ART, a low level of HIV-1 RNA, i.e., low-level viremia (LLV), may still be identified in 3% to 10% of the patients. LLV is capable of impacting the immunological and clinical outcomes of patients and serves as a risk factor for transmission. The underlying mechanism of LLV is not yet certain, and the effects of LLV on patient outcomes remain under evaluation. Understanding LLV will allow effective prevention and control strategies to be designed for the benefit of PLWH.

Insights into the HIV-1 Latent Reservoir and Strategies to Cure HIV-1 Infection.

Since the first discovery of human immunodeficiency virus 1 (HIV-1) in 1983, the targeted treatment, antiretroviral therapy (ART), has effectively limited the detected plasma viremia below a very low level and the technique has been improved rapidly. However, due to the persistence of the latent reservoir of replication-competent HIV-1 in patients treated with ART, a sudden withdrawal of the drug inevitably results in HIV viral rebound and HIV progression. Therefore, more understanding of the HIV-1 latent reservoir (LR) is the priority before developing a cure that thoroughly eliminates the reservoir. HIV-1 spreads through both the release of cell-free particles and by cell-to-cell transmission. Mounting evidence indicates that cell-to-cell transmission is more efficient than cell-free transmission of particles and likely influences the pathogenesis of HIV-1 infection. This mode of viral transmission also influences the generation and maintenance of the latent reservoir, which represents the main obstacle for curing the infection. In this review, the definition, establishment, and maintenance of the HIV-1 LR, along with the state-of-the-art quantitative approaches that directly quantify HIV-1 intact proviruses, are elucidated. Strategies to cure HIV infection are highlighted. This review will renew hope for a better and more thorough cure of HIV infection for mankind and encourage more clinical trials to achieve ART-free HIV remission.

Exploring the biological function of immune cell-related genes in human immunodeficiency virus (HIV)-1 infection based on weighted gene co-expression network analysis (WGCNA).

BACKGROUND: Acquired immunodeficiency syndrome (AIDS) is a chronic infectious disease characterized by consistent immune dysfunction. The objective of this study is to determine whether immune cell-related genes can be used as biomarkers for the occurrence of AIDS and potential molecular mechanisms. METHODS: A weighted gene co-expression network analysis was performed using the GSE6740 dataset from the Gene Expression Synthesis Database to identify the Hub gene, which contained microarray data from HIV-1 positive (HIV-1+) and HIV-1 negative (HIV-1-) individuals. The HIV-1+-related differentially expressed genes were then identified using the limma package. Subsequently, the characteristic immune cell-related genes were identified as diagnostic biomarkers for HIV-1+ using the random forest model (RF), support vector machine model, and generalized linear model. RESULTS: MEdarkgreen exhibited the strongest correlation with HIV clinical features of any of these modules. As the best model for diagnosing HIV-1±, RF was used to select four critical immune cell-related genes, namely, ARRB1, DPEP2, LTBP3, and RGCC, and a nomogram model was created to predict the occurrence of HIV-1 infection based on four key immune cell-related genes. Diagnostic genes were shown to be engaged in immune-related pathways, suggesting that immunological molecules, immune cells, and immune pathways all have a role in HIV-1 infection. The CTD database was explored for prospective medications or molecular compounds that might be utilized to treat HIV-1+ patients. = Moreover, in HIV-1+ individuals, the ceRNA network revealed that ARRB1, DPEP2, LTBP3, and RGCC could be regulated by lncRNAs through the corresponding miRNAs. Ultimately, RT-PCR results from clinical blood samples demonstrated that the four diagnostic genes were significantly downregulated in HIV-1+ patients. CONCLUSION: We screened four immune cell-related genes, ARRB1, DPEP2, LTBP3, and RGCC, which may be considered as the diagnostic markers for HIV-1/AIDS. Our findings reveal that immune related genes and pathways involved in HIV-1 pathogenesis were regulated on both genetic and epigenetic levels by constructing a ceRNA network associated with lncRNA.

Persistent Inflammation and Non-AIDS Comorbidities During ART: Coming of the Age of Monocytes.

Monocytes are innate immune cells that serve as the first line of defense against pathogens by engulfing and destroying pathogens or by processing and presenting antigens to initiate adaptive immunity and stimulate immunological responses. Monocytes are classified into three types: classical, intermediate, and non-classical monocytes, each of which plays a particular function in response to pathogens. Human immunodeficiency virus type 1 (HIV-1) infection disrupts the balance of monocyte subsets, and the quantity and function of monocytes will not fully recover even with long-term antiretroviral therapy (ART). Monocytes are vital for the establishment and maintenance of HIV-1 latent viral reservoirs and are closely related to immune dysfunction even after ART. Therefore, the present review focuses on the phenotypic function of monocytes and their functions in HIV-1 infection to elucidate their roles in HIV patients.

Benefits and Risks of Rapid Initiation of Antiretroviral Therapy: A Systematic Review and Meta-Analysis.

Objectives: To compare the benefits and risks between Rapid ART and standard/delayed treatment for HIV. Methods: Databases of PubMed, Cochrane Library, Embase and Web of science were searched from the inception to 28 October 2021. Two investigators independently screened studies related to Rapid ART, extracted data, and evaluated the literature quality. The risk of bias was assessed by Cochrane Collaboration Risk of Bias Tool and the statistical software Stata15.0 was used for meta-analysis. Results: Ten eligible studies were included in this meta-analysis, the results showed Rapid ART was superior to standard/delayed treatment in continuing care for at least 8 months (RR = 1.13, 95%CI: 1.03∼1.25, Z = 2.44, p = 0.015), and severe bacterial infection (RR = 0.42, 95%CI: 0.25∼0.70, Z = 3.33, p = 0.001). At 12 months following treatment, there was no statistically significant difference in viral load <100 copies/mL (RR = 1.05, 95%CI: 0.80∼1.39, Z = 0.35, p = 0.726), mortality (RR = 0.77, 95%CI: 0.47∼1.24, Z = 1.09, p = 0.277), or the incidence of adverse events (RR = 0.52, 95%CI: 0.16∼1.76, Z = 1.05, p = 0.294) compared with standard/delayed treatment. Conclusion: In comparison to standard/delayed treatment, rapid ART can reduce the incidence of TB and severe bacterial infections in HIV patients. Our findings suggest that rapid ART should be utilized when clinical conditions and the patient's physical state allow. Systematic Review Registration: [https://inplasy.com/?s=202210004], identifier [INPLASY202210004].

Identification of Diagnostic Markers Correlated With HIV+ Immune Non-response Based on Bioinformatics Analysis.

Background: HIV-infected immunological non-responders (INRs) are characterized by their inability to reconstitute CD4+ T cell pools after antiretroviral therapy. The risk of non-AIDS-related diseases in INRs is increased, and the outcome and prognosis of INRs are inferior to that of immunological responders (IRs). However, few markers can be used to define INRs precisely. In this study, we aim to identify further potential diagnostic markers associated with INRs through bioinformatic analyses of public datasets. Methods: This study retrieved the microarray data sets of GSE106792 and GSE77939 from the Gene Expression Omnibus (GEO) database. After merging two microarray data and adjusting the batch effect, differentially expressed genes (DEGs) were identified. Gene Ontology (GO) resource and Kyoto Encyclopedia of Genes and Genomes (KEGG) resource were conducted to analyze the biological process and functional enrichment. We performed receiver operating characteristic (ROC) curves to filtrate potential diagnostic markers for INRs. Gene Set Enrichment Analysis (GSEA) was conducted to perform the pathway enrichment analysis of individual genes. Single sample GSEA (ssGSEA) was performed to assess scores of immune cells within INRs and IRs. The correlations between the diagnostic markers and differential immune cells were examined by conducting Spearman's rank correlation analysis. Subsequently, miRNA-mRNA-TF interaction networks in accordance with the potential diagnostic markers were built with Cytoscape. We finally verified the mRNA expression of the diagnostic markers in clinical samples of INRs and IRs by performing RT-qPCR. Results: We identified 52 DEGs in the samples of peripheral blood mononuclear cells (PBMC) between INRs and IRs. A few inflammatory and immune-related pathways, including chronic inflammatory response, T cell receptor signaling pathway, were enriched. FAM120AOS, LTA, FAM179B, JUN, PTMA, and SH3YL1 were considered as potential diagnostic markers. ssGSEA results showed that the IRs had significantly higher enrichment scores of seven immune cells compared with IRs. The miRNA-mRNA-TF network was constructed with 97 miRNAs, 6 diagnostic markers, and 26 TFs, which implied a possible regulatory relationship. Conclusion: The six potential crucial genes, FAM120AOS, LTA, FAM179B, JUN, PTMA, and SH3YL1, may be associated with clinical diagnosis in INRs. Our study provided new insights into diagnostic and therapeutic targets.

STAR mutations causing non­classical lipoid adrenal hyperplasia manifested as familial glucocorticoid deficiency.

Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease characterized by single cortisol deficiency but normal aldosterone and renin levels. Beginning from the discovery of the disease to that of the pathogenic genes over a period of 30 years, the development of gene detection technology has identified a large number of FGD­related genes. Despite the fact that the genetic defect underlying this disease is known for approximately 70% of the patients diagnosed with FGD, there are still several unknown factors causing it. FGD is divided into type 1, type 2 and non­classical type according to the mutant gene. The case described in the present study reported two patients, who were siblings, having skin hyperpigmentation and undergone treatment in adulthood. The gonadal development was normal and the proband had a 10­year­old son. Laboratory tests suggested glucocorticoid deficiency and a mild lack of mineralocorticoid, indicating hyponatremia and hypotension in the proband. In addition, cortisol deficiency was not affected by adrenocorticotropic hormone treatment, while the adrenal glands in the two patients did not show any hyperplasia. Gene analysis revealed two compound heterozygote mutations c.533T>A (p. Leu178Gln) and c.737A>G (p. Asp246Gly) in the steroid hormone acute regulatory protein (STAR) gene in both patients, which may have been obtained from their parents and the proband passed one of the mutations to her son. The present study results revealed that STAR mutations cause non­classic congenital lipoid adrenal hyperplasia in China.

The accumulation of brain injury leads to severe neuropathological and neurobehavioral changes after repetitive mild traumatic brain injury.

Traumatic brain injury (TBI) is a major public health problem with long-term neurobehavioral sequela. The evidences have revealed that TBI is a risk factor for later development of neurodegenerative disease and both the single and repetitive brain injury can lead to the neurodegeneration. But whether the effects of accumulation play an important role in the neurodegenerative disease is still unknown. We utilized the Sprague Dawley (SD) rats to develop the animal models of repetitive mild TBI and single mild TBI in order to detect the neurobehavioral changes. The results of neurobehavioral test revealed that the repetitive mild TBI led to more severe behavioral injuries than the single TBI. There were more activated microglia cells and astrocytes in the repetitive mild TBI group than the single TBI group. In consistent with this, the levels of TNF-α and IL-6 were higher and the expression of IL-10 was lower in the repetitive mild TBI group compared with the single TBI group. The expression of amyloid precursor protein (APP) increased in the repetitive TBI group detected by ELISA and western blot. But the levels of total tau (Tau-5) and P-tau (ser202) seem no different between the two groups in most time point. In conclusion, repetitive mild TBI could lead to more severe neurobehavioral impairments and the effects of accumulation may be associated with the increased inflammation in the brain.

Intermittent hypoxia caused cognitive dysfunction relate to miRNAs dysregulation in hippocampus.

Intermittent hypoxia (IH) is a characteristic pathophysiological change of obstructive sleep apnea (OSA), a commonly diagnosed chronic sleep disorder. With the process of OSA, patients will suffer from the nervous system damage and appear to multiple cognitive dysfunction. The mechanism that how IH causes cognitive impairment is still unknown. Both control and experimental rats were placed in conditions absence and presence of intermittent hypoxia (IH) for 8h a day for a week, two weeks and four weeks, and then followed by behavioral assessments with Morris Water Maze (MWM) test. The results showed that the escape latency of the tested animals to IH significantly increased the escape latency on the last four training days in comparison to the control group. Consistent with this, the expressions of apoptosis/anti-apoptosis proteins were both changed in the hippocampus. Then we utilized the miRNA microarray assay to investigate the level of miRNA expression in rat hippocampus which suffered from intermittent hypoxia. It is noteworthy that the expressions of miR-26b and miR-207 were consistently dysregulated in all the experimental groups post IH. And we utilized qRT-PCR methods to verify the microarray results. Our results showed that microarray based analysis of microRNA expression in rat hippocampus after IH has shown that some microRNAs such as miR-26b and miR-207 could be involved in the OSA-induced cognitive impairments.