Biomarkers of cell damage, neutrophil and macrophage activation associated with in-hospital mortality in geriatric COVID-19 patients.

BACKGROUND: The risk for symptomatic COVID-19 requiring hospitalization is higher in the older population. The course of the disease in hospitalised older patients may show significant variation, from mild to severe illness, ultimately leading to death in the most critical cases. The analysis of circulating biomolecules involved in mechanisms of inflammation, cell damage and innate immunity could lead to identify new biomarkers of COVID-19 severity, aimed to improve the clinical management of subjects at higher risk of severe outcomes. In a cohort of COVID-19 geriatric patients (n= 156) who required hospitalization we analysed, on-admission, a series of circulating biomarkers related to neutrophil activation (neutrophil elastase, LL-37), macrophage activation (sCD163) and cell damage (nuclear cfDNA, mithocondrial cfDNA and nuclear cfDNA integrity). The above reported biomarkers were tested for their association with in-hospital mortality and with clinical, inflammatory and routine hematological parameters. Aim of the study was to unravel prognostic parameters for risk stratification of COVID-19 patients. RESULTS: Lower n-cfDNA integrity, higher neutrophil elastase and higher sCD163 levels were significantly associated with an increased risk of in-hospital decease. Median (IQR) values observed in discharged vs. deceased patients were: 0.50 (0.30-0.72) vs. 0.33 (0.22-0.62) for n-cfDNA integrity; 94.0 (47.7-154.0) ng/ml vs. 115.7 (84.2-212.7) ng/ml for neutrophil elastase; 614.0 (370.0-821.0) ng/ml vs. 787.0 (560.0-1304.0) ng/ml for sCD163. The analysis of survival curves in patients stratified for tertiles of each biomarker showed that patients with n-cfDNA integrity < 0.32 or sCD163 in the range 492-811 ng/ml had higher risk of in-hospital decease than, respectively, patients with higher n-cfDNA integrity or lower sCD163. These associations were further confirmed in multivariate models adjusted for age, sex and outcome-related clinical variables. In these models also high levels of neutrophil elastase (>150 ng/ml) appeared to be independent predictor of in-hospital death. An additional analysis of neutrophil elastase in patients stratified for n-cfDNA integrity levels was conducted to better describe the association of the studied parameters with the outcome. CONCLUSIONS: On the whole, biomarkers of cell-free DNA integrity, neutrophil and macrophage activation might provide a valuable contribution to identify geriatric patients with high risk of COVID-19 in-hospital mortality.

CHI3L1 and CHI3L2 overexpression in motor cortex and spinal cord of sALS patients.

BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterized by the degeneration and death of upper (UMN) and lower (LMN) motor neurons. In the last decade, it has been shown that Chitinases are an important prognostic indicator of neuro-inflammatory damage induced by microglia and astrocytes. MATERIALS AND METHODS: We analyzed microarray datasets obtained from the Array Express in order to verify the expression levels of CHI3L1 and CHI3L2 in motor cortex biopsies of sALS patients with different survival times. We also divided the sALS patients into smokers and non-smokers. In order to extend our analysis, we explored two additional microarray datasets, GSE833 and GSE26927, of post-mortem spinal cord biopsies from sALS patients. RESULTS: The analysis showed that CHI3L1 and CHI3L2 expression levels were significantly upregulated in the motor cortex of sALS patients, compared to the healthy controls. Moreover, their expression levels were negatively correlated with survival time. Interesting results were obtained when we compared the expression levels of Chitinases among smokers. We showed that CHI3L1 and CHI3L2 were significantly upregulated in sALS smokers compared to non-smokers. Furthermore, we found that four genes belonging to the Chitinases network (SERPINA3, C1s, RRAD, HLA-DQA1) were significantly upregulated in the motor cortex of sALS patients and positively correlated with Chitinases expression levels. Similar results were obtained during the exploration of the two-microarray dataset. CONCLUSIONS: This study suggests that CHI3L1 and CHI3L2 are associated with the progression of neurodegeneration in motor cortex and spinal cord of sALS patients.

Vitamin D3 regulates LAMP3 expression in monocyte derived dendritic cells.

The family of lysosome-associated membrane proteins (LAMPs) encompassing LAMP1, LAMP2 and DC-LAMP (LAMP3) are the major constituents of the glycoconjugates coat present on the inside of the lysosomal membrane. LAMP3 is highly expressed only in certain cell types and during the differentiation stages. Its expression is linked the maturation of dendritic cells, inflammation, poor prognosis of certain tumors, and the locus where it is encoded was identified as a risk factor for Parkinson's disease (PD). Here, we investigated the capacity of Vitamin D3 to modulate the expression of LAMP3 during the dendritic cells differentiation and maturation. Our results demonstrated that the Vitamin D3 reduce the LAMP3 mRNA/protein expression during the dendritic cells differentiation and maturation, via NFκB pathways. Furthermore, we demonstrated that the Vitamin D3 was able to modulate the expression of LAMP3 likewise to in vitro tolerogenic dendritic cells. In summary, these data showed that the decrease of LAMP3 expression by Vitamin D3could enhance the tolerogenic characteristic of dendritic cells.

CD4+ T-cell gene expression of healthy donors, HIV-1 and elite controllers: Immunological chaos.

OBJECTIVES: T-cell repertoire dysfunction characterizes human immunodeficiency virus type 1 (HIV-1) infection, but the pathogenic mechanisms remain unclear. Disease progression is probably due to a profound dysregulation of Th1, Th2, Th17 and Treg patterns. The aim of this study was to analyze the features of CD4+ T cells in HIV-positive patients with different viroimmunological profile. METHODS: we used a gene expression dataset of CD4+ T cells from healthy donors, HIV+ naive patients and Elite Controllers (EC), obtained from the NCBI Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/, accession number GSE18233). RESULTS: Principal Component Analysis (PCA) showed an almost complete overlap between the HIV-infected and EC patients, which cannot easily explain the different responses to HIV infection of these two group of patients. We have found that HIV patients and the EC showed an upregulation of the Th1 pro-inflammatory cytokines and chemokines, compared to the controls. Also, we have surprisingly identified IL28B, which resulted downregulated in HIV and EC compared to healthy controls. We focused attention also on genes involved in the constitution of the immunological synapse and we showed that HLA class I and II genes resulted significantly upregulated in HIV and in EC compared to the control. In addition to it, we have found the upregulation of others syncytial molecules, including LAG3, CTLA4, CD28 and CD3, assisting the formation of syncytia with APC cells. CONCLUSIONS: Understanding the mechanisms of HIV-associated immunological chaos is critical to strategically plan focused interventions.

Serum chitotriosidase in postmenopausal women with severe osteoporosis.

UNLABELLED: Human chitotriosidase (Chit) increases during the osteoclast differentiation and their activity. We demonstrated that serum Chit was significantly higher in osteoporotic subjects than in healthy control ones and revealed a negative correlation between Chit and bone mineral density (BMD). This is the first study showing a correlation between Chit and severe postmenopausal osteoporosis. INTRODUCTION: Mammalian chitinases exert important biological roles in the monocyte lineage and chronic inflammatory diseases. In particular, Chit seems to promote bone resorption in vitro. No in vivo studies have been performed to confirm this finding. We aim to evaluate Chit activity in postmenopausal women affected by severe osteoporosis. METHODS: In this cross-sectional study, 91 postmenopausal women affected by osteoporosis and 61 with either osteopenia or normal BMD were screened. All subjects were assessed by dual-energy X-ray absorptiometry (DXA) and X-ray vertebral morphometry. Osteoporotic subjects were considered eligible if they were affected by at least one vertebral osteoporotic fracture (group A = 57 subjects). Osteopenic or healthy subjects were free from osteoporotic fractures (group B = 51 subjects). Enzymatic Chit and serum ß-CrossLaps (CTX) were measured in the whole population. RESULTS: Group A showed higher serum levels of beta-CTX compared to group B (0.40 ± 0.26 ng/mL vs 0.29 ± 0.2 ng/mL, p = 0.022). Chit was significantly higher in group A than in group B (1042 ± 613 nmol/mL/h vs 472 ± 313 nmol/mL/h, p < 0.001, respectively) even after adjustment for age (p < 0.001). Spearman correlation test revealed a negative correlation between Chit and BMD at each site (lumbar spine: r = -0.38, p = 0.001, femoral neck: r = -0.35, p = 0.001, total femur: r = -0.39, p < 0.001). Furthermore, a positive correlation between Chit and PTH was observed (r = 0.26, p = 0.013). No significant correlation was found between Chit and beta-CTX (r = 0.12, p = 0.229). After a multivariate analysis, a positive correlation between severe osteoporosis and Chit (p < 0.001), beta-CTX (p = 0.013), and age (p < 0.001) was observed. CONCLUSION: This is the first clinical study showing a correlation between Chit and severe postmenopausal osteoporosis. Larger and prospective studies are needed to evaluate if Chit may be a promising clinical biomarker and/or therapeutic monitor in subjects with osteoporosis.

Bone disease in the setting of HIV infection: update and review of the literature.

The advent of highly active antiretroviral therapy (HAART) in the mid-1990s has transformed Human Immunodeficiency Virus (HIV) infection into a chronic disease. HIV-infected patients are living longer and are facing several non-AIDS-associated morbidities related with aging, including diabetes mellitus, cardiovascular disease, osteoporosis, osteopenia and fragility fractures. The prevalence of bone disease is higher among HIV-infected subjects. In addition to traditional risk factors, HAART, chronic inflammation and the virus itself have been suggested to contribute to bone loss in the setting of HIV infection. In the present review, we summarize the current knowledge about risk factors for low bone mineral density in HIV-positive patients as well as current recommendations for fracture screening and treatment in this specific population.

Kidney disease in HIV-infected patients.

The introduction of highly active antiretroviral therapy (HAART) has reduced mortality and improved life expectancy of HIV-positive patients. However, increased survival is associated with increased prevalence of comorbidities, such as cardiovascular disease, hepatic and renal disease. Kidney disease, including HIV-associated nephropathy, acute renal failure and chronic kidney disease, represents one of the main causes of morbidity and mortality, especially if associated to other risk factors, i.e. hypertension, diabetes, older age, black race and hepatitis C coinfection. Careful evaluation of renal function may help identifying kidney disease in its early stages. In addition, proper management of hypertension and diabetes is recommended. Even if HAART has changed the natural course of HIV-associated nephropathy, reducing the risk of End-stage Renal Disease (ERDS), some antiretroviral regimens have been related with the development of acute or chronic kidney disease. Further studies are needed to optimize the management of renal disease among HIV-infected patients.

Vitamin D deficiency in HIV infection: an underestimated and undertreated epidemic.

Hypovitaminosis D is a very common disorder, regarding both Western and developing countries. A growing amount of data over the last years have shown vitamin D deficiency to be high prevalent among HIV-positive subjects. In addition to "classic" risk factors, such as female sex, low dietary intake, dark skin pigmentation and low sun exposure, HIV-related factors, including immune activation and antiretroviral adverse effects, may affect vitamin D status. Even if both protease inhibitors and non-nucleoside reverse transcriptase inhibitors have been associated with low vitamin D levels, available evidences have failed to univocally associate hypovitaminosis D with specific antiretroviral class effects. Low vitamin D is known to have a negative impact not only on bone health, but also on neurocognitive, metabolic, cardiovascular and immune functions. Similarly to the general population, several studies conducted on HIV-infected subjects have associated hypovitaminosis D with a greater risk of developing osteopenia/osteoporosis and fragility fractures. Analogously, vitamin D deficiency has been described as an independent risk factor for cardiovascular disease and metabolic disorders, such as insulin resistance and type 2 diabetes mellitus. Last EACS guidelines suggest to screen for hypovitaminosis D every HIV-positive subject having a history of bone disease, chronic kidney disease or other known risk factors for vitamin D deficiency. Vitamin D repletion is recommended when 25-hydroxyvitamin D levels are below 10 ng/ml. Furthermore, it may be indicated in presence of 25OHD values between 10 and 30 ng/ml, if associated with osteoporosis, osteomalacia or increased parathyroid hormone levels. The optimal repletion and maintenance dosing regimens remain to be established, as well as the impact of vitamin D supplementation in preventing comorbidities.

LPS and HIV gp120 modulate monocyte/macrophage CYP27B1 and CYP24A1 expression leading to vitamin D consumption and hypovitaminosis D in HIV-infected individuals.

AIM: Vitamin D deficiency is very common among HIV-infected subjects. We cross-sectionally evaluated the prevalence and risk factors for hypovitaminosis D in 91 HIV-infected Italian patients. PATIENTS AND METHODS: We studied in a cohort of 91 HIV-infected Italian patients the metabolism of Vitamin D by evaluating the in vitro expression of CYP27B1, CYP24A1 and vitamin D receptor (VDR) by monocytes and macrophages stimulated with the viral envelope protein gp120 or lipopolysaccharide (LPS). RESULTS: The prevalence of vitamin D deficiency (25OHD < 10 ng/ml) and vitamin D insufficiency (25OHD 10-30 ng/ml) was 31% and 57%, respectively. In univariate analysis, female sex (p = 0.01), increasing age (p = 0.05), higher highly sensitive-C reactive protein (p = 0.025), higher parathyroid hormone (PTH) (p = 0.043) and lower BMI (p = 0.04) were associated with vitamin D deficiency. In multivariate analysis, the association was still significant only for PTH (p = 0.03) and female sex (p = 0.03). Monocyte stimulation with LPS (100 ng/ml) or gp120 (1 µg/ml) significantly upregulated CYP27B1 mRNA expression. Moreover, gp120 significantly increased VDR mRNA levels. On the contrary, neither LPS nor gp120 modified CYP24A1 levels. Macrophage stimulation with LPS (100 ng/ml) significantly upregulated CYP27B1 and CYP24A1 mRNA expression. When monocytes were cultured in the presence of 25OHD (40 ng/ml) and stimulated with LPS we detected significantly lower levels of 25OHD in the supernatant. CONCLUSIONS: Vitamin D deficiency was very common in our cohort of HIV-infected patients. Chronic inflammation, including residual viral replication, may contribute to hypovitaminosis D, by modulating vitamin D metabolism and catabolism. Systematic screening may help identifying subjects requiring supplementation.

Acquired SERPINC1/antithrombin deficiency during oral contraceptive consumption: a case report.

BACKGROUND: SERPINC1 is a glycoprotein that regulates blood coagulation. SERPINC1 congenital or acquired deficiencies represent a significant risk factor for thromboembolic disease. SERPINC1 acquired defects are observed in very few cases and can occur in many clinical conditions such as treatment with L-asparaginase or oral contraceptive (particularly estrogen derivatives), but these conditions are not routinely investigated. CASE PRESENTATION: A 50-year-old Caucasian woman who took gestodene 75 µg/ethinylestradiol 20 µg as oral contraceptive, was sent to our thrombophilia clinic because, on thrombophilia testing, a reduction of SERPINC1 (74%) and a slight increase in circulating D-dimer and homocysteine were found. We investigated triggers of such SERPINC1 reduction, and identified gestodene 75 µg/ethinylestradiol 20 µg use as the most likely candidate. Two months after the discontinuation of the oral contraceptive, SERPINC1 value returned to normal (92%) and D-dimer and homocysteine were normalized. CONCLUSION: Each patient has a different sensitivity to contraceptive use. Genetic (or epigenetic) regulation of anticoagulant proteins might account for a different rate of consumption of anticoagulant proteins as oral contraceptives and probably determine the susceptibility to thrombotic events.

MacroH2A1.1 as a crossroad between epigenetics, inflammation and metabolism of mesenchymal stromal cells in myelodysplastic syndromes.

Ineffective hematopoiesis is a hallmark of myelodysplastic syndromes (MDS). Hematopoietic alterations in MDS patients strictly correlate with microenvironment dysfunctions, eventually affecting also the mesenchymal stromal cell (MSC) compartment. Stromal cells are indeed epigenetically reprogrammed to cooperate with leukemic cells and propagate the disease as "tumor unit"; therefore, changes in MSC epigenetic profile might contribute to the hematopoietic perturbations typical of MDS. Here, we unveil that the histone variant macroH2A1 (mH2A1) regulates the crosstalk between epigenetics and inflammation in MDS-MSCs, potentially affecting their hematopoietic support ability. We show that the mH2A1 splicing isoform mH2A1.1 accumulates in MDS-MSCs, correlating with the expression of the Toll-like receptor 4 (TLR4), an important pro-tumor activator of MSC phenotype associated to a pro-inflammatory behavior. MH2A1.1-TLR4 axis was further investigated in HS-5 stromal cells after ectopic mH2A1.1 overexpression (mH2A1.1-OE). Proteomic data confirmed the activation of a pro-inflammatory signature associated to TLR4 and nuclear factor kappa B (NFkB) activation. Moreover, mH2A1.1-OE proteomic profile identified several upregulated proteins associated to DNA and histones hypermethylation, including S-adenosylhomocysteine hydrolase, a strong inhibitor of DNA methyltransferase and of the methyl donor S-adenosyl-methionine (SAM). HPLC analysis confirmed higher SAM/SAH ratio along with a metabolic reprogramming. Interestingly, an increased LDHA nuclear localization was detected both in mH2A1.1-OE cells and MDS-MSCs, probably depending on MSC inflammatory phenotype. Finally, coculturing healthy mH2A1.1-OE MSCs with CD34+ cells, we found a significant reduction in the number of CD34+ cells, which was reflected in a decreased number of colony forming units (CFU-Cs). These results suggest a key role of mH2A1.1 in driving the crosstalk between epigenetic signaling, inflammation, and cell metabolism networks in MDS-MSCs.

Immuno-modulatory effects of vitamin D3 in human monocyte and macrophages.

Vitamin D3 [1α,25-(OH)(2)D(3)], involved in the regulation of body calcium homeostasis, promotes immature myeloid precursor cells differentiation into monocytes/macrophages. In this study we compared the regulatory interaction between 1α,25-(OH)(2)D(3) and tumor necrosis factor (TNF)-α or lipopolysaccharide (LPS) in the mRNA expression of interleukin (IL)-1ß, (IL)-6, TNF-α, toll like receptors (TLR)-2 and (TLR)-4 in freshly isolated human monocyte (MonoT0) and in macrophages cultured for seven days (MØT7). Additionally, we detected the effect of 1α,25-(OH)(2)D(3) on macrophages chemotaxis. The expression of IL-1ß, IL-6 and TNF-α, as well as TLR-2 and TLR-4 in MonoT0 and in MØT7 was examined by real time RT-PCR. Macrophages chemotaxis was analyzed by using horizontal chemotaxis agarose spot assay. We found that 1α,25-(OH)(2)D(3) influences macrophages chemotaxis and differently modulates the expression of IL-1ß, IL-6, TNF-α and TLRs in the two different stages of monocytes/macrophage maturation. In conclusion our data add new information about the role of 1α,25-(OH)(2)D(3) on the expression of inflammatory mediators in human monocyte/macrophages, underlying the complex function of these cells. Investigating the differences in the pattern of expression of immune-mediators produced by MonoT0 and MØT7 may provide a new way to examine their biochemical and molecular function and may constitute a model system with well-defined behavior with respect to early or tardive events in the innate immune response.

Non-AIDS-defining cancers among HIV-infected people.

The natural history of HIV infection has been greatly changed by the introduction of highly active antiretroviral therapy (HAART). As a consequence of improved immune function, the incidence of AIDS-defining cancers (ADCs), such as Kaposi's sarcoma, non-Hodgkin's lymphoma (NHL) and invasive cervical cancer, has significantly declined. On the contrary, non-AIDS-defining cancers (NADCs), such as hepatocellular carcinoma, anal cancer, lung cancer, colorectal cancer and Hodgkin's lymphoma, have gradually emerged as a major fraction of the overall cancer burden. The reasons are still partially unknown. Some of the increased risk may be explained by a high prevalence of cancer risk factors, such as smoking, alcohol consumption, human papilloma virus (HPV) infection and HCV infection among HIV-infected people. The role of immunosuppression in the development of NADCs is controversial, as several studies have not found a clear-cut evidence of an association between the degree of immunosuppression and the development of NADCs. Analogously, the impact of HAART is still not well defined. Future research should focus on the etiology of NADCs, in order to shed light on the pathogenesis of cancer and ultimately to work for prevention; moreover, additional studies should evaluate the best therapeutic approaches to NADCs and the impact of cancer screening interventions among HIV-infected people, in an effort to diagnose cancer at an earlier stage.

Hepatocellular carcinoma in HIV positive patients.

Highly active antiretroviral therapy (HAART) has dramatically changed the natural history of HIV-1-infected patients leading to increased survival and a better quality of life. Hepatitis C virus (HCV) and hepatitis B virus (HBV) infections are common among HIV-1-infected subjects and represent the most important risk factors for hepatocellular carcinoma (HCC). Whether HIV plays a direct role in hepatocellular carcinoma (HCC) pathogenesis remains to be established.HCC clinical course depends on stage of cancer disease, performance status and comorbidities. Therapeutic options include liver transplantation, local antiblastic chemotherapy and biological drugs. In the HIV setting few data are available about treatment options. The increased longevity of patients with HIV imposes new strategies for prevention and therapeutic management of patients. The aim of this article is to provide an up-to-date review of HIV-related HCC in the HAART era.

Non-AIDS defining cancers: a comprehensive update on diagnosis and management.

The increasing incidence of chronic pathologies and especially non-AIDS defining cancers, such as lung cancer, hepatocellular carcinoma, breast cancer, colorectal cancer, prostate cancer, and Hodgkin's lymphoma after the introduction of combined antiretroviral therapy requires the infectious diseases specialist to know how and when to suspect and diagnose cancer in people living with HIV. The aim of this review is to provide updated studies and information about non-AIDS defining cancers and their management in PLWH sheading a light on possible futures scenarios.

Biological properties of Cakile maritima Scop. (Brassicaceae) extracts.

OBJECTIVE: Cakile maritima scop. (CKM) is a herbaceous plant (Brassicaceae) growing also in high salinity environment. It is an annual plant growing in clumps or mounds in the sand on beaches and bluffs. MATERIALS AND METHODS: Stems, seeds, leaves and flowers of CKM were used to obtain 70% of ethanol extracts. The phenolic content of the different extracts was evaluated by the Folin-Ciocalteu method. The separation of phytochemical compounds was based on ultra-performance liquid chromatography coupled to mass spectrometry. Radical scavenging activity was determined by 1,1-diphenyl-2-picrylhydrazyl assay. The qualitative assay for the inhibition of α-glucosidase was quantified spectrophotometrically and the anti-inflammatory activity was determined in the U937 cell line by using gene expression of pro-inflammatory cytokines. Cell viability assay was done in U937, MM1S, and U266 cells by using the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. The antimicrobial activity was investigated by MIC determination, "double-triple combinations assay", and growth inhibition curves analysis, using the extracts individually or in various combination. Statistical analysis was performed by the Student's t-test and ANOVA. RESULTS: All parts of the plant exhibited a high antioxidant capacity as measured by DPPH assay. Furthermore, all extracts reduced (about 10 folds) the expression of inflammatory cytokines in macrophage following LPS treatment. As regards the antibacterial activity, only the seeds extract was able to inhibit both Gram-negative and Gram-positive bacteria when tested alone, whereas dual combinations of different extracts (leaves, flowers, stems and seeds) caused bacterial inhibition exhibiting a synergic action. Finally, we showed that the extracts did not exhibit cytotoxic effects in normal cells and that, surprisingly, it exhibited an anti-proliferative effect (inhibition ≈80%) in multiple myeloma U266 cells. CONCLUSIONS: Our study suggests that CKM possesses antioxidant, anti-inflammatory, antibacterial, anti-proliferative activities and such pleiotropic effects may be exploited under various pathological conditions.

OAS Gene Family Expression Is Associated with HIV-Related Neurocognitive Disorders.

HIV-associated neurocognitive disorders are common in HIV-infected individuals, even in the combination antiretroviral therapy (c-ART) era. Several mechanisms are involved in neuronal damage, including chronic inflammation immune activation. Mammalian 2'-5'-oligoadenylate synthetase (OAS) genes are produced in response to interferon (IFN), mainly by monocytes, and exert their antiviral functions by activation of RNase L that degrades viral and cellular RNAs. In this study, we aimed at exploring OAS gene family RNA expression in simian immunodeficiency virus encephalitis (SIVE), in HIV-associated neurocognitive disorders (HAND), and in HIV-associate dementia (HAD). We analyzed three microarray datasets obtained from the NCBI in order to assess the expression levels of OAS gene family network in brain biopsies of macaques with SIVE vs uninfected animals, as well as post-mortem brain of individuals with HAND (on or off ART) vs uninfected controls and three brain regions of HIV-infected individuals with both neurocognitive impairment (HAD) and encephalitis (HIVE). All OAS genes were upregulated both in SIVE and in HAND. OAS expression was significantly higher in high-viremic individuals; increased expression levels persisted in cART subjects when compared to healthy controls. OAS gene network analysis showed that several genes belonging to the type I IFN pathway, especially CXCL10 and IFIT3, were similarly upregulated in SIVE/HAND. Furthermore, we identified a significant upregulation of OAS gene family RNA expression in basal ganglia, white matter, and frontal cortex of HIV-1, HAD, and HAD/HIVE patients compared to healthy subjects. OAS gene family expression is increased in brain sections from individuals with HAND, HAD, and HIVE as well as macaques with SIVE. OAS family expression is likely to be induced by IFN as a consequence of viral replication in the CNS. Its long-term upregulation may contribute to the chronic inflammatory status and neurocognitive impairment we still observe in virologically suppressed individuals on c-ART.

Leptin increases serotonin turnover by inhibition of brain nitric oxide synthesis.

Leptin administration inhibits diencephalic nitric oxide synthase (NOS) activity and increases brain serotonin (5-HT) metabolism in mice. We evaluated food intake, body-weight gain, diencephalic NOS activity, and diencephalic content of tryptophan (TRP), 5-HT, hydroxyindoleacetic acid (5-HIAA), and 5-HIAA/5-HT ratio after intracerebroventricular (ICV) or intraperitoneal (IP) leptin injection in mice. Five consecutive days of ICV or IP leptin injections induced a significant reduction in neuronal NOS (nNOS) activity, and caused a dose-dependent increase of 5-HT, 5-HIAA, and the 5-HIAA/5-HT ratio. Diencephalic 5-HT metabolism showed a significant increase in 5-HT, 5-HIAA, and the 5-HIAA/5-HT ratio 3 hours after a single leptin injection. This effect was maintained for 3 hours and had disappeared by 12 hours after injection. After a single IP leptin injection, the peak for 5-HT, 5-HIAA, and the 5-HIAA/5-HT ratio was achieved at 6 hours. Single injections of ICV or IP leptin significantly increased diencephalic 5-HT content. Leptin-induced 5-HT increase was antagonized by the coadministration of L-arginine only when the latter was ICV injected, whereas D-arginine did not influence leptin effects on brain 5-HT content. Finally, in nNOS-knockout mice, the appetite-suppressant activity of leptin was strongly reduced, and the leptin-induced increase in brain 5-HT metabolism was completely abolished. Our results indicate that the L-arginine/NO pathway is involved in mediating leptin effects on feeding behavior, and demonstrate that nNOS activity is required for the effects of leptin on brain 5-HT turnover.

Altered plasma cytokine levels in Alzheimer's disease: correlation with the disease progression.

Increasing evidence supports a propensity towards inflammation in Alzheimer's disease (AD) pathogenesis. In our previous studies we observed high levels of IL-16, IL-18 and TGF-beta1 mRNA expression in monocyte-macrophages of the peripheral blood of AD patients. The aim of this investigation was to determine the plasma levels of IL-12, IL-16, IL-18 and TGF-beta1 in AD patients at different stages of the disease and to correlate the production of these cytokines with the disease progression. The levels of IL-12, IL-16, IL-18 and TGF-beta1 resulted higher in AD-mild patients, were slightly lower in AD-moderate patients, whereas no significant difference was observed between AD-severe patients and non-demented age-matched subjects. The correlation values between cytokine plasma levels were dependent on the disease progression. Our data indicate that plasma levels of these inflammatory molecules follow the degree of AD suggesting a gradual decline of immune responsiveness in AD.