Alter Disease Severity Research Articles

Investigation of SARS-CoV-2 IgG Binding Capability to Variants of the SARS-CoV-2 Virus.

The SARS-CoV-2 pandemic has confirmed that the ability to rapidly mutate may be extremely beneficial for a virus. Not long after the first wave, new variants emerged with altered infectivity, disease severity, and mortality. These new strains most notably had numerous mutations of the spike (S) protein, a surface protein responsible for binding to and entering the host cell. The Delta and Omicron strains demonstrated increased immune evasion and improved binding affinity to the host cell receptor, angiotensin-converting enzyme 2 (ACE2). This study examines the ability of wild-type SARS-CoV-2 IgG to bind Delta and Omicron antigens, as well as their functional binding capabilities to two different S-ACE2 complexes. Twenty SARS-CoV-2 positive samples from patients who had recovered from infection with ancestral SARS-CoV-2 in the first wave of COVID-19 and 10 pre-pandemic control samples were studied. SARS-CoV-2 exposed patients showed significantly higher levels of IgG to SARS-CoV-2 S1/RBD (p < 0.001), N protein (p < 0.001), and Omicron spike variant (p = 0.01), but not to Delta spike variant (p = 0.966) when compared with controls. Furthermore, patient samples showed significantly greater inhibition of SARS-CoV-2 S1/RBD and E484K spike to ACE2 binding (p < 0.001 and p = 0.015, respectively). Conversely, there was no correlation between the binding inhibition of S1/RBD and E484K spike to ACE2 receptor. This study shows there is considerable cross-reactivity of IgG generated by wild-type SARS-CoV-2 infection to the Delta and Omicron variants.

The Staphylococcus aureus CamS lipoprotein is a repressor of toxin production that shapes host-pathogen interaction.

Lipoproteins of the opportunistic pathogen Staphylococcus aureus play a crucial role in various cellular processes and host interactions. Consisting of a protein and a lipid moiety, they support nutrient acquisition and anchor the protein to the bacterial membrane. Recently, we identified several processed and secreted small linear peptides that derive from the secretion signal sequence of S. aureus lipoproteins. Here, we show, for the first time, that the protein moiety of the S. aureus lipoprotein CamS has a biological role that is distinct from its associated linear peptide staph-cAM373. The small peptide was shown to be involved in interspecies horizontal gene transfer, the primary mechanism for the dissemination of antibiotic resistance among bacteria. We provide evidence that the CamS protein moiety is a potent repressor of cytotoxins, such as α-toxin and leukocidins. The CamS-mediated suppression of toxin transcription was reflected by altered disease severity in in vivo infection models involving skin and soft tissue, as well as bloodstream infections. Collectively, we have uncovered the role of the protein moiety of the staphylococcal lipoprotein CamS as a previously uncharacterized repressor of S. aureus toxin production, which consequently regulates virulence and disease outcomes. Notably, the camS gene is conserved in S. aureus, and we also demonstrated the muted transcriptional response of cytotoxins in 2 different S. aureus lineages. Our findings provide the first evidence of distinct biological functions of the protein moiety and its associated linear peptide for a specific lipoprotein. Therefore, lipoproteins in S. aureus consist of 3 functional components: a lipid moiety, a protein moiety, and a small linear peptide, with putative different biological roles that might not only determine the outcome of host-pathogen interactions but also drive the acquisition of antibiotic resistance determinants.

Mechanistic Insights on Viral Factors Involved in Asymptomatic COVID-19 Pathogenesis

Abstract: SARS-CoV-2 infection may cause asymptomatic, pre-symptomatic or symptomatic COVID-19 disease. While symptomatic infections are at the centre stage for disease diagnosis and treatment, asymptomatic and pre-symptomatic cases heighten the challenge of transmission tracking ultimately leading to failure of control interventions. Asymptomatic cases appear due to a variety of host and viral factors and contribute substantially to the total number of infections. Through this article, we have tried to assemble existing information about the role of viral factors and mechanisms involved in the development of asymptomatic COVID-19. The significance of ‘PLpro’- a protease of Nidovirales order that removes ubiquitin and ISG15 from host proteins to regulate immune responses against the virus and hence disease presentation has been highlighted. PL-pro dampens inflammatory and antiviral responses, leading to asymptomatic infection. 11083G&gt;T-(L37F) mutation in ‘Nsp6’ of SARS-CoV-2 also diminishes the innate immune response leading to asymptomatic infections. It is, therefore, pertinent to understand the role of proteins like PLpro and Nsp6 in SARS-CoV-2 biology for the development of transmission control measures against COVID-19. This review focuses on viral molecular mechanisms that alter disease severity and highlights compounds that work against such regulatory SARS-CoV-2 proteins.

Downregulation of monocyte miRNAs: implications for immune dysfunction and disease severity in drug-resistant tuberculosis.

Monocyte miRNAs govern both protective and pathological responses during tuberculosis (TB) through their differential expression and emerged as potent targets for biomarker discovery and host-directed therapeutics. Thus, this study examined the miRNA profile of sorted monocytes across the TB disease spectrum [drug-resistant TB (DR-TB), drug-sensitive TB (DS-TB), and latent TB] and in healthy individuals (HC) to understand the underlying pathophysiology and their regulatory mechanism. We sorted total monocytes including three subsets (HLA-DR+CD14+, HLA-DR+CD14+CD16+, and HLA-DR+CD16+cells) from peripheral blood mononuclear cells (PBMCs) of healthy and TB-infected individuals through flow cytometry and subjected them to NanoString-based miRNA profiling. The outcome was the differential expression of 107 miRNAs particularly the downregulation of miRNAs in the active TB groups (both drug-resistant and drug-sensitive). The miRNA profile revealed differential expression signatures: i) decline of miR-548m in DR-TB alone, ii) decline of miR-486-3p in active TB but significant elevation only in LTB iii) elevation of miR-132-3p only in active TB (DR-TB and DS-TB) and iv) elevation of miR-150-5p in DR-TB alone. The directionality of functions mediated by monocyte miRNAs from Gene Set Enrichment Analysis (GSEA) facilitated two phenomenal findings: i) a bidirectional response between active disease (activation profile in DR-TB and DS-TB compared to LTB and HC) and latent infection (suppression profile in LTB vs HC) and ii) hyper immune activation in the DR-TB group compared to DS-TB. Thus, monocyte miRNA signatures provide pathological clues for altered monocyte function, drug resistance, and disease severity. Further studies on monocyte miRNAs may shed light on the immune regulatory mechanism for tuberculosis.

Clinical Outcomes of Zinc Supplementation Among COVID-19 Patients

Zinc supplementation is frequently prescribed during the treatment of COVID-19. However, the evidence supporting the efficacy of this intervention is mixed. Establish the clinical utility of zinc supplementation to alter disease severity in COVID- 19 illness. We performed a multicenter, retrospective, observational chart review of patients admitted to Ascension St. John Hospital or Detroit Medical Center from January 1st, 2020 to May 31st, 2020. All included patients received concomitant hydroxychloroquine due to its zinc ionophore activity. Our primary outcome was a change in Sequential Organ Failure Assessment (SOFA) score with secondary outcomes including all-cause mortality, need for intubation, and QTc prolongation as a safety outcome. We identified 489 patients who received zinc and 587 patients who did not. The primary outcome showed a small difference in the change in SOFA score in patients receiving zinc in univariate analysis (1.08 vs. 1.43, p=0.02), but this difference was not significant after adjustment for confounding factors such as receipt of corticosteroids and ICU admission. Mortality was not different between those that received zinc compared to those that did not (32.7% vs. 35.9%, p=0.268). Our retrospective study, including 1064 patients hospitalized in Detroit, demonstrated no differences in mortality or disease severity with zinc combination. Furthermore, prospective studies are needed to establish the utility of zinc in the treatment of COVID-19.

Severe acute respiratory syndrome coronavirus 2 and influenza A virus co-infection alters viral tropism and haematological composition in Syrian hamsters.

The ongoing coronavirus disease 2019 pandemic and its overlap with the influenza season lead to concerns over severe disease caused by the influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) co‐infections. Using a Syrian hamster co‐infection model with SARS‐CoV‐2 and the pandemic influenza virus A/California/04/2009 (H1N1), we found (a) more severe disease in co‐infected animals, compared to those infected with influenza virus alone but not SARS‐CoV‐2 infection alone; (b) altered haematological changes in only co‐infected animals and (c) altered influenza virus tropism in the respiratory tracts of co‐infected animals. Overall, our study revealed that co‐infection with SARS‐CoV‐2 and influenza virus is associated with altered disease severity and tissue tropism, as well as haematological changes, compared to infection with either virus alone.

Mutational Spectra of Sars-Cov-2 And Ace 2 Can Modify Infectivity, Immunogenicity and Disease Severity: A Review

COVID 19 is primarily characterized as severe respiratory syndrome, careful review revealed that it has multisystem involvement (Mao et al 2020). Due to its potentially damaging effects on respiratory system it is termed as SARS- COV 2 (severe acute respiratory syndrome corona virus 2). However, severity of the disease differentially changes from one to another geographical area and on the viral load of people affected. It has been shown from recent studies that the virus acquired several mutations on the spike protein which is the receptor binding domain of the virus particle. These mutations also alter the glycosylation pattern of the viral envelop. Mutation also differentially glycosylate the S1 and S1 domain of the spike protein and thereby modulate its infectivity through changes the potentiality of binding with ACE2 receptor. Changes in infectivity may also alter immunogenicity and manifestation spectra of the disease. ACE 2 receptor mutation site also perturb the glycosylation pattern and therefore alters the binding capacity with virus. All these mutations may potentially alter disease severity which is reported worldwide. Mutation of SARS-CoV 2 and ACE2 receptor in combination or in alone therefore modulate the entire picture of disease scenario which is the most interested part of COVID research. In this review we are going to unrevealing these areas of COVID -19 disease spectra.

SARS-CoV-2 variants and vaccination.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused global destruction since its emergence in late 2019. Over the past two years, the virus has continuously evolved in human host, leading to emergence of variants with changed viral transmission, disease severity, and evasion of immunity. Although vaccines have been developed for the coronavirus disease 2019 (COVID-19) at an unprecedently pace, the variants have constantly posed threats to the effectiveness of the approved vaccines. In this short communication, we review the key variants and discuss their implications in viral replication, transmission, and immune evasion.

HIV status alters disease severity and immune cell responses in Beta variant SARS-CoV-2 infection wave.

There are conflicting reports on the effects of HIV on COVID-19. Here, we analyzed disease severity and immune cell changes during and after SARS-CoV-2 infection in 236 participants from South Africa, of which 39% were people living with HIV (PLWH), during the first and second (Beta dominated) infection waves. The second wave had more PLWH requiring supplemental oxygen relative to HIV-negative participants. Higher disease severity was associated with low CD4 T cell counts and higher neutrophil to lymphocyte ratios (NLR). Yet, CD4 counts recovered and NLR stabilized after SARS-CoV-2 clearance in wave 2 infected PLWH, arguing for an interaction between SARS-CoV-2 and HIV infection leading to low CD4 and high NLR. The first infection wave, where severity in HIV negative and PLWH was similar, still showed some HIV modulation of SARS-CoV-2 immune responses. Therefore, HIV infection can synergize with the SARS-CoV-2 variant to change COVID-19 outcomes.

Latent tuberculosis co-infection is associated with heightened levels of humoral, cytokine and acute phase responses in seropositive SARS-CoV-2 infection

ObjectivesLatent Tuberculosis infection (LTBI) is postulated to modulate immune responses and alter disease severity in SARS-CoV-2 co-infection. However, no data exist on the effect of LTBI on the immune responses in SARS-CoV-2 co-infected individuals.MethodsWe examined the SARS-CoV-2 specific antibody responses, plasma cytokines, chemokines, acute phase proteins and growth factor levels in LTBI positive and negative individuals with SARS-CoV-2 infection.ResultsOur results demonstrated that individuals with LTBI (LTBI+) and seropositive for SARS-CoV-2 infection were associated with elevated SARS-CoV-2 specific IgM, IgG and IgA antibodies, as well as enhanced neutralization activity compared to those negative for LTBI (LTBI-) individuals. Our results also demonstrate that LTBI+ individuals exhibited significantly higher plasma levels of IFNγ, IL-2, TNFα, IL-1α, IL-1β, IL-6, IL-12, IL-15, IL-17, IL-3, GM-CSF, IL-10, IL-25, IL-33, CCL3 and CXCL10 compared to LTBI- individuals. Finally, our results show that LTBI+ individuals exhibit significantly higher levels of C-reactive protein, alpha-2 macroglobulin, VEGF and TGFα compared to LTBI- individuals.ConclusionsThus, our data clearly demonstrates that LTBI+ individuals seropositive for SARS-CoV-2 infection exhibit heightened levels of humoral, cytokine and acute phase responses compared to LTBI- individuals. Thus, LTBI is associated with modulation of antibody and cytokine responses as well as systemic inflammation in individuals seropositive for SARS-CoV-2 infection.

Rhinovirus Reduces the Severity of Subsequent Respiratory Viral Infections by Interferon-Dependent and -Independent Mechanisms.

ABSTRACTCoinfection by heterologous viruses in the respiratory tract is common and can alter disease severity compared to infection by individual virus strains. We previously found that inoculation of mice with rhinovirus (RV) 2 days before inoculation with a lethal dose of influenza A virus [A/Puerto Rico/8/34 (H1N1) (PR8)] provides complete protection against mortality. Here, we extended that finding to a second lethal respiratory virus, pneumonia virus of mice (PVM), and analyzed potential mechanisms of RV-induced protection. RV completely prevented mortality and weight loss associated with PVM infection. Major changes in host gene expression upon PVM infection were delayed compared to PR8. RV induced earlier recruitment of inflammatory cells, which were reduced at later times in RV-inoculated mice. Findings common to both virus pairs included the upregulated expression of mucin-associated genes and dampening of inflammation-related genes in mice that were inoculated with RV before lethal virus infection. However, type I interferon (IFN) signaling was required for RV-mediated protection against PR8 but not PVM. IFN signaling had minor effects on PR8 replication and contributed to controlling neutrophilic inflammation and hemorrhagic lung pathology in RV/PR8-infected mice. These findings, combined with differences in virus replication levels and disease severity, suggest that the suppression of inflammation in RV/PVM-infected mice may be due to early, IFN-independent suppression of viral replication, while that in RV/PR8-infected mice may be due to IFN-dependent modulation of immune responses. Thus, a mild upper respiratory viral infection can reduce the severity of a subsequent severe viral infection in the lungs through virus-dependent mechanisms.IMPORTANCE Respiratory viruses from diverse families cocirculate in human populations and are frequently detected within the same host. Although clinical studies suggest that infection by multiple different respiratory viruses may alter disease severity, animal models in which we can control the doses, timing, and strains of coinfecting viruses are critical to understanding how coinfection affects disease severity. Here, we compared gene expression and immune cell recruitment between two pairs of viruses (RV/PR8 and RV/PVM) inoculated sequentially in mice, both of which result in reduced severity compared to lethal infection by PR8 or PVM alone. Reduced disease severity was associated with suppression of inflammatory responses in the lungs. However, differences in disease kinetics and host and viral gene expression suggest that protection by coinfection with RV may be due to distinct molecular mechanisms. Indeed, we found that antiviral cytokine signaling was required for RV-mediated protection against lethal infection by PR8 but not PVM.

Nutritional status impacts dengue virus infection in mice

BackgroundDengue virus (DENV) is estimated to infect 390 million people annually. However, few host factors that alter disease severity are known. Malnutrition, defined as both over- and undernutrition, is a growing problem worldwide and has long been linked to dengue disease severity by epidemiological and anecdotal observations. Accordingly, we sought to establish a mouse model to assess the impact of nutritional status on DENV disease severity.ResultsUsing transiently immunocompromised mice, we established a model of mild dengue disease with measurable viremia. We then applied it to study the effects of healthy weight, obese, and low-protein diets representing normal, over-, and undernutrition, respectively. Upon infection with DENV serotype 2, obese mice experienced more severe morbidity in the form of weight loss and thrombocytopenia compared to healthy weight groups. Additionally, obesity altered cytokine expression following DENV infection. Although low protein-fed mice did not lose significant weight after DENV2 infection, they also experienced a reduction in platelets as well as increased spleen pathology and viral titers.ConclusionsOur results indicate that obese or undernourished mice incur greater disease severity after DENV infection. These studies establish a role for nutritional status in DENV disease severity.

Cannabis and the Gastrointestinal Tract.

The objective of the present paper is to elucidate the role of Cannabis consumption in GI system. An additional aim is to review the information on the function of Cannabis in non-alcoholic fatty liver disease (NAFLD). This review summarizes the recent findings on the role of cannabinoid receptors, their synthetic or natural ligands, as well as their metabolizing enzymes in normal GI function and its disorders, including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD) and possible adverse events. The synergism or antagonism between Cannabis' active ingredients and the "entourage" plays a role in the efficacy of various strains. Some elements of Cannabis may alter disease severity as over-activation of Cannabis receptors CB1 and CB2 can lead to changes of the commensal gut flora. The endocannabinoid system (ECS) contributes to gut homeostasis. The ability of ECS to modulate inflammatory responses demonstrates the capacity of ECS to preserve gastrointestinal (GI) function. Alterations of the ECS may predispose patients to pathologic disorders, including IBD. Clinical studies in IBD demonstrate that subjects benefit from Cannabis consumption as seen through a reduction of the IBD-inflammation, as well as through a decreased need for other medication. NAFLD is characterized by fat accumulation in the liver. The occurrence of inflammation in NAFLD leads to non-alcoholic-steatohepatitis (NASH). The use of Cannabis might reduce liver inflammation. With limited evidence of efficacy and safety of Cannabis in IBD, IBS, and NAFLD, randomized controlled studies are required to examine its therapeutic efficacy. Moreover, since long term use of the plant leads to drug use disorders the patients should be followed continuously.

Pertussis toxin treatment promotes a B cell driven disease during TH17 EAE

Abstract Pertussis toxin (PTX) is an enigmatic co-adjuvant that is required for disease induction in active Experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. The objective of this study was to investigate the functional role of PTX during adoptive transfer TH17-EAE. TH17-EAE was induced by transferring myelin-specific TH17 cells, harvested and cultured from MOG35–55 immunized wild type (WT) donor mice, into WT or B cell deficient (μMT) recipient mice. Recipient mice were treated with PTX or PBS on days 0 and 2 and monitored for paralysis. In WT mice, PTX delayed disease onset but did not alter disease severity or incidence. We found that PTX reduced trafficking of myeloid cells and inflammatory T helper cells in the CNS. Importantly, PTX treatment increased the number of B cells in the brain with increased antigen presenting function, suggesting an altered disease toward a B cell-dependent pathology. When disease progression was compared between WT and μMT mice treated with PTX or PBS, there was no significant difference in TH17-EAE in the PBS treated groups. However, PTX treatment significantly delayed disease onset, severity and incidence in the μMT mice vs. WT. In conclusion, our current data suggests that during TH17-EAE, PTX restricts the trafficking of pathogenic T helper cells and myeloid cells into the CNS and thereby delays the disease onset. However, not only PTX does not alter trafficking of B cells into the CNS it also stimulates a more inflammatory B cell phenotype and therefore promotes a B cell driven disease. This study provides novel insights to interactions between TH17 and B cells in mice and has defined a new model to study B cell activity during multiple sclerosis.

Characterizing the gut microbiota in patients with chronic kidney disease

ABSTRACT Objectives: Emerging evidence suggests that gut microbiota dysbiosis plays a critical role in chronic kidney disease (CKD). However, the relationship between altered gut microbiome profiles and disease severity remains unclear. In this study, we sought to characterize the gut microbiota in CKD patients compared to healthy controls, and to explore potential relationships between gut microbiota composition and disease severity. Methods: Fecal samples were collected from 95 patients at different stages of CKD (non-dialysis patients from stage 1 to 5) and 20 healthy controls. Bacterial DNA was extracted for 16S ribosomal DNA sequencing targeting the V3-V4 region. The diversity and relative abundance of gut microbiota were analyzed as outcome indicators. Results: Differences were observed in the microbial composition and diversity of fecal samples from CKD patients and healthy controls. Specifically, disease severity was found to alter gut microbiota composition. Compared to that in healthy controls, CKD patients showed an increased abundance of Proteobacteria and decreased Synergistetes, most notably in disease stage 5. Lower levels of butyrate-producing bacteria and higher levels of potential pathogens were also detected in CKD patients. Further, Pyramidobacter and Prevotellaceae_UCG-001 were significantly decreased in the CKD1 group compared with healthy controls. Notably, nine microbial genera, including Escherichia-Shigella, Parabacteroides, Roseburia, rectale_group, Ruminococcaceae_NK4A214_group, Prevotellaceae_UCG.001, Hungatella, Intestinimonas, and Pyramidobacter, identified using a random forest model, distinguished between patients with CKD and healthy controls with high accuracy. Functional analysis also revealed that fatty acid and inositol phosphate metabolism were enriched in the CKD group, while aminoacyl-tRNA biosynthesis, oxidative phosphorylation, phenylalanine, tyrosine, and tryptophan biosynthesis, thiamine metabolism, pantothenate, and CoA biosynthesis, as well as valine, leucine, and isoleucine biosynthesis were enriched in healthy controls. Conclusion: Gut microbiota composition and function are associated with CKD severity. And, specific gut microbes are potentially helpful for CKD early diagnosis and prognosis monitoring.

Hypertension, Antihypertensive Use and the Delayed-Onset of Huntington's Disease.

BackgroundHypertension is a modifiable cardiovascular risk factor implicated in neurodegeneration and dementia risk. In Huntington's disease, a monogenic neurodegenerative disease, autonomic and vascular abnormalities have been reported. This study's objective was to examine the relationship between hypertension and disease severity and progression in Huntington's disease.MethodsUsing longitudinal data from the largest worldwide observational study of Huntington's disease (n = 14,534), we assessed the relationship between hypertension, disease severity, and rate of clinical progression in Huntington's disease mutation carriers. Propensity score matching was used to statistically match normotensive and hypertensive participants for age, sex, body mass index, ethnicity, and CAG length.ResultsHuntington's disease patients had a lower prevalence of hypertension compared with age‐matched gene‐negative controls. Huntington's disease patients with hypertension had worse cognitive function, a higher depression score, and more marked motor progression over time compared with Huntington's disease patients without hypertension. However, hypertensive patients taking antihypertensive medication had less motor, cognitive, and functional impairment than Huntington's disease patients with untreated hypertension and a later age of clinical onset compared with untreated hypertensive patients and normotensive individuals with Huntington's disease.ConclusionsWe report the novel finding that hypertension and antihypertensive medication use are associated with altered disease severity, progression, and clinical onset in patients with Huntington's disease. These findings have implications for the management of hypertension in Huntington's disease and suggest that prospective studies of the symptomatic or disease‐modifying potential of antihypertensives in neurodegenerative diseases are warranted. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Innate and adaptive immune interactions in Coccidioides infection

Abstract Protective immunity against the fungal pathogen Coccidioides requires specific T helper cellular responses. Mouse infection and vaccine studies have defined CD4 T helper (Th)1 and Th17 cells in the resolution of infection and in effective protection, while patients with chronic Coccidioides infection demonstrate reduced cellular responses. Several gaps in knowledge preclude our ability to develop new diagnostics and therapeutics for treating this infection. Little is known about the microenvironment in human lung tissue during infection, and the types of immune cells that promote effective control of the fungus within this specialized location. How variations on local immune populations alter disease severity and ability of the fungus to disseminate have not been explored. We recently identified several peripheral blood biomarkers during acute infection that distinguish pediatric patients that resolve infection from those that develop chronic disease. Patients with chronic disease had reduced Th17 and elevated Treg frequencies compared to patients that resolved disease. The inability to clear Coccidioides infection may be a result of elevated Treg frequency and functional capacity, or of skewed effector differentiation. We use mouse Coccidioides infection and in vitro culture assays to uncover the host immune players that promote effective immunity, and to identify fungal morphology changes and fungal burden differences at the innate and adaptive immune interface.

The investigation of the relationships of demodex density with inflammatory response and oxidative stress in rosacea

The relationships of demodex density with systemic oxidative stress, inflammatory response, and clinical severity in rosacea are not clear. This study aimed to (a) analyze the levels of systemic oxidative stress, antioxidant capacity, inflammatory parameters, and matrix metalloproteinases (MMPs) in systemic circulation in patients with rosacea, (b) identify the relationship between mite density and both oxidative stress and inflammation, and (c) investigate the role of photoaging and sebum secretion in etiopathogenesis. Forty patients with rosacea and 40 age-, sex-, and skin phenotype-matched healthy volunteers were included in the study. Clinical disease severity of the patients was determined. Sebum levels were measured in both the groups, and photoaging was evaluated. Reflectance confocal microscopy was used to calculate demodex density. Serum total antioxidant capacity (TAC), total oxidant capacity (TOC), myeloperoxidase (MPO), MMP-1, MMP-9, arylesterase (ARES), interleukin-1β (IL-1β), paraoxonase-1 (PON-1), and tumor necrosis factor-α (TNF-α) levels were also analyzed. The patients with rosacea had significantly higher serum TOC and lower TAC levels (p < 0.001). The serum ARES and PON-1 levels were significantly lower (p = 0.045 and p < 0.001, respectively); however, the serum levels of MMP-1, MMP-9, IL-1β and MPO were higher in the patient group. Demodex parameters were higher in the patient group compared to the control group. There was no significant correlation between the number of mites and disease severity. In addition, the number of mites was not correlated with the serum levels of TAC, TOC, OSI, MPO, MMP-1, MMP-9, ARES, PON-1, TNF-α, and IL-1β. However, sebum levels were directly proportional to the number of mites. Photoaging severity was similar between the patients and control subjects. The changing sebaceous microenvironment in rosacea leads to an increase in the number of demodex mites. However, increased demodex density does not alter disease severity, level of oxidative stress, or inflammation. Although none of the patients with rosacea had any underlying systemic disease, patients' systemic oxidative stress and inflammation parameters were found high in systemic circulation. It is assumed that the patients with rosacea are more prone to systemic diseases.

Oxidative Stress in Spinocerebellar Ataxia Type 7 Is Associated with Disease Severity.

Spinocerebellar ataxia type 7 is a neurodegenerative inherited disease caused by a CAG expansion in the coding region of the ATXN7 gene, which results in the synthesis of polyglutamine-containing ataxin-7. Expression of mutant ataxin-7 disturbs different cell processes, including transcriptional regulation, protein conformation and clearance, autophagy, and glutamate transport; however, mechanisms underlying neurodegeneration in SCA7 are still unknown. Implication of oxidative stress in the pathogenesis of various neurodegenerative diseases, including polyglutamine disorders, has recently emerged. We perform a cross-sectional study to determine for the first time pheripheral levels of different oxidative stress markers in 29 SCA7 patients and 28 age- and sex-matched healthy subjects. Patients with SCA7 exhibit oxidative damage to lipids (high levels of lipid hydroperoxides and malondialdehyde) and proteins (elevated levels of advanced oxidation protein products and protein carbonyls). Furthermore, SCA7 patients showed enhanced activity of various anti-oxidant enzymes (glutathione reductase, glutathione peroxidase, and paraoxonase) as well as increased total anti-oxidant capacity, which suggest that activation of the antioxidant defense system might occur to counteract oxidant damage. Strikingly, we found positive correlation between some altered oxidative stress markers and disease severity, as determined by different clinical scales, with early-onset patients showing a more severe disturbance of the redox system than adult-onset patients. In summay, our results suggest that oxidative stress might contribute to SCA7 pathogenesis. Furthermore, oxidative stress biomarkers that were found relevant to SCA7 in this study could be useful to follow disease progression and monitor therapeutic intervention.

Abstract P290: Unilateral Cervical Vagotomy Protects Against Renal Injury and Hypertension in a Mouse Model of Lupus Hypertension

Chronic renal inflammation has been implicated in hypertension. The vagus nerve controls inflammation by immunoregulatory mechanisms like the hypothalamic-pituitary-adrenal axis and the cholinergic anti-inflammatory pathway. It is not clear whether changes in vagal activity affect inflammation downstream in the kidney. We hypothesized that decreasing vagal neurotransmission would impede these anti-inflammatory mechanisms, exacerbate renal inflammation and promote hypertension. To study this, we used a mouse model of systemic lupus erythematosus (SLE) that develops hypertension after the onset of autoimmunity. Female SLE ( NZBWF1) and control (NZW) mice received right unilateral cervical vagotomy (Vx) or sham surgery (n=4-6/group) and 3 weeks later had catheters implanted to measure blood pressure. Sham-operated SLE mice had elevated plasma double-stranded DNA autoantibodies (3.8 x 10 5 ± 1.3 x 10 4 vs. 1.1 x 10 5 ± 5.0 x 10 4 activity units; all p&lt;0.05 unless otherwise noted), a hallmark of the disease; enlarged spleens (239.1 ± 80.4 vs. 124.1 ± 11.4 mg); and an elevated splenic CD3+CD4+ T cell population (flow cytometry; 21.9 ± 2.1 vs. 14.6 ± 2.8%) relative to controls. Vagotomy did not alter disease severity (3.2 x 10 5 ± 3.5 x 10 4 ; p = 0.20), but prevented splenomegaly (119.7 ± 24.2 mg) and reduced CD3+CD4+ T cells (14.7 ± 0.7) in SLE mice. SLE mice trended toward higher renal cortical TNF-α than controls (3.5 x 10 6 ± 1.7 x 10 6 vs. 7.6 x 10 4 ; normalized to total protein; p = 0.22), although SLE/Vx mice had lower concentrations than SLE/sham mice (4.9 x 10 5 ± 1.3 x 10 5 vs. 3.5 x 10 6 ± 1.7 x 10 6 ). SLE mice had higher albumin excretion rates (AER) than controls (1.2 x 10 4 ± 3.6 x 10 3 vs. 2.0 x 10 1 ± 4.8 μg/day) and Vx decreased AER in SLE mice (1.2 x 10 4 ± 3.6 x 10 3 ). SLE mice were hypertensive compared to controls (158 ± 10 mmHg vs. 108 ± 4 mmHg) and vagotomy protected SLE mice from hypertension (133 ± 4). In sum, these data counter our initial hypothesis—unilateral vagotomy reduced renal inflammation and halted the progression of SLE hypertension. The vagus nerves have myriad functions and perhaps other neuroimmune interactions compensate for the ligation of one nerve. Future studies will investigate whether our findings may be due to long-term adaptation following unilateral vagotomy.