Cytomegalovirus infection is a risk factor for venous thromboembolism in ANCA-associated vasculitis.

BACKGROUND: Venous thromboembolism (VTE) is a common complication in patients with anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) and confers significant morbidity and mortality. Both acute and past cytomegalovirus (CMV) infection have been identified as risk factors for VTE in immunocompetent and immunosuppressed individuals. Here, we examine whether past exposure to CMV is a risk factor for VTE amongst patients with AAV. METHODS: We retrospectively analysed outcomes of patients with a new diagnosis of AAV from a UK cohort. All confirmed cases of VTE where CMV IgG serology was available were recorded. Retrospective collection of the same data for patients at a North American centre was used as a validation cohort. RESULTS: VTE was common with 12% of patients from the study cohort (total 259 patients) developing an event during the median follow-up period of 8.5 years of which 60% occurred within the first 12 months following diagnosis. Sixteen percent of CMV seropositive patients developed a VTE compared with 5% of patients who were seronegative (p = 0.007) and CMV seropositivity remained an independent predictor of VTE in multivariable analysis (HR 2.96 [1.094-8.011] p = 0.033). CMV seropositivity at diagnosis was confirmed as a significant risk factor for VTE in the American validation cohort (p = 0.032). CONCLUSIONS: VTE is common in patients with AAV, especially within the first year of diagnosis. Past infection with CMV is an independent risk factor associated with VTE in AAV.

Persistence of procoagulable thromboelastography results in hospitalized COVID-19 patients despite clinical improvement.

OBJECTIVE: COVID-19 patients have been shown to be hypercoagulable, increasing the risk for thromboembolic events. The kinetics of the blood coagulation process were monitored daily throughout hospitalization in COVID-19 positive patients. PATIENTS AND METHODS: Thromboelastography (TEG) was used to assess blood coagulation in 48 adult patients hospitalized for COVID-19 in this prospective cohort study. Clinical risk was assessed via National Early Warning Scores (NEWS) for each day of hospitalization. RESULTS: During hospitalization, 98% of patients had one or more procoagulable TEG result. Thromboelastography results remained prothrombotic upon discharge in 80% of patients. NEWS significantly decreased by discharge compared to the peak scores. CONCLUSIONS: Overall, patients were discharged from the hospital with significant clinical improvement, but without abnormal TEG results returning to a normal range. All patients in our study survived and few had thromboembolic events, so if and for how long these patients remain at risk for future complications warrants further investigation.

Antibody responses after first and second Covid-19 vaccination in patients with chronic lymphocytic leukaemia.

B-cell chronic lymphocytic leukaemia (CLL) is associated with immunosuppression and patients are at increased clinical risk following SARS-CoV-2 infection. Covid-19 vaccines offer the potential for protection against severe infection but relatively little is known regarding the profile of the antibody response following first or second vaccination. We studied spike-specific antibody responses following first and/or second Covid-19 vaccination in 299 patients with CLL compared with healthy donors. 286 patients underwent extended interval (10-12 week) vaccination. 154 patients received the BNT162b2 mRNA vaccine and 145 patients received ChAdOx1. Blood samples were taken either by venepuncture or as dried blood spots on filter paper. Spike-specific antibody responses were detectable in 34% of patients with CLL after one vaccine (n = 267) compared to 94% in healthy donors with antibody titres 104-fold lower in the patient group. Antibody responses increased to 75% after second vaccine (n = 55), compared to 100% in healthy donors, although titres remained lower. Multivariate analysis showed that current treatment with BTK inhibitors or IgA deficiency were independently associated with failure to generate an antibody response after the second vaccine. This work supports the need for optimisation of vaccination strategy in patients with CLL including the potential utility of booster vaccines.

Cytomegalovirus seropositivity is independently associated with cardiovascular disease in non-dialysis dependent chronic kidney disease.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of early death in patients with chronic kidney disease (CKD). Previous work has described an association between Cytomegalovirus (CMV) seropositivity and CVD amongst patients with dialysis dependent end stage renal disease. Whether CMV seropositivity is associated with CVD in non-dialysis dependent CKD has not been established. AIM: Investigate whether past CMV infection is associated with prevalent CVD in patients with non-dialysis dependent CKD. DESIGN: A retrospective observational study using the Renal Impairment in Secondary Care cohort, a study evaluating bio-clinical determinants of outcomes in patients with progressive CKD. METHODS: We assayed cryopreserved serum samples collected at inception for anti-CMV IgG antibodies from 764 patients with stages 2 to 5 CKD (pre-dialysis) and investigated its relationship with prevalent CVD. RESULTS: Median estimated glomerular filtration was 24 ml/min/1.73 m2 (IQR 19-32). Sixty-eight percent of patients were CMV seropositive. CMV seropositivity was associated with older age, non-Caucasian ethnicity, diabetes and higher social deprivation index score. On univariable analysis, CMV seropositivity correlated with higher systolic blood pressure (P = 0.044), prevalent CVD (P < 0.001), ischaemic heart disease (P < 0.001) and cerebrovascular disease (P = 0.022). On multivariable analysis, CMV seropositive patients nearly twice as likely to have CVD compared to seronegative patients [Odds Ratio (OR) = 1.998, CI 1.231-3.242, P = 0.005]. CONCLUSIONS: In patients with non-dialysis CKD, CMV seropositivity is independently associated with a higher prevalence of CVD.

The application of a haemorrhage assessment tool in evaluating control of bleeding in a pilot trauma haemorrhage trial.

OBJECTIVES: To determine whether it was feasible to use a haemorrhage assessment tool (HAT) within a trauma trial and whether the data obtained could differentiate patients who had achieved haemostasis. BACKGROUND: Major haemorrhage is one of the leading causes of death worldwide, affecting 40% of trauma patients. Clinical trials evaluating haemostatic interventions often use transfusion outcomes as a primary endpoint. Transfusion is highly dependent on local practice, limiting its reliability as a robust, transferable endpoint. METHODS: A five-point HAT questionnaire was applied to participants enrolled into the EFIT-1 trial. This RCT evaluated the feasibility of administering a 6 g fibrinogen concentrate to patients with severe trauma haemorrhage. RESULTS: Of participants, 98% completed a HAT; 75% participants had 'achieved haemostasis' at the time of tool completion, as determined by clinical acumen alone. HAT scores were able to differentiate which participants required transfusion after 3 h. Of participants, 56% were transfused red blood cells when they scored 0-2, compared to 17% with HAT scores between 3 and 5. CONCLUSION: This study has confirmed the feasibility of using a HAT during the emergency care of patients suffering trauma haemorrhage, and future studies should be conducted to determine its value as an endpoint in haemostasis studies.

Escherichia coli bloodstream infection outcomes and preventability: a six-month prospective observational study.

BACKGROUND: Escherichia coli bloodstream infection (BSI) is a common and serious problem, and incidence and antibiotic resistance are increasing. AIM: To understand the drivers of outcomes and factors associated with preventable cases at the study institution. METHODS: Between 1st November 2017 and 30th April 2018, cases of E. coli BSI in adults treated as inpatients at the study institution were included in a prospective cohort. Clinical, demographic and laboratory features were recorded, with seven-, 30- and 90-day mortality and length of hospital stay post BSI. Qualitative data on preventability were reviewed independently by two infection specialists. FINDINGS: In total, 195 cases in 188 patients were included in the analysis. Empirical antibiotics showed in-vitro resistance in 30.9% of cases. Thirty-day mortality was 23.6%, with a median length of hospital stay of seven days. On multi-variable analysis, 30-day mortality was associated with higher Charlson score, residential home residency, higher respiratory rate and higher serum urea, whilst prolonged length of stay was associated with hospital-acquired E. coli BSI. Fifty patients were felt to have avoidable BSI, all of which were health care associated; urinary catheter use, antibiotic-related and procedural complications were the areas of preventability. CONCLUSIONS: E. coli BSI has an appreciable mortality, with little in the way of modifiable risk factors for mortality or prolonged hospital stay. Attention to urinary catheter use is likely to be the most useful way to reduce the incidence, but current UK reduction targets may be unachievable.

Ninety day mortality following pancreatoduodenectomy in England: has the optimum centre volume been identified?

BACKGROUND: Mortality following pancreatoduodenectomy is related to centre volume although the optimal volume is not defined. METHODS: Patients undergoing PD between 2001 and 2016 were identified from UK national databases. The effects of patient variables, centre volume and time period upon 90 day mortality were studied. RESULTS: 90 day mortality (970/14,935, 6.5%) was related to advanced age, comorbidity, diagnosis, ethnicity, deprivation, centre volume and time period. Mortality rates fell markedly from 10.0% in 2001-4 to 4.1% in 2013-16. There was no difference in 90 day mortality between high (36 -60 PD per year) and very high volume (>60) centres. However, patients operated upon at very high volume centres were more elderly (66, 58 -73 vs 65, 56 -72; median, IQR; p = 0.006), deprived (38.7 vs 34.6%; p < 0.001) and co morbid (48.9 vs 46.1%; p = 0.027). CONCLUSION: Although a plateau in the centre volume and mortality relationship appears to have been demonstrated those patients treated at the highest volume centres were at higher risk of mortality. This data suggests therefore that to further understand outcomes from specialist centres characteristics of the patient population should be defined, not just centre volume.

Maternal effector T cells within decidua: The adaptive immune response to pregnancy?

In human pregnancy the maternal immune system plays a critical role in the regulation of many aspects of human reproduction including implantation, placentation and defence against infection. Interest has been focussed on the role of uterine natural killer cells (uNK) in the maternal decidua whereas effector CD4+ and CD8+ T cells have received much less attention despite the observation that they represent a major proportion of decidual leucocytes in the latter phase of pregnancy. A range of recent studies have demonstrated that human decidual T cells are highly differentiated, express a range of cytokines and cytotoxic markers, and demonstrate a unique transcriptional profile characterized by high level expression of genes involved in interferon-signalling. Moreover, subpopulations of effector T cells demonstrate specificity for fetal tissue and are regulated through expression of inhibitory checkpoint proteins and T regulatory cells. Nevertheless, many questions remain to be answered, such as the potential role of maternal effector T cells in either supporting successful pregnancy or potentially clearing fetal cells that have entered the maternal circulation. In addition, there is an increasing interest in the role of maternal effector T cells in the pathogenesis of disorders such as chronic villitis miscarriage, stillbirth, fetal growth restriction and pre-eclampsia. Current debates in relation to these questions will be discussed within this review.

Fourteen days of etoricoxib 60 mg improves pain, hyperalgesia and physical function in individuals with knee osteoarthritis: a randomized controlled trial.

OBJECTIVE: Mounting evidence points to the heterogeneity of osteoarthritis (OA) pain, increasing the need for more comprehensive assessment of the efficacy of standard interventions. This study investigated whether 14 days of the selective Cox-2 inhibitor etoricoxib (60 mg/day) would modify self-report of pain intensity and quality, and physical measures of hyperalgesia and function in individuals with knee OA. DESIGN: This double-blind placebo-controlled trial included 80 community-recruited volunteers with painful knee OA (≥3/10 VAS), randomly allocated to Active or Placebo groups. Self-report measures of pain, stiffness, function Western Ontario and McMaster University Osteoarthritis Index (WOMAC) and pain quality (PainDETECT, Pain Quality Assessment Scale [PQAS]) and physical measures of locomotion and local (knee) and widespread (elbow) hyperalgesia were assessed at Days 0, 4 and 14. Repeated Measures ANOVA analysed group differences. RESULTS: Significant group × time interaction effects were found for all measures of pain (all p < 0.001), with WOMAC pain sub-score improving by 30.7% by Day 14 and index knee mechanical hyperalgesia improving by 32.6%, whilst Placebo group values worsened. Both self-report and physical tests of function improved (p < 0.001-p = 0.006): WOMAC-function by 28.4%, sit-to-stand and walk time by 13%, pain during locomotion tasks by 12.4-32.6%. Pain quality also significantly improved for the Active and declined for the Placebo group (p < 0.001): PainDETECT score reduced by 23.6% and PQAS paroxsysmal and surface sub-scores by 36.9% and 29.4%. There were also significant improvements in local cold hyperalgesia and widespread mechanical hyperalgesia (10-13.8%). CONCLUSION: Just 14 days of etoricoxib significantly improves pain intensity and quality, function and local and widespread hyperalgesia, measured by both self-report and physical tests.

Validação do Nanolipe ® como método para determinar a digestibilidade aparente dos nutrientes pelos equinos / Validation of Nanolipe ® as method to assess the apparent digestibility of nutrients on horses

O NANOLIPE® é o indicador de digestibilidade LIPE® com incorporação de nano partículas que se misturam de forma mais homogênea e rápida na digesta, permitindo redução do período de adaptação e maiores taxas de recuperação daquele quando comparado com outros indicadores usados em equinos. Objetivou-se neste trabalho comparar a digestibilidade dos nutrientes de dieta em equinos obtida pelo método padrão (coleta total de fezes - CTF), estimada por dois indicadores internos (fibra em detergente ácido indigestível - FDAi; lignina Klason - LK) e por indicador externo NANOLIPE®, visando à validação deste último para uso na nutrição equina. Em delineamento de blocos ao acaso, oito éguas Mangalarga Marchador adultas (média de 380kg PV) foram usadas para avaliação dos tratamentos (CTF, FDAi, LK, NANOLIPE®). A dieta foi composta por 1,5% PV de feno de coast cross, 1,0% PV de concentrado comercial com 13% PB, dividido em dois tratos diários fornecidos às oito e às 17h, além de água e sal mineral à vontade. O experimento teve duração de 13 dias, sendo os oito iniciais para adaptação à dieta e ao manejo e os cinco finais para coleta de fezes. O NANOLIPE® foi fornecido no terceiro e quarto dias da coleta de fezes, sendo administrado uma vez por dia, por meio de cápsulas de 0,25g/animal/dia via oral. Houve diferença (P<0,05) entre os valores de produção fecal estimados pela FDAi (0,86kg MS) e LK (0,60kg MS) em comparação aos observados na CTF (2,16kg MS) e NANOLIPE® (2,17kg MS), com sub ou superestimação dos coeficientes de digestibilidade da MS, FDN, FDA, HEM, ED, MO e PB estimados pelos indicadores internos. O NANOLIPE® obteve alta taxa de recuperação (100,46%) e os coeficientes de digestibilidade de todos nutrientes foram semelhantes aos obtidos pela CTF. O indicador NANOLIPE® foi eficiente para estimativa da produção fecal e digestibilidade aparente dos nutrientes da dieta em equinos, quando fornecido por dois dias, sendo uma aplicação diária e com início da coleta de fezes, 24 horas após sua administração.(AU)

NANOLIPE® is the LIPE®digestibility indicator incorporating nano particles that blend more smoothly and quickly in digesta, allowing reduction of the induction period, and higher recovery rates that compared with other indicators used in horses. The objective of this work was to compare the digestibility of the diet of nutrients in horses obtained by standard method (total collection of feces - TCF) and estimated by two internal indicators ( Klason Lignin - KL and indigestible Acid Detergent Fiber.- iADF) ) and external indicator NANOLIPE®, aiming to validate the latter for use in equine nutrition. In a randomized block design, eight Mangalarga Marchador adult mares were used to evaluate treatments (CBC, iADF, LK, NANOLIPE®). The diet was composed of 1.5% PV hay Coast Cross, 1.0% PV of commercial concentrate, divided into two daily treatment.. The trial lasted 13 days, with 8 adaptation to the diet and the handling and 5 for the experimental procedures. In the first five days of the experimental period total feces was collected and in the 3th and 4th day the animals received NANOLIPE® administered once a day through capsules of 0.25 g / animal / day orally. Using the method of TFC as standart, the Klason Lignin and iADF proved inadequate (P<0,05) and NANOLIPE® was considered efficient (P>0,05) for estimating the digestibility of nutrients in the equine species. There were differences (P <0.05) between fecal production values estimated by iADF (0.86 kg DM) and LK (0.60 kg DM) compared to those observed in CTF (2.16 kg DM) and NANOLIPE® (2.17 kg DM) with under- or overestimation of the digestibility of DM, NDF, ADF, HEM, ED, OM and CP estimated by internal indicators. The NANOLIPE® got high recovery rate (100.46%) and the digestibility coefficients of all nutrients were similar to those obtained by the CTF. The NANOLIPE® indicator was efficient to estimate fecal output and apparent digestibility of dietary nutrients in horses when provided for two days, with a daily application and start collecting feces 24 hours after administration.(AU)

Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma.

Multiple myeloma (MM), an incurable plasma cell malignancy, requires localisation within the bone marrow. This microenvironment facilitates crucial interactions between the cancer cells and stromal cell types that permit the tumour to survive and proliferate. There is increasing evidence that the bone marrow mesenchymal stem cell (BMMSC) is stably altered in patients with MM-a phenotype also postulated to exist in patients with monoclonal gammopathy of undetermined significance (MGUS) a benign condition that precedes MM. In this study, we describe a mechanism by which increased expression of peptidyl arginine deiminase 2 (PADI2) by BMMSCs in patients with MGUS and MM directly alters malignant plasma cell phenotype. We identify PADI2 as one of the most highly upregulated transcripts in BMMSCs from both MGUS and MM patients, and that through its enzymatic deimination of histone H3 arginine 26, PADI2 activity directly induces the upregulation of interleukin-6 expression. This leads to the acquisition of resistance to the chemotherapeutic agent, bortezomib, by malignant plasma cells. We therefore describe a novel mechanism by which BMMSC dysfunction in patients with MGUS and MM directly leads to pro-malignancy signalling through the citrullination of histone H3R26.

Cytomegalovirus infection is associated with an increase in systolic blood pressure in older individuals.

BACKGROUND: Cytomegalovirus (CMV) is a chronic infection that is widely distributed in the population. CMV infects a range of tissues, including endothelium, and viral replication is suppressed by the host immune system. Infection is associated with increased risk of mortality from vascular disease in older people, but the mechanisms behind this have not been determined. AIM: We investigated the association between CMV infection and cardiovascular phenotype in a cohort of healthy elderly donors. DESIGN: CMV serostatus and cardiovascular parameters were determined in the Lothian Birth cohort, which comprises 1091 individuals aged 70 years in whom many environmental, biochemical and radiological correlates of vascular function have been determined. METHODS: CMV serostatus was determined by enzyme-linked immunosorbant assay and correlated with a range of biochemical and phenotypic measures. RESULTS: Sixty-five percent of participants were CMV seropositive, which indicates chronic infection. The mean sitting systolic blood pressure (SBP) was 149.2 mmHg in CMV seropositive individuals compared with 146.2 mmHg in CMV seronegative subjects (SD 18.7 vs. 19.7; P < 0.017). This association between CMV infection and SBP was not attenuated after adjustment for a wide range of biological and socio-economic factors. CONCLUSIONS: These data show that CMV infection is associated with an increase in SBP in individuals at age 70 years. The magnitude is comparable to environmental variables such as obesity, diabetes or high salt intake. This is the first evidence to show that a chronic infection may be an important determinant of blood pressure and could have significant implications for the future management of hypertension.

Greatly reduced risk of EBV reactivation in rituximab-experienced recipients of alemtuzumab-conditioned allogeneic HSCT.

EBV-associated post-transplant lymphoproliferative disease (PTLD) remains an important complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT). We retrospectively analysed the incidence and risk factors for EBV reactivation in 186 adult patients undergoing consecutive allo-HSCT with alemtuzumab T-cell depletion at a single centre. The cumulative incidence of EBV reactivation was 48% (confidence interval (CI) 41-55%) by 1 year, with an incidence of high-level EBV reactivation of 18% (CI 13-24%); 8 patients were concurrently diagnosed with PTLD. Amongst patients with high-level reactivation 31/38 (82%) developed this within only 2 weeks of first EBV qPCR positivity. In univariate analysis age⩾50 years was associated with significantly increased risk of EBV reactivation (hazard ratio (HR) 1.54, CI 1.02-2.31; P=0.039). Furthermore, a diagnosis of non-Hodgkin lymphoma (NHL) was associated with greatly reduced risk of reactivation (HR 0.10, CI 0.03-0.33; P=0.0001) and this was confirmed in multivariate testing. Importantly, rituximab therapy within 6 months prior to allo-HSCT was also highly predictive for lack of EBV reactivation (HR 0.18, CI 0.07-0.48; P=0.001) although confounding with NHL was apparent. Our data emphasise the risk of PTLD associated with alemtuzumab. Furthermore, we report the clinically important observation that rituximab, administered in the peri-transplant period, may provide effective prophylaxis for PTLD.

Cytomegalovirus-Associated CD4(+) CD28(null) Cells in NKG2D-Dependent Glomerular Endothelial Injury and Kidney Allograft Dysfunction.

Emerging data suggest that expansion of a circulating population of atypical, cytotoxic CD4(+) T cells lacking costimulatory CD28 (CD4(+) CD28(null) cells) is associated with latent cytomegalovirus (CMV) infection. The purpose of the current study was to increase the understanding of the relevance of these cells in 100 unselected kidney transplant recipients followed prospectively for a median of 54 months. Multicolor flow cytometry of peripheral blood mononuclear cells before transplantation and serially posttransplantation was undertaken. CD4(+) CD28(null) cells were found predominantly in CMV-seropositive patients and expanded in the posttransplantation period. These cells were predominantly effector-memory phenotype and expressed markers of endothelial homing (CX3CR1) and cytotoxicity (NKG2D and perforin). Isolated CD4(+) CD27(-) CD28(null) cells proliferated in response to peripheral blood mononuclear cells previously exposed to CMV-derived (but not HLA-derived) antigens and following such priming incubation with glomerular endothelium resulted in signs of endothelial damage and apoptosis (release of fractalkine and von Willebrand factor; increased caspase 3 expression). This effect was mitigated by NKG2D-blocking antibody. Increased CD4(+) CD28(null) cell frequencies were associated with delayed graft function and lower estimated glomerular filtration rate at end follow-up. This study suggests an important role for this atypical cytotoxic CD4(+) CD28(null) cell subset in kidney transplantation and points to strategies that may minimize the impact on clinical outcomes.

Primary care management of early stage chronic lymphocytic leukaemia is safe and effective.

BACKGROUND: Chronic lymphocytic leukaemia (CLL) is the commonest leukaemia in western society. Most patients are detected incidentally at an early stage and require 'watch and wait' follow-up. In the UK, management of Stage A0 CLL varies with some centres advising regular outpatient haematology follow-up, whereas others recommend management within primary care. The safety and effectiveness of these two management options are currently unknown. METHODS: An observational retrospective cohort study in outpatient Haematology clinics at Queen Elizabeth Hospital Birmingham (QEH) and Birmingham Heartlands Hospital (BHH) and primary care practices in West Midlands, UK. All patients diagnosed with stable stage A0 CLL since 2002 at BHH or QEH were identified. At BHH, patients were discharged to primary care follow-up, whilst QEH patients remained under haematology for follow-up. Evidence of disease progression, need for treatment and overall mortality was documented. RESULTS: Two hundred and forty-six Stage A0 CLL patients were identified. One hundred and five (43%) patients were discharged to primary care, whilst 141 (57%) patients were followed up in haematology outpatient clinics. No difference in mortality or need for treatment was found between the two groups. Of those discharged, 93 (66%) remained in primary care. CONCLUSION: The management of stable-stage A0 CLL within primary or secondary care leads to equivalent clinical outcomes. The prevalence of early-stage CLL is expected to increase with the ageing population and management within primary care should be considered as a potentially effective approach.

Macrophage-sensory neuronal interaction in HIV-1 gp120-induced neurotoxicity‡.

BACKGROUND: Human immunodeficiency virus (HIV)-associated sensory neuropathy (SN) is the most frequent neurological complication of HIV disease. Among the probable mechanisms underlying HIV-SN are neurotoxicity induced by the HIV glycoprotein gp120 and antiretroviral therapies (ART). Since HIV-SN prevalence remains high in patients who have not been exposed to toxic ART drugs, here we focused on gp120-mediated mechanisms underlying HIV-SN. METHODS: We hypothesized that a direct gp120-sensory neurone interaction is not the cause of neurite degeneration; rather, an indirect interaction of gp120 with sensory neurones involving macrophages underlies axonal degeneration. Rat dorsal root ganglion (DRG) cultures were used to assess gp120 neurotoxicity. Rat bone marrow-derived macrophage (BMDM) cultures and qPCR array were used to assess gp120-associated gene expression changes. RESULTS: gp120 induced significant, but latent onset, neurite degeneration until 24 h after application. gp120-neurone interaction occurred within 1 h of application in <10% of DRG neurones, despite neurite degeneration having a global effect. Application of culture media from gp120-exposed BMDMs induced a significant reduction in DRG neurite outgrowth. Furthermore, gp120 significantly increased the expression of 25 cytokine-related genes in primary BMDMs, some of which have been implicated in other painful polyneuropathies. The C-C chemokine receptor type 5 (CCR5) antagonist, maraviroc, concentration-dependently inhibited gp120-induced tumour necrosis factor-α gene expression, indicating that these effects occurred via gp120 activation of CCR5. CONCLUSIONS: Our findings highlight macrophages in the pathogenesis of HIV-SN and upstream modulation of macrophage response as a promising therapeutic strategy.

Targeting ß2 adrenergic receptors regulate human T cell function directly and indirectly.

It is well-established that central nervous system activation affects peripheral blood mononuclear cell (PBMCs) function through the release of the catecholamines (Epi) and norepinephrine (NE), which act on ß2-adrenergic receptors (ß2AR). However, most studies have used non-specific stimulation of cells rather than antigen-specific responses. Likewise, few studies have parsed out the direct effects of ß2AR stimulation on T cells versus indirect effects via adrenergic stimulation of antigen presenting cells (APC). Here we report the effect of salmeterol (Sal), a selective ß2AR agonist, on IFN-γ(+) CD4 and IFN-γ(+) CD8 T cells following stimulation with Cytomegalovirus lysate (CMVL-strain AD169) or individual peptides spanning the entire region of the HCMV pp65 protein (pp65). Cells were also stimulated with Staphylococcal enterotoxin B. Additionally, we investigated the effect of Epi and Sal on cytotoxic cell killing of transfected target cells at the single cell level using the CD107a assay. The results show that Sal reduced the percentage of IFN-γ(+) CD4 and IFN-γ(+) CD8 T cells both when applied directly to isolated T cells, and indirectly via treatment of APC. These inhibitory effects were mediated via a ß2 adrenergic-dependent pathway and were stronger for CD8 as compared to CD4 T cells. Similarly, the results show that Sal suppressed cytotoxicity of both CD8 T and NK cells in vitro following stimulation with Chinese hamster ovary cell line transfected with MICA(*009) (T-CHO) and the human erythromyeloblastoid leukemic (K562) cell line. The inhibitory effect on cytotoxicity following stimulation with T-CHO was stronger in NK cells compared with CD8 T cells. Thus, targeting the ß2AR on lymphocytes and on APC leads to inhibition of inflammatory cytokine production and target cell killing. Moreover, there is a hierarchy of responses, with CD8 T cells and NK cells inhibited more effectively than CD4 T cells.