General Anesthesia for Cesarean Delivery for Thrombocytopenia in Hypertensive Disorders of Pregnancy: Findings From the Obstetric Airway Management Registry.

BACKGROUND: In resource-limited environments, spinal anesthesia (SA) is preferred for cesarean delivery. In women at risk of spinal epidural hematoma, particularly those with hypertensive disorders of pregnancy, thrombocytopenia should be excluded before neuraxial blockade. In the context of emergency surgery for fetal distress, this investigation may be hampered by laboratory services being unavailable or off-site. METHODS: The Obstetric Airway Management Registry (ObAMR) is currently active across all anesthesia training institutions affiliated with the University of Cape Town. This multicenter observational study aimed to estimate the proportion of patients receiving general anesthesia (GA) for either confirmed or suspected thrombocytopenia, which was not excluded due to unavailability of laboratory results. To establish the number of GA uses that may have been avoided if platelet counts were available, we retrospectively searched for subsequent platelet counts in patients for whom thrombocytopenia was suspected. An algorithm was proposed, including a simple decision aid for estimating risk versus benefit of SA versus GA, to be followed in the setting of hypertensive disorders of pregnancy and thrombocytopenia. RESULTS: Thrombocytopenia was the indication for GA in 100 of 591 patients (16.9%) captured in the registry. In total, 48 of 591 (8.1%) had confirmed thrombocytopenia, and 52 of 591 (8.8%) had suspected thrombocytopenia. Of these patients, 91 of 100 had a hypertensive disorder of pregnancy. In the confirmed thrombocytopenia group, the indication for GA was a platelet count <75 × 10 9 /L. In the suspected thrombocytopenia group, 46 of 52 (88.5%) platelet counts could be retrospectively traced. The median (interquartile range) platelet count was 178 × 10 9 /L (93 - 233 × 10 9 /L), and platelets exceeded 75 × 10 9 /L in 41 of 46 patients (89.1%). In the 5 of 46 patients with retrospectively confirmed thrombocytopenia, 2 had hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome, 2 had antepartum hemorrhage with preeclampsia, and 1 had isolated thrombocytopenia with preeclampsia. CONCLUSIONS: In 17% of patients, the indication for GA was thrombocytopenia. Of these, 52 of 100, or nearly 9% of the total of 591, received GA because a platelet count was unavailable at the time of surgery. The importance of early laboratory assessment, when available, should be emphasized. Overall, 41 of 591 (6.9%) had a platelet count >75 × 10 9 /L and would not have needed GA if their platelet count had been known. After following the constructed algorithm and applying the decision aid to assess risk and benefit, there may be circumstances in which the clinician justifiably opts for SA when a platelet count is indicated but unavailable.

Lower White Matter Volume and Worse Executive Functioning Reflected in Higher Levels of Plasma GFAP among Older Adults with and Without Cognitive Impairment.

OBJECTIVE: There are minimal data directly comparing plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in aging and neurodegenerative disease research. We evaluated associations of plasma NfL and plasma GFAP with brain volume and cognition in two independent cohorts of older adults diagnosed as clinically normal (CN), mild cognitive impairment (MCI), or Alzheimer's dementia. METHODS: We studied 121 total participants (Cohort 1: n = 50, age 71.6 ± 6.9 years, 78% CN, 22% MCI; Cohort 2: n = 71, age 72.2 ± 9.2 years, 45% CN, 25% MCI, 30% dementia). Gray and white matter volumes were obtained for total brain and broad subregions of interest (ROIs). Neuropsychological testing evaluated memory, executive functioning, language, and visuospatial abilities. Plasma samples were analyzed in duplicate for NfL and GFAP using single molecule array assays (Quanterix Simoa). Linear regression models with structural MRI and cognitive outcomes included plasma NfL and GFAP simultaneously along with relevant covariates. RESULTS: Higher plasma GFAP was associated with lower white matter volume in both cohorts for temporal (Cohort 1: ß = -0.33, p = .002; Cohort 2: ß = -0.36, p = .03) and parietal ROIs (Cohort 1: ß = -0.31, p = .01; Cohort 2: ß = -0.35, p = .04). No consistent findings emerged for gray matter volumes. Higher plasma GFAP was associated with lower executive function scores (Cohort 1: ß = -0.38, p = .01; Cohort 2: ß = -0.36, p = .007). Plasma NfL was not associated with gray or white matter volumes, or cognition after adjusting for plasma GFAP. CONCLUSIONS: Plasma GFAP may be more sensitive to white matter and cognitive changes than plasma NfL. Biomarkers reflecting astroglial pathophysiology may capture complex dynamics of aging and neurodegenerative disease.

Cardiac Structure and Function in Morbidly Obese Parturients: An Echocardiographic Study.

BACKGROUND: The increasing prevalence of obesity worldwide is a major threat to global health. Cardiac structural and functional changes are well documented for obesity as well as for pregnancy, but there is limited literature on morbidly obese parturients. We hypothesized that there are both cardiac structural and functional differences between morbidly obese pregnant women and pregnant women of normal body mass index (BMI). METHODS: This prospective cross-sectional study was performed in 2 referral maternity units in Cape Town, South Africa, over a 3-month period. Forty morbidly obese pregnant women of BMI ≥40 kg·m (group O) were compared to 45 pregnant women of BMI ≤30 kg·m (group N). Cardiac structure and function were assessed by transthoracic echocardiography, according to the recommendations of the British Society of Echocardiography. The 2-sample t-test with unequal variances was used for the comparison of the mean values between the groups. RESULTS: Acceptable echocardiographic images were obtained in all obese women. Statistical significance was defined as P < .0225 after applying the Benjamini-Hochberg correction for multiple testing. Mean (standard deviation) mean arterial pressure was higher in group O (91 [8.42] vs 84 [9.49] mm Hg, P < .001). There were no between-group differences in heart rate, stroke volume, or cardiac index (84 [12] vs 79 [13] beats·minute, P = .103; 64.4 [9.7] vs 59.5 [13.5] mL, P = .069; 2551 [474] vs 2729 [623] mL·minute·m, P = .156, for groups O and N, respectively). Stroke volume index was lower, and left ventricular mass was higher in group O (30.14 [4.51] vs 34.25 [7.00] mL·m, P = .003; 152 [24] vs 115 [29] g, P < .001). S' septal was lower in group O (8.43 [1.20] vs 9.25 [1.64] cm·second, P = .012). Considering diastolic function, isovolumetric relaxation time was significantly prolonged in group O (73 [15] vs 61 [15] milliseconds, P < .001). The septal tissue Doppler index E' septal was lower in group O (9.08 [1.69] vs 11.28 [3.18], P < .001). There were no between-group differences in E' average (10.7 [2.3] vs 12.0 [2.7], P = .018, O versus N) or E/E' average (7.85 [1.77] vs 7.27 [1.68], P = .137, O versus N). Right ventricular E'/A' was lower in group O (1.07 [0.47] vs 1.29 [0.32], P = .016). CONCLUSIONS: Cardiac index did not differ between obese pregnant women and those with normal BMI. Their increased left ventricular mass and lower stroke volume index could indicate a limited adaptive reserve. Obese women had minor decreases in septal left ventricular tissue Doppler velocity, but the E/E' average values did not suggest clinically significant diastolic dysfunction.

A Systematic Review of Outcomes Associated With Withholding or Continuing Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Before Noncardiac Surgery.

BACKGROUND: The global rate of major noncardiac surgical procedures is increasing annually, and of those patients presenting for surgery, increasing numbers are taking either an angiotensin-converting enzyme inhibitor (ACE-I) or an angiotensin receptor blocker (ARB). The current recommendations of whether to continue or withhold ACE-I and ARB in the perioperative period are conflicting. Previous meta-analyses have linked preoperative ACE-I/ARB therapy to the increased incidence of postinduction hypotension; however, they have failed to correlate this with adverse patient outcomes. The aim of this meta-analysis was to determine whether continuation or withholding ACE-I or ARB therapy in the perioperative period is associated with mortality and major morbidity. METHODS: This meta-analysis was prospectively registered on PROSPERO (CRD42017055291). A comprehensive search of MEDLINE (PubMed), CINAHL (EBSCO host), ProQuest, Cochrane database, Scopus, and Web of Science was conducted on December 6, 2016. We included adult patients >18 years of age on chronic ACE-I or ARB therapy who underwent noncardiac surgery in which ACE-I or ARB was either withheld or continued on the morning of surgery. Primary outcomes included all-cause mortality and major cardiac events (MACE). Secondary outcomes included the risk of congestive heart failure, acute kidney injury, stroke, intraoperative/postoperative hypotension, and the length of hospital stay. RESULTS: After abstract review, the full text of 25 studies was retrieved, of which 9 fulfilled the inclusion criteria: 5 were randomized control trials, and 4 were cohort studies. These studies included a total of 6022 patients on chronic ACE-I/ARB therapy before noncardiac surgery. A total of 1816 patients withheld treatment the morning of surgery and 4206 continued their ACE-I/ARB. Preoperative demographics were similar between the 2 groups. Withholding ACE-I/ARB therapy was not associated with a difference in mortality (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.62-1.52; I = 0%) or MACE (OR, 1.12; 95% CI, 0.82-1.52; I = 0%). However, withholding therapy was associated with significantly less intraoperative hypotension (OR, 0.63; 95% CI, 0.47-0.85; I = 71%). No effect estimate could be pooled concerning length of hospital stay and congestive heart failure. CONCLUSIONS: This meta-analysis did not demonstrate an association between perioperative administration of ACE-I/ARB and mortality or MACE. It did, however, confirm the current observation that perioperative continuation of ACE-I/ARBs is associated with an increased incidence of intraoperative hypotension. A large randomized control trial is necessary to determine the appropriate perioperative management of ACE-I and ARBs.

Methamphetamine alters microglial immune function through P2X7R signaling.

BACKGROUND: Purinoceptors have emerged as mediators of chronic inflammation and neurodegenerative processes. The ionotropic purinoceptor P2X7 (P2X7R) is known to modulate proinflammatory signaling and integrate neuronal-glial circuits. Evidence of P2X7R involvement in neurodegeneration, chronic pain, and chronic inflammation suggests that purinergic signaling plays a major role in microglial activation during neuroinflammation. In this study, we investigated the effects of methamphetamine (METH) on microglial P2X7R. METHODS: ESdMs were used to evaluate changes in METH-induced P2X7R gene expression via Taqman PCR and protein expression via western blot analysis. Migration and phagocytosis assays were used to evaluate functional changes in ESdMs in response to METH treatment. METH-induced proinflammatory cytokine production following siRNA silencing of P2X7R in ESdMs measured P2X7R-dependent functional changes. In vivo expression of P2X7R and tyrosine hydroxylase (TH) was visualized in an escalating METH dose mouse model via immunohistochemical analysis. RESULTS: Stimulation of ESdMs with METH for 48 h significantly increased P2X7R mRNA (*p < 0.0336) and protein expression (*p < 0.022). Further analysis of P2X7R protein in cellular fractionations revealed increases in membrane P2X7R (*p < 0.05) but decreased cytoplasmic expression after 48 h METH treatment, suggesting protein mobilization from the cytoplasm to the membrane which occurs upon microglial stimulation with METH. Forty-eight hour METH treatment increased microglial migration towards Fractalkine (CX3CL1) compared to control (****p < 0.0001). Migration toward CX3CL1 was confirmed to be P2X7R-dependent through the use of A 438079, a P2X7R-competitive antagonist, which reversed the METH effects (****p < 0.0001). Similarly, 48 h METH treatment increased microglial phagocytosis compared to control (****p < 0.0001), and pretreatment of P2X7R antagonist reduced METH-induced phagocytosis (****p < 0.0001). Silencing the microglial P2X7R decreased TNF-α (*p < 0.0363) and IL-10 production after 48 h of METH treatment. Additionally, our studies demonstrate increased P2X7R and decreased TH expression in the striata of escalating dose METH animal model compared to controls. CONCLUSIONS: This study sheds new light on the functional role of P2X7R in the regulation of microglial effector functions during substance abuse. Our findings suggest that P2X7R plays an important role in METH-induced microglial activation responses. P2X7R antagonists may thus constitute a novel target of therapeutic utility in neuroinflammatory conditions by regulating pathologically activated glial cells in stimulant abuse.

Relative Role of Akt, ERK and CREB in Alcohol-Induced Microglia P2X4R Receptor Expression.

AIMS: Previously we have demonstrated altered microglia P2X4R expression in response to alcohol and pharmacological blockade with a selective P2X4R antagonist can reverse the action, suggesting that P2X4R play a role in mediating alcohol-induced effects on microglia. In the present study, we investigated the underlying signaling mediators, which may play a role in modulating P2X4R expression in microglia cells in response to alcohol. METHODS: Embryonic stem cell-derived microglia (ESdM) cells were used to investigate the potential mechanisms involved in the regulation of P2X4R in response to alcohol. Selective P2X4R antagonist and kinase inhibitors were used to further corroborate the signal transduction pathway through which alcohol modulates P2X4R expression in microglia. RESULTS: Alcohol (100 mM) suppressed phosphorylated AKT and ERK cascades in native ESdM cells. This alcohol-induced suppression was confirmed to be P2X4R-dependent through the use of a selective P2X4R antagonist and knockdown of P2XR4 by siRNA. Alcohol increased transcriptional activity of CREB. P2X4R antagonist blocked alcohol-induced effects on CREB, suggesting a P2X4R-mediated effect. CONCLUSION: These findings provide important clues to the underlying mechanism of purinoceptors in alcohol-induced microglia immune suppression.

Online radiographic survey of midshaft clavicular fractures: no consensus on treatment for displaced fractures.

The choice of treatment for midshaft clavicular fractures is not straightforward, but depends on fracture characteristics such as comminution, angulation and displacement. An online survey was conducted amongst trauma and orthopaedic surgeons to determine the preferred treatment for midshaft clavicular fractures, based on anteroposterior radiographs, for 17 randomly selected displaced or comminuted midshaft clavicular fractures. The background and experience of the respondents were documented. Data were analyzed using a Generalized Estimating Equations (GEE) model. The 102 respondents preferred non-operative treatment more frequently for displaced fractures than for comminuted fractures (OR 3.24, 95% CI 2.55-4.12). Locking plate fixation was more often preferred over other surgical modalities for comminuted than for displaced fractures (OR 1.50, 95% CI 1.17-1.91). In clinical practice, there is no consensus between surgeons on the choice of treatment for displaced or comminuted midshaft clavicular fractures. This lack of agreement calls for evidence-based treatment guidelines for these fractures.

Online radiographic survey of midshaft clavicular fractures: no consensus on treatment for displaced fractures.

The choice of treatment for midshaft clavicular fractures is not straightforward, but depends on fracture characteristics such as comminution, angulation and displacement. An online survey was conducted amongst trauma and orthopaedic surgeons to determine the preferred treatment for midshaft clavicular fractures, based on anteroposterior radiographs, for 17 randomly selected displaced or comminuted midshaft clavicular fractures. The background and experience of the respondents were documented. Data were analyzed using a Generalized Estimating Equations (GEE) model. The 102 respondents preferred non-operative treatment more frequently for displaced fractures than for comminuted fractures (OR 3.24, 95% CI 2.55-4.12). Locking plate fixation was more often preferred over other surgical modalities for comminuted than for displaced fractures (OR 1.50, 95% CI 1.17-1.91). In clinical practice, there is no consensus between surgeons on the choice of treatment for displaced or comminuted midshaft clavicular fractures. This lack of agreement calls for evidence-based treatment guidelines for these fractures.

Inflammatory Mechanisms and Cascades Contributing to Neurocognitive Impairment in HIV/AIDS.

Neurocognitive impairment caused by chronic human immunodeficiency virus (HIV) infection is a growing concern. In this chapter we discuss the inflammatory mechanisms underlying the pathology of asymptomatic and mild neurocognitive impairment in the context of antiretroviral therapy. We discuss the role of HIV, viral proteins, and virally infected cells on the development of neuroinflammation and the effect of viral proteins on the cells of the central nervous system.We examine how these collective factors result in an inflammatory context that triggers the development of neurocognitive impairment in HIV. We assess the contribution of antiretrovirals and drugs of abuse, including methamphetamine, cannabis, and opioids, to the neurotoxic and neuroinflammatory milieu that leads to the development of neurocognitive impairment in HIV-infected individuals. We also examined circulating biomarkers, NF-L, sCD163, and sCD14, pertinent to identifying changes in the CNS that could indicate real-time changes in patient physiology. Lastly, we discuss future studies, such as exosomes and the microbiome, which could play a role in the HIV-induced neuroinflammation that eventually manifests as cognitive impairment.

Preeclampsia in 2021-a Perioperative Medical Challenge for the Anesthesiologist.

The authors provide a review of recent advances in the understanding of pathophysiology and perioperative management of preeclampsia and eclampsia, from the perspective of the anesthesiologist. This review includes aspects of assessment of severity of disease, hemodynamic monitoring, peripartum anesthesia care, and postpartum management. The perioperative management of patients with eclampsia is also discussed.

Elevated complement mediator levels in endothelial-derived plasma exosomes implicate endothelial innate inflammation in diminished brain function of aging humans.

We test the hypothesis that endothelial cells adopt an inflammatory phenotype in functionally intact aged human subjects with radiographic evidence of white matter hyperintensity (WMH) suggestive of small cerebrovascular disease. Components of all three complement effector pathways and regulatory proteins were quantified in extracts of plasma endothelial-derived exosomes (EDE) of 11 subjects (age 70-82) with and 15 without evidence of WMH on MRI. Group differences and associations with plasma markers of immune activation (IL6, ICAM1), cognition and neuroimaging were calculated via regression modelling. EDE complement factors within the alternative and classical pathways were found to be higher and regulatory proteins lower in subjects with WMH. EDE levels of some complement components demonstrated significant associations with cognitive slowing and elevated systolic blood pressure. The inhibitor of the membrane attack complex, CD46, showed a significant positive association with cerebral grey matter volume. Plasma inflammatory markers, IL6 and ICAM1, were positively associated with EDE levels of several complement components. These findings provide the first in vivo evidence of the association of endothelial cell inflammation with white matter disease, age-associated cognitive changes, and brain degeneration in functionally normal older individuals. Future endothelial biomarker development may permit recognition of early or preclinical stages of vascular contributions to cognitive impairment and dementia.

Tropical rhodolith beds are a major and belittled reef fish habitat.

Understanding habitat-level variation in community structure provides an informed basis for natural resources' management. Reef fishes are a major component of tropical marine biodiversity, but their abundance and distribution are poorly assessed beyond conventional SCUBA diving depths. Based on a baited-video survey of fish assemblages in Southwestern Atlantic's most biodiverse region we show that species composition responded mainly to the two major hard-bottom megahabitats (reefs and rhodolith beds) and to the amount of light reaching the bottom. Both megahabitats encompassed typical reef fish assemblages but, unexpectedly, richness in rhodolith beds and reefs was equivalent. The dissimilar fish biomass and trophic structure in reefs and rhodolith beds indicates that these systems function based on contrasting energy pathways, such as the much lower herbivory recorded in the latter. Rhodolith beds, the dominant benthic megahabitat in the tropical Southwestern Atlantic shelf, play an underrated role as fish habitats, and it is critical that they are considered in conservation planning.

Centrally Acting Angiotensin-Converting Enzyme Inhibitor Suppresses Type I Interferon Responses and Decreases Inflammation in the Periphery and the CNS in Lupus-Prone Mice.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multi-organ damage. Neuropsychiatric lupus (NPSLE) is one of the most common manifestations of human SLE, often causing depression. Interferon-α (IFNα) is a central mediator in disease pathogenesis. Administration of IFNα to patients with chronic viral infections or cancers causes depressive symptoms. Angiotensin-converting enzyme (ACE) is part of the kallikrein-kinin/renin-angiotensin (KKS/RAS) system that regulates many physiological processes, including inflammation, and brain functions. It is known that ACE degrades bradykinin (BK) into inactive peptides. We have previously shown in an in vitro model of mouse bone-marrow-derived dendritic cells (BMDC) and human peripheral blood mononuclear cells that captopril (a centrally acting ACE inhibitor-ACEi) suppressed Type I IFN responsive gene (IRG) expression. In this report, we used the MRL/lpr lupus-prone mouse model, an established model to study NPSLE, to determine the in vivo effects of captopril on Type I IFN and associated immune responses in the periphery and brain and effects on behavior. Administering captopril to MRL/lpr mice decreased expression of IRGs in brain, spleen and kidney, decreased circulating and tissue IFNα levels, decreased microglial activation (IBA-1 expression) and reduced depressive-like behavior. Serotonin levels that are decreased in depression were increased by captopril treatment. Captopril also reduced autoantibody levels in plasma and immune complex deposition in kidney and brain. Thus, ACEi's may have potential for therapeutic use for systemic and NPSLE.

Plasma Glial Fibrillary Acidic Protein Levels Differ Along the Spectra of Amyloid Burden and Clinical Disease Stage.

BACKGROUND: Measuring plasma glial fibrillary acidic protein (GFAP) alongside cortical amyloid-ß (Aß) may shed light on astrocytic changes in aging and Alzheimer's disease (AD). OBJECTIVE: To examine associations between plasma GFAP and cortical Aß deposition in older adults across the typical aging-to-AD dementia spectrum. METHODS: We studied two independent samples from UCSF (Cohort 1, N = 50; Cohort 2, N = 37) covering the spectra of clinical severity (CDR Sum of Boxes; CDR-SB) and Aß-PET burden. Aß-PET was completed with either florbetapir or Pittsburgh Compound B and standardized uptake value ratios were converted to the Centiloid (CL) scale for analyses. All participants with CDR-SB > 0 were Aß-PET positive, while clinically normal participants (CDR-SB = 0) were a mix of Aß-PET positive and negative. Regression analyses evaluated main effect and interaction associations between plasma GFAP, Aß-PET, and clinical severity. RESULTS: In both cohorts, plasma GFAP increased linearly with Aß-PET CLs in clinically normal older adults. In Cohort 2, which included participants with more severe clinical dysfunction and Aß-PET burden, the association between Aß and GFAP became curvilinear (inverted U-shape; quadratic model R2 change = 0.165, p = 0.009), and Aß-PET interacted with CDR-SB (R2 change = 0.164, p = 0.007): older adults with intermediate functional impairment (CDR-SB = 0.5-4.0) showed a weak (negative) association between Aß-PET CLs and plasma GFAP, while older adults with dementia (CDR-SB > 4.0) showed a strong, negative association of higher Aß-PET CLs with lower plasma GFAP. CONCLUSION: The relationship between astrocytic integrity and cortical Aß may be highly dynamic, with linear, positive associations early in disease that diverge in more severe disease stages.

Anesthesia for Urgent Cesarean Section.

Cesarean section (CS) is a common surgical procedure worldwide. The anesthesiologist is responsible, together with obstetrician and neonatologist, for safe perioperative management. A continuum of risk exists for urgent CS. The decision-to-delivery interval is an important audit tool, to ensure international standards are upheld and good outcomes for mother and neonate are achieved. Urgent CS may be performed under either GA or RA, with benefits and risks attributable to each. Specific clinical scenarios require an individualized approach to anesthesia, including hemorrhage, hypertensive disorders, cardiac disease, the difficult airway and fetal compromise. Ongoing training is integral to the provision of safe anesthesia.

Profile of neuronal exosomes in HIV cognitive impairment exposes sex differences.

OBJECTIVE: To use plasma neuron-derived exosomes (NDEs) to detect proteins that diagnose HIV-associated neurocognitive disorders (HAND). To compare NDE cargo from HAND with Alzheimer's disease. DESIGN: Eighty plasma samples were assayed including men (n = 29) and women (n = 51) with and without HAND. METHODS: Plasma NDEs were isolated by immunoadsorption with neuron specific L1 cell adhesion molecule antibody. NDE proteins were quantified by ELISA and proximity extension assays for 184 targets. RESULTS: Neuronal enrichment of NDE was confirmed with elevated synaptophysin and normalized to the exosomal marker, apoptosis-linked gene-2-interacting protein X (ALIX). NDE from men and women had significant divergent results. High mobility group box 1 and neurofilament light were significantly increased in NDE from cognitively impaired men and were unchanged in women. NDE from HIV+ men had decreased p-T181-tau, a marker increased in Alzheimer's disease, compared with no difference in women. NDE amyloid beta was not increased in cognitive impairment. Proximity extension assays analysis showed 25 proteins were differentially expressed in HIV infection alone. Seven proteins identified asymptomatic and mild cognitive impairment in HIV+ women. NDE from women had significantly decreased cathepsin S, total tau, neuronal cell adhesion molecule and contactin 5 in mild impairment. Twelve proteins were increased in NDE from cognitively impaired men, including carboxypeptidase M, cadherin 3, colony stimulating factor 2 receptor alpha subunit and mesencephalic astrocyte-derived neurotropic factor. CONCLUSION: NDE proteins differ in HIV infection alone and cognitive impairment between men and women suggesting mechanistic sex differences associated with HAND. Several NDE targets are different from that reported for Alzheimer's disease.

Kallikrein-Kinin System Suppresses Type I Interferon Responses: A Novel Pathway of Interferon Regulation.

The Kallikrein-Kinin System (KKS), comprised of kallikreins (klks), bradykinins (BKs) angiotensin-converting enzyme (ACE), and many other molecules, regulates a number of physiological processes, including inflammation, coagulation, angiogenesis, and control of blood pressure. In this report, we show that KKS regulates Type I IFN responses, thought to be important in lupus pathogenesis. We used CpG (TLR9 ligand), R848 (TLR7 ligand), or recombinant IFN-α to induce interferon-stimulated genes (ISGs) and proteins, and observed that this response was markedly diminished by BKs, klk1 (tissue kallikrein), or captopril (an ACE inhibitor). BKs significantly decreased the ISGs induced by TLRs in vitro and in vivo (in normal and lupus-prone mice), and in human PBMCs, especially the induction of Irf7 gene (p < 0.05), the master regulator of Type I IFNs. ISGs induced by IFN-α were also suppressed by the KKS. MHC Class I upregulation, a classic response to Type I IFNs, was reduced by BKs in murine dendritic cells (DCs). BKs decreased phosphorylation of STAT2 molecules that mediate IFN signaling. Among the secreted pro-inflammatory cytokines/chemokines analyzed (IL-6, IL12p70, and CXCL10), the strongest suppressive effect was on CXCL10, a highly Type I IFN-dependent cytokine, upon CpG stimulation, both in normal and lupus-prone DCs. klks that break down into BKs, also suppressed CpG-induced ISGs in murine DCs. Captopril, a drug that inhibits ACE and increases BK, suppressed ISGs, both in mouse DCs and human PBMCs. The effects of BK were reversed with indomethacin (compound that inhibits production of PGE2), suggesting that BK suppression of IFN responses may be mediated via prostaglandins. These results highlight a novel regulatory mechanism in which members of the KKS control the Type I IFN response and suggest a role for modulators of IFNs in the pathogenesis of lupus and interferonopathies.

Assessment of algorithms for high throughput detection of genomic copy number variation in oligonucleotide microarray data.

BACKGROUND: Genomic deletions and duplications are important in the pathogenesis of diseases, such as cancer and mental retardation, and have recently been shown to occur frequently in unaffected individuals as polymorphisms. Affymetrix GeneChip whole genome sampling analysis (WGSA) combined with 100 K single nucleotide polymorphism (SNP) genotyping arrays is one of several microarray-based approaches that are now being used to detect such structural genomic changes. The popularity of this technology and its associated open source data format have resulted in the development of an increasing number of software packages for the analysis of copy number changes using these SNP arrays. RESULTS: We evaluated four publicly available software packages for high throughput copy number analysis using synthetic and empirical 100 K SNP array data sets, the latter obtained from 107 mental retardation (MR) patients and their unaffected parents and siblings. We evaluated the software with regards to overall suitability for high-throughput 100 K SNP array data analysis, as well as effectiveness of normalization, scaling with various reference sets and feature extraction, as well as true and false positive rates of genomic copy number variant (CNV) detection. CONCLUSION: We observed considerable variation among the numbers and types of candidate CNVs detected by different analysis approaches, and found that multiple programs were needed to find all real aberrations in our test set. The frequency of false positive deletions was substantial, but could be greatly reduced by using the SNP genotype information to confirm loss of heterozygosity.

Impaired Subset Progression and Polyfunctionality of T Cells in Mice Exposed to Methamphetamine during Chronic LCMV Infection.

Methamphetamine (METH) is a widely used psychostimulant that severely impacts the host's innate and adaptive immune systems and has profound immunological implications. T cells play a critical role in orchestrating immune responses. We have shown recently how chronic exposure to METH affects T cell activation using a murine model of lymphocytic choriomeningitis virus (LCMV) infection. Using the TriCOM (trinary state combinations) feature of GemStone™ to study the polyfunctionality of T cells, we have analyzed how METH affected the cytokine production pattern over the course of chronic LCMV infection. Furthermore, we have studied in detail the effects of METH on splenic T cell functions, such as cytokine production and degranulation, and how they regulate each other. We used the Probability State Modeling (PSM) program to visualize the differentiation of effector/memory T cell subsets during LCMV infection and analyze the effects of METH on T cell subset progression. We recently demonstrated that METH increased PD-1 expression on T cells during viral infection. In this study, we further analyzed the impact of PD-1 expression on T cell functional markers as well as its expression in the effector/memory subsets. Overall, our study indicates that analyzing polyfunctionality of T cells can provide additional insight into T cell effector functions. Analysis of T cell heterogeneity is important to highlight changes in the evolution of memory/effector functions during chronic viral infections. Our study also highlights the impact of METH on PD-1 expression and its consequences on T cell responses.