Multiple SNPs within and surrounding the apolipoprotein E gene influence cerebrospinal fluid apolipoprotein E protein levels

The epsilon4 allele of the apolipoprotein E gene (APOE) is associated with increased risk and earlier age at onset in late onset Alzheimer's disease (AD). Other factors, such as expression level of apolipoprotein E protein (apoE), have been postulated to modify the APOE related risk of developing AD. Multiple loci in and outside of APOE are associated with a high risk of AD. The aim of this exploratory hypothesis generating investigation was to determine if some of these loci predict cerebrospinal fluid (CSF) apoE levels in healthy non-demented subjects. CSF apoE levels were measured from healthy non-demented subjects 21-87 years of age (n=134). Backward regression models were used to evaluate the influence of 21 SNPs, within and surrounding APOE, on CSF apoE levels while taking into account age, gender, APOE epsilon4 and correlation between SNPs (linkage disequilibrium). APOE epsilon4 genotype does not predict CSF apoE levels. Three SNPs within the TOMM40 gene, one APOE promoter SNP and two SNPs within distal APOE enhancer elements (ME1 and BCR) predict CSF apoE levels. Further investigation of the genetic influence of these loci on apoE expression levels in the central nervous system is likely to provide new insight into apoE regulation as well as AD pathogenesis.     

Psychiatric comorbidity in adult attention deficit hyperactivity disorder: findings from multiplex families

OBJECTIVE: Patterns of psychiatric comorbidity were assessed in adults with and without attention deficit hyperactivity disorder (ADHD) identified through a genetic study of families containing multiple children with ADHD. METHOD: Lifetime ADHD and comorbid psychopathology were assessed in 435 parents of children with ADHD. Rates and mean ages at onset of comorbid psychopathology were compared in parents with lifetime ADHD, parents with persistent ADHD, and those without ADHD. Age-adjusted rates of comorbidity were compared with Kaplan-Meier survival curves. Logistic regression was used to assess additional risk factors for conditions more frequent in ADHD subjects. RESULTS: The parents with ADHD were significantly more likely to be unskilled workers and less likely to have a college degree. ADHD subjects had more lifetime psychopathology; 87% had at least one and 56% had at least two other psychiatric disorders, compared with 64% and 27%, respectively, in non-ADHD subjects. ADHD was associated with greater disruptive behavior, substance use, and mood and anxiety disorders and with earlier onset of major depression, dysthymia, oppositional defiant disorder, and conduct disorder. Group differences based on Kaplan-Meier age-corrected risks were consistent with those for raw frequency distributions. Male sex added risk for disruptive behavior disorders. Female sex and oppositional defiant disorder contributed to risk for depression and anxiety. ADHD was not a significant risk factor for substance use disorders when male sex, disruptive behavior disorders, and socioeconomic status were controlled. CONCLUSIONS: Adult ADHD is associated with significant lifetime psychiatric comorbidity that is not explained by clinical referral bias.     

The actions of capsaicin applied topically to the skin of the rat on C-fibre afferents, antidromic vasodilatation and substance P levels.

1. Single applications of solutions of capsaicin were made to the intact skin of anaesthetized rats and the effects on cutaneous blood flow and the firing of C-nociceptor afferents determined. Blood flow was measured by laser-Doppler flowmetry. C-fibre activity was recorded from filaments dissected from the saphenous nerve. 2. Following the application of a capsaicin solution (concentration > or = 1 mM) to rat saphenous skin, low frequency firing occurred in C-polymodal nociceptors that sometimes continued for > 10 min. At the some time, large increases in skin blood flow occurred exceeding 300% in some instances. 3. After the initial excitation, some C-polymodal nociceptors lost their sensitivity to pressure whilst their sensitivity to heat was lost or enhanced depending on the vehicle used. 4. Sensitivity of C-polymodal nociceptors to heat recovered in < 1 day following a single application of 33 mM capsaicin. Thresholds to mechanical pressure, however, were still significantly elevated by 123% on day 1, but had recovered on day 2. 5. Vasodilatation in response to saphenous nerve stimulation ('antidromic vasodilatation') was significantly reduced by 35%, 2 days after a single application of 33 mM capsaicin, but was normal at 4 days. 6. Following a single application of 33 mM capsaicin, skin substance P levels fell to only half the normal value at day 1 and remained at this level throughout the 4 day period examined. 7. It is suggested that the ability of relatively low concentrations of capsaicin to desensitize C-fibre nociceptors may underlie the analgesic action of topical capsaicin in man.     

HIV Prevention Among Young Women in South Africa: Understanding Multiple Layers of Risk

Despite concerted prevention efforts, young South African women remain at the epicenter of the HIV epidemic. Although these women have grown up in a community powerfully affected by HIV, systematic investigation into how this “second generation” of HIV-affected youth navigates HIV risk is lacking. This study qualitatively explored a complex interplay of factors influencing HIV risk among young pregnant women in KwaZulu-Natal, South Africa. We conducted in-depth interviews with 35 pregnant women (22 HIV-uninfected and 13 HIV-infected) aged 18–21, 18 healthcare providers, and focus groups with 19 community stakeholders. Among the young women, HIV knowledge was high, and many reported taking some action to prevent pregnancy or HIV; however, these efforts were not routinely implemented. Themes related to HIV acquisition risk from all participants were organized using a socioecological framework and revolved around individual and developmental experiences (personal experience with HIV, perceived invincibility), family barriers (lack of adult supervision, pressure to leave school), relational barriers (lack of disclosure and partner communication, “burn out” around attempts to discuss condom use with partners, overdependence on partners), community-level barriers (township environment, lack of structured activities), and social barriers (poverty, HIV-related stigma). Some novel concepts emerged from the data, including an understanding of how overdependence on the romantic relationship may develop. Current HIV prevention efforts, including traditional HIV counseling and testing, condom distribution, and biomedical agents for HIV prevention, are unlikely to be effective without a broader, ecological up-to-date understanding of the evolving, intertwined, and complex constellation of factors that drive HIV risk behavior in this high-risk population.     

Transcription Factor PU.1 Promotes Conventional Dendritic Cell Identity and Function via Induction of Transcriptional Regulator DC-SCRIPT

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Serological response to influenza vaccination among adults hospitalized with community‐acquired pneumonia

Ninety‐five adults enrolled in the Etiology of Pneumonia in the Community study with negative admission influenza polymerase chain reaction (PCR) tests received influenza vaccination during hospitalization. Acute and convalescent influenza serology was performed. After vaccination, seropositive (≥1:40) hemagglutination antibody titers (HAI) were achieved in 55% to influenza A(H1N1)pdm09, 58% to influenza A(H3N2), 77% to influenza B (Victoria), and 74% to influenza B (Yamagata) viruses. Sixty‐six (69%) patients seroconverted (≥4‐fold HAI rise) to ≥1 strain. Failure to seroconvert was associated with diabetes, bacterial detection, baseline seropositive titers for influenza B (Yamagata), and influenza vaccination in the previous season.     

A novel class of endotoxin receptor agonists with simplified structure, toll-like receptor 4-dependent immunostimulatory action, and adjuvant activity.

A series of novel, synthetic compounds containing lipids linked to a phosphate-containing acyclic backbone are shown to have similar biological properties to lipopolysaccharide (LPS). These compounds showed intrinsic agonistic properties when tested for their ability to stimulate tumor necrosis factor-alpha in human whole blood and interleukin-6 in U373 human glioblastoma cells without added LPS coreceptor CD14. The presence of the LPS antagonist E5564 completely blocked responses, suggesting that the novel compounds and LPS share a common mechanism of cell activation. Stereoselectivity of the molecules was observed in vitro; compounds with an R,R,R,R-configuration were strongly agonistic, whereas compounds with an R,S,S,R-configuration were much weaker in their activity on human whole blood and U373 cells. We also tested the effect of the compounds in cells transfected with the LPS receptor Toll-like receptor 4 (TLR4), with similar results, further supporting a shared mechanism with LPS. This was confirmed in vivo where the agonists failed to elicit cytokine responses in C3H/HeJ mice lacking TLR4 signaling. Because LPS-like molecules enhance immune responses, the compounds were mixed with tetanus toxoid and administered to mice in an immunization protocol to test for adjuvant activity. They enhanced the generation of specific antibodies against tetanus toxoid. Our results indicate that these unique compounds behave as agonists of TLR4, resulting in responses similar to those elicited by LPS. They display adjuvant activity in vivo and may be useful for the development of vaccine therapies.