Longitudinal analysis of CSF HIV RNA in untreated people with HIV: Identification of CSF controllers.

Interindividual variation of human immunodeficiency virus (HIV) RNA setpoint in cerebrospinal fluid (CSF) and its determinants are poorly understood, but relevant for HIV neuropathology, brain reservoirs, viral escape, and reseeding after antiretroviral interruptions. Longitudinal multicentric study on demographic, clinical, and laboratory correlates of CSF HIV RNA in 2000 follow-up visits from 597 people with HIV (PWH) off antiretroviral therapy (ART) and with plasma HIV RNA > the lower limit of quantification (LLQ). Factors associated with CSF control (CSFC; CSF HIV RNA < LLQ while plasma HIV RNA > LLQ) and with CSF/plasma discordance (CSF > plasma HIV RNA > LLQ) were also assessed through mixed-effects models. Posthoc and sensitivity analyses were performed for persistent CSFC and ART-naïve participants, respectively. Over a median follow-up of 2.1 years, CSF HIV RNA was associated with CD4+ and CD8+ T cells, CSF leukocytes, blood-brain barrier (BBB) integrity, biomarkers of iron and lipid metabolism, serum globulins, past exposure to lamivudine, and plasma HIV RNA (model p < 0.0001). CSFC (persistent in 7.7% over 3 years) and CSF/plasma discordance (persistent in <0.01% over 1 year) were variably associated with the same parameters (model p < 0.001). Sensitivity analyses confirmed most of the previous associations in participants never exposed to ART. Persistent CSFC was associated with higher CD4+ T-cell count nadir (p < 0.001), lower serum globulins (p = 0.003), and lower CSF leukocytes (p < 0.001). Without ART, one in 13 PWH had persistently undetectable CSF HIV RNA, while persistent CSF/plasma discordance was extremely rare over years. Immune responses, inflammation, BBB permeability, and iron and lipid metabolism were all associated with HIV replication in CSF.

Colloid solutions for fluid resuscitation.

BACKGROUND: Colloids are widely used in the replacement of fluid volume. However, doubts remain as to which colloid is best. Different colloids vary in their molecular weight and therefore in the length of time they remain in the circulatory system. Because of this, and their other characteristics, they may differ in their safety and efficacy. OBJECTIVES: To compare the effects of different colloid solutions in patients thought to need volume replacement. SEARCH METHODS: We searched the Cochrane Injuries Specialised Register (searched 1 December 2011), the Cochrane Central Register of Controlled Trials 2011, issue 4 (The Cochrane Library); MEDLINE (Ovid) (1948 to November Week 3 2011); EMBASE (Ovid) (1974 to 2011 Week 47); ISI Web of Science: Science Citation Index Expanded (1970 to 1 December 2011); ISI Web of Science: Conference Proceedings Citation Index-Science (1990 to 1 December 2011); CINAHL (EBSCO) (1982 to 1 December 2011); National Research Register (2007, Issue 1) and PubMed (searched 1 December 2011). Bibliographies of trials retrieved were searched, and for the initial version of the review drug companies manufacturing colloids were contacted for information (1999). SELECTION CRITERIA: Randomised controlled trials comparing colloid solutions in critically ill and surgical patients thought to need volume replacement. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted the data and assessed the quality of the trials. The outcomes sought were death, amount of whole blood transfused, and incidence of adverse reactions. MAIN RESULTS: Eighty-six trials, with a total of 5,484 participants, met the inclusion criteria. Quality of allocation concealment was judged to be adequate in 33 trials and poor or uncertain in the rest.Deaths were reported in 57 trials. For albumin or plasma protein fraction (PPF) versus hydroxyethyl starch (HES) 31 trials (n = 1719) reported mortality. The pooled relative risk (RR) was 1.06 (95% confidence interval (CI) 0.86 to 1.31). When the trials by Boldt were removed from the analysis the pooled RR was 0.90 (95% CI 0.68 to 1.20). For albumin or PPF versus gelatin, nine trials (n = 824) reported mortality. The RR was 0.89 (95% CI 0.65 to 1.21). Removing the study by Boldt from the analysis did not change the RR or CIs. For albumin or PPF versus dextran four trials (n = 360) reported mortality. The RR was 3.75 (95% CI 0.42 to 33.09). For gelatin versus HES 22 trials (n = 1612) reported mortality and the RR was 1.02 (95% CI 0.84 to 1.26). When the trials by Boldt were removed from the analysis the pooled RR was 1.03 (95% CI 0.84 to 1.27). RR was not estimable in the gelatin versus dextran and HES versus dextran groups.Forty-one trials recorded the amount of blood transfused; however, quantitative analysis was not possible due to skewness and variable reporting. Twenty-four trials recorded adverse reactions, with two studies reporting possible adverse reactions to gel and one to HES. AUTHORS' CONCLUSIONS: From this review, there is no evidence that one colloid solution is more effective or safe than any other, although the CIs were wide and do not exclude clinically significant differences between colloids. Larger trials of fluid therapy are needed if clinically significant differences in mortality are to be detected or excluded.

Suppression of adjuvant disease in the rat by heterologous antilymphocyte globulin.

The effect of antilymphocyte globulin (ALG) on adjuvant arthritis, an immunologically induced disease in the rat, was studied. ALG was prepared from the serum of rabbits immunized against rat lymphocytes. Adjuvant arthritis was induced in rats by a single intracutaneous injection of Freund's complete adjuvant; after 9 to 12 days, all control rats developed polyarthritis. Administration of antilymphocyte globulin about the time of adjuvant injection produced marked inhibition of clinical disease. Some suppression was apparent even when ALG was started after the onset of arthritis. Rats receiving ALG remained conspicuously healthy compared to controls. Urinary findings and renal histology showed no evidence of nephritis. The results of serum corticosterone determinations made it unlikely that adrenal stimulation contributed to the actions of ALG. Antilymphocyte preparations lowered peripheral lymphocyte counts and suppressed primary antibody responses to sheep erythrocytes, but had little effect on the skin reaction to PPD, even in rats protected from arthritis. All rats given ALG developed antibodies to rabbit globulin; there was no evidence that ALG inhibited the appearance of antibodies to itself, and prior hyperimmunization of rats with rabbit globulin did not interfere with the biological activity of ALG subsequently injected. Antisera produced separately against lymph node and thymus cells had identical properties with regard to agglutination of lymphocytes and thymus cells. Administered to rats, these preparations were equally potent in lowering lymphocyte counts and suppressing both adjuvant arthritis and the primary antibody response to sheep erythrocytes. It is concluded that ALG, as used in these experiments, is a potent immunosuppressive agent without obvious toxic effects.

[Efficacy of intravenous immunoglobulin in Arndt-Gottron scleromyxedema]. / Efficacité des veinoglobulines dans le scléromyxoedème d'Arndt-Gottron.

BACKGROUND: Arndt-Gottron scleromyxedema is characterized by cutaneous mucinosis occasionally associated with systemic disorders, and it has a chronic and unpredictable course. The lesions are due to abnormal fibroblastic activity leading to acid mucopolysaccharide deposits in tissue. We report the case of a 50-year-old woman treated with intravenous immunoglobulin (IVIG), with excellent results in terms of her cutaneous lesions. CASE REPORT: A 50-year-old woman presented with multifocal micropapular lesions and cutaneous sclerosis that progressively limited joint movement and mouth opening and which were associated with a circulating monoclonal IgG Kappa. Previous treatments, including steroids, PUVA therapy, interferon, acitretin, methotrexate, melphalan and D-penicillamin were either ineffective or were stopped because of adverse effects. IVIG resulted in a remarkable and durable response at decreased dosage (0.5 g/kg per day for 3 days) with a 2-month treatment interval. DISCUSSION: IVIG at a dose of 2g/kg for 5 days constitutes a valuable alternative treatment because of its immunomodulatory effect. In scleromyxedema without systemic lesions, we propose a maintenance regimen at lower dosage, i.e. 0.5 g/kg per day for 3 days. CONCLUSION: Since Arndt-Gottron scleromyxedema is a rare disease, no standardized treatment has been yet established. The combination of minimal adverse effects and real efficacy makes IVIG an interesting alternative treatment for this disease.

Antibody Prophylaxis Against Dengue Virus 2 Infection in Non-Human Primates.

Passive immunization with anti-dengue virus (DENV) immune serum globulin (ISG) or monoclonal antibodies (Mabs) may serve to supplement or replace vaccination for short-term dengue immune prophylaxis. In the present study, we sought to establish proof-of-concept by evaluating several DENV-neutralizing antibodies for their ability to protect rhesus macaques against viremia following live virus challenge, including human anti-dengue ISG, and a human Mab (Mab11/wt) and its genetically engineered variant (Mab11/mutFc) that is unable to bind to cells with Fc gamma receptors (FcγR) and potentiate antibody-dependent enhancement (ADE). In the first experiment, groups of animals received ISG or Mab11/wt at low doses (3-10 mg/kg) or a saline control followed by challenge with DENV-2 at day 10 or 30. After passive immunization, only low-titered circulating virus-neutralizing antibody titers were measured in both groups, which were undetectable by day 30. After challenge at day 10, a reduction in viremia duration compared with the control was seen only in the ISG group (75%). However, after a day 30 challenge, no reduction in viremia was observed in both immunized groups. In a second experiment to test the effect of higher antibody doses on short-term protection, groups received either ISG, Mab11/wt, Mab11/mutFc (each at 25 mg/kg) or saline followed by challenge with DENV-2 on day 10. Increased virus-neutralizing antibody titers were detected in all groups at day 5 postinjection, with geometric mean titers (GMTs) of 464 (ISG), 313 (Mab11/wt), and 309 (Mab11/mutFc). After challenge, there was complete protection against viremia in the group that received ISG, and a reduction in viremia duration of 89% and 83% in groups that received Mab11/wt and Mab11/mutFc, respectively. An in vitro ADE assay in Fcγ receptor-bearing K562 cells with sera collected immediately before challenge showed increased DENV-2 infection levels in the presence of both ISG and Mab11/wt, which peaked at a serum dilution of 1:90, but not in Mab11/mutFc containing sera. The results suggest that antibody prophylaxis for dengue might be beneficial in eliminating or reducing viral loads thereby minimizing disease progression. Our results also suggest that blocking FcγR interactions through Mab11 Fc engineering may further prevent ADE.

Inhibition of hemorrhagic and edematogenic activities of snake venoms by a broad-spectrum protease inhibitor, murinoglobulin; the effect on venoms from five different genera in Viperidae family.

In order to obtain basic data on the effect of broad-spectrum protease inhibitor against local symptoms of Viperidae snake envenomation, inhibitory capacity of rat murinoglobulin on local hemorrhagic and edematogenic activities of venoms from Crotalus atrox, Bothrops jararaca, Lachesis muta muta, Trimeresurus flavoviridis and Echis carinatus sochureki were examined. Murinoglobulin, pre-incubated with the crude venoms at 37 degrees C for 15 min, inhibited hemorrhagic activity of all five venoms to various extents. The activity of C. atrox was almost completely inhibited at the murinoglobulin/venom ratio (w/w) of 20. The activity of B. jararaca, Lachesis muta muta and T. flavoviridis venoms was considerably inhibited at the ratio of 20 (77.2, 80.0 and 86.2% inhibition, respectively), however some of the activity still remained even at the ratio of 40 (84.2, 79.8 and 86.2% inhibition, respectively). Among the five venoms, E. c. sochureki venom is quite resistant to murinoglobulin treatment and statistically significant inhibition was only found at the ratio of 40 (64.1% inhibition). Fibrinolytic and gelatinase activities were more susceptible to murinoglobulin inhibition. The treatment at the ratios of 10 and 20 almost completely inhibited respectively the fibrinolytic and the gelatinase activities of all the venoms. Murinoglobulin treatment also significantly inhibited the edematogenic activity of L. muta muta, T. flavoviridis and Echis carinatus sochureki. The treatment of murinoglobulin at the ratio of 40 considerably suppressed the swelling up to 60 min after subcutaneous injection of L. muta muta and E. c. sochureki venoms, and up to 30 min after T. flavoviridis venom injection. Murinoglobulin is a potent inhibitor against local effects of multiple snake venoms in Viperidae family.