Amelioration of murine immune thrombocytopenia by CD44 antibodies: a potential therapy for ITP?

To explore the potential for monoclonal antibodies as a treatment for immune thrombocytopenia (ITP) and to further explore their mechanisms of action, we tested 8 monoclonal CD44 antibodies in murine ITP and found 4 antibodies that could successfully ameliorate ITP; 2 of these antibodies function at a full 3-log fold lower dosage compared with IVIg. Further characterization of the 2 most successful antibodies (5035-41.1D and KM114) demonstrated that, similar to IVIg: (1) the presence of the inhibitory IgG receptor FcγRIIB was required for their ameliorative function, (2) complement-deficient mice responded to anti-CD44 treatment, and (3) human transgenic FcγRIIA-expressing mice also responded to the CD44 therapeutic modality. Dissimilar to IVIg, the Fc portion of the CD44 antibody was not required. These data demonstrate that CD44 antibodies can function therapeutically in murine ITP and that they could potentially provide a very-low-dose recombinant therapy for the amelioration of human ITP.     

Endoscopic therapy of Barrett esophagus--a supplement to drug and surgical options?

Within the last few years intestinal metaplasia at the gastroesophageal junction (Barrett's esophagus) has turned out to be a "shooting star" in the field of gastrointestinal diseases. The detection rate of Barrett's epithelium by the endoscopists and pathologists has raised dramatically as well as the incidence of the carcinoma at the gastroesophageal junction. Furthermore the "short Barrett" was discovered as a relevant risk factor for cancer development. To date ablation techniques with thermal devices, photodynamic techniques (PDT) and the mucosal resection (EMR) compete as local endoscopic treatment methods. However to date it is still in discussion whether in case of nondysplastic Barrett's esophagus endoscopic therapy is an "overtreatment" and an "undertreatment" in case of Barrett's with high-grade dysplasia or early cancer. The currently available data are discussed.     

Pre-exposure prophylaxis and antiretroviral resistance: HIV prevention at a cost?

Pre-exposure prophylaxis (PrEP), the use of antiretrovirals (ARVs) by human immunodeficiency virus (HIV)-uninfected individuals to prevent acquisition of the virus during high-risk sexual encounters, enjoyed its first 2 major successes with the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 and the Pre-Exposure Prophylaxis Initiative (iPrEx). These successes were buoyed by additional positive results from the TDF2 and Partners PrEP trials. Although no seroconverters in either arm of CAPRISA developed resistance to tenofovir, 2 participants in iPrEx with undetected, seronegative acute HIV infection were randomized to receive daily oral tenofovir-emtricitabine and resistance to emtricitabine was later discovered in both men. A similar case in the TDF2 study resulted in resistance to both ARVs. These cases prompted us to examine existing literature on the nature of resistance mutations elicited by ARVs used for PrEP. Here, we discuss the impact of signature mutations selected by PrEP, how rapidly these emerge with daily ARV exposure, and the individual-level and public health consequences of ARV resistance.     

Are countries using global fund support to implement HIV drug resistance surveillance? A review of funded HIV grants

The Global Fund to Fight AIDS, Tuberculosis and Malaria (Global Fund) is the largest funder of human immunodeficiency virus (HIV) prevention and treatment programs worldwide. Since 2002, the Global Fund has encouraged grant recipients to implement drug resistance surveillance (DRS) as part of treatment programs. We reviewed documentation of 147 grants funded in 2004-2008 (funding rounds 4-8) to assess grantees' use of funds to support HIV DRS. Overall, 94 grants (64%) described HIV DRS as part of the national treatment program. However, only 32 grants (22%) specifically documented DRS as a grant-funded activity. This review provides baseline information suggesting limited use by countries of Global Fund financing to support HIV DRS. Additional assessment is required to evaluate barriers to using Global Fund grants to support DRS.     

Quercetin as a potential anti-allergic drug: which perspectives?

Flavonoids polyphenolic compounds that exert many anti-inflammatory and anti-microbial effects, and exhibit an anti-allergic action. Quercetin is a flavonoids that recently has raised many issues and shown evidence about its action as a potential drug to allergy. A Chinese herbal formula, known as Food Allergy Herbal Formula (FAHF) has been related with blocking of anaphylaxis to peanuts (PNA) in mouse models. Quercetin appears to possess the same potential of FAHF as a safe anti-allergic substance but it opens only a wide perspective, at the moment, due to several complex issues that hamper the possibility to use natural medicine and phytochemicals as true drugs.     

Thromboelastography: potential bedside tool to assess the effects of antiplatelet therapy?

Modified thrombelastography (TEG) is a simple point of care test that provides an overall assessment of ex vivo clot formation and currently has limited clinical application. We evaluated the ability of TEG to assess the effects of antiplatelet therapy on clot formation using a novel assessment parameter (the area under curve). Forty healthy volunteers were divided into four groups of 10. Group A took aspirin 75 mg once daily for 7 days followed by aspirin 75 mg and clopidogrel 75 mg once daily in combination for 7 more days. Blood samples were taken for analysis at day 0 and days 7 and 14. Group B took a single 300 mg dose of aspirin. Group C took 600 mg of clopidogrel only. Group D took 300 mg of aspirin and 600 mg of clopidogrel at the same time. For groups B, C and D blood was taken prior to drug administration and at 2, 6 and 24 h afterwards. Each sample was tested by TEG in four channels following activation using (1) kaolin, (2) activator F (Act F), a direct activator of fibrin, (3) Act F + arachidonic acid (AA) and (4) Act F + adenosine diphosphate (ADP). Parameters measured included the maximum amplitude (MA) of the clot and the area under the TEG-generated curve at 1 h. Significant, time-dependent reductions in MA and area were seen in the AA-activated samples following administration of aspirin in all groups as compared to baseline. By contrast, there were no significant differences in MA or area in the AA-activated samples with clopidogrel alone. Significant reductions were also seen in MA and area in ADP-activated samples from volunteers treated with clopidogrel as compared to baseline. Three out of 10 subjects receiving 600 mg clopidogrel had a reduction in their responses of 30% or less, thus identifying them as relatively resistant to the drug. This study identifies a rapid, reliable method for assessing the time-dependent effects of antiplatelet therapy on clotting using a novel parameter of area of the TEG trace, which could have an important clinical application as a point of care test of efficacy, particularly in the context of acute coronary syndromes and percutaneous coronary intervention.     

P-Glycoprotein and transporter MRP1 reduce HIV protease inhibitor uptake in CD4 cells: potential for accelerated viral drug resistance?

BACKGROUND: The multidrug transporters P-glycoprotein (P-gp) and MRP1 are functionally expressed in several subclasses of lymphocytes. HIV-1 protease inhibitors interact with both; consequently the transporters could reduce the local concentration of HIV-1 protease inhibitors and, thus, influence the selection of viral mutants. OBJECTIVES: To study the effect of the expression of P-gp and MRP1 on the transport and accumulation of HIV-1 protease inhibitors in human lymphocytes and to study the effects of specific P-gp and MRP1 inhibitors. METHODS: The initial rate and the steady-state intracellular accumulation of radiolabelled ritonavir, indinavir, saquinavir and nelfinavir was measured in three human lymphocyte cell lines: control CEM cells, CEM-MDR cells, which express 30-fold more P-gp than CEM cells, and CEM-MRP cells, which express fivefold more MRP1 protein than CEM cells. The effect of specific inhibitors of P-gp (GF 120918) and MRP1 (MK 571) was also examined. RESULTS: Compared with CEM cells, the initial rates of uptake and the steady-state intracellular concentrations of all protease inhibitors are significantly reduced in CEM-MDR cells. The intracellular concentrations of the protease inhibitors are increased upon co-administration with GF 120918, in some cases to levels approaching those in CEM cells. The intracellular concentrations of the protease inhibitors are also significantly reduced in CEM-MRP cells. Co-administration with MK -571 can partially overcome these effects. CONCLUSIONS: The overexpression of multidrug transporters significantly reduces the accumulation of protease inhibitors at this major site of virus replication, which, potentially, could accelerate the acquisition of viral resistance. Targeted inhibition of P-gp may represent an important strategy by which this problem can be overcome.     

Lymphedema: which drug therapy?

Treatment of primary or secondary lymphedema includes essentially complex decongestive physiotherapy. For many years now, drugs active in reducing volume of lymphedema are prospected. But few studies are available. Only few drugs have been tested. Diuretics have been the first to be used with short and brief efficacy. Benzopyrones were the most tested product with encouraging but conflicting results. New treatments are proposed without randomized controlled studies. Prevention of lymphedema remains essential in particular after treatment of breast cancer.     

Virologic and immunologic response to antiretroviral therapy and predictors of HIV type 1 drug resistance in children receiving treatment in Abidjan, Côte d'Ivoire

We describe changes in HIV-1 viral load, CD4+ T cell percentage, and incidence of drug resistance and factors associated with drug resistance for 134 children receiving antiretroviral therapy (ART) for approximately 1 year in Abidjan. Between August 1998 and September 2003, ART was initiated for 395 HIV-infected children ages 0-15 years in the C?te d'Ivoire national drug access initiative. All 1-year samples with detectable HIV RNA >1000 copies/ml were tested for HIV-1 drug resistance and changes in viral load and CD4+ T cell counts were also determined. At treatment initiation, 80% of children had CD4+ T cell percentages <15% and a median viral RNA load of 5.6 log copies/ml. The median age at treatment initiation was 7 years with only 25% of patients less than 4 years of age. Of the 134 children receiving therapy, 72 (54%) had undetectable viral load. The estimated 1-year viral load decline was 1.9 log10 copies/ml and the CD4+ T cell percentage increase was 10.9%. The estimated 1-year cumulative probability for developing any class of drug resistance was 0.44 (95% CI, 0.35, 0.53). In a multivariate analysis, the magnitude of virologic response to therapy was inversely associated with development of drug resistance. Children with less CD4+ T cell rise from baseline values and the use of dual therapy were also associated with the development of drug resistance. Guidelines are needed for the treatment of pediatric HIV infection in Africa in order to minimize the occurrence of drug resistance and enhance better virologic, immunologic, and clinical outcomes.     

Resistance to obesity and resistance to atherosclerosis: Is there a metabolic link?

AimThis review deals with the question whether resistance to obesity affects resistance to atherosclerosis.Data synthesisResistance to diet-induced obesity in inbred mouse strains involves an adequate response to Leptin, the main regulator of the energy balance cycle. Leptin, an adipokine with both central and peripheral targets, regulates food intake and energy expenditure. Adequate response to leptin involves repression of stearoyl-CoA desaturase, activation of Amp-activated protein-kinase and uncoupling proteins, resulting in fatty acid oxidation and energy expenditure. Most of the obesity-resistant strains are also resistant to atherosclerosis, but so far no information concerning the response to the leptin cycle is available in these strains when bred onto a LDLR^−/− or apoE^−/− background. Recent studies in mouse strains on an atherosclerosis permissive background have identified genetic links between obesity and atherosclerosis. Moreover, information derived from studies on mice was applied in order to learn about the metabolic effectors in humans and is included in this review.ConclusionsThe data presented in this review provide recent information concerning metabolic pathways that play an important role in the regulation of energy balance, a prerequisite for resistance to obesity. Hopefully they will provide a background for future genetic studies involved in resistance to atherosclerosis.