Variation in human platelet glycoprotein VI content modulates glycoprotein VI-specific prothrombinase activity

- Glycoprotein VI (GPVI) is a platelet-specific receptor for collagen that figures prominently in signal transduction. An addition to binding to type I and III collagens, GPVI is also bound specifically by collagen-related peptide and convulxin (CVX), a snake venom protein. We developed a quantitative assay of platelet GPVI in which biotin-conjugated CVX binds selectively to GPVI in separated total platelet proteins by a ligand blot procedure. Using this approach, we have documented a 5-fold range in platelet GPVI content among 23 normal healthy subjects. In addition, we have determined that CVX-induced or collagen-related peptide-induced prothrombinase activity is directly proportional to the platelet content of GPVI. A statistically significant correlation was observed at 2 CVX concentrations: 14.7 ng/mL (R(2)=0.854 and P<0.001, n=11) and 22 ng/mL (R(2)=0.776 and P<0.001, n=12). In previous studies, we established a similar range of expression of the integrin collagen receptor alpha(2)beta(1) on platelets of normal subjects. Among 15 donors, there is a direct correlation between platelet alpha(2)beta(1) density and GPVI content (R(2)=0.475 and P=0.004). In view of the well-documented association of GPVI with platelet procoagulant activity, this study suggests that the variation in GPVI content is a potential risk factor that may predispose individuals to hemorrhagic or thromboembolic disorders.

Discordant responses to potent antiretroviral treatment in previously naive HIV-1-infected adults initiating treatment in resource-constrained countries: the antiretroviral therapy in low-income countries (ART-LINC) collaboration

OBJECTIVES: To assess the frequency of and risk factors for discordant responses at 6 months on highly active antiretroviral therapy (HAART) in previously treatment-naive HIV patients from resource-limited countries. METHODS: The Antiretroviral Therapy in Low-Income Countries Collaboration is a network of clinics providing care and treatment to HIV-infected patients in Africa, Latin America, and Asia. Patients who initiated therapy between 1996 and 2004, were aged 16 years or older, and had a baseline CD4 cell count were included in this analysis. Responses were defined based on plasma viral load (PVL) and CD4 cell count at 6 months as complete virologic and immunologic (VR(+)IR(+)), virologic only (VR(+)IR(-)), immunologic only (VR(-)IR(+)), and nonresponse (VR(-)IR(-)). Multinomial logistic regression was used to assess the association between therapy responses and clinical and demographic variables. RESULTS: Of the 3111 patients eligible for analysis, 1914 had available information at 6 months of therapy: 1074 (56.1%) were VR(+)IR(+), 364 (19.0%) were VR(+)IR(-), 283 (14.8%) were (VR(-)IR(+)), and 193 (10.1%) were VR(-)IR(-). OF THE 3111 patients eligible for analysis, 1914 had available information at 6 months of therapy: 1074 (56.1%) were VRIR, 364 (19.0%) were VRIR, 283 (14.8%) were (VRIR), and 193 (10.1%) were VRIR. Compared with complete responders, virologic-only responders were older, had a higher baseline CD4 cell count, had a lower baseline PVL, and were more likely to have received a nonstandard HAART regimen; immunologic-only responders were younger, had a lower baseline CD4 cell count, had a higher baseline PVL, and were more likely to have received a protease inhibitor-based regimen. CONCLUSIONS: The frequency of and risk factors for discordant responses were comparable to those observed in developed countries. Longer follow-up is needed to assess the long-term impact of discordant responses on mortality in these resource-limited settings.

Synthesis of the bicyclo-[4.3.0]thymidyl nucleoside via Pd(II)-mediated ring expansion chemistry

A variety of modified nucleosides to improve antisense oligodeoxynucleotide properties such as target affinity, nuclease resistance, and pharmacokinetics were developed in the last two decades. In the context of conformational restriction we present here the synthesis of the [4.3.0]-bicyclo-DNA thymine monomer via Pd(II)-mediated ring expansion of an intermediate of the tricyclo-DNA synthesis.

Photochemically induced RNA and DNA abasic sites

Two phosphoramidite building blocks were synthesized that can easily be deprotected by UV light to reveal natural abasic sites in oligoribonucleotides as well as in oligodeoxyribonucleotides. Another building block which releases a 2 ′-O-methylated abasic site upon UV radiation is also described.

Meta-analysis: chondroitin for osteoarthritis of the knee or hip

BACKGROUND: Previous meta-analyses described moderate to large benefits of chondroitin in patients with osteoarthritis. However, recent large-scale trials did not find evidence of an effect. PURPOSE: To determine the effects of chondroitin on pain in patients with osteoarthritis. DATA SOURCES: The authors searched the Cochrane Central Register of Controlled Trials (1970 to 2006), MEDLINE (1966 to 2006), EMBASE (1980 to 2006), CINAHL (1970 to 2006), and conference proceedings; checked reference lists; and contacted authors. The last update of searches was performed on 30 November 2006. STUDY SELECTION: Studies were included if they were randomized or quasi-randomized, controlled trials that compared chondroitin with placebo or with no treatment in patients with osteoarthritis of the knee or hip. There were no language restrictions. DATA EXTRACTION: The authors extracted data in duplicate. Effect sizes were calculated from the differences in means of pain-related outcomes between treatment and control groups at the end of the trial, divided by the pooled SD. Trials were combined by using random-effects meta-analysis. DATA SYNTHESIS: 20 trials (3846 patients) contributed to the meta-analysis, which revealed a high degree of heterogeneity among the trials (I2 = 92%). Small trials, trials with unclear concealment of allocation, and trials that were not analyzed according to the intention-to-treat principle showed larger effects in favor of chondroitin than did the remaining trials. When the authors restricted the analysis to the 3 trials with large sample sizes and an intention-to-treat analysis, 40% of patients were included. This resulted in an effect size of -0.03 (95% CI, -0.13 to 0.07; I2 = 0%) and corresponded to a difference of 0.6 mm on a 10-cm visual analogue scale. A meta-analysis of 12 trials showed a pooled relative risk of 0.99 (CI, 0.76 to 1.31) for any adverse event. LIMITATIONS: For 9 trials, the authors had to use approximations to calculate effect sizes. Trial quality was generally low, heterogeneity among the trials made initial interpretation of results difficult, and exploring sources of heterogeneity in meta-regression and stratified analyses may be unreliable. CONCLUSIONS: Large-scale, methodologically sound trials indicate that the symptomatic benefit of chondroitin is minimal or nonexistent. Use of chondroitin in routine clinical practice should therefore be discouraged.

[Lys40(Ahx-DTPA-111In)NH2]-Exendin-4 is a highly efficient radiotherapeutic for glucagon-like peptide-1 receptor-targeted therapy for insulinoma

PURPOSE: Although metabolic changes make diagnosis of insulinoma relatively easy, surgical removal is hampered by difficulties in locating it, and there is no efficient treatment for malignant insulinoma. We have previously shown that the high density of glucagon-like peptide-1 receptors (GLP-1R) in human insulinoma cells provides an attractive target for molecular imaging and internal radiotherapy. In this study, we investigated the therapeutic potential of [Lys(40)(Ahx-DTPA-(111)In)NH(2)]-Exendin-4, an (111)In-labeled agonist of GLP-1, in a transgenic mouse model of human insulinoma. EXPERIMENTAL DESIGN: [Lys(40)(Ahx-DTPA-(111)In)NH(2)]-Exendin-4 was assessed in the Rip1Tag2 mouse model of pancreatic beta-cell carcinogenesis, which exhibits a GLP-1R expression comparable with human insulinoma. Mice were injected with 1.1, 5.6, or 28 MBq of the radiopeptide and sacrificed 7 days after injection. Tumor uptake and response, the mechanism of action of the radiopeptide, and therapy toxicity were investigated. RESULTS: Tumor uptake was >200% injected activity per gram, with a dose deposition of 3 Gy/MBq at 40 pmol [Lys(40)(Ahx-DTPA-(111)In)NH(2)]-Exendin-4. Other GLP-1R-positive organs showed > or =30 times lower dose deposition. A single injection of [Lys(40)(Ahx-DTPA-(111)In)NH(2)]-Exendin-4 resulted in a reduction of the tumor volume by up to 94% in a dose-dependent manner without significant acute organ toxicity. The therapeutic effect was due to increased tumor cell apoptosis and necrosis and decreased proliferation. CONCLUSIONS: The results suggest that [Lys(40)(Ahx-DTPA-(111)In)NH(2)]-Exendin-4 is a promising radiopeptide capable of selectively targeting insulinoma. Furthermore, Auger-emitting radiopharmaceuticals such as (111)In are able to produce a marked therapeutic effect if a high tumor uptake is achieved.

Surveillance systems for sexually transmitted diseases in Switzerland

BACKGROUND: In Switzerland (population 7.4 million), 3 different systems contribute to surveillance for sexually transmitted infections. GOAL: The goal of this study was to compare time trends from surveillance systems for chlamydia, gonorrhea, and syphilis. STUDY DESIGN: We studied surveillance data (1997-2003) from laboratory reports in women and men, men attending dermatology clinics, and women attending gynecologists. RESULTS: Laboratory reports of episodes of Chlamydia trachomatis and Neisseria gonorrhoeae increased by 31% (from 2573 to 3449 cases) and 104% (from 259 to 528 cases), respectively. Over the same period, chlamydia reports from men attending dermatology clinics and women attending gynecologists did not change and dermatology clinic-based reports of gonorrhea in men increased only slightly. Syphilis reports from dermatology clinics increased by 127% (from 22 to 50 cases). CONCLUSIONS: Increases in laboratory reports of chlamydia and gonorrhea were not consistently detected in sentinel populations. Numbers of cases reported to all 3 systems were low. The performance of surveillance systems for sexually transmitted infections should be evaluated regularly.