Changes in biomarkers of liver disease during successful combination antiretroviral therapy in HIV-HCV-coinfected individuals.

BACKGROUND: We investigated changes in biomarkers of liver disease in HIV-HCV-coinfected individuals during successful combination antiretroviral therapy (cART) compared to changes in biomarker levels during untreated HIV infection and to HIV-monoinfected individuals. METHODS: Non-invasive biomarkers of liver disease (hyaluronic acid [HYA], aspartate aminotransferase-to-platelet ratio index [APRI], Fibrosis-4 [FIB-4] index and cytokeratin-18 [CK-18]) were correlated with liver histology in 49 HIV-HCV-coinfected patients. Changes in biomarkers over time were then assessed longitudinally in HIV-HCV-coinfected patients during successful cART (n=58), during untreated HIV-infection (n=59), and in HIV-monoinfected individuals (n=17). The median follow-up time was 3.4 years on cART. All analyses were conducted before starting HCV treatment. RESULTS: Non-invasive biomarkers of liver disease correlated significantly with the histological METAVIR stage (P<0.002 for all comparisons). The mean ±sd area under the receiver operating characteristic (AUROC) curve values for advanced fibrosis (≥F3 METAVIR) for HYA, APRI, FIB-4 and CK-18 were 0.86 ±0.05, 0.84 ±0.08, 0.80 ±0.09 and 0.81 ±0.07, respectively. HYA, APRI and CK-18 levels were higher in HIV-HCV-coinfected compared to HIV-monoinfected patients (P<0.01). In the first year on cART, APRI and FIB-4 scores decreased (-35% and -33%, respectively; P=0.1), mainly due to the reversion of HIV-induced thrombocytopaenia, whereas HYA and CK-18 levels remained unchanged. During long-term cART, there were only small changes (<5%) in median biomarker levels. Median biomarker levels changed <3% during untreated HIV-infection. Overall, 3 patients died from end-stage liver disease, and 10 from other causes. CONCLUSIONS: Biomarkers of liver disease highly correlated with fibrosis in HIV-HCV-coinfected individuals and did not change significantly during successful cART. These findings suggest a slower than expected liver disease progression in many HIV-HCV-coinfected individuals, at least during successful cART.

Place de l'aspirine en prévention primaire des maladies cardiovasculaires [The role of aspirin in the primary prevention of cardiovascular disease]

For persons without cardiovascular disease, the benefit of aspirin in primary prevention has been controversial until the recent publication of several major randomized controlled trials. Since then, several medical societies recommend that clinicians discuss aspirin prevention with adults at high cardiovascular risk. Patients with low cardiovascular risk are unlikely to benefit from aspirin, as potential harms (hemorrhagic strokes, gastrointestinal bleedings) may outweigh benefits. Aspirin should be recommended in primary prevention only in patients with a 10-year cardiovascular risk > or = 10% or in diabetic patients aged > or = 40 years with a concomitant cardiovascular risk factor, after assessing contraindications for aspirin and individual's preferences for the risks and benefits associated with aspirin.

Thrombin-receptor antagonist vorapaxar in acute coronary syndromes

Background: Vorapaxar is a new oral protease-activatedreceptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation. Methods: In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization. RESULTS: Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (KaplanMeier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P = 0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P = 0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups. Conclusions: In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.)

Medroxyprogesterone abrogates the inhibitory effects of estradiol on vascular smooth muscle cells by preventing estradiol metabolism.

Sequential conversion of estradiol (E) to 2/4-hydroxyestradiols and 2-/4-methoxyestradiols (MEs) by CYP450s and catechol-O-methyltransferase, respectively, contributes to the inhibitory effects of E on smooth muscle cells (SMCs) via estrogen receptor-independent mechanisms. Because medroxyprogesterone (MPA) is a substrate for CYP450s, we hypothesized that MPA may abrogate the inhibitory effects of E by competing for CYP450s and inhibiting the formation of 2/4-hydroxyestradiols and MEs. To test this hypothesis, we investigated the effects of E on SMC number, DNA and collagen synthesis, and migration in the presence and absence of MPA. The inhibitory effects of E on cell number, DNA synthesis, collagen synthesis, and SMC migration were significantly abrogated by MPA. For example, E (0.1micromol/L) reduced cell number to 51+/-3.6% of control, and this inhibitory effect was attenuated to 87.5+/-2.9% by MPA (10 nmol/L). Treatment with MPA alone did not alter any SMC parameters, and the abrogatory effects of MPA were not blocked by RU486 (progesterone-receptor antagonist), nor did treatment of SMCs with MPA influence the expression of estrogen receptor-alpha or estrogen receptor-beta. In SMCs and microsomal preparations, MPA inhibited the sequential conversion of E to 2-2/4-hydroxyestradiol and 2-ME. Moreover, as compared with microsomes treated with E alone, 2-ME formation was inhibited when SMCs were incubated with microsomal extracts incubated with E plus MPA. Our findings suggest that the inhibitory actions of MPA on the metabolism of E to 2/4-hydroxyestradiols and MEs may negate the cardiovascular protective actions of estradiol in postmenopausal women receiving estradiol therapy combined with administration of MPA.

Emerging viral infections after hematopoietic cell transplantation.

This overview summarizes recent data on emerging viruses after hematopoietic cell transplantation (HCT), including adenovirus, BK virus, human metapneumovirus (hMPV), and human herpesvirus (HHV) 6. The increased recognition of these infections is due to improved molecular detection methods, increased surveillance and more profound immunosuppression in the host. Adenovirus can cause serious disease especially in T-cell depleted transplant recipients. Adenovirus viremia is an important risk factor for disease in this setting. BK virus has been associated with hemorrhagic cystitis in HCT recipients. BK viremia is significantly associated with hemorrhagic cystitis. hMPV shows a seasonal distribution and can cause fatal pneumonia in HCT recipients. hMPV may be the etiology of some cases previously categorized as idiopathic pneumonia syndrome. HHV-6 commonly leads to viremia in HCT recipients. HHV-6 has been strongly associated with encephalitis and delayed platelet engraftment. Prospective studies are needed to further examine epidemiology, disease associations, and management strategies for these viruses.

Rationale and design of a randomized, double-blind, parallel-group study of terutroban 30 mg/day versus aspirin 100 mg/day in stroke patients: the prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) study.

BACKGROUND: Ischemic stroke is the leading cause of mortality worldwide and a major contributor to neurological disability and dementia. Terutroban is a specific TP receptor antagonist with antithrombotic, antivasoconstrictive, and antiatherosclerotic properties, which may be of interest for the secondary prevention of ischemic stroke. This article describes the rationale and design of the Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic Attack (PERFORM) Study, which aims to demonstrate the superiority of the efficacy of terutroban versus aspirin in secondary prevention of cerebrovascular and cardiovascular events. METHODS AND RESULTS: The PERFORM Study is a multicenter, randomized, double-blind, parallel-group study being carried out in 802 centers in 46 countries. The study population includes patients aged > or =55 years, having suffered an ischemic stroke (< or =3 months) or a transient ischemic attack (< or =8 days). Participants are randomly allocated to terutroban (30 mg/day) or aspirin (100 mg/day). The primary efficacy endpoint is a composite of ischemic stroke (fatal or nonfatal), myocardial infarction (fatal or nonfatal), or other vascular death (excluding hemorrhagic death of any origin). Safety is being evaluated by assessing hemorrhagic events. Follow-up is expected to last for 2-4 years. Assuming a relative risk reduction of 13%, the expected number of primary events is 2,340. To obtain statistical power of 90%, this requires inclusion of at least 18,000 patients in this event-driven trial. The first patient was randomized in February 2006. CONCLUSIONS: The PERFORM Study will explore the benefits and safety of terutroban in secondary cardiovascular prevention after a cerebral ischemic event.

Prise en charge des plaies, quoi de neuf? [Advances in wound care]

Wound care made great progress during last years related to several factors. The first is an awakening of the importance of wounds. The progress made in the comprehension of the physiopathology of wounds led to innovations in all stages of this complex process which is the wound healing. Autologus platelet concentrate producing growth factors are in use to stimulate the first phase of the healing. The second phase which is the phase of proliferation and secretion is currently better managed with new categories of bandages which are true local treatments. The nutrition became one of the pillars of wound treatments especially among old patients. The reconstructive surgery took great steps since the physiology and the vascular anatomy of the skin and soft tissues are better known. Finally the bio-engineering has entered the treatment of the wound there is more than 20 years ago and methods have improved and become more reliable

Bilateral periorbital ecchymoses. An often missed sign of amyloid purpura.

Immunoglobulin light chain (AL) amyloidosis is a systemic disease caused by a plasma cell clone synthesizing an unstable light chain, which forms amyloid fibrils. Deposition of amyloid fibrils affects primarily kidney, heart, nervous system, spleen, liver, gastrointestinal tract and the skin. Skin bleeding in these patients is called amyloid purpura. Classically, it occurs spontaneously and bilaterally in the periorbital region. Vessel wall fragility and damage by amyloid are the principal causes of periorbital and gastrointestinal bleeding. Additionally, coagulation factor inhibitory circulating paraprotein, hyperfibrinolysis, platelet dysfunction or isolated acquired factor X deficiency may contribute to even more severe, diffuse bleedings. Early diagnosis remains essential for improving prognosis of patients with AL amyloidosis. Although pictures of amyloid purpura have been often reported in the literature, the clinical diagnosis may be delayed. We report a case of cutaneous manifestation of AL amyloidosis diagnosed not until one year after the appearance of the first symptoms. Diagnostic work-up revealed that the patient suffered from multiple myeloma with secondary AL amyloidosis. Atraumatic ecchymoses at the face, particularly the eyelids as well as in the neck should raise the suspicion of AL amyloidosis.

Nonactivated versus thrombin-activated platelets on wound healing and fibroblast-to-myofibroblast differentiation in vivo and in vitro.

Background: Platelet preparations for tissue healing are usually preactivated before application to deliver concentrated growth factors. In this study, the authors investigated the differences between nonactivated and thrombin-activated platelets in wound healing.Methods: The healing effects (i.e., wound closure, myofibroblast formation, and angiogenesis) of nonactivated and thrombin-activated platelets were compared in experimental wounds in diabetic (db/db) animals. In vitro, fibroblast phenotype and function were tested in response to platelets and activated platelets. No treatment served as a negative control.Results: Wounds treated with platelets reached 90 percent closure after 15 days, faster than activated platelets (26 days), and with higher levels of myofibroblasts and angiogenesis. In vitro, platelets enhanced cell migration and induced twofold higher myofibroblast differentiation and contraction compared with activated platelets.Conclusions: Platelets stimulate wound healing more efficiently compared with activated platelets by enhancing fibroblast differentiation and contractile function. Similar levels of growth factors may induce different biological effects when delivered "on demand" rather than in an initial bolus. (Plast. Reconstr. Surg. 129: 46e, 2012.)

Infectivity of Lactobacillus rhamnosus and Lactobacillus paracasei isolates in a rat model of experimental endocarditis.

The potential pathogenicity of selected (potentially) probiotic and clinical isolates of Lactobacillus rhamnosus and Lactobacillus paracasei was investigated in a rat model of experimental endocarditis. In addition, adhesion properties of the lactobacilli for fibrinogen, fibronectin, collagen and laminin, as well as the killing activity of the platelet-microbicidal proteins fibrinopeptide A (FP-A) and connective tissue activating peptide 3 (CTAP-3), were assessed. The 90 % infective dose (ID(90)) of the L. rhamnosus endocarditis isolates varied between 10(6) and 10(7) c.f.u., whereas four of the six (potentially) probiotic L. rhamnosus isolates showed an ID(90) that was at least 10-fold higher (10(8) c.f.u.) (P<0.001). In contrast, the two other probiotic L. rhamnosus isolates exhibited an ID(90) (10(6) and 10(7) c.f.u.) comparable to the ID(90) of the clinical isolates of this species investigated (P>0.05). Importantly, these two probiotic isolates shared the same fluorescent amplified fragment length polymorphism cluster type as the clinical isolate showing the lowest ID(90) (10(6) c.f.u.). L. paracasei tended to have a lower infectivity than L. rhamnosus (ID(90) of 10(7) to > or =10(8) c.f.u.). All isolates had comparable bacterial counts in cardiac vegetations (P>0.05). Except for one L. paracasei strain adhering to all substrates, all tested lactobacilli adhered only weakly or not at all. The platelet peptide FP-A did not show any microbicidal activity against the tested lactobacilli, whereas CTAP-3 killed the majority of the isolates. In general, these results indicate that probiotic lactobacilli display a lower infectivity in experimental endocarditis compared with true endocarditis pathogens. However, the difference in infectivity between L. rhamnosus endocarditis and (potentially) probiotic isolates could not be explained by differences in adherence or platelet microbicidal protein susceptibility. Other disease-promoting factors may exist in these organisms and warrant further investigation.

Early prediction of response to sunitinib after imatinib failure by 18F-fluorodeoxyglucose positron emission tomography in patients with gastrointestinal stromal tumor.

PURPOSE: Positron emission tomography with (18)F-fluorodeoxyglucose (FDG-PET) was used to evaluate treatment response in patients with gastrointestinal stromal tumors (GIST) after administration of sunitinib, a multitargeted tyrosine kinase inhibitor, after imatinib failure. PATIENTS AND METHODS: Tumor metabolism was assessed with FDG-PET before and after the first 4 weeks of sunitinib therapy in 23 patients who received one to 12 cycles of sunitinib therapy (4 weeks of 50 mg/d, 2 weeks off). Treatment response was expressed as the percent change in maximal standardized uptake values (SUV). The primary end point of time to tumor progression was compared with early PET results on the basis of traditional Response Evaluation Criteria in Solid Tumors (RECIST) criteria. RESULTS: Progression-free survival (PFS) was correlated with early FDG-PET metabolic response (P < .0001). Using -25% and +25% thresholds for SUV variations from baseline, early FDG-PET response was stratified in metabolic partial response, metabolically stable disease, or metabolically progressive disease; median PFS rates were 29, 16, and 4 weeks, respectively. Similarly, when a single FDG-PET positive/negative was considered after 4 weeks of sunitinib, the median PFS was 29 weeks for SUVs less than 8 g/mL versus 4 weeks for SUVs of 8 g/mL or greater (P < .0001). None of the patients with metabolically progressive disease subsequently responded according to RECIST criteria. Multivariate analysis showed shorter PFS in patients who had higher residual SUVs (P < .0001), primary resistance to imatinib (P = .024), or nongastric GIST (P = .002), regardless of the mutational status of the KIT and PDGFRA genes. CONCLUSION: Week 4 FDG-PET is useful for early assessment of treatment response and for the prediction of clinical outcome. Thus, it offers opportunities to individualize and optimize patient therapy.

Aspirin vs anticoagulation in carotid artery dissection: a study of 298 patients

BACKGROUND: No randomized study has yet compared efficacy and safety of aspirin and anticoagulants in patients with spontaneous dissection of the cervical carotid artery (sICAD). METHODS: Prospectively collected data from 298 consecutive patients with sICAD (56% men; mean age 46 +/- 10 years) treated with anticoagulants alone (n = 202) or aspirin alone (n = 96) were retrospectively analyzed. Admission diagnosis was ischemic stroke in 165, TIA in 37, retinal ischemia in 8, and local symptoms and signs (headache, neck pain, Horner syndrome, cranial nerve palsy) in 80 patients, while 8 patients were asymptomatic. Clinical follow-up was obtained after 3 months by neurologic examination (97% of patients) or structured telephone interview. Outcome measures were 1) new cerebral ischemic events, defined as ischemic stroke, TIA, or retinal ischemia, 2) symptomatic intracranial hemorrhage, and 3) major extracranial bleeding. RESULTS: During follow-up, ischemic events were rare (ischemic stroke, 0.3%; TIA, 3.4%; retinal ischemia, 1%); their frequency did not significantly differ between patients treated with anticoagulants (5.9%) and those treated with aspirin (2.1%). The same was true for hemorrhagic adverse events (anticoagulants, 2%; aspirin, 1%). New ischemic events were significantly more frequent in patients with ischemic events at onset (6.2%) than in patients with local symptoms or asymptomatic patients (1.1%). CONCLUSIONS: Within the limitations of a nonrandomized study, our data suggest that frequency of new cerebral and retinal ischemic events in patients with spontaneous dissection of the cervical carotid artery is low and probably independent of the type of antithrombotic treatment (aspirin or anticoagulants).

Glial hyaluronate-binding protein expression in aggregating brain cell cultures.

We analyzed the expression of glial hyaluronate-binding protein (GHAP), an integral component of the extracellular matrix, in aggregating brain cell cultures of fetal rat telencephalon using immunofluorescence. GHAP immunoreactivity appeared after 1 week in culture, simultaneous with the first deposits of myelin basic protein, and showed a development-dependent increase. Comparison of glia-enriched and neuron-enriched cultures showed that only glial cells express GHAP. Three peptide growth factors, epidermal growth factor, fibroblast growth factor and platelet-derived growth factor, which are known to stimulate the differentiation of glial cells, modulated the deposit of GHAP immunoreactivity. The 3-dimensional structure of aggregate cultures promoted GHAP deposition, suggesting that cell-cell interactions are required for extracellular matrix formation. Furthermore GHAP production seemed to depend on the developmental stage of the glial cells.

Effect of cocoa powder in the prevention of cardiovascular disease: biological, consumption and inflammatory biomarkers. A metabolomic approach

Numerous health benefits have been attributed to cocoa and its derived products in the last decade including antioxidant, anti-platelet and positive effects on lipid metabolism and vascular function. Inflammation plays a key role in the initiation and progression of atherosclerosis. However, cocoa feeding trials focused on inflammation are still rare and the results yielded are controversial. Health effects derived from cocoa consumption have been partly attributed to its polyphenol content, in particular of flavanols. Bioavailability is a key issue for cocoa polyphenols in order to be able to exert their biological activities. In the case of flavanols, bioavailability is strongly influenced by several factors, such as their degree of polymerization and the food matrix in which the polyphenols are delivered. Furthermore, gut has become an active site for the metabolism of procyanidins (oligomeric and polymeric flavanols). Estimation of polyphenol consumption or exposure is also a very challenging task in Food and Nutrition Science in order to correlate the intake of phytochemicals with in vivo health effects. In the area of nutrition, modern analytical techniques based on mass spectrometry are leading to considerable advances in targeted metabolite analysis and particularly in Metabolomics or global metabolite analysis. In this chapter we have summarized the most relevant results of our recent research on the bioavailability of cocoa polyphenols in humans and the effect of the matrix in which cocoa polyphenols are delivered considering both targeted analysis and a metabolomic approach. Furthermore, we have also summarized the effect of long-term consumption of cocoa powder in patients at high risk of cardiovascular disease (CVD) on the inflammatory biomarkers of atherosclerosis.