Safety, efficacy, and pharmacokinetics of adefovir dipivoxil in children and adolescents (age 2 to <18 years) with chronic hepatitis B

This study investigated the efficacy, safety, and pharmacokinetics of adefovir dipivoxil (ADV) in children and adolescents with chronic hepatitis B (CHB). A total of 173 treatment-naive and treatment-experienced children with hepatitis B e antigen (HBeAg)+ CHB were randomized to ADV or placebo. Randomization was stratified by age (2 to <7 years; >7 to <12 years; >12 to <18 years) and prior treatment. Significantly more ADV-treated subjects aged 12 to <18 years achieved the primary efficacy endpoint (serum hepatitis B virus [HBV] DNA <1,000 copies/mL and normal alanine aminotransferase) compared to placebo-treated subjects (23% versus 0%; P = 0.007). In the younger groups, differences between ADV and placebo at the end of blinded treatment were not statistically significant. More ADV-treated subjects had HBeAg seroconversion: 18 of 113 (15.9%) versus three of 57 (5.3%) (but P = 0.051), and more met the combined endpoint of HBeAg seroconversion, HBV DNA <1,000 copies/mL and normal alanine aminotransferase (12/113 versus 0/57; P = 0.009). No subject developed an ADV-associated mutation that has been linked to HBV DNA rebound (that is, mutations rtN236T or rtA181V). ADV plasma concentrations were comparable across groups and within the target range. ADV treatment was well tolerated; no new safety issues were identified. Treatment-related adverse events were reported for 12% of ADV-treated and 10% of placebo-treated subjects. After 48 weeks of ADV treatment, antiviral efficacy in subjects ages 12 to <18 years with HBeAg+ CHB was similar to that observed in a study in adult treatment-naive subjects with HBeAg+ CHB. ADV was not different from placebo in subjects aged 2 to 11 years despite adequate plasma ADV exposure in all three age groups. CONCLUSION: ADV showed significant antiviral efficacy in subjects aged 12 to 17 years with HBeAg+ CHB, but was not different from placebo in subjects aged 2 to 11 years.     

Mechanism of recurrence after radiofrequency catheter ablation of atrial fibrillation guided by complex fractionated atrial electrograms

Background A better understanding of the mechanisms of recurrent atrial fibrillation (AF) after radiofrequency ablation of complex, fractionated atrial electrograms (CFAEs) may be helpful for refining AF ablation strategies. Methods and results Electrogram-guided ablation (EGA) was repeated in 30 consecutive patients (mean age = 59 ± 8 years) for recurrent paroxysmal AF, 10 ± 4 months after the first ablation. During the first procedure, CFAEs were targeted without isolating all pulmonary veins (PVs). During repeat ablation, all PVs and the superior vena cava (SVC) were mapped with a circular catheter and the left atrium was mapped for CFAEs. EGA was performed until AF was rendered noninducible or all identified CFAEs were eliminated. During repeat ablation, ≥1 PV tachycardia was found in 83 PVs in 29 of the 30 patients (97%). Among these 83 PVs, 63 (76%) had not been completely isolated previously. During repeat ablation, drivers originating in a PV or PV antrum were identified only after infusion of isoproterenol (20 μg/min) in 12 patients (40%). At 9 ± 4 months of follow-up after the repeat ablation procedure, 21 of the 30 patients (70%) were free from recurrent AF and flutter without antiarrhythmic drugs. Conclusions Recurrence of AF after EGA is usually due to PV tachycardias. Therefore, it may be preferable to systematically map and isolate all PVs during the first procedure. High-dose isoproterenol may be helpful to identify AF drivers.     

The influence of patient adherence on anticoagulation control with warfarin: results from the International Normalized Ratio Adherence and Genetics (IN-RANGE) Study

BACKGROUND: Warfarin sodium is a highly efficacious drug, but proper levels of anticoagulation are difficult to maintain. Conflicting data exist on the influence of patient adherence on anticoagulation control. METHODS: We performed a prospective cohort study at 3 anticoagulation clinics to determine the effect of adherence on anticoagulation control. Patients treated with warfarin with a target international normalized ratio of 2.0 to 3.0 were monitored with electronic Medication Event Monitoring System (MEMS) medication bottle caps. Detailed information was collected on other factors that might alter warfarin response. RESULTS: Among 136 participants observed for a mean of 32 weeks, 92% had at least 1 missed or extra bottle opening; 36% missed more than 20% of their bottle openings; and 4% had more than 10% extra bottle openings. In multivariable analyses, there was a significant association between underadherence and underanticoagulation. For each 10% increase in missed pill bottle openings, there was a 14% increase in the odds of underanticoagulation (P<.001); participants with more than 20% missed bottle openings (1-2 missed days each week) had more than a 2-fold increase in the odds of underanticoagulation (adjusted odds ratio, 2.10; 95% confidence interval, 1.48-2.96). Participants who had extra pill bottle openings on more than 10% of days had a statistically significant increase in overanticoagulation (adjusted odds ratio, 1.73; 95% confidence interval, 1.09-2.74). CONCLUSION: Patients have substantial difficulties maintaining adequate adherence with warfarin regimens, and this poor adherence has a significant effect on anticoagulation control.     

Low Molecular Weight Heparin and Unfractionated Heparin in the Early Pharmacologic Management of Acute Coronary Syndromes: A Meta-analysis of Randomized Clinical Trials

Background: The standard of care in Acute Coronary Syndromes (ACS) includes a full complement of antischemic and antithrombotic therapy. Although aspirin is used widely and concomitant anticoagulation is recommended, the comparative benefits of low molecular weight heparin (LMWH) and unfractionated heparin (UFH) have not been defined. Methods/Results: A meta-analysis including all randomized clinical trials comparing LMWH and UFH for the treatment of non-ST segment elevation acute coronary syndromes was performed. Risk ratios (RR), using the DerSimonian-Laird Model, were calculated from a total of 13,320 patients. Death (RR 0.98, 95% CI 0.73–1.31), death and myocardial infarction (MI) (RR 0.86, 95% CI 0.74–1.01), death, MI, recurrent angina or revascularization (RR 0.89, 95% CI 0.74–1.07) and major hemorrhage (RR 1.01, 95% CI 0.81–1.25) occurred with similar frequencies for the anticoagulant-based strategies. Conclusions: Fixed dose LMWH therapy given subcutaneously compares favorably with UFH titrated to a target level of anticoagulation and should be considered a safe, effective, and clinically acceptable alternative in the early management of patients with non-ST segment elevation ACS. The superiority of LMWH preparations characterized by high in vitro factor Xa to thrombin inhibitory capacity is supported by clinic trial data but requires further investigation.     

Trophoblast differentiation in embryoid bodies derived from human embryonic stem cells

Trophoblast differentiation and early placental development are essential for the establishment of pregnancy, yet these critical events are not readily investigated in human pregnancy. We used embryoid bodies (EBs) prepared from human embryonic stem (hES) cells as an in vitro model of early human development. The levels of human chorionic gonadotropin (hCG), progesterone, and estradiol-17beta in medium from hES cell-derived EBs grown in suspension culture for 1 wk were higher than unconditioned culture medium or medium from undifferentiated hES cells or spontaneously differentiated hES cell colonies. EBs were explanted into Matrigel (MG) "rafts" and cultured for up to 53 d. During the first 7-10 d of three-dimensional growth in MG, small protrusions appeared on the outer surface of EBs, some of which subsequently extended into multicellular outgrowths. The secretion of hCG, progesterone, and estradiol-17beta began to increase on approximately d 20 of MG culture and remained dramatically elevated over the next 30 d. EBs maintained in suspension culture failed to demonstrate this elevation in hormone secretion. Suspension-cultured and MG-embedded EBs exhibited widespread expression of cytokeratins 7/8, demonstrating extensive epithelial differentiation as well as consistent hCG expression. We propose that hES cell-derived EBs may be a useful model for investigation of human trophoblast differentiation and placental morphogenesis.     

An IL-7-dependent rebound in thymic T cell output contributes to the bone loss induced by estrogen deficiency

The bone wasting induced by estrogen deficiency is, in part, a consequence of increased T cell production of the osteoclastogenic cytokine TNF-alpha. This phenomenon is due to an expansion of T cells, but the responsible mechanism is unknown. We now show that ovariectomy (ovx) disregulates T lymphopoiesis and induces bone loss by stimulating, through a rise in IL-7 levels, both thymic-dependent differentiation of bone marrow-derived progenitors and thymic-independent, peripheral expansion of mature T cells. Attesting to the relevance of the thymic effects, thymectomy decreases by approximately 50% the bone loss and the stimulation of T lymphopoiesis induced by ovx. In contrast, in vivo attenuation of the elevated IL-7 completely prevents the stimulation of T lymphopoiesis and the bone loss that follow ovx. Thus, the disruption of both T cell and bone homeostasis induced by ovx is mediated by IL-7 and due to both the thymic and extrathymic mechanisms. We conclude that IL-7 is a pivotal upstream target through which estrogen regulates hematopoietic and immune functions that are critical for bone homeostasis.     

Age-related macular disease: how to assess the retina using scanning laser techniques?

Age-related macular disease (AMD) is the leading cause of legal blindness among the elderly in Western nations. The magnitude of the problem will undoubtedly grow, as age is a significant risk factor and the number of people aged 65 and over is projected to increase. The most frequent cause of severe visual loss associated with AMD is irreversible degeneration of the overlying neurosensory retina, caused by the growth of choroidal neovascularization or, alternatively, the development of geographic atrophy of the retinal pigment epithelium. Today, we are able to image the human retina in vivo. Recently developed imaging techniques provide better assessment of retinal pathology than conventional ophthalmoscopy alone. This overview presents the most recent devices available for retinal imaging, which mainly exploit laser technology such as scanning laser ophthalmoscopy. Its basic principles, as well as its characteristics for imaging and functional assessment of the retina, are described. Lastly, potential benefits for clinical routine, rehabilitation strategies in AMD, and future research aspects are discussed.     

Minimal disease activity, remission, and the long-term outcomes of rheumatoid arthritis

OBJECTIVE: To determine the prevalence of minimal disease activity (MDA) and remission in patients with rheumatoid arthritis (RA), to assess the effect of anti-tumor necrosis factor (anti-TNF) therapy on MDA, and to determine the extent to which MDA status improves long-term outcomes. METHODS: Using the Patient Activity Scale (PAS) as a surrogate, we assessed the prevalence of MDA and remission in 18,062 patients with RA using the newly developed Outcome Measures in Rheumatology Clinical Trials (OMERACT) criteria for MDA. RESULTS: MDA was noted in 20.2% of 18,062 patients and persistent MDA, operationally defined as having MDA during >or=2 consecutive 6-month observation periods, occurred in 13.5% of 7,433 patients followed longitudinally. Disease activity at remission levels was noted in 7%. Among patients with MDA, 82% received disease-modifying antirheumatic drugs or biologic agents. Following anti-TNF initiation, the cumulative probability of achieving MDA at 2 and 6 years was 4.1% and 7.6%, respectively, and persistent MDA probabilities were 2.7% and 4.5%, respectively. Regardless of RA duration, patients with MDA had substantially better outcomes, including a 10-fold reduction in work disability and an approximately 2-fold reduction in total joint replacement and mortality. CONCLUSION: Remission remains uncommon in RA, and the prevalence of new remission in community practice is substantially lower than noted in published trials of biologic therapy. On average, persons with MDA appear to have persistently mild RA. This might be the effect of milder RA and/or more effective treatment in early RA. The PAS had satisfactory levels of agreement with the full MDA criteria and appears suitable for use in clinical and epidemiologic research.     

Do tumor necrosis factor inhibitors cause uveitis? A registry-based study

OBJECTIVE: Population-based studies of patients with ankylosing spondylitis indicate that tumor necrosis factor (TNF) inhibitors prevent uveitis. Paradoxically, anecdotal reports implicate etanercept as a cause of uveitis. Therefore, using the information from 2 drug events databases, the purpose of this study was to assess reported cases of uveitis associated with the use of TNF inhibitors. METHODS: Uveitis cases occurring in the US associated with etanercept, infliximab, or adalimumab therapy that were reported to 2 spontaneous reporting databases prior to January 1, 2006 were reviewed. RESULTS: Overall, there were 43 cases of uveitis associated with etanercept, 14 associated with infliximab, and 2 associated with adalimumab. After normalizing for the estimated number of patients treated with each medication, etanercept was associated with a greater number of uveitis cases than infliximab (P < 0.001) and adalimumab (P < 0.01), while no such association was found between adalimumab and infliximab (P > 0.5). Using a priori criteria to avoid including patients whose underlying disease was associated with uveitis, 20 cases associated with etanercept, 4 cases associated with infliximab, and 2 cases associated with adalimumab were identified. A repeat analysis again revealed a greater number of uveitis cases associated with etanercept (P < 0.001 versus infliximab). CONCLUSION: Etanercept therapy is associated with a significantly greater number of reported uveitis cases in comparison with infliximab and adalimumab in 2 medication side effect registries. These results are consistent with previous studies and suggest that this relationship is drug specific and not related to TNF inhibitors as a whole. However, our findings do not support the use of infliximab over etanercept; rather, if a patient develops uveitis during etanercept therapy, then a change to infliximab may be warranted.     

Valve structure and survival in quinquagenarians having aortic valve replacement for aortic stenosis (+/-aortic regurgitation) with versus without coronary artery bypass grafting at a single US medical center (1993 to 2005)

The purpose of this study was to determine the effect of simultaneous coronary artery bypass grafting (CABG) and the influence of valve structure on both early and late survival in quinquagenarians having aortic valve replacement (AVR) for aortic stenosis (AS) (with or without aortic regurgitation). We analyzed survival and valve structure in 120 quinquagenarians having AVR for AS from 1993 through 2005 at Baylor University Medical Center, including 44 (37%) with and 76 (63%) without simultaneous CABG. Of the 120 patients, 2 (2%) died within 30 days of operation and none from 31 to 60 days postoperatively. Fifteen other patients (13%) died from >60 days to up to 13 years postoperatively. The unadjusted survival analysis showed that late survival was significantly better in the unicuspid/bicuspid valve structure group than in the tricuspid valve structure group (log-rank test p = 0.001), but that it was not affected by gender (male vs female), preoperative severity of the AS (transvalvular peak pressure gradient >50 vs < or =50 mm Hg), or by performance of CABG. The aortic valve was congenitally unicuspid in 18 patients (15%), congenitally bicuspid in 84 (70%), and 3-cuspid in 18 (15%). In conclusion, aortic valve structure affected the unadjusted late survival in quinquagenarians undergoing AVR for AS, but concomitant CABG, gender, and transvalvular peak systolic gradient had no effect.