Treatment of chronic hepatitis B in children: Current status

Acquisition of hepatitis B virus during infancy or childhood leads to the majority of chronic infections responsible for the morbidity associated with this disease. Although most of these infections do not manifest clinically for several decades, some children develop significant liver disease early in life, so some children with chronic hepatitis B (CHB) are candidates for treatment. Two medications are currently licensed for use in children, and it is anticipated that others will be available in the next several years. Issues regarding treatment of CHB in children include rationale for treatment, patient selection, and pros and cons of the current and expected therapeutic options.     

Short-Term Treatment with Sevelamer Increases Serum Fetuin-A Concentration and Improves Endothelial Dysfunction in Chronic Kidney Disease Stage 4 Patients

Background and objectives: Vascular calcification and endothelial dysfunction contribute to the development of cardiovascular disease in patients with chronic kidney disease (CKD). Sevelamer, a non–calcium-based phosphate binder, has been shown to attenuate cardiovascular calcification in CKD patients, although the exact mechanism has not been clarified. This study was designed to investigate the effect of short-term sevelamer treatment on both serum fetuin-A concentrations and endothelial dysfunction seen in CKD patients.Design, setting, participants, & measurements: Fifty nondiabetic stage 4 CKD patients whose phosphate levels were ≥5.5 mg/dl were enrolled in this 8-wk randomized prospective study. Thirty-six healthy volunteers served as matched controls. Patients were treated with either sevelamer (n = 25, 12 males) or calcium acetate (n = 25, 13 males). Fetuin-A, high-sensitivity C-reactive protein, Ca × PO₄ product, flow-mediated dilation (FMD), insulin, and homeostasis model assessment (HOMA) were obtained at baseline and after the treatment period.Results: As expected, CKD patients had significantly lower levels of fetuin-A and FMD, and significantly higher levels of intact parathyroid hormone, Ca × PO₄ product, and high-sensitivity C-reactive protein than controls (P < 0.001 for all). The use of sevelamer led to a significant increase in the fetuin-A concentration with improvement in FMD, whereas no significant difference was observed in the calcium acetate group. In a multiple regression analysis, FMD levels were independently related to fetuin-A both before (β = 0.63, P < 0.001) and after (β = 0.38, P = 0.004) treatment.Conclusions: This small, randomized, prospective study shows that short-term sevelamer treatment significantly increases fetuin-A levels and improves FMD in nondiabetic stage 4 CKD patients.Cardiovascular disease (CVD) is prevalent in patients with chronic kidney disease (CKD) (1). Strong correlation between the derangement in mineral metabolism, such as hyperphosphatemia, hyperparathyroidism, as well as elevated calcium × phosphorus product (Ca × PO₄) and mortality has been reported in hemodialysis (HD) patients (2). These derangements have also been shown to result in vascular calcification, an independent risk factor for cardiovascular mortality (3,4). Elevated Ca × PO₄ product and higher doses of oral calcium ingestion significantly predicted coronary artery calcification (CAC) in patients with end-stage kidney disease (5). Moreover, London et al. (4) have shown significant association between the uses of calcium-based phosphate binders and arterial medial calcification in HD patients. Based on the deleterious effect of high calcium intake on vascular calcification, a calcium-free nonabsorbed phosphate binder, sevelamer hydrochloride, has been developed for the treatment of hyperphosphatemia in CKD patients (6). Studies have shown that sevelamer provides effective control in serum PO₄ levels without inducing hypercalcemia (6,7). Additionally, these studies have also shown beneficial effects of sevelamer on the progression of vascular calcification, although the underlying mechanisms were not clarified (8). Recent studies on vascular calcification have evaluated a number of circulating systemic calcification inhibitors, such as fetuin-A, matrix-Gla protein, osteoprotegrin, etc. (9). Fetuin-A, the major circulating inhibitor of vascular calcification, has been shown to be lower in dialysis patients and to be associated with cardiovascular mortality (10).Recent data have shown a relationship between vascular calcification and endothelial dysfunction (ED) in vascular disease. Nigam et al. (11) showed that there was a significant correlation between ED and large conduit vessel stiffness in patients with coronary artery disease (CAD). Additionally, in 201 healthy subjects, Budoff et al. (12) evaluated the relation between arterial distensibility, arterial reactivity, and CAC scores (electron beam computed tomography). They showed a significant relationship between brachial artery reactivity and CAC. In accordance, Huang et al. (13) have also reported a significant relationship between CAC and ED in patients with suspected CAD.This study was designed to investigate whether the suggested beneficial effects of sevelamer on vascular calcification are related to changes in serum fetuin-A concentration in patients with CKD. On the basis of the recent evidence linking vascular calcification and ED, we also evaluated the effect of sevelamer treatment on ED.     

TandemHeart Insertion via a Femoral Arterial GORE-TEX Graft Conduit in a High-Risk Patient

The TandemHeart® percutaneous ventricular assist device (pVAD), which provides temporary circulatory support of the left ventricle, can be used in high-risk and hemodynamically unstable patients. The easily inserted TandemHeart provides cardiac support superior to that from the use of intra-aortic balloon pumps. Herein, we discuss TandemHeart implantation via end-to-side femoral arterial grafting in a cardiac patient whose sepsis and multiorgan failure were complicated by coagulopathy and thromboembolism.A 47-year-old woman, on intra-aortic balloon and intravenous inotropic support after an acute myocardial infarction and emergency coronary artery bypass grafting, was transferred to our institution via helicopter. She developed sepsis and multiorgan failure. Her condition was further complicated by coagulopathy and a left-lower-extremity thromboembolism. After 6 weeks of aggressive pharmacologic and intermittent intra-aortic balloon treatment, the patient developed cardiogenic shock and received a TandemHeart pVAD for short-term circulatory support. A GORE-TEX® access graft, sewn end-to-side to the femoral artery because of the patient''s leg ischemia and very small vessels, served as a conduit for the TandemHeart''s femoral arterial inflow cannula. Her difficult circulatory, anatomic, and coagulopathic status stabilized after 2 weeks of TandemHeart support, and she was bridged to the long-term MicroMed DeBakey VAD® Child in anticipation of heart transplantation.The case of our patient shows that high-risk patients who have experienced cardiogenic shock with multiorgan failure and coagulopathy can benefit from the TandemHeart pVAD as a bridge to other therapeutic options, even when creative approaches to treatment and to TandemHeart insertion are required.Key words: Cardiac output, low/therapy; equipment design; heart failure/surgery/therapy; heart valve prosthesis implantation/methods; heart-assist devices; patient selection; risk factors; shock, cardiogenic/therapy; treatment outcome; ventricular dysfunction, left/therapyLeft ventricular assist devices (LVADs) can provide several therapeutic options for patients who are experiencing end-stage heart failure: short-term support, bridging to transplantation, bridging to recovery, or destination therapy.^1–3 One percutaneous ventricular assist device (pVAD), the TandemHeart® (CardiacAssist, Inc.; Pittsburgh, Pa), can be used in high-risk patients to unload the left ventricle (LV) preoperatively and to provide mechanical circulatory support during the perioperative and postoperative period until cardiac function sufficiently recovers or until a LVAD can be implanted for long-term support.⁴ The TandemHeart continuously withdraws oxygenated blood from the left atrium through a transseptal cannula that is placed in the femoral vein. The pump then returns the blood to the femoral artery, whereupon the patient''s cardiac output and blood pressure are increased and the preload and myocardial oxygen consumption are decreased⁴ (Fig. 1). The TandemHeart, which has proved to be safe and effective in the treatment of cardiogenic shock, provides hemodynamic support superior to that from intra-aortic balloon pumps (IABPs).^5,6 This pVAD can also be used for right ventricular support and during high-risk coronary interventions.^7,8 The most common sequelae include thromboembolism, distal leg ischemia, and bleeding from the cannulation site.^4–6Open in a separate windowFig. 1 Schematic depiction of the TandemHeart percutaneous ventricular assist device with a groin-access graft. The TandemHeart continuously withdraws oxygenated blood from the left atrium through a transseptal cannula in the femoral vein and returns the blood into the femoral artery via the access graft.Here, we report the implantation of the TandemHeart pVAD in a patient who was experiencing end-stage heart failure, multiorgan failure, coagulopathy, and cardiogenic shock after an acute myocardial infarction and coronary artery bypass grafting (CABG). Implantation of the TandemHeart was achieved by means of a GORE-TEX® access graft (W.L. Gore & Associates; Flagstaff, Ariz) that was sewn to the femoral artery.     

Site-specific characterization of threonine, serine, and tyrosine glycosylations of amyloid precursor protein/amyloid beta-peptides in human cerebrospinal fluid

The proteolytic processing of human amyloid precursor protein (APP) into shorter aggregating amyloid β (Aβ)-peptides, e.g., Aβ1-42, is considered a critical step in the pathogenesis of Alzheimer's disease (AD). Although APP is a well-known membrane glycoprotein carrying both N- and O-glycans, nothing is known about the occurrence of released APP/Aβ glycopeptides in cerebrospinal fluid (CSF). We used the 6E10 antibody and immunopurified Aβ peptides and glycopeptides from CSF samples and then liquid chromatography-tandem mass spectrometry for structural analysis using collision-induced dissociation and electron capture dissociation. In addition to 33 unglycosylated APP/Aβ peptides, we identified 37 APP/Aβ glycopeptides with sialylated core 1 like O-glycans attached to Thr(-39, -21, -20, and -13), in a series of APP/AβX-15 glycopeptides, where X was -63, -57, -52, and -45, in relation to Asp1 of the Aβ sequence. Unexpectedly, we also identified a series of 27 glycopeptides, the Aβ1-X series, where X was 20 (DAEFRHDSGYEVHHQKLVFF), 19, 18, 17, 16, and 15, which were all uniquely glycosylated on Tyr10. The Tyr10 linked O-glycans were (Neu5Ac)(1-2)Hex(Neu5Ac)HexNAc-O- structures with the disialylated terminals occasionally O-acetylated or lactonized, indicating a terminal Neu5Acα2,8Neu5Ac linkage. We could not detect any glycosylation of the Aβ1-38/40/42 isoforms. We observed an increase of up to 2.5 times of Tyr10 glycosylated Aβ peptides in CSF in six AD patients compared to seven non-AD patients. APP/Aβ sialylated O-glycans, including that of a Tyr residue, the first in a mammalian protein, may modulate APP processing, inhibiting the amyloidogenic pathway associated with AD.     

Safety and Feasibility of a Novel Dosing Regimen of Tirofiban Administered in Patients with Acute Myocardial Infarction with ST Elevation Before Primary Coronary Angioplasty: A Pilot Study

BACKGROUND: Intravenous glycoprotein GP IIb/IIIa receptor antagonists administered to patients with acute coronary syndromes limit platelet-dependent thrombus formation and vasoconstriction and lower the complication rate of PCI. The efficacy of glycoprotein IIb/IIIa inhibitors critically depends on appropriate suppression of platelet aggregation. A growing body of evidence indicates that regimen of tirofiban used in several recent trials may be suboptimal. We investigated if a novel regimen of dosage of tirofiban administered to patients with acute myocardial infarction with ST elevation (STEMI) before primary angioplasty is safe, feasible and whether such treatment improves coronary flow in infarct-related artery. METHODS: It was an open-label, non-randomized, prospective observational study. 253 consecutive patients with STEMI, qualified to PCI were included. 104 of patients (group 1) received heparin plus tirofiban at a novel regimen (10 microg/kg bolus, followed by 0.4 microg/kg/min for 30 min and then 0.1 microg/kg/min for 12-24 hours) and the remaining 149 of the patients (group 2) received a standard dose of heparin prior to PCI. Bleeding complications were recorded. The primary end point of the study was combined TIMI 1 + 2 + 3 grade flow at the time of first contrast medium injection during angiography for primary PCI. RESULTS: Heparin was administered 50.3 +/- 58.1 minutes (group 1) or 62.3 +/- 67.3 minutes (group 2) ( p = 0.205). Tirofiban was administered for an average of 14.5 +/- 14.4 minutes before TIMI assessment (group 1). In patients treated with heparin + tirofiban the rate of combined TIMI 1 + 2 + 3 coronary flow was higher (38.4% vs. 24.8%, p = 0.020) as compared to patients treated with heparin alone. The difference in the rate of TIMI > or = 2 coronary blood flow between the groups 1 and 2 (24.0% vs. 20.1%) has not reached statistical significance ( p = 0.459). At the same time the significant difference in the rate of TIMI 1 coronary blood flow between the groups 1 and 2 was noted (14.4 vs. 4.7%, p = 0.007). In hospital mortality in the groups 1 and 2 was similar (5.3 vs. 4.8%, p = 0.838). Significant difference was noted between the groups 1 and 2 with regard to minor bleeding complications (17.3 vs. 8.7%, p = 0.041). CONCLUSION: In patients undergoing primary angioplasty for acute myocardial infarction the novel regimen of tirofiban is well tolerated and feasible, and is associated with improvement in coronary blood flow in the infarct related artery. Larger studies assessing the effects of tirofiban on clinical outcomes of patients with AMI undergoing primary angioplasty seem worthwhile.     

Treatment of experimental meconium aspiration syndrome with surfactant lung lavage and conventional vs. asymmetric high-frequency jet ventilation

Respiratory failure caused by meconium aspiration requires combined strategies. We hypothesized that surfactant lung lavage with asymmetric high-frequency jet ventilation (AHFJV) can increase the removal of meconium and improve lung function. During conventional ventilation (CV), a suspension of human meconium (25 mg/ml, 4 ml/kg) was instilled into the tracheal tube of anesthetized rabbits to cause respiratory failure. Animals were then divided into four groups: saline lavage + CV (Sal-CV), surfactant lavage + CV (Surf-CV), saline lavage + HFJV (Sal-HFJV), and surfactant lavage + HFJV (Surf-HFJV). Lung lavage (10 ml/kg in 3 portions) was performed with diluted surfactant (Curosurf, 100 mg of phospholipids/kg) or saline during CV (frequency (f), 30/min; inspiration time (Ti), 50%) or AHFJV (f, 300/min; Ti, 70%). Animals were ventilated for an additional hour with either CV or HFJV (Ti, 50%). Surfactant lavage with both CV and AHFJV removed more meconium than saline lavage. However, the highest removal was found in the Surf-HFJV group vs. all other groups (P < 0.05). The oxygenation index decreased after surfactant lavage in both groups compared to controls (P < 0.001), and more prominently in the Surf-CV group. Elimination of CO(2) was significantly higher in the Surf-HFJV group vs. all other groups (P < 0.05). The ventilation efficiency index increased after lavage in both surfactant groups vs. saline controls (P < 0.05). Dynamic lung-thorax compliance gradually increased, and right-to-left pulmonary shunts decreased in both surfactant groups vs. saline controls after lavage (P < 0.05). Combination of surfactant lavage with both CV and AHFJV was beneficial in rabbits with meconium aspiration syndrome. While AHFJV was more effective in the removal of meconium, CV had a more favorable effect on lung function in the postlavage period.     

The role of fondaparinux as an adjunct to thrombolytic therapy in acute myocardial infarction: a subgroup analysis of the OASIS-6 trial.

AIMS: No antithrombotic therapy has been shown to reduce mortality when used with thrombolytics in acute myocardial infarction (AMI). In the OASIS-6 trial, fondaparinux significantly reduced mortality and reinfarction without increasing bleeding in 12 092 patients with acute ST elevation MI. METHODS AND RESULTS: We report the results of a subgroup analysis in the 5436 patients (45%) receiving thrombolytics. According to local practice, 4415 patients did not have an indication for unfractionated heparin (stratum 1) and 1021 did (stratum 2). Fondaparinux reduced the primary study outcome of death or MI at 30 days [Hazard ratio (HR) 0.79, 95% confidence interval (CI) 0.68-0.92] with consistent reductions in both mortality (HR and CI) and reinfarction (HR and CI). There was a non-significantly lower rate of stroke (HR 0.77, CI 0.48-1.25). The risk of severe bleeding was significantly reduced (HR 0.62, CI 0.40-0.94), and thus the balance of benefit and risk (death, MI and severe haemorrhage) was clearly reduced by fondaparinux (HR 0.77, 95% CI 0.67-0.90). Results were consistent in the two strata, by the different types of thrombolytics and across various time intervals from symptom onset to treatment. CONCLUSION: In STEMI patients treated with thrombolytic agents (predominantly streptokinase), fondaparinux significantly reduced the risk of death, re-MI and severe bleeds.     

Paranasal computed tomography results in asthma patients: association between sinus sites and allergen types

Chronic rhinosinusitis (CRS) is a common comorbidity of asthma. The aim of this study was to investigate the relationships between the presence of rhinosinusitis, sinus site involvement, and total computed tomography (CT) sinus scores and the presence of allergy, allergen type, and severity of disease. Asthma patients (128 subjects), consisting of 57 allergic and 71 nonallergic patients, were included in the study. Presence of rhinosinusitis and sinus scores were evaluated by CT. CRS was determined in 45 (78.9%) allergic asthma patients and 44 (62.0%) nonallergic asthma patients (p<0.05). Ethmoid sinus involvement was higher among allergic asthma patients compared with nonallergic patients (68.4% versus 43.7%; p=0.005). House-dust mite allergy (71.4% versus 46.5%; p=0.008) and pollen allergy (73.5% versus 47.9%; p=0.01) showed positive correlations with ethmoid sinus involvement. No correlation was found between severity of disease and mean total CT sinus scores (p>0.05). The present study has shown the prevalence of chronic sinusitis to be higher in patients with allergic asthma, particularly in patients allergic to house-dust mites and pollens, with no correlation between severity of disease and presence of CRS. Investigating chronic sinusitis together with allergen sensitivity early in asthma diagnosis may contribute positively to patient treatment.     

Acoustic radiation force impulse (ARFI) elastography in acute liver failure: necrosis mimics cirrhosis

Acoustic radiation force Impulse (ARFI) technology correlates shear-wave velocity with fibrosis. It can differentiate between advanced fibrosis and normal tissue in chronic liver disease. However, specificity is impaired by cholestasis, inflammation or oedema in acute hepatitis. In patients with acute liver failure (ALF) necessitating liver transplantation ARFI has not been evaluated yet. We investigated 3 patients with ALF and compared their ARFI results to those of healthy controls (n = 33) and cases with liver cirrhosis (n = 21). In the 3 ALF patients shear-wave velocities were 3.0, 2.5, and 2.7 m/s, respectively. These results were significantly increased compared to those of healthy controls (median: 1.13 m/s; p < 0.001) and similar to those of cirrhotic individuals (median: 2.93 m/s). Two individuals underwent liver transplantation. Explants showed massive necrosis, but no signs of chronic liver disease. Patient 3 recovered spontaneously and showed decreasing ARFI results during follow-up. In conclusion, hepatic necrosis can mimic liver cirrhosis at ARFI evaluation in ALF patients and this impairs the specificity of ARFI.     

BRAF mutation associated with other genetic events identifies a subset of aggressive papillary thyroid carcinoma

Purpose BRAF ^V600E mutation represents the most common oncogenic event in sporadic papillary thyroid cancer (PTC). There are, however, significant discrepancies regarding the overall frequency, its prevalence in PTC‐variants, and its relationship with clinico‐pathological parameters of poor outcome. Moreover, the impact of BRAF^V600E mutants on tumour‐related patient's death has not been evaluated. Design We analysed, by PCR‐SSCP and/or PCR‐direct sequencing, exons 8, 10, 11 and 15 of BRAF in 113 tumour samples from 49 PTC‐patients. Matched lymph node metastases and/or distant metastases (DMs) were screened in 35 patients. Focal changes in the growth pattern or microscopic grade within the primary tumour (Pt) or the metastases were separately genotyped. Mutations at H‐, K‐, N‐ras and PIK3CA exons 9 and 20 were also investigated. For comparison with PTC cases, the BRAF and Ras mutational status was evaluated in 89 specimens obtained from 24 poorly differentiated thyroid carcinomas (PDCs) and 36 anaplastic thyroid carcinomas (ATCs). Results BRAF ^V600E was found in 13/16 classical PTCs (CL‐PTCs), 6/17 follicular variant PTCs (FV‐PTCs) and 8/16 mixed (papillary/follicular) PTCs (Mx‐PTCs), being significantly associated with CL‐PTCs (P = 0·015). BRAF^V600E segregated with metastatic PTC‐cells in 43% of the patients, but only one DM disclosed the mutation. PTC‐tumours featuring concurrent less‐differentiated foci were BRAF wild‐type in both components. Noteworthy, the frequency of BRAF mutations among PDCs and ATCs resulted considerably lower (16·6% and 25%, respectively) than in PTCs (55%). The prevalence of Ras mutations among PDCs and ATCs (46% and 36%, respectively) was, however, much higher than in PTCs (14%). Five (71%) of the patients who died of PTC displayed somatic mutations. Four of them had other gene alteration associated with BRAF^V600E and the only one that did not, BRAF^V600E was restricted to the Pt. The occurrence of BRAF^V600E associated with other genetic events was an independent predictor of DMs during follow‐up, recurrence and tumour‐related death. Remarkably, two PDCs (8·3%) and five ATCs (14%) revealed concurrent BRAF and Ras mutations. Conclusion BRAF ^V600E‘alone’ does not represent a marker for poor outcome, however, when associated with alterations in other genes identifies a subset of PTCs with increased risk of recurrence and decreased survival.