Correction: Energy-dependent nucleolar localization of p53 in vitro requires two discrete regions within the p53 carboxyl terminus.

Following the publication of this article the authors noted that two images were duplicated in Figure 2B. The corrected figure 2B is below. The authors wish to apologize for any inconvenience caused.

Treatment of hepatitis C virus leads to economic gains related to reduction in cases of hepatocellular carcinoma and decompensated cirrhosis in Japan.

Hepatocellular carcinoma (HCC) is a serious complication of hepatitis C virus (HCV) infection. Sustained virologic response (SVR) for HCV is associated with a reduction in cirrhosis, HCC and mortality and their associated costs. Japanese HCV patients are older with higher prevalence of HCC. Here we used a decision-analytic Markov model to estimate the economic benefit of HCV cure by reducing HCC and DCC burden in Japan. A cohort of 10 000 HCV genotype 1b (GT1b) Japanese patients was modelled with a hybrid decision tree and Markov state-transition model capturing natural history of HCV over a lifetime horizon. Treatment options were approved all-oral direct-acting anti-virals (DAAs) vs no treatment. Treatment efficacy was based on clinical trials and transition rates and costs obtained from Japan-specific data. Cases of HCC, decompensated cirrhosis (DCC) and quality-adjusted life years (QALYs) were projected for patients treated with DAAs vs NT. QALYs were monetized using a willingness-to-pay threshold of ¥4-to-¥6 million. Incremental savings with treatment were calculated by adding the projected cost of complications avoided to the monetized gains in QALYs. The model showed that DAA treatment vs no treatment, reduces 2057 cases of HCC and 1478 cases of decompensated cirrhosis and saves ¥850 446.73 and ¥338 229.90 per patient (ppt). Additionally, treatment can lead to additional 2.64 QALYs gained per patient. The indirect economic gains associated with treatment-related QALY improvements were ¥10 576 000, ¥13 220 000 and ¥15 864 000 ppt (willingness-to-pay thresholds of ¥4 million, ¥5 million and ¥6 million). Total economic savings of treatment with DAAs (vs no treatment) was ¥7 526 372.63, ¥10 170 372.63 and ¥12 814 372.63, at these different willingness-to-pay thresholds. In conclusion treatment of HCV GT1b with all-oral DAAs in Japan can lead to significant direct and indirect savings related to avoidance of HCC and DCC.

Direct medical costs associated with the extrahepatic manifestations of hepatitis C infection in Europe.

Hepatitis C virus (HCV) infection is a systemic disease associated with both hepatic and extrahepatic manifestations. The burden associated with the hepatic manifestation of HCV infection has been well documented in Europe, although that of HCV extrahepatic manifestations remains unknown. In this study, we estimated the annual direct medical costs associated with HCV extrahepatic manifestations in five European countries. A previously validated economic model was used to estimate the annual direct medical cost associated with HCV extrahepatic manifestations. Global excess prevalence of extrahepatic manifestations in HCV patients relative to that in non-HCV patients was obtained from a recent meta-analysis. Per-patient per-year inpatient, outpatient and medication costs to treat each extrahepatic manifestation were from the literature, national databases or expert opinion if unavailable otherwise. All costs were adjusted to 2016 euros (€). The overall direct medical costs associated with HCV extrahepatic manifestations were calculated by multiplying the total per-patient per-year costs of each by the respective excess prevalence rates and then by the size of the HCV-infected population in each country. Treatment impact with direct-acting antivirals (DAAs) was explored using HCV extrahepatic manifestations excess prevalence rates among cured patients compared to untreated HCV patients, as sourced from a meta-analysis. The total annual direct medical cost associated with HCV extrahepatic manifestations was estimated to be 2.17 billion euro (€), with a per-HCV-patient cost ranging from €899 to €1647 annually. DAA treatment was projected to result in cost savings of €316 million per year. We find that the annual economic burden of extrahepatic manifestations is significant and may be partly mitigated by treatment with DAAs.

Impact of eradicating hepatitis C virus on the work productivity of chronic hepatitis C (CH-C) patients: an economic model from five European countries.

CH-C negatively affects work productivity (WP), creating a large economic burden. The aim of this study was to model the impact of sustained virologic response (SVR) on WP in CHC genotype 1 (GT1) patients in five European countries (EU5). Work Productivity and Activity Index-Specific Health Problem questionnaire was administered to patients across the ION clinical trials (n = 629 European patients). The analysis modelled a population of GT1 CHC patients over one year, who had been either not treated or treated with LDV/SOF. Sensitivity analyses assessed the possibility that CHC patients' labour costs were lower than the general population's and presented results by fibrosis stage. Before initiation of treatment, EU patients with CHC GT1 exhibited absenteeism and presenteeism impairments of 3.54% and 9.12%, respectively. About 91.8% of EU patients in the ION trials achieved SVR and improved absenteeism and presenteeism impairments by 16.3% and 19.5%, respectively. Monetizing these data, treatment with LDV/SOF resulted in an annual productivity gain of €435 million and a weighted average per-employed patient (PEP) gain of €900 in the EU5. PEP gains from treatment are projected to be higher in cirrhotic than in noncirrhotic patients. If CHC patients are assumed to earn 20% less than the general population, gains of €348 million (€720 PEP) annually are projected. CHC results in a significant economic burden to European society. Due to improvements in WP, SVR with treatment could provide substantial economic gains, partly offsetting the direct costs related to its widespread use.

Energy-dependent nucleolar localization of p53 in vitro requires two discrete regions within the p53 carboxyl terminus.

The p53 tumor suppressor is a nucleocytoplasmic shuttling protein that is found predominantly in the nucleus of cells. In addition to mutation, abnormal p53 cellular localization is one of the mechanisms that inactivate p53 function. To further understand features of p53 that contribute to the regulation of its trafficking within the cell, we analysed the subnuclear localization of wild-type and mutant p53 in human cells that were either permeabilized with detergent or treated with the proteasome inhibitor MG132. We, here, show that either endogenously expressed or exogenously added p53 protein localizes to the nucleolus in detergent-permeabilized cells in a concentration- and ATP hydrolysis-dependent manner. Two discrete regions within the carboxyl terminus of p53 are essential for nucleolar localization in permeabilized cells. Similarly, localization of p53 to the nucleolus after proteasome inhibition in unpermeabilized cells requires sequences within the carboxyl terminus of p53. Interestingly, genotoxic stress markedly decreases the association of p53 with the nucleolus, and phosphorylation of p53 at S392, a site that is modified by such stress, partially impairs its nucleolar localization. The possible significance of these findings is discussed.

Differential cardiorespiratory effects of endomorphin 1, endomorphin 2, DAMGO, and morphine.

The novel endogenous mu-opioid receptor (MOR) agonists endomorphin 1 (EM1) and 2 (EM2) were tested for their cardiorespiratory effects in conscious, freely behaving rats. After systemic (intravenous) administration of EM1, EM2, or the selective MOR agonist DAMGO, analgesia, minute ventilation (V E), heart rate (HR) and mean arterial blood pressure (BP) were measured. The threshold dose for analgesia was similar for all 3 peptides ( approximately 900 nmol/kg). All 3 compounds elicited biphasic V E responses, with marked, short-lived V E depressions (4-6 s) followed by more sustained V E increases (10-12 min). However, compared with responses elicited by EM2 or DAMGO, EM1 decreased V E only at higher doses, and produced greater V E stimulation. Morphine produced a V E decrease, but no subsequent V E increase. EM2 and DAMGO decreased HR and BP, while EM1 decreased HR, but did not decrease BP in conscious rats at doses up to 9,600 nmol/kg. In anesthetized rats, all 3 peptides decreased HR and BP. The decreases in V E, HR, and BP were blocked by the MOR antagonist, naloxone HCI (NIx). Only the HR and BP responses, however, were blocked by naloxone-methiodide (MeNIx), indicating central mediation of V E responses and peripheral mediation of cardiovascular responses. We conclude that MOR-selective compounds vary in their cardiorespiratory response characteristics which could be linked to differential cellular actions. The results support the concept that the analgesic, respiratory, and cardiovascular effects of MOR agonists can be dissociated and that EM1-like compounds could provide the basis for novel, safer analgesics.

Pulmonary risk factors compromising postoperative recovery after surgical repair for congenital heart disease.

STUDY OBJECTIVES: To identify pulmonary risk factors associated with prolonged ICU stay in young children (< or = 2 years) undergoing surgical repair for congenital heart disease (CHD). DESIGN: Retrospective case series analysis. SETTING: Tertiary-care facility. PATIENTS: Clinical records of 134 consecutive patients aged < or = 2 years undergoing cardiac surgery for CHD were reviewed, and 37 were excluded according to inclusion criteria. Thus, 97 patients were allocated to two groups based on the duration of ICU stay: < or = 7 days (group 1, n = 57), and > 7 days (group 2, n = 40). RESULTS: Mean ICU duration for groups 1 and 2 was 3.0 +/- 0.4 days and 28.1 +/- 4.4 days, respectively (p < 0.001). In group 1, there were three extubation failures, whereas 41 extubation failures occurred in group 2 (p < 0.0001). A total of 22 patients (4 in group 1 and 18 in group 2) developed noninfectious pulmonary complications, such as airway problems, including extrinsic airway compression and tracheobronchomalacia (n = 6); pulmonary hypertension (n = 5); phrenic nerve palsy (n = 7); and pleural effusion (n = 8). These 22 patients (23%) contributed to the majority of total ventilator days (67%) as well as ICU stay (61%). CONCLUSIONS: Pulmonary complications in general, and central airway problems in particular, are a frequent cause for delayed recovery following cardiac surgery in young children.

Young inner-city children visiting the emergency room (ER) for asthma: risk factors and chronic care behaviors.

Inner-city children visiting emergency rooms (ER) for asthma often rely on the ER as their primary source of care. To evaluate chronic asthma control, structured interviews were conducted with the adult accompanying a sample of 46 children, 2-6 years old, presenting to an inner-city pediatric ER for asthma. Fifty-one percent had 10 or more prior ER visits and 46% had 2 or more previous hospitalizations. Seventy-two percent had functional severity scores in the moderate to severe range. Only 11% used daily inhaled anti-inflammatory medication. Not one patient had a written self-management plan. Most young children visiting an inner-city ER for asthma have poorly controlled and poorly managed chronic asthma.

Heterozygous alpha 1-antitrypsin deficiency (PiSZ) in an adolescent with asthma.

Although alpha 1-antitrypsin deficiency has been associated with obstructive lung disease in individuals possessing a homozygous phenotype (PiZZ), this association has not been as clearly documented in heterozygous individuals (PiMZ, PiMS, and PiSZ phenotypes). Information regarding the heterozygous adolescent population is particularly lacking, making the evaluation and treatment of such patients difficult. We present the case of an adolescent with a history of asthma and heterozygous (PiSZ) alpha 1-antitrypsin deficiency and outline our management with reference to appropriate literature.

Use of nasal continuous positive airway pressure as treatment of childhood obstructive sleep apnea.

OBJECTIVE: To determine the safety and efficacy of nasal continuous positive airway pressure (CPAP) for obstructive sleep apnea (OSA) during childhood and the effects of growth and maturation on CPAP requirements. DESIGN: Retrospective study with use of a written questionnaire administered to pediatric practitioners treating sleep disorders. SETTING: Nine academic pediatric sleep disorders centers. RESULTS: Data were obtained for 94 patients. Three percent of patients receiving CPAP were less than 1 year, 29% were 1 to 5 years, 36% were 6 to 12 years, and 32% were 13 to 19 years of age; 64% were boys. The longest duration of CPAP use was 4 years. Indications for CPAP included OSA associated with obesity (27%), craniofacial anomalies (25%), idiopathic OSA persisting after adenoidectomy and tonsillectomy (17%), and trisomy 21 (13%). Continuous positive airway pressure was effective in 81 patients (86%), in one patient it was unsuccessful, and in 12 patients compliance was inadequate. The median pressure required was 8 cm H2O (range, 4 to 20 cm H2O); pressure requirements were independent of age or diagnosis. Twenty-two percent of patients eventually required a modification of CPAP levels. Complications of CPAP were minor. Sixty-four percent of centers reported difficulty in obtaining funding for CPAP. CONCLUSIONS: Continuous positive airway pressure is safe, effective, and well tolerated by children and adolescents with OSA. Experience in infants is limited. As pressure requirements change with patient growth, we recommend that CPAP requirements be regularly reevaluated over time. The marked center-to-center variability in CPAP use suggests that specific indications for this therapy require clarification.

Granulocyte-macrophage colony stimulating factor and Pneumocystis carinii pneumonia in mice.

We hypothesized that therapy with granulocyte-macrophage colony stimulating factor (GM-CSF) would decrease intensity of murine Pneumocystis carinii pneumonia by upregulating alveolar macrophage function. Mice were depleted of CD4+ T lymphocytes and then inoculated intratracheally with P. carinii. Four weeks later, they received recombinant murine GM-CSF (rmGM-CSF) 5 micrograms/d subcutaneously for 7 and 14 d. At the end of therapy lung tissue was scored for intensity of P. carinii infection by silver methenamine stain and for inflammation by hematoxylin-eosin stain. We found that rmGM-CSF therapy significant decreased the intensity scores of PCP infection in comparison to control mice (1.88 +/- 0.47 vs 3.06 +/- 0.12, p < 0.001). Inflammation scores were not significantly different in the rmGM-CSF group compared with the control group (1.83 +/- 0.47 vs 2.83 +/- 0.67). Alveolar macrophages from mice treated with rmGM-CSF released significantly more tumor necrosis factor-alpha (TNF-alpha) than cells from control mice after in vitro stimulation with lipopolysaccharide (LPS) alone (2.65 +/- 0.30 vs 1.45 +/- 0.26 ng/ml, p = 0.01) or with LPS plus murine recombinant interferon-gamma (4.16 +/- 0.51 vs 2.25 +/- 0.34 ng/ml, p = 0.01). We conclude that GM-CSF therapy reduces the intensity of PCP and this effect is associated with an enhanced alveolar macrophage TNF-alpha production.