Impact of anti-hepatitis Bc-positive grafts on the outcome of liver transplantation for HBV-related cirrhosis

BACKGROUND: The present scarcity of organ donors requires consideration of grafts from sources not previously used. Several studies have addressed the use of grafts from donors who have antibodies to the hepatitis B core antigen (anti-HBc+). The aim of this study was to evaluate the impact of the use of anti-HBc+ grafts in patients transplanted for hepatitis B virus (HBV)-related cirrhosis. METHODS: Recipients of first hepatic transplants from donors with antibodies to HBV were identified retrospectively. All patients who had serology suggestive of active HBV and were negative for hepatitis C and D were included in the analysis. The Kaplan-Meier method was used to assess the actuarial recurrence-free survival on patients with graft survival longer than 1.5 months. The stepwise Cox regression model was used to identify independent predictors of HBV recurrence. RESULTS: One thousand seven hundred seventeen first liver transplants were performed at the Thomas E. Starzl Transplantation Institute from September 1, 1990, to December 31, 1999. HBV was the cause of cirrhosis in 112 patients (6.5%). Thirty-three patients had coexistent viral infection (23 HCV and 10 HDV). Fourteen donors (17.2%) were positive for HBV markers, with nine anti-HBc+ and with five both anti-HBc+ and anti-HB surface-positive; of these, 13 anti-HBc+ organ recipients had long-term survival. Nine (69.2%) of these cases were reinfected versus 20 (35.7%) in the group that received grafts from HBV- donors (P<0.05, Fisher's exact test). The mean time to reinfection was shorter in the anti-HBc+ group (2.9 yr vs. 6.4 yr, P<0.005). There were no statistical differences in graft or patient survival between the two groups. HBV prophylaxis with combined lamivudine and hepatitis B immunoglobulin (HBIG) significantly reduced the reinfection rate (P<0.03). Hepatitis Be (Hbe) antigen-positive recipients trended to faster reinfection (not significant). Cox regression analysis revealed that both anti-HBc graft donor status (RR, 2.796; P=0.020) and combination of lamivudine/HBIG (RR, 0.249; P=0.021) are independently associated with reinfection. CONCLUSIONS: The use of anti-HBc+ liver grafts does not affect graft or patient survival. However, patients who receive these organs are 2.5 times more likely to develop HBV recurrence. Lamivudine and HBIG combination decreases HBV recurrence 4-fold.     

Endovascular repair of abdominal aortic aneurysms: risk stratified outcomes

OBJECTIVE: The impact of co-morbid conditions on early and late clinical outcomes after endovascular treatment of abdominal aortic aneurysm (AAA) was assessed in concurrent cohorts of patients stratified with respect to risk for intervention. SUMMARY BACKGROUND DATA: As a minimally invasive strategy for the treatment of AAA, endovascular repair has been embraced with enthusiasm for all prospective patients who are suitable anatomical candidates because of the promise of achieving a durable result with a reduced risk of perioperative morbidity and mortality. METHODS: From April 1994 to March 2001, endovascular AAA repair was performed in 236 patients using commercially available systems. A subset of patients considered at increased risk for intervention (n = 123) were categorized, as such, based on a preexisting history of ischemic coronary artery disease, with documentation of myocardial infarction (60%) or congestive heart failure (35%), or due to the presence of chronic obstructive disease (21%), liver disease, or malignancy. RESULTS: Perioperative mortality (30-day) was 6.5% in the increased-risk patients as compared to 1.8% among those classified as low risk (P = NS). There was no difference between groups in age (74 +/- 9 years vs. 72 +/- 6 years; mean +/- SD), surgical time (235 +/- 95 minutes vs. 219 +/- 84 minutes), blood loss (457 +/- 432 mL vs. 351 +/- 273 mL), postoperative hospital stay (4.8 +/- 3.4 days vs. 4.0 +/- 3.9 days), or days in the ICU (1.3 +/- 1.8 days vs. 0.5 +/- 1.6 days). Patients at increased risk of intervention had larger aneurysms than low-risk patients (59 +/- 13 mm vs. 51 +/- 14 mm; P <.05). Stent grafts were successfully implanted in 116 (95%) increased-risk versus 107 (95%) low-risk patients (P = NS). Conversion rates to open operative repair were similar in increased-risk and low-risk groups at 3% and 5%, respectively. The initial endoleak rate was 22% versus 20%, based on the first CT performed (either at discharge or 1 month; P = NS). To date, increased-risk patients have been followed for 17.4 +/- 15 months and low-risk patients for 16.3 +/- 14 months. Kaplan-Meier analysis for cumulative patient survival demonstrated a reduced probability of survival among those patients initially classified as at increased risk for intervention (P <.05, Mantel-Cox test). Both cohorts had similar two-year primary and secondary clinical success rates of approximately 75% and 80%, respectively. CONCLUSIONS: Early and late clinical outcomes are comparable after endovascular repair of AAA, regardless of risk-stratification. Notably, 2 years after endovascular repair, at least one in five patients was classified as a clinical failure. Given the need for close life-long surveillance and the continued uncertainty associated with clinical outcome, caution is dictated in advocating endovascular treatment for the patient who is otherwise considered an ideal candidate for standard open surgical repair.     

Phosphatidylinositol 3-kinase inhibition by LY294002 radiosensitizes human cervical cancer cell lines.

PURPOSE: The phosphatidylinositol 3-kinase (PI3K) catalytic subunit is amplified in cervical cancers, implicating PI3K in cervical carcinogenesis. We evaluated the radiosensitizing effect of PI3K inhibition by LY294002 on clonogenic survival, growth characteristics, and gene expression in cervical cancer cell lines (HeLa and CaSki). EXPERIMENTAL DESIGN: Cervical cancer cells were treated separately and concurrently with the PI3K inhibitor LY294002 (10 micromol/L) and radiation (2 Gy) with serial analysis of cell count, apoptosis, and flow cytometry. PI3K inhibition was assessed by protein analysis of phosphorylated Akt. Clonogenic assays were done with varying doses of radiation and LY294002 and varied time points of administration of LY294002 proximate to the radiation dose. Surviving fractions and dose modification factors (DMF) were calculated. Each experiment was done in triplicate and analyzed using ANOVA regression analysis and Dunnett's t Test. Microarray gene expression analysis was done on the HeLa cell line. RESULTS: PI3K inhibition with LY294002 alone did not decrease cell survival. However, treatment with LY294002 significantly radiosensitized HeLa and CaSki cell lines with DMFs (1 log cell kill) of 1.95 and 1.37, respectively. Compared with post-irradiation, pretreatment produced more radiosensitization (P < 0.0001). DMFs were 2.2, 2.0, 2.0, and 1.2 for LY294002 added at 6, 2, and 0.5 hours before irradiation and 6 hours after irradiation, respectively. LY294002 pretreatment in irradiated HeLa cells led to altered gene expression. CONCLUSIONS: Although LY294002 alone did not produce cytotoxic effects, PI3K inhibition with LY294002 produced significant radiosensitization, showed significant time-dependent effects, increased apoptosis, and altered gene expression. These findings support future investigation of PI3K inhibitors in combination with radiation therapy for carcinoma of the cervix.     

Ganaxolone for treating intractable infantile spasms: a multicenter, open-label, add-on trial

This is a multicenter, open-label, add-on trial, investigating the safety and efficacy of ganaxolone (GNX) in a population of children with refractory infantile spasms, or with continuing seizures after a prior history of infantile spasms. A total of 20 children aged 7 months to 7 years were enrolled in this dose-escalation study, after baseline seizure frequencies were established. Concomitant antiepilepsy drugs were maintained throughout the study period. The dose of GNX was progressively increased to 36 mg/kg/d (or to the maximally tolerated dose) over a period of 4 weeks, then maintained for 8 weeks before tapering and discontinuation. Seizure diaries were maintained by the families, and spasm frequency was compared with the baseline period. The occurrence of adverse events was clinically monitored, and global evaluations of seizure severity and response to treatment were obtained. A total of 16 of the 20 subjects completed the study, 15 of whom had refractory infantile spasms at the time of study enrollment. Spasm frequency was reduced by at least 50% in 33% of these subjects, with an additional 33% experiencing some improvement (25-50% reduction in spasm frequency). Ganaxolone was well tolerated, and adverse events attributed to GNX were generally mild. Ganaxolone was safe and effective in treating this group of refractory infantile spasms patients in an open-label, add-on trial. Further investigation with randomized, controlled study design is warranted.     

Low-dose inhaled nitric oxide for neonates with pulmonary hypertension

Objective : Inhaled nitric oxide (iNO) has been shown to cause selective pulmonary vasodilatation and improve ventilation-perfusion matching and may be an important therapeutic option for the treatment of persistent pulmonary hypertension of the newborn (PPHN). We report our experience on the use of iNO in neonates with severe PPHN.
Methodology : Inhaled NO was administered to 10 infants with PPHN and persistent hypoxaemia (meconium aspiration syndrome, n = 9; pneumonia, n = 1) after failure of conventional therapy to improve oxygenation. With the exception of one infant, iNO was commenced at 10 ppm.
Results : After 30 min exposure to iNO, the arterial oxygen tension (PaO₂) rose from a median of 49 mmHg (6.5 kPa) [range 12-82 mmHg (1.6-10.9 kPa)] to 75 mmHg (10 kPa) [range 17-450 mmHg (2.3-60 kPa)] ( P = 0.005), while the median oxygenation index fell (pre-iNO of 37 vs post-iNO 20) ( P = 0.005) and median systemic arterial pressure rose (pre-iNO 46.5 mmHg (6.2 kPa) [range 32-63 mmHg (4.3 to 8.4 kPa vs post-iNO 54.5 mmHg (7.3 kPa) [range 36-74 kPa]) P = 0.005). All infants subsequently continued to receive iNO with the duration of exposure to iNO ranging from 12 to 168 h (median duration 100 h). Three infants died despite showing an initial beneficial response to iNO. The mean duration of intubation for survivors was 11.9 ± 2.6 days. Methaemoglobinaemia and toxic levels of nitrogen dioxide were not seen during iNO administration. Of the seven survivors, 12 month follow up in two infants and 4 month follow up in four infants showed age-appropriate neurodevelopmental skills, with one infant having very mild hearing loss.
Conclusions : Inhaled NO reduces the oxygenation index by improving the PaO₂ and decreasing ventilation pressures, and appears to be clinically useful in severely hypoxaemic infants with PPHN refractory to conventional treatment.     

Inhaled nitric oxide during emergency neonatal transportation

ABSTRACT Inhaled nitric oxide is currently being investigated as a selective pulmonary vasodilator for neonates with persistent pulmonary hypertension. The use of continuous inhaled nitric oxide during emergency transportation of three critically ill neonates with meconium aspiration and pulmonary hypertension is described. The successful application of this technique may allow safer transportation of neonates who require high level intensive care including ongoing nitric oxide, high frequency ventilation and/or extracorporeal life support. Regionally based nitric oxide-equipped retrieval teams may relieve the pressure on smaller neonatal intensive care units to provide inhaled nitric oxide therapy and allow centralization of nitric oxide resources, thus facilitating development of expertise and the completion of meaningful research programs with substantial recruitment.     

Health care and its costs for children with perinatally acquired HIV infection

Objective : To describe survival patterns, use of health services and related costs for Australian children with perinatally acquired human immunodeficiency virus (HIV) infection.
Methodology : A retrospective cross-sectional survey was made of 20 children with HIV infection (91% of those diagnosed) and 13 children with maternal antibodies who subsequently seroreverted, treated at 10 medical centres. Details of disease progression and use of health services were obtained from hospital medical records. Monthly costs for three phases of infection were estimated by linking service usage rates with estimates of the unit cost of each service. The average lifetime cost was estimated by combining monthly costs and phase duration estimates from the literature.
Results : Patterns of disease progression were similar to those reported internationally, with a median survival of 8 years. Use, of health services increased with severity of illness. Mean monthly costs were $120 per month (1992 Australian dollars) for children with maternal antibodies who subsequently seroreverted, $320 per month for children with HIV infection but no acquired immunodeficiency syndrome (AIDS)-defining illness, and $1830 per month for children with AIDS. The present value of total lifetime cost for a child with HIV infection was $48174,46% of which was for treatment of AIDS.
Discussion : The mean lifetime cost for a perinatally infected child was just over half that for a man with HIV in Australia. Health service usage and costs were lower for Australian than American children with HIV.     

Molecular analysis of PKU in Ireland

Classical phenylketonuria (PKU: McKusick No. 261600) is caused by mutations occurring at the phenylalanine hydroxylase (PAH) locus on chromosome 12 and has a prevalence in Ireland of 1 in 4500. We examined 304 independent alleles from 350 patients for the presence of six mutations and have characterized VNTR alleles within the minisatellite region 3' to the PAH gene in patients carrying the most prevalent mutation. R408W was the most common mutation found, with a relative frequency of 42%. All other mutations had relative frequencies of <10%. VNTR analysis showed that the R408W mutation is associated with the VNTR-8 allele in the Irish population, indicating that R408W is associated with RFLP haplotype 1. This differs from that reported from eastern Europe where R408W is associated with RFLP haplotype 2/VNTR-3; an observation which has led several groups to propose a Balto-Slavic origin for this mutation. These results support the hypothesis of a second, independent founding event for the R408W mutation on an RFLP haplotype 1 VNTR-8 chromsome background in the Irish/Celtic population.