Prospective Assessment of Cytomegalovirus Immunity in High-Risk Donor-Seropositive/Recipient-Seronegative Liver Transplant Recipients Receiving Either Preemptive Therapy or Antiviral Prophylaxis.

The differential impact of preemptive therapy (PET) and antiviral prophylaxis (AP) on development of cytomegalovirus (CMV)-specific neutralizing antibody (nAb) and T-cell responses have not previously been directly compared in high-risk donor-seropositive/recipient-seronegative (D+R-) organ transplant recipients. We prospectively assessed T-cell and nAb responses 3 months after transplantation in cohorts of high-risk D+R- liver transplant recipients who received either PET (n = 15) or AP (n = 25) and a control group of CMV-seropositive transplant recipients (R+) (AP; n = 24). CMV phosphoprotein 65 (pp65)- and immediate early protein 1-specific multifunctional T-cell responses were determined by means of intracellular cytokine staining and nAbs against BADrUL131-Y4 CMV in adult retinal pigment epithelial cell line-19 human epithelial cells; nAbs were detected in 8 of 12 (67%) in the PET group, none of 17 in the AP group, and 20 of 22 (91%) in the R+ group. Multifunctional CD8 and CD4 T-cell responses to pp65 were generally similar between PET and R+ groups, and lower for the AP group; multifunctional CD4 responses were similar across all groups. Among D+R- liver transplant recipients, PET was associated with the development of greater nAb and multifunctional CD8 T-cell responses compared with AP, providing a potential mechanism to explain the relative protection against late-onset disease with PET. Future studies are needed to define specific immune parameters predictive of late-onset CMV disease with AP.

Increased prevalence of elevated blood pressures in HIV-infected children, adolescents and young adults.

BACKGROUND: HIV-infected children and young adults have cardiovascular disease risk factors reflecting chronic infection and the effects of combination antiretroviral (ARV) therapy. We thus sought to characterize the prevalence of and risk factors for high blood pressure (HBP) in this population. METHODS: Retrospective chart review classified subjects aged 2-25 years based on a single clinic blood pressure (BP) reading as normal BP, pre-HBP or HBP. Variables suspected to contribute to elevated BP were compared including body mass index, tobacco use, medical comorbidities, ARV or other medication use, dyslipidemia, ethnicity and family history. RESULTS: In all, 47 of 266 subjects (18%) were found to have HBP. Among children and adolescents aged 2-17 years, 21 of 107 (20%) had HBP. Comorbidities believed to elevate BP, such as polycystic ovarian syndrome, obstructive sleep apnea or cocaine exposure, were significant risk factors for elevated BP, with 35% of subjects with these comorbidities having HBP, compared with 16% of subjects without (P = 0.01). Male gender and tobacco use were also risk factors associated with elevated BPs. HBP was more common in overweight subjects (26%) than not overweight (15%) but did not reach statistical significance (P = 0.15). ARV medication use and higher HIV-1 RNA were not associated with HBP. CONCLUSIONS: Our finding of 20% prevalence of HBP in a cohort of HIV-infected children represents a potentially alarming figure. The explanation for this finding is unclear, but even if it is because of comorbid conditions, the life-long cardiovascular risks associated with HIV infection and its management mandate the need for closer monitoring and possibly treatment of elevated BP in this population.

Glutamate cysteine ligase modifier subunit deficiency and gender as determinants of acetaminophen-induced hepatotoxicity in mice.

The analgesic and antipyretic drug acetaminophen (APAP) is bioactivated to the reactive intermediate N-acetyl-p-benzoquinoneimine, which is scavenged by glutathione (GSH). APAP overdose can deplete GSH leading to the accumulation of APAP-protein adducts and centrilobular necrosis in the liver. N-acetylcysteine (NAC), a cysteine prodrug and GSH precursor, is often given as a treatment for APAP overdose. The rate-limiting step in GSH biosynthesis is catalyzed by glutamate cysteine ligase (GCL) a heterodimer composed of catalytic and modifier (GCLM) subunits. Previous studies have indicated that GCL activity is likely to be an important determinant of APAP toxicity. In this study, we investigated APAP toxicity, and NAC or GSH ethyl ester (GSHee)-mediated rescue in mice with normal or compromised GCLM expression. Gclm wild-type, heterozygous, and null mice were administered APAP (500 mg/kg) alone, or immediately following NAC (800 mg/kg) or GSHee (168 mg/kg), and assessed for hepatotoxicity 6 h later. APAP caused GSH depletion in all mice. Gclm null and heterozygous mice exhibited more extensive hepatic damage compared to wild-type mice as assessed by serum alanine aminotransferase activity and histopathology. Additionally, male Gclm wild-type mice demonstrated greater APAP-induced hepatotoxicity than female wild-type mice. Cotreatment with either NAC or GSHee mitigated the effects of APAP in Gclm wild-type and heterozygous mice, but not in Gclm null mice. Collectively, these data reassert the importance of GSH in protection against APAP-induced hepatotoxicity, and indicate critical roles for GCL activity and gender in APAP-induced liver damage in mice.