Functions of the unique N-terminal region of glycoprotein E in the pathogenesis of varicella-zoster virus infection

Varicella-zoster virus (VZV) is an alphaherpesvirus that infects skin, lymphocytes, and sensory ganglia. VZV glycoprotein E (gE) has a unique N-terminal region (aa1-188), which is required for replication and includes domains involved in secondary envelopment, efficient cell-cell spread, and skin infection in vivo. The nonconserved N-terminal region also mediates binding to the insulin-degrading enzyme (IDE), which is proposed to be a VZV receptor. Using viral mutagenesis to make the recombinant rOka-ΔP27-G90, we showed that amino acids in this region are required for gE/IDE binding in infected cells; this deletion reduced cell-cell spread in vitro and skin infection in vivo. However, a gE point mutation, linker insertions, and partial deletions in the aa27-90 region, and deletion of a large portion of the unique N-terminal region, aa52-187, had similar or more severe effects on VZV replication in vitro and in vivo without disrupting the gE/IDE interaction. VZV replication in T cells in vivo was not impaired by deletion of gE aa27-90, suggesting that these gE residues are not essential for VZV T cell tropism. However, the rOka-ΔY51-P187 mutant failed to replicate in T cell xenografts as well as skin in vivo. VZV tropism for T cells and skin, which is necessary for its life cycle in the human host, requires this nonconserved region of the N-terminal region of VZV gE.     

Pharmacokinetics of acyclovir in the term human pregnancy and neonate.

Concern about neonatal herpes often leads to cesarean delivery of infants in women with a history of genital herpes. The antiviral drug acyclovir has been used effectively to suppress genital herpes simplex virus recurrences in nonpregnant adults. Its administration to pregnant women with recurrent genital herpes may reduce herpes simplex virus recurrences and thus may decrease the cesarean section rate among this population. To study the pharmacokinetics, safety, and patient tolerance of suppressive oral acyclovir, either 200 mg (n = 7) or 400 mg (n = 8) was administered orally every 8 hours to pregnant women with a history of recurrent herpes simplex virus, from 38 weeks' gestation until delivery. The mean +/- SD plasma levels for the 200 and 400 mg groups, respectively, were: first dose peak, 1.7 +/- 0.6 and 2.3 +/- 1.0 mumol/L; steady-state trough, 0.7 +/- 0.3 and 0.8 +/- 0.6 mumol/L; steady-state peak, 1.9 +/- 1.0 and 3.3 +/- 1.0 mumol/L. In late gestation maternal acyclovir pharmacokinetics were similar to those of nonpregnant adults from other studies. Acyclovir was concentrated in the amniotic fluid; however, there was no accumulation in the fetus (mean maternal/infant plasma ratio at delivery was 1.3). Acyclovir was well tolerated, and no toxicity was seen in the mothers or infants. The administration of acyclovir, 400 mg every 8 hours, appears appropriate for use in an efficacy and safety study regarding suppression of herpes simplex virus recurrences during the last weeks of pregnancy.     

Varlirix (GlaxoSmithKline)

GlaxoSmithKline (formerly SmithKline Beecham) has developed and launched Varilrix, a preparation of live, attenuated Oka-strain varicella zoster virus, for immunization against varicella zoster infections [455138]. By the end of 1998, Varilrix was available in a few European countries and in India [284490], [455138]. By 2001, the vaccine was also available in Brazil and Hong Kong [396267].     

Diagnosis and management of spontaneous cerebrospinal fluid otorrhea.

OBJECTIVE: To describe the clinical presentation, diagnosis, surgical management, and outcome of patients with spontaneous cerebrospinal fluid otorrhea. STUDY DESIGN: Retrospective case series. SETTING: Tertiary referral center. METHODS: The authors conducted a chart review of all previously unreported cases of surgically confirmed cerebrospinal fluid otorrhea at their institution between September 1996 and February 2005. Acquired cases were excluded from this study. Eleven cases of spontaneous cerebrospinal fluid otorrhea were identified among 10 patients. RESULTS: Nine of the 10 patients presenting with spontaneous cerebrospinal fluid otorrhea were women. Ages ranged from 34 to 79 years. Eight patients presented with serous otitis media, and two women presented with meningitis. High-resolution computed tomography demonstrated a tegmen defect with a sensitivity of 80%. Nine tegmen defects were repaired using a transmastoid approach without recurrence. One patient with a contracted mastoid and a meningoencephalocele herniating from the tegmen tympani into the attic required the temporal craniotomy approach for definitive repair. Another patient with a tegmen tympani defect developed a recurrence of cerebrospinal fluid otorrhea 8 years after a transmastoid repair using only fascia and fibrin glue. A recurrent tegmen defect in this patient was repaired using a transmastoid approach and a multilayered closure technique. CONCLUSION: The diagnosis of spontaneous cerebrospinal fluid otorrhea requires clinical suspicion in the setting of persistent serous otitis media. High-resolution computed tomography can confirm the diagnosis. The authors' findings indicate that repair through a transmastoid approach is effective if the tegmen defect can be widely visualized. The authors advocate a multilayered closure technique.     

Associations among adolescent risk behaviours and self-esteem in six domains

BACKGROUND: This study investigated associations among adolescents' self-esteem in 6 domains (peers, school, family, sports/athletics, body image and global self-worth) and risk behaviours related to substance use, bullying, suicidality and sexuality. METHOD: A multistage stratified sampling strategy was used to select a representative sample of 939 English-, Afrikaans- and Xhosa-speaking students in Grades 8 and 11 at public high schools in Cape Town, South Africa. Participants completed the multidimensional Self-Esteem Questionnaire (SEQ; DuBois, Felner, Brand, Phillips, & Lease, 1996) and a self-report questionnaire containing items about demographic characteristics and participation in a range of risk behaviours. It included questions about their use of tobacco, alcohol, cannabis, solvents and other substances, bullying, suicidal ideation and attempts, and risky sexual behaviour. Data was analysed using a series of logistic regression models, with the estimation of model parameters being done through generalised estimation equations. RESULTS: Scores on each self-esteem scale were significantly associated with at least one risk behaviour in male and female adolescents after controlling for the sampling strategy, grade and race. However, specific self-esteem domains were differentially related to particular risk behaviours. After taking the correlations between the self-esteem scales into account, low self-esteem in the family and school contexts and high self-esteem in the peer domain were significantly independently associated with multiple risk behaviours in adolescents of both sexes. Low body-image self-esteem and global self-worth were also uniquely associated with risk behaviours in girls, but not in boys. CONCLUSIONS: Overall, the findings suggest that interventions that aim to protect adolescents from engaging in risk behaviours by increasing their self-esteem are likely to be most effective and cost-efficient if they are aimed at the family and school domains.     

Trends in adolescent alcohol and other drug use: findings from three sentinel sites in South Africa (1997-2001)

This paper aims to provide surveillance information about the extent and consequences of alcohol and other drug (AOD) use by adolescents for three sentinel sites in South Africa (Cape Town, Durban and Gauteng province). From 1997 to 2001, data were gathered from multiple sources, including specialist treatment centres, trauma units, school students, rave party attenders, and arrestees. Since the start of surveillance, an increasing proportion of South African adolescents are using AODs. Surveys point to high levels of alcohol misuse among high school students, with alcohol being the most common substance of abuse. Cannabis is the most frequently reported illicit drug of abuse among adolescents. This is reflected in the large proportion of adolescents receiving treatment for cannabis, cannabis-positive arrestees, and cannabis-positive trauma patients. Cannabis smoked together with methaqualone is the second most common primary drug of abuse in Cape Town. Arrestee data highlights the potentially negative effect of adolescent methaqualone use. Cocaine and heroin are emerging as problem drugs of abuse among adolescents in large metropolitan centres. Ecstasy (MDMA) use occurs mainly among adolescents who attend rave parties and clubs. The study points to the need for AOD intervention programmes that target young people and the need for continued monitoring of adolescent AOD use in the future.