Pharmacokinetics and safety of single-dose tenofovir disoproxil fumarate and emtricitabine in HIV-1-infected pregnant women and their infants

Tenofovir (TFV) is effective in preventing simian immunodeficiency virus (SIV) transmission in a macaque model, is available as the oral agent tenofovir disoproxil fumarate (TDF), and may be useful in the prevention of mother-to-child transmission of human immunodeficiency virus (HIV). We conducted a trial of TDF and TDF-emtricitabine (FTC) in HIV-infected pregnant women and their infants. Women received a single dose of either 600 mg TDF, 900 mg TDF, or 900 mg TDF-600 mg FTC at labor onset or prior to a cesarean section. Infants received no drug or a single dose of TDF at 4 mg/kg of body weight or of TDF at 4 mg/kg plus FTC at 3 mg/kg as soon as possible after birth. All regimens were safe and well tolerated. Maternal areas under the serum concentration-time curve (AUC) and concentrations at the end of sampling after 24 h (C(24)) were similar between the two doses of TDF; the maximum concentrations of the drugs in serum (C(max)) and cord blood concentrations were higher in women delivering via cesarean section than in those who delivered vaginally (P = 0.04 and 0.046, respectively). The median ratio of the TFV concentration in cord blood to that in the maternal plasma at delivery was 0.73 (range, 0.26 to 1.95). Without TDF administration, infants had a median TFV concentration of 12 ng/ml 12 h after birth. Following administration of a single dose of TDF at 4 mg/kg, infant TFV concentrations fell below the targeted level, 50 ng/ml, by 24 h postdose. In HIV-infected pregnant women and their infants, 600 mg of TDF is acceptable as a single dose during labor. Low concentrations at birth support infant dosing as soon after birth as possible. Rapidly decreasing TFV levels in infants suggest that multiple or higher doses of TDF will be necessary to maintain concentrations that are effective for viral suppression.     

Abnormal brain activation during working memory in children with prenatal exposure to drugs of abuse: the effects of methamphetamine, alcohol, and polydrug exposure

Structural and metabolic abnormalities in fronto-striatal structures have been reported in children with prenatal methamphetamine (MA) exposure. The current study was designed to quantify functional alterations to the fronto-striatal circuit in children with prenatal MA exposure using functional magnetic resonance imaging (fMRI). Because many women who use MA during pregnancy also use alcohol, a known teratogen, we examined 50 children (age range 7-15), 19 with prenatal MA exposure, 15 of whom had concomitant prenatal alcohol exposure (the MAA group), 13 with heavy prenatal alcohol but no MA exposure (ALC group), and 18 unexposed controls (CON group). We hypothesized that MA exposed children would demonstrate abnormal brain activation during a visuospatial working memory (WM) "N-Back" task. As predicted, the MAA group showed less activation than the CON group in many brain areas, including the striatum and frontal lobe in the left hemisphere. The ALC group showed less activation than the MAA group in several regions, including the right striatum. We found an inverse correlation between performance and activity in the striatum in both the CON and MAA groups. However, this relationship was significant in the caudate of the CON group but not the MAA group, and in the putamen of the MAA group but not the CON group. These findings suggest that structural damage in the fronto-striatal circuit after prenatal MA exposure leads to decreased recruitment of this circuit during a WM challenge, and raise the possibility that a rewiring of cortico-striatal networks may occur in children with prenatal MA exposure.     

Optimal elevation of β-cell 11β-hydroxysteroid dehydrogenase type 1 is a compensatory mechanism that prevents high-fat diet-induced β-cell failure

Type 2 diabetes ultimately results from pancreatic β-cell failure. Abnormally elevated intracellular regeneration of glucocorticoids by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in fat or liver may underlie pathophysiological aspects of the metabolic syndrome. Elevated 11β-HSD1 is also found in pancreatic islets of obese/diabetic rodents and is hypothesized to suppress insulin secretion and promote diabetes. To define the direct impact of elevated pancreatic β-cell 11β-HSD1 on insulin secretion, we generated β-cell-specific, 11β-HSD1-overexpressing (MIP-HSD1) mice on a strain background prone to β-cell failure. Unexpectedly, MIP-HSD1(tg/+) mice exhibited a reversal of high fat-induced β-cell failure through augmentation of the number and intrinsic function of small islets in association with induction of heat shock, protein kinase A, and extracellular signal-related kinase and p21 signaling pathways. 11β-HSD1(-/-) mice showed mild β-cell impairment that was offset by improved glucose tolerance. The benefit of higher β-cell 11β-HSD1 exhibited a threshold because homozygous MIP-HSD1(tg/tg) mice and diabetic Lep(db/db) mice with markedly elevated β-cell 11β-HSD1 levels had impaired basal β-cell function. Optimal elevation of β-cell 11β-HSD1 represents a novel biological mechanism supporting compensatory insulin hypersecretion rather than exacerbating metabolic disease. These findings have immediate significance for current therapeutic strategies for type 2 diabetes.     

Relations between suicide and traumatic brain injury, psychiatric diagnoses, and relationship problems, active component, U.S. Armed Forces, 2001-2009

This retrospective case-control study of members of the active component of the U.S. Armed Forces compared those who died from suicide to controls matched by service, gender, race, age, date of entry into the active component, and years of service. Th e surveillance period was 2001 to 2009. The groups were compared with respect to numbers of deployments and documented diagnoses of traumatic brain injury (TBI), mood disorders, alcohol dependence, post-traumatic stress disorder (PTSD), partner relationship problems, and family circumstance problems. Cases and controls were similar regarding frequencies and types of TBIs and numbers of deployments. In multivariate analyses, increased odds of suicide were associated with mood disorders, partner relationship problems, and family circumstance problems, but not with mild TBI, alcohol dependence, or PTSD. A separate analysis revealed that psychiatric comorbidities increased odds of suicide. Limitations are discussed, including the possibility that some controls with mild TBIs may have died from suicide after their military service.     

Memory complaint questionnaire performed poorly as screening tool: validation against psychometric tests and affective measures

ObjectiveThis study examined the internal and external validity of the Memory Complaint Questionnaire (MAC-Q), a brief measure of subjective memory complaint in people with normal cognitive function.Study Design and SettingThe Study of Health Outcomes in Aircraft Maintenance Personnel was a retrospective cohort study investigating the association between aircraft fuel tank deseal/reseal activities and health status in Royal Australian Air Force personnel. Cross-sectional comparison tests included measures of executive functioning, psychomotor speed, attention/working memory, new learning/memory, depression, and anxiety. An adjusted regression analysis accounted for confounders including age, dates of posting, rank, education, alcohol use, tobacco use, and affective status.ResultsEight hundred seventy-nine participants completed the MAC-Q. Although the MAC-Q tested as highly reliable and internally valid, it was highly associated with affective status and was only associated with Digit Symbol Coding after adjustment for depression/anxiety.ConclusionThe MAC-Q is greatly influenced by affective status but not memory performance. It is probably not useful as a specific screen of memory complaint for general population research.