Tau filaments are tethered within brain extracellular vesicles in Alzheimer's disease.

The abnormal assembly of tau protein in neurons is the pathological hallmark of multiple neurodegenerative diseases, including Alzheimer's disease (AD). In addition, assembled tau associates with extracellular vesicles (EVs) in the central nervous system of patients with AD, which is linked to its clearance and prion-like propagation between neurons. However, the identities of the assembled tau species and the EVs, as well as how they associate, are not known. Here, we combined quantitative mass spectrometry, cryo-electron tomography and single-particle cryo-electron microscopy to study brain EVs from AD patients. We found filaments of truncated tau enclosed within EVs enriched in endo-lysosomal proteins. We observed multiple filament interactions, including with molecules that tethered filaments to the EV limiting membrane, suggesting selective packaging. Our findings will guide studies into the molecular mechanisms of EV-mediated secretion of assembled tau and inform the targeting of EV-associated tau as potential therapeutic and biomarker strategies for AD.

Using Technology to Improve Adherence to HIV Medications in Transitional Age Youth: Research Reviewed, Methods Tried, Lessons Learned.

In transitional age youth living with HIV or AIDS, non-adherence (<80%) to anti-retroviral medication is associated with viral resistance, disease progression, and an increased risk of death. This feasibility study investigated the Maya MedMinder electronic pillbox and cell phone texting with personalized motivational interviewing strategies to improve medication adherence in non-adherent youth. Twenty patients out of 30 identified as non-adherent by the Pediatric HIV team at the Medical University of South Carolina were approached, and 15 were recruited (Ages 12 to 20; 13.3% male, 86.7% female; 100% African-American). Following baseline MedMinder monitoring, subjects were randomized to intervention groups with reminder signals on or off. The time medications were taken was collected by the MedMinder, resulting in adherence scores. All were interviewed for readiness to change utilizing the Motivational Interviewing (MI) Stages of Change scores. Viral load and CD4 labs were scheduled every 6 weeks. Despite monetary incentives and personalized support, recruitment and adherence to the protocol was a challenge. Only 6/15 subjects completed the entire study scheduled for 6-months .Stages of change scores revealed that those that transitioned to making changes had higher CD4 percentages midway through the study. Challenges included missed appointments and labs despite efforts by text and phone to schedule convenient appointment times with participants. Device challenges included the large size of the MedMinder and faulty electronic signaling, especially from rural areas. The methodology was feasible with these patients. This small feasibility study highlights that technological tools to promote adherence and motivational enhancement strategies in teens and young adults who are non-adherent to HIV medication regimens can enhance biomarker outcomes associated with medication adherence.

Oral famciclovir for suppression of recurrent genital herpes simplex virus infection in women. A multicenter, double-blind, placebo-controlled trial. Collaborative Famciclovir Genital Herpes Research Group.

OBJECTIVE: To evaluate the efficacy and safety of oral famciclovir in the suppression of genital herpes. METHODS: In this randomized, double-blind, placebo-controlled trial that was performed at 11 university and 9 private ambulatory care referral centers, 375 women who were 18 years of age or older and had a history of 6 or more episodes of genital herpes during 12 of the last 24 months in the absence of suppressive therapy were treated for 4 months with oral famciclovir, 125 mg once daily or twice daily, 250 mg once daily or twice daily, 500 mg once daily, or placebo. The primary outcome measures included the time to first clinically and virologically confirmed recurrences, and safety as measured by clinical laboratory tests and adverse experiences. RESULTS: The median time to first recurrence was 82 days in the placebo group, 114 days in those receiving famciclovir, 125 mg once daily, and more than 120 days in the other treatment groups. When compared with placebo recipients, the time to the first clinical recurrence was significantly prolonged in subjects who received famciclovir, 125 mg twice daily (hazard ratio, 1.8; 95% confidence interval, 1.0-3.0; P = .03), and in those who received famciclovir, 250 mg twice daily (hazard ratio, 3.6; 95% confidence interval, 1.9-6.9; P < .001). Treatment was well tolerated, and there was no evidence of emergence of resistance during or after suppressive famciclovir therapy. CONCLUSIONS: Oral famciclovir, 250 mg, given twice daily for 4 months is an effective, well-tolerated treatment for the suppression of genital herpes in women with frequent recurrences, but single daily doses produced less complete suppression of genital herpes.

Assessment of adherence with medications in human immunodeficiency virus-infected children.

The purpose of this study was to determine the reliability of screening for medication adherence in HIV-infected children. The results suggest that caregivers who are unable to describe the medication regimen or who are nonadherent with appointments are unlikely to adhere to the medication regimen. Adherence with at least 90% of medication doses was associated with a virologic response.

A double-blind randomized clinical study of the safety, tolerability and efficacy of Hexabrix in pediatric angiocardiography.

Hexabrix, a low-osmolality radiographic contrast agent consisting of the meglumine and sodium salt of ioxaglic acid (600 mOsm/kg), was evaluated in 50 children undergoing cardiac catheterization in a randomized double-blind manner. In comparison with a conventional radiographic contrast agent (Renografin-76), Hexabrix produced a marked reduction in the pain or discomfort after the injection. Neither agent produced any significant change in pulse or respiratory rates or blood pressure. Changes in left and right ventricular pressures were small and comparable for both groups. Significant dysrhythmias were not noted. There was no evidence of deterioration in renal or hepatic function in either group. Serum LDH and CPK increased comparably with both contrast agents but without any definite evidence of myocardial injury. Postinjection increases in serum osmolality were slightly, but not significantly, higher with Renografin. In the first few hours following the procedure there was an increase in circulating segmented neutrophils and a reciprocal decrease in lymphocytes; this was transient and gone by 24 hours. Radiographic image quality was judged good or excellent in almost all cases. Hexabrix is a contrast agent that is significantly better tolerated than conventional agents and is associated with no greater incidence of side-effects while producing radiographic images of equivalent quality.

Evidence for person-to-person transmission of Candida lusitaniae in a neonatal intensive-care unit.

Candida lusitaniae is an increasingly important nosocomial bloodstream pathogen. Epidemiological investigation and molecular typing techniques identified three neonates infected with identical strains of C lusitaniae that were distinguished readily from epidemiologically unrelated strains from other locations in the hospital. The results of this study provide evidence for nosocomial transmission of C lusitaniae in a neonatal intensive-care unit and suggest that these infants are at increased risk for infection with this agent.

Pediatric HIV Long-Term Nonprogressors.

Patients infected with HIV are best categorized along a continuum from rapid progressors to HIV long-term nonprogressors. Long-term nonprogressors (LTNPs) are those in which AIDS develop many years after being infected with HIV, often beyond the 10-year mark, and represent 15-20% of the HIV infected patients. Many of these patients are able to control their infection and maintain undetectable viral loads for long periods of time without antiretroviral therapy. After a comprehensive literature search, we found extensive data related to HIV LTNPs in the adult population; however, very limited data was available related to LTNPs within the pediatric population. We present a case of pediatric HIV LTNPs, perinatally infected patient with undetectable viral loads, despite never receiving ART. Although there are not many instances of LTNPs among children, this child may be one, though she had intermittent viremia. She has continued to manifest serologic evidence of infection, with yearly ELISA and western blot positive tests. Based on the viral fitness studies that were performed, this case exemplifies an adolescent LTNP.

Herpes simplex virus-1 replication in histiotypic rotation-mediated reaggregated murine brain.

Inbred mouse strains exhibit varying susceptibilities to severe herpes simplex virus (HSV)-1-related neurologic disease. HSV-1 replication was examined in neural tissue obtained from mouse strains susceptible (A/J, SJL), moderately resistant (Balb/c), or resistant (C57BL/6) to severe HSV-1 disease. Reaggregated brain cultures were prepared from mechanically dissociated fetal mouse brains maintained with constant rotation. The resulting aggregates each contain neurons, astrocytes, oligodendrocytes, and microglia. These were inoculated with 10(-2)-10(4) plaque-forming units (pfu) HSV-1 MacIntyre/aggregate. Aggregates and media were harvested at 24, 48, 72, and 96 hr post-inoculation (p.i.) and assayed for virus production by plaque titration. Brain cultures prepared from A/J, SJL, Balb/c, and C57BL/6 mice supported HSV-1 replication equally well: by 96 hr p.i., titers of 10(6) pfu/ml were produced by each strain at each inoculum. ID50s were similar for A/J and C57BL/6 cultures. There was no increased capacity for HSV-1 replication or for permissiveness for HSV-1 infection in histiotypic brain cultures from mouse strains susceptible to severe HSV-1 disease.

Outcome of herpes simplex virus type 2 infection in guinea pigs.

Factors that influence the outcome of genital herpes simplex virus (HSV) infection were explored in a guinea pig model. The viral inoculum required to establish infection in 50% of animals (ID50) was similar for inbred (strain 2) and outbred (Hartley) guinea pigs. However, the viral inoculum required to produce clinical disease in 50% of the animals (CD50) was 10 times greater for strain 2 compared to Hartley animals. HSV infection of both inbred and outbred animals was more likely to result in death of weanling than adult animals. The duration and severity of genital disease and the magnitude of vaginal viral replication were similar for strain 2 and Hartley animals in both young and adult animals. The lethal dose for 50% of animals (LD50) was 100-fold greater than the CD50 for Hartley animals, but the LD50 and the CD50 were equal in strain 2 guinea pigs. Viral cultures of homogenized neural tissues from infected animals revealed that HSV ascended to the level of the temporal cortex in strain 2 guinea pigs while virus was never recovered above the lumbar spinal cord in Hartley animals. Endogenous peripheral blood mononuclear cell-mediated cytolytic activity against HSV-infected targets was greater prior to HSV inoculation in survivors compared to animals that died. A fatal outcome of genital HSV-2 may relate to the failure to limit CNS viral replication. Death is more common among guinea pigs that have low endogenous HSV-directed natural killer activity, such as occurs among strain 2 and young animals whether inbred or outbred.