Short communication: Phenotypic protease inhibitor resistance and cross-resistance in the clinic from 2006 to 2008 and mutational prevalences in HIV from patients with discordant tipranavir and darunavir susceptibility phenotypes

To test tipranavir (TPV) or darunavir (DRV) as treatment options for patients with phenotypic resistance to protease inhibitors (PIs), including lopinavir, saquinavir, atazanavir, and fosamprenavir, the PhenoSense GT database was analyzed for susceptibility to DRV or TPV among PI-resistant isolates. The Monogram Biosciences HIV database (South San Francisco, CA) containing 7775 clinical isolates (2006-2008) not susceptible to at least one first-generation PI was analyzed. Phenotypic responses [resistant (R), partially susceptible (PS), or susceptible (S)] were defined by upper and lower clinical cut-offs to each PI. Genotypes were screened for amino acid substitutions associated with TPV-R/DRV-S and TPV-S/DRV-R phenotypes. In all, 4.9% (378) of isolates were resistant to all six PIs and 31.0% (2407) were resistant to none. Among isolates resistant to all four first-generation PIs, DRV resistance increased from 21.2% to 41.9% from 2006 to 2008, respectively, and resistance to TPV remained steady (53.9 to 57.3%, respectively). Higher prevalence substitutions in DRV-S/TPV-R isolates versus DRV-R/TPV-S isolates, respectively, were 82L/T (44.4% vs. 0%) and 83D (5.8% vs. 0%). Higher prevalence substitutions in DRV-R/TPV-S virus were 50V (0.0% vs. 28.9%), 54L (1.0% vs. 36.1%), and 76V (0.4% vs. 15.5%). Mutations to help predict discordant susceptibility to DRV and TPV in isolates with reduced susceptibility to other PIs were identified. DRV resistance mutations associated with improved virologic response to TPV were more prevalent in DRV-R/TPV-S isolates. TPV resistance mutations were more prevalent in TPV-R and DRV-S isolates. These results confirm the impact of genotype on phenotype, illustrating how HIV genotype and phenotype data assist regimen optimization.     

Wake detection capacity of actigraphy during sleep

STUDY OBJECTIVES: To evaluate the ability of actigraphy compared to polysomnography (PSG) to detect wakefulness in subjects submitted to 3 sleep conditions with different amounts of wakefulness: a nocturnal sleep episode and 2 daytime recovery sleep episodes, one with placebo and one with caffeine. A second objective was to compare the ability of 4 different scoring algorithms (2 threshold algorithms and 2 regression analysis algorithms) to detect wake in the 3 sleep conditions. DESIGN: Three nights of simultaneous actigraphy (Actiwatch-L, Mini-Mitter/Respironics) and PSG recordings in a within-subject design. SETTING: Chronobiology laboratory. PARTICIPANTS: Fifteen healthy subjects aged between 20 and 60 years (7M, 8F). INTERVENTIONS: 200 mg of caffeine and daytime recovery sleep. RESULTS: An epoch-by-epoch comparison between actigraphy and PSG showed a significant decrease in actigraphy accuracy with increased wakefulness in sleep conditions due to the low sleep specificity of actigraphy (generally <50%). Actigraphy overestimated total sleep time and sleep efficiency more strongly in conditions involving more wakefulness. Compared to the 2 regression algorithms, the 2 threshold algorithms were less able to detect wake when the sleep episode involved more wakefulness, and they tended to alternate more between wake and sleep in the scoring of long periods of wakefulness resulting in an overestimation of the number of awakenings. CONCLUSION: The very low ability of actigraphy to detect wakefulness casts doubt on its validity to measure sleep quality in clinical populations with fragmented sleep or in situations where the sleep-wake cycle is challenged, such as jet lag and shift work.     

Social recognition memory requires protein synthesis after reactivation

Recent evidence indicates that reactivation of consolidated memories returns them to a protein-synthesis-dependent state called reconsolidation. The hypothesis that memories reconsolidate has never been assessed in social memory. The authors tested whether sheep (Ovis aries) mothers' memory of their lambs undergoes reconsolidation upon reactivation. After 7 days of mother-young contact, ewes were separated from their lambs for 8 hr, after which the lambs were reintroduced to their mothers for a 10-min reactivation session. Before reactivation, mothers received a subcutaneous injection of either the protein-synthesis inhibitor cycloheximide (CY, 1 mg/kg) or vehicle. Mothers' lamb memory was tested 1 hr (short-term memory [STM]) or 16 hr (long-term memory [LTM]) after reactivation. Mothers treated with CY exhibited intact STM but deficient LTM. CY injection without reactivation or before presentation of an alien lamb induced no deficit in LTM. CY-induced LTM deficit was alleviated by (a) introducing a reminder just before the LTM test, (b) extending mother-young contact, and (c) preventing suckling by the familiar lamb during reactivation. Thus, reconsolidation can be shown to exist in social memory, and some of its boundary conditions are discussed.     

Vestibular system may provide equivalent motor actions regardless of the number of body segments involved in the task

The vestibulospinal system likely plays an essential role in motor equivalence—the ability to reach the desired motor goal despite intentional or imposed changes in the number of body segments involved in the task. To test this hypothesis, we compared the ability of healthy subjects and patients with unilateral vestibular lesions (surgical acoustic neuroma resection 0.6 to 6.7 yr before the study) to maintain either the same hand position or the same trajectory of within arm reach movements while flexing the trunk, in the absence of vision. In randomly selected trials, the trunk motion was prevented by an electromagnetic device. Healthy subjects were able to preserve the hand position or trajectory by modifying the elbow and shoulder joint rotations in a condition-dependent way, at a minimal latency of about 60 ms after the trunk movement onset. In contrast, six of seven patients showed deficits in the compensatory angular modifications at least in one of two tasks so that 30–100% of the trunk displacement was not compensated and thus influenced the hand position or trajectory. Results suggest that vestibular influences evoked by the head motion during trunk flexion play a major role in maintaining the consistency of arm motor actions in external space despite changes in the number of body segments involved. Our findings also suggest that despite long-term plasticity in the vestibular system and related neural structures, unilateral vestibular lesion may reduce the capacity of the nervous system to achieve motor equivalence.     

Development of visual texture segregation during the first year of life: a high-density electrophysiological study

There are important developmental changes occurring during infancy in visual cortical structures that underlie higher-order perceptual abilities. Using high-density electrophysiological recording techniques, the present study aimed to examine the development of visual mechanisms, during the first year of life, associated with texture segregation. Forty-two normal full term infants were tested at 1, 3, 6 or 12 months of age. Visual-evoked potentials to low-level stimuli varying in orientation (oriVEP) and higher-level textured stimuli (texVEP) were recorded from 128 scalp electrodes. Difference potentials were obtained to extract the VEP component associated specifically with texture segregation (tsVEP). Results show a clear developmental pattern regarding amplitude, latency and scalp distribution of tsVEP, which appears at around 3 months but does not reach maturity by 12 months of age. A reduction in latency is particularly evident between 3 and 6 months, whereas amplitude shows a gradual increase with a marked increment between 3 and 6 months for low-level orientation stimuli and between 6 and 12 months for higher-level textured stimuli. These developmental patterns are attributed to neural maturational processes such as myelination and synaptogenesis. The differential developmental rates can be explained by delayed maturational processes of brain regions involved in more complex visual processing.     

Primary health care organizational characteristics associated with better accessibility: data from the QUALICO-PC survey in Quebec

Background

First-contact accessibility remains an important problem in Canada, with this indicator staying the worst of all Organization for Economic Co-operation and Development countries. In the province of Quebec, a number of primary healthcare (PHC) organizations have adopted measures to improve access (e.g. advance access scheduling, expanded nursing role, electronic medical record, financial incentives). The impact of those changes is unknown. The goal of this study is to assess which PHC organizations’ characteristics are associated with improved first-contact accessibility.

Methods

We conducted a secondary data analysis of the Quebec survey, conducted as part of the QUALICO-PC study on primary care performance. QUALICO-PC is a cross-sectional study to assess quality, costs and equity in PHC across 35 countries and jurisdictions. Organizational characteristics were measured from the family practitioners’ questionnaire. First-contact accessibility was measured from the patient questionnaire filled by patients who received care in the participating PHC organizations. Multi-level logistic regression was used to assess the association of organizational characteristics as predictors of patient-reported accessibility.

Results

A total of 218 family practitioners participated in the study with 1798 of their patients. PHC organizations characteristics associated with increased first-contact accessibility included the possibility to have a same-day appointment or to walk in the clinic without an appointment, higher number of physicians per clinic and higher number of hours worked by the family physician. Electronic medical record and expanded nursing role were not associated with increased accessibility.

Conclusions

Same-day access and higher family physician working hours are associated with improved patient-reported accessibility. Other PHC organizations characteristics targeted by recent reforms were not associated with improved accessibility.

     

Prevalence of diabetes in france and drug use: study based on the French pharmacovigilance database

AIM: The aim of this study was to investigate the use of the French Pharmacovigilance Database to estimate characteristics of drug utilization in specific diseases. MATERIALS AND METHOD: We identified diabetic patients from the French Pharmacovigilance Database between 2002 and 2005. In this population, we studied demographic characteristics, and the patterns of drug use, particularly hypoglycemiant drug use and other drug exposure. In order to validate this approach, we compared our data to a population of patients with diabetes identified from the French Health Insurance System claims database in one French area. RESULTS: The estimation of prevalence of diabetes was very close in the sources: 2.7% in the French Pharmacovigilance Database and 3.2% in the French Health Insurance System claims database. We found similar results as well for demographic characteristics as for hypoglycemiant drug use and other drug exposure. CONCLUSION: These results suggest that the French Pharmacovigilance Database may be used to investigate drug utilization patterns.     

The screening of Alzheimer’s patients with CSF biomarkers,modulates the distribution of APOE genotype: impact on clinical trials

Polymorphism of the apolipoprotein E gene (APOE) plays a role in the level of neuropathological lesions and in drug response in Alzheimer’s disease (AD). The aim of this study was to investigate whether the selection of AD patients based on cerebrospinal fluid (CSF) biomarkers assessment may be biased by their APOE distribution. We studied the relationships between APOE genotype and CSF biomarkers levels in a total of 432 patients (AD, n = 244; non-AD, n = 188) explored for cognitive disorders. We studied the distribution of APOE genotypes among AD patient subgroups selected by various cut-offs of CSF biomarkers. Strategies of screening based on CSF Aβ1–42 lead to overselection of ε4/ε4 patients in the AD group. Screening based on tau levels did not change Apoe4 distribution in the AD group. CSF Aβ1–42 discriminated better AD patients with at least one ε4 than AD patients with no ε4. A strong allele-effect relationship was detected between APOE genotype and CSF amyloid-β (Aβ1–42) in AD patients. Selecting AD patients on CSF amyloid levels only may create an overselection of ε4/ε4 carriers, and might potentially bias the population of patients included in clinical trial studies.