Genetic and Non-Genetic Determinants of Raltegravir Penetration into Cerebrospinal Fluid: A Single Arm Pharmacokinetic Study

Background

Antiretroviral drugs vary in their central nervous system penetration, with better penetration possibly conferring neurocognitive benefit during human immunodeficiency virus (HIV) therapy. The efflux transporter gene ABCB1 is expressed in the blood-brain barrier, and an ABCB1 variant (3435C→T) has been reported to affect ABCB1 expression. The integrase inhibitor raltegravir is a substrate for ABCB1. We examined whether ABCB1 3435C→T affects raltegravir disposition into cerebrospinal fluid (CSF), and explored associations with polymorphisms in other membrane transporter genes expressed in the blood-brain barrier.

Methods

Forty healthy, HIV-negative adults of European descent (20 homozygous for ABCB1 3435 C/C, 20 homozygous for 3435 T/T, each group divided equally between males and females) were given raltegravir 400 mg twice daily for 7 days. With the final dose, plasma was collected for pharmacokinetic analysis at 9 timepoints over 12 hours, and CSF collected 4 hours post dose.

Results

The 4-hour CSF concentration correlated more strongly with 2-hour (r²=0.76, P=1.12x10^-11) than 4-hour (r²=0.47, P=6.89x10^-6) single timepoint plasma concentration, and correlated strongly with partial plasma area-under-the-curve values (AUC_0-4h r²=0.86, P=5.15x10^-16). There was no significant association between ABCB1 3435C→T and ratios of CSF-to-plasma AUC or concentration (p>0.05 for each comparison). In exploratory analyses, CSF-to-plasma ratios were not associated with 276 polymorphisms across 16 membrane transporter genes.

Conclusions

Among HIV-negative adults, CSF raltegravir concentrations do not differ by ABCB1 3435C→T genotype but strongly correlate with plasma exposure.

Trial Registration

ClinicalTrials.gov NCT00729924 http://clinicaltrials.gov/show/NCT00729924     

Impact of Perfusion Map Analysis on Early Survival Prediction Accuracy in Glioma Patients

Studies investigating dynamic susceptibility contrast magnetic resonance imaging-determined relative cerebral blood volume (rCBV) maps as a metric of treatment response assessment have generated conflicting results. We evaluated the potential of various analytical techniques to predict survival of patients with glioma treated with chemoradiation. rCBV maps were acquired in patients with high-grade gliomas at 0, 1, and 3 weeks into chemoradiation therapy. Various analytical techniques were applied to the same cohort of serial rCBV data for early assessment of survival. Three different methodologies were investigated: 1) percentage change of whole tumor statistics (i.e., mean, median, and percentiles), 2) physiological segmentation (low rCBV, medium rCBV, or high rCBV), and 3) a voxel-based approach, parametric response mapping (PRM). All analyses were performed using the same tumor contours, which were determined using contrast-enhanced T1-weighted and fluid attenuated inversion recovery images. The predictive potential of each response metric was assessed at 1-year and overall survival. PRM was the only analytical approach found to generate a response metric significantly predictive of patient 1-year survival. Time of acquisition and contour volume were not found to alter the sensitivity of the PRM approach for predicting overall survival. We have demonstrated the importance of the analytical approach in early response assessment using serial rCBV maps. The PRM analysis shows promise as a unified early and robust imaging biomarker of treatment response in patients diagnosed with high-grade gliomas.     

Characterization of stirrers for screening studies of enzymatic biomass hydrolyses on a milliliter scale

The evaluation of mixing quality is an important factor for improving the geometry of stirred-tank reactors and impellers used in bioprocess engineering applications, such as the enzymatic hydrolysis of plant materials. Homogeneity depends on different factors, including the stirrer type and the reactor type (e.g., ratio of diameter/height, ratio of impeller tip diameter/reactor diameter) with or without baffles. This study compares two impellers for enzymatic hydrolysis of suspensions of biomass particles on a milliliter scale. Both impellers were derived from industrially relevant geometries, such as blade and grid stirrers, although the geometry of the second stirrer was slightly modified to an asymmetric shape. The stirrers were investigated with different stirrer–reactor configurations. This was done experimentally and with the aid of computational fluid dynamics. The flow field, mixing numbers, power characteristics and initial conversion rates of sugars were considered to compare the two stirrers. The simulated mixing numbers and power characteristics in baffled and unbaffled milliliter-scale reactors were found to be in good agreement with the measured mixing times and power consumption. The mixing numbers required to reach homogeneity were much higher for the symmetric impeller and remained at least twice as high as the mixing numbers required when using the asymmetric impeller. The highest initial sugar releases from milled corn stover suspensions were achieved with the asymmetric impeller shape. Regardless of the differences in the flow fields or mixing times, diverging enzymatic sugar releases could be confirmed for Newtonian media only.     

INPPO Actions and Recognition as a Driving Force for Progress in Plant Proteomics: Change of Guard,INPPO Update,and Upcoming Activities

The International Plant Proteomics Organization (INPPO) is a non‐profit organization whose members are scientists involved or interested in plant proteomics. Since the publication of the first INPPO highlights in 2012, continued progress on many of the organization's mandates/goals has been achieved. Two major events are emphasized in this second INPPO highlights. First, the change of guard at the top, passing of the baton from Dominique Job, INPPO founding President to Ganesh Kumar Agrawal as the incoming President. Ganesh K. Agrawal, along with Dominique Job and Randeep Rakwal initiated the INPPO. Second, the most recent INPPO achievements and future targets, mainly the organization of first the INPPO World Congress in 2014, tentatively planned for Hamburg (Germany), are mentioned.     

Estimates of Excess Medically Attended Acute Respiratory Infections in Periods of Seasonal and Pandemic Influenza in Germany from 2001/02 to 2010/11

Background

The number of patients seeking health care is a central indicator that may serve several different purposes: (1) as a proxy for the impact on the burden of the primary care system; (2) as a starting point to estimate the number of persons ill with influenza; (3) as the denominator data for the calculation of case fatality rate and the proportion hospitalized (severity indicators); (4) for economic calculations. In addition, reliable estimates of burden of disease and on the health care system are essential to communicate the impact of influenza to health care professionals, public health professionals and to the public.

Methodology/Principal Findings

Using German syndromic surveillance data, we have developed a novel approach to describe the seasonal variation of medically attended acute respiratory infections (MAARI) and estimate the excess MAARI attributable to influenza. The weekly excess inside a period of influenza circulation is estimated as the difference between the actual MAARI and a MAARI-baseline, which is established using a cyclic regression model for counts. As a result, we estimated the highest ARI burden within the last 10 years for the influenza season 2004/05 with an excess of 7.5 million outpatient visits (CI95% 6.8–8.0). In contrast, the pandemic wave 2009 accounted for one third of this burden with an excess of 2.4 million (CI95% 1.9–2.8). Estimates can be produced for different age groups, different geographic regions in Germany and also in real time during the influenza waves.     

A single nucleotide substitution in TaHKT1;5-D controls shoot Na+ accumulation in bread wheat

Improving salinity tolerance in the most widely cultivated cereal, bread wheat (Triticum aestivum L.), is essential to increase grain yields on saline agricultural lands. A Portuguese landrace, Mocho de Espiga Branca accumulates up to sixfold greater leaf and sheath sodium (Na⁺) than two Australian cultivars, Gladius and Scout, under salt stress in hydroponics. Despite high leaf and sheath Na⁺ concentrations, Mocho de Espiga Branca maintained similar salinity tolerance compared to Gladius and Scout. A naturally occurring single nucleotide substitution was identified in the gene encoding a major Na⁺ transporter TaHKT1;5-D in Mocho de Espiga Branca, which resulted in a L190P amino acid residue variation. This variant prevents Mocho de Espiga Branca from retrieving Na⁺ from the root xylem leading to a high shoot Na⁺ concentration. The identification of the tissue-tolerant Mocho de Espiga Branca will accelerate the development of more elite salt-tolerant bread wheat cultivars.     

Pharmacological Characterization of a Betaine/GABA Transporter 1 (BGT1) Inhibitor Displaying an Unusual Biphasic Inhibition Profile and Anti-seizure Effects

Neurochemical Research - Focal epileptic seizures can in some patients be managed by inhibiting γ-aminobutyric acid (GABA) uptake via the GABA transporter 1 (GAT1) using tiagabine...     

Evolution under pH stress and high population densities leads to increased density-dependent fitness in the protist Tetrahymena thermophila

Abiotic stress is a major force of selection that organisms are constantly facing. While the evolutionary effects of various stressors have been broadly studied, it is only more recently that the relevance of interactions between evolution and underlying ecological conditions, that is, eco-evolutionary feedbacks, have been highlighted. Here, we experimentally investigated how populations adapt to pH-stress under high population densities. Using the protist species Tetrahymena thermophila, we studied how four different genotypes evolved in response to stressfully low pH conditions and high population densities. We found that genotypes underwent evolutionary changes, some shifting up and others shifting down their intrinsic rates of increase (r₀). Overall, evolution at low pH led to the convergence of r₀ and intraspecific competitive ability (α) across the four genotypes. Given the strong correlation between r₀ and α, we argue that this convergence was a consequence of selection for increased density-dependent fitness at low pH under the experienced high density conditions. Increased density-dependent fitness was either attained through increase in r₀, or decrease of α, depending on the genetic background. In conclusion, we show that demography can influence the direction of evolution under abiotic stress.     

Soil-transmitted helminth infection,anemia, and malnutrition among preschool-age children in Nangapanda subdistrict,Indonesia

BackgroundSoil-transmitted helminth (STH) infections are still prevalent in Indonesia, with roughly one-third of infected population being preschool-age children (PSC), which are generally at higher risk of morbidity such as malnutrition and anemia. This study aimed to investigate the association of STH infections with nutritional status and anemia among PSC in Nangapanda subdistrict, Ende, East Nusa Tenggara.MethodsA cross-sectional survey involving PSC ranging from 12 to 59 months old from Nangapanda subdistrict, Ende district, East Nusa Tenggara was performed. Socio-demographic, breastfeeding, and complementary feeding information was obtained from structured questionnaires, while nutritional and anemia status was determined from anthropometry and hemoglobin measurements, respectively. Anthropometric z-scores were calculated based on the World Health Organization 2006 standards and stool samples were examined using Kato-Katz method.ResultsA total of 393 PSC randomly selected from 22 villages were examined. The prevalence of underweight, stunting, wasting, and anemia were 33.1%, 40.2%, 17.1%, and 60.3%, respectively. STH infection, predominated by Ascaris lumbricoides, was found in 160 (58.8%) PSC. Single STH infection, but not multiple infection, was independently associated with a lower risk of anemia (odds ratio [OR] 0.320, 95% confidence interval [CI]: 0.126–0.809, p = 0.016). Similar association with anemia was also found on mild STH infection (OR 0.318 [95% CI: 0.114–0.887], p = 0.029). On the other hand, younger children were found to have a higher risk of anemia and stunting. None of the examined variables were independently associated with underweight and wasting.ConclusionSTH infection as well as anemia and malnutrition were prevalent in this region. However in this study, current STH infections seemed to have minimal negative impact on children’s nutritional status.