High affinity, bioavailable 3-amino-1,4-benzodiazepine-based gamma-secretase inhibitors

In this paper, we describe the development of a novel series of high affinity, orally bioavailable 3-amino-1,4 benzodiazepine-based gamma-secretase inhibitors for the potential treatment of Alzheimer's disease. We disclose structure-activity relationships based around the 1, 3 and 5 positions of the benzodiazepine core structure.     

Decreases in organ blood flows associated with increases in sublingual PCO2 during hemorrhagic shock

Earlier studies demonstrated that not only thestomach but also the esophageal wall served as an appropriate site forestimating the severity of circulatory shock by using tonometricmethods. We then conceived of the option of sublingual tonometry. Inthe present study, we tested the hypothesis that the changes insublingual PCO₂ serve as indicatorsof decreases in blood flow to sublingual and visceraltissue. In Sprague-Dawley rats, sublingual PCO₂ increased from 50 to 127 Torrand arterial blood lactate increased from 0.9 to 11.2 mmol/l duringbleeding. Sublingual blood flow simultaneously decreased to ~32% ofpreshock values. After reinfusion of shed blood, organ blood flows andsublingual PCO₂ were promptlyrestored to near-baseline values. There were corresponding decreases inblood flows in the tongue, stomach, jejunum, colon, and kidneys duringhemorrhagic shock. Increases in sublingualPCO₂ were highly correlated with decreases in sublingual blood flow (r = 0.80), tongue blood flow (r = 0.81),gastric blood flow (r = 0.74), jejunalblood flow (r = 0.65), colon bloodflow (r = 0.80), and renal blood flow (r = 0.75). Unbled control animalsdemonstrated no significant changes. Therefore, we anticipate thatsublingual tonometry will provide a useful, noninvasive alternative formonitoring visceral PCO₂.

     

Potent Functional Antibody Responses Elicited by HIV-I DNA Priming and Boosting with Heterologous HIV-1 Recombinant MVA in Healthy Tanzanian Adults

Vaccine-induced HIV antibodies were evaluated in serum samples collected from healthy Tanzanian volunteers participating in a phase I/II placebo-controlled double blind trial using multi-clade, multigene HIV-DNA priming and recombinant modified vaccinia Ankara (HIV-MVA) virus boosting (HIVIS03). The HIV-DNA vaccine contained plasmids expressing HIV-1 gp160 subtypes A, B, C, Rev B, Gag A, B and RTmut B, and the recombinant HIV-MVA boost expressed CRF01_AE HIV-1 Env subtype E and Gag-Pol subtype A. While no neutralizing antibodies were detected using pseudoviruses in the TZM-bl cell assay, this prime-boost vaccination induced neutralizing antibodies in 83% of HIVIS03 vaccinees when a peripheral blood mononuclear cell (PBMC) assay using luciferase reporter-infectious molecular clones (LucR-IMC) was employed. The serum neutralizing activity was significantly (but not completely) reduced upon depletion of natural killer (NK) cells from PBMC (p=0.006), indicating a role for antibody-mediated Fcγ-receptor function. High levels of antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies against CRF01_AE and/or subtype B were subsequently demonstrated in 97% of the sera of vaccinees. The magnitude of ADCC-mediating antibodies against CM235 CRF01_AE IMC-infected cells correlated with neutralizing antibodies against CM235 in the IMC/PBMC assay. In conclusion, HIV-DNA priming, followed by two HIV-MVA boosts elicited potent ADCC responses in a high proportion of Tanzanian vaccinees. Our findings highlight the potential of HIV-DNA prime HIV-MVA boost vaccines for induction of functional antibody responses and suggest this vaccine regimen and ADCC studies as potentially important new avenues in HIV vaccine development.

Trial Registration

Controlled-Trials ISRCTN90053831 The Pan African Clinical Trials Registry ATMR2009040001075080 (currently PACTR2009040001075080)     

Are the Recent Secular Increases in Waist Circumference among Children and Adolescents Independent of Changes in BMI?

Background

Several studies have shown that the waist circumference of children and adolescents has increased over the last 25 years. However, given the strong correlation between waist circumference and BMI, it is uncertain if the secular trends in waist circumference are independent of those in BMI.

Methods

We analyzed data from 6- to 19-year-olds who participated in the 1988–1994 through 2011–2012 cycles of the National Health and Nutrition Examination Survey to assess whether the trends in waist circumference were independent of changes in BMI, race-ethnicity and age.

Results

Mean, unadjusted levels of waist circumference increased by 3.7 cm (boys) and 6.0 cm (girls) from 1988–94 through 2011–12, while mean BMI levels increased by 1.1 kg/m² (boys) and 1.6 kg/m² (girls). Overall, the proportional changes in mean levels of both waist circumference and BMI were fairly similar among boys (5.3%, waist vs. 5.6%, BMI) and girls (8.7%, waist vs. 7.7%, BMI). As assessed by the area under the curve, adjustment for BMI reduced the secular increases in waist circumference by about 75% (boys) and 50% (girls) beyond that attributable to age and race-ethnicity. There was also a race-ethnicity interaction (p < 0.001). Adjustment for BMI reduced the secular trend in waist circumference among non-Hispanic (NH) black children (boys and girls) to a greater extent (about 90%) than among other children.

Conclusions

Our results indicate that among children in the U.S., about 75% (boys) and 50% (girls) of the secular increases in waist circumference since 1988–94 can be accounted for by changes in BMI. The reasons for the larger independent effects among girls and among NH blacks are uncertain.     

Rangewide microsatellite phylogeography of the endangered tidewater goby, <Emphasis Type="Italic">Eucyclogobius newberryi</Emphasis> (Teleostei: Gobiidae), a genetically subdivided coastal fish with limited marine dispersal

The federally endangered tidewater goby, Eucyclogobius newberryi, is the most locally differentiated vertebrate with marine dispersal on the California Coast. It inhabits seasonally closed estuaries along the California coast; a habitat heavily impacted by anthropogenic filling and artificial opening, and exhibits varied metapopulation behavior as a consequence of hydrologic variation and anthropogenic impact. We describe 19 taxon-specific microsatellite loci, and assess genetic variation across the taxon range relative to genetic subdivision. A highly divergent southern clade, with reduced genetic variation, now confined to Northern San Diego County, appears to merit status as a separate species. The mid-coast is subdivided into regional groups with overall similarity to, and minor differences from previous mitochondrial sequence based clades. The northernmost region, although locally differentiated, forms a star phylogeny with limited geographic structure which we attribute to dispersal during Pleistocene/Holocene sea-level rise followed by increasing isolation during the Holocene. Bottleneck/founder events are evident in some habitats thought to have experienced (anthropogenic) extirpation. Further work with more, and larger, samples will be required to assess local and regional differences. Analytical methods employed include Analysis of Molecular Variance (AMOVA), Neighbor-Joining, Bayesian/STRUCTURE analysis and Principle Components Analysis (PCA).     

The development of dopamine overflow from foetal nigral grafts in the intact rat striatum and their influence on contralateral striatal dopamine overflow.

In this study, cell suspensions of foetal rat ventral mesencephalic dopaminergic tissue were grafted to the intact (non-lesioned) striatum of adult rats. Differential pulse voltammetry at carbon-fibre micro electrodes (12 microm diameter) was employed to first, monitor the development of dopamine overflow over a 20 week period within the grafts and secondly, their influence on contralateral striatal dopamine overflow. At 8 and 20 weeks, animals were pre-treated with pargyline and both striata were monitored for dopamine overflow for 90 min following d-amphetamine administration. Amphetamine led to a significant increase in dopamine overflow in both the grafted striatum and the contralateral striatum. The time course of dopamine overflow in both the grafted striatum and the striatum contralateral to the graft was similar in all groups of animals. Although the actual concentration of dopamine measured in 20 week old grafts was more (approximately 21%) than that measured in 8 week old grafts, there was no significant difference between the two time points. The concentration of dopamine measured in the striatum contralateral to 8 week old grafts was significantly lower (approximately 43%) than that measured in the striatum of a normal control rats. There was no significant difference between the concentration of dopamine measured in the striatum contralateral to 20 week old grafts and normal control rats. In conclusion, dopamine overflow from a ventral mesencephalic graft does not change significantly between 8 and 20 weeks following grafting. However, the grafted tissue causes a decrease of d-amphetamine-induced dopamine overflow in the contralateral side 8 weeks following grafting, which is restored 12 weeks later.     

Raptor mortality due to West Nile virus in the United States, 2002

West Nile virus (WNV) has affected many thousands of birds since it was first detected in North America in 1999, but the overall impact on wild bird populations is unknown. In mid-August 2002, wildlife rehabilitators and local wildlife officials from multiple states began reporting increasing numbers of sick and dying raptors, mostly red-tailed hawks (Buteo jamaicensis) and great horned owls (Bubo virginianus). Commonly reported clinical signs were nonspecific and included emaciation, lethargy, weakness, inability to perch, fly or stand, and nonresponse to danger. Raptor carcasses from 12 states were received, and diagnostic evaluation of 56 raptors implicated WNV infection in 40 (71%) of these cases. Histologically, nonsuppurative encephalitis and myocarditis were the salient lesions (79% and 61%, respectively). Other causes of death included lead poisoning, trauma, aspergillosis, and Salmonella spp. and Clostridium spp. infections. The reason(s) for the reported increase in raptor mortality due to WNV in 2002 compared with the previous WNV seasons is unclear, and a better understanding of the epizootiology and pathogenesis of the virus in raptor populations is needed.