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.