Right atrial dimension-pressure relation during volume expansion is unaltered by pregnancy in the rat

Blood volume expands significantly during pregnancy, but afferent signals from cardiac receptors are reduced. In addition, during exogenous volume expansion, right atrial pressure (RAP) increases more for equivalent volumes in pregnant animals, implying reduced atrial compliance. To examine possible gestational alterations in atrial dimension during volume expansion, we compared the effects of volume expansion on RAP and right atrial dimension (RAD) in pregnant vs. virgin rats. Anesthetized animals were ventilated and catheterized for measurement of arterial pressure and RAP and for drug infusion. Through a parasternal incision, ultrasonic crystals were glued to the medial and lateral surfaces of the right atrium for measurement of RAD. Plasma volume and hematocrit were determined before experimentation. RAP, RAD, and arterial pressure were recorded at baseline and during progressive volume expansion (6% dextran, 60% of initial blood volume). Baseline RAP was similar in the two groups: 2.82 +/- 0.40 and 2.72 +/- 0.47 mmHg in pregnant and virgin rats, respectively. Basal RAD was significantly larger in pregnant than in virgin rats: 4.36 +/- 0.66 vs. 3.36 +/- 0.48 mm. Despite increased basal RAD in pregnant rats, the slope of the RAD-RAP relation during volume expansion was similar in the two groups. Results indicate that resting RAD is increased in pregnant rats and that the change in dimension during volume loads is similar to that in virgin rats. Thus, during pregnancy, the right atrium appears to accommodate the increased blood volume, and reduced afferent signaling most likely is due to mechanisms other than mechanical alterations of the atrium by expanded volume.     

Psilostachyin, acetylated pseudoguaianolides and their analogues: preparation and evaluation of their anti-inflammatory potential

Naturally occurring acetylated pseudoguaianolides and psilostachyin including their analogues were synthesized. The structure of semi-synthetic psilostachyin was also confirmed by X-ray crystallography. The anti-inflammatory potential of all the derivatives has been evaluated through in vitro expression of TNF-α, IL-1β and IL-6 in murine neutrophils.     

Optimizing Tuberculosis Case Detection through a Novel Diagnostic Device Placement Model: The Case of Uganda

Background

Xpert MTB/RIF (Xpert) is being widely adopted in high TB burden countries. Analysis is needed to guide the placement of devices within health systems to optimize the tuberculosis (TB) case detection rate (CDR).

Methods

We used epidemiological and operational data from Uganda (139 sites serving 87,600 individuals tested for TB) to perform a model-based comparison of the following placement strategies for Xpert devices: 1) Health center level (sites ranked by size from national referral hospitals to health care level III centers), 2) Smear volume (sites ranked from highest to lowest volume of smear microscopy testing), 3) Antiretroviral therapy (ART) volume (sites ranked from greatest to least patients on ART), 4) External equality assessment (EQA) performance (sites ranked from worst to best smear microscopy performance) and 5) TB prevalence (sites ranked from highest to lowest). We compared two clinical algorithms, one where Xpert was used only for smear microscopy negative samples versus another replacing smear microscopy. The primary outcome was TB CDR; secondary outcomes were detection of multi-drug resistant TB, number of sites requiring device placement to achieve specified rollout coverage, and cost.

Results

Placement strategies that prioritized sites with higher TB prevalence maximized CDR, with an incremental rate of 6.2–12.6% compared to status quo (microscopy alone). Diagnosis of MDR-TB was greatest in the TB Prevalence strategy when Xpert was used in place of smear microscopy. While initial implementation costs were lowest in the Smear Volume strategy, cost per additional TB case detected was lowest in the TB prevalence strategy.

Conclusion

In Uganda, placement of Xpert devices in sites with high TB prevalence yielded the highest TB CDR at the lowest cost per additional case diagnosed. These results represent novel use of program level data to inform the optimal placement of new technology in resource-constrained settings.     

Structure-based design, synthesis, and biological evaluation of dihydroquinazoline-derived potent β-secretase inhibitors

Structure-based design, synthesis, and biological evaluation of a series of dihydroquinazoline-derived β-secretase inhibitors incorporating thiazole and pyrazole-derived P2-ligands are described. We have identified inhibitor 4f which has shown potent enzyme inhibitory (K(i)=13nM) and cellular (IC(50)=21nM in neuroblastoma cells) assays. A model of 4f was created based upon the X-ray structure of 3a-bound β-secretase. The model suggested possible interactions in the active site.     

Identification of compositionally distinct regions in genomes using the centroid method

MOTIVATION: It is known that most genomic regions of special interest, e.g. horizontally acquired sequences, genomic islands, etc. have distinct word (m-mer) compositions. Most of the earlier work along this direction, addressed di- and tri-nucleotide compositions. We present an approach that can be applied to analyze compositions of any given word size. The method, called the centroid approach, can reveal compositionally distinct regions in genomic sequences for any given word size. RESULTS: We applied our method to 50 bacterial genomes and demonstrated its ability to identify embedded sequences of varying lengths from distantly related organisms. We also investigated the genetic makeup of the regions identified as compositionally distinct by our method, for four organisms from our dataset. Pathogenicity island (PAI) components and genes encoding strain-specific proteins are all frequently seen to be constituents of these regions. AVAILABILITY: Program is available on request from the authors. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.     

Some lessons from the tissue transglutaminase knockout mouse

Transglutaminase 2 (TG2) is an inducible transamidating acyltransferase that catalyzes Ca²⁺-dependent protein modifications. It acts as a G protein in transmembrane signaling and as a cell surface adhesion mediator, this distinguishes it from other members of the transglutaminase family. The sequence motifs and domains revealed in the TG2 structure, can each be assigned distinct cellular functions, including the regulation of cytoskeleton, cell adhesion, and cell death. Though many biological functions of the enzyme have already been described or proposed previously, studies of TG2 null mice by our laboratory during the past years revealed several novel in vivo roles of the protein. In this review we will discuss these novel roles in their biological context.     

Oxygen Consumption and Respiration During and After two Yoga Relaxation Techniques

Cyclic meditation (CM) is a technique which combines ‘stimulating’ and ‘calming’ practices, based on a statement in ancient yoga texts suggesting that such a combination may be especially helpful to reach a state of mental equilibrium. The oxygen consumption, breath rate and breath volume of 50 male volunteers (group mean age±SD, 27±6.3 years) were assessed before, during, and after sessions of CM and sessions of supine rest in the corpse posture (shavasana, SH). The sessions were one day apart and the order was alternated. The oxygen consumption, breath rate and breath volume increased during the ‘stimulating’ practices of CM, returned to the baseline during the ‘calming’ practices, and the oxygen consumption decreased by 19.3 percent below baseline values after CM. During the SH session the oxygen consumption, breath rate and breath volume reduced; however the decrease in oxygen consumption after SH was less than after CM (i.e., 4.8 percent). The results support the idea that a combination of yoga postures with supine rest (in CM) reduces the oxygen consumption more than resting supine alone does.     

Low Molecular Weight Mannogalactofucans Derived from <Emphasis Type="Italic">Undaria pinnatifida</Emphasis> Induce Apoptotic Death of Human Prostate Cancer Cells In Vitro and In Vivo

Low molecular weight mannogalactofucans (LMMGFs) prepared by enzymatic degradation of high molecular weight Undaria galactofucan (MF) were evaluated for their anti-cancer effects against human prostate cancer. Correlation NMR and linkage analyses confirmed that LMMGFs consist mainly of α-fucose and β-galactose units: α-fucose units are 1,3-linked; β-galactose units are terminal, 1,3- and/or 1,6-linked; both sugars are partially sulphated, fucose at positions O-2 and/or O-4 and galactose at O-3. Mannose residue, as a minor sugar, presents as the 1,4-linked terminal units. LMMGFs more significantly induced cell cycle arrest at the G0/G1 phase and cell death via suppression of the Akt/GSK-3β/β-catenin pathway than MF in human PC-3 prostate cancer cells. LMMGFs upregulated mRNA expression of death receptor-5 (DR-5), the ratio of Bax to Bcl-2, the cleavage of caspases and PARP, the depolarisation of mitochondrial membrane potential, and ROS generation. LMMGFs (200–400 mg/kg) effectively reduced both tumour volume and size in a xenografted mouse model. These results demonstrated that LMMGFs attenuate the growth of human prostate cancer cells both in vitro and in vivo, suggesting that LMMGFs can be used as a potent functional ingredient in health-beneficial foods or as a therapeutic agent to prevent or treat androgen-independent human prostate cancer.

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Graphical Abstract