Novel Paracrine Action of Endothelium Enhances Glucose Uptake in Muscle and Fat.

[Figure: see text].

A case series describing the multidisciplinary management of pulmonary arterial hypertension in pregnancy: Time for optimism.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a high-risk condition during pregnancy, with recent literature describing mortality rates of up to 23%. AIM: To describe the course and outcomes of pregnancy for women with PAH in a major Australian metropolitan referral centre over a 15-year period. METHODS: Retrospective review of medical records of all pregnant women with PAH over the period 2005-2020. RESULTS: We report the outcomes of nine pregnancies in six women. In five women, seven pregnancies proceeded to term with birth of a healthy neonate, five vaginal births and two caesareans. Two women opted for a termination of pregnancy in the first trimester following counselling. The planning of care and patient-centred decision-making was individually tailored by a multidisciplinary team. The pulmonary hypertension clinic provided specialist support including the management of pulmonary vasodilators. All women who delivered a live offspring received neuraxial anaesthesia. CONCLUSIONS: Women with this condition are ideally managed in a centre with expertise in PAH; counselling regarding the risks is imperative. Regional anaesthesia, irrespective of the mode of delivery, facilitated safe delivery and improved patient experience. The option of aiming for a term vaginal birth needs to be considered in these complex women.

PTPRD and DCC Are Novel BACE1 Substrates Differentially Expressed in Alzheimer's Disease: A Data Mining and Bioinformatics Study.

The ß-site Amyloid precursor protein Cleaving Enzyme 1 (BACE1) is an extensively studied therapeutic target for Alzheimer's disease (AD), owing to its role in the production of neurotoxic amyloid beta (Aß) peptides. However, despite numerous BACE1 inhibitors entering clinical trials, none have successfully improved AD pathogenesis, despite effectively lowering Aß concentrations. This can, in part, be attributed to an incomplete understanding of BACE1, including its physiological functions and substrate specificity. We propose that BACE1 has additional important physiological functions, mediated through substrates still to be identified. Thus, to address this, we computationally analysed a list of 533 BACE1 dependent proteins, identified from the literature, for potential BACE1 substrates, and compared them against proteins differentially expressed in AD. We identified 15 novel BACE1 substrates that were specifically altered in AD. To confirm our analysis, we validated Protein tyrosine phosphatase receptor type D (PTPRD) and Netrin receptor DCC (DCC) using Western blotting. These findings shed light on the BACE1 inhibitor failings and could enable the design of substrate-specific inhibitors to target alternative BACE1 substrates. Furthermore, it gives us a greater understanding of the roles of BACE1 and its dysfunction in AD.

Development of an automated, GMP compliant FASTlab™ radiosynthesis of [18 F]GE-179 for the clinical study of activated NMDA receptors.

N-(2-chloro-5-(S-2-[18 F]fluoroethyl)thiophenyl)-N'-(3-thiomethylphenyl)-N'-methylguanidine, ([18 F]GE-179), has been identified as a promising positron emission tomography (PET) ligand for the intra-channel phencyclidine (PCP) binding site of the N-methyl-D-aspartate (NMDA) receptor. The radiosynthesis of [18 F]GE-179 has only been performed at low radioactivity levels. However, the manufacture of a GMP compliant product at high radioactivity levels was required for clinical studies. We describe the development of a process using the GE FASTlab™ radiosynthesis platform coupled with HPLC purification. The radiosynthesis is a two-step process, involving the nucleophilic fluorination of ethylene ditosylate, 11, followed by alkylation to the deprotonated thiol precursor, N-(2-chloro-5-thiophenol)-N'-(3-thiomethylphenyl)-N'-methyl guanidine, 8. The crude product was purified by semi-preparative HPLC to give the formulated product in an activity yield (AY) of 7 ± 2% (n = 15) with a total synthesis time of 120 minutes. The radioactive concentration (RAC) and radiochemical purity (RCP) were 328 ± 77 MBq/mL and 96.5 ± 1% respectively and the total chemical content was 2 ± 1 µg. The final formulation volume was 14 mL. The previously described radiosynthesis of [18 F]GE-179 was successfully modified to deliver an process on the FASTlab™ that allows the manufacture of a GMP quality product from high starting radioactivitity (up to 80 GBq) and delivers a product suitable for clinical use.

Mainstreaming gender into global health programming to improve women's health.

In this paper, a case is made for mainstreaming gender into global women's health programming and policies. The potential implications of conflating "gender" with "women'" in the design and evaluation of women's health programming are first considered. HIV/AIDS case studies are then used to depict examples of (a) where gender has been well integrated and (b) where policies fall short of gender mainstreaming. Finally, practical approaches to mainstream gender in a meaningful way into the design and evaluation of women's health programming and policies are provided for practitioners and researchers.

Discovery and lead optimisation of a potent, selective and orally bioavailable RARß agonist for the potential treatment of nerve injury.

Oxadiazole replacement of an amide linkage in an RARα agonist template 1, followed by lead optimisation, has produced a highly potent and selective RARß agonist 4-(5-(4,7-dimethylbenzofuran-2-yl)-1,2,4-oxadiazol-3-yl)benzoic acid (10) with good oral bioavailability in the rat and dog. This molecule increases neurite outgrowth in vitro and induces sensory axon regrowth in vivo in a rodent model of avulsion and crush injury, and thus has the potential for the treatment of nerve injury.

Strain differences in hearing in song canaries.

Belgian Waterslager song canaries, bred for hundreds of years for a low-pitched song, have also acquired an inherited high-frequency hearing loss associated with hair cell abnormalities. Here, auditory thresholds measured using auditory brainstem responses and psychophysical methods in three different strains of canaries are compared: Belgian Waterslagers, American Singers, and Borders. Border canaries have not been bred for song characteristics while American Singer canaries have been bred for song only since the 1930s. Results show that American Singer canaries also have elevated high frequency thresholds that are similar to those of the Belgian Waterslager, while Border canaries have normal thresholds. These results strengthen the case that song canary breeders in selecting for song characteristics may have inadvertently selected for hearing abnormalities.

Cre/lox Studies Identify Resident Macrophages as the Major Source of Circulating Coagulation Factor XIII-A.

OBJECTIVE: To establish the cellular source of plasma factor (F)XIII-A. APPROACH AND RESULTS: A novel mouse floxed for the F13a1 gene, FXIII-Aflox/flox (Flox), was crossed with myeloid- and platelet-cre-expressing mice, and cellular FXIII-A mRNA expression and plasma and platelet FXIII-A levels were measured. The platelet factor 4-cre.Flox cross abolished platelet FXIII-A and reduced plasma FXIII-A to 23±3% (P<0.001). However, the effect of platelet factor 4-cre on plasma FXIII-A was exerted outside of the megakaryocyte lineage because plasma FXIII-A was not reduced in the Mpl-/- mouse, despite marked thrombocytopenia. In support of this, platelet factor 4-cre depleted FXIII-A mRNA in brain, aorta, and heart of floxed mice, where FXIII-Apos cells were identified as macrophages as they costained with CD163. In the integrin αM-cre.Flox and the double copy lysozyme 2-cre.cre.Flox crosses, plasma FXIII-A was reduced to, respectively, 75±5% (P=0.003) and 30±7% (P<0.001), with no change in FXIII-A content per platelet, further consistent with a macrophage origin of plasma FXIII-A. The change in plasma FXIII-A levels across the various mouse genotypes mirrored the change in FXIII-A mRNA expression in aorta. Bone marrow transplantation of FXIII-A+/+ bone marrow into FXIII-A-/- mice both restored plasma FXIII-A to normal levels and replaced aortic and cardiac FXIII-A mRNA, while its transplantation into FXIII-A+/+ mice did not increase plasma FXIII-A levels, suggesting that a limited population of niches exists that support FXIII-A-releasing cells. CONCLUSIONS: This work suggests that resident macrophages maintain plasma FXIII-A and exclude the platelet lineage as a major contributor.

Design and synthesis of a potent, highly selective, orally bioavailable, retinoic acid receptor alpha agonist.

A ligand-based virtual screening exercise examining likely bioactive conformations of AM 580 (2) and AGN 193836 (3) was used to identify the novel, less lipophilic RARα agonist 4-(3,5-dichloro-4-ethoxybenzamido)benzoic acid 5, which has good selectivity over the RARß, and RARγ receptors. Analysis of the medicinal chemistry parameters of the 3,5-substituents of derivatives of template 5 enabled us to design a class of drug-like molecules with lower intrinsic clearance and higher oral bioavailability which led to the novel RARα agonist 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoic acid 56 that has high RARα potency and excellent selectivity versus RARß (2 orders of magnitude) and RARγ (4 orders of magnitude) at both the human and mouse RAR receptors with improved drug-like properties. This RARα specific agonist 56 has high oral bioavailability (>80%) in both mice and dogs with a good PK profile and was shown to be inactive in cytotoxicity and genotoxicity screens.

Perceptions of why Malawians engage in concurrent sexual partnerships among a select population of radio listeners: findings from an exploratory study.

Concurrent sexual partnerships have been identified as a potential driver in the HIV epidemic in Southern Africa. This study utilised an innovative approach to explore perceptions of why Malawians may engage in these relationships, and their suggestions for reducing the practice among a select population of radio listeners. Using radio listener feedback in the form of text messages, we analysed approximately 1 000 text messages sent by individuals who listened to a reality radio programme that included real stories, told by Malawians, on topics related to HIV/AIDS. Listeners suggested that lack of satisfaction with one's partner was the overarching reason why individuals had concurrent sexual partnerships. Within the context of lack of satisfaction, listeners cited alcohol use, poor communication and gendered norms as factors related to satisfaction. Listeners suggested that couple communication could increase satisfaction, which, in turn, could reduce concurrent sexual partnerships. Prevention efforts should consider how to utilise couple communication to improve satisfaction as an approach to reduce HIV risk in Southern Africa.

Influence of product placement in children's movies on children's snack choices.

BACKGROUND: Media exposure affects health, including obesity risk. Children's movies often contain food placements-frequently unhealthy foods. However, it is not known if these cues influence children's food choices or consumption after viewing. We explored whether children's snack choices or consumption differs based on: 1) recent exposure to movies with high versus low product placement of unhealthy foods; and 2) children's weight status. METHODS: Children ages 9-11 were assigned to watch a high ("Alvin and the Chipmunks," n = 54) or low ("Stuart Little," n = 60) product-placement movie. After viewing, participants selected a snack choice from each of five categories, several of which were specifically featured in "Alvin." Uneaten snacks from each participant were weighed upon completion. Snack choice and amount consumed by movie were compared by t-tests, and differences in snack choices by movie were tested with logistic regression. RESULTS: Participants consumed an average of 800.8 kcal; mean kcal eaten did not vary by movie watched. Participants who watched the high product-placement movie had 3.1 times the odds (95% CI 1.3-7.2) of choosing cheese balls (most featured snack) compared to participants who watched the low product-placement movie. Children who were overweight or obese consumed a mean of 857 kcal (95% CI: 789-925) compared to 783 kcal (95% CI: 742-823, p = 0.09) for children who were underweight or healthy weight. Children's weight status did not significantly affect their choice of snack. CONCLUSIONS: Branding and obesogenic messaging in children's movies influenced some choices that children made about snack foods immediately following viewing, especially food with greatest exposure time in the film, but did not affect total calories consumed. Future studies should examine how the accumulation of these messages affects children's long-term food choices.

Use of a novel floxed mouse to characterise the cellular source of plasma coagulation FXIII-A.

BACKGROUND: Coagulation factor XIII-A has a crucial role in thrombus stabilisation and tissue repair. Factor XIII-A deficiency causes a severe bleeding phenotype and impaired wound healing, but the cellular origin of Factor XIII-A is unknown. To identify the cells that maintain the plasma pool, we generated a mouse floxed in coding exon7 of the factor XIII-A gene (F13A1). These mice were crossed with mice transgenic for Pf4-Cre-recombinase (thrombopoietic deletion) or Cd11b-Cre-recombinase (myeloid deletion). The resultant mice were compared with a Mpl-/- (thrombopoietin receptor knockout) thrombocytopenic murine model. METHODS: Factor XIII-A recombination was evaluated by quantitative PCR assay of genomic DNA from liver and spleen. Factor XIII-A enzyme activity was measured in plasma and platelets with a biotin incorporation assay. quantitative PCR was performed to determine factor XIII-A mRNA levels in aortic and cardiac tissue. Factor XIII-A transcripts were assayed in human umbilical blood haemopoietic cell lineages. FINDINGS: Selectivity of Pf4-Cre and Cd11b-Cre mediated deletion was confirmed in liver and spleen. A 40% decrease in factor XIII-A plasma activity was observed in Cd11b mice, whereas plasma activity was decreased by 85% and absent in platelets from Pf4 mice. By contrast, plasma factor XIII-A was normal in Mpl mice. Cd11b mice showed no reduction in factor XIII-A mRNA in cardiac tissue and a 54·6% reduction in aorta. A major decrease in factor XIII-A mRNA was observed in the aorta (91·6%) and heart (99·2%) of Pf4 mice, but there was no change in expression in either tissue from Mpl mice. In a human stem-cell study, factor XIII-A mRNA transcription increased as common myeloid progenitors committed to become granulocyte-macrophage progenitors and as megakaryocyte-erythroid progenitors differentiated to both megakaryocytes and erythroblasts. INTERPRETATION: These results raise the possibility that a unique Pf4-dependent, Mpl-independent progenitor cell is the major source of the plasma pool. These findings might have implications for the management of factor XIII-A deficiency states. FUNDING: British Heart Foundation.

The activation peptide cleft exposed by thrombin cleavage of FXIII-A(2) contains a recognition site for the fibrinogen α chain.

Formation of a stable fibrin clot is dependent on interactions between factor XIII and fibrin. We have previously identified a key residue on the αC of fibrin(ogen) (Glu396) involved in binding activated factor XIII-A(2) (FXIII-A(2)*); however, the functional role of this interaction and binding site(s) on FXIII-A(2)* remains unknown. Here we (1) characterized the functional implications of this interaction; (2) identified by liquid-chromatography-tandem mass spectrometry the interacting residues on FXIII-A(2)* following chemical cross-linking of fibrin(ogen) αC389-402 peptides to FXIII-A(2)*; and (3) carried out molecular modeling of the FXIII-A(2)*/peptide complex to identify contact site(s) involved. Results demonstrated that inhibition of the FXIII-A(2)*/αC interaction using αC389-402 peptide (Pep1) significantly decreased incorporation of biotinamido-pentylamine and α2-antiplasmin to fibrin, and fibrin cross-linking, in contrast to Pep1-E396A and scrambled peptide controls. Pep1 did not inhibit transglutaminase-2 activity, and incorporation of biotinyl-TVQQEL to fibrin was only weakly inhibited. Molecular modeling predicted that Pep1 binds the activation peptide cleft (AP-cleft) within the ß-sandwich domain of FXIII-A(2)* localizing αC cross-linking Q366 to the FXIII-A(2)* active site. Our findings demonstrate that binding of fibrin αC389-402 to the AP-cleft is fundamental to clot stabilization and presents this region of FXIII-A(2)* as a potential site involved in glutamine-donor substrate recognition.

Reducing Concurrent Sexual Partnerships Among Blacks in the Rural Southeastern United States: Development of Narrative Messages for a Radio Campaign.

In the United States, heterosexual transmission of HIV infection is dramatically higher among Blacks than among Whites. Overlapping (concurrent) sexual partnerships promote HIV transmission. The authors describe their process for developing a radio campaign (Escape the Web) to raise awareness among 18-34-year-old Black adults of the effect of concurrency on HIV transmission in the rural South. Radio is a powerful channel for the delivery of narrative-style health messages. Through six focus groups (n = 51) and 42 intercept interviews, the authors explored attitudes toward concurrency and solicited feedback on sample messages. Men were advised to (a) end concurrent partnerships and not to begin new ones; (b) use condoms consistently with all partners; and (c) tell others about the risks of concurrency and benefits of ending concurrent partnerships. The narrative portrayed risky behaviors that trigger initiation of casual partnerships. Women were advised to (a) end partnerships in which they are not their partner's only partner; (b) use condoms consistently with all partners; and (c) tell others about the risks of concurrency and benefits of ending concurrent partnerships. Messages for all advised better modeling for children.

Sexual health knowledge and health practices of female sex workers in Liuzhou, China, differ by size of venue.

We conducted qualitative interviews with 48 female sex workers (FSW) recruited from entertainment venues in Liuzhou, China. Analyses found that HIV knowledge and sexual health seeking strategies differed by size of venue: (1) Women in smaller venues said they douched before/after sex and used condoms with all but their regular partners and clients. Most found the brochures distributed by Chinese CDC workers "irrelevant" or "boring" and relied on friends for health advice. (2) FSW in middle and large venues were less concerned about prevention, claiming their clients were "healthy." They relied more on the Internet for health information and were less concerned about the cost of seeing a doctor. (3) Pregnancies and abortions were frequent, especially among the younger women in large venues. This research documents the need to develop tailored HIV-related messages and prevention strategies with the help of FSW to address differences among FSW working in venues of different sizes.

The role of companionship, esteem, and informational support in explaining physical activity among young women in an online social network intervention.

The primary objective of the current study was to examine the relationship between social support and physical activity within the theory of planned behavior (TPB) theoretical framework. This study used data from the Internet Support for Healthy Associations Promoting Exercise randomized controlled trial. A total of 134 female undergraduate students participated in the study, which included baseline and post measures of perceived social support for physical activity (esteem, informational, and companionship), TPB variables related to physical activity (perceived behavioral control, intention, and attitude), and physical activity behavior. Path analysis revealed a significant indirect relationship between change in companionship support and physical activity mediated by change in intention (.13, p < .01) and a significant direct relationship between change in esteem support and change in physical activity (.26, p = .03). The model explained 27% of the variance in physical activity and 59% of the variance in intention. Overall, change in social support exerted a small to medium amount of influence on change in physical activity in this modified TPB model when controlling for traditional model constructs. Encouraging companionship and esteem support should be considered as a strategy for increasing physical activity in this population.

Parents of children with eating disorders: developing theory-based health communication messages to promote caregiver well-being.

Parents of children with eating disorders experience extreme emotional burden because of the intensity and duration of the recovery process. While parental involvement in a child's eating disorder treatment improves outcomes, parents often neglect their own well-being, which can impede their child's recovery. This study extends the research on caregivers and on health theory in practice by conducting formative research to develop a theory-based communication intervention encouraging parents to engage in adaptive coping and self-care behaviors. The Transactional Model of Stress and Coping and the Transtheoretical Model guided qualitative assessments of the determinants of parents' coping behaviors. Three focus groups with 19 parents of children with eating disorders and 19 semi-structured interviews with experts specializing in eating disorders were conducted. Findings indicate that parents and experts see parents' need for permission to take time for themselves as the main barrier to self-care. The main motivator for parents to engage in coping behaviors is awareness of a connection between self-care and their child's health outcomes. Participant evaluation of six potential messages for main themes and effectiveness revealed that theory-based elements, such as certain processes of change within the Transtheoretical Model, were important to changing health behavior.

The ß-Secretase BACE1 Drives Fibroblast Activation in Systemic Sclerosis through the APP/ß-Catenin/Notch Signaling Axis.

BACE1 is well-known for its role in the development of Alzheimer's disease. Recent publications, including our own, have demonstrated a role for this enzyme in other chronic diseases. The aim of this study was to investigate the role of BACE1 in the autoimmune disease systemic sclerosis (SSc). BACE1 protein levels were elevated in the skin of patients with SSc. Inhibition of BACE1 with small-molecule inhibitors or small interfering RNA blocked SSc and fibrotic stimuli-mediated fibroblast activation. Furthermore, we show that BACE1 regulation of dermal fibroblast activation is dependent on ß-catenin and Notch signaling. The neurotropic factor brain-derived neurotrophic factor negatively regulates BACE1 expression and activity in dermal fibroblasts. Finally, sera from patients with SSc show higher ß-amyloid and lower brain-derived neurotrophic factor levels than healthy controls. The ability of BACE1 to regulate SSc fibroblast activation reveals a therapeutic target in SSc. Several BACE1 inhibitors have been shown to be safe in clinical trials for Alzheimer's disease and could be repurposed to ameliorate fibrosis progression.