Myeloid cell microsomal prostaglandin E synthase-1 fosters atherogenesis in mice

Microsomal prostaglandin E synthase-1 (mPGES-1) in myeloid and vascular cells differentially regulates the response to vascular injury, reflecting distinct effects of mPGES-1–derived PGE₂ in these cell types on discrete cellular components of the vasculature. The cell selective roles of mPGES-1 in atherogenesis are unknown. Mice lacking mPGES-1 conditionally in myeloid cells (Mac-mPGES-1-KOs), vascular smooth muscle cells (VSMC-mPGES-1-KOs), or endothelial cells (EC-mPGES-1-KOs) were crossed into hyperlipidemic low-density lipoprotein receptor-deficient animals. En face aortic lesion analysis revealed markedly reduced atherogenesis in Mac-mPGES-1-KOs, which was concomitant with a reduction in oxidative stress, reflective of reduced macrophage infiltration, less lesional expression of inducible nitric oxide synthase (iNOS), and lower aortic expression of NADPH oxidases and proinflammatory cytokines. Reduced oxidative stress was reflected systemically by a decline in urinary 8,12-iso-iPF_2α-VI. In contrast to exaggeration of the response to vascular injury, deletion of mPGES-1 in VSMCs, ECs, or both had no detectable phenotypic impact on atherogenesis. Macrophage foam cell formation and cholesterol efflux, together with plasma cholesterol and triglycerides, were unchanged as a function of genotype. In conclusion, myeloid cell mPGES-1 promotes atherogenesis in hyperlipidemic mice, coincident with iNOS-mediated oxidative stress. By contrast, mPGES-1 in vascular cells does not detectably influence atherogenesis in mice. This strengthens the therapeutic rationale for targeting macrophage mPGES-1 in inflammatory cardiovascular diseases.Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce pain and inflammation by suppressing the formation of proinflammatory prostaglandins (PGs), particularly prostaglandin E₂ (PGE₂) formed by cyclooxygenase-2 (COX-2) (1). However, the development of NSAIDs specific for inhibition of COX-2 revealed a cardiovascular hazard attributable to suppression of cardioprotective PGs, especially prostacyclin (PGI₂) (2). This risk appears to extend to some of the older NSAIDs, like diclofenac, that also inhibit specifically COX-2 (3, 4). These developments prompted interest in microsomal PGE synthase (mPGES)-1 as a downstream alternative drug target to COX-2 (5): it is the dominant source among PGES enzymes in the biosynthesis of PGE₂ (6). Unlike NSAIDs, inhibitors of mPGES-1 would spare PGI₂ from suppression. Indeed, blockade or deletion of mPGES-1 results in accumulation of its PGH₂ substrate, rendering it available for metabolism by other PG synthases, including PGI₂ synthase (PGIS) (7).Consistent with these observations, we have found that whereas deletion of COX-2 in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) renders mice susceptible to thrombosis and hypertension (2), deletion of mPGES-1 in vascular cells has no such effect (8). Indeed, global deficiency of mPGES-1 restrains atherogenesis (9), the proliferative response to vascular injury (10) and angiotensin-induced aortic aneurysm formation (11) in mice.Despite this attractive cardiovascular profile, mPGES-1 is a complex drug target. The dominant prostanoid products of substrate rediversion differ among cell types. For example, whereas PGI₂ might be augmented in vascular cells, the consequence of mPGES-1 blockade in other cells might be an increase in thromboxane (Tx)A₂, a PG that promotes platelet activation, vasoconstriction, and atherogenesis (9). Even if an increase in PGI₂ afforded a desirable cardiovascular profile, it might undermine the analgesic efficacy of mPGES-1 inhibitors. Although the impacts of global deletion of mPGES-1 and COX-2 in many mouse models of analgesia are indistinguishable (12, 13), in some, PGI₂ rather than PGE₂ predominates (14) and thus may be the dominant mediator in certain subtypes of human pain. Finally, the consequences of PGE₂ suppression might differ between cell types. PGE₂ activates four E prostanoid (EP) receptors with contrasting intracellular signaling and consequent biology (15, 16). Indeed, the contrasting effect of mPGES-1 deletion in myeloid vs. vascular cells on the proliferative response to vascular injury reflects the differential consequences of EP activation rather than substrate rediversion (8).A potentially discriminating feature among inhibitors of COX-2 and mPGES-1 is their effect on atherosclerosis. Global postnatal deletion of COX-2 accelerates atherogenesis in hyperlipidemic mice (17), an observation that accords with a similar effect of deleting the PGI₂ receptor (the IP) (18, 19) and with the delayed detection of a cardiovascular hazard in randomized trials of COX-2 inhibitors in patients initially selected for being at low cardiovascular risk (20). By contrast, global deletion of mPGES-1 restrains atherogenesis in mice; in this case suppression of PGE₂ coincides with an increase in biosynthesis of PGI₂ (9). Here, we wished to segregate the effects on atherosclerosis of mPGES-1 depletion in myeloid from vascular cells. Our results strengthen the rationale for targeting macrophage mPGES-1 in the treatment of inflammatory cardiovascular disease.     

Current Zika virus epidemiology and recent epidemics

The Zika virus (ZIKV) is a mosquito-borne flavivirus (Aedes), similar to other arboviruses, first identified in Uganda in 1947. Few human cases were reported until 2007, when a Zika outbreak occurred in Yap, Micronesia, even though ZIKV activity had been reported in Africa and in Asia through virological surveillance and entomological studies. French Polynesia has recorded a large outbreak since October 2013. A great number of cases and some with neurological and autoimmune complications have been reported in a context of concurrent circulation of dengue viruses. The clinical presentation is a “dengue-like syndrome”. Until the epidemic in French Polynesia, no severe ZIKV disease had been described so far. The diagnosis is confirmed by viral genome detection by genomic amplification (RT- PCR) and viral isolation. These two large outbreaks occurred in a previously unaffected area in less than a decade. They should raise awareness as to the potential for ZIKV to spread especially since this emergent disease is not well known and that some questions remain on potential reservoirs and transmission modes as well as on clinical presentations and complications. ZIKV has the potential to spread to new areas where the Aedes mosquito vector is present and could be a risk for Southern Europe. Strategies for the prevention and control of ZIKV disease should include the use of insect repellent and mosquito vector eradication.     

Substance P and neurokinin A variations throughout the rat estrous cycle; comparison with ovariectomized and male rats: I. Plasma,hypothalamus, anterior and posterior pituitary

The concentrations of Substance P and Neurokinin A were measured in plasma, and the hypothalamo-pituitary complex of 4-day-cycling female, ovariectomized and male rats. Estrous cycle-related fluctuations were recorded for these two neurokinins. The patterns of plasma concentrations of Substance P and Neurokinin A, however, were not similar throughout the rat estrous cycle. The plasma concentration of Substance P increased on proestrus at 19.00 hr, while Neurokinin A decreased. The plasma concentration of Substance P was positively correlated with plasma 17β-estradiol levels. In the ovariectomized rat, the absence of ovarian steroids led to low levels of plasma Neurokinin A, but the plasma concentration of Substance P did not show any change as compared to the estrous cycle. In the male rat, a similar observation was made in the presence of a testosterone environment. The largest variations in tissue concentration of both peptides were observed in the anterior pituitary. Substance P and Neurokinin A contents were higher throughout the proestrous day than the 3 other days. However, the level fell at 18.00 hr on proestrus, and there were similar falls in the hypothalamic contents of Substance P and Neurokinin A at 19.00 hr. In the ovariectomized rat, with no gonadal steroids, the hypothalamic and/or anterior pituitary levels of Substance P were in the same range as during the estrous cycle. However, the hypothalamic levels of Neurokinin A were lower and Neurokinin A was undetectable in the anterior pituitary. Substance P and Neurokinin A concentrations in the posterior pituitary were stable throughout the estrous cycle, with the exception of rises for both peptides on estrous day. Substance P levels were much lower in ovariectomized and male rats. These results describe large fluctuations in hypothalamic and pituitary Substance P and Neurokinin A contents through the estrous cycle in the female rat. They also strongly suggest the involvement of gonadal steroids in the differential regulation of Substance P and Neurokinin A in the female and male rat. © 1996 Wiley-Liss, Inc.     

Prescription,Compliance, and Burden Associated with Salt-Restricted Diets in Heart Failure Patients: Results from the French National OFICSel Observatory

(1) Background: There is much debate about the use of salt-restricted diet for managing heart failure (HF). Dietary guidelines are inconsistent and lack evidence. (2) Method: The OFICSel observatory collected data about adults hospitalised for HF. The data, collected using study-specific surveys, were used to describe HF management, including diets, from the cardiologists’ and patients’ perspectives. Cardiologists provided the patients’ clinical, biological, echocardiography, and treatment data, while the patients provided dietary, medical history, sociodemographic, morphometric, quality of life, and burden data (burden scale in restricted diets (BIRD) questionnaire). The differences between the diet recommended by the cardiologist, understood by the patient, and the estimated salt intake (by the patient) and diet burden were assessed. (3) Results: Between March and June 2017, 300 cardiologists enrolled 2822 patients. Most patients (90%) were recommended diets with <6 g of salt/day. Mean daily salt consumption was 4.7 g (standard deviation (SD): 2.4). Only 33% of patients complied with their recommended diet, 34% over-complied, and 19% under-complied (14% unknown). Dietary restrictions in HF patients were associated with increased burden (mean BIRD score of 8.1/48 [SD: 8.8]). (4) Conclusion: Healthcare professionals do not always follow dietary recommendations, and their patients do not always understand and comply with diets recommended. Restrictive diets in HF patients are associated with increased burden. An evidence-based approach to developing and recommending HF-specific diets is required.     

CDK13-related disorder: Report of a series of 18 previously unpublished individuals and description of an epigenetic signature

PurposeRare genetic variants in CDK13 are responsible for CDK13-related disorder (CDK13-RD), with main clinical features being developmental delay or intellectual disability, facial features, behavioral problems, congenital heart defect, and seizures. In this paper, we report 18 novel individuals with CDK13-RD and provide characterization of genome-wide DNA methylation.MethodsWe obtained clinical phenotype and neuropsychological data for 18 and 10 individuals, respectively, and compared this series with the literature. We also compared peripheral blood DNA methylation profiles in individuals with CDK13-RD, controls, and other neurodevelopmental disorders episignatures. Finally, we developed a support vector machine–based classifier distinguishing CDK13-RD and non–CDK13-RD samples.ResultsWe reported health and developmental parameters, clinical data, and neuropsychological profile of individuals with CDK13-RD. Genome-wide differential methylation analysis revealed a global hypomethylated profile in individuals with CDK13-RD in a highly sensitive and specific model that could aid in reclassifying variants of uncertain significance.ConclusionWe describe the novel features such as anxiety disorder, cryptorchidism, and disrupted sleep in CDK13-RD. We define a CDK13-RD DNA methylation episignature as a diagnostic tool and a defining functional feature of the evolving clinical presentation of this disorder. We also show overlap of the CDK13 DNA methylation profile in an individual with a functionally and clinically related CCNK-related disorder.     

Are Playground Injuries Inevitable?

Since the ACOG guidelines for exercise and pregnancy were released almost one year ago, they have been the subject of some controversy. Some critics contend that the guidelines are too general, others think they're too specific. ACOG stands behind the guidelines.