Reprint of: the paradox of α-adrenergic coronary vasoconstriction revisited

Activation of coronary vascular α-adrenoceptors results in vasoconstriction which competes with metabolic vasodilation during sympathetic activation. Epicardial conduit vessel constriction is largely mediated by α(1)-adrenoceptors; the constriction of the resistive microcirculation largely by α(2)-adrenoceptors, but also by α(1)-adrenoceptors. There is no firm evidence that α-adrenergic coronary vasoconstriction exerts a beneficial effect on transmural blood flow distribution. In fact, α-blockade in anesthetized and conscious dogs improves blood flow to all transmural layers, during normoperfusion and hypoperfusion. Also, in patients with coronary artery disease, blockade of α(1)- and α(2)-adrenoceptors improves coronary blood flow, myocardial function and metabolism. This article is part of a Special Issue entitled "Coronary Blood Flow".     

Lessons from human coronary aspirate

The interventional implantation of a stent into an atherosclerotic coronary artery is a unique and paradigmatic scenario of plaque rupture in humans. The use of protection devices not only prevents the released plaque particles and the superimposed thrombotic material from being washed and embolized into the coronary microcirculation of the individual patient, but permits also the retrieval and ex vivo analysis of particulate plaque debris and soluble substances. The particulate debris comprises typical cholesterol crystals, foam cells, hyalin material and calcium deposits from the atheroma as well as platelets and coagulation material; soluble substances include vasoconstrictors, such as serotonin and thromboxane, as well as inflammatory mediators, such as TNFα which amplifies vasoconstriction by inducing endothelial dysfunction. The vasoconstriction observed in a bioassay ex vivo correlates to clinical symptoms, angiographic stenosis and plaque burden, as assessed by intravascular ultrasound. The release of TNFα into the aspirate correlates to restenosis. Detailed analysis of the human coronary aspirate may promote a better understanding of the pathophysiology of the vulnerable atherosclerotic plaque and help to better antagonize the microvascular consequences of coronary microembolization, including the no reflow phenomenon. This article is part of a Special Issue entitled “Coronary Blood Flow.”     

Choline-releasing glycerophosphodiesterase EDI3 drives tumor cell migration and metastasis

Metastasis from primary tumors remains a major problem for tumor therapy. In the search for markers of metastasis and more effective therapies, the tumor metabolome is relevant because of its importance to the malignant phenotype and metastatic capacity of tumor cells. Altered choline metabolism is a hallmark of cancer. More specifically, a decreased glycerophosphocholine (GPC) to phosphocholine (PC) ratio was reported in breast, ovarian, and prostate cancers. Improved strategies to exploit this altered choline metabolism are therefore required. However, the critical enzyme cleaving GPC to produce choline, the initial step in the pathway controlling the GPC/PC ratio, remained unknown. In the present work, we have identified the enzyme, here named EDI3 (endometrial differential 3). Purified recombinant EDI3 protein cleaves GPC to form glycerol-3-phosphate and choline. Silencing EDI3 in MCF-7 cells decreased this enzymatic activity, increased the intracellular GPC/PC ratio, and decreased downstream lipid metabolites. Downregulating EDI3 activity inhibited cell migration via disruption of the PKCα signaling pathway, with stable overexpression of EDI3 showing the opposite effect. EDI3 was originally identified in our screening study comparing mRNA levels in metastasizing and nonmetastasizing endometrial carcinomas. Both Kaplan-Meier and multivariate analyses revealed a negative association between high EDI3 expression and relapse-free survival time in both endometrial (P < 0.001) and ovarian (P = 0.029) cancers. Overall, we have identified EDI3, a key enzyme controlling GPC and choline metabolism. Because inhibition of EDI3 activity corrects the GPC/PC ratio and decreases the migration capacity of tumor cells, it represents a possible target for therapeutic intervention.     

After treat-to-target: can a targeted ultrasound initiative improve RA outcomes?

For patients with rheumatoid arthritis (RA), remission can be achieved with tight control of inflammation and early use of disease modifying agents. The importance of remission as an outcome has been recently highlighted by European League Against Rheumatism recommendations. However, remission when defined by clinical remission criteria (disease activity score, simplified disease activity index, etc) does not always equate to the complete absence of inflammation as measured by new sensitive imaging techniques such as ultrasound (US) . There is evidence that imaging synovitis is frequently found in these patients and associated with adverse clinical and functional outcomes. This article reviews the data regarding remission, ultrasound imaging and outcomes in patients with RA to provide the background to a consensus statement from an international collaboration of ultrasonographers and rheumatologists who have recently formed a research network--the Targeted Ultrasound Initiative (TUI) group. The statement proposes that targeting therapy to PD activity provides superior outcomes compared with treating to clinical targets alone and introduces the rationale for a new randomised trial using targeted ultrasound in RA.     

Self-referential processing influences functional activation during cognitive control: an fMRI study

Rostral anterior cingulate cortex (rACC) plays a central role in the pathophysiology of major depressive disorder (MDD). As we reported in our previous study (Wagner et al., 2006), patients with MDD were characterized by an inability to deactivate this region during cognitive processing leading to a compensatory prefrontal hyperactivation. This hyperactivation in rACC may be related to a deficient inhibitory control of negative self-referential processes, which in turn may interfere with cognitive control task execution and the underlying fronto-cingulate network activation. To test this assumption, a functional magnetic resonance imaging study was conducted in 34 healthy subjects. Univariate and functional connectivity analyses in statistical parametric mapping software 8 were used. Self-referential stimuli and the Stroop task were presented in an event-related design. As hypothesized, rACC was specifically engaged during negative self-referential processing (SRP) and was significantly related to the degree of depressive symptoms in participants. BOLD signal in rACC showed increased valence-dependent (negative vs neutral SRP) interaction with BOLD signal in prefrontal and dorsal anterior cingulate regions during Stroop task performance. This result provides strong support for the notion that enhanced rACC interacts with brain regions involved in cognitive control processes and substantiates our previous interpretation of increased rACC and prefrontal activation in patients during Stroop task.     

Paternal deprivation alters the development of catecholaminergic innervation in the prefrontal cortex and related limbic brain regions

The impact of paternal care on the development of catecholaminergic fiber innervations in the prefrontal cortex, nucleus accumbens, hippocampus and the amygdala was quantitatively investigated in the biparental Octodon degus. Two age (juvenile, adult) and rearing groups: (1) degus reared without father and (2) degus raised by both parents were compared. Juvenile father-deprived animals showed significantly elevated densities of TH-immunoreactive fibers in all analyzed regions, except in the orbitofrontal cortex, as compared to biparentally reared animals. This difference between the two rearing groups was still evident in adulthood in the prelimbic and infralimbic cortices and in the hippocampal formation. Interestingly, the elevated TH fiber density in both nucleus accumbens subregions was reversed in adulthood, i.e. adult father-deprived animals showed strongly reduced TH fiber densities as compared to biparentally reared animals. We show here that paternal care plays a critical role in the functional maturation of catecholaminergic innervation patterns in prefrontal and limbic brain circuits.     

Singleton–Merten syndrome: An autosomal dominant disorder with variable expression

In 1973, Singleton and Merten described two females with abnormal dentition, unique radiographic changes especially of the hands, and severe calcification and intimal weakening of the aortic arch and valve. Since then three additional cases with similar features have been reported and the diagnosis was suggested in another three individuals. We present an update of one case and the detailed clinical phenotype of six other cases with Singleton–Merten syndrome. The occurrence of the disorder in six members of two families and vertical male‐to‐male transmission indicate an autosomal dominant pattern of inheritance. Variability in phenotype, also within a single family, is significant. Core manifestations are marked aortic calcification, dental anomalies (delayed eruption and immature root formation of primarily the anterior permanent teeth, and early loss of permanent teeth due to short roots, acute root resorption, high caries, and aggressive alveolar bone loss), osteopenia and acro‐osteolysis, and to a lesser extend also glaucoma, psoriasis, muscle weakness, and joint laxity. Additional clinical characteristics described here include particular facial characteristics (high anterior hairline, broad forehead, smooth philtrum, thin upper vermillion) and abnormal joint and muscle ligaments. The cause and pathogenesis of this syndrome remain unknown. © 2013 Wiley Periodicals, Inc.