A common gustatory and interoceptive representation in the human mid‐insula

The insula serves as the primary gustatory and viscerosensory region in the mammalian cortex. It receives visceral and gustatory afferent projections through dedicated brainstem and thalamic nuclei, which suggests a potential role as a site for homeostatic integration. For example, while human neuroimaging studies of gustation have implicated the dorsal mid‐insular cortex as one of the primary gustatory regions in the insula, other recent studies have implicated this same region of the insula in interoception. This apparent convergence of gustatory and interoceptive information could reflect a common neural representation in the insula shared by both interoception and gustation. This idea finds support in translational studies in rodents, and may constitute a medium for integrating homeostatic information with feeding behavior. To assess this possibility, healthy volunteers were asked to undergo fMRI while performing tasks involving interoceptive attention to visceral sensations as well as a gustatory mapping task. Analysis of the unsmoothed, high‐resolution fMRI data confirmed shared representations of gustatory and visceral interoception within the dorsal mid‐insula. Group conjunction analysis revealed overlapping patterns of activation for both tasks in the dorsal mid‐insula, and region‐of‐interest analyses confirmed that the dorsal mid‐insula regions responsive for visceral interoception also exhibit strong responses to tastants. Hum Brain Mapp 36:2996–3006, 2015. © 2015 Wiley Periodicals, Inc.     

Methodological recommendations for a heartbeat detection‐based measure of interoceptive sensitivity

Heartbeat detection tasks are often used to measure cardiac interoceptive sensitivity—the ability to detect sensations from one's heart. However, there is little work to guide decisions on the optimum number of trials to use, which should balance reliability and power against task duration and participant burden. Here, 174 participants completed 100 trials of a widely used heartbeat detection task where participants attempt to detect whether presented tones occurred synchronously or asynchronously with their heartbeats. First, we quantified measurement reliability of the participant's accuracy derived from differing numbers of trials of the task using a correlation metric; we found that at least 40–60 trials were required to yield sufficient reliability. Next, we quantified power by simulating how the number of trials influenced the ability to detect a correlation between cardiac interoceptive sensitivity and other variables that differ across participants, including a variable measured from our sample (body mass index) as well as simulated variables of varying effect sizes. Using these simulations, we quantified the trade‐offs between sample size, effect size, and number of trials in the heartbeat detection task such that a researcher can easily determine any one of these variables at given values of the other two variables. We conclude that using fewer than 40 trials is typically insufficient due to poor reliability and low power in estimating an effect size, although the optimal number of trials can differ by study.     

Dexamethasone attenuates the embryotoxic effect of endometriotic peritoneal fluid in a murine model

Purpose

The in vitro fertilization (IVF) pregnancy rate of women with advanced stage endometriosis is nearly half that of the general population, suggesting incomplete targeting of the pathophysiology underlying endometriosis-associated infertility. Compelling evidence highlights inflammation as the etiologic link between endometriosis and infertility and a potential target for adjunctive treatment. The objective of this study was to examine the effect of dexamethasone on murine embryos exposed to human endometriotic peritoneal fluid (PF) using the established murine embryo assay model.

Methods

PF was obtained from women with and without severe endometriosis. Murine embryos were harvested and randomly allocated to five groups of culture media conditions: (1) human tubal fluid (HTF), (2) HTF and 10 % PF from women without endometriosis, (3) HTF and 10 % PF from women with endometriosis (PF-E), (4) HTF with PF-E and 0.01 mcg/mL dexamethasone, and (5) HTF with PF-E and 0.1 mcg/mL dexamethasone. Embryos were cultured in standard conditions and evaluated for blastocyst development.

Results

A total of 266 mouse embryos were cultured. Baseline blastulation rates were 63.6 %. The addition of peritoneal fluid from women with endometriosis decreased the blastocyst development rate to 38.9 % (P = 0.008). The addition of 0.1 mcg/mL of dexamethasone to the culture media restored the blastulation rate to near baseline levels (61.2 %; P = 0.019).

Conclusions

The results of our in vitro study demonstrate the capacity of dexamethasone to mitigate the deleterious impact of endometriotic PF on embryo development. If confirmed in vivo, dexamethasone may prove a useful adjunct for the treatment of endometriosis-associated infertility.     

Notch activation results in phenotypic and functional changes consistent with endothelial-to-mesenchymal transformation

Various studies have identified a critical role for Notch signaling in cardiovascular development. In this and other systems, Notch receptors and ligands are expressed in regions that undergo epithelial-to-mesenchymal transformation. However, there is no direct evidence that Notch activation can induce mesenchymal transdifferentiation. In this study we show that Notch activation in endothelial cells results in morphological, phenotypic, and functional changes consistent with mesenchymal transformation. These changes include downregulation of endothelial markers (vascular endothelial [VE]-cadherin, Tie1, Tie2, platelet-endothelial cell adhesion molecule-1, and endothelial NO synthase), upregulation of mesenchymal markers (alpha-smooth muscle actin, fibronectin, and platelet-derived growth factor receptors), and migration toward platelet-derived growth factor-BB. Notch-induced endothelial-to-mesenchymal transformation does not seem to require external regulation and is restricted to cells expressing activated Notch. Jagged1 stimulation of endothelial cells induces a similar mesenchymal transformation, and Jagged1, Notch1, and Notch4 are expressed in the ventricular outflow tract during stages of endocardial cushion formation. This is the first evidence that Jagged1-Notch interactions induce endothelial-to-mesenchymal transformation, and our findings suggest that Notch signaling may be required for proper endocardial cushion differentiation and/or vascular smooth muscle cell development.     

Critical care medicine training and certification for emergency physicians

Demand for critical care services is increasing. Unless the supply of intensivists increases, critically ill patients will not have access to intensivists. Recent critical care society recommendations include increased graduate medical education support and expansion of the J-1 visa waiver program for foreign medical graduates. This article proposes additional recommendations, based on strengthening the relationship between emergency medicine and critical care medicine. Critical care is a continuum that includes out-of-hospital, emergency department (ED), and ICU care teams. Both emergency medicine and critical care medicine require expertise in treating life-threatening acute illness, with many critically ill patients often presenting first to the ED. Increased patient volumes and acuity have resulted in longer ED lengths of stay and more critical care delivery in the ED. However, the majority of critical care medicine fellowships do not accept emergency medicine residents, and those who do successfully complete a fellowship do not have access to a US certification examination in critical care medicine. Despite these barriers, interest in critical care medicine training among emergency physicians is increasing. Dual emergency medicine- and critical care medicine-trained physicians will not only help alleviate the intensivist shortage but also strengthen critical care delivery in the ED and facilitate coordination at the ED-ICU interface. We therefore propose that all accreditation bodies work cooperatively to create a route to critical care medicine certification for emergency physicians who complete a critical care fellowship.     

A comparison of iopromide and iopamidol,two acidoCEST MRI contrast media that measure tumor extracellular pH

Acidosis within tumor and kidney tissues has previously been quantitatively measured using a molecular imaging technique known as acidoCEST MRI. The previous studies used iopromide and iopamidol, two iodinated contrast agents that are approved for clinical CT diagnoses and have been repurposed for acidoCEST MRI studies. We aimed to compare the performance of the two agents for measuring pH by optimizing image acquisition conditions, correlating pH with a ratio of CEST effects from an agent, and evaluating the effects of concentration, endogenous T₁ relaxation time and temperature on the pH–CEST ratio correlation for each agent. These results showed that the two agents had similar performance characteristics, although iopromide produced a pH measurement with a higher dynamic range while iopamidol produced a more precise pH measurement. We then compared the performance of the two agents to measure in vivo extracellular pH (pHe) within xenograft tumor models of Raji lymphoma and MCF‐7 breast cancer. Our results showed that the pHe values measured with each agent were not significantly different. Also, iopromide consistently measured a greater region of the tumor relative to iopamidol in both tumor models. Therefore, an iodinated contrast agent for acidoCEST MRI should be selected based on the measurement properties needed for a specific biomedical study and the pharmacokinetic properties of a specific tumor model. Copyright © 2015 John Wiley & Sons, Ltd.     

Clinical trial of halofantrine with modified doses for treatment of malaria in the hospital for tropical diseases

The spread of falciparum malaria resistant to chloroquine all over Southeast Asian continent has led to increasing use of alternative antimalarial drugs. Halofantrine has been shown to be effective against multidrug resistant Plasmodium falciparum. One hundred and twenty falciparum malaria cases were randomly assigned to one of three different halofantrine regimes. Group I (HA1) received 500 mg three times daily for 3 days (total dose: 4,500 mg), group II (HA2) received 500 mg three times daily for the first and the third day (total dose: 3,000 mg) and group III (HA3) received 500 mg three times for one day followed by 500 mg once daily for 7 days (total dose: 4,500 mg). No significant difference in the cure rate was observed among the three regimes (cure rate: 89%, 73%, 97% respectively). However, the cure rate was significantly higher in the HA3 group when compared to the HA2 group. There were no overt cardiac problems seen in this study. Thus, halofantrine has high efficacy in the recommended treatment dose of 500 mg three times after meals on the first day followed by 500 mg once a day after a meal for 7 days (total dose: 4,500 mg).     

Endocrine changes during natural spawning in the white sucker, Catostomus commersoni. I. Gonadotropin, growth hormone, and thyroid hormones

White suckers (Catostomus commersoni; Cypriniformes, Teleosteii) spawning in a small stream in central Alberta were captured during different stages of their spawning migrations in 1981 and 1982, blood was sampled, and the fish were examined to determine their reproductive condition. Blood samples were analyzed for gonadotropin (GtH), growth hormone (GH), triiodothyronine (T3), and thyroxine (T4) by radioimmunoassay. GtH levels in both sexes were lowest prior to the onset of spawning, increased significantly in spawning males, females in which germinal vesicle migration had begun, and ovulated females and then dropped significantly in spent fish of both sexes. GH was lowest in prespawning females, increased significantly at ovulation, and remained high in spent females. In contrast, GH levels in males were relatively constant throughout spawning. In both sexes, highest T4 levels were found in prespawning fish, and T4 decreased significantly in spent fish. Although a similar decline was seen in T3 in 1981, in 1982 there were no T3 changes associated with changes in reproductive condition. No significant diurnal variations were detected in the levels of GtH or T3; T4 levels appeared to vary on a diurnal basis in prespawning males only. Spawning activity in both sexes therefore appears to be associated with increases in GtH occurring at ovulation in females and at the initiation of spawning in males. GH levels may also be related to reproductive condition in females, but not in males. The relationship of thyroid hormone levels to reproductive condition is less clear, however, and these levels may reflect both endocrine and environmental influences on thyroid function.