Effects of Developmental Hypoxia on the Vertebrate Cardiovascular System.

Developmental hypoxia has profound and persistent effects on the vertebrate cardiovascular system, but the nature, magnitude, and long-term outcome of the hypoxic consequences are species specific. Here we aim to identify common and novel cardiovascular responses among vertebrates that encounter developmental hypoxia, and we discuss the possible medical and ecological implications.

Circulating extracellular choline acetyltransferase regulates inflammation.

BACKGROUND: Choline acetyltransferase (ChAT) is required for the biosynthesis of acetylcholine, the molecular mediator that inhibits cytokine production in the cholinergic anti-inflammatory pathway of the vagus nerve inflammatory reflex. Abundant work has established the biology of cytoplasmic ChAT in neurons, but much less is known about the potential presence and function of ChAT in the extracellular milieu. OBJECTIVES: We evaluated the hypothesis that extracellular ChAT activity responds to inflammation and serves to inhibit cytokine release and attenuate inflammation. METHODS: After developing novel methods for quantification of ChAT activity in plasma, we determined whether ChAT activity changes in response to inflammatory challenges. RESULTS: Active ChAT circulates within the plasma compartment of mice and responds to immunological perturbations. Following the administration of bacterial endotoxin, plasma ChAT activity increases for 12-48 h, a time period that coincides with declining tumor necrosis factor (TNF) levels. Further, a direct activation of the cholinergic anti-inflammatory pathway by vagus nerve stimulation significantly increases plasma ChAT activity, whereas the administration of bioactive recombinant ChAT (r-ChAT) inhibits endotoxin-stimulated TNF production and anti-ChAT antibodies exacerbate endotoxin-induced TNF levels, results of which suggest that ChAT activity regulates endogenous TNF production. Administration of r-ChAT significantly attenuates pro-inflammatory cytokine production and disease activity in the dextran sodium sulfate preclinical model of inflammatory bowel disease. Finally, plasma ChAT levels are also elevated in humans with sepsis, with the highest levels observed in a patient who succumbed to infection. CONCLUSION: As a group, these results support further investigation of ChAT as a counter-regulator of inflammation and potential therapeutic agent.

Developmental plasticity of the cardiovascular system in oviparous vertebrates: effects of chronic hypoxia and interactive stressors in the context of climate change.

Animals at early life stages are generally more sensitive to environmental stress than adults. This is especially true of oviparous vertebrates that develop in variable environments with little or no parental care. These organisms regularly experience environmental fluctuations as part of their natural development, but climate change is increasing the frequency and intensity of these events. The developmental plasticity of oviparous vertebrates will therefore play a critical role in determining their future fitness and survival. In this Review, we discuss and compare the phenotypic consequences of chronic developmental hypoxia on the cardiovascular system of oviparous vertebrates. In particular, we focus on species-specific responses, critical windows, thresholds for responses and the interactive effects of other stressors, such as temperature and hypercapnia. Although important progress has been made, our Review identifies knowledge gaps that need to be addressed if we are to fully understand the impact of climate change on the developmental plasticity of the oviparous vertebrate cardiovascular system.

Short communication: Characterizing arterial and venous blood gases over the gas exchange surface, the chorioallantoic membrane, of embryonic American alligators (Alligator mississippiensis) at two points of development.

Assessments of arterial and venous blood gases are required to understand the function of respiratory organs in animals at different stages of development. We measured blood gases in the arteries entering and veins leaving the chorioallantoic membrane (CAM) in embryonic alligators (Alligator mississippiensis). The CAM accounts for virtually all gas exchange in these animals, and we hypothesized that the CAM vasculature would be larger in eggs incubated in hypoxia (10% O2 for 50% or 70% of incubation), which would be reflected in a lower partial pressure of CO2 (PCO2). Contrary to this hypothesis, our measurements revealed no effects of hypoxic incubation on PCO2, and seemingly no increase in vascularization of the CAM in response to incubation in 10% O2. PCO2 was lower on the venous side, but only significantly different from arterial blood at 70% of incubation. The calculated blood flow to the CAM increased with development and was lower in both groups of alligators that had been incubated in hypoxia. Future studies should include measurements of blood parameters taken from embryos held in conditions that mirror incubation O2 levels, in combination with direct measurements of CAM artery blood flow.

Short communication: Baroreflex function in embryonic emus (Dromiceius novaehollandiae).

The baroreflex involves cardiovascular homeostatic mechanisms that buffer the system against acute deviations in arterial blood pressure. It is comprised of the cardiac limb which involves adjustments in heart rate and the peripheral limb which involves adjustments in vascular resistance. This negative feedback loop mechanism has been investigated in numerous species of adult vertebrates, however our understanding of the maturation and functional importance of the reflex in developing animals remains poorly understood. In egglaying species, our knowledge of this mechanism is limited to the domestic chicken embryo and the embryonic alligator. While each of these species possess a cardiac baroreflex prior to hatching, they differ in the timing when it becomes functional, with the embryonic chicken possessing the reflex at 90% of incubation, while the alligator possesses the reflex at 70% of incubation. In an effort to determine if bird species might share similar patterns of active baroreflex function, we studied embryonic emus (Dromiceius novaehollandiae). However, we hypothesized that emus would possess a pattern of baroreflex function similar to that of the American alligator given the emu embryo possesses functional vagal tone at 70% of incubation, possibly indicating a more mature collection of cardiovascular control mechanism than those found in embryonic chickens. Our findings illustrate that emu embryos possess a hypotensive baroreflex at 90% of incubation. Therefore, our data fail to support our original hypothesis. While only two species of birds have been studied in this context, it could indicate that baroreflex function is not essential for cardiovascular homeostasis in birds for the majority of in ovo development.

Galantamine ameliorates experimental pancreatitis.

BACKGROUND: Acute pancreatitis is a common and serious inflammatory condition currently lacking disease modifying therapy. The cholinergic anti-inflammatory pathway (CAP) is a potent protective anti-inflammatory response activated by vagus nerve-dependent α7 nicotinic acetylcholine receptor (α7nAChR) signaling using splenic CD4+ T cells as an intermediate. Activating the CAP ameliorates experimental acute pancreatitis. Galantamine is an acetylcholinesterase inhibitor (AChEI) which amplifies the CAP via modulation of central muscarinic ACh receptors (mAChRs). However, as mAChRs also activate pancreatitis, it is currently unknown whether galantamine would be beneficial in acute pancreatitis. METHODS: The effect of galantamine (1-6 mg/kg-body weight) on caerulein-induced acute pancreatitis was evaluated in mice. Two hours following 6 hourly doses of caerulein (50 µg/kg-body weight), organ and serum analyses were performed with accompanying pancreatic histology. Experiments utilizing vagotomy, gene knock out (KO) technology and the use of nAChR antagonists were also performed. RESULTS: Galantamine attenuated pancreatic histologic injury which was mirrored by a reduction in serum amylase and pancreatic inflammatory cytokines and an increase the anti-inflammatory cytokine IL-10 in the serum. These beneficial effects were not altered by bilateral subdiaphragmatic vagotomy, KO of either choline acetyltransferase+ T cells or α7nAChR, or administration of the nAChR ganglionic blocker mecamylamine or the more selective α7nAChR antagonist methyllycaconitine. CONCLUSION: Galantamine improves acute pancreatitis via a mechanism which does not involve previously established physiological and molecular components of the CAP. As galantamine is an approved drug in widespread clinical use with an excellent safety record, our findings are of interest for further evaluating the potential benefits of this drug in patients with acute pancreatitis.

Transient Receptor Potential Ankyrin-1-expressing vagus nerve fibers mediate IL-1ß induced hypothermia and reflex anti-inflammatory responses.

BACKGROUND: Inflammation, the physiological response to infection and injury, is coordinated by the immune and nervous systems. Interleukin-1ß (IL-1ß) and other cytokines produced during inflammatory responses activate sensory neurons (nociceptors) to mediate the onset of pain, sickness behavior, and metabolic responses. Although nociceptors expressing Transient Receptor Potential Ankyrin-1 (TRPA1) can initiate inflammation, comparatively little is known about the role of TRPA1 nociceptors in the physiological responses to specific cytokines. METHODS: To monitor body temperature in conscious and unrestrained mice, telemetry probes were implanted into peritoneal cavity of mice. Using transgenic and tissue specific knockouts and chemogenetic techniques, we recorded temperature responses to the potent pro-inflammatory cytokine IL-1ß. Using calcium imaging, whole cell patch clamping and whole nerve recordings, we investigated the role of TRPA1 during IL-1ß-mediated neuronal activation. Mouse models of acute endotoxemia and sepsis were used to elucidate how specific activation, with optogenetics and chemogenetics, or ablation of TRPA1 neurons can affect the outcomes of inflammatory insults. All statistical tests were performed with GraphPad Prism 9 software and for all analyses, P ≤ 0.05 was considered statistically significant. RESULTS: Here, we describe a previously unrecognized mechanism by which IL-1ß activates afferent vagus nerve fibers to trigger hypothermia, a response which is abolished by selective silencing of neuronal TRPA1. Afferent vagus nerve TRPA1 signaling also inhibits endotoxin-stimulated cytokine storm and significantly reduces the lethality of bacterial sepsis. CONCLUSION: Thus, IL-1ß activates TRPA1 vagus nerve signaling in the afferent arm of a reflex anti-inflammatory response which inhibits cytokine release, induces hypothermia, and reduces the mortality of infection. This discovery establishes that TRPA1, an ion channel known previously as a pro-inflammatory detector of cold, pain, itch, and a wide variety of noxious molecules, also plays a specific anti-inflammatory role via activating reflex anti-inflammatory activity.

Do air-breathing fish suffer branchial oxygen loss in hypoxic water?

In hypoxia, air-breathing fish obtain O2 from the air but continue to excrete CO2 into the water. Consequently, it is believed that some O2 obtained by air-breathing is lost at the gills in hypoxic water. Pangasionodon hypophthalmus is an air-breathing catfish with very large gills from the Mekong River basin where it is cultured in hypoxic ponds. To understand how P. hypophthalmus can maintain high growth in hypoxia with the presumed O2 loss, we quantified respiratory gas exchange in air and water. In severe hypoxia (PO2: ≈ 1.5 mmHg), it lost a mere 4.9% of its aerial O2 uptake, while maintaining aquatic CO2 excretion at 91% of the total. Further, even small elevations in water PO2 rapidly reduced this minor loss. Charting the cardiovascular bauplan across the branchial basket showed four ventral aortas leaving the bulbus arteriosus, with the first and second gill arches draining into the dorsal aorta while the third and fourth gill arches drain into the coeliacomesenteric artery supplying the gut and the highly trabeculated respiratory swim-bladder. Substantial flow changes across these two arterial systems from normoxic to hypoxic water were not found. We conclude that the proposed branchial oxygen loss in air-breathing fish is likely only a minor inefficiency.

Diabetes distress mediates the relationship between depressive symptoms and glycaemic control among adults with type 2 diabetes: Findings from a multi-site diabetes peer support intervention.

AIMS: Diabetes distress is positively associated with HbA1c and may mediate the relationship between depressive symptoms and HbA1c . This study examined these relationships in a geographically, socioeconomically, and ethnically diverse sample of adults with type 2 diabetes. METHODS: Using data from five US sites evaluating peer support for diabetes management (n = 917), Structural Equation Modeling (SEM) examined whether diabetes distress (four items from Diabetes Distress Scale) mediated the relationship between depressive symptoms (PHQ-8) and HbA1c . Sites compared interventions of varying content and duration with control conditions. Time from Baseline Assessment to Final Assessment varied from six to 18 months. Site characteristics were controlled by entering site as a covariate along with age, sex, education, diabetes duration, insulin use, and intervention/control assignment. RESULTS: Depressive symptoms, diabetes distress, and HbA1c were all intercorrelated cross-sectionally and from Baseline to Final Assessment (rs from 0.10 to 0.57; ps <0.05). In SEM analyses, diabetes distress at Final Assessment mediated the relationship between Baseline depressive symptoms and HbA1c at Final Assessment (indirect effect: b = 0.031, p < 0.001), controlling for Baseline HbA1c and covariates. Parallel analysis of whether depressive symptoms mediated the relationship between Baseline diabetes distress and HbA1c at Final Assessment was not significant. CONCLUSIONS: In this diverse sample, diabetes distress mediated the influence of depressive symptoms on HbA1c but the reverse, depressive symptoms mediating the effect of distress, was not found. These findings add to the evidence that diabetes distress is a worthy intervention target to improve clinical status and quality of life among individuals with type 2 diabetes.

Early Follow-Up after Arteriovenous Fistula Creation is Associated with Improved Access-Related Outcomes.

BACKGROUND: Up to 60% of arteriovenous fistulas (AVF) require intervention to assist maturation, which prolongs the time until it can be used for hemodialysis (HD). Current guidelines recommend early postoperative AVF examination to detect and address immaturity to decrease time to maturation. This study evaluates how the timing of postoperative follow-up to assess AVF maturity affects patients' outcomes. METHODS: All patients who underwent AVF creation between 2017 and 2021 in an academic medical center were retrospectively reviewed, excluding patients lost to follow-up or not on HD. Outcomes were compared between patients that had delayed follow-up to assess AVF maturity, >8 weeks post surgery, versus early follow-up, <8 weeks post-surgery. AVF evaluation for maturity consisted of physical examination and duplex ultrasound. Primary endpoints were time to first cannulation (interval from AVF creation to first successful cannulation) and time to catheter-free dialysis (interval from AVF creation to central venous catheter removal). RESULTS: A total of 400 patients were identified: 111 in the delayed follow-up group and 289 in the early follow-up group. The median time to follow-up was 78 days (interquartile range [IQR], 66-125) in the delayed follow-up group versus 39 days (IQR, 36-47) in the early follow-up group, (P < 0.0001). The maturation rate was 87% in the delayed follow-up group versus 81% in the early follow-up group, (P = 0.1) and both groups had similar rates of interventions to assist maturation (66% vs. 57%, P = 0.2). The early follow-up group had a significantly shorter median time to first cannulation (50 vs. 88 days; P < 0.0001) and shorter time to catheter-free HD (75 vs. 118 days; P <0.0001). At 4 months after AVF creation, the incidence of first cannulation was 74% in the early follow-up group versus 63% in the delayed follow-up group (P = 0.001). Similarly, the incidence of catheter-free dialysis was 65% in the early follow-up group versus 50% in the delayed follow-up group at 4 months postoperatively, (P = 0.036). CONCLUSIONS: Early postoperative follow-up for evaluation of fistula maturation is associated with reduced time to first successful cannulation of AVF for HD and reduced time to catheter-free dialysis.

Exposure to hypoxia during embryonic development affects blood flow patterns and heart rate in juvenile American alligators during digestion.

The developmental environment can alter an organism's phenotype through epigenetic mechanisms. We incubated eggs from American alligators in 10% O2 (hypoxia) to investigate the functional plasticity of blood flow patterns in response to feeding later in life. Digestion is associated with marked elevations of metabolism, and we therefore used the feeding-induced stimulation of tissue O2 demand to determine whether there are lasting effects of developmental hypoxia on the cardiovascular response to digestion later in life. In all animals studied, digestion elicited tachycardia and an elevation of blood flow in the right aorta, left aorta, and the pulmonary artery, whereas flows in the carotid and subclavian artery did not change. We found that heart rate and systemic blood flow remained elevated for a longer time period in juvenile alligators that had been incubated in hypoxia; we also found that the pulmonary blood flow was elevated at 24, 36, and 48 h. Collectively, our findings demonstrate that exposure to hypoxia during incubation has lasting effects on the hemodynamics of juvenile alligators 4 years after hatching.

Surgical debulking is associated with improved survival for patients with neuroendocrine liver metastases of unknown primary.

BACKGROUND: Resection of neuroendocrine tumors (NET) with surgical debulking of liver metastasis (NETLM) is associated with improved survival. In patients with an unknown primary (UP-NETLM), the effects of debulking remains unclear. METHODS: The National Cancer Database (2004-2016) was queried for patients with small intestine (SI) and pancreas (P) NETLMs. If the liver was listed as the primary site, the patient's disease was classified as UP-NETLM. RESULTS: Patients with UP-NETLM, SI-NETLM, and P-NETLM who were managed non-operatively demonstrated a significant difference in 5-year overall survival (OS) (21.5% vs. 39.2% vs. 17.1%; p < 0.0001). OS in patients who underwent debulking was higher (63.7% vs. 73.2% vs. 54.2%). Patients with UP-NETLMs who underwent debulking had similar OS to patient with SI-NETLM (p = 0.051), but significantly higher OS, depending on tumor differentiation, compared to patients with P-NETLMs. If well-differentiated, surgery for UP-NETLMs was associated with a higher rate of OS (p = 0.009), while no difference was observed if moderately (p = 0.209) or poorly/undifferentiated (p = 0.633). P-NETLMs were associated with worse OS (p < 0.001) on multivariate analysis. DISCUSSION: Debulking in patients with UP-NETLMs was associated with similar OS compared to patients with SI-NETLMs and better or similar OS compared to patient with P-NETLMs.

Famotidine activates the vagus nerve inflammatory reflex to attenuate cytokine storm.

BACKGROUND: Severe COVID-19 is characterized by pro-inflammatory cytokine release syndrome (cytokine storm) which causes high morbidity and mortality. Recent observational and clinical studies suggest famotidine, a histamine 2 receptor (H2R) antagonist widely used to treat gastroesophageal reflux disease, attenuates the clinical course of COVID-19. Because evidence is lacking for a direct antiviral activity of famotidine, a proposed mechanism of action is blocking the effects of histamine released by mast cells. Here we hypothesized that famotidine activates the inflammatory reflex, a brain-integrated vagus nerve mechanism which inhibits inflammation via alpha 7 nicotinic acetylcholine receptor (α7nAChR) signal transduction, to prevent cytokine storm. METHODS: The potential anti-inflammatory effects of famotidine and other H2R antagonists were assessed in mice exposed to lipopolysaccharide (LPS)-induced cytokine storm. As the inflammatory reflex is integrated and can be stimulated in the brain, and H2R antagonists penetrate the blood brain barrier poorly, famotidine was administered by intracerebroventricular (ICV) or intraperitoneal (IP) routes. RESULTS: Famotidine administered IP significantly reduced serum and splenic LPS-stimulated tumor necrosis factor (TNF) and IL-6 concentrations, significantly improving survival. The effects of ICV famotidine were significantly more potent as compared to the peripheral route. Mice lacking mast cells by genetic deletion also responded to famotidine, indicating the anti-inflammatory effects are not mast cell-dependent. Either bilateral sub-diaphragmatic vagotomy or genetic knock-out of α7nAChR abolished the anti-inflammatory effects of famotidine, indicating the inflammatory reflex as famotidine's mechanism of action. While the structurally similar H2R antagonist tiotidine displayed equivalent anti-inflammatory activity, the H2R antagonists cimetidine or ranitidine were ineffective even at very high dosages. CONCLUSIONS: These observations reveal a previously unidentified vagus nerve-dependent anti-inflammatory effect of famotidine in the setting of cytokine storm which is not replicated by high dosages of other H2R antagonists in clinical use. Because famotidine is more potent when administered intrathecally, these findings are also consistent with a primarily central nervous system mechanism of action.

No evidence for pericardial restraint in the snapping turtle (Chelydra serpentina) following pharmacologically induced bradycardia at rest or during exercise.

Most animals elevate cardiac output during exercise through a rise in heart rate (fH), whereas stroke volume (VS) remains relatively unchanged. Cardiac pacing reveals that elevating fH alone does not alter cardiac output, which is instead largely regulated by the peripheral vasculature. In terms of myocardial oxygen demand, an increase in fH is more costly than that which would incur if VS instead were to increase. We hypothesized that fH must increase because any substantial rise in VS would be constrained by the pericardium. To investigate this hypothesis, we explored the effects of pharmacologically induced bradycardia, with ivabradine treatment, on VS at rest and during exercise in the common snapping turtle (Chelydra serpentina) with intact or opened pericardium. We first showed that, in isolated myocardial preparations, ivabradine exerted a pronounced positive inotropic effect on atrial tissue but only minor effects on ventricle. Ivabradine reduced fH in vivo, such that exercise tachycardia was attenuated. Pulmonary and systemic VS rose in response to ivabradine. The rise in pulmonary VS largely compensated for the bradycardia at rest, leaving total pulmonary flow unchanged by ivabradine, although ivabradine reduced pulmonary blood flow during swimming (exercise × ivabradine interaction, P < 0.05). Although systemic VS increased, systemic blood flow was reduced by ivabradine both at rest and during exercise, despite ivabradine's potential to increase cardiac contractility. Opening the pericardium had no effect on fH, VS, or blood flows before or after ivabradine, indicating that the pericardium does not constrain VS in turtles, even during pharmacologically induced bradycardia.

Developmental oxygen preadapts ventricular function of juvenile American alligators, Alligator mississippiensis.

Developmental oxygen is a powerful stressor that can induce morphological and functional changes in the cardiovascular systems of embryonic and juvenile vertebrates. This plasticity has been ascribed, at least in part, to the unique status of the developing cardiovascular system, which undergoes organogenesis while meeting the tissue oxygen demands of the embryo. We have previously reported an array of functional and morphological changes in embryonic American alligators that persist into juvenile life. Most notably, cardiac enlargement as well as functional parameters of anesthetized juvenile alligators remains after embryonic hypoxic exposure. Because the effects of developmental oxygen in crocodilians have only been investigated in anesthetized animals, we explored the pressure dynamics of both ventricles as well as systemic pressure in response to stressors of acute hypoxia and swimming. Our current findings demonstrate that developmental programming of cardiac function (intraventricular pressure and heart rate) does persist into juvenile life, but it is chamber-specific and depends on the experimental manipulation. Acute hypoxic exposure revealed that juvenile alligators that had experienced 10% O2 as embryos maintain right ventricle function and increase left ventricle function during exposure. Finally, the data indicate blood flow in the left aorta must originate from the left ventricle during acute hypoxia and swimming.

Infant Sex-Specific Associations between Prenatal Food Insecurity and Low Birthweight: A Multistate Analysis.

BACKGROUND: Low birthweight is associated with increased risk of neonatal mortality and adverse outcomes among survivors. As maternal sociodemographic factors do not explain all of the risk in low birthweight, exploring exposures occurring during critical periods, such as maternal food insecurity, should be considered from a life course perspective. OBJECTIVES: To explore the association between prenatal food insecurity and low birthweight, as well as whether or not there may be a sex-specific response using a multistate survey. METHODS: Pregnancy Risk Assessment Monitoring System (PRAMS) data of live births from 11 states during 2009-2017 were used, restricting to women with a singleton birth. Food insecurity was determined by a single question in PRAMS, and low birthweight was defined as a birth <2500 g. Multivariable logistic regression was used, stratified by infant sex and adjusted for maternal sociodemographic and prepregnancy health characteristics. RESULTS: There were n = 50,915 women from 2009 to 2017, with 9.1% experiencing food insecurity. Unadjusted results revealed that food-insecure mothers had an increased odds ratio of delivering a low-birthweight baby (OR: 1.38; 95% CI: 1.25, 1.53). Adjustment for covariates appeared to explain the association among male infants, whereas magnitudes remained greater among female infants (adjusted OR: 1.13; 95% CI: 0.94, 1.35). CONCLUSIONS: Findings suggest a sex-specific response to prenatal food insecurity, particularly among female offspring. Future studies are warranted with more precise measures of food insecurity and to understand the difference by infant sex.

Fast pesticide analysis using low-pressure gas chromatography paired with a triple quadrupole mass spectrometer equipped with short collision cell technology.

RATIONALE: A proof of concept showing GC-MS/MS analysis time for pesticides can be dramatically reduced while maintaining a similar separation efficiency by combining a low-pressure gas chromatography (LPGC) column with the enhanced selected reaction monitoring (SRM) switching speed of the short collision cell of a JEOL JMS-TQ4000GC. METHODS: Triple-quadrupole tandem mass spectrometry (standard EI + at 70 eV) was used to measure pesticides eluting from a low-pressure gas chromatograph capillary column. Three transitions for each of 244 pesticide compounds were measured within an 11-min analysis time, and the data were checked to confirm the method's reproducibility and ability to distinguish all three transitions for each pesticide. RESULTS: All three transitions for all 244 pesticides were detected in the standard mixture at 1X concentration within the 11-min analysis time. Relative standard deviation (RSD) of peak areas was less than 15% for 242 pesticides, and I/Q RSDs were less than 10% for 242 compounds. Retention time RSD over 15 replicates was less than 0.1%. CONCLUSIONS: Results show that analysis time can be markedly decreased using an LPGC column, and that the ability of the short collision cell to distinguish a large number of coeluting peaks makes the two technologies a natural pairing. The effective measurement of pesticides within a short time could benefit any scientists doing pesticide analysis work.

Update on Image-Guided Thermal Lung Ablation: Society Guidelines, Therapeutic Alternatives, and Postablation Imaging Findings.

Percutaneous image-guided thermal ablation (IGTA) has been endorsed by multiple societies as a safe and effective lung-preserving treatment of primary lung cancer and metastases involving the lung and chest wall. This article reviews the role of IGTA in the care continuum of patients with thoracic neoplasms and discusses strategies to identify the optimal local therapy considering patient and tumor characteristics. The advantages and disadvantages of percutaneous thermal ablation compared with surgical resection and stereotactic body radiotherapy are summarized. Principles of radiofrequency ablation, microwave ablation, and cryoablation, as well as the emerging use of transbronchial thermal ablation, are described. Specific considerations are presented regarding the role of thermal ablation for early-stage non-small cell lung cancer (NSCLC), multifocal primary NSCLC, pulmonary metastases, salvage of recurrent NSCLC after surgery or radiation, and pain palliation for tumors involving the chest wall. Recent changes to professional society guidelines regarding the role of thermal ablation in the lung, including for treatment of oligometastatic disease, are highlighted. Finally, recommendations are provided for imaging follow-up after thermal ablation of lung tumors, accompanied by examples of expected postoperative findings and patterns of disease recurrence.

Structure activity relationships leading to the identification of the indirect activator of AMPK, R419.

Using an in-cell AMPK activation assay, we have developed structure-activity relationships around a hit pyridine dicarboxamide 5 that resulted in 40 (R419). A particular focus was to retain the on-target potency while also improving microsomal stability and reducing off-target activities, including hERG inhibition. We were able to show that removing a tertiary amino group from the piperazine unit of hit compound 5 improved microsomal stability while hERG inhibition was improved by modifying the substitution of the central core pyridine ring. The SAR resulted in 40, which continues to maintain on-target potency. Compound 40 was able to activate AMPK in vivo after oral administration and showed efficacy in animal models investigating activation of AMPK as a therapy for glucose control (both db/db and DIO mouse models).

Intracranial Hemorrhage Secondary to Vitamin K Deficiency Bleeding in a Newborn.

We present a case of a 6-week-old infant who presented with seizure-like activity. Workup revealed abnormal coagulation and imaging confirmed intracranial hemorrhage. Parental refusal of vitamin K treatment at birth suggested vitamin K deficiency bleeding (VKDB) in this newborn. Though VKDB is rare in developed countries, rates have been rising which coincides with an increasing trend of parental refusal of vitamin K prophylaxis at birth.