Cellular metabolism of substance P produces neurokinin-1 receptor peptide agonists with diminished cyclic AMP signaling.

Substance P (SP) is released from sensory nerves in the arteries and heart. It activates neurokinin-1 receptors (NK1Rs) causing vasodilation, immune modulation, and adverse cardiac remodeling. The hypothesis was tested: SP and SP metabolites activate different second messenger signaling pathways. Macrophages, endothelial cells, and fibroblasts metabolized SP to N- and C-terminal metabolites to varying extents. SP 5-11 was the most abundant metabolite followed by SP 1-4, SP 7-11, SP 6-11, SP 3-11, and SP 8-11. In NK1R-expressing human embryonic kidney 293 (HEK293) cells, SP and some C-terminal SP metabolites stimulate the NK1R, promoting the dissociation of several Gα proteins, including Gαs and Gαq from their ßγ subunits. SP increases intracellular calcium concentrations ([Ca]i) and cyclic 3',5'-adenosine monophosphate (cAMP) accumulation with similar -log EC50 values of 8.5 ± 0.3 and 7.8 ± 0.1 M, respectively. N-terminal metabolism of SP by up to five amino acids and C-terminal deamidation of SP produce peptides that retain activity to increase [Ca]i but not to increase cAMP. C-terminal metabolism results in the loss of both activities. Thus, [Ca]i and cAMP signaling are differentially affected by SP metabolism. To assess the role of N-terminal metabolism, SP and SP 6-11 were compared with cAMP-mediated activities in NK1R-expressing 3T3 fibroblasts. SP inhibits nuclear factor κB (NF-κB) activity, cell proliferation, and wound healing and stimulates collagen production. SP 6-11 had little or no activity. Cyclooxygenase-2 (COX-2) expression is increased by SP but not by SP 6-11. Thus, metabolism may select the cellular response to SP by inhibiting or redirecting the second messenger signaling pathway activated by the NK1R.NEW & NOTEWORTHY Endothelial cells, macrophages, and fibroblasts metabolize substance P (SP) to N- and C-terminal metabolites with SP 5-11 as the most abundant metabolite. SP activates neurokinin-1 receptors to increase intracellular calcium and cyclic AMP. In contrast, SP metabolites of N-terminal metabolism and C-terminal deamidation retain the ability to increase calcium but lose the ability to increase cyclic AMP. These new insights indicate that the metabolism of SP directs cellular functions by regulating specific signaling pathways.

Development of a novel tau propagation mouse model endogenously expressing 3 and 4 repeat tau isoforms.

The phenomenon of 'prion-like propagation' in which aggregates of abnormal amyloid-fibrilized protein propagate between neurons and spread pathology, is attracting attention as a new mechanism in neurodegenerative diseases. There is a strong correlation between the accumulation or spread of abnormal tau aggregates and the clinical symptoms of tauopathies. Microtubule-associated protein tau (MAPT) contains a microtubule-binding domain that consists of three or four repeats (3R/4R) due to alternative mRNA splicing of transcripts for the MAPT gene. Although a number of models for tau propagation have been reported, most use 4R human tau transgenic mice or adult wild-type mice expressing only endogenous 4R tau and these models have not been able to reproduce the pathology of Alzheimer's disease in which 3R and 4R tau accumulate simultaneously, or that of Pick's disease in which only 3R tau is aggregated. These deficiencies may reflect differences between human and rodent tau isoforms in the brain. To overcome this problem, we used genome editing techniques to generate mice that express an equal ratio of endogenous 3R and 4R tau, even after they become adults. We injected these mice with sarkosyl-insoluble fractions derived from the brains of human tauopathy patients such as those afflicted with Alzheimer's disease (3R and 4R tauopathy), corticobasal degeneration (4R tauopathy) or Pick's disease (3R tauopathy). At 8-9 months following intracerebral injection of mice, histopathological and biochemical analyses revealed that the abnormal accumulation of tau was seed-dependent, with 3R and 4R tau in Alzheimer's disease-injected brains, 4R tau only in corticobasal degeneration-injected brains and 3R tau only in Pick disease-injected brains, all of which contained isoforms related to those found in the injected seeds. The injected abnormal tau was seeded, and accumulated at the site of injection and at neural connections, predominantly within the same site. The abnormal tau newly accumulated was found to be endogenous in these mice and to have crossed the species barrier. Of particular importance, Pick's body-like inclusions were observed in Pick's disease-injected mice, and accumulations characteristic of Pick's disease were reproduced, suggesting that we have developed the first model that recapitulates the pathology of Pick's disease. These models are not only useful for elucidating the mechanism of propagation of tau pathology involving both 3R and 4R isoforms, but can also reproduce the pathology of tauopathies, which should lead to the discovery of new therapeutic agents.

Searching for Scalar Dark Matter via Coupling to Fundamental Constants with Photonic, Atomic, and Mechanical Oscillators.

We present a way to search for light scalar dark matter (DM), seeking to exploit putative coupling between dark matter scalar fields and fundamental constants, by searching for frequency modulations in direct comparisons between frequency stable oscillators. Specifically we compare a cryogenic sapphire oscillator (CSO), hydrogen maser (HM) atomic oscillator, and a bulk acoustic wave quartz oscillator (OCXO). This work includes the first calculation of the dependence of acoustic oscillators on variations of the fundamental constants, and demonstration that they can be a sensitive tool for scalar DM experiments. Results are presented based on 16 days of data in comparisons between the HM and OCXO, and 2 days of comparison between the OCXO and CSO. No evidence of oscillating fundamental constants consistent with a coupling to scalar dark matter is found, and instead limits on the strength of these couplings as a function of the dark matter mass are determined. We constrain the dimensionless coupling constant d_{e} and combination |d_{m_{e}}-d_{g}| across the mass band 4.4×10^{-19}≲m_{φ}≲6.8×10^{-14} eV c^{-2}, with most sensitive limits d_{e}≳1.59×10^{-1}, |d_{m_{e}}-dg|≳6.97×10^{-1}. Notably, these limits do not rely on maximum reach analysis (MRA), instead employing the more general coefficient separation technique. This experiment paves the way for future, highly sensitive experiments based on state-of-the-art acoustic oscillators, and we show that these limits can be competitive with the best current MRA-based exclusion limits.

Rare Events Detected with a Bulk Acoustic Wave High Frequency Gravitational Wave Antenna.

This work describes the operation of a high frequency gravitational wave detector based on a cryogenic bulk acoustic wave cavity and reports observation of rare events during 153 days of operation over two separate experimental runs (run 1 and run 2). In both run 1 and run 2, two modes were simultaneously monitored. Across both runs, the third overtone of the fast shear mode (3B) operating at 5.506 MHz was monitored; whereas in run 1, the second mode was chosen to be the fifth overtone of the slow shear mode (5C) operating at 8.392 MHz. However, in run 2, the second mode was selected to be closer in frequency to the first mode; and it was chosen to be the third overtone of the slow shear mode (3C) operating at 4.993 MHz. Two strong events were observed as transients responding to energy deposition within acoustic modes of the cavity. The first event occurred during run 1 on 12 May 2019 (UTC), and it was observed in the 5.506 MHz mode; whereas the second mode at 8.392 MHz observed no event. During run 2, a second event occurred on 27 November 2019 (UTC) and was observed by both modes. Timings of the events were checked against available environmental observations as well as data from other detectors. Various possibilities explaining the origins of the events are discussed.

Combat-Sustained Peripheral Nerve Injuries in the United States Military.

PURPOSE: Combat-sustained peripheral nerve injuries (CSPNIs) are often the result of high-energy blast mechanisms and are increasing in frequency and severity among US forces engaged in contemporary warfare. The purpose of this study was to describe CSPNIs and report outcomes after evaluation in a military multidisciplinary peripheral nerve clinic. We hypothesized that a shorter time to evaluation by a multidisciplinary peripheral nerve team would improve outcomes. METHODS: The Peripheral Nerve Consortium (PNC) maintains an electronic database of all active duty service members who sustained a peripheral nerve injury (PNI) and were treated by the PNC between 2004 and 2009. This database was queried for service member demographic information, injury characteristics, wounding patterns, CSPNI description, surgical procedures, and Medical Research Council final motor and sensory outcome. RESULTS: Among the 104 service members treated by the PNC in the 6-year period reviewed, there were 138 PNIs. Average age was 27 years, time to initial evaluation by the PNC was 4 (±7) months, and average follow-up was 18 (±18) months. Associated injuries included fractures (31.1%), multiple PNIs (76.8%), vascular injury (30.4%), and traumatic brain injury (34.1%). There was no association between Sunderland classification and time to evaluation, mechanism of injury, or nerve injured. However, Sunderland classification was correlated with final motor and final sensory scores. Service members with better final sensory score (S1 or S2) had shorter time to initial evaluation than did patients with a final sensory score of S0 (<0.05). This did not hold true for final motor score. CONCLUSIONS: Service members with more severe initial injuries had worse final outcomes. Although timely referral does not occur for most CSPNIs, a shorter time to presentation also led to improved sensory recovery. Complex combat-sustained PNIs may be best understood and treated within a multidisciplinary team. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

MANAGEMENT OF GIANT RETINAL TEARS USING TRANSSCLERAL DIODE LASER RETINOPEXY AND SHORT-TERM POSTOPERATIVE TAMPONADE WITH PERFLUORO-N-OCTANE.

PURPOSE: To determine the results of pars plana vitrectomy for giant retinal tear detachments using transscleral diode laser retinopexy and short-term postoperative tamponade with perfluoro-n-octane (PFnO). METHODS: Twenty consecutive patients with fresh giant retinal tears were enrolled in a single-arm prospective study. One case was withdrawn for technical reasons. The remainder all underwent pars plana vitrectomy, PFnO injection, transscleral diode laser retinopexy to the edge of the giant retinal tear, and short-term postoperative heavy liquid tamponade. None of the cases had scleral buckling or lensectomy. RESULTS: Nineteen cases (18 male and 1 female) with a mean age of 41 years (range 10-69 years) were followed up for a period of 6 months. Postoperative tamponade with PFnO was maintained for a mean of 7.6 days (range 4-21 days), after which it was exchanged for sulfur hexafluoride (SF6), perfluoropropane (C3F8) gas, or balanced salt solution. Final reattachment rate was 100%, with 3 (15.7%) patients requiring additional surgery. Best-corrected visual acuity at final follow-up was 20/40 or better in 11 eyes (58%), between 20/60 and 20/200 in 7 (37%), and 20/400 in 1 (5%). CONCLUSION: In this series of acute giant retinal tears, transscleral diode laser retinopexy together with the use of PFnO for short-term postoperative tamponade achieved excellent anatomical and visual results.

AUSTRALIAN AND NEW ZEALAND STUDY OF PHOTODYNAMIC THERAPY IN CHOROIDAL AMELANOTIC MELANOMA.

PURPOSE: To evaluate the safety and efficacy of primary photodynamic therapy (PDT) for posterior choroidal amelanotic melanomas. METHODS: Patients with posterior choroidal amelanotic melanomas up to 6 mm in height were treated with PDT using verteporfin as the photosensitizing agent. Treatment was repeated every 3 months until the tumor was flat up to a maximum of 6 treatments. Tumor response and recurrence was assessed by clinical examination, photography, and ultrasonography. Patients were monitored 3 monthly for a minimum of 3 years. RESULTS: Thirty-six of 41 (88%) patients had complete regression after an initial course of PDT. Of them, 20 (56%) had no recurrence, 3 (8%) had recurrences that were successfully treated with further PDT, and 13 (36%) had recurrences that failed or were not amenable to further PDT. None of the measured baseline characteristics predicted treatment outcomes. There was no reduction in visual acuity due to PDT. The mean follow-up time was 3.5 years. CONCLUSION: In this large series, primary PDT was highly effective in achieving initial regression of posterior choroidal amelanotic melanomas. Photodynamic therapy is a vision-preserving treatment option for these tumors; however, patients need to be followed up closely because there is a significant rate of recurrence.

SURGICAL MANAGEMENT OF TRAUMATIC MACULAR HOLE: Optical Coherence Tomography Features and Outcomes.

PURPOSE: To report the outcomes of eyes receiving surgical management for traumatic macular holes. To describe the preoperative and postoperative optical coherence tomography features of traumatic macular holes and to explore associations between preoperative clinical and optical coherence tomography features, and visual outcome. METHODS: Retrospective study of patients undergoing vitrectomy for traumatic macular hole and entered into the Australian and New Zealand Society of Retinal Specialists surgical registry. Preoperative clinical data, surgical details, and 3-month postoperative outcomes were recorded prospectively. Longer-term outcomes at 12 months were requested retrospectively, as were preoperative and postoperative optical coherence tomography scans. RESULTS: Hole closure was achieved in 91% (21/23) of patients with a single procedure. The average preoperative visual acuity was 20/120. At 3 months postoperatively, the mean visual acuity had improved to 20/70 (P < 0.001), 11/23 (48%) of eyes improved ≥15 letters, and the number of eyes with 20/40 acuity or better increased from 1/23 to 7/23. Eyes with worse visual outcomes (visual acuity < 20/80) had larger holes, worse preoperative acuity, and a greater extent of preoperative ellipsoid band attenuation than those with better postoperative visual acuity. CONCLUSION: Eyes receiving surgical management for traumatic macular hole achieved good anatomical results and approximately half had a substantial improvement in acuity. Ellipsoid band attenuation on preoperative optical coherence tomography and worse preoperative acuity were associated with poorer visual outcomes.

Comparison Between the Hyperelastic Behavior of Fresh and Frozen Equine Articular Cartilage in Various Joints.

Fresh and frozen cartilage samples of the fetlock, carpus, and stifle were collected from 12 deceased horses. Half were measured immediately following extraction, and half were frozen for seven days and then measured. Seven indentations (various normalized displacements) were implemented with an indention rate of 0.1 mm/s. Solid phase aggregate modulus (Es), hyperelastic material constant (α), and fluid load fraction (F') of equine articular cartilage were assessed using the Ogden hyperelastic model. The properties were statistically compared in various joints (fetlock, carpus, and stifle), and between fresh and frozen samples using various statistical models. There was no statistical difference between the fetlock and carpus in the aggregate modulus (p = 0.5084), while both were significantly different from the stifle (fetlock: p = 0.0017 and carpus: p = 0.0406). For the hyperelastic material constant, no statistical differences between joints were observed (p = 0.3310). For the fluid load fraction, the fetlock and stifle comparison showed a difference (p = 0.0333), while the carpus was not different from the fetlock (p = 0.1563) or stifle (p = 0.3862). Comparison between the fresh and frozen articular cartilage demonstrated no significant difference among the joints in the three material properties: p = 0.9418, p = 0.7031, and p = 0.9313 for the aggregate modulus, the hyperelastic material constant, and the fluid load fraction, respectively.

The Histamine 3 Receptor Is Expressed in the Heart and Its Activation Opposes Adverse Cardiac Remodeling in the Angiotensin II Mouse Model.

Histamine is a basic amine stored in mast cells, with its release capable of activating one of four histamine receptors. The histamine 3 receptor (H3R) is known to be cardioprotective during acute ischemia by acting to limit norepinephrine release. However, a recent study reported that myofibroblasts isolated from the infarct zone of rat hearts responded to H3R activation by up-regulating collagen production. Thus, it is necessary to clarify the potential role of the H3R in relation to fibrosis in the heart. We identified that the mouse left ventricle (LV) expresses the H3R. Isolation of mouse cardiac fibroblasts determined that while angiotensin II (Ang II) increased levels of the H3R, these cells did not produce excess collagen in response to H3R activation. Using the Ang II mouse model of adverse cardiac remodeling, we found that while H3R blockade had little effect on cardiac fibrosis, activation of the H3R reduced cardiac fibrosis and macrophage infiltration. These findings suggest that when activated, the H3R is anti-inflammatory and anti-fibrotic in the mouse heart and may be a promising target for protecting against cardiac fibrosis.

GPR40 is a low-affinity epoxyeicosatrienoic acid receptor in vascular cells.

Endothelium-derived epoxyeicosatrienoic acids (EETs) have numerous vascular activities mediated by G protein-coupled receptors. Long-chain free fatty acids and EETs activate GPR40, prompting us to investigate the role of GPR40 in some vascular EET activities. 14,15-EET, 11,12-EET, arachidonic acid, and the GPR40 agonist GW9508 increase intracellular calcium concentrations in human GPR40-overexpressing HEK293 cells (EC50 = 0.58 ± 0.08 µm, 0.91 ± 0.08 µm, 3.9 ± 0.06 µm, and 19 ± 0.37 nm, respectively). EETs with cis- and trans-epoxides had similar activities, whereas substitution of a thiirane sulfur for the epoxide oxygen decreased the activities. 8,9-EET, 5,6-EET, and the epoxide hydrolysis products 11,12- and 14,15-dihydroxyeicosatrienoic acids were less active than 11,12-EET. The GPR40 antagonist GW1100 and siRNA-mediated GPR40 silencing blocked the EET- and GW9508-induced calcium increases. EETs are weak GPR120 agonists. GPR40 expression was detected in human and bovine endothelial cells (ECs), smooth muscle cells, and arteries. 11,12-EET concentration-dependently relaxed preconstricted coronary arteries; however, these relaxations were not altered by GW1100. In human ECs, 11,12-EET increased MAP kinase (MAPK)-mediated ERK phosphorylation, phosphorylation and levels of connexin-43 (Cx43), and expression of cyclooxygenase-2 (COX-2), all of which were inhibited by GW1100 and the MAPK inhibitor U0126. Moreover, siRNA-mediated GPR40 silencing decreased 11,12-EET-induced ERK phosphorylation. These results indicated that GPR40 is a low-affinity EET receptor in vascular cells and arteries. We conclude that epoxidation of arachidonic acid to EETs enhances GPR40 agonist activity and that 11,12-EET stimulation of GPR40 increases Cx43 and COX-2 expression in ECs via ERK phosphorylation.

Epoxyeicosatrienoic acid analog EET-B attenuates post-myocardial infarction remodeling in spontaneously hypertensive rats.

Epoxyeicosatrienoic acids (EETs) and their synthetic analogs have cardiovascular protective effects. Here, we investigated the action of a novel EET analog EET-B on the progression of post-myocardial infarction (MI) heart failure in spontaneously hypertensive rats (SHR). Adult male SHR were divided into vehicle- and EET-B (10 mg/kg/day; p.o., 9 weeks)-treated groups. After 2 weeks of treatment, rats were subjected to 30-min left coronary artery occlusion or sham operation. Systolic blood pressure (SBP) and echocardiography (ECHO) measurements were performed at the beginning of study, 4 days before, and 7 weeks after MI. At the end of the study, tissue samples were collected for histological and biochemical analyses. We demonstrated that EET-B treatment did not affect blood pressure and cardiac parameters in SHR prior to MI. Fractional shortening (FS) was decreased to 18.4 ± 1.0% in vehicle-treated MI rats compared with corresponding sham (30.6 ± 1.0%) 7 weeks following MI induction. In infarcted SHR hearts, EET-B treatment improved FS (23.7 ± 0.7%), markedly increased heme oxygenase-1 (HO-1) immunopositivity in cardiomyocytes and reduced cardiac inflammation and fibrosis (by 13 and 19%, respectively). In conclusion, these findings suggest that EET analog EET-B has beneficial therapeutic actions to reduce cardiac remodeling in SHR subjected to MI.

The case of the missing pulmonary vein: A focused update on anomalous pulmonary venous connection in congenital cardiovascular disease.

Partial anomalous pulmonary venous connection is defined by one or more of the pulmonary veins draining to the heart into a location other than the left atrium. Depending on the location of the anomalous venous connection, they can be categorized as supracardiac, infracardiac, cardiac, and mixed types. In some cases, there is no hemodynamic consequence; in others, it can result in tricuspid regurgitation, right heart dilation, and pulmonary hypertension. Frequently, the reason for referral can be asymptomatic right heart dilation of unknown significance. Diagnosis is often difficult by transthoracic echocardiogram unless there is a high index of suspicion, and the appropriate views are obtained. Cardiac CT (computed tomography) or cardiac MRI (magnetic resonance imaging) can provide more precise anatomic detail as needed. The current article reviews the etiology and pathophysiology of partial anomalous pulmonary venous connection, and also reviews the current knowledge on their treatment.

Resilience in medical doctors: a systematic review.

INTRODUCTION: Resilience can be difficult to conceptualise and little is known about resilience in medical doctors. AIMS: This systematic review discusses the existing literature on influences on resilience levels of medical doctors. METHODS: The bibliographic databases PubMed, MEDLINE, EMBASE and PsycINFO were searched from 2008 to November 2018 using keyword search terms resilience* AND ("medical physician*" OR doctor* OR surgeon* OR medical trainee* or clinician*). RESULTS: Twenty-four studies were deemed eligible for inclusion. A narrative synthesis was performed. The following influences on resilience in doctors were identified: demographics, personality factors, organisational or environmental factors, social support, leisure activities, overcoming previous adversity and interventions to improve resilience. CONCLUSIONS: Resilience is not limited to a doctor's own personal resource. Published studies also highlight the influence of other modifiable factors.

Deactivation of 12(S)-HETE through (ω-1)-hydroxylation and ß-oxidation in alternatively activated macrophages.

Polarization of macrophages to proinflammatory M1 and to antiinflammatory alternatively activated M2 states has physiological implications in the development of experimental hypertension and other pathological conditions. 12/15-Lipoxygenase (12/15-LO) and its enzymatic products 12(S)- and 15(S)-hydroxyeicosatetraenoic acid (HETE) are essential in the process since disruption of the gene encoding 12/15-LO renders the mice unsusceptible to hypertension. The objective was to test the hypothesis that M2 macrophages catabolize 12(S)-HETE into products that are incapable of promoting vasoconstriction. Cultured M2 macrophages metabolized externally added [14C]12(S)-HETE into more polar metabolites, while M1 macrophages had little effect on the catabolism. The major metabolites were identified by mass spectrometry as (ω-1)-hydroxylation and ß-oxidation products. The conversion was inhibited by both peroxisomal ß-oxidation inhibitor, thioridazine, and cytochrome P450 inhibitors. Quantitative PCR analysis confirmed that several cytochrome P450 enzymes (CYP2E1 and CYP1B1) and peroxisomal ß-oxidation markers were upregulated upon M2 polarization. The identified 12,19-dihydroxy-5,8,10,14-eicosatetraenoic acid and 8-hydroxy-6,10-hexadecadienoic acid metabolites were tested on abdominal aortic rings for biological activity. While 12(S)-HETE enhanced vasoconstrictions to angiotensin II from 15% to 25%, the metabolites did not. These results indicate that M2, but not M1, macrophages degrade 12(S)-HETE into products that no longer enhance the angiotensin II-induced vascular constriction, supporting a possible antihypertensive role of M2 macrophages.

Study of Healthcare Personnel with Influenza and other Respiratory Viruses in Israel (SHIRI): study protocol.

BACKGROUND: The Study of Healthcare Personnel with Influenza and other Respiratory Viruses in Israel (SHIRI) prospectively follows a cohort of healthcare personnel (HCP) in two hospitals in Israel. SHIRI will describe the frequency of influenza virus infections among HCP, identify predictors of vaccine acceptance, examine how repeated influenza vaccination may modify immunogenicity, and evaluate influenza vaccine effectiveness in preventing influenza illness and missed work. METHODS: Cohort enrollment began in October, 2016; a second year of the study and a second wave of cohort enrollment began in June 2017. The study will run for at least 3 years and will follow approximately 2000 HCP (who are both employees and members of Clalit Health Services [CHS]) with routine direct patient contact. Eligible HCP are recruited using a stratified sampling strategy. After informed consent, participants complete a brief enrollment survey with questions about occupational responsibilities and knowledge, attitudes, and practices about influenza vaccines. Blood samples are collected at enrollment and at the end of influenza season; HCP who choose to be vaccinated contribute additional blood one month after vaccination. During the influenza season, participants receive twice-weekly short message service (SMS) messages asking them if they have acute respiratory illness or febrile illness (ARFI) symptoms. Ill participants receive follow-up SMS messages to confirm illness symptoms and duration and are asked to self-collect a nasal swab. Information on socio-economic characteristics, current and past medical conditions, medical care utilization and vaccination history is extracted from the CHS database. Information about missed work due to illness is obtained by self-report and from employee records. Respiratory specimens from self-collected nasal swabs are tested for influenza A and B viruses, respiratory syncytial virus, human metapneumovirus, and coronaviruses using validated multiplex quantitative real-time reverse transcription polymerase chain reaction assays. The hemagglutination inhibition assay will be used to detect the presence of neutralizing influenza antibodies in serum. DISCUSSION: SHIRI will expand our knowledge of the burden of respiratory viral infections among HCP and the effectiveness of current and repeated annual influenza vaccination in preventing influenza illness, medical utilization, and missed workdays among HCP who are in direct contact with patients. TRIAL REGISTRATION: NCT03331991 . Registered on November 6, 2017.

Identification of candidates for PFO closure in the echocardiography laboratory.

A patent foramen ovale (PFO) is implicated in several pathologic processes, including that of cryptogenic stroke (cCVA). Recent trials identify "high-risk" PFOs in patients with cCVA as likely to benefit from percutaneous closure. The younger the patient (<60 years old) the more likely a PFO may be attributable to the cCVA. The RoPE Score index helps determine the likelihood that an existing PFO is related to a cCVA. This may help guide the clinician and patient when contemplating percutaneous PFO closure. When evaluating a patient for possible percutaneous closure, one should identify the CVA as a typical ischemic type stroke. In order to "rule-out" other causes of CVA, imaging of the intracranial arteries, cervical, and aortic arch vessels should be performed. Small vessel disease or a lacunar-type infarct should be excluded. To rule out atrial fibrillation, prolonged monitoring should be performed. An index has been developed to determine the probability that a PFO is the causative etiology and calculates the risk of recurrence. This may help guide the clinician and patient in the decision for PFO closure. In addition, one should consider a work-up for a hypercoagulable state. We will obtain an ultrasound of the lower extremities or consider deep pelvic vein thrombosis (prolonged sitting or malignancy). If the closure is to be performed, the Food and Drug Administration (FDA) has approved the Amplatzer PFO Occluder and the GORE Cardioform Septal Occluder for percutaneous closure. These devices are both approved in patients predominately between ages 18 and 60 years with a cCVA due to presumed paradoxical embolism as verified by a neurologist and cardiologist and when other causes of ischemic CVA have been excluded. "High-risk" PFOs appear to achieve the most potential benefit from percutaneous closure.

Inter-rater reliability determination for two tests of ulnar nerve conduction across the elbow.

INTRODUCTION: The inter-rater variability in determination of ulnar nerve conduction across the elbow compromises test accuracy. The extent of this variability is unknown. The objective of this study was to determine and compare inter-rater reliability of variables derived from 2 different ulnar nerve conduction studies (NCSs) across the elbow. METHODS: Two investigators performed a standard ulnar NCS and a 6-cm conduction time (Six-Centimeter Conduction Time test, SCCT) on 60 extremities of asymptomatic subjects. In the standard test, below-elbow (BE) and above-elbow (AE) stimulation points were ≥ 10 cm apart, measured along a curved path, to calculate across-elbow NCV. In SCCT, BE and AE were precisely 6 cm apart measured linearly to calculate CTE (conduction time elbow). Inter-rater reliability was assessed by means of intraclass correlation coefficients (ICC). RESULTS: ICC for across-elbow NCV and CTE were 0.726 and 0.801, respectively. CONCLUSIONS: Reliability of CTE and across-elbow NCV are similar. Shorter distances, if measured linearly, can be used to determine across-elbow ulnar nerve conduction. Muscle Nerve 55: 664-668, 2017.

Orally Active Epoxyeicosatrienoic Acid Analogs.

Biologically active epoxyeicosatrienoic acid (EET) regioisomers are synthesized from arachidonic acid by cytochrome P450 epoxygenases of endothelial, myocardial, and renal tubular cells. EETs relax vascular smooth muscle and decrease inflammatory cell adhesion and cytokine release. Renal EETs promote sodium excretion and vasodilation to decrease hypertension. Cardiac EETs reduce infarct size after ischemia-reperfusion injury and decrease fibrosis and inflammation in heart failure. In diabetes, EETs improve insulin sensitivity, increase glucose tolerance, and reduce the renal injury. These actions of EETs emphasize their therapeutic potential. To minimize metabolic inactivation, 14,15-EET agonist analogs with stable epoxide bioisosteres and carboxyl surrogates were developed. In preclinical rat models, a subset of agonist analogs, termed EET-A, EET-B, and EET-C22, are orally active with good pharmacokinetic properties. These orally active EET agonists lower blood pressure and reduce cardiac and renal injury in spontaneous and angiotensin hypertension. Other beneficial cardiovascular actions include improved endothelial function and cardiac antiremodeling actions. In rats, EET analogs effectively combat acute and chronic kidney disease including drug- and radiation-induced kidney damage, hypertension and cardiorenal syndrome kidney damage, and metabolic syndrome and diabetes nephropathy. The compelling preclinical efficacy supports the prospect of advancing EET analogs to human clinical trials for kidney and cardiovascular diseases.

Evaluation of athletes with complex congenital heart disease.

As a result of improvements in congenital heart surgery, there are more adults alive today with congenital heart disease (CHD) than children. Individuals with cardiac birth defects may be able to participate in physical activities but require proper cardiovascular evaluation. The American Heart Association and American College of Cardiology released guidelines in 2015 for athletes with cardiovascular abnormalities. The guidelines express that although restriction from competitive athletics may be indicated for some, the majority of individuals with CHD can and should engage in some form of physical activity. This case study demonstrates the importance of combining all aspects of history, physical examination, ECG, and imaging modalities to evaluate cardiac anatomy and function in young athletes with complex CHD.