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Introduction Preterm babies increasingly survive the neonatal period as a result of advanced care practices. Accordingly, anesthesiologists are likely to encounter these patients with greater frequency. Ex-premature infants and term neonates are known to have an increased risk of post-operative apneas following surgery and anaesthesia. Methods Following approval from the Institutional Review Board, we performed a retrospective chart review of neonates 0-28 days of age who underwent general anaesthesia procedures over two years. Data collected included age days, sex, weight, gestational age, American Society of Anaesthesiologists (ASA) physical status, type of anaesthetic (general/regional/spinal), airway management, surgical procedure, intraoperative adverse events, duration of anaesthesia, medications administered, post-operative recovery location, the occurrence of apneic events, medical co-morbidities, duration of post anaesthesia care unit (PACU) admission, a requirement for neonatal intensive care unit (NICU) admission, and duration of hospital admission. Results A total of 239 charts were reviewed from January 1, 2015, to December 31, 2016. Ninety-five cases were excluded for required postoperative mechanical ventilation. For the remaining 144 cases, the mean age was 12.8 days, 65% male, 35% female, mean gestational age 38.6 weeks, mean post-menstrual age 40.5 weeks, mean ASA status 3.5, and mean weight 3.46 kg. Post-operative apnea was observed in two neonates (1.4%). Risk factors for postoperative apnea included lower gestational age at birth (median 37.5 vs. 39.1 weeks, p=0.26), lower post-menstrual age (median 38.5 vs. 41.0 weeks, p=0.18), and lower weight (median 2.8 vs. 3.5kg, p=0.27), respectively. ASA classification, preoperative anaemia, and known pathology were all significant risk factors for apnea (p<0.05). Significant factors from the bivariate analysis were preoperative anaemia, known pathology, age, duration of anaesthesia, weight, intraoperative fentanyl, and amount of neuromuscular blocker. Age and preoperative anaemia were significant predictors for recovery location. The odds of going to PACU vs NICU/PICU for post-operative recovery were 7.4 times greater for every two weeks greater age (95% CI=(2.80-19.31), p<0.001).  Conclusion This study corroborates previous findings of predictive risk factors for post-anaesthesia apnea in preterm and term neonates. Previously reported risk factors, including low gestational/post-menstrual age, lower weight, and intraoperative narcotic use, were likely contributors to one of the apneic events in our study. A larger sample size is warranted to confirm a valid predictive model. Standardized universal guidelines would be useful in eliminating local variation in PACU monitoring and discharge criteria in this vulnerable age group., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Fanelli et al.)

Septic shock, the most severe complication associated with sepsis, is manifested by tissue hypoperfusion due, in part, to cardiovascular and autonomic dysfunction. In many cases, the splanchnic circulation becomes vasoplegic. The celiac-superior mesenteric ganglion (CSMG) sympathetic neurons provide the main autonomic input to these vessels. We used the cecal ligation puncture (CLP) model, which closely mimics the hemodynamic and metabolic disturbances observed in septic patients, to examine the properties and modulation of Ca2+ channels by G protein-coupled receptors in acutely dissociated rat CSMG neurons. Voltage-clamp studies 48 hr post-sepsis revealed that the Ca2+ current density in CMSG neurons from septic rats was significantly lower than those isolated from sham control rats. This reduction coincided with a significant increase in membrane surface area and a negligible increase in Ca2+ current amplitude. Possible explanations for these findings include either cell swelling or neurite outgrowth enhancement of CSMG neurons from septic rats. Additionally, a significant rightward shift of the concentration-response relationship for the norepinephrine (NE)-mediated Ca2+ current inhibition was observed in CSMG neurons from septic rats. Testing for the presence of opioid receptor subtypes in CSMG neurons, showed that mu opioid receptors were present in ~70% of CSMG, while NOP opioid receptors were found in all CSMG neurons tested. The pharmacological profile for both opioid receptor subtypes was not significantly affected by sepsis. Further, the Ca2+ current modulation by propionate, an agonist for the free fatty acid receptors GPR41 and GPR43, was not altered by sepsis. Overall, our findings suggest that CSMG function is affected by sepsis via changes in cell size and α2-adrenergic receptor-mediated Ca2+ channel modulation.

Background: The endogenous opioid peptide, nociception (Noc), contributes to the regulation of systemic blood pressure and regional blood flow. Recent clinical and animal studies have reported that Noc and its receptor (nociceptin/orphanin FQ [NOP]) are involved in inflammation and sepsis. The purpose of the present study was to examine the modulation of Ca(2+) channels by Noc in acutely isolated stellate ganglion (SG) neurons from control and septic rats., Materials and Methods: Sepsis was induced in male Sprague-Dawley rats via cecal ligation and puncture. SG neurons were isolated 24 and 72 h after sepsis induction. Thereafter, the concentration-response relationships for the Noc-stimulated NOP receptor Ca(2+) current inhibition were determined using the whole-cell patch clamp technique. In addition, the Noc precursor (prepronociceptin [PNOC]) and NOP receptor messenger RNA (mRNA) levels were determined by quantitative real-time polymerase chain reaction, and PNOC protein levels were measured by Western blot analysis., Results: Comparison of the Noc concentration-response relationships in SG neurons from control and septic rats 24 h after sepsis revealed similar potency and efficacy. Moreover, 72 h after sepsis, neurons from control and septic rats exhibited an increased potency compared with both groups at the 24-h time point--an effect that was more pronounced in neurons from septic rats. PNOC mRNA levels were significantly greater in SG neurons isolated from septic rats compared with control neurons, but NOP receptor mRNA levels remained unchanged during the 72-h period., Conclusions: Our study demonstrates the cecal ligation and puncture model-induced temporal upregulation of components within the NOP receptor signaling pathway in rat sympathetic neurons. As SG neurons provide the main sympathetic input to the heart, an increased Noc release and potency during sepsis may compromise cardiovascular function., (Copyright © 2013 Elsevier Inc. All rights reserved.)

A computational methodology based on Metropolis Monte Carlo (MC) and the weighted histogram analysis method (WHAM) has been developed to calculate the absolute binding free energy between functionalized nanocarriers (NC) and endothelial cell (EC) surfaces. The calculated NC binding free energy landscapes yield binding affinities that agree quantitatively when directly compared against analogous measurements of specific antibody-coated NCs (100 nm in diameter) to intracellular adhesion molecule-1 (ICAM-1) expressing EC surface in in vitro cell-culture experiments. The effect of antibody surface coverage (σ(s)) of NC on binding simulations reveals a threshold σ(s) value below which the NC binding affinities reduce drastically and drop lower than that of single anti-ICAM-1 molecule to ICAM-1. The model suggests that the dominant effect of changing σ(s) around the threshold is through a change in multivalent interactions; however, the loss in translational and rotational entropies are also important. Consideration of shear flow and glycocalyx does not alter the computed threshold of antibody surface coverage. The computed trend describing the effect of σ(s) on NC binding agrees remarkably well with experimental results of in vivo targeting of the anti-ICAM-1 coated NCs to pulmonary endothelium in mice. Model results are further validated through close agreement between computed NC rupture-force distribution and measured values in atomic force microscopy (AFM) experiments. The three-way quantitative agreement with AFM, in vitro (cell-culture), and in vivo experiments establishes the mechanical, thermodynamic, and physiological consistency of our model. Hence, our computational protocol represents a quantitative and predictive approach for model-driven design and optimization of functionalized nanocarriers in targeted vascular drug delivery.

An ultrasound-based molecular imaging technique capable of detecting endothelial cell markers of inflammation may allow early, non-invasive assessment of vascular disease. Clinical application of targeted, acoustically-active microbubbles requires optimization of microbubble-endothelial adhesion strength to maximize image signal-to-noise ratio, as well as the ability to discern the degree of inflammation along a continuum of dysfunction. Accordingly, we hypothesized that adhesion of intercellular adhesion molecule-1 (ICAM-1)-targeted microbubbles is dependent on the degree of endothelial inflammation, and that microbubbles multi-targeted to both ICAM-1 (via anti-ICAM-1 antibodies) and selectins (via sialyl Lewisx) demonstrate greater adhesion strength than microbubbles targeted to either inflammatory marker alone. In a radial flow chamber, microbubbles were perfused across endothelial cells activated with interleukin-1beta to four different levels of inflammation, as assessed by quantitative ICAM-1 expression. ICAM-1-targeted microbubble adhesion strength increased with increasing degree of inflammation, with a relationship that was both positive and linear (r > 0.99). Microbubble adhesion strength was significantly higher for the multi-targeted microbubbles than either of the single-targeted microbubbles. These data thus demonstrate that multi-targeting of contrast microbubbles may offer improved adhesion characteristics, allowing for greater sensitivity to inflammation. Furthermore, the adhesion strength of targeted microbubbles is linearly dependent on the degree of inflammation, suggesting that targeted ultrasound imaging may offer differentiation between various degrees of endothelial dysfunction, and thus detect not only the presence, but also the severity of inflammatory disease processes., ((c) 2005 Wiley Periodicals, Inc.)

Endothelial cells (EC) of angiogenic tumor vasculature are characterized by altered expression of molecular markers on their surface. Numerous peptides have been identified that specifically bind tumor angiogenic endothelium, including the tripeptide arginine-arginine-leucine (RRL). We hypothesized that ultrasound contrast microbubbles (MB) targeted via linkage with RRL would specifically adhere to tumor angiogenic endothelium versus normal myocardium, and that this selective adhesion could be detected ultrasonically. Microbubbles were conjugated to cyclic peptides containing either RRL (RRL-MB) or a glycine control sequence (control-MB). As measured in a parallel plate flow chamber, in vitro adhesion of RRL-MBs was three times greater to cultured tumor-derived ECs than to normal ECs (P < 0.01), demonstrating selective binding of RRL-MBs to tumor endothelium. Mice bearing s.c. Clone C or PC3 tumors were given i.v. injections of fluorescent RRL to show in vivo localization to tumor vasculature or were ultrasonically imaged following i.v. injections of targeted contrast MBs. Ultrasound images showed strong RRL-MB contrast enhancement within the tumors but not the control tissue myocardium. Control-MBs caused minimal enhancement in either tissue. Quantitative acoustic videointensity was significantly greater for the tumors than the hearts (5 +/- 1 versus 0.5 +/- 1 intensity units; P = 0.001). These data show that ultrasound contrast MBs targeted to tumor vasculature via RRL preferentially adhere to tumor versus normal vasculature and that this selective adherence can be detected with ultrasound. Targeted microbubbles may thus offer a noninvasive contrast-enhanced ultrasound imaging technique for the functional imaging of tumor neovascularization, and may have further implications for therapeutic tumor targeting.

Background: Noninvasive techniques for detecting acute cardiac transplant rejection are limited. We hypothesized that ultrasound contrast microbubbles targeted to the endothelial cell (EC) inflammatory marker intercellular adhesion molecule-1 (ICAM-1) would selectively bind to rejecting versus nonrejecting myocardium and that myocardial contrast echocardiography can therefore detect acute rejection., Methods and Results: Lipid-based microbubbles were conjugated to anti-rat ICAM-1 (MBICAM) or isotype control antibody (MBControl). In vitro MBICAM adhesion to cultured rat ECs, as assessed in a parallel plate flow apparatus, was greater to inflammatory versus normal ECs (11+/-3 versus 3+/-2 microbubbles/EC, P<0.005). In vivo abdominal heterotopic heart transplantation was performed in rats (rejection group: Brown Norway to Lewis strain; control group: Lewis to Lewis or Brown Norway to Brown Norway). Triggered myocardial contrast echocardiography was performed during intravenous MBICAM or MBControl (2.5x10(6)) injection on postoperative day 5. Myocardial videointensity from adhered MBICAM was significantly higher in rejecting (n=8) versus control (n=7) rats (10+/-4 versus 1+/-4 U, P=0.01). Postmortem histology showed normal myocardium in control rats, whereas allograft myocardium demonstrated grade III to IV rejection and strong immunohistochemical ICAM-1 staining., Conclusions: Preferential adherence of ICAM-1-targeted microbubbles to rejecting versus nonrejecting rat cardiac transplant myocardium can be detected ultrasonically. Targeted microbubbles may thus offer a noninvasive ultrasound imaging technique for the detection of acute cardiac transplant rejection and other processes characterized by endothelial dysfunction.

The early stages of atherosclerosis are characterized by increased endothelial cell (EC) surface expression of leukocyte adhesion molecules (LAMs). Ultrasound detection of acoustically active LAM-targeted microbubbles might provide a means to noninvasively assess the functional status of the endothelium. Toward this end, a lipid-based perfluorobutane-filled microbubble was synthesized with various densities of anti-ICAM-1 monoclonal antibodies conjugated to the bubble shell. We hypothesized that modulating the surface antibody density would permit regulation of the adhesion characteristics of the microbubbles, and that microbubble adhesion would be dependent on local wall shear rate. Coverslips of cultured human coronary artery ECs were exposed to microbubbles with various surface antibody densities (1%, 5%, 10%, 50%, 75%, and 100% of maximum coverage) at various wall shear rates (100, 175, 250, 350, and 500 s-1) in a parallel plate perfusion chamber. ECs were either normal or activated by interleukin-1 beta to overexpress ICAM-1. Adhesion was greater to activated vs. normal ECs (p < 0.001), increased with increasing surface antibody density (p < 0.01), and decreased with increasing wall shear rate (p = 0.02). We conclude that shell antibody density and wall shear rate are critical parameters controlling differential microbubble adhesion. This phenomenon might ultimately permit imaging of clinically relevant LAM expression in vivo.

Objective: We determined the relative value of teleradiology and radiology resident coverage of the emergency department by measuring and comparing the effects of physician specialty, training level, and image display method on accuracy of radiograph interpretation., Materials and Methods: A sample of four faculty emergency medicine physicians, four emergency medicine residents, four faculty radiologists, and four radiology residents participated in our study. Each physician interpreted 120 radiographs, approximately half containing a clinically important index finding. Radiographs were interpreted using the original films and high-resolution digital monitors. Accuracy of radiograph interpretation was measured as the area under the physicians' receiver operating characteristic (ROC) curves., Results: The area under the ROC curve was 0.15 (95% confidence interval [CI], 0.10-0.20) greater for radiologists than for emergency medicine physicians, 0.07 (95% CI, 0.02-0.12) greater for faculty than for residents, and 0.07 (95% CI, 0.02-0.12) greater for films than for video monitors. Using these results, we estimated that teleradiology coverage by faculty radiologists would add 0.09 (95% CI, 0.03-0.15) to the area under the ROC curve for radiograph interpretation by emergency medicine faculty alone, and radiology resident coverage would add 0.08 (95% CI, 0.02-0.14) to this area., Conclusion: We observed significant differences between the interpretation of radiographs on film and on digital monitors. However, we observed differences of equal or greater magnitude associated with the training level and physician specialty of each observer. In evaluating teleradiology services, observer characteristics must be considered in addition to the quality of image display.

Purpose: We have used receiver operating characteristic (ROC) analysis to compare screen assessment of digitized radiographic films transmitted by a teleradiology system, with evaluation of the original radiographs on film., Material and Methods: The material contained 120 cases (about 50% with selected pathology) that were difficult to diagnose. Four radiologists each evaluated half of the cases on film, and half on computer screen. The screen display was 1024 x 836 pixels with 8 bits/pixel., Results: We found the accuracy and sensitivity of the teleradiology system to be clearly inferior to film evaluation., Conclusion: Improvement is needed both in the teleradiology system, and in the training of radiologists to work on the electronic workstation.

Purpose: To compare accuracy of interpretation by radiologists and emergency medicine physicians of conventional radiographs and digitized images on a workstation., Materials and Methods: One author selected 120 radiographs from the radiology department library, including 62 musculoskeletal, 20 abdominal, and 38 chest examinations. Analog radiographs were digitized. There were 60 positive and 60 control cases. Positive cases demonstrated clinically important disease and had a high degree of diagnostic difficulty. Thirty-one cases were judged to be critical to the patient's immediate care, requiring prompt accurate interpretation. Four groups of readers were used: staff radiologists and emergency medicine physicians and second-year radiology and emergency medicine residents., Results: All reader groups performed better when interpreting conventional radiographs than digitized images. Differences in favor of radiograph reading were statistically significant for overall accuracy related to all cases and to critical cases (P < .05, one-tailed test)., Conclusion: Results with the teleradiology system were found unacceptable for primary interpretation of the spectrum of radiographs seen in an emergency department.