Publications by authors named "Oonagh Dowling"

20 Publications

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Single dose perioperative intrathecal ketamine as an adjuvant to intrathecal bupivacaine: A systematic review and meta-analysis of adult human randomized controlled trials.

J Clin Anesth 2021 Oct 5;73:110331. Epub 2021 May 5.

Zucker School of Medicine at Hofstra/Northwell, Department of Anesthesiology, Northwell Health, New Hyde Park, NY, United States of America.

Study Objective: To identify whether adding intrathecal ketamine to intrathecal bupivacaine prolongs the time to first analgesic request in adult humans.

Design: A meta-analysis of randomized controlled trials in humans.

Setting: The majority of data was obtained in an operating room and postoperative recovery area.

Patients: A total of 750 ASA physical status I and II patients were included in the study. Procedures performed include: cesarean section, lower abdominal surgery, lower limb surgery, and urologic surgery.

Interventions: Databases including PubMed, Embase, Web of Science, and Cochrane were searched. Google Scholar was also queried. Multiple reviewers screened the papers for inclusion.

Measurements: The primary outcome assessed was time to first analgesic request. Secondary outcomes included onset of sensory blockade, onset of motor blockade, duration of sensory blockade, and duration of motor blockade. Data were extracted to include means, 95% confidence intervals, tests for heterogeneity, and use of the Cochrane Collaboration guidelines to assess for publication bias.

Main Results: Eleven randomized controlled trials met inclusion criteria. When comparing intrathecal bupivacaine plus ketamine to intrathecal bupivacaine alone, the time to first analgesic request was prolonged (effect size = 58.23 min (95% CI 37.36 to 79.10) p < 0.0001). Secondary outcomes showed the onset time of sensory blockade was shortened (effect size = -0.87 min (95% CI -1.361 to 0.378) p = 0.0005), the onset time of motor blockade was reduced (effect size = -0.88 min (95% CI -1.77 to 0.013) p = 0.05), the duration of sensory blockade was prolonged (effect size = 39.73 min (95% CI 15.97 to 63.50) p = 0.001), and the duration of motor blockade was prolonged (effect size = 4.02 min (95% CI 3.27 to 4.78) p < 0.0001). Studies were shown to have high heterogeneity. Egger tests for all outcomes were non-significant and funnel plots assessing publication bias were all asymmetrical.

Conclusions: The studies analyzed suggest there may be a benefit to using intrathecal ketamine as an adjunct to bupivacaine. Additional studies are warranted to optimize dosing, clarify the safety and efficacy of this intrathecal drug combination, and examine the various ketamine formulations as intrathecal bupivacaine adjuvants.
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http://dx.doi.org/10.1016/j.jclinane.2021.110331DOI Listing
October 2021

Periarticular Knee Injection With Liposomal Bupivacaine and Continuous Femoral Nerve Block for Postoperative Pain Management After Total Knee Arthroplasty: A Randomized Controlled Trial.

J Arthroplasty 2019 03 23;34(3):495-500. Epub 2018 Nov 23.

Department of Anesthesiology, Trident Anesthesiology Group, Charleston, SC.

Background: Local periarticular infiltration (PAI) analgesia has emerged as an important component of multimodal approaches to treat total knee arthroplasty postoperative pain. Liposomal bupivacaine may provide prolonged analgesic duration when injected into the surrounding tissues. The purpose of this study was to compare the analgesic efficacy and serum bupivacaine levels of a continuous femoral nerve block (CFNB) with bupivacaine to PAI with liposomal bupivacaine.

Methods: Sixty-five patients undergoing primary unilateral total knee arthroplasty were randomized into 2 groups: (1) CFNB and PAI with bupivacaine (CFNB group) or (2) PAI with bupivacaine:liposomal bupivacaine mixture at the end of surgery (LB group). The primary outcome was pain intensity at maximum knee flexion 24 hours following surgery. Secondary outcomes included pain intensities at rest and movement at timed intervals and serum bupivacaine levels.

Results: Patients in the CFNB group experienced lower pain scores at maximum knee flexion at 24 hours (7.91; 95% confidence interval, 7.19-8.61) compared to the LB group (8.95; 95% confidence interval, 8.42-9.48; P = .02). The mean peak serum bupivacaine level in the LB group up to 72 hours was 0.55 μg/mL versus 1.4 μg/mL for CFNB group (P = .0008) with one patient in the CFNB group exceeding the reported minimum serum bupivacaine threshold for toxicity.

Conclusion: While similar pain control was observed on the day of surgery for both groups, patients with a CFNB experienced lower pain intensities during maximum knee flexion at 24 hours. Total serum concentrations in LB group remained below the toxicity threshold over the study period.
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http://dx.doi.org/10.1016/j.arth.2018.11.025DOI Listing
March 2019

Remote Video Auditing to Verify OR Cleaning: A Quality Improvement Project.

AORN J 2018 12;108(6):634-642

There are many sources of contamination in the perioperative environment. Patient experience can be negatively affected by the presence of environmental contamination, especially if it is the cause of a surgical site infection. Perioperative and environmental services staff members and leaders are tasked with ensuring a clean and safe environment for their patients while maintaining an awareness of time and budgetary constraints. In addition, leaders are responsible for the competency of their staff members and must address performance issues when needed. New technological advances designed to streamline monitoring and reporting processes related to OR cleanliness are available for use. This article describes the quality improvement project that one multifacility organization completed related to the use of remote video auditing and the positive effect it had on the organization's environmental contamination.
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http://dx.doi.org/10.1002/aorn.12426DOI Listing
December 2018

Smoking and alcohol drinking effect on radiotherapy associated risk of second primary cancer and mortality among breast cancer patients.

Cancer Epidemiol 2018 12 22;57:97-103. Epub 2018 Oct 22.

Department of Occupational Medicine, Epidemiology and Prevention, Feinstein Institute for Medical Research, Northwell Health, Great Neck, NY, USA; Hofstra School of Medicine, Northwell Health, Hempstead, NY, USA. Electronic address:

Background: Smoking and alcohol consumption are potential risk factors for breast cancer (BC) and may modify the risk of radiotherapy-associated second primary cancer (SPC) occurrence and total mortality. We explored the joint effect of smoking, or alcohol drinking, and radiotherapy on the risk of SPC and overall mortality among BC survivals.

Methods: We conducted a cancer registry-based study of 10,676 BC cases (stage 0-III) with data on smoking and alcohol consumption at time of diagnosis and clinical and therapeutics characteristics. Multivariable Cox proportional hazard models were used to estimate Hazard Ratios [HRs] and 95% confidence interval [CI] of total and site-specific SPC and mortality adjusting for demographic and cancer related characteristics.

Results: The SPC risk associated with radiotherapy was higher among ever-smokers than never-smokers (p for interaction = 0.04). Compared to never-smokers/unirradiated, the adjusted HR for ever-smokers/irradiated was 1.79 (95%CI, 1.43-2.23), and for never-smokers/irradiated was 1.31 (95%CI, 1.06-1.63). Analysis by cancer site showed that for ever-smokers/irradiated the risk for hematological, gastrointestinal, gynecological urological and lung/pulmonary cancer was significantly increased by two to five-fold. Mortality was significantly higher for ever-smokers/irradiated (HR = 1.25; 95%CI, 1.06-1.47), but was lower for never-smokers/irradiated (HR = 0.85; 95%CI, 0.73-0.99). Alcohol consumption did not alter the association between radiotherapy and SPC risk, but was associated with lower mortality risk.

Conclusion: Patients who received radiotherapy and smoked before or at time of BC diagnosis have an increased risk for specific SPCs; drinking alcohol did not alter the effect of radiotherapy. Smoking significantly increased mortality risk reducing the protective effect of radiotherapy treatment.
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http://dx.doi.org/10.1016/j.canep.2018.10.002DOI Listing
December 2018

Position change during colonoscopy improves caecal intubation rate, mucosal visibility, and adenoma detection in patients with suboptimal caecal preparation.

Prz Gastroenterol 2017 14;12(4):296-302. Epub 2017 Dec 14.

Department of Gastroenterology, Metrowell Health Center, NY, USA.

Introduction: Most colonoscopies are completed in the left lateral (LL) position but in cases of suboptimal caecal preparation, changing the patient's position to supine (S) and, if needed, to right lateral (RL) improves caecal intubation rate, mucosal visibility, and adenoma detection.

Aim: To determine if position change during colonoscopy facilitates optimal visualisation of the caecum.

Material And Methods: A total of 359 patients were grouped into three categories based on the initial caecal intubation position. After caecal intubation, caecal visibility was scored on a four-point scale depending on the number of imaginary quadrants of the caecum completely visualized - Arya Caecal Prep Score. A score of 1 or 2 was unsatisfactory, while 3 or 4 was considered satisfactory. In patients with unsatisfactory score, position was changed from LL to S and then RL and visibility was scored again.

Results: The initial caecal intubation in the LL position was achieved in 66.8% of patients, S in 28.5%, and RL in 4.8% of patients. 84.5% (300/355) of patients had an acceptable visualisation score at the initial caecal intubation position. Of the 55 patients with unsatisfactory caecum visualisation scores in the initial intubation position, 30 (8.5%) had satisfactory scores after the first position change (95% CI: 5.77-11.84). Twenty-five (7.04%) subjects required two position changes (95% CI: 4.61-10.22%). An additional 9.3% (11/118) of adenomas were detected in caecum and ascending colon following position change.

Conclusions: Changing patient position improves caecal intubation rate, mucosal visibility, and adenoma detection.
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http://dx.doi.org/10.5114/pg.2017.72106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771455PMC
December 2017

Implementation of remote video auditing with feedback and compliance for manual-cleaning protocols of endoscopic retrograde cholangiopancreatography endoscopes.

Am J Infect Control 2018 05 28;46(5):594-596. Epub 2017 Nov 28.

Administration, Long Island Jewish Medical Center at Forest Hills Hospital, Northwell Health, Forest Hills, NY.

A pilot initiative to assess the use of remote video auditing in monitoring compliance with manual-cleaning protocols for endoscopic retrograde cholangiopancreatography (ERCP) endoscopes was performed. Compliance with manual-cleaning steps following the initiation of feedback was measured. A video feed of the ERCP reprocessing room was provided to remote auditors who scored items of an ERCP endoscope manual-cleaning checklist. Compliance feedback was provided in the form of reports and reeducation. Outcomes were reported as checklist compliance. The use of remote video auditing to document manual processing is a feasible approach and feedback and reeducation increased manual-cleaning compliance from 53.1% (95% confidence interval, 34.7-71.6) to 98.9% (95.0% confidence interval, 98.1-99.6).
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http://dx.doi.org/10.1016/j.ajic.2017.10.007DOI Listing
May 2018

Inpatient Choledocholithiasis Requiring ERCP and Cholecystectomy: Outcomes of a Combined Single Inpatient Procedure Versus Separate-Session Procedures.

J Gastrointest Surg 2018 03 2;22(3):451-459. Epub 2017 Oct 2.

Hofstra Northwell School of Medicine, Northwell Health System, Division of Gastroenterology, Department of Medicine, Long Island Jewish Medical Center, 270-05 76th Avenue, New Hyde Park, NY, 11040, USA.

Objectives: Separate-session endoscopic retrograde cholangiography (ERCP) and laparoscopic cholecystectomy (LC) is the usual method for management of inpatient choledocholithiasis. Our goal was to compare single operative-session LC and ERCP to a multi-session approach for both the same hospitalization and within 30 days after; there is limited data comparing the three groups.

Methods: A retrospective review on inpatients with choledocholithiasis that underwent ERCP and LC was performed. Single operative-session ERCP + LC (SOS group) and separate hospitalization ERCP + LC (DH group) were compared against the control cohort: separate-session ERCP + LC performed during the same hospitalization (SH group).

Results: Among the 214 cases, 37 (17%) had LC + ERCP performed under a single operative session (SOS), 130 (60.7%) cases had LC + ERCP performed in separate operative sessions during the same hospitalization (SH), and 47 (22%) cases had LC + ERCP performed in different hospitalizations, within 30 days (DH). There was no statistically significant difference in efficacy or adverse events. The SOS group had a statistically significant mean shorter length of hospital stay as compared to the SH and DH groups (5.46 vs 7.15 vs 9.38; p = 0.05 and 0.02). There was a statistically significant reduction in the total cost of care in the SOS group versus the SH group ($59,221 vs $75, 808; p = 0.007).

Conclusion: The SOS approach is safe, efficacious, and cost-efficient when compared to separate operative sessions. This approach can be considered in situations where it is preferable for the patient to undergo a single session of anesthesia, without compromising technical success and safety.
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http://dx.doi.org/10.1007/s11605-017-3588-6DOI Listing
March 2018

Massive hemoptysis during general endotracheal anesthesia in adults with Cystic Fibrosis.

J Clin Anesth 2017 11 30;42:17-18. Epub 2017 Aug 30.

Hofstra Northwell School of Medicine, Long Island Jewish Medical Center, Department of Anesthesiology, 270-05 76th Ave., New Hyde Park, NY 11040, United States. Electronic address:

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http://dx.doi.org/10.1016/j.jclinane.2017.08.007DOI Listing
November 2017

Response to: 'Statistical analysis of differences in turnover times among operating theatres' by Dexter.

BMJ Qual Saf 2016 09 19;25:e4. Epub 2016 Sep 19.

Department of Anaesthesiology, Hofstra North Shore-LIJ, New Hyde Park, New York, USA.

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http://dx.doi.org/10.1136/bmjqs-2016-005271DOI Listing
September 2016

Association of Opioids and Sedatives with Increased Risk of In-Hospital Cardiopulmonary Arrest from an Administrative Database.

PLoS One 2016 25;11(2):e0150214. Epub 2016 Feb 25.

Department of Anesthesiology, Stony Brook University (SUNY), Stony Brook, NY, United States of America.

Background: While opioid use confers a known risk for respiratory depression, the incremental risk of in-hospital cardiopulmonary arrest, respiratory arrest, or cardiopulmonary resuscitation (CPRA) has not been studied. Our aim was to investigate the prevalence, outcomes, and risk profile of in-hospital CPRA for patients receiving opioids and medications with central nervous system sedating side effects (sedatives).

Methods: A retrospective analysis of adult inpatient discharges from 2008-2012 reported in the Premier Database. Patients were grouped into four mutually exclusive categories: (1) opioids and sedatives, (2) opioids only, (3) sedatives only, and (4) neither opioids nor sedatives.

Results: Among 21,276,691 inpatient discharges, 53% received opioids with or without sedatives. A total of 96,554 patients suffered CPRA (0.92 per 1000 hospital bed-days). Patients who received opioids and sedatives had an adjusted odds ratio for CPRA of 3.47 (95% CI: 3.40-3.54; p<0.0001) compared with patients not receiving opioids or sedatives. Opioids alone and sedatives alone were associated with a 1.81-fold and a 1.82-fold (p<0.0001 for both) increase in the odds of CPRA, respectively. In opioid patients, locations of CPRA were intensive care (54%), general care floor (25%), and stepdown units (15%). Only 42% of patients survived CPRA and only 22% were discharged home. Opioid patients with CPRA had mean increased hospital lengths of stay of 7.57 days and mean increased total hospital costs of $27,569.

Conclusions: Opioids and sedatives are independent and additive risk factors for in-hospital CPRA. The impact of opioid sparing analgesia, reduced sedative use, and better monitoring on CPRA incidence deserves further study.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0150214PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767404PMC
August 2016

Remote video auditing with real-time feedback in an academic surgical suite improves safety and efficiency metrics: a cluster randomised study.

BMJ Qual Saf 2016 12 11;25(12):947-953. Epub 2015 Dec 11.

Department of Anesthesiology, Hofstra North Shore-LIJ School of Medicine, Long Island Jewish Medical Center, New Hyde Park, New York, USA.

Importance: Compliance with the surgical safety checklist during operative procedures has been shown to reduce inhospital mortality and complications but proper execution by the surgical team remains elusive.

Objective: We evaluated the impact of remote video auditing with real-time provider feedback on checklist compliance during sign-in, time-out and sign-out and case turnover times.

Design, Setting: Prospective, cluster randomised study in a 23-operating room (OR) suite.

Participants: Surgeons, anaesthesia providers, nurses and support staff.

Exposure: ORs were randomised to receive, or not receive, real-time feedback on safety checklist compliance and efficiency metrics via display boards and text messages, followed by a period during which all ORs received feedback.

Main Outcomes And Measures: Checklist compliance (Pass/Fail) during sign-in, time-out and sign-out demonstrated by (1) use of checklist, (2) team attentiveness, (3) required duration, (4) proper sequence and duration of case turnover times.

Results: Sign-in, time-out and sign-out PASS rates increased from 25%, 16% and 32% during baseline phase (n=1886) to 64%, 84% and 68% for feedback ORs versus 40%, 77% and 51% for no-feedback ORs (p<0.004) during the intervention phase (n=2693). Pass rates were 91%, 95% and 84% during the all-feedback phase (n=2001). For scheduled cases (n=1406, 71%), feedback reduced mean turnover times by 14% (41.4 min vs 48.1 min, p<0.004), and the improvement was sustained during the all-feedback period. Feedback had no effect on turnover time for unscheduled cases (n=587, 29%).

Conclusions And Relevance: Our data indicate that remote video auditing with feedback improves surgical safety checklist compliance for all cases, and turnover time for scheduled cases, but not for unscheduled cases.
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http://dx.doi.org/10.1136/bmjqs-2015-004226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5256234PMC
December 2016

Nicotinic acetylcholine receptor agonists attenuate septic acute kidney injury in mice by suppressing inflammation and proteasome activity.

PLoS One 2012 7;7(5):e35361. Epub 2012 May 7.

The Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, New York, USA.

Sepsis is one of the leading causes of acute kidney injury (AKI). Septic patients who develop acute kidney injury (AKI) are at increased risk of death. To date there is no effective treatment for AKI or septic AKI. Based on their anti-inflammatory properties, we examined the effects of nicotinic acetylcholine receptor agonists on renal damage using a mouse model of lipopolysaccharide (LPS)-induced AKI where localized LPS promotes inflammation-mediated kidney damage. Administration of nicotine (1 mg/kg) or GTS-21 (4 mg/kg) significantly abrogated renal leukocyte infiltration (by 40%) and attenuated kidney injury. These renoprotective effects were accompanied by reduced systemic and localized kidney inflammation during LPS-induced AKI. Consistent with these observations, nicotinic agonist treatment significantly decreased renal IκBα degradation and NFκB activation during LPS-induced AKI. Treatment of human kidney cells with nicotinic agonists, an NFκB inhibitor (Bay11), or a proteasome inhibitor (MG132) effectively inhibited their inflammatory responses following stimulation with LPS or TNFα. Renal proteasome activity, a major regulator of NFκB-mediated inflammation, was enhanced by approximately 50% during LPS-induced AKI and elevated proteasome activity was significantly blunted by nicotinic agonist administration in vivo. Taken together, our results identify enhanced renal proteasome activity during LPS-induced AKI and the suppression of both proteasome activity and inflammation by nicotinic agonists to attenuate LPS-induced kidney injury.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0035361PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3346807PMC
September 2012

Magnesium sulfate ameliorates maternal and fetal inflammation in a rat model of maternal infection.

Am J Obstet Gynecol 2011 Apr 26;204(4):364.e1-8. Epub 2011 Jan 26.

Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, NY, USA.

Objective: Magnesium sulfate is proposed to have neuroprotective effects in the offspring. We examined the effects of maternal magnesium sulfate administration on maternal and fetal inflammatory responses in a rat model of maternal infection.

Study Design: Pregnant rats were injected with saline, Gram-negative bacterial endotoxin lipopolysaccharide or lipopolysaccharide with magnesium sulfate (pre- and/or after lipopolysaccharide) to mimic infection. Maternal blood, amniotic fluid, fetal blood, and fetal brains were collected 4 hours after lipopolysaccharide and assayed for tumor necrosis factor, interleukin-6, monocyte chemoattractant protein-1, and growth-related oncogene-KC. In addition, the effect of magnesium sulfate on cytokine production by an astrocytoma cell line was assessed.

Results: Lipopolysaccharide administration induced tumor necrosis factor, interleukin-6, monocyte chemoattractant protein-1, and growth-related oncogene-KC expression in maternal and fetal compartments. Maternal magnesium sulfate treatment significantly attenuated lipopolysaccharide-induced multiple proinflammatory mediator levels in maternal and fetal compartments.

Conclusion: Antenatal magnesium sulfate administration significantly ameliorated maternal, fetal, and gestational tissue-associated inflammatory responses in an experimental model of maternal infection.
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http://dx.doi.org/10.1016/j.ajog.2010.11.006DOI Listing
April 2011

Ion-exchange chromatography: basic principles and application to the partial purification of soluble mammalian prolyl oligopeptidase.

Methods Mol Biol 2011 ;681:215-28

School of Biotechnology, Dublin City University, Dublin, Ireland.

Ion-exchange chromatography (IEC) allows for the separation of ionizable molecules on the basis of differences in charge properties. Its large sample-handling capacity, broad applicability (particularly to proteins and enzymes), moderate cost, powerful resolving ability, and ease of scale-up and automation have led to it becoming one of the most versatile and widely used of all liquid chromatography (LC) techniques. In this chapter, we review the basic principles of IEC, as well as the broader criteria for selecting IEC conditions. By way of further illustration, we outline protocols necessary to partially purify a serine peptidase from bovine whole brain cytosolic fraction, covering crude tissue extract preparation through to partial purification of the target enzyme using anion-exchange chromatography. Protocols for assaying total protein and enzyme activity in both pre- and post-IEC fractions are also described. The target serine peptidase, prolyl oligopeptidase (POP, EC3.4.21.26), is an 80-kDa enzyme with endopeptidase activity towards peptide substrates of ≤30 amino acids. POP is a ubiquitous post-proline cleaving enzyme with particularly high expression levels in the mammalian brain, where it participates in the metabolism of neuroactive peptides and peptide-like hormones (e.g. thyroliberin, gonadotropin-releasing hormone).
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http://dx.doi.org/10.1007/978-1-60761-913-0_12DOI Listing
February 2011

Progesterone suppresses the fetal inflammatory response ex vivo.

Am J Obstet Gynecol 2009 Aug;201(2):211.e1-9

Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY, USA.

Objective: Progesterone supplementation has been shown to be efficacious in preventing preterm birth. We sought to investigate the effects of progesterone on fetal inflammatory responses.

Study Design: Fetal mononuclear cells were isolated from umbilical cord blood and exposed to vehicle or progesterone (P4) for 1 hour prior to lipopolysaccharide (LPS) stimulation. Supernatants were assayed for tumor necrosis factor-alpha. Similar experiments were performed using cyclic adenosine monophosphate (cAMP) and progesterone modulators. The effect of P4 treatment on intracellular cAMP levels was also determined.

Results: LPS treatment led to a significant increase in cytokine production by fetal mononuclear cells. Despite the lack of detectable nuclear progesterone receptors, P4 suppressed this inflammatory response. R5020 (progesterone agonist), forskolin (cAMP inducer), and dibutyryl cAMP (cAMP agonist) all achieved immunosuppression. The cAMP antagonist, Rp-cAMP, blocked the inhibitory effect of progesterone. P4 significantly increased intracellular cAMP levels.

Conclusion: Progesterone rapidly suppresses the fetal inflammatory response, possibly via nongenomic activation of the cAMP cascade.
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http://dx.doi.org/10.1016/j.ajog.2009.05.012DOI Listing
August 2009

Cholinergic neural signals to the spleen down-regulate leukocyte trafficking via CD11b.

J Immunol 2009 Jul;183(1):552-9

The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.

The cholinergic anti-inflammatory pathway is a physiological mechanism that inhibits cytokine production and diminishes tissue injury during inflammation. Recent studies demonstrate that cholinergic signaling reduces adhesion molecule expression and chemokine production by endothelial cells and suppresses leukocyte migration during inflammation. It is unclear how vagus nerve stimulation regulates leukocyte trafficking because the vagus nerve does not innervate endothelial cells. Using mouse models of leukocyte trafficking, we show that the spleen, which is a major point of control for cholinergic modulation of cytokine production, is essential for vagus nerve-mediated regulation of neutrophil activation and migration. Administration of nicotine, a pharmacologic agonist of the cholinergic anti-inflammatory pathway, significantly reduces levels of CD11b, a beta(2)-integrin involved in cell adhesion and leukocyte chemotaxis, on the surface of neutrophils in a dose-dependent manner and this function requires the spleen. Similarly, vagus nerve stimulation significantly attenuates neutrophil surface CD11b levels only in the presence of an intact and innervated spleen. Further mechanistic studies reveal that nicotine suppresses F-actin polymerization, the rate-limiting step for CD11b surface expression. These studies demonstrate that modulation of leukocyte trafficking via cholinergic signaling to the spleen is a specific, centralized neural pathway positioned to suppress the excessive accumulation of neutrophils at inflammatory sites. Activating this mechanism may have important therapeutic potential for preventing tissue injury during inflammation.
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http://dx.doi.org/10.4049/jimmunol.0802684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806576PMC
July 2009

Nicotine inhibits cytokine production by placenta cells via NFkappaB: potential role in pregnancy-induced hypertension.

Mol Med 2007 Nov-Dec;13(11-12):576-83

The Susan and Herman Merinoff Center for Patient-Oriented Research, The Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, NY 11030, USA.

Pregnancy-induced hypertension (PIH), also known as preeclampsia, is one of the major causes of maternal and fetal death. While the precise cause of PIH is not known, aberrant cytokine production and placenta participation are considered to be important factors. Gestational cigarette smoking, which is widely accepted to be harmful to both the mother and fetus, is protective against PIH. Based on the antiinflammatory activity of nicotine, the major component of cigarettes, we examined the effect of nicotine and other cholinergic agonists on placental inflammatory responses ex vivo. We observed that nicotine and other cholinergic agonists significantly suppress placenta cytokine production following stimulation. Placenta cells express the alpha7 nicotinic acetylcholine receptor (alpha7nAChR), and using cholinergic antagonists, we demonstrated that the antiinflammatory effect of nicotine and other cholinergic agonists is, in part, mediated through the nAChR pathway. By contrast, cholinergic stimulation had no effect on the expression of soluble fms-like tyrosine kinase (sFlt), an antiangiogenic substance implicated in maternal vascular dysfunction during PIH. Mechanistic studies reveal that cholinergic agonists exert their antiinflammatory effects through the NFkappaB pathway. Taken together, our results suggest that cholinergic agonists, including nicotine, may reduce cytokine production by placenta cells via NFkappaB to protect against PIH.
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http://dx.doi.org/10.2119/2007-00067.DowlingDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1978252PMC
February 2008

Loss of MMP-2 disrupts skeletal and craniofacial development and results in decreased bone mineralization, joint erosion and defects in osteoblast and osteoclast growth.

Hum Mol Genet 2007 May 30;16(9):1113-23. Epub 2007 Mar 30.

Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.

The 'vanishing bone' or inherited osteolysis/arthritis syndromes represent a heterogeneous group of skeletal disorders characterized by mineralization defects of affected bones and joints. Differing in anatomical distribution, severity and associated syndromic features, gene identification in each 'vanishing bone' disorder should provide unique insights into genetic/molecular pathways contributing to the overall control of skeletal growth and development. We previously described and then demonstrated that the novel autosomal recessive osteolysis/arthritis syndrome, multicentric osteolysis with arthritis (MOA) (MIM #605156), was caused by inactivating mutations in the MMP2 gene [Al Aqeel, A., Al Sewairi, W., Edress, B., Gorlin, R.J., Desnick, R.J. and Martignetti, J.A. (2000) Inherited multicentric osteolysis with arthritis: A variant resembling Torg syndrome in a Saudi family. Am. J. Med. Genet., 93, 11-18.]. These in vivo results were counterintuitive and unexpected since previous in vitro studies suggested that MMP-2 overexpression and increased activity, not deficiency, would result in the bone and joint features of MOA. The apparent lack of a murine model [Itoh, T., Ikeda, T., Gomi, H., Nakao, S., Suzuki, T. and Itohara, S. (1997) Unaltered secretion of beta-amyloid precursor protein in gelatinase A (matrix metalloproteinase 2)-deficient mice. J. Biol. Chem., 272, 22389-22392.] has hindered studies on disease pathogenesis and, more fundamentally, in addressing the paradox of how functional loss of a single proteolytic enzyme results in an apparent increase in bone loss. Here, we report that Mmp2-/- mice display attenuated features of human MOA including progressive loss of bone mineral density, articular cartilage destruction and abnormal long bone and craniofacial development. Moreover, these changes are associated with markedly and developmentally restricted decreases in osteoblast and osteoclast numbers in vivo. Mmp2-/- mice have approximately 50% fewer osteoblasts and osteoclasts than control littermates at 4 days of life but these differences have nearly resolved by 4 weeks of age. In addition, despite normal cell numbers in vivo at 8 weeks of life, Mmp2-/- bone marrow cells are unable to effectively support osteoblast and osteoclast growth and differentiation in culture. Targeted inhibition of MMP-2 using siRNA in human SaOS2 and murine MC3T3 osteoblast cell lines resulted in decreased cell proliferation rates. Taken together, our findings suggest that MMP-2 plays a direct role in early skeletal development and bone cell growth and proliferation. Thus, Mmp2-/- mice provide a valuable biological resource for studying the pathophysiological mechanisms underlying the human disease and defining the in vivo physiological role of MMP-2.
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http://dx.doi.org/10.1093/hmg/ddm060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2576517PMC
May 2007

Magnesium sulfate suppresses inflammatory responses by human umbilical vein endothelial cells (HuVECs) through the NFkappaB pathway.

J Reprod Immunol 2007 Apr 6;73(2):101-107. Epub 2006 Sep 6.

The Susan & Herman Merinoff Center for Patient Oriented Research, The Feinstein Institute for Medical Research North Shore-LIJ Health System, 350 Community Drive, Manhasset, NY 11030, USA. Electronic address:

Dysfunctional endothelial cell activation and cytokines are implicated in preterm labor, a condition commonly treated with the tocolytic agent, magnesium sulfate (MgSO(4)). Based on recent findings showing the inflammatory effects of magnesium deficiency, we examined the effect of MgSO(4) on human umbilical vein endothelial cell (HuVEC) inflammatory responses in vitro. HuVECs isolated from term umbilical cords were incubated with MgSO(4) prior to stimulation with lipopolysaccharide (LPS) and then assessed for endothelial cell activation. Endothelial cell supernatants were assayed for inflammatory mediator production (interleukin-8; IL-8), and endothelial cell-associated intercellular adhesion molecule (ICAM-1) expression was determined. In the absence of LPS stimulation, MgSO(4) had no effect on HuVEC responses. Treatment of HuVECs with MgSO(4) prior to LPS stimulation inhibited inflammatory mediator production (p<0.05) and cell adhesion molecule expression (p<0.05) in a dose-dependent manner. Mechanistic studies showed that MgSO(4) reduced NFkappaB nuclear translocation and protected cytoplasmic IkappaBalpha from degradation in LPS-treated HuVECs. In conclusion, MgSO(4) inhibits endothelial cell activation, as measured by levels of IL-8 and ICAM-1 expression, via NFkappaB. Our results support the hypothesis that MgSO(4) treatment may function as an anti-inflammatory agent during preterm labor.
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http://dx.doi.org/10.1016/j.jri.2006.06.004DOI Listing
April 2007

Mutations in capillary morphogenesis gene-2 result in the allelic disorders juvenile hyaline fibromatosis and infantile systemic hyalinosis.

Am J Hum Genet 2003 Oct 12;73(4):957-66. Epub 2003 Sep 12.

Department of Human Genetics, Mount Sinai School of Medicine, New York, NY 10029, USA.

Juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH) are autosomal recessive syndromes of unknown etiology characterized by multiple, recurring subcutaneous tumors, gingival hypertrophy, joint contractures, osteolysis, and osteoporosis. Both are believed to be allelic disorders; ISH is distinguished from JHF by its more severe phenotype, which includes hyaline deposits in multiple organs, recurrent infections, and death within the first 2 years of life. Using the previously reported chromosome 4q21 JHF disease locus as a guide for candidate-gene identification, we identified and characterized JHF and ISH disease-causing mutations in the capillary morphogenesis factor-2 gene (CMG2). Although CMG2 encodes a protein upregulated in endothelial cells during capillary formation and was recently shown to function as an anthrax-toxin receptor, its physiologic role is unclear. Two ISH family-specific truncating mutations, E220X and the 1-bp insertion P357insC that results in translation of an out-of-frame stop codon, were generated by site-directed mutagenesis and were shown to delete the CMG-2 transmembrane and/or cytosolic domains, respectively. An ISH compound mutation, I189T, is predicted to create a novel and destabilizing internal cavity within the protein. The JHF family-specific homoallelic missense mutation G105D destabilizes a von Willebrand factor A extracellular domain alpha-helix, whereas the other mutation, L329R, occurs within the transmembrane domain of the protein. Finally, and possibly providing insight into the pathophysiology of these diseases, analysis of fibroblasts derived from patients with JHF or ISH suggests that CMG2 mutations abrogate normal cell interactions with the extracellular matrix.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1180616PMC
http://dx.doi.org/10.1086/378781DOI Listing
October 2003