Publications by authors named "Nirav B Patel"

24 Publications

  • Page 1 of 1

Are You Ready to Negotiate Your First Employment Contract? Experience of More Than 700 Plastic Surgeons.

Plast Reconstr Surg 2021 Mar;147(3):761-771

From the Division of Plastic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine; the Department of Surgery, Texas Children's Hospital; Marietta Plastic Surgery; and G. Dallas Horton and Associates.

Background: Plastic surgeons have been shown to be unprepared to negotiate their first employment contracts. Previous survey studies have attempted to assess plastic surgeons' first employment contracts to outline common pitfalls in contract negotiation. With this study, the authors aim to expand these previous studies and help plastic surgeons become prepared to negotiate their employment contracts.

Methods: A seven-question, cross-sectional survey was sent to attending-level surgeon members of the California Society of Plastic Surgeons, the American Society of Plastic Surgeons, the Texas Society of Plastic Surgeons, and the American Cleft Palate-Craniofacial Association. Questions investigated plastic surgeons' first contracts. Correlations were determined using a two-sample Wilcoxon rank sum test in an attempt to link these questions with overall satisfaction.

Results: From the 3908 distributed surveys, 782 (20 percent) responses were collected, and 744 were included for analysis. The majority of respondents were found to join a group-centered, private practice following residency. Surprisingly, 69 percent of surgeons did not use attorney assistance when negotiating their contract. Although greater than 70 percent of respondents reported a salary of $200,000 or less, satisfaction with one's contract was most strongly correlated with a salary of greater than $300,000 (p < 0.0001). However, only 12 percent of respondent surgeons were able to secure such a salary.

Conclusions: This study examined the largest, most diverse plastic surgeon cohort to date regarding surgeons' first employment contract. Although the authors' findings indicate that certain factors should be prioritized when approaching a first employment contract, they ultimately recommend that all surgeons take into account their personal priorities and attempt to proactively define their terms of employment before signing a contract.
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http://dx.doi.org/10.1097/PRS.0000000000007685DOI Listing
March 2021

Enhanced Killing of Triple-Negative Breast Cancer Cells by Reassortant Reovirus and Topoisomerase Inhibitors.

J Virol 2019 12 13;93(23). Epub 2019 Nov 13.

Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA

Breast cancer is the second leading cause of cancer-related deaths in women in the United States. Triple-negative breast cancer constitutes a subset of breast cancer that is associated with higher rates of relapse, decreased survival, and limited therapeutic options for patients afflicted with this type of breast cancer. Mammalian orthoreovirus (reovirus) selectively infects and kills transformed cells, and a serotype 3 reovirus is in clinical trials to assess its efficacy as an oncolytic agent against several cancers. It is unclear if reovirus serotypes differentially infect and kill triple-negative breast cancer cells and if reovirus-induced cytotoxicity of breast cancer cells can be enhanced by modulating the activity of host molecules and pathways. Here, we generated reassortant reoviruses by forward genetics with enhanced infective and cytotoxic properties in triple-negative breast cancer cells. From a high-throughput screen of small-molecule inhibitors, we identified topoisomerase inhibitors as a class of drugs that enhance reovirus infectivity and cytotoxicity of triple-negative breast cancer cells. Treatment of triple-negative breast cancer cells with topoisomerase inhibitors activates DNA damage response pathways, and reovirus infection induces robust production of type III, but not type I, interferon (IFN). Although type I and type III IFNs can activate STAT1 and STAT2, triple-negative breast cancer cellular proliferation is only negatively affected by type I IFN. Together, these data show that reassortant viruses with a novel genetic composition generated by forward genetics in combination with topoisomerase inhibitors more efficiently infect and kill triple-negative breast cancer cells. Patients afflicted by triple-negative breast cancer have decreased survival and limited therapeutic options. Reovirus infection results in cell death of a variety of cancers, but it is unknown if different reovirus types lead to triple-negative breast cancer cell death. In this study, we generated two novel reoviruses that more efficiently infect and kill triple-negative breast cancer cells. We show that infection in the presence of DNA-damaging agents enhances infection and triple-negative breast cancer cell killing by reovirus. These data suggest that a combination of a genetically engineered oncolytic reovirus and topoisomerase inhibitors may provide a potent therapeutic option for patients afflicted with triple-negative breast cancer.
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http://dx.doi.org/10.1128/JVI.01411-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854488PMC
December 2019

Ivabradine in Congestive Heart Failure: Patient Selection and Perspectives.

Cureus 2019 Apr 13;11(4):e4448. Epub 2019 Apr 13.

Internal Medicine, Lasante Health, Jersey City, USA.

Heart failure (HF) is the fourth-most frequent cause of death and remains a challenge for public health. Therapy goals for HF with reduced ejection fraction (HFrEF) are the improvement in the quality of life, prolonged survival, a reduction of signs and symptoms, and the prevention of hospitalization. Angiotensin-converting enzyme inhibitors, beta-blockers, and mineralocorticoid receptor antagonists are the treatments of choice for HFrEF. Although ivabradine is not available in all countries, it is likely a new promising approach to improve outcomes in patients with HFrEF, either alone or with beta-blockers. Here, we review the current knowledge about ivabradine in HFrEF and assess its effect on outcomes in HF.
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http://dx.doi.org/10.7759/cureus.4448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561528PMC
April 2019

Outcomes of Desidustat Treatment in People with Anemia and Chronic Kidney Disease: A Phase 2 Study.

Am J Nephrol 2019 21;49(6):470-478. Epub 2019 May 21.

Drug Metabolism and Pharmacokinetic, Cadila Healthcare Ltd., Ahmedabad, India.

Background: Desidustat (ZYAN1) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) that stimulates erythropoiesis. Stabilizing HIF via PHI is developing as a new therapeutic approach to treat anemia secondary to chronic kidney disease (CKD). This trial evaluated the safety, tolerability, and efficacy of Desidustat in adult CKD patients with anemia, who were not on dialysis.

Methods: This was a Phase 2, randomized, double-blind, 6-week, placebo-controlled, dose-ranging, safety and efficacy study. A total of 117 eligible patients were randomized to 4 arms: 100, 150, 200 mg, or placebo. The investigational product was administered every alternate day for 6 weeks in fasting conditions. The primary endpoint was change in hemoglobin (Hb) from baseline to week 6.

Results: Baseline demographics were well balanced among all the treatment arms. In the modified intent-to-treat (mITT) population, a mean Hb increase of 1.57, 2.22, and 2.92 g/dL in Desidustat 100, 150, and 200 mg arms, respectively, was observed post 6 weeks treatment. The responder rate (≥1 g/dL increase) was 66% in 100 mg, 75% in 150 mg, and 83% in 200 mg treatment arms, in the mITT population. Eighteen patients had at least one treatment emergent adverse event (TEAE), and 5 patients reported at least one drug-related mild TEAE. No death or serious adverse event was reported during the trial.

Conclusion: There was dose-related increase in Hb across all doses compared to placebo in mITT and per-protocol populations. Desidustat also increased pharmacokinetic parameters Cmax and AUC in dose-related manner. There was no significant change in vital signs, electrocardiographic parameters, or safety laboratory values. Clinical Trial Registration Number CTRI/2017/05/008534 (registered on May 11, 2017).
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http://dx.doi.org/10.1159/000500232DOI Listing
July 2020

Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance.

Cell 2019 05 9;177(5):1153-1171.e28. Epub 2019 May 9.

Division of Vaccine Discovery, La Jolla Institute for Immunology (LJI), La Jolla, CA 92037, USA; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (Scripps CHAVI-ID), The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA. Electronic address:

Conventional immunization strategies will likely be insufficient for the development of a broadly neutralizing antibody (bnAb) vaccine for HIV or other difficult pathogens because of the immunological hurdles posed, including B cell immunodominance and germinal center (GC) quantity and quality. We found that two independent methods of slow delivery immunization of rhesus monkeys (RMs) resulted in more robust T follicular helper (T) cell responses and GC B cells with improved Env-binding, tracked by longitudinal fine needle aspirates. Improved GCs correlated with the development of >20-fold higher titers of autologous nAbs. Using a new RM genomic immunoglobulin locus reference, we identified differential IgV gene use between immunization modalities. Ab mapping demonstrated targeting of immunodominant non-neutralizing epitopes by conventional bolus-immunized animals, whereas slow delivery-immunized animals targeted a more diverse set of epitopes. Thus, alternative immunization strategies can enhance nAb development by altering GCs and modulating the immunodominance of non-neutralizing epitopes.
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http://dx.doi.org/10.1016/j.cell.2019.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6619430PMC
May 2019

Diagnosis and Management of a Cardiac Amyloidosis Case Mimicking Hypertrophic Cardiomyopathy.

Cureus 2018 Dec 18;10(12):e3749. Epub 2018 Dec 18.

Internal Medicine, American University of Integrative Sciences, Tucker, BRB.

Cardiac amyloidosis is an acquired heart disease secondary to the deposition of β-pleated amyloid proteins in heart tissue. Amyloid light chain (AL) amyloidosis is usually secondary to multiple myeloma and can rapidly deteriorate cardiac function, with high mortality. Up to 50% of AL patients have cardiac involvement presenting as heart failure, conduction abnormalities, and cardiomyopathies. One of the rare presentations is the likely simulation of disease with hypertrophic cardiomyopathies like left ventricular outflow tract (LVOT) obstruction due to the systolic anterior motion of the mitral valve and irregular septal hypertrophy secondary to amyloid deposits. We present a case of cardiac amyloidosis secondary to multiple myeloma who presented with dynamic LVOT obstruction resembling hypertrophic obstructive cardiomyopathy and complicated by acute pulmonary edema. These complicated cases can be initially treated for pulmonary edema with an elevation of the head of the bed, furosemide, and nitroglycerin intravenously. For multiple myeloma, chemotherapy was continued. Beta-blockers, calcium channel blockers and angiotensin-converting enzyme inhibitors, and aldosterone receptor blocker were avoided due to poor tolerability. After symptomatic control, the patient can likely be scheduled for septal myotomy and the placement of a pacemaker or implantable cardiac defibrillator to prevent any arrhythmias causing sudden cardiac death in these subsets of patients.
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http://dx.doi.org/10.7759/cureus.3749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6388819PMC
December 2018

West Nile Virus-Inclusive Single-Cell RNA Sequencing Reveals Heterogeneity in the Type I Interferon Response within Single Cells.

J Virol 2019 03 5;93(6). Epub 2019 Mar 5.

Department of Pediatrics, Division of Infectious Disease, Emory University School of Medicine, Atlanta, Georgia, USA

West Nile virus (WNV) is a neurotropic mosquito-borne flavivirus of global importance. Neuroinvasive WNV infection results in encephalitis and can lead to prolonged neurological impairment or death. Type I interferon (IFN-I) is crucial for promoting antiviral defenses through the induction of antiviral effectors, which function to restrict viral replication and spread. However, our understanding of the antiviral response to WNV infection is mostly derived from analysis of bulk cell populations. It is becoming increasingly apparent that substantial heterogeneity in cellular processes exists among individual cells, even within a seemingly homogenous cell population. Here, we present WNV-inclusive single-cell RNA sequencing (scRNA-seq), an approach to examine the transcriptional variation and viral RNA burden across single cells. We observed that only a few cells within the bulk population displayed robust transcription of IFN-β mRNA, and this did not appear to depend on viral RNA abundance within the same cell. Furthermore, we observed considerable transcriptional heterogeneity in the IFN-I response, with genes displaying high unimodal and bimodal expression patterns. Broadly, IFN-stimulated genes negatively correlated with viral RNA abundance, corresponding with a precipitous decline in expression in cells with high viral RNA levels. Altogether, we demonstrated the feasibility and utility of WNV-inclusive scRNA-seq as a high-throughput technique for single-cell transcriptomics and WNV RNA detection. This approach can be implemented in other models to provide insights into the cellular features of protective immunity and identify novel therapeutic targets. West Nile virus (WNV) is a clinically relevant pathogen responsible for recurrent epidemics of neuroinvasive disease. Type I interferon is essential for promoting an antiviral response against WNV infection; however, it is unclear how heterogeneity in the antiviral response at the single-cell level impacts viral control. Specifically, conventional approaches lack the ability to distinguish differences across cells with varying viral abundance. The significance of our research is to demonstrate a new technique for studying WNV infection at the single-cell level. We discovered extensive variation in antiviral gene expression and viral abundance across cells. This protocol can be applied to primary cells or models to better understand the underlying cellular heterogeneity following WNV infection for the development of targeted therapeutic strategies.
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http://dx.doi.org/10.1128/JVI.01778-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401468PMC
March 2019

The plastic surgeon as employee: Survey of the American Society of Plastic Surgeons.

J Plast Reconstr Aesthet Surg 2019 Jan 13;72(1):137-171. Epub 2018 Nov 13.

Department of Surgery, Division of Plastic Surgery, University of California Davis Medical Center, Sacramento, CA, United States.

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http://dx.doi.org/10.1016/j.bjps.2018.10.032DOI Listing
January 2019

Carglumic Acid Treatment of a Patient with Recurrent Valproic Acid-induced Hyperammonemia: A Rare Case Report.

Cureus 2018 Sep 12;10(9):e3292. Epub 2018 Sep 12.

Medical Student, American University of Integrative Sciences, Bridgewater, BRB.

Valproic acid, first manufactured as an anticonvulsant, is commonly used to treat both neurological and psychiatric conditions. A rare and deadly side effect of this medication is hyperammonemia, presenting as lethargy, confusion, seizure, and, ultimately, coma. In rare circumstances, hyperammonemia can be recurrent and devastating, especially in patients with an underlying N-acetyl glutamate synthase (NAGS) deficiency, as the valproic acid can enhance this enzyme deficiency and inhibit the conversion of ammonia into urea in the liver. For these subtypes of patients, the United States Food and Drug Administration (US FDA) has recently approved carglumic acid, a medication that can act as a scavenger by effectively increasing the levels of NAGS, ultimately enhancing the conversion of ammonia to urea. In our case report, we have mentioned a patient with treatment-resistant bipolar disorder, who presented with elevated ammonia levels secondary to valproic acid treatment. Valproic acid was the only drug that was effective in his case, so we initiated therapy to reduce his elevated ammonia levels. After a thorough evaluation, we found the patient had a genetic NAGS deficiency. Carglumic acid was initiated and proved efficacious in our patient.
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http://dx.doi.org/10.7759/cureus.3292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6235635PMC
September 2018

Progestin-based contraception regimens modulate expression of putative HIV risk factors in the vaginal epithelium of pig-tailed Macaques.

Am J Reprod Immunol 2018 10 3;80(4):e13029. Epub 2018 Aug 3.

Division of HIV/AIDS Prevention, CDC, Atlanta, Georgia.

Problem: In women, the use of progestin-based contraception may increase the risk of vaginal HIV acquisition. We previously showed in macaques that there is a significantly higher simian-human immunodeficiency virus (SHIV) acquisition rate in the luteal phase of the menstrual cycle, which presents a naturally high-progesterone state, and this may be attributable to altered expression of innate immune factors. We hypothesized that progestin-based contraception, especially depot medroxyprogesterone acetate (DMPA), would, in a similar way, affect mucosal immune factors that influence HIV acquisition risk.

Method Of Study: We used a pig-tailed macaque model to evaluate the effects of two progestin-based contraceptives, DMPA, and levonorgestrel (LNG)/ethinyl estradiol (EE)-based combined oral contraceptives (COCs), on innate mucosal factors. We compared the vaginal epithelial thickness data from previous studies and used cytokine profiling and microarray analysis to evaluate contraception-induced molecular changes in the vagina.

Results: The administration of DMPA caused a reduction in the thickness of the vaginal epithelium relative to that of the follicular or luteal phase. DMPA also induced a significant increase in vaginal levels of the anti-inflammatory cytokine IL-10. Both DMPA- and LNG-based contraception induced a signature of gene expression similar to that of the luteal phase, only more exacerbated, including widespread downregulation of antiviral genes.

Conclusion: The use of progestin-based contraception might engender a milieu that poses an increased risk of HIV acquisition as compared to both the luteal and follicular phases of the menstrual cycle.
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http://dx.doi.org/10.1111/aji.13029DOI Listing
October 2018

Pulmonary Involvement in Crohn's Disease: A Rare Case Report.

Cureus 2018 May 30;10(5):e2710. Epub 2018 May 30.

Graduate, Pontifical Catholic University of Ecuador, Chagrin Falls, USA.

Crohn's disease (CD) is a granulomatous inflammatory disease that can involve any part of the gastrointestinal tract, from mouth to anus. In most cases, it remits and relapses in the terminal ileum, requiring treatment via steroid boluses. In rare cases, however, CD can involve the pulmonary system presenting as dyspnea on exertion and dry cough. We present a case of a 38-year-old man who developed shortness of breath, cough, and wheezing for one month after a colectomy procedure due to recurrent toxic megacolon. He recovered and tolerated extubation successfully and was prescribed mesalamine as maintenance therapy for CD. His pulmonary symptoms after the colectomy, along with his imaging and pulmonary function tests, indicated pulmonary involvement in the lungs as a progression of the primary inflammatory bowel disease. After confirming this diagnosis, he was treated with oral high-dose steroids after successful diagnosis, and the patient's symptoms improved dramatically. This case highlights often overlooked CD bronchopulmonary involvement in the postoperative period.
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http://dx.doi.org/10.7759/cureus.2710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065616PMC
May 2018

Pulmonary Involvement in Crohn's Disease: A Rare Case Report.

Cureus 2018 May 30;10(5):e2710. Epub 2018 May 30.

Graduate, Pontifical Catholic University of Ecuador, Chagrin Falls, USA.

Crohn's disease (CD) is a granulomatous inflammatory disease that can involve any part of the gastrointestinal tract, from mouth to anus. In most cases, it remits and relapses in the terminal ileum, requiring treatment via steroid boluses. In rare cases, however, CD can involve the pulmonary system presenting as dyspnea on exertion and dry cough. We present a case of a 38-year-old man who developed shortness of breath, cough, and wheezing for one month after a colectomy procedure due to recurrent toxic megacolon. He recovered and tolerated extubation successfully and was prescribed mesalamine as maintenance therapy for CD. His pulmonary symptoms after the colectomy, along with his imaging and pulmonary function tests, indicated pulmonary involvement in the lungs as a progression of the primary inflammatory bowel disease. After confirming this diagnosis, he was treated with oral high-dose steroids after successful diagnosis, and the patient's symptoms improved dramatically. This case highlights often overlooked CD bronchopulmonary involvement in the postoperative period.
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http://dx.doi.org/10.7759/cureus.2710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6065616PMC
May 2018

Commentary on: Intra-Areolar Pexy: The "Compass Rose" Suture Technique for Small and Moderate Areola Herniation.

Aesthet Surg J 2019 03;39(4):403-404

Aesthetic fellow at a private plastic surgical practice in Birmingham, AL.

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http://dx.doi.org/10.1093/asj/sjy146DOI Listing
March 2019

BALDR: a computational pipeline for paired heavy and light chain immunoglobulin reconstruction in single-cell RNA-seq data.

Genome Med 2018 03 20;10(1):20. Epub 2018 Mar 20.

Division of Microbiology and Immunology, Yerkes National Primate Research Center, Atlanta, GA, USA.

B cells play a critical role in the immune response by producing antibodies, which display remarkable diversity. Here we describe a bioinformatic pipeline, BALDR (BCR Assignment of Lineage using De novo Reconstruction) that accurately reconstructs the paired heavy and light chain immunoglobulin gene sequences from Illumina single-cell RNA-seq data. BALDR was accurate for clonotype identification in human and rhesus macaque influenza vaccine and simian immunodeficiency virus vaccine induced vaccine-induced plasmablasts and naïve and antigen-specific memory B cells. BALDR enables matching of clonotype identity with single-cell transcriptional information in B cell lineages and will have broad application in the fields of vaccines, human immunodeficiency virus broadly neutralizing antibody development, and cancer.BALDR is available at https://github.com/BosingerLab/BALDR .
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http://dx.doi.org/10.1186/s13073-018-0528-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859752PMC
March 2018

Pressure Sores and Systemic Inflammatory Response Syndrome: UC Davis Quality Improvement Initiative.

Ann Plast Surg 2018 05;80(5S Suppl 5):S308-S310

From the Division of Plastic Surgery, Department of Surgery, University of California Davis Medical Center, Sacramento, CA.

Background: The National Pressure Ulcer Advisory Panel estimates pressure sore care to approach $11 billion annually. It is not uncommon for these patients to present to the emergency department (ED) with a chief concern of a pressure sore, while concurrently carrying an undiagnosed infectious process that is the culprit for the acute presentation, rather than the chronic pressure injury. We aim to identify patients who met systemic inflammatory response syndrome (SIRS) criteria at ED presentation who were referred to plastic and reconstructive surgery for pressure sore debridement prior to a complete medical workup. We hypothesize that a restructuring of the ED triaging system would help conserve hospital resources, reduce costs of pressure sore management, and improve patient care and outcomes by first treating primary, underlying pathologies.

Methods: This is a retrospective chart review of 36 patients who presented to the University of California, Davis Medical Center Emergency Department with a pressure sore and met SIRS criteria, but obtained a plastic surgery consult prior to a full medical workup. We defined SIRS based on standardized criteria: temperature greater than 100.4°F or less than 96.8°F, pulse rate greater than 90 beats/min, respiratory rate greater than 20 breaths/min or PaCO2 less than 32 mm Hg, white blood cell count greater than 12,000, less than 4000, or greater than 10% bands.

Results: Fifty percent of patients (18/36) met SIRS criteria at ED presentation for their pressure sores. Of these SIRS patients, 9 (50%) had a diagnosis of urinary tract infection or urosepsis, 6 (33.3%) had sepsis of undefined origin, and 3 (16.7%) had other diagnoses such as osteomyelitis or acute respiratory distress syndrome.

Conclusions: Half of patients consulted while in the University of California, Davis Medical Center Emergency Department with pressure sores met SIRS criteria and received a plastic and reconstructive surgery consult prior to a full medical workup. We propose a new algorithm for triaging pressure sore patients be established in our institution that emphasizes a medical and surgical collaborative approach in order to reduce cost, conserve resources, and improve patient care.
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http://dx.doi.org/10.1097/SAP.0000000000001378DOI Listing
May 2018

Sooty mangabey genome sequence provides insight into AIDS resistance in a natural SIV host.

Nature 2018 01;553(7686):77-81

Emory Vaccine Center and Yerkes National Primate Research Center, Emory University, Atlanta, Georgia 30329, USA.

In contrast to infections with human immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in macaques, SIV infection of a natural host, sooty mangabeys (Cercocebus atys), is non-pathogenic despite high viraemia. Here we sequenced and assembled the genome of a captive sooty mangabey. We conducted genome-wide comparative analyses of transcript assemblies from C. atys and AIDS-susceptible species, such as humans and macaques, to identify candidates for host genetic factors that influence susceptibility. We identified several immune-related genes in the genome of C. atys that show substantial sequence divergence from macaques or humans. One of these sequence divergences, a C-terminal frameshift in the toll-like receptor-4 (TLR4) gene of C. atys, is associated with a blunted in vitro response to TLR-4 ligands. In addition, we found a major structural change in exons 3-4 of the immune-regulatory protein intercellular adhesion molecule 2 (ICAM-2); expression of this variant leads to reduced cell surface expression of ICAM-2. These data provide a resource for comparative genomic studies of HIV and/or SIV pathogenesis and may help to elucidate the mechanisms by which SIV-infected sooty mangabeys avoid AIDS.
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http://dx.doi.org/10.1038/nature25140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5843367PMC
January 2018

The Vertical Rectus Abdominis Musculocutaneous Flap As a Versatile and Viable Option for Perineal Reconstruction.

Eplasty 2017 16;17:ic2. Epub 2017 Jan 16.

Division of Plastic & Reconstructive Surgery, University of California, Davis, Sacramento, Ca.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5247671PMC
January 2017

Systems biology of immunity to MF59-adjuvanted versus nonadjuvanted trivalent seasonal influenza vaccines in early childhood.

Proc Natl Acad Sci U S A 2016 Feb 11;113(7):1853-8. Epub 2016 Jan 11.

WHO Collaborative Center for Vaccine Immunology, Departments of Pathology-Immunology and Pediatrics, University of Geneva, 1211 Geneva, Switzerland

The dynamics and molecular mechanisms underlying vaccine immunity in early childhood remain poorly understood. Here we applied systems approaches to investigate the innate and adaptive responses to trivalent inactivated influenza vaccine (TIV) and MF59-adjuvanted TIV (ATIV) in 90 14- to 24-mo-old healthy children. MF59 enhanced the magnitude and kinetics of serum antibody titers following vaccination, and induced a greater frequency of vaccine specific, multicytokine-producing CD4(+) T cells. Compared with transcriptional responses to TIV vaccination previously reported in adults, responses to TIV in infants were markedly attenuated, limited to genes regulating antiviral and antigen presentation pathways, and observed only in a subset of vaccinees. In contrast, transcriptional responses to ATIV boost were more homogenous and robust. Interestingly, a day 1 gene signature characteristic of the innate response (antiviral IFN genes, dendritic cell, and monocyte responses) correlated with hemagglutination at day 28. These findings demonstrate that MF59 enhances the magnitude, kinetics, and consistency of the innate and adaptive response to vaccination with the seasonal influenza vaccine during early childhood, and identify potential molecular correlates of antibody responses.
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http://dx.doi.org/10.1073/pnas.1519690113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763735PMC
February 2016

Extended fasciocutaneous flaps for autologous augmentation mastopexy with upper body lift after massive weight loss: an early experience.

Ann Plast Surg 2015 May;74 Suppl 1:S41-5

From the Division of Plastic Surgery, University of California, Davis, Sacramento, CA.

Introduction: Common upper body findings after massive weight loss (MWL) include breast ptosis, projection loss, flattening, inframammary fold descent, and back rolls. Although implants address volume loss, manifestations of circumferential excess (ie, back rolls) are ignored. We review our experience with extended lateral fasciocutaneous flaps incorporating circumferential excess tissue, typically removed in upper body lifts (UBLs), for autologous augmentation mastopexy.

Methods: We reviewed all cases of simultaneous autoaugmentation mastopexy and UBL, using extended lateral chest wall fasciocutaneous flaps, performed after MWL. Donor sites were designed with scars residing within the bra line (UBL) or midaxillary line [modified UBL (mUBL)]. We analyzed demographics, clinical indications, and complications.

Results: Between 2007 and 2013, 7 patients underwent 13 extended fasciocutaneous flap reconstructions for autoaugmentation mastopexy, combined with UBL or mUBL. All patients underwent procedures with flaps taken from the back or from the midaxillary line. Mean initial body mass index (BMI) was 50.1 kg/m2 with a preoperative, post-MWL BMI of 28.5 kg/m2, weight loss of 58 kg, and BMI decrease of 21.6 kg/m2. Among 6 patients who underwent bariatric surgery, the average interval between gastric bypass and autoaugmentation mastopexy was 41 months. Five patients underwent these procedures for aesthetic reasons, whereas 2 patients underwent breast reconstruction. Follow-up averaged 18 months. Complications occurred in 3 patients, with only 1 requiring reoperation.

Conclusions: Massive weight loss patients frequently present with breast volume loss and ptotic upper body soft tissue excess. Simultaneous mastopexy augmentation can be safely and reliably performed using extended fasciocutaneous flaps to autologously may be placed in aesthetically acceptable locations. Patients undergoing mUBLs with midaxillary line donor scars may conceal them with arms at their sides. Patients choosing back donor scars may conceal them within the bra line while having greater volumes available for augmentation. As is true with all flaps, one should assess distal tip perfusion before final inset, especially when using a flap extending to the midline back.
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http://dx.doi.org/10.1097/SAP.0000000000000413DOI Listing
May 2015

Identification of pigment epithelium-derived factor as an adipocyte-derived inflammatory factor.

Mol Med 2012 Oct 24;18:1161-8. Epub 2012 Oct 24.

Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York 11030, United States of America.

Obesity is a major risk factor for insulin resistance, type 2 diabetes mellitus and cardiovascular disease. The pathophysiology of obesity is associated with chronic low-grade inflammation. Adipose tissue in obesity is significantly infiltrated by macrophages that secrete cytokines. The mechanisms of interaction between macrophages and adipocytes, leading to macrophage activation and increased cytokine release, remain to be elucidated. We reasoned that an adipocyte-derived factor might stimulate activation of macrophages. We have identified pigment epithelium-derived factor (PEDF) as a mediator of inflammation that is secreted by adipocytes and mediates macrophage activation. Recombinant PEDF activates macrophages to release tumor necrosis factor (TNF) and interleukin-1 (IL-1). The PEDF receptor adipose triglyceride lipase (ATGL) is required for PEDF-mediated macrophage activation. Selective inhibition of ATGL on macrophages attenuates PEDF-induced TNF production, and PEDF enhances the phosphorylation of p38 and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases. PEDF administration to rats results in increased serum TNF levels, and insulin resistance. Together, these findings suggest that PEDF secreted by adipocytes contributes to the onset and maintenance of chronic inflammation in obesity, and may be a therapeutic target in ameliorating insulin resistance.
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http://dx.doi.org/10.2119/molmed.2012.00156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510299PMC
October 2012

The human respiratory syncytial virus nonstructural protein 1 regulates type I and type II interferon pathways.

Mol Cell Proteomics 2012 May 8;11(5):108-27. Epub 2012 Feb 8.

Protein Discovery Centre, Queensland Institute of Medical Research, Herston, Queensland 4029, Australia.

Respiratory syncytial viruses encode a nonstructural protein (NS1) that interferes with type I and III interferon and other antiviral responses. Proteomic studies were conducted on human A549 type II alveolar epithelial cells and type I interferon-deficient Vero cells (African green monkey kidney cells) infected with wild-type and NS1-deficient clones of human respiratory syncytial virus to identify other potential pathway and molecular targets of NS1 interference. These analyses included two-dimensional differential gel electrophoresis and quantitative Western blotting. Surprisingly, NS1 was found to suppress the induction of manganese superoxide dismutase (SOD2) expression in A549 cells and to a much lesser degree Vero cells in response to infection. Because SOD2 is not directly inducible by type I interferons, it served as a marker to probe the impact of NS1 on signaling of other cytokines known to induce SOD2 expression and/or indirect effects of type I interferon signaling. Deductive analysis of results obtained from cell infection and cytokine stimulation studies indicated that interferon-γ signaling was a potential target of NS1, possibly as a result of modulation of STAT1 levels. However, this was not sufficient to explain the magnitude of the impact of NS1 on SOD2 induction in A549 cells. Vero cell infection experiments indicated that NS1 targeted a component of the type I interferon response that does not directly induce SOD2 expression but is required to induce another initiator of SOD2 expression. STAT2 was ruled out as a target of NS1 interference using quantitative Western blot analysis of infected A549 cells, but data were obtained to indicate that STAT1 was one of a number of potential targets of NS1. A label-free mass spectrometry-based quantitative approach is proposed as a means of more definitive identification of NS1 targets.
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http://dx.doi.org/10.1074/mcp.M111.015909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3418853PMC
May 2012

The selective alpha7 agonist GTS-21 attenuates cytokine production in human whole blood and human monocytes activated by ligands for TLR2, TLR3, TLR4, TLR9, and RAGE.

Mol Med 2009 Jul-Aug;15(7-8):195-202. Epub 2009 Apr 27.

Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.

The cholinergic antiinflammatory pathway modulates inflammatory cytokine production through a mechanism dependent on the vagus nerve and the alpha7 subunit of the nicotinic acetylcholine receptor. GTS-21 [3-(2,4-dimethoxybenzylidene) anabaseine], a selective alpha7 agonist, inhibits inflammatory cytokine production in murine and human macrophages and in several models of inflammatory disease in vivo, but to date its antiinflammatory efficacy in human monocytes has not been characterized. We report here our findings that GTS-21 attenuates tumor necrosis factor (TNF) and interleukin 1beta levels in human whole blood activated by exposure to endotoxin. GTS-21 inhibited TNF production in endotoxin-stimulated primary human monocytes in vitro at the transcriptional level. The suppressive effect of GTS-21 was more potent than nicotine in whole blood and monocytes. Furthermore, GTS-21 attenuated TNF production in monocytes stimulated with peptidoglycan, polyinosinic-polycytidylic acid, CpG, HMGB1 (high-mobility group box 1 protein), and advanced glycation end product-modified albumin. GTS-21 decreased TNF levels in endotoxin-stimulated whole blood obtained from patients with severe sepsis. These findings establish the immunoregulatory effect of GTS-21 on human monocytes, and indicate the potential benefits of further exploration of GTS-21's therapeutic uses in human inflammatory disease.
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http://dx.doi.org/10.2119/molmed.2009.00039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2707516PMC
September 2009

Cholinergic anti-inflammatory pathway activity and High Mobility Group Box-1 (HMGB1) serum levels in patients with rheumatoid arthritis.

Mol Med 2007 Mar-Apr;13(3-4):210-5

The Feinstein Institute for Medical Research, and Department of Emergency Medicine, North Shore University Hospital, Manhasset, NY 11030, USA.

High Mobility Group Box-1 (HMGB1) is a cytokine implicated in the pathogenesis of rheumatoid arthritis (RA) and other inflammatory diseases. The cholinergic anti-inflammatory pathway, a vagus nerve-dependent mechanism, inhibits HMGB1 release in experimental disease models. Here, we examine the relationship between vagus nerve activity and HMGB1 in patients with RA. We compared RR interval variability, an index of cardiac vagal modulation, HMGB1 and hsCRP serum levels, and disease activity scores in thirteen RA patients and eleven age- and sex-matched controls. In RA patients, serum levels of HMGB1 and hsCRP were elevated as compared with controls (HMGB1=71 ng/mL [45-99] vs. 18 ng/mL [0-40], P<0.0001; hsCRP=14.5 mg/L [0.7-59] vs. 1 mg/L [0.4-2.9], P<0.001). RR interval variability in RA patients was significantly decreased as compared with controls (HF=38 msec2 [14-80] vs. 288 msec2 [38-364], P<0.0001; rMSSD=20.9+/-9.79 msec, 52.6+/-35.3 msec, P<0.01). HMGB1 levels and RR interval variability were significantly related (rho=-0.49, P<0.01). HMGB1 serum levels significantly correlated with disease activity scores (DAS-28) in patients with RA (P=0.004). The study design does not enable a determination of causality, but the results are consistent with the hypothesis that decreased cholinergic anti-inflammatory pathway activity is associated with increased HMGB1 levels in patients with RA.
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http://dx.doi.org/10.2119/2006–00108.GoldsteinDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1899837PMC
August 2007