Publications by authors named "Richard J Noel"

54 Publications

Building a Diverse Workforce and Thinkforce to Reduce Health Disparities.

Int J Environ Res Public Health 2021 Feb 7;18(4). Epub 2021 Feb 7.

Xavier University of Louisiana, New Orleans, LA 70125, USA.

The Research Centers in Minority Institutions (RCMI) Program was congressionally mandated in 1985 to build research capacity at institutions that currently and historically recruit, train, and award doctorate degrees in the health professions and health-related sciences, primarily to individuals from underrepresented and minority populations. RCMI grantees share similar infrastructure needs and institutional goals. Of particular importance is the professional development of multidisciplinary teams of academic and community scholars (the "workforce") and the harnessing of the heterogeneity of thought (the "thinkforce") to reduce health disparities. The purpose of this report is to summarize the presentations and discussion at the RCMI Investigator Development Core (IDC) Workshop, held in conjunction with the RCMI Program National Conference in Bethesda, Maryland, in December 2019. The RCMI IDC Directors provided information about their professional development activities and Pilot Projects Programs and discussed barriers identified by new and early-stage investigators that limit effective career development, as well as potential solutions to overcome such obstacles. This report also proposes potential alignments of professional development activities, targeted goals and common metrics to track productivity and success.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijerph18041569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915161PMC
February 2021

Alternating Hemiplegia of Childhood: gastrointestinal manifestations and correlation with neurological impairments.

Orphanet J Rare Dis 2020 09 3;15(1):231. Epub 2020 Sep 3.

Division of Pediatric Neurology and Developmental Medicine, Duke University Health System, 2301 Erwin Rd., Durham, NC, 27710, USA.

Background: Alternating Hemiplegia of Childhood (AHC) is caused by mutations of the ATP1A3 gene which is expressed in brain areas that include structures controling autonomic, gastrointestinal, gut motility and GABAergic functions. We aimed to investigate, in a cohort of 44 consecutive AHC patients, two hypotheses: 1) AHC patients frequently manifest gastrointestinal, particularly motility, problems. 2) These problems are often severe and their severity correlates with neurological impairments.

Results: 41/44 (93%) exhibited gastrointestinal symptoms requiring medical attention. For these 41 patients, symptoms included constipation (66%), swallowing problems (63%), vomiting (63%), anorexia (46%), diarrhea (44%), nausea (37%), and abdominal pain (22%). Symptoms indicative of dysmotility occurred in 33 (80%). The most common diagnoses were oropharyngeal dysphagia (63%) and gastroesophageal reflux (63%). 16 (39%) required gastrostomy and two fundoplication. Severity of gastrointestinal symptoms correlated with non-paroxysmal neurological disability index, Gross Motor Function Classification System scores, and with the presence/absence of non-gastrointestinal autonomic dysfunction (p = 0.031, 0.043, Spearman correlations and 0.0166 Cramer's V, respectively) but not with the paroxysmal disability index (p = 0.408).

Conclusions: Most AHC patients have gastrointestinal problems. These are usually severe, most commonly are indicative of dysmotility, often require surgical therapies, and their severity correlates with that of non-paroxysmal CNS manifestations. Our findings should help in management-anticipatory guidance of AHC patients. Furthermore, they are consistent with current understandings of the pathophysiology of AHC and of gastrointestinal dysmotility, both of which involve autonomic and GABAergic dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-020-01474-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469407PMC
September 2020

TGFβRI antagonist inhibits HIV-1 Nef-induced CC chemokine family ligand 2 (CCL2) in the brain and prevents spatial learning impairment.

J Neuroinflammation 2019 Dec 11;16(1):262. Epub 2019 Dec 11.

Department of Basic Sciences, Ponce Health Sciences University-Ponce Medical School, Ponce Research Institute, P.O. Box 7004, Ponce, PR, 00731, USA.

Background: HIV-1-associated neurocognitive disorders (HAND) progression is related to continued inflammation despite undetectable viral loads and may be caused by early viral proteins expressed by latently infected cells. Astrocytes represent an HIV reservoir in the brain where the early viral neurotoxin negative factor (Nef) is produced. We previously demonstrated that astrocytic expression of Nef in the hippocampus of rats causes inflammation, macrophage infiltration, and memory impairment. Since these processes are affected by TGFβ signaling pathways, and TGFβ-1 is found at higher levels in the central nervous system of HIV-1+ individuals and is released by astrocytes, we hypothesized a role for TGFβ-1 in our model of Nef neurotoxicity.

Methods: To test this hypothesis, we compared cytokine gene expression by cultured astrocytes expressing Nef or green fluorescent protein. To determine the role of Nef and a TGFβRI inhibitor on memory and learning, we infused astrocytes expressing Nef into the hippocampus of rats and then treated them daily with an oral dose of SD208 (10 mg/kg) or placebo for 7 days. During this time, locomotor activity was recorded in an open field and spatial learning tested in the novel location recognition paradigm. Postmortem tissue analyses of inflammatory and signaling molecules were conducted using immunohistochemistry and immunofluorescence.

Results: TGFβ-1 was induced in cultures expressing Nef at 24 h followed by CCL2 induction which was prevented by blocking TGFβRI with SD208 (competitive inhibitor). Interestingly, Nef seems to change the TGFβRI localization as suggested by the distribution of the immunoreactivity. Nef caused a deficit in spatial learning that was recovered upon co-administration of SD208. Brain tissue from Nef-treated rats given SD208 showed reduced CCL2, phospho-SMAD2, cluster of differentiation 163 (CD163), and GFAP immunoreactivity compared to the placebo group.

Conclusions: Consistent with our previous findings, rats treated with Nef showed deficits in spatial learning and memory in the novel location recognition task. In contrast, rats treated with Nef + SD208 showed better spatial learning suggesting that Nef disrupts memory formation in a TGFβ-1-dependent manner. The TGFβRI inhibitor further reduced the induction of inflammation by Nef which was concomitant with decreased TGFβ signaling. Our findings suggest that TGFβ-1 signaling is an intriguing target to reduce neuroHIV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12974-019-1664-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905066PMC
December 2019

Infusion of HIV-1 Nef-expressing astrocytes into the rat hippocampus induces enteropathy and interstitial pneumonitis and increases blood-brain-barrier permeability.

PLoS One 2019 27;14(11):e0225760. Epub 2019 Nov 27.

Department of Basic Sciences, Ponce Health Sciences University, Ponce Research Institute, Ponce, Puerto Rico, United States of America.

Even though HIV-1 replication can be suppressed by combination antiretroviral therapy (cART) inflammatory processes still occur, contributing to comorbidities. Comorbidities are attributed to variety of factors, including HIV-1 mediated inflammation. Several HIV-1 proteins mediate central nervous system (CNS) inflammation, including Nef. Nef is an early HIV-1 protein, toxic to neurons and glia and is sufficient to cause learning impairment similar to some deficits observed in HIV-1 associated neurocognitive disorders. To determine whether hippocampal Nef expression by astrocytes contributes to comorbidities, specifically peripheral inflammation, we infused Sprague Dawley rats with GFP- (control) or Nef-transfected astrocytes into the right hippocampus. Brain, lung, and ileum were collected postmortem for the measurement of inflammatory markers. Increased blood-brain-barrier permeability and serum IL-1β levels were detected in the Nef-treated rats. The lungs of Nef-treated rats demonstrated leukocyte infiltration, macrophage upregulation, and enhanced vascular permeability. Ileal tissue showed reactive follicular lymphoid hyperplasia, increased permeability and macrophage infiltration. The intracerebroventricular application of IL-1 receptor antagonist reduced infiltration of immune cells into ileum and lung, indicating the important role of IL-1β in mediating the spread of inflammation from the brain to other tissues. This suggests that localized expression of a single viral protein, HIV-1 Nef, can contribute to a broader inflammatory response by upregulation of IL-1β. Further, these results suggest that Nef contributes to the chronic inflammation seen in HIV patients, even in those whose viremia is controlled by cART.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225760PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881014PMC
March 2020

The Research Centers in Minority Institutions (RCMI) Translational Research Network: Building and Sustaining Capacity for Multi-Site Basic Biomedical, Clinical and Behavioral Research.

Ethn Dis 2019 21;29(Suppl 1):135-144. Epub 2019 Feb 21.

University of California, Los Angeles, CA.

The Research Centers in Minority Institutions (RCMI) program was established by the US Congress to support the development of biomedical research infrastructure at minority-serving institutions granting doctoral degrees in the health professions or in a health-related science. RCMI institutions also conduct research on diseases that disproportionately affect racial and ethnic minorities (ie, African Americans/Blacks, American Indians and Alaska Natives, Hispanics, Native Hawaiians and Other Pacific Islanders), those of low socioeconomic status, and rural persons. Quantitative metrics, including the numbers of doctoral science degrees granted to underrepresented students, NIH peer-reviewed research funding, peer-reviewed publications, and numbers of racial and ethnic minorities participating in sponsored research, demonstrate that RCMI grantee institutions have made substantial progress toward the intent of the Congressional legislation, as well as the NIH/NIMHD-linked goals of addressing workforce diversity and health disparities. Despite this progress, nationally, many challenges remain, including persistent disparities in research and career development awards to minority investigators. The continuing underrepresentation of minority investigators in NIH-sponsored research across multiple disease areas is of concern, in the face of unrelenting national health inequities. With the collaborative network support by the RCMI Translational Research Network (RTRN), the RCMI community is uniquely positioned to address these challenges through its community engagement and strategic partnerships with non-RCMI institutions. Funding agencies can play an important role by incentivizing such collaborations, and incorporating metrics for research funding that address underrepresented populations, workforce diversity and health equity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18865/ed.29.S1.135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428183PMC
June 2020

Pediatric Feeding Disorder: Consensus Definition and Conceptual Framework.

J Pediatr Gastroenterol Nutr 2019 01;68(1):124-129

Developmental-Behavioral Pediatrics University Health System, Uniformed Services University, San Antonio, TX.

Pediatric feeding disorders (PFDs) lack a universally accepted definition. Feeding disorders require comprehensive assessment and treatment of 4 closely related, complementary domains (medical, psychosocial, and feeding skill-based systems and associated nutritional complications). Previous diagnostic paradigms have, however, typically defined feeding disorders using the lens of a single professional discipline and fail to characterize associated functional limitations that are critical to plan appropriate interventions and improve quality of life. Using the framework of the World Health Organization International Classification of Functioning, Disability, and Health, a unifying diagnostic term is proposed: "Pediatric Feeding Disorder" (PFD), defined as impaired oral intake that is not age-appropriate, and is associated with medical, nutritional, feeding skill, and/or psychosocial dysfunction. By incorporating associated functional limitations, the proposed diagnostic criteria for PFD should enable practitioners and researchers to better characterize the needs of heterogeneous patient populations, facilitate inclusion of all relevant disciplines in treatment planning, and promote the use of common, precise, terminology necessary to advance clinical practice, research, and health-care policy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPG.0000000000002188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314510PMC
January 2019

Safety of Appetite Manipulation in Children with Feeding Disorders Admitted to an Inpatient Feeding Program.

J Pediatr Gastroenterol Nutr 2018 05;66(5):e127-e130

Feeding, Swallowing and Nutrition Center, Division of Pediatric Gastroenterology, Hepatology & Nutrition, Medical College of Wisconsin.

Objective: Appetite manipulation can be effective in weaning children off gastrostomy tube feeding dependence but can cause dehydration, hypoglycaemia, and ketone body production, which is anorexigenic. As the safety of this approach has not been described, our aim was to describe adverse events observed when weaning children from G-tube dependence using our appetite manipulation protocol.

Methods: This was a retrospective study of prospectively collected data of patients who completed our inpatient tube-weaning protocol. Daily safety parameters included twice-daily urine specific gravities and urine ketones and fasting capillary blood glucose. Graded clinical interventions to manage adverse events were collected.

Results: A total of 143 children with a mean age of 4.8 ± 2.4 years were seen in the inpatient feeding program of which 74 (51.7%) were male. The children were hospitalized 10.1 ± 2.5 days with the vast majority being discharged between days 11 and 14. Overall, 78.2% of patients experienced at least 1 adverse event: urine specific gravity >1.020 was seen in 60.5%, ketonuria in 48.9%, and hypoglycemia (≤60 mg/dL) in 13.4%. Only 2 children had blood glucose levels <40 mg/dL and these were corrected with oral supplementation. Graded clinical interventions to manage adverse events included oral rehydration in 89.9% of children and supplemental tube feeding in 25.2%.

Conclusions: Adverse effects are common when appetite manipulation is used to wean children off G-tube dependence. Anticipating, monitoring, and having a clear intervention plan in a closely monitored setting are necessary to safely use this method.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPG.0000000000001849DOI Listing
May 2018

A Problem That Is Difficult to Swallow.

J Pediatr 2017 02 6;181:7-8. Epub 2016 Dec 6.

Department of Pediatrics Medical College of Wisconsin Milwaukee, Wisconsin.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpeds.2016.11.052DOI Listing
February 2017

The 22nd Scientific Conference of the Society on Neuroimmune Pharmacology.

J Neuroimmune Pharmacol 2016 Apr;11 Suppl 1:S1-2

Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute and Department of Psychiatry, University of California, San Diego, 10901 N. Torrey Pines Road, La Jolla, CA, 92037, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11481-016-9661-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5734631PMC
April 2016

Longitudinal Analysis of Cerebrospinal Fluid and Plasma HIV-1 Envelope Sequences Isolated From a Single Donor with HIV Asymptomatic Neurocognitive Impairment.

J Virol Antivir Res 2015;4(1)

Department of Microbiology, Ponce Health Sciences University- School of Medicine/Ponce Research Institute, Ponce, PR 00716, USA.

Objective: Combined antiretroviral treatment (cART) has changed the clinical presentation of HIV-associated neurocognitive disorders (HAND) to that of the milder forms of the disease. Asymptomatic neurocognitive impairment (ANI) is now more prevalent and is associated with increased morbidity and mortality risk in HIV-1-infected people. HIV-1 envelope () genetic heterogeneity has been detected within the central nervous system (CNS) of individuals with ANI. Changes within determine co-receptor use, cellular tropism, and neuropathogenesis. We hypothesize that compartmental changes are associated with HIV-1 C2V4 during ANI and sought to analyze paired HIV-1 sequences from plasma and cerebrospinal fluid (CSF) of a female subject undergoing long-term cART.

Methods: Paired plasma and CSF samples were collected at 12-month intervals and HIV-1 C2V4 was cloned and sequenced.

Results: Phylogenetic analysis of paired samples consistently showed genetic variants unique to the CSF. Phenotypic prediction showed CCR5 (R5) variants for all CSF-derived sequences and showed minor X4 variants (or dual-tropic) in the plasma at later time points. Viral compartmentalization was evident throughout the study, suggesting that the occurrence of distinctive strains may contribute to the neuropathogenesis of HAND.

Conclusions: Our study provides new insights about the genetic characteristics within the C2V4 of HIV-1 that persist after long-term cART and during the course of persistent ANI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498488PMC
http://dx.doi.org/10.4172/2324-8955.1000135DOI Listing
January 2015

Beyond the GRE: using a composite score to predict 
the success of Puerto Rican students in a biomedical 
PhD program.

CBE Life Sci Educ 2015 ;14(2)

*MBRS-RISE Program, , Ponce Health Sciences University and Ponce Research Institute, Ponce, PR 00732 Department of Physiology and Pharmacology, Ponce Health Sciences University and Ponce Research Institute, Ponce, PR 00732

The use and validity of the Graduate Record Examination General Test (GRE) to predict the success of graduate school applicants is heavily debated, especially for its possible impact on the selection of underrepresented minorities into science, technology, engineering, and math fields. To better identify candidates who would succeed in our program with less reliance on the GRE and grade point average (GPA), we developed and tested a composite score (CS) that incorporates additional measurable predictors of success to evaluate incoming applicants. Uniform numerical values were assigned to GPA, GRE, research experience, advanced course work or degrees, presentations, and publications. We compared the CS of our students with their achievement of program goals and graduate school outcomes. The average CS was significantly higher in those students completing the graduate program versus dropouts (p < 0.002) and correlated with success in competing for fellowships and a shorter time to thesis defense. In contrast, these outcomes were not predicted by GPA, science GPA, or GRE. Recent implementation of an impromptu writing assessment during the interview suggests the CS can be improved further. We conclude that the CS provides a broader quantitative measure that better predicts success of students in our program and allows improved evaluation and selection of the most promising candidates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1187/cbe.14-11-0216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477729PMC
December 2015

Another step towards celiac screening.

Authors:
Richard J Noel

Pediatrics 2015 Apr 2;135(4):752-3. Epub 2015 Mar 2.

Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Duke University Medical Center, Durham, North Carolina

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1542/peds.2015-0209DOI Listing
April 2015

HIV gp120 sequence variability associated with HAND in Hispanic Women.

J Virol Antivir Res 2015;4(3). Epub 2015 Oct 6.

Department of Microbiology and Medical Zoology, University of Puerto Rico Medical Sciences Campus, San Juan, PR.

Objective: HIV-1 variants with different tropisms are associated with various neuropathologies. This study intends to determine if this correlation is determined by unique viral sequences. We hypothesize that HIV-1 envelope gene sequence changes are associated with cognition status.

Methods: Viral RNA was extracted from peripheral blood mononuclear cells (PBMCs) co-cultures derived from HIV-1 infected Hispanic women that had been characterized for HIV associated neurocognitive disorders (HAND).

Results: Analyses of the C2V4 region of HIV gp120 demonstrated that increased sequence diversity correlates with cognition status as sequences derived from subjects with normal cognition exhibited less diversity than sequences derived from subjects with cognitive impairment. In addition, differences in V3 and V4 loop charges were also noted as well as differences in the N-glycosylation of the V4 region.

Conclusions: Our data suggest that the genetic signature within the C2V4 region may contribute to the pathogenesis of HAND. HIV sequence characteristics for the isolates grouped in milder forms of HAND can provide insightful information of prognostic value to assess neurocognitive status in HIV subjects, particularly during the era of highly prevalent milder forms of HAND.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4172/2324-8955.1000143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4922650PMC
October 2015

Otolaryngologic surgeries are frequent in children with eosinophilic esophagitis.

Ann Otol Rhinol Laryngol 2015 May 10;124(5):355-60. Epub 2014 Nov 10.

Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, Wisconsin, USA

Objective: The aim was to study the prevalence of otolaryngologic surgeries in pediatric patients with eosinophilic esophagitis (EoE).

Methods: Retrospective cohort study at a tertiary care center. The type of otolaryngologic surgeries performed in patients with diagnosis of EoE was recorded during a 5-year period.

Results: Seventy-five percent of patients were male, with average age of EoE diagnosis at 7.5 years with an 83% incidence of atopy. Cohort analysis revealed that 33% (119/362) had a total of 275 otolaryngologic surgeries. Surgeries performed on 119 patients are as follows: 20% bilateral myringotomy with tubes, 14% tonsillectomy, 18.5% adenoidectomy, 1.4% sinus irrigation, 3.3% bronchoscopy, and 1.4% laryngotracheoplasty (LTP); 63% of patients underwent multiple procedures. Thirty percent of patients undergoing bilateral myringotomy with tube placement (BMT) needed additional tubes. Four of 5 LTP patients had successful operations. Twelve percent of patients had EoE diagnosis prior to an otolaryngologic surgery.

Conclusion: Thirty-three percent of children with EoE required otolaryngologic surgical intervention and nearly one-third who underwent BMT required additional ear tubes. A large fraction of children with EoE will undergo an otolaryngologic surgery, only a minority with a preoperative EoE diagnosis. Until the nature of this relationship is clarified, the high coincidence with otolaryngologic surgeries dictates that otolaryngologists should be familiar with diagnosis of EoE in patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0003489414558108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627634PMC
May 2015

Twin and family studies reveal strong environmental and weaker genetic cues explaining heritability of eosinophilic esophagitis.

J Allergy Clin Immunol 2014 Nov 22;134(5):1084-1092.e1. Epub 2014 Sep 22.

Departments of Environmental Health, Pediatrics, Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; Divisions of Biostatistics and Epidemiology; Human Genetics; Pathology; Rheumatology, Center for Autoimmune Genomics and Etiology; Gastroenterology, Hepatology and Nutrition; Allergy and Immunology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address:

Background: Eosinophilic esophagitis (EoE) is a chronic antigen-driven allergic inflammatory disease, likely involving the interplay of genetic and environmental factors, yet their respective contributions to heritability are unknown.

Objective: To quantify the risk associated with genes and environment on familial clustering of EoE.

Methods: Family history was obtained from a hospital-based cohort of 914 EoE probands (n = 2192 first-degree "Nuclear-Family" relatives) and an international registry of monozygotic and dizygotic twins/triplets (n = 63 EoE "Twins" probands). Frequencies, recurrence risk ratios (RRRs), heritability, and twin concordance were estimated. Environmental exposures were preliminarily examined.

Results: Analysis of the Nuclear-Family-based cohort revealed that the rate of EoE, in first-degree relatives of a proband, was 1.8% (unadjusted) and 2.3% (sex-adjusted). RRRs ranged from 10 to 64, depending on the family relationship, and were higher in brothers (64.0; P = .04), fathers (42.9; P = .004), and males (50.7; P < .001) than in sisters, mothers, and females, respectively. The risk of EoE for other siblings was 2.4%. In the Nuclear-Family cohort, combined gene and common environment heritability was 72.0% ± 2.7% (P < .001). In the Twins cohort, genetic heritability was 14.5% ± 4.0% (P < .001), and common family environment contributed 81.0% ± 4% (P < .001) to phenotypic variance. Probandwise concordance in monozygotic co-twins was 57.9% ± 9.5% compared with 36.4% ± 9.3% in dizygotic co-twins (P = .11). Greater birth weight difference between twins (P = .01), breast-feeding (P = .15), and fall birth season (P = .02) were associated with twin discordance in disease status.

Conclusions: EoE RRRs are increased 10- to 64-fold compared with the general population. EoE in relatives is 1.8% to 2.4%, depending on relationship and sex. Nuclear-Family heritability appeared to be high (72.0%). However, the Twins cohort analysis revealed a powerful role for common environment (81.0%) compared with additive genetic heritability (14.5%).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2014.07.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253562PMC
November 2014

Glutamate metabolism and HIV-associated neurocognitive disorders.

J Neurovirol 2014 Aug 28;20(4):315-31. Epub 2014 May 28.

Department of Microbiology, Ponce School of Medicine and Health Sciences, Ponce, 00716, Puerto Rico.

HIV-1 infection can lead to neurocognitive impairment collectively known as HIV-associated neurocognitive disorders (HAND). Although combined antiretroviral treatment (cART) has significantly ameliorated HIV's morbidity and mortality, persistent neuroinflammation and neurocognitive dysfunction continue. This review focuses on the current clinical and molecular evidence of the viral and host factors that influence glutamate-mediated neurotoxicity and neuropathogenesis as an important underlying mechanism during the course of HAND development. In addition, discusses potential pharmacological strategies targeting the glutamatergic system that may help prevent and improve neurological outcomes in HIV-1-infected subjects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13365-014-0258-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098898PMC
August 2014

Astrocytic expression of HIV-1 viral protein R in the hippocampus causes chromatolysis, synaptic loss and memory impairment.

J Neuroinflammation 2014 Mar 22;11:53. Epub 2014 Mar 22.

Department of Biochemistry, Ponce School of Medicine and Health Sciences, P,O Box 7004, 00731 Ponce, PR, USA.

Background: HIV-infected individuals are at an increased risk of developing neurological abnormalities. HIV induces neurotoxicity by host cellular factors and individual viral proteins. Some of these proteins including viral protein R (Vpr) promote immune activation and neuronal damage. Vpr is known to contribute to cell death of cultured rat hippocampal neurons and suppresses axonal growth. Behavioral studies are limited and suggest hyperactivity in the presence of Vpr. Thus Vpr may play a role in hippocampal loss of function. The purpose of this study is to determine the ability of HIV-1 Vpr production by astrocytes in the hippocampus to cause neurological deficits and memory impairments.

Methods: We tested the performance of rats in novel object and novel location tasks after hippocampal infusion with astrocytes expressing HIV-1 Vpr. Synaptic injury and morphological changes were measured by synaptophysin immunoreactivity and Nissl staining.

Results: Vpr-infused rats showed impaired novel location and novel object recognition compared with control rats expressing green fluorescent protein (GFP). This impairment was correlated with a significant decrease in synaptophysin immunoreactivity in the hippocampal CA3 region, suggesting synaptic injury in HIV-1 Vpr-treated animals. In addition, Nissl staining showed morphological changes indicative of neuronal chromatolysis in the Vpr group. The Vpr-induced neuronal damage and synaptic loss suggest that neuronal dysfunction caused the spatial and recognition memory deficits found in the Vpr-infused animals.

Conclusions: In this study, we demonstrate that HIV-1 Vpr produced by astrocytes in the hippocampus impairs hippocampal-dependent learning. The data suggest Vpr is a neurotoxin with the potential to cause learning impairment in HIV-1 infected individuals even under conditions of limited viral replication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1742-2094-11-53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994341PMC
March 2014

HIV-1 Tat-mediated induction of CCL5 in astrocytes involves NF-κB, AP-1, C/EBPα and C/EBPγ transcription factors and JAK, PI3K/Akt and p38 MAPK signaling pathways.

PLoS One 2013 11;8(11):e78855. Epub 2013 Nov 11.

Division of Pharmacology and Toxicology, UMKC-School of Pharmacy, Kansas City, Missouri, United States of America.

The incidence of HIV-associated neurological disorders (HAND) has increased during recent years even though the highly active antiretroviral therapy (HAART) has significantly curtailed the virus replication and increased the life expectancy among HIV-1 infected individuals. These neurological deficits have been attributed to HIV proteins including HIV-1 Tat. HIV-1 Tat is known to up-regulate CCL5 expression in mouse astrocytes, but the mechanism of up-regulation is not known. The present study was undertaken with the objective of determining the mechanism(s) underlying HIV-1 Tat-mediated expression of CCL5 in astrocytes. SVGA astrocytes were transiently transfected with a plasmid encoding Tat, and expression of CCL5 was studied at the mRNA and protein levels using real time RT-PCR and multiplex cytokine bead array, respectively. HIV-1 Tat showed a time-dependent increase in the CCL5 expression with peak mRNA and protein levels, observed at 1 h and 48 h post-transfection, respectively. In order to explore the mechanism(s), pharmacological inhibitors and siRNA against different pathway(s) were used. Pre-treatment with SC514 (NF-κB inhibitor), LY294002 (PI3K inhibitor), AG490 (JAK2 inhibitor) and Janex-1 (JAK3 inhibitor) showed partial reduction of the Tat-mediated induction of CCL5 suggesting involvement of JAK, PI3K/Akt and NF-κB in CCL5 expression. These results were further confirmed by knockdown of the respective genes using siRNA. Furthermore, p38 MAPK was found to be involved since the knockdown of p38δ but not other isoforms showed partial reduction in CCL5 induction. This was further confirmed at transcriptional level that AP-1, C/EBPα and C/EBPγ were involved in CCL5 up-regulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0078855PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3823997PMC
August 2014

Human immunodeficiency virus type 1 viral protein R (Vpr) induces CCL5 expression in astrocytes via PI3K and MAPK signaling pathways.

J Neuroinflammation 2013 Nov 13;10:136. Epub 2013 Nov 13.

Division of Pharmacology and Toxicology, School of Pharmacy, University of Missouri, Kansas City, MO 64108, USA.

Background: Neurocognitive impairments remain prevalent in HIV-1 infected individuals despite current antiretroviral therapies. It is increasingly becoming evident that astrocytes play a critical role in HIV-1 neuropathogenesis through the production of proinflammatory cytokines/chemokines. HIV-1 viral protein R (Vpr) plays an important role in neuronal dysfunction; however, its role in neuroinflammation is not well characterized. The major objective of this study was to determine the effect of Vpr in induction of proinflammatory chemokine CCL5 in astrocytes and to define the underlying mechanism(s).

Methods: SVGA astrocytes were either mock transfected or were transfected with a plasmid encoding HIV-1 Vpr, and the cells were harvested at different time intervals. The mRNA level of CCL5 expression was quantified using real-time RT-PCR, and cell culture supernatants were assayed for CCL5 protein concentration. Immunocytochemistry was performed on HIV-1 Vpr transfected astrocytes to check CCL5 expression. Various signaling mechanisms such as p38 MAPK, PI3K/Akt, NF-κB and AP-1 were explored using specific chemical inhibitors and siRNAs.

Results: HIV-1 Vpr transfected astrocytes exhibited time-dependent induction of CCL5 as compared to mock-transfected astrocytes at both the mRNA and protein level. Immunostained images of astrocytes transfected with HIV-1 Vpr also showed much higher accumulation of CCL5 in comparison to untransfected and mock-transfected astrocytes. Pre-treatment with NF-κB (SC514) and PI3K/Akt (LY294002) inhibitor partially abrogated CCL5 mRNA and protein expression levels as opposed to untreated controls after HIV-1 Vpr transfection. Specific siRNAs against p50 and p65 subunits of NF-κB, p38δ MAPK, Akt-2 and Akt-3, and AP-1 transcription factor substantially inhibited the production of CCL5 in HIV-1 Vpr transfected astrocytes.

Conclusion: These results demonstrate the ability of HIV-1 Vpr to induce CCL5 in astrocytes in a time-dependent manner. Furthermore, this effect was observed to be mediated by transcription factors NF-κB and AP-1 and involved the p38-MAPK and PI3K/Akt pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1742-2094-10-136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831867PMC
November 2013

Feeding dysfunction in children with single ventricle following staged palliation.

J Pediatr 2014 Feb 22;164(2):243-6.e1. Epub 2013 Oct 22.

Division of Cardiology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI; Division of Adult Cardiovascular Medicine, Department of Internal Medicine, Medical College of Wisconsin, Milwaukee, WI.

Objective: To determine the prevalence of feeding dysfunction in children with single ventricle defects and identify associated risk factors.

Study Design: Patients aged 2-6 years with single ventricle physiology presenting for routine cardiology follow-up at the Children's Hospital of Wisconsin were prospectively identified. Parents of the patients completed 2 validated instruments for assessment of feeding dysfunction. Chart review was performed to retrospectively obtain demographic and diagnostic data.

Results: Instruments were completed for 56 patients; median age was 39 months. Overall, 28 (50%) patients had some form of feeding dysfunction. Compared with a normal reference population, patients with single ventricle had statistically significant differences in dysfunctional food manipulation (P < .001), mealtime aggression (P = .002), choking/gagging/vomiting (P < .001), resistance to eating (P < .001), and parental aversion to mealtime (P < .001). Weight and height for age z-scores were significantly lower in subjects with feeding dysfunction (-0.84 vs -0.33; P < .05 and -1.46 vs -0.56; P = .001, respectively). Multivariable analysis identified current gastrostomy tube use (P = .02) and a single parent household (P = .01) as risk factors for feeding dysfunction.

Conclusion: Feeding dysfunction is common in children with single ventricle defects, occurring in 50% of our cohort. Feeding dysfunction is associated with worse growth measures. Current gastrostomy tube use and a single parent household were identified as independent risk factors for feeding dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jpeds.2013.09.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3946833PMC
February 2014

Identification and molecular characterization of SIV Vpr R50G mutation associated with long term survival in SIV-infected morphine dependent and control macaques.

Virology 2013 Nov 28;446(1-2):144-51. Epub 2013 Aug 28.

Department of Microbiology, Ponce School of Medicine and Health Sciences, Ponce, PR 00716, USA.

Viral protein R (Vpr) is an accessory protein of HIV and SIV involved in the pathogenesis of viral infection. In this study, we monitored SIV evolution in the central nervous system and other organs from morphine-dependent and control animals by sequencing vpr in an attempt to understand the relationship between drug abuse, disease progression, and compartmentalization of viral evolution. Animals in the morphine group developed accelerated disease and died within twenty weeks post-infection. A unique mutation, R50G, was identified in the macaques that survived regardless of morphine exposure. Functional studies revealed that the R50G mutation exhibited altered cellular localization and decreased the expression levels of both IL-6 and IL-8. Our results, therefore, suggest that sequence changes within the SIV/17E-Fr vpr occur regardless of drug abuse but correlate with survival, and that they alter disease progression rates by affecting Vpr functions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.virol.2013.07.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3844929PMC
November 2013

Nutritional and psychosocial outcomes of gastrostomy tube-dependent children completing an intensive inpatient behavioral treatment program.

J Pediatr Gastroenterol Nutr 2013 Nov;57(5):668-72

*Division of Pediatric Gastroenterology, Medical College of Wisconsin †Division of Pediatric Psychiatry and Behavioral Medicine, Children's Hospital of Wisconsin, Milwaukee, WI ‡Department of Psychology, the University of Memphis, Memphis, TN.

Objectives: Limited published data describe the long-term effects of behavioral strategies to wean children from gastrostomy tube (GT) feeding dependence. This study presents data relating to nutritional and psychosocial outcomes observed during a 1-year period in medically complex GT feeding-dependent patients who completed an inpatient behavioral-based tube weaning protocol.

Methods: This was a retrospective study of prospectively and retrospectively collected data associated with a clinical cohort of 77 children diagnosed as having a feeding disorder, GT feeding dependence (>1 year), and an inability to maintain acceptable growth via oral feeding completing an inpatient tube weaning protocol. Nutritional data (percentage of ideal body weight, and oral energy intake as percent ofenergy goal) and psychosocial data (mealtime behavior problems, quality of caregiver and child interactions, and parenting stress) were assessed pre- and post-hospitalization. Nutritional data were also monitored longitudinally at 1, 3, 6, and 12 months postreatment. Data were grouped for retrospective analysis.

Results: Mealtime environment and feeding behaviors significantly improved, and all of the patients demonstrated reductions in tube dependence aside from 1 treatment failure. Fifty-one percent of patients were fully weaned from tube feeding after 2 weeks and an additional 12% completed weaning in the outpatient follow-up clinic within 1 year. Patients maintained nutritional stability at the 1-year posttreatment follow-up appointment.

Conclusions: Inpatient behavioral interventions are highly effective and safe for transitioning long-term tube feeding children to oral feeding.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPG.0b013e3182a027a3DOI Listing
November 2013

Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome.

J Allergy Clin Immunol 2013 Jun 25;131(6):1611-23. Epub 2013 Mar 25.

Laboratory of Clinical Infectious Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1684, USA.

Background: Mutations in signal transducer and activator of transcription (STAT) 1 cause a broad spectrum of disease, ranging from severe viral and bacterial infections (amorphic alleles) to mild disseminated mycobacterial disease (hypomorphic alleles) to chronic mucocutaneous candidiasis (CMC; hypermorphic alleles). The hypermorphic mutations are also associated with arterial aneurysms, autoimmunity, and squamous cell cancers.

Objective: We sought to investigate the role of STAT1 gain-of-function mutations in phenotypes other than CMC.

Methods: We initially screened patients with CMC and autoimmunity for STAT1 mutations. We functionally characterized mutations in vitro and studied immune profiles and regulatory T (Treg) cells. After our initial case identifications, we explored 2 large cohorts of patients with wild-type forkhead box protein 3 and an immune dysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX)-like phenotype for STAT1 mutations.

Results: We identified 5 children with polyendocrinopathy, enteropathy, and dermatitis reminiscent of IPEX syndrome; all but 1 had a variety of mucosal and disseminated fungal infections. All patients lacked forkhead box protein 3 mutations but had uniallelic STAT1 mutations (c.629 G>T, p.R210I; c.1073 T>G, p.L358W, c.796G>A; p.V266I; c.1154C>T, T385M [2 patients]). STAT1 phosphorylation in response to IFN-γ, IL-6, and IL-21 was increased and prolonged. CD4(+) IL-17-producing T-cell numbers were diminished. All patients had normal Treg cell percentages in the CD4(+) T-cell compartment, and their function was intact in the 2 patients tested. Patients with cells available for study had normal levels of IL-2-induced STAT5 phosphorylation.

Conclusions: Gain-of-function mutations in STAT1 can cause an IPEX-like phenotype with normal frequency and function of Treg cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2012.11.054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672257PMC
June 2013

Astrocytic expression of HIV-1 Nef impairs spatial and recognition memory.

Neurobiol Dis 2013 Jan 25;49:128-36. Epub 2012 Aug 25.

Department of Biochemistry, Ponce School of Medicine and Health Sciences, Ponce, PR, USA. Electronic address:

Despite the widespread use of antiretroviral therapy that effectively limits viral replication, memory impairment remains a dilemma for HIV infected people. In the CNS, HIV infection of astrocytes leads to the production of the HIV-1 Nef protein without viral replication. Post mortem studies have found Nef expression in hippocampal astrocytes of people with HIV associated dementia suggesting that astrocytic Nef may contribute to HIV associated cognitive impairment even when viral replication is suppressed. To test whether astrocytic expression of Nef is sufficient to induce cognitive deficits, we examined the effect of implanting primary rat astrocytes expressing Nef into the hippocampus on spatial and recognition memory. Rats implanted unilaterally with astrocytes expressing Nef showed impaired novel location and novel object recognition in comparison with controls implanted with astrocytes expressing green fluorescent protein (GFP). This impairment was correlated with an increase in chemokine ligand 2 (CCL2) expression and the infiltration of peripheral macrophages into the hippocampus at the site of injection. Furthermore, the Nef exposed rats exhibited a bilateral loss of CA3 neurons. These results suggest that Nef protein expressed by the implanted astrocytes activates the immune system leading to neuronal damage and spatial and recognition memory deficits. Therefore, the continued expression of Nef by astrocytes in the absence of viral replication has the potential to contribute to HIV associated cognitive impairment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nbd.2012.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530662PMC
January 2013

Expression of human endogenous retrovirus type K (HML-2) is activated by the Tat protein of HIV-1.

J Virol 2012 Aug 16;86(15):7790-805. Epub 2012 May 16.

Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Human endogenous retroviruses (HERVs) make up 8% of the human genome. The expression of HERV-K (HML-2), the family of HERVs that most recently entered the genome, is tightly regulated but becomes markedly increased after infection with HIV-1. To better understand the mechanisms involved in this activation, we explored the role of the HIV-1 Tat protein in inducing the expression of these endogenous retroviral genes. Administration of recombinant HIV-1 Tat protein caused a 13-fold increase in HERV-K (HML-2) gag RNA transcripts in Jurkat T cells and a 10-fold increase in primary lymphocytes, and the expression of the HERV-K (HML-2) rec and np9 oncogenes was also markedly increased. This activation was seen especially in lymphocytes and monocytic cells, the natural hosts for HIV-1 infection. Luciferase reporter gene assays demonstrated that the effect of Tat on HERV-K (HML-2) expression occurred at the level of the transcriptional promoter. The transcription factors NF-κB and NF-AT contribute to the Tat-induced activation of the promoter, as shown by chromatin immunoprecipitation assays, mutational analysis of the HERV-K (HML-2) long terminal repeat, and treatments with agents that inhibit NF-κB or NF-AT activation. These studies demonstrate that HIV-1 Tat plays an important role in activating expression of HERV-K (HML-2) in the setting of HIV-1 infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/JVI.07215-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3421662PMC
August 2012

Endoscopic management of gastrointestinal bleeding from multifocal lymphangioendotheliomatosis with thrombocytopenia: limited efficacy and complications.

J Pediatr Gastroenterol Nutr 2012 Jun;54(6):822-4

Department of Pediatrics, Division of Gastroenterology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MPG.0b013e31822aa2dbDOI Listing
June 2012

Correlation between CD4 T cell counts and virus compartmentalization in genital and systemic compartments of HIV-infected females.

Virology 2011 Sep 13;417(2):320-6. Epub 2011 Jul 13.

AIDS Research Program, Ponce School of Medicine, Ponce, PR-00732, Puerto Rico.

The majority of infection by the human immunodeficiency virus (HIV-1) across the world occurs by heterosexual transmission and is likely mediated by virus present in genital secretions. In spite of this, infection is followed by clinical markers of the virus present in blood, which may not be representative of the virus involved in transmission. In fact, several studies have demonstrated that the genital tract represents a unique compartment for the virus. We assessed the relationship between immune system integrity, represented by CD4+ T cell counts, and the maintenance of viral compartmentalization between plasma and vaginal fluid virus in treatment naïve women from the Dominican Republic infected by the heterosexual transmission route. We cloned and sequenced cell free virus from plasma and genital fluid samples from six women to assess viral evolution, phylogenetic relatedness, and calculated co-receptor use for the C2V3 region of the envelope. Our analyses demonstrated plasma and vaginal fluid virus compartments remained intact only in samples from women with CD4+ T cell counts over 350 cells/μl. The majority of viral forms were predicted to use the CCR5 co-receptor, although several dual tropic forms were also identified. None of the clones were found to use the CXCR4 co-receptor even though many of the patients showed severe disease. Our findings lend further support to the role of an intact immune system in maintaining compartmentalization across blood and genital quasispecies and provide a compelling rationale to specifically consider genital tract viral forms in therapeutic and vaccine research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.virol.2011.06.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3204360PMC
September 2011

Eosinophilic esophagitis: updated consensus recommendations for children and adults.

J Allergy Clin Immunol 2011 Jul 7;128(1):3-20.e6; quiz 21-2. Epub 2011 Apr 7.

Center for Pediatric Eosinophilic Disorders, Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

Eosinophilic esophagitis (EoE) is a clinicopathologic condition of increasing recognition and prevalence. In 2007, a consensus recommendation provided clinical and histopathologic guidance for the diagnosis and treatment of EoE; however, only a minority of physicians use the 2007 guidelines, which require fulfillment of both histologic and clinical features. Since 2007, the number of EoE publications has doubled, providing new disease insight. Accordingly, a panel of 33 physicians with expertise in pediatric and adult allergy/immunology, gastroenterology, and pathology conducted a systematic review of the EoE literature (since September 2006) using electronic databases. Based on the literature review and expertise of the panel, information and recommendations were provided in each of the following areas of EoE: diagnostics, genetics, allergy testing, therapeutics, and disease complications. Because accumulating animal and human data have provided evidence that EoE appears to be an antigen-driven immunologic process that involves multiple pathogenic pathways, a new conceptual definition is proposed highlighting that EoE represents a chronic, immune/antigen-mediated disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. The diagnostic guidelines continue to define EoE as an isolated chronic disorder of the esophagus diagnosed by the need of both clinical and pathologic features. Patients commonly have high rates of concurrent allergic diatheses, especially food sensitization, compared with the general population. Proved therapeutic options include chronic dietary elimination, topical corticosteroids, and esophageal dilation. Important additions since 2007 include genetic underpinnings that implicate EoE susceptibility caused by polymorphisms in the thymic stromal lymphopoietin protein gene and the description of a new potential disease phenotype, proton pump inhibitor-responsive esophageal eosinophila. Further advances and controversies regarding diagnostic methods, surrogate disease markers, allergy testing, and treatment approaches are discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jaci.2011.02.040DOI Listing
July 2011

Short communication: Lack of immune response in rapid progressor morphine-dependent and SIV/SHIV-infected rhesus macaques is correlated with downregulation of TH1 cytokines.

AIDS Res Hum Retroviruses 2010 Aug;26(8):919-22

AIDS Research Program, Ponce School of Medicine, Ponce, Puerto Rico 00732-7004, USA.

Our previous studies have shown two distinct disease patterns (rapid and normal onset of clinical symptoms) in morphine-dependent SHIV/SIV-inoculated rhesus macaques. We have also shown that control as well as 50% of morphine-dependent macaques (normal progressor) developed humoral and cellular immune responses whereas the other half of the morphine-dependent macaques (rapid progressor) did not develop antiviral immune responses after infection with SIV/SHIV. In the present study, we analyzed the association between cytokine production, immune response, and disease progression. To study the immunological effects of morphine at cytokine levels in the context of a lentiviral infection, we inoculated rhesus macaques with a mixture of SHIV(KU-18), SHIV(89.6)P, and SIV/17E-Fr. These animals were followed for a period of 56 weeks for cytokine level production in plasma. Drug-dependent rapid disease progressors exhibited an increase in IL-18 and IL-1Ra and a decrease in IL-12 levels in the plasma. Morphine-dependent normal progressors and control macaques exhibited an increase in both IL-18 and IL-12, whereas IL-Ra levels remained constant throughout the observation period. These results suggest that rapid disease progression in relation to morphine dependency may be the result of an altered cytokine profile.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/aid.2010.0012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2957625PMC
August 2010