Publications by authors named "David Matson"

60 Publications

Levels of Urgency for Orthopaedic Procedures: Reliability and Adoption of a Consensus-driven Classification.

J Am Acad Orthop Surg 2020 Nov 25. Epub 2020 Nov 25.

From the Department of Orthopedic Surgery, University of Minnesota, and M Health Fairview Hospitals, Minneapolis, MN.

Introduction: The current COVID-19 disease pandemic has delayed nonurgent orthopaedic procedures to adequately care for those affected by the severe acute respiratory syndrome coronavirus 2, resulting in a backlog in orthopaedic surgical care. As the capacity for orthopaedic surgeries expands or contracts, allocation of limited resources in a manner that adequately reflects medical necessity and urgency is paramount. An orthopaedic surgery-specific prioritization schema with proven reliability is lacking. The primary aim of this study was to assess the reliability of a newly developed prioritization list used for the phased reinstatement of orthopaedic surgical procedures during the COVID-19 pandemic and afterward. The secondary aim was to report its implementation.

Methods: A consensus-based, orthopaedic surgery-specific, tiered prioritization list reflecting various levels of urgency was created by a committee of orthopaedic surgeons covering all subspecialties and representing academic, multispecialty, and private community practices. Reliability was tested for 63 randomized cases representing all orthopaedic subspecialties. Four raters evaluated the cases independently at two separate time points, at least one week apart. Fleiss kappa was used to assess intrarater and interrater agreement. Implementation were assessed by surveying both surgeons and the surgery scheduling administrative personnel at each surgical facility within a large health system for any adoption issues.

Results: Case distributions within tiers 1, 2, 3, and 4 were 35%, 14%, 27%, and 24%, respectively. Interrater agreement ranged from 0.63 (95% confidence interval [CI] 0.57 to 0.69) to 0.72 (95% CI 0.66 to 0.78) for the ratings. Intrarater reliability ranged from 0.62 to 1.0. The highest levels of agreement were in tiers 1, 4, and the subspecialties oncology and foot/ankle. The time from development to full scale adoption and implementation by all orthopaedic surgeons was rapid.

Discussion: This tiered prioritization list for orthopaedic procedures is both adoptable and reliable during the phased reinstatement of procedures during the COVID-19 pandemic and afterward. Further refinements may enhance utility.

Levels Of Evidence: Reliability study: Level I (Evid Based Spine Care J 2014 October;5(2):166. doi: 10.1055/s-0034-1394106).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5435/JAAOS-D-20-00631DOI Listing
November 2020

Sacral Dysmorphism and Lumbosacral Transitional Vertebrae (LSTV) Review.

Int J Spine Surg 2020 Feb 10;14(Suppl 1):14-19. Epub 2020 Feb 10.

Department of Orthopaedic Surgery, University of Minnesota, Minneapolis, Minnesota.

Background: Anatomic variation in the relationship between the lumbar spine and sacrum was first described in the literature nearly a century ago and continues to play an important role in spine deformity, low back pain (LBP), and pelvic trauma. This review will focus on the clinical and surgical implications of abnormal lumbosacral anatomy in the context of sacroiliac joint (SIJ) disease, spine deformity, and pelvic trauma.

Methods: A PubMed search using the keywords "lumbosacral transitional vertebrae," "LSTV," "transitional lumbosacral vertebrae," "TLSV," and "sacral dysmorphism" was performed. The articles presented here were evaluated by the authors.

Clinical Significance: The prevalence of LSTV varies widely in the literature from 3.9-% to 35.6% in the spine literature, and sacral dysmorphism is described in upwards of 50% of the population in the trauma literature. The relationship between LSTV and LBP is well established. While there is no agreed-on etiology, the source of pain is multifactorial and may be related to abnormal biomechanics and alignment, disc degeneration, and arthritic changes.

Surgical Implications: Understanding abnormal lumbosacral anatomy is crucial for preoperative planning of SIJ fusion, spine deformity, and pelvic trauma surgery. LSTV can alter spinopelvic parameters crucial in planning spine deformity correction. Traditional safe zones for sacroiliac screw placement do not apply in the first sacral segment in sacral dysmorphism and risk iatrogenic nerve injury.

Conclusions: LSTV and sacral dysmorphism are common anatomic variants found in the general population. Abnormal lumbosacral anatomy plays a significant role in clinical evaluation of LBP and surgical planning in SIJ fusion, spine deformity, and pelvic trauma. Further studies evaluating the influence of abnormal lumbosacral anatomy on LBP and surgical technique would help guide treatment for these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14444/6075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041668PMC
February 2020

The discovery of benzoxazine sulfonamide inhibitors of Na1.7: Tools that bridge efficacy and target engagement.

Bioorg Med Chem Lett 2017 08 1;27(15):3477-3485. Epub 2017 Jun 1.

Department of Medicinal Chemistry, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, United States.

The voltage-gated sodium channel Na1.7 has received much attention from the scientific community due to compelling human genetic data linking gain- and loss-of-function mutations to pain phenotypes. Despite this genetic validation of Na1.7 as a target for pain, high quality pharmacological tools facilitate further understanding of target biology, establishment of target coverage requirements and subsequent progression into the clinic. Within the sulfonamide class of inhibitors, reduced potency on rat Na1.7 versus human Na1.7 was observed, rendering in vivo rat pharmacology studies challenging. Herein, we report the discovery and optimization of novel benzoxazine sulfonamide inhibitors of human, rat and mouse Na1.7 which enabled pharmacological assessment in traditional behavioral rodent models of pain and in turn, established a connection between formalin-induced pain and histamine-induced pruritus in mice. The latter represents a simple and efficient means of measuring target engagement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2017.05.070DOI Listing
August 2017

Pharmacologic Characterization of AMG8379, a Potent and Selective Small Molecule Sulfonamide Antagonist of the Voltage-Gated Sodium Channel Na1.7.

J Pharmacol Exp Ther 2017 07 4;362(1):146-160. Epub 2017 May 4.

Department of Neuroscience (T.J.K., R.Y., S.A, C.P.I., M.J., D.J., J.H.L., S.G.L., J.Li., D.L., J.Lu., D.M., D.O., K.T., J.W., V.Y., D.X.D.Z., R.T.F., B.D.M.), Department of Medicinal Chemistry (M.M.W.), and Department of Pharmacokinetics and Drug Metabolism (X.B., V.B., J.R.), Amgen Inc., Cambridge, Massachusetts and Thousand Oaks, California

Potent and selective antagonists of the voltage-gated sodium channel Na1.7 represent a promising avenue for the development of new chronic pain therapies. We generated a small molecule atropisomer quinolone sulfonamide antagonist AMG8379 and a less active enantiomer AMG8380. Here we show that AMG8379 potently blocks human Na1.7 channels with an IC of 8.5 nM and endogenous tetrodotoxin (TTX)-sensitive sodium channels in dorsal root ganglion (DRG) neurons with an IC of 3.1 nM in whole-cell patch clamp electrophysiology assays using a voltage protocol that interrogates channels in a partially inactivated state. AMG8379 was 100- to 1000-fold selective over other Na family members, including Na1.4 expressed in muscle and Na1.5 expressed in the heart, as well as TTX-resistant Na channels in DRG neurons. Using an ex vivo mouse skin-nerve preparation, AMG8379 blocked mechanically induced action potential firing in C-fibers in both a time-dependent and dose-dependent manner. AMG8379 similarly reduced the frequency of thermally induced C-fiber spiking, whereas AMG8380 affected neither mechanical nor thermal responses. In vivo target engagement of AMG8379 in mice was evaluated in multiple Na1.7-dependent behavioral endpoints. AMG8379 dose-dependently inhibited intradermal histamine-induced scratching and intraplantar capsaicin-induced licking, and reversed UVB radiation skin burn-induced thermal hyperalgesia; notably, behavioral effects were not observed with AMG8380 at similar plasma exposure levels. AMG8379 is a potent and selective Na1.7 inhibitor that blocks sodium current in heterologous cells as well as DRG neurons, inhibits action potential firing in peripheral nerve fibers, and exhibits pharmacodynamic effects in translatable models of both itch and pain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/jpet.116.239590DOI Listing
July 2017

Crystal structures of human glycine receptor α3 bound to a novel class of analgesic potentiators.

Nat Struct Mol Biol 2017 02 19;24(2):108-113. Epub 2016 Dec 19.

Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, USA.

Current therapies to treat persistent pain and neuropathic pain are limited by poor efficacy, side effects and risk of addiction. Here, we present a novel class of potent selective, central nervous system (CNS)-penetrant potentiators of glycine receptors (GlyRs), ligand-gated ion channels expressed in the CNS. AM-1488 increased the response to exogenous glycine in mouse spinal cord and significantly reversed mechanical allodynia induced by nerve injury in a mouse model of neuropathic pain. We obtained an X-ray crystal structure of human homopentameric GlyRα3 in complex with AM-3607, a potentiator of the same class with increased potency, and the agonist glycine, at 2.6-Å resolution. AM-3607 binds a novel allosteric site between subunits, which is adjacent to the orthosteric site where glycine binds. Our results provide new insights into the potentiation of cysteine-loop receptors by positive allosteric modulators and hold promise in structure-based design of GlyR modulators for the treatment of neuropathic pain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nsmb.3329DOI Listing
February 2017

Inhibition of Inactive States of Tetrodotoxin-Sensitive Sodium Channels Reduces Spontaneous Firing of C-Fiber Nociceptors and Produces Analgesia in Formalin and Complete Freund's Adjuvant Models of Pain.

PLoS One 2015 17;10(9):e0138140. Epub 2015 Sep 17.

Department of Diagnostics and Biological Sciences, University of Minnesota School of Dentistry, Minneapolis, Minnesota, United States of America.

While genetic evidence shows that the Nav1.7 voltage-gated sodium ion channel is a key regulator of pain, it is unclear exactly how Nav1.7 governs neuronal firing and what biophysical, physiological, and distribution properties of a pharmacological Nav1.7 inhibitor are required to produce analgesia. Here we characterize a series of aminotriazine inhibitors of Nav1.7 in vitro and in rodent models of pain and test the effects of the previously reported "compound 52" aminotriazine inhibitor on the spiking properties of nociceptors in vivo. Multiple aminotriazines, including some with low terminal brain to plasma concentration ratios, showed analgesic efficacy in the formalin model of pain. Effective concentrations were consistent with the in vitro potency as measured on partially-inactivated Nav1.7 but were far below concentrations required to inhibit non-inactivated Nav1.7. Compound 52 also reversed thermal hyperalgesia in the complete Freund's adjuvant (CFA) model of pain. To study neuronal mechanisms, electrophysiological recordings were made in vivo from single nociceptive fibers from the rat tibial nerve one day after CFA injection. Compound 52 reduced the spontaneous firing of C-fiber nociceptors from approximately 0.7 Hz to 0.2 Hz and decreased the number of action potentials evoked by suprathreshold tactile and heat stimuli. It did not, however, appreciably alter the C-fiber thresholds for response to tactile or thermal stimuli. Surprisingly, compound 52 did not affect spontaneous activity or evoked responses of Aδ-fiber nociceptors. Results suggest that inhibition of inactivated states of TTX-S channels, mostly likely Nav1.7, in the peripheral nervous system produces analgesia by regulating the spontaneous discharge of C-fiber nociceptors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0138140PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575030PMC
June 2016

Analysis by rotavirus gene 6 reverse transcriptase-polymerase chain reaction assay of rotavirus-positive gastroenteritis cases observed during the vaccination phase of the Rotavirus Efficacy and Safety Trial (REST).

Hum Vaccin Immunother 2014 ;10(8):2267-75

a Department of Pediatrics; Eastern Virginia Medical School; Norfolk, VA USA.

During the vaccination phase of the Rotavirus Efficacy and Safety Trial (REST), the period between the administration of dose 1 through 13 days after the administration of dose 3, there were more wild-type rotavirus gastroenteritis (RVGE) cases among vaccine recipients compared with placebo recipients using the protocol-specified microbiological plaque assay in the clinical-efficacy cohort, a subset of subjects where vaccine efficacy against RVGE of any severity was assessed. In this study, a rotavirus genome segment 6-based reverse transcriptase-polymerase chain reaction assay was applied post hoc to clarify the accuracy of type categorization of all these RVGE cases in vaccine recipients during the vaccination phase of REST. The assay characterized 147 (90%) of 163 re-assayed RVGE cases or rotavirus-associated health care contacts as type-determinable: either wild-type or vaccine-type rotavirus strains. In the clinical-efficacy cohort (N = 5673), 19 (18.8%) of 101 samples from RVGE cases contained wild-type rotavirus, 70 (69.3%) vaccine virus, and 12 (11.9%) were indeterminable. In the large-scale cohort (N = 68,038), 10 (34.5%) of 29 samples from RVGE-related health care contacts contained wild-type rotavirus strains, 15 (51.7%) vaccine-type rotavirus strains, and 4 (13.8%) were indeterminable. Of the 33 samples from RVGE cases in placebo recipients, all were confirmed to contain wild-type rotaviruses. Altogether, this post-hoc re-evaluation showed that the majority (75%) of type-determinable RVGE cases or health care contacts that occurred during the vaccination phase of REST in vaccine recipients were associated with vaccine-type rotavirus strains rather than wild-type rotavirus strains.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4161/hv.29176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896777PMC
July 2015

Global Nav1.7 knockout mice recapitulate the phenotype of human congenital indifference to pain.

PLoS One 2014 4;9(9):e105895. Epub 2014 Sep 4.

Department of Neuroscience, Amgen Inc., Cambridge, Massachusetts, United States of America.

Clinical genetic studies have shown that loss of Nav1.7 function leads to the complete loss of acute pain perception. The global deletion is reported lethal in mice, however, and studies of mice with promoter-specific deletions of Nav1.7 have suggested that the role of Nav1.7 in pain transduction depends on the precise form of pain. We developed genetic and animal husbandry strategies that overcame the neonatal-lethal phenotype and enabled construction of a global Nav1.7 knockout mouse. Knockouts were anatomically normal, reached adulthood, and had phenotype wholly analogous to human congenital indifference to pain (CIP): compared to littermates, knockouts showed no defects in mechanical sensitivity or overall movement yet were completely insensitive to painful tactile, thermal, and chemical stimuli and were anosmic. Knockouts also showed no painful behaviors resulting from peripheral injection of nonselective sodium channel activators, did not develop complete Freund's adjuvant-induced thermal hyperalgesia, and were insensitive to intra-dermal histamine injection. Tetrodotoxin-sensitive sodium current recorded from cell bodies of isolated sensory neurons and the mechanically-evoked spiking of C-fibers in a skin-nerve preparation each were reduced but not eliminated in tissue from knockouts compared to littermates. Results support a role for Nav1.7 that is conserved between rodents and humans and suggest several possibly translatable biomarkers for the study of Nav1.7-targeted therapeutics. Results further suggest that Nav1.7 may retain its key role in persistent as well as acute forms of pain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0105895PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154897PMC
April 2015

The public health leadership certificate: a public health and primary care interprofessional training opportunity.

Health Promot Pract 2014 Mar;15(1 Suppl):64S-70S

1Eastern Virginia Medical School, Norfolk, VA, USA.

This article describes a public health leadership certificate curriculum developed by the Commonwealth Public Health Training Center for employees in public health and medical trainees in primary care to share didactic and experiential learning. As part of the program, trainees are involved in improving the health of their communities and thus gain a blended perspective on the effectiveness of interprofessional teams in improving population health. The certificate curriculum includes eight one-credit-hour didactic courses offered through an MPH program and a two-credit-hour, community-based participatory research project conducted by teams of trainees under the mentorship of health district directors. Fiscal sustainability is achieved by sharing didactic courses with MPH degree students, thereby enabling trainees to take advantage of a reduced, continuing education tuition rate. Public health employee and primary care trainees jointly learn knowledge and skills required for community health improvement in interprofessional teams and gain an integrated perspective through opportunities to question assumptions and broaden disciplinary approaches. At the same time, the required community projects have benefited public health in Virginia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1524839913509275DOI Listing
March 2014

Burden of rotavirus hospitalisations in young children in three paediatric hospitals in the United States determined by active surveillance compared to standard indirect methods.

J Paediatr Child Health 2012 Aug 25;48(8):698-704. Epub 2012 Apr 25.

Graduate Program in Public Health, Eastern Virginia Medical School and Old Dominion University, Norfolk, VA 23501, USA.

Aim:   The number of rotavirus hospitalisations is usually estimated from assigned diagnosis codes for gastroenteritis despite lack of validation for these indirect methods. Reliable estimates before and after introduction of vaccines are needed to quantify the absolute impact of new immunisation programs.

Methods:   This 2-year study conducted at three hospitals prior to the licensure of the rotavirus vaccines in the USA compared two indirect methods for estimating hospitalisations for rotavirus gastroenteritis with estimates derived from prospective recruitment of children presenting with diarrhoea, vomiting or fever. For active surveillance, rotavirus gastroenteritis was confirmed by demonstration of stool antigen. The indirect residual and proportional methods assumed rotavirus to have caused a proportion of hospitalisations coded as acute gastroenteritis identified from computerised records.

Results:   There were 447 rotavirus hospitalisations among inpatients 31 days through 4 years of age admitted with vomiting and/or diarrhoea, compared with 306 and 228 hospitalisations identified by the two indirect methods. Only 52% of children hospitalised with gastroenteritis received a qualifying diagnosis code at discharge. Relative to active surveillance, the sensitivity and specificity (95% confidence interval (CI)) in identifying rotavirus-attributable hospitalisations was 45% (95% CI: 43-48%) and 89% (88-90%) for the residual method and 34% (30-39%) and 92% (90-94%) for the proportional method.

Conclusions:   Many children admitted to the hospital with diarrhoea, vomiting or fever were not assigned discharge codes for acute gastroenteritis. Consequently, standard indirect methods missed a substantial number of rotavirus-associated hospitalisations, thereby underestimating the absolute number of children who could potentially benefit from vaccination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1440-1754.2012.02445.xDOI Listing
August 2012

Discovery and optimization of aminopyrimidinones as potent and state-dependent Nav1.7 antagonists.

Bioorg Med Chem Lett 2012 Jan 6;22(2):1055-60. Epub 2011 Dec 6.

Department of Chemistry Research and Discovery, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA.

Clinical genetic data have shown that the product of the SCN9A gene, voltage-gated sodium ion channel Nav1.7, is a key control point for pain perception and a possible target for a next generation of analgesics. Sodium channels, however, historically have been difficult drug targets, and many of the existing structure-activity relationships (SAR) have been defined on pharmacologically modified channels with indirect reporter assays. Herein we describe the discovery, optimization, and SAR of potent aminopyrimidinone Nav1.7 antagonists using electrophysiology-based assays that measure the ligand-receptor interaction directly. Within this series, rapid functionalization at the polysubstituted aminopyrimidinone head group enabled exploration of SAR and of pharmacokinetic properties. Lead optimized N-Me-aminopyrimidinone 9 exhibited improved Nav1.7 potency, minimal off-target hERG liability, and improved rat PK properties.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2011.11.111DOI Listing
January 2012

Identification of a potent, state-dependent inhibitor of Nav1.7 with oral efficacy in the formalin model of persistent pain.

J Med Chem 2011 Jul 2;54(13):4427-45. Epub 2011 Jun 2.

Department of Chemistry Research and Discovery, Amgen Inc., Cambridge, Massachusetts 02142, United States.

Clinical human genetic studies have recently identified the tetrodotoxin (TTX) sensitive neuronal voltage gated sodium channel Nav1.7 (SCN9A) as a critical mediator of pain sensitization. Herein, we report structure-activity relationships for a novel series of 2,4-diaminotriazines that inhibit hNav1.7. Optimization efforts culminated in compound 52, which demonstrated pharmacokinetic properties appropriate for in vivo testing in rats. The binding site of compound 52 on Nav1.7 was determined to be distinct from that of local anesthetics. Compound 52 inhibited tetrodotoxin-sensitive sodium channels recorded from rat sensory neurons and exhibited modest selectivity against the hERG potassium channel and against cloned and native tetrodotoxin-resistant sodium channels. Upon oral administration to rats, compound 52 produced dose- and exposure-dependent efficacy in the formalin model of pain.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm200018kDOI Listing
July 2011

Efficacy of the pentavalent rotavirus vaccine, RotaTeq® (RV5), between doses of a 3-dose series and with less than 3 doses (incomplete regimen).

Hum Vaccin 2011 May 1;7(5):563-8. Epub 2011 May 1.

The Alpert Medical School of Brown University and Hasbro Children's Hospital, Providence, RI, USA.

Post-hoc analyses of the Rotavirus Efficacy and Safety Trial (REST) were conducted to determine whether the pentavalent rotavirus vaccine (RV5) confers early protection against rotavirus gastroenteritis (RVGE) before completion of the 3-dose regimen. To evaluate the efficacy of RV5 between doses in reducing the rates of RVGE-related hospitalizations and emergency department (ED) visits in infants who ultimately received all 3 doses of RV5/placebo, events occurring from 2 weeks after the first and second doses to receipt of the subsequent dose (Analysis A) and events occurring from 2 weeks after the first and second doses to 2 weeks after the subsequent dose (Analysis B) were analyzed. In Analysis A, RV5 reduced the rates of combined hospitalizations and ED visits for G1-G4 RVGE or RVGE regardless of serotype between doses 1 and 2 by 100% (95% confidence interval [CI]: 72-100%) or 82% (95% CI: 39-97%), respectively, and between doses 2 and 3, RV5 reduced the rates of combined hospitalizations and ED visits for G1-G4 RVGE or RVGE regardless of serotype by 91% (95% CI: 63-99%) or 84% (95% CI: 54-96%), respectively. Similar rate reductions were observed in Analysis B. These data suggest that RV5 provides a high level of protection between doses against hospitalizations and ED visits for RVGE starting as early as 14 days after the first dose.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4161/hv.7.5.15406DOI Listing
May 2011

Rotavirus genotypes among hospitalized children in Egypt, 2000-2002.

J Infect Dis 2010 Sep;202 Suppl:S263-5

Center for Pediatric Research, Norfolk, Virginia, USA.

Rotavirus type surveillance is essential to assess the success of rotavirus vaccines. Rotavirus strains collected in 2000-2002 during hospital-based surveillance for diarrhea in Egyptian children were genotyped. Of the 259 (25.2%) rotavirus-positive specimens, 82.4% were common strains (G1p[8], G2p[4], G4p[8]), and the emergent G9 type was detected in 5.3% of samples.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1086/653581DOI Listing
September 2010

Robustness of the healthcare utilization results from the Rotavirus Efficacy and Safety Trial (REST) evaluating the human-bovine (WC3) reassortant pentavalent rotavirus vaccine (RV5).

BMC Pediatr 2010 Jun 11;10:42. Epub 2010 Jun 11.

Merck Research Laboratories, West Point, Pennsylvania, USA.

Background: The Rotavirus Efficacy and Safety Trial was a placebo-controlled Phase III study that evaluated the safety and efficacy of a three-dose pentavalent rotavirus vaccine (RV5) including its effect on healthcare utilization for rotavirus gastroenteritis (RVGE). The per-protocol (PP) analyses, which counted events occurring 14 days after dose 3 among infants without protocol violations, have already been published. This paper evaluates the consistency of the healthcare utilization results based on the modified intention to treat (MITT) analyses with the PP analyses. The MITT analyses include all infants receiving at least one dose of vaccine or placebo and follow-up begins after dose 1. The paper also explores the consistency of the results for different subgroups of the study population with different types of surveillance.

Methods: Data on healthcare utilization for acute gastroenteritis were collected via telephone interviews after administration of the first dose. Parents were either contacted every 6 weeks or every 2 weeks depending on the substudy in which they were enrolled. Those contacted every 2 weeks were also asked to complete symptom diaries. Poisson regression was used to evaluate the effect of RV5 on the rates of RVGE-associated healthcare encounters in all of the analyses.

Results: In the first 2 years after vaccination, RV5 reduced the combined rate of hospitalizations and emergency department (ED) visits 88.9% (95% CI: 84.9, 91.9) for all RVGE regardless of serotype in the MITT analysis compared with a 94.5% (95% CI: 91.2, 96.6) reduction based on the G1-G4 PP analysis. By type of surveillance, the rate reductions for the G1-G4 PP analysis were 91.0% (95% CI: 81.7, 95.5) and 95.9% (95% CI: 92.2, 97.8) among parents contacted every 2 weeks (number evaluable = 4,451) and every 6 weeks (number evaluable = 52,683) respectively.

Conclusions: Our analyses demonstrated that the effect of RV5 on reducing the rate of hospitalizations and ED visits based on the MITT analyses were generally consistent with the PP analyses. The rate of events for subgroups with different intensities of surveillance differed but the effect of RV5 on the relative rate reductions were consistent with the results that have already been published.

Trial Registration: ClinicalTrials.gov number, NCT00090233.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1471-2431-10-42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2905347PMC
June 2010

Locomotor activity in a novel environment as a test of inflammatory pain in rats.

Methods Mol Biol 2010 ;617:67-78

Amgen Inc, Cambridge, MA, USA.

Creating a robust and unbiased assay for the study of current and novel analgesics has been a daunting task. Traditional rodent models of pain and inflammation typically rely on a negative reaction to various forms of evoked stimuli to elicit a pain response and are subject to rater interpretation. Recently, models such as weight bearing and gait analysis have been developed to address these drawbacks while detecting a drug's analgesic properties. We have recently developed the Reduction of Spontaneous Activity by Adjuvant (RSAA) model as a quick, unbiased method for the testing of potential analgesics. Rats, following prior administration of an activity-decreasing inflammatory insult, will positively increase spontaneous locomotor exploration when given single doses of known analgesics. The RSAA model capitalizes on a rat's spontaneous exploratory behavior in a novel environment with the aid of computer tracking software to quantify movement and eliminate rater bias.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/978-1-60327-323-7_6DOI Listing
June 2010

Discovery of novel 6,6-heterocycles as transient receptor potential vanilloid (TRPV1) antagonists.

J Med Chem 2010 Apr;53(8):3330-48

Neurogen Corporation, 35 Northeast Industrial Road, Branford, Connecticut 06405, USA.

The transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is a nonselective cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation in an attempt to identify novel agents for pain treatment. The design and synthesis of a series of novel TRPV1 antagonists with a variety of different 6,6-heterocyclic cores is described, and an extensive evaluation of the pharmacological and pharmacokinetic properties of a number of these compounds is reported. For example, the 1,8-naphthyridine 52 was characterized as an orally bioavailable and brain penetrant TRPV1 antagonist. In vivo, 52 fully reversed carrageenan-induced thermal hyperalgesia (CITH) in rats and dose-dependently potently reduced complete Freund's adjuvant (CFA) induced chronic inflammatory pain after oral administration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jm100051gDOI Listing
April 2010

Pharmacological effects of nonselective and subtype-selective nicotinic acetylcholine receptor agonists in animal models of persistent pain.

Pain 2010 Apr 18;149(1):33-49. Epub 2010 Feb 18.

Department of Neuroscience, Amgen, Inc., 360 Binney Street, Cambridge MA 02142, USA Department of Neuroscience, Amgen, Inc., One Amgen Center Drive, Thousand Oaks CA 91320, USA Department of Protein Sciences, Amgen, Inc., One Amgen Center Drive, Thousand Oaks CA 91320, USA Department of Lead Discovery, Amgen, Inc., Josef-Engert-St. 11, D-93053 Regensburg, Germany Department of Inflammation, Amgen, Inc., One Amgen Center Drive, Thousand Oaks CA 91320, USA Department of Pharmacokinetics and Drug Metabolism, Amgen, Inc., 360 Binney Street, Cambridge MA 02142, USA Department of Chemistry Research and Development, Amgen, Inc., 360 Binney Street, Cambridge MA 02142, USA.

Nicotinic acetylcholine receptors (nAChRs) are longstanding targets for a next generation of pain therapeutics, but the nAChR subtypes that govern analgesia remain unknown. We tested a series of nicotinic agonists, including many molecules used or tried clinically, on a panel of cloned neuronal nAChRs for potency and selectivity using patch-clamp electrophysiology and a live cell-based fluorescence assay. Nonselective nicotinic agonists as well as compounds selective either for alpha4beta2 or for alpha7 nAChRs were then tested in the formalin and complete Freund's adjuvant models of pain. Nonselective nAChR agonists ABT-594 and varenicline were effective analgesics. By contrast, the selective alpha4beta2 agonist ispronicline and a novel alpha4beta2-selective potentiator did not appear to produce analgesia in either model. alpha7-selective agonists reduced the pain-related endpoint, but the effect could be ascribed to nonspecific reduction of movement rather than to analgesia. Neither selective nor nonselective alpha7 nicotinic agonists affected the release of pro-inflammatory cytokines in response to antigen challenge. Electrophysiological recordings from spinal cord slice showed a strong nicotine-induced increase in inhibitory synaptic transmission that was mediated partially by alpha4beta2 and only minimally by alpha7 subtypes. Taken with previous studies, the results suggest that agonism of alpha4beta2 nAChRs is necessary but not sufficient to produce analgesia, and that the spinal cord is a key site where the molecular action of nAChRs produces analgesia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pain.2010.01.007DOI Listing
April 2010

A cross-sectional evaluation of the first cohort of young adults conceived by in vitro fertilization in the United States.

Fertil Steril 2010 Nov 16;94(6):2043-9. Epub 2010 Feb 16.

Graduate Program in Public Health, Eastern Virginia Medical School, Norfolk, Virginia 23507, USA.

Objective: To assess the quality of life and susceptibility for chronic disease development of the oldest generation of young adults conceived by IVF in the U.S.

Design: Cross-sectional.

Setting: Single tertiary clinic.

Patient(s): Young adults conceived by standard IVF between 1981 and 1990.

Intervention(s): Self-administered questionnaire.

Main Outcome Measure(s): Indicators of physical, psychologic, and behavioral health.

Result(s): A total of 173 (31%) of 560 eligible young adults completed the questionnaire. Mean age was 21.2 years (range 18-26 years) and male-to-female ratio was 3:4. A limited number were conceived through gamete donation but none through oocyte/embryo micromanipulation. Prevalence rates of overweight and obesity were 35% and 10%, respectively. More than 65% were ever diagnosed with a chronic condition; most diagnoses were psychiatric, ocular, respiratory, and cardiometabolic in nature. Almost 40% of respondents were lifetime smokers, 62% reported binge drinking in the previous year, and >90% were physically active in the preceding month. Survey participants were mostly similar to a subsample of the 1999-2004 National Health and Nutrition Examination Survey on selected health indicators.

Conclusion(s): Young adults conceived by IVF appear to be healthy and well adjusted, although the preponderance of psychologic health problems requires further investigation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.fertnstert.2009.12.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2955173PMC
November 2010

Impact of polycystic ovary syndrome on selected indicators of in vitro fertilization and intracytoplasmic sperm injection treatment success.

J Womens Health (Larchmt) 2009 May;18(5):717-23

Graduate Program in Public Health, Eastern Virginia Medical School, 1123 Lewis Hall, 700 W. Olney Road, Norfolk, VA 23501-1980, USA.

Objectives: To examine the effect of polycystic ovary syndrome (PCOS), a marker of the metabolic syndrome, on selected indicators of in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment success.

Methods: A retrospective cohort study was conducted using existing data on 69 IVF/ICSI treatment cycles undergone by PCOS women and a caliper-matched sample of 69 IVF/ICSI treatment cycles undergone by non-PCOS women over a 7-year period at a major fertility treatment center. Matching criteria were age and date at IVF/ICSI treatment initiation. Process and outcome measures were used to define successful IVF/ICSI treatment. Statistical significance was determined at an alpha level of 0.05.

Results: The total number of oocytes and the number of immature oocytes retrieved in the process of an IVF/ICSI cycle were significantly higher in the context of PCOS. No significant differences were observed among PCOS and non-PCOS groups on various IVF/ICSI cycle outcomes, including high-grade embryo, pregnancy achievement, miscarriage, and live birth status.

Conclusions: Although IVF/ICSI yields more oocytes in the context of PCOS, IVF/ICSI outcomes do not differ significantly by PCOS status. Prospective cohort studies are needed to examine short-term and long-term health effects of PCOS in the context of IVF/ICSI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/jwh.2008.1149DOI Listing
May 2009

Burden of rotavirus disease among children visiting pediatric emergency departments in Cincinnati, Ohio, and Oakland, California, in 1999-2000.

Pediatrics 2008 Nov;122(5):971-7

Division of Viral Diseases, Epidemic Intelligence Service Program, Office of Workforce and Career Development, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA.

Objective: We assessed the incidence of rotavirus disease requiring an emergency department visit among children <5 years of age.

Methods: We conducted active surveillance for acute gastroenteritis in pediatric emergency departments in Cincinnati, Ohio, and Oakland, California, from March 1999 to May 2000, among children 2 weeks to 59 months of age with acute diarrhea and/or vomiting. We obtained clinical and demographic information from participants and tested their stool specimens for rotavirus.

Results: Approximately 9% of all emergency department visits at the study sites were attributable to acute gastroenteritis. A total of 1433 children were eligible at the 2 sites; 85% were enrolled and 68% provided a stool specimen. Overall, rotavirus was detected in specimens from 27% of children (30% in Cincinnati and 24% in Oakland). Rotavirus detection was higher in bulk stools, compared with rectal swabs, at both Cincinnati (37% vs 23%) and Oakland (46% vs 18%). Patients with rotavirus had more-severe disease than did those with nonrotavirus gastroenteritis. We estimated that the mean annual incidence of emergency department visits attributable to rotavirus was 12 cases per 1000 children in Cincinnati and 15 cases per 1000 children in Oakland. Through extrapolation, we estimated that rotavirus infection causes approximately 260,910 emergency department visits per year among US children.

Conclusion: Active surveillance demonstrated that the burden of laboratory-confirmed rotavirus disease treated in emergency department settings among US children is substantial and greater than estimated previously.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1542/peds.2007-1609DOI Listing
November 2008

Automated assessment of ovarian follicles using a novel three-dimensional ultrasound software.

Fertil Steril 2009 Nov 19;92(5):1562-8. Epub 2008 Oct 19.

Jones Institute for Reproductive Medicine, Eastern Virginia Medical School, Norfolk, Virginia, USA.

Objective: To evaluate the accuracy, efficiency, and applicability of a new automated method of follicular assessment.

Design: Retrospective review of three-dimensional ultrasonographic ovarian volumes.

Setting: Academic center.

Patient(s): Three-dimensional ovarian volumes from patients undergoing IVF.

Intervention(s): Three-dimensional volumes of gonadotropin-stimulated ovaries and simulated ovarian follicles (SOFs) of known volume were evaluated with the new automated follicular assessment software (SonoAVC).

Main Outcome Measure(s): [1] Maximum absolute error for the SonoAVC in assessing the volumes of the SOFs; [2] correlations between the automated and manual follicular measurements; [3] time required to analyze all of the follicles in a given ovarian volume.

Result(s): The SOF of 4, 6, and 10 mm were evaluated. The SonoAVC's maximum absolute error for the volumes of the 4, 6, and 10 mm SOFs was 0 (0%), 0.01 (8.3%), and 0.02 (3.8%) cc, respectively. Three hundred forty-seven follicles, ranging in diameter from 2.3-32 mm, were evaluated. The correlation coefficient for the SonoAVC-generated relaxed follicular diameter and the manual measured mean follicular diameter was 0.99. The time required to analyze all of the follicles in a given ovarian volume for the automated and manual method was 133 versus 361 seconds, respectively.

Conclusion(s): The SonoAVC proved to be a very accurate and efficient way to measure ovarian follicles. The measurements obtained by the SonoAVC correlated extremely well with the manual measurements we obtained.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.fertnstert.2008.08.102DOI Listing
November 2009

Inhibition of norovirus replication by morpholino oligomers targeting the 5'-end of the genome.

Virology 2008 Oct 9;380(2):328-37. Epub 2008 Sep 9.

Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, DHHS, 50 South Drive, Bldg. 50, Room 6316, Bethesda, MD 20892, USA.

Noroviruses are an important cause of non-bacterial epidemic gastroenteritis, but no specific antiviral therapies are available. We investigated the inhibitory effect of phosphorodiamidiate morpholino oligomers (PMOs) targeted against norovirus sequences. A panel of peptide-conjugated PMOs (PPMOs) specific for the murine norovirus (MNV) genome was developed, and two PPMO compounds directed against the first AUG of the ORF1 coding sequence near the 5'-end of the genome proved effective in inhibiting MNV replication in cells. A consensus PPMO (designated Noro 1.1), designed to target the corresponding region of several diverse human norovirus genotypes, decreased the efficiency of protein translation in a cell-free luciferase reporter assay and inhibited Norwalk virus protein expression in replicon-bearing cells. Our data suggest that PPMOs directed against the relatively conserved 5'-end of the norovirus genome may show broad antiviral activity against this genetically diverse group of viruses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.virol.2008.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3703767PMC
October 2008

Characterization of N-(adamantan-1-ylmethyl)-5-[(3R-amino-pyrrolidin-1-yl)methyl]-2-chloro-benzamide, a P2X7 antagonist in animal models of pain and inflammation.

J Pharmacol Exp Ther 2008 Dec 4;327(3):620-33. Epub 2008 Sep 4.

Department of Pharmacology, Neurogen Corporation, Branford, Connecticut, USA.

Recent evidence suggests that the P2X(7) receptor may play a role in the pathophysiology of preclinical models of pain and inflammation. Therefore, pharmacological agents that target this receptor may potentially have clinical utility as anti-inflammatory and analgesic therapy. We investigated and characterized the previously reported P2X(7) antagonist N-(adamantan-1-ylmethyl)-5-[(3R-amino-pyrrolidin-1-yl)methyl]-2-chloro-benzamide, hydrochloride salt (AACBA; GSK314181A). In vitro, AACBA was a relatively potent inhibitor of both human P2X(7)-mediated calcium flux and quinolinium,4-[(3-methyl-2(3H)-benzoxazolylidene)methyl]-1-[3-(triemethylammonio)propyl]-diiodide (YO-PRO-1) uptake assays, with IC(50) values of approximately 18 and 85 nM, respectively. Compared with the human receptor, AACBA was less potent at the rat P2X(7) receptor, with IC(50) values of 29 and 980 nM in the calcium flux and YO-PRO-1 assays, respectively. In acute in vivo models of pain and inflammation, AACBA dose-dependently reduced lipopolysaccharide-induced plasma interleukin-6 release and prevented or reversed carrageenan-induced paw edema and mechanical hypersensitivity. In chronic in vivo models of pain and inflammation, AACBA produced a prophylactic, but not therapeutic-like, prevention of the clinical signs and histopathological damage of collagen-induced arthritis. Finally, AACBA could not reverse L(5) spinal nerve ligation-induced tactile allodynia when given therapeutically. Consistent with previous literature, these results suggest that P2X(7) receptors do play a role in animal models of pain and inflammation. Further study of P2X(7) antagonists both in preclinical and clinical studies will help elucidate the role of the P2X(7) receptor in pain and inflammatory mechanisms and may help identify potential clinical benefits of such molecules.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/jpet.108.141853DOI Listing
December 2008

New frontiers in assessing pain and analgesia in laboratory animals.

Expert Opin Drug Discov 2008 Sep;3(9):1099-108

Neurogen Corporation, Branford, CT 06405, USA.

Background: Translating promising analgesic compounds into reliable pain therapeutics in humans is made particularly challenging by the difficulty in measuring the pain quantitatively. This problem is manifest not only in clinical settings in which patient pain assessments involve mostly subjective measures but also in preclinical settings wherein laboratory animals, most commonly rodents, are typically evaluated in stimulus-evoked response tests.

Objective: Given the limitations of traditional pain tests, we sought out new approaches to measure pain, and analgesia, in laboratory animals.

Methods: We reviewed the peer reviewed literature to identify pain tests that could be utilized in preclinical settings to understand the effects of new and established analgesics.

Results/conclusions: The tests identified include weight bearing differential, suppression of feeding, reduction in locomotor activity, gait analysis, conditioning models and functional MRI. Although the pharmacology of known and new analgesics has not been broadly established in these models, they hold the promise of better predictive utility for the discovery of pain relievers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1517/17460441.3.9.1099DOI Listing
September 2008

Aminoquinazolines as TRPV1 antagonists: modulation of drug-like properties through the exploration of 2-position substitution.

Bioorg Med Chem Lett 2008 Aug 15;18(16):4573-7. Epub 2008 Jul 15.

Neurogen Corporation, 35 N. E. Industrial Road, Branford, CT 06405, USA.

A focused SAR exploration of the lead 4-aminoquinazoline TRPV1 antagonist 2 led to the discovery of compound 18. In rats, compound 18 is readily absorbed following oral dosing and demonstrates excellent in vivo potency and efficacy in an acute inflammatory pain model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2008.07.036DOI Listing
August 2008

Efficacy of a pentavalent rotavirus vaccine in reducing rotavirus-associated health care utilization across three regions (11 countries).

Int J Infect Dis 2007 Nov;11 Suppl 2:S29-35

University of Tampere Medical School, Tampere, Finland.

Objective: To evaluate the effect of a human-bovine reassortant pentavalent rotavirus vaccine (PRV) on health care encounters in nearly 70 000 subjects randomized in three regions - Europe, the United States, and Latin America/the Caribbean - in the Rotavirus Efficacy and Safety Trial (REST).

Methods: Healthy 6- to 12-week-old infants received 3 doses of PRV or placebo at 4- to 10-week intervals. The exact binomial method for ratios of Poisson counts was used to evaluate the effect of PRV on the rate of rotavirus-related hospitalizations and emergency department (ED) visits involving rotavirus G-types 1-4 occurring > or =14 days after the third dose of vaccine for up to 2 years.

Results: In fully vaccinated infants, reductions in rotavirus-associated hospitalizations and ED visits were 94.7% (95% CI: 90.9, 96.9) in Europe, 94.9% (95% CI: 84.0, 98.9) in the United States, and 90.0% (95% CI: 29.4, 99.8) in the Latin American/Caribbean regions.

Conclusions: PRV reduced hospitalizations and ED visits within each region in REST. Results were consistent across regions and across the overall study cohort.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1201-9712(07)60019-8DOI Listing
November 2007

Virus-specific antiviral treatment for controlling severe and fatal outbreaks of feline calicivirus infection.

Am J Vet Res 2008 Jan;69(1):23-32

Laboratory for Calicivirus Studies, College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA.

Objective: To test the life-sparing and therapeutic effect of a parenterally administered virus-specific antiviral phosphorodiamidate morpholino oligomer (PMO) for treating kittens during outbreaks of severe viral disease.

Animals: 112 kittens of various sex and age in 4 trials involving 3 outbreaks of naturally developing caliciviral disease.

Procedures: Each trial provided an opportunity to investigate the disease. A calicivirus isolated from the liver of a cat that died with hemorrhage and hepatitis was sequenced, and a PMO that had sequence specificity complementary to a 5' region was synthesized. In vitro efficacy of the PMO was tested against the isolate, followed by 3 trials in outbreaks of severe caliciviral disease. The PMO was administered starting on day 1 of disease onset (0.7 to 5.0 mg/kg, SC, q 24 h) and continuing for up to 7 days. Survival time, clinical recovery, and caliciviral shedding were compared by use of various antiviral dosages. In a fourth trial involving nonfatal disease, a control treatment was administered for comparison.

Results: In vitro blockage of caliciviral replication by the PMO was dose dependent. In trials 1 to 3 in which survival was the endpoint, 47 of 59 cats receiving PMO survived but only 3 of 31 survived without PMO treatment. Antiviral treatment reduced viral shedding and hastened clinical recovery, as measured by weight gains and clinical condition.

Conclusions And Clinical Relevance: These data provided evidence that virus-specific PMOs were effective in treating kittens with severe Vesivirus disease and suggested a broader application for other viruses and species, including humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2460/ajvr.69.1.23DOI Listing
January 2008

Rotavirus antigenemia in children is associated with viremia.

PLoS Med 2007 Apr;4(4):e121

Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, United States of America.

Background: Antigenemia is commonly detected in rotavirus-infected children. Although rotavirus RNA has been detected in serum, definitive proof of rotavirus viremia has not been shown. We aimed to analyze a defined patient population to determine if infectious virus could be detected in sera from children with rotavirus antigenemia.

Methods And Findings: Serum samples obtained upon hospitalization from children with gastroenteritis (57 stool rotavirus-positive and 41 rotavirus-negative), children with diagnosed bronchiolitis of known (n = 58) or unknown (n = 17) viral etiology, children with noninfectious, nonchronic conditions (n = 17), and healthy adults (n = 28) were tested for rotavirus antigen by enzyme immunoassay (EIA). Results of serum antigen testing were assessed for association with clinical and immunological attributes of the children. Rotavirus antigenemia was detected in 90% (51/57) of children with rotavirus-positive stools, in 89% (8/9) of children without diarrhea but with rotavirus-positive stools, in 12% (2/17) of children with bronchiolitis of unknown etiology without gastroenteritis, and in 12% (5/41) of children with gastroenteritis but with rotavirus-negative stools. Antigenemia was not detected in sera from children with noninfectious nonchronic conditions, children with bronchiolitis of known etiology and no gastroenteritis, or healthy adults. Neither age nor timing of serum collection within eight days after onset of gastroenteritis significantly affected levels of antigenemia, and there was no correlation between antigenemia and viral genotype. However, there was a negative correlation between serum rotavirus antigen and acute rotavirus-specific serum IgA (r = -0.44, p = 0.025) and IgG (r = -0.40, p = 0.01) titers. We examined 11 antigen-positive and nine antigen-negative sera for infectious virus after three blind serial passages in HT-29 cells using immunofluorescence staining for rotavirus structural and nonstructural proteins. Infectious virus was detected in 11/11 (100%) sera from serum antigen-positive children and in two out of nine (22%) sera samples from antigen-negative children (p = 0.002).

Conclusions: Most children infected with rotavirus are viremic. The presence of viremia is directly related to the detection of antigenemia and is independent of the presence of diarrhea. Antigenemia load is inversely related to the titer of antirotavirus antibody in the serum. The finding of infectious rotavirus in the blood suggests extraintestinal involvement in rotavirus pathogenesis; however, the impact of rotavirus viremia on clinical manifestations of infection is unknown.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pmed.0040121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1852122PMC
April 2007