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1.
Lupus ; 30(11): 1756-1763, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34266320

ABSTRACT

OBJECTIVE: To compare the frequency of rare variants in genes of the pathophysiologically relevant endosomal Toll-like receptor (eTLR) pathway and any quantifiable differences in variant rarity, predicted deleteriousness, or molecular proximity in patients with systemic lupus erythematosus (SLE) and healthy controls. PATIENTS AND METHODS: 65 genes associated with the eTLR pathway were identified by literature search and pathway analysis. Using next generation sequencing techniques, these were compared in two randomised cohorts of patients with SLE (n = 114 and n = 113) with 197 healthy controls. Genetically determined ethnicity was used to normalise minor allele frequencies (MAF) for the identified genetic variants and these were then compared by their frequency: rare (MAF < 0.005), uncommon (MAF 0.005-0.02), and common (MAF >0.02). This was compared to the results for 65 randomly selected genes. RESULTS: Patients with SLE are more likely to carry a rare nonsynonymous variant affecting proteins within the eTLR pathway than healthy controls. Furthermore, individuals with SLE are more likely to have multiple rare variants in this pathway. There were no differences in rarity, Combined Annotation Dependent Depletion (CADD) score, or molecular proximity for rare eTLR pathway variants. CONCLUSIONS: Rare non-synonymous variants are enriched in patients with SLE in the eTLR pathway. This supports the hypothesis that SLE arises from several rare variants of relatively large effect rather than many common variants of small effect.


Subject(s)
Lupus Erythematosus, Systemic , Toll-Like Receptors , Endosomes/genetics , Gene Frequency , Genetic Predisposition to Disease , Genome-Wide Association Study , High-Throughput Nucleotide Sequencing , Humans , Lupus Erythematosus, Systemic/genetics , Mutation , Toll-Like Receptors/genetics
2.
Cell Rep Med ; 2(12): 100475, 2021 12 21.
Article in English | MEDLINE | ID: mdl-35028616

ABSTRACT

We identify an intronic deletion in VANGL1 that predisposes to renal injury in high risk populations through a kidney-intrinsic process. Half of all SLE patients develop nephritis, yet the predisposing mechanisms to kidney damage remain poorly understood. There is limited evidence of genetic contribution to specific organ involvement in SLE.1,2 We identify a large deletion in intron 7 of Van Gogh Like 1 (VANGL1), which associates with nephritis in SLE patients. The same deletion occurs at increased frequency in an indigenous population (Tiwi Islanders) with 10-fold higher rates of kidney disease compared with non-indigenous populations. Vangl1 hemizygosity in mice results in spontaneous IgA and IgG deposition within the glomerular mesangium in the absence of autoimmune nephritis. Serum transfer into B cell-deficient Vangl1+/- mice results in mesangial IgG deposition indicating that Ig deposits occur in a kidney-intrinsic fashion in the absence of Vangl1. These results suggest that Vangl1 acts in the kidney to prevent Ig deposits and its deficiency may trigger nephritis in individuals with SLE.


Subject(s)
Antibodies/adverse effects , Carrier Proteins/genetics , Gene Deletion , Kidney Diseases/pathology , Membrane Proteins/genetics , Adult , Aged , Animals , Biopsy , Cohort Studies , DNA Copy Number Variations/genetics , Homozygote , Humans , Introns/genetics , Kidney/metabolism , Kidney/pathology , Lupus Nephritis/genetics , Membrane Proteins/deficiency , Membrane Proteins/metabolism , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Risk Factors
3.
Sci Immunol ; 5(49)2020 07 24.
Article in English | MEDLINE | ID: mdl-32709702

ABSTRACT

The role unconventional T cells play in protective immunity in humans is unclear. Mucosal-associated invariant T (MAIT) cells are an unconventional T cell subset restricted to the antigen-presenting molecule MR1. Here, we report the discovery of a patient homozygous for a rare Arg31His (R9H in the mature protein) mutation in MR1 who has a history of difficult-to-treat viral and bacterial infections. MR1R9H was unable to present the potent microbially derived MAIT cell stimulatory ligand. The MR1R9H crystal structure revealed that the stimulatory ligand cannot bind due to the mutation lying within, and causing structural perturbation to, the ligand-binding domain of MR1. While MR1R9H could bind and be up-regulated by a MAIT cell inhibitory ligand, the patient lacked circulating MAIT cells. This shows the importance of the stimulatory ligand for MAIT cell selection in humans. The patient had an expanded γδ T cell population, indicating a compensatory interplay between these unconventional T cell subsets.


Subject(s)
Histocompatibility Antigens Class I/genetics , Intraepithelial Lymphocytes/immunology , Minor Histocompatibility Antigens/genetics , Mucosal-Associated Invariant T Cells , Primary Immunodeficiency Diseases/genetics , Humans , Point Mutation , Primary Immunodeficiency Diseases/immunology
4.
Nat Commun ; 10(1): 2201, 2019 05 17.
Article in English | MEDLINE | ID: mdl-31101814

ABSTRACT

Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Genetic Predisposition to Disease , Lupus Erythematosus, Systemic/genetics , Membrane Proteins/genetics , src-Family Kinases/genetics , Adaptor Proteins, Signal Transducing/metabolism , Adolescent , Adult , Animals , B-Lymphocytes/cytology , B-Lymphocytes/immunology , B-Lymphocytes/metabolism , Case-Control Studies , Cell Line , Cell Nucleus/immunology , Cell Nucleus/metabolism , Child , Disease Models, Animal , Female , Gene Frequency , HEK293 Cells , Healthy Volunteers , Humans , Interferon Regulatory Factors/immunology , Interferon Regulatory Factors/metabolism , Interferon Type I/immunology , Interferon Type I/metabolism , Lupus Erythematosus, Systemic/blood , Lupus Erythematosus, Systemic/immunology , Male , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mutation, Missense , Exome Sequencing , src-Family Kinases/metabolism
5.
J Pediatr Hematol Oncol ; 40(3): 208-215, 2018 04.
Article in English | MEDLINE | ID: mdl-29557918

ABSTRACT

We report the cardioprotective effects of moderate aerobic exercise from parallel pediatric murine models of doxorubicin (Doxo) exposure in non-tumor-bearing immune competent (NTB-IC) mice and tumor-bearing nude mice (TB-NM). In both models, animals at 4 weeks of age underwent Doxo treatment with or without 2 weeks of simultaneous exercise. In sedentary NTB-IC or TB-NM mice, Doxo treatment resulted in a statistically significant decrease in ejection fraction and fractional shortening compared with control animals. Interestingly, moderate aerobic exercise during Doxo treatment significantly mitigated decreases in ejection fraction and fractional shortening. In contrast, these protective effects of exercise were not observed when exercise was started after completion of Doxo treatments. Moreover, in the TB-NM model, Doxo caused a decrease in heart mass: tibia length and in body weight that was prevented by exercise, whereas NTB-IC mice exhibited no change in these measurements. Doxo delivery to the hearts of TB-NM was decreased by consistent moderate aerobic exercise before Doxo injection. These findings demonstrate the important but subtle differences in cardiotoxicity observed in different mouse models. Collectively, these results also strongly suggest that aerobic exercise during early-life Doxo exposure mitigates cardiotoxicity, possibly through altered delivery of Doxo to myocardial tissue.


Subject(s)
Antibiotics, Antineoplastic/toxicity , Cardiotoxicity/physiopathology , Doxorubicin/toxicity , Heart/drug effects , Physical Conditioning, Animal , Animals , Cardiotoxicity/etiology , Cardiotoxicity/prevention & control , Disease Models, Animal , Mice , Mice, Inbred C57BL , Mice, Nude , Neoplasms, Experimental/physiopathology
6.
J Acoust Soc Am ; 141(2): 847, 2017 02.
Article in English | MEDLINE | ID: mdl-28253653

ABSTRACT

Previous headphone experiments have shown that listeners can lateralize high-frequency sine-wave amplitude-modulated (SAM) tones based on interaural time differences in the envelope. However, when SAM tones are presented to listeners in free field or in a room, diffraction by the head or reflections from room surfaces alter the modulation percentages and change the shapes of the envelopes, potentially degrading the envelope cue. Amplitude modulation is transformed into mixed modulation. This article presents a mathematical transformation between the six spectral parameters for a modulated tone and six mixed-modulation parameters for each ear. The transformation was used to characterize the stimuli in the ear canals of listeners in free-field localization experiments. The mixed modulation parameters were compared with the perceived changes in localization attributable to the modulation for five different listeners, who benefited from the modulation to different extents. It is concluded that individual differences in the response to added modulation were not systematically related to the physical modulation parameters themselves. Instead, they were likely caused by individual differences in processing of envelope interaural time differences.


Subject(s)
Acoustic Stimulation/methods , Acoustics , Cues , Sound Localization , Adult , Female , Humans , Male , Middle Aged , Sound Spectrography , Time Factors , Young Adult
7.
Proc Natl Acad Sci U S A ; 113(29): 8057-63, 2016 07 19.
Article in English | MEDLINE | ID: mdl-27274051

ABSTRACT

The Ice Free Corridor has been invoked as a route for Pleistocene human and animal dispersals between eastern Beringia and more southerly areas of North America. Despite the significance of the corridor, there are limited data for when and how this corridor was used. Hypothetical uses of the corridor include: the first expansion of humans from Beringia into the Americas, northward postglacial expansions of fluted point technologies into Beringia, and continued use of the corridor as a contact route between the north and south. Here, we use radiocarbon dates and ancient mitochondrial DNA from late Pleistocene bison fossils to determine the chronology for when the corridor was open and viable for biotic dispersals. The corridor was closed after ∼23,000 until 13,400 calendar years ago (cal y BP), after which we find the first evidence, to our knowledge, that bison used this route to disperse from the south, and by 13,000 y from the north. Our chronology supports a habitable and traversable corridor by at least 13,000 cal y BP, just before the first appearance of Clovis technology in interior North America, and indicates that the corridor would not have been available for significantly earlier southward human dispersal. Following the opening of the corridor, multiple dispersals of human groups between Beringia and interior North America may have continued throughout the latest Pleistocene and early Holocene. Our results highlight the utility of phylogeographic analyses to test hypotheses about paleoecological history and the viability of dispersal routes over time.


Subject(s)
Bison/genetics , Animals , Canada , DNA, Mitochondrial/genetics , Fossils , Phylogeography
8.
Proc Natl Acad Sci U S A ; 111(47): 16842-7, 2014 Nov 25.
Article in English | MEDLINE | ID: mdl-25349412

ABSTRACT

Viruses preserved in ancient materials provide snapshots of past viral diversity and a means to trace viral evolution through time. Here, we use a metagenomics approach to identify filterable and nuclease-resistant nucleic acids preserved in 700-y-old caribou feces frozen in a permanent ice patch. We were able to recover and characterize two viruses in replicated experiments performed in two different laboratories: a small circular DNA viral genome (ancient caribou feces associated virus, or aCFV) and a partial RNA viral genome (Ancient Northwest Territories cripavirus, or aNCV). Phylogenetic analysis identifies aCFV as distantly related to the plant-infecting geminiviruses and the fungi-infecting Sclerotinia sclerotiorum hypovirulence-associated DNA virus 1 and aNCV as within the insect-infecting Cripavirus genus. We hypothesize that these viruses originate from plant material ingested by caribou or from flying insects and that their preservation can be attributed to protection within viral capsids maintained at cold temperatures. To investigate the tropism of aCFV, we used the geminiviral reverse genetic system and introduced a multimeric clone into the laboratory model plant Nicotiana benthamiana. Evidence for infectivity came from the detection of viral DNA in newly emerged leaves and the precise excision of the viral genome from the multimeric clones in inoculated leaves. Our findings indicate that viral genomes may in some circumstances be protected from degradation for centuries.


Subject(s)
Feces/virology , Genome, Viral , Animals , Arctic Regions , Molecular Sequence Data , Reindeer
9.
Am J Physiol Heart Circ Physiol ; 307(10): H1379-89, 2014 Nov 15.
Article in English | MEDLINE | ID: mdl-25217655

ABSTRACT

Since the modern era of cancer chemotherapy that began in the mid-1940s, survival rates for children afflicted with cancer have steadily improved from 10% to current rates that approach 80% (60). Unfortunately, many long-term survivors of pediatric cancer develop chemotherapy-related health effects; 25% are afflicted with a severe or life-threatening medical condition, with cardiovascular disease being a primary risk (96). Childhood cancer survivors have markedly elevated incidences of stroke, congestive heart failure (CHF), coronary artery disease, and valvular disease (96). Their cardiac mortality is 8.2 times higher than expected (93). Anthracyclines are a key component of most curative chemotherapeutic regimens used in pediatric cancer, and approximately half of all childhood cancer patients are exposed to them (78). Numerous epidemiologic and observational studies have linked childhood anthracycline exposure to an increased risk of developing cardiomyopathy and CHF, often decades after treatment. The acute toxic effects of anthracyclines on cardiomyocytes are well described; however, myocardial tissue is comprised of additional resident cell types, and events occurring in the cardiomyocyte do not fully explain the pathological processes leading to late cardiomyopathy and CHF. This review will summarize the current literature regarding the cellular and molecular responses to anthracyclines, with an important emphasis on nonmyocyte cardiac cell types as well as those that mediate the myocardial injury response.


Subject(s)
Anthracyclines/adverse effects , Antibiotics, Antineoplastic/adverse effects , Heart Diseases/chemically induced , Myocytes, Cardiac/drug effects , Survivors , Age Factors , Animals , Gene Expression Regulation/drug effects , Heart Diseases/genetics , Heart Diseases/metabolism , Heart Diseases/mortality , Heart Diseases/pathology , Humans , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Prognosis , Risk Assessment , Risk Factors , Signal Transduction/drug effects , Time Factors
10.
Cell Rep ; 7(1): 79-85, 2014 Apr 10.
Article in English | MEDLINE | ID: mdl-24656816

ABSTRACT

Negative elongation factor (NELF) is known to enforce promoter-proximal pausing of RNA polymerase II (Pol II), a pervasive phenomenon observed across multicellular genomes. However, the physiological impact of NELF on tissue homeostasis remains unclear. Here, we show that whole-body conditional deletion of the B subunit of NELF (NELF-B) in adult mice results in cardiomyopathy and impaired response to cardiac stress. Tissue-specific knockout of NELF-B confirms its cell-autonomous function in cardiomyocytes. NELF directly supports transcription of those genes encoding rate-limiting enzymes in fatty acid oxidation (FAO) and the tricarboxylic acid (TCA) cycle. NELF also shares extensively transcriptional target genes with peroxisome proliferator-activated receptor α (PPARα), a master regulator of energy metabolism in the myocardium. Mechanistically, NELF helps stabilize the transcription initiation complex at the metabolism-related genes. Our findings strongly indicate that NELF is part of the PPARα-mediated transcription regulatory network that maintains metabolic homeostasis in cardiomyocytes.


Subject(s)
Myocytes, Cardiac/metabolism , Transcription Factors/metabolism , Animals , Cardiomyopathies/genetics , Cardiomyopathies/metabolism , Echocardiography , Energy Metabolism/genetics , Homeostasis , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Myocytes, Cardiac/cytology , PPAR alpha/genetics , PPAR alpha/metabolism , RNA Polymerase II/metabolism , Transcription Factors/genetics , Transcription, Genetic
11.
Echocardiography ; 31(3): 375-84, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24103064

ABSTRACT

Echocardiography is a robust tool for assessing cardiac function in both humans and laboratory animals. Conventional echocardiographic measurements, including chamber dimensions, wall thickness, and ejection fraction are routinely obtained to assess cardiac function in mice. Recently, myocardial strain and strain rate measurements have been added to functional assessments to provide additional details on regional abnormalities that are not evident using conventional measurements. To date, all studies of strain and strain rate in mice or rats have involved adult animals. This study serves to outline methods for acquiring echocardiographic images in pediatric mice and to provide myocardial strain and strain rate values for healthy C57BL/6J mice between 3 and 11 weeks old. Between weeks 3 and 11, left ventricular radial strain ranged from 32 to 43% and longitudinal strain ranged from -15 to -19%, with analysis over time showing no significant changes with aging (radial strain, P = 0.192 and longitudinal strain, P = 0.264; n = 4 for each time point evaluated). In conclusion, myocardial strain analysis in pediatric mice is technically feasible and has potential application in studying the pathophysiology of pediatric cardiovascular disease.


Subject(s)
Animals, Newborn , Echocardiography, Doppler/methods , Heart Ventricles/diagnostic imaging , Ventricular Function, Left/physiology , Analysis of Variance , Animals , Mice , Mice, Inbred C57BL , Models, Animal , Myocardial Contraction/physiology , Sensitivity and Specificity , Stroke Volume
12.
Int J Pediatr Otorhinolaryngol ; 77(5): 813-6, 2013 May.
Article in English | MEDLINE | ID: mdl-23489887

ABSTRACT

OBJECTIVE: A comparison of histologic findings from the post-cricoid region versus nasopharyngeal pH probe results in the diagnosis of laryngopharyngeal reflux (LPR) in the pediatric patient. STUDY DESIGN: Retrospective review. SETTING: Outpatient pediatric otolaryngology private practice. SUBJECT AND METHODS: 63 consecutive patients, age 6-months to 17-years between June 1, 2009 and October 6, 2010, tested by simultaneous post cricoid biopsy and nasopharyngeal pH probe monitoring using the Restech Dx-pH Measurement System (Respiratory Technology Corporation, San Diego, CA). RESULTS: Of the 63 total patients (age 6-months to 17-years), 11 (17%) were excluded due to a pulled probe, one additional patient did not have a biopsy taken and one probe failed after insertion making a total of 50 patients with complete data sets. Thirty-six of those 50 patients had a positive probe with a negative biopsy (72%). Four (8%) had both a positive probe and biopsy and 10 (16%) had a negative probe and negative biopsy. No patients had a negative probe and positive biopsy. Symptoms used to identify patients suspected of reflux included: throat clearing, nasal congestion, cough, history of recurrent sinusitis with negative radiographic findings, halitosis, culture negative sore throat, post nasal drip, otalgia, poor appetite and stomach ache. CONCLUSION: Eighty percent of our patients (40) were either positive for reflux by pH probe or by pH probe and biopsy. The Restech Dx-pH Measurement System appeared to be well tolerated in all age groups. There were no complications. We found this a useful tool in confirming clinical suspicion of LPR.


Subject(s)
Laryngopharyngeal Reflux/pathology , Larynx/pathology , Pharynx/pathology , Adolescent , Biopsy , Child , Child, Preschool , Female , Humans , Hydrogen-Ion Concentration , Infant , Male , Private Practice , Retrospective Studies
13.
Proteomics Clin Appl ; 7(7-8): 516-27, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23532927

ABSTRACT

The left ventricle (LV) responds to a myocardial infarction with an orchestrated sequence of events that result in fundamental changes to both the structure and function of the myocardium. This collection of responses is termed as LV remodeling. Myocardial ischemia resulting in necrosis is the initiating event that culminates in the formation of an extracellular matrix (ECM) rich infarct scar that replaces necrotic myocytes. While the cardiomyocyte is the major cell type that responds to ischemia, infiltrating leukocytes and cardiac fibroblasts coordinate the subsequent wound healing response. The matrix metalloproteinase family of enzymes regulates the inflammatory and ECM responses that modulate scar formation. Matridomics is the proteomic evaluation focused on ECM, while degradomics is the proteomic evaluation of proteases as well as their inhibitors and substrates. This review will summarize the use of proteomics to better understand matrix metalloproteinase roles in post myocardial infarction LV remodeling.


Subject(s)
Extracellular Matrix/metabolism , Proteomics/methods , Ventricular Remodeling , Animals , Extracellular Matrix/pathology , Extracellular Matrix Proteins/metabolism , Humans , Proteolysis
14.
Proc Natl Acad Sci U S A ; 109(22): 8471-6, 2012 May 29.
Article in English | MEDLINE | ID: mdl-22586127

ABSTRACT

For decades, the peopling of the Americas has been explored through the analysis of uniparentally inherited genetic systems in Native American populations and the comparison of these genetic data with current linguistic groupings. In northern North America, two language families predominate: Eskimo-Aleut and Na-Dene. Although the genetic evidence from nuclear and mtDNA loci suggest that speakers of these language families share a distinct biological origin, this model has not been examined using data from paternally inherited Y chromosomes. To test this hypothesis and elucidate the migration histories of Eskimoan- and Athapaskan-speaking populations, we analyzed Y-chromosomal data from Inuvialuit, Gwich'in, and Tlich populations living in the Northwest Territories of Canada. Over 100 biallelic markers and 19 chromosome short tandem repeats (STRs) were genotyped to produce a high-resolution dataset of Y chromosomes from these groups. Among these markers is an SNP discovered in the Inuvialuit that differentiates them from other Aboriginal and Native American populations. The data suggest that Canadian Eskimoan- and Athapaskan-speaking populations are genetically distinct from one another and that the formation of these groups was the result of two population expansions that occurred after the initial movement of people into the Americas. In addition, the population history of Athapaskan speakers is complex, with the Tlich being distinct from other Athapaskan groups. The high-resolution biallelic data also make clear that Y-chromosomal diversity among the first Native Americans was greater than previously recognized.


Subject(s)
Chromosomes, Human, Y/genetics , Genetic Variation , Indians, North American/genetics , Inuit/genetics , Phylogeny , Canada , Chromosomes, Human, Pair 19/genetics , Emigration and Immigration , Gene Frequency , Genetics, Population/methods , Genotype , Geography , Haplotypes/genetics , Humans , Male , Microsatellite Repeats/genetics , Mutation , Mutation Rate , Polymorphism, Single Nucleotide
15.
Ageing Res Rev ; 11(1): 1-9, 2012 Jan.
Article in English | MEDLINE | ID: mdl-22115588

ABSTRACT

Cell- and tissue-based biosensors comprise genetically engineered proteins that are incorporated into cells ex vivo or into cells of tissues in vivo. They enable the investigator to sense levels of hormones, drugs, or toxins, continuously and noninvasively, using biophotonics or other physical principles, and could potentially be used over the entire lifespan of an experimental animal. The present work reviews the state of the art of cell- and tissue-based biosensors and discusses how they could be of value in aging research. Examples of recently developed biosensors are given, including those that detect levels of a cytokine (TNFα) and drugs (activators of the mTOR pathway). Finally, we discuss the hurdles that would have to be overcome for biosensor technology to be used in humans in monitoring health status and disease treatment in late life.


Subject(s)
Aging/physiology , Biomedical Research/methods , Biosensing Techniques/methods , Disease Models, Animal , Models, Animal , Aged , Aged, 80 and over , Aging/drug effects , Aging/pathology , Animals , Biomedical Research/instrumentation , Biomedical Research/trends , Biosensing Techniques/instrumentation , Biosensing Techniques/trends , Geriatrics/methods , Geriatrics/trends , Humans
16.
Ann Thorac Surg ; 84(3): 1031-3, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17720432

ABSTRACT

We present a case report of an infant who underwent successful reconstruction of a traumatic tracheal and carinal chemically induced corrosive injury using an esophageal flap to reconstruct the trachea and subsequently re-establishing gastrointestinal continuity with a colon interposition.


Subject(s)
Esophagus/surgery , Trachea/injuries , Trachea/surgery , Bronchoscopy , Colon/transplantation , Corrosion , Female , Humans , Infant , Surgical Flaps
17.
Circulation ; 111(14): 1747-55, 2005 Apr 12.
Article in English | MEDLINE | ID: mdl-15809368

ABSTRACT

BACKGROUND: Lipid lowering with statins prevents adverse cardiac events. Both lipid-lowering and antioxidant therapies may favorably affect vasomotor function and thereby improve ischemia. METHODS AND RESULTS: In a randomized, double-blind, placebo-controlled trial, 300 patients with stable coronary disease, a positive exercise treadmill test, 48-hour ambulatory ECG with > or =1 episode of ischemia, and fasting total cholesterol of 180 to 250 mg/dL were assigned to 1-year treatment with intensive atorvastatin to reduce LDL to <80 mg/dL (n=96), intensive atorvastatin to reduce LDL to <80 mg/dL plus antioxidant vitamins C (1000 mg/d) and E (800 mg/d) (n=101), or diet and low-dose lovastatin, if needed, to reduce LDL to <130 mg/dL (n=103; control group). Ischemia end points, including ambulatory ECG monitoring and exercise treadmill testing, and endothelial assessment using brachial artery flow-mediated dilation were obtained at baseline and at 6 and 12 months. Baseline characteristics were similar in all groups. LDL decreased from approximately 153 mg/dL at baseline in the 2 atorvastatin groups to approximately 83 mg/dL at 12 months (each P<0.0001) and from 147 to 120 mg/dL in the control group (P<0.0001). During ambulatory ECG monitoring, mean number of ischemic episodes per 48 hours decreased 31% to 61% in each group (each P<0.001; P=0.15 across groups), without a change in daily heart rate activity. Mean duration of ischemia for 48 hours decreased 26% to 62% in each group (each P<0.001; P=0.06 across groups). Mean exercise duration to 1-mm ST-segment depression significantly increased in each group, but total exercise duration and mean sum of maximum ST depression were unchanged. Angina frequency decreased in each group. There was no incremental effect of supplemental vitamins C and E on any ischemia outcome. Flow-mediated dilation studies indicated no meaningful changes. CONCLUSIONS: Intensive lipid lowering with atorvastatin to an LDL level of 80 mg/dL, with or without antioxidant vitamins, does not provide any further benefits in ambulatory ischemia, exercise time to onset of ischemia, and angina frequency than moderate lipid lowering with diet and low-dose lovastatin to an LDL level of <120 mg/dL.


Subject(s)
Antioxidants/administration & dosage , Heptanoic Acids/administration & dosage , Lipid Metabolism , Myocardial Ischemia/drug therapy , Pyrroles/administration & dosage , Angina Pectoris/drug therapy , Antioxidants/pharmacokinetics , Ascorbic Acid/administration & dosage , Ascorbic Acid/blood , Atorvastatin , Coronary Artery Disease/drug therapy , Coronary Artery Disease/therapy , Diet Therapy , Dose-Response Relationship, Drug , Exercise Test , Female , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Lipids/blood , Lipoproteins, LDL/blood , Male , Myocardial Ischemia/therapy , Vasomotor System/drug effects , Vitamin E/administration & dosage , Vitamin E/blood
18.
Curr Opin Otolaryngol Head Neck Surg ; 11(6): 409-15, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14631171

ABSTRACT

PURPOSE OF REVIEW: Although antibiotic resistance is not often considered an exciting topic for pediatric surgical subspecialists, we face the consequences of increasing antibiotic resistance daily in our clinical practice. By the very nature that our patients are often referred to us after extended periods of medical therapy, antibiotic resistance becomes a significant factor in management of patients both medically and surgically. Antibiotic resistance is increasing, and a number of organisms demonstrate multiple-drug resistance. The purpose of this review is to outline the scope of antibiotic resistance as it relates to pediatric otolaryngology. Specifically, the mechanisms of resistance, the pharmacodynamics involved, and selected infections are discussed. RECENT FINDINGS: The children particularly at risk for infections with resistant organisms are those 2 years of age or younger with exposure to daycare and treatment with antimicrobials within the last 30 days. Although there is increasing resistance to antibiotics commonly used for outpatient infections such as otitis media, sinusitis, and tonsillitis, many of the first-line therapies still show significant therapeutic advantage. Vaccines to pneumococcal bacteria have been shown to decrease severe infections. However, there has been only a slight decline in the number of outpatient otolaryngologic infections after vaccination. SUMMARY: Therefore, children who have received multiple courses of antibiotics, are 2 years of age or younger, attend daycare, or have received antimicrobial therapy within the last 30 days may need high-dose therapy or antimicrobial therapy with an increased spectrum of coverage. Those children with infections that do not respond clinically to appropriate therapy should be treated with the suspicion of multiple-drug resistant strains being present. Continued surveillance of resistance patterns within individual communities, especially areas served by children's hospitals, are important, as there are distinct local and regional differences in antimicrobial resistance.


Subject(s)
Anti-Bacterial Agents/pharmacology , Drug Resistance, Bacterial/physiology , Otorhinolaryngologic Diseases/microbiology , Anti-Bacterial Agents/therapeutic use , Child , Child, Preschool , Humans , Infant , Otorhinolaryngologic Diseases/drug therapy , Otorhinolaryngologic Diseases/physiopathology
19.
Am J Med ; 112(1): 26-30, 2002 Jan.
Article in English | MEDLINE | ID: mdl-11812403

ABSTRACT

PURPOSE: Lay beliefs about illness are a potential barrier to improving the control of hypertension. We investigated the extent to which lay beliefs about hypertension diverge from current medical understanding. METHODS: We conducted street intercept interviews and focus group discussions in six predominantly African-American census tracts in the southern sector of Dallas County, Texas. Sixty subjects, aged 18 to 67 years, were stopped along popular thoroughfares and administered a brief survey. Additionally, 107 participants were interviewed in 12 homogeneous focus groups, balanced by sex and age (18 to 74 years). Participants were asked about the meaning, causes, consequences, and treatment of high blood pressure. RESULTS: The street intercept data indicated that 35% (n = 21) of respondents related high blood pressure to eating pork or other foods that makes the blood travel too fast to the head, and only 15% (n = 9) related hypertension to an elevated pressure in blood vessels. The focus group data indicated that hypertension was causally linked to eating pork in 8 of the 12 groups; was perceived as a symptomatic illness in all 12 groups; and was considered treatable with vitamins, garlic, and other herbs in 11 groups, with prescription medications in 10 groups and with lifestyle modifications such as weight loss in 8 groups. Hypertension was mentioned as a leading cause of death among African Americans in none of the 4 focus groups of 18-year-old to 29-year-old participants, in 2 of the 4 focus groups of 30-year-old to 49-year-old participants, and in 3 of the 4 focus groups of 50-year-old to 74-year-old participants. CONCLUSIONS: In a low- to middle-income urban African-American community, the predominant beliefs about hypertension diverged sharply from current medical understanding. Lack of appreciation of these lay beliefs by providers may contribute to noncompliance and poor rates of hypertension control.


Subject(s)
Black or African American , Health Knowledge, Attitudes, Practice , Hypertension , Adult , Black or African American/psychology , Aged , Female , Humans , Hypertension/epidemiology , Hypertension/prevention & control , Hypertension/psychology , Male , Middle Aged , Socioeconomic Factors , Texas , Urban Population
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