Biomedical subjects
Publications and source records attributed to K Freeman.
Post-transplant complications are common among patients receiving immunosuppressive medications, including pain syndromes. Recently, a pain syndrome, calcineurin-inhibitor induced pain syndrome (CIPS) has been described. To our knowledge, this article is the second report of tacrolimus-associated CIPS, and the first report in the pediatric setting.
This study aimed at measuring the functional consequences and the pulmonary cytology changes following a simulation of pulmonary haemorrhage. Pulmonary function tests including lobeline-induced hyperventilation, cytology of tracheo-bronchial wash (TBW) and thoracic radiographs were performed before, as well as 1, 7, 14 and 28 days after, the instillation of 300 ml of blood into the lungs of 4 horses deemed free of exercise-induced pulmonary haemorrhage (Group 1). Control data (Group 2) were obtained by instilling the same volume of saline into the lungs of the same horses in a crossover design (control). The instillation of blood or saline resulted in an increase in the number of neutrophils in the TBW. Thoracic radiographs showed increased opacity in the caudodorsal region of the lungs in 4/4 (Day 1) and 2/4 horses (Day 7), in Group 1, and in 2/4 (Day 1) and 0/4 horses (Day 7) in the control group. These changes were attributed to the instillation procedure rather than the nature of the instilled material. Breathing mechanics and arterial blood gases at rest were not affected in either Groups 1 or 2. However, the maximal expiratory peak flow recorded during lobeline-induced hyperventilation was significantly lower (P<0.05) and the total pulmonary resistance significantly higher (P<0.05) on Day 1 in Group 1, but not Group 2. These observations suggest that expiratory flows might be partly limited in bleeders when breathing at high airflow.
OBJECTIVE: To identify the effect of attending a cognitive-behavioural arthritis education programme on the health status of participants with newly diagnosed rheumatoid arthritis (RA) compared with a control group. DESIGN: Randomized controlled trial. SETTING: Hospital based. SUBJECTS: Newly diagnosed with RA. INTERVENTION: Participation in either a cognitive-behavioural arthritis education programme or a standard arthritis education programme (control group). Sessions for both groups lasted for 2 hours per week for four weeks. Subjects were examined at home by an assessor blinded to group allocation, prior to and three and six months following attendance. OUTCOME MEASURES: The main outcome measure was the Physical Function subscale of the Arthritis Impact Measurement Scale Two. Other outcome measures included erythrocyte sedimentation rate (ESR), joint count scores, assessments of pain and psychological status. RESULTS: Fifty-four subjects (mean time since diagnosis 4.5 months) took part. Baseline analysis revealed that the control group had significantly better levels of functional ability (U = 185; p = 0.009) and lower levels of helplessness (U = 168; p = 0.002) prior to intervention. This difference remained unchanged three months later. Six months following the intervention no significant differences were noted between the groups for any measure of health status. There were no significant changes in health status over time in either group. CONCLUSION: Attending a cognitive-behavioural arthritis education programme had no significant effect on the health status of individuals newly diagnosed with RA. The move to early use of these programmes should be examined further, with a larger sample size and longer duration of follow-up.
BACKGROUND: It is unclear whether antimicrobial treatment after an Ixodes scapularis tick bite will prevent Lyme disease. METHODS: In an area of New York where Lyme disease is hyperendemic we conducted a randomized, double-blind, placebo-controlled trial of treatment with a single 200-mg dose of doxycycline in 482 subjects who had removed attached I. scapularis ticks from their bodies within the previous 72 hours. At base line, three weeks, and six weeks, subjects were interviewed and examined, and serum antibody tests were performed, along with blood cultures for Borrelia burgdorferi. Entomologists confirmed the species of the ticks and classified them according to sex, stage, and degree of engorgement. RESULTS: Erythema migrans developed at the site of the tick bite in a significantly smaller proportion of the subjects in the doxycycline group than of those in the placebo group (1 of 235 subjects [0.4 percent] vs. 8 of 247 subjects [3.2 percent], P<0.04). The efficacy of treatment was 87 percent (95 percent confidence interval, 25 to 98 percent). Objective extracutaneous signs of Lyme disease did not develop in any subject, and there were no asymptomatic seroconversions. Treatment with doxycycline was associated with more frequent adverse effects (in 30.1 percent of subjects, as compared with 11.1 percent of those assigned to placebo; P<0.001), primarily nausea (15.4 percent vs. 2.6 percent) and vomiting (5.8 percent vs. 1.3 percent). Erythema migrans developed more frequently after untreated bites from nymphal ticks than after bites from adult female ticks (8 of 142 bites [5.6 percent] vs. 0 of 97 bites [0 percent], P=0.02) and particularly after bites from nymphal ticks that were at least partially engorged with blood (8 of 81 bites [9.9 percent], as compared with 0 of 59 bites from unfed, or flat, nymphal ticks [0 percent]; P=0.02). CONCLUSIONS: A single 200-mg dose of doxycycline given within 72 hours after an I. scapularis tick bite can prevent the development of Lyme disease.
Over 40 different mutations in the cardiac myosin heavy chain gene (MYH7) have been associated with familial hypertrophic cardiomyopathy (FHC), but no study has analyzed variation at this locus within the normal human population. Here we determine the extent and distribution of nucleotide variation in the 5808-bp MYH7 coding sequence in 25 normal individuals without FHC. We identified six single-nucleotide polymorphisms, none of which changes the encoded amino acid. At one of these sites, the frequencies of both alleles are equal; at the other five sites, the frequency of the rarer allele varies from 0.02 to 0.08. The nucleotide diversity (pi) calculated from these data is 1.73x10(-4)+/-0.49x10(-4), which is lower than the nucleotide diversity found in most other human autosomal genes. Substitution analysis of homologous genes between human and rodent also indicates that the MYH7 sequence has evolved at a very slow rate. The rate of both synonymous and nonsynonymous substitutions, especially in the portion of the sequence that encodes the alpha-helical myosin rod, is extremely low. The low level of even silent sequence variation in MYH7 in comparisons between human sequences and between human and rodent sequences may be a consequence of strong selective pressure against mutations that cause cardiomyopathy.
It has recently been shown that UDP-glucose is a potent agonist of the orphan G-protein-coupled receptor (GPCR) KIAA0001. Here we report cloning and analysis of the rat and mouse orthologs of this receptor. In accordance with GPCR nomenclature, we have renamed the cDNA clone, KIAA0001, and its orthologs GPR105 to reflect their functionality as G-protein-coupled receptors. The rat and mouse orthologs show 80% and 83% amino acid identity, respectively, to the human GPR105 protein. We demonstrate by genomic Southern blot analysis that there are no genes in the mouse or rat genomes with higher sequence similarity. Chromosomal mapping shows that the mouse and human genes are located on syntenic regions of chromosome 3. Further analyses of the rat and mouse GPR105 proteins show that they are activated by the same agonists as the human receptor, responding to UDP-glucose and closely related molecules with similar affinities. The mouse and rat receptors are widely expressed, as is the human receptor. Thus we conclude that we have identified the rat and mouse orthologs of the human gene GPR105.
Gulfwatch, established in 1991, is an international contaminant monitoring program in which the blue mussel, Mytilus edulis, is used as an indicator of the level and extent of contamination in the Gulf of Maine. Since 1991, trace metals, PAHs, PCBs, and OC pesticides have been measured in mussel tissues at 56 sites. The distribution of most metals was relatively uniform throughout the Gulf with the exception of Ag, Pb and Cr. However, the concentration of organic contaminants increased in a north-to-south direction. High concentrations of contaminants were correlated with large human population density and proximity to large rivers. Temporal analysis of five sites revealed that the majority of contaminant concentrations were either unchanged or decreasing. The concentrations of most contaminants were lower than the median of the National Status and Trends (NS & T) Mussel Watch with the exceptions of Cr, Hg, Pb and sigma PCB24. Hg concentrations at > 80% of the Gulfwatch sites exceeded the NS & T median +1 SD. Gulfwatch continues as a primary contaminant monitoring program in the Gulf of Maine.
A 14-year-old domestic short-hair cat presented with a history of intermittent malaise and increased drinking. A diagnosis of hyperthyroidism and cholelithiasis was made by a combination of blood testing, radiography and ultrasonography. After medical management of hyperthyroidism, thyroidectomy and cholecystectomy were successfully performed. Removed choleliths were comprised of calcium carbonate and bilirubinate. Histopathological analysis of tissue suggested low grade pancreatic and hepatobiliary disease, as well as hyperthyroidism, might have contributed to stone formation.
OBJECTIVE: Although different pain scales often have been used interchangeably, it is not known whether interchanging them is appropriate. The purpose of this report was twofold: to better understand the statistical properties of the Faces Rating Scale (FRS) so it can be used appropriately in clinical settings and to describe the mathematical relationship between the Visual Analogue Scale (VAS) and the FRS when they are used to quantify pressure ulcer pain in hospitalized elderly patients. DESIGN: Secondary data analyses were performed as part of a cross-sectional study. SETTING AND SUBJECTS: A quality assurance program was undertaken to evaluate pressure ulcer pain perceived by elderly hospitalized patients. All patients without aphasia participated. INSTRUMENTS: The VAS used was a 0 to 100 mm horizontal line demonstrated to have ratio scale properties with high validity and reproducibility, and the FRS used was 6 faces ordered horizontally from smiling to crying, labeled 0 to 5 beneath each face, respectively. METHODS: Nonlinear least squares regression with a Gauss-Newton iterative procedure was used. RESULTS: Among models with cubic, quadratic, and linear terms, only the quadratic term was significant (P <.05). With use of the equation derived, VAS = 3.33*(FRS)(2), the resulting reliability coefficient was r = 0.92. CONCLUSIONS: The nonlinear relationship indicated high reliability between VAS and FRS for pain assessment in populations with diminished verbal and abstract thinking abilities. For readers who would like to translate results from one scale to another, a quadratic equation is provided.
OBJECTIVE: Joint protection aims to reduce pain and local inflammation, preserve the integrity of joint structures and improve function. There is evidence that it can improve pain and function in the short term, but the long-term effects are uncertain. This study evaluated the effects of joint protection in early rheumatoid arthritis (RA). METHODS: A randomized, controlled, assessor-blinded trial of duration 1 yr was conducted. Two interventions (both 8 h) were compared: standard arthritis education, including 2.5 h of joint protection education based on typical UK practice; and a joint protection arthritis education programme, using educational-behavioural teaching methods. Assessments were made at entry and 6 and 12 months. RESULTS: Sixty-five people with RA attended the joint protection programme and 62 the standard programme. The groups were matched for age (51 and 49 yr), disease duration (21 and 17.5 months) and use of non-steroidal anti-inflammatory drugs and disease-modifying anti-rheumatic drugs. In comparison with the standard group, the joint protection group significantly improved with respect to adherence to the joint protection programme (P=0.001), hand pain (P=0.02), general pain (P=0.05), early morning stiffness (P=0.01), self-reported number of disease flare-ups (P=0.004), visits to the doctor for arthritis (P<0.01), and the AIMS2 (Arthritis Impact Measurement Scales) activities of daily living scale (P=0.04). A trend to improved swollen joint counts was identified (P=0.07). Within-group analyses also showed improvements in arthritis self-efficacy and perceived control. Hand deformity scores continued to increase in both groups. CONCLUSION: We found significant improvements in adherence, pain, disease status and functional ability amongst those attending the joint protection programme. Benefits became more apparent with time, suggesting that joint protection can help slow the progression of the effects of RA over and above the effects of drug therapy.
Although the current indirect immunofluorescent assay (IFA) diagnostic antibody test for human babesiosis is sensitive and specific, an immunoblot antibody test may be easier to standardize and to perform. Our objective, therefore, was to determine the efficacy of and develop interpretive criteria for an immunoblot antibody test for diagnosing acute human babesiosis using a Babesia microti whole-cell lysate as the antigen. We compared the reactivity of sera to a B. microti immunoblot assay in 24 human subjects experiencing symptoms and expressing laboratory evidence of babesiosis, 28 subjects who experienced Lyme disease, 12 subjects who experienced human granulocytic ehrlichiosis, and 51 subjects who reported no history of any of these diseases and whose sera did not react against B. microti antigen in an IFA test. Immunoblot strips were impregnated with proteins derived from the GI strain of B. microti that had been electrophoresed in an acrylamide sodium dodecyl sulfate gel, followed by electroblotting onto nitrocellulose membranes. The sera of all subjects who experienced babesiosis reacted against the B. microti antigen in the IFA and against at least one of nine immunoblot protein bands specific to B. microti. In contrast, none of the sera from people who appeared not to have experienced this infection reacted against the B. microti antigen in the IFA (compared to 4% in the immunoblot assay). When two reactive bands were considered as definitive, immunoblot test sensitivity was 96%, while specificity was 99% and predictive positivity and predictive negativity were 96 and 99%, respectively. Our B. microti immunoblot procedure shows promise as a sensitive, specific, and reproducible assay for routine clinical diagnosis of acute babesiosis.
A mouse model of hypertrophic cardiomyopathy (HCM) was created by expression of a cardiac alpha-myosin transgene including the R(403)Q mutation and a deletion of a segment of the actin-binding domain. HCM mice show early histopathology and hypertrophy, with progressive hypertrophy in females and ventricular dilation in older males. To test the hypothesis that dilated cardiomyopathy (DCM) is part of the pathological spectrum of HCM, we studied chamber morphology, exercise tolerance, hemodynamics, isolated heart function, adrenergic sensitivity, and embryonic gene expression in 8- to 11-mo-old male transgenic animals. Significantly impaired exercise tolerance and both systolic and diastolic dysfunction were seen in vivo. Contraction and relaxation parameters of isolated hearts were also decreased, and lusitropic responsiveness to the beta-adrenergic agonist isoproterenol was modestly reduced. Myocardial levels of the G protein-coupled beta-adrenergic receptor kinase 1 (beta-ARK1) were increased by more than twofold over controls, and total beta-ARK1 activity was also significantly elevated. Induction of fetal gene expression was also observed in transgenic hearts. We conclude that transgenic male animals have undergone cardiac decompensation resulting in a DCM phenotype. This supports the idea that HCM and DCM may be part of a pathological continuum rather than independent diseases.
The medical treatment of chronic heart failure has undergone a dramatic transition in the past decade. Short-term approaches for altering hemodynamics have given way to long-term, reparative strategies, including beta-adrenergic receptor (betaAR) blockade. This was once viewed as counterintuitive, because acute administration causes myocardial depression. Cardiac myocytes from failing hearts show changes in betaAR signaling and excitation-contraction coupling that can impair cardiac contractility, but the role of these abnormalities in the progression of heart failure is controversial. We therefore tested the impact of different manipulations that increase contractility on the progression of cardiac dysfunction in a mouse model of hypertrophic cardiomyopathy. High-level overexpression of the beta(2)AR caused rapidly progressive cardiac failure in this model. In contrast, phospholamban ablation prevented systolic dysfunction and exercise intolerance, but not hypertrophy, in hypertrophic cardiomyopathy mice. Cardiac expression of a peptide inhibitor of the betaAR kinase 1 not only prevented systolic dysfunction and exercise intolerance but also decreased cardiac remodeling and hypertrophic gene expression. These three manipulations of cardiac contractility had distinct effects on disease progression, suggesting that selective modulation of particular aspects of betaAR signaling or excitation-contraction coupling can provide therapeutic benefit.
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Uridine 5'-diphosphoglucose (UDP-glucose) has a well established biochemical role as a glycosyl donor in the enzymatic biosynthesis of carbohydrates. It is less well known that UDP-glucose may possess pharmacological activity, suggesting that a receptor for this molecule may exist. Here, we show that UDP-glucose, and some closely related molecules, potently activate the orphan G protein-coupled receptor KIAA0001 heterologously expressed in yeast or mammalian cells. Nucleotides known to activate P2Y receptors were inactive, indicating the distinctly novel pharmacology of this receptor. The receptor is expressed in a wide variety of human tissues, including many regions of the brain. These data suggest that some sugar-nucleotides may serve important physiological roles as extracellular signaling molecules in addition to their familiar role in intermediary metabolism.
6. From this cohort, a matched-pair analysis was performed to better assess the role of EBT and TIPPB (n = 215). PSA relapse-free survival was based on the American Society for Therapeutic Radiology and Oncology Consensus Panel definition. Kaplan-Meier actuarial survival curves were compared to assess various prognostic factors. The median follow-up for all 215 matched patients was 44 months (range, 24-81) with an actuarial PSA relapse-free survival (RFS) at 5 years of 81.1%. Patients treated with EBT and TIPPB had a 5-year PSA RFS of 83.5% whereas patients treated with TIPPB only had a 5-year PSA RFS of 79.4% (p = 0.715)10 ng/ml. Risk group analysis combining PSA, Gleason score, and stage failed to identify any risk group for which the addition of EBT was significant. Analysis of postimplant dosimetry using the dose to 90% of the prostate volume (D90) failed to distinguish any difference between groups. A significant advantage for combining EBT and TIPPB could not be demonstrated in this retrospective matched-pair analysis. These data indicate that the role and rationale of combined treatment in prostate brachytherapy requires better clarification, with a prospective randomized trial.
Astronomers believe that the baryon (stellar) halo of the Milky Way retains a fossil imprint of how it was formed. But a vast literature shows that the struggle to interpret the observations within a consistent framework continues. The evidence indicates that the halo has built up through a process of accretion and merging over billions of years, which is still going on at a low level. Future satellite missions to derive three-dimensional space motions and heavy element (metal) abundances for a billion stars will disentangle the existing web and elucidate how galaxies like our own came into existence.