Autochthonous visceral leishmaniasis in dogs in North America.
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Animals↗
Biomedical subjects
J C Fox
Publications and source records attributed to J C Fox.
Comparison of the novel quantitative ARMS assay and an enriched PCR-ASO assay for K-ras mutations with conventional cytology on endobiliary brush cytology from 312 consecutive extrahepatic biliary stenoses.
BACKGROUND: Extrahepatic biliary stenosis (EBS) has malignant and benign causes. Patients with EBS are at risk of having or developing malignancy. Accurate diagnostic tests for early detection and surveillance are needed. The sensitivity of biliary cytology for malignancy is low. K-ras mutation analysis on brush cytology is a valuable adjunct, but specificity is low. A quantitative test for K-ras mutations has been developed: the amplification refractory mutation system (ARMS). AIM: To assess the test characteristics and additional value of ARMS in diagnosing the cause of EBS. METHODS: Brush samples from endoscopic retrograde cholangiopancreatography were collected from 312 patients with EBS. K-ras mutation analysis was performed using ARMS-allele specific amplification was coupled with real time fluorescent detection of PCR products. Results were compared with conventional cytology and K-ras mutation analysis using allele specific oligonucleotide (ASO) hybridisation, and evaluated in view of the final diagnosis. RESULTS: The test characteristics of ARMS and ASO largely agreed. Sensitivity for detecting malignancy was 49% and 42%, specificity 93% and 88%, and positive predictive value (PPV) 96% and 91%, respectively. The sensitivity of ARMS and cytology combined was 71%, and PPV was 93%. The specificity of ARMS could be increased to 100% by setting limits for the false positives, but reduced sensitivity from 49% to 43%. CONCLUSIONS: ARMS can be considered supplementary to conventional cytology, and comparable to ASO in diagnosing malignant EBS. A specificity of 100% can be achieved with ARMS, which should be considered in the surveillance of patients at risk for pancreatic cancer.
Adult↗
Day-to-day reproducibility of anorectal sensorimotor assessments in healthy subjects.
The reproducibility of tests widely utilized to assess anorectal sensorimotor functions is not well established. Our aims were to assess the intra-individual day-to-day reproducibility of these parameters in healthy subjects. Anal sphincter pressures were assessed by perfusion manometry on two separate days in 19 healthy subjects. Rectal pressure-volume (p-v) curves and sensory thresholds were assessed in 12/19 subjects by inflating a highly compliant polyethylene balloon from 0 to 32 mmHg in 4 mmHg steps. Subjects also rated intensity of perception by visual analogue scale (VAS) during phasic distentions 8, 16 and 24 mmHg above operating pressure, in randomized sequence. Resting and squeeze anal pressures and rectal compliance were highly reproducible (r(s) > or = 0.7) in the same subject on separate days. Pressure thresholds for urgency appeared less reproducible than thresholds for initial perception and the desire to defecate. VAS scores were highly reproducible only during the 24-mmHg distention. Thus, anal pressures and rectal compliance are highly reproducible within healthy subjects on separate days, while sensory thresholds are reproducible to a variable degree, dependent on the intensity of stimulation and the perception being assessed.
Adult↗
Decision rule and utility of routine urine toxicology screening of trauma patients.
The objective of this study was to determine the impact of urine drug screening of major trauma victims on patient care and derive a decision rule for selective screening. Retrospective chart review of 170 trauma patients at a Level I Trauma Center, certified by the American College of Surgeons, was undertaken. The decision rule was developed by Classification and Regression Tree (CART) analysis to maximize sensitivity, with secondary attention to specificity. Eighty-nine percent of trauma patients were screened, while 26.0% had positive tests for illicit drugs. Serum ethanol was positive in 31.2%, over the legal limit of 0.08 g/dl. Both a legally intoxicated ethanol level and positive illicit drug screen were found in 11.0%. Additionally, 42.5% of patients with a positive illicit drug screen were also intoxicated (blood alcohol level above legal limit). Conversely, 35.4% of legally intoxicated patients also had positive illicit screens. Drug treatment referral occurred in 17.5% of positive drug screens. For urgent surgery, median time to drug screen result was 117 min, while median time to operation was 110 min. Of operative patients, 57% had the drug screen result recorded on the chart at any time, but only 14.3% of illicit screens were noted in the anaesthesia record. For all patients with and without operations, 71.1% had the result noted on the chart. We derived a 'low risk rule' to identify most patients with positive illicit drug screens (95% sensitivity, 55% specificity, 66% positive and 93% negative predictive values; accuracy 74%), while limiting the number of unnecessary tests. The rule avoids screening 48% of patients, missing only 5% of true positives. It is concluded that urine screening for illicit drugs in trauma patients can be performed selectively according to a decision rule based on demographics, mechanism of injury and time of presentation. This rule, which captures most positive screens while eliminating screening in low risk patients, could result in significant cost savings. Only prospective validation of these rules in patient populations of other trauma centres will offer confidence that the decision points are valid. Urine drug screening infrequently affected patient management or resulted in drug treatment referral in our sample. We call for increased vigilance in recording results and referring patients for treatment.
Adult↗
Further evidence to support the melanocytic origin of MDA-MB-435.
BACKGROUND/AIMS: Until recently, the cell line MDA-MB-435 was widely accepted as originating from a breast cancer. However, microarray derived data have suggested that this cell line may in fact originate from an occult melanoma. This study was designed to investigate this hypothesis further. METHODS: Quantitative reverse transcription polymerase chain reaction and immunohistochemistry were used to investigate the tissue of origin of two sublines of MDA-MB-435 (MDA-MB-435 S and MDA-MB-435 HGF). The expression of a panel of genes typical of breast cells or melanocytes was analysed. RESULTS: The MDA-MD-435 cell lines expressed none of the genes characteristic of breast cancer cells but did express several genes commonly expressed by melanocytes. CONCLUSIONS: These results strongly suggest that MDA-MB-435 is indeed of melanoma origin.
Animals↗
A prospective evaluation of lipoprotein-associated phospholipase A(2) levels and the risk of future cardiovascular events in women.
OBJECTIVES: We sought to determine prospectively whether lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) was a predictor of future cardiovascular risk in women. BACKGROUND: Inflammatory markers may help predict cardiovascular risk. Lp-PLA(2) levels have recently been hypothesized to be an independent predictor of cardiovascular risk in hypercholesterolemic men. METHODS: We conducted a prospective, nested case-control study among 28,263 apparently healthy middle-aged women to assess the risk of death from coronary heart disease, non-fatal myocardial infarction, and stroke associated with baseline levels of Lp-PLA(2) over a mean follow-up of three years. RESULTS: In univariate analysis, mean levels of Lp-PLA(2) correlated strongly with low-density lipoprotein cholesterol (r = 0.51; p = 0.0001), were lower among women currently using hormone replacement therapy (mean 0.98 mg/l vs. 1.23 mg/l; p = 0.0001) and were significantly higher at baseline among cases (n = 123) than controls (n = 123) (mean 1.20 mg/l vs. 1.05 mg/l; p = 0.016). However, the predictive value of Lp-PLA(2) was markedly attenuated after adjustment for these and other cardiovascular risk factors. Specifically, the multivariate relative risks of future cardiovascular events for women in the lowest (referent) to highest quartiles of Lp-PLA(2) were 1.00, 0.75, 0.64 and 1.17, respectively (all p values non-significant). In contrast, the adjusted relative risks of future cardiovascular events for each increasing quartile of C-reactive protein (another marker of low-grade inflammation) were 1.00, 1.78, 2.02 and 4.66, respectively (p-value for trend = 0.002). Inclusion of Lp-PLA(2) levels did not significantly attenuate this latter observation. CONCLUSIONS: In contrast to prior data among hyperlipidemic men, the current data suggest that Lp-PLA(2) is not a strong predictor of future cardiovascular risk among unselected women.
1-Alkyl-2-acetylglycerophosphocholine Esterase↗
Trabecular eccentricity and bone adaptation.
It is well established that bones functionally adapt by mechanisms that control tissue density, whole bone geometry, and trabecular orientation. In this study, we propose the existence of another such powerful mechanism, namely, trabecular eccentricity, i.e. non-central placement of trabecular bone within a cortical envelope. In the human femoral neck, trabecular eccentricity results in a thicker cortical shell on the inferior than superior aspect. In an overall context of expanding understanding of bone adaptation, the goal of this study was to demonstrate the biomechanical significance of, and provide a mechanistic explanation for, the relationship between trabecular eccentricity and stresses in the human femoral neck. Using composite beam theory, we showed that the biomechanical effects of eccentricity during a habitual loading situation were to increase the stress at the superior aspect of the neck and decrease the stress at the inferior aspect, resulting in an overall protective effect. Further, increasing eccentricity had a stress-reducing effect equivalent to that of increasing cortical thickness or increasing trabecular modulus. We conclude that an asymmetric placement of trabecular bone within a cortical bone envelope represents yet another mechanism by which whole bones can adapt to mechanical demands.
Adaptation, Physiological↗
Kirsten ras mutations in patients with colorectal cancer: the 'RASCAL II' study.
Researchers worldwide with information about the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer were invited to provide that data in a schematized format for inclusion in a collaborative database called RASCAL (The Kirsten ras in-colorectal-cancer collaborative group). Our results from 2721 such patients have been presented previously and for the first time in any common cancer, showed conclusively that different gene mutations have different impacts on outcome, even when the mutations occur at the same site on the genome. To explore the effect of Ki-ras mutations at different stages of colorectal cancer, more patients were recruited to the database, which was reanalysed when information on 4268 patients from 42 centres in 21 countries had been entered. After predetermined exclusion criteria were applied, data on 3439 patients were entered into a multivariate analysis. This found that of the 12 possible mutations on codons 12 and 13 of Kirsten ras, only one mutation on codon 12, glycine to valine, found in 8.6% of all patients, had a statistically significant impact on failure-free survival (P = 0.004, HR 1.3) and overall survival (P = 0.008, HR 1.29). This mutation appeared to have a greater impact on outcome in Dukes' C cancers (failure-free survival, P = 0.008, HR 1.5; overall survival P = 0.02, HR 1.45) than in Dukes' B tumours (failure-free survival, P = 0.46, HR 1.12; overall survival P = 0.36, HR 1.15). Ki-ras mutations may occur early in the development of pre-cancerous adenomas in the colon and rectum. However, this collaborative study suggests that not only is the presence of a codon 12 glycine to valine mutation important for cancer progression but also that it may predispose to more aggressive biological behaviour in patients with advanced colorectal cancer.
Adolescent↗
Vitreous-induced modulation of integrins in retinal pigment epithelial cells: effects of fibroblast growth factor-2.
Growth in the presence of vitreous results in transformation of human RPE cells from an epithelioid to a fibroblast-like appearance and leads to an elevation of the expression of alpha(5) and alpha(2) integrins, while the level of alpha(3) integrin is reduced. These changes are inhibited by the presence of FGF-2. Vitreous treatment increases mobility, as does antibody neutralization of FGF-2 or antibody blockade of FGF receptors. The vitreous-induced rise in mobility depends on an increase in alpha(5) integrin expression since it is inhibited by anti-alpha(5) integrin antibodies. Expression of alpha(5) integrin as a result of infection of RPE cells with an alpha(5) integrin-encoding adenovirus induced morphological transformation and an increase in mobility similar to that seen with vitreous. It is concluded that a decrease in FGF-2 plays an important role in vitreous-induced alterations of RPE cell morphology, integrin expression and mobility. High FGF-2 levels prevent at least some of the increased mobility of RPE cells induced by vitreous. This is mediated via extracellular FGF-2 binding to FGF receptor(s) since antibodies to FGF-2 or to its receptor(s) mimic the effects of vitreous. Changes in mobility and morphology involve altered alpha(5) integrin expression since mobility is blocked by antibodies against these proteins while elevated alpha(5) integrin expression increases mobility and leads to morphological changes.
Autoradiography↗
Barriers to help seeking for mental disorders in a rural impoverished population.
This study examined barriers to seeking mental health care reported by individuals in a rural impoverished population, by screening 646 randomly selected adults for depression, anxiety, and alcohol abuse. Respondents who screened positive were randomly assigned to one of three groups: (1) no intervention, (2) an educational intervention alone, or (3) the educational intervention in the presence of a significant other. Those who screened positive for disorders cited barriers to care at significantly higher rates than respondents who screened negative. Respondents who received the educational intervention endorsed several barriers at significantly lower rates in the follow-up telephone call (subsequent to the intervention) than in the original interview (prior to the intervention). Virtually all respondents in a subsample of 142 subjects (99.3%) said they would seek mental health care if they thought mental health services would help them.
Adult↗
Outcome in cardiac arrest patients found to have cardiac standstill on the bedside emergency department echocardiogram.
UNLABELLED: Patients presenting in cardiac arrest frequently have poor outcomes despite heroic resuscitative measures in the field. Many emergency medical systems have protocols in place to stop resuscitative measures in the field; however, further predictors need to be developed for cardiac arrest patients brought to the emergency department (ED). OBJECTIVE: To examine the predictive value of cardiac standstill visualized on bedside ED echocardiograms during the initial presentations of patients receiving cardiopulmonary resuscitation (CPR). METHODS: The study took place in a large urban community hospital with an emergency medicine residency program and a high volume of cardiac arrest patients. As part of routine care, all patients arriving with CPR in progress were subject to immediate and brief subxiphoid or parasternal cardiac ultrasound examination. This was followed by brief repeat ultrasound examination during the resuscitation when pulses were checked. A 2.5-MHz phased-array probe was used for imaging. Investigators filled out standardized data sheets. Examinations were taped for review. Statistical analysis included descriptive statistics, positive and negative predictive values, and likelihood ratios. RESULTS: One hundred sixty-nine patients were enrolled in the study. One hundred thirty-six patients had cardiac standstill on the initial echocardiogram. Of these, 71 patients had an identifiable rhythm on monitor. No patient with sonographically identified cardiac standstill survived to leave the ED regardless of his or her initial electrical rhythm. Cardiac standstill on echocardiogram resulted in a positive predictive value of 100% for death in the ED, with a negative predictive value of 58%. CONCLUSIONS: Patients presenting with cardiac standstill on bedside echocardiogram do not survive to leave the ED regardless of their electrical rhythms. This finding was uniform regardless of downtime. Although larger studies are needed, this may be an additional marker for cessation of resuscitative efforts.
Adult↗
ARMS allele-specific amplification-based detection of mutant p53 DNA and mRNA in tumors of the breast.
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Biomarkers, Tumor↗
Autocrine signaling through Ras prevents apoptosis in vascular smooth muscle cells in vitro.
Vascular smooth muscle cell (SMC) apoptosis contributes to physiological and pathological vascular remodeling. Autocrine fibroblast growth factor (FGF) signaling promotes survival in SMC in vitro. Interruption of autocrine FGF signaling results in apoptosis that can be rescued by other growth factors such as PDGF (platelet-derived growth factor) or EGF (epidermal growth factor). Such heterologous growth factor rescue is prevented by pharmacological inhibition of MAPK, implicating signaling through Ras in mediating survival. This study was designed to test the hypothesis that signaling through Ras is both necessary and sufficient to mediate SMC survival in vitro. Recombinant adenoviruses encoding dominant-negative (Ras(N17)) and constitutively active (Ras(L61)) mutants of Ras were used. Ras(N17) blocks growth factor-mediated MAPK activation and can itself induce SMC apoptosis. Ras(N17) is synergistic with inhibition of autocrine FGF signaling in triggering apoptosis and prevents heterologous growth factor rescue. Conversely, Ras(L61) prevents apoptosis resulting from inhibition of autocrine FGF signaling. Rescue by Ras(L61) can be partially prevented by pharmacological inhibition of MEK or phosphatidylinositol 3-kinase, two downstream effectors of Ras. These results suggest that Ras signaling is both necessary and sufficient to mediate survival in SMC in vitro. Further work is required to determine how these signaling events are regulated in the context of vascular remodeling in vivo.
Animals↗
Adenoviral-mediated expression of antisense RNA to basic fibroblast growth factor reduces tangential stress in arterialized vein grafts.
PURPOSE: The purpose of this study was to test whether basic fibroblast growth factor (bFGF) participates in arterialized vein graft remodeling. METHODS: Rabbits underwent in vivo gene transfer and carotid interposition vein grafting. Segments of external jugular vein were infected with an adenovirus that expressed antisense bFGF RNA (Ad.ASbFGF) at 1 x 10(10) PFU/mL to inhibit new synthesis of bFGF by cells in the vein graft wall. Control rabbits were treated with either adenovirus that encoded beta-galactosidase (Ad.lacZ) at 1 x 10(10) PFU/mL or vehicle (phosphate-buffered saline solution [PBS]). At 3 days, 3 grafts per treatment group were harvested for the determination of gene expression of ASbFGF RNA by reverse transcriptase-polymerase chain reaction. Rabbits were killed, and perfusion was fixed 2 months after the grafting. Total wall thickness and lumen circumference of vein grafts and normal arteries were measured in cross sections. Calculated mean tangential stress (+/-SD) for the ASbFGF-treated group and controls was compared for significance. Grafts were immunohistochemically stained to assess bFGF protein production. RESULTS: Only the grafts infected with the Ad.ASbFGF gene expressed ASbFGF RNA. Grafts that were treated with Ad.ASbFGF displayed lower tangential stress (10.9 +/- 2.3 dynes/cm(2)) than PBS alone (22 +/- 2.8 dynes/cm(2)) or Ad. lacZ-treated controls (20.6 +/- 5.4 dynes/cm(2); P <.001). Tangential stress in the Ad.ASbFGF group was comparable to a normal carotid artery (13.9 +/- 2.1 dynes/cm(2)). The difference in mean total wall thickness was significant among the 3 treatment groups: Ad.ASbFGF, 164 +/- 3.4 microm); Ad.lacZ, 100 +/- 3.3 microm; and PBS, 96 +/- 3.6 microm; P <.01). Luminal circumference was not different among the groups. The Ad.ASbFGF-treated vein graft wall was composed of thick layers of concentric smooth muscle cells and elastin fibers in contrast to the sponge-like appearance observed in control arterialized vein grafts. Reduction in bFGF protein was noted only in the Ad.ASbFGF-treated group. CONCLUSION: Inhibition of bFGF synthesis in vivo with the use of adenoviral gene transfer of antisense RNA to bFGF promotes a vein graft with decreased tangential stress while maintaining the luminal area. The vein graft wall is remodeled and qualitatively resembles an artery so that wall tangential stress in Ad.ASbFGF and normal artery are not significantly different. The lack of significant difference in lumen circumference among groups suggests that wall thickening in the Ad. ASbFGF grafts is not at the expense of luminal narrowing. Our results suggest that ASbFGF RNA expression may represent an effective strategy in limiting the failure of arterialized venous conduits.
Adenoviridae↗
Physician versus computer knowledge of potential drug interactions in the emergency department.
INTRODUCTION: Proliferation of Food and Drug Administration-approved drugs makes it impossible for emergency medicine (EM) faculty to stay current on potential interactions between drugs, and with diseases, laboratory tests, and ethanol. A computer database may augment physician knowledge. OBJECTIVES: To compare the performance of EM faculty and an "expert" emergency physician (EP) with that of a criterion standard computer database in identifying potential drug interactions, and to report the incidence of drug-ethanol and drug-laboratory test interactions. METHODS: This was a retrospective review of 276 emergency department charts for drug, ethanol, lab, and medical history. Evaluation by both EM faculty and an "expert" EP of patient history was done to identify potential interactions, and comparison with the Micromedex Drug-Reax database for potential interactions (graded minor, moderate, or major) was made. Clinical significance of potential interactions was judged by a second EM faculty member. RESULTS: Seventeen percent of the patients had potential drug-drug interactions, and 25% of these were judged to be clinically significant. Up to 52% of the patients had potential drug-ethanol interactions, while 38% of the patients could have potential drug-lab interactions. Sensitivity, specificity, and positive and negative predictive values of the EM faculty for potential drug-drug interactions compared with the computer were poor, at 14%, 58%, 6%, and 23%, respectively. The corresponding values for the "expert" EP were 25%, 86%, 26%, and 85%. The "expert" EP was statistically better than the EM faculty, but still less sensitive and predictive than the computer. CONCLUSIONS: A computer can aid the physician in avoiding potential drug interactions. Prospective validation of these findings should be done.
California↗
Improvement of western blot test specificity for detecting equine serum antibodies to Sarcocystis neurona.
Equine protozoal myeloencephalitis (EPM) is a neurological disease of horses and ponies caused by the apicomplexan protozoan parasite Sarcocystis neurona. The purposes of this study were to develop the most stringent criteria possible for a positive test result, to estimate the sensitivity and specificity of the EPM Western blot antibody test, and to assess the ability of bovine antibodies to Sarcocystis cruzi to act as a blocking agent to minimize false-positive results in the western blot test for S. neurona. Sarcocystis neurona merozoites harvested from equine dermal cell culture were heat denatured, and the proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis in a 12-20% linear gradient gel. Separated proteins were electrophoretically transferred to polyvinylidene fluoride membranes and blocked in 1% bovine serum albumin and 0.5% Tween-Tris-buffered saline. Serum samples from 6 horses with S. neurona infections (confirmed by culture from neural tissue) and 57 horses without infections (horses from the Eastern Hemisphere, where S. neurona does not exist) were tested by Western blot. Horses from both groups had reactivity to the 62-, 30-, 16-, 13-, 11-, 10.5-, and 10-kD bands. Testing was repeated with another step. Blots were treated with bovine S. cruzi antibodies prior to loading the equine samples. After this modification of the Western blot test, positive infection status was significantly associated with reactivity to the 30- and 16-kD bands (P<0.001, Fisher's exact test). The S. cruzi antibody-blocked Western blot had a sample sensitivity of 100% and sample specificity of 98%. It is concluded that the specificity of the Western blot test is improved by blocking proteins not specific to S. neurona and using reactivity to the 30- and 16-kD bands as the criterion for a positive test.
Animals↗
Efficacy of a modified polymerase chain reaction assay for detection of Ehrlichia canis infection.
Detection of Ehrlichia canis in acutely infected and convalescent dogs is important for effective treatment and control. However, accurate detection has been difficult to achieve, in part because dogs that have been treated therapeutically often remain seropositive for extended periods. A new method, polymerase chain reaction (PCR) assay using biotinylated E. canis-specific primers (PCR-BP), was developed for detection of E. canis. Four dogs experimentally infected with E. canis by intravenous inoculation of whole blood from carrier dogs and 2 naturally infected convalescent carriers were used to compare the specificity and sensitivity of the new method with that of microscopy/blood smear evaluation, serologic test, and conventional PCR assay using E. canis-specific primers. In experimentally infected animals, infection was detected as early as 7 days post-exposure using PCR-BP. Although the 2 naturally infected dogs were positive by serologic test and PCR-BP, both were negative by conventional PCR. Results suggest that the new method is a sensitive assay for detection of E. canis infection. In addition, results were obtained more rapidly than with other PCR-based assays.
Animals↗
Coordinate regulation of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 expression in human vascular smooth muscle cells.
The expression of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) by human vascular smooth muscle cells (SMC) was monitored as a function of the phenotypic modulation in vitro. Cell phenotype was manipulated by varying serum concentration and cell density. Synthetic phenotype was characterized by a minimum expression of the contractile proteins and a maximal proliferation rate. Contractile phenotype was quiescent and expressed a maximal level of contractile proteins. Synthetic cells expressed the highest levels of both MMP-1 and TIMP-1 and displayed maximal collagenolytic activity. No significant change was detected in MMP-2 expression or catalytic activity. Enzyme immunoassays revealed that MMP-1 expression fell by 77+/-2.4-95+/-0.5%, and that of TIMP-1 by 34+/-0.5-59+/-1.9%, as the cells acquired a contractile phenotype. The level of the MMP-1/TIMP-1 complex was similarly reduced by 78+/-2.9-85+/-1.6%. These data demonstrate that the expression of MMP-1 and TIMP-1 are coordinately regulated with SMC phenotype.
Adult↗