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Suit filed in Oklahoma alleging twenty-four infants died after being denied beneficial medical treatment.
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Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.
The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.
State action, due process, and regulated health care: the downstream effects of American Manufacturers Mutual Insurance Company v. Sullivan.
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Ultrasound imaging of the canine tympanic bulla.
A procedure for imaging the canine tympanic bulla, external ear canal and adjacent structures using currently available ultrasound equipment was established. Lateral and ventral transducer positions were identified for this purpose and a 6.5 MHz curvilinear transducer was considered to be optimal. The sonographic appearance of these structures in cadavers and live dogs unaffected by ear disease is documented. Fluid was introduced into the tympanic bullae of the cadavers and its presence could be identified through the bony wall of the bulla. The ability of ultrasound to differentiate between gas and fluid within the bulla has important clinical implications as this is a common occurrence in dogs with middle ear disease. Ultrasound has several advantages over other imaging modalities and the examination procedure was well tolerated by unsedated dogs.
Comparison of ultrasonography, radiography and a single computed tomography slice for the identification of fluid within the canine tympanic bulla.
Fluid accumulation within the tympanic bulla (TB) is an important diagnostic indicator in clinical cases of canine otitis media although its identification can be a challenge using currently available imaging techniques. The aim of this study was to compare ultrasound with radiography and a single computed tomography (CT) slice for the identification of fluid within the TB of canine cadavers. A random number of TB in 66 cadavers were filled with ultrasound gel. Rostrocaudal open mouth (RCdoM) radiographs and CT images were interpreted by 2 blinded radiologists and ultrasound examinations were performed by 2 blinded sonographers. The heads were then frozen and sectioned to confirm the contents of each TB. Although CT remained the most accurate method, comparable results were obtained by one of the sonographers and even the inexperienced sonographer produced results superior to radiography. Ultrasound has several advantages over the other imaging techniques and this study suggests that it may have an application in the investigation of canine otitis media although further work in live animals would be required to confirm this.
Subcellular localization of low-abundance human immunodeficiency virus nucleic acid sequences visualized by fluorescence in situ hybridization.
Detection and subcellular localization of human immunodeficiency virus (HIV) were investigated using sensitive high-resolution in situ hybridization methodology. Lymphocytes infected with HIV in vitro or in vivo were detected by fluorescence after hybridization with either biotin or digoxigenin-labeled probes. At 12 hr after infection in vitro, a single intense signal appeared in the nuclei of individual cells. Later in infection, when cytoplasmic fluorescence became intense, multiple nuclear foci frequently appeared. The nuclear focus consisted of newly synthesized HIV RNA as shown by hybridization in the absence of denaturation and by susceptibility to RNase and actinomycin D. Virus was detected in patient lymphocytes and it was shown that a singular nuclear focus also characterizes cells infected in vivo. The cell line 8E5/LAV containing one defective integrated provirus revealed a similar focus of nuclear RNA, and the single integrated HIV genome was unequivocally visualized on a D-group chromosome. This demonstrates an extremely sensitive single-cell assay for the presence of a single site of HIV transcription in vitro and in vivo and suggests that it derives from one (or very few) viral genomes per cell. In contrast, productive Epstein-Barr virus infection exhibited many foci of nuclear RNA per cell.
A case of Stevens-Johnson syndrome.
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Bone scintigraphy in the investigation of occult lameness in the dog.
99mTechnetium methylene diphosphonate (99mTc-MDP) scintigraphy was performed in 14 dogs of different breeds after clinical lameness examination, radiography and synovial fluid analysis failed to localise lameness to a specific area of pain. The scintigraphic protocol included an intravenous injection of 17 MBq 99mTc-MDP/kg bodyweight and vascular, soft tissue and bone phase scans in standardised positions with a low-energy all-purpose collimator. Confirmation of diagnosis was achieved in nine dogs by arthroscopy, repeated lesion-orientated radiography, computed tomography and response to treatment. In seven cases, bone phase scans showed single elbow uptakes, in two cases unilateral limb uptake, and in one case each a single shoulder and tibia uptake; in three cases there was no increased uptake. Vascular and soft tissue phase images did not reveal additional information. Diagnosis of humeral condyle fissures, a fragmented medial coronoid process, panosteitis and arthropathy was possible in nine cases. Skeletal pathology was ruled out in three normal scintigrams. In two dogs with unilateral uptake of multiple joints, no diagnostic benefit was gained from scintigraphy. The highly sensitive and relatively specific uptake allowed localisation and characterisation or exclusion of skeletal lesions in most dogs.
Effects of a 16-month randomized controlled exercise trial on body weight and composition in young, overweight men and women: the Midwest Exercise Trial.
BACKGROUND: In light of the current obesity epidemic, treatment models are needed that can prevent weight gain or provide weight loss. We examined the long-term effects of a supervised program of moderate-intensity exercise on body weight and composition in previously sedentary, overweight and moderately obese men and women. We hypothesized that a 16-month program of verified exercise would prevent weight gain or provide weight loss in the exercise group compared with controls. METHODS: This was a randomized controlled efficacy trial. Participants were recruited from 2 midwestern universities and their surrounding communities. One hundred thirty-one participants were randomized to exercise or control groups, and 74 completed the intervention and all laboratory testing. Exercise was supervised, and the level of energy expenditure of exercise was measured. Controls remained sedentary. All participants maintained ad libitum diets. RESULTS: Exercise prevented weight gain in women and produced weight loss in men. Men in the exercise group had significant mean +/- SD decreases in weight (5.2 +/- 4.7 kg), body mass index (calculated as weight in kilograms divided by the square of height in meters) (1.6 +/- 1.4), and fat mass (4.9 +/- 4.4 kg) compared with controls. Women in the exercise group maintained baseline weight, body mass index, and fat mass, and controls showed significant mean +/- SD increases in body mass index (1.1 +/- 2.0), weight (2.9 +/- 5.5 kg), and fat mass (2.1 +/- 4.8 kg) at 16 months. No significant changes occurred in fat-free mass in either men or women; however, both had significantly reduced visceral fat. CONCLUSIONS: Moderate-intensity exercise sustained for 16 months is effective for weight management in young adults.
Disseminated pyogenic Mycoplasma pneumoniae infection in a renal transplant recipient, detected by broad-range polymerase chain reaction.
Although extrapulmonary manifestations of Mycoplasma pneumoniae infection are generally immune-mediated, disseminated infections occasionally occur. We describe a renal transplant recipient who developed disseminated pyogenic M. pneumoniae infection that was detected by broad-range polymerase chain reaction and that manifested by prosthetic arterial graft infection, psoas abscess, and septic arthritis.
Topography of cardiac ganglia in the adult human heart.
Published descriptions of the topography of cardiac ganglia in the human heart are limited and present conflicting results. This study was carried out to determine the distribution of cardiac ganglia in adult human hearts and to address these conflicts. Hearts obtained from autopsies and heart transplant procedures were sectioned, stained, and examined. Results indicate that the largest populations of cardiac ganglia are near the sinoatrial and atrioventricular nodes. Smaller collections of ganglia exist on the superior left atrial surface, the interatrial septum, and the atrial appendage-atrial junctions. Ganglia also exist at the base of the great vessels and the base of the ventricles. The right atrial free wall, atrial appendages, trunk of the great vessels, and most of the ventricular myocardium are devoid of cardiac ganglia. These findings suggest modifications to surgical procedures involving incisions through regions concentrated with ganglia to minimize arrhythmias and related complications. Repairs of septal defects, valvular procedures, and congenital reconstructions, such as the Senning and Fontan operations, involve incisions through areas densely populated with cardiac ganglia. The current standard procedure for orthotopic heart transplantation severs cardiac ganglia and their projections to nodal and muscular tissue. One modification of the current heart transplantation procedure, involving bicaval anastomosis, preserves atrial anatomy and the cardiac ganglia. Preservation of cardiac ganglia within the donor heart may provide additional neuronal substrate for intracardiac processing and targets for regenerating nerve fibers to the donor heart.
Quantifying losses to the donated blood supply due to donor deferral and miscollection.
BACKGROUND: Donors are deferred for multiple reasons. Losses related to disease marker rates are well established. Donor and donation losses for other reasons, however, have not been extensively quantified. STUDY DESIGN AND METHODS: To quantify these losses, three data sets from the Blood Centers of the Pacific were combined, permitting detailed analysis of year 2000 allogeneic whole-blood donations. RESULTS: During 2000, 13.6 percent of 116,165 persons who presented for donation were deferred at presentation. Short-term deferral accounted for 68.5 percent (hematocrit was most common at 60%); long-term deferral accounted for 21 percent (travel to a malarial area and tattoo or other nonintravenous drug use needle exposure were most common at 59 and 29%, respectively); and multiple-year or permanent deferral accounted for 10.5 percent (UK travel [variant Creutzfeldt-Jakob disease] risk and emigration from a malarial area were most common at 38 and 11%, respectively). Disease-marker-reactive donations represented 0.9 percent of donor outcomes. The prevalence of deferral and also miscollection (under- and overweight units) varied by age, sex, and first-time versus repeat donor status. Overall, miscollection led to a loss of 3.8 percent of 100,141 collections, ranging from 1.9 percent in repeat male donors 40 to 54 years of age to 10.7 percent in first-time female donors 16 to 24 years of age. CONCLUSION: Loss of units from both first-time and repeat donors due to temporary deferral and loss of units from miscollection are more common events than losses due to disease marker testing. Some of these losses may be avoidable and could increase the blood supply without having to recruit new donors.
Evidence for a subsurface ocean on Europa.
Ground-based spectroscopy of Jupiter's moon Europa, combined with gravity data, suggests that the satellite has an icy crust roughly 150 km thick and a rocky interior. In addition, images obtained by the Voyager spacecraft revealed that Europa's surface is crossed by numerous intersecting ridges and dark bands (called lineae) and is sparsely cratered, indicating that the terrain is probably significantly younger than that of Ganymede and Callisto. It has been suggested that Europa's thin outer ice shell might be separated from the moon's silicate interior by a liquid water layer, delayed or prevented from freezing by tidal heating; in this model, the lineae could be explained by repetitive tidal deformation of the outer ice shell. However, observational confirmation of a subsurface ocean was largely frustrated by the low resolution (>2 km per pixel) of the Voyager images. Here we present high-resolution (54 m per pixel) Galileo spacecraft images of Europa, in which we find evidence for mobile 'icebergs'. The detailed morphology of the terrain strongly supports the presence of liquid water at shallow depths below the surface, either today or at some time in the past. Moreover, lower-resolution observations of much larger regions suggest that the phenomena reported here are widespread.
Thoracic high-resolution computed tomographic findings in dogs with canine idiopathic pulmonary fibrosis.
OBJECTIVES: To identify features of canine idiopathic pulmonary fibrosis (CIPF) using high-resolution computed tomography (HRCT), and to correlate these features with clinical stages of the disease. METHODS: Ten dogs with signalment, history and clinical signs highly suggestive of CIPF were investigated. Thoracic radiography, haematology and biochemistry profiles, bronchoscopy and bronchoalveolar lavage and HRCT were performed in each case. The dogs were classified as having mild, moderate or severe stages of the disease based on their clinical presentation and radiographic signs. Features identified by HRCT were correlated with these disease stages. RESULTS: HRCT showed a spectrum of pulmonary changes and it was possible to match some of these to the stage of CIPF. CLINICAL SIGNIFICANCE: HRCT is used extensively in humans in the diagnosis and treatment planning of idiopathic pulmonary fibrosis. This preliminary study identifies the high-resolution computed tomographic features of CIPF in a small group of dogs. With further work it may be possible to use HRCT as a non-invasive tool for diagnosing, staging and therapeutically monitoring CIPF.
Gender differences in labetalol kinetics: importance of determining stereoisomer kinetics for racemic drugs.
STUDY OBJECTIVE: To evaluate the impact of gender on labetalol kinetics. DESIGN: Part of a randomized, crossover study. SETTING: Academic medical center. PATIENTS: Nineteen hypertensive patients (14 men, 5 women; 6 blacks, 13 whites). INTERVENTIONS: Participants had labetalol dosages titrated to a specific antihypertensive response, then underwent ambulatory blood pressure monitoring (ABPM) and a pharmacokinetic study. Labetalol plasma concentrations were measured by high-performance liquid chromatography (HPLC) and labetalol stereoisomer ratios were determined in a single plasma sample by chiral HPLC, both with fluorescence detection. MEASUREMENTS AND MAIN RESULTS: Labetalol concentrations were 80% higher in women (area under the concentration-time curve [AUC]/dose x 1000: 6.79 +/- 2.11 in women vs 3.82 +/- 1.37 hr/L in men, p<0.05), yet both genders had a similar antihypertensive response by 24-hour ABPM. Dose-corrected AUC (AUC/dose x 1000) for labetalol's stereoisomers in women and men, respectively, were S,R-labetalol 7.55 +/- 1.47 and 4.83 +/- 1.54 hr/L (p<0.05), S,S-labetalol 8.23 +/- 2.93 and 4.65 +/- 1.78 hr/L (p<0.05), R,S-labetalol 6.99 +/- 3.30 and 4.25 +/- 2.35 hr/L (p=0.11), and R,R-labetalol 3.91 +/- 2.57 and 3.55 +/- 3.08 hr/L (NS). CONCLUSION: The higher labetalol concentration in women than in men was explained largely by differences in inactive and alpha1-blocking stereoisomers. However, concentrations were similar between genders for the beta-blocking stereoisomer (R,R-labetalol), possibly explaining the similarity in antihypertensive response to the drug. This study highlights the importance of determining stereoisomer kinetics for agents administered as racemates, particularly when relating concentrations to pharmacologic response.
A phase 2 study of high-activity 186Re-HEDP with autologous peripheral blood stem cell transplant in progressive hormone-refractory prostate cancer metastatic to bone.
PURPOSE: We investigated the potential for improvement in disease control by use of autologous peripheral blood stem cell transplant (PBSCT) to permit administration of high activities of (186)Re-hydroxyethylidene diphosphonate (HEDP) in patients with progressive hormone-refractory prostate cancer (HRPC). METHODS: Eligible patients had progressive HRPC metastatic to bone, good performance status and minimal soft tissue disease. Patients received 5,000 MBq of (186)Re-HEDP i.v., followed 14 days later by PBSCT. Response was assessed using PSA, survival, pain scores and quality of life. RESULTS: Thirty-eight patients with a median age of 67 years (range 50-77) and a median PSA of 57 ng/ml (range 4-3,628) received a median activity of 4,978 MBq (186)Re-HEDP (range 4,770-5,100 MBq). The most serious toxicity was short-lived grade 3 thrombocytopenia in 8 (21%) patients. The median survival of the group is 21 months (95%CI 18-24 months) with Kaplan-Meier estimated 1- and 2-year survival rates of 83% and 40% respectively. Thirty-one patients (81%, 95% CI 66-90%) had stable or reduced PSA levels 3 months post therapy while 11 (29%, 95% CI 15-49%) had PSA reductions of >50% lasting >4 weeks. Quality of life measures were stable or improved in 27 (66%) at 3 months. CONCLUSION: We have shown that it is feasible and safe to deliver high-activity radioisotope therapy with PBSCT to men with metastatic HRPC. Response rates and survival data are encouraging; however, further research is needed to define optimal role of this treatment approach.
Pharmacokinetics of dapsone administered daily and weekly in human immunodeficiency virus-infected children.
Although dapsone is a commonly used alternative agent for prophylaxis against Pneumocystis carinii pneumonia in children intolerant to trimethoprim-sulfamethoxazole, there are few data that describe dapsone pharmacokinetics in children. We studied dapsone pharmacokinetics in 30 children (median age, 2.8 years; age range, 0. 3 to 12 years) receiving a new proprietary liquid preparation by three dosing regimens (1 mg/kg of body weight daily, 2 mg/kg daily, or 4 mg/kg weekly). Dosing of children with 2 mg/kg daily or 4 mg/kg weekly resulted in peak concentrations equivalent to those reached in adults receiving 100-mg tablets daily. For the entire population, the median half-life was 22.2 h (range, 7.1 to 40.3 h), the median oral clearance was 0.0365 liter/kg/h (range, 0.0104 to 0.1021 liter/kg/h), and the median oral apparent volume of distribution was 1.13 liters/kg (range, 0.50 to 2.32 liters/kg). The median dapsone oral clearance was significantly increased in those infants less than 2 years of age compared to the oral clearance in those over 2 years of age (0.0484 versus 0.0278 liter/kg/h; P = 0.011). These data suggest that absorption of this liquid preparation is adequate and that the concentrations in the sera of children receiving 2 mg/kg daily or 4 mg/kg weekly are equivalent to those seen in adults receiving standard dapsone dosing. Dapsone oral clearance appears to be increased in children under 2 years of age.