Potential impact of evidence-based medicine in acute coronary syndromes: insights from GUSTO-IIb. Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes trial

OBJECTIVES: The purpose of this study to determine whether use of cardiac medications reflects evidence-based recommendations for patients with non-ST elevation acute coronary syndromes. BACKGROUND: Agency for Health Care Policy and Research practice guidelines for unstable angina recommend the use of cardiac medications based on evidence from randomized trials. It is unknown whether practitioners in the U.S., Canada and Europe follow these recommendations in patients with non-ST elevation acute coronary syndromes. METHODS: We studied 7,743 patients with non-ST elevation acute coronary syndromes enrolled in the international Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes trial. The use of aspirin, beta-adrenergic blocking agents, angiotensin-converting enzyme inhibitors and calcium channel blocking agents was determined at discharge for all patients and "ideal" patients (those with indications and no contraindications). Using published estimates of relative mortality reductions with these drugs, we calculated the lives that could have been saved at 1 year if discharge medication use had better matched guideline recommendations. RESULTS: Overall, guideline adherence at discharge in "ideal" patients was 85.6% for aspirin, 59.1% for beta-blockers and 51.7% for angiotensin-converting enzyme inhibitors. Calcium channel blockers were given to 26.7% of patients with a contraindication to these drugs. These rates were similar across locations of enrollment. Women and older patients less often received aspirin when "ideal," and younger patients more often received calcium channel blockers when they were contraindicated. If medication use had been more evidence-based, 1-year mortality might have been reduced by a relative 22%. CONCLUSIONS: There is significant room for improvement in the use of recommended drugs in patients with non-ST elevation acute coronary syndromes. Medication use that more closely follows recommendations could reduce mortality in this population.     

Suppression of protein synthesis in brain during hibernation involves inhibition of protein initiation and elongation

Protein synthesis (PS) has been considered essential to sustain mammalian life, yet was found to be virtually arrested for weeks in brain and other organs of the hibernating ground squirrel, Spermophilus tridecemlineatus. PS, in vivo, was below the limit of autoradiographic detection in brain sections and, in brain extracts, was determined to be 0.04% of the average rate from active squirrels. Further, it was reduced 3-fold in cell-free extracts from hibernating brain at 37 degreesC, eliminating hypothermia as the only cause for protein synthesis inhibition (active, 0.47 +/- 0.08 pmol/mg protein per min; hibernator, 0.16 +/- 0.05 pmol/mg protein per min, P < 0.001). PS suppression involved blocks of initiation and elongation, and its onset coincided with the early transition phase into hibernation. An increased monosome peak with moderate ribosomal disaggregation in polysome profiles and the greatly increased phosphorylation of eIF2alpha are both consistent with an initiation block in hibernators. The elongation block was demonstrated by a 3-fold increase in ribosomal mean transit times in cell-free extracts from hibernators (active, 2.4 +/- 0.7 min; hibernator, 7.1 +/- 1.4 min, P < 0.001). No abnormalities of ribosomal function or mRNA levels were detected. These findings implicate suppression of PS as a component of the regulated shutdown of cellular function that permits hibernating ground squirrels to tolerate "trickle" blood flow and reduced substrate and oxygen availability. Further study of the factors that control these phenomena may lead to identification of the molecular mechanisms that regulate this state.     

Entry into primary care and continuity: the effects of access

OBJECTIVES: This study examined the relationship between access and use of primary care physicians as sources of first contact and continuity with the medical system. METHODS: Data from the 1987 National Medical expenditure Survey were used to examine the effects of access on use of primary care physicians as sources of first contact for new episodes of care (by logistic regression) and as sources of continuity for all ambulatory visits (by multi-variate linear regression). RESULTS: No after-hours care, longer office waits, and longer travel times reduced the chances of a first-contact visit with a primary care physician for acute health problems. Longer appointment waits, no insurance, and no after-hours care were associated with lower levels of continuity. Generalists provided more first-contact care than specialists acting as primary care physicians, largely because of their more accessible practices. CONCLUSIONS: These data provide support for the linkage between access and care seeking with primary care physicians.     

Conceptual design of the KSTAR Motor Generator

The Korean Superconducting Tokamak Advanced Research (KSTAR) superconducting magnet power supply is composed of a Poloidal Field Magnet Power Supply (PF MPS) and a Toroidal Field Magnet Power Supply (TF MPS). When the PF MPS is operated, it requires a large amount of power instantaneously from the KSTAR electric power system. To achieve the KSTAR operational goal, with a long pulse scenario, a peak power of 200 MVA is required and the total power demand for the KSTAR system can exceed 200 MVA. The available grid power is only 100 MVA at the KSTAR site. Increasing the available grid power was uneconomical and inefficient which is why NFRI are installing a Motor Generator (MG).National Fusion Research Institute (NFRI) has made a contract with Vitzrotech and Converteam to design, manufacture and install the MG. Converteam has designed the electromagnetic and mechanical specification of the MG and Variable Voltage Variable Frequency (VVVF) converter.In this paper we discuss the conceptual design, including energy saving and electrical capacity of the MG system and the performance of the MG to satisfy the KSTAR 300 s operation scenario. In addition, the manufacturing and installation plan for the KSTAR MG is discussed.     

Differential titin isoform expression in human skeletal muscle

Mammalian skeletal muscle expresses at least two isoforms of the cytoskeletal protein titin (connectin; MW approximately 3000 kDa). These isoforms are associated with different passive force curves, and thus may affect physical performance. To study the distribution of titin and its possible influence on performance in humans, muscle biopsies were obtained from 15 males (mean +/- SE; age = 25.4 +/- 2.9 years, height = 177.7 +/- 1.8 cm, weight = 76.5 +/- 2.2 kg). Two biopsies were obtained on separate occasions from both the right and left vastus lateralis, and one biopsy each from the lateral head of the right gastrocnemius and the right soleus, with all biopsies handled identically. Fibre type analyses were performed via mATPase histochemistry. Expression of titin and myosin heavy chain isoforms were determined by SDS-PAGE. Titin bands in the resulting gels were highly repeatable and were verified by migration patterns, as well as Western blot analysis. Two groups of subjects were identified: group 1 (n = 10) expressed only one titin isoform (titin-1) in all biopsies, and group 2 (n = 5) expressed two titin isoforms (titin-1 and titin-2) in all biopsies. No significant differences (P > 0.05) between groups were observed for percentage fibre types, percentage fibre type areas, fibre type cross-sectional areas, and percentage myosin heavy chain expression when comparing individual muscles, sampling times or bilateral comparisons. This is the first report of differential titin isoform expression in healthy, mature human skeletal muscle, but it is not clear why this occurs or what influence this may have on performance.     

Onychomycosis associated with Onychocola canadensis: ten case reports and a review of the literature

BACKGROUND: Onychocola canadensis is a nondermatophyte mold associated with onychomycosis particularly in temperate climates (eg, Canada, New Zealand, and France). The slow growth rate of O canadensis and lack of resemblance to any other known nail-infecting fungus may have delayed its discovery. We are aware of 23 mycologically confirmed cases of O canadensis in the literature. OBJECTIVE: We describe 10 previously unreported Canadian patients, specimens from whom grew O canadensis. We also review the literature on infections associated with this organism. METHODS: Cases of O canadensis onychomycosis were diagnosed on the basis of (1) the finding of compatible filaments on direct microscopy of nail and (2) consistent culture from repeated specimens. All patients from whom O canadensis was isolated were followed up, but those in whom outgrowth was not consistent were not accepted as having "authentic" infections. RESULTS: In 10 patients O canadensis was found to be associated with distal lateral subungual onychomycosis (6 patients), white superficial onychomycosis (1 patient), and as an insignificant contaminant in the nails of 3 patients. Less commonly the organism may cause tinea manuum or tinea pedis interdigitalis. O canadensis appears to be more frequent in the elderly, especially females. It is not unusual for a patient with onychomycosis caused by O canadensis to be a gardener or farmer, suggesting that the infectious inoculum may originate from the soil. The optimal therapy for onychomycosis caused by this organism remains unclear. CONCLUSION: O canadensis may be the etiologic agent of distal and lateral subungual or white superficial onychomycosis; however, it may sometimes be present in an abnormal-appearing nail as an insignificant finding, not acting as a pathogen.     

Neural precursor differentiation into astrocytes requires signaling through the leukemia inhibitory factor receptor

The differentiation of precursor cells into neurons or astrocytes in the developing brain has been thought to be regulated in part by growth factors. We show here that neural precursors isolated from the developing forebrain of mice that are deficient in the gene for the low-affinity leukemia inhibitory factor receptor (LIFR-/-) fail to generate astrocytes expressing glial fibrillary acidic protein (GFAP) when cultured in vitro. Precursors from mice heterozygous for the null allele show normal levels of GFAP expression. These findings support the in vivo findings that show extremely low levels of GFAP mRNA in brains of embryonic day 19 LIFR-/- mice. In addition, monolayers of neural cells from LIFR-/- mice are far less able to support the neuronal differentiation of normal neural precursors than are monolayers from heterozygous or wild-type animals, indicating that endogenous signaling through the LIFR is required for the expression of both functional and phenotypic markers of astrocyte differentiation. LIFR-/- precursors are not irreversibly blocked from differentiating into astrocytes: they express GFAP after long-term passaging or stimulation with bone morphogenetic protein-2. These findings strongly implicate the LIF family of cytokines in the regulation of astrocyte differentiation and indeed the LIF-deficient animals show a significant reduction in the number of GFAP cells in the hippocampus. However, because this reduction is only partial it suggests that LIF may not be the predominant endogenous ligand signaling through the LIFR.     

Overexpression of leptin receptors in pancreatic islets of Zucker diabetic fatty rats restores GLUT-2, glucokinase, and glucose-stimulated insulin secretion

The high-Km glucose transporter, GLUT-2, and the high-Km hexokinase of beta cells, glucokinase (GK), are required for glucose-stimulated insulin secretion (GSIS). GLUT-2 expression in beta cells of Zucker diabetic fatty (ZDF) rats is profoundly reduced at the onset of beta-cell dysfunction of diabetes. Because ZDF rats are homozygous for a mutation in their leptin receptor (OB-R) gene and are therefore leptin-insensitive, we expressed the wild-type OB-R gene in diabetic islets by infusing a recombinant adenovirus (AdCMV-OB-Rb) to determine whether this reversed the abnormalities. Leptin induced a rise in phosphorylated STAT3, indicating that the transferred wild-type OB-R was functional. GLUT-2 protein rose 17-fold in AdCMV-OB-Rb-treated ZDF islets without leptin, and leptin caused no further rise. GK protein rose 7-fold without and 12-fold with leptin. Preproinsulin mRNA increased 64% without leptin and rose no further with leptin, but leptin was required to restore GSIS. Clofibrate and 9-cis-retinoic acid, the partner ligands for binding to peroxisome proliferator-activator receptor alpha (PPARalpha) and retinoid X receptor, up-regulated GLUT-2 expression in islets of normal rats, but not in ZDF rats, in which PPARalpha is very low. Because the fat content of islets of diabetic ZDF rats remains high unless they are treated with leptin, it appears that restoration of GSIS requires normalization of intracellular nutrient homeostasis, whereas up-regulation of GLUT-2 and GK is leptin-independent, requiring only high expression of OB-Rb.     

Randomized, double-blind clinical trial of amphotericin B colloidal dispersion vs. amphotericin B in the empirical treatment of fever and neutropenia

The possibility that there is an inhibitory component to auditory covert orienting was addressed. Each trial consisted of a cue followed by a target, and listeners were required to detect, localize, or identify the frequency of the target. At 150-msec stimulus onset asynchrony (SOA), performance was best when stimuli sounded from the same location or were of the same frequency. However, at 750-msec SOA, performance was best when stimuli differed in location or were of different frequencies. These results document the existence of both location-based and frequency-based auditory inhibition of return.