Prediction of indications for valve replacement among asymptomatic or minimally symptomatic patients with chronic aortic regurgitation and normal left ventricular performance

BACKGROUND: Optimal criteria for valve replacement are unclear in asymptomatic/minimally symptomatic patients with aortic regurgitation (AR) and normal left ventricular (LV) performance at rest. Moreover, previous studies have not assessed the prognostic capacity of load-adjusted LV performance ("contractility") variables, which may be fundamentally related to clinical state. Therefore, 18 years ago, we set out to test prospectively the hypothesis that objective noninvasive measures of LV size and performance and, specifically, of load-adjusted variables, assessed at rest and during exercise (ex), could predict the development of currently accepted indications for operation for AR. METHODS AND RESULTS: Clinical variables and measures of LV size, performance, and end-systolic wall stress (ESS) were assessed annually in 104 patients by radionuclide cineangiography at rest and maximal ex and by echocardiography at rest; ESS was derived during ex. During an average 7.3-year follow-up among patients who had not been operated on, 39 of 104 patients either died suddenly (n = 4) or developed operable symptoms only (n = 22) or subnormal LV performance with or without symptoms (n = 13) (progression rate=6.2%/y). By multivariate Cox model analysis, change (delta) in LV ejection fraction (EF) from rest to ex, normalized for deltaESS from rest to ex (deltaLVEF-deltaESS index), was the strongest predictor of progression to any end point or to sudden cardiac death alone. Unadjusted deltaLVEF was almost as efficient. Symptom status modified prediction on the basis of the deltaLVEF-deltaESS index. The population tercile at highest risk by deltaLVEF-deltaESS progressed to end points at a rate of 13.3%/y, and the lowest-risk tercile progressed at 1.8%/y. CONCLUSIONS: Currently accepted symptom and LV performance indications for valve replacement, as well as sudden cardiac death, can be predicted in asymptomatic/minimally symptomatic patients with AR by load-adjusted deltaLVEF-deltaESS index, which includes data obtained during exercise.     

Functional knockout of the transient outward current, long-QT syndrome, and cardiac remodeling in mice expressing a dominant-negative Kv4 alpha subunit

Amino acid changes S180A (S-->A at site 180), H197Y, Y277F, T285A, and A308S are known to shift the maximum wavelength of absorption (lambda max) of red and green visual pigments toward blue, essentially in an additive fashion. To test the generality of this "five-sites" rule, we have determined the partial amino acid sequences of red and green pigments from five mammalian orders (Artiodactyla, Carnivora, Lagomorpha, Perissodactyla, and Rodentia). The result suggests that cat (Felis catus), dog (Canis familiaris), and goat (Capra hircus) pigments all with AHYTA at the five critical sites have lambda max values of approximately 530 nm, whereas rat (Rattus norvegicus) pigment with AYYTS has a lambda max value of approximately 510 nm, which is accurately predicted by the five-sites rule. However, the observed lambda max values of the orthologous pigments of European rabbit (Oryctolagus cuniculus), white-tailed deer (Odocoileus virginianus), gray squirrel (Sciurus carolinensis), and guinea pig (Cavia procellus) are consistently more than 10 nm higher than the predicted values, suggesting the existence of additional molecular mechanisms for red and green color vision. The inferred amino acid sequences of ancestral organisms suggest that the extant mammalian red and green pigments appear to have evolved from a single ancestral green-red hybrid pigment by directed amino acid substitutions.     

Traffic of dynamin within individual Drosophila synaptic boutons relative to compartment-specific markers

Presynaptic terminals contain several specialized compartments, which have been described by electron microscopy. We show in an identified Drosophila neuromuscular synapse that several of these compartments-synaptic vesicle clusters, presynaptic plasma membrane, presynaptic cytosol, and axonal cytoskeleton-labeled by specific reagents may be resolved from one another by laser scanning confocal microscopy. Using a panel of compartment-specific markers and Drosophila shibire(ts1) mutants to trap an intermediate stage in synaptic vesicle recycling, we have examined the localization and redistribution of dynamin within single synaptic varicosities at the larval neuromuscular junction. Our results suggest that dynamin is not a freely diffusible molecule in resting nerve terminals; rather, it appears localized to synaptic sites by association with yet uncharacterized presynaptic components. In shi(ts1) nerve terminals depleted of synaptic vesicles, dynamin is quantitatively redistributed to the plasma membrane. It is not, however, distributed uniformly over presynaptic plasmalemma; instead, fluorescence images show "hot spots" of dynamin on the plasma membrane of vesicle-depleted nerve terminals. We suggest that these dynamin-rich domains may mark the active zones for synaptic vesicle endocytosis first described at the frog neuromuscular junction.     

Anisotropy of radiance in tissue phantoms and Dunning R3327 rat tumors: radiance measurements with flat cleaved fiber probes

OBJECTIVE: To compare the prevalence of conduct problems (CP) according to level of urbanization and to determine which factors account for the potential difference in prevalence rates. METHOD: Study 1 used a questionnaire survey of a nationally representative sample of 10,462 Norwegian adolescents. Study 2 used a questionnaire survey of a representative sample of 1,346 adolescents living in Oslo. Self-reported CP included most DSM-III-R criteria for conduct disorder. RESULTS: CP rates were similar in all levels of urbanization, except for the only semimetropolitan city in the country, the capital Oslo, which had CP rates twice those of the rest of the country. This increase rate could not be explained by a series of commonly advocated explanations: family structure and parental practices, social network, socioeconomic status, integration in community activities, religious involvement, and race. However, involvement in "soft" drugs and associating with antisocial peers could explain the statistically differential rates. Furthermore, in the Oslo study, adolescents' CP did not vary according to density of population or region within the city. CONCLUSIONS: The results support previous studies showing increased rates of CP in urban areas. However, urbanization must pass a certain threshold before it has this effect. Moreover, the lack of support for commonly advocated explanations for the difference between urban and nonurban areas suggests that investigations specifically addressing potential explanations for this difference should be conducted. The results indicate that the increased rates of substance use in highly urbanized areas may account for the difference in CP rates by prolonging and aggravating CP.     

Organizational Commitment: Clarifying the Concept and Simplifying the Existing Construct Typology

This paper examines popular concepts and "types" of organizational commitment in light of the definition of commitment and common factors that pertain to all commitments. It argues that a commitment is best conceptualized as a single, fundamental construct that may vary according to differences in focus, terms, and time-specific evaluation. Analysis of affective commitment measures indicates that certain measures contain more than one set of terms and make assumptions about evaluation that add constraints to the basic meaning of commitment. Recommendations include the argument that commitment measures address one set of terms and avoid evaluative phraseology.     

The fine structure of the interrenal cells of the duck (Anas platyrhynchos) with evidence for possible exocytotic release of steroids

The duck interrenal cell possesses ultrastructural characteristics common to other steroid-secreting cells. Lipid droplets and mitochondria are abundant and lie principally at the apical end of the cell. Lipid droplets are not membrane-limited. Cisternae of smooth endoplasmic reticulum that are occasionally continuous with the less abundant rough endoplasmic reticulum are a prominent feature of the interrenal cell. Tubular profiles of rough endoplasmic reticulum often lie tangentially to mitochondria and ribosomes are either free, grouped in polyribosomal clusters, or bound to the endoplasmic reticulum. Mitochondria possess tubular cristae in the inner regions of the gland and frequently contain a paracrystalline array of small 10nm (o.d.) tubules and less frequently a hexagonal array of 40 nm trilaminar rings. Other cytoplasmic components include dense bodies, residual bodies, microtubules, microfilaments and specialized single membrane-bound vesicles. Gap junctions, intermediate junctions and interdigitating processes constitute the main intercellular associations. No tight junctions were identified. The single membrane-bound vesicles which are occasionally filled with a low electron-dense, lipid-like material form septate-like "junctions" with the plasma membrane. The septa bridge an intracellular gap of 15-17 nm. The vesicles are usually located near the subendothelial space at the basal and basilateral regions of the cell. Occasionally, vesicles fuse with the plasma membrane. It is suggested that these vesicles represent morphological evidence for the exocytotic release of steroid hormones.     

The relationship of education to blood pressure: findings on 40,000 employed Chicagoans

The relationship of education to both actual blood pressure and the prevalence of high blood pressure, based on a systolic pressure of 160 mm Hg or greater or a diastolic pressure of 95 mm Hg or greater, was analyzed among 27,033 men and women, white and black, age 25-44 and 45-64, from the Chicago Heart Association Detection Project in Industry. The educational status of each individual was categorized as not a high school graduate, high school graduate, some college, or college graduate. A statistically significant inverse association between education and high blood pressure was present in all groups of whites. This association could not be "accounted for" by differences in age, relative weight, and heart rate among the educational strata. Controlling for these variables did, however, lessen the association. Among black males a significant inverse association between education level and blood pressure was found for the younger group. For the older black males there was a clear inverse association although with the small numbers it did not achieve statistical significance. For black females there was no clear association.     

Serotonin 5-HT2 receptors in schizophrenia: a PET study using [18F]setoperone in neuroleptic-naive patients and normal subjects

BACKGROUND: In the FRISC trial, dalteparin 120 IU/kg body weight twice daily for unstable coronary artery disease was safe and reduced the risk of new coronary events. This risk reduction was maintained during the following extended treatment with a fixed dose of 7500 IU dalteparin once daily. METHODS AND RESULTS: Minor bleeding was more frequent in women compared with men: relative risk (CI) 2.88 (1.78 to 4.67) during the weight-adjusted and 2.36 (1.37 to 2.63) during the fixed dose treatment. The anti-Xa activity determined in samples (n = 175) obtained during the acute phase treatment was higher in women compared with men (P <.001) and in nonsmokers compared with smokers (<.001) in multiple regression analysis. Also, during the fixed-dose treatment (n = 131) an independent relation between anti-Xa activity and sex (P <.001), but not smoking habits, persisted. CONCLUSION: To improve future low-molecular-weight heparin dose regimens for the treatment of acute coronary syndromes, it might be important to consider the influence of sex and smoking habits.     

Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia

OBJECTIVE: Dopamine D2 receptor occupancy measurements provide a valid predictor of antipsychotic response, extrapyramidal side effects, and elevation of prolactin levels. The new antipsychotics clozapine, risperidone, and olanzapine obtain antipsychotic response with few extrapyramidal side effects and little prolactin elevation. The purpose of this study was to compare the D2 and serotonin 5-HT2 receptor occupancies of these drugs in patients receiving multiple-dose, steady-state regimens. METHOD: Forty-four patients with schizophrenia (16 taking risperidone, 2-12 mg/day; 17 taking olanzapine, 5-60 mg/day; and 11 taking clozapine, 75-900 mg/day) had their D2 and 5-HT2 occupancies determined with the use of [11C]raclopride and [18F]setoperone, respectively, and positron emission tomography imaging. RESULTS: Clozapine showed a much lower D2 occupancy (16%-68%) than risperidone (63%-89%) and olanzapine (43%-89%). Risperidone and olanzapine gave equal D2 occupancies at doses of 5 and 20 mg/day, respectively. All three drugs showed greater 5-HT2 than D2 occupancy at all doses, although the difference was greatest for clozapine. CONCLUSIONS: Clozapine, at doses known to be effective in routine clinical settings, showed a D2 occupancy clearly lower than that of typical antipsychotics, while risperidone and olanzapine at their usual clinical doses gave the same level of D2 occupancy as low-dose typical antipsychotics. The results also suggest that some previous clinical comparisons of antipsychotics may have been confounded by different levels of D2 occupancy. Clinical comparisons of these drugs, matching for D2 occupancy, may provide a better measure of their true "atypicality" and will help in understanding the contribution of non-D2 receptors to antipsychotic effects.     

Prevention of type 2 diabetes

Type 2 diabetes is a major cause of morbidity and mortality resulting from its microangiopathic and macroangiopathic complications. Current approaches to its management and to the prevention of diabetic complications are difficult to implement effectively, and there is little evidence to date that these approaches are reducing the impact of this disease. The recognition that type 2 diabetes usually has a prolonged prediabetic phase raises the possibility that the emergence of hyperglycemia and the atherosclerotic complications associated with diabetes may be preventable by the institution of early treatment modalities. Sufficient data suggest that life-style modification or pharmacotherapy directed at improving insulin sensitivity or insulin secretion in subjects with impaired glucose tolerance may reduce progression to diabetes. Two long-term prospective, controlled trials have been initiated to test this hypothesis.