Reduced brain serotonin transporter availability in major depression as measured by [123I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane and single photon emission computed tomography

BACKGROUND: Prior research has suggested reductions in the density of serotonin transporter (SERT) binding sites in blood platelets and post-mortem brain tissue of depressed patients. We sought to determine whether patients with unipolar major depression have diminished SERT availability as assessed by both brainstem [123I] beta-CIT SPECT and platelet [3H]paroxetine binding. METHODS: Drug-free depressed and healthy subjects were injected with 211 +/- 22 MBq [123I] beta-CIT and imaged 24 +/- 2 h later under equilibrium conditions. A ratio of specific to nonspecific brain uptake (V3" = (brainstem-occipital)/occipital), a measure proportional to the binding potential (Bmax/Kd), was used for all comparisons. RESULTS: Results showed a statistically significant reduction in brainstem V3" values in depressed as compared to healthy subjects (3.1 +/- .9 vs. 3.8 +/- .8, p = .02). Platelet [3H]paroxetine binding was not altered (Bmax = 2389 +/- 484 vs. 2415 +/- 538 fmol/mg protein, p = .91) and was not significantly correlated with brainstem [123I] beta-CIT binding (r = -0.14, p = .48). CONCLUSIONS: These data are the first to suggest reductions in the density of brain SERT binding sites in living depressed patients. These findings provide further support for a preeminent role for alterations in serotonergic neurons in the pathophysiology of depression.     

Domain flexibility in retroviral proteases: structural implications for drug resistant mutations

Rigid body rotation of five domains and movements within their interfacial joints provide a rational context for understanding why HIV protease mutations that arise in drug resistant strains are often spatially removed from the drug or substrate binding sites. Domain motions associated with substrate binding in the retroviral HIV-1 and SIV proteases are identified and characterized. These motions are in addition to closure of the flaps and result from rotations of approximately 6-7 degrees at primarily hydrophobic interfaces. A crystal structure of unliganded SIV protease (incorporating the point mutation Ser 4 His to stabilize the protease against autolysis) was determined to 2.0 A resolution in a new space group, P3221. The structure is in the most "open" conformation of any retroviral protease so far examined, with six residues of the flaps disordered. Comparison of this and unliganded HIV structures, with their respective liganded structures by difference distance matrixes identifies five domains of the protease dimer that move as rigid bodies against one another: one terminal domain encompassing the N- and C-terminal beta sheet of the dimer, two core domains containing the catalytic aspartic acids, and two flap domains. The two core domains rotate toward each other on substrate binding, reshaping the binding pocket. We therefore show that, for enzymes, mutations at interdomain interfaces that favor the unliganded form of the target active site will increase the off-rate of the inhibitor, allowing the substrate greater access for catalysis. This offers a mechanism of resistance to competitive inhibitors, especially when the forward enzymatic reaction rate exceeds the rate of substrate dissociation.     

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.     

Task-Space Modular Dynamics for Dual-Arms Expressed through a Relative Jacobian

This paper presents modular dynamics for dual-arms, expressed in terms of the kinematics and dynamics of each of the stand-alone manipulators. The two arms are controlled as a single manipulator in the task space that is relative to the two end-effectors of the dual-arm robot. A modular relative Jacobian, derived from a previous work, is used which is expressed in terms of the stand-alone manipulator Jacobians. The task space inertia is expressed in terms of the Jacobians and dynamics of each of the stand-alone manipulators. When manipulators are combined and controlled as a single manipulator, as in the case of dual-arms, our proposed approach will not require an entirely new dynamics model for the resulting combined manipulator. But one will use the existing Jacobians and dynamics model for each of the stand-alone manipulators to come up with the dynamics model of the combined manipulator. A dual-arm KUKA is used in the experimental implementation.     

Design and validation of an Individual Health Report (IHR)

This research focused on developing a general health report that conveys an individual’s health readings in a clear, concise and explanatory manner and demonstrating the report’s usefulness. The research examined the need for such a report and focused the design on the determined need and communication through visual display. The designed “Individual Health Report (IHR)” was evaluated using data obtained from an online survey developed for this research. The analysis involved t-tests, McNemar’s tests, linear regression and ANOVA. Results included the finding that the IHR significantly improved respondent’s ability to correctly answer questions about their health status and preventive health in general (p < 0.0001, n = 61). The study also showed that introduction of the IHR by healthcare providers would significantly improve the respondents’ view that they get the preventive healthcare information they need to make appropriate decisions (p = 0.0007, n = 61).In an era when costs of healthcare are of great concern and prevention is starting to gain traction as compared to strictly treatment, an IHR could be a very practical and beneficial step toward prevention focused healthcare. An IHR could be considered as a tool to provide increased public awareness of health status, with resulting gains in proactive and effective health management choices.

Relevance to Industry

Degraded health and associated healthcare costs are of significant concerns to industry performance and profits. As several references highlighted in this research have indicated, a lack of health literacy and awareness of critical health indicators are significant concerns in helping employees to manage their own health status. From an economic and societal perspective, it may be considered cost effective for employers to work with healthcare providers to support presentation of employee health status and results of recent healthcare evaluations by means of an IHR. An IHR of the type tested in this research can be seen to both provide clear and understandable health status information, and improve health literacy, for wide sections of the population. Presenting employee information via this type of IHR can effectively supplement healthcare information delivered by healthcare providers. The IHR tested in this research represents a form of clear information presentation and visualization that overcomes issues of jargon that degrades communication between healthcare providers and employees.