Global alterations to the choroid plexus blood-CSF barrier in amyotrophic lateral sclerosis.

The choroid plexus (CP) is a highly vascularized structure located in the ventricles that forms the blood-CSF barrier (BCSFB) and separates the blood from the cerebrospinal fluid (CSF). In addition to its role as a physical barrier, the CP functions in CSF secretion, transport of nutrients into the central nervous system (CNS) and a gated point of entry of circulating immune cells into the CNS. Aging and neurodegeneration have been reported to affect CP morphology and function and increase protein leakage from blood to the CSF. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with both upper and lower motor neuron loss, as well as altered proteomic and metabolomic signatures in the CSF. The role of the BCSFB and the CP in ALS is unknown. Here we describe a transcriptomic and ultrastructural analysis of BCSFB and CP alterations in human postmortem tissues from ALS and non-neurologic disease controls. ALS-CP exhibited widespread disruptions in tight junctional components of the CP epithelial layer and vascular integrity. In addition, we detected loss of pericytes around ALS blood vessels, accompanied by activation of platelet aggregation markers vWF and Fibrinogen, reminiscent of vascular injury. To investigate the immune component of ALS-CP, we conducted a comprehensive analysis of cytokines and chemokine panels in CP lysates and found a significant down-regulation of M-CSF and V-CAM1 in ALS, as well as up-regulation of VEGF-A protein. This phenotype was accompanied by an infiltration of MERTK positive macrophages into the parenchyma of the ALS-CP when compared to controls. Taken together, we demonstrate widespread structural and functional disruptions of the BCSFB in human ALS increasing our understanding of the disease pathology and identifying potential new targets for ALS therapeutic development.

Psychosocial risk factors associated with cocaine use during pregnancy: a case-control study.

OBJECTIVE: To investigate whether psychosocial risk factors predict cocaine use during pregnancy. METHODS: We sampled 229 pregnant women from an urban prenatal clinic. Drug use ascertainment was based on self-report and urine toxicology, with 102 subjects classified as drug users and 127 as nonusers. A questionnaire measuring seven psychosocial risk factors was administered. The predictive relation between these characteristics and drug use was ascertained through multivariate analyses, controlling for potential sociodemographic confounders. RESULTS: Six of the seven psychosocial risk factors were significant predictors for this sociodemographic group. Women who used cocaine during pregnancy were more likely to have a family history of alcohol or drug problems, to have been introduced to drugs by a male partner, to be depressed, to have less social support, to have current partners who were substance users, and to have less-stable living situations. Both groups of subjects had high rates of childhood sexual abuse, but this alone was not predictive of drug use. In addition, cigarette smoking was a strong predictor of illicit drug use. CONCLUSION: Identification of multiple psychosocial risk factors has implications for the identification and treatment of substance-using pregnant women. Because cocaine users and nonusers did not differ in gestational age at entry into prenatal care, opportunities exist for intervention during pregnancy. Based on the study findings, evaluation of the following aspects of a patient's lifestyle can aid in the detection of cocaine use during pregnancy: smoking status, family history of alcohol or drug problems, and current drug use by a male partner.

Relation between changes in neural responsivity and reductions in desire to eat high-calorie foods following gastric bypass surgery.

Reductions in reward-related (e.g. striatal) neural activation have been noted following obesity surgery. It has been speculated that these postoperative neural changes may be related to documented postoperative changes in food preferences; however, this relation has not been previously established. In this study, functional magnetic resonance imaging and rating scales were used to assess neural responsivity, desire to eat (i.e. wanting), and liking for high- and low-calorie food cues in 14 females one month pre- and one month post-Roux-en-Y gastric bypass (RYGB) surgery. Pre- to post-RYGB changes in all variables were assessed, and postoperative changes in neural responsivity were regressed on postoperative changes in desire to eat and liking of foods. Results revealed significant postoperative reductions in mesolimbic (e.g. striatal) neural responsivity, desire to eat (wanting), and liking for high- relative to low-calorie food cues. Postoperative reductions in mesolimbic responsivity were associated with postoperative reductions in wanting, but not liking, for high- versus low-calorie foods. Interestingly, reductions in food wanting were also related to reductions in inhibitory (e.g. dorsolateral prefrontal cortex) activation following RYGB. Results are consistent with the hypothesized delineation between wanting and liking, supporting the notion that wanting, but not liking, is processed through the dopaminergic reward pathway. Concurrent reductions in both reward-related and inhibitory activation-predicted reductions in desire to eat might suggest that less dietary inhibition was elicited to resist potential overconsumption as the anticipated reward value of high-calorie foods decreased following RYGB.

Reducing complications from alcohol use during pregnancy through screening.

Prenatal providers are reluctant to discuss alcohol use in the clinical setting, even though heavy alcohol use is associated with fetal alcohol syndrome (FAS) and fetal alcohol effects (FAE), sometimes known as alcohol-related neurodevelopmental disorder. Fourteen percent to 20% of pregnant women report drinking some alcohol during pregnancy. Approximately 0.2% to 1% meet the criteria for heavy drinking. Reducing drinking during pregnancy has the potential to reduce the risk for FAS and FAE. Routine screening for alcohol use during pregnancy followed by referrals for those considered to be at risk is recommended. Women are often more receptive to intervention during pregnancy, as they focus on positive health behaviors. A number of brief screening tools designed for use on a routine basis are reviewed. Physicians who learn to comfortably discuss alcohol use during pregnancy can help substantially reduce the impact of these disorders.

Health risk appraisal: process, problems, and prospects for nursing practice and research.

A number of methodological concerns and certain dimensions relevant to future development are generated in the above research: 1. The issue of test reactivity is especially critical in health risk appraisal instruments, since more advanced tools are designed to stimulate the recipient to take actions that might alter post-test results. Therefore, research studies using health risk appraisals need to control for the interaction effects of testing. Since health risk appraisals are reactive, the interaction of test effects with other experimental treatment (e.g. counseling) cannot be handled by use of non-reactive measures, as methodologists frequently suggest. 2. A second major threat to validity is the issue of experimental mortality. The clients who complete the health risk appraisal instrument are usually assumed to be self-motivated. Where engaged in large scale trials, however, their participation may be coerced at the outset but not enforced throughout the course of the study. Because of this some studies have a high proportion of dropouts. 3. Where this has not been the case, a third threat to validity, selectivity, is often a paramount concern, inasmuch as the populations who have subscribed to the instrument under their own motivation may be already pre-selected as very low risk individuals. In light of the paucity of controlled studies using health risk appraisals, it is difficult to draw conclusions regarding the state of the art. In summary, some general dimensions of the activity surround the development and use of health risk appraisals are: 1. The health risk appraisal appears to be more effective in motivating change with older rather than younger individuals. 2. Individuals given a health risk assessment within a supportive educational process do better than individuals exposed only to the results of a health risk appraisal. 3. Individuals given only a health risk appraisal and results without supportive education do better than individuals given no health risk appraisal. 4. Research participants and users of the instrument are, in almost every study, a self-selected group and appear to be healthier than the general population. One might question whether they are the more motivated population.

Why the islands move.

Micronesian navigators routinely make voyages across large expanses of open ocean. To do this, a navigator must judge both the direction in which he is sailing and the distance he has travelled. The rising and setting points of the stars (and other cues) provide instantaneous information about direction, but distance can only be judged by integrating velocity-related information over time. Micronesian navigators judge distance in a way that seems odd. When they are out of sight of land, they imagine that the canoe is stationary and that the islands move back past them. For each voyage, they 'attend' to an island off to the side of the course which is out of sight over the horizon. As they sail, they imagine the island moving back along the horizon changing in bearing until it is imagined to be under the bearing it is known to have from the destination island. Then they know they are near their destination. There is good reason for using a frame of reference whose origin is defined by the boat. We show how it finesses a perceptual paradox--the rising and setting points of the stars do not exhibit motion parallax.

Comparison of experimental and analytical torque-angle relationships of the human elbow joint complex.

The human elbow joint complex (EJC) is an intricate joint that is currently being modeled with eight musculotendon actuators for the analysis of flexion-extension and pronation-supination movements. The musculotendon length (LMT), musculotendon velocity (VMT), and muscular moment arm (MA) for each actuator have been investigated based on joint anatomy and joint angle position. Musculotendon parameters necessary for the muscle model have been collected from various sources. These parameters, along with the musculoskeletal geometry, are used in a static muscle model to compute the force and joint torque generated by each muscle. The results are plotted as torque-angle curves and compared with experimental joint torque data.

Designing a curriculum in a clinical setting: an iterative process.

A curriculum for the training of medical students was designed and implemented in a functioning clinical setting. The multidisciplinary, multiprofessional staff of a primary care center participated with professional educators in an iterative process for curriculum development. A three-stage plan was conceived: behaviorally oriented educational objectives were constructed, instructional methodologies to satisfy these objectives were created, and evaluation instruments were designed. Throughout each stage the educators facilitated the process by teaching the staff the necessary techniques for the design and implementation of the curriculum. The curriculum that resulted from this process is focused on those issues that are important to team delivery of primary care. An important outcome of the project is the increased enthusiasm and competence of the professional staff in the teaching of students in the health professions.

Development and evaluation of a musculoskeletal model of the elbow joint complex.

This paper describes the development and evaluation of a musculoskeletal model that represents human elbow flexion-extension and forearm pronation-supination. The length, velocity, and moment arm for each of the eight musculotendon actuators were based on skeletal anatomy and joint position. Musculotendon parameters were determined for each actuator and verified by comparing analytical moment-angle curves with experimental joint torque data. The parameters and skeletal geometry were also utilized in the musculoskeletal model for the analysis of ballistic (rapid-directed) elbow joint complex movements. The key objective was to develop a computational model, guided by parameterized optimal control, to investigate the relationship among patterns of muscle excitation, individual muscle forces, and to determine the effects of forearm and elbow position on the recruitment of individual muscles during a variety of ballistic movements. The model was partially verified using experimental kinematic, torque, and electromyographic data from volunteer subjects performing both isometric and ballistic elbow joint complex movements. This verification lends credibility to the time-varying muscle force predictions and the recruitment of muscles that contribute to both elbow flexion-extension and forearm pronation-supination.

TNF-alpha receptor signaling and IL-10 gene therapy regulate the innate and humoral immune responses to recombinant adenovirus in the lung.

Recombinant adenovirus-mediated gene therapy has demonstrated great promise for the delivery of genes to the pulmonary epithelium. However, dose-dependent inflammation and local immune responses abbreviate transgene expression. The purpose of these studies was to determine the role of TNF-alpha and individual TNF receptor signaling to adenovirus clearance and immune responses, and whether coexpression of human IL-10 could reduce inflammation and extend the duration of transgene expression in the lung. beta-Galactosidase expression in mice receiving intratracheal instillation of Adv/beta-gal (adenovirus construct expressing beta-galactosidase) was transient (less than 14 days), but a significant early increase of beta-galactosidase expression was seen in mice lacking either or both TNF-alpha receptors. Absence of TNF-alpha or the p55 receptor significantly attenuated the Ab response to both adenovirus and beta-galactosidase. Human IL-10 expression in the lung suppressed local TNF-alpha production following AdV/hIL-10 (adenovirus construct expressing human IL-10) delivery, but did not lead to increased or prolonged transgene expression when coexpressed with beta-galactosidase. Expression of human IL-10 following AdV/hIL-10 instillation extended at least 14 days, was nonimmunogenic, and suppressed the development of neutralizing Abs against adenoviral proteins as well as against human IL-10. We conclude that TNF-alpha signaling through both the p55 and p75 receptor plays important roles in the clearance of adenoviral vectors and the magnitude of the humoral immune response. Additionally, although coexpression of human IL-10 with beta-galactosidase had only modest effects on transgene expression, we demonstrate that AdV/hIL-10 is well tolerated, has extended expression compared with beta-galactosidase, and is nonimmunogenic in the lung.