Fidelity of supported employment programs and employment outcomes

This study attempted to identify critical components of a supported employment program that were strongly correlated with competitive employment outcomes in a state mental health system. Researchers used a supported employment fidelity scale to rate programs at ten community mental health centers in Vermont. The staff at the centers concurrently assessed competitive employment outcomes for 2,639 clients who had been diagnosed as having severe and persistent mental illness. Higher competitive employment rates were strongly correlated with overall program fidelity and with two program components, namely, providing services in the community as opposed to providing them in the clinic and using full-time employment specialists as opposed to staff with mixed roles.     

Influence of Local Cooling on Proprioceptive Acuity in the Quadriceps Muscle

OBJECTIVE: To test the influence of cooling on proprioceptive acuity as reflected in the ability to discriminate weights. DESIGN AND SETTING: Participants were trained to perform a weight-discrimination task. Their ability to correctly report small increments in weight was compared before and after local cooling (a 20-minute application of a crushed-ice pack) of the quadriceps muscle group. Data were collected at a university research laboratory. SUBJECTS: Twenty young, physically active adults (undergraduate students; 14 men, 6 women; mean age, 22.1 +/- 2.6 years). MEASUREMENTS: We calculated overall performance in the weight-discrimination task (percentage of discrimination correct) for each participant to estimate the differential threshold (ie, minimal increment in weight that yields a probability of 75% correct responses). RESULTS: Before local cooling, participants discriminated increments in the order of 4% to 10% from the standard weight (mean threshold, 0.17 +/- 0.06 kg). After local cooling, the discriminative performance remained, on average, very similar to that seen before cooling (mean threshold, 0.17 +/- 0.08 kg; paired t test: t = 0.24, P =.81). Only a small group of participants (n = 5) showed evidence of a decreased ability to discriminate weight after cooling. CONCLUSIONS: The perception of force signals required for weight discrimination does not appear to be affected by local cooling of the quadriceps muscle group. This finding provides additional evidence for the relative safety of cold applications and their effect on proprioceptive perceptual abilities.     

Defective insulin-induced GLUT4 translocation in skeletal muscle of high fat-fed rats is associated with alterations in both Akt/protein kinase B and atypical protein kinase C (zeta/lambda) activities

The cellular mechanism by which high-fat feeding induces skeletal muscle insulin resistance was investigated in the present study. Insulin-stimulated glucose transport was impaired ( approximately 40-60%) in muscles of high fat-fed rats. Muscle GLUT4 expression was significantly lower in these animals ( approximately 40%, P < 0.05) but only in type IIa-enriched muscle. Insulin stimulated the translocation of GLUT4 to both the plasma membrane and the transverse (T)-tubules in chow-fed rats. In marked contrast, GLUT4 translocation was completely abrogated in the muscle of insulin-stimulated high fat-fed rats. High-fat feeding markedly decreased insulin receptor substrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase activity but not insulin-induced tyrosine phosphorylation of the insulin receptor and IRS proteins in muscle. Impairment of PI 3-kinase function was associated with defective Akt/protein kinase B kinase activity (-40%, P < 0.01) in insulin-stimulated muscle of high fat-fed rats, despite unaltered phosphorylation (Ser473/Thr308) of the enzyme. Interestingly, basal activity of atypical protein kinase C (aPKC) was elevated in muscle of high fat-fed rats compared with chow-fed controls. Whereas insulin induced a twofold increase in aPKC kinase activity in the muscle of chow-fed rats, the hormone failed to further increase the kinase activity in high fat-fed rat muscle. In conclusion, it was found that GLUT4 translocation to both the plasma membrane and the T-tubules is impaired in the muscle of high fat-fed rats. We identified PI 3-kinase as the first step of the insulin signaling pathway to be impaired by high-fat feeding, and this was associated with alterations in both Akt and aPKC kinase activities.     

Reliability of a method for analyzing three-dimensional knee kinematics during gait

BACKGROUND: Different attachment systems have been proposed in an effort to reduce skin movement artifacts when recording knee bone movement during gait. One such system, called exoskeleton, has shown promising accuracy but little is known concerning its reliability. The objective of this study was to determine the intra- and inter-observer reliability of this attachment system for recording 3D knee kinematics during gait. METHODS: Two separate studies were conducted. The intra-observer study involved one observer who reinstalled the exoskeleton on 15 healthy subjects and recorded gait kinematics four times for each subject. The inter-observer study also involved 15 healthy subjects and for each of these subjects, three observers reinstalled and recorded gait kinetics three times in randomized order. FINDINGS: In the intra-observer setting, ICC values were 0.92, 0.94 and 0.88 for knee flexion/extension, abduction/adduction and internal/external tibial rotation, respectively. In the inter-observer setting, the corresponding values were 0.94, 0.92 and 0.89. INTERPRETATION: The high ICC values found indicate very high reliability of the exoskeleton for recording 3D knee kinematics despite reinstallation. Moreover, the values between both settings are very similar which indicates that reliability is independent of the observer who performs the installation. Therefore, evaluations may be carried out by several different clinicians without impacting reliability.     

Comparative validity assessment of five activity monitors: does being a child matter?

The purpose of this study was to determine the effects of age and leg length on the energy-expenditure predictions of five activity monitors. Participants (N=86, ages 8-40 years) performed three progressive bouts of treadmill activity ranging from 4 to 12 km/hr. Differences between measured energy expenditure (VO2) and activity-monitor-predicted energy expenditure were assessed across five leg length categories to determine the influence of leg length. Accelerometer counts or pedometer steps along with age, weight, and leg length accounted for 85-94% of measured energy expenditure. The addition of age and leg length as predictor variables explained a larger amount of variance in energy expenditure across all speeds. Differences in leg length and age might affect activity-monitor validity and, therefore, should be controlled for when estimating physical activity energy expenditure.     

Effects of age and age-related hearing loss on the brain

It is well documented that aging adversely affects the ability to perceive time-varying acoustic cues. Here we review how physiological measures are being used to explore the effects of aging (and concomitant hearing loss) on the neural representation of temporal cues. Also addressed are the implications of current research findings on the rehabilitation of older hearing-impaired adults. LEARNER OUTCOMES: (1) Identify one evoked potential that reflects age-related physiological changes in the brain. (2) List three contributing factors for why older adults have difficult understanding speech in noise. (3) Give an example of a top-down approach to auditory rehabilitation.     

LFA-1 Antagonists as Agents Limiting Human Immunodeficiency Virus Type 1 Infection and Transmission and Potentiating the Effect of the Fusion Inhibitor T-20

Adhesion molecules are known to play major roles in the initiation and stabilization of cell-to-cell contacts during the immunological response. Human immunodeficiency virus type 1 (HIV-1) exploits those interactions to facilitate infection and propagation processes. The primary objective of the present study was to investigate the ability of antagonists specific for lymphocyte function-associated antigen 1 (LFA-1) to diminish HIV-1 infection and transmission. We demonstrate here that LFA-1 antagonists can significantly reduce HIV-1 replication in primary human cells and virus propagation by affecting cell-to-cell interactions. Moreover, the inhibition of LFA-1-mediated adhesion events also potentiates the antiviral efficacy of the peptide fusion inhibitor T-20. Altogether, our data suggest that LFA-1 antagonists represent promising antiviral agents. Antiadhesion therapy could be considered a complementary strategy targeting cellular functions essential for HIV-1 spreading and against which the combined therapy currently used displays a limited efficacy.Actual strategies to treat human immunodeficiency virus type 1 (HIV-1)-infected individuals make use of highly active antiretroviral therapy. It has been demonstrated that it reduces viral load, improves survival time, and decreases AIDS-associated mortality. Unfortunately, highly active antiretroviral therapy presents numerous severe drawbacks including the emergence of resistant strains, cross-resistance to other drugs within the same class, transmission of drug-resistant strains, extensive and adverse side effects for patients under treatment, and considerable costs. Therefore, the development of alternative therapeutic approaches aimed at novel targets is urgently needed.The present work focuses on the membrane glycoprotein lymphocyte function-associated antigen 1 (LFA-1), an integrin playing crucial roles in leukocyte trafficking, inflammation, and the orchestration of the immune response. Interactions between LFA-1 and its counterreceptors, called intercellular adhesion molecules (ICAMs), initiate the immune response by strengthening the adhesion between antigen-presenting cells (APCs), such as dendritic cells (DCs), macrophages, or B cells, and CD4⁺ T lymphocytes through the formation of the immunological synapse and by participating in leukocyte migration toward inflamed tissues or secondary lymphoid organs. LFA-1 is a heterodimeric receptor constituted of CD11a (α chain) and CD18 (β chain). LFA-1-mediated adhesion is regulated by conformational changes (affinity), lateral diffusion, and the spatial organization (avidity) of this integrin within the plasma membrane (19, 36, 54, 55, 61).Cell-to-cell transmission is the most rapid and potent mechanism by which HIV-1 can infect CD4⁺ T cells (12). Indeed, the virus takes advantage of the normal communication between immune cells for its own propagation. A virological synapse (VS) is formed by the recruitment of multiple HIV-1 receptors and coreceptors, virus-encoded gp120 and gp41, adhesion molecules, and cytoskeleton elements at the interface of HIV-1 donor and target cells, thus favoring the directed budding and fusion of newly synthesized virions. The VS can be created between infected and uninfected CD4⁺ T cells (34, 44) as well as between DCs or other carrier cells exposed to viral particles and target T cells (1, 2, 7, 16, 59). VS formation relies on LFA-1-mediated adhesion via ICAMs, particularly ICAM-1 and ICAM-3 (4, 30, 31, 33, 35, 51). It has been demonstrated that interactions of LFA-1 and ICAM-1 can modulate HIV-1 transfer from immature DCs (iDCs) to CD4⁺ T cells (51). Moreover, the importance of interactions between LFA-1 and ICAM-1 in HIV-1 transmission has been confirmed using T cells from leukocyte adhesion deficiency type 1 patients (30). Furthermore, interactions between LFA-1 and ICAMs play relevant roles in cell-free HIV-1 infection. Virions are efficiently released by infected cells in the external environment, and even though free viruses have a short life span (25), a number of them can bind and productively infect target cells. The efficiency of this mode of infection is strongly increased by the incorporation of certain host molecules into the viral envelope. Indeed, it was previously shown that the insertion of host-derived ICAM-1 within HIV-1 particles significantly increases the infection process of primary human CD4⁺ T cells expressing cell surface LFA-1 molecules (21-23, 56).Immune hyperactivation is an important feature of HIV-1 pathogenesis during the chronic phase of infection. Chronically infected individuals share multiple immune abnormalities, including a rapid turnover of CD4⁺ T cells, T-cell depletion, polyclonal B-cell activation, destruction of the architecture of some secondary lymphoid tissues, and immunodeficiency. A number of these clinical manifestations share similarities with the ones observed for allergic and autoimmune diseases. Interestingly, some of those conditions are currently being treated with agents that can block interactions between LFA-1 and ICAM-1 (13, 14, 29, 32).Given the involvement of LFA-1 in different important physiological processes, the pharmaceutical industry has devoted great efforts to the development of potent antagonists over the past decade, with the aim of treating cancer as well as multiple inflammatory and autoimmune diseases. Consequently, various classes of LFA-1 inhibitors have been tested, which has allowed the highlighting of the complex mechanism of action of this integrin in various processes such as rolling, migration, and firm adhesion. Among those compounds, statins such as lovastatin and other molecules like XVA143 have been demonstrated to antagonize LFA-1-mediated cellular adhesion in different manners. For instance, lovastatin restrains the association between LFA-1 and ICAM-1 and impairs LFA-1-mediated immune functions such as homotypic adhesion, rolling, and transmigration in addition to inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (49). Likewise, in the presence of XVA143, ICAM-1 interactions are not strong enough to allow firm attachment (52, 53), but an increase of the rolling of the immune cells on the endothelium is still observed (49).It was previously reported that lovastatin inhibits the infection of CD4⁺ T cells by cell-free ICAM-1-bearing HIV-1 (26, 28). Moreover, lovastatin was also found to reduce viral load and increase CD4⁺ T-cell counts in chronically HIV-1-infected patients (15). Therefore, in an attempt to provide additional information on the efficacy of LFA-1 antagonists in limiting virus infection and propagation, we tested the capacity of XVA143 and lovastatin to modulate HIV-1 infection in monocultures enriched in activated CD4⁺ T cells and in cocultures containing iDCs and autologous CD4⁺ T cells. In addition, to investigate whether LFA-1 antagonists could help antiretroviral compounds prevent virus infection, experiments using T-20 in combination with LFA-1 antagonists were also performed.     

The neural representation of consonant-vowel transitions in adults who wear hearing AIDS

Hearing aids help compensate for disorders of the ear by amplifying sound; however, their effectiveness also depends on the central auditory system's ability to represent and integrate spectral and temporal information delivered by the hearing aid. The authors report that the neural detection of time-varying acoustic cues contained in speech can be recorded in adult hearing aid users using the acoustic change complex (ACC). Seven adults (50-76 years) with mild to severe sensorineural hearing participated in the study. When presented with 2 identifiable consonant-vowel (CV) syllables ("shee" and "see"), the neural detection of CV transitions (as indicated by the presence of a P1-N1-P2 response) was different for each speech sound. More specifically, the latency of the evoked neural response coincided in time with the onset of the vowel, similar to the latency patterns the authors previously reported in normal-hearing listeners.