Extracellular matrix: a new player in memory maintenance and psychiatric disorders

How the brain performs higher cognitive functions such as learning and memory is traditionally studied by investigating how neurons work. However, over the past two decades, evidence has accumulated which suggests that components of the extracellular matrix contribute to the storing of information through learning processes. Thus, matrix regulation – either changes in the protein composition of the perineural network surrounding neurons or cleavage of this network by specific metalloproteases – could be relevant to the many psychiatric disorders that are shaped by previous experiences, i.e. by learning and plasticity. This includes disorders which are a direct consequence of past experiences and ones where previous experiences constitute a risk factor. Psychotherapy is one of the first-line treatments for most psychiatric conditions, and involves learning and plasticity. Here, we review selected publications pertaining to experience dependence in psychiatric conditions and summarise evidence of roles for the extracellular matrix in learning and memory. We then suggest how control of the extracellular matrix could be leveraged for innovative treatments and, more generally, discuss possible aetiological effects of extracellular matrix alterations in psychiatric disorders

Functional immunomics: Microarray analysis of IgG autoantibody repertoires predicts the future response of NOD mice to an inducer of accelerated diabetes

One's present repertoire of antibodies encodes the history of one's past immunological experience. Can the present autoantibody repertoire be consulted to predict resistance or susceptibility to the future development of an autoimmune disease? Here we developed an antigen microarray chip and used bioinformatic analysis to study a model of type 1 diabetes developing in non-obese diabetic (NOD) male mice in which the disease was accelerated and synchronized by exposing the mice to cyclophosphamide at 4 weeks of age. We obtained sera from 19 individual mice, treated the mice to induce cyclophosphamide-accelerated diabetes (CAD), and found, as expected, that 9 mice became severely diabetic while 10 mice permanently resisted diabetes. We again obtained serum from each mouse afterCAD induction. We then analyzed the patterns of antibodies in the individualmice to 266 different antigens spotted on the antigen chip. We identified a select panel of 27 different antigens (10% of the array) that revealed a pattern of IgG antibody reactivity in the pre-CAD serathat discriminated between the mice resistant or susceptible to CAD with 100% sensitivity and 82% specificity (p=0.017). Surprisingly, the set of IgG antibodies that was informative before CAD induction did not separate the resistant and susceptible groups after the onset of CAD; new antigens became criticalfor post-CAD repertoire discrimination. Thus, at least for a model disease, present antibody repertoires can predict future disease; predictive and diagnostic repertoires can differ; and decisive information about immune system behavior can be mined by bioinformatic technology. Repertoires matter.Comment: See Advanced Publication on the PNAS website for final versio

Strategic management of the health workforce in developing countries: what have we learned?

The study of the health workforce has gained in prominence in recent years, as the dynamic interconnections between human resource issues and health system effectiveness have come into sharper focus. This paper reviews lessons relating to strategic management challenges emerging from the growing literature in this area. Workforce issues are strategic: they affect overall system performance as well as the feasibility and sustainability of health reforms. Viewing workforce issues strategically forces health authorities to confront the yawning gaps between policy and implementation in many developing countries. Lessons emerge in four areas. One concerns imbalances in workforce structure, whether from a functional specialization, geographical or facility lens. These imbalances pose a strategic challenge in that authorities must attempt to steer workforce distribution over time using a limited range of policy tools. A second group of lessons concerns the difficulties of central-level steering of the health workforce, often critically weak due to the lack of proper information systems and the complexities of public sector decentralization and service commercialization trends affecting the grassroots. A third cluster examines worker capacity and motivation, often shaped in developing countries as much by the informal norms and incentives as by formal attempts to support workers or to hold them accountable. Finally, a range of reforms centering on service contracting and improvements to human resource management are emerging. Since these have as a necessary (but not sufficient) condition some flexibility in personnel practices, recent trends towards the sharing of such functions with local authorities are promising. The paper identifies a number of current lines of productive research, focusing on the relationship between health policy reforms and the local institutional environments in which the workforce, both public and private, is deployed

Emotional Speech Perception Unfolding in Time: The Role of the Basal Ganglia

The basal ganglia (BG) have repeatedly been linked to emotional speech processing in studies involving patients with neurodegenerative and structural changes of the BG. However, the majority of previous studies did not consider that (i) emotional speech processing entails multiple processing steps, and the possibility that (ii) the BG may engage in one rather than the other of these processing steps. In the present study we investigate three different stages of emotional speech processing (emotional salience detection, meaning-related processing, and identification) in the same patient group to verify whether lesions to the BG affect these stages in a qualitatively different manner. Specifically, we explore early implicit emotional speech processing (probe verification) in an ERP experiment followed by an explicit behavioral emotional recognition task. In both experiments, participants listened to emotional sentences expressing one of four emotions (anger, fear, disgust, happiness) or neutral sentences. In line with previous evidence patients and healthy controls show differentiation of emotional and neutral sentences in the P200 component (emotional salience detection) and a following negative-going brain wave (meaning-related processing). However, the behavioral recognition (identification stage) of emotional sentences was impaired in BG patients, but not in healthy controls. The current data provide further support that the BG are involved in late, explicit rather than early emotional speech processing stages

An Exploratory Study of Primary Care Physician Decision Making Regarding Total Joint Arthroplasty

BACKGROUND: For patients to experience the benefits of total joint arthroplasty (TJA), primary care physicians (PCPs) ought to know when to refer a patient for TJA and/or optimize nonsurgical treatment options for osteoarthritis (OA). OBJECTIVE: To evaluate the ability of physicians to make clinical treatment decisions. DESIGN AND PARTICIPANTS: A survey, using ten clinical vignettes, of PCPs in Indiana. MEASUREMENTS: A test score (range 0 to 10) was computed based on the number of correct answers consistent with published explicit appropriateness criteria for TJA. We also collected demographic characteristics and physicians’ perceived success rate of TJA in terms of pain relief and functional improvement. RESULTS: There were 149 PCPs (response rate = 61%) who participated. The mean test score was 6.5 ± 1.5. Only 17% correctly identified the published success rate of TJA (i.e., ≥90%). In multivariate analysis, the only physician-related variables associated with test score were ethnicity, board status, and perceived success rate of TJA. Physicians who were white (P = .001), board-certified (P = .04), and perceived a higher success rate of TJA (P = .004) had higher test scores. CONCLUSIONS: PCP knowledge with respect to guideline-concordant care for OA could be improved, specifically in deciding when to consider TJA versus optimizing nonsurgical options. Moreover, the perception of the success rate of TJA may influence a clinician’s decision making

Mitochondrial Fusion Is Increased by the Nuclear Coactivator PGC-1β

Background There is no evidence to date on whether transcriptional regulators are able to shift the balance between mitochondrial fusion and fission events through selective control of gene expression. Methodology/Principal Findings Here, we demonstrate that reduced mitochondrial size observed in knock-out mice for the transcriptional regulator PGC-1β is associated with a selective reduction in Mitofusin 2 (Mfn2) expression, a mitochondrial fusion protein. This decrease in Mfn2 is specific since expression of the remaining components of mitochondrial fusion and fission machinery were not affected. Furthermore, PGC-1β increases mitochondrial fusion and elongates mitochondrial tubules. This PGC-1β-induced elongation specifically requires Mfn2 as this process is absent in Mfn2-ablated cells. Finally, we show that PGC-1β increases Mfn2 promoter activity and transcription by coactivating the nuclear receptor Estrogen Related Receptor α (ERRα). Conclusions/Significance Taken together, our data reveal a novel mechanism by which mammalian cells control mitochondrial fusion. In addition, we describe a novel role of PGC-1β in mitochondrial physiology, namely the control of mitochondrial fusion mainly through Mfn2

New fluoroscopic imaging technique for investigation of 6DOF knee kinematics during treadmill gait

<p>Abstract</p> <p>Introduction</p> <p>This report presents a new imaging technique for non-invasive study of six degrees of freedom (DOF) knee kinematics during treadmill gait.</p> <p>Materials and methods</p> <p>A treadmill was integrated into a dual fluoroscopic imaging system (DFIS) to formulate a gait analysis system. To demonstrate the application of the system, a healthy subject walked on the treadmill at four different speeds (1.5, 2.0, 2.5 and 3.0 MPH) while the DFIS captured the knee motion during three strides under each speed. Characters of knee joint motion were analyzed in 6DOF during the treadmill walking.</p> <p>Results</p> <p>The speed of the knee motion was lower than that of the treadmill. Flexion amplitudes increased with increasing walking speed. Motion patterns in other DOF were not affected by increase in walking speed. The motion character was repeatable under each treadmill speed.</p> <p>Conclusion</p> <p>The presented technique can be used to accurately measure the 6DOF knee kinematics at normal walking speeds.</p

Structural and Functional Changes of the Human Macula during Acute Exposure to High Altitude

Background: This study aimed to quantify structural and functional changes at the macula during acute exposure to high altitude and to assess their structure/function relationship. This work is related to the Tuebingen High Altitude Ophthalmology (THAO) study. Methodology/Principal Findings: Spectral domain optical coherence tomography and microperimetry were used to quantify changes of central retinal structure and function in 14 healthy subjects during acute exposure to high altitude (4559 m). High-resolution volume scans and fundus-controlled microperimetry of the posterior pole were performed in addition to best-corrected visual acuity (BCVA) measurements and assessment of acute mountain sickness. Analysis of measurements at altitude vs. baseline revealed increased total retinal thickness (TRT) in all four outer ETDRS grid subfields during acute altitude exposure (TRTouter = 2.8061.00 mm; mean change695%CI). This change was inverted towards the inner four subfields (TRT inner = 21.8960.97 mm) with significant reduction of TRT in the fovea (TRT foveal = 26.6260.90 mm) at altitude. BCVA revealed no significant difference compared to baseline (0.0660.08 logMAR). Microperimetry showed stable mean sensitivity in all but the foveal subfield (MSfoveal = 21.1260.68 dB). At baseline recordings before and.2 weeks after high altitude exposure, all subjects showed equal levels with no sign of persisting structural or functional sequels. Conclusions/Significance: During acute exposure to high altitude central retinal thickness is subject to minor, ye