Treatment of neuroinflammation by soluble tumor necrosis factor receptor Type II fused to a thermally responsive carrier

OBJECT: Biochemical irritation of the dorsal root ganglion (DRG) after intervertebral disc herniation contributes to radiculopathy through tumor necrosis factor-alpha (TNFalpha)-mediated inflammation. Soluble TNF receptor Type II (sTNFRII) sequesters this cytokine, providing clinical benefit. Previous work involving conjugation of sTNFRII with thermally responsive elastin-like polypeptide (ELP) yielded a chimeric protein (ELP-sTNFRII) with in vitro anti-TNFalpha bioactivity. Furthermore, temperature-triggered ELP aggregation into a "depot" prolongs protein residence time following perineural injection. In this study the authors evaluated the inflammatory phenotype of DRG explants after TNFalpha stimulation, and assessed the abilities of sTNFRII or ELP-sTNFRII to attenuate these neuro-inflammatory changes. METHODS: Rat lumbar DRGs (35 animals) were treated in 6 groups, as follows: control; TNFalpha (25 ng/ml); TNFalpha with low-(0.2 microg/ml) or high-dose (1 microg/ml) sTNFRII; and TNFalpha with low-(52.5 microg/ml) or high-dose (262.5 microg/ml) ELP-sTNFRII. After 24 hours, supernatant was evaluated for inflammatory cytokines (interleukin [IL]-1, IL-6, and IL-10); prostaglandin E2; and metabolites (glutamate, lactate, and pyruvate). Single-factor analysis of variance with post hoc Dunn analysis (alpha = 0.05) was used to assess treatment differences. RESULTS: Incubation of explants with TNFalpha caused metabolic stress reflected by an increased lactate/pyruvate ratio (1.8 +/- 0.5-fold) and extracellular glutamate (79 +/- 8% increase). Inflammatory activation was observed with heightened IL-6 release (5.2 +/- 1.4-fold) and prostaglandin E2 production (14 +/- 3-fold). An autoregulatory response occurred with an 11.8 +/- 0.6-fold increase in sTNFRI shedding. Treatment with high doses of sTNFRII or ELP-sTNFRII reversed all changes. Values are expressed as the mean +/- standard deviation. CONCLUSIONS: These results demonstrate that TNFalpha stimulation of DRG explants yields a phenotype of neurotoxic metabolite release and inflammatory mediator expression. Coincubation with either sTNFRII or ELP-sTNFRII antagonizes TNFalpha activity to abrogate these changes, suggesting potential for therapeutic intervention to treat peripheral nerve inflammatory disease.     

Mechanisms of variability in strength loss after muscle-lengthening actions

PURPOSE: Profound strength loss is a marker of exercise-induced muscle damage; however, there is a large intersubject variability in the response, even when subjects are exposed to standardized exercise protocols. We sought to identify factors including neural drive and peripheral function underlying variability in early development of muscle strength loss after lengthening actions. We objectively characterized subjects on the basis of postexercise strength loss and analyzed voluntary and stimulated muscle function before and after exercise to test the hypothesis that greater strength loss would be associated with greater losses in peripheral, but not central, function. METHODS: Forty-six subjects were tested. Central measures were integrated electromyographic activity (iEMG), compound muscle action potential (CMAP), and central activation ratio (CAR). Peripheral measures were maximal isometric and eccentric voluntary action torques and stimulated tetanic and twitch torques. Subjects performed 50 maximal lengthening (eccentric) actions of the elbow flexors. Isometric strength was assessed pre- and postexercise and for 4 d after exercise. Central and peripheral functions were assessed before and 5 min after exercise. RESULTS: Cluster analysis of isometric strength loss at 0 and 24 h after exercise generated three groups: higher responders (HR) (N = 21; 49% average loss), lower responders (LR) (N = 22; 23% average loss), and nonresponders (N = 3; no loss). Maximal eccentric torque losses were greater in the HR group than in the LR group. Greater dysfunction was found for all peripheral measures (torque after tetanic stimuli; torque after twitch stimuli) in the HR group, whereas central measures (iEMG, CMAP, and CAR) were not different between groups (P > 0.05). CONCLUSION: Greater voluntary strength loss after lengthening exercise was associated with greater impairment of peripheral function, but similar central function, suggesting that the mechanism(s) driving variations in strength loss after lengthening actions are localized within the periphery.     

Post-traumatic bone loss of the femur treated with segmental bone allograft and bone morphogenetic protein: a case report

Reconstruction of a major bone loss remains a challenge for the orthopaedic surgeon. Most of the bone defects result from a bone tumour resection whereas a post-traumatic bone loss is more rare due to the numerous options available for bone fixation. However in high-energy trauma, the injury to bone may be so extensive as to justify removal of fragmented bone. A 57-year-old man presented with a severe injury at the thigh after a hunting accident, including a comminuted fracture of the femoral shaft. After thorough debridement, he was left with a large diaphyseal bone defect which was subsequently treated with a structural bone allograft, autogenous graft and rhBMP-7. Bone healing was achieved after several months.     

Altered perception of apparent motion in schizophrenia spectrum disorder

Apparent motion (AM), the Gestalt perception of motion in the absence of physical motion, was used to study perceptual organization and neurocognitive binding in schizophrenia. Associations between AM perception and psychopathology as well as meaningful subgroups were sought. Circular and stroboscopic AM stimuli were presented to 68 schizophrenia spectrum patients and healthy participants. Psychopathology was measured using the Positive and Negative Syndrome Scale (PANSS). Psychopathology was related to AM perception differentially: Positive and disorganization symptoms were linked to reduced gestalt stability; negative symptoms, excitement and depression had opposite regression weights. Dimensions of psychopathology thus have opposing effects on gestalt perception. It was generally found that AM perception was closely associated with psychopathology. No difference existed between patients and controls, but two latent classes were found. Class A members who had low levels of AM stability made up the majority of inpatients and control subjects; such participants were generally young and male, with short reaction times. Class B typically contained outpatients and some control subjects; participants in class B were older and showed longer reaction times. Hence AM perceptual dysfunctions are not specific for schizophrenia, yet AM may be a promising stage marker.     

Predictors of late menarche and adult height in children with anorexia nervosa

OBJECTIVES: The onset of anorexia nervosa (AN) during childhood can affect the timing of puberty and adult height. The aim of the study was to evaluate the determinants of late menarche and adult height in children with AN. PATIENTS AND METHODS: We carried out a retrospective, longitudinal, university hospital-based study. All prepubertal or early pubertal girls diagnosed with AN between 1998 and 2002 were selected for the study. Participants (n = 33) were studied at a median age of 21 (19.8-24.3) years. AN was diagnosed at 11.8 (10.7-12.3) years. RESULTS: Patients with AN reached menarche at significantly greater ages than their mothers [15.4 (13.5-16.8) vs. 13.2 (12.0-14.5) years, P < 0.01]. Chronological age at onset of AN and lowest body mass index (BMI) were important independent predictive factors for delayed menarche (P < 0.01). Adult height was 165.0 (163.0-172.0) cm, 2.5 (-1.5 to 5.0) cm above target height. Twelve patients (36%) did not reach their target height and had a median height deficit of -3.9 cm with respect to their target height. The duration of hospitalization, a marker of disease severity and chronicity, was an independent predictor of the difference between adult height and target height for a given individual (beta coefficient = -0.07; P = 0.01). The other factors studied (i.e. age at onset of AN, pubertal stage at diagnosis of AN, lowest BMI reached, associated comorbidity if any, type of AN, age at menarche) had no significant effect on adult height. CONCLUSION: The intensity of the disease affects the timing of menarche but not adult height in most patients. Hospitalization, despite often being an effective means of managing AN, does not reduce the impact of AN on growth.     

Beyond indicators: advances in global HIV monitoring and evaluation during the PEPFAR era

Monitoring and evaluation (M&E) is fundamental to global HIV program implementation and has been a cornerstone of the President's Emergency Plan for AIDS Relief (PEPFAR). Rapid results were crucial to demonstrating feasibility and scalability of HIV care and treatment services early in PEPFAR. When national HIV M&E systems were nascent, the rapid influx of funds and the emergency expansion of HIV services contributed to the development of uncoordinated "parallel" information systems to serve donor demands for information. Close collaboration of PEPFAR with multilateral and national partners improved harmonization of indicators, standards, methods, tools, and reports. Concurrent PEPFAR investments in surveillance, surveys, program monitoring, health information systems, and human capacity development began to show signs of progress toward sustainable country-owned systems. Awareness of the need for and usefulness of data increased, far beyond discussions of indicators and reporting. Emphasis has turned toward ensuring the quality of data and using available data to improve the quality of care. Assessing progress toward an AIDS-free generation requires that the global community can measure the reduction of new HIV infections in children and adults and monitor the coverage, quality, and outcomes of highly efficacious interventions in combination. Building national M&E systems requires sustained efforts over long periods of time with effective leadership and coordination. PEPFAR, in close collaboration with its global and national partners, is well positioned to transform the successes and challenges associated with early rapid scale-up into future opportunities for sustainable, cost-effective, country-owned programs and systems.     

Controversies in prediabetes: do we have a diagnosis?

It is estimated that more than one-third of US adults exhibit intermediate glycemic control, termed "prediabetes" or "impaired glucose regulation," and many individuals with prediabetes or diabetes are unaware of their glycemic state. Prediabetes confers significant risks for developing type 2 diabetes mellitus (T2DM) and cardiovascular comorbidities. Early lifestyle intervention and pharmacotherapy have demonstrated success in preventing or delaying onset of T2DM. Thus, early screening and diagnosis of prediabetes, along with subsequent recommendations on preventative measures, are vital in preventing or delaying progression to T2DM. However, a consensus among organizations on the diagnostic criteria defining prediabetes has not been reached, complicating the screening and diagnostic process and resulting in varying subpopulations of patients diagnosed with prediabetes. In this article, the guidelines issued by several organizations are reviewed, as well as recent studies analyzing the predictive value of various diagnostic criteria for the progression to T2DM. Recent trials investigating the effects of lifestyle modification and/or pharmacotherapy on the prevention or delay of development of T2DM have suggested some complex outcomes that require further clarification, but offer some hope for the future. These results, and the varying guidelines for the diagnosis of prediabetes, suggest a need for informed scientific debate on diagnostic criteria and recommendations for preventive care of prediabetic states.