Macrophage migration inhibitory factor and its binding partner HTRA1 are expressed by olfactory ensheathing cells.

Macrophage migration inhibitory factor (MIF) is an important regulator of innate immunity with key roles in neural regeneration and responses to pathogens, amongst a multitude of other functions. The expression of MIF and its binding partners has been characterised throughout the nervous system, with one key exception: the primary olfactory nervous system. Here, we showed in young mice (postnatal day 10) that MIF is expressed in the olfactory nerve by olfactory ensheathing glial cells (OECs) and by olfactory nerve fibroblasts. We also examined the expression of potential binding partners for MIF, and found that the serine protease HTRA1, known to be inhibited by MIF, was also expressed at high levels by OECs and olfactory fibroblasts in vivo and in vitro. We also demonstrated that MIF mediated segregation between OECs and J774a.1 cells (a monocyte/macrophage cell line) in co-culture, which suggests that MIF contributes to the fact that macrophages are largely absent from olfactory nerve fascicles. Phagocytosis assays of axonal debris demonstrated that MIF strongly stimulates phagocytosis by OECs, which indicates that MIF may play a role in the response of OECs to the continual turnover of olfactory axons that occurs throughout life.

Toxicologic and Inhibitory Receptor Actions of the Etomidate Analog ABP-700 and Its Metabolite CPM-Acid.

BACKGROUND: The etomidate analog ABP-700 produces involuntary muscle movements that could be manifestations of seizures. To define the relationship (if any) between involuntary muscle movements and seizures, electroencephalographic studies were performed in Beagle dogs receiving supra-therapeutic (~10× clinical) ABP-700 doses. γ-aminobutyric acid type A (GABAA) and glycine receptor studies were undertaken to test receptor inhibition as the potential mechanism for ABP-700 seizures. METHODS: ABP-700 was administered to 14 dogs (6 mg/kg bolus followed by a 2-h infusion at 1 mg · kg(-1) · min(-1), 1.5 mg · kg(-1) · min(-1), or 2.3 mg · kg(-1) · min(-1)). Involuntary muscle movements were documented, electroencephalograph was recorded, and plasma ABP-700 and CPM-acid concentrations were measured during and after ABP-700 administration. The concentration-dependent modulatory actions of ABP-700 and CPM-acid were defined in oocyte-expressed α1ß3γ2L GABAA and α1ß glycine receptors (n = 5 oocytes/concentration) using electrophysiologic techniques. RESULTS: ABP-700 produced both involuntary muscle movements (14 of 14 dogs) and seizures (5 of 14 dogs). However, these phenomena were temporally and electroencephalographically distinct. Mean peak plasma concentrations were (from lowest to highest dosed groups) 35 µM, 45 µM, and 102 µM (ABP-700) and 282 µM, 478 µM, and 1,110 µM (CPM-acid). ABP-700 and CPM-acid concentration-GABAA receptor response curves defined using 6 µM γ-aminobutyric acid exhibited potentiation at low and/or intermediate concentrations and inhibition at high ones. The half-maximal inhibitory concentrations of ABP-700 and CPM-acid defined using 1 mM γ-aminobutyric acid were 770 µM (95% CI, 590 to 1,010 µM) and 1,450 µM (95% CI, 1,340 to 1,560 µM), respectively. CPM-acid similarly inhibited glycine receptors activated by 1 mM glycine with a half-maximal inhibitory concentration of 1,290 µM (95% CI, 1,240 to 1,330 µM). CONCLUSIONS: High dose ABP-700 infusions produce involuntary muscle movements and seizures in Beagle dogs via distinct mechanisms. CPM-acid inhibits both GABAA and glycine receptors at the high (~100× clinical) plasma concentrations achieved during the dog studies, providing a plausible mechanism for the seizures.

Variation in Integrated Head and Neck Cancer Care: Impact of Patient and Hospital Characteristics.

Background: Monitoring and effectively improving oncologic integrated care requires dashboard information based on quality registrations. The dashboard includes evidence-based quality indicators (QIs) that measure quality of care. This study aimed to assess the quality of current integrated head and neck cancer care with QIs, the variation between Dutch hospitals, and the influence of patient and hospital characteristics. Methods: Previously, 39 QIs were developed with input from medical specialists, allied health professionals, and patients' perspectives. QI scores were calculated with data from 1,667 curatively treated patients in 8 hospitals. QIs with a sample size of >400 patients were included to calculate reliable QI scores. We used multilevel analysis to explain the variation. Results: Current care varied from 29% for the QI about a case manager being present to discuss the treatment plan to 100% for the QI about the availability of a treatment plan. Variation between hospitals was small for the QI about patients discussed in multidisciplinary team meetings (adherence: 95%, range 88%-98%), but large for the QI about malnutrition screening (adherence: 50%, range 2%-100%). Higher QI scores were associated with lower performance status, advanced tumor stage, and tumor in the oral cavity or oropharynx at the patient level, and with more curatively treated patients (volume) at hospital level. Conclusions: Although the quality registration was only recently launched, it already visualizes hospital variation in current care. Four determinants were found to be influential: tumor stage, performance status, tumor site, and volume. More data are needed to assure stable results for use in quality improvement.

Feedback preferences of patients, professionals and health insurers in integrated head and neck cancer care.

BACKGROUND: Audit and feedback on professional practice and health care outcomes are the most often used interventions to change behaviour of professionals and improve quality of health care. However, limited information is available regarding preferred feedback for patients, professionals and health insurers. OBJECTIVE: Investigate the (differences in) preferences of receiving feedback between stakeholders, using the Dutch Head and Neck Audit as an example. METHODS: A total of 37 patients, medical specialists, allied health professionals and health insurers were interviewed using semi-structured interviews. Questions focussed on: "Why," "On what aspects" and "How" do you prefer to receive feedback on professional practice and health care outcomes? RESULTS: All stakeholders mentioned that feedback can improve health care by creating awareness, enabling self-reflection and reflection on peers or colleagues, and by benchmarking to others. Patients prefer feedback on the actual professional practice that matches the health care received, whereas medical specialists and health insurers are interested mainly in health care outcomes. All stakeholders largely prefer a bar graph. Patients prefer a pie chart for patient-reported outcomes and experiences, while Kaplan-Meier survival curves are preferred by medical specialists. Feedback should be simple with firstly an overview, and 1-4 times a year sent by e-mail. Finally, patients and health professionals are cautious with regard to transparency of audit data. CONCLUSIONS: This exploratory study shows how feedback preferences differ between stakeholders. Therefore, tailored reports are recommended. Using this information, effects of audit and feedback can be improved by adapting the feedback format and contents to the preferences of stakeholders.

Unusual Extensive Synovial Chondromatosis of the Temporomandibular Joint.

Synovial chondromatosis is a benign, usually monoarticular synovial disease characterized by osteocartilaginous loose body formation within the synovium and joint space. The authors present a patient with an unusually extensive form of this disease, and discuss clinical impact and patient care.

A leptin-mediated central mechanism in analgesia-enhanced opioid reward in rats.

Opioid analgesics are commonly used in chronic pain management despite a potential risk of rewarding. However, it remains unclear whether opioid analgesia would enhance the opioid rewarding effect thereby contributing to opioid rewarding. Utilizing a rat paradigm of conditioned place preference (CPP) combined with ankle monoarthritis as a condition of persistent nociception, we showed that analgesia induced by either morphine or the nonsteroid anti-inflammatory drug ibuprofen increased CPP scores in arthritic rats, suggesting that analgesia itself had a rewarding effect. However, arthritic rats exhibited a significantly higher CPP score in response to morphine than ibuprofen. Thus, the rewarding effect of morphine was enhanced in the presence of persistent nociception, producing a phenomenon of analgesia-enhanced opioid reward. At the cellular level, administration of morphine activated a cascade of leptin expression, glial activation, and dopamine receptor upregulation in the nucleus accumbens (NAc), while administration of ibuprofen decreased glial activation with no effect on leptin expression in the NAc. Furthermore, the morphine rewarding effect was blocked in leptin deficient ob/ob mice or by neutralizing leptin or interleukin-1ß in the NAc without diminishing morphine analgesia. The data indicate that systemic opioid can activate a leptin-mediated central mechanism in the NAc that led to the enhanced opioid rewarding effect. These findings provide evidence for an interaction between opioid analgesia and opioid rewarding, which may have implications in clinical opioid dose escalation in chronic pain management.

Living with ME/CFS. challenge for scientists?

A Graded Exercise Therapy (GET) - Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS) Running Anomaly. Imagine you have been disabled with ME/CFS's cluster of symptoms for 19 years. Yet, this morning you just ran an easy 10K with no flare up of your exercise intolerance symptoms during the run or post-exertional malaise after the run. Then later in the day you go browsing for books and after 30 minutes or so your exercise intolerance and post-exertional malaise symptoms flare up. You experience a wave of exhaustion, achy muscles and additional cognitive fog, all of which carry into the next day. To me, this is a confusing anomaly that needs an explanation.

Cortical depth-specific microvascular dilation underlies laminar differences in blood oxygenation level-dependent functional MRI signal.

Changes in neuronal activity are accompanied by the release of vasoactive mediators that cause microscopic dilation and constriction of the cerebral microvasculature and are manifested in macroscopic blood oxygenation level-dependent (BOLD) functional MRI (fMRI) signals. We used two-photon microscopy to measure the diameters of single arterioles and capillaries at different depths within the rat primary somatosensory cortex. These measurements were compared with cortical depth-resolved fMRI signal changes. Our microscopic results demonstrate a spatial gradient of dilation onset and peak times consistent with "upstream" propagation of vasodilation toward the cortical surface along the diving arterioles and "downstream" propagation into local capillary beds. The observed BOLD response exhibited the fastest onset in deep layers, and the "initial dip" was most pronounced in layer I. The present results indicate that both the onset of the BOLD response and the initial dip depend on cortical depth and can be explained, at least in part, by the spatial gradient of delays in microvascular dilation, the fastest response being in the deep layers and the most delayed response in the capillary bed of layer I.

A patient-prioritized ability assessment in haemophilia: the Canadian Occupational Performance Measure.

Assessment of musculoskeletal function in individuals with haemophilia has been attempted with clinimetric instruments, which use predetermined domains for assessing the same. This study introduces the application of an instrument, the Canadian Occupational Performance Measure (COPM), which is an open-ended questionnaire that allows patients to prioritize their needs and rate their performance in different tasks of daily living as well as their satisfaction in performing them. To study the utility of COPM in evaluating the musculoskeletal functional status of patients with haemophilia and to assess its effectiveness in planning individualized management plans for them. COPM was administered to 67 individuals with haemophilia aged 10-55 years and the data were compared with functional deficits identified through FISH (Functional Independence Score for Haemophilia). A total of 31 performance difficulties in the areas of self-care (62%), productivity (21%) and leisure (17%) were identified by COPM. All eight domains of FISH were identified in COPM as problems in self-care. In addition to these, COPM identified problems in the areas of productivity and leisure. In 78% of the responses on COPM, there was concordance between the performance and satisfaction scores. However, there was discordance between the two in the remaining 22% of responses. COPM is a useful tool for assessment of musculoskeletal dysfunction in haemophilia. It provides a greater insight into the needs of each patient and helps in planning individualized intervention strategies.

Hemodynamic management and outcome of patients treated for cerebral vasospasm with intraarterial nicardipine and/or milrinone.

BACKGROUND: Vasospasm is a potentially devastating complication after aneurysmal subarachnoid hemorrhage. Although endovascular treatment with intraarterial nicardipine and milrinone is an accepted clinical treatment strategy, there is little information either on hemodynamic management during treatment or on outcome and consequences of the hemodynamic management. We tested 2 hypotheses: (1) intraarterial administration of nicardipine and milrinone to treat cerebral vasospasm would require increased administration of vasoconstrictor to support arterial blood pressure at target levels; and (2) high-dose vasopressors administered to increase blood pressure in these patients would lead to systemic acidosis and end-organ ischemic damage. METHODS: We conducted a single-center, retrospective review of consecutive patients with clinically symptomatic vasospasm after aneurysmal subarachnoid hemorrhage that failed medical management with "triple H therapy" and subsequently received intraarterial nicardipine and/or milrinone between March 2005 and July 2007. RESULTS: Of 160 endovascular interventions in 73 patients (aged 52 +/- 10 years; 50 women), 96 received only nicardipine, 5 only milrinone, and 59 both drugs. General anesthesia with muscle relaxation was performed for 93% of procedures. During treatment, both the number and dose of vasopressors required to maintain arterial blood pressure at target levels increased; the median dose of phenylephrine increased from 200 (n = 121) to 325 microg/min (n = 122), norepinephrine increased from 12 (n = 60) to 24.5 microg/min (n = 87), and vasopressin infusions increased from 7 to 24. Nonetheless, arterial blood pressure decreased 13% during treatment. In >90% of procedures, the postprocedure angiogram showed improved vessel caliber. A single patient demonstrated troponin T increase; no patients had a decrease in renal function, bowel or peripheral ischemia, systemic acidosis, or acute stroke. Overall mortality was 11%. CONCLUSIONS: Intraarterial administration of nicardipine and/or milrinone requires use of vasopressors to maintain arterial blood pressure. Despite high doses of vasoconstrictors, treatment has low mortality, minimal end-organ ischemic damage or systemic acidosis, and results in improved caliber of cerebral vessels affected by vasospasm.

Anterior skull base olfactory tumours, which is what? A case report and review.

Intracranial schwannomas not originating from cranial nerves are rare. In this paper, we report a case of a 50-year-old male who presented with worsening headaches, diplopia and nausea over two years. Radiological imaging revealed a large tumour arising from the olfactory groove region with a preoperative diagnosis of olfactory groove meningioma (OGM). Intraoperatively, the tumour originated from the region of the attachment of the falx to the crista galli. The patient recovered without complication and histopathology reported an unexpected diagnosis of WHO Grade 1 schwannoma. However, as olfactory groove schwannomas (OGSs) cannot be distinguished from olfactory ensheathing cell tumours (OECTs), it is possible that the tumour could have been either an OGS or an OECT. Distinguishing between OGSs, OECTs and OGMs preoperatively is difficult. OGMs exhibit distinct histopathological features from OGSs/OECTs, however, OGSs and OECTs currently cannot be distinguished from each other. Here, we review the literature to discuss the differentiating features and cellular origins of these three tumours.

The plant natural product 2-methoxy-1,4-naphthoquinone stimulates therapeutic neural repair properties of olfactory ensheathing cells.

Olfactory ensheathing cells (OECs) are crucial for promoting the regeneration of the primary olfactory nervous system that occurs throughout life. Transplantation of OECs has emerged as a promising therapy for nervous system injuries, in particular for spinal cord injury repair. Functional outcomes in both animals and humans are, however, highly variable, primarily because it is difficult to rapidly obtain enough OECs for transplantation. Compounds which can stimulate OEC proliferation without changing the phenotype of the cells are therefore highly sought after. Additionally, compounds which can stimulate favourable cell behaviours such as migration and phagocytic activity are desirable. We conducted a medium-throughput screen testing the Davis open access natural product-based library (472 compounds) and subsequently identified the known plant natural product 2-methoxy-1,4-naphthoquinone as a stimulant of OEC viability. We showed that 2-methoxy-1,4-naphthoquinone: (i) strongly stimulates proliferation over several weeks in culture whilst maintaining the OEC phenotype; (ii) stimulates the phagocytic activity of OECs, and (iii) modulates the cell cycle. We also identified the transcription factor Nrf2 as the compound's potential molecular target. From these extensive investigations we conclude that 2-methoxy-1,4-naphthoquinone may enhance the therapeutic potential of OECs by stimulating proliferation prior to transplantation.

Key differences between olfactory ensheathing cells and Schwann cells regarding phagocytosis of necrotic cells: implications for transplantation therapies.

Transplantation of peripheral nervous system glia is being explored for treating neural injuries, in particular central nervous system injuries. These glia, olfactory ensheathing cells (OECs) and Schwann cells (SCs), are thought to aid regeneration by clearing necrotic cells, (necrotic bodies, NBs), as well as myelin debris. The mechanism by which the glia phagocytose and traffic NBs are not understood. Here, we show that OECs and SCs recognize phosphatidylserine on NBs, followed by engulfment and trafficking to endosomes and lysosomes. We also showed that both glia can phagocytose and process myelin debris. We compared the time-course of glial phagocytosis (of both NBs and myelin) to that of macrophages. Internalization and trafficking were considerably slower in glia than in macrophages, and OECs were more efficient phagocytes than SCs. The two glial types also differed regarding their cytokine responses after NB challenge. SCs produced low amounts of the pro-inflammatory cytokine TNF-α while OECs did not produce detectable TNF-α. Thus, OECs have a higher capacity than SCs for phagocytosis and trafficking, whilst producing lower amounts of pro-inflammatory cytokines. These findings suggest that OEC transplantation into the injured nervous system may lead to better outcomes than SC transplantation.

The effect of mesenchymal populations and vascular endothelial growth factor delivered from biodegradable polymer scaffolds on bone formation.

The capacity to deliver, temporally, bioactive growth factors in combination with appropriate progenitor and stem cells to sites of tissue regeneration promoting angiogenesis and osteogenesis offers therapeutic opportunities in regenerative medicine. We have examined the bone regenerative potential of encapsulated vascular endothelial growth factor (VEGF(165)) biodegradable poly(DL-lactic acid) (PLA) scaffolds created using supercritical CO(2) fluid technology to encapsulate and release solvent-sensitive and thermolabile growth factors in combination with human bone marrow stromal cells (HBMSC) implanted in a mouse femur segmental defect (5 mm) for 4 weeks. HBMSC seeded on VEGF encapsulated PLA scaffolds showed significant bone regeneration in the femur segmental defect compared to the scaffold alone and scaffold seeded with HBMSC as analysed by indices of increased bone volume (BV mm(3)), trabecular number (Tb.N/mm) and reduced trabecular separation (Tb.Sp.mm) in the defect region using micro-computed tomography. Histological examination confirmed significant new bone matrix in the HBMSC seeded VEGF encapsulated scaffold group as evidenced by Sirius red/alcian blue and Goldner's trichrome staining and type I collagen immunocytochemistry expression in comparison to the other groups. These studies demonstrate the ability to deliver, temporally, a combination of VEGF released from scaffolds with seeded HBMSC to sites of bone defects, results in enhanced regeneration of a bone defect.

Controlling protein release from scaffolds using polymer blends and composites.

We report the development of three protein loaded polymer blend and composite materials that modify the release kinetics of the protein from poly(dl-lactic acid) (P(dl)LA) scaffolds. P(dl)LA has been combined with either poly(ethylene glycol) (PEG), poly(caprolactone) (PCL) microparticles or calcium alginate fibres using supercritical CO(2) (scCO(2)) processing to form single and dual protein release scaffolds. P(dl)LA was blended with the hydrophilic polymer PEG using scCO(2) to increase the water uptake of the resultant scaffold and modify the release kinetics of an encapsulated protein. This was demonstrated by the more rapid release of the protein when compared to the release rate from P(dl)LA only scaffolds. For the P(dl)LA/alginate scaffolds, the protein loaded alginate fibres were processed into porous protein loaded P(dl)LA scaffolds using scCO(2) to produce dual release kinetics from the scaffolds. Protein release from the hydrophilic alginate fibres was more rapid in the initial stages, complementing the slower release from the slower degrading P(dl)LA scaffolds. In contrast, when protein loaded PCL particles were loaded into P(dl)LA scaffolds, the rate of protein release was retarded from the slow degrading PCL phase.

Enhancing the Therapeutic Potential of Olfactory Ensheathing Cells in Spinal Cord Repair Using Neurotrophins.

Autologous olfactory ensheathing cell (OEC) transplantation is a promising therapy for spinal cord injury; however, the efficacy varies between trials in both animals and humans. The main reason for this variability is that the purity and phenotype of the transplanted cells differs between studies. OECs are susceptible to modulation with neurotrophic factors, and thus, neurotrophins can be used to manipulate the transplanted cells into an optimal, consistent phenotype. OEC transplantation can be divided into 3 phases: (1) cell preparation, (2) cell administration, and (3) continuous support to the transplanted cells in situ. The ideal behaviour of OECs differs between these 3 phases; in the cell preparation phase, rapid cell expansion is desirable to decrease the time between damage and transplantation. In the cell administration phase, OEC survival and integration at the injury site, in particular migration into the glial scar, are the most critical factors, along with OEC-mediated phagocytosis of cellular debris. Finally, continuous support needs to be provided to the transplantation site to promote survival of both transplanted cells and endogenous cells within injury site and to promote long-term integration of the transplanted cells and angiogenesis. In this review, we define the 3 phases of OEC transplantation into the injured spinal cord and the optimal cell behaviors required for each phase. Optimising functional outcomes of OEC transplantation can be achieved by modulation of cell behaviours with neurotrophins. We identify the key growth factors that exhibit the strongest potential for optimizing the OEC phenotype required for each phase.

Incorporation of proteins within alginate fibre-based scaffolds using a post-fabrication entrapment method.

In this study, a physical entrapment process was explored for the incorporation of proteins within preformed fibrous alginates and the release profile was tuned by varying the processing parameters. The entrapment process was carried out in a series of aqueous solutions at room temperature and involved pre-swelling of the fibrous alginate within a Na(+)-rich solution, followed by exposure to the protein of choice and entrapping it by re-establishing cross-links of alginate with BaCl2. Entrapment and release of fluorescein isothiocyanate-labelled bovine serum albumin (FITC-BSA), a model protein, was studied. It was found that a sustained release of the incorporated protein in cell culture medium for about 6 days was achieved. The main factors determining the release profile included the NaCl/CaCl2 ratio in the pre-swelling solution, protein concentration, and the exposure time. To retard protein release, alginate fibres with entrapped FITC-BSA were processed together with poly(D, L-lactide) (PDLLA) into porous alginate fibre/PDLLA composites using supercritical CO2. In this manner, release of the protein for up to 3 months was achieved.

Vertebral augmentation complicated by perioperative addisonian crisis.

BACKGROUND: We describe a case of perioperative Addisonian crisis induced by vertebral augmentation. While several complications of vertebral augmentation have been reported previously, related to the technical procedure, to our knowledge, perioperative Addisonian crisis from vertebral augmentation has not been reported in the literature. OBJECTIVE: To report an Addisonian crisis perioperative to vertebral augmentation. DESIGN: Case report. METHOD: Retrospective case review. RESULTS: The patient had a history of adrenal insufficiency treated previously with steroids. He developed an L3 vertebral compression fracture, failed conservative therapy and was eventually referred for vertebral augmentation. Immediately after starting the procedure, the patient developed profound hypotension unresponsive to intravenous fluids and vasopressors, consistent with Addisonian crisis. After intravenous steroids had resolved the Addisonian crisis, he underwent vertebral augmentation without further complication. CONCLUSION: Addisonian crisis may be triggered by vertebral augmentation. Practitioners need to recognize immediately this potentially lethal disorder in patients with known or suspected adrenal insufficiency and treat with intravenous hydrocortisone.

Stimulating the proliferation, migration and lamellipodia of Schwann cells using low-dose curcumin.

Transplantation of peripheral glia is being trialled for neural repair therapies, and identification of compounds that enhance the activity of glia is therefore of therapeutic interest. We have previously shown that curcumin potently stimulates the activity of olfactory glia. We have now examined the effect of curcumin on Schwann cell (SC) activities including proliferation, migration and the expression of protein markers. SCs were treated with control media and with different concentrations of curcumin (0.02-20 µM). Cell proliferation was determined by MTS assay and migration changes were determined by single live cell migration tracking. We found that small doses of curcumin (40 nM) dramatically increased the proliferation and migration in SCs within just one day. When compared with olfactory glia, curcumin stimulated SC proliferation more rapidly and at lower concentrations. Curcumin significantly increased the migration of SCs, and also increased the dynamic activity of lamellipodial waves which are essential for SC migration. Expression of the activated form of the MAP kinase p38 (p-p38) was significantly decreased in curcumin-treated SCs. These results show that curcumin's effects on SCs differ remarkably to its effects on olfactory glia, suggesting that subtypes of closely related glia can be differentially stimulated by curcumin. Overall these results demonstrate that the therapeutically beneficial activities of glia can be differentially enhanced by curcumin which could be used to improve outcomes of neural repair therapies.