Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex.

Chronic pain hypersensitivity depends on N-methyl-D-aspartate receptors (NMDARs). However, clinical use of NMDAR blockers is limited by side effects resulting from suppression of the physiological functions of these receptors. Here we report a means to suppress pain hypersensitivity without blocking NMDARs, but rather by inhibiting the binding of a key enhancer of NMDAR function, the protein tyrosine kinase Src.

The apolar channel in Cerebratulus lacteus hemoglobin is the route for O2 entry and exit.

The major pathway for O2 binding to mammalian myoglobins (Mb) and hemoglobins (Hb) involves transient upward movement of the distal histidine (His-64(E7)), allowing ligand capture in the distal pocket. The mini-globin from Cerebratulus lacteus (CerHb) appears to have an alternative pathway between the E and H helices that is made accessible by loss of the N-terminal A helix. To test this pathway, we examined the effects of changing the size of the E7 gate and closing the end of the apolar channel in CerHb by site-directed mutagenesis.

An interfaculty pain curriculum: lessons learned from six years experience.

Minimal pain content has been documented in pre-licensure curricula and students lack important pain knowledge at graduation. To address this problem, we have implemented and evaluated a mandatory Interfaculty Pain Curriculum (IPC) yearly since 2002 for students (N=817 in 2007) from six Health Science Faculties/Departments. The 20-h pain curriculum continues to involve students from Dentistry, Medicine, Nursing, Pharmacy, Physical Therapy, and Occupational Therapy as part of their 2nd or 3rd year program.

NMDA receptors in clinical neurology: excitatory times ahead.

Since the N-methyl-D-aspartate receptor (NMDAR) subunits were cloned less than two decades ago, a substantial amount of research has been invested into understanding their physiological function in the healthy CNS. Research has also been directed at their pathological roles in various neurological diseases, including disorders resulting from acute excitotoxic insults (eg, ischaemic stroke, traumatic brain injury), diseases due to chronic neurodegeneration (eg, Alzheimer's, Parkinson's, and Huntington's diseases and amyotrophic lateral sclerosis), disorders arising from sensitisation of neurons (eg, epilepsy, neuropathic pain), and neurodevelopmental disorders associated with NMDAR hypofunction (eg, schizophrenia). Selective NMDAR antagonists have not produced positive results in clinical trials.

Effectiveness of PSD95 inhibitors in permanent and transient focal ischemia in the rat.

Background And Purpose: Postsynaptic density-95 inhibitors reduce ischemic brain damage without inhibiting excitatory neurotransmission, circumventing the negative consequences of glutamatergic inhibition. However, their efficacy in permanent ischemia and in providing permanent neuroprotection and neurobehavioral improvement in a practical therapeutic window is unproven. These were tested here under conditions that included fever, which is a common occurrence in clinical stroke.

The role of men in women's acceptance of an intravaginal gel in a randomized clinical trial in Blantyre, Malawi: a qualitative and quantitative analysis.

Survey questionnaires and focus group discussions were used to investigate the association between a female participant's acceptance and her perception of her male partner's acceptance of an intravaginal gel as a prototype microbicide. Women who perceived their male partners would accept using the gel were more likely to highly accept the gel as compared to women who perceived their male partners would not accept using the gel (OR=24.57; 95%CI: 16.

Bench-to-bedside review: the value of cardiac biomarkers in the intensive care patient.

The use of cardiac biomarkers in the intensive care setting is gaining increasing popularity. There are several reasons for this increase: there is now the facility for point-of-care biomarker measurement providing a rapid diagnosis; biomarkers can be used as prognostic tools; biomarkers can be used to guide therapy; and, compared with other methods such as echocardiography, the assays are easier and much more affordable. Two important characteristics of the ideal biomarker are disease specificity and a linear relationship between the serum concentration and disease severity.

ErbB4 is a suppressor of long-term potentiation in the adult hippocampus.

ErbB4 has emerged as a leading susceptibility gene for schizophrenia but the function of the ErbB4 receptor in the adult brain is unknown. Here, we show in the adult hippocampus that long-term potentiation (LTP) of transmission at Schaffer collateral CA1 synapses was markedly enhanced in mutant mice lacking ErbB4. Concordantly, LTP was enhanced by acutely blocking ErbB4 in wild-type animals, indicating that ErbB4 activity constitutively suppresses LTP.

The mechanisms of acute ischemic injury in the cell processes of developing white matter astrocytes.

Astrocytes are fundamentally important to the maintenance and proper functioning of the central nervous system. During the period of development when myelination is occurring, white matter astrocytes are particularly sensitive to ischemic injury and their failure to regulate glutamate during ischemic conditions may be an important factor in excitotoxic injury. Here, we have identified key mechanisms of injury that operate on the processes of immature white matter astrocytes during oxygen-glucose deprivation (OGD) using GFAP-GFP mice.

Transformation of the output of spinal lamina I neurons after nerve injury and microglia stimulation underlying neuropathic pain.

Background: Disinhibition of neurons in the superficial spinal dorsal horn, via microglia - neuron signaling leading to disruption of chloride homeostasis, is a potential cellular substrate for neuropathic pain. But, a central unresolved question is whether this disinhibition can transform the activity and responses of spinal nociceptive output neurons to account for the symptoms of neuropathic pain.

Results: Here we show that peripheral nerve injury, local spinal administration of ATP-stimulated microglia or pharmacological disruption of chloride transport change the phenotype of spinal lamina I output neurons, causing them to 1) increase the gain of nociceptive responsiveness, 2) relay innocuous mechanical input and 3) generate spontaneous bursts of activity.

PDZ protein interactions underlying NMDA receptor-mediated excitotoxicity and neuroprotection by PSD-95 inhibitors.

In neuronal synapses, PDZ domains [postsynaptic density-95 (PSD-95)/Discs large/zona occludens-1] of PSD-95 proteins interact with C termini of NMDA receptor [NMDAR (NR)] subunits, linking them to downstream neurotoxic signaling molecules. Perturbing NMDAR/PSD-95 interactions with a Tat peptide comprising the nine C-terminal residues of the NR2B subunit (Tat-NR2B9c) reduces neurons' vulnerability to excitotoxicity and ischemia. However, NR subunit C termini may bind many of >240 cellular PDZs, any of which could mediate neurotoxic signaling independently of PSD-95.

Pharmacological properties of the enhanced-affinity glucocorticoid fluticasone furoate in vitro and in an in vivo model of respiratory inflammatory disease.

Fluticasone furoate (FF) is a novel enhanced-affinity glucocorticoid that has been developed as topical therapy for allergic rhinitis. The pharmacological properties of FF have been investigated using a number of in vitro experimental systems. FF demonstrated very potent glucocorticoid activity in several key pathways downstream of the glucocorticoid receptor (GR) as follows: the transrepression nuclear factor-kappaB (NF-kappaB) pathway, the transactivation glucocorticoid response element pathway, and inhibition of the proinflammatory cytokine tumor necrosis factor-alpha.

The development of scalemic multidentate niobium complexes as catalysts for the highly stereoselective ring opening of meso-epoxides and meso-aziridines.

The discovery and development of a new Lewis acid system based on a complex formed from niobium(V) methoxide and (R)-3,3'-bis(2-hydroxy-3-isopropylbenzyl)-1,1'-binaphthalene-2,2'-diol, a novel tetradentate BINOL derivative, is presented. The system was shown to be extremely effective in promoting the desymmetrative ring opening of linear and cyclic meso-epoxides using anilines as nucelophiles, delivering the corresponding (R,R) anti-amino alcohols in good to excellent yields (up to quantitative) and excellent enantioselectivity (up to 96% ee). Furthermore, the catalyst system displays a remarkable sensitivity to steric bulk at the beta-carbon of the epoxide, selectively facilitating ring opening of smaller epoxides in the presence of more sterically hindered epoxides.

GFP imaging of live astrocytes: regional differences in the effects of ischaemia upon astrocytes.

The basic division between white matter 'fibrous' astrocytes and grey matter 'protoplasmic' astrocytes is well established in terms of their morphological differences. The availability of transgenic animals with green fluorescent protein (GFP) expression restricted to specific glial cell types now provides an approach for looking at changes in cell number and morphology in the two astrocyte types in whole mount preparations. This is an important goal, as the ease of generating astrocyte cultures has led to a proliferation of studies that have examined ischaemic effects on astrocytes in vitro.

Plant protein extraction.

A method is presented for the extraction of total protein from Arabidopsis thaliana tissue. The protocol was designed for the solubilization of a range of proteins and their efficient and quantitative recovery. It is especially compatible with the small quantities of available tissue often associated with this species and was originally intended for Western blot preparations.

Extraction of plant RNA.

This protocol details an RNA preparation for medium-scale, high-purity RNA production from higher plants. It uses hot acid phenol with standard sodium acetate ethanol precipitation and is suitable for producing RNA for both Northern blotting and enzyme-based downstream applications such as RT-PCR and microarray studies.

Stereological and somatotopic analysis of the spinal microglial response to peripheral nerve injury.

The involvement of glia, and glia-neuronal signalling in enhancing nociceptive transmission has become an area of intense scientific interest. In particular, a role has emerged for activated microglia in the development and maintenance of neuropathic pain following peripheral nerve injury. Following activation, spinal microglia proliferate and release many substances which are capable of modulating neuronal excitability within the spinal cord.

Recent advances in basic neurosciences and brain disease: from synapses to behavior.

Understanding basic neuronal mechanisms hold the hope for future treatment of brain disease. The 1st international conference on synapse, memory, drug addiction and pain was held in beautiful downtown Toronto, Canada on August 21-23, 2006. Unlike other traditional conferences, this new meeting focused on three major aims: (1) to promote new and cutting edge research in neuroscience; (2) to encourage international information exchange and scientific collaborations; and (3) to provide a platform for active scientists to discuss new findings.

TRPV1+ sensory neurons control beta cell stress and islet inflammation in autoimmune diabetes.

In type 1 diabetes, T cell-mediated death of pancreatic beta cells produces insulin deficiency. However, what attracts or restricts broadly autoreactive lymphocyte pools to the pancreas remains unclear. We report that TRPV1(+) pancreatic sensory neurons control islet inflammation and insulin resistance.

Tightly clustered outbreak of group A streptococcal disease at a long-term care facility.

Objective: To describe investigation of a tightly clustered outbreak of invasive group A streptococcal (GAS) disease associated with a high mortality rate in a long-term care facility (LTCF).

Design: Cross-sectional carriage survey and epidemiologic investigation of LTCF resident and employee cohorts.

Setting: A 104-bed community LTCF between March 1 and April 7, 2004.