Periaqueductal Grey EP3 Receptors Facilitate Spinal Nociception in Arthritic Secondary Hypersensitivity.

UNLABELLED: Descending controls on spinal nociceptive processing play a pivotal role in shaping the pain experience after tissue injury. Secondary hypersensitivity develops within undamaged tissue adjacent and distant to damaged sites. Spinal neuronal pools innervating regions of secondary hypersensitivity are dominated by descending facilitation that amplifies spinal inputs from unsensitized peripheral nociceptors. Cyclooxygenase-prostaglandin (PG) E2 signaling within the ventrolateral periaqueductal gray (vlPAG) is pronociceptive in naive and acutely inflamed animals, but its contributions in more prolonged inflammation and, importantly, secondary hypersensitivity remain unknown. In naive rats, PG EP3 receptor (EP3R) antagonism in vlPAG modulated noxious withdrawal reflex (EMG) thresholds to preferential C-nociceptor, but not A-nociceptor, activation and raised thermal withdrawal thresholds in awake animals. In rats with inflammatory arthritis, secondary mechanical and thermal hypersensitivity of the hindpaw developed and was associated with spinal sensitization to A-nociceptor inputs alone. In arthritic rats, blockade of vlPAG EP3R raised EMG thresholds to C-nociceptor activation in the area of secondary hypersensitivity to a degree equivalent to that evoked by the same manipulation in naive rats. Importantly, vlPAG EP3R blockade also affected responses to A-nociceptor activation, but only in arthritic animals. We conclude that vlPAG EP3R activity exerts an equivalent facilitation on the spinal processing of C-nociceptor inputs in naive and arthritic animals, but gains in effects on spinal A-nociceptor processing from a region of secondary hypersensitivity. Therefore, the spinal sensitization to A-nociceptor inputs associated with secondary hypersensitivity is likely to be at least partly dependent on descending prostanergic facilitation from the vlPAG. SIGNIFICANCE STATEMENT: After tissue damage, sensitivity to painful stimulation develops in undamaged areas (secondary hypersensitivity). This is found in many painful conditions, particularly arthritis. The periaqueductal gray (PAG) is an important center that controls spinal nociceptive processing, on which secondary hypersensitivity depends. Prostaglandins (PGs) are mediators of inflammation with pronociceptive actions within the PAG under normal conditions. We find that secondary hindpaw hypersensitivity in arthritic rats results from spinal sensitization to peripheral A-nociceptor inputs. In the PAG of arthritic, but not naive, rats, there is enhanced control of spinal A-nociceptor processing through PG EP3 receptors. The descending facilitatory actions of intra-PAG PGs play a direct and central role in the maintenance of inflammatory secondary hypersensitivity, particularly relating to the processing of A-fiber nociceptive information.

Causes of progressive cerebellar ataxia: prospective evaluation of 1500 patients.

BACKGROUND: Cerebellar ataxias are the result of diverse disease processes that can be genetic or acquired. Establishing a diagnosis requires a methodical approach with expert clinical evaluation and investigations. We describe the causes of ataxia in 1500 patients with cerebellar ataxia. METHODS: All patients were referred to the Sheffield Ataxia Centre, UK, and underwent extensive investigations, including, where appropriate genetic testing using next-generation sequencing (NGS). Patients were followed up on a 6-monthly basis for reassessment and further investigations if indicated. RESULTS: A total of 1500 patients were assessed over 20 years. Twenty per cent had a family history, the remaining having sporadic ataxia. The commonest cause of sporadic ataxia was gluten ataxia (25%). A genetic cause was identified in 156 (13%) of sporadic cases with other causes being alcohol excess (12%) and cerebellar variant of multiple system atrophy (11%). Using NGS, positive results were obtained in 32% of 146 patients tested. The commonest ataxia identified was EA2. A genetic diagnosis was achieved in 57% of all familial ataxias. The commonest genetic ataxias were Friedreich's ataxia (22%), SCA6 (14%), EA2 (13%), SPG7 (10%) and mitochondrial disease (10%). The diagnostic yield following attendance at the Sheffield Ataxia Centre was 63%. CONCLUSIONS: Immune-mediated ataxias are common. Advances in genetic testing have significantly improved the diagnostic yield of patients suspected of having a genetic ataxia. Making a diagnosis of the cause of ataxia is essential due to potential therapeutic interventions for immune and some genetic ataxias.

The documentation of consent and disclosure of neurogenetic testing outside clinical genetics.

Neurogenetic tests are increasingly requested by clinical neurologists without any formal training in clinical genetics. The aim of our study was to assess the documentation of consent and disclosure of genetic test results in a large regional clinical neuroscience centre. Documentation of some form of consent was evident in only 26/132 (20 %) of tests. However, the higher proportion of both positive and negative results disclosed (50/132, 38 %) suggest that the former figure may underestimate actual rates of undocumented consent within the clinical setting. Our findings highlight the need for a review of established practices surrounding consent in clinical neurology.

Atraumatic neck pain and rigidity: a case of calcific retropharyngeal tendonitis.

Neck pain with associated rigidity is a concerning clinical presentation that emergency physicians encounter regularly.We present the case of a 58-year-old man with acute neck pain, worsened by movement and swallowing, that was found to be secondary to acute calcific retropharyngeal tendonitis. Patients with severe neck pain, neck stiffness, and odynophagia may have this condition. The diagnosis can be confirmed with imaging, and response to conservative treatment is often dramatic.

Qualitative interview study exploring the patient experience of living with axial spondyloarthritis and fatigue: difficult, demanding and draining.

OBJECTIVE: To explore patients' lived experiences of axial spondyloarthritis (axSpA) and fatigue. DESIGN: Interpretative phenomenological analysis (lived experience) was used as the study design. Analysis drew together codes with similar meaning to create superordinate and subordinate themes. SETTING: Rheumatology departments in three National Health Service Foundation Trusts in the north, midlands and south of England. PARTICIPANTS: A purposive sample of seventeen axSpA patients were recruited. The age range was 22-72 years (median age 46), nine were male and eight, female. RESULTS: A central concept of achieving balance was identified as the active process of integrating axSpA symptoms and fatigue into daily life, working with and not against their condition to lead a fulfilled life. This was conveyed through three superordinate themes: struggling to find energy, engaging in everyday life and persevering through difficulties. Struggling to find energy was the challenge of retaining enough stamina to do things in daily life. Engaging in everyday life highlighted dedication to being active and organised, learning through experience and acceptance of a changed way of being. Persevering through difficulties identified the physical and emotional effort required to keep moving forward and the importance of feeling supported. CONCLUSION: Achieving balance through finding energy, engaging and persevering everyday was fundamental to having the best possible life. The experience of energy emerged as a distinct but related component of fatigue. However, while energy could be maintained or replenished, fatigue was more difficult to overcome and required greater effort. Energy may be a useful indicator of an individual's current state and ability to sustain activities that supports their well-being, such as exercise. Awareness of the elements of achieving balance in axSpA may enable patients and clinicians to work together to tailor treatments to individual patient need.

Further pitfalls in the diagnosis of mtDNA mutations: homoplasmic mt-tRNA mutations.

BACKGROUND: Mitochondrial DNA (mtDNA) mutations are important causes of human genetic disease, with mutations in tRNA genes particularly prevalent. In many patients, mutations are heteroplasmic, affecting a population of mtDNA molecules. Establishing the pathogenicity of homoplasmic mitochondrial tRNA (mt-tRNA) mutations, in which the mutation is present in every mtDNA molecule, is extremely difficult. These mutations must conform to specific pathogenic criteria, documenting unequivocally a functional defect of the mutant mt-tRNA. AIMS: To investigate the pathogenic nature of two homoplasmic mt-tRNA(Thr) deletions, m.15940delT (previously reported as pathogenic) and m.15937delA, by assessing the steady state levels of the mutant mt-tRNA in tissue and cell-line samples from six unrelated families, in which affected individuals were thoroughly investigated for mitochondrial DNA disease on the basis of clinical presentations. Rates of de novo mitochondrial protein synthesis were also examined in control and m.15937delA mutant fibroblasts. RESULTS: Our data strongly suggest that both single nucleotide deletions are neutral polymorphisms; no obvious defects were apparent in either steady state mt-tRNA(Thr) levels or rates of mitochondrial protein synthesis. CONCLUSIONS: These findings have important implications for the investigation of other families with suspected mtDNA disease, in particular the requirement to fulfil strict and established pathogenic criteria in order to avoid misattribution of pathogenicity to mt-tRNA variants.

Experimental platform to facilitate novel back brace development for the improvement of spine stability.

The spine or 'back' has many functions including supporting our body frame whilst facilitating movement, protecting the spinal cord and nerves and acting as a shock absorber. In certain instances, individuals may develop conditions that not only cause back pain but also may require additional support for the spine. Common movements such as twisting, standing and bending motions could exacerbate these conditions and intensify this pain. Back braces can be used in certain instances to constrain such motion as part of an individual's therapy and have existed as both medical and retail products for a number of decades. Arguably, back brace designs have lacked the innovation expected in this time. Existing designs are often found to be heavy, overly rigid, indiscrete and largely uncomfortable. In order to facilitate the development of new designs of back braces capable of being optimised to constrain particular motions for specific therapies, a numerical and experimental design strategy has been devised, tested and proven for the first time. The strategy makes use of an experimental test rig in conjunction with finite element analysis simulations to investigate and quantify the effects of back braces on flexion, extension, lateral bending and torsional motions as experienced by the human trunk. This paper describes this strategy and demonstrates its effectiveness through the proposal and comparison of two novel back brace designs.

Tumor promoter arsenite activates extracellular signal-regulated kinase through a signaling pathway mediated by epidermal growth factor receptor and Shc.

Although arsenite is an established carcinogen, the mechanisms underlying its tumor-promoting properties are poorly understood. Previously, we reported that arsenite treatment leads to the activation of the extracellular signal-regulated kinase (ERK) in rat PC12 cells through a Ras-dependent pathway. To identify potential mediators of the upstream signaling cascade, we examined the tyrosine phosphorylation profile in cells exposed to arsenite. Arsenite treatment rapidly stimulated tyrosine phosphorylation of several proteins in a Ras-independent manner, with a pattern similar to that seen in response to epidermal growth factor (EGF) treatment. Among these phosphorylated proteins were three isoforms of the proto-oncoprotein Shc as well as the EGF receptor (EGFR). Tyrosine phosphorylation of Shc allowed for enhanced interactions between Shc and Grb2 as identified by coimmunoprecipitation experiments. The arsenite-induced tyrosine phosphorylation of Shc, enhancement of Shc and Grb2 interactions, and activation of ERK were all drastically reduced by treatment of cells with either the general growth factor receptor poison suramin or the EGFR-selective inhibitor tyrphostin AG1478. Down-regulation of EGFR expression through pretreatment of cells with EGF also attenuated ERK activation and Shc tyrosine phosphorylation in response to arsenite treatment. These results demonstrate that the EGFR and Shc are critical mediators in the activation of the Ras/ERK signaling cascade by arsenite and suggest that arsenite acts as a tumor promoter largely by usurping this growth factor signaling pathway.

gadd153/Chop10, a potential target gene of the transcriptional repressor ATF3.

Recently, we demonstrated that the function of ATF3, a stress-inducible transcriptional repressor, is negatively regulated by a bZip protein, gadd153/Chop10. In this report, we present evidence that ATF3 can repress the expression of its own inhibitor, gadd153/Chop10. First, ATF3 represses a chloramphenicol acetyltransferase reporter gene driven by the gadd153/Chop10 promoter when assayed by a transfection assay in vivo and a transcription assay in vitro. Second, the gadd153/Chop10 promoter contains two functionally important binding sites for ATF3: an AP-1 site and a C/EBP-ATF composite site, a previously unidentified binding site for ATF3. The absence of either site reduces the ability of ATF3 to repress the promoter. Third, overexpression of ATF3 by transient transfection results in a reduction of the endogenous gadd153/Chop10 mRNA level. Fourth, as described previously, ATF3 is induced in the liver upon CCl4 treatment. Intriguingly, we show in this report that gadd153/Chop10 mRNA is not present in areas where ATF3 is induced. Taken together, these results strongly suggest that ATF3 represses the expression of gadd153/Chop10. The mutual negative regulation between ATF3 and gadd153/Chop10 is discussed.

Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state.

gadd153, also known as chop, is a highly stress-inducible gene that is robustly expressed following disruption of homeostasis in the endoplasmic reticulum (ER) (so-called ER stress). Although all reported types of ER stress induce expression of Gadd153, its role in the stress response has remained largely undefined. Several studies have correlated Gadd153 expression with cell death, but a mechanistic link between Gadd153 and apoptosis has never been demonstrated. To address this issue we employed a cell model system in which Gadd153 is constitutively overexpressed, as well as two cell lines in which Gadd153 expression is conditional. In all cell lines, overexpression of Gadd153 sensitized cells to ER stress. Investigation of the mechanisms contributing to this effect revealed that elevated Gadd153 expression results in the down-regulation of Bcl2 expression, depletion of cellular glutathione, and exaggerated production of reactive oxygen species. Restoration of Bcl2 expression in Gadd153-overexpressing cells led to replenishment of glutathione and a reduction in levels of reactive oxygen species, and it protected cells from ER stress-induced cell death. We conclude that Gadd153 sensitizes cells to ER stress through mechanisms that involve down-regulation of Bcl2 and enhanced oxidant injury.

Regulation of p21WAF1/CIP1 expression through mitogen-activated protein kinase signaling pathway.

p21WAF1/CIP1 is a cyclin-dependent kinase inhibitor whose expression in mammalian tissues is highly induced in response to stress as well as during normal development and differentiation. Induction of p21WAF1/CIP1 in response to DNA damage occurs through a transcriptional mechanism that is dependent on the activation of the tumor suppressor protein p53. Recent evidence indicates that p21WAF1/CIP1 can also be induced independently of p53, but the signal transduction mechanisms involved in regulating p21WAF1/CIP1 expression in these situations have not been elucidated. In this study, we have addressed the role of the mitogen-activated protein kinase signaling pathway in the induction of p21WAF1/CIP1 in response to growth factor treatment. Using an experimental approach involving cotransfection of a p21WAF1/CIP1 promoter-luciferase construct with a variety of plasmids expressing dominant positive or dominant negative mutant proteins involved in this signaling pathway, we provide evidence to support a role for mitogen-activated protein kinase in the transcriptional activation of p21WAF1/CIP1 by growth factor stimulation.

An Exploratory Study of the Experience of Ageing with Ankylosing Spondylitis: 'Same Backdrop but a Changing Scene'.

OBJECTIVES: People are living longer with a long-term health condition. Our aim was to develop a greater understanding of the experience and needs of people as they age with ankylosing spondylitis (AS). METHODS: Ethical approval was obtained for six focus groups, with participants over 60 years of age, to explore experiences through peer group discussion. The groups were recorded and transcribed. Transcripts were coded and a thematic analysis was conducted using NVIVO 10. RESULTS: Four women and 28 men, with an average age of 68 (range 60-83) years, consented to participate. Analysis identified a central organizing concept, 'same backdrop but a changing scene', which conceptualizes the continued impact of AS set against a backdrop of people transitioning into a new phase of their lives and facing differing challenges. Five themes underpin this concept: 'it doesn't go away' (AS remains active with continuing functional and symptomatic challenges); 'wheels fall off after 60' (perceptions of disease progression within the context of 'normal ageing'); 'keep on pushing, keep on doing' (challenges of remaining active and motivated); 'living a fulfilling life' (actively engaging with life) and a 'price to pay' (significant psychological, physical and financial consequences on participants and their families). CONCLUSIONS: As people living with AS make the transition into retirement, many aspire to live active lives while facing new challenges in relation to their lifestyles and priorities. There is a need to offer tailored interventions to enable older people to remain active and continue to lead the lives they choose within the context of an active and often debilitating condition. Copyright © 2015 John Wiley & Sons, Ltd.

Cloning and characterisation of cDNAs encoding a novel non-receptor tyrosine kinase, brk, expressed in human breast tumours.

Using a polymerase chain reaction based differential screening approach, we have isolated and characterised a cDNA from a human metastatic breast tumour representing a novel protein tyrosine kinase (brk). Sequencing of brk cDNAs isolated from T-47D and MCF-7 human breast tumour cell lines indicate that they encode a protein with the features of a novel nonreceptor tyrosine kinase, including amino terminal SH3 and SH2 domains. When synthesised in recombinant baculovirus and bacterial expression systems, brk protein products are capable of autophosphorylation on tyrosine residues. Initial expression studies have detected low levels of brk transcripts in some human breast tumours and breast tumour cell lines, but not in normal breast tissue.

Expression patterns of the novel receptor-like tyrosine kinase, DDR, in human breast tumours.

Using a reverse transcriptase-polymerase chain reaction based differential screening procedure, we have identified the discoidin domain receptor as a protein tyrosine kinase that is expressed in lymph nodes containing breast tumour metastases. By Northern blotting and in situ hybridisation we have demonstrated the expression of the discoidin domain receptor in human primary breast tumour samples, metastasis-containing lymph nodes and a number of normal tissues. Direct comparison of malignant breast and adjacent normal epithelial tissue revealed over expression in the tumour cells.

Modulation of CCAAT/enhancer-binding protein-alpha gene expression by metabolic signals in rodent adipocytes.

The transcription factor CCAAT/enhancer-binding protein-alpha (C/EBPalpha) is a positive modulator of transcription for several adipocyte-specific genes that play a role in energy metabolism. However, there is little information available regarding the regulation of its expression by metabolic signals. Exposure to insulin for 5-24 h attenuated C/EBPalpha expression when 3T3-L1 adipocytes were incubated in 24 mM glucose, but not in 5.7 mM glucose. Nuclear run-on transcription assays indicated a transcriptional repression of C/EBPalpha gene, but not that of C/EBPbeta. Glucosamine, a product of the hexosamine pathway, in the presence of low glucose mimicked high glucose's ability to reduce C/EBPalpha messenger RNA expression in insulin-treated cells. Similar results were obtained with xylitol, an activator of the pentose phosphate pathway. There was no correlation between the accumulation of hexosamine pathway metabolites (e.g. UDP-N-acetylhexosamines) and/or changes in intracellular protein glycosylation with the ability of high glucose, glucosamine, or xylitol to down-regulate C/EBPalpha gene expression. None of these treatments caused a reduction in intracellular ATP levels. Stable transfection of 3T3-L1 cells with the 5'-flanking 468-bp sequence of the mouse C/EBPalpha gene fused to luciferase demonstrated that promoter activity was also reduced by these nutrients. Of interest, treatment of rats with glucose or glucosamine led to a reduction in C/EBPalpha messenger RNA levels in epididymal, but not omental, fat. Taken together, these results suggest that metabolic signals serve to down-regulate C/EBPalpha expression both in vitro and in vivo.

A double-blind multicenter trial comparing sertraline and fluoxetine in outpatients with major depression.

BACKGROUND: Sertraline and fluoxetine have pharmacokinetic and pharmacologic differences, which may be of clinical relevance. METHOD: A randomized, double-blind, parallel-group study of 6 weeks' duration comparing the efficacy and safety of sertraline (50-100 mg/day) with those of fluoxetine (20-40 mg/day) was conducted in 286 psychiatric outpatients with DSM-III-R major depression or bipolar disorder (depressed). Primary efficacy measurements consisted of the 17-item Hamilton Rating Scale for Depression (HAM-D) and the Clinical Global Impressions (CGI) scale. Secondary measurements included the Hamilton Rating Scale for Anxiety (HAM-A), the Raskin Depression Scale, the Covi Anxiety Scale, and the Leeds Sleep Questionnaire. Additionally, scores for two items and five factors from the HAM-D were analyzed. RESULTS: Efficacy was based on 124 evaluable patients in each treatment group. As measured by HAM-D and CGI-Severity scores, there was a significant (p < .001) improvement from baseline to each follow-up visit in both treatment groups with no statistically significant difference between groups. There was also no significant difference in the proportion of responders in each group. CGI-Improvement responder rates were 69% for sertraline and 67% for fluoxetine. Results of secondary efficacy measurements followed the same trend, although from the second week of treatment there was a numerical advantage (not statistically significant) for sertraline over fluoxetine in improving anxiety symptoms as measured by the total HAM-A score. Headache and nausea were the most frequently reported events for both drugs. The incidence of early patient withdrawals due to treatment-emergent adverse events was 14% for sertraline and 13% for fluoxetine. The starting dosage (sertraline 50 mg/day, fluoxetine 20 mg/day) was the final dosage in 76% of patients in both treatment groups. CONCLUSION: Sertraline and fluoxetine were equally effective and well tolerated in patients with major depression and associated anxiety.

Pseudo-random procedures for rapid presentation rates using optical imaging and spectroscopy.

Optical imaging of rat barrel cortex has provided detailed spatio-temporal maps of functional cortical architecture. We describe an event-related procedure (ERP) for optical imaging based on selective signal averaging as reported by Burock et al., using an anti-correlative pseudo-random event sequence. The sequence used 1 s vibrissal stimulation at 5 Hz, with an interevent interval of 2 s. This rapid presentation rate allows for greater statistical power per unit time, and allows for direct comparison of event-related studies with other imaging modalities. The spatio-temporal characteristics of single wavelength and spectrographic results were found to be comparable with those obtained by standard techniques, although a general lessening of haemodynamic response function (HRF) was noted. We also describe a method of locating barrel activity by spectral analysis of summed event data. Using this technique, the power spectrum of remitted light from the barrel region was found to peak within +/- 0.12 Hz of the inter-event interval frequency.

Integration of neural responses originating from different regions of the cortical somatosensory map.

The neural pathways responsible for detecting peripheral tactile stimuli are well known; however, the interactions between different somatosensory regions have been less well investigated. This study demonstrates how the contralateral sensory response of rat barrel cortex to whisker stimulation is affected by stimulation of contralateral forepaw and ipsilateral whisker and forepaw. The barrel cortex in the right hemisphere was located using optical imaging. A 16-channel multielectrode was used to measure field potentials evoked by contralateral electrical stimulation of the whisker pad. A standard response in the right barrel cortex to single pulse electrical stimulation of the contralateral whisker pad was modulated by applying conditioning stimulation to one of three other regions of the body (the ipsilateral whisker pad, the ipsilateral or contralateral forepaws). In conditions where the standard contralateral whisker stimulus preceded the conditioning pulse, the size of response was identical to when it was stimulated alone. However, when the ipsilateral whisker and contralateral forepaw conditioning stimuli preceded the contralateral whisker pad stimulation, up to a 35% reduction in the contralateral whisker response was observed. These results confirm and extend previous studies [Proc. Natl. Acad. Sci. U. S. A. 97 (2000) 11026-11031; J. Neurosci. 21 (2001) 5251-5261], which show bilateral integration of neural activity within the rat somatosensory system. Furthermore, the longer latency of the inhibition following stimulation of the contralateral forepaw suggests the possible involvement of extracortical circuitry.

Inhibition of C-fibre mediated sensory transmission in the rat following intraplantar formalin.

Using extracellular recordings from deep dorsal horn neurones in the anaesthetized rat, the effects of intraplantar (i.pl.) administration of formalin were examined. Phasic patterns of dorsal horn firing were observed which temporally concur with previously described behavioural responses following i.pl. formalin. However, unexpectedly, formalin abolished C-fibre mediated transmission, and significantly reduced responses to noxious mechanical stimulation, while electrically evoked A-fibre responses were unaffected. This suggests that whilst the first phase formalin response is mediated by direct afferent stimulation, the second phase behavioural response is dependant on a central hyperexcitability of the recipient second-order dorsal horn neurones, which may be maintained by peripheral input only from A-fibres. This study therefore provides further evidence for a centrally-mediated secondary component of the formalin model, and for the first time, describes loss of high-threshold C-fibre input to the spinal cord during this phase.

The Virginia generalist initiative: lessons learned in a statewide consortium.

In response to Virginia's need for an increased supply of generalist physicians, the state's three medical schools--Eastern Virginia Medical School, Virginia Commonwealth University School of Medicine, and the University of Virginia School of Medicine--have formed a partnership with key governmental stakeholders in the Virginia Generalist Initiative funded by The Robert Wood Johnson Foundation's Generalist Physician Initiative. These state-supported medical schools historically have functioned independently, with little cooperative effort. This paper describes the consortium, its activities, its successes, and its unmet objectives, and uses a series of cases in point to illustrate relevant lessons learned. Some of these lessons are that (1) stakeholders must be involved from the beginning of planning to identify mutual goals and establish consortium protocols; (2) all partners must share a philosophical commitment to the consortium's mission, as well as the time and resources needed; (3) an atmosphere that enables risk-taking behavior must be created; (4) stakeholders must be willing to revise goals and sustain an environment conductive to change; and (5) trust is essential and must be vigilantly maintained. The paper concludes that the Virginia Generalist Initiative has dramatically altered the goals, objectives and programs of the three schools and has succeeded in aligning the schools' strategic objectives with the state's priorities.