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1.  A Partial Gene Deletion of SLC45A2 Causes Oculocutaneous Albinism in Doberman Pinscher Dogs 
PLoS ONE  2014;9(3):e92127.
The first white Doberman pinscher (WDP) dog was registered by the American Kennel Club in 1976. The novelty of the white coat color resulted in extensive line breeding of this dog and her offspring. The WDP phenotype closely resembles human oculocutaneous albinism (OCA) and clinicians noticed a seemingly high prevalence of pigmented masses on these dogs. This study had three specific aims: (1) produce a detailed description of the ocular phenotype of WDPs, (2) objectively determine if an increased prevalence of ocular and cutaneous melanocytic tumors was present in WDPs, and (3) determine if a genetic mutation in any of the genes known to cause human OCA is causal for the WDP phenotype. WDPs have a consistent ocular phenotype of photophobia, hypopigmented adnexal structures, blue irides with a tan periphery and hypopigmented retinal pigment epithelium and choroid. WDPs have a higher prevalence of cutaneous melanocytic neoplasms compared with control standard color Doberman pinschers (SDPs); cutaneous tumors were noted in 12/20 WDP (<5 years of age: 4/12; >5 years of age: 8/8) and 1/20 SDPs (p<0.00001). Using exclusion analysis, four OCA causative genes were investigated for their association with WDP phenotype; TYR, OCA2, TYRP1 and SLC45A2. SLC45A2 was found to be linked to the phenotype and gene sequencing revealed a 4,081 base pair deletion resulting in loss of the terminus of exon seven of SLC45A2 (chr4∶77,062,968–77,067,051). This mutation is highly likely to be the cause of the WDP phenotype and is supported by a lack of detectable SLC45A2 transcript levels by reverse transcriptase PCR. The WDP provides a valuable model for studying OCA4 visual disturbances and melanocytic neoplasms in a large animal model.
doi:10.1371/journal.pone.0092127
PMCID: PMC3960214  PMID: 24647637
2.  Assessment of Sleep in Children with Mucopolysaccharidosis Type III 
PLoS ONE  2014;9(2):e84128.
Sleep disturbances are prevalent in mucopolysaccharidosis Type III (MPS III), yet there is a lack of objective, ecologically valid evidence detailing sleep quantity, quality or circadian system. Eight children with MPS III and eight age-matched typically developing children wore an actigraph for 7–10 days/nights. Saliva samples were collected at three time-points on two separate days, to permit analysis of endogenous melatonin levels. Parents completed a sleep questionnaire and a daily sleep diary. Actigraphic data revealed that children with MPS III had significantly longer sleep onset latencies and greater daytime sleep compared to controls, but night-time sleep duration did not differ between groups. In the MPS III group, sleep efficiency declined, and sleep onset latency increased, with age. Questionnaire responses showed that MPS III patients had significantly more sleep difficulties in all domains compared to controls. Melatonin concentrations showed an alteration in the circadian system in MPS III, which suggests that treatment for sleep problems should attempt to synchronise the sleep-wake cycle to a more regular pattern. Actigraphy was tolerated by children and this monitoring device can be recommended as a measure of treatment success in research and clinical practice.
doi:10.1371/journal.pone.0084128
PMCID: PMC3913580  PMID: 24504123
3.  Interleukin-6 Signaling Drives Fibrosis in Unresolved Inflammation 
Immunity  2014;40(1):40-50.
Summary
Fibrosis in response to tissue damage or persistent inflammation is a pathological hallmark of many chronic degenerative diseases. By using a model of acute peritoneal inflammation, we have examined how repeated inflammatory activation promotes fibrotic tissue injury. In this context, fibrosis was strictly dependent on interleukin-6 (IL-6). Repeat inflammation induced IL-6-mediated T helper 1 (Th1) cell effector commitment and the emergence of STAT1 (signal transducer and activator of transcription-1) activity within the peritoneal membrane. Fibrosis was not observed in mice lacking interferon-γ (IFN-γ), STAT1, or RAG-1. Here, IFN-γ and STAT1 signaling disrupted the turnover of extracellular matrix by metalloproteases. Whereas IL-6-deficient mice resisted fibrosis, transfer of polarized Th1 cells or inhibition of MMP activity reversed this outcome. Thus, IL-6 causes compromised tissue repair by shifting acute inflammation into a more chronic profibrotic state through induction of Th1 cell responses as a consequence of recurrent inflammation.
Highlights
•Repeated acute resolving inflammation leads to excessive tissue damage•IL-6 regulates profibrotic IFN-γ-secreting T cells•IFN-γ increases detrimental STAT1 signaling in stromal tissue•STAT1 activity alters homeostatic control of extracellular matrix to promote fibrosis
doi:10.1016/j.immuni.2013.10.022
PMCID: PMC3919204  PMID: 24412616
4.  Interleukin-6 limits influenza-induced inflammation and protects against fatal lung pathology 
European journal of immunology  2013;43(10):10.1002/eji.201243018.
SUMMARY
Balancing the generation of immune responses capable of controlling virus replication with those causing immunopathology is critical for the survival of the host and resolution of influenza-induced inflammation. Based on the capacity of interleukin-6 (IL-6) to govern both optimal T-cell responses and inflammatory resolution, we hypothesised that IL-6 plays an important role in maintaining this balance. Comparison of innate and adaptive immune responses in influenza-infected wild-type control and IL-6 deficient mice revealed striking differences in virus clearance, lung immunopathology and generation of heterosubtypic immunity. Mice lacking IL-6 displayed a profound defect in their ability to mount an anti-viral T-cell response. Failure to adequately control virus was further associated with an enhanced infiltration of inflammatory monocytes into the lung and an elevated production of the pro-inflammatory cytokines IFN-α and TNF-α. These events were associated with severe lung damage, characterised by profound vascular leakage, and death. Our data highlight an essential role for IL-6 in orchestrating anti-viral immunity through an ability to limit inflammation, promote protective adaptive immune responses and prevent fatal immunopathology.
doi:10.1002/eji.201243018
PMCID: PMC3886386  PMID: 23857287
Adaptive Immunity; Heterosubtypic Immunity; IL-6; Innate Immunity; Pulmonary Damage
5.  The effect of high dose antibiotic impregnated cement on rate of surgical site infection after hip hemiarthroplasty for fractured neck of femur: a protocol for a double-blind quasi randomised controlled trial 
Background
Mortality following hip hemiarthroplasty is in the range of 10-40% in the first year, with much attributed to post-operative complications. One such complication is surgical site infection (SSI), which at the start of this trial affected 4.68% of patients in the UK having this operation. Compared to SSI rates of elective hip surgery, at less than 1%, this figure is elevated. The aim of this quasi randomised controlled trial (RCT) is to determine if high dose antibiotic impregnated cement can reduce the SSI in patients at 12-months after hemiarthroplasty for intracapsular fractured neck of femur.
Methods
848 patients with an intracapsular fractured neck of femur requiring a hip hemiarthroplasty are been recruited into this two-centre double-blind quasi RCT. Participants were recruited before surgery and quasi randomised to standard care or intervention group. Participants, statistician and outcome assessors were blind to treatment allocation throughout the study. The intervention consisted of high dose antibiotic impregnated cement consisting of 1 gram Clindamycin and 1 gram of Gentamicin. The primary outcome is Health Protection Agency (HPA) defined deep surgical site infection at 12 months. Secondary outcomes include HPA defined superficial surgical site infection at 30 days, 30 and 90-day mortality, length of hospital stay, critical care stay, and complications.
Discussion
Large randomised controlled trials assessing the effectiveness of a surgical intervention are uncommon, particularly in the speciality of orthopaedics. The results from this trial will inform evidence-based recommendations for antibiotic impregnated cement in the management of patients with a fractured neck of femur undergoing a hip hemiarthroplasty. If high dose antibiotic impregnated cement is found to be an effective intervention, implementation into clinical practice could improve long-term outcomes for patients undergoing hip hemiarthroplasty.
Trial registration
Current Controlled Trials: ISRCTN25633145
doi:10.1186/1471-2474-14-356
PMCID: PMC3878442  PMID: 24344672
6.  Distinct bone marrow-derived and tissue resident macrophage-lineages proliferate at key stages during inflammation 
Nature communications  2013;4:10.1038/ncomms2877.
The general paradigm is that monocytes are recruited to sites of inflammation and terminally-differentiate into macrophages. There has been no demonstration of proliferation of peripherally-derived inflammatory macrophages under physiological conditions. Here we show that proliferation of both bone marrow-derived inflammatory and tissue resident macrophage lineage branches is a key feature of the inflammatory process with major implications for the mechanisms underlying recovery from inflammation. Both macrophage lineage branches are dependent on M-CSF during inflammation, and thus the potential for therapeutic interventions is marked. Furthermore, these observations are independent of Th2 immunity. These studies indicate that the proliferation of distinct macrophage populations provides a general mechanism for macrophage expansion at key stages during inflammation, and separate control mechanisms are implicated.
doi:10.1038/ncomms2877
PMCID: PMC3842019  PMID: 23695680
7.  Signal One and Two Blockade Are Both Critical for Non-Myeloablative Murine HSCT across a Major Histocompatibility Complex Barrier 
PLoS ONE  2013;8(10):e77632.
Non-myeloablative allogeneic haematopoietic stem cell transplantation (HSCT) is rarely achievable clinically, except where donor cells have selective advantages. Murine non-myeloablative conditioning regimens have limited clinical success, partly through use of clinically unachievable cell doses or strain combinations permitting allograft acceptance using immunosuppression alone. We found that reducing busulfan conditioning in murine syngeneic HSCT, increases bone marrow (BM):blood SDF-1 ratio and total donor cells homing to BM, but reduces the proportion of donor cells engrafting. Despite this, syngeneic engraftment is achievable with non-myeloablative busulfan (25 mg/kg) and higher cell doses induce increased chimerism. Therefore we investigated regimens promoting initial donor cell engraftment in the major histocompatibility complex barrier mismatched CBA to C57BL/6 allo-transplant model. This requires full myeloablation and immunosuppression with non-depleting anti-CD4/CD8 blocking antibodies to achieve engraftment of low cell doses, and rejects with reduced intensity conditioning (≤75 mg/kg busulfan). We compared increased antibody treatment, G-CSF, niche disruption and high cell dose, using reduced intensity busulfan and CD4/8 blockade in this model. Most treatments increased initial donor engraftment, but only addition of co-stimulatory blockade permitted long-term engraftment with reduced intensity or non-myeloablative conditioning, suggesting that signal 1 and 2 T-cell blockade is more important than early BM niche engraftment for transplant success.
doi:10.1371/journal.pone.0077632
PMCID: PMC3798400  PMID: 24147041
8.  Treatment of hip dysplasia in patients with mucopolysaccharidosis type I after hematopoietic stem cell transplantation: results of an international consensus procedure 
Background
Mucopolysaccharidosis type I (MPS-I) is a lysosomal storage disorder characterized by progressive multi-organ disease. The standard of care for patients with the severe phenotype (Hurler syndrome, MPS I-H) is early hematopoietic stem cell transplantation (HSCT). However, skeletal disease, including hip dysplasia, is almost invariably present in MPS I-H, and appears to be particularly unresponsive to HSCT. Hip dysplasia may lead to pain and loss of ambulation, at least in a subset of patients, if left untreated. However, there is a lack of evidence to guide the development of clinical guidelines for the follow-up and treatment of hip dysplasia in patients with MPS I-H. Therefore, an international Delphi consensus procedure was initiated to construct consensus-based clinical practice guidelines in the absence of available evidence.
Methods
A literature review was conducted, and publications were graded according to their level of evidence. For the development of consensus guidelines, eight metabolic pediatricians and nine orthopedic surgeons with experience in the care of MPS I patients were invited to participate. Eleven case histories were assessed in two written rounds. For each case, the experts were asked if they would perform surgery, and they were asked to provide information on the aspects deemed essential or complicating in the decision-making process. In a subsequent face-to-face meeting, the results were presented and discussed. Draft consensus statements were discussed and adjusted until consensus was reached.
Results
Consensus was reached on seven statements. The panel concluded that early corrective surgery for MPS I-H patients with hip dysplasia should be considered. However, there was no full consensus as to whether such a procedure should be offered to all patients with hip dysplasia to prevent complications or whether a more conservative approach with surgical intervention only in those patients who develop clinically relevant symptoms due to the hip dysplasia is warranted.
Conclusions
This international consensus procedure led to the construction of clinical practice guidelines for hip dysplasia in transplanted MPS I-H patients. Early corrective surgery should be considered, but further research is needed to establish its efficacy and role in the treatment of hip dysplasia as seen in MPS I.
doi:10.1186/1750-1172-8-155
PMCID: PMC3852175  PMID: 24088413
Mucopolysaccharidosis type I; Hurler syndrome; Hematopoietic stem cell transplantation; Dysostosis multiplex; Hip dysplasia; Surgical treatment; Consensus
9.  Myeloid/Microglial Driven Autologous Hematopoietic Stem Cell Gene Therapy Corrects a Neuronopathic Lysosomal Disease 
Molecular Therapy  2013;21(10):1938-1949.
Mucopolysaccharidosis type IIIA (MPSIIIA) is a lysosomal storage disorder caused by mutations in N-sulfoglucosamine sulfohydrolase (SGSH), resulting in heparan sulfate (HS) accumulation and progressive neurodegeneration. There are no treatments. We previously demonstrated improved neuropathology in MPSIIIA mice using lentiviral vectors (LVs) overexpressing SGSH in wild-type (WT) hematopoietic stem cell (HSC) transplants (HSCTs), achieved via donor monocyte/microglial engraftment in the brain. However, neurological disease was not corrected using LVs in autologous MPSIIIA HSCTs. To improve brain expression via monocyte/microglial specificity, LVs expressing enhanced green fluorescent protein (eGFP) under ubiquitous phosphoglycerate kinase (PGK) or myeloid-specific promoters were compared in transplanted HSCs. LV-CD11b-GFP gave significantly higher monocyte/B-cell eGFP expression than LV-PGK-GFP or LV-CD18-GFP after 6 months. Subsequently, autologous MPSIIIA HSCs were transduced with either LV-PGK-coSGSH or LV-CD11b-coSGSH vectors expressing codon-optimized SGSH and transplanted into MPSIIIA mice. Eight months after HSCT, LV-PGK-coSGSH vectors produced bone marrow SGSH (576% normal activity) similar to LV-CD11b-coSGSH (473%), but LV-CD11b-coSGSH had significantly higher brain expression (11 versus 7%), demonstrating improved brain specificity. LV-CD11b-coSGSH normalized MPSIIIA behavior, brain HS, GM2 ganglioside, and neuroinflammation to WT levels, whereas LV-PGK-coSGSH partly corrected neuropathology but not behavior. We demonstrate compelling evidence of neurological disease correction using autologous myeloid driven lentiviral-HSC gene therapy in MPSIIIA mice.
doi:10.1038/mt.2013.141
PMCID: PMC3808137  PMID: 23748415
10.  The Kynurenine Pathway in Stem Cell Biology 
The kynurenine pathway (KP) is the main catabolic pathway of the essential amino acid tryptophan. The KP has been identified to play a critical role in regulating immune responses in a variety of experimental settings. It is also known to be involved in several neuroinflammatory diseases including Huntington’s disease, amyotrophic lateral sclerosis, and Alzheimer’s disease. This review considers the current understanding of the role of the KP in stem cell biology. Both of these fundamental areas of cell biology have independently been the focus of a burgeoning research interest in recent years. A systematic review of how the two interact has not yet been conducted. Several inflammatory and infectious diseases in which the KP has been implicated include those for which stem cell therapies are being actively explored at a clinical level. Therefore, it is highly relevant to consider the evidence showing that the KP influences stem cell biology and impacts the functional behavior of progenitor cells.
doi:10.4137/IJTR.S12626
PMCID: PMC3782398  PMID: 24092986
kynurenine pathway; tryptophan; indoleamine 2; 3-dioxygenase; embryonic stem cell; haematopoietic stem cell; mesenchymal stem cell; neural stem cell
11.  Serum Phosphate as a Risk Factor for Cardiovascular Events in People with and without Chronic Kidney Disease: A Large Community Based Cohort Study 
PLoS ONE  2013;8(9):e74996.
Background
Serum phosphate is a known risk factor for cardiovascular events and mortality in people with chronic kidney disease (CKD), however data on the association of these outcomes with serum phosphate in the general population are scarce. We investigate this relationship in people with and without CKD in a large community-based population.
Methods
Three groups from an adult cohort of the Quality Improvement in Chronic Kidney Disease (QICKD) cluster randomised trial (ISRCTN56023731) were followed over a period of 2.5 years: people with normal renal function (N = 24,184), people with CKD stages 1–2 (N = 20,356), and people with CKD stages 3–5 (N = 13,292). We used a multilevel logistic regression model to determine the association between serum phosphate, in these groups, and a composite outcome of all-cause mortality, cardiovascular events, and advanced coronary artery disease. We adjusted for known cardiovascular risk factors.
Findings
Higher phosphate levels were found to correlate with increased cardiovascular risk. In people with normal renal function and CKD stages 1–2, Phosphate levels between 1.25 and 1.50 mmol/l were associated with increased cardiovascular events; odds ratio (OR) 1.36 (95% CI 1.06–1.74; p = 0.016) in people with normal renal function and OR 1.40 (95% CI 1.09–1.81; p = 0.010) in people with CKD stages 1–2. Hypophosphatemia (<0.75 mmol/l) was associated with fewer cardiovascular events in people with normal renal function; OR 0.59 (95% CI 0.36–0.97; p = 0.049). In people with CKD stages 3–5, hyperphosphatemia (>1.50 mmol/l) was associated with increased cardiovascular risk; OR 2.34 (95% CI 1.64–3.32; p<0.001). Other phosphate ranges were not found to have a significant impact on cardiovascular events in people with CKD stages 3–5.
Conclusions
Serum phosphate is associated with cardiovascular events in people with and without CKD. Further research is required to determine the mechanisms underlying these associations.
doi:10.1371/journal.pone.0074996
PMCID: PMC3769279  PMID: 24040373
12.  Vision-guided ocular growth in a mutant chicken model with diminished visual acuity 
Experimental eye research  2012;102C:59-69.
Visual experience is known to guide ocular growth. We tested the hypothesis that vision-guided ocular growth is disrupted in a model system with diminished visual acuity. We examine whether ocular elongation is influenced by form-deprivation (FD) and lens-imposed defocus in the Retinopathy, Globe Enlarged (RGE) chicken. Young RGE chicks have poor visual acuity, without significant retinal pathology, resulting from a mutation in guanine nucleotide-binding protein β3 (GNB3), also known as transducin β3 or Gβ3. The mutation in GNB3 destabilizes the protein and causes a loss of Gβ3 from photoreceptors and ON-bipolar cells. (Ritchey et al. 2010)FD increased ocular elongation in RGE eyes in a manner similar to that seen in wild-type (WT) eyes. By comparison, the excessive ocular elongation that results from hyperopic defocus was increased, whereas myopic defocus failed to significantly decrease ocular elongation in RGE eyes. Brief daily periods of unrestricted vision interrupting FD prevented ocular elongation in RGE chicks in a manner similar to that seen in WT chicks. Glucagonergic amacrine cells differentially expressed the immediate early gene Egr1 in response to growth-guiding stimuli in RGE retinas, but the defocus-dependent up-regulation of Egr1 was lesser in RGE retinas compared to that of WT retinas. We conclude that high visual acuity, and the retinal signaling mediated by Gβ3, is not required for emmetropization and the excessive ocular elongation caused by FD and hyperopic defocus. However, the loss of acuity and Gβ3 from RGE retinas causes enhanced responses to hyperopic defocus and diminished responses to myopic defocus.
doi:10.1016/j.exer.2012.07.001
PMCID: PMC3432719  PMID: 22824538
13.  A Large Animal Model for CNGB1 Autosomal Recessive Retinitis Pigmentosa 
PLoS ONE  2013;8(8):e72229.
Retinal dystrophies in dogs are invaluable models of human disease. Progressive retinal atrophy (PRA) is the canine equivalent of retinitis pigmentosa (RP). Similar to RP, PRA is a genetically heterogenous condition. We investigated PRA in the Papillon breed of dog using homozygosity mapping and haplotype construction of single nucleotide polymorphisms within a small family group to identify potential positional candidate genes. Based on the phenotypic similarities between the PRA-affected Papillons, mouse models and human patients, CNGB1 was selected as the most promising positional candidate gene. CNGB1 was sequenced and a complex mutation consisting of the combination of a one basepair deletion and a 6 basepair insertion was identified in exon 26 (c.2387delA;2389_2390insAGCTAC) leading to a frameshift and premature stop codon. Immunohistochemistry (IHC) of pre-degenerate retinal sections from a young affected dog showed absence of labeling using a C-terminal CNGB1 antibody. Whereas an antibody directed against the N-terminus of the protein, which also recognizes the glutamic acid rich proteins arising from alternative splicing of the CNGB1 transcript (upstream of the premature stop codon), labeled rod outer segments. CNGB1 combines with CNGA1 to form the rod cyclic nucleotide gated channel and previous studies have shown the requirement of CNGB1 for normal targeting of CNGA1 to the rod outer segment. In keeping with these previous observations, IHC showed a lack of detectable CNGA1 protein in the rod outer segments of the affected dog. A population study did not identify the CNGB1 mutation in PRA-affected dogs in other breeds and documented that the CNGB1 mutation accounts for ∼70% of cases of Papillon PRA in our PRA-affected canine DNA bank. CNGB1 mutations are one cause of autosomal recessive RP making the CNGB1 mutant dog a valuable large animal model of the condition.
doi:10.1371/journal.pone.0072229
PMCID: PMC3747135  PMID: 23977260
14.  Characterization of a canine model of autosomal recessive retinitis pigmentosa due to a PDE6A mutation 
Purpose
To characterize a canine model of autosomal recessive RP due to a PDE6A gene mutation.
Methods
Affected and breed- and age-matched control puppies were studied by electroretinography (ERG), light and electron microscopy, immunohistochemistry and by assay for retinal PDE6 levels and enzymatic activity.
Results
The mutant puppies failed to develop normal rod-mediated ERG responses and had reduced light-adapted a-wave amplitudes from an early age. The residual ERG waveforms originated primarily from cone-driven responses. Development of photoreceptor outer segments was halted and rod cells were lost by apoptosis. Immunohistochemistry demonstrated a marked reduction in rod-opsin immunostaining outer segments and relative preservation of cones early in the disease process. With exception of rod bipolar cells that appeared to be reduced in number relatively early in the disease process other inner retinal cells were preserved in the early stages of the disease although there was marked and early activation of Müller glia. Western blotting showed that the PDE6A mutation not only resulted in a lack of PDE6A protein but the affected retinas also lacked the other PDE6 subunits, suggesting expression of PDE6A is required for normal expression of PDE6B and PDE6G. Affected retinas lacked PDE6 enzymatic activity.
Conclusions
This represents the first characterization of a PDE6A model of autosomal recessive retinitis pigmentosa and the PDE6A mutant dog shows promise as a large animal model for investigation of therapies to rescue mutant rod photoreceptors and to preserve cone photoreceptors in the face a rapid loss of rod cells.
doi:10.1167/iovs.08-2562
PMCID: PMC3720143  PMID: 18775863
15.  Using wireless technology in clinical practice: does feedback of daily walking activity improve walking outcomes of individuals receiving rehabilitation post-stroke? Study protocol for a randomized controlled trial 
BMC Neurology  2013;13:93.
Background
Regaining independent ambulation is the top priority for individuals recovering from stroke. Thus, physical rehabilitation post-stroke should focus on improving walking function and endurance. However, the amount of walking completed by individuals with stroke attending rehabilitation is far below that required for independent community ambulation. There has been increased interest in accelerometer-based monitoring of walking post-stroke. Walking monitoring could be integrated within the goal-setting process for those with ambulation goals in rehabilitation. The feedback from these devices can be downloaded to a computer to produce reports. The purpose of this study is to determine the effect of accelerometer-based feedback of daily walking activity during rehabilitation on the frequency and duration of walking post-stroke.
Methods
Participants will be randomly assigned to one of two groups: feedback or no feedback. Participants will wear accelerometers daily during in- and out-patient rehabilitation and, for participants in the feedback group, the participants’ treating physiotherapist will receive regular reports of walking activity. The primary outcome measures are the amount of daily walking completed, as measured using the accelerometers, and spatio-temporal characteristics of walking (e.g. walking speed). We will also examine goal attainment, satisfaction with progress towards goals, stroke self-efficacy, and community-integration.
Discussion
Increased walking activity during rehabilitation is expected to improve walking function and community re-integration following discharge. In addition, a focus on altering walking behaviour within the rehabilitation setting may lead to altered behaviour and increased activity patterns after discharge.
Trial registration
ClinicalTrials.gov NCT01521234
doi:10.1186/1471-2377-13-93
PMCID: PMC3723815  PMID: 23865593
Stroke; Rehabilitation; Walking; Physical activity; Goal setting; Technology
16.  Successful immune tolerance induction to enzyme replacement therapy in CRIM-negative infantile Pompe disease 
Purpose
Infantile Pompe disease resulting from a deficiency of lysosomal acid α-glucosidase (GAA) requires enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA). Cross-reactive immunologic material negative (CRIM-negative) Pompe patients develop high-titer antibody to the rhGAA and do poorly. We describe successful tolerance induction in CRIM-negative patients.
Methods
Two CRIM-negative patients with preexisting anti-GAA antibodies were treated therapeutically with rituximab, methotrexate, and gammaglobulins. Two additional CRIM-negative patients were treated prophylactically with a short course of rituximab and methotrexate, in parallel with initiating rhGAA.
Results
In both patients treated therapeutically, anti-rhGAA was eliminated after 3 and 19 months. All four patients are immune tolerant to rhGAA, off immune therapy, showing B-cell recovery while continuing to receive ERT at ages 36 and 56 months (therapeutic) and 18 and 35 months (prophylactic). All patients show clinical response to ERT, in stark contrast to the rapid deterioration of their nontolerized CRIM-negative counterparts.
Conclusion
The combination of rituximab with methotrexate ± intravenous gammaglobulins (IVIG) is an option for tolerance induction of CRIM-negative Pompe to ERT when instituted in the naïve setting or following antibody development. It should be considered in other conditions in which antibody response to the therapeutic protein elicits robust antibody response that interferes with product efficacy.
doi:10.1038/gim.2011.4
PMCID: PMC3711224  PMID: 22237443
immune tolerance; methotrexate; Pompe disease; rituximab
17.  The Characteristic Features of Auditory Verbal Hallucinations in Clinical and Nonclinical Groups: State-of-the-Art Overview and Future Directions 
Schizophrenia Bulletin  2012;38(4):724-733.
Despite a growing interest in auditory verbal hallucinations (AVHs) in different clinical and nonclinical groups, the phenomenological characteristics of such experiences have not yet been reviewed and contrasted, limiting our understanding of these phenomena on multiple empirical, theoretical, and clinical levels. We look at some of the most prominent descriptive features of AVHs in schizophrenia (SZ). These are then examined in clinical conditions including substance abuse, Parkinson’s disease, epilepsy, dementia, late-onset SZ, mood disorders, borderline personality disorder, hearing impairment, and dissociative disorders. The phenomenological changes linked to AVHs in prepsychotic stages are also outlined, together with a review of AVHs in healthy persons. A discussion of key issues and future research directions concludes the review.
doi:10.1093/schbul/sbs061
PMCID: PMC3406519  PMID: 22499783
hallucinations; hallucinosis; hearing voices; psychosis; transdiagnostic
18.  Taking Back the Brain: Could Neurofeedback Training Be Effective for Relieving Distressing Auditory Verbal Hallucinations in Patients With Schizophrenia? 
Schizophrenia Bulletin  2012;38(4):678-682.
Progress in identifying the neural correlates of auditory verbal hallucinations (AVHs) experienced by patients with schizophrenia has not fulfilled its promise to lead to new methods of treatments. Given the existence of a large number of such patients who have AVHs that are refractory to traditional treatments, there is the urgent need for the development of new effective interventions. This article proposes that the technique of neurofeedback may be an appropriate method to allow the translation of pure research findings from AVH-research into a clinical intervention. Neurofeedback is a method through which individuals can self-regulate their neural activity in specific neural regions/frequencies, following operant conditioning of their intentional manipulation of visually presented real-time feedback of their neural activity. Four empirically testable hypotheses are proposed as to how neurofeedback may be employed to therapeutic effect in patients with AVHs.
doi:10.1093/schbul/sbs006
PMCID: PMC3406539  PMID: 22323675
psychosis; brain-computer interface; hearing voices
19.  LAB/NTAL Facilitates Fungal/PAMP-induced IL-12 and IFN-γ Production by Repressing β-Catenin Activation in Dendritic Cells 
PLoS Pathogens  2013;9(5):e1003357.
Fungal pathogens elicit cytokine responses downstream of immunoreceptor tyrosine-based activation motif (ITAM)-coupled or hemiITAM-containing receptors and TLRs. The Linker for Activation of B cells/Non-T cell Activating Linker (LAB/NTAL) encoded by Lat2, is a known regulator of ITAM-coupled receptors and TLR-associated cytokine responses. Here we demonstrate that LAB is involved in anti-fungal immunity. We show that Lat2−/− mice are more susceptible to C. albicans infection than wild type (WT) mice. Dendritic cells (DCs) express LAB and we show that it is basally phosphorylated by the growth factor M-CSF or following engagement of Dectin-2, but not Dectin-1. Our data revealed a unique mechanism whereby LAB controls basal and fungal/pathogen-associated molecular patterns (PAMP)-induced nuclear β-catenin levels. This in turn is important for controlling fungal/PAMP-induced cytokine production in DCs. C. albicans- and LPS-induced IL-12 and IL-23 production was blunted in Lat2−/− DCs. Accordingly, Lat2−/− DCs directed reduced Th1 polarization in vitro and Lat2−/− mice displayed reduced Natural Killer (NK) and T cell-mediated IFN-γ production in vivo/ex vivo. Thus our data define a novel link between LAB and β-catenin nuclear accumulation in DCs that facilitates IFN-γ responses during anti-fungal immunity. In addition, these findings are likely to be relevant to other infectious diseases that require IL-12 family cytokines and an IFN-γ response for pathogen clearance.
Author Summary
Fungal infections are a major healthcare problem and the incidence of fungal infections has increased significantly in recent years. Mortality rates are high even with treatment, highlighting the need for a better understanding of anti-fungal immunity in order to develop improved therapies. Adaptive T-helper 1 and T-helper 17 (Th1 and Th17) responses are important mediators of anti-fungal immunity. Dendritic cells express Dectin-1, Dectin-2 and Toll-like receptors, which interact with fungal pathogens to induce these adaptive immune responses. Here we identify LAB as an important facilitator of IFN-γ production by regulating β-catenin activation. Susceptibility to fungal infections is increased in the absence of LAB, in association with reduced IFN-γ production. β-catenin activation in dendritic cells inhibits the IL-12 production required for IFN-γ production. Thus targeting β-catenin therapeutically could help to promote efficient IFN-γ production in patients suffering from fungal infections. These findings are important for fungal infections and potentially for other diseases where IFN-γ production is important for disease outcome.
doi:10.1371/journal.ppat.1003357
PMCID: PMC3649983  PMID: 23675302
20.  Modeling Parasite Dynamics on Farmed Salmon for Precautionary Conservation Management of Wild Salmon 
PLoS ONE  2013;8(4):e60096.
Conservation management of wild fish may include fish health management in sympatric populations of domesticated fish in aquaculture. We developed a mathematical model for the population dynamics of parasitic sea lice (Lepeophtheirus salmonis) on domesticated populations of Atlantic salmon (Salmo salar) in the Broughton Archipelago region of British Columbia. The model was fit to a seven-year dataset of monthly sea louse counts on farms in the area to estimate population growth rates in relation to abiotic factors (temperature and salinity), local host density (measured as cohort surface area), and the use of a parasiticide, emamectin benzoate, on farms. We then used the model to evaluate management scenarios in relation to policy guidelines that seek to keep motile louse abundance below an average three per farmed salmon during the March–June juvenile wild Pacific salmon (Oncorhynchus spp.) migration. Abiotic factors mediated the duration of effectiveness of parasiticide treatments, and results suggest treatment of farmed salmon conducted in January or early February minimized average louse abundance per farmed salmon during the juvenile wild salmon migration. Adapting the management of parasites on farmed salmon according to migrations of wild salmon may therefore provide a precautionary approach to conserving wild salmon populations in salmon farming regions.
doi:10.1371/journal.pone.0060096
PMCID: PMC3618109  PMID: 23577082
21.  Evaluation of Lateral Spread of Transgene Expression following Subretinal AAV–Mediated Gene Delivery in Dogs 
PLoS ONE  2013;8(4):e60218.
Dog models with spontaneously occurring mutations in retinal dystrophy genes are an invaluable resource for preclinical development of retinal gene therapy. Adeno-associated virus (AAV) vectors have been most successful; to target the outer retina and RPE they are delivered by subretinal injection, causing a temporary retinal detachment with some potential for retinal morbidity. A recent reporter gene study using an AAV2/8 vector in dogs reported transgene expression beyond the boundary of the subretinal bleb. This could be a desirable feature which increases the area of retina treated while minimizing the retinal detachment and any associated morbidity. We performed a detailed study of the lateral spread of transgene expression beyond the subretinal injection site following subretinally delivered AAV vectors in normal dogs. Vectors expressed green fluorescent protein (GFP) using a small chicken beta-actin promoter. AAV2/2 (quadruple tyrosine to phenylalanine (Y-F) capsid mutant), self-complementary (sc) AAV2/8 (single Y-F capsid mutant) and a scAAV2/5 were used. We found that in all eyes GFP expression involved retina beyond the initial post-injection subretinal bleb boundary. In all eyes there was post-injection spread of the retinal detachment within the first 3 days post procedure and prior to retinal reattachment. In 11/16 eyes this accounted for the entire “lateral spread” of GFP expression while in 5/16 eyes a very slight extension of GFP expression beyond the final boundary of the subretinal bleb could be detected. All 3 AAV constructs induced GFP expression in the nerve fiber layer with spread to the optic nerve. Patients treated by subretinal injection should be monitored for possible expansion of the subretinal injection bleb prior to reattachment. Injections in the para-foveal region may expand to lead to a foveal detachment that may be undesirable. Cell-specific promoters may be required to limit spread of expressed transgene to the brain with these AAV serotypes.
doi:10.1371/journal.pone.0060218
PMCID: PMC3616166  PMID: 23560080
22.  Exclusion of eleven candidate genes for ocular melanosis in cairn terriers 
Background
Ocular melanosis of Cairn terrier dogs is an inherited defect characterized by progressive pigmentation of both eyes which can result in glaucoma and blindness. Pedigree analysis suggests the trait has an autosomal dominant mode of inheritance. We selected 11 potential candidate genes and used an exclusion analysis approach to investigate the likelihood that one of the candidate gene loci contained the Cairn terrier-ocular melanosis locus.
Results
Two polymorphic loci were identified within or close to each candidate gene. Genotyping of at least 10 ocular melanosis Cairn terriers for each marker showed that there was no single shared allele for either of the two polymorphic markers identified in ASIP, COMT, GPNMB, GSK3B, LYST, MC1R, MITF, SILV, TYR, TYRP1,and TYRP2. This is strong evidence to exclude each locus as the site of the ocular melanosis mutation (probability of a false exclusion calculated for each gene ranged from 1.59 × 10-4 to 1 × 10-9).
Conclusions
None of the 11 potential candidate genes selected are likely to be the gene locus for ocular melanosis in Cairn terriers.
doi:10.1186/1477-5751-12-6
PMCID: PMC3599239  PMID: 23448350
Dog; Glaucoma; Ocular melanosis; Pigmentary glaucoma; Candidate gene
23.  Stop, look, listen: the need for philosophical phenomenological perspectives on auditory verbal hallucinations 
One of the leading cognitive models of auditory verbal hallucinations (AVHs) proposes such experiences result from a disturbance in the process by which inner speech is attributed to the self. Research in this area has, however, proceeded in the absence of thorough cognitive and phenomenological investigations of the nature of inner speech, against which AVHs are implicitly or explicitly defined. In this paper we begin by introducing philosophical phenomenology and highlighting its relevance to AVHs, before briefly examining the evolving literature on the relation between inner experiences and AVHs. We then argue for the need for philosophical phenomenology (Phenomenology) and the traditional empirical methods of psychology for studying inner experience (phenomenology) to mutually inform each other to provide a richer and more nuanced picture of both inner experience and AVHs than either could on its own. A critical examination is undertaken of the leading model of AVHs derived from phenomenological philosophy, the ipseity disturbance model. From this we suggest issues that future work in this vein will need to consider, and examine how interdisciplinary methodologies may contribute to advances in our understanding of AVHs. Detailed suggestions are made for the direction and methodology of future work into AVHs, which we suggest should be undertaken in a context where phenomenology and physiology are both necessary, but neither sufficient.
doi:10.3389/fnhum.2013.00127
PMCID: PMC3620561  PMID: 23576974
hallucination; phenomenology; psychosis; schizophrenia; interdisciplinary
24.  Anaesthesia and airway management in mucopolysaccharidosis 
This paper provides a detailed overview and discussion of anaesthesia in patients with mucopolysaccharidosis (MPS), the evaluation of risk factors in these patients and their anaesthetic management, including emergency airway issues. MPS represents a group of rare lysosomal storage disorders associated with an array of clinical manifestations. The high prevalence of airway obstruction and restrictive pulmonary disease in combination with cardiovascular manifestations poses a high anaesthetic risk to these patients. Typical anaesthetic problems include airway obstruction after induction or extubation, intubation difficulties or failure [can’t intubate, can’t ventilate (CICV)], possible emergency tracheostomy and cardiovascular and cervical spine issues. Because of the high anaesthetic risk, the benefits of a procedure in patients with MPS should always be balanced against the associated risks. Therefore, careful evaluation of anaesthetic risk factors should be made before the procedure, involving evaluation of airways and cardiorespiratory and cervical spine problems. In addition, information on the specific type of MPS, prior history of anaesthesia, presence of cervical instability and range of motion of the temporomandibular joint are important and may be pivotal to prevent complications during anaesthesia. Knowledge of these risk factors allows the anaesthetist to anticipate potential problems that may arise during or after the procedure. Anaesthesia in MPS patients should be preferably done by an experienced (paediatric) anaesthetist, supported by a multidisciplinary team (ear, nose, throat surgeon and intensive care team), with access to all necessary equipment and support.
Electronic supplementary material
The online version of this article (doi:10.1007/s10545-012-9563-1) contains supplementary material, which is available to authorized users.
doi:10.1007/s10545-012-9563-1
PMCID: PMC3590422  PMID: 23197104
25.  Differential Dependencies of Monocytes and Neutrophils on Dectin-1, Dectin-2 and Complement for the Recognition of Fungal Particles in Inflammation 
PLoS ONE  2012;7(9):e45781.
We have re-investigated the role of the complement system and the non-opsonic pattern recognition receptors dectin-1 and dectin-2 in the recognition of fungal particles by inflammatory neutrophils, monocytes and macrophages. We have used in vivo and ex vivo models to study the recognition and response of these cells: i) We confirm previous observations regarding the importance of complement to neutrophil but not monocytic responses; ii) We show that dectin-1 is important for driving inflammatory cell recruitment to fungal stimuli and that it biases the immediate inflammatory response to one that favors neutrophil over monocyte recruitment; iii) We show that dectin-2 contributes to the physical recognition of fungal particles by inflammatory monocytes/macrophages, but is also expressed on neutrophils, where we show it has the potential to contribute to cellular activation; iv) Additionally, we show that serum-opsonization has the potential to interfere with non-opsonic recognition of fungal particles by dectin-1 and dectin-2, presumably through masking of ligands. Collectively these roles are consistent with previously described roles of dectin-1 and dectin-2 in driving inflammatory and adaptive immune responses and complement in containing fungal burdens. This study emphasizes the importance of heterogeneity of receptor expression across myeloid cell subsets in protective immune responses.
doi:10.1371/journal.pone.0045781
PMCID: PMC3458947  PMID: 23049859

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