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Daniel J Asby,1 Clare L Killick-Cole,1 Lisa J Boulter,1 William GB Singleton,1,2 Claire A Asby,3 Marcella J Wyatt,1 Neil U Barua,1,2 Alison S Bienemann,1 Steven S Gill1,2 1Functional Neurosurgery Research Group, Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; 2Department of Neurosurgery, North Bristol NHS Trust, Southmead Hospital, Bristol, UK; 3Department of Neurology, North Bristol NHS Trust, Southmead Hospital, Bristol, UK Background: Diffuse intrinsic pontine glioma (DIPG) is a lethal type of pediatric brain tumor that is resistant to conventional chemotherapies. Palbociclib is a putative novel DIPG treatment that restricts the proliferation of rapidly dividing cancer cells via selective inhibition of cyclin-dependent kinase (CDK) 4 and CDK6. However, implementing palbociclib as a monotherapy for DIPG is unfeasible, as CDK4/6 inhibitor resistance is commonplace and palbociclib does not readily cross the blood–brain barrier (BBB) or persist in the central nervous system. To inhibit the growth of DIPG cells, we aimed to use palbociclib in combination with the rapamycin analog temsirolimus, which is known to ameliorate resistance to CDK4/6 inhibitors and inhibit BBB efflux.Materials and methods: We tested palbociclib and temsirolimus in three patient-derived DIPG cell lines. The expression profiles of key proteins in the CDK4/6 and mammalian target of rapamycin (mTOR) signaling pathways were assessed, respectively, to determine feasibility against DIPG. Moreover, we investigated effects on cell viability and examined in vivo drug toxicity.Results: Immunoblot analyses revealed palbociclib and temsirolimus inhibited CDK4/6 and mTOR signaling through canonical perturbation of phosphorylation of the retinoblastoma (RB) and mTOR proteins, respectively; however, we observed noncanonical downregulation of mTOR by palbociclib. We demonstrated that palbociclib and temsirolimus inhibited cell proliferation in all three DIPG cell lines, acting synergistically in combination to further restrict cell growth. Flow cytometric analyses revealed both drugs caused G1 cell cycle arrest, and clonogenic assays showed irreversible effects on cell proliferation. Palbociclib did not elicit neurotoxicity in primary cultures of normal rat hippocampi or when infused into rat brains.Conclusion: These data illustrate the in vitro antiproliferative effects of CDK4/6 and mTOR inhibitors in DIPG cells. Direct infusion of palbociclib into the brain, in combination with systemic delivery of temsirolimus, represents a promising new approach to developing a much-needed treatment for DIPG. Keywords: palbociclib, temsirolimus, brain tumor, DIPG, retinoblastoma protein, cyclin-dependent kinase

WG Singleton,1,2 AM Collins,3 AS Bienemann,1 CL Killick-Cole,1 HR Haynes,4 DJ Asby,1 CP Butts,5 MJ Wyatt,1 NU Barua,1,2 SS Gill1,2 1Functional Neurosurgery Research Group, School of Clinical Sciences, University of Bristol, 2Department of Neurosurgery, North Bristol NHS Trust, 3Bristol Centre for Functional Nanomaterials, School of Physics, HH Wills Physics Laboratory, 4Brain Tumour Research Group, School of Clinical Sciences, 5School of Chemistry, University of Bristol, Bristol, UKBackground: The pan-histone deacetylase inhibitor panobinostat is a potential therapy for malignant glioma, but it is water insoluble and does not cross the blood–brain barrier when administered systemically. In this article, we describe the in vitro and in vivo efficacy of a novel water-soluble nano-micellar formulation of panobinostat designed for administration by convection enhanced delivery (CED).Materials and methods: The in vitro efficacy of panobinostat-loaded nano-micelles against rat F98, human U87-MG and M059K glioma cells and against patient-derived glioma stem cells was measured using a cell viability assay. Nano-micelle distribution in rat brain was analyzed following acute CED using rhodamine-labeled nano-micelles, and toxicity was assayed using immunofluorescent microscopy and synaptophysin enzyme-linked immunosorbent assay. We compared the survival of the bioluminescent syngenic F98/Fischer344 rat glioblastoma model treated by acute CED of panobinostat-loaded nano-micelles with that of untreated and vehicle-only-treated controls.Results: Nano-micellar panobinostat is cytotoxic to rat and human glioma cells in vitro in a dose-dependent manner following short-time exposure to drug. Fluorescent rhodamine-labelled nano-micelles distribute with a volume of infusion/volume of distribution (Vi/Vd) ratio of four and five respectively after administration by CED. Administration was not associated with any toxicity when compared to controls. CED of panobinostat-loaded nano-micelles was associated with significantly improved survival when compared to controls (n=8 per group; log-rank test, P

Neurodegeneration with brain iron accumulation encompasses a heterogeneous group of rare neurodegenerative disorders that are characterized by iron accumulation in the brain. Severe generalized dystonia is frequently a prominent symptom and can be very disabling, causing gait impairment, difficulty with speech and swallowing, pain and respiratory distress. Several case reports and one case series have been published concerning therapeutic outcome of pallidal deep brain stimulation in dystonia caused by neurodegeneration with brain iron degeneration, reporting mostly favourable outcomes. However, with case studies, there may be a reporting bias towards favourable outcome. Thus, we undertook this multi-centre retrospective study to gather worldwide experiences with bilateral pallidal deep brain stimulation in patients with neurodegeneration with brain iron accumulation. A total of 16 centres contributed 23 patients with confirmed neurodegeneration with brain iron accumulation and bilateral pallidal deep brain stimulation. Patient details including gender, age at onset, age at operation, genetic status, magnetic resonance imaging status, history and clinical findings were requested. Data on severity of dystonia (Burke Fahn Marsden Dystonia Rating Scale-Motor Scale, Barry Albright Dystonia Scale), disability (Burke Fahn Marsden Dystonia Rating Scale-Disability Scale), quality of life (subjective global rating from 1 to 10 obtained retrospectively from patient and caregiver) as well as data on supportive therapy, concurrent pharmacotherapy, stimulation settings, adverse events and side effects were collected. Data were collected once preoperatively and at 2-6 and 9-15 months postoperatively. The primary outcome measure was change in severity of dystonia. The mean improvement in severity of dystonia was 28.5% at 2-6 months and 25.7% at 9-15 months. At 9-15 months postoperatively, 66.7% of patients showed an improvement of 20% or more in severity of dystonia, and 31.3% showed an improvement of 20% or more in disability. Global quality of life ratings showed a median improvement of 83.3% at 9-15 months. Severity of dystonia preoperatively and disease duration predicted improvement in severity of dystonia at 2-6 months; this failed to reach significance at 9-15 months. The study confirms that dystonia in neurodegeneration with brain iron accumulation improves with bilateral pallidal deep brain stimulation, although this improvement is not as great as the benefit reported in patients with primary generalized dystonias or some other secondary dystonias. The patients with more severe dystonia seem to benefit more. A well-controlled, multi-centre prospective study is necessary to enable evidence-based therapeutic decisions and better predict therapeutic outcomes.

Alzheimer's disease (AD) is a highly prevalent condition that predominantly affects older adults. AD is a complex multifactorial disorder with a number of genetic, epigenetic and environmental factors which ultimately lead to premature neuronal death. Predictive and susceptibility genes play a role in AD. Early-onset familial AD is a rare autosomal dominant disorder. Genome-wide association studies have identified many potential susceptibility genes for late-onset AD, but the clinical relevance of many of these susceptibility genes is unclear. The genetic variation by susceptibility genes plays a crucial role in determining the risk of late-onset AD, as well as the onset of the disease, the course of the AD and the therapeutic response of patients to conventional drugs for AD. The newer understanding of the epigenetics in AD has also been highlighted. Recent advances in genetics, epigenetics and pharmacogenetics of AD pose new challenges to the future management of AD. [ABSTRACT FROM AUTHOR]

Enzymatic degradation contributes to the control of intracerebral amyloid-β (Aβ) peptide levels. Previous studies have demonstrated the therapeutic potential of viral vector-mediated neprilysin (NEP) gene therapy in mouse models of Alzheimer's disease (AD). However, clinical translation of NEP gene therapy is limited by ethical and practical considerations. In this study we have assessed the potential of convection-enhanced delivery (CED) as a means of elevating intracerebral NEP level and activity and degrading endogenous Aβ. We analyzed the interstitial and perivascular distribution of NEP following CED into rat striatum. We measured NEP protein level, clearance, activity, and toxicity by ELISA for NEP and synaptophysin, NEP-specific activity assay, and immunohistochemistry for NEP, NeuN, glial fibrillary acidic protein and Iba1. We subsequently performed CED of NEP in normal aged rats and measured endogenous Aβ by ELISA. CED resulted in widespread distribution of NEP, and a 20-fold elevation of NEP protein level with preservation of enzyme activity and without evidence of toxicity. CED in normal, aged rats resulted in a significant reduction in endogenous Aβ(40) (p = 0.04), despite rapid NEP clearance from the brain (half-life ~3 h). CED of NEP has therapeutic potential as a dynamically controllable Aβ(40)-degrading therapeutic strategy for AD. Further studies are required to determine the longer term effects on Aβ (including Aβ(42)) and on cognitive function. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine whether current antipsychotic use among older persons without diabetes is associated with a higher risk of hospital visits for hyperglycemia, as previous studies in this population have yielded conflicting results. DESIGN, SETTING AND PARTICIPANTS: A nested case-control study within a population-based cohort of persons aged 66 years or older without diabetes, who initiated antipsychotic therapy between April 1, 2002, and March 31, 2006. Cohort members were identified using health databases from Ontario, Canada, and were followed from treatment start until March 31, 2007. MEASUREMENTS: Cases were patients with a hospital visit (emergency department visit or hospital admission) for hyperglycemia. We matched each case with up to 10 controls. We compared the risk of hyperglycemia among current antipsychotic users to that of remote users (discontinued > 180 days). RESULTS: The cohort consisted of 44,121 subjects, mean age of 78.3 years, followed for a mean of 2.2 years. Compared to remote antipsychotic use, current treatment with any antipsychotic was associated with a significantly increased risk of hospital visits for hyperglycemia (adjusted odds ratio [aOR]: 1.52; 95% confidence interval [CI]: 1.07-2.17). The risk was elevated for both atypical (aOR: 1.44; 95% CI: 1.01-2.07) and typical (aOR: 2.86; 95% CI: 1.46-5.59) antipsychotic agents. CONCLUSIONS: Current use of either atypical or typical antipsychotic agents was associated with a significantly increased risk of hospital visits for hyperglycemia among older persons without diabetes. These findings highlight the need for close glucose monitoring during antipsychotic therapy in older populations. [ABSTRACT FROM AUTHOR]

OBJECTIVES: : Cholinesterase inhibitors (ChEIs) may interact with muscle relaxants given during general anesthesia (GA), increasing the risk of postoperative complications. We evaluated the effects of ChEIs on the postoperative outcomes of older adults who underwent hip fracture surgery. DESIGN: : Population-based cohort study using linked administrative databases. PARTICIPANTS: : All individuals with dementia age 66 years or older, who underwent hip fracture surgery between April 1, 2003, and December 31, 2007, in Ontario, Canada. EXPOSURES:: Use of any ChEI (donepezil, rivastigmine, or galantamine) before surgery. OUTCOMES: : The primary composite outcome included any of the following: 30-day postoperative mortality; intensive care unit admissions; or in-hospital resuscitation. Secondary outcomes included postoperative respiratory failure and pneumonia. ANALYSIS: : We stratified the study sample on the basis of residence (community or long-term care [LTC]) and type of anesthetic (general or regional) to create four residence/anesthesia groups. We used propensity scores to match users and nonusers of ChEIs within the residence/anesthesia strata. We then calculated the relative risks (RR) and 95% confidence intervals (CI) for outcomes associated with ChEIs in the matched groups. RESULTS: : A total of 624 pairs of individuals from the community and 725 pairs from LTC were created among individuals who received GA. High rates of postoperative mortality and complications were observed in both ChEI users and nonusers. The RR of the primary outcome associated with ChEI use for individuals receiving GA was 0.88 (95% CI: 0.68-1.16; [chi] = 0.93; df = 1; p = 0.34) and 0.82 (95% CI: 0.63-1.04; [chi] = 2.59; df = 1; p = 0.11) in the community and LTC groups, respectively. In addition, ChEIs were not associated with any significant increased risk of postoperative respiratory complications. CONCLUSIONS: : ChEI use was not associated with an increased risk of postoperative complications among older adults with dementia who underwent hip fracture surgery. However, the poor postoperative outcomes overall reinforced the need to prevent fractures and improve outcomes in this population. [ABSTRACT FROM AUTHOR]

Congenital dislocation of the subtalar joint is one of the rarest forms of presentation of a calcaneo-valgus foot. We report the second case of this type published; an 18-month female child aged was seen with calcaneo-valgus deformity of left foot since birth. She was walking over the medial malleolus and medial border of foot. Radiographs and 3D CT scan of the left foot confirmed the diagnosis of a congenital subtalar dislocation. Surgical correction was achieved through a posterolateral incision, and the reduced joint was fixed with a k-wires for 6 weeks; the foot was immobilized in below knee cast for another 6 weeks, and an ankle foot orthosis was used for another 3 years. At 3 years post-surgical follow up, the child has a plantigrade foot with no functional impairment. Follow up radiographs and 3D CT scan confirmed the maintenance of well aligned talo-calcaneal joint. This type of dislocation should be considered in the differential diagnosis of calcaneo-valgus foot; a clear understanding of the pathology, a precise operative reduction, and long-term use of orthosis results in a favourable outcome. [ABSTRACT FROM AUTHOR]

Context: Many treatments for pressure ulcers are promoted, but their relative efficacy is unclear.Objective: To systematically review published randomized controlled trials (RCTs) evaluating therapies for pressure ulcers.Data Sources and Study Selection: The databases of MEDLINE, EMBASE, and CINAHL were searched (from inception through August 23, 2008) to identify relevant RCTs published in the English language.Data Extraction: Methodological characteristics and outcomes were extracted by 3 investigators.Data Synthesis: A total of 103 RCTs met inclusion criteria. Of these, 83 did not provide sufficient information about authors' potential financial conflicts of interest. Methodological quality was variable. Most trials were conducted in acute care (38 [37%]), mixed care (25 [24%]), or long-term care (22 [21%]) settings. Among 12 RCTs evaluating support surfaces, no clear evidence favored one support surface over another. No trials compared a specialized support surface with a standard mattress and repositioning. Among 7 RCTs evaluating nutritional supplements, 1 higher-quality trial found that protein supplementation of long-term care residents improved wound healing compared with placebo (improvement in Pressure Ulcer Scale for Healing mean [SD] score of 3.55 [4.66] vs 3.22 [4.11], respectively; P < .05). Other nutritional supplement RCTs showed mixed results. Among 54 RCTs evaluating absorbent wound dressings, 1 found calcium alginate dressings improved healing compared with dextranomer paste (mean wound surface area reduction per week, 2.39 cm(2) vs 0.27 cm(2), respectively; P<.001). No other dressing was superior to alternatives. Among 9 RCTs evaluating biological agents, several trials reported benefits with different topical growth factors. However, the incremental benefit of these biological agents over less expensive standard wound care remains uncertain. No clear benefit was identified in 21 RCTs evaluating adjunctive therapies including electric current, ultrasound, light therapy, and vacuum therapy.Conclusions: Little evidence supports the use of a specific support surface or dressing over other alternatives. Similarly, there is little evidence to support routine nutritional supplementation or adjunctive therapies compared with standard care. [ABSTRACT FROM AUTHOR]

Context: The neglected tropical diseases include 13 conditions that occur in areas of extreme poverty and are poverty promoting. The neglected tropical diseases produce a disease burden almost as great as that associated with human immunodeficiency virus/AIDS, tuberculosis, or malaria, yet are virtually unknown by health care workers in North America, because they occur almost exclusively in the poorest regions of the world. Seven of the most prevalent diseases have existing oral drug treatments. Identifying treatments that are effective against more than 1 disease could facilitate efficient and inexpensive treatment.Objectives: To systematically review the evidence for drug treatments and to increase awareness that neglected tropical diseases exist and that treatments are available.Data Sources and Study Selection: Using a MEDLINE search (1966 through June 2007), randomized controlled trials (RCTs) were reviewed that examined simultaneous treatment of 2 or more of the 7 most prevalent neglected tropical diseases using oral drug therapy.Data Synthesis: Twenty-nine RCTs were identified, of which 3 targeted 4 diseases simultaneously, 20 targeted 3 diseases, and 6 targeted 2 diseases. Trials were published between 1972 and 2005 and baseline prevalence of individual diseases varied among RCTs. Albendazole plus diethylcarbamazine significantly reduced prevalence of elephantiasis (16.7% to 5.3%), hookworm (10.3% to 1.9%), roundworm (34.5% to 2.3%), and whipworm (55.5% to 40.3%). Albendazole plus ivermectin significantly reduced prevalence of elephantiasis (12.6% to 4.6%), hookworm (7.8% to 0%), roundworm (33.5% to 6.1%), and whipworm (42.7% to 8.9%). Levamisole plus mebendazole significantly reduced prevalence of hookworm (94.0% to 71.8%), roundworm (62.0% to 1.4%), and whipworm (93.1% to 74.5%). Pyrantel-oxantel significantly reduced hookworm (93.4% to 85.2%), roundworm (22.8% to 1.4%), and whipworm (86.8% to 59.5%), while albendazole alone significantly reduced prevalence of hookworm (8.1% to 1.3%), roundworm (28.4% to 0.9%), and whipworm (51.9% to 31.9%). No RCT examined treatment of river blindness or trachoma as part of an intervention to target 2 or more neglected tropical diseases. Adverse events were generally inadequately reported.Conclusions: At least 2 of the most prevalent neglected tropical diseases can be treated simultaneously with existing oral drug treatments, facilitating effective and efficient treatment. Increasing awareness about neglected tropical diseases, their global impact, and the availability of oral drug treatments is an essential step in controlling these diseases. [ABSTRACT FROM AUTHOR]

Background: The safety and efficacy of corticosteroid injection for the treatment of Achilles tendinopathy is not known, with some reports indicating the hazard of tendon rupture and others extolling the efficacy of such injections. This study was undertaken to assess the safety of fluoroscopically guided corticosteroid injections into the peritendinous space for the treatment of Achilles tendinopathy.Methods: A series of patients was treated with fluoroscopically guided corticosteroid injections into the space surrounding the Achilles tendon. Major and minor complications were recorded, as were the number of repeat injections, the duration of symptomatic relief attained with the injection, and a subjective rating of symptoms related to the Achilles tendon.Results: Of eighty-three patients who had been treated, seventy-eight were available for follow-up and forty-three met our requirement for a minimum two-year follow-up (average duration of follow-up, 37.4 months). No major complications and one minor complication occurred in the forty-three patients. Seventeen (40%) of the patients reported improvement after the procedure, twenty-three (53%) thought that their condition was unchanged, and three (7%) felt that their condition was worse than it had been prior to the injection.Conclusions: This retrospective cohort study establishes the safety of low-volume injections of corticosteroids for the treatment of Achilles tendinopathy when the needle is carefully inserted into the peritendinous space under direct fluoroscopic visualization. [ABSTRACT FROM AUTHOR]