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1.
Neuroimage Clin ; 25: 102172, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-32032817

RESUMO

The imaging and subsequent accurate diagnosis of paediatric brain tumours presents a radiological challenge, with magnetic resonance imaging playing a key role in providing tumour specific imaging information. Diffusion weighted and perfusion imaging are commonly used to aid the non-invasive diagnosis of children's brain tumours, but are usually evaluated by expert qualitative review. Quantitative studies are mainly single centre and single modality. The aim of this work was to combine multi-centre diffusion and perfusion imaging, with machine learning, to develop machine learning based classifiers to discriminate between three common paediatric tumour types. The results show that diffusion and perfusion weighted imaging of both the tumour and whole brain provide significant features which differ between tumour types, and that combining these features gives the optimal machine learning classifier with >80% predictive precision. This work represents a step forward to aid in the non-invasive diagnosis of paediatric brain tumours, using advanced clinical imaging.

2.
Semin Cancer Biol ; 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31923457

RESUMO

Malignant Rhabdoid Tumours (MRT) are the quintessential example of an epigenetic cancer. Mutation of a single gene, SMARCB1 or more rarely SMARCA4, is capable of causing one of the most aggressive and lethal cancers of early childhood and infancy. SMARCB1 encodes a core subunit of the SWI/SNF complex and its mutation evokes genome-wide downstream effects which may be counteracted therapeutically. Here we review and discuss the use of translational genomics in the study of MRT biology and the ways in which this has impacted clinical practice or may do so in the future. First, the diagnosis and definition of MRT and the transition from a histopathological to a molecular definition. Second, epigenetic and transcriptomic subgroups within MRT, their defining features and potential prognostic or therapeutic significance. Third, functional genomic studies of MRT by mouse modelling and forced re-expression of SMARCB1 in MRT cells. Fourth, studies of underlying epigenetic mechanisms (e.g. EZH2, HDACs) or deregulated kinases (e.g. PDGFR, FGFR1) and the potential therapeutic opportunities these provide. Finally, we discuss likely future directions and proffer opinion on how future translational genomics should be integrated into future biological/clinical studies to select and evaluate the best anti-MRT therapeutic agents.

3.
Vet Immunol Immunopathol ; 220: 109994, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31877483

RESUMO

Doramapimod (BIRB-796-BS), is an anti-inflammatory compound, acting through p38 MAPK inhibition, but its anti-inflammatory effects have not previously been studied in the horse. Whole blood aliquots from healthy horses diluted 1:1 with cell culture medium were incubated for 21 h with 1 µg/ml of lipopolysaccharide (LPS), lipoteichoic acid (LTA) or peptidoglycan (PGN) in the presence of increasing concentrations of doramapimod (3 × 10-8 M to 10-5 M). Cell bioassays were used to measure TNF-α and IL-1ß activity. Doramapimod significantly and potently inhibited TNF-α and IL-1ß activity induced by all three bacterial toxins. There was no significant difference in IC50 or maximum inhibition of TNF-α or IL-1ß production between any of the toxins. Maximum inhibition of IL-1ß was higher than that of TNF-α for all toxins, and this difference was significant for LPS (P = 0.04). Doramapimod was a potent inhibitor of TNF-α and IL-1ß for inflammation induced by LPS, LTA and PGN, with potency much greater than that of other drugs previously tested using similar methods.

4.
J Equine Vet Sci ; 83: 102811, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31791524

RESUMO

Much of the equine population is obese and therefore predisposed to the development of additional health concerns such as equine metabolic syndrome (EMS). However, pharmacologic treatments for EMS are limited. Omega-3 fatty acid supplementation is a therapeutic strategy in humans with metabolic dysfunction that improves insulin sensitivity and reduces inflammation, but the effects of omega-3 fatty acid supplementation in horses with EMS are unclear. Therefore, in this pilot study, 10 mixed-sex and mixed-breed horses with EMS were fed a docosahexaenoic acid (DHA)-rich microalgae containing 16 g DHA/horse/d or served as controls for 46 days. Inflammatory status was measured using serologic enzyme-linked immunosorbent assay and in peripheral blood mononuclear cells (PBMCs) using flow cytometry and reverse transcription polymerase chain reaction. Circulating fatty acids, triglyceride, leptin, and adiponectin concentrations were also determined. Insulin and glucose dynamics were assessed with oral sugar test (OST) and frequently sampled intravenous glucose tolerance testing. Postsupplementation, treated horses had an increase in many circulating fatty acids, including DHA (P < .001). Treated horses also had lower serum triglycerides postsupplementation (P = .02) and a trend (P = .07) for reduced PBMC tumor necrosis factor α. Interestingly, after 46 days, control horses had an increase in insulin responses to the OST (P = .01), whereas treated horses did not (P = .69). These pilot data indicate that DHA-rich microalgae supplementation alters circulating fatty acids, modulates metabolic parameters, and may reduce inflammation in horses with EMS.

5.
BMJ Qual Saf ; 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31796574

RESUMO

BACKGROUND: Over the past decade, acute kidney injury (AKI) has become a global priority for improving patient safety and health outcomes. In the UK, a confidential inquiry into AKI led to the publication of clinical guidance and a range of policy initiatives. National patient safety directives have focused on the mandatory establishment of clinical decision support systems (CDSSs) within all acute National Health Service (NHS) trusts to improve the detection, alerting and response to AKI. We studied the organisational work of implementing AKI CDSSs within routine hospital care. METHODS: An ethnographic study comprising non-participant observation and interviews was conducted in two NHS hospitals, delivering AKI quality improvement programmes, located in one region of England. Three researchers conducted a total of 49 interviews and 150 hours of observation over an 18-month period. Analysis was conducted collaboratively and iteratively around emergent themes, relating to the organisational work of technology adoption. RESULTS: The two hospitals developed and implemented AKI CDSSs using very different approaches. Nevertheless, both resulted in adaptive work and trade-offs relating to the technology, the users, the organisation and the wider system of care. A common tension was associated with attempts to maximise benefit while minimise additional burden. In both hospitals, resource pressures exacerbated the tensions of translating AKI recommendations into routine practice. CONCLUSIONS: Our analysis highlights a conflicted relationship between external context (policy and resources), and organisational structure and culture (eg, digital capability, attitudes to quality improvement). Greater consideration is required to the long-term effectiveness of the approaches taken, particularly in light of the ongoing need for adaptation to incorporate new practices into routine work.

6.
Kidney Int ; 96(5): 1150-1161, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31530477

RESUMO

Norepinephrine exacerbates renal medullary hypoxia in experimental septic acute kidney injury. Here we examined whether dexmedetomidine, an α2-adrenergic agonist, can restore vasopressor responsiveness, decrease the requirement for norepinephrine and attenuate medullary hypoxia in ovine gram-negative sepsis. Sheep were instrumented with pulmonary and renal artery flow probes, and laser Doppler and oxygen-sensing probes in the renal cortex and medulla. Conscious sheep received an infusion of live Escherichia coli for 30 hours. Eight sheep in each group were randomized to receive norepinephrine, norepinephrine with dexmedetomidine, dexmedetomidine alone or saline vehicle, from 24-30 hours of sepsis. Sepsis significantly reduced the average mean arterial pressure (84 to 67 mmHg), average renal medullary perfusion (1250 to 730 perfusion units), average medullary tissue pO2 (40 to 21 mmHg) and creatinine clearance (2.50 to 0.78 mL/Kg/min). Norepinephrine restored baseline mean arterial pressure (to 83 mmHg) but worsened medullary hypoperfusion (to 330 perfusion units) and medullary hypoxia (to 9 mmHg). Dexmedetomidine (0.5 µg/kg/h) co-administration significantly reduced the norepinephrine dose (0.8 to 0.4 µg/kg/min) required to restore baseline mean arterial pressure, attenuated medullary hypoperfusion (to 606 perfusion units), decreased medullary tissue hypoxia (to 29 mmHg), and progressively increased creatinine clearance (to 1.8 mL/Kg/min). Compared with vehicle time-control, dexmedetomidine given alone significantly prevented the temporal reduction in mean arterial pressure, but had no significant effects on medullary perfusion and oxygenation or creatinine clearance. Thus, in experimental septic acute kidney injury, dexmedetomidine reduced norepinephrine requirements, attenuated its adverse effects on the renal medulla, and maintained renal function.

7.
J Neurooncol ; 145(1): 177-184, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31522324

RESUMO

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) is a rare clinically, neuro-radiologically, and molecularly defined malignancy of the brainstem with a median overall survival of approximately 11 months. Our aim is to evaluate the current tendency for its treatment in Europe in order to develop (inter)national consensus guidelines. METHODS: Healthcare professionals specialized in DIPG were asked to fill in an online survey with questions regarding usual treatment strategies at diagnosis and at disease progression in their countries and/or their centers, respectively. RESULTS: Seventy-four healthcare professionals responded to the survey, of which 87.8% were pediatric oncologists. Only 13.5% of the respondents biopsy all of their patients, 41.9% biopsy their patients infrequently. More than half of the respondents (54.1%) treated their patients with radiotherapy only at diagnosis, whereas 44.6% preferred radiotherapy combined with chemotherapy. When the disease progresses, treatment strategies became even more diverse, and the tendency for no treatment increased from 1.4% at diagnosis to 77.0% after second progression. 36.5% of the healthcare professionals treat children younger than 3 years differently than older children at diagnosis. This percentage decreased, when the disease progresses. Most of the participants (51.4%) included less than 25% of their patients in clinical trials. CONCLUSION: This survey demonstrates a large heterogeneity of treatment regimens, especially at disease progression. We emphasize the need for international consensus guidelines for the treatment of DIPG, possible by more collaborative clinical trials.

8.
Blood Adv ; 3(14): 2118-2127, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31300419

RESUMO

FOXO1 has an oncogenic role in adult germinal center-derived lymphomas, in which mutations, predominately within the AKT recognition motif, cause nuclear retention of FOXO1, resulting in increased cell proliferation. To determine the prevalence and distribution of FOXO1 mutations in pediatric Burkitt lymphoma (BL), we sequenced a large number of sporadic and endemic BL patient samples. We report a high frequency of FOXO1 mutations in both sporadic and endemic BL at diagnosis, occurring in 23/78 (29%) and 48/89 (54%) samples, respectively, as well as 8/16 (50%) cases at relapse. Mutations of T24 were the most common in sporadic BL but were rare in endemic cases, in which mutations of residue S22, also within the AKT recognition motif, were the most frequent. FOXO1 mutations were almost always present in the major tumor cell clone but were not associated with outcome. Analysis of other recurrent mutations reported in BL revealed that FOXO1 mutations were associated with mutations of DDX3X and ARID1A, but not MYC, TCF3/ID3, or members of the phosphatidylinositol 3-kinase signaling pathway. We further show common nuclear retention of the FOXO1 protein, irrespective of mutation status, suggesting alternative unknown mechanisms for maintaining FOXO1 transcriptional activity in BL. CRISPR/Cas9 knockout of FOXO1 in an endemic cell line produced a significant decrease in cell proliferation, supporting an oncogenic role for FOXO1 in endemic BL. Thus, FOXO1 is frequently mutated in both sporadic and endemic BL and may offer a potential therapeutic target for pediatric BL patients worldwide.

9.
Acta Neuropathol ; 138(2): 309-326, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31076851

RESUMO

In 2012, an international consensus paper reported that medulloblastoma comprises four molecular subgroups (WNT, SHH, Group 3, and Group 4), each associated with distinct genomic features and clinical behavior. Independently, multiple recent reports have defined further intra-subgroup heterogeneity in the form of biologically and clinically relevant subtypes. However, owing to differences in patient cohorts and analytical methods, estimates of subtype number and definition have been inconsistent, especially within Group 3 and Group 4. Herein, we aimed to reconcile the definition of Group 3/Group 4 MB subtypes through the analysis of a series of 1501 medulloblastomas with DNA-methylation profiling data, including 852 with matched transcriptome data. Using multiple complementary bioinformatic approaches, we compared the concordance of subtype calls between published cohorts and analytical methods, including assessments of class-definition confidence and reproducibility. While the lowest complexity solutions continued to support the original consensus subgroups of Group 3 and Group 4, our analysis most strongly supported a definition comprising eight robust Group 3/Group 4 subtypes (types I-VIII). Subtype II was consistently identified across all component studies, while all others were supported by multiple class-definition methods. Regardless of analytical technique, increasing cohort size did not further increase the number of identified Group 3/Group 4 subtypes. Summarizing the molecular and clinico-pathological features of these eight subtypes indicated enrichment of specific driver gene alterations and cytogenetic events amongst subtypes, and identified highly disparate survival outcomes, further supporting their biological and clinical relevance. Collectively, this study provides continued support for consensus Groups 3 and 4 while enabling robust derivation of, and categorical accounting for, the extensive intertumoral heterogeneity within Groups 3 and 4, revealed by recent high-resolution subclassification approaches. Furthermore, these findings provide a basis for application of emerging methods (e.g., proteomics/single-cell approaches) which may additionally inform medulloblastoma subclassification. Outputs from this study will help shape definition of the next generation of medulloblastoma clinical protocols and facilitate the application of enhanced molecularly guided risk stratification to improve outcomes and quality of life for patients and their families.

10.
J Equine Vet Sci ; 77: 31-35, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31133313

RESUMO

Donkeys are often kept, especially in industrialized countries, as companion animals. Donkeys have greater digestive efficiency and tend to expend less energy than horses or ponies, which contributes to obesity in nonworking donkeys. Obesity in all equine species increases risk of chronic health conditions such as laminitis and insulin resistance. Previous studies in horses and ponies have documented obesity's potential effects on glucose-insulin dynamics with lower insulin sensitivity and higher insulin responses to glucose. However, limited studies on obesity and its health impacts in donkeys exist, so these effects on glucose-insulin dynamics have not been fully studied. Twenty-four donkeys were selected according to initial body condition score (BCS) and divided into three categories with eight donkeys in each: thin, moderate, and obese. A frequently sampled glucose-insulin tolerance test was performed with subsequent MINMOD analysis to determine the effects of BCS on glucose-insulin dynamics. Basal insulin was highest in obese donkeys when compared with moderate and thin donkeys (P = .02 and P = .01, respectively). There was an overall trend across groups for BCS to lower insulin sensitivity (P = .06). No other effect was found. Body condition score seems to affect donkeys in a similar manner to horses and ponies as higher BCS was associated with higher basal insulin and may lower insulin sensitivity. Higher basal insulin concentrations in obese donkeys could negatively influence health and contribute to serious, chronic conditions.

11.
Sociol Health Illn ; 41(5): 882-899, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30756403

RESUMO

Although sociological studies of quality and safety have identified competing epistemologies in the attempt to measure and improve care, there are gaps in our understanding of how finance and accounting practices are being used to organise this field. This analysis draws on what others have elsewhere called 'financialisation' in order to explore the quantification of qualitatively complex care practices. We make our argument using ethnographic data of a quality improvement programme for acute kidney injury (AKI) in a publicly funded hospital in England. Our study is thus concerned with tracing the effects of financialisation in the emergence and assembly of AKI as an object of concern within the hospital. We describe three linked mechanisms through which this occurs: (1) representing and intervening in kidney care; (2) making caring practices count and (3) decision-making using kidney numbers. Together these stages transform care practices first into risks and then from risks into costs. We argue that this calculative process reinforces a separation between practice and organisational decision-making made on the basis of numbers. This elevates the status of numbers while diminishing the work of practitioners and managers. We conclude by signalling possible future avenues of research that can take up these processes.

12.
Drug Test Anal ; 11(6): 804-812, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30489688

RESUMO

CJC-1295 is a 30 amino acid peptide-based drug that stimulates the release of growth hormone (GH) from the pituitary gland. It is unique among performance-enhancing peptides due to the presence of a reactive maleimidopropionic acid group that covalently links the peptide to free thiols on the surface of plasma proteins. Once conjugated, CJC-1295 remains active in the bloodstream for significantly longer than non-conjugated peptide-based drugs that are rapidly excreted. Conjugation of CJC-1295 to plasma proteins prevents its detection by top-down mass-spectrometry-based peptide screening protocols as it effectively becomes a macromolecular protein with an undefined molecular weight. Using a pair of monoclonal antibodies raised against the CJC-1295 peptide, we present an immuno-polymerase chain reaction (I-PCR) assay that is capable of detecting the CJC-1295-protein conjugate at concentrations down to 0.8 pg/mL. Detection of endogenous equine GHRH necessitated a screening threshold for CJC-1295 in equine plasma of 50 pg/mL. The effectiveness of the assay for controlling the illicit use of CJC-1295 was confirmed in equine blood samples after administration in thoroughbred race horses.


Assuntos
Hormônio Liberador de Hormônio do Crescimento/análogos & derivados , Cavalos/sangue , Fragmentos de Peptídeos/sangue , Animais , Anticorpos Monoclonais/química , Hormônio Liberador de Hormônio do Crescimento/administração & dosagem , Hormônio Liberador de Hormônio do Crescimento/sangue , Imunoensaio/métodos , Limite de Detecção , Fragmentos de Peptídeos/administração & dosagem , Reação em Cadeia da Polimerase/métodos , Detecção do Abuso de Substâncias/métodos , Ressonância de Plasmônio de Superfície/métodos
13.
Pediatr Blood Cancer ; 66(2): e27509, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30408313

RESUMO

BACKGROUND: Surveillance magnetic resonance imaging (MRI) is routinely used to detect recurrence in children with high-grade central nervous system (CNS) tumors, although no consensus has been reached regarding its effectiveness and whether earlier detection is associated with improved patient outcomes. This review aimed to evaluate this practice and any associated benefits and harms. METHODS: Systematic searches for relevant studies were undertaken in a number of databases, including MEDLINE and EMBASE, from 1985 to August 2018. Study selection and data extraction was undertaken independently by two reviewers. Due to heterogeneity between studies, no pooling of data was undertaken. Reporting followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: No comparative studies were identified. Three retrospective observational studies involving 306 patients were reviewed. All had high risk of bias by virtue of study design. Two studies reported outcomes by symptomatic status-both recurrence rates and overall survival for asymptomatic patients were comparable with those for clinically symptomatic patients. No quality-of-life outcomes were reported. CONCLUSION: There is a paucity of evidence to guide clinical practice as to the effectiveness of MRI surveillance in pediatric patients with high-grade CNS tumors. These studies do not clearly demonstrate benefit or harm for the practice. With more research needed, there is a role for researchers to build into future trials data collection on surveillance imaging to give more information for the assessment of imaging frequency and duration in asymptomatic patients. This is an important question not only to clinicians and patients and their families but also from a health service resource perspective.


Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Detecção Precoce de Câncer/métodos , Imagem por Ressonância Magnética/métodos , Recidiva Local de Neoplasia/diagnóstico por imagem , Criança , Progressão da Doença , Humanos
14.
Shock ; 51(3): 348-355, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29489737

RESUMO

INTRODUCTION: Supra-clinical doses of clonidine appear beneficial in experimental sepsis, but there is limited understanding of the effects of clonidine at clinically relevant doses. METHODS: In conscious sheep, with implanted renal and pulmonary artery flow probes, sepsis was induced by infusion of live Escherichia coli. At 24 h, a high clinical dose of clonidine (HCDC) [1.0 µg/kg/h], a low clinical dose of clonidine (LCDC) [0.25 µg/kg/h] or vehicle, was infused for 8 h. RESULTS: Animals developed hyperdynamic, hypotensive sepsis with acute kidney injury. The HCDC decreased heart rate (153 ±â€Š6 to 119 ±â€Š7 bpm) and cardiac output (5.6 ±â€Š0.4 to 5.0 ±â€Š0.4 L/min), with no reduction in mean arterial pressure (MAP). In contrast, LCDC increased cardiac output with peripheral vasodilatation. Both doses induced a large transient increase in urine output, an increase in plasma osmolality and, with the high dose, an increase in plasma arginine vasopressin. Sepsis increased plasma interleukin-6 (IL-6) and IL-10 and clonidine further increased IL-10 (1.6 ±â€Š0.1 to 3.3 ±â€Š0.7 ng/mL), but not IL-6. Clonidine reduced rectal temperature. During recovery from sepsis, MAP returned to baseline values more rapidly in the HCDC group (P < 0.001). CONCLUSIONS: In hyperdynamic, hypotensive sepsis, the effects of clonidine at clinically relevant doses are complex and dose dependent. HCDC attenuated sepsis-related increases in heart rate and cardiac output, with little effect on arterial pressure. It also induced a water diuresis, increased AVP, reduced body temperature, and had an anti-inflammatory action. Low-dose clonidine had similar but less pronounced effects, except that it induced moderate vasodilatation and increased cardiac output.

15.
J Vet Intern Med ; 33(1): 280-286, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30520164

RESUMO

BACKGROUND: The importance of including exercise with dietary modification for the management of obese equids is not clearly understood. OBJECTIVES: To evaluate the effect of a practical low-intensity exercise regimen, in addition to dietary restriction, on indices of insulin sensitivity (SI) and plasma adipokine concentrations in obese equids. ANIMALS: Twenty-four obese (body condition score [BCS] ≥ 7/9) horses and ponies. METHODS: Over a 12-week period, animals received either dietary restriction only (DIET) or dietary restriction plus low-intensity exercise (DIET+EX). All animals were provided with a restricted ration of grass hay at 1.25% body weight (BW) on a dry matter basis, providing 82.5% estimated digestible energy requirements. The DIET+EX group undertook low-intensity exercise 5 days per week on an automated horse walker. Before and after weight loss, total body fat mass (TBFM) was determined, indices of SI were calculated using minimal model analysis of a frequently sampled IV glucose tolerance test, and adipokines plus inflammatory biomarkers were measured using validated assays. RESULTS: Decreases in BCS, BW, and TBFM were similar between groups (all P > .05). After weight loss, animals in both groups had decreased basal insulin and leptin concentrations, and increased adiponectin concentrations (all P < .001). Furthermore, animals in the DIET+EX group had significantly improved SI and decreased serum amyloid A concentrations relative to animals in the DIET group (both P = .01). CONCLUSIONS AND CLINICAL IMPORTANCE: Regular low-intensity exercise provided additional health benefits compared with dietary restriction alone in this population of obese equids.


Assuntos
Dieta Redutora/veterinária , Terapia por Exercício/veterinária , Doenças dos Cavalos/terapia , Resistência à Insulina , Obesidade/veterinária , Animais , Feminino , Doenças dos Cavalos/dietoterapia , Cavalos , Masculino , Obesidade/dietoterapia , Obesidade/terapia , Distribuição Aleatória , Perda de Peso
16.
PeerJ ; 6: e5945, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30519508

RESUMO

Background: In horses and ponies, insulin dysregulation leading to hyperinsulinemia may be associated with increased risk of laminitis, and prolonged infusion of insulin can induce the condition. It is unclear whether insulin may have a direct or indirect effect on the lamellar tissues. Insulin is structurally related to insulin-like growth factor (IGF-1), and can bind the IGF-1 receptor, albeit at a lower affinity than IGF-1. Methods: Immunohistochemistry was performed on formalin-fixed lamellar tissue sections from six normal horses, euthanised for non-research purposes, using an anti-IGF-1 receptor antibody. In further studies, lamellar epithelial cells were obtained by collagenase digestion from the hooves of 18 normal horses, also euthanised for non-research purposes, and incubated for 48 h in the presence of insulin (0-2,000 m IU/ml). The increase in cell numbers was determined using a cell proliferation assay, and compared to the effect of zero insulin using one-way ANOVA. Results: Immunohistochemistry demonstrated IGF-1 receptors on lamellar epidermal epithelial cells. With cultured cells, insulin caused a concentration-dependent increase in cell proliferation compared to untreated cells (maximal effect 63.3 ± 12.8% more cells after 48 h with 1,000 m IU/ml insulin; P < 0.01). Co-incubation with a blocking antibody against the IGF-1 receptor significantly inhibited the proliferative effect of insulin (P < 0.01). Discussion: These results demonstrate that IGF-1 receptors are present on lamellar epithelial cells. At high physiological concentrations, insulin may activate these cells, by a mechanism involving IGF-1 receptors, resulting in a proliferative effect. This mechanism could help to explain the link between hyperinsulinemia and laminitis.

17.
Pediatr Hematol Oncol ; 35(3): 196-202, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30239249

RESUMO

Wilms tumor (WT) has a survival rate above 90% in high income countries. Reported survival rates in sub-Saharan Africa are much lower and long-term outcome is not well known as follow-up is challenging. In Blantyre, Malawi, an adapted WT treatment guideline with preoperative chemotherapy, supportive care, and strategies to enable children and parents to complete treatment was introduced in 2006. Between 2006 and 2011, 73 children with a unilateral WT were treated. Follow-up, including home visits when needed, was done. Median follow-up time is 5 years (range 14-95 months). Two and five-year event free survivals are 46 and 42%. Causes of treatment failure are: 7% (5/73) abandonment of treatment, 15% (11/73) death during treatment and 30% (22/73) disease-related deaths (persistent disease and relapse). Long-term follow-up is challenging but necessary to be able to assess outcome and the true impact of interventions.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Renais/mortalidade , Recidiva Local de Neoplasia/mortalidade , Tumor de Wilms/mortalidade , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Malaui , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Prognóstico , Taxa de Sobrevida , Tumor de Wilms/tratamento farmacológico , Tumor de Wilms/patologia
18.
Pediatr Blood Cancer ; 65(12): e27377, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30084225

RESUMO

BACKGROUND: Optic pathway gliomas (OPGs) are low-grade tumours of the visual pathway. Although survival rates are high, there is considerable morbidity and hence treatment focuses on preservation of vison and quality of life. The multiple, complex issues faced by these patients are often confounded by a concurrent diagnosis of neurofibromatosis type-1 (NF1). As there is a paucity of literature addressing the current practices of the multi-professional team (MPT) caring for children diagnosed with an OPG, individual professional experiences often guide the MPT's approach to the care of these children and their families. AIMS: This study aimed to gain views on the management of children with OPGs, from MPT members involved in their care, in order to inform recommendations on how to improve the service offered to these children and their families. METHODS: A qualitative design collected experiential data from MPT members via semi-structured interviews. MPT focus groups were used to validate the data. RESULTS: Data collected from 20 MPT members resulted in the overarching themes of Issues Faced by the Patient and Family and Challenges to the Holistic Care of the Patient. Four recommendations are suggested, namely (1) the production of an MPT training resource, (2) improved visual team links, (3) an OPG patient passport and (4) a joint NF1-OPG clinic. CONCLUSION: There are many challenges to MPT members providing holistic care to patients with OPGs. As no OPG clinical practice guidelines currently exist, it is suggested that the above recommendations be piloted with evaluation to validate their use.


Assuntos
Determinação de Necessidades de Cuidados de Saúde , Glioma do Nervo Óptico , Equipe de Assistência ao Paciente , Criança , Feminino , Humanos , Masculino , Oncologia , Pesquisa Qualitativa
20.
J Neurooncol ; 139(3): 507-522, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29948767

RESUMO

BACKGROUND: Magnetic resonance imaging (MRI) is routinely used as a surveillance tool to detect early asymptomatic tumour recurrence with a view to improving patient outcomes. This systematic review aimed to assess its utility in children with low-grade CNS tumours. METHODS: Using standard systematic review methods, twelve databases were searched up to January 2017. RESULTS: Seven retrospective case series studies (n = 370 patients) were included, with average follow-up ranging from 5.6 to 7 years. No randomised controlled trials (RCTs) were identified. Due to study heterogeneity only a descriptive synthesis could be undertaken. Imaging was most frequent in the first year post-surgery (with 2-4 scans) reducing to around half this frequency in year two and annually thereafter for the duration of follow-up. Diagnostic yield ranged from 0.25 to 2%. Recurrence rates ranged from 5 to 41%, with most recurrences asymptomatic (range 65-100%). Collectively, 56% of recurrences had occurred within the first year post-treatment (46% in the first 6-months), 68% by year two and 90% by year five. Following recurrence, 90% of patients underwent treatment changes, mainly repeat surgery (72%). Five-year OS ranged from 96 to 100%, while five-year recurrence-free survival ranged from 67 to 100%. None of the studies reported quality of life measures. CONCLUSION: This systematic review highlights the paucity of evidence currently available to assess the utility of MRI surveillance despite it being routine clinical practice and costly to patients, their families and healthcare systems. This needs to be evaluated within the context of an RCT.


Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Detecção Precoce de Câncer , Imagem por Ressonância Magnética , Recidiva Local de Neoplasia/diagnóstico por imagem , Adolescente , Neoplasias do Sistema Nervoso Central/patologia , Criança , Pré-Escolar , Detecção Precoce de Câncer/métodos , Humanos , Lactente , Recém-Nascido , Gradação de Tumores , Adulto Jovem
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