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2.
Orphanet J Rare Dis ; 17(1): 193, 2022 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-35550173

RESUMO

BACKGROUND: Lysosomal acid lipase deficiency (LALD) is an ultra-rare, inherited metabolic disease within the category of lysosomal storage disorders, affecting an infant's ability to metabolise cholesterol. Developments in treatment, including Enzyme Replacement Therapy, have proven successful, with some children living for a number of years with treatment, although the future still remains unknown. The aim of this study was to explore the lived experiences of parents of children with LALD. MAIN TEXT: Participants were recruited from across the United Kingdom between 2020 and 2021. Eight parents (five mothers and three fathers) whose child had a confirmed diagnosis of LALD were interviewed. Data collected from the semi-structured interviews were audio-record, transcribed and analysed using Interpretative Phenomenological Analysis (IPA). Three superordinate and nine subordinate themes emerged from the data: (1) Uncertainty-a double-edged sword (plunged into an uncertain world, living life with worry and walking the tightrope of stability), (2) Powerless against a shared battle with LALD (a helpless parent, a joint battle, protection against distress and a vulnerable parent needing help) and 3) Accepting a life with LALD (coming to terms with a diagnosis of LALD and a hidden condition). CONCLUSIONS: The findings of this study highlight that the diagnosis of LALD proves to be a very challenging and emotionally distressing time in parents' lives, with increased uncertainty about what the future will hold for their child. This study signified the importance of healthcare pathways and service provisions to support parents and their children throughout diagnosis and beyond.


Assuntos
Doença de Wolman , Criança , Terapia de Reposição de Enzimas , Feminino , Humanos , Lactente , Mães , Pais/psicologia , Pesquisa Qualitativa , Doença de Wolman/diagnóstico , Doença de Wolman
3.
Sci Rep ; 11(1): 22400, 2021 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-34789788

RESUMO

UVA1 radiation (340-400 nm), especially longwave UVA1 (> 370 nm), is often ignored when assessing sun protection due to its low sunburning potential, but it generates reactive oxygen species (ROS) and is poorly attenuated by sunscreens. This study aimed to investigate if α-tocopherol phosphate, (α-TP) a promising new antioxidant, could protect against long-wave UVA1 induced cell death and scavenge UVA1 induced ROS in a skin cell model. HaCaT keratinocyte cell viability (24 h) was assessed with Alamar Blue and Neutral Red assays. The metabolism of α-TP into α-T, assessed using mass spectrometry, and the compound's radical scavenging efficacy, assessed by the dichlorodihydrofluorescein (H2DCFDA) ROS detection assay, was monitored in HaCaTs. The mechanism of α-TP ROS scavenging was determined using non-cell based DPPH and ORAC assays. In HaCaT keratinocytes, irradiated with 226 J/cm2 UVA1 in low-serum (2%, starved) cell culture medium, pretreatment with 80 µM α-TP significantly enhanced cell survival (88%, Alamar Blue) compared to control, whereas α-T pre-treatment had no effect survival (70%, Alamar Blue). Pre-treatment of cells with 100 µM α-TP or 100 µM α-T before 57 J/cm2 UVA1 also significantly reduced ROS generation over 2 h (24.1% and 23.9% respectively) compared to the control and resulted in α-TP bioconversion into α-T. As α-TP displayed weak antioxidant activity in the cell-free assays thus its photoprotection was assigned to its bioconversion to α-T by cellular phosphatases. Through this mechanism α-TP prevented long-wave UVA1 induced cell death and scavenged UVA1 induced ROS in skin cells when added to the starved cell culture medium before UVA1 exposure by bioconversion into α-T.


Assuntos
Queratinócitos/efeitos dos fármacos , Queratinócitos/efeitos da radiação , Protetores contra Radiação/farmacologia , Raios Ultravioleta/efeitos adversos , alfa-Tocoferol/análogos & derivados , Antioxidantes , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Células Cultivadas , Relação Dose-Resposta à Radiação , Humanos , Espécies Reativas de Oxigênio/metabolismo , alfa-Tocoferol/farmacologia
4.
Mol Genet Metab ; 132(2): 94-99, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32713717

RESUMO

Respiratory outcomes in Mucopolysaccharidosis Type I (MPS I), have mainly focused on upper airway obstruction, with the evolution of the restrictive lung disease being poorly documented. We report the long-term pulmonary function outcomes and examine the potential factors affecting these in 2 cohorts of MPS I patients, those who have undergone Haematopoietic Stem Cell Transplantation (HSCT) and those treated with Enzyme Replacement Therapy (ERT). The results were stratified using the American Thoracic Society (ATS) guidelines. 66 patients, capable of adequately performing testing, were identified by a retrospective case note review, 46 transplanted (45 Hurler, 1 Non-Hurler) and 20 having ERT (17 Non-Hurler and 3 Hurler diagnosed too late for HSCT). 5 patients died; 4 in the ERT group including the 3 Hurler patients. Overall 14% of patients required respiratory support (non-invasive ventilation (NIV) or supplemental oxygen)) at the end of follow up. Median length of follow-up was 12.2 (range = 4.9-32) years post HSCT and 14.34 (range = 3.89-20.4) years on ERT. All patients had restrictive lung disease. Cobb angle and male sex were significantly associated with more severe outcomes in the HSCT cohort, with 49% having severe to very severe disease. In the 17 Non-Hurler ERT treated patients there was no variable predictive of severity of disease with 59% having severe to very severe disease. During the course of follow up 67% of the HSCT cohort had no change or improved pulmonary function as did 52% of the ERT patients. However, direct comparison between therapeutic modalities was not possible. This initial evidence would suggest that a degree of restrictive lung disease is present in all treated paediatrically diagnosed MPS I and is still a significant cause of morbidity, though further stratification incorporating diffusing capacity for carbon monoxide (DLCO) is needed.


Assuntos
Obstrução das Vias Respiratórias/terapia , Pneumopatias Obstrutivas/terapia , Mucopolissacaridose I/terapia , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Obstrução das Vias Respiratórias/complicações , Obstrução das Vias Respiratórias/epidemiologia , Obstrução das Vias Respiratórias/patologia , Monóxido de Carbono/metabolismo , Criança , Pré-Escolar , Terapia de Reposição de Enzimas , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Lactente , Pneumopatias Obstrutivas/complicações , Pneumopatias Obstrutivas/epidemiologia , Pneumopatias Obstrutivas/patologia , Masculino , Pessoa de Meia-Idade , Mucopolissacaridose I/complicações , Mucopolissacaridose I/epidemiologia , Mucopolissacaridose I/patologia , Adulto Jovem
5.
Childs Nerv Syst ; 34(9): 1705-1716, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29946810

RESUMO

PURPOSE: This study examines the long-term outcomes of paediatric Morquio (MPS IVA) patients undergoing cervical spine surgery and evaluates the factors that impacting this. METHODS: A retrospective review was performed on all MPS IVA patients undergoing cervical spine surgery, since the introduction of standardised neuroradiological screening. The impact of preoperative neurological status, growth, genotype and radiological status on outcome is assessed, whilst long-term surgical, radiological and neurological outcomes are documented. RESULTS: Twenty-six of the eighty-two MPS IVA patients (31%) reviewed underwent cervical spine surgery at a median age of 6.1 years (range, 1.45 to 15.24). Preoperatively, cord signal change was seen in 11 patients with 5 being myelopathic; however, 6 clinically manifesting patients had no overt cord signal change. Postoperatively, none of the 14 preoperatively clinically asymptomatic patients followed long term progressed neurologically during a median follow-up of 77.5 months (range = 18-161). Of the ten preoperatively clinically symptomatic patients who were followed up for the same duration, seven continued to deteriorate, two initially improved and one remained stable. Radiological follow-up performed for a median duration of 7 years (range = 0.5-16) has shown a degree of stenosis at the level immediately caudal to the termination of the graft in 76% of patients, though only one has become clinically symptomatic and required revision. CONCLUSIONS: Once clinically elicitable neurological signs become evident in patients with MPS IVA, they tend to progress despite surgical intervention. Referring clinicians should also not be falsely reassured by the lack of T2 spinal cord signal change but should consider surgical intervention in the face of new clinical symptomology or radiological signs of progressive canal stenosis or instability.


Assuntos
Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/cirurgia , Mucopolissacaridose IV/diagnóstico por imagem , Mucopolissacaridose IV/cirurgia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Resultado do Tratamento
6.
Soft Matter ; 14(18): 3497-3503, 2018 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-29707727

RESUMO

Gas trapping is an important mechanism in both Water or Surfactant Alternating Gas (WAG/SAG) and foam injection processes in porous media. Foams for enhanced oil recovery (EOR) can increase sweep efficiency as they decrease the gas relative permeability, and this is mainly due to gas trapping. However, gas trapping mechanisms are poorly understood. Some studies have been performed during corefloods, but little work has been carried out to describe the bubble trapping behaviour at the pore scale. We have carried out foam flow tests in a micromodel etched with an irregular hexagonal pattern. Image analysis of the foam flow allowed the bubble centres to be tracked and local velocities to be obtained. It was found that the flow in the micromodel is dominated by intermittency and localized zones of trapped gas. The quantity of trapped gas was measured both by considering the fraction of bubbles that were trapped (via velocity thresholding) and by measuring the area fraction containing immobile gas (via image analysis). A decrease in the quantity of trapped gas was observed for both increasing total velocity and increasing foam quality. Calculations of the gas relative permeability were made with the Brooks Corey equation, using the measured trapped gas saturations. The results showed a decrease in gas relative permeabilities, and gas mobility, for increasing fractions of trapped gas. It is suggested that the shear thinning behaviour of foam could be coupled to the saturation of trapped gas.

7.
Clin Exp Immunol ; 193(1): 37-46, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29437229

RESUMO

The cytokine interleukin (IL)-6 is a major therapeutic target for the treatment of various inflammatory and autoimmune diseases. While IL-6 receives considerable attention in studies of innate and adaptive immunity, the IL-6-related family member IL-27 is recognized increasingly for its effects on cellular proliferation, differentiation and leucocyte effector functions. Both cytokines activate responses in myeloid and stromal tissue cells, where they direct the transition from innate to adaptive immunity. However, they are identified frequently as lymphokines that control responses in T cells and B cells. In this regard, IL-27 often opposes the action of IL-6. Here, we will review the role of IL-6 and IL-27 in inflammation, with a particular focus on inflammatory arthritis, and discuss their importance in the diagnosis, stratification and treatment of autoimmune disease.


Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Interleucina-6/imunologia , Interleucinas/imunologia , Imunidade Adaptativa/imunologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Humanos , Imunidade Inata/imunologia , Inflamação/imunologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/genética , Interleucinas/antagonistas & inibidores , Interleucinas/genética , Polimorfismo de Nucleotídeo Único/genética , Transdução de Sinais/imunologia
8.
J Orthop Surg (Hong Kong) ; 25(1): 2309499016684700, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28118806

RESUMO

AIM: To identify whether the location of refractory patella tendinopathy (PT) has an effect on treatment modality (radial extracorporeal shock wave therapy (rESWT) or arthroscopic debridement). METHODS: Between 2012 and 2014, 40 patients with PT underwent a magnetic resonance imaging (MRI) scan. This confirmed the diagnosis as either involving the tendon itself (group A, 20) or with retropatella fat pad extension (group B, 20). All patients underwent rESWT. If there was no improvement patients proceeded with surgery in the form of arthroscopic debridement (by senior authors CW and AG). Outcomes were assessed before and after treatment using the Victorian Institute of Sports Assessment-Patella (VISA-P) score. RESULTS: There were 18 males and 2 females in group A and 15 males and 5 females in group B. The mean age was 41.4 years in group A (23-59) and 34.7 in group B (19-52). Seventeen of 20 in group A reported good or excellent outcomes and did not require surgical intervention (remaining three improved after second course of ESWT). All patients in group B failed to improve with rESWT, resulting in arthroscopic debridement and reported good or excellent outcomes. After 6 months, group A mean VISA-P score increased from 50.2 to 65.0 ( p = 0.01) and group B from 39.6 to 78.4 ( p = <0.001). CONCLUSION: An MRI should be performed to determine the precise location of tendinosis in patients with refractory PT who fail standard conservative management. If the MRI scan shows intratendon changes only, ESWT should be performed and those with extension into the fat pad should proceed to arthroscopic debridement without rESWT.


Assuntos
Artroscopia , Desbridamento , Ligamento Patelar , Tendinopatia/cirurgia , Terapia por Ultrassom , Adulto , Tratamento Conservador , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Estudos Retrospectivos , Tendinopatia/diagnóstico por imagem , Resultado do Tratamento , Adulto Jovem
9.
Orphanet J Rare Dis ; 11(1): 96, 2016 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-27406185

RESUMO

BACKGROUND: Hematopoietic stem cell transplants, alongside enzyme replacement therapy and good multi-disciplinary care, have dramatically improved the life expectancy in children with Mucopolysaccharidosis (MPS) I, with better objective and functional outcomes. Despite these improvements, children with both the attenuated (non-Hurler) and severe (Hurler) variants of the disease have marked residual morbidity. Children with MPS I suffer with head and neck disease including obstructive sleep apnoea and hearing loss. The impact of these on quality of life has been poorly researched and no previous work has been published looking at patients' perception of their own health, an important domain when considering the impact of treatment. METHODS: This exploratory qualitative study aimed to discover the effect of head and neck disease, alongside that of MPS I as a whole, on the quality of life of affected children. A grounded theory approach was used to conduct this study. Children and their parents were invited to participate in semi-structured interviews. The transcribed interviews were coded and emergent themes explored until saturation occurred. RESULTS: The families of eleven children with MPS I were interviewed, five with Hurler's and six with the attenuated non-Hurler's. Important themes to emerge were- the fear of dying associated with obstructive sleep apnoea, difficulties communicating at school due to the delayed acquisition of language, chronic pain and restricted mobility, physical differences and restricted participation in social activities such as sports secondary to the musculoskeletal disease burden. The overall theme running through the analysis was the desire to fit in with ones peers. CONCLUSION: Parents and children with MPS 1 worry about 'fitting-in' with broader society. The presence of airway disease has a profound impact on the emotional well being of parents whilst language delay and musculoskeletal disease have the biggest impact on the quality of life of the children themselves. It is important to understand the impact of MPS I on the quality of life of children and their families so that we may improve future treatment and management of this sub-group of children who have an increasing life span.


Assuntos
Mucopolissacaridose I/patologia , Mucopolissacaridose I/fisiopatologia , Adolescente , Criança , Pré-Escolar , Terapia de Reposição de Enzimas , Feminino , Perda Auditiva/etiologia , Perda Auditiva/patologia , Perda Auditiva/fisiopatologia , Humanos , Lactente , Masculino , Mucopolissacaridose I/complicações , Mucopolissacaridose I/tratamento farmacológico , Estudos Prospectivos , Pesquisa Qualitativa , Qualidade de Vida , Respiração , Apneia Obstrutiva do Sono/etiologia , Apneia Obstrutiva do Sono/patologia , Apneia Obstrutiva do Sono/fisiopatologia
10.
JIMD Rep ; 29: 95-102, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26825088

RESUMO

The long-term cognitive and functional outcomes of children with mucopolysaccharidosis type I (MPS-IH) post-hematopoietic cell transplant (HCT) are not well documented, and the role of genetic and treatment factors in these outcomes has yet to be defined. In this multi-site, international study, we (1) characterize the cognitive and functional status of 47 individuals (ages 2-25, mean of 10.6 years) with MPS-IH who are 1-24 years post HCT (mean = 9 years) and (2) examine contributions of genotype, transplant characteristics, and sociodemographic factors to cognitive ability, adaptive behavior, and quality of life. The overall cognitive ability of our sample was mildly impaired, more than two standard deviations below general population norms. Parent reported adaptive behaviors (i.e., communication, daily living, and motor skills) were similarly impaired with a relative strength in socialization. Quality of life, as reported by parents, fell more than two standard deviations below population norms for physical functioning; however, psychosocial quality of life (emotional well-being) approximated population norms. In linear regression analysis, adjusted for demographic and treatment factors, mutation severity was associated with lower cognitive ability (p = 0.005) and adaptive functioning (p = 0.004), but not parent ratings of children's quality of life. Older age at HCT was associated with poorer physical quality of life (p = 0.002); lower socioeconomic status (p = 0.028) and unrelated bone marrow HCT (p = 0.010) were associated with poorer psychosocial quality of life. Implications for screening and early intervention for children at risk for poorer cognitive and functional outcomes are described.

11.
J Anim Sci ; 93(3): 956-64, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26020874

RESUMO

Bovine respiratory disease complex (BRDC) is the most expensive disease in beef cattle in the United States costing the industry at least US$1 billion annually. Bovine respiratory disease complex causes damage to lung tissue resulting in persistent lung lesions observable at slaughter. Severe lung lesions at harvest have been associated with decreased preharvest ADG and increased clinical BRDC in the feedlot. Our objective was to identify SNP that are associated with severe lung lesions observed at harvest in feedlot cattle. We conducted a genomewide association study (GWAS) using a case-control design for severe lung lesions in fed cattle at slaughter using the Illumina Bovine HD array (approximately 770,000 SNP) and sample pooling. Lung samples were collected from 11,520 young cattle, a portion of which had not been treated with antibiotics (participating in a "natural" marketing program), at a large, commercial beef processing plant in central Nebraska. Lung samples with lesions (cases) and healthy lungs (controls) were collected when both phenotypes were in close proximity on the viscera (offal) table. We constructed 60 case and 60 control pools with 96 animals per pool. Pools were constructed by sampling sequence to ensure that case and control pool pairs were matched by proximity on the processing line. The Bovine HD array (770,000 SNP) was run on all pools. Fourteen SNP on BTA 2, 3, 4, 9, 11, 14, 15, 22, 24, and 25 were significant at the genomewide experiment-wise error rate of 5% ( ≤ 1.49 × 10). Eighty-five SNP on 28 chromosomes achieved a false discovery rate of 5% ( ≤ 5.38 × 10). Significant SNP were near (±100 kb) genes involved in tissue repair and regeneration, tumor suppression, cell proliferation, apoptosis, control of organ size, and immunity. Based on 85 significantly associated SNP in or near a collection of genes with diverse function on 28 chromosomes, we conclude that the genomic footprint of lung lesions is complex. A complex genomic footprint (genes and regulatory elements that affect the trait) is consistent with what is known about the cause of the disease: complex interactions among multiple viral and bacterial pathogens along with several environmental factors including dust, commingling, transportation, and stress. Characterization of sequence variation near significant SNP will enable accurate and cost effective genome-enhanced genetic evaluations for BRDC resistance in AI bulls and seed stock populations.


Assuntos
Complexo Respiratório Bovino/genética , Estudo de Associação Genômica Ampla/veterinária , Animais , Complexo Respiratório Bovino/patologia , Bovinos , Variação Genética , Genoma , Genômica , Pulmão/patologia , Masculino , Nebraska , Fenótipo , Estados Unidos
12.
J Vet Intern Med ; 29(2): 644-50, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25818219

RESUMO

BACKGROUND: Serum bile acid concentrations (SBA) and a histopathological biopsy score [Equine Vet J 35 (2003) 534] are used prognostically in equine hepatic disease. HYPOTHESIS: Histopathologic features and scores, but not SBA, differ between survivors and nonsurvivors and correlate with histopathologic evidence of hepatic inflammation and fibrosis. ANIMALS: Retrospective study. Records (1999-2011) of horses with hepatic disease diagnosed by biopsy and with concurrent measurements of SBA. METHODS: Retrospective cohort study. Biopsies were examined for inflammatory cell infiltration including type and distribution, fibrosis, irreversible cytopathology affecting hepatocytes, hemosiderin, or other pigment deposition and bile duct proliferation. SBA, histopathological findings and a histological score [Equine Vet J 35 (2003) 534] were compared between short- (survival to discharge) and long-term (>6 months) survivors and correlations between SBA and histopathological findings investigated. RESULTS: Of 81 cases 90% survived short-term and 83% long-term. Short-term and long-term nonsurvival were associated with SBA (P = .009; P = .006), overall (P = .001; P = .002) and parenchymal (short-term only; P = .01) inflammation, portal and bridging fibrosis (all P < .001), apoptosis or single cell necrosis (P < .001; P = .008), hemosiderin deposition in hepatocytes (P = .011; P = .028), biliary (both P < .001), vascular (P = .003; P = .045) and endothelial (P < .001; P = .02) hyperplasia, nucleic changes (P = .004; P < .001) and the histopathological score (both P < .001). SBA were significantly and positively correlated with overall (P = .001), parenchymal (P < .001) and portal (P = .004) inflammation and portal (P = .036) and bridging (P = .002) fibrosis. CONCLUSIONS AND CLINICAL IMPORTANCE: SBA, histopathological findings and scores differ between survivors and nonsurvivors. SBA concentrations are associated with inflammation and fibrosis suggesting interference with hepatic function. A histopathological score >2 and, less so, SBA >20 µmol/L are specific but not sensitive indicators of nonsurvival.


Assuntos
Ácidos e Sais Biliares/sangue , Doenças dos Cavalos/sangue , Hepatopatias/veterinária , Animais , Biópsia/veterinária , Doenças dos Cavalos/patologia , Cavalos , Hepatopatias/sangue , Hepatopatias/patologia , Estudos Retrospectivos , Análise de Sobrevida
13.
Int J Pediatr Otorhinolaryngol ; 77(8): 1255-8, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23773334

RESUMO

UNLABELLED: Mucopolysaccharidoses (MPS) are a group of rare inherited metabolic disorders resulting from deficiencies of particular enzymes involved in the breakdown of glycosaminoglycans. Amongst the manifestations of MPS within the head and neck patients may develop conductive, mixed or sensorineural hearing loss. OBJECTIVE: The main objective of this paper is to describe the management of profound sensorineural hearing loss in children with Mucopolysaccaridosis. The primary outcome measures for this case series were improvement in auditory performance and speech perception scores following cochlear implantation. Secondary outcome measures included surgical complications. METHODS: We carried out a casenote review of the first two cases of cochlear implantation (CI) to rehabilitate profound sensory neural hearing loss in Mucopolysaccharidoses. Improvement in auditory performance was measured by categories of auditory performance (CAP) score, speech reception score (SRS) and the IHR McCormick toy discrimination test. RESULTS: Both patients with MPS had demonstrable benefit from CI in terms of auditory performance and speech perception. The first patient improved from pre-operatively only managing to recognise environmental sounds to understanding conversation without lip-reading with a familiar talker. Following CI, the second patient can discriminate speech in noisy environments to a degree, without lip-reading. No peri-operative complications were noted in either patient. CONCLUSION: As the medical management of the MPS has progressed there is likely to be a corresponding increase in survival. This increased life-expectancy will likely lead to greater numbers of patients with MPS surviving long enough to develop profound hearing loss. Likewise, when considering the risks and benefits of quality of life interventions such as CI in patients with MPS, it is more likely that the risks of surgery and general anaesthesia will be considered acceptable. Clinicians managing such patients will need to be aware of these developments.


Assuntos
Implante Coclear , Implantes Cocleares , Perda Auditiva Neurossensorial/terapia , Mucopolissacaridoses/complicações , Adolescente , Limiar Auditivo/fisiologia , Criança , Pré-Escolar , Estudos de Viabilidade , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Masculino , Mucopolissacaridoses/fisiopatologia , Mucopolissacaridoses/cirurgia , Percepção da Fala/fisiologia , Resultado do Tratamento
14.
Mol Pharm ; 9(3): 563-9, 2012 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-22229274

RESUMO

Determining bioequivalence for solution pressurized metered dose inhalers (pMDI) is difficult because the critical characteristics of such products are poorly defined. The aim of this study was to elucidate the non-aerodynamic properties of the emitted aerosol particles from two solution pMDI products that determine their biopharmaceutical differences after deposition. Novel particle capture and analysis techniques were employed to characterize the physicochemical and biopharmaceutical properties of two beclomethasone dipropionate (BDP) products: QVAR and Sanasthmax. The BDP particles emitted from the Sanasthmax inhaler were discernibly different those emitted from QVAR in terms of size (50% larger, less porous), solid state (less crystalline) and dissolution (20-fold slower). When deposited onto the surface of respiratory epithelial cell layers, QVAR delivered ∼50% more BDP across the cell layer in 60 min than Sanasthmax. Biopharmaceutical performance was not attributable to individual particle properties as these were manifold with summative and/or competing effects. The cell culture dissolution-absorption model revealed the net effect of the particle formed on drug disposition and was predictive of human systemic absorption of BDP delivered by the test inhalers. This illustrates the potential of the technique to detect the effect of formulation on the performance of aerosolized particles and contribute to assessment of bioequivalence.


Assuntos
Corticosteroides/administração & dosagem , Aerossóis/química , Inaladores Dosimetrados , Absorção , Beclometasona/química , Linhagem Celular , Células Epiteliais/metabolismo , Humanos
16.
J Pharm Pharmacol ; 62(6): 730-7, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20636860

RESUMO

OBJECTIVES: The aim of this study was to demonstrate the effect of a novel permeation enhancer system using two existing marketed nail lacquers and the delivery of terbinafine through human nail samples in vitro. METHODS: Initially a modified Franz cell was used, where sections of human nail serve as the barrier through which drug penetrates into an agar-filled chamber infected with dermatophytes. A second study was performed using a novel infected nail model where dermatophytes are incubated with and grow into human nail and ATP levels are used as biological marker for antimicrobial activity. KEY FINDINGS: The novel permeation enhancing system increased the permeation of both existing drugs formulated in nail lacquers and terbinafine through human nail sections mounted in a modified Franz cell. Furthermore the ATP assay confirmed that the system also enhanced the permeation of terbinafine through infected cadaver nail resulting in a decrease in ATP levels equivalent to those of uninfected negative control samples. CONCLUSIONS: This study has clearly demonstrated that the use of a novel permeation enhancing system, which fundamentally alters the chemical structure of the nail, not only enhances the efficacy of the existing topical formulations but also enables the delivery and efficacy of terbinafine when applied ungually. Such a topically applied system has the possibility of overcoming the systemic side effects when terbinafine is delivered orally.


Assuntos
Antifúngicos/farmacocinética , Doenças da Unha/tratamento farmacológico , Onicomicose/tratamento farmacológico , Trifosfato de Adenosina/metabolismo , Administração Tópica , Antifúngicos/administração & dosagem , Cadáver , Ciclopirox , Humanos , Técnicas In Vitro , Morfolinas/administração & dosagem , Morfolinas/farmacocinética , Doenças da Unha/microbiologia , Unhas/metabolismo , Unhas/microbiologia , Naftalenos/administração & dosagem , Naftalenos/farmacocinética , Onicomicose/microbiologia , Permeabilidade , Piridonas/administração & dosagem , Piridonas/farmacocinética , Terbinafina
17.
J Bone Joint Surg Br ; 91(9): 1154-7, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19721039

RESUMO

Between December 2004 and June 2006, 136 patients (156 total hip replacements), were sent from the waiting list of the Cardiff Vale NHS Trust to the NHS Treatment Centre, Weston-super-Mare, in an attempt to reduce the waiting time for total hip replacement. Because of concerns about their outcome, each patient was contacted and invited to attend a review appointment with a consultant specialising in hip and revision hip replacement. A total of 98 patients (113 hips) were reviewed after a mean of 23 months (11 to 30). There were 104 cemented hips, seven hybrid and two cementless. An acetabular inclination of > 55 degrees was seen in 18 (16%). Radiolucent lines around the acetabular component were seen in 76 (67%). The femoral component was in more than 4 degrees of varus in 47 (42%). The medial floor had been breached in 13 (12%) and there was a leg-length discrepancy of more than 1 cm in ten (9%). There were three dislocations, one femoral fracture, one pulmonary embolus, one deep infection and two superficial wound infections. To date, 13% (15 hips) have been revised and a further 4% (five hips) await revision, mostly for a painful loose acetabular component. The revision rate far exceeds the 0.5% five-year failure rate reported in the Swedish Registry for the components used. This initiative and the consequent need for correction of the problems created, has significantly increased the workload of our unit.


Assuntos
Acetábulo/cirurgia , Artroplastia de Quadril/normas , Prótese de Quadril/normas , Encaminhamento e Consulta/estatística & dados numéricos , Acetábulo/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Artroplastia de Quadril/efeitos adversos , Artroplastia de Quadril/estatística & dados numéricos , Inglaterra , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Programas Nacionais de Saúde/estatística & dados numéricos , Radiografia , Reoperação/estatística & dados numéricos , Resultado do Tratamento , Listas de Espera , Carga de Trabalho
18.
Eur J Pharm Biopharm ; 72(2): 437-43, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19462480

RESUMO

The influence of the size and surface properties of nanoparticles (NP) upon respiratory epithelial cell uptake and translocation is difficult to study, because NP properties are often modified upon suspension in biological fluids. However, a recently developed novel fluorescently labelled poly(vinyl alcohol) (PVA) NP, which does not aggregate in simple biological fluids, is suitable for drug delivery and can be produced with a range of surface properties is a pertinent advance in this field. The aim of this study was to employ the PVA NP to investigate how surface properties influence particle uptake and translocation across Calu-3 epithelial cell layers. Several grades of PVA were synthesised, characterised and labelled covalently with carboxyfluorescein. The labelled PVA was used to fabricate trackable NP that displayed either neutral or positive charge when suspended in Hank's Balanced Salt Solution. The NP were applied to the apical surface of Calu-3 cell layers which internalised up to 11% of the applied particle dose. The maximum fraction that translocated the Calu-3 barrier in 14 h was 1.3%.


Assuntos
Brônquios/metabolismo , Nanopartículas , Álcool de Polivinil/metabolismo , Brônquios/citologia , Linhagem Celular , Células Cultivadas , Células Epiteliais/citologia , Humanos , Técnicas In Vitro , Espectrometria de Fluorescência , Propriedades de Superfície
19.
J Bone Joint Surg Br ; 91(3): 321-6, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19258606

RESUMO

We have studied the natural history of a first episode of dislocation after primary total hip replacement (THR) to clarify the incidence of recurrent dislocation, the need for subsequent revision and the quality of life of these patients. Over a six-year period, 99 patients (101 hips) presented with a first dislocation of a primary THR. A total of 61 hips (60.4%) had dislocated more than once. After a minimum follow-up of one year, seven patients had died. Of the remaining 94 hips (92 patients), 47 underwent a revision for instability and one awaits operation (51% in total). Of these, seven re-dislocated and four needed further surgery. The quality of life of the patients was studied using the Oxford Hip Score and the EuroQol-5 Dimension (EQ-5D) questionnaire. A control group of patients who had not dislocated was also studied. At a mean follow-up of 4.5 years (1 to 20), the mean Oxford Hip Score was 26.7 (15 to 47) after one episode of dislocation, 27.2 (12 to 45) after recurrent dislocation, 34.5 (12 to 54) after successful revision surgery, 42 (29 to 55) after failed revision surgery and 17.4 (12 to 32) in the control group. The EuroQol-5 dimension questionnaire revealed more health problems in patients undergoing revision surgery.


Assuntos
Artroplastia de Quadril/efeitos adversos , Articulação do Quadril/cirurgia , Luxações Articulares/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Artroplastia de Quadril/métodos , Feminino , Seguimentos , Prótese de Quadril , Humanos , Luxações Articulares/etiologia , Instabilidade Articular/etiologia , Instabilidade Articular/cirurgia , Masculino , Pessoa de Meia-Idade , Falha de Prótese , Qualidade de Vida , Recidiva , Reoperação/métodos , Reoperação/reabilitação , Resultado do Tratamento
20.
J Orthop Surg (Hong Kong) ; 15(2): 167-9, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17709854

RESUMO

PURPOSE: To assess short- to medium-term outcome of the Omnifit constrained acetabular component in preventing dislocation in at-risk patients after total hip arthroplasty (THA). METHODS: 81 patients (mean age, 77 years) underwent either primary or revision THA with an Omnifit constrained acetabular component and were followed up clinically and radiologically for a mean period of 24 months. RESULTS: There was one dislocation and one revision for avulsion of the acetabulum. The remaining prostheses remained well fixed. CONCLUSIONS: In the short- to medium-term, the Omnifit constrained acetabular component is effective in preventing primary and recurrent dislocation in at-risk patients. Long-term follow-up is needed to assess whether good fixation is maintained. The Omnifit acetabular cup is recommended for elderly patients with limited life expectancy and functional demands.


Assuntos
Artroplastia de Quadril/efeitos adversos , Luxação do Quadril/prevenção & controle , Prótese de Quadril , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Luxação do Quadril/diagnóstico por imagem , Luxação do Quadril/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Quadril/cirurgia , Complicações Pós-Operatórias , Desenho de Prótese , Falha de Prótese , Radiografia , Reoperação , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
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