RESUMO
As interventional radiology (IR) treatments have evolved, they have become less invasive, enabling rapid recovery, which expedites ambulation and promotes same-day discharge. As a result of this, a significant proportion of IR elective work can be provided using a day-case service model. Reconfiguration of IR services to increase day-case procedures using a dedicated IR day-case unit (RDU) to facilitate the passage of patients is vital to ensure best medical practice. The aim of this review is to discuss the benefits of day-case IR procedures, the optimal structure of an RDU, and to inform radiologists how to introduce and/or improve day-case IR services in their IR practice.
Assuntos
Assistência ao Paciente , Radiologia Intervencionista , Humanos , Radiologia Intervencionista/métodosRESUMO
This review describes the rationale in support of admitting rights for interventional radiologists and presents options for the management of interventional radiology (IR) inpatients. The manuscript also discusses wider aspects of IR involvement in inpatient treatment, such as income and funding for IR services, and the implications for IR as a clinical specialty.
Assuntos
Assistência ao Paciente , Radiologia Intervencionista , Humanos , Hospitalização , Pacientes Internados , RadiologistasRESUMO
AIM: To gauge current final year medical students' exposure to interventional radiology (IR)and assess their perceptions of IR as a prospective career option. MATERIALS AND METHODS: An online questionnaire comprising of questions that gauge final-year medical students' understanding of and exposure to IR based on the recommendations set out by the British Society of Interventional Radiology (BSIR), was sent out to final-year students across 34 UK medical schools. RESULTS: Five hundred and ten responses were collected from 33 out of 34 eligible medical schools. Sixty-four per cent of respondents rated their own IR knowledge as inadequate. On average, only 50% of all subtopics proposed in the BSIR undergraduate curriculum was covered during medical school and 32.7% of respondents were not exposed to any fundamental IR principles and techniques recommended by the BSIR during medical school. Regarding careers, 2.7% of respondents reported a definite interest in pursuing a career in IR. Most respondents (89.8%) felt that there was insufficient undergraduate teaching on IR and that they lacked information to consider pursuing a career in IR (87.5%). CONCLUSION: Insufficient exposure and teaching on IR throughout medical schools have led to a lack of awareness and consideration of IR as a future career choice amongst UK medical students. The re-evaluation of IR teaching in the medical school curricula is needed. In the long-term, such recommendations could provide the much-needed solution to the workforce shortages seen in IR.
Assuntos
Educação de Graduação em Medicina , Estudantes de Medicina , Humanos , Estudos Prospectivos , Radiologia Intervencionista/educação , Educação de Graduação em Medicina/métodos , Currículo , Inquéritos e Questionários , Escolha da ProfissãoRESUMO
Nitisinone has been approved for treatment of alkaptonuria (AKU). Non-invasive biomarkers of joint tissue remodelling could aid in understanding the molecular changes in AKU pathogenesis and how these can be affected by treatment. Serological and urinary biomarkers of type I collagen and II collagen in AKU were investigated in patients enrolled in the randomized SONIA 2 (NCT01916382) clinical study at baseline and yearly until the end of the study (Year 4). The trajectories of the biomarkers over time were observed. After treatment with nitisinone, the biomarkers of type I collagen remodelling increased at Year 1 (19% and 40% increase in CTX-I and PRO-C1, respectively), which was potentially reflected in the higher degree of mobility seen following treatment. The biomarkers of type II collagen remodelling decreased over time in the nitisinone group: C2M showed a 9.7% decline at Year 1, and levels then remained stable over the following visits; CTX-II showed a 26% decline at Year 3 and 4 in the nitisinone-treated patients. Nitisinone treatment induced changes in biomarkers of bone and cartilage remodelling. These biomarkers can aid patient management and deepen our knowledge of the molecular mechanisms of this rare disease.
Assuntos
Alcaptonúria , Humanos , Alcaptonúria/tratamento farmacológico , Biomarcadores , Cartilagem/patologia , Colágeno Tipo IRESUMO
Alkaptonuria is an inherited disease caused by homogentisate 1,2-dioxygenase (HGD) deficiency. Circulating homogentisic acid (HGA) is elevated and deposits in connective tissues as ochronotic pigment. In this study, we aimed to define developmental and adult HGD tissue expression and determine the location and amount of gene activity required to lower circulating HGA and rescue the alkaptonuria phenotype. We generated an alkaptonuria mouse model using a knockout-first design for the disruption of the HGD gene. Hgd tm1a -/- mice showed elevated HGA and ochronosis in adulthood. LacZ staining driven by the endogenous HGD promoter was localised to only liver parenchymal cells and kidney proximal tubules in adulthood, commencing at E12.5 and E15.5 respectively. Following removal of the gene trap cassette to obtain a normal mouse with a floxed 6th HGD exon, a double transgenic was then created with Mx1-Cre which conditionally deleted HGD in liver in a dose dependent manner. 20% of HGD mRNA remaining in liver did not rescue the disease, suggesting that we need more than 20% of liver HGD to correct the disease in gene therapy. Kidney HGD activity which remained intact reduced urinary HGA, most likely by increased absorption, but did not reduce plasma HGA nor did it prevent ochronosis. In addition, downstream metabolites of exogenous 13C6-HGA, were detected in heterozygous plasma, revealing that hepatocytes take up and metabolise HGA. This novel alkaptonuria mouse model demonstrated the importance of targeting liver for therapeutic intervention, supported by our observation that hepatocytes take up and metabolise HGA.
Assuntos
Alcaptonúria/enzimologia , Homogentisato 1,2-Dioxigenase/genética , Ácido Homogentísico/metabolismo , Fígado/enzimologia , Alcaptonúria/genética , Alcaptonúria/metabolismo , Animais , Modelos Animais de Doenças , Técnicas de Inativação de Genes , Homogentisato 1,2-Dioxigenase/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Regiões Promotoras GenéticasRESUMO
Osteoarthritis (OA) is one of the most prevalent conditions in the world, particularly in the developed world with a significant increase in cases and their predicted impact as we move through the twenty-first century and this will be exacerbated by the covid pandemic. The degeneration of cartilage and bone as part of this condition is becoming better understood but there are still significant challenges in painting a complete picture to recognise all aspects of the condition and what treatment(s) are most appropriate in individual causes. OA encompasses many different types and this causes some of the challenges in fully understanding the condition. There have been examples through history where much has been learnt about common disease(s) from the study of rare or extreme phenotypes, particularly where Mendelian disorders are involved. The often early onset of symptoms combined with the rapid and aggressive pathogenesis of these diseases and their predictable outcomes give an often-under-explored resource. It is these "rarer forms of disease" that William Harvey referred to that offer novel insights into more common conditions through their more extreme presentations. In the case of OA, GWAS analyses demonstrate the multiple genes that are implicated in OA in the general population. In some of these rarer forms, single defective genes are responsible. The extreme phenotypes seen in conditions such as Camptodactyly Arthropathy-Coxa Vara-pericarditis Syndrome, Chondrodysplasias and Alkaptonuria all present potential opportunities for greater understanding of disease pathogenesis, novel therapeutic interventions and diagnostic imaging. This review examines some of the rarer presenting forms of OA and linked conditions, some of the novel discoveries made whilst studying them, and findings on imaging and treatment strategies.
Assuntos
COVID-19 , Coxa Vara , Osteoartrite , Sinovite , Humanos , Osteoartrite/genética , SARS-CoV-2RESUMO
Alkaptonuria (AKU) is characterised by increased circulating homogentisic acid and deposition of ochronotic pigment in collagen-rich connective tissues (ochronosis), stiffening the tissue. This process over many years leads to a painful and severe osteoarthropathy, particularly affecting the cartilage of the spine and large weight bearing joints. Evidence in human AKU tissue suggests that pigment binds to collagen. The exposed collagen hypothesis suggests that collagen is initially protected from ochronosis, and that ageing and mechanical loading causes loss of protective molecules, allowing pigment binding. Schmorl's staining has previously demonstrated knee joint ochronosis in AKU mice. This study documents more comprehensively the anatomical distribution of ochronosis in two AKU mouse models (BALB/c Hgd-/-, Hgd tm1a-/-), using Schmorl's staining. Progression of knee joint pigmentation with age in the two AKU mouse models was comparable. Within the knee, hip, shoulder, elbow and wrist joints, pigmentation was associated with chondrons of calcified cartilage. Pigmented chondrons were identified in calcified endplates of intervertebral discs and the calcified knee joint meniscus, suggesting that calcified tissues are more susceptible to pigmentation. There were significantly more pigmented chondrons in lumbar versus tail intervertebral disc endplates (p = 0.002) and clusters of pigmented chondrons were observed at the insertions of ligaments and tendons. These observations suggest that loading/strain may be associated with increased pigmentation but needs further experimental investigation. The calcified cartilage may be the first joint tissue to acquire matrix damage, most likely to collagen, through normal ageing and physiological loading, as it is the first to become susceptible to pigmentation.
Assuntos
Alcaptonúria , Cartilagem/patologia , Condrócitos/patologia , Ocronose , Alcaptonúria/patologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Ocronose/patologia , PigmentaçãoRESUMO
A large alkaptonuria (AKU) cohort was studied to better characterize the poorly understood spondyloarthropathy of rare disease AKU. Eighty-seven patients attended the National Alkaptonuria Centre (NAC) between 2007 and 2020. Seven only attended once. Fifty-seven attended more than once and received nitisinone 2 mg daily. Twenty-three attended at least twice without receiving nitisinone. Assessments included questionnaire analysis, 18F Positron emission tomography computerised tomography (PETCT), as well as photographs of ochronotic pigment in eyes and ears at baseline when 2 mg nitisinone was commenced and yearly thereafter. Blood and urine samples were collected for chemical measurement. The prevalence of ochronosis, as well as pain, PETCT and combined pain and PETCT scores, was greatly increased at 90.5%, 85.7%, 100%, and 100%, respectively. Joint pain scores were greatest in proximal joints in upper and lower limbs. PETCT joint scores were higher in proximal joints in upper limb but higher in distal joints in the lower limb. Spine pain scores were highest in lumbar, followed by cervical, thoracic, and cervical regions at 77.4%, 59.5%, 46.4%, and 25%, respectively. PETCT spine scores were highest in thoracic followed by lumbar, cervical, and sacroiliac regions at 74.4%, 70.7%, 64.6%, and 47.8% respectively; ochronosis associated closely with spondyloarthropathy scores (R = .65; P < .0001). Nitisinone reversed ochronosis significantly, with a similar pattern of decreased joint and spine disease. Spondyloarthropathy is a highly prevalent feature in this NAC cohort. Ochronosis appears to be associated with spondyloarthropathy. Nitisinone decreases ochronosis and had a similar nonsignificant effect pattern on spondyloarthropathy.
Assuntos
Alcaptonúria/tratamento farmacológico , Cicloexanonas/administração & dosagem , Ácido Homogentísico/metabolismo , Articulações/patologia , Nitrobenzoatos/administração & dosagem , Ocronose/tratamento farmacológico , Coluna Vertebral/patologia , Idoso , Alcaptonúria/metabolismo , Estudos de Coortes , Feminino , Humanos , Articulações/diagnóstico por imagem , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Ocronose/metabolismo , Fenótipo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Índice de Gravidade de Doença , Coluna Vertebral/diagnóstico por imagem , Reino UnidoRESUMO
Arthroplasty in the spondyloarthropathy (SPOND) of alkaptonuria (AKU) in incompletely characterised. The aim was to improve the understanding of arthroplasty in AKU through a study of patients attending the National Alkaptonuria Centre (NAC). Eighty-seven patients attended the NAC between 2007 and 2020. Seven only attended once. Fifty-seven attended more than once and received nitisinone 2 mg daily. Twenty-three attended at least twice without receiving nitisinone. Assessments including questionnaire analysis eliciting details of arthroplasty and other surgical treatments for SPOND, 18 FPETCT and CT densitometry at the neck of hip and lumbar spine, as well as photographs of the eyes and ears were acquired from patients attending the National Alkaptonuria Centre (NAC) at baseline when 2 mg nitisinone was commenced, and yearly thereafter. Photographs were scored to derive ochronosis scores. Blood and urine samples were collected for chemical analyses. The prevalence of arthroplasty was 36.8%, similar in males and females, occurring especially in the knees, hips and shoulders. Multiple arthroplasties were found in 29 patients (33.3%) in this cohort. Incident arthroplasty was 6.5% in the nitisinone group and 7.1% in the no-nitisinone group. Incident arthroplasty was 11.3% in the group with baseline arthroplasty and 3.51% in the group without. A strong association of arthroplasty with SPOND (R = 0.5; P << .0001) and ochronosis (R = 0.54; P < .0001) was seen. Nitisinone had no significant effect on incident arthroplasty. Arthroplasty due to ochronosis and SPOND is common in AKU. Nitisinone decreased ochronosis but had no effect on arthroplasty in this cohort.
Assuntos
Alcaptonúria/complicações , Artroplastia/estatística & dados numéricos , Ocronose/complicações , Espondiloartropatias/diagnóstico por imagem , Espondiloartropatias/cirurgia , Idoso , Alcaptonúria/tratamento farmacológico , Estudos de Coortes , Cicloexanonas/administração & dosagem , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Nitrobenzoatos/administração & dosagem , Ocronose/tratamento farmacológico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Reino UnidoRESUMO
Alkaptonuria (AKU) is caused by homogentisate 1,2-dioxygenase deficiency that leads to homogentisic acid (HGA) accumulation, ochronosis and severe osteoarthropathy. Recently, nitisinone treatment, which blocks HGA formation, has been effective in AKU patients. However, a consequence of nitisinone is elevated tyrosine that can cause keratopathy. The effect of tyrosine and phenylalanine dietary restriction was investigated in nitisinone-treated AKU mice, and in an observational study of dietary intervention in AKU patients. Nitisinone-treated AKU mice were fed tyrosine/phenylalanine-free and phenylalanine-free diets with phenylalanine supplementation in drinking water. Tyrosine metabolites were measured pre-nitisinone, post-nitisinone, and after dietary restriction. Subsequently an observational study was undertaken in 10 patients attending the National Alkaptonuria Centre (NAC), with tyrosine >700 µmol/L who had been advised to restrict dietary protein intake and where necessary, to use tyrosine/phenylalanine-free amino acid supplements. Elevated tyrosine (813 µmol/L) was significantly reduced in nitisinone-treated AKU mice fed a tyrosine/phenylalanine-free diet in a dose responsive manner. At 3 days of restriction, tyrosine was 389.3, 274.8, and 144.3 µmol/L with decreasing phenylalanine doses. In contrast, tyrosine was not effectively reduced in mice by a phenylalanine-free diet; at 3 days tyrosine was 757.3, 530.2, and 656.2 µmol/L, with no dose response to phenylalanine supplementation. In NAC patients, tyrosine was significantly reduced (P = .002) when restricting dietary protein alone, and when combined with tyrosine/phenylalanine-free amino acid supplementation; 4 out of 10 patients achieved tyrosine <700 µmol/L. Tyrosine/phenylalanine dietary restriction significantly reduced nitisinone-induced tyrosinemia in mice, with phenylalanine restriction alone proving ineffective. Similarly, protein restriction significantly reduced circulating tyrosine in AKU patients.
Assuntos
Alcaptonúria/dietoterapia , Alcaptonúria/tratamento farmacológico , Cicloexanonas/farmacologia , Dieta com Restrição de Proteínas , Nitrobenzoatos/farmacologia , Tirosinemias/dietoterapia , Alcaptonúria/metabolismo , Animais , Feminino , Humanos , Masculino , Camundongos , Fenilalanina/metabolismo , Tirosina/metabolismo , Tirosinemias/metabolismoRESUMO
For over two decades, nitisinone (NTBC) has been successfully used to manipulate the tyrosine degradation pathway and save the lives of many children with hereditary tyrosinaemia type 1. More recently, NTBC has been used to halt homogentisic acid accumulation in alkaptonuria (AKU) with evidence suggesting its efficacy as a disease modifying agent. NTBC-induced hypertyrosinaemia has been associated with cognitive impairment and potentially sight-threatening keratopathy. In the context of a non-lethal condition (ie, AKU), these serious risks call for an evaluation of the wider impact of NTBC on the tyrosine pathway. We hypothesised that NTBC increases the tyrosine pool size and concentrations in tissues. In AKU mice tyrosine concentrations of tissue homogenates were measured before and after treatment with NTBC. In humans, pulse injection with l-[13 C9 ]tyrosine and l-[d8 ]phenylalanine was used along with compartmental modelling to estimate the size of tyrosine pools before and after treatment with NTBC. We found that NTBC increased tyrosine concentrations in murine tissues by five to nine folds. It also significantly increased the tyrosine pool size in humans (P < .001), suggesting that NTBC increases tyrosine not just in serum but also in tissues (ie, acquired tyrosinosis). This study provides, for the first time, the experimental proof for the magnitude of NTBC-related acquired tyrosinosis which should be overcome to ensure the safe use of NTBC in AKU.
Assuntos
Alcaptonúria/tratamento farmacológico , Alcaptonúria/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/etiologia , Cicloexanonas/farmacologia , Nitrobenzoatos/farmacologia , Adulto , Idoso , Animais , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Fenilalanina/metabolismo , Tirosina/metabolismo , Adulto JovemRESUMO
The clinical effects of alkaptonuria (AKU) are delayed and ageing influences disease progression. Morbidity of AKU is secondary to high circulating homogentisic acid (HGA) and ochronosis. It is not known whether HGA is produced by or processed in the kidney in AKU. Data from AKU patients from four studies were merged to form a single AKU group. A control group of non-AKU subjects was generated by merging data from two non-AKU studies. Data were used to derive renal clearance and fractional excretion (FE) ratios for creatinine, HGA, phenylalanine (PHE) and tyrosine (TYR) using standard calculations, for comparison between the AKU and the control groups. There were 225 AKU patients in the AKU group and 52 in the non-AKU control group. Circulating HGA increased with age (P < 0.001), and was significantly associated with decreased HGA clearance (CLHGA ) (P < 0.001) and FEHGA (P < 0.001). CLHGA and FEHGA were increased beyond the theoretical maximum renal plasma flow, confirming renal production and emphasising the greater contribution of net tubular secretion than glomerular filtration to renal elimination of HGA. The kidneys are crucial to elimination of HGA. Elimination of HGA is impaired with age resulting in worsening disease over time. The kidney is an important site for production of HGA. Tubular secretion of HGA contributes more to elimination of HGA in AKU than glomerular filtration.
Assuntos
Alcaptonúria/metabolismo , Taxa de Filtração Glomerular , Ácido Homogentísico/metabolismo , Rim/metabolismo , Ocronose/etiologia , Adulto , Alcaptonúria/fisiopatologia , Estudos de Casos e Controles , Creatinina/metabolismo , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Ocronose/fisiopatologia , Fenilalanina/metabolismo , Fatores Sexuais , Tirosina/metabolismoRESUMO
Alkaptonuria (AKU) is a rare disease characterized by high levels of homogentisic acid (HGA); patients suffer from tissue ochronosis: dark brown pigmentation, especially of joint cartilage, leading to severe early osteoarthropathy. No molecular mechanism links elevated HGA to ochronosis; the pigment's chemical identity is still not known, nor how it induces joint cartilage degradation. Here we give key insight on HGA-derived pigment composition and collagen disruption in AKU cartilage. Synthetic pigment and pigmented human cartilage tissue both showed hydroquinone-resembling NMR signals. EPR spectroscopy showed that the synthetic pigment contains radicals. Moreover, we observed intrastrand disruption of collagen triple helix in pigmented AKU human cartilage, and in cartilage from patients with osteoarthritis. We propose that collagen degradation can occur via transient glycyl radicals, the formation of which is enhanced in AKU due to the redox environment generated by pigmentation.
Assuntos
Alcaptonúria/metabolismo , Cartilagem Articular/metabolismo , Osteoartrite/metabolismo , Pigmentação , Espectroscopia de Ressonância de Spin Eletrônica , Ácido Homogentísico/metabolismo , Humanos , Espectroscopia de Ressonância Magnética , Oxirredução , Pigmentos Biológicos/químicaRESUMO
BACKGROUND: Identification of unknown chemical entities is a major challenge in metabolomics. To address this challenge, we developed a comprehensive targeted profiling strategy, combining 3 complementary liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) techniques and in-house accurate mass retention time (AMRT) databases established from commercial standards. This strategy was used to evaluate the effect of nitisinone on the urinary metabolome of patients and mice with alkaptonuria (AKU). Because hypertyrosinemia is a known consequence of nitisinone therapy, we investigated the wider metabolic consequences beyond hypertyrosinemia. METHODS: A total of 619 standards (molecular weight, 45-1354 Da) covering a range of primary metabolic pathways were analyzed using 3 liquid chromatography methods-2 reversed phase and 1 normal phase-coupled to QTOF-MS. Separate AMRT databases were generated for the 3 methods, comprising chemical name, formula, theoretical accurate mass, and measured retention time. Databases were used to identify chemical entities acquired from nontargeted analysis of AKU urine: match window theoretical accurate mass ±10 ppm and retention time ±0.3 min. RESULTS: Application of the AMRT databases to data acquired from analysis of urine from 25 patients with AKU (pretreatment and after 3, 12, and 24 months on nitisinone) and 18 HGD -/- mice (pretreatment and after 1 week on nitisinone) revealed 31 previously unreported statistically significant changes in metabolite patterns and abundance, indicating alterations to tyrosine, tryptophan, and purine metabolism after nitisinone administration. CONCLUSIONS: The comprehensive targeted profiling strategy described here has the potential of enabling discovery of novel pathways associated with pathogenesis and management of AKU.
Assuntos
Alcaptonúria/metabolismo , Cicloexanonas/farmacologia , Metaboloma/efeitos dos fármacos , Nitrobenzoatos/farmacologia , Idoso , Alcaptonúria/tratamento farmacológico , Animais , Cromatografia Líquida/métodos , Cromatografia Líquida/estatística & dados numéricos , Bases de Dados de Compostos Químicos , Feminino , Técnicas de Silenciamento de Genes , Homogentisato 1,2-Dioxigenase/genética , Humanos , Masculino , Espectrometria de Massas/métodos , Espectrometria de Massas/estatística & dados numéricos , Metabolômica/métodos , Camundongos , Pessoa de Meia-Idade , FenótipoRESUMO
Ochronosis is the process in alkaptonuria (AKU) that causes all the debilitating morbidity. The process involves selective deposition of homogentisic acid (HGA)-derived pigment in tissues altering the properties of these tissues, leading to their failure. Some tissues like cartilage are more easily affected by ochronosis while others such as the liver and brain are unaffected for reasons that are still not understood. In vitro and mouse models of ochronosis have confirmed the dose relationships between HGA and ochronosis and also their modulation by p-hydroxyphenylpyruvate dioxygenase inhibition. Ochronosis cannot be fully reversed and is a key factor in influencing treatment decisions. Earlier detection of ochronosis preferably by noninvasive means is desirable. A cause-effect relationship between HGA and ochronosis is discussed. The similarity in AKU and familial hypercholesterolaemia is explored and lessons learnt. More research is needed to more fully understand the crucial nature of ochronosis.
Assuntos
Alcaptonúria/patologia , Condrócitos/citologia , Ácido Homogentísico/metabolismo , Ocronose/patologia , Alcaptonúria/metabolismo , Animais , Cartilagem/metabolismo , Cartilagem/patologia , Condrócitos/metabolismo , Humanos , Camundongos , Oxirredução , PigmentaçãoRESUMO
AIM: To identify and characterise the ideal-sized (defined as at least 2.7 mm based on the experience of plastic surgeons at Hull Royal Infirmary) perforators using magnetic resonance angiography (MRA). The study also evaluated a presumption that perforators on the left are generally larger than on the right. MATERIALS AND METHODS: Fifty consecutive patients who had undergone MRA prior to deep inferior epigastric perforator (DIEP) reconstruction were included. MRA acquisition sequences, MRA images, radiologist reports, and surgical entry database were reviewed retrospectively. Intraoperative findings were compared. The diameter and characteristics of the perforators fulfilling the criteria of being "ideal-sized", at least 2.7 mm were collected. Wilcoxon's test was used to compare the size of the left and right perforators. RESULTS: Ninety-three ideal-sized perforators were identified (diameter of 2.8-4.2 mm). Fifty-one of these were located on the left, and 42 on the right. The left perforators were indeed larger than the right (Wilcoxon's test, p=0.017). Most of the perforators were found in the superior region and medial rows. Additionally, lateral row perforators were observed to have a shorter intramuscular course. CONCLUSION: Contrast-enhanced MRA is a useful preoperative imaging technique to locate ideal DIEPs for breast reconstruction. Perforators on the left were found to be larger than the right, and more ideal-sized perforators were located on the left.
Assuntos
Meios de Contraste , Artérias Epigástricas/diagnóstico por imagem , Aumento da Imagem/métodos , Angiografia por Ressonância Magnética/métodos , Mamoplastia/métodos , Retalho Perfurante , Adulto , Idoso , Artérias Epigástricas/cirurgia , Feminino , Humanos , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
"Fundamental diseases" is a term introduced by the charity Findacure to describe rare genetic disorders that are gateways to understanding common conditions and human physiology. The concept that rare diseases have important lessons for biomedical science has been recognised by some of the great figures in the history of medical research, including Harvey, Bateson and Garrod. Here we describe some of the recently discovered lessons from the study of the iconic genetic disease alkaptonuria (AKU), which have shed new light on understanding the pathogenesis of osteoarthritis. In AKU, ochronotic pigment is deposited in cartilage when collagen fibrils become susceptible to attack by homogentisic acid (HGA). When HGA binds to collagen, cartilage matrix becomes stiffened, resulting in the aberrant transmission of loading to underlying subchondral bone. Aberrant loading leads to the formation of pathophysiological structures including trabecular excrescences and high density mineralised protrusions (HDMPs). These structures initially identified in AKU have subsequently been found in more common osteoarthritis and appear to play a role in joint destruction in both diseases.
Assuntos
Alcaptonúria/diagnóstico , Doenças Raras/diagnóstico , Alcaptonúria/genética , Alcaptonúria/fisiopatologia , Animais , Humanos , Camundongos , Ocronose/etiologia , Ocronose/fisiopatologia , Osteoartrite/etiologia , Osteoartrite/fisiopatologia , Doenças Raras/genética , Doenças Raras/fisiopatologiaRESUMO
OBJECTIVE: Alkaptonuria (AKU) is a rare autosomal recessive disease resulting from a single enzyme deficiency in tyrosine metabolism. As a result, homogentisic acid cannot be metabolized, causing systemic increases. Over time, homogentisic acid polymerizes and deposits in collagenous tissues, leading to ochronosis. Typically, this occurs in joint cartilages, leading to an early onset, rapidly progressing osteoarthropathy. The aim of this study was to examine tissue turnover in cartilage affected by ochronosis and its role in disease initiation and progression. METHODS: With informed patient consent, hip and knee cartilages were obtained at surgery for arthropathy due to AKU (n = 6; 2 knees/4 hips) and OA (n = 12; 5 knees/7 hips); healthy non-arthritic (non-OA n = 6; 1 knee/5 hips) cartilages were obtained as waste from trauma surgery. We measured cartilage concentrations (normalized to dry weight) of racemized aspartate, GAG, COMP and deamidated COMP (D-COMP). Unpaired AKU, OA and non-OA samples were compared by non-parametric Mann-Whitney U test. RESULTS: Despite more extractable total protein being obtained from AKU cartilage than from OA or non-OA cartilage, there was significantly less extractable GAG, COMP and D-COMP in AKU samples compared with OA and non-OA comparators. Racemized Asx (aspartate and asparagine) was significantly enriched in AKU cartilage compared with in OA cartilage. CONCLUSIONS: These novel data represent the first examination of cartilage matrix components in a sample of patients with AKU, representing almost 10% of the known UK alkaptonuric population. Compared with OA and non-OA, AKU cartilage demonstrates a very low turnover state and has low levels of extractable matrix proteins.
Assuntos
Envelhecimento/metabolismo , Alcaptonúria/metabolismo , Cartilagem Articular/metabolismo , Artropatias/metabolismo , Ocronose/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Ácido Aspártico/metabolismo , Biomarcadores/metabolismo , Proteína de Matriz Oligomérica de Cartilagem/metabolismo , Estudos de Casos e Controles , Feminino , Glicosaminoglicanos/metabolismo , Articulação do Quadril , Humanos , Articulação do Joelho , Masculino , Pessoa de Meia-Idade , Osteoartrite do Quadril/metabolismo , Osteoartrite do Joelho/metabolismo , Adulto JovemRESUMO
BACKGROUND: Alkaptonuria (AKU) is a serious genetic disease characterised by premature spondyloarthropathy. Homogentisate-lowering therapy is being investigated for AKU. Nitisinone decreases homogentisic acid (HGA) in AKU but the dose-response relationship has not been previously studied. METHODS: Suitability Of Nitisinone In Alkaptonuria 1 (SONIA 1) was an international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response study. The primary objective was to investigate the effect of different doses of nitisinone once daily on 24-h urinary HGA excretion (u-HGA24) in patients with AKU after 4â weeks of treatment. Forty patients were randomised into five groups of eight patients each, with groups receiving no treatment or 1 mg, 2 mg, 4 mg and 8â mg of nitisinone. FINDINGS: A clear dose-response relationship was observed between nitisinone and the urinary excretion of HGA. At 4â weeks, the adjusted geometric mean u-HGA24 was 31.53 mmol, 3.26 mmol, 1.44 mmol, 0.57 mmol and 0.15â mmol for the no treatment or 1 mg, 2 mg, 4 mg and 8â mg doses, respectively. For the most efficacious dose, 8â mg daily, this corresponds to a mean reduction of u-HGA24 of 98.8% compared with baseline. An increase in tyrosine levels was seen at all doses but the dose-response relationship was less clear than the effect on HGA. Despite tyrosinaemia, there were no safety concerns and no serious adverse events were reported over the 4â weeks of nitisinone therapy. CONCLUSIONS: In this study in patients with AKU, nitisinone therapy decreased urinary HGA excretion to low levels in a dose-dependent manner and was well tolerated within the studied dose range. TRIAL REGISTRATION NUMBER: EudraCT number: 2012-005340-24. Registered at ClinicalTrials.gov: NCTO1828463.