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ObjectivesOchronotic spondyloarthropathy represents one of the main clinical manifestations of alkaptonuria (AKU); however, prospective data and description of the effect of nitisinone treatment are lacking.MethodsPatients with AKU aged 25 years or older were randomly assigned to receive either oral nitisinone 10 mg/day (N=69) or no treatment (N=69). Spine radiographs were recorded yearly at baseline, 12, 24, 36 and 48 months, and the images were scored for the presence of intervertebral space narrowing, soft tissue calcifications, vacuum phenomena, osteophytes/hyperostosis and spinal fusion in the cervical, thoracic and lumbosacral segment at each of the time points.ResultsAt baseline, narrowing of the intervertebral spaces, the presence of osteophytes/hyperostosis and calcifications were the three most frequent radiographic features in AKU. The rate of progression of the five main features during the 4 years, ranked from the highest to lowest was as follows: intervertebral spaces narrowing, calcifications, vacuum phenomena, osteophytes/hyperostosis and fusions. The rate of progression did not differ between the treated and untreated groups in any of the five radiographic parameters except for a slower rate of progression (sum of all five features) in the treatment group compared with the control group (0.45 (1.11) nitisinone vs 0.74 (1.11) controls, p=0.049) in the thoracic segment.ConclusionThe present study shows a relatively slow but significant worsening of radiographic features in patients with AKU over 4 years. Our results demonstrate a modest beneficial effect of 10 mg/day of nitisinone on the slowly progressing spondylosis in AKU during the relatively limited follow-up time.Trial registration numberNCT01916382.

IntroductionPaget’s disease of bone (PDB) is characterised by increased and disorganised bone remodelling affecting one or more skeletal sites. Complications include bone pain, deformity, deafness and pathological fractures. Mutations in sequestosome-1 (SQSTM1) are strongly associated with the development of PDB. Bisphosphonate therapy can improve bone pain in PDB, but there is no evidence that treatment alters the natural history of PDB or prevents complications. The Zoledronate in the Prevention of Paget’s disease trial (ZiPP) will determine if prophylactic therapy with the bisphosphonate zoledronic acid (ZA) can delay or prevent the development of PDB in people who carrySQSTM1mutations.Methods and analysisPeople with a family history of PDB aged >30 years who test positive forSQSTM1mutations are eligible to take part. At the baseline visit, participants will be screened for the presence of bone lesions by radionuclide bone scan. Biochemical markers of bone turnover will be measured and questionnaires completed to assess pain, health-related quality of life (HRQoL), anxiety and depression. Participants will be randomised to receive a single intravenous infusion of 5 mg ZA or placebo and followed up annually for between 4 and 8 years at which point baseline assessments will be repeated. The primary endpoint will be new bone lesions assessed by radionuclide bone scan. Secondary endpoints will include changes in biochemical markers of bone turnover, pain, HRQoL, anxiety, depression and PDB-related skeletal events.Ethics and disseminationThe study was approved by the Fife and Forth Valley Research Ethics Committee on 22 December 2008 (08/S0501/84). Following completion of the trial, a manuscript will be submitted to a peer-reviewed journal. The results of this trial will inform clinical practice by determining if early intervention with ZA in presymptomatic individuals withSQSTM1mutations can prevent or slow the development of bone lesions with an adverse event profile that is acceptable.Trial registration numberISRCTN11616770

Alkaptonuria (AKU) is a rare autosomal recessive condition caused by deficiency of the enzyme homogentisate 1,2 dioxygenase, resulting in widespread deposition of oxidised homogentisic acid (HGA) polymer, primarily in joint tissues but also in other connective tissues. Macroscopic pigmentation of connective tissues in AKU is well documented and is the end point of a process that is not understood. Deposition in less common regions may provide clues to the pigment formation process. This is the first report of detection of ochronotic pigment in acinar cells and lumina in the submandibular gland of a patient with AKU. Deposition was noted in the apical region of the cells. A lobar duct presented a large calculus with unusual deposits possibly associated with calcium salts. This report highlights the effect that local and intracellular factors may have on converting HGA into polymeric derivatives in the absence of an extracellular matrix.

BACKGROUND: Hypersecretion of insulinotropic factors such as glucose dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1(7-36)amide (GLP-1) have been postulated to account for the hyperinsulinaemia of obesity. AIMS: To examine the role of GLP-1 and GIP in obese women and matched controls. SUBJECTS: Six lean and six obese women subjects matched for age. METHODS: The gut hormone, plasma glucose, and serum triglyceride responses were studied over 180 minutes after oral carbohydrate and fat meals. Heparin (10,000 units) was given intravenously at 120 minutes. RESULTS: There was pronounced attenuation of plasma GLP-1 secretion to oral carbohydrate in the obese compared with lean subjects but no such difference in response to oral fat load. There were no differences in the plasma GIP responses to carbohydrate or fat feeding. There was an apparent fall in plasma GLP-1 values in all subjects after administration of heparin. CONCLUSION: Postprandial GLP-1 secretion in response to oral carbohydrate is considerably attenuated in obese subjects. The cause of this attenuation of GLP-1 secretion is not known although we suggest that both this fall and the overall reduction in GLP-1 values in obese subjects may be related to an increase in plasma non-esterified fatty acids.

Context Involvement and leading on quality improvement projects by trainees is currently recognised as an essential part of training to build up on future NHS leaders. Our aim was to empower our trainees to identify potentials for quality improvement projects. Problem Many trainees who rotate to our neonatal unit have had some exposure to neonatology before, but they generally have other sub-interests, hence, they lack ideas for quality improvement projects in the speciality. Assessment of problem and analysis of its causes Trainees are generally motivated but they lack ideas and support to lead on quality improvement projects. We identified the need to create a platform for identifying potential projects which lead to practicing up to date evidence based medicine and subsequent improvement in quality of care. Intervention Initiated and established a journal club to discuss evidence base practice and to identify potentials for quality improvement projects. Study design Identified personnel responsible for the overall running of the club, booking the venues, allocating trainees to lead on each club and advertising and inviting staff to attend the club. Strategy for change Trainees are encouraged and assisted by the club responsible personnel to identify journal articles which may have a potential to change clinical practice and to lead to quality improvement. They are encouraged to lead on projects following discussions with their educational supervisors. Measurement of improvement Trainees satisfaction with the culture created to identify potentials for quality improvement. Effects of changes Creating a culture of continuously identifying potential ideas for quality improvement by practicing up to date evidence based medicine. Lessons learnt Trainees are more aware of their need to be involved with quality improvement projects. Establishing a journal club which provides a platform to discuss potential ideas, overcomes the difficulty which some trainees face with identifying potentials for quality improvement. Message for others Journal clubs can be a useful platform for creating a culture of looking for quality improvement ideas. Trainees should be encouraged and assisted to actively participate in leading clubs and identifiyng potentials for improvements.

Alkaptonuria (AKU) is a rare autosomal recessive condition with a prevalence of 1 in 250 000–1 000 0001 caused by the deficiency of homogentisate 1,2 dioxygenase, the enzyme responsible for breaking down homogentisic acid (HGA).2 Without this enzyme, levels of HGA within the tissues increase, even with highly efficient renal clearance of HGA. Urinary excretion of HGA is the only manifestation of AKU in children, and symptoms appear in adults due to joint damage. HGA has a high affinity for collagenous tissues, primarily the articular cartilages where it deposits as a pigmented polymer. Deposition also occurs at non-collagenous sites, suggesting that factors other than the presence of HGA in the tissues may favour or promote ochronosis.2 3 Ochronotic pigment does not stain with Perl's reaction and can be highlighted in histological sections by Schmorl's stain.4 We report the case of a 51-year-old woman with shoulder joint arthritis who had been diagnosed previously with AKU elsewhere at the age of 50 years; the diagnosis was confirmed by urinary measurement of HGA. She attended the Liverpool AKU clinical evaluation unit where routine assessment by whole-body MRI revealed a 9 cm diameter, partly calcified mass in the anterior mediastinum (figure 1). In 1995, she was diagnosed with hyperthyroidism and had …

Simon Laxon, who was diagnosed with a rare genetic disorder, alkaptonuria, soon after birth, describes his journey in understanding the condition and finding hope for a cure I was born in 1966, and within a few days of my birth my parents knew that something was wrong. There were dark purple stains in my nappies, so my mother took me to a consultant at my local hospital for investigation. After a meeting of specialist doctors, one of my nappies was sent for tests. The doctors suspected porphyria, but the test came back negative. A urine test led to the discovery of a rare genetic disorder. The doctors explained it would cause a type of arthritis: not crippling like rheumatoid arthritis, but one that would cause aches and pains as well as turning the cartilage in my ears blue. My parents felt there was no need to worry, so I grew up fairly normally. I was quite athletic at school and trained several times a week. In 1987 I developed a duodenal ulcer and had to go into hospital, where doctors rediscovered the genetic disorder (my original records had been lost). This time a name was put to it: alkaptonuria. The doctors knew little about it, but told me I would develop mild arthritis and that my urine would turn black if left to stand. We explained about the meeting of the specialists when I was only a couple of weeks old and the stained nappies. The doctors said that this was a symptom of alkaptonuria and was nothing to worry about, as the genetic defect was harmless. It took me a year to overcome the ulcer. By this time I was starting to suffer with aches and pains in my lower back. I found that I could not get back …